First Report of Black Spots on Avocado Fruit Caused by Neofusicoccum parvum in Mexico.
Avocado (Persea americana L.) production for export markets has increased in Mexico during the past 10 years. The production system, however, is affected by several sanitation factors, including diseases. During the spring of 2009, smooth, black, circular spots were noted on the surface of avocado fruit. A study was conducted during the winter of 2010 to ascertain the etiology and identify the fungus associated with black spot symptoms on avocado fruit in orchards of Nuevo Parangaricutiro County (19°25'00″ and 102°07'43″) in Michoacan, Mexico. Several fungal isolates were obtained on potato dextrose agar (PDA) from the margin of lesions on immature fruit. The internal transcribed spacer region (ITS) of the rDNA from representative isolates was sequenced with universal primers ITS5 and ITS4 (2). BLAST searches in GenBank showed 100% similarity of the nucleotide sequences with Neofusicoccum parvum (Pennycook & Samuels) Crous, Slippers & A.J.L. Phillips, GenBank Accession Nos. GU188001 to GU188007 and GU187985 to GU187987. A representative nucleotide sequence of this region was deposited in GenBank under the Accession No. JN203129. Strains of N. parvum produced aerial and compact mycelium on acidified PDA, the anamorph state of Botryosphaeria parva. Mycelium was initially white, turning gradually gray to black. Conidia were one celled, hyaline, ellipsoidal to fusiform, externally smooth, thin walled, nonseptate, with one or two septa with age, and an average length and width of 14.5 (9.5 to 19) × 5.8 (4.0 to 7.2) μm (n = 100). Pathogenicity tests were conducted with six avocado fruit cv. Hass. Fruit were inoculated at three evenly spaced locations on the fruit surface, either by wounding the tissue with a needle that had been dipped in a conidial mass from an 8-day-old monoconidial culture of N. parvum strain CIAD-021-11 or by placing 5 μl of 1 × 106 conidia ml-1 suspension on each inoculation site. Inoculated fruit were maintained in a moist chamber at 25°C for 2 weeks. Black lesions appeared on all wounded sites 2 days postinoculation (dpi) and on unwounded sites 4 dpi. The delay of symptom development was likely due to penetration through the lenticels, which took longer to initiate infection. No symptoms were observed in the control fruit. The pathogen was reisolated from the lesions of all inoculated fruit, thus fulfilling Koch's postulates. The results confirmed the pathogenic potential of this fungus and indicated its possible involvement in the etiology of black spot on avocado fruit. N. parvum is a cosmopolitan, plurivorous pathogen causing disease in several hosts of economic importance, such as grapes and kiwi, as well as causing stem-end rot of avocado fruit in New Zealand (1) and avocado twigs in Spain (3). To our knowledge, this is the first report of N. parvum causing black spots on avocado fruit in Mexico. References: (1) W. F. T. Hartill et al. N.Z.J. Crop Hortic. Sci. 30:249. 2002. (2) T. J. White et al. Page: 315 in: PCR Protocols: A Guide to Methods and Application. M. A. Innis et al., eds. Academic Press, San Diego, CA, 1990. (3) T. Zea-Bonilla et al. Plant Dis. 91:1052, 2007.


Critical role for Kit-mediated Src kinase but not PI 3-kinase signaling in pro T and pro B cell development.
The Kit receptor functions in hematopoiesis, lymphocyte development, gastrointestinal tract motility, melanogenesis, and gametogenesis. To investigate the roles of different Kit signaling pathways in vivo, we have generated knock-in mice in which docking sites for PI 3-kinase (KitY719) or Src kinase (KitY567) have been mutated. Whereas steady-state hematopoiesis is normal in KitY719F/Y719F and KitY567F/Y567F mice, lymphopoiesis is affected differentially. The KitY567F mutation, but not the KitY719F mutation, blocks pro T cell and pro B cell development in an age-dependent manner. Thus, the Src family kinase, but not the PI 3-kinase docking site in Kit, mediates a critical signal for lymphocyte development. In agreement with these results, treatment of normal mice with the Kit tyrosine kinase inhibitor imatinib (Gleevec) leads to deficits in pro T and pro B cell development, similar to those seen in KitY567F/Y567F and KitW/W mice. The two mutations do not affect embryonic gametogenesis but the KitY719F mutation blocks spermatogenesis at the spermatogonial stages and in contrast the KitY567F mutation does not affect this process. Therefore, Kit-mediated PI 3-kinase signaling and Src kinase family signaling is highly specific for different cellular contexts in vivo.


Impact of the South African Mental Health Care Act No. 17 of 2002 on regional and district hospitals designated for mental health care in KwaZulu-Natal.
The South African Mental Health Care Act (the Act) No. 17 of 2002 stipulated that regional and district hospitals be designated to admit, observe and treat mental health care users (MHCUs) for 72 hours before they are transferred to a psychiatric hospital. Medical managers in 49 'designated' hospitals in KwaZulu-Natal (KZN) were surveyed on infrastructure, staffing, administrative requirements and mental health care user case load pertaining to the Act for the month of July 2009. Thirty-six (73.4%) hospitals responded to the survey; 30 (83.3%) stated that the Act improved mental health care for MHCUs through the protection of their rights, provision of least restrictive care, and reduction of discrimination; 10 (27.8%) had a psychiatric unit and, of the remaining 26 hospitals, 11 (30.6%) had general ward beds dedicated for psychiatric admissions; 16 (44.4%) had some form of seclusion facility; and 24 (66.7%) provided an outpatient psychiatric service. Seventy-six per cent of admissions were involuntary or assisted. Thirteen of the 32 (40.6%) state psychiatrists in KZN were employed at 8 of these hospitals. Designated hospitals expressed dissatisfaction with the substantial administrative load required by the Act. The Review Board had not visited 29 (80.6 %) hospitals in the preceding 6 months. Although 'designated' hospitals admit and treat assisted and involuntary MHCUs, they do so against a backdrop of inadequate infrastructure and staff, a high administrative load, and a low level of contact with Review Boards.


The role of the traditional leader in implementing maternal, newborn and child health policy in Malawi.
Traditional leaders play a prominent role at the community level in Malawi, yet limited research has been undertaken on their role in relation to policy implementation. This article seeks to analyse the role of traditional leaders in implementing national maternal, newborn and child health (MNCH) policy and programmes at the community level. We consider whether the role of the chief embodies a top-down (utilitarian) or bottom-up (empowerment) approach to MNCH policy implementation. Primary data were collected in 2014/15, through 85 in-depth interviews and 20 focus group discussions in two districts in Malawi. We discovered that traditional leaders play a pivotal role in supporting MNCH service utilization, through mobilization for MNCH campaigns, and encouraging women to give birth at the health facility rather than at home or in the community setting. Women and their families responded to bylaws to deliver in the facility out of respect for the traditional leader, which is ingrained in Malawian culture. Fines were imposed on women for delivering at home, in the form of goats, chickens and money. Fear and coercion were often used by traditional leaders to ensure that women delivered at the health facility. Chiefs who failed to enforce these bylaws were also fined. Although the role of the traditional leader was often positive and encouraging in relation to MNCH service utilization, this was sometimes carried out in a coercive manner. Results show evidence of a utilitarian top-down model of policy implementation, where the goal of health service utilization justified the means, through encouragement, fear, punishment or coercion. Although the bottom-up approach would be associated with a more empowerment approach, it is unlikely that this would have been successful in Malawi, given the hierarchical nature of society. Further research on policy implementation in the context of community participation is needed.


Effect of l-dopa on sympathetic nerve activity and blood pressure in the spontaneously hypertensive rat.
We examined the effect of L-Dopa, after peripheral L-amino acid decarboxylase inhibition, on sympathetic nerve activity (SNA) and blood pressure in spontaneously hypertensive rats (SHR) and in normotensive control rats. L-Dopa reduced SNA in both groups of animals. The SHRs were significantly more sensitive to the depressor effect of L-dopa than were the control animals, the threshold dose for reduction of SNA being 3 mg/kg in the SHR and 15 mg/kg in control rats. Similarly, the magnitude of inhibition of SNA was substantially greater in the SHR than in normotensive rats. The reduction in SNA in the SHR accompanied by a parallel fall in blood pressure. In contrast, blood pressure in control rats did not change significantly, even though SNA was diminished. Studies of the penetration of L-dopa into the cerebral parenchyma revealed that equivalent amounts of the amino acid entered the brains of the two groups of rats. These results suggest that the SHRs are more sensitive to the SNA-inhibiting effects of L-dopa than are normotensive rats. In addition, they confirm our previous suggestion that excessive SNA plays a causative role in the hypertension of the SHR.


The corticotropin-releasing hormone test in the diagnosis of ACTH-dependent Cushing's syndrome: a reappraisal.
Stimulation with corticotropin-releasing hormone (CRH) is one of principal tools for the differential diagnosis of ACTH-dependent Cushing's syndrome. However, different dosages and species of CRH may be employed; further, ACTH levels can be measured by radioimmunoassay (RIA) or immunoradiometric assay (IRMA). The aims of the present study were to perform a reappraisal of the diagnostic accuracy of the CRH test taking these different testing modalities into consideration and to study the correlation between basal ACTH and cortisol levels and their responses to CRH in patients with Cushing's disease. The study population comprised 148 patients with Cushing's disease and 12 patients with ectopic ACTH secretion collected through an Italian multicentre study. Patients were submitted to stimulation with 100 microg human or ovine CRH (36% and 64% of subjects, respectively) and ACTH measured either by RIA or IRMA (28% and 72%, respectively). A 50% increase in ACTH and cortisol levels was considered indicative of Cushing's disease. Mean peak ACTH levels measured by RIA and IRMA were comparable, as was the diagnostic accuracy of the test with the two assays (87% for IRMA and 84% for RIA, ns). In patients with Cushing's disease, stimulation with ovine CRH induced greater hormonal responses compared to testing with human CRH although only the cortisol response reached statistical significance (ACTH: 247.5 +/- 28.0% vs. 168.5 +/- 21.3% over baseline, P = 0.06; cortisol: 89.3 +/- 8.5% vs. 60.8 +/- 9.6% over baseline, P < 0.05 for ovine and human CRH, respectively). No appreciable rise in ACTH and cortisol levels was registered among patients with ectopic ACTH secretion. Diagnostic accuracy of the cortisol response was significantly greater with the ovine than with human peptide (71% vs. 49%, P < 0.05, for ovine and human CRH, respectively) while the ACTH response yielded equal diagnostic accuracy (86% vs. 87%, ns, for the ovine and human peptide, respectively). Interestingly, the correlation between ACTH and cortisol peak responses in patients with Cushing's disease was significantly greater for human than for ovine CRH (r = 0.68 vs. r = 0.41, P < 0.01, respectively). In addition, baseline cortisol levels exhibited a significant negative correlation with both the ACTH and cortisol response to CRH suggesting the persistence of the negative cortisol feedback in patients with Cushing's disease. (A) Both RIA and IRMA can be used indifferently for the assessment of the ACTH response to CRH. (B) Human and ovine CRH provide the same diagnostic accuracy as regards the ACTH response which, incidentally, represents the most accurate criterion for the evaluation of the CRH test; ovine CRH is superior to the human peptide in the evaluation of the cortisol response. (C) In patients with Cushing's disease, endogenous cortisol maintains the ability to negatively modulate CRH-stimulated corticotropin secretion.


