Discourses and critiques of breastfeeding and their implications for midwives and health professionals.
This article is a discussion of the recently emerging critique of pro-breastfeeding discourses in academic literature, and what this means for midwives and other professionals who find themselves promoting breastfeeding because of professional expectations or indeed workplace policies. Various strands in the debate are explored, starting with dominant and familiar 'evidence' and descriptions of breastfeeding and breastmilk that are carried through to international policies that advocate breast over formula feeding. We then consider evidence predominantly from social science literature that has found some women's experiences of infant feeding to be at variance with the dominant pro-breastfeeding ideology. We argue that midwives and others delivering maternity care are the means to deliver the policy aspirations contained in the World Health Organization (WHO, 2018) Baby Friendly Hospital Initiative document that makes selective positive claims about breastfeeding without adequately considering its potential drawbacks. We conclude that although the benefits of breastfeeding tend to be exaggerated in promotional material, on balance the weight of evidence still favours breast over formula feeding. We challenge the charge that breastfeeding jeopardises women's financial position by arguing that it is not breastfeeding per se that impacts negatively on women's economic prospects, but rather the way in which society is socially organised.


Cost effectiveness of drug-eluting stents in acute myocardial infarction patients in Germany: results from administrative data using a propensity score-matching approach.
The high number of patients with acute myocardial infarction (AMI) has facilitated greater research, resulting in the development of innovative medical devices. So far, results from economic evaluations that compared drug-eluting stents (DES) and bare-metal stents (BMS) have not shown clear evidence that one intervention is more cost effective than the other. The aim of this study was to measure the cost effectiveness of DES compared with BMS in routine care. We used administrative data from a large German sickness fund to compare the costs and effectiveness of DES and BMS in patients with AMI. Patients with hospital admission after AMI in 2004 and 2005 were followed up for 1 year after hospital discharge. The cost of treatment and survival after 365 days were compared for patients treated with DES and BMS. We adjusted for covariates defined according to the Ontario Acute Myocardial Infarction Mortality Prediction Rules using propensity score matching. After matching, we calculated incremental cost-effectiveness ratios (ICERs) by (i) using sample means based on bootstrapping procedures and (ii) estimating generalized linear mixed models for costs and survival. After propensity score matching, the sample included 719 patients treated with DES and 719 patients treated with BMS. A comparison of sample means resulted in average costs of € 12 714 and € 11 714 for DES and BMS, respectively, in 2005 German euros. Difference in 365-day survival was not statistically significant (700 patients with DES and 701 with BMS). The ICER of DES versus BMS was -€ 718 709 per life saved. Bootstrapping resulted in DES being dominated by BMS in 54.5% of replications and DES being a dominant strategy in 2.7% of replications. Results from regression models and sensitivity analyses confirm these results. Treatment with DES after admission with AMI is less cost effective than treatment with BMS. Our results are in line with other cost-effectiveness analyses that used administrative data, i.e. under routine care conditions. However, our results do not preclude that DES may be cost effective in specific patient subgroups.


Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes.
Despite accumulating evidence suggesting local self-maintenance of tissue macrophages in the steady state, the dogma remains that tissue macrophages derive from monocytes. Using parabiosis and fate-mapping approaches, we confirmed that monocytes do not show significant contribution to tissue macrophages in the steady state. Similarly, we found that after depletion of lung macrophages, the majority of repopulation occurred by stochastic cellular proliferation in situ in a macrophage colony-stimulating factor (M-Csf)- and granulocyte macrophage (GM)-CSF-dependent manner but independently of interleukin-4. We also found that after bone marrow transplantation, host macrophages retained the capacity to expand when the development of donor macrophages was compromised. Expansion of host macrophages was functional and prevented the development of alveolar proteinosis in mice transplanted with GM-Csf-receptor-deficient progenitors. Collectively, these results indicate that tissue-resident macrophages and circulating monocytes should be classified as mononuclear phagocyte lineages that are independently maintained in the steady state.


Oral immunization with F4 fimbriae and CpG formulated with carboxymethyl starch enhances F4-specific mucosal immune response and modulates Th1 and Th2 cytokines in weaned pigs.
F4 fimbriae are a potential candidate for an oral subunit vaccine for prevention of post-weaning diarrhea in swine due to infection with F4-positive enterotoxigenic Escherichia coli. However, large quantities of F4 fimbriae are required to induce a specific antibody response. The aim of the present study was to evaluate the effect of supplementation of F4 fimbriae with Cytosine-phosphate-Guanosine-oligodeoxynucleotide (CpG-A D19) or with complete cholera toxin (CT) as adjuvants on the F4-specific antibody response and cytokine production in weaned pigs following oral administration of F4 fimbrial antigen formulated with Carboxymethyl Starch (CMS). Oral dosage forms of F4 fimbriae alone or supplemented with CpG-A D19 or with CT were formulated with CMS as monolithic tablets, obtained by direct compression, and administered to weaned pigs. Blood and faecal samples were collected to determine the systemic and mucosal immune status of animals at various times until necropsy. During necropsy, contents of the jejunum and ileum were collected for determination of mucosal F4 specific antibodies. Segments of jejunum and ileum were also used to measure mRNA cytokine production. The presence of CpG in the formulation of the fimbriae significantly increased F4-specific immunoglobulin (Ig) IgM and IgG levels in intestinal secretions, and enhanced Th1 (Interferon-gamma / IFN-γ, Tumour Necrosis Factor-alpha / TNF-α, Interleukin-12p40 / IL-12p40, IL-1β) and Th2 (IL-4, IL-6) cytokine production in intestinal tissues. Supplementation with CT did not result in induction of F4-specific antibodies in secretions, although a significant Th1 response (IFN-α, IFN-γ, IL-18) was detected in tissues. Neither F4-specific systemic antibodies, nor intestinally secreted IgA were detected throughout the immunization trial for all groups. CpG-A D19 appeared to be a promising adjuvant for an oral F4 subunit vaccine formulated with CMS excipient as monolithic tablets. This matrix afforded gastro-protection and delivered the F4 fimbriae at their intestinal sites.


Top-down modulation: bridging selective attention and working memory.
Selective attention, the ability to focus our cognitive resources on information relevant to our goals, influences working memory (WM) performance. Indeed, attention and working memory are increasingly viewed as overlapping constructs. Here, we review recent evidence from human neurophysiological studies demonstrating that top-down modulation serves as a common neural mechanism underlying these two cognitive operations. The core features include activity modulation in stimulus-selective sensory cortices with concurrent engagement of prefrontal and parietal control regions that function as sources of top-down signals. Notably, top-down modulation is engaged during both stimulus-present and stimulus-absent stages of WM tasks; that is, expectation of an ensuing stimulus to be remembered, selection and encoding of stimuli, maintenance of relevant information in mind and memory retrieval.


Essential role for autophagy during invariant NKT cell development.
Autophagy is an evolutionarily conserved cellular homeostatic pathway essential for development, immunity, and cell death. Although autophagy modulates MHC antigen presentation, it remains unclear whether autophagy defects impact on CD1d lipid loading and presentation to invariant natural killer T (iNKT) cells and on iNKT cell differentiation in the thymus. Furthermore, it remains unclear whether iNKT and conventional T cells have similar autophagy requirements for differentiation, survival, and/or activation. We report that, in mice with a conditional deletion of the essential autophagy gene Atg7 in the T-cell compartment (CD4 Cre-Atg7(-/-)), thymic iNKT cell development--unlike conventional T-cell development--is blocked at an early stage and mature iNKT cells are absent in peripheral lymphoid organs. The defect is not due to altered loading of intracellular iNKT cell agonists; rather, it is T-cell-intrinsic, resulting in enhanced susceptibility of iNKT cells to apoptosis. We show that autophagy increases during iNKT cell thymic differentiation and that it developmentally regulates mitochondrial content through mitophagy in the thymus of mice and humans. Autophagy defects result in the intracellular accumulation of mitochondrial superoxide species and subsequent apoptotic cell death. Although autophagy-deficient conventional T cells develop normally, they show impaired peripheral survival, particularly memory CD8(+) T cells. Because iNKT cells, unlike conventional T cells, differentiate into memory cells while in the thymus, our results highlight a unique autophagy-dependent metabolic regulation of adaptive and innate T cells, which is required for transition to a quiescent state after population expansion.


Syk and Src family kinases regulate C-type lectin receptor 2 (CLEC-2)-mediated clustering of podoplanin and platelet adhesion to lymphatic endothelial cells.
The interaction of C-type lectin receptor 2 (CLEC-2) on platelets with Podoplanin on lymphatic endothelial cells initiates platelet signaling events that are necessary for prevention of blood-lymph mixing during development. In the present study, we show that CLEC-2 signaling via Src family and Syk tyrosine kinases promotes platelet adhesion to primary mouse lymphatic endothelial cells at low shear. Using supported lipid bilayers containing mobile Podoplanin, we further show that activation of Src and Syk in platelets promotes clustering of CLEC-2 and Podoplanin. Clusters of CLEC-2-bound Podoplanin migrate rapidly to the center of the platelet to form a single structure. Fluorescence lifetime imaging demonstrates that molecules within these clusters are within 10 nm of one another and that the clusters are disrupted by inhibition of Src and Syk family kinases. CLEC-2 clusters are also seen in platelets adhered to immobilized Podoplanin using direct stochastic optical reconstruction microscopy. These findings provide mechanistic insight by which CLEC-2 signaling promotes adhesion to Podoplanin and regulation of Podoplanin signaling, thereby contributing to lymphatic vasculature development.


Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: the regulatory role of perivascular adipose tissue.
Oxidative stress plays a critical role in the vascular complications of type 2 diabetes. We examined the effect of type 2 diabetes on NADPH oxidase in human vessels and explored the mechanisms of this interaction. Segments of internal mammary arteries (IMAs) with their perivascular adipose tissue (PVAT) and thoracic adipose tissue were obtained from 386 patients undergoing coronary bypass surgery (127 with type 2 diabetes). Type 2 diabetes was strongly correlated with hypoadiponectinemia and increased vascular NADPH oxidase-derived superoxide anions (O2˙(-)). The genetic variability of the ADIPOQ gene and circulating adiponectin (but not interleukin-6) were independent predictors of NADPH oxidase-derived O2˙(-). However, adiponectin expression in PVAT was positively correlated with vascular NADPH oxidase-derived O2˙(-). Recombinant adiponectin directly inhibited NADPH oxidase in human arteries ex vivo by preventing the activation/membrane translocation of Rac1 and downregulating p22(phox) through a phosphoinositide 3-kinase/Akt-mediated mechanism. In ex vivo coincubation models of IMA/PVAT, the activation of arterial NADPH oxidase triggered a peroxisome proliferator-activated receptor-γ-mediated upregulation of the adiponectin gene in the neighboring PVAT via the release of vascular oxidation products. We demonstrate for the first time in humans that reduced adiponectin levels in individuals with type 2 diabetes stimulates vascular NADPH oxidase, while PVAT "senses" the increased NADPH oxidase activity in the underlying vessel and responds by upregulating adiponectin gene expression. This PVAT-vessel interaction is identified as a novel therapeutic target for the prevention of vascular complications of type 2 diabetes.


Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole-genome sequencing.
The Gram-negative bacteria Klebsiella pneumoniae is a major cause of nosocomial infections, primarily among immunocompromised patients. The emergence of strains resistant to carbapenems has left few treatment options, making infection containment critical. In 2011, the U.S. National Institutes of Health Clinical Center experienced an outbreak of carbapenem-resistant K. pneumoniae that affected 18 patients, 11 of whom died. Whole-genome sequencing was performed on K. pneumoniae isolates to gain insight into why the outbreak progressed despite early implementation of infection control procedures. Integrated genomic and epidemiological analysis traced the outbreak to three independent transmissions from a single patient who was discharged 3 weeks before the next case became clinically apparent. Additional genomic comparisons provided evidence for unexpected transmission routes, with subsequent mining of epidemiological data pointing to possible explanations for these transmissions. Our analysis demonstrates that integration of genomic and epidemiological data can yield actionable insights and facilitate the control of nosocomial transmission.


Association between age and risk of stroke or death from carotid endarterectomy and carotid stenting: a meta-analysis of pooled patient data from four randomised trials.
Age was reported to be an effect-modifier in four randomised controlled trials comparing carotid artery stenting (CAS) and carotid endarterectomy (CEA), with better CEA outcomes than CAS outcomes noted in the more elderly patients. We aimed to describe the association of age with treatment differences in symptomatic patients and provide age-specific estimates of the risk of stroke and death within narrow (5 year) age groups. In this meta-analysis, we analysed individual patient-level data from four randomised controlled trials within the Carotid Stenosis Trialists' Collaboration (CSTC) involving patients with symptomatic carotid stenosis. We included only trials that randomly assigned patients to CAS or CEA and only patients with symptomatic stenosis. We assessed rates of stroke or death in 5-year age groups in the periprocedural period (between randomisation and 120 days) and ipsilateral stroke during long-term follow-up for patients assigned to CAS or CEA. We also assessed differences between CAS and CEA. All analyses were done on an intention-to-treat basis. Collectively, 4754 patients were randomly assigned to either CEA or CAS treatment in the four studies. 433 events occurred over a median follow-up of 2·7 years. For patients assigned to CAS, the periprocedural hazard ratio (HR) for stroke and death in patients aged 65-69 years compared with patients younger than 60 years was 2·16 (95% CI 1·13-4·13), with HRs of roughly 4·0 for patients aged 70 years or older. We noted no evidence of an increased periprocedural risk by age group in the CEA group (p=0·34). These changes underpinned a CAS-versus CEA periprocedural HR of 1·61 (95% CI 0·90-2·88) for patients aged 65-69 years and an HR of 2·09 (1·32-3·32) for patients aged 70-74 years. Age was not associated with the postprocedural stroke risk either within treatment group (p≥0·09 for CAS and 0·83 for CEA), or between treatment groups (p=0·84). In these RCTs, CEA was clearly superior to CAS in patients aged 70-74 years and older. The difference in older patients was almost wholly attributable to increasing periprocedural stroke risk in patients treated with CAS. Age had little effect on CEA periprocedural risk or on postprocedural risk after either procedure. None.


Trends in future health financing and coverage: future health spending and universal health coverage in 188 countries, 2016-40.
Achieving universal health coverage (UHC) requires health financing systems that provide prepaid pooled resources for key health services without placing undue financial stress on households. Understanding current and future trajectories of health financing is vital for progress towards UHC. We used historical health financing data for 188 countries from 1995 to 2015 to estimate future scenarios of health spending and pooled health spending through to 2040. We extracted historical data on gross domestic product (GDP) and health spending for 188 countries from 1995 to 2015, and projected annual GDP, development assistance for health, and government, out-of-pocket, and prepaid private health spending from 2015 through to 2040 as a reference scenario. These estimates were generated using an ensemble of models that varied key demographic and socioeconomic determinants. We generated better and worse alternative future scenarios based on the global distribution of historic health spending growth rates. Last, we used stochastic frontier analysis to investigate the association between pooled health resources and UHC index, a measure of a country's UHC service coverage. Finally, we estimated future UHC performance and the number of people covered under the three future scenarios. In the reference scenario, global health spending was projected to increase from US$10 trillion (95% uncertainty interval 10 trillion to 10 trillion) in 2015 to $20 trillion (18 trillion to 22 trillion) in 2040. Per capita health spending was projected to increase fastest in upper-middle-income countries, at 4·2% (3·4-5·1) per year, followed by lower-middle-income countries (4·0%, 3·6-4·5) and low-income countries (2·2%, 1·7-2·8). Despite global growth, per capita health spending was projected to range from only $40 (24-65) to $413 (263-668) in 2040 in low-income countries, and from $140 (90-200) to $1699 (711-3423) in lower-middle-income countries. Globally, the share of health spending covered by pooled resources would range widely, from 19·8% (10·3-38·6) in Nigeria to 97·9% (96·4-98·5) in Seychelles. Historical performance on the UHC index was significantly associated with pooled resources per capita. Across the alternative scenarios, we estimate UHC reaching between 5·1 billion (4·9 billion to 5·3 billion) and 5·6 billion (5·3 billion to 5·8 billion) lives in 2030. We chart future scenarios for health spending and its relationship with UHC. Ensuring that all countries have sustainable pooled health resources is crucial to the achievement of UHC. The Bill & Melinda Gates Foundation.


A review of the likely effects of climate change on anadromous Atlantic salmon Salmo salar and brown trout Salmo trutta, with particular reference to water temperature and flow.
The present paper reviews the effects of water temperature and flow on migrations, embryonic development, hatching, emergence, growth and life-history traits in light of the ongoing climate change with emphasis on anadromous Atlantic salmon Salmo salar and brown trout Salmo trutta. The expected climate change in the Atlantic is for milder and wetter winters, with more precipitation falling as rain and less as snow, decrease in ice-covered periods and frequent periods with extreme weather. Overall, thermal limits for salmonids are species specific. Scope for activity and growth and optimal temperature for growth increase with temperature to an optimal point before constrain by the oxygen content of the water. The optimal temperature for growth decreases with increasing fish size and varies little among populations within species, whereas the growth efficiency may be locally adapted to the temperature conditions of the home stream during the growth season. Indirectly, temperature influences age and size at smolting through its effect on growth. Time of spawning, egg hatching and emergence of the larvae vary with temperature and selective effects on time of first feeding. Traits such as age at first maturity, longevity and fecundity decrease with increasing temperature whilst egg size increases with temperature. Water flow influences the accessibility of rivers for returning adults and speed of both upstream and downstream migration. Extremes in water flow and temperature can decrease recruitment and survival. There is reason to expect a northward movement of the thermal niche of anadromous salmonids with decreased production and population extinction in the southern part of the distribution areas, migrations earlier in the season, later spawning, younger age at smolting and sexual maturity and increased disease susceptibility and mortality. Future research challenges are summarized at the end of the paper.


Northern Slavs from Serbia do not show a founder effect at autosomal and Y-chromosomal STRs and retain their paternal genetic heritage.
Studies on Y-chromosomal markers revealed significant genetic differentiation between Southern and Northern (Western and Eastern) Slavic populations. The northern Serbian region of Vojvodina is inhabited by Southern Slavic Serbian majority and, inter alia, Western Slavic (Slovak) and Eastern Slavic (Ruthenian) minorities. In the study, 15 autosomal STR markers were analysed in unrelated Slovaks, Ruthenians and Serbs from northern Serbia and western Slovakia. Additionally, Slovak males from Serbia were genotyped for 17 Y-chromosomal STR loci. The results were compared to data available for other Slavic populations. Genetic distances for autosomal markers revealed homogeneity between Serbs from northern Serbia and Slovaks from western Slovakia and distinctiveness of Serbian Slovaks and Ruthenians. Y-STR variation showed a clear genetic departure of the Slovaks and Ruthenians inhabiting Vojvodina from their Serbian neighbours and genetic similarity to the Northern Slavic populations of Slovakia and Ukraine. Admixture estimates revealed negligible Serbian paternal ancestry in both Northern Slavic minorities of Vojvodina, providing evidence for their genetic isolation from the Serbian majority population. No reduction of genetic diversity at autosomal and Y-chromosomal markers was found, excluding genetic drift as a reason for differences observed at autosomal STRs. Analysis of molecular variance detected significant population stratification of autosomal and Y-chromosomal microsatellites in the three Slavic populations of northern Serbia, indicating necessity for separate databases used for estimations of frequencies of autosomal and Y-chromosomal STR profiles in forensic casework. Our results demonstrate that regarding Y-STR haplotypes, Serbian Slovaks and Ruthenians fit in the Eastern European metapopulation defined in the Y chromosome haplotype reference database.


