Fim de emergências de saúde inacabadas e as redes de cuidados com a síndrome congênita do Zika vírus / The end of unfinished health emergencies and the Congenital Zika Syndrome

Resumo Entendendo que problemas de saúde sempre são inacabadas, este trabalho examina consequências da declaração do fim de uma emergência de saúde sobre práticas de diferentes redes de cuidado interconectadas. Parte da pesquisa "Etnografando Cuidados...", é um estudo de caso qualitativo de três documentos produzidos depois do anúncio do fim da epidemia da síndrome congênita de Zika vírus. Mostra contextos de produção de narrativas envolvendo redes de pesquisadores, gestores/prestadores de serviço, mães e famílias de acometidos e associações de mães e suas perspectivas diferentes sobre o que é cuidado. Análises de uma apresentação para pesquisadores e de um texto de discussão no IPEA questionam a narrativa técnica da celebração do fim da emergência com base em conhecimento e atendimento, sem tomar em conta a importância dos cuidados relacionais e afetivos e políticos (das redes de mães/familiares e de associações), deixando-os invisibilizados. Descreve o processo da elaboração da moção para o Fórum Zika na Pandemia, elencando e sistematizando propostas de ações através de um diálogo explícito entre integrante das diferentes redes para abordar questões inacabadas pós-emergenciais. Sugere que práticas semelhantes de diálogo entre redes possam promover maior inclusão e sensibilidade a cuidados que contribuem para diminuir sofrimento e defender direitos de pessoas que continuam a conviver cotidianamente com uma síndrome ou doença cujas consequências persistem.

Abstract Understanding health problems as always unfinished, this article examines consequences of the declaration of the end of a health emergency on the practice of different and interconnected care networks. As part of the "Action Ethnography on Care…" research project, this is a qualitative case study of three documents produced after the announcement of the end of the Congenital Zika Virus Syndrome epidemic. It shows the contexts of narrative production involving researchers, managers/ public service workers, mothers and families of the ill, and mothers' associations and their different perspectives about what care is. Analyses of a presentation for researchers and of a working paper for the Applied Economics Research Institute (IPEA) question the technical narrative celebrating the end of the emergency based on knowledge and health service without taking into account the relational, affective and political care (of mothers, families and associations), leaving the latter invisible. It describes the process of elaboration of a motion by the Zika Pandemic Forum, listing and systematizing action proposals produced in an explicit dialogue among participants in different care networks to approach unfinished post-emergency questions. It suggests that similar practices of dialogue between networks can promote greater inclusion and sensitivity to care that contribute to reducing suffering and defending the rights of people who continue to live daily with a syndrome or disease whose consequences persist.

A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Loss-of-function HSD17ß13 mutations protect against the development of chronic liver disease. HSD17ß13 inhibition represents a potential approach to treat liver diseases, such as non-alcoholic steatohepatitis (NASH). ARO-HSD is an RNA interference (RNAi) therapeutic designed to selectively reduce expression of HSD17ß13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected NASH. METHODS: The safety, tolerability, and pharmacodynamics of ARO-HSD were evaluated in 32 NHVs and 18 patients with confirmed/clinically suspected NASH. Double-blind NHV cohorts received single escalating doses of ARO-HSD (25, 50, 100, or 200 mg) or placebo subcutaneously on Day 1. Open-label patient cohorts received ARO-HSD (25, 100, or 200 mg) subcutaneously on Days 1 and 29. Liver biopsy was performed pre-dose and on Day 71 to evaluate expression levels of HSD17ß13 mRNA and protein. RESULTS: ARO-HSD treatment was well tolerated with no treatment-related serious adverse events or drug discontinuations. The most frequently reported treatment-emergent adverse events were mild injection site reactions, which were short in duration. Mean changes in hepatic HSD17ß13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17ß13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17ß13 protein levels were similarly reduced across doses. In patients, mean changes in alanine aminotransferase from baseline to Day 71 were -7.7% (25 mg), -39.3% (100 mg), and -42.3% (200 mg) (p <0.001 for pooled cohorts). CONCLUSIONS: ARO-HSD was well tolerated at doses ≤200 mg. This proof-of-concept study demonstrated that short-term treatment with ARO-HSD reduces hepatic HSD17ß13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase. GOV NUMBER: NCT04202354. IMPACTS AND IMPLICATIONS: There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17ß13 expression and hence to phenocopy the protective effect seen in individuals with HSD17ß13 loss-of-function. The reductions in HSD17ß13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17ß13, a drug target with substantial genetic validation, as an important modulator of human liver disease.

