Non lipid, dose-dependent effects of pravastatin treatment on hemostatic system and inflammatory response

Objectives: The aim of the present study was to evaluate the effects of pravastatin treatment on lipid, inflammation, and coagulation parameters in patients suffering from myocardial infarction with or without carotid atherosclerotic lesions (groups 1 and 2, respectively). Methods: In the first phase of the study, a cross-sectional comparison of lipid, inflammation, and coagulation parameters was performed between the patients and the control group (group 3). Highly significant differences in these parameters were observed, especially in group 1. In the second phase of the study, we assessed the effects of a persistent reduction in cholesterol synthesis induced by increasing doses of pravastatin (20 mg daily for 8 weeks and 40 mg daily for a further 8 weeks). In addition to the well-established lipid-lowering effect, significant changes in inflammation and coagulation parameters were observed. In particular, pravastatin at a dosage of 20 mg/day significantly reduced only fibrinogen levels, while at a dosage of 40 mg/day significantly reduced factor VII, fibrinogen, prothrombin fragments 1 and 2, thrombin–antithrombin complexes, tissue plasminogen activator antigen (tPA:Ag) before venous occlusion (b.o.), inhibitor of plasminogen activator activity (PAI) b.o., PAI activity after occlusion (a.o.), the human autoantibodies against oxidized low-density lipoprotein (LDL), and the c fraction of the third component system levels, and significantly increased tPA:Ag a.o. levels. Results: Our results show that in patients suffering from myocardial infarction the risk of thrombotic complications can be decreased with pravastatin, especially by larger doses. However, the relationship must be further investigated because the observed reductions in the hemostatic system and inflammatory response seemed to be dose dependent, while the effects of pravastatin treatment were not significantly correlated with total and LDL cholesterol changes. Received: 14 June 1999 / Accepted in revised form: 9 March 2000     

Systematic review of radiological imaging for hepatocellular carcinoma in cirrhotic patients

We systematically reviewed the evidence for determining the best radiological imaging for characterizing hepatocellular carcinoma (HCC) in cirrhotic patients in 997 articles between 1995 and 2001. We selected only prospective and retrospective cohorts of patients, excluding both case reports and studies without separate data on HCC. Only 29 studies, comprising 918 patients, fulfilled the inclusion criteria: 10 used the explanted liver as the reference standard of diagnosis. All except one, either found no statistically significant difference between imaging modalities or had no direct comparison of sensitivity between different modalities of imaging; 16 studies evaluated HCC among cirrhotic patients and had biopsy or imaging as the reference standard for diagnosis. However, no one imaging technique was shown to be superior. In two studies, data of a HCC subgroup was derived from the studies evaluating different kinds of focal hepatic lesions. No conclusion could be drawn because of the small sample size. One study addressed the issue of therapeutic impact. The evidence for choosing the best modality of imaging for characterizing HCC in cirrhotic patients is inadequate. Large multicentre studies with defined reference standards for diagnosis, and studies evaluating therapeutic impact are needed.     

Hepatitis B virus infection among health care workers at an urban teaching hospital in southern Italy: A low occupational hazard?

A prevalence study of HBV serologic markers was carried out among hospital employees of ten departments of the Second School of Medicine in Naples, an urban area with a high prevalence of HBV infection.Departments and occupational categories were selected to represent a spectrum of different exposure to B virus infection. Workers in a large electronic plant in the same geographical area were screened as controls. HBsAg prevalence was 4.8% in the hospital community and 4.0% in control group. It rises to 4.3% in the Campania Region, where all screened workers live, and in some specific areas of the same region it rises to 12%. But no significant difference among seropositivities for at least 1 marker of HBV, considered to be a better indicator of occupational hazard, was found among personnel of different departments or belonging to different occupational categories. None of the occupational and non-occupational risk factors studied was found to be significantly associated with HBV infection.Two years later, an incidence study was carried out among susceptible subjects. Seropositivity for 1 marker was 2.2% among hospital workers and 2.8% in the control group. These figures are lower than the annual attack rate (5%) required for an acceptable cost-benefit ratio of vaccination against hepatitis B.Our results indicate that in a geographical area with HBV endemicity the occupational hazard for B virus infection is low in hospital workers because of the high number of immunized subjects and the contacts with infected people out of the hospital.     

Homocysteinemia is inversely correlated with platelet count and directly correlated with sE- and sP-selectin levels in females homozygous for C677T methylenetetrahydrofolate reductase

Plasma homocysteine levels depend in part on the molecular nature of the methylenetetrahydrofolate reductase (MTHFR) and on blood folate intake. Little has been reported on platelet counts in the presence of hyperhomocysteinemia and MTHFR polymorphisms, with the exception of delayed platelet recovery in homozygous MTHFR C677T subjects after treatment with methotrexate for ovarian cancer. The aim of this investigation was to evaluate the possibility of a link between the platelet count and plasma homocysteine levels in different MTHFR variants in 165 female patients. Determinations of plasma homocysteine levels were by ELISA and of MTHFR polymorphisms (A1298C and C677T) were by inverse hybridization. Serum P- and E-selectin concentrations were obtained by ELISA. An inverse correlation (R=-0.88, P<0.001) was observed between blood platelet counts and plasma homocysteine levels in the women homozygous for MTHFR C677T. This correlation did not depend on pregnancy or other variables reported. Serum concentrations of sE- and sP-selectin, markers of endothelial and platelet activation, were significantly and positively correlated with homocysteine levels. These findings suggest that homocysteine affects platelet numbers in women with MTHFR C677T possibly consequent to endothelial and platelet activation.     

