A nutraceutical combination improves insulin sensitivity in patients with metabolic syndrome

AIM:To test the efficacy of a proprietary nutraceutical combination in reducing insulin resistance associated with the metabolic syndrome(MetS).METHODS:Sixty-four patients with MetS followed at a tertiary outpatient clinic were randomly assigned to receive either placebo or a proprietary nutraceutical combination(AP)consisting of berberine,policosanol and red yeast rice,in a prospective,double-blind,placebo-controlled study.Evaluations were performed at baseline and after 18 wk of treatment.The homeostasis model assessment of insulin resistance(HOMAIR)index was the primary outcome measure.Secondary endpoints included lipid panel,blood glucose and insulin fasting,after a standard mixed meal and after an oral glucose tolerance test(OGTT),ow-mediated dilation(FMD),and waist circumference.RESULTS:Fifty nine patients completed the study,2 withdrew because of adverse effects.After 18 wk there was a signif icant reduction in the HOMA-IR index in the AP group compared with placebo(ΔHOMA respectively-0.6 ± 1.2 vs 0.4 ± 1.9;P < 0.05).Total and low density lipoprotein cholesterol also significantly decreased in the treatment arm compared with placebo(Δlow density lipoprotein cholesterol-0.82 ± 0.68 vs-0.13 ± 0.55 mmol/L;P < 0.001),while triglycerides,high density lipoprotein cholesterol,and the OGTT were not affected.In addition,there were significant reductions in blood glucose and insulin after the standard mixed meal,as well as an increase in FMD(ΔFMD 1.9 ± 4.2 vs 0 ± 1.9 %;P < 0.05)and a significant reduction in arterial systolic blood pressure in the AP arm.CONCLUSION:This short-term study shows that AP has relevant beneficial effects on insulin resistance and many other components of MetS.     

Cardiovascular safety of acute recombinant human thyrotropin administration to patients monitored for differentiated thyroid cancer

Eleven patients who had undergone total thyroidectomy for differentiated thyroid cancer and who were on chronic TSH-suppressive therapy with levothyroxine (L-T4), underwent 24-h Holter electrocardiogram and Doppler-echocardiography before and after acute recombinant human TSH (rhTSH) administration for disease staging. The treatment, which was generally well tolerated, did not affect circulating thyroid hormones levels, nor did it have measurable effects on heart rate, rhythm, left ventricular morphology, or systo-diastolic function. Notably, arterial blood pressure tended to be slightly reduced after rhTSH administration, although in no instance did the patients become frankly symptomatic. Our data demonstrate that rhTSH does not alter cardiovascular function acutely. Consequently, it can safely be used in the routine staging of patients affected by differentiated thyroid cancer.     

Fistulosphincterotomy in the Endoscopic Approach to Biliary Tract Diseases

We report our experience with 49 patients who underwent fistulosphincterotomy (FS) after cannulation of the common bile duct (CBD) by standard approaches had failed, due to suspected CBD obstruction. Only 4% of our cases turned out to have no biliary obstruction at all. The morbidity rate was 16%, and the mortality rate was 2%. In our series, FS raised the success rate of CBD cannulation from 90% to 96%. Ninety-five percent of successful cannulations were followed by endoscopic treatment. There were no cases of perforation or hemorrhage, and no difference in the success rate between FS in flat papillas and FS in bulging papillas, thanks, perhaps, to the technique we used. Our findings would indicate that FS is a useful procedure involving additional but not prohibitive risks. Nonetheless, it should be used only when CBD obstruction is strongly suspected and standard methods are not successful.     

Antiestrogens upregulate estrogen receptor beta expression and inhibit adrenocortical H295R cell proliferation

The molecular mechanisms involved in adrenocortical tumorigenesis are still not completely understood. In this study, using the H295R cell line as a model system, we investigated the role of estrogens and estrogen receptor (ER) alpha and ER beta in the growth regulation of adrenocortical tumors. We demonstrated that H295R cells are able to convert androgens to estrogens by a constitutive expression of active cytochrome P450 aromatase protein and express ER beta to a greater extent than ER alpha. Moreover, physiological concentrations of 17beta-estradiol (E2) determined an increase of thymidine incorporation, suggesting the presence of an autocrine mechanism in maintaining H295R cell proliferation. Evaluating the response to ER antagonists like 4-hydroxytamoxifen (OHT) and ICI 182 780 (ICI), we observed an up-regulation of ER beta and a dose-dependent inhibition of H295R cell proliferation. Whereas ICI determined the growth arrest of H295R cells, OHT induced morphological changes that were characteristic of apoptosis. According to the above-mentioned observations, OHT but not ICI clearly induced a marked expression of FasL and the cleavage of both caspase-8 and caspase-3. Interestingly, the apoptotic effects of OHT in H295R cells may be consequent to the enhanced levels of ER beta which stimulate the expression of FasL interacting with activating protein (AP)-1 sites located within its promoter sequence. In conclusion, we have demonstrated that H295R cells are able to transform androgens to estrogens that activate an autocrine mechanism, mediated by their own receptors, and contribute to regulate the proliferation of these cells. Moreover, this study points towards a role for ER beta as an important mediator of the repressive effects exerted by antiestrogens on H295R cells; however, further studies are needed to clarify its role in the control of adrenocortical cell proliferation and on the potential benefits of antiestrogens for treatment of adrenocortical cancer.     

Three cases of bartonellosis (cat scratch disease)

In the last years the number of Bartonella species has conspicuously increased, with better clinical and diagnostic definitions of the different related illnesses. We report, in the present article, 3 cases of cat-scratch disease, a particular bartonellosis mainly caused by Bartonella henselae which is transmitted by the cat. After an incubation period, cat-scratch disease clinically manifests as a regional lymphoadenitis, with the appearance of a small cutaneous lesion at the site of inoculation of the germ. The pathogenetic agent is susceptible to a number of antibacterial agents, such as penicillin, cephalosporins, aminoglycosides, tetracyclines, macrolides, quinolones, trimethoprim combined with sulphamethoxazole and rifampicin. The prognosis is usually favorable.     

Targeted Gene Addition in Human Epithelial Stem Cells by Zinc-finger Nuclease-mediated Homologous Recombination

Preclinical and clinical studies showed that autologous transplantation of epidermis derived from genetically modified epithelial stem cells (EpSCs) leads to long-term correction of inherited skin adhesion defects. These studies were based on potentially genotoxic retroviral vectors. We developed an alternative gene transfer strategy aimed at targeting a “safe harbor” locus, the adeno-associated virus integration site 1 (AAVS1), by zinc-finger nuclease (ZFN)-induced homologous recombination (HR). Delivery of AAVS1-specific ZFNs and a GFP-expressing HR cassette by integration-defective lentiviral (LV) vectors (IDLVs) or adenoviral (Ad) vectors resulted in targeted gene addition with an efficiency of >20% in a human keratinocyte cell line, >10% in immortalized keratinocytes, and <1% in primary keratinocytes. Deep sequencing of the AAVS1 locus showed that ZFN-induced double-strand breaks are mostly repaired by nonhomologous end joining (NHEJ) in primary cells, indicating that poor induction of the HR-dependent DNA repair pathway may be a significant limitation for targeted gene integration. Skin equivalents derived from unselected keratinocyte cultures coinfected with a GFP-IDLV and a ZFN-Ad vector were grafted onto immunodeficient mice. GFP-positive clones were observed in all grafts up to 18 weeks post-transplantation. By histological and molecular analysis, we were able to demonstrate highly efficient targeting of the AAVS1 locus in human repopulating EpSCs.