Insulin affects synaptosomal GABA and glutamate transport under oxidative stress conditions

In this study, we investigated the in vitro effect of exogenously administered insulin on the susceptibility to oxidative stress and on the accumulation of the amino acid neurotransmitters gamma-aminobutyric acid (GABA) and glutamate in a synaptosomal fraction isolated from male Wistar rat brain cortex. Insulin (1 microM) did not affect synaptosomal lipid peroxidation induced by the oxidant pair ascorbate/Fe(2+), although under these conditions an increase in thiobarbituric acid reactive substances (TBARS) levels was observed. Under control conditions, the presence of insulin did not change the uptake of [3H]GABA or [3H]glutamate. In contrast, under oxidizing conditions, we observed a 1.8- and a 2.2-fold decrease in [3H]GABA and [3H]glutamate accumulation, respectively, and insulin reverted the lower levels of both [3H]GABA and [3H]glutamate accumulation (to 86.74+/-6.26 and 67.01+/-6.65% of control, respectively). Insulin also increased the extrasynaptosomal levels of GABA and glutamate, determined both in control and oxidizing conditions. From this study, we can conclude that insulin is a modulator of amino acid neurotransmitter transport, either directly, as seems to occur under normal conditions, or via the decrease in ATP levels and the subsequent reversion of the amino acid transporters, as seems to occur under oxidative stress conditions. The modulation of both GABA and glutamate transport might be implicated in the neuroprotective role of insulin.     

Subcellular localization of adenosine A(1) receptors in nerve terminals and synapses of the rat hippocampus

Adenosine is a neuromodulator in the CNS that mainly acts through pre- and postsynaptic A(1) receptors to inhibit the release of excitatory neurotransmitters and NMDA receptor function. This might result from a highly localized distribution of A(1) receptors in the active zone and postsynaptic density of CNS synapses that we now investigated in the rat hippocampus. The binding density of the selective A(1) receptor antagonist, [3H]1,3-dipropyl-8-cyclopentylxanthine ([3H]DPCPX), was enriched in membranes from Percoll-purified nerve terminals (B(max)=1839+/-52 fM/mg protein) compared to total membranes from the hippocampus (B(max)=984+/-31 fM/mg protein), the same occurring with A(1) receptor immunoreactivity. [3H]DPCPX binding occurred mainly to the plasma membrane rather than to intracellular sites, since the binding of the membrane permeable A(1) receptor ligand [3H]DPCPX to intact hippocampal nerve terminals (B(max)=1901+/-192 fM/mg protein) was markedly reduced (B(max)=321+/-30 fM/mg protein) by the membrane impermeable adenosine receptor antagonist, 8-sulfophenyltheophilline (25 microM). Further subcellular fractionation of hippocampal nerve terminals revealed that A(1) receptor immunoreactivity was strategically located in the active zone of presynaptic nerve terminals, as expected to understand the efficiency of A(1) receptors to depress neurotransmitter release. A(1) Receptors were also present in nerve terminals outside the active zone in accordance with the existence of a presynaptic A(1) receptor reserve. Finally, A(1) receptor immunoreactivity was evident in the postsynaptic density together with NMDA receptor subunits 1, 2A and 2B and with N-and P/Q-type calcium channel immunoreactivity, emphasizing the importance of A(1) receptors in the control of dendritic integration.     

Placebo and placebo effects--a review

Placebo controls in clinical trials are usually employed to filter out undesired, psychological or non-specific effects from "true" therapeutic effects. Although this is useful in the context of clinical trials for the purpose of proving pharmacological efficacy, it is misleading to generalize this strategy to therapy as a whole. This would imply that placebo effects are irrelevant. Precisely this opinion is criticized in this paper. After some consideration about an appropriate notion of placebo, some empirical evidence is reviewed which underlines the importance of placebo effects. It is likely that the unspecific effects due to the individual meaning of an intervention are an important factor of any therapeutic approach. It would be therapeutically desirable to maximize these factors. This point of view would also have consequences on how interventions have to be evaluated.     

Nosocomial transmission of HCV in a cardiology ward during the window phase of infection: an epidemiological and molecular investigation

Nosocomial spread of HCV and other blood-borne pathogens continues to occur in the Western world despite the screening of blood products. Using molecular and epidemiological methods we investigated an outbreak of HCV involving 3 patients following percutaneous coronary intervention at a Swedish hospital. The most likely mode of transmission was contamination of a multidose vial of saline used for the flushing of intravenous catheters. It may, therefore, be prudent to restrict the use of such vials, in addition to promoting vigorous adherence to standard hygiene procedures in order to prevent the recurrence of similar outbreaks in the future.     

hMLH1 and hMSH2 gene mutation in Brazilian families with suspected hereditary nonpolyposis colorectal cancer

Background The aim of this study was to search for mutations in the humanmutS homolog 2 (hMSH2) and humanmutL homolog 1 (hMLH1) genes in 25 unrelated Brazilian kindreds with suspected hereditary nonpolyposis colorectal cancer (HNPCC). Methods The families were grouped according to the following clinical criteria: Amsterdam I or II; familial colorectal cancer (CRC); an early age of onset of CRC in the proband only; or with at least one or two relatives who had HNPCC-related cancers; CRC in the proband only. All patients were studied with direct sequencing. Results Ten mutations were detected (10 of 25 [40%]); of nine different mutations, seven were novel. ThehMLH1 gene had a higher mutation detection rate thanhMSH2 (8 of 25 [32%] vs. 2 of 25 [8%]). Only 3 of these 10 families fulfilled the Amsterdam criteria. Two different polymorphisms were detected in thehMLH1 gene and four in thehMSH2 gene. Conclusions ThehMLH1 gene had a higher mutation detection rate thanhMSH2. The physician who deals with CRC must take into consideration the heredity issue with patients who present with an early age of onset or a familial history of CRC- or HNPCC-related cancers, including gastric cancer, even if they do not fulfill the former Amsterdam criteria.     