Distributed-feedback dye-doped solgel silica lasers.
Dye-doped solgel silica lasers with distributed feedback were demonstrated. Solgel silica slabs doped with Rhodamine 6G or Coumarin 460 dyes were fabricated. Periodic gain modulation in dye-doped solgel silica slabs were created by the interference pattern of the pumped laser beams diffracted by a holographic grating. Laser pulse trains with subnanosecond spikes were induced. Laser emission wavelengths were centered at 480 and 585 nm for Rhodamine 6G and Coumarin 460, respectively. It was possible for us to tune approximately 20 nm around the emission centers by varying the intersection angle. The laser linewidth was of the order of 60 pm.


Regulation of mitochondrial morphological dynamics during apoptosis by Bcl-2 family proteins: a key in Bak?
Early during apoptosis, the mitochondrial network collapses into short punctuate fragments. The seemingly morphological change, called mitochondrial fragmentation, contributes to mitochondrial injury. Mitochondrial morphology is dictated by two opposing processes, fission and fusion. It is unclear how the fission-fusion balance is tilted during apoptosis, resulting in mitochondrial fragmentation. Emerging evidence has now suggested a regulation of mitochondrial morphological dynamics by Bcl-2 family proteins. In this regulation, Bak appears to be a key. Through interaction with mitofusins, Bak may block mitochondrial fusion to induce fragmentation. By this function, Bak may collaborate with Bax to permeabilize mitochondrial outer membrane, leading to the release of apoptogenic factors.


Daily almond consumption in cardiovascular disease prevention via LDL-C change in the U.S. population: a cost-effectiveness analysis.
Heart disease is the leading cause of death in the United States. The U.S. Food and Drug Administration approved the health claim that 1.5 oz (42.5 g) of nut intake may reduce the risk of cardiovascular disease. Previous studies have focused on the cost-effectiveness of other foods or dietary factors on primary cardiovascular disease prevention, yet not in almond consumption. This study aimed to examine the cost-effectiveness of almond consumption in cardiovascular disease primary prevention. This study assessed the cost-effectiveness of consuming 42.5 g of almond from the U.S. healthcare sector perspective. A decision model was developed for 42.5 g of almond per day versus no almond consumption and cardiovascular disease in the U.S. Parameters in the model were derived from the literature, which included the probabilities of increasing low-density lipoprotein cholesterol, developing acute myocardial infarction and stroke, treating acute myocardial infarction, dying from the disease and surgery, as well as the costs of the disease and procedures in the U.S. population, and the quality-adjusted life years. The cost of almonds was based on the current price in the U.S. market. Sensitivity analyses were conducted for different levels of willingness-to-pay, the probabilistic sensitivity analysis, ten-year risk prevention, different costs of procedures and almond prices, and patients with or without cardiovascular disease. The almond strategy had $363 lower cost and 0.02 higher quality-adjusted life years gain compared to the non-almond strategy in the base-case model. The annual net monetary benefit of almond consumption was $1421 higher per person than no almond consumption, when the willingness to pay threshold was set at $50,000 for annual health care expenditure. Almond was more cost-effective than non-almond in cardiovascular disease prevention in all the sensitivity analyses. Consuming 42.5 g of almonds per day is a cost-effective approach to prevent cardiovascular disease in the short term and potentially in the long term.


A Large-Scale Analysis of Genetic Variants within Putative miRNA Binding Sites in Prostate Cancer.
Prostate cancer is the second most common malignancy among men worldwide. Genome-wide association studies have identified 100 risk variants for prostate cancer, which can explain approximately 33% of the familial risk of the disease. We hypothesized that a comprehensive analysis of genetic variations found within the 3' untranslated region of genes predicted to affect miRNA binding (miRSNP) can identify additional prostate cancer risk variants. We investigated the association between 2,169 miRSNPs and prostate cancer risk in a large-scale analysis of 22,301 cases and 22,320 controls of European ancestry from 23 participating studies. Twenty-two miRSNPs were associated (P<2.3×10(-5)) with risk of prostate cancer, 10 of which were within 7 genes previously not mapped by GWAS studies. Further, using miRNA mimics and reporter gene assays, we showed that miR-3162-5p has specific affinity for the KLK3 rs1058205 miRSNP T-allele, whereas miR-370 has greater affinity for the VAMP8 rs1010 miRSNP A-allele, validating their functional role. Findings from this large association study suggest that a focus on miRSNPs, including functional evaluation, can identify candidate risk loci below currently accepted statistical levels of genome-wide significance. Studies of miRNAs and their interactions with SNPs could provide further insights into the mechanisms of prostate cancer risk.


Secularizing the pain of footbinding in China: missionary and medical stagings of the universal body.
How did foreign Christian anti-footbinding activists treat the distinctive forms of human embodiment they encountered in China? What were their assumptions? How should we understand the transition from religious to secular imaginings of the body and its pains? Here I discuss late nineteenth and early twentieth century religion and medicalized hygiene through the voices of two English people who campaigned against and wrote extensively about footbinding. Not an easy story about God traded for Nature, but a far more uneasy and subliminal borrowing and cross-fertilization of tropes between the religious and the scientific. In both evangelical religion and biological science our protagonists created powerful narrative technologies for making cultural process disappear into nature, and thus to re-channel agency, making it available for new projects. Here we see the secular and the religious informing and reinforcing one another as moments in the creation of the modern.


Dual requirement for the yeast MMS19 gene in DNA repair and RNA polymerase II transcription.
Genetic and biochemical studies of Saccharomyces cerevisiae have indicated the involvement of a large number of protein factors in nucleotide excision repair (NER) of UV-damaged DNA. However, how MMS19 affects this process has remained unclear. Here, we report on the isolation of the MMS19 gene and the determination of its role in NER and other cellular processes. Genetic and biochemical evidence indicates that besides its function in NER, MMS19 also affects RNA polymerase II (Pol II) transcription. mms19delta cells do not grow at 37 degrees C, and mutant extract exhibits a thermolabile defect in Pol II transcription. Thus, Mms19 protein resembles TFIIH in that it is required for both transcription and DNA repair. However, addition of purified Mms19 protein does not alleviate the transcriptional defect of the mms19delta extract, nor does it stimulate the incision of UV-damaged DNA reconstituted from purified proteins. Interestingly, addition of purified TFIIH corrects the transcriptional defect of the mms19delta extract. Mms19 is, however, not a component of TFIIH or of Pol II holoenzyme. These and other results suggest that Mms19 affects NER and transcription by influencing the activity of TFIIH as an upstream regulatory element. It is proposed that mutations in the human MMS19 counterpart could result in syndromes in which both NER and transcription are affected.


The mouse has a Polycomb-like chromobox gene.
The Drosophila gene Polycomb (Pc) has been implicated in the clonal inheritance of determined states and is a trans-regulator of the Antennapedia-like homeobox genes. Pc shares a region of homology (the chromobox) with the Drosophila gene Heterochromatin Protein 1 (HP1), a component of heterochromatin. The Pc chromobox has been used to isolate a mouse chromobox gene, M33, which encodes a predicted 519 amino acid protein. The M33 chromodomain is more similar to that in the Pc protein, than that in the HP1 protein. In addition to the chromodomain, the M33 and Pc proteins also share a region of homology at their C termini. The temporal and spatial expression patterns of M33 have been studied by in situ hybridization and northern analysis. During the final 10 days of embryonic development, M33 expression mirrors that of the cell-cycle-specific cyclin B gene. It is therefore suggested that the rate of cellular proliferation controls M33 expression. From comparisons of the characteristics of M33 with those of Pc it is proposed that M33 is a Pc-like chromobox gene. The roles of M33 and Pc in models of cellular memory are examined and implications of the memory models addressed.


Correlated evolution of senescence and ephemeral substrate use in the Sordariomycetes.
Evolutionary theory predicts that senescence--a decline in reproduction and survival with increasing age--can evolve as a trade-off between investment in reproduction on one side and in somatic maintenance and repair on the other. The ecology of a species is crucial because it provides the external causes of death that determine the statistical limit to a species' lifespan. Filamentous fungi are generally believed to be nonsenescent, and there are indeed spectacular examples of very old fungal individuals in nature. However, some fungi utilize ephemeral resources, and therefore, senescence is expected to have evolved, like in the coprophilic Podospora anserina, the only well-studied filamentous fungus with intrinsic senescence. Here, we hypothesize that rapid senescence is more common in fungi than generally believed and that the phylogenetic distribution of senescence correlates with ecology. We collected lifespan data for a set of Sordariomycetes and constructed phylogenies based on several nuclear sequences. Several of the strains were from the CBS culture collection, originally isolated from various substrates, some of which ephemeral. In addition, we isolated new strains from short-lived substrates. Senescence was observed throughout the phylogeny. Correlation tests support the hypothesis that in the Sordariomycetes, senescence is a trait that has arisen in response to ephemeral substrates, and that it has evolved repeatedly and independently along the phylogeny.


