High-density lipoproteins protect isolated rat hearts from ischemia-reperfusion injury by reducing cardiac tumor necrosis factor-alpha content and enhancing prostaglandin release

The incidence and severity of primary cardiac events are inversely related to the plasma concentration of high-density lipoproteins (HDLs). We investigated whether HDLs may exert a direct cardioprotection in buffer-perfused isolated rat hearts, which underwent a 20-minute low-flow ischemia followed by a 30-minute reperfusion. The administration of HDLs at physiological concentrations (0.5 and 1.0 mg/mL) during the 10 minutes immediately before ischemia rapidly and remarkably improved postischemic functional recovery and decreased creatine kinase release in the coronary effluent. Reconstituted HDLs containing apolipoprotein A-I (apoA-I) and phosphatidylcholine, but not lipid-free apoA-I or phosphatidylcholine liposomes, were also effective in protecting the heart from ischemia-reperfusion injury. HDLs at reperfusion were less effective than when given before ischemia. HDLs caused a dose-dependent reduction of ischemia-induced cardiac tumor necrosis factor-alpha (TNF-alpha) expression and content, which correlated with the improved functional recovery. A parallel increase of TNF-alpha release in the coronary effluent was observed, due to a direct binding of cardiac TNF-alpha to HDLs. Taken together, these findings argue for a cause-effect relationship between the HDL-mediated removal of TNF-alpha from the ischemic myocardium and the HDL-induced cardioprotection. Indeed, etanercept, a recombinant TNF-alpha-blocking protein, caused a dose-dependent improvement of postischemic functional recovery. HDLs also enhanced ischemia-induced prostaglandin release, which may contribute to the cardioprotective effect. A low plasma HDL level may expose the heart to excessive ischemia-reperfusion damage, and HDL-targeted therapies may be helpful to induce immediate or delayed myocardial protection from ischemia-reperfusion injury.     

Distribution of sigma receptors in EMT-6 cells: preliminary biological evaluation of PB167 and potential for in-vivo PET

Sigma(1) and sigma(2) receptors have been detected in many tissues and are highly expressed in several tumour cell lines from various tissues. The high level of expression observed for sigma receptors and their involvement in cell proliferation and apoptosis has led to the development of several sigma ligands in order to obtain a molecular probe for in-vivo diagnostic imaging techniques such as positron emission tomography (PET) and single photon emission computerized tomography (SPECT). The EMT-6 cells implanted in mice were a good model for evaluating the proliferation of solid tumours by in-vivo PET. Moreover, we developed the sigma ligand PB167, a cyclohexylpiperazine derivative, previously evaluated for sigma(2) receptor affinity and activity in standard protocols. The related results encouraged us to verify if this compound could be developed as a radiotracer for in-vivo PET in order to visualize sigma(2) receptors expressed in EMT-6 cells when implanted in mice. This perspective was thought to be favourable because PB167 bears a methoxy substituent on the tetraline nucleus, an easy point for (11)C labelling. The aims of this preliminary study were both to assess the relative distribution of sigma(1) and sigma(2) receptors in EMT-6 cells and to verify if PB167 could be developed as a sigma(2) radiotracer for in-vivo PET. The results showed that both sigma(1) and sigma(2) receptors were overexpressed in EMT-6 cells and that the ligand PB167 can be positively considered for radiosynthesis preparation in order to suitably visualize sigma(2) receptors by the in-vivo PET technique and correlate their presence to tumour proliferation.     

Newborns' preference for face-relevant stimuli: effects of contrast polarity

There is currently no agreement as to how specific or general are the mechanisms underlying newborns' face preferences. We address this issue by manipulating the contrast polarity of schematic and naturalistic face-related images and assessing the preferences of newborns. We find that for both schematic and naturalistic face images, the contrast polarity is important. Newborns did not show a preference for an upright face-related image unless it was composed of darker areas around the eyes and mouth. This result is consistent with either sensitivity to the shadowed areas of a face with overhead (natural) illumination and/or to the detection of eye contact.     

Impact of the renin-angiotensin system on lipid and carbohydrate metabolism

PURPOSE OF REVIEW: This review is intended to provide an update of the impact of the renin-angiotensin system on lipid and carbohydrate metabolism and of its relationship with adipose-tissue and skeletal muscle activities. RECENT FINDINGS: The components of the renin-angiotensin system are fully represented in the adipose tissue and appear to be upregulated in obesity--a condition associated with enhanced circulating angiotensinogen levels. The local renin-angiotensin system plays a role in adipocyte differentiation and possibly in body-fat accumulation. In humans, angiotensin II produced by mature adipocytes appears to inhibit the differentiation of adipocyte precursors, thus decreasing the percentage of small insulin-sensitive adipocytes. In turn, the lipid-storage capacity of adipose tissue could become reduced and triglycerides might accumulate in liver and skeletal muscle, contributing to insulin resistance. Randomized controlled trials indicating that pharmacological renin-angiotensin system blockade improves insulin sensitivity and reduces the risk of type 2 diabetes are in keeping with this possibility. The local renin-angiotensin system in skeletal muscle may affect exercise performance and the individual response to different types of muscular performance. The concept that the local renin-angiotensin system plays a role in body-fat storage and in lipid and carbohydrate metabolism is further supported by genetic studies showing that susceptibility to weight gain and possibly insulin resistance is greater in individuals carrying certain renin-angiotensin system allelic variants associated with alterations in systemic and local angiotensinogen levels and angiotensin-converting enzyme activity. SUMMARY: In summary, the aforementioned data imply that the renin-angiotensin system plays a substantial role in obesity, insulin resistance and the associated increase in blood pressure.     