Relationship of low molecular weight fluorophore levels with clinical factors and fenofibrate effects in adults with type 2 diabetes.

People with diabetes are at risk of chronic complications and novel biomarkers, such as Advanced glycation end-products (AGEs) may help stratify this risk. We assessed whether plasma low-molecular weight AGEs, also known as LMW-fluorophores (LMW-F), are associated with risk factors, predict complications, and are altered by fenofibrate in adults with type 2 diabetes. Plasma LMW-F were quantified at baseline, after six weeks fenofibrate, and one year post-randomisation to fenofibrate or placebo. LMW-F associations with existing and new composite vascular complications were determined, and effects of fenofibrate assessed. LMW-F correlated positively with age, glycated haemoglobin (HbA1c), pulse pressure, kidney dysfunction and inflammation; and negatively with urate, body mass index, oxidative stress and leptin, albeit weakly (r = 0.04-0.16, all p < 0.01). Independent determinants of LMW-F included smoking, diastolic blood pressure, prior cardiovascular disease or microvascular complications, Caucasian ethnicity, kidney function, HbA1c and diabetes duration (all p ≤ 0.01). Baseline LMW-F tertiles correlated with on-trial macrovascular and microvascular complications (trend p < 0.001) on univariate analyses only. Six weeks of fenofibrate increased LMW-F levels by 21% (p < 0.001). In conclusion, LMW-F levels correlate with many risk factors and chronic diabetes complications, and are increased with fenofibrate. LMW-F tertiles predict complications, but not independently of traditional risk factors.

Lipoprotein apheresis and PCSK9 inhibitors for severe familial hypercholesterolaemia: Experience from Australia and New Zealand.

INTRODUCTION: Severe familial hypercholesterolaemia (FH) causes premature disability and death due to atherosclerotic cardiovascular disease and is refractory to standard lipid-lowering therapies. Lipoprotein apheresis (LA) has long been a standard of care for patients with severe FH, but is invasive, expensive and time-consuming for patients and their caregivers. Newer drug therapies, including the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, may reduce the need for LA. MATERIALS AND METHODS: We audited the records of 16 patients (eight homozygous, eight heterozygous) treated with LA in Australia and New Zealand, 14 of whom subsequently commenced PCSK9 inhibitor therapy. LA was performed by cascade filtration in all centres. RESULTS: LDL-cholesterol was acutely lowered by 69 ± 7% in patients with homozygous FH and by 72 ± 9% in those with heterozygous FH, representing time-averaged reductions of 36 ± 12% and 34 ± 5%, respectively. LA was well-tolerated, and patients reported comparable quality of life to population and disease-related norms. After commencement of PCSK9 inhibitors, four of seven patients with homozygous FH had meaningful biochemical responses, with a reduction in the frequency of LA permitted in one patient and complete cessation in another. Four of seven patients with heterozygous FH were able to be managed without LA after commencing PCSK9 inhibitors. CONCLUSION: While PCSK9 inhibitors have reduced the need for LA, some patients with severe FH continue to require LA, and will require it for the foreseeable future. However, emerging therapies, including angiopoetin-like 3 inhibitors, may further reduce the need for LA.

A transposição do rio São Francisco e a saúde do povo Pipipã, em Floresta, Pernambuco / The São Francisco River transposition and Pipipã people's health, in Floresta, Pernambuco, Brazil