The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity.
There are three prolyl hydroxylases (PHD1, 2 and 3) that regulate the hypoxia-inducible factors (HIFs), the master transcriptional regulators that respond to changes in intracellular O(2) tension. In high O(2) tension (normoxia) the PHDs hydroxylate two conserved proline residues on HIF-1α, which leads to binding of the von Hippel-Lindau (VHL) tumour suppressor, the recognition component of a ubiquitin-ligase complex, initiating HIF-1α ubiquitylation and degradation. However, it is not known whether PHDs and VHL act separately to exert their enzymatic activities on HIF-1α or as a multiprotein complex. Here we show that the tumour suppressor protein LIMD1 (LIM domain-containing protein) acts as a molecular scaffold, simultaneously binding the PHDs and VHL, thereby assembling a PHD-LIMD1-VHL protein complex and creating an enzymatic niche that enables efficient degradation of HIF-1α. Depletion of endogenous LIMD1 increases HIF-1α levels and transcriptional activity in both normoxia and hypoxia. Conversely, LIMD1 expression downregulates HIF-1 transcriptional activity in a manner depending on PHD and 26S proteasome activities. LIMD1 family member proteins Ajuba and WTIP also bind to VHL and PHDs 1 and 3, indicating that these LIM domain-containing proteins represent a previously unrecognized group of hypoxic regulators.


Prognostic factors and prevention of radioembolization-induced liver disease.
Radioembolization (RE)-induced liver disease (REILD) has been defined as jaundice and ascites appearing 1 to 2 months after RE in the absence of tumor progression or bile duct occlusion. Our aims were to study the incidence of REILD in a large cohort of patients and the impact of a series of changes introduced in the processes of treatment design, activity calculation, and the routine use of ursodeoxycholic acid and low-dose steroids (modified protocol). Between 2003 and 2011, 260 patients with liver tumors treated by RE were studied (standard protocol: 75, modified protocol: 185). REILD appeared only in patients with cirrhosis or in noncirrhosis patients exposed to systemic chemotherapy prior to RE. Globally, the incidence of REILD was reduced in the modified protocol group from 22.7% to 5.4% and the incidence of severe REILD from 13.3% to 2.2% (P<0.0001). Treatment efficacy was not jeopardized since 3-month disease control rates were virtually identical in both groups (66.7% and 67.2%, P=0.93). Exposure to chemotherapy in the 2-month period following RE and being treated by the standard protocol were independent predictors of REILD among noncirrhosis patients. In cirrhosis, the presence of a small liver (total volume<1.5 L), an abnormal bilirubin (>1.2 mg/dL), and treatment in a selective fashion were independently associated with REILD. REILD is an uncommon but relevant complication that appears when liver tissue primed by cirrhosis or prior and subsequent chemotherapy is exposed to the radiation delivered by radioactive microspheres. We designed a comprehensive treatment protocol that reduces the frequency and the severity of REILD.


Tuning the gas phase redox properties of copper(II) ternary complexes of terpyridines to control the formation of nucleobase radical cations.
Electrospray ionization (ESI) tandem mass spectrometry (MS/MS) of ternary copper(II) complexes of [Cu(terpyX)(M)]2+ (where terpyX = is a substituted 2,2':6',2''-terpyridine ligand; M = the nucleobases: adenine, guanine, thymine and cytosine) was examined as a means of forming radical cations of nucleobases in the gas phase. The following substituents were examined: 4'-NMe2-2,2':6',6''-terpyridine; 4'-OH-2,2':6',6''-terpyridine; 4'-F-2,2':6',6''-terpyridine; 2,2':6',6''-terpyridine; 4'-Cl-2,2':6',6''-terpyridine; 4'-Br-2,2':6',6''-terpyridine; 4'-CO2H-2,2':6',6''-terpyridine; 4'-NO2-2,2':6',6''-terpyridine and 6,6''-dibromo-2',2:6',2''-terpyridine. Each of the ternary complexes [Cu(terpyX)(M)]2+ was mass selected and subjected to collision induced dissociation (CID) in a quadrupole ion trap. The types of fragmentation reactions observed for these complexes depend on the nature of the substituent on the terpyridine ligand, while the yields of the radical cations of the nucleobases follow the order of their ionization energies (IEs): G (lowest IE) > A > C > T (highest IE). In general, radical cation formation is favoured for electron withdrawing substituents (e.g. NO2) while loss of the neutral nucleobase is favoured for electron donating substituents (e.g. NMe2). Loss of the protonated nucleobase is a major fragmentation pathway for the OH substituted terpyridine system, consistent with its ability to bind to a metal centre as a deprotonated ligand. Crystal structure determinations of (6,6''-dibromo-2',2:6',2''-terpyridine)bis(nitrato)copper(II) and diaqua(4'-oxo-2,2':6',6''-terpyridine)copper(II) nitrate monohydrate were performed and correlated with the ESI results.


Kaiso is required for MTG16-dependent effects on colitis-associated carcinoma.
The myeloid translocation gene family member MTG16 is a transcriptional corepressor that relies on the DNA-binding ability of other proteins to determine specificity. One such protein is the ZBTB family member Kaiso, and the MTG16:Kaiso interaction is necessary for repression of Kaiso target genes, such as matrix metalloproteinase-7. Using the azoxymethane and dextran sodium sulfate (AOM/DSS) murine model of colitis-associated carcinoma, we previously determined that MTG16 loss accelerates tumorigenesis and inflammation. However, it was unknown whether this effect was modified by Kaiso-dependent transcriptional repression. To test for a genetic interaction between MTG16 and Kaiso in inflammatory carcinogenesis, we subjected single and double knockout (DKO) mice to the AOM/DSS protocol. Mtg16-/- mice demonstrated increased colitis and tumor burden; in contrast, disease severity in Kaiso-/- mice was equivalent to wild-type controls. Surprisingly, Kaiso deficiency in the context of MTG16 loss reversed injury and pro-tumorigenic responses in the intestinal epithelium following AOM/DSS treatment, and tumor numbers were returned to near to wild-type levels. Transcriptomic analysis of non-tumor colon tissue demonstrated that changes induced by MTG16 loss were widely mitigated by concurrent Kaiso loss, and DKO mice demonstrated downregulation of metabolism and cytokine-associated gene sets with concurrent activation of DNA damage checkpoint pathways as compared with Mtg16-/-. Further, Kaiso knockdown in intestinal enteroids reduced stem- and WNT-associated phenotypes, thus abrogating the induction of these pathways observed in Mtg16-/- samples. Together, these data suggest that Kaiso modifies MTG16-driven inflammation and tumorigenesis and suggests that Kaiso deregulation contributes to MTG16-dependent colitis and CAC phenotypes.


Validation of the Montreal cognitive assessment versus mini-mental state examination against hypertension and hypertensive arteriopathy after transient ischemic attack or minor stroke.
Lack of reduced cognitive impairment with blood pressure (BP) lowering in trials may reflect use of the Mini-Mental State Examination (MMSE), which is insensitive to mild cognitive impairment after cerebrovascular events compared with the Montreal Cognitive Assessment. We determined relationships between impairment on MMSE versus Montreal Cognitive Assessment (MoCA) with the major physiological determinant of vascular cognitive impairment: hypertension and hypertensive arteriopathy. Cognitive impairment in consecutive patients 6 months after transient ischemic attack or minor stroke was defined as significant, mild, or none (MMSE<23, 23-26, ≥27; MoCA<20, 20-24, ≥25) and related to 20 premorbid systolic BP readings, home BP measurement (3 measurements, 3×daily for 1 month), and hypertensive arteriopathy (creatinine, stroke versus transient ischemic attack, leukoaraiosis) by ordinal regression. Of 463 patients, 45% versus 28% had at least mild cognitive impairment on the MoCA versus MMSE (P<0.001). Hypertensive arteriopathy was more strongly associated with cognitive impairment on the MoCA than MMSE (creatinine: odds ratio=3.99; 95% confidence interval, 2.06-7.73 versus 2.16, 1.08-4.33; event: 1.53, 1.06-2.19 versus 1.23, 0.81-1.85; leukoaraiosis: 2.09, 1.42-3.06 versus 1.34, 0.87-2.07). Premorbid and home BP measurement systolic BP were more strongly associated with impairment on vascular subdomains of the MoCA than MMSE (odds ratio/10 mm Hg: visuospatial 1.29 versus 1.05; attention 1.18 versus 1.07; language 1.22 versus 0.91; naming 1.07 versus 0.86). The stronger relationship between impairment on the MoCA with hypertensive arteriopathy, independent of age, indicates a greater sensitivity for vascular-origin cognitive impairment. Use of MoCA should improve sensitivity for cognitive impairment and treatment effects in future studies.


Antibody-mediated encephalitis: a treatable cause of schizophrenia.
Psychiatrists need to be vigilant for the newly recognised and treatable disorder of antibody-mediated encephalitis. Psychiatric symptoms are common, and individuals with the disorder often present initially to psychiatric services. We describe the clinical features of the disorder and make recommendations for further investigations.


[The strengthening of subjects in health management: advances and challenges in the experience of Fortaleza, state of Ceará].
This research deals with the potential and limitations of the strengthening of subjects in health management, based on the experience in Fortaleza in the period from 2005 to 2008. The subject is approached from a historical-cultural standpoint, which considers the dialectical interaction between the individual and the collective in deepening human consciousness on the self and the world. Focus groups were conducted with managers linked to Primary Healthcare and secondary data were utilized. An attempt was made to understand the meaning of the narratives constructed using a hermeneutic dialectic approach. Empirical categories were identified and analyzed as well as co-intentionality of change, political and conceptual drives, human management, reduction of hierarchy, fragmentation of work processes and concentration of decision-making power. Reflections arose on three main strategic policies: co-management, humanization, and continuous health education. It was concluded that, despite the persistence of obstacles, in order to improve the quality of healthcare services it is essential to establish a democratic management system through organizational arrangements and participatory methods that enhance integration and commitment of the Unified Health System players (SUS).


Role of KATP channels in glucose-regulated glucagon secretion and impaired counterregulation in type 2 diabetes.
Glucagon, secreted by pancreatic islet α cells, is the principal hyperglycemic hormone. In diabetes, glucagon secretion is not suppressed at high glucose, exacerbating the consequences of insufficient insulin secretion, and is inadequate at low glucose, potentially leading to fatal hypoglycemia. The causal mechanisms remain unknown. Here we show that α cell KATP-channel activity is very low under hypoglycemic conditions and that hyperglycemia, via elevated intracellular ATP/ADP, leads to complete inhibition. This produces membrane depolarization and voltage-dependent inactivation of the Na(+) channels involved in action potential firing that, via reduced action potential height and Ca(2+) entry, suppresses glucagon secretion. Maneuvers that increase KATP channel activity, such as metabolic inhibition, mimic the glucagon secretory defects associated with diabetes. Low concentrations of the KATP channel blocker tolbutamide partially restore glucose-regulated glucagon secretion in islets from type 2 diabetic organ donors. These data suggest that impaired metabolic control of the KATP channels underlies the defective glucose regulation of glucagon secretion in type 2 diabetes.