Cerebral D2 and 5-HT2 receptor occupancy in Schizophrenic patients treated with olanzapine or clozapine

We report the results of a double-blind, randomized prospective trial on D2 and 5-HT2 receptor occupancy and the clinical effects of olanzapine versus clozapine in a sample of neuroleptic-refractory schizophrenic patients. Receptor occupancy was evaluated in different cortical areas and in basal ganglia using [18F] fluoro-ethyl-spiperone ([18F] FESP) and positron emission tomography (PET). A total of 15 neuroleptic-free patients completed the study undergoing a baseline and a post-treatment PET scan (olanzapine, nine patients, one female; clozapine, six patients, three female) 8 weeks after starting treatment. PET data were analysed both by regions of interest and on a voxel-by-voxel basis using Statistical Parametric Mapping (SPM96). Olanzapine and clozapine induced a similar and significant inhibition of [18F] FESP binding index in the cortex. In the basal ganglia, receptor occupancy was significantly higher with olanzapine than with clozapine (p=0.0018). By contrast, no differences in receptor occupancy were detected at the level of the pituitary gland. Clinical outcomes, in particular a full extra pyramidal tolerability, were similar. In this sample of neuroleptic-refractory schizophrenic patients, olanzapine and clozapine showed a different pattern of occupancy of D2-like receptor despite a common lack of extrapyramidal side-effects.     

Bleeding small bowel angiodysplasia: unusual form of conservative treatment

The authors report a case of gastrointestinal bleeding caused by angiodysplasia of the small bowel. They stress the rarity of the lesion and consider the difficulties involved in obtaining a preoperative diagnosis. Intra- or pre-operative enteroscopy seems to be the most suitable method for identifying the source of occult small-bowel bleeding. The optimal management is uncertain and depends on the severity and rate of the bleeding. A conservative medical approach is indicated for many patients, while surgery constitutes definitive treatment in cases of massive haemorrhage or recurrent bleeding. The authors describe a case in which the diagnosis was reached only at intra-operative enteroscopy and an unusual conservative surgical treatment was performed based on ligation of the vascular elements of the angiodysplasia. This method makes it possible to avoid an intestinal resection and yields good results.     

A1 adenosine receptors inhibit multiple voltage-gated Ca2+ channel subtypes in acutely isolated rat basolateral amygdala neurons

1. The anticonvulsant properties of 2-chloroadenosine (CADO) in the basolateral amygdala rely on the activation of adenosine-specific heptahelical receptors. We have utilized whole-cell voltage-clamp electrophysiology to examine the modulatory effects of CADO and other adenosine receptor agonists on voltage-gated calcium channels in dissociated basolateral amygdala neurons. 2. CADO, adenosine, and the A1 subtype-selective agonists N6-(L-2-Phenylisopropyl)adenosine (R-PIA) and 2-chloro-N6-cyclopentyladenosine (CCPA) reversibly modulated whole cell Ba2+ currents in a concentration-dependent fashion. CADO inhibition of barium currents was also sensitive to the A1 antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). 3. The A2A-selective agonist 4-[2-[[6-Amino-9-(N-ethyl-beta-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid (CGS21680) was without effect. 4. CADO inhibition was predominantly voltage-dependent and sensitive to the sulphydryl-modifying reagent N:-ethylmaleimide, implicating a membrane-delimited, G(i/o)-coupled signal transduction pathway in the channel regulation. 5. Using Ca2+ channel subtype-selective antagonists, CADO inhibition appeared to target multiple channel subtypes, with the inhibition of omega-conotoxin GVIA-sensitive calcium channels being more prominent. 6. Our results indicate that the anti-convulsant effects CADO in the basolateral amygdala may be mediated, in part, by the A1 receptor-dependent inhibition of voltage gated calcium channels.     

Does an asthma education program improve quality of life? A two-year randomized trial.

Asthma education programs result in clinical improvement. However, most studies involved programs of up to 1 year of follow-up, and their efficacy in improving quality of life (QoL) is still controversial. The aim of this study was to evaluate the effectiveness of a program of patient education in asthmatics over 2 years. Thirty-seven asthmatic patients were randomly allocated to group A (usual treatment) and 32 to group B (usual treatment plus patient education program). The effectiveness of the education program was evaluated by comparing morbidity outcomes at baseline and 12 and 24 months afterwards. At baseline, no intergroup difference emerged in age, sex, smoking, asthma severity, atopy, FEV1, symptom-free days, use of rescue salbutamol, and QoL. One year later, group B subjects had an improvement in the overall QoL (from 5.8 +/- 0.8 to 6.1 +/- 0.7, p < 0.005), and in "Activities" (from 5.3 +/- 0.9 to 5.7 +/- 0.8, p < 0.05) and "Environment" (from 6.4 +/- 1.0 to 6.8 +/- 0.4, p < 0.05) domains. Two years later the "Activities" domain score increased in group B (from 5.3 +/- 0.9 to 5.7 +/- 1.1, p < 0.05). QoL did not vary in group A. The education program was ineffective in all other parameters at both follow-up time-points. In group A, a significant increase in medication expenses and a significant decrease in rescue salbutamol use was found 1 and 2 years after baseline, respectively. In conclusion, this education program improved QoL for 1 year, but the improvement was not sustained in the 2nd year.