Involvement of adenosine A1 and A2A receptors in the motor effects of caffeine after its acute and chronic administration.

The involvement of adenosine A(1) and A(2A) receptors in the motor effects of caffeine is still a matter of debate. In the present study, counteraction of the motor-depressant effects of the selective A(1) receptor agonist CPA and the A(2A) receptor agonist CGS 21680 by caffeine, the selective A(1) receptor antagonist CPT, and the A(2A) receptor antagonist MSX-3 was compared. CPT and MSX-3 produced motor activation at the same doses that selectively counteracted motor depression induced by CPA and CGS 21680, respectively. Caffeine also counteracted motor depression induced by CPA and CGS 21680 at doses that produced motor activation. However, caffeine was less effective than CPT at counteracting CPA and even less effective than MSX-3 at counteracting CGS 21680. On the other hand, when administered alone in habituated animals, caffeine produced stronger motor activation than CPT or MSX-3. An additive effect on motor activation was obtained when CPT and MSX-3 were coadministered. Altogether, these results suggest that the motor-activating effects of acutely administered caffeine in rats involve the central blockade of both A(1) and A(2A) receptors. Chronic exposure to caffeine in the drinking water (1.0 mg/ml) resulted in tolerance to the motor effects of an acute administration of caffeine, lack of tolerance to amphetamine, apparent tolerance to MSX-3 (shift to the left of its 'bell-shaped' dose-response curve), and true cross-tolerance to CPT. The present results suggest that development of tolerance to the effects of A(1) receptor blockade might be mostly responsible for the tolerance to the motor-activating effects of caffeine and that the residual motor-activating effects of caffeine in tolerant individuals might be mostly because of A(2A) receptor blockade.     

Laparoscopic and open gastric resections for malignant lesions: A prospective comparative study

Background Whereas laparoscopy for benign diseases provides clear advantages over traditional surgery, the benefits of laparoscopic gastric resection for malignant diseases are less clear. The objectives of this study were to compare prospectively the clinical outcomes between completely laparoscopic and open total and partial gastrectomies for malignant diseases and to assess whether laparoscopic gastrectomies obtain adequate margins and follow oncologic principles.Methods Between April 1995 and March 2004, a prospective comparative study was performed comparing eight patients who underwent laparoscopic total gastrectomy with 11 patients who underwent open total gastrectomy, and 16 patients who underwent laparoscopic partial gastrectomy with 17 who patients underwent open partial gastrectomy. Stage, extent of lymphadenectomy, and long-term follow-up were examined. The intraoperative and postoperative details of the two groups were compared.Results The laparoscopic group patients had fewer intraoperative complications while the operative time was similar to that of the open group. Both ambulation and hospital stay were significantly shorter in the laparoscopic groups than in the open groups. The short-term morbidity was lower in the laparoscopic groups and there were no cases of death, whereas one case of postoperative death occurred after an open total gastrectomy. There was no need to convert to open surgery. The number of lymph nodes obtained in the laparoscopic and open procedures was not significantly different. In addition, all resected margins were tumor free in the laparoscopic group, whereas tumor involvement was presented in the margin of one specimen in the open group.Conclusions The totally laparoscopic approach to total and partial gastrectomies had good results and was proven to be a feasible and safe procedure. In addition, the laparoscopic procedures are superior to open surgeries in terms of faster postoperative recovery, shorter hospital stay, and better cosmetic outcomes. A totally laparoscopic approach for early and advanced gastric cancer can obtain adequate margins and follow oncologic principles.     

