Simvastatin,transdermal patch,and oral estrogen-progestogen preparation in early-postmenopausal hypercholesterolemic women: a randomized,placebo-controlled clinical trial

Hormone replacement therapy (HRT) seems to have a favorable influence on the plasma lipid profile. Only a few investigations have examined the effects of HRT versus hepatic hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors. We compared the relative effects of different hypolipidemic strategies on lipoproteins and coagulative parameters in women with recent-onset spontaneous menopause. In this 24-week, placebo-controlled trial, 60 consecutive healthy women aged >/= 45 years, with amenorrhea from 6 to 60 months (mean, 1.9 +/- 1.4 years), serum follicle stimulating hormone (FSH) greater than 40 U/L, and slight to moderate hypercholesterolemia (low-density lipoprotein-cholesterol [LDL-C] 160 to 250 mg/dL, high-density lipoprotein-cholesterol [HDL-C] < 75 mg/dL, and triglycerides < 200 mg/dL) were enrolled and randomized to dietetic advice (placebo group), simvastatin 10 mg, 0.625 mg of conjugated equine estrogen (CEE), or 50 microg estrogen transdermal patch (ETP). In the latter 2 cases, the progestative nomegestrol was added to estrogens (days 17 to 28 of the cicle). Lipoprotein parameters were evaluated after separating very-low-density lipoproteins (VLDLs) by ultracentrifugation, while fasting glucose and insulin, homocysteine, and hemocoagulative parameters were determined in plasma. Fifty-four patients completed the trial. Total cholesterