Metabolic syndrome and adipose tissue: new clinical aspects and therapeutic targets

The metabolic syndrome is a long-term process, explained by the interaction of genetic and environmental factors, that starts early in life and is involved in the pathophysiology of a large percentage of cases with type 2 diabetes and atherosclerosis. A number of clinical studies have demonstrated the importance of fat distribution and especially the contribution of visceral fat accumulation to the development of metabolic disorders. Visceral adipose tissue can be studied through different imaging techniques. The accumulation of visceral adipose tissue, as opposed to subcutaneous fat, increases the risk of developing metabolic disease and cardiovascular diseases (CVD). Visceral adipocytes secrete a variety of cytokines known as adipocytokines suggesting that adipose tissue is an endocrine organ that may affect the function of other organs. Weight loss, particularly a reduction in waist circumference, improves insulin sensitivity, lipid profile, and serum adipocytokines, reducing the risk of developing chronic disease and CVD. Waist circumference is a required component of metabolic syndrome under the International Diabetes Federation (IDF) criteria, rather than an optional component as used by other previous classifications. Studies have shown that using a lower waist circumference threshold within the context of metabolic syndrome increases the prevalence, but decreases the risk of mortality and type 2 diabetes. It is possible that waist circumference acts as a marker for other risk factors. These findings reinforce the notion that reductions in visceral adipose tissue should be a primary aim of strategies designed to reduce health risks associated with metabolic syndrome.     

Identification of human liver cytochrome P450 enzymes involved in the metabolism of SCH 351125, a CCR5 antagonist

The identification and relative contribution of human cytochrome P450 enzyme(s) involved in the metabolism of SCH 351125 were investigated. In human liver microsomes, O-deethylation was the major metabolic pathway, whereas aromatization of a piperidine ring to pyridine and the reduction of the N-oxide moiety were minor routes. Recombinant human CYP3A4 and CYP2C9 both exhibited catalytic activity with respect to the formation of rotameric O-deethylated metabolites (M12, M13), the metabolites resulting from aromatization (M22/M24) and N-oxide reduction (M31). Using the relative activity factor (RAF) approach, the relative contributions of CYP3A4 and CYP2C9 to M13 formation were estimated to be 76 and 24%, respectively. There was a high correlation (r?>?0.96) between the rate of formation of M12 and M13 and 6β-hydroxylation of testosterone catalysed by CYP3A4/5. Ketoconazole (2?µM) and CYP3A4/5-specific inhibitory monoclonal antibody inhibited the formation of M12 and M13 from human liver microsomes by approximately 60 and 71%, respectively. The results demonstrate that the in vitro metabolism of SCH 351125 is mediated primarily via CYP3A4 and that CYP2C9 plays a minor role. Clinical study designs should encompass these enzymology data to address any potential drug interactions.     

Expression of progesterone receptors in solid-cystic tumour of the pancreas

A role for sex hormones in the pathogenesis of solid-cystic tumour (SCT) of the pancreas is suggested by its predilection for young fertile women. Controversial data have been provided for the presence of progesterone receptors (PR) and/or oestrogen receptors (ER) in SCT. We report the immunohistochemical detection of PR in ten cases of SCT. Eight were from young women. The remaining two were from a post-menopausal woman and a young boy. All cases showed PR immunoreactivity in the large majority of neoplastic cells, whereas none exhibited ER positivity. In one tumour two types of cell populations were noted, the more anaplastic invasivetype being PR negative, whereas the more typical was PR positive. PR immunoreactivity in the absence of ER may simply reflect a lower sensitivity of ER antibody failing to reveal the biochemically detectable ER, or that the PR in cells of SCT are constitutively synthesized in an oestrogen-independent way, as in T47D breast carcinoma cell line, meningioma cells and some gastric cancer cells. Our findings support the hypothesis of a possible pathogenetic role of progesterone in SCT, independent of the patient's sex and age.     

