Structure-toxicity relationships of saturated and unsaturated free fatty acids for elucidating the lipotoxic effects in human EndoC-ßH1 beta-cells.

Lipotoxicity has been considered a major cause for beta-cell dysfunction in type 2 diabetes mellitus. However, the underlying mechanisms are still unclear. To achieve a better understanding of the toxicity a wide range of structurally different free fatty acids (FFAs) has been analyzed in human EndoC-ßH1 beta-cells. Exposure of human EndoC-ßH1 beta-cells to physiological saturated and monounsaturated long-chain FFAs induced apoptosis. Particularly noteworthy was that the toxicity increased more rapidly with increasing chain length of saturated than of unsaturated FFAs. The highest toxicity was observed in the presence of very long-chain FFAs (C20-C22), whereas polyunsaturated FFAs were not toxic. Long-chain FFAs increased peroxisomal hydrogen peroxide generation slightly, while very long-chain FFAs increased hydrogen peroxide generation more potently in both peroxisomes and mitochondria. The greater toxicity of very long-chain FFAs was accompanied by hydroxyl radical formation, along with cardiolipin peroxidation and ATP depletion. Intriguingly, only saturated very long-chain FFAs activated ER stress. On the other hand saturated very long-chain FFAs did not induce lipid droplet formation in contrast to long-chain FFAs and unsaturated very long-chain FFAs. The present data highlight the importance of structure-activity relationship analyses for the understanding of the mechanisms of lipotoxicity. Chain length and degree of saturation of FFAs are crucial factors for the toxicity of FFAs, with peroxisomal, mitochondrial, and ER stress representing the major pathogenic factors for induction of lipotoxicity. The results might provide a guide for the composition of a healthy beta-cell protective diet.

The monounsaturated fatty acid oleate is the major physiological toxic free fatty acid for human beta cells.

Free fatty acids (FFAs) can cause glucose intolerance and diabetes. Lipotoxicity to the pancreatic beta cells is considered to be a major underlying cause for this phenomenon. The aim of this study was to analyse the toxicity profile of FFAs in the human EndoC-ßH1 beta-cell line and to compare the results with isolated rat and human islets with special reference to the physiologically most prevalent FFAs palmitic acid (PA) and oleic acid (OA). Toxicity after a 2-day incubation with the different FFAs was analysed by the caspase-3 assay and confirmed by the propidium iodide and annexin V staining tests. The long-chain saturated PA (C16:0) and the monounsaturated OA (C18:1) were both toxic to human EndoC-ßH1 beta cells and pseudoislets, as well as to rat islets, and, as confirmed in a pilot experiment, also to human islets. Furthermore, OA provided no protection against the toxicity of PA. Likewise, elaidic acid (EA, the trans isomer of OA; trans-OA) was significantly toxic, in contrast to the non-metabolisable analogues methylated PA (MePA) and methylated OA (MeOA). Fatty acids with a chain length < C16 were not toxic in EndoC-ßH1 beta cells. Caspase-3 was also activated by linoleic acid (LA)(C18:2) but not by γ-linolenic acid (γ-LNA)(C18:3). Overall, only long-chain FFAs with chain lengths > C14, which generate hydrogen peroxide in the peroxisomal beta-oxidation, were toxic. This conclusion is also supported by the toxicity of the branched-chain FFA pristanic acid, which is exclusively metabolised in the peroxisomal beta-oxidation. The lack of a protective effect of the monounsaturated fatty acid OA has important consequences for a beta-cell protective lipid composition of a diet. A cardioprotective diet with a high OA content does not fulfil this requirement.

[Specialized home care of medical diseases in an urban tertiary university hospital. Coordination between the medical services of the hospital and the primary health care]. / Atención especializada domiciliaria de patologías médicas desde un hospital universitario terciario urbano. Coordinación entre los servicios médicos del hospital y la Atención Primaria de salud del territorio.

INTRODUCTION: The experience of an urban Tertiary University Hospital in the design and implementation of Hospital at Home Program (HaHP) integrated in a Department of Internal Medicine and highly coordinated with Medical Services of the Hospital and the Primary Health Care, that contemplates the like main objectives of the promotion of specialized home care medical diseases and the improvement of the coordination with the primary health care. PATIENTS AND METHOD: Systematic collection in all the patients admitted between April 2006 and March 2007 in the HaHP of the following variables: age, gender, service of origin, main diagnosis, Barthel and Charlson index, number of visits per day to doctors and nurses, destination on discharge and medical team. The descriptive statistical analysis was made in April 2007. The results are presented globally and differentiated by teams (internal medicine, respiratory and nutritional support teams). RESULTS: 506 admissions in 390 patients with a mean age of 66.5 (18) years, 53% being women. The Charlson index was 2 (2.2) and the Barthel index 63.5 (40,4). Average stay was 7.9 (8.2) days. The main reasons for admission were the infections and domiciliary intravenous antibiotic therapy in 153 (30.5%) cases, followed by patients with chronic obstructive pulmonary disease or cardiac failure in 107 (21%) cases, and home enteral and parenteral nutrition in 102 (20%) cases. Two hundred (39.5) patients were subsequently controlled by their primary care team after discharger, 241 (47.5) patients were followed-up in the hospital consultations, and 45 (9%) of the patients had to return directly to the hospital. CONCLUSIONS: The creation of a HaHP, for medical diseases, in internal medicine department that is highly coordinated with medical services of the hospital, especially with emergency, respiratory, and nutritional support teams, and with the primary health care, facilitates specialized home care of medical diseases and improves coordination with the primary health care.