Periconceptional ethanol exposure induces a sex specific diuresis and increase in AQP2 and AVPR2 in the kidneys of aged rat offspring.
Maternal alcohol consumption can impair renal development and program kidney dysfunction in offspring. Given that most women who drink alcohol cease consumption upon pregnancy recognition, we aimed to investigate the effect of alcohol around the time of conception (PC:EtOH) on offspring renal development and function. Rats received a liquid diet ±12.5% v/v ethanol from 4 days before to 4 days after mating. At postnatal day 30, nephron number was assessed. Urine flow and electrolyte (Na, K, Cl) excretion was measured at 6 and 19 months and blood pressure at 12 months. At 19 months, kidneys were collected for gene and protein analysis and assessment of collecting duct length. At postnatal day 30, PC:EtOH offspring had fewer nephrons. At 6 months, PC:EtOH exposure did not alter urine flow nor affect blood pressure at 12 months. At 19 months, female but not male offspring exposed to PC:EtOH drank more water and had a higher urine flow despite no differences in plasma arginine vasopressin (AVP) concentrations. Aqp2 mRNA and Avpr2 mRNA and protein expression was increased in kidneys from female PC:EtOH offspring but collecting duct lengths were similar. Immunofluorescent staining revealed diffuse cytoplasmic distribution of AQP2 protein in kidneys from PC:EtOH females, compared with controls with apical AQP2 localization. PC:EtOH resulted in a low nephron endowment and in female offspring, associated with age-related diuresis. Changes in expression and cellular localization of AQP2 likely underpin this disturbance in water homeostasis and highlight the need for alcohol to be avoided in early pregnancy.


Isoniazid conjugated poly(lactide-co-glycolide): long-term controlled drug release and tissue regeneration for bone tuberculosis therapy.
Bone tuberculosis (TB) is one of the most common extrapulmonary TB. Effective integration of chemotherapy and bone regeneration is an optimal solution for bone TB therapy. Herein, we produce a composite scaffold drug delivery system fabricated with an isoniazid conjugated star poly(lactide-co-glycolide) (PLGA-INH4) and β-TCP. The cytological assay indicated the composite system possesses good biocompatibility. The in vitro and in vivo drug release evaluations showed that the composite system can intactly release the pristine INH and maintain effective INH concentration in a controlled manner for more than 100 days, and achieve high localized drug concentration and low systemic drug concentration. The rabbit radius repair experiment testified the scaffold has good bone regeneration capacity. Our work demonstrate the composite system can simultaneously achieve localized long-term drug controlled release and bone regeneration, which provides a promising route for improved bone TB treatment.


Ultrafast dynamics of charge density waves in 4H(b)-TaSe2 probed by femtosecond electron diffraction.
The dynamics of the photoinduced commensurate-to-incommensurate charge density wave (CDW) phase transition in 4H(b)-TaSe(2) are investigated by femtosecond electron diffraction. In the perturbative regime, the CDW re-forms on a 150-ps time scale, which is two orders of magnitude slower than in other transition-metal dichalcogenides. We attribute this to a weak coupling between the CDW carrying T layers and thus demonstrate the importance of three-dimensionality for the existence of CDWs. With increasing optical excitation, the phase transition is achieved, showing a second-order character, in contrast to the first-order behavior in thermal equilibrium.


Emerging viral disease risk to pollinating insects: ecological, evolutionary and anthropogenic factors.
The potential for infectious pathogens to spillover and emerge from managed populations to wildlife communities is poorly understood, but ecological, evolutionary and anthropogenic factors are all likely to influence the initial exposure and subsequent infection, spread and impact of disease. Fast-evolving RNA viruses, known to cause severe colony losses in managed honeybee populations, deserve particular attention for their propensity to jump between host species and thus threaten ecologically and economically important wild pollinator communities. We review the literature on pollinator viruses to identify biological and anthropogenic drivers of disease emergence, highlight gaps in the literature, and discuss potential management strategies. We provide evidence that many wild pollinator species are exposed to viruses from commercial species, resulting in multiple spillover events. However, it is not clear whether species become infected as a result of spillover or whether transmission is occurring within these wild populations. Ecological traits of pollinating insects, such as overlapping ranges, niches and behaviours, clearly promote cross-species transmission of RNA viruses. Moreover, we conclude that the social behaviour and phylogenetic relatedness of social pollinators further facilitate within- and between-host transmission, leaving these species particularly vulnerable to emerging diseases. We argue that the commercial use of pollinators is a key driver of disease emergence in these beneficial insects and that this must be addressed by management and policy. Synthesis and applications. There are important knowledge gaps, ranging from disease distribution and prevalence, to pathogen life history and virulence, to the impacts of disease emergence, which need to be addressed as research priorities. It is clear that avoiding anthropogenic pathogen spillover is crucial to preventing and managing disease emergence in pollinators, with far-reaching effects on our food security, ecosystem services and biodiversity. We argue that it is crucial to prevent the introduction of diseased pollinators into natural environments, which can be achieved through improved monitoring and management practices.


Bacteria isolated from hospital, municipal and slaughterhouse wastewaters show characteristic, different resistance profiles.
Multidrug-resistant bacteria cause difficult-to-treat infections and pose a risk for modern medicine. Sources of multidrug-resistant bacteria include hospital, municipal and slaughterhouse wastewaters. In this study, bacteria with resistance to 3rd generation cephalosporins were isolated from all three wastewater biotopes, including a maximum care hospital, municipal wastewaters collected separately from a city and small rural towns and the wastewaters of two pig and two poultry slaughterhouses. The resistance profiles of all isolates against clinically relevant antibiotics (including β-lactams like carbapenems, the quinolone ciprofloxacin, colistin, and trimethoprim/sulfamethoxazole) were determined at the same laboratory. The bacteria were classified according to their risk to human health using clinical criteria, with an emphasis on producers of carbapenemases, since carbapenems are prescribed for hospitalized patients with infections with multi-drug resistant bacteria. The results showed that bacteria that pose the highest risk, i. e., bacteria resistant to all β-lactams including carbapenems and ciprofloxacin, were mainly disseminated by hospitals and were present only in low amounts in municipal wastewater. The isolates from hospital wastewater also showed the highest rates of resistance against antibiotics used for treatment of carbapenemase producers and some isolates were susceptible to only one antibiotic substance. In accordance with these results, qPCR of resistance genes showed that 90% of the daily load of carbapenemase genes entering the municipal wastewater treatment plant was supplied by the clinically influenced wastewater, which constituted approximately 6% of the wastewater at this sampling point. Likewise, the signature of the clinical wastewater was still visible in the resistance profiles of the bacteria isolated at the entry into the wastewater treatment plant. Carbapenemase producers were not detected in slaughterhouse wastewater, but strains harboring the colistin resistance gene mcr-1 could be isolated. Resistances against orally available antibiotics like ciprofloxacin and trimethoprim/sulfamethoxazole were widespread in strains from all three wastewaters.


Elevated protein requirements in cirrhosis of the liver investigated by whole body protein turnover studies.
1. In patients with cirrhosis of the liver and in healthy control subjects, the rates of nitrogen flux, protein synthesis and protein breakdown were studied, using a single oral dose of 200 mg of [15N]glycine as a tracer. The nitrogen flux through the amino acid pool was measured separately with both urinary ammonia and urinary urea as end products; the average value was used for further calculations. 2. Subjects were studied in the fed state, both on an adequate and a protein-restricted diet, and also in the fasting state. 3. The rates of protein synthesis were markedly increased in the patients, not only in the fed but also in the fasting state. Protein breakdown rates were increased in the patients in the fed state. 4. The nitrogen balance in steady-state conditions in the fed state was more positive in the patients, while their nitrogen loss in the fasting state was no higher than that of control subjects. 5. A hypothesis is put forward that the high protein requirements of cirrhotic patients could be caused by small and inadequate liver glycogen stores; due to these small stores, gluconeogenesis from amino acids will take place and lead to an extra amino acid loss even during short-term fasting. This increased amino acid loss could explain the elevated protein requirements in cirrhotic patients.


Structural reevaluation of the electrophilic hypervalent iodine reagent for trifluoromethylthiolation supported by the crystalline sponge method for X-ray analysis.
Hypervalent iodine λ3-benziodoxoles are common electrophilic transfer reagents known for their enhanced stability compared to their non-cyclic analogues. Herein we present data showing that chlorobenziodoxole reacts with two different thiolate nucleophiles (thiocyanate and trifluoromethylthiolate), resulting in the formation of stable thioperoxy complexes rather than the expected benziodoxole derivatives. We further report a revised structure for the earlier described electrophilic trifluoromethylthiolation reagent (1), which was previously believed to contain the benziodoxole framework. Our findings, which are based on a combination of analytical techniques, including the recently introduced crystalline sponge method for X-ray analysis, unambiguously demonstrate that 1 is a thioperoxy compound both in solution and the solid state.


A Human iPSC-derived 3D platform using primary brain cancer cells to study drug development and personalized medicine.
A high throughput histology (microTMA) platform was applied for testing drugs against tumors in a novel 3D heterotypic glioblastoma brain sphere (gBS) model consisting of glioblastoma tumor cells, iPSC-derived neurons, glial cells and astrocytes grown in a spheroid. The differential responses of gBS tumors and normal neuronal cells to sustained treatments with anti-cancer drugs temozolomide (TMZ) and doxorubicin (DOX) were investigated. gBS were exposed to TMZ or DOX over a 7-day period. Untreated gBS tumors increased in size over a 4-week culture period, however, there was no increase in the number of normal neuronal cells. TMZ (100 uM) and DOX (0.3 uM) treatments caused ~30% (P~0.07) and ~80% (P < 0.001) decreases in the size of the tumors, respectively. Neither treatment altered the number of normal neuronal cells in the model. The anti-tumor effects of TMZ and DOX were mediated in part by selective induction of apoptosis. This platform provides a novel approach for screening new anti-glioblastoma agents and evaluating different treatment options for a given patient.


Natural Gum-Based Functional Bioactive Films and Coatings: A Review.
Edible films and coatings are a current and future food packaging trend. In the food and envi-ronmental sectors, there is a growing need to understand the role of edible packaging and sus-tainability. Gums are polysaccharides of natural origin that are frequently utilized as thickeners, clarifying agents, gelling agents, emulsifiers, and stabilizers in the food sector. Gums come in a variety of forms, including seed gums, mucilage gums, exudate gums, and so on. As a biodegradable and sustainable alternative to petrochemical-based film and coatings, gums could be a promising option. Natural plant gum-based edible packaging helps to ensure extension of shelf-life of fresh and processed foods while also reducing microbiological alteration and/or oxidation processes. In this review, the possible applications of gum-based polymers and their functional properties in development of edible films and coatings, were comprehensively dis-cussed. In the future, technology for developing natural gum-based edible films and coatings might be applied commercially to improve shelf life and preserve the quality of foods.