Discovering misattributed paternity in genetic counselling: different ethical perspectives in two countries.
Misattributed paternity or 'false' paternity is when a man is wrongly thought, by himself and possibly by others, to be the biological father of a child. Nowadays, because of the progression of genetics and genomics the possibility of finding misattributed paternity during familial genetic testing has increased. In contrast to other medical information, which pertains primarily to individuals, information obtained by genetic testing and/or pedigree analysis necessarily has implications for other biologically related members in the family. Disclosing or not a misattributed paternity has a number of different biological and social consequences for the people involved. Such an issue presents important ethical and deontological challenges. The debate centres on whether or not to inform the family and, particularly, whom in the family, about the possibility that misattributed paternity might be discovered incidentally, and whether or not it is the duty of the healthcare professional (HCP) to disclose the results and to whom. In this paper, we consider the different perspectives and reported problems, and analyse their cultural, ethical and legal dimensions. We compare the position of HCPs from an Italian and British point of view, particularly their role in genetic counselling. We discuss whether the Oviedo Convention of the Council of Europe (1997) can be seen as a basis for enriching the debate.


Metabolic dysregulation in vitamin E and carnitine shuttle energy mechanisms associate with human frailty.
Global ageing poses a substantial economic burden on health and social care costs. Enabling a greater proportion of older people to stay healthy for longer is key to the future sustainability of health, social and economic policy. Frailty and associated decrease in resilience plays a central role in poor health in later life. In this study, we present a population level assessment of the metabolic phenotype associated with frailty. Analysis of serum from 1191 older individuals (aged between 56 and 84 years old) and subsequent longitudinal validation (on 786 subjects) was carried out using liquid and gas chromatography-mass spectrometry metabolomics and stratified across a frailty index designed to quantitatively summarize vulnerability. Through multivariate regression and network modelling and mROC modeling we identified 12 significant metabolites (including three tocotrienols and six carnitines) that differentiate frail and non-frail phenotypes. Our study provides evidence that the dysregulation of carnitine shuttle and vitamin E pathways play a role in the risk of frailty.


Penalized likelihood phenotyping: unifying voxelwise analyses and multi-voxel pattern analyses in neuroimaging: penalized likelihood phenotyping.
Neuroimage phenotyping for psychiatric and neurological disorders is performed using voxelwise analyses also known as voxel based analyses or morphometry (VBM). A typical voxelwise analysis treats measurements at each voxel (e.g., fractional anisotropy, gray matter probability) as outcome measures to study the effects of possible explanatory variables (e.g., age, group) in a linear regression setting. Furthermore, each voxel is treated independently until the stage of correction for multiple comparisons. Recently, multi-voxel pattern analyses (MVPA), such as classification, have arisen as an alternative to VBM. The main advantage of MVPA over VBM is that the former employ multivariate methods which can account for interactions among voxels in identifying significant patterns. They also provide ways for computer-aided diagnosis and prognosis at individual subject level. However, compared to VBM, the results of MVPA are often more difficult to interpret and prone to arbitrary conclusions. In this paper, first we use penalized likelihood modeling to provide a unified framework for understanding both VBM and MVPA. We then utilize statistical learning theory to provide practical methods for interpreting the results of MVPA beyond commonly used performance metrics, such as leave-one-out-cross validation accuracy and area under the receiver operating characteristic (ROC) curve. Additionally, we demonstrate that there are challenges in MVPA when trying to obtain image phenotyping information in the form of statistical parametric maps (SPMs), which are commonly obtained from VBM, and provide a bootstrap strategy as a potential solution for generating SPMs using MVPA. This technique also allows us to maximize the use of available training data. We illustrate the empirical performance of the proposed framework using two different neuroimaging studies that pose different levels of challenge for classification using MVPA.


Myocardial regeneration: expanding the repertoire of thymosin β4 in the ischemic heart.
Efficient cardiac regeneration postinfarction (MI) requires the replacement of lost cardiomyocytes, formation of new coronary vessels and appropriate modulation of the inflammatory response. However, insight into how to stimulate repair of the human heart is currently limited. Using the embryonic paradigm of regeneration, we demonstrated that the actin-binding peptide thymosin β4 (Tβ4), required for epicardium-derived coronary vasculogenesis, can recapitulate its embryonic role and activate quiescent adult epicardial cells (EPDCs). Once stimulated, EPDCs facilitate neovascularization of the ischemic adult heart and, moreover, contribute bona fide cardiomyocytes. EPDC-derived cardiomyocytes structurally and functionally integrate with resident muscle to regenerate functional myocardium, limiting pathological remodeling, and effecting an improvement in cardiac function. Alongside pro-survival and anti-inflammatory properties, these regenerative roles, via EPDCs, markedly expand the range of therapeutic benefits of Tβ4 to sustain and repair the myocardium after ischemic damage.


Visceral adiposity and left ventricular remodeling: The Multi-Ethnic Study of Atherosclerosis.
Visceral fat (VF) is a source of pro-inflammatory adipokines implicated in cardiac remodeling. We sought to determine the impact of visceral fat and subcutaneous fat (SQ) depots on left ventricular (LV) structure, function, and geometry in the Multi-Ethnic Study of Atherosclerosis (MESA). We performed a post-hoc analysis on 1151 participants from MESA with cardiac magnetic resonance quantification of LV mass and LV mass-to-volume ratio (LVMV, an index of concentricity) and computed tomographic-derived SQ and VF area. Multivariable regression models to estimate association between height-indexed SQ and VF area (per cm(2)/m) with height-indexed LV mass (per height(2.7)) and LVMV were constructed, adjusted for clinical, biochemical, and demographic covariates. We found that both VF and SQ area were associated with height-indexed LV mass (ρ = 0.36 and 0.12, P < 0.0001, respectively), while only VF area was associated with LVMV (ρ = 0.28, P < 0.0001). Individuals with above-median VF had lower LV ejection fraction, greater indexed LV volumes and mass, and higher LVMV (all P < 0.001). In multivariable models adjusted for weight, VF (but not SQ) area was associated with LV concentricity and LV mass index, across both sexes. Visceral adiposity is independently associated with LV concentricity, a precursor to heart failure. Further study into the role of VF in LV remodeling as a potential therapeutic target is warranted.


Focus article: report of the NIH Task Force on Research Standards for Chronic Low Back Pain.
Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement. A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes.


Electro-acupuncture stimulation at acupoints reduced the severity of hypotension during anesthesia in patients undergoing liver transplantation.
Patients with end-stage liver diseases who undergo liver transplantation may suffer from hypotension related to the liver disease itself or related to the surgical procedure. Because electro-acupuncture (EA) at the Neiguan (PC-6) and the Jianshi (PC-5) points influences hemodynamics, we hypothesize that electro-acupuncture at the traditionally used acupuncture points will reduce the severity of hypotension in patients who undergo liver transplantation. Forty patients with end-stage liver disease who underwent orthotropic deceased donor liver transplantation were randomized into two groups. The norepinephrine (NE) group received norepinephrine as a vasoconstrictor, and the electro-acupuncture group received EA at the PC-5 and the PC-6 points for treatment of hypotension during anesthesia for the liver transplantation. The patients were monitored, during the three stages of liver transplantation by using hemodynamic parameters. During the three stages of liver transplantation, there were no significant differences in the hemodynamic measurements including the mean arterial pressure, heart rate and central venous pressure between the two groups (p>0.05). Electro-acupuncture at the acupuncture points reduced the severity and the incidence of hypotension during anesthesia for liver transplantation.


Differential effects of olanzapine and risperidone on plasma adiponectin levels over time: results from a 3-month prospective open-label study.
Second-generation antipsychotics (SGA), especially clozapine and olanzapine, are associated with an increased metabolic risk. Recent research showed that plasma adiponectin levels, an adipocyte-derived hormone that increases insulin sensitivity, vary in the same way in schizophrenic patients as in the general population according to gender, adiposity and metabolic syndrome (MetS). The aim of the present study was to investigate whether different SGAs differentially affect plasma adiponectin levels independent of body mass index (BMI) and MetS status. 113 patients with schizophrenia (65.5% males, 32.3years old) who were free of antipsychotic medication were enrolled in this open-label prospective single-center study and received either risperidone (n=54) or olanzapine (n=59). They were followed prospectively for 12weeks. Average daily dose was 4.4mg/day for risperidone and 17.4mg/day for olanzapine. Plasma adiponectin levels as well as fasting metabolic parameters were measured at baseline, 6weeks and 12weeks. The two groups had similar baseline demographic and metabolic characteristics. A significant increase in body weight was observed over time. This increase was significantly larger in the olanzapine group than in the risperidone group (+7.0kg versus +3.1kg, p<0.0002). Changes in fasting glucose and insulin levels and in HOMA-IR, an index of insulin resistance, were not significantly different in both treatment groups. MetS prevalence increased significantly more in the olanzapine group as compared to the risperidone groups where the prevalence did not change over time. We observed a significant (p=0.0015) treatment by time interaction showing an adiponectin increase in the risperidone-treated patients (from 10,154 to 11,124ng/ml) whereas adiponectin levels decreased in olanzapine treated patients (from 11,280 to 8988ng/ml). This effect was independent of BMI and the presence/absence of MetS. The differential effect of antipsychotic treatment (risperidone versus olanzapine) on plasma adiponectin levels over time, independent of changes in waist circumference and antipsychotic dosing, suggests a specific effect on adipose tissues, similar to what has been observed in animal models. The observed olanzapine-associated reduction in plasma adiponectin levels may at least partially contribute to the increased metabolic risk of olanzapine compared to risperidone.