Resumo Ações governamentais de implantação de projetos de desenvolvimento nos territórios indígenas, cujo modelo explorador está vinculado à expectativa de suposto progresso econômico e social, vêm afetando as perspectivas de futuro dos povos em diversos países e no Brasil. O estudo analisou os processos socioambientais de vulnerabilização do povo Pipipã, localizados no município de Floresta, Pernambuco, decorrentes da transposição do rio São Francisco. A pesquisa foi realizada na perspectiva da determinação social da saúde e propõe o movimento dialético, no intuito de promover os diálogos necessários para a devida compreensão da complexidade dos problemas de saúde. Os procedimentos metodológicos se pautaram na técnica qualitativa de coleta e análise de dados. As estratégias de pesquisa utilizadas no estudo foram análise de documentos, entrevistas e observação participante, que favoreceram a compreensão dos processos sociais destrutivos determinados pela transposição do São Francisco e das percepções do povo Pipipã sobre a relação com a saúde e a doença. A pesquisa evidenciou que, em função da transposição do São Francisco, os Pipipã foram vulnerabilizados material e simbolicamente, e novas territorialidades e vulnerabilidades foram estabelecidas compulsoriamente, encontrando-se, portanto, a etnia ameaçada em seus processos de reprodução social.

Abstract Government actions to implement development projects in indigenous territories, whose operational model is linked to the prospect of supposed economic and social progress, have affected the perspectives for the future of people in several countries and in Brazil. This study analyzed the socioenvironmental processes of vulnerabilization of the Pipipã people resulting from the transposition of the São Francisco River in the municipality of Floresta, Pernambuco, Brazil. The research used the perspective of social determination of health and proposed a dialectical movement aiming to favor the needed dialogues for a proper understanding of the complexity of health problems. Qualitative research methodological procedures were used for data collection and analysis. Documents, interviews and participant observation were analyzed, emphasizing the understanding of the destructive social processes determined by the transposition of São Francisco river and the perceptions of the Pipipã people about the relationship between health and disease. The research evidenced that the São Francisco river transposition made the Pipipã people materially and symbolically more vulnerable, created compulsorily new territorialities and vulnerabilities raising a threat to the processes of social reproduction of the Ethnic group.

Itinerários terapêuticos, cuidados e atendimento na construção de ideias sobre maternidade e infância no contexto da Zika / Itinerarios terapéuticos, cuidados y atención en la construcción de ideas sobre maternidad e infancia en el contexto del Zika / Therapeutic paths, care and assistance in the construction of ideas about maternity and childhood in the context of the Zika virus

Com pesquisa de campo etnográfico, seguimos itinerários terapêuticos de cuidadoras de filhos com Síndrome Congênita do Zika para compreender como diferentes contextos (descoberta, casa, unidades de saúde, assistência social, associações) contribuem para formar noções sobre maternidade e infância. O conceito de "conjunturas vitais" em ritos de passagem geracionais singulariza experiências que levam a estabilizações e/ou caminhos invertidos na passagem entre etapas. A construção prática e simbólica de maternidade e infância oscila entre uma multiplicidade de significados marcados pela obrigatoriedade de mulheres se empenharem na tarefa de cuidar, vivendo sofrimento e sacralização do cuidado, numa realidade cotidiana que amarra suas vidas a buscas de explicações causais e respostas terapêuticas diversas sem mudanças geracionais marcadas. Quem trilha esses itinerários terapêuticos constrói uma imagem multifacetada de si mesma em relação, direta ou indiretamente, à maternidade, à infância e à filiação biológica e social.(AU)

Con investigación de campo etnográfico seguimos itinerarios terapéuticos de cuidadoras de hijos con Síndrome congénito del zika para comprender cómo diferentes contextos (descubrimiento, casa, unidades de salud, asistencia social, asociaciones) contribuyen para formar nociones sobre maternidad e infancia. El concepto de "coyunturas vitales" en ritos de pasaje generacionales singulariza experiencias que llevan a estabilizaciones y/o caminos invertidos en el paso entre etapas. La construcción práctica y simbólica de maternidad e infancia oscila entre una multiplicidad de significados marcados por la obligatoriedad de que las mujeres se empeñen en la tarea de cuidar, viviendo el sufrimiento y la sacralización del cuidado, en una realidad cotidiana que amarra sus vidas a búsquedas de explicaciones causales y respuestas terapéuticas diversas sin cambios generacionales marcados. Quien recorre estos itinerarios terapéuticos construye una imagen multi-facetada de sí misma en relación, directa o indirectamente, a la maternidad, a la infancia y a la filiación biológica y social.(AU)