A longitudinal MR study of the presymptomatic phase in a patient with clinically definite multiple sclerosis.

We describe the dynamics and the nature of the presymptomatic phase of multiple sclerosis (MS) in a patient for whom MR abnormalities suggestive of MS were found before the development of clinical symptoms. The patient was monitored with serial monthly MR imaging of the brain and spinal cord for 5 months. Disease activity during the presymptomatic phase showed imaging characteristics comparable to that of early relapsing-remitting MS in terms of enhancing lesions, duration of enhancement, and new lesions depicted by T2-weighted imaging. Measurements derived from magnetization transfer imaging suggested that the amount and degree of tissue destruction within and outside the lesions revealed by T2-weighted imaging were mild. This, together with the fact that only one of the 43 new lesions that developed during the presymptomatic phase was located in a neurologically eloquent area, may be the reason why, for a relatively long period, the patient had no clinical manifestations of MS despite the marked MR findings of disease activity.     

自体骨髓干细胞移植治疗心力衰竭的研究进展

细胞移植已为病损心脏细胞重建及衰竭心脏功能恢复提供了一种全新的治疗方法。骨髓干细胞具有自我更新、定向分化成为包括心肌细胞等多种组织细胞的潜能,其增殖分化能力能持续终生,已成为细胞移植治疗心力衰竭的主要细胞源。本文就自体骨髓干细胞治疗心力衰竭可行性、与其他移植细胞相比较的优势、临床应用现状及目前问题与展望作一综述。     

One protein to rule them all: modulation of cell surface receptors and molecules by HIV Nef

The HIV-1, HIV-2 and SIV Nef protein are known to modulate the expression of several cell surface receptors and molecules to escape the immune system, to alter T cell activation, to enhance viral replication, infectivity and transmission and overall to ensure the optimal environment for infection outcome. Consistent and continuous efforts have been made over the years to characterize the modulation of expression of each of these molecules, in the hope that a better understanding of these processes essential for HIV infection and/or pathogenesis will eventually highlight new therapeutic targets. In this article we provide an extensive review of the knowledge gained so far on this important and evolving topic.     

Incidence of high chromogranin A serum levels in patients with non metastatic prostate adenocarcinoma

Background

ChromograninA in prostate carcinoma (PC) indicate NE differentiation. This tumour is more aggressive and resistant to hormone therapy.

Patients and methods

We analyzed the incidence of pre-operative ChromograninA serum levels in non metastatic PC patients. Serum PSA and ChromograninA were analyzed before treatment. Clinicopathological parameters were evaluated in relation to serum ChromograninA. 486 patients were enrolled.

Results

We found 352 pT2 and 134 pT3. 21 patients were N+. 278 patients had Gleason score levels <7; 173 patients had levels = 7 (122 were 3+4 and 51 4+3); and 35 patients with levels >7. Median PSA pre-operative level was 7.61 ng/ml. PSA was significantly associated with pT stage (pT2 with PSA abnormal 23.6% vs pT3 48.5%, p < 0.0001) and with a Gleason score (PSA abnormal 60% in the Gleason score was >7 vs 29.5% in the Gleason score = 7 vs 27.3% in the Gleason score <7, p < 0.0001). In 114 patients pre-operative ChromograninA levels were elevated (23.5%). Serum ChromograninA levels had no significant association with PSA (p = 0.44) and pT stage (p = 0.89). abnormal ChromograninA levels increased from a Gleason score of <7 (25.5%) to >7 (31.4%) (p = 0.12). The serum ChromograninA levels in the two groups of patients were subdivided before and after 2005 on the basis of different used assays, showing no correlation with serum ChromograninA and other parameters.

Conclusions

This study showed that ChromograninA levels correlated to NE differentiation and possible aggressiveness of PC. Pre-operative circulating ChromograninA could complement PSA in selecting more aggressive PC cases, particularly in the presence of a higher Gleason score. Complementary information is provided by the absence of a correlation between serum ChromograninA and PSA levels.