Out of Africa: modern human origins special feature: explaining worldwide patterns of human genetic variation using a coalescent-based serial founder model of migration outward from Africa.
Studies of worldwide human variation have discovered three trends in summary statistics as a function of increasing geographic distance from East Africa: a decrease in heterozygosity, an increase in linkage disequilibrium (LD), and a decrease in the slope of the ancestral allele frequency spectrum. Forward simulations of unlinked loci have shown that the decline in heterozygosity can be described by a serial founder model, in which populations migrate outward from Africa through a process where each of a series of populations is formed from a subset of the previous population in the outward expansion. Here, we extend this approach by developing a retrospective coalescent-based serial founder model that incorporates linked loci. Our model both recovers the observed decline in heterozygosity with increasing distance from Africa and produces the patterns observed in LD and the ancestral allele frequency spectrum. Surprisingly, although migration between neighboring populations and limited admixture between modern and archaic humans can be accommodated in the model while continuing to explain the three trends, a competing model in which a wave of outward modern human migration expands into a series of preexisting archaic populations produces nearly opposite patterns to those observed in the data. We conclude by developing a simpler model to illustrate that the feature that permits the serial founder model but not the archaic persistence model to explain the three trends observed with increasing distance from Africa is its incorporation of a cumulative effect of genetic drift as humans colonized the world.


Neogene origins and implied warmth tolerance of Amazon tree species.
Tropical rain forest has been a persistent feature in South America for at least 55 million years. The future of the contemporary Amazon forest is uncertain, however, as the region is entering conditions with no past analogue, combining rapidly increasing air temperatures, high atmospheric carbon dioxide concentrations, possible extreme droughts, and extensive removal and modification by humans. Given the long-term Cenozoic cooling trend, it is unknown whether Amazon forests can tolerate air temperature increases, with suggestions that lowland forests lack warm-adapted taxa, leading to inevitable species losses. In response to this uncertainty, we posit a simple hypothesis: the older the age of a species prior to the Pleistocene, the warmer the climate it has previously survived, with Pliocene (2.6-5 Ma) and late-Miocene (8-10 Ma) air temperature across Amazonia being similar to 2100 temperature projections under low and high carbon emission scenarios, respectively. Using comparative phylogeographic analyses, we show that 9 of 12 widespread Amazon tree species have Pliocene or earlier lineages (>2.6 Ma), with seven dating from the Miocene (>5.6 Ma) and three >8 Ma. The remarkably old age of these species suggest that Amazon forests passed through warmth similar to 2100 levels and that, in the absence of other major environmental changes, near-term high temperature-induced mass species extinction is unlikely.


A Cost-Effectiveness Analysis of Shortened Direct-Acting Antiviral Treatment in Genotype 1 Noncirrhotic Treatment-Naive Patients With Chronic Hepatitis C Virus.
Direct-acting antivirals are successful in curing hepatitis C virus infection in more than 95% of patients treated for 12 weeks, but they are expensive. Shortened treatment durations, which may have lower cure rates, have been proposed to reduce costs. To evaluate the lifetime cost-effectiveness of different shortened treatment durations for genotype 1 noncirrhotic treatment-naive patients. Assuming a UK National Health Service perspective, we used a probabilistic decision tree and Markov model to compare 3 unstratified shortened treatment durations (8, 6, and 4 weeks) against a standard 12-week treatment duration. Patients failing shortened first-line treatment were re-treated with a 12-week treatment regimen. Parameter inputs were taken from published studies. The 8-week treatment duration had an expected incremental net monetary benefit of £7737 (95% confidence interval £3242-£11 819) versus the standard 12-week treatment, per 1000 patients. The 6-week treatment had a positive incremental net monetary benefit, although some uncertainty was observed. The probability that the 8- and 6-week treatments were the most cost-effective was 56% and 25%, respectively, whereas that for the 4-week treatment was 17%. Results were generally robust to sensitivity analyses, including a threshold analysis that showed that the 8-week treatment was the most cost-effective at all drug prices lower than £40 000 per 12-week course. Shortening treatments licensed for 12 weeks to 8 weeks is cost-effective in genotype 1 noncirrhotic treatment-naive patients. There was considerable uncertainty in the estimates for 6- and 4-week treatments, with some indication that the 6-week treatment may be cost-effective.


Impact of positron emission tomography/computed tomography surveillance at 12 and 24 months for detecting head and neck cancer recurrence.
In head and neck cancer (HNC), 3-month post-treatment positron emission tomography (PET)/computed tomography (CT) reliably identifies persistent/recurrent disease. However, further PET/CT surveillance has unclear benefit. The impact of post-treatment PET/CT surveillance on outcomes is assessed at 12 and 24 months. A 10-year retrospective analysis of HNC patients was carried out with long-term serial imaging. Imaging at 3 months included either PET/CT or magnetic resonance imaging, with all subsequent imaging comprised of PET/CT. PET/CT scans at 12 and 24 months were evaluated only if preceding interval scans were negative. Of 1114 identified patients, 284 had 3-month scans, 175 had 3- and 12-month scans, and 77 had 3-, 12-, and 24-month scans. PET/CT detection rates in clinically occult patients were 9% (15 of 175) at 12 months, and 4% (3 of 77) at 24 months. No difference in outcomes was identified between PET/CT-detected and clinically detected recurrences, with similar 3-year disease-free survival (41% vs 46%, P = .91) and 3-year overall survival (60% vs 54%, P = .70) rates. Compared with 3-month PET/CT, 12-month PET/CT demonstrated fewer equivocal reads (26% vs 10%, P < .001). Of scans deemed equivocal, 6% (5 of 89) were ultimately found to be positive. HNC patients with negative 3-month imaging appear to derive limited benefit from subsequent PET/CT surveillance. No survival differences were observed between PET/CT-detected and clinically detected recurrences, although larger prospective studies are needed for further investigation.


Broadband cortical desynchronization underlies the human psychedelic state.
Psychedelic drugs produce profound changes in consciousness, but the underlying neurobiological mechanisms for this remain unclear. Spontaneous and induced oscillatory activity was recorded in healthy human participants with magnetoencephalography after intravenous infusion of psilocybin--prodrug of the nonselective serotonin 2A receptor agonist and classic psychedelic psilocin. Psilocybin reduced spontaneous cortical oscillatory power from 1 to 50 Hz in posterior association cortices, and from 8 to 100 Hz in frontal association cortices. Large decreases in oscillatory power were seen in areas of the default-mode network. Independent component analysis was used to identify a number of resting-state networks, and activity in these was similarly decreased after psilocybin. Psilocybin had no effect on low-level visually induced and motor-induced gamma-band oscillations, suggesting that some basic elements of oscillatory brain activity are relatively preserved during the psychedelic experience. Dynamic causal modeling revealed that posterior cingulate cortex desynchronization can be explained by increased excitability of deep-layer pyramidal neurons, which are known to be rich in 5-HT2A receptors. These findings suggest that the subjective effects of psychedelics result from a desynchronization of ongoing oscillatory rhythms in the cortex, likely triggered by 5-HT2A receptor-mediated excitation of deep pyramidal cells.


Mesenchymal stromal cells for treatment of steroid-refractory GvHD: a review of the literature and two pediatric cases.
Severe acute graft versus host disease (GvHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. Human mesenchymal stromal cells (MSCs) play an important role in endogenous tissue repair and possess strong immune-modulatory properties making them a promising tool for the treatment of steroid-refractory GvHD. To date, a few reports exist on the use of MSCs in treatment of GvHD in children indicating that children tend to respond better than adults, albeit with heterogeneous results.We here present a review of the literature and the clinical course of two instructive pediatric patients with acute steroid-refractory GvHD after haploidentical stem cell transplantation, which exemplify the beneficial effects of third-party transplanted MSCs in treatment of acute steroid-refractory GvHD. Moreover, we provide a meta-analysis of clinical studies addressing the outcome of patients with steroid-refractory GvHD and treatment with MSCs in adults and in children (n = 183; 122 adults, 61 children). Our meta-analysis demonstrates that the overall response-rate is high (73.8%) and confirms, for the first time, that children indeed respond better to treatment of GvHD with MSCs than adults (complete response 57.4% vs. 45.1%, respectively).These data emphasize the significance of this therapeutic approach especially in children and indicate that future prospective studies are needed to assess the reasons for the observed differential response-rates in pediatric and adult patients.


Social class and gender patterning of insomnia symptoms and psychiatric distress: a 20-year prospective cohort study.
Psychiatric distress and insomnia symptoms exhibit similar patterning by gender and socioeconomic position. Prospective evidence indicates a bi-directional relationship between psychiatric distress and insomnia symptoms so similarities in social patterning may not be coincidental. Treatment for insomnia can also improve distress outcomes. We investigate the extent to which the prospective patterning of distress over 20 years is associated with insomnia symptoms over that period. 999 respondents to the Twenty-07 Study had been followed for 20 years from approximately ages 36-57 (73.2% of the living baseline sample). Psychiatric distress was measured using the GHQ-12 at baseline and at 20-year follow-up. Gender and social class were ascertained at baseline. Insomnia symptoms were self-reported approximately every five years. Latent class analysis was used to classify patterns of insomnia symptoms over the 20 years. Structural Equation Models were used to assess how much of the social patterning of distress was associated with insomnia symptoms. Missing data was addressed with a combination of multiple-imputation and weighting. Patterns of insomnia symptoms over 20 years were classified as either healthy, episodic, developing or chronic. Respondents from a manual social class were more likely to experience episodic, developing or chronic patterns than those from non-manual occupations but this was mostly explained by baseline psychiatric distress. People in manual occupations experiencing psychiatric distress however were particularly likely to experience chronic patterns of insomnia symptoms. Women were more likely to experience a developing pattern than men, independent of baseline distress. Psychiatric distress was more persistent over the 20 years for those in manual social classes and this effect disappeared when adjusting for insomnia symptoms. Irrespective of baseline symptoms, women, and especially those in a manual social class, were more likely than men to experience distress at age 57. This overall association for gender, but not the interaction with social class, was explained after adjusting for insomnia symptoms. Sensitivity analyses supported these findings. Gender and socioeconomic inequalities in psychiatric distress are strongly associated with inequalities in insomnia symptoms. Treatment of insomnia or measures to promote healthier sleeping may therefore help alleviate inequalities in psychiatric distress.