Based on an ethnographic field research, we followed the therapeutic paths of caregivers of children with the Zika congenital syndrome in order to understand the way different contexts (discovery, household, health units, social work, associations) contribute to creating notions about maternity and childhood. The concept of "vital conjunctures" in generational rites of passage singularizes experiences that lead to stabilization and/or inverted paths in the passage between stages. The practical and symbolic construction of maternity and childhood oscillates among a multiplicity of meanings marked by the obligatoriness of women to strive in the task of caring and experiencing suffering and care sacralization, in a daily reality that ties their lives to searches for causal explanations and diverse therapeutic answers without marked generational changes. Those who take these therapeutic paths build a multifaceted image of themselves in a direct or indirect relationship to maternity, childhood and their social and biological affiliation.(AU)

Causes of Death in a Contemporary Cohort of Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease: Insights From the TECOS Trial.

OBJECTIVE: We evaluated the specific causes of death and their associated risk factors in a contemporary cohort of patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD). RESEARCH DESIGN AND METHODS: We used data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study (n = 14,671), a cardiovascular (CV) safety trial adding sitagliptin versus placebo to usual care in patients with type 2 diabetes and ASCVD (median follow-up 3 years). An independent committee blinded to treatment assignment adjudicated each cause of death. Cox proportional hazards models were used to identify risk factors associated with each outcome. RESULTS: A total of 1,084 deaths were adjudicated as the following: 530 CV (1.2/100 patient-years [PY], 49% of deaths), 338 non-CV (0.77/100 PY, 31% of deaths), and 216 unknown (0.49/100 PY, 20% of deaths). The most common CV death was sudden death (n = 145, 27% of CV death) followed by acute myocardial infarction (MI)/stroke (n = 113 [MI n = 48, stroke n = 65], 21% of CV death) and heart failure (HF) (n = 63, 12% of CV death). The most common non-CV death was malignancy (n = 154, 46% of non-CV death). The risk of specific CV death subcategories was lower among patients with no baseline history of HF, including sudden death (hazard ratio [HR] 0.4; P = 0.0036), MI/stroke death (HR 0.47; P = 0.049), and HF death (HR 0.29; P = 0.0057). CONCLUSIONS: In this analysis of a contemporary cohort of patients with diabetes and ASCVD, sudden death was the most common subcategory of CV death. HF prevention may represent an avenue to reduce the risk of specific CV death subcategories.

PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the effect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder. METHODS: This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia, Asia, Europe, New Zealand, North America, and South Africa between Feb 7 and Dec 19, 2013. 331 eligible patients (18-80 years of age), who met clinical criteria for heterozygous familial hypercholesterolaemia and were on stable lipid-lowering therapy for at least 4 weeks, with a fasting LDL cholesterol concentration of 2·6 mmol/L or higher, were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks, evolocumab 420 mg monthly, or subcutaneous placebo every 2 weeks or monthly for 12 weeks. Randomisation was computer generated by the study sponsor, implemented by a computerised voice interactive system, and stratified by LDL cholesterol concentration at screening (higher or lower than 4·1 mmol/L) and by baseline ezetimibe use (yes/no). Patients, study personnel, investigators, and Amgen study staff were masked to treatment assignments within dosing frequency groups. The coprimary endpoints were percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01763918. FINDINGS: Of 415 screened patients, 331 were eligible and were randomly assigned to the four treatment groups: evolocumab 140 mg every 2 weeks (n=111), evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or placebo monthly (n=55). 329 patients received at least one dose of study drug. Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59·2% reduction [95% CI 53·4-65·1], monthly dose: 61·3% reduction [53·6-69·0]; both p<0·0001) and at the mean of weeks 10 and 12 (60·2% reduction [95% CI 54·5-65·8] and 65·6% reduction [59·8-71·3]; both p<0·0001). Evolocumab was well tolerated, with rates of adverse events similar to placebo. The most common adverse events occurring more frequently in the evolocumab-treated patients than in the placebo groups were nasopharyngitis (in 19 patients [9%] vs five [5%] in the placebo group) and muscle-related adverse events (ten patients [5%] vs 1 [1%]). INTERPRETATION: In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo. FUNDING: Amgen Inc.