Characterization of COR627 and COR628, two novel positive allosteric modulators of the GABA(B) receptor

The potential efficacy of GABA(B) receptor agonists in the treatment of pain, drug addiction, epilepsy, cognitive dysfunctions, and anxiety disorders is supported by extensive preclinical and clinical evidence. However, the numerous side effects produced by the GABA(B) receptor agonist baclofen considerably limit the therapeutic use of this compound. The identification of positive allosteric modulators (PAMs) of the GABA(B) receptor may constitute a novel approach in the pharmacological manipulation of the GABA(B) receptor, leading to fewer side effects. The present study reports the identification of two novel compounds, methyl 2-(1-adamantanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR627) and methyl 2-(cyclohexanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR628), which act as GABA(B) PAMs in 1) rat cortical membranes and 2) in vivo assay. Both compounds potentiated GABA- and baclofen-stimulated guanosine 5'-O-(3-[(35)S]thio)-triphosphate binding to native GABA(B) receptors, while producing no effect when given alone. GABA concentration-response curves in the presence of fixed concentrations of COR627 and COR628 revealed an increase of potency of GABA rather than its maximal efficacy. In radioligand binding experiments [displacement of the GABA(B) receptor antagonist, 3-N-[1-((S)-3,4dichlorophenyl)-ethylaminol]-2-(S)hydroxypropyl cyclo-hexylmethyl phosphinic acid ([(3)H]CGP54626)], both COR627 and COR628 increased the affinity of high- and low-affinity binding sites for GABA, producing no effect when administered alone up to a concentration of 1 mM. In vivo experiments indicated that pretreatment with per se ineffective doses of COR627 and COR628 potentiated the sedative/hypnotic effect of baclofen. In conclusion, COR627 and COR628 may represent two additional tools for use in investigating the roles and functions of positive allosteric modulatory binding sites of the GABA(B) receptor.     

Comprehensive geriatric assessment in female elderly patients with Alzheimer disease and other types of dementia

The most visible manifestation of dementia is the progressive inability to activities of daily living (ADL) and to instrumental activities of daily living (IADL). The comprehensive geriatric assessment (CGA) is the validated and recommended instrument to a correct evaluation and decision making in elderly patients. To judge if the decline in cognitive functions is associated with a worsening in functional, emotional and clinical status measured by CGA, we also compared CGA in the same patients stratified for mild, moderate and severe dementia. From September 2004 to November 2005 we studied 47 institutionalized female patients with Alzheimer's disease (AD) and other types of dementia. Mean age was 83.70+/-0.88 years (range 70-101). Their multidimensional evaluation was performed by the CGA. We evaluated geriatric syndromes (AGS, 2004), polypharmacy, frailty, hemoglobin (Hb), serum creatinine (CR) and white blood cells (WBC). We stratified the population in 3 groups for the mini mental state examination (MMSE): severe (MMSE 0-9; 5 patients), moderate (MMSE 10-29; 23 patients) and mild dementia group (MMSE 20-30; 19 patients), and searched for statistical differences in the parameters of CGA. MMSE was significantly related to dependence in ADL (mean=x=1.85), IADL (x=0.57), cumulative illness rating scale-geriatrics (CIRS-G) (x=9.55), geriatric depression scale (GDS) (x=8.71), geriatric syndromes (x=2.49), Hb, CR, WBC and number of drugs (x=6.51, range 2-15) (p=0.001). MMSE low score was also correlated with a worse mini nutritional assessment (MNA) (x=19.5; p=0.003). Frail patients were 61.7%. We found a statistically significant difference in the prevalence of geriatric syndromes between mild vs. moderate dementia group (p=0.02). Mild vs. moderate group, and moderate vs severe group were significantly different concerning Hb levels (p=0.009 and 0.002, respectively). Patients with severe cognitive impairment are more likely to be dependent at ADL and IADL; to present a larger number of comorbidity and geriatric syndromes; to have lower !evels of Hb and higher levels of CR; to be in a worse nutritional status and to take a larger number of drugs. Polypharmacy maybe related to high comorbidity but the risk of irrational drug use should be evaluated. We suggest single testing with CGA as an effective tool providing a comprehensive assessment of elderly, and able to detect unaddressed corrigible problems.     