Safety and efficacy of home intravenous antimicrobial infusion therapy in older patients: a comparative study with younger patients.

BACKGROUND: Home intravenous antimicrobial infusion therapy has proved its safety and efficacy in a great number of infections. Despite this there are few published studies about this way of managing in the elderly patient. OBJECTIVE: To study the safety and efficacy of home intravenous antimicrobial infusion therapy in elderly patients. STUDY DESIGN: A prospective and comparative study of an elderly group of patients > or =70 years old vs. a cohort of younger adult patients as a control group. All patients were followed until 3 months after discharge. SETTING: Hospital at Home Programme (HHP) as part of the Internal Medicine Department at Valle de Hebrón Hospital, Barcelona, Spain. PATIENTS: All patients admitted to HHP diagnosed of infections requiring intravenous antibiotic therapy between March 2006 and March 2007. RESULTS: We included 145 patients, 90 of whom were 70 years or older. Diabetes mellitus, heart failure and respiratory tract infection were more frequent in these elderly patients. In this group 14 (12%) developed some type of adverse event during treatment, phlebitis being the most common. The majority of those in the elderly patients group were discharged because of satisfactory clinical evolution and only 7 (7%) were re-admitted to hospital. Another 13 (14%) were re-admitted to hospital 3 months after discharge from HHP, mostly for chronic diseases. There were no significant differences between these results and those obtained from the control group. CONCLUSION: Home intravenous antimicrobial infusion therapy in elderly patients is safe and effective.

[Fast specialized ambulatory care of medical disease in an urban tertiary university hospital. Fast care consultation]. / Atención especializada ambulatoria rápidade patologías médicas desde un hospital universitario terciario. Consulta de atención inmediata.

INTRODUCTION: The experience of an urban tertiary university hospital in the design and establishment of Specialized Ambulatory Consultation (SAC) of Internal Medicine is presented. The purpose of this consultation is fast specialized ambulatory care of medical diseases, decrease of inappropriate hospitalizations and improvement of coordination with primary health care. PATIENTS AND METHOD: Systematic collection of the following variables in all the patients who visited the SAC between March 2006 and February 2007: origin, syndromic diagnosis and reason for consultation, age and gender, number of visits, examinations made, and destination on discharge. The descriptive statistical analysis was made in March 2007. RESULTS: A total of 744 patients with 1248 visits were seen (successive/first ratio of 0.67). Mean age was 62.56 (18.6) years and 50.6% were women. The hospital origin/primary origin went from 3.5 - 4 in the first quarter to between 2.6 - 2.8 in the last quarter. The main reasons for consultation due to patient with constitutional or anemic syndromes with suspicion of serious disease and patients with decompensation of chronic diseases or infectious disease. Half of the patients returned to primary care and the rest were distributed among different hospital resources. It stands out that 30% were sent to the hospital consultations and 10% required hospitalization or transfer to the emergency room. CONCLUSIONS: The SAC is a Fast Consultation Care (diagnosis and treatment) of general internal medicine located in a tertiary university hospital with a good capacity of resolution. It facilitates Specialized Ambulatory Care of medical diseases, decreasing inappropriate hospitalization and improving coordination with the Primary Health Care.

Impact of a harm-reduction policy on HIV and hepatitis C virus transmission among drug users: recent French data--the ANRS-Coquelicot Study.

In France a harm-reduction policy was implemented in the late 1980s with the aim of reducing the prevalence of HIV and hepatitis C virus (HCV) infection among drug users. The ANRS-Coquelicot survey was designed to measure the prevalence of HIV and HCV infection among drug users and to examine determinants of at-risk behaviors. In 2002, information was collected from 166 drug users recruited in all types of services specializing in drug use intervention and harm reduction in Marseille, France. Self-reported HIV and HCV serostatus was compared with the results of serological tests done on capillary blood collected on filter paper. The self-reported and biologically documented prevalence rates of HIV infection were identical (22%). In contrast, the self-reported prevalence of HCV infection was 52%, whereas the biologically documented prevalence was 73%. Overall, 30% of HCV-infected drug users were unaware of their status. Forty-four percent of drug users under 30 years of age were HCV seropositive, suggesting that they had been infected early during drug use. The harm-reduction policy seems to have had a marked impact on HIV transmission among drug users but a much more limited impact on HCV transmission. The limitations and implications of the study are discussed.