Environmental suitability models predict population density, performance and body condition for microendemic salamanders.
Species can show strong variation of local abundance across their ranges. Recent analyses suggested that variation in abundance can be related to environmental suitability, as the highest abundances are often observed in populations living in the most suitable areas. However, there is limited information on the mechanisms through which variation in environmental suitability determines abundance. We analysed populations of the microendemic salamander Hydromantes flavus, and tested several hypotheses on potential relationships linking environmental suitability to population parameters. For multiple populations across the whole species range, we assessed suitability using species distribution models, and measured density, activity level, food intake and body condition index. In high-suitability sites, the density of salamanders was up to 30-times higher than in the least suitable ones. Variation in activity levels and population performance can explain such variation of abundance. In high-suitability sites, salamanders were active close to the surface, and showed a low frequency of empty stomachs. Furthermore, when taking into account seasonal variation, body condition was better in the most suitable sites. Our results show that the strong relationship between environmental suitability and population abundance can be mediated by the variation of parameters strongly linked to individual performance and fitness.


Caffeic acid phenethyl ester inhibits 3-MC-induced CYP1A1 expression through induction of hypoxia-inducible factor-1α.
Caffeic acid phenethyl ester (CAPE), a natural component of propolis, is reported to have anticarcinogenic properties, although its precise chemopreventive mechanism remains unclear. In this study, we examined the effects of CAPE on 3-methylcholanthrene (3-MC)-induced CYP1A1 expression and activities. CAPE reduced the formation of the benzo[a]pyrene-DNA adduct. Moreover, CAPE inhibited 3-MC-induced CYP1A1 activity, mRNA expression, protein level, and promoter activity. CAPE treatment also decreased 3-MC-inducible xenobiotic-response element (XRE)-linked luciferase, aryl hydrocarbons receptor (AhR) transactivation and nuclear localization. CAPE induced hypoxia inducible factor-1α (HIF-1α) protein level and HIF-1α responsible element (HRE) transcriptional activity. CAPE-mediated HIF-1α reduced 3-MC-inducible CYP1A1 protein expression. Taken together, CAPE decreases 3-MC-mediated CYP1A1 expression, and this inhibitory response is associated with inhibition of AhR and HIF-1α induction.


Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic.
In March and early April 2009, a new swine-origin influenza A (H1N1) virus (S-OIV) emerged in Mexico and the United States. During the first few weeks of surveillance, the virus spread worldwide to 30 countries (as of May 11) by human-to-human transmission, causing the World Health Organization to raise its pandemic alert to level 5 of 6. This virus has the potential to develop into the first influenza pandemic of the twenty-first century. Here we use evolutionary analysis to estimate the timescale of the origins and the early development of the S-OIV epidemic. We show that it was derived from several viruses circulating in swine, and that the initial transmission to humans occurred several months before recognition of the outbreak. A phylogenetic estimate of the gaps in genetic surveillance indicates a long period of unsampled ancestry before the S-OIV outbreak, suggesting that the reassortment of swine lineages may have occurred years before emergence in humans, and that the multiple genetic ancestry of S-OIV is not indicative of an artificial origin. Furthermore, the unsampled history of the epidemic means that the nature and location of the genetically closest swine viruses reveal little about the immediate origin of the epidemic, despite the fact that we included a panel of closely related and previously unpublished swine influenza isolates. Our results highlight the need for systematic surveillance of influenza in swine, and provide evidence that the mixing of new genetic elements in swine can result in the emergence of viruses with pandemic potential in humans.


Assessment of Vascular Event Prevention and Cognitive Function Among Older Adults With Preexisting Vascular Disease or Diabetes: A Secondary Analysis of 3 Randomized Clinical Trials.
Acquisition of reliable randomized clinical trial evidence of the effects of cardiovascular interventions on cognitive decline is a priority. To estimate the association of cognitive aging with the avoidance of vascular events in cardiovascular intervention trials and understand whether reports of nonsignificant results exclude worthwhile benefit. This secondary analysis of 3 randomized clinical trials in participants with preexisting occlusive vascular disease or diabetes included survivors to final in-trial follow-up in the Heart Protection Study (HPS), Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), and Treatment of HDL (High-Density Lipoprotein) to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trials of lipid modification for prevention of cardiovascular events. Data were collected from February 1994 through January 2013 and analyzed from January 2015 through December 2018. Incident vascular events and diabetes and statin therapy. Cognitive function was assessed at the end of a mean (SD) of 4.9 (1.5) years of follow-up using a 14-item verbal test. Associations of the incidence of vascular events and new-onset diabetes during the trials, with cognitive function at final in-trial follow-up were estimated and expressed as years of cognitive aging (using the association of the score with age >60 years). The benefit on cognitive aging mediated through the effects of lowering low-density lipoprotein cholesterol levels on events was estimated by applying these findings to nonfatal event differences observed with statin therapy in the HPS trial. Among 45 029 participants undergoing cognitive assessment, mean (SD) age was 67.9 (8.0) years; 80.7% were men. Incident stroke (n = 1197) was associated with 7.1 (95% CI, 5.7-8.5) years of cognitive aging; incident transient ischemic attack, myocardial infarction, heart failure, and new-onset diabetes were associated with 1 to 2 years of cognitive aging. In HPS, randomization to statin therapy for 5 years resulted in 2.0% of survivors avoiding a nonfatal stroke or transient ischemic attack and 2.4% avoiding a nonfatal cardiac event, which yielded an expected reduction in cognitive aging of 0.15 (95% CI, 0.11-0.19) years. With 15 926 participants undergoing cognitive assessment, HPS had 80% power to detect a 1-year (ie, 20% during the 5 years) difference in cognitive aging. The expected cognitive benefits of the effects of preventive therapies on cardiovascular events during even the largest randomized clinical trials may have been too small to be detectable. Hence, nonsignificant findings may not provide good evidence of a lack of worthwhile benefit on cognitive function with prolonged use of such therapies. isrctn.com and ClinicalTrials.gov Identifiers: ISRCTN48489393, ISRCTN74348595, and NCT00461630.


Development of an anatomically detailed MRI-derived rabbit ventricular model and assessment of its impact on simulations of electrophysiological function.
Recent advances in magnetic resonance (MR) imaging technology have unveiled a wealth of information regarding cardiac histoanatomical complexity. However, methods to faithfully translate this level of fine-scale structural detail into computational whole ventricular models are still in their infancy, and, thus, the relevance of this additional complexity for simulations of cardiac function has yet to be elucidated. Here, we describe the development of a highly detailed finite-element computational model (resolution: approximately 125 microm) of rabbit ventricles constructed from high-resolution MR data (raw data resolution: 43 x 43 x 36 microm), including the processes of segmentation (using a combination of level-set approaches), identification of relevant anatomical features, mesh generation, and myocyte orientation representation (using a rule-based approach). Full access is provided to the completed model and MR data. Simulation results were compared with those from a simplified model built from the same images but excluding finer anatomical features (vessels/endocardial structures). Initial simulations showed that the presence of trabeculations can provide shortcut paths for excitation, causing regional differences in activation after pacing between models. Endocardial structures gave rise to small-scale virtual electrodes upon the application of external field stimulation, which appeared to protect parts of the endocardium in the complex model from strong polarizations, whereas intramural virtual electrodes caused by blood vessels and extracellular cleft spaces appeared to reduce polarization of the epicardium. Postshock, these differences resulted in the genesis of new excitation wavefronts that were not observed in more simplified models. Furthermore, global differences in the stimulus recovery rates of apex/base regions were observed, causing differences in the ensuing arrhythmogenic episodes. In conclusion, structurally simplified models are well suited for a large range of cardiac modeling applications. However, important differences are seen when behavior at microscales is relevant, particularly when examining the effects of external electrical stimulation on tissue electrophysiology and arrhythmia induction. This highlights the utility of histoanatomically detailed models for investigations of cardiac function, in particular for future patient-specific modeling.


Underutilization of therapy for hepatocellular carcinoma in the medicare population.
The incidence of hepatocellular carcinoma (HCC) is increasing in the United States, and the care of these patients remains highly specialized and complex. Multiple treatment options are available for HCC but their use and effectiveness remain unknown. Using Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data, 8730 patients who were diagnosed with HCC between 1991 and 2005 were identified. Therapy included surgical resection (8.7%), liver transplantation (1.4%), ablation (3.6%), or transarterial chemoembolization (16%). Patients who received no or palliative-only treatment were grouped together (NoTx; 70.3%). Patient, disease, and tumor factors were examined as determinants of therapy. HCC is increasing in the Medicare population. The median age at diagnosis was 75.1 years and 73.6% of patients were coded as white, 17.2% as Asian, 8.3% as black, and 0.9% as other race. The rate of therapy increased over time, but only 29.7% of patients overall underwent therapy. In patients with early stage HCC, only 43.1% underwent therapy. In the NoTx group, 49.4% did not have cirrhosis, 36.0% had tumors that measured <5 cm, and 39.8% were diagnosed with stage I or II disease when variables were complete. The use of therapy for all HCC patients increased over time, correlating with a commensurate increase in median survival. In multivariate regression analysis, patients who received any modality of treatment achieved significant benefit compared with the NoTx group (odds ratio, 0.41; 95% confidence interval, 0.39-0.43). In the Medicare population, HCC patients who received therapy experienced a substantial survival advantage over their nonoperative peers (NoTx). Despite evidence that many patients had favorable biological characteristics, <30% of patients diagnosed with HCC received any treatment.


Exposure to fluoridated water and attention deficit hyperactivity disorder prevalence among children and adolescents in the United States: an ecological association.
Epidemiological and animal-based studies have suggested that prenatal and postnatal fluoride exposure has adverse effects on neurodevelopment. The aim of this study was to examine the relationship between exposure to fluoridated water and Attention-Deficit Hyperactivity Disorder (ADHD) prevalence among children and adolescents in the United States. Data on ADHD prevalence among 4-17 year olds collected in 2003, 2007 and 2011 as part of the National Survey of Children's Health, and state water fluoridation prevalence from the Centers for Disease Control and Prevention (CDC) collected between 1992 and 2008 were utilized. State prevalence of artificial water fluoridation in 1992 significantly positively predicted state prevalence of ADHD in 2003, 2007 and 2011, even after controlling for socioeconomic status. A multivariate regression analysis showed that after socioeconomic status was controlled each 1% increase in artificial fluoridation prevalence in 1992 was associated with approximately 67,000 to 131,000 additional ADHD diagnoses from 2003 to 2011. Overall state water fluoridation prevalence (not distinguishing between fluoridation types) was also significantly positively correlated with state prevalence of ADHD for all but one year examined. Parents reported higher rates of medically-diagnosed ADHD in their children in states in which a greater proportion of people receive fluoridated water from public water supplies. The relationship between fluoride exposure and ADHD warrants future study.