Validity of self-reports of reasons for hospitalization by young adults and risk factors for discordance with medical records: the Coronary Artery Risk Development in Young Adults (CARDIA) Study

This research focused on the validity of young adults' (mean age=33 years; standard deviation, 3.9) self-reports of reasons for hospitalization and factors affecting validity in a longitudinal cohort study of over 5,000 young adults in four US cities (1985-1998). Self-reported reasons were considered discordant if they differed from those in medical records. Of the 321 self-reported hospitalizations, overall concordance was 92.5%; concordance ranged from 80% for infections to 100% for injuries/fractures and procedures/surgeries. There were no significant differences among mail, telephone, or face-to-face methods of collecting self-reports. In generalized estimating equations analyses, Black race (odds ratio=4.23, 95% confidence interval: 1.72, 10.40; p=0.002) and intravenous drug use (odds ratio=6.06, 95% confidence interval: 1.17, 31.22; p=0.03) were positively associated with discordance. Nonetheless, self-reports by Blacks were 90.0% concordant. Self-reports by Whites were 95.7% concordant. These results suggest that young adults' self-reported reasons for hospitalization are overwhelmingly concordant with medical records. This has important implications, since obtaining medical records has become more costly and logistically difficult.     

Modelling and multivariable control in anaesthesia using neural-fuzzy paradigms. Part I. Classification of depth of anaesthesia and development of a patient model

OBJECTIVE: The first part of this research relates to two strands: classification of depth of anaesthesia (DOA) and the modelling of patient's vital signs. METHODS AND MATERIAL: First, a fuzzy relational classifier was developed to classify a set of wavelet-extracted features from the auditory evoked potential (AEP) into different levels of DOA. Second, a hybrid patient model using Takagi-Sugeno Kang fuzzy models was developed. This model relates the heart rate, the systolic arterial pressure and the AEP features with the effect concentrations of the anaesthetic drug propofol and the analgesic drug remifentanil. The surgical stimulus effect was incorporated into the patient model using Mamdani fuzzy models. RESULTS: The result of this study is a comprehensive patient model which predicts the effects of the above two drugs on DOA while monitoring several vital patient's signs. CONCLUSION: This model will form the basis for the development of a multivariable closed-loop control algorithm which administers "optimally" the above two drugs simultaneously in the operating theatre during surgery.     

Oxidative stress: the old enemy in Alzheimer's disease pathophysiology

The complex nature and genesis of oxidative damage in Alzheimer disease can be partly answered by mitochondrial and redox-active metal abnormalities. By releasing high levels of hydrogen peroxide, dysfunctional mitochondria propagate a series of interactions between redox-active metals and oxidative response elements. In the initial phase of disease development, amyloid-beta deposition and hyperphosphorylated tau may function as compensatory responses and downstream adaptations to ensure that neuronal cells do not succumb to oxidative injuries. However, during the progression of the disease, the antioxidant activity of both agents evolves into pro-oxidant activity representing a typical gain-of-function transformation, which can result from an increase in reactive species and a decrease in clearance mechanisms.     

Screening detected celiac disease in children with type 1 diabetes mellitus: effect on the clinical course (a case control study)

OBJECTIVE: To investigate clinical and metabolic characteristics of diabetic children with screening detected celiac disease in a multicenter case-control study. METHODS: Cases: 98 diabetic patients were diagnosed as having silent celiac disease by screening with endomysial antibodies and subsequent biopsy. Controls: two controls in the same center were chosen, (stratified by age and age-at-diabetes onset) who were negative for endomysial antibodies (n = 195). Height, weight, HbA1c, insulin dosage and acute complications were documented for at least 1 year of follow up. RESULTS: Mean age of diabetes manifestation was 6.5 +/- 4.1 years and diagnosis of celiac disease was made at 10.0 +/- 5.4 years. Biopsy showed total or subtotal mucosal atrophy in 74 patients. The mean observation period after the diagnosis of celiac disease was 3.3 +/- 1.9 years. Mean HbA1c levels were similar between cases and controls (8.63% +/- 1.45% versus 8.50% +/- 1.39%; P = 0.35). There was also no difference in the frequency of severe hypoglycemia, ketoacidosis and the applied insulin dosage (P = 0.45). Body mass index-standard deviation score at celiac disease diagnosis (0.57 +/- 1.24 versus 0.52 +/- 1.07) and height-standard deviation score (0.14 +/- 1.13 versus 0.30 +/- 0.95) did not differ between cases and controls. After diagnosis of celiac disease, weight gain was diminished in boys with celiac disease compared with their controls (P < 0.05). Female cases also had a lower body mass index than female controls (P = 0.067). CONCLUSION: In a cohort of diabetic children, silent celiac disease had no obvious effect on metabolic control but negatively influenced weight gain.