Albuminuria and Estimated GFR as Risk Factors for Dementia in Midlife and Older Age: Findings From the ARIC Study.
Evidence is limited on how estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR) relate to dementia at different ages. We evaluated eGFR and UACR in midlife and older age as risk factors for dementia. Additionally, we assessed whether the association between eGFR and dementia is altered when cystatin C and β2-microglobulin (B2M) levels are used for GFR estimation. Prospective cohort study. Two baselines from the Atherosclerosis Risk in Communities (ARIC) Study were used: visit 4 (1996-1998), including 9,967 participants 54 to 74 years old, and visit 5 (2011-2013), including 4,626 participants 70 to 90 years old. Participants were followed up until 2017. Log(UACR); eGFR based on creatinine, cystatin C, creatinine and cystatin C, or B2M levels (denoted as eGFRcr, eGFRcys, eGFRcr-cys, and eGFRB2M). Incident dementia. Multivariable Cox proportional hazards regression models fit separately for each of the 5 predictors and based on a change in the predictor equivalent to the interquartile range for that predictor at visit 4 (IQRV4). eGFR models were adjusted for log(UACR) and log(UACR) models were adjusted for eGFRcys. We observed 1,821 dementia cases after visit 4 and 438 cases after visit 5. Dementia risk increased with higher albuminuria levels (HRs per IQRV4 [equivalent to 4.2-fold greater log albuminuria] of 1.15 [95% CI, 1.09-1.21] after visit 4 and 1.27 [95% CI, 1.13-1.42] after visit 5). An association with lower eGFR was seen for only eGFRcys (HRs per IQRV4 [equivalent to 24.3mL/min/1.73m2 lesser eGFRcys] of 1.12 [95% CI, 1.04-1.21] after visit 4 and 1.30 [95% CI, 1.12-1.52] after visit 5) and eGFRB2M (HRs per IQRV4 [equivalent to 18.3mL/min/1.73m2 lesser eGFRB2M] of 1.15 [95% CI, 1.07-1.23] after visit 4 and 1.34 [95% CI, 1.17-1.55] after visit 5). Differences between these associations in midlife and older age were not statistically significant. Changes in potentially time-varying covariates were not measured. Dementia was not subclassified by cause. Albuminuria was consistently associated with dementia incidence. Lower eGFR based on cystatin C or B2M, but not creatinine, levels was also associated with dementia. Risk associations were similar when kidney measures were assessed at midlife and older age.


Psychiatric Diagnoses Differ Considerably in Their Associations With Alcohol/Drug-Related Problems Among Adolescents. A Norwegian Population-Based Survey Linked With National Patient Registry Data.
The aim of this study was to examine alcohol/drug use and problems across psychiatric diagnoses and to what extent associations between each psychiatric diagnosis and alcohol/drug use and problems were independent from the potential confounding effects of psychiatric comorbidity, socioeconomic status, sex and age. We used a dataset comprising a linkage between a large population-based and cross-sectional study among Norwegian adolescents (the youth@hordaland conducted in 2012) and national registry-based data on specialist mental health care use during the 4 years prior to the survey (2008 to 2011). The study sample included 16 to 19 year olds who participated in the youth@hordaland survey and consented to the linkage with patient registry data (n = 9,408). Among these, 853 (9%) had received specialist mental health care and comprised the clinical group, while the rest (n = 8,555) comprised the comparison group. The main outcome variables were several self-reported indicators for alcohol/drug use, including any alcohol use, frequent alcohol intoxication, high-level alcohol consumption, and lifetime illicit drug use, as well as one indicator for potential alcohol/drug-related problems: a positive CRAFFT-score. Adolescents receiving specialist mental health care (n = 853) reported more frequently alcohol/drug use and problems compared to adolescents not receiving these services (Cohens d's ranging from 0.09 to 0.29, all p ≤ 0.01). Anxiety, depression, conduct disorders, eating disorders, ADHD, and trauma-related disorders were all associated with single measures of alcohol/drug use and problems, with odds ratios (ORs) ranging from 1.58 to 4.63, all p < 0.05) in unadjusted models. Trauma-related disorders, depression and conduct disorders were also positively associated with higher scores on a combined indicator of alcohol/drug use and problems (ORs ranging from 1.89 to 3.15, all p < 0.01), even after the full adjustment from psychiatric comorbidity and sociodemographic variables (adjusted odds ratios ranging from 1.61 to 2.79, p < 0.05). These results suggest that alcohol/drug use and problems were slightly more common among adolescents who received specialist mental health care during the past 4 years compared with the general adolescent population, and adolescents with trauma-related disorders, depression and conduct disorders were high-risk groups for alcohol/drug use and problems.


A novel gene essential for the development of single positive thymocytes.
A critical step during intrathymic T-cell development is the transition of CD4(+) CD8(+) double-positive (DP) cells to the major histocompatibility complex class I (MHC-I)-restricted CD4(-) CD8(+) and MHC-II-restricted CD4(+) CD8(-) single-positive (SP) cell stage. Here, we identify a novel gene that is essential for this process. Through the T-cell phenotype-based screening of N-ethyl-N-nitrosourea (ENU)-induced mutant mice, we established a mouse line in which numbers of CD4 and CD8 SP thymocytes as well as peripheral CD4 and CD8 T cells were dramatically reduced. Using linkage analysis and DNA sequencing, we identified a missense point mutation in a gene, E430004N04Rik (also known as themis), that does not belong to any known gene family. This orphan gene is expressed specifically in DP and SP thymocytes and peripheral T cells, whereas in mutant thymocytes the levels of protein encoded by this gene were drastically reduced. We generated E430004N04Rik-deficient mice, and their phenotype was virtually identical to that of the ENU mutant mice, thereby confirming that this gene is essential for the development of SP thymocytes.


Productivity savings from colorectal cancer prevention and control strategies.
Lost productivity represents a considerable portion of the total economic burden of colorectal cancer (CRC), but cost-effectiveness studies of CRC prevention and control have not included these costs and therefore underestimate potential savings from CRC prevention and control. To use microsimulation modeling study to estimate and project productivity costs of CRC and to model the savings from four approaches to reducing CRC incidence and mortality: risk factor reduction, improved screening, improved treatment, and a simultaneous approach where all three strategies are implemented. A model was developed to project productivity losses from CRC using the U.S. population with CRC incidence and mortality projected through the year 2020. Outcome measures were CRC mortality, morbidity, and productivity savings. With 2005 levels in risk factors, screening, and treatment, 48,748 CRC deaths occurred in 2010, amounting to $21 billion of lost productivity. Using prevention and treatment strategies simultaneously, 3586 deaths could have been avoided in 2010, leading to a savings of $1.4 billion. Cumulatively, by 2020, simultaneous strategies that reduce risk factors and increase screening and treatment could result in 101,353 deaths avoided and $33.9 billion in savings in reduced productivity loss. Improved screening rates alone led to nearly $14.7 billion in savings between 2005 and 2020, followed by risk factor reduction ($12.4 billion) and improved treatment ($8.4 billion). The savings in productivity loss from strategies to reduce CRC incidence and mortality are substantial, providing evidence that CRC prevention and control strategies are likely to be cost-saving.


Effect of preconditioning ischemia on reperfusion arrhythmias after coronary artery occlusion and reperfusion in the rat.
Severe arrhythmias occur predictably on reperfusion after 5 minutes of coronary occlusion in the rat. There is little data available on whether ischemic preconditioning (PC) of hearts can reduce the incidence of such arrhythmias. The effect of PC (three cycles of 2 minutes of coronary occlusion and 5 minutes of reperfusion) on development of arrhythmias after a subsequent 5-minute coronary artery occlusion and reperfusion was studied. Rats (n = 16 each group) underwent 5-minute occlusion and reperfusion alone or preceded by PC; arrhythmias were monitored during ischemia and for 10 minutes of reperfusion, and biopsies were taken for creatine phosphate and adenosine triphosphate in ischemic and nonischemic zones of the left ventricle. PC reduced the incidence of ventricular tachycardia (VT) during occlusion (81% control versus 13% PC, p less than 0.001). On subsequent reperfusion, ventricular fibrillation (VF) developed in zero PC animals versus 13 (81%) of controls (p less than 0.001), and irreversible VF in zero of PC versus seven (44%) of controls (p = 0.007). VT occurred in four (25%) of PC versus all (100%) of controls (p less than 0.001). PC reduced mean duration of VT plus VF from 320 +/- 54 to 5 +/- 1 seconds (p less than 0.001) and delayed arrhythmia onset from 8 +/- 2 to 85 +/- 35 seconds after reperfusion. There was no difference in creatine phosphate levels in the ischemic zone at the end of reperfusion in PC animals compared with controls without irreversible VF (16.2 +/- 4.1 versus 15.5 +/- 3.9 nmol/mg protein, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)


Melatonin suppresses methamphetamine-triggered endoplasmic reticulum stress in C6 cells glioma cell lines.
Methamphetamine (METH) is a neurotoxic drug that causes brain damage by inducing neuronal and glial cell death together with glial cell hyperactivity-mediated progressive neurodegeneration. Previous studies have shown that METH induced glial cell hyperactivity and death via oxidative stress, the inflammatory response, and endoplasmic reticulum stress (ER stress) mechanisms, and melatonin could reverse these effects. However, the exact mechanism of the protective role of melatonin in METH-mediated ER stress has not been understood. This study investigated the protective effect of melatonin against METH toxicity-mediated ER stress in glial cells. Our study demonstrated that METH increased glial cell toxicity related to METH-induced ER stress by stimulating the unfolded protein response (UPR) to activate the expression of ER stress transducers, including phosphorylated double-stranded RNA-activated protein kinase (PKR)-like ER kinase (p-PERK), activating transcription factor (ATF6), and phosphorylated inositol-requiring enzyme 1 (p-IRE1). Moreover, the expression of binding immunoglobulin protein (Bip), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, phosphorylated eukaryotic translation initiation factor 2 alpha (p-eIF2α) and spliced X-box-binding protein-1 (XBP-1) mRNA were also increased. Melatonin reduced ER stress induced by METH toxicity by reducing the expression of ER stress response genes and proteins in a concentration-dependent manner. In addition, melatonin promoted the expression of Bip chaperone in a concentration-dependent manner. Taken together, our findings suggest that melatonin can protect against ER stress-induced glial cell death induced by METH.