Factors affecting diabetes mellitus onset in cystic fibrosis: evidence from a 10-year follow-up study

This study reports the results of genotype characterization and of a 10-y prospective evaluation of clinical status, glucose tolerance and insulin secretion in 28 originally normoglycaemic patients with cystic fibrosis (CF). The aim of the study was to assess whether any genetic, clinical or metabolic parameters could identify in advance those patients at risk of developing diabetes mellitus over time. During the follow-up 42.8% of patients became diabetic. Neither gender, age nor clinical parameters were significantly different at entry in the patients who eventually developed diabetes compared with those who did not. Insulin secretion during oral glucose tolerance tests (OGTT) deteriorated over time in both groups, whereas a progressive deterioration of glucose tolerance was only evident in the patients who developed diabetes and increased baseline glucose areas were the only predictive parameter of diabetes onset. Genotype analysis revealed significant differences between patients with and without diabetes: ΔF508 homozygosis was more frequent in the first group and N1303K mutation in the second group. In conclusion, in CF: (i) increased glucose areas during OGTT and deterioration of glucose tolerance over time can predict the evolution towards diabetes; and (ii) ΔF508 homozygosis may predispose to the risk of diabetes, whilst N1303K mutation seems to play a protective role.     

Methyl-beta-cyclodextrin treatment affects the thermotropic behaviour of membranes and detergent-resistant membrane fractions of cultured A431 cells

Membranes and detergent-resistant membrane fractions isolated from human epidermoid carcinoma A431 cells after treatment with methyl-beta-cyclodextrin, a compound commonly used in pharmaceutical applications and in manipulation of membrane cholesterol content, display thermotropic transitions at about 15 degrees C and above 37 degrees C, respectively, when analyzed by differential scanning calorimetry. The transitions, absent in untreated cells, were reversible upon cycling through heating and cooling scans, and attributable to lipid components of the membranes, possibly sphingolipids. These results suggest that, after treatment with methyl-beta-cyclodextrin, membranes may show thermotropic transitions, an unusual feature for cellular bilayers, which is likely to influence biological functions.     

The Nutraceutical N-Palmitoylethanolamide (PEA) Reveals Widespread Molecular Effects Unmasking New Therapeutic Targets in Murine Varicocele

Varicocele is an age-related disease with no current medical treatments positively impacting infertility. Toll-like receptor 4 (TLR4) expression is present in normal testis with an involvement in the immunological reactions. The role of peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor, in fertility is still unclear. N-Palmitoylethanolamide (PEA), an emerging nutraceutical compound present in plants and animal foods, is an endogenous PPAR-α agonist with well-demonstrated anti-inflammatory and analgesics characteristics. In this model of mice varicocele, PPAR-α and TLR4 receptors’ roles were investigated through the administration of ultra-micronized PEA (PEA-um). Male wild-type (WT), PPAR-α knockout (KO), and TLR4 KO mice were used. A group underwent sham operation and administration of vehicle or PEA-um (10 mg/kg i.p.) for 21 days. Another group (WT, PPAR-α KO, and TLR4 KO) underwent surgical varicocele and was treated with vehicle or PEA-um (10 mg/kg i.p.) for 21 days. At the end of treatments, all animals were euthanized. Both operated and contralateral testes were processed for histological and morphometric assessment, for PPAR-α, TLR4, occludin, and claudin-11 immunohistochemistry and for PPAR-α, TLR4, transforming growth factor-beta3 (TGF-β3), phospho-extracellular signal-Regulated-Kinase (p-ERK) 1/2, and nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) Western blot analysis. Collectively, our data showed that administration of PEA-um revealed a key role of PPAR-α and TLR4 in varicocele pathophysiology, unmasking new nutraceutical therapeutic targets for future varicocele research and supporting surgical management of male infertility.     

Multimodal imaging of dry age‐related macular degeneration

Purpose: The purpose of this study was to understand clinical significance of near‐infrared reflectance (NIR), blue fundus autofluorescence (FAF) and near‐infrared autofluorescence (NIA) in dry age‐related macular degeneration (AMD), by correlation with fluorescein angiography (FA) and cross‐sectional spectral domain optical coherence tomography (SD OCT). Methods: We evaluated 110 eyes (62 patients, mean age: 64 ± 8 years) diagnosed with dry AMD between January 2010 and December 2010, which underwent NIR (λ = 830 nm), FAF and FA (excitation λ = 488 nm; emission λ > 500 nm), NIA (excitation λ = 787 nm; emission λ > 800 nm), and simultaneous SD OCT scanning using a combined confocal scanning laser ophthalmoscope/SD OCT device (Spectralis HRA + OCT; Heidelberg Engineering, Heidelberg, Germany). Results: Drusen showed variable increased/decreased NIR, FAF, NIA and FA, which corresponded to variable increased/decreased thickness of the retinal pigment epithelium (RPE) and possible presence of subretinal deposits on SD OCT. Geographic atrophy (GA) was present in 43/110 eyes (39.0%) and showed increased NIR and fluorescence (FA), absent FAF and NIA, and loss of RPE on SD OCT. The hyperautofluorescence of the GA margin was never larger in FAF than that in NIA, while in 16.2% of cases, it was larger in NIA than that in FAF and corresponded to mild choroidal hyperreflectivity on SD OCT. Conclusions: Simultaneous recording of SD OCT scans provided ultrastructural data for the evaluation of NIR, FAF, NIA and FA in dry AMD. Near‐infrared autofluorescence might detect earlier than FAF areas of RPE cell loss at the GA margin.