Hepatitis C virus genotypes: distribution and clinical significance in patients with cirrhosis type C seen at tertiary referral centres in Europe

The aim of this study was to evaluate the distribution and clinical significance of hepatitis C virus (HCV) genotypes in European patients with compensated cirrhosis due to hepatitis C (Child class A) seen at tertiary referral centres. HCV genotypes were determined by genotype-specific primer PCR in 255 stored serum samples obtained from cirrhotics followed for a median period of 7 years. Inclusion criteria were biopsy-proven cirrhosis, absence of complications of cirrhosis and exclusion of all other potential causes of chronic liver disease. The proportion of patients with types 1b, 2, 3a, 1a, 4 and 5 were 69%, 19%, 6%, 5%, 0.5% and 0.5%, respectively. Kaplan–Meier 5-year risk of hepatocellular carcinoma (HCC) was 6% and 4% for patients infected by type 1b and non-1b, respectively ( P =0.8); the corresponding figures for decompensation were 18% and 7% ( P =0.0009) and for event-free survival were 79% and 89% ( P =0.09), respectively. After adjustment for baseline clinical and serological features, HCV type 1b did not increase the risk for HCC [adjusted relative risk=1.0 (95% confidence interval=0.47–2.34)], whereas it increased the risk for decompensation by a factor of 3 (1.2–7.4) and decreased event-free survival by a factor of 1.7 (0.9–3.10). In conclusion, type 1b and, to a lesser extent, type 2, are the most common HCV genotypes in European patients with cirrhosis. HCV type 1b is not associated with a greater risk for HCC, but increases the risk for decompensation by threefold in patients with cirrhosis.     

PI3Kγ within a nonhematopoietic cell type negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance

Obesity is associated with a chronic low-grade inflammation, and specific antiinflammatory interventions may be beneficial for the treatment of type 2 diabetes and other obesity-related diseases. The lipid kinase PI3Kγ is a central proinflammatory signal transducer that plays a major role in leukocyte chemotaxis, mast cell degranulation, and endothelial cell activation. It was also reported that PI3Kγ activity within hematopoietic cells plays an important role in obesity-induced inflammation and insulin resistance. Here, we show that protection from insulin resistance, metabolic inflammation, and fatty liver in mice lacking functional PI3Kγ is largely consequent to their leaner phenotype. We also show that this phenotype is largely based on decreased fat gain, despite normal caloric intake, consequent to increased energy expenditure. Furthermore, our data show that PI3Kγ action on diet-induced obesity depends on PI3Kγ activity within a nonhematopoietic compartment, where it promotes energetic efficiency for fat mass gain. We also show that metabolic modulation by PI3Kγ depends on its lipid kinase activity and might involve kinase-independent signaling. Thus, PI3Kγ is an unexpected but promising drug target for the treatment of obesity and its complications.     

No Association Between NRG1 and ErbB4 Genes and Psychopathological Symptoms of Schizophrenia

Neuregulin 1 (NRG1) and v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4) have been extensively studied in schizophrenia susceptibility because of their pivotal role in key neurodevelopmental processes. One of the reasons for the inconsistencies in results could be the fact that the phenotype investigated has mostly the diagnosis of schizophrenia per se, which is widely heterogeneous, both clinically and biologically. In the present study we tested, in a large cohort of 461 schizophrenia patients recruited in Scotland, whether several SNPs in NRG1 and/or ErbB4 are associated with schizophrenia symptom dimensions as evaluated by the Positive and Negative Syndrome Scale (PANSS). We then followed up nominally significant results in a second cohort of 439 schizophrenia subjects recruited in Germany. Using linear regression, we observed two different groups of polymorphisms in NRG1 gene: one showing a nominal association with higher scores of the PANSS positive dimension and the other one with higher scores of the PANSS negative dimension. Regarding ErbB4, a small cluster located in the 5′ end of the gene was detected, showing nominal association mainly with negative, general and total dimensions of the PANSS. These findings suggest that some regions of NRG1 and ErbB4 are functionally involved in biological processes that underlie some of the phenotypic manifestations of schizophrenia. Because of the lack of significant association after correction for multiple testing, our analyses should be considered as exploratory and hypothesis generating for future studies.