[Lipid profile frequency and relevancy as an initial test for peripheral vertigo].
Determining the prevalence of requesting lipid profile as a first-line diagnostic method in patients having a clinical impression of peripheral vertigo and also determining such request's cost- benefit ratio. This was a retrospective cross-sectional study of 201 clinical charts regarding patients diagnosed as having peripheral vertigo at the Teletón teaching hospital's outpatient services in Chía between January 2005 and July 2008. Clinical charts drawn up by both general practitioners and medical specialists at first-time visit were compiled and analyzed. The patients were aged 6 to 87 years old; 36 % were males and 64 % females. Lipid profile was requested for 76 % of the patients as initial diagnostic method; it was found that 80 % of the results revealed no abnormality. Although a high prevalence regarding a request for lipid profile first-line study was found for patients having peripheral vertigo, there was no scientific evidence supporting such requirement. Ordering this kind of study not only increases unnecessary costs concerning diagnostic methods but also involves unjustified treatment. Feedback is needed for both doctors and first attention staff to ensure that this type of practice becomes changed.


A blind spot? Confronting the stigma of hepatitis B virus (HBV) infection - A systematic review.
Background: Stigma, poverty, and lack of knowledge present barriers to the diagnosis and treatment of chronic infection, especially in resource-limited settings. Chronic Hepatitis B virus (HBV) infection is frequently asymptomatic, but accounts for a substantial long-term burden of morbidity and mortality. In order to improve the success of diagnostic, treatment and preventive strategies, it is important to recognise, investigate and tackle stigma. We set out to assimilate evidence for the nature and impact of stigma associated with HBV infection, and to suggest ways to tackle this challenge. Methods: We carried out a literature search in PubMed using the search terms 'hepatitis B', 'stigma' to identify relevant papers published between 2007 and 2017 (inclusive), with a particular focus on Africa. Results: We identified a total of 32 articles, of which only two studies were conducted in Africa. Lack of knowledge of HBV was consistently identified, and in some settings there was no local word to describe HBV infection. There were misconceptions about HBV infection, transmission and treatment. Healthcare workers provided inaccurate information to individuals diagnosed with HBV, and poor understanding resulted in lack of preventive measures. Stigma negatively impacted on help-seeking, screening, disclosure, prevention of transmission, and adherence to treatment, and had potential negative impacts on mental health, wellbeing, employment and relationships. Conclusion: Stigma is a potentially major barrier to the successful implementation of preventive, diagnostic and treatment strategies for HBV infection, and yet we highlight a 'blind spot', representing a lack of data and limited recognition of this challenge. There is a need for more research in this area, to identify and evaluate interventions that can be used effectively to tackle stigma, and to inform collaborative efforts between patients, clinical services, policy makers, traditional healers, religious leaders, charity organisations and support groups.


L11 domain rearrangement upon binding to RNA and thiostrepton studied by NMR spectroscopy.
Ribosomal proteins are assumed to stabilize specific RNA structures and promote compact folding of the large rRNA. The conformational dynamics of the protein between the bound and unbound state play an important role in the binding process. We have studied those dynamical changes in detail for the highly conserved complex between the ribosomal protein L11 and the GTPase region of 23S rRNA. The RNA domain is compactly folded into a well defined tertiary structure, which is further stabilized by the association with the C-terminal domain of the L11 protein (L11(ctd)). In addition, the N-terminal domain of L11 (L11(ntd)) is implicated in the binding of the natural thiazole antibiotic thiostrepton, which disrupts the elongation factor function. We have studied the conformation of the ribosomal protein and its dynamics by NMR in the unbound state, the RNA bound state and in the ternary complex with the RNA and thiostrepton. Our data reveal a rearrangement of the L11(ntd), placing it closer to the RNA after binding of thiostrepton, which may prevent binding of elongation factors. We propose a model for the ternary L11-RNA-thiostrepton complex that is additionally based on interaction data and conformational information of the L11 protein. The model is consistent with earlier findings and provides an explanation for the role of L11(ntd) in elongation factor binding.


Nerve transfer for restoration of lower motor neuron-lesioned bladder and urethra function: establishment of a canine model and interim pilot study results.
Previous patient surveys have shown that patients with spinal cord or cauda equina injuries prioritize recovery of bladder function. The authors sought to determine if nerve transfer after long-term decentralization restores bladder and sphincter function in canines. Twenty-four female canines were included in this study. Transection of sacral roots and hypogastric nerves (S Dec) was performed in 6 animals, and 7 animals underwent this procedure with additional transection of the L7 dorsal roots (L7d+S Dec). Twelve months later, 3 L7d+S Dec animals underwent obturator-to-pelvic nerve and sciatic-to-pudendal nerve transfers (L7d+S Dec+Reinn). Eleven animals served as controls. Squat-and-void behaviors were tracked before and after decentralization, after reinnervation, and following awake bladder-filling procedures. Bladders were cystoscopically injected with Fluoro-Gold 3 weeks before euthanasia. Immediately before euthanasia, transferred nerves were stimulated to evaluate motor function. Dorsal root ganglia were assessed for retrogradely labeled neurons. Transection of only sacral roots failed to reduce squat-and-void postures; L7 dorsal root transection was necessary for significant reduction. Three L7d+S Dec animals showing loss of squat-and-void postures post-decentralization were chosen for reinnervation and recovered these postures 4-6 months after reinnervation. Each showed obturator nerve stimulation-induced bladder contractions and sciatic nerve stimulation-induced anal sphincter contractions immediately prior to euthanasia. One showed sciatic nerve stimulation-induced external urethral sphincter contractions and voluntarily voided twice following nonanesthetized bladder filling. Reinnervation was confirmed by increased labeled cells in L2 and the L4-6 dorsal root ganglia (source of obturator nerve in canines) of L7d+S Dec+Reinn animals, compared with controls. New neuronal pathways created by nerve transfer can restore bladder sensation and motor function in lower motor neuron-lesioned canines even 12 months after decentralization.


[Comparison of the therapeutic effects of electroacupuncture and probiotics combined with deanxit in treating diarrhea-predominant irritable bowel syndrome].
To study and compare the therapeutic effects of electroacupuncture and probiotics combine Deanxit in treating diarrhea predominant irritable bowel syndrome (D-IBS). Totally 64 D-IBS patients accompanied with anxiety and/or depression were randomly assigned to the Western medicine group (Group A) and the electroacupuncture (EA) group (Group B), 30 patients in Group A and 34 patients in Group B. Patients in Group A took Bacillus licheniformis and Deanxit, while those in Group B received EA. Four weeks consisted of one therapeutic course. Three-month follow-up was carried out. The scoring for the digestive tract symptoms, HAMA score, and HAMD score were evaluated before and after treatment. The recurrence in the 3-month follow-up was also observed. The total effect rate was 86.67% in Group A and 88.24% in Group B with no statistical difference between the two groups (P > 0.05). There was statistical difference in the scoring for the digestive tract symptoms, HAMA score, and HAMD score (P < 0.05, P < 0.01). There was no statistical difference in the improvement of defecation frequency score, HAMA score, HAMD score between the two groups after treatment (P > 0.05). Better effects on improving abdominal pain score and abdominal distention score was obtained in Group B (P < 0.01), while better effects on improving the stool form score and mucus score were obtained in Group A (P < 0.01). There was no statistical difference in the recurrence rate between the two groups within the two-month follow-up (P > 0.05). The recurrence rate within the 3-month follow-up was obviously lower in Group B than in Group A (P < 0.05). EA and Western medicine (probiotics combined Deanxit) could effectively treat D-IBS patients accompanied with anxiety and/or depression. Both of them had different superiorities in improving symptoms. But EA had better long-term therapeutic effects.


Contrasting male and female trends in tobacco-attributed mortality in China: evidence from successive nationwide prospective cohort studies.
Chinese men now smoke more than a third of the world's cigarettes, following a large increase in urban then rural usage. Conversely, Chinese women now smoke far less than in previous generations. We assess the oppositely changing effects of tobacco on male and female mortality. Two nationwide prospective studies 15 years apart recruited 220,000 men in about 1991 at ages 40-79 years (first study) and 210,000 men and 300,000 women in about 2006 at ages 35-74 years (second study), with follow-up during 1991-99 (mid-year 1995) and 2006-14 (mid-year 2010), respectively. Cox regression yielded sex-specific adjusted mortality rate ratios (RRs) comparing smokers (including any who had stopped because of illness, but not the other ex-smokers, who are described as having stopped by choice) versus never-smokers. Two-thirds of the men smoked; there was little dependence of male smoking prevalence on age, but many smokers had not smoked cigarettes throughout adult life. Comparing men born before and since 1950, in the older generation, the age at which smoking had started was later and, particularly in rural areas, lifelong exclusive cigarette use was less common than in the younger generation. Comparing male mortality RRs in the first study (mid-year 1995) versus those in the second study (mid-year 2010), the proportional excess risk among smokers (RR-1) approximately doubled over this 15-year period (urban: RR 1·32 [95% CI 1·24-1·41] vs 1·65 [1·53-1·79]; rural: RR 1·13 [1·09-1·17] vs 1·22 [1·16-1·29]), as did the smoking-attributed fraction of deaths at ages 40-79 years (urban: 17% vs 26%; rural: 9% vs 14%). In the second study, urban male smokers who had started before age 20 years (which is now typical among both urban and rural young men) had twice the never-smoker mortality rate (RR 1·98, 1·79-2·19, approaching Western RRs), with substantial excess mortality from chronic obstructive pulmonary disease (COPD RR 9·09, 5·11-16·15), lung cancer (RR 3·78, 2·78-5·14), and ischaemic stroke or ischaemic heart disease (combined RR 2·03, 1·66-2·47). Ex-smokers who had stopped by choice (only 3% of ever-smokers in 1991, but 9% in 2006) had little smoking-attributed risk more than 10 years after stopping. Among Chinese women, however, there has been a tenfold intergenerational reduction in smoking uptake rates. In the second study, among women born in the 1930s, 1940s, 1950s, and since 1960 the proportions who had smoked were, respectively, 10%, 5%, 2%, and 1% (3097/30,943, 3265/62,246, 2339/97,344, and 1068/111,933). The smoker versus non-smoker RR of 1·51 (1·40-1·63) for all female mortality at ages 40-79 years accounted for 5%, 3%, 1%, and <1%, respectively, of all the female deaths in these four successive birth cohorts. In 2010, smoking caused about 1 million (840,000 male, 130,000 female) deaths in China. Smoking will cause about 20% of all adult male deaths in China during the 2010s. The tobacco-attributed proportion is increasing in men, but low, and decreasing, in women. Although overall adult mortality rates are falling, as the adult population of China grows and the proportion of male deaths due to smoking increases, the annual number of deaths in China that are caused by tobacco will rise from about 1 million in 2010 to 2 million in 2030 and 3 million in 2050, unless there is widespread cessation. Wellcome Trust, MRC, BHF, CR-UK, Kadoorie Charitable Foundation, Chinese MoST and NSFC.