The economic burden of disabling hip and knee osteoarthritis (OA) from the perspective of individuals living with this condition.

OBJECTIVE: To estimate the direct and indirect arthritis-attributable costs to individuals with disabling hip and/or knee osteoarthritis (OA). METHODS: An established population cohort with disabling hip and/or knee OA from two regions of Ontario, Canada was surveyed to determine participant and caregiver costs related to OA, and the predictors of these costs. RESULTS: The response rate was 87.2%. Of 1378 respondents, 1258 had OA (mean age 73.1 yr, range 59-100). Sixty per cent (n = 758) reported OA-related costs. Among these individuals, the average annual cost was 12,200 dollars(CDN dollars in 2002, where 1.00 CDN dollar approximately 0.81 US dollar). Time lost from employment and leisure by participants and their unpaid caregivers accounted for 80% of the total. Men were less likely than women to report costs (adjusted odds ratio 0.54, P < 0.0001), but when they did their expenditures were significantly higher (P = 0.004). Greater disability was associated with higher costs: compared with individuals with WOMAC total scores <15, those with scores > or = 55 were 15 times more likely to report costs, and their costs were 3 times greater (both P < 0.0001). Both the young (<65 yr) and very old were more likely to incur costs (P < 0.0001), and when they did their costs were higher (P < 0.001). CONCLUSION: Costs incurred were mainly for time lost from employment and leisure, and for unpaid informal caregivers. Failure to value such indirect costs significantly underestimates the true burden of OA. Costs increased with worsening health status and greater OA severity. After adjustment, men were less likely to incur costs, possibly due to greater social resources.

[Geriatric physical performance assessment in an emergency department]. / Valoración geriátrica de la función física en un Servicio de Urgencias.

BASIS: Premorbid situation with regard to daily life activities is an important prognostic factor in elderly people who needs medical care. This work analyzes the way the parameter evaluation of core processes of daily life (CPDL) is made in patients over 70 years cared in an Emergency Service because of diverse medical conditions. PATIENTS AND METHODS: A prospective study, carried out in a third level medical institution, on 200 patients over 70 years cared in the Emergency medical Service, with questioning a group of 60 physicians on duty (POD) about the informal or subjective assessments of five parameters of CPDL (to get dressed, to be fed, sphincter control, walking, and transfer). POD evaluation is compared with evaluation carried out formally by the research physician. Assessments are evaluated, grouping the patients according to the degree of dependency, age, or sex. RESULTS: 82% of most dependent patients and 53% of those older than 80 years were poorly assessed, and both parameters were statistically significant. The analysis with multiple linear regression showed that the intensity of these errors is only determined by a variable: the greater degree of dependency. CONCLUSIONS: Correct performance assessment of elderly patients in emergency services, especially of those older and most dependent, requires a specific training of professionals in this regard and the use of formal instruments of evaluation.

[Predictors factors about functional decline in community-dwelling older persons]. / Factores predictores del deterioro funcional geriátrico.

OBJECTIVES: The goal of this work was to prove the usefulness of simple standard geriatrics tools as a predictors of basic daily activities or quality of life decline in one year in older patients apparent healthy to apply in primary care. DESIGN: Prospective study of a randomised sample of 100 patients. SETTING: Urban primary care center. PATIENTS: A systematic sample of 100 patients of 75 years old or older, with Barthel index > or =90, Karnofsky scale > or =70 and without any neoformation process evaluated prospectively. MEASUREMENTS: A comprehensive geriatric assessment was done that include: physical performance, neural-psychologist performance, organic assessment, social assessment. After 12 month were assessed again basic activities of daily living (Barthel) and quality of life (Karnofsky). To estimate the odds ratio (OR) of association we used logistic regression models. RESULTS: The alterations in cognition trials (Pfeiffer >2) and in instrumental activities of daily living (Lawton <7) showed predictors about decline in basic activities of daily living (OR=4.66; CI, 1.33-16.22), (OR=4.89; CI, 1.65-14.48). The alterations in instrumental activities of daily living (Lawton <7) and in performance tests (abbreviated Guralnik test <4) showed predictors about decline in quality of life (OR=4.31; CI, 1.62-11.44), (OR=7.41; CI, 1.54-35.62). CONCLUSION: In primary care geriatric assessment tools based in instrumental activities of daily living, cognition and performance tests predict decline in basic activities of daily living and quality of life.