Relationship between plasma coenzyme Q10, asymmetric dimethylarginine and arterial stiffness in patients with phenotypic or genotypic familial hypercholesterolemia on long-term statin therapy.

OBJECTIVE: We investigated whether statin-treated heterozygous familial hypercholesterolemic (FH) patients have lower plasma coenzyme Q(10) (CoQ(10)) levels than low-density lipoprotein receptor (LDLR) mutation negative FH patients on equivalent statin doses, and whether lower CoQ(10) concentrations are associated with increased arterial stiffness. METHODS: Thirty LDLR mutation negative patients with clinical FH and 30 mutation positive FH patients matched for gender, statin duration and dose, and a further 30 controls were studied. Plasma CoQ(10) and asymmetric dimethylarginine (ADMA) levels were measured by HPLC and the augmentation index by pulse wave analysis. RESULTS: Plasma CoQ(10) levels, and the ratios of CoQ(10) to total cholesterol and LDL-cholesterol were similar in treated FH patients with identified LDLR mutations to mutation negative patients on equivalent doses of statin therapy (p>0.05). CoQ(10) and lipid levels were also comparable to controls not using any lipid modifying treatment. Arterial stiffness was higher in mutation negative patients (p=0.04) and there was a trend for an increase in mutation positive patients (p=0.09). ADMA was higher in the mutation positive group (p<0.01). The augmentation index corrected for age, blood pressure, and heart rate, was negatively correlated with plasma CoQ(10) within FH patients (p<0.05). CONCLUSION: Long-term, high-dose statin therapy does not lead to subnormal CoQ(10) concentrations in patients with phenotypic or genotypic FH. Arterial stiffness is elevated in FH patients compared to untreated controls, and low CoQ(10) levels are associated with increased arterial stiffness. CoQ(10) supplementation trials are warranted in FH patients.

Consumption of a plant sterol-based spread derived from rice bran oil is effective at reducing plasma lipid levels in mildly hypercholesterolaemic individuals.

To establish the effectiveness of a new phytosterol-containing spread derived from rice bran oil (RBO), a randomised, double-blind, cross-over human clinical trial was conducted over 12 weeks. A total of eighty mildly hypercholesterolaemic (total blood cholesterol level ≥ 5 and ≤ 7·5 mmol/l with a serum TAG level of ≤ 4·5 mmol/l) individuals were randomised into two groups (n 40). Group 1 consumed spread only daily for 4 weeks. They were randomised to consume 20 g RBO spread (RBOS), 20 g standard spread (SS) or 20 g phytosterol-enriched spread (PS). After a 4-week period, individuals changed to the next randomised treatment until all three treatments had been consumed. Group 2 consumed spread plus oil daily for 4 weeks. They consumed 20 g RBOS plus 30 ml RBO, 20 g SS plus 30 ml sunflower oil or 20 g RBOS. Blood samples were collected for the analysis of lipid parameters, and 3 d diet records were collected. Compared with SS, RBOS significantly reduced total cholesterol by 2·2 % (P = 0·045), total cholesterol:HDL by 4·1 % (P = 0·005) and LDL-cholesterol by 3·5 % (P = 0·016), but was not as effective overall as PS, which reduced total cholesterol by 4·4 % (P = 0·001), total cholesterol:HDL by 3·4 % (P = 0·014) and LDL-cholesterol by 5·6 % (P = 0·001). In group 2, the addition of RBO to the RBOS produced no differences in cholesterol levels. These results confirm that RBOS is effective in lowering serum cholesterol when consumed as part of a normal diet.

The morbidity of Clostridium difficile infection after elective colonic resection-results from a national population database.