Oesophageal cancer in Area 2 of Kwazulu-Natal: predictors of late presentation.
There are limited prospective data sets on clinical characteristics, stage of presentation and treatment of patients with Oesophageal Squamous Cell Carcinoma (OSCC) in South Africa. This study aimed to assess the frequency and severity of clinical characteristics associated with late presentation of patients with OSCC presenting to a cancer referral centre in KwaZulu-Natal, South Africa. A prospective consecutive series of patients presenting with confirmed OSCC treated at Greys Hospital in 2016/2017 were enrolled. Data collected included: age, gender, home language, referral centre, clinical and laboratory characteristics: dysphagia score, Eastern Cooperative Oncology Group (ECOG) performance status, body mass index (BMI), serum albumin, tumour pathology and treatment administered. One hundred patients were analysed. Ninety four percent spoke isiZulu. The mean age was 61 with a male to female ratio of 1.5:1 Ninety percent had palliative treatment as their overall assessment precluded curative treatment. Five patients underwent curative treatment. The age standardised incidence (ASR) was 25.2 per 100 000. The factors associated with late presentation and their frequency were: advanced dysphagia grade ( </=2 in 68%), malnutrition (BMI <18.5kg/m2 in 49%), hypoalbuminaemia (serum albumin < 35 g/l in 70%), poor performance status (ECOG</=2 in 50% ) and moderate to poor tumour differentiation in 95% of patients. OSCC in Kwazulu-Natal has double the ASR of South Africa and places a significant burden on the region's health care system. Factors associated with late presentation occur in the majority and alone or in combination preclude curative therapies. The frequency of these factors serve as a benchmark for comparison, and reduction in their frequency may indicate effectiveness of interventions designed to improve awareness and access to proper care.


Impact of the mitochondrial genetic background in complex III deficiency.
In recent years clinical evidence has emphasized the importance of the mtDNA genetic background that hosts a primary pathogenic mutation in the clinical expression of mitochondrial disorders, but little experimental confirmation has been provided. We have analyzed the pathogenic role of a novel homoplasmic mutation (m.15533 A>G) in the cytochrome b (MT-CYB) gene in a patient presenting with lactic acidosis, seizures, mild mental delay, and behaviour abnormalities. Spectrophotometric analyses of the respiratory chain enzyme activities were performed in different tissues, the whole muscle mitochondrial DNA of the patient was sequenced, and the novel mutation was confirmed by PCR-RFLP. Transmitochondrial cybrids were constructed to confirm the pathogenicity of the mutation, and assembly/stability studies were carried out in fibroblasts and cybrids by means of mitochondrial translation inhibition in combination with blue native gel electrophoresis. Biochemical analyses revealed a decrease in respiratory chain complex III activity in patient's skeletal muscle, and a combined enzyme defect of complexes III and IV in fibroblasts. Mutant transmitochondrial cybrids restored normal enzyme activities and steady-state protein levels, the mutation was mildly conserved along evolution, and the proband's mother and maternal aunt, both clinically unaffected, also harboured the homoplasmic mutation. These data suggested a nuclear genetic origin of the disease. However, by forcing the de novo functioning of the OXPHOS system, a severe delay in the biogenesis of the respiratory chain complexes was observed in the mutants, which demonstrated a direct functional effect of the mitochondrial genetic background. Our results point to possible pitfalls in the detection of pathogenic mitochondrial mutations, and highlight the role of the genetic mtDNA background in the development of mitochondrial disorders.


The Pheromone Module SteC-MkkB-MpkB-SteD-HamE Regulates Development, Stress Responses and Secondary Metabolism in Aspergillus fumigatus.
In order for eukaryotes to efficiently detect and respond to environmental stimuli, a myriad of protein signaling pathways are utilized. An example of highly conserved signaling pathways in eukaryotes are the mitogen-activated protein kinase (MAPK) pathways. In fungi, MAPK pathways have been shown to regulate a diverse array of biological processes, such as asexual and sexual development, stress responses and the production of secondary metabolites (SMs). In the model fungus Aspergillus nidulans, a MAPK pathway known as the pheromone module is utilized to regulate both development and SM production. This signaling cascade consists of the three kinases SteC, MkkB, and MpkB, as well as the SteD adaptor protein and the HamE scaffold. In this study, homologs of each of these proteins have been identified in the opportunistic human pathogen A. fumigatus. By performing epitope tagging and mass spectrometry experiments, we have shown that these proteins form a pentameric complex, similar to what is observed in A. nidulans. This complex has been shown to assemble in the cytoplasm and MpkB enters the nucleus, where it would presumably interact with various transcription factors. Pheromone module mutant strains exhibit drastic reductions in asexual sporulation, vegetative growth rate and production of SMs, such as gliotoxin. Mutants also display increased sensitivity to cell wall and oxidative stress agents. Overall, these data provide evidence of the existence of a conserved MAP kinase signaling pathway in Aspergillus species and suggest that this pathway is critical for the regulation of fungal development and secondary metabolism.


The CCN family member Wisp3, mutant in progressive pseudorheumatoid dysplasia, modulates BMP and Wnt signaling.
In humans, loss-of-function mutations in the gene encoding Wnt1 inducible signaling pathway protein 3 (WISP3) cause the autosomal-recessive skeletal disorder progressive pseudorheumatoid dysplasia (PPD). However, in mice there is no apparent phenotype caused by Wisp3 deficiency or overexpression. Consequently, the in vivo activities of Wisp3 have remained elusive. We cloned the zebrafish ortholog of Wisp3 and investigated its biologic activity in vivo using gain-of-function and loss-of-function approaches. Overexpression of zebrafish Wisp3 protein inhibited bone morphogenetic protein (BMP) and Wnt signaling in developing zebrafish. Conditioned medium-containing zebrafish and human Wisp3 also inhibited BMP and Wnt signaling in mammalian cells by binding to BMP ligand and to the Wnt coreceptors low-density lipoprotein receptor-related protein 6 (LRP6) and Frizzled, respectively. Wisp3 proteins containing disease-causing amino acid substitutions found in patients with PPD had reduced activity in these assays. Morpholino-mediated inhibition of zebrafish Wisp3 protein expression in developing zebrafish affected pharyngeal cartilage size and shape. These data provide a biologic assay for Wisp3, reveal a role for Wisp3 during zebrafish cartilage development, and suggest that dysregulation of BMP and/or Wnt signaling contributes to cartilage failure in humans with PPD.


The University of California, San Francisco Cancer of the Prostate Risk Assessment score: a straightforward and reliable preoperative predictor of disease recurrence after radical prostatectomy.
Multivariate prognostic instruments aim to predict risk of recurrence among patients with localized prostate cancer. We devised a novel risk assessment tool which would be a strong predictor of outcome across various levels of risk, and which could be easily applied and intuitively understood. We studied 1,439 men diagnosed between 1992 and 2001 who had undergone radical prostatectomy and were followed in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database, a longitudinal, community based disease registry of patients with prostate cancer. Disease recurrence was defined as prostate specific antigen (PSA) 0.2 ng/ml or greater on 2 consecutive occasions following prostatectomy or a second cancer treatment more than 6 months after surgery. The University of California, San Francisco-Cancer of the Prostate Risk Assessment (UCSF-CAPRA) score was developed using preoperative PSA, Gleason score, clinical T stage, biopsy results and age. The index was developed and validated using Cox proportional hazards and life table analyses. A total of 210 patients (15%) had recurrence, 145 by PSA criteria and 65 by second treatment. Based on the results of the Cox analysis, points were assigned based on PSA (0 to 4 points), Gleason score (0 to 3), T stage (0 to 1), age (0 to 1) and percent of biopsy positive cores (0 to 1). The UCSF-CAPRA score range is 0 to 10, with roughly double the risk of recurrence for each 2-point increase in score. Recurrence-free survival at 5 years ranged from 85% for a UCSF-CAPRA score of 0 to 1 (95% CI 73%-92%) to 8% for a score of 7 to 10 (95% CI 0%-28%). The concordance index for the UCSF-CAPRA score was 0.66. The UCSF-CAPRA score is a straightforward yet powerful preoperative risk assessment tool. It must be externally validated in future studies.


Development of a decision support intervention for family members of adults who lack capacity to consent to trials.
Informed consent is required for participation in clinical trials, however trials involving adults who lack capacity to consent require different enrolment processes. A family member usually acts as a proxy to make a decision based on the patient's 'presumed will', but these decisions can be challenging and families may experience an emotional and decisional burden. Decisions made on behalf of others are conceptually different from those made for ourselves. Innovations have been developed to improve informed consent processes for research, including a number of decision aids, however there are no interventions for proxies who are faced with more complex decisions. This article outlines the development of a novel decision aid to support families making decisions about research participation on behalf of an adult who lacks capacity to consent. Decision support interventions should be developed using rigorous and evidence-based methods. This intervention was developed using MRC guidance for the development of complex interventions, and a conceptual framework for the development and evaluation of decision aids for people considering taking part in a clinical trial. The intervention was informed by a systematic review and analysis of existing information provision. Previous qualitative research with families who acted as proxies enabled the development of a theoretical framework to underpin the intervention. The intervention was iteratively developed with the involvement of lay advisors and relevant stakeholders. Previous research, theoretical frameworks, and decision aid development frameworks were used to identify and develop the intervention components. The decision aid includes information about the proxy's role and utilises a values clarification exercise and decision support methods to enable a more informed and better-quality decision. Stakeholders, including those representing implementers and receivers of the intervention, contributed to the design and comprehensibility of the decision aid to ensure that it would be acceptable for use. Frameworks for the development of decision aids for people considering participating in a clinical trial can be used to develop interventions for family members acting as proxy decision-makers. The decision support tool is acceptable to users. Feasibility testing and outcome measure development is required prior to any evaluation of its effectiveness.


Residents' mental model of bag-mask ventilation.
Our objectives were to characterize resident knowledge of bag-mask ventilation (BMV) and to identify predictors of a well-developed mental model of BMV. A pilot survey of airway experts identified 6 steps considered essential in situations of difficult BMV. Subsequently, residents from pediatric, emergency medicine, and medicine-pediatric programs at a tertiary care hospital completed the same pediatric scenario-based item given to airway experts. Of all surveys, 75% (n = 103) were completed. No resident identified all 6 maneuvers for difficult BMV. With decreasing frequency, the items identified were as follows: reposition patient/airway (82%), oral airway (61%), nasal airway (39%), jaw thrust (37%), 2-person technique (7%), and call for help (4%). Emergency medicine residents had a higher mean (SD) score than the medicine-pediatric and pediatric residents of a possible 6 (2.71 (1.26) vs 2.01 (1.07), P = 0.004) and were significantly more likely to identify certain maneuvers: oral airway (81% vs 52%, P = 0.006), nasal airway (57% vs 29%, P = 0.006), and 2-person technique (14% vs 3%, P = 0.042). Only 15% of all residents were able to identify 4 or more essential maneuvers. Higher level of training was associated with identifying the 2-person technique. In addition, residents who completed 1 month of pediatric or adult anesthesia were more likely to identify use of nasal airway, oral airway and 2-person technique, and to identify 4 or more maneuvers. Emergency medicine residents identified more steps to optimize difficult BMV, although most residents exhibited a poorly developed mental model for difficult BMV compared with the consistent mental model of airway experts. Future research should investigate strategies for improving residents' mental model of BMV and its impact on patient care.