Altered regulation of the 5-HT system in the brain of MAO-A knock-out mice.

Genetic deficiency of monoamine oxidase-A (MAO-A) induces major alterations of mood and behaviour in human. Because serotonin (5-HT) is involved in mood regulation, and MAO-A is responsible for the catabolism of 5-HT, we investigated 5-HT mechanisms in knock-out mice (2-month-old) lacking MAO-A, using microdialysis, electrophysiological, autoradiographic and molecular biology approaches. Compared to paired wild-type mice, basal extracellular 5-HT levels were increased in ventral hippocampus (+202%), frontal cortex (+96%) and dorsal raphe nucleus (DRN, +147%) of MAO-A mutant mice. Conversely, spontaneous firing rate of 5-HT neurons in the DRN (recorded under chloral hydrate anaesthesia) was approximately 40% lower in mutants. Acute 5-HT reuptake blockade by citalopram (0.2 and 0.8 mg/kg i.v.) produced a much larger increase in extracellular 5-HT levels (by approximately 4 fold) and decrease in DRN neuronal firing (with a approximately 4.5 fold decrease in the drug's ED50) in MAO-A knock-out mice, which expressed lower levels of the 5-HT transporter throughout the brain (-13 to -34% compared to wild-type levels). The potency of the 5-HT1A agonist 8-OH-DPAT to produce hypothermia and to reduce the firing of DRN serotoninergic neurons was significantly less in the mutants, indicating a desensitization of 5-HT1A autoreceptors. This was associated with a decreased autoradiographic labelling of these receptors (-27%) in the DRN. Altogether, these data indicate that, in MAO-A knock-out mice, the enhancement of extracellular 5-HT levels induces a down-regulation of the 5-HT transporter, and a desensitization of 5-HT1A autoreceptors which allows the maintenance of tonic activity of 5-HT neurons in the DRN.

A new decline in preventive behaviours among homosexual men : the role of highly active antiretroviral therapy?

The articles published in this issue of Eurosurveillance on recent trends of preventive behaviours in homosexual men in Spain, Switzerland, and the Netherlands, all conclude that the practice of safer sex is declining. They emphasise increases in anal penetration (regardless of the nature of the relationship), non-protected anal intercourse, and ejaculation in the mouth, in particular among casual partners. The increase of diagnoses of acute sexually transmitted diseases (such as gonorrhoea and syphilis) in different European countries - illustrated in this issue by the data from the Netherlands - is the first tangible consequence of this decline.

Muscarinic and PACAP receptor interactions at pontine level in the rat: significance for REM sleep regulation.

Cholinergic and PACAPergic systems within the oral pontine reticular nucleus (PnO) play a critical role in REM sleep generation in rats. In this present work, we have investigated whether REM sleep enhancement induced by carbachol (a cholinergic agonist) or PACAP, depends on an interaction between muscarinic and PACAP receptors. This hypothesis was tested by recording sleep-wake cycles in freely moving rats injected into the PnO with PACAP in combination with the muscarinic receptor antagonist atropine, or with carbachol in combination with the PACAP receptor antagonist PACAP6-27. When administered alone, PACAP (3 pmol) or carbachol (110 pmol) induced an enhancement of REM sleep during 8 h (+61%, n = 8; +70%, n = 5), which was totally prevented by infusion of atropine (290 pmol) for PACAP, or of PACAP6-27 (3 pmol) for carbachol. Quantitative autoradiographic studies indicated that (i) PACAP (10-9-10-7 M) induced in the PnO an increase (+35%) of the specific binding of the muscarinic antagonist [3H]quinuclidinyl benzylate, which could be completely prevented by PACAP6-27 (IC50 = 8 x 10-8 M) and (ii) both carbachol and PACAP enhanced [35S]GTP-gamma-S binding in a concentration-dependent manner in the PnO. The maximal increase due to carbachol was significantly higher in the presence (+126%) than in the absence (+102%) of PACAP (0.1 microM). These data showed that interactions between muscarinic and PACAP receptors do exist within the PnO and play a role in the local mechanisms of REM sleep control in the rat.

[The risk factors for Clostridium difficile infection in elderly patients. A case-control study]. / Factores de riesgo de infección por Clostridium difficile en pacientes ancianos. Estudio de casos y controles.

BACKGROUND: To study the main risk factors associated with Clostridium difficile infection in a geriatric unit. PATIENTS AND METHOD: Retrospective case-control study. RESULTS: In a multivariate analysis, tube feeding (OR = 6.73; IC 95%, 1.01-45.35) and length of antibiotic therapy (OR = 1.15; IC, 95% 1.01-1.28) were independent variables which associated with C. difficile infection. CONCLUSIONS: Antibiotic treatment, tube feeding and fragility are associated with C. difficile infection.