BACKGROUND: Clostridium difficile (CD), a gram-positive rod bacterium, resides normally within the human colon. Antibiotic treatment alters normal colonic flora, potentiating abnormal overgrowth of CD. METHODS: This study examined the 2004 to 2006 Nationwide Inpatient Sample to determine outcomes of CD colitis after 695,010 elective colonic resections. RESULTS: CD infection, occurring in 1.4% of patients, was associated with higher pulmonary (12.1% vs 6.4%) and gastrointestinal (12.8% vs 10.5%) complications as well as an increased length of stay (22.6 vs 10.9 days) and mortality (16.2% vs 4.9%; all P < .001). CD colitis patients more frequently held Medicare insurance (68% vs 51%) and underwent small segmental colonic resection as opposed to a defined anatomic resection (20.0% vs 9.9%; P < .001). An underlying diagnosis of colon cancer was associated with a lower incidence of CD colitis (odds ratio, .71; 95% confidence interval, .59-.84; P < .001). CONCLUSIONS: CD colitis is associated with worse outcomes after elective colonic resection.

Inter- and under-canopy soil water, leaf-level and whole-plant gas exchange dynamics of a semi-arid perennial C4 grass.

It is not clear if tree canopies in savanna ecosystems exert positive or negative effects on soil moisture, and how these might affect understory plant carbon balance. To address this, we quantified rooting-zone volumetric soil moisture (θ(25 cm)), plant size, leaf-level and whole-plant gas exchange of the bunchgrass, bush muhly (Muhlenbergia porteri), growing under and between mesquite (Prosopis velutina) in a southwestern US savanna. Across two contrasting monsoon seasons, bare soil θ(25 cm) was 1.0-2.5% lower in understory than in the intercanopy, and was consistently higher than in soils under grasses, where θ(25 cm) was similar between locations. Understory plants had smaller canopy areas and volumes with larger basal diameters than intercanopy plants. During an above-average monsoon, intercanopy and understory plants had similar seasonal light-saturated leaf-level photosynthesis (A(net-sat)), stomatal conductance (g(s-sat)), and whole-plant aboveground respiration (R(auto)), but with higher whole-plant photosynthesis (GEP(plant)) and transpiration (T(plant)) in intercanopy plants. During a below-average monsoon, intercanopy plants had higher diurnally integrated GEP(plant), R(auto), and T(plant). These findings showed little evidence of strong, direct positive canopy effects to soil moisture and attendant plant performance. Rather, it seems understory conditions foster competitive dominance by drought-tolerant species, and that positive and negative canopy effects on soil moisture and community and ecosystem processes depends on a suite of interacting biotic and abiotic factors.

Fibrates plus betaine: a winning combination?

Because most of the cardiac risk remains despite successful statin therapy there has been renewed interest in fibrate therapy for persisting hyperlipidaemia. Fibrate therapy lowers triglycerides but causes the urinary loss of betaine, which is an essential metabolite that is involved in osmoregulation, in methyl group metabolism, and which also affects lipid partitioning in the body. Loss of betaine is associated with an elevation of homocysteine and may compromise the potential benefits of fibrate therapy. However, betaine deficiency could be easily and inexpensively corrected by concurrent betaine supplementation. Clinical trials of combinations of betaine and fibrate, to complement statin therapy, are needed to determine the value of these agents in reducing the residual cardiovascular disease risk.

Growing season ecosystem and leaf-level gas exchange of an exotic and native semiarid bunchgrass.

The South African grass, Lehmann lovegrass (Eragrostis lehmanniana), may alter ecosystem processes across extensive semiarid grasslands and savannahs of western North America. We compared volumetric soil moisture (theta), total and green tissue leaf area index (LAI), ecosystem (i.e. whole-plant and soil), and leaf-level gas exchange of Lehmann lovegrass and the native bush muhly (Muhlenbergia porteri) over the 2008 monsoon season in a semiarid savanna in southern Arizona, USA, to see if these were consistent with high productivity associated with lovegrass invasive success. theta across 0-5 and 0-25 cm was higher while evapotranspiration (ET) was similar between lovegrass and bush muhly plots, except shortly after rainfall, when ET was 32-81% higher in lovegrass plots. Lehmann lovegrass had lower, quickly developing LAI with greater leaf proportions than bush muhly. When early season theta was high, net ecosystem CO(2) exchange (NEE) was similar, but as storm frequency and theta declined, NEE was more negative in lovegrass (-0.69 to -3.00 micromol m(-2) s(-1)) than bush muhly (+1.75 to -1.55 micromol m(-2) s(-1)). Ecosystem respiration (R (eco)) responded quickly to monsoon onset and late-season rains, and was lower in lovegrass (2.44-3.74 micromol m(-2) s(-1)) than bush muhly (3.60-5.3 micromol m(-2) s(-1)) across the season. Gross ecosystem photosynthesis (GEP) was greater in Lehmann lovegrass, concurrent with higher leaf-level photosynthesis and stomatal conductance. We conclude that canopy structure facilitates higher theta under Lehmann lovegrass, reducing phenological constraints and stomatal limitations to whole-plant carbon uptake through the short summer monsoon growing season.