Loci of the release from fMRI adaptation for changes in facial expression, identity, and viewpoint.
Face recognition involves collaboration of a distributed network of neural correlates. However, how different attributes of faces are represented has remained unclear. We used functional magnetic resonance imaging-adaptation (fMRIa) to investigate the representation of viewpoint, expression, and identity of faces in the fusiform face area (FFA) and the occipital face area (OFA). In an event-related experiment, subjects viewed sequences of two faces and judged whether they depicted the same person. The images could vary in viewpoint, expression and/or identity. Critically, the physical similarity between view-changed and between expression-changed faces of the same person were matched by the Gabor-jet metric, a measure that predicts almost perfectly the effects of image similarity on face discrimination performance. In FFA, changes of identity produced the largest release from adaptation followed by changes of expression; but the release caused by changes of viewpoint was smaller and not reliable. OFA was sensitive only to changes in identity, even when image changes produced by identity variations were matched to those of expression and orientation. These results suggest that FFA is involved in the perception of both identity and expression of faces, a result contrary to the hypothesis of independent processing of changeable and invariant attributes of faces in the face-processing network.


Study-protocol for a randomized controlled trial comparing clinical and radiological results after three different posterior decompression techniques for lumbar spinal stenosis: the Spinal Stenosis Trial (SST) (part of the NORDSTEN Study).
There are several posterior decompression techniques for lumbar spinal stenosis (LSS). There is a trend towards performing less invasive surgical procedures, but no multicentre randomized controlled trials have evaluated the relative efficacy of these techniques at short and long-term. A multicentre randomized controlled trial [the Spinal Stenosis Trial (SST) (part of the NORDSTEN study)] including 465 patients aged 18-80 years with neurogenic claudication or radiating pain and MRI findings indicating lumbar spinal stenosis without spondylolisthesis is performed to compare three posterior decompression techniques: unilateral laminotomy with crossover, bilateral laminotomy and spinous process osteotomy. The primary outcome is change in Oswestry Disability Index (ODI 2 years postoperatively). Secondary outcomes are change in EQ-5D, Zurich Claudication Questionnaire, and Numeric Rating Scale for leg-pain and back-pain. Also recorded were Global Perceived Effect score, complications, length of hospital stay, reoperation rate 2 years postoperatively, difference in recurrence of symptoms or postoperative instability, and MRI change in the dural sac area. Further, a 5 and 10 years follow-up is planned with the same outcome measures. Newer and less invasive techniques are increasingly favoured in surgery for LSS. This trial will compare the clinical and radiological results of three different techniques, and may contribute to better clinical decision making in the surgical treatment of LSS. ClinicalTrials.gov reference: NCT02007083 (November 22, 2013).


Clinical evaluation of CyberKnife in the treatment of vestibular schwannomas.
This study assessed the posttreatment tumor control and auditory function of vestibular schwannoma (VS) patients after CyberKnife (CK) and analyzed the possible prognostic factors of hearing loss. We retrospectively studied 117 VS patients, with Gardner-Robertson (GR) classification grades I to IV, who underwent CK between 2006 and 2012. Data including radiosurgery treatment parameters, pre- and postoperative tumor size, and auditory function were collected and examined. With CK, 117 patients had excellent tumor control rates (99.1%), with a mean imaging followup of 61.1 months. Excluding 52 patients (GR III-IV pretreatment), 53 (81.5%) of the remaining 65 patients (initial GR I-II) maintained GR I or II hearing after CK, with a mean audiometric followup of 64.5 months. Twelve patients experienced hearing degradation (91.6% were GR II pretreatment); they appeared to have significantly larger tumor sizes, significantly smaller cochlear sizes, and higher prescribed cochlear doses, compared to the patients with preserved hearing. Our data showed that CK treatment provided an excellent tumor control rate and a comparable hearing preservation rate in VS patients. Patients with pretreatment GR II hearing levels, larger tumor volumes, smaller cochlear sizes, and higher prescribed cochlear doses may have poor hearing prognoses.


Repeated Excessive Exercise Attenuates the Anti-Inflammatory Effects of Exercise in Older Men.
Introduction/Purpose: A number of studies have investigated the effect of training with a moderate exercise dose (3-6 h/weekly) on the inflammatory profile in blood, and the data are inconsistent. Cross-sectional studies indicate a positive effect of physical activity level on inflammation levels and risk of metabolic disease. However, it is not clear whether this may be dose dependent and if very prolonged repeated exercise therefore may be beneficial for low-grade inflammation. Based on this we studied how excessive repeated prolonged exercise influenced low-grade inflammation and adipose tissue anti-inflammatory macrophage content in six older male recreationally trained cyclists. Low-grade inflammation and adipose tissue macrophage content were investigated in six older trained men (age: 61 ± 4 years; VO2peak: 48 ± 2 mL kg-1 min-1) following repeated prolonged exercise. Methods: Cycling was performed daily for 14 days covering in total 2,706 km (1,681 miles). Maximal oxygen uptake (VO2peak) was measured before and after the cycling. Duration and intensity of the exercise were determined from heart rates sampled during cycling. An adipose tissue biopsy from subcutaneous abdominal fat and a blood sample were obtained at rest in the overnight fasted state before and after the cycling. Anti-inflammatory adipose tissue macrophages (ATM) were immunohistochemically stained in cross sectional sections using a CD163 binding antibody. The ATM and adipocyte sizes were analyzed blindly. Results: The cyclists exercised daily for 10 h and 31 ± 37 min and average intensity was 53 ± 1% of VO2peak. Body weight remained unchanged and VO2peak decreased by 6 ± 2% (P = 0.04). Plasma inflammatory cytokines, TNFα and IL-18 remained unchanged, as did hsCRP, but plasma IL-6 increased significantly. CD163 macrophage content remained unchanged, as did adipocyte cell size. The HbA1c was not significantly decreased, but there was a trend (P < 0.07) toward an increased insulin resistance as estimated by the Quicki Index. Conclusion: The regular prolonged exercise did not influence abdominal adipose tissue inflammation, but the higher plasma IL-6 concentration concurrent with a trend toward higher insulin resistance and decreased VO2peak implies that the excessive amount of exercise probably attenuated the possible potential anti-inflammatory effects of exercise.


Explaining change in quality of life of children and adolescents with anorectal malformations or Hirschsprung disease.
The purpose of this work was to examine changes in quality of life, disease-specific functioning, and psychosocial competencies of children and adolescents (8-16 years of age) with anorectal malformations or Hirschsprung disease and to identify predictors of change in quality of life by testing an explanatory model in which background variables explained changes in quality of life via changes in disease-specific functioning and psychosocial competencies. Questionnaires were administered to 129 patients with anorectal malformations and 121 patients with Hirschsprung disease within a 3-year interval. Clinical and sociodemographic background variables were measured on the first occasion. Quality of life (physical and mental), disease-specific functioning (defecation-related), and psychosocial competencies (self-esteem, athletic competencies, and school attitude) were measured on both occasions. Patients improved in disease-specific functioning and mental quality of life. Changes in quality of life were indeed explained by the explanatory model. Among other things, the results indicated that patients with a severe form of the disease or with additional congenital diseases showed worsening of school attitude, which in turn affected change in mental quality of life negatively. Children and adolescents with anorectal malformations or Hirschsprung disease reported better quality of life over time. To improve and maintain an optimal level of children's and adolescents' quality of life, it is important to direct treatment both to reducing symptoms and enhancing psychosocial competencies, in particular by paying attention to school attitude.


Protective Effects of Blueberry Anthocyanins against H2O2-Induced Oxidative Injuries in Human Retinal Pigment Epithelial Cells.
Blueberry anthocyanins are considered protective of eye health because of their recognized antioxidant properties. In this study, blueberry anthocyanin extract (BAE), malvidin (Mv), malvidin-3-glucoside (Mv-3-glc), and malvidin-3-galactoside (Mv-3-gal) all reduced H2O2-induced oxidative stress by decreasing the levels of reactive oxygen species and malondialdehyde and increasing the levels of superoxide dismutase, catalase, and glutathione peroxidase in human retinal pigment epithelial cells. BAE and the anthocyanin standards enhanced cell viability from 63.69 ± 3.36 to 86.57 ± 6.92% (BAE), 115.72 ± 23.41% (Mv), 98.15 ± 9.39% (Mv-3-glc), and 127.97 ± 20.09% (Mv-3-gal) and significantly inhibited cell apoptosis (P < 0.01 for all). Mitogen-activated-protein-kinase pathways, including ERK1/2 and p38, were involved in the bioactivities. In addition, the anthocyanins decreased vascular-endothelial-cell-growth-factor levels and activated Akt-signal pathways. These combined results supported the hypothesis that blueberry anthocyanins could inhibit the induction and progression of age-related macular degeneration (AMD) through antioxidant mechanisms.


Antioxidant, anticancer and antibacterial potential of Zakhm-e-hayat rhizomes crude extract and fractions.
Bergenia ciliata (locally known as Zakhm-e-hayat; wound healer) is commonly employed for wound healing, curing diarrhea and vomiting, fever, cough and pulmonary affections. Local community uses this plant as tea decoction with table salt. B. ciliata crude extract and its fractions were subjected to antibacterial, antioxidant effects as well as determination of total flavonoids and phenolics, DNA damage and anticancerous activities following standard protocols. Increased percentage inhibition of free radical in DPPH assay as well as elevated phenolic and flavonoid contents revealed antioxidant potential of this potent herb. Ethyl acetate and aqueous extracts showed IC(50) of 0.7 and 0.3 mg/ml respectively, against H157 cell line. Antibacterial analysis showed MIC 0.4-10mg/ml for crude extract and fractions. The results obtained conclude that extracts of B. ciliata contain remedial latent and can be used as possible source for drug development by pharmaceutical industries.


