Wilson Jacob-Filho

Adverse drug reactions in an elderly hospitalised population : Inappropriate prescription is a leading cause

ObjectiveAdverse drug reactions (ADRs) represent a major public health problem in the aged. In order to better evaluate this problem in Brazil, this study was designed to assess the prevalence of ADRs in an elderly hospitalised population, identify the most common ADRs and the principal medications involved, evaluate the appropriateness of use of these drugs in elderly people and determine the risk factors implicated in the appearance of such ADRs.MethodsThe study population was comprised of 186 elderly patients (≤60 years of age) admitted to the internal medicine service of a teaching hospital. The patients were assessed by a single observer using an intensive drug surveillance method to identify and report ADRs. The degree of probability for each adverse reaction was determined using the Naranjo algorithm.ResultsThe mean (± SD) age of the patients studied was 73.6 ± 9.1 years. Up to 115 patients (61.8%) of the study population presented at least one ADR. A total of 199 ADRs were found, at an average of 1.7 per patient. The ADRs appeared during hospitalisation in 46.2% of the study population, were present at the time of the admission but did not cause hospitalisation in 17.2% of patients, and were the cause of admission in 11.3% of patients. The most frequent ADR that caused hospitalisation was digitalis toxicity (22.7% of such ADRs). Hypokalaemia as a result of diuretics was the most prevalent ADR both during hospitalisation (11.8%) and at the time of admission without being the cause (12.1%). Captopril was the most frequently prescribed drug (138 prescriptions), and led to an ADR in 18.1% of patients who received the drug. Almost a quarter of the patients presenting an ADR were prescribed drugs considered inappropriate for the elderly. By means of a multiple logistic regression model, the following were considered to be significant risk factors for the appearance of ADRs: number of diagnoses (odds ratio [OR] 1.40; 95% CI 1.06, 1.86), number of drugs (OR 1.07; 95% CI 1.01, 1.13) and use of drug that is inappropriate for the elderly (OR 2.32; 95% CI 1.17, 4.59).DiscussionThe main contribution of the present study was identification of use of drugs that are considered inappropriate for elderly populations as a major risk factor for presenting an ADR. This finding is useful for continuous education programmes, therapeutic committees and policy makers, because adverse effects complicate the course of diseases in aged patients, cause hospitalisation and/or require the prescription of additional drugs. In addition to contributing to a reduction in healthcare costs, continuous efforts to promote rational drug use could also benefit elderly patients by preventing some avoidable drug toxicity.ConclusionA significant prevalence of ADRs was found among hospitalised elderly people. The risk factors associated with ADRs in this population included use of drugs considered to be inappropriate for that population, number of previous diagnoses and number of administered drugs. More appropriate drug prescription could avoid part of this burden of disease by minimising preventable ADRs.

The dorsal raphe nucleus shows phospho-tau neurofibrillary changes before the transentorhinal region in Alzheimer's disease. A precocious onset?

Aims: Alzheimers disease (AD) is a progressive and irreversible disease. There is strong evidence that the progression of the phospho‐tau neurofibrillary cytoskeletal changes, rather than the β‐amyloid burden, is crucial in determining the severity of the dementia in AD. The Braak and Braak staging system (BB) focuses mainly on the cortical cytoskeletal pathology and classifies this progressive pathology into six stages, spreading from the transentorhinal region to primary cortices. Although it is reported elsewhere that the midbrains dorsal raphe nucleus (DR), which is connected with those areas of the cerebral cortex undergoing early changes during BB I and II, exhibits AD‐related cytoskeletal pathology, this nucleus has not been considered by the BB. Methods: To determine during which BB stage and how frequently the DR is affected by AD‐related neurofibrillary changes, we studied the DR of 118 well‐characterized individuals of the Brain Bank of the Brazilian Aging Brain Study Group categorized according to the BB. Thirty‐eight of these individuals were staged as BB = 0, and 80 as BB ≥ 1. Results: In all of the BB ≥ 1 individuals (cortical neurofibrillary changes were present at least in the transentorhinal region) and in more than 1/5 of the BB = 0 individuals neurofibrillary changes were detected in the supratrochlear subnucleus of the DR. Conclusions: These observations: (i) support the hypothesis of transneuronal spread of neurofibrillary changes from the DR to its interconnected cortical brain areas; and (ii) indicate that the supratrochlear subnucleus of the DR is affected by neurofibrillary changes before the transentorhinal cortex during the disease process underlying AD.