Fibrates may cause an abnormal urinary betaine loss which is associated with elevations in plasma homocysteine.

PURPOSE: Betaine is an osmolyte, supplies methyl groups, and controls plasma homocysteine. Abnormal urinary loss of betaine is common in patients with the metabolic syndrome or diabetes mellitus. These patients are often treated with fibrates which alter renal function and raise plasma homocysteine concentrations. We suggest there is a connection between fibrate treatment and betaine excretion. METHODS: We identified 32 fibrate-treated patients in several studies (total of 740 subjects) and compared the betaine excretion by these with the excretion by other patients, both in the separate studies and in the combined group. We investigated the correlation of betaine excretion with homocysteine in these groups. RESULTS: Patients taking bezafibrate had higher betaine excretion than patients not taking fibrates, p < 0.00001 in some studies with n < 10. Of 32 patients taking bezafibrate, 20 had abnormal (>97.5 %-ile) betaine excretion. Plasma homocysteine correlated positively with betaine excretion in male patients with lipid disorders who were not taking fibrate (n = 68, p = 0.043), but the relationship was stronger if patients taking bezafibrate were included (n = 76, p < 0.00001). In elderly (>65 years) subjects with hypertension there was a similar correlation (n = 19, p = 0.047), which was stronger when a subject taking bezafibrate was included (n = 20, p = 0.013). CONCLUSIONS: Abnormal betaine excretion is common in patients treated with bezafibrate. Bezafibrate appears to exacerbate betaine loss, which will cause a rise in plasma homocysteine. Betaine supplementation could be considered in conjunction with fibrate therapy.

Quorum-sensing signal production by Agrobacterium vitis strains and their tumor-inducing and tartrate-catabolic plasmids.

Agrobacterium vitis strains, their tumor-inducing (pTi) and tartrate utilization (pTr) plasmid transconjugants and grapevine tumors were analyzed for the presence of N-acyl-homoserine lactones (AHLs). All wild-type A. vitis strains produced long-chain signals. PCR analysis of the A. vitis long-chain AHL synthase gene, avsI, showed the predicted amplicon. Agrobacterium tumefaciens UBAPF2 harboring various A. vitis pTi plasmids produced N-(3-oxo-octanoyl)-l-homoserine lactone encoded also by pTis of A. tumefaciens. UBAPF2 transconjugants carrying pTrs except for pTrTm4 and pTrAB3, also produced an AHL. UBAPF2 transconjugants carrying pTrAT6, pTrAB4 and pTrRr4 or pTiNi1 produced two additional AHLs not observed in the corresponding wild-type strains. We also provide evidence for in situ production of AHLs in grapevine crown gall tumors of greenhouse and field origin.

Adiponectin attenuates endothelial dysfunction induced by oxidised low-density lipoproteins.

We investigated whether the adipocytokine, adiponectin, protected the endothelium against damage induced by oxidised low-density lipoprotein cholesterol (oxLDL). Human umbilical vein endothelial cells were cultured with either 200 or 350 microg/ml oxLDL, with or without adiponectin purified from human serum (12 microg/ml). Cellular oxidative status was assessed by measuring reactive oxygen species (ROS), peroxynitrite and glutathione (GSH) levels, while cell function was evaluated by measuring nitric oxide (NO) levels and immunohistochemical examination of proteins in the adherens cell junction. At a concentration of 200 microg/ml, oxLDL induced a small increase in ROS and peroxynitrite levels, a two-fold increase in GSH levels and no changes in NO levels or localisation of proteins in the adherens junction. However, 350 microg/ml of oxLDL induced a marked increase in ROS and peroxynitrite levels, a four-fold reduction in GSH levels and a significant decrease in NO levels and disruption of the adherens junctions. Addition of adiponectin to the cultures resulted in maintenance of normal ROS, peroxynitrite and GSH levels, with no change in either NO levels or protein localisation in the adherens junction. This study demonstrates that adiponectin protects against endothelial dysfunction and cellular disruption induced by oxLDL, with this effect being due, in part, to maintenance of intracellular GSH levels.