A common single nucleotide polymorphism in endoplasmic reticulum aminopeptidase 2 induces a specificity switch that leads to altered antigen processing.
Endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2) cooperate to trim antigenic peptide precursors for loading onto MHC class I molecules and help regulate the adaptive immune response. Common coding single nucleotide polymorphisms in ERAP1 and ERAP2 have been linked with predisposition to human diseases ranging from viral and bacterial infections to autoimmunity and cancer. It has been hypothesized that altered Ag processing by these enzymes is a causal link to disease etiology, but the molecular mechanisms are obscure. We report in this article that the common ERAP2 single nucleotide polymorphism rs2549782 that codes for amino acid variation N392K leads to alterations in both the activity and the specificity of the enzyme. Specifically, the 392N allele excises hydrophobic N-terminal residues from epitope precursors up to 165-fold faster compared with the 392K allele, although both alleles are very similar in excising positively charged N-terminal amino acids. These effects are primarily due to changes in the catalytic turnover rate (k(cat)) and not in the affinity for the substrate. X-ray crystallographic analysis of the ERAP2 392K allele suggests that the polymorphism interferes with the stabilization of the N terminus of the peptide both directly and indirectly through interactions with key residues participating in catalysis. This specificity switch allows the 392N allele of ERAP2 to supplement ERAP1 activity for the removal of hydrophobic N-terminal residues. Our results provide mechanistic insight to the association of this ERAP2 polymorphism with disease and support the idea that polymorphic variation in Ag processing enzymes constitutes a component of immune response variability in humans.


The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2003 update.
The Texas Medication Algorithm Project (TMAP) has been a public-academic collaboration in which guidelines for medication treatment of schizophrenia, bipolar disorder, and major depressive disorder were used in selected public outpatient clinics in Texas. Subsequently, these algorithms were implemented throughout Texas and are being used in other states. Guidelines require updating when significant new evidence emerges; the antipsychotic algorithm for schizophrenia was last updated in 1999. This article reports the recommendations developed in 2002 and 2003 by a group of experts, clinicians, and administrators. A conference in January 2002 began the update process. Before the conference, experts in the pharmacologic treatment of schizophrenia, clinicians, and administrators reviewed literature topics and prepared presentations. Topics included ziprasidone's inclusion in the algorithm, the number of antipsychotics tried before clozapine, and the role of first generation antipsychotics. Data were rated according to Agency for Healthcare Research and Quality criteria. After discussing the presentations, conference attendees arrived at consensus recommendations. Consideration of aripiprazole's inclusion was subsequently handled by electronic communications. The antipsychotic algorithm for schizophrenia was updated to include ziprasidone and aripiprazole among the first-line agents. Relative to the prior algorithm, the number of stages before clozapine was reduced. First generation antipsychotics were included but not as first-line choices. For patients refusing or not responding to clozapine and clozapine augmentation, preference was given to trying monotherapy with another antipsychotic before resorting to antipsychotic combinations. Consensus on algorithm revisions was achieved, but only further well-controlled research will answer many key questions about sequence and type of medication treatments of schizophrenia.


Quality of life and functional status among homeless men attending a day shelter in Louisville, Kentucky.
The homeless present important social and medical problems in most parts of the United States, including urban areas of Kentucky. While some studies have examined the health status of the homeless, very little is known about their quality of life or functional status. In the present study, 188 homeless men attending St. John's Day Shelter in Louisville completed an interviewer-assisted instrument that assessed self-perceived quality of life using the Perceived Quality of Life (PQOL) scale and self-perceived functional status using the Dartmouth COOP charts. The instrument also included questions on demographics and health risk behaviors of the homeless men. The results show that the typical homeless male attending St. John's is an unmarried, white, middle-aged high school graduate who is unemployed. In terms of quality of life, these men indicate general satisfaction with their physical and cognitive abilities, but significantly lower satisfaction with the social aspects of their lives. With regard to functional status, the homeless men report that they function best in terms of physical fitness and ability to perform daily activities. They report lower assessments of overall health, feelings, quality of life, and social support. These results suggest that poor social role functioning among homeless men is a major contributor to their poor quality of life. Thus, improving their health and quality of life may require an emphasis on social services in addition to routine medical care.


Green tea and coffee intake and risk of pancreatic cancer in a large-scale, population-based cohort study in Japan (JPHC study).
Pancreatic cancer is one of the most aggressive and treatment-refractory malignancies in humans. The most effective means of reducing pancreatic cancer mortality may be primary prevention. Although laboratory studies have demonstrated that green tea possesses anticancer activities, results from epidemiological studies have failed to show a consistent cancer-preventive effect. In addition, there is a lingering concern that coffee mighty increase the risk of pancreatic cancer although the most recent epidemiological studies showed no overall association between coffee and risk. Here, we examined the association between the drinking of green tea or coffee and the risk of pancreatic cancer in a large population-based cohort study in Japan (JPHC study). In total, 102 137 participants were followed for an average of 11 years through to the end of 2003. A total of 233 incident cases of pancreatic cancer were identified among 1 116 945 person-years of follow-up. Overall, the risk of pancreatic cancer was not associated with either green tea or coffee intake in our population, although a reduced risk was apparent among men who drank at least three cups of coffee per day compared with those who did not drink any or only rarely drank coffee. In conclusion, our findings support the idea that green tea or coffee consumption does not have a substantial impact on pancreatic cancer risk in general.


Biospecimen Reporting for Improved Study Quality.
Human biospecimens are subject to a number of different collection, processing, and storage factors that can significantly alter their molecular composition and consistency. These biospecimen preanalytical factors, in turn, influence experimental outcomes and the ability to reproduce scientific results. Currently, the extent and type of information specific to the biospecimen preanalytical conditions reported in scientific publications and regulatory submissions varies widely. To improve the quality of research utilizing human tissues, it is critical that information regarding the handling of biospecimens be reported in a thorough, accurate, and standardized manner. The Biospecimen Reporting for Improved Study Quality recommendations outlined herein are intended to apply to any study in which human biospecimens are used. The purpose of reporting these details is to supply others, from researchers to regulators, with more consistent and standardized information to better evaluate, interpret, compare, and reproduce the experimental results. The Biospecimen Reporting for Improved Study Quality guidelines are proposed as an important and timely resource tool to strengthen communication and publications around biospecimen-related research and help reassure patient contributors and the advocacy community that the contributions are valued and respected.


The perspectives of politicians on tobacco control in Turkey.
Tobacco use is a leading but preventable cause of non-communicable diseases and premature death. The legislature has a key role in setting tobacco control policies. Smoking trends are decreasing thanks to the introduction of effective tobacco control policies in Turkey and these policies may have been shaped by how politicians' interpreted social problems that were prominent during the development and implementation of tobacco regulations. This paper explores the long-term national relationship between tobacco consumption, tobacco control policies and the associated political discourse in Turkey, considering the varying influences through national leadership on this important public health agenda. This relationship is studied by comparing a time series analysis of tobacco consumption trends with a policy analysis of the minutes of deliberations at the Grand National Assembly of Turkey (GNAT). This study uses Bayesian time series analysis in order investigate whether the tobacco control policies and related activities influenced the annual per adult cigarette consumption in Turkey. We used a novel method to identify change points in tobacco trends and whether they correspond with key policy changes intended to alter usage after adjusting for the effect of other non-policy related covariates, such as the purchasing power. The policy analysis included an examination of the minutes of deliberations at the GNAT-which is the Turkish parliament and unicameral Turkish legislature-1 year before and 1 year after the break years associated with an increase or decrease in tobacco consumption. Tobacco consumption increased with the encouragement of tobacco production and the entrance of multinational companies in the country in 1976 and 1993, respectively. The National Tobacco Law of 1996 and comprehensive amendments in 2008, including smoke-free public places and tax increases, appear to have helped reduce tobacco consumption in Turkey. The focus of Parliamentary discussions throughout this period changed, becoming less supportive of tobacco over time. However, throughout the period there remained discussions focussing on concerns around the implications for the economy and the privatization agenda, national agriculture and the welfare of farmers. Effective control appears to require certain political ingredients to be implemented: politicians who are well informed on tobacco control measures and understand the range of issues surrounding the policies (not only those directly health-related); and supportive public health information in the community. Evidence-based public health policy should be introduced to the politicians.


Neurotensin expression and release in human colon cancers.
Neurotensin (NT), a distal gut peptide released by intraluminal fats, is trophic for normal small bowel and colonic mucosa. In addition, NT stimulates growth of certain colon cancers; the mechanism for this effect is not known. The purpose of this study was to determine whether human colon cancers (HCC) (1) express the mRNA for NT/neuromedin N (N), (2) produce NT peptide, and (3) express the mRNA for a functional NT receptor (NTR). RNA was extracted from four HCC cell lines in culture, nine HCC lines established in athymic nude mice, and from six HCC and adjacent normal mucosa from freshly resected operative specimens; the RNA was analyzed for NT/N mRNA by Northern hybridization with a complementary DNA probe. Neurotensin peptide content, NTR expression, and intracellular Ca++ ([Ca++]i) mobilization in response to NT were evaluated in three HCC cell lines (LoVo, HT29, HCT116). Neurotensin/N mRNA transcripts were identified in all four of the HCC cell lines and in one of nine HCC in nude mice. Neurotensin expression was found in two of six freshly resected HCC and in none of the six corresponding samples of normal mucosa. Neurotensin peptide was identified by RIA in LoVo, HT29, and HCT116. In addition, NTR mRNA was found in HT29 and HCT116. Neurotensin stimulated [Ca++]i mobilization in HCT116 (without serum) and in LoVo (with 0.25% serum). These findings demonstrate the presence of NT/N mRNA and NT peptide and the presence of a functional NTR in certain HCC. Neurotensin, a potent trophic factor for normal gut mucosa, may function as an autocrine growth factor in certain human colon cancers.


Molecular dynamics simulations of the d(CCAACGTTGG)(2) decamer: influence of the crystal environment.
Molecular dynamics (MD) simulations of the DNA duplex d(CCAACGTTGG)(2) were used to study the relationship between DNA sequence and structure. Two crystal simulations were carried out; one consisted of one unit cell containing two duplexes, and the other of two unit cells containing four duplexes. Two solution simulations were also carried out, one starting from canonical B-DNA and the other starting from the crystal structure. For many helicoidal parameters, the results from the crystal and solution simulations were essentially identical. However, for other parameters, in particular, alpha, gamma, delta, (epsilon - zeta), phase, and helical twist, differences between crystal and solution simulations were apparent. Notably, during crystal simulations, values of helical twist remained comparable to those in the crystal structure, to include the sequence-dependent differences among base steps, in which values ranged from 20 degrees to 50 degrees per base step. However, in the solution simulations, not only did the average values of helical twist decrease to approximately 30 degrees per base step, but every base step was approximately 30 degrees, suggesting that the sequence-dependent information may be lost. This study reveals that MD simulations of the crystal environment complement solution simulations in validating the applicability of MD to the analysis of DNA structure.