Effects of Aerobic Training on Airway Inflammation in Asthmatic Patients

PURPOSE there is evidence suggesting that physical activity has anti-inflammatory effects in many chronic diseases; however, the role of exercise in airway inflammation in asthma is poorly understood. We aimed to evaluate the effects of an aerobic training program on eosinophil inflammation (primary aim) and nitric oxide (secondary aim) in patients with moderate or severe persistent asthma. METHODS sixty-eight patients randomly assigned to either control (CG) or aerobic training (TG) groups were studied during the period between medical consultations. Patients in the CG (educational program + breathing exercises; N = 34) and TG (educational program + breathing exercises + aerobic training; N = 34) were examined twice a week during a 3-month period. Before and after the intervention, patients underwent induced sputum, fractional exhaled nitric oxide (FeNO), pulmonary function, and cardiopulmonary exercise testing. Asthma symptom-free days were quantified monthly, and asthma exacerbation was monitored during 3 months of intervention. RESULTS at 3 months, decreases in the total and eosinophil cell counts in induced sputum (P = 0.004) and in the levels of FeNO (P = 0.009) were observed after intervention only in the TG. The number of asthma symptom-free days and VO(2max) also significantly improved (P < 0.001), and lower asthma exacerbation occurred in the TG (P < 0.01). In addition, the TG presented a strong positive relationship between baseline FeNO and eosinophil counts as well as their improvement after training (r = 0.77 and r = 0.9, respectively). CONCLUSIONS aerobic training reduces sputum eosinophil and FeNO in patients with moderate or severe asthma, and these benefits were more significant in subjects with higher levels of inflammation. These results suggest that aerobic training might be useful as an adjuvant therapy in asthmatic patients under optimized medical treatment.

Nutritional status of selenium in Alzheimer's disease patients

Studies have shown that various antioxidants are decreased in different age-related degenerative diseases and thus, oxidative stress would have a central role in the pathogenesis of many disorders that involve neuronal degeneration, including Alzheimers disease (AD). The present study aimed to assess the nutritional status of Se in AD patients and to compare with control subjects with normal cognitive function. The case-control study was carried out on a group of elderly with AD (n 28) and compared with a control group (n 29), both aged between 60 and 89 years. Se intake was evaluated by using a 3-d dietary food record. Se was evaluated in plasma, erythrocytes and nails by using the method of hydride generation atomic absorption spectroscopy. Deficient Se intake was largely observed in the AD group. AD patients showed significantly lower Se levels in plasma, erythrocytes and nails (32.59 microg/l, 43.74 microg/l and 0.302 microg/g) when compared with the control group (50.99 microg/l, 79.16 microg/l and 0.400 microg/g). The results allowed us to suggest that AD has an important relation with Se deficiency.

Cell number changes in Alzheimer's disease relate to dementia, not to plaques and tangles.

Alzheimers disease is the commonest cause of dementia in the elderly, but its pathological determinants are still debated. Amyloid-β plaques and neurofibrillary tangles have been implicated either directly as disruptors of neural function, or indirectly by precipitating neuronal death and thus causing a reduction in neuronal number. Alternatively, the initial cognitive decline has been attributed to subtle intracellular events caused by amyloid-β oligomers, resulting in dementia after massive synaptic dysfunction followed by neuronal degeneration and death. To investigate whether Alzheimers disease is associated with changes in the absolute cell numbers of ageing brains, we used the isotropic fractionator, a novel technique designed to determine the absolute cellular composition of brain regions. We investigated whether plaques and tangles are associated with neuronal loss, or whether it is dementia that relates to changes of absolute cell composition, by comparing cell numbers in brains of patients severely demented with those of asymptomatic individuals-both groups histopathologically diagnosed as Alzheimers-and normal subjects with no pathological signs of the disease. We found a great reduction of neuronal numbers in the hippocampus and cerebral cortex of demented patients with Alzheimers disease, but not in asymptomatic subjects with Alzheimers disease. We concluded that neuronal loss is associated with dementia and not the presence of plaques and tangles, which may explain why subjects with histopathological features of Alzheimers disease can be asymptomatic; and exclude amyloid-β deposits as causes for the reduction of neuronal numbers in the brain. We found an increase of non-neuronal cell numbers in the cerebral cortex and subcortical white matter of demented patients with Alzheimers disease when compared with asymptomatic subjects with Alzheimers disease and control subjects, suggesting a reactive glial cell response in the former that may be related to the symptoms they present.