Cause-specific mortality in insulin-treated diabetic patients: a 20-year follow-up.

BACKGROUND: Diabetes is one of the most common chronic diseases in Western populations. There have been few large published cohort studies of diabetes with 20 years of follow-up worldwide, and none other than the present one in NZ. AIMS: To establish cause-specific death rates, by age and sex in insulin-treated diabetic individuals living in Canterbury, NZ. METHODS: Insulin-treated diabetic subjects on the Canterbury Diabetes Registry were followed over 20 years and vital status determined. Following notification of deaths, age- and sex-specific mortality rates, and sex-specific mortality ratios (SMRs) were calculated. RESULTS: During follow-up 966 diabetic subjects contributed 13,495 person-years and 525 deaths occurred (261 females and 264 males). At all ages mortality rates were considerably higher than expected mortality. Relative mortalities were increased for cardiovascular (SMR women 3.73, 95% CI: 3.16-4.30; men 3.27, 95% CI: 2.76-3.78), renal (SMR women 5.55, 95% CI: 2.53-8.57; men 7.15, 95% CI: 3.40-10.90), respiratory disease (SMR women 3.31, 95% CI: 1.98-4.63; men 2.32, 95% CI: 1.41-3.23) and malignancy (SMR women 4.99, 95% CI: 2.99-6.99; men 2.19, 95% CI: 1.42-2.96) with cardiovascular disease accounting for the single greatest cause of excess death at all ages. CONCLUSIONS: Mortality rates for diabetic individuals remain high, resulting in shortened life spans relative to the general population. To reduce these death rates attention must be paid to the early detection and treatment of CVD and associated risk factors.

Comparison of plasma adiponectin levels in New Zealand Maori and Caucasian individuals.

AIMS: Adiponectin is an adipocytokine with insulin-sensitising and anti-atherosclerotic effects. Low plasma adiponectin levels are known to predispose to the development of Type 2 diabetes mellitus. Given the increased prevalence of Type 2 diabetes in the Maori population in New Zealand, we carried out a study to compare plasma adiponectin levels between non-diabetic Maori and Caucasian subjects. METHODS: Plasma adiponectin levels were measured in 111 pairs of non-diabetic Maori and Caucasian individuals, matched for gender, age (+/-6 years), body mass index (+/-4 kg/m2), waist circumference (+/-8 cm), and presence or absence of insulin resistance. Other data collected included anthropometric measurements, indices of glycaemic control and insulin sensitivity and plasma lipid profile. The data were analysed using paired t tests, Wilcoxon signed rank tests and correlation, and linear regression analyses. RESULTS: Statistical analysis showed the two ethnic groups were well matched with the exception of smoking habits, intercurrent medications, and clinically insignificant differences in HbA1C and total cholesterol levels. Mean plasma adiponectin levels were significantly lower in the Maori group compared with the Caucasian group (7.32+/-SD 4.02 mcg/ml vs 8.32+/-SD 4.15 mcg/ml; p=0.03). The prevalence of abnormally low plasma adiponectin levels (less than or equal to 4.0 mcg/ml) was two times higher in Maori than in Caucasians. The difference in mean plasma adiponectin levels of 1.0 mcg/ml between the two groups was relatively small and less than the normal biological variability for adiponectin measured in our laboratory. In both ethnic groups, there was a significant correlation between plasma adiponectin levels and gender and characteristics of the metabolic syndrome, but not with age, percentage body fat, or smoking habits. DISCUSSION: These results indicate that Maori people tend to have lower plasma adiponectin levels than Caucasian people of similar age, body shape, and insulin sensitivity. The reason(s) for this ethnic difference remain unclear, but may be related to differences in body composition or genetic control of adiponectin synthesis. Prospective studies are required to determine the etiological importance of these low adiponectin levels in the Maori population.