Temporal scale dependent interactions between multiple environmental disturbances in microcosm ecosystems.
Global environmental change has negative impacts on ecological systems, impacting the stable provision of functions, goods, and services. Whereas effects of individual environmental changes (e.g. temperature change or change in resource availability) are reasonably well understood, we lack information about if and how multiple changes interact. We examined interactions among four types of environmental disturbance (temperature, nutrient ratio, carbon enrichment, and light) in a fully factorial design using a microbial aquatic ecosystem and observed responses of dissolved oxygen saturation at three temporal scales (resistance, resilience, and return time). We tested whether multiple disturbances combine in a dominant, additive, or interactive fashion, and compared the predictability of dissolved oxygen across scales. Carbon enrichment and shading reduced oxygen concentration in the short term (i.e. resistance); although no other effects or interactions were statistically significant, resistance decreased as the number of disturbances increased. In the medium term, only enrichment accelerated recovery, but none of the other effects (including interactions) were significant. In the long term, enrichment and shading lengthened return times, and we found significant two-way synergistic interactions between disturbances. The best performing model (dominant, additive, or interactive) depended on the temporal scale of response. In the short term (i.e. for resistance), the dominance model predicted resistance of dissolved oxygen best, due to a large effect of carbon enrichment, whereas none of the models could predict the medium term (i.e. resilience). The long-term response was best predicted by models including interactions among disturbances. Our results indicate the importance of accounting for the temporal scale of responses when researching the effects of environmental disturbances on ecosystems.


A phase 2 study of high-activity 186Re-HEDP with autologous peripheral blood stem cell transplant in progressive hormone-refractory prostate cancer metastatic to bone.
We investigated the potential for improvement in disease control by use of autologous peripheral blood stem cell transplant (PBSCT) to permit administration of high activities of (186)Re-hydroxyethylidene diphosphonate (HEDP) in patients with progressive hormone-refractory prostate cancer (HRPC). Eligible patients had progressive HRPC metastatic to bone, good performance status and minimal soft tissue disease. Patients received 5,000 MBq of (186)Re-HEDP i.v., followed 14 days later by PBSCT. Response was assessed using PSA, survival, pain scores and quality of life. Thirty-eight patients with a median age of 67 years (range 50-77) and a median PSA of 57 ng/ml (range 4-3,628) received a median activity of 4,978 MBq (186)Re-HEDP (range 4,770-5,100 MBq). The most serious toxicity was short-lived grade 3 thrombocytopenia in 8 (21%) patients. The median survival of the group is 21 months (95%CI 18-24 months) with Kaplan-Meier estimated 1- and 2-year survival rates of 83% and 40% respectively. Thirty-one patients (81%, 95% CI 66-90%) had stable or reduced PSA levels 3 months post therapy while 11 (29%, 95% CI 15-49%) had PSA reductions of >50% lasting >4 weeks. Quality of life measures were stable or improved in 27 (66%) at 3 months. We have shown that it is feasible and safe to deliver high-activity radioisotope therapy with PBSCT to men with metastatic HRPC. Response rates and survival data are encouraging; however, further research is needed to define optimal role of this treatment approach.


Mapping the determinants of health inequalities in social space: can Bourdieu help us?
Considerable research effort has been devoted to describing and explaining, at a variety of spatial scales, geographical inequalities in health outcomes within the developed world. Following Bourdieu, we argue that structures of the social world may be revealed in different kinds of 'social' space. We outline the relational thinking that underlies these ideas. We then 'map', using correspondence analysis (on which Bourdieu himself drew), the structure of social space according to the differential availability of some forms of capital, across four study areas in north-west England. We use logistic regression analysis to explain variation in psychological morbidity (GHQ-score) and then portray the significant predictors of morbidity using multiple correspondence analysis. The area of residence of the survey respondents is used to associate them with particular locations in these social spaces.


A GWAS Study on Liver Function Test Using eMERGE Network Participants.
Liver enzyme levels and total serum bilirubin are under genetic control and in recent years genome-wide population-based association studies have identified different susceptibility loci for these traits. We conducted a genome-wide association study in European ancestry participants from the Electronic Medical Records and Genomics (eMERGE) Network dataset of patient medical records with available genotyping data in order to identify genetic contributors to variability in serum bilirubin levels and other liver function tests and to compare the effects between adult and pediatric populations. The process of whole genome imputation of eMERGE samples with standard quality control measures have been described previously. After removing missing data and outliers based on principal components (PC) analyses, 3294 samples from European ancestry were used for the GWAS study. The association between each single nucleotide polymorphism (SNP) and total serum bilirubin and other liver function tests was tested using linear regression, adjusting for age, gender, site, platform and ancestry principal components (PC). Consistent with previous results, a strong association signal has been detected for UGT1A gene cluster (best SNP rs887829, beta = 0.15, p = 1.30x10-118) for total serum bilirubin level. Indeed, in this region more than 176 SNPs (or indels) had p<10-8 spanning 150Kb on the long arm of chromosome 2q37.1. In addition, we found a similar level of magnitude in a pediatric group (p = 8.26x10-47, beta = 0.17). Further imputation using sequencing data as a reference panel revealed association of other markers including known TA7 repeat indels (rs8175347) (p = 9.78x10-117) and rs111741722 (p = 5.41x10-119) which were in proxy (r2 = 0.99) with rs887829. Among rare variants, two Asian subjects homozygous for coding SNP rs4148323 (G71R) were identified. Additional known effects for total serum bilirubin were also confirmed including organic anion transporters SLCO1B1-SLCO1B3, TDRP and ZMYND8 at FDR<0.05 with no gene-gene interaction effects. Phenome-wide association studies (PheWAS) suggest a protective effect of TA7 repeat against cerebrovascular disease in an adult cohort (OR = 0.75, p = 0.0008). Among other liver function tests, we also confirmed the previous effect of the ABO blood group locus for variation in serum alkaline phosphatase (rs579459, p = 9.44x10-15). Taken together, our data present interesting findings with strong confirmation of previous effects by simply using the eMERGE electronic health record phenotyping. In addition, our findings indicate that similar to the adult population, the UGT1A1 is the main locus responsible for normal variation of serum bilirubin in pediatric populations.


Visceral adipose tissue loss and insulin resistance 6 months after laparoscopic gastric banding surgery: a preliminary study.
Increased visceral adipose tissue (VAT) is thought to be a risk factor for cardiovascular and metabolic diseases. There are only limited data on whether VAT loss after laparoscopic gastric banding surgery (LGBS) is related to risk factor reduction. This study determined whether improvements in risk markers, in particular insulin resistance, were related to VAT reduction at 6 months after LGBS (T2). Thirty-four LGBS patients and 17 normal weight controls underwent initial and T2 testing. Fasting venous blood samples were taken to evaluate glucose, insulin, hemoglobin A(1c), lipids, C-reactive protein (CRP), and hormone profiles. Insulin resistance was estimated using the homeostasis model assessment (HOMA) index. VAT was measured using CT techniques. Data were analyzed using repeated measures ANOVA and regression analysis. Results at T2 showed that patients had significant improvements in body composition, HOMA, and hemoglobin A(1c). There were also reductions in plasma renin activity and leptin, and increases in ghrelin and GLP-1. Reductions in VAT were significantly correlated with reductions in insulin, HOMA, and glucose. While high density lipoprotein cholesterol, triglycerides, CRP, and the apolipoprotein A1/B ratio were also improved, VAT reduction was significantly correlated only with an increased apolipoprotein A1/B ratio. These data indicate that 6 months after LGBS there were significant improvements in many cardiovascular and metabolic risk markers. However, VAT reduction was most strongly associated with reductions in insulin resistance. Body weight loss was not associated with markers of improved insulin sensitivity.


High-resolution analysis of tomato leaf elongation: the application of novel time-series analysis techniques.
This paper demonstrates the use of a novel suite of data-based, recursive modelling techniques for the investigation of biological and other time-series data, including high resolution leaf elongation. The Data-Based Mechanistic (DBM) modelling methodology rejects the common practice of empirical curve fitting for a more objective approach where the model structure is not assumed a priori, but instead is identified directly from the data series in a stochastic form. Further, this novel approach takes advantage of the latest techniques in optimal recursive estimation of non-stationary and non-linear time-series. Here, the utility and ease of use of these techniques is demonstrated in the examination of two time-series of leaf elongation in an expanding leaf of tomato (Lycopersicon esculentum L. cv. Ailsa Craig) growing in a root pressure vessel (RPV). Using this analysis, the component signals of the elongation series are extracted and considered in relation to physiological processes. It is hoped that this paper will encourage the wider use of these new techniques, as well as the associated Data-Based Mechanistic (DBM) modelling strategy, in analytical plant physiology.


Is self-weighing an effective tool for weight loss: a systematic literature review and meta-analysis.
There is a need to identify effective behavioural strategies for weight loss. Self-weighing may be one such strategy. To examine the effectiveness of self-weighing for weight loss. A systematic review and meta-analysis of randomised controlled trials that included self-weighing as an isolated intervention or as a component within an intervention. We used sub groups to analyse differences in frequency of weighing instruction (daily and weekly) and also whether including accountability affected weight loss. Only one study examined self-weighing as a single strategy and there was no evidence it was effective (-0.5 kg 95 % CI -1.3 to 0.3). Four trials added self-weighing/self-regulation techniques to multi-component programmes and resulted in a significant difference of -1.7 kg (95 % CI -2.6 to -0.8). Fifteen trials comparing multi-component interventions including self-weighing compared with no intervention or minimal control resulted in a significant mean difference of -3.4 kg (95 % CI -4.2 to -2.6). There was no significant difference in the interventions with weekly or daily weighing. In trials which included accountability there was significantly greater weight loss (p = 0.03). There is a lack of evidence of whether advising self-weighing without other intervention components is effective. Adding self-weighing to a behavioural weight loss programme may improve weight loss. Behavioural weight loss programmes that include self-weighing are more effective than minimal interventions. Accountability may improve the effectiveness of interventions that include self-weighing.