Load Monitoring Variables in Training and Competition Situations: A Systematic Review Applied to Wheelchair Sports.
The aim of this review was to identify the main variables for load monitoring in training and competition situations in wheelchair sports. Studies were identified from a systematic search of three databases (PubMed, Web of Science, and SportDiscuss), with search phrases constructed from MeSH terms, alone or in combination, limited to English-language literature, and published up to January 2016. Our main findings were that variables related to external load (distance, speed, and duration) are used to monitor load in competition. In training situations, researchers have used variables related to internal load (heart rate and VO2); in both training and competition situations, researchers used internal load measurements (training impulse and ratings of perceived exertion). We conclude that the main variables for load monitoring in competitive situations were distance, speed, and duration, whereas the variables for training situations were heart rate, VO2, training impulse, and ratings of perceived exertion.


Rapid identification of dengue virus serotypes by using polymerase chain reaction.
Four primer pairs were selected on the basis of the published sequence data of four dengue virus serotypes so that each unique target sequence size could be amplified for each serotype by polymerase chain reaction. The procedure consists of (i) RNA preparation, (ii) reverse transcription, and (iii) polymerase chain reaction, all of which could be completed within 2 h in a single tube for each specimen. The amplified sequence size revealed by ethidium bromide-stained agarose gel electrophoresis was unique for each serotype, using infected culture fluid of isolates from dengue fever or dengue hemorrhagic fever patients in Thailand, Indonesia, and the Philippines as well as from prototype viruses, thus facilitating simultaneous identification and typing.


Clinical implications of cardiac hyperpolarized magnetic resonance imaging.
Alterations in cardiac metabolism are now considered a cause, rather than a result, of cardiac disease. Although magnetic resonance spectroscopy has allowed investigation of myocardial energetics, the inherently low sensitivity of the technique has limited its clinical application in the study of cardiac metabolism. The development of a novel hyperpolarization technique, based on the process of dynamic nuclear polarization, when combined with the metabolic tracers [1-(13)C] and [2-(13)C] pyruvate, has resulted in significant advances in the understanding of real time myocardial metabolism in the normal and diseased heart in vivo. This review focuses on the changes in myocardial substrate selection and downstream metabolism of hyperpolarized 13C labelled pyruvate that have been shown in diabetes, ischaemic heart disease, cardiac hypertrophy and heart failure in animal models of disease and how these could translate into clinical practice with the advent of clinical grade hyperpolarizer systems.


[Legal decisions on access to medicines in Pernambuco, Northeastern Brazil].
To analyze decisions from the legal system concerning the population's access to medicines within the Brazilian Public Health System through judicial channels, with regard to decision-making criteria and possible political and economic pressure. This was a descriptive retrospective study on documents with a quantitative and qualitative approach. Data were gathered from the State of Pernambuco Superintendency for Pharmaceutical Care, and the data sources used were 105 lawsuits and administrative reports between January and June 2009. It was ascertained which medications have a patent or patent request in the database of the Brazilian Patent Office (INPI), in order to identify the frequency with which patents feature in lawsuits. The data obtained were classified according to Anatomical and Therapeutic Chemical System. To analyze the judicial decisions, the theory of autopoietic social systems was used. There were lawsuits involving 134 medications, with an estimated value of R$ 4.5 million for attending the treatments requested. 70.9% of the medications had a patent or a patent request and they were concentrated in three therapeutic classes: antineoplastic and immunomodulating agents; digestive tract and metabolism; and sensory organs. Six central ideas within judges' decision-making criteria were identified (the federal constitution and medical prescriptions), along with pressure between the legal, economic and political systems concerning access to medications. The analysis on judicial decisions based on the theory of autopoietic social systems made it possible to identify mutual stimulation (dependency) between the legal system and other social systems in relation to the issue of citizens' access to medications. This dependency was represented by the federal constitution and intellectual property. The federal constitution and medical prescription were identified as decision-making criteria in lawsuits. Intellectual property represented possible political and economic pressure, especially in cases of launching medications into the market.


Contribution of pollinator-mediated crops to nutrients in the human food supply.
The contribution of nutrients from animal pollinated world crops has not previously been evaluated as a biophysical measure for the value of pollination services. This study evaluates the nutritional composition of animal-pollinated world crops. We calculated pollinator dependent and independent proportions of different nutrients of world crops, employing FAO data for crop production, USDA data for nutritional composition, and pollinator dependency data according to Klein et al. (2007). Crop plants that depend fully or partially on animal pollinators contain more than 90% of vitamin C, the whole quantity of Lycopene and almost the full quantity of the antioxidants β-cryptoxanthin and β-tocopherol, the majority of the lipid, vitamin A and related carotenoids, calcium and fluoride, and a large portion of folic acid. Ongoing pollinator decline may thus exacerbate current difficulties of providing a nutritionally adequate diet for the global human population.


Metabotropic glutamate receptor agonists for schizophrenia.
A drug acting at metabotropic glutamate receptors has recently been reported to be an effective antipsychotic, breaking the rule that only dopamine receptor-blocking drugs have this property. The finding complements accumulating evidence that glutamatergic abnormalities are important in the pathophysiology of schizophrenia.


Deguelin attenuates reperfusion injury and improves outcome after orthotopic lung transplantation in the rat.
The main goal of adequate organ preservation is to avoid further cellular metabolism during the phase of ischemia. However, modern preservation solutions do rarely achieve this target. In donor organs hypoxia and ischemia induce a broad spectrum of pathologic molecular mechanisms favoring primary graft dysfunction (PGD) after transplantation. Increased hypoxia-induced transcriptional activity leads to increased vascular permeability which in turn is the soil of a reperfusion edema and the enhancement of a pro-inflammatory response in the graft after reperfusion. We hypothesize that inhibition of the respiration chain in mitochondria and thus inhibition of the hypoxia induced mechanisms might reduce reperfusion edema and consecutively improve survival in vivo. In this study we demonstrate that the rotenoid Deguelin reduces the expression of hypoxia induced target genes, and especially VEGF-A, dose-dependently in hypoxic human lung derived cells. Furthermore, Deguelin significantly suppresses the mRNA expression of the HIF target genes VEGF-A, the pro-inflammatory CXCR4 and ICAM-1 in ischemic lungs vs. control lungs. After lung transplantation, the VEGF-A induced reperfusion-edema is significantly lower in Deguelin-treated animals than in controls. Deguelin-treated rats exhibit a significantly increased survival-rate after transplantation. Additionally, a downregulation of the pro-inflammatory molecules ICAM-1 and CXCR4 and an increase in the recruitment of immunomodulatory monocytes (CD163+ and CD68+) to the transplanted organ involving the IL4 pathway was observed. Therefore, we conclude that ischemic periods preceding reperfusion are mainly responsible for the increased vascular permeability via upregulation of VEGF. Together with this, the resulting endothelial dysfunction also enhances inflammation and consequently lung dysfunction. Deguelin significantly decreases a VEGF-A induced reperfusion edema, induces the recruitment of immunomodulatory monocytes and thus improves organ function and survival after lung transplantation by interfering with hypoxia induced signaling.


The role of acupuncture in assisted reproductive technology.
The aim of this paper was to provide reliable evidence by performing a systematic review and meta-analysis for evaluating the role of acupuncture in assisted reproductive technology. All randomized controlled trials that evaluated the effects of acupuncture, including manual, electrical, and laser acupuncture (LA) techniques, on the clinical pregnancy rate (CPR) and live birth rate (LBR) of in vitro fertilization (IVF) or artificial insemination were included. The controlled groups consisted of no acupuncture and sham acupuncture groups. The sham acupuncture included sham acupuncture at acupoints, sham acupuncture at non- or inappropriate points, sham LA, and adhesive tapes. Twenty-three trials (a total of 5598 participants) were included in this paper. The pooled CPR from all acupuncture groups was significantly higher than that from all controlled groups, whereas the LBR was not significantly different between the two groups. However, the results were quite distinct when the type of control and/or different acupuncture times were examined in a sensitivity analysis. The results mainly indicate that acupuncture, especially around the time of the controlled ovarian hyperstimulation, improves pregnancy outcomes in women undergoing IVF. More positive effects from acupuncture in IVF can be expected if a more individualized acupuncture programs are used.


HAE international home therapy consensus document.
Hereditary angioedema (C1 inhibitor deficiency, HAE) is associated with intermittent swellings which are disabling and may be fatal. Effective treatments are available and these are most useful when given early in the course of the swelling. The requirement to attend a medical facility for parenteral treatment results in delays. Home therapy offers the possibility of earlier treatment and better symptom control, enabling patients to live more healthy, productive lives. This paper examines the evidence for patient-controlled home treatment of acute attacks ('self or assisted administration') and suggests a framework for patients and physicians interested in participating in home or self-administration programmes. It represents the opinion of the authors who have a wide range of expert experience in the management of HAE.