Progressive resistance training in elderly hiv-positive patients: does it work?

BACKGROUND Elderly people present alterations in body composition and physical fitness, compromising their quality of life. Chronic diseases, including HIV/AIDS, worsen this situation. Resistance exercises are prescribed to improve fitness and promote healthier and independent aging. Recovery of strength and physical fitness is the goal of exercise in AIDS wasting syndrome. OBJECTIVE This study describes a case series of HIV-positive elderly patients who participated in a progressive resistance training program and evaluates their body composition, muscular strength, physical fitness and the evolution of CD4+ and CD8+ cell counts. METHODS Subjects were prospectively recruited for nine months. The training program consisted of three sets of 8–12 repetitions of leg press, seated row, lumbar extension and chest press, performed with free weight machines hts, twice/week for one year. Infectious disease physicians followed patients and reported all relevant clinical data. Body composition was assessed by anthropometric measures and dual-energy x-ray absorptiometry before and after the training program. RESULTS Fourteen patients, aged 62–71 years old, of both genders, without regular physical activity who had an average of nine years of HIV/AIDS history were enrolled. The strengths of major muscle groups increased (74%–122%, p=0.003–0.021) with a corresponding improvement in sit-standing and walking 2.4 m tests (p=0.003). There were no changes in clinical conditions and body composition measures, but triceps and thigh skinfolds were significantly reduced (p=0.037). In addition, there were significant increases in the CD4+ counts (N=151 cells; p=0.008) and the CD4+/CD8+ ratio (0.63 to 0.81, p=0.009). CONCLUSION Resistance training increased strength, improved physical fitness, reduced upper and lower limb skinfolds, and were associated with an improvement in the CD4+ and CD4+/CD8+ counts in HIV positive elderly patients without significant side effects.

Predictors of in-hospital mortality among older patients

OBJECTIVE: The objective of this study was to determine predictors of in-hospital mortality among older patients admitted to a geriatric care unit. INTRODUCTION: The growing number of older individuals among hospitalized patients demands a thorough investigation of the factors that contribute to their mortality. METHODS: This was a prospective observational study implemented from February 2004 to October 2007 in a tertiary university hospital. A consecutive sample of 922 patients was evaluated for possible inclusion in this study. Patients hospitalized for palliative care, those who declined to participate, and those with incomplete data were excluded, resulting in a group of 856 patients aged 60 to 104 years. Bivariate and multivariate analyses were performed to determine associations between in-patient mortality and gender, age, length of stay, number of prescribed medications and diagnoses at admission, history of heart failure, neoplastic disease, immobility syndrome, delirium, infectious disease, and laboratory tests at admission (serum albumin and creatinine). RESULTS: The overall mortality rate was 16.4%. The following factors were associated with higher in-hospital mortality: delirium (OR=4.13, CI=2.65–6.44, P<.001), neoplastic disease (OR=3.38, CI=2.11–5.42, P<.001), serum albumin levels at admission <3.3mg/dL (OR=3.23, CI=2.03–5.13, P<.001), serum creatinine levels at admission ≥ 1.3mg/dL (OR=2.39, CI=1.53–3.72, P<.001), history of heart failure (OR=1.97, CI=1.20–3.22, P=.007), immobility (OR=1.84, CI=1.16–2.92, P =.009), and advanced age (OR=1.03, CI=1.01–1.06, P=.019). CONCLUSIONS: This study strengthens the perception of delirium as a mortality predictor among older inpatients. Cancer, immobility, low albumin levels, elevated creatinine levels, history of heart failure and advanced age were also related to higher mortality rates in this population.

d-serine levels in Alzheimer's disease: implications for novel biomarker development.

Alzheimer’s disease (AD) is a severe neurodegenerative disorder still in search of effective methods of diagnosis. Altered levels of the NMDA receptor co-agonist, d-serine, have been associated with neurological disorders, including schizophrenia and epilepsy. However, whether d-serine levels are deregulated in AD remains elusive. Here, we first measured D-serine levels in post-mortem hippocampal and cortical samples from nondemented subjects (n=8) and AD patients (n=14). We next determined d-serine levels in experimental models of AD, including wild-type rats and mice that received intracerebroventricular injections of amyloid-β oligomers, and APP/PS1 transgenic mice. Finally, we assessed d-serine levels in the cerebrospinal fluid (CSF) of 21 patients with a diagnosis of probable AD, as compared with patients with normal pressure hydrocephalus (n=9), major depression (n=9) and healthy controls (n=10), and results were contrasted with CSF amyloid-β/tau AD biomarkers. d-serine levels were higher in the hippocampus and parietal cortex of AD patients than in control subjects. Levels of both d-serine and serine racemase, the enzyme responsible for d-serine production, were elevated in experimental models of AD. Significantly, d-serine levels were higher in the CSF of probable AD patients than in non-cognitively impaired subject groups. Combining d-serine levels to the amyloid/tau index remarkably increased the sensitivity and specificity of diagnosis of probable AD in our cohort. Our results show that increased brain and CSF d-serine levels are associated with AD. CSF d-serine levels discriminated between nondemented and AD patients in our cohort and might constitute a novel candidate biomarker for early AD diagnosis.

Effect of progressive resistance exercise on strength evolution of elderly patients living with HIV compared to healthy controls

OBJECTIVES: Human Immunodeficiency Virus (HIV) infection worsens the frailty of elderly people, compromising their quality of life. In this study we prospectively evaluated eleven patients living with HIV and 21 controls older than 60 years and without prior regular physical activity, who engaged in a one-year progressive resistance exercise program to compare its effects on muscular strength, physical fitness and body composition. METHODS: Exercises for major muscular groups were performed 2 times/week, under professional supervision. Strength increase was evaluated bimonthly, while body composition, lipid and glycaemic profiles (only of those living with HIV) and physical fitness were evaluated before and after the one-year training. RESULTS: The participants living with HIV were lighter, had smaller Body Mass Index and were initially much weaker than controls. However, their strength increased more (1.52-2.33 times the baseline values for those living with HIV x 1.21-1.48 times for controls, p<0.01), nullifying the differences initially seen. These effects were seen independently of gender, age or baseline physical activity. In addition, those living with HIV improved their fasting glucose levels and showed a tendency to improve their lipids after the one year training program. These effects were slightly more pronounced among those not using protease inhibitors, although not significantly. CONCLUSIONS: Resistance exercise safely increased the strength of older patients living with HIV adults, allowing them to achieve performance levels observed among otherwise healthy controls. These findings favor the recommendation of resistance exercise for elderly adults living with HIV adults.

Repair of oxidative DNA damage, cell-cycle regulation and neuronal death may influence the clinical manifestation of Alzheimer's disease.

Alzheimer’s disease (AD) is characterized by progressive cognitive decline associated with a featured neuropathology (neuritic plaques and neurofibrillary tangles). Several studies have implicated oxidative damage to DNA, DNA repair, and altered cell-cycle regulation in addition to cell death in AD post-mitotic neurons. However, there is a lack of studies that systematically assess those biological processes in patients with AD neuropathology but with no evidence of cognitive impairment. We evaluated markers of oxidative DNA damage (8-OHdG, H2AX), DNA repair (p53, BRCA1, PTEN), and cell-cycle (Cdk1, Cdk4, Cdk5, Cyclin B1, Cyclin D1, p27Kip1, phospho-Rb and E2F1) through immunohistochemistry and cell death through TUNEL in autopsy hippocampal tissue samples arrayed in a tissue microarray (TMA) composed of three groups: I) “clinical-pathological AD” (CP-AD) - subjects with neuropathological AD (Braak≥IV and CERAD = B or C) and clinical dementia (CDR≥2, IQCODE>3.8); II) “pathological AD” (P-AD) - subjects with neuropathological AD (Braak≥IV and CERAD = B or C) and without cognitive impairment (CDR 0, IQCODE<3.2); and III) “normal aging” (N) - subjects without neuropathological AD (Braak≤II and CERAD 0 or A) and with normal cognitive function (CDR 0, IQCODE<3.2). Our results show that high levels of oxidative DNA damage are present in all groups. However, significant reductions in DNA repair and cell-cycle inhibition markers and increases in cell-cycle progression and cell death markers in subjects with CP-AD were detected when compared to both P-AD and N groups, whereas there were no significant differences in the studied markers between P-AD individuals and N subjects. This study indicates that, even in the setting of pathological AD, healthy cognition may be associated with a preserved repair to DNA damage, cell-cycle regulation, and cell death in post-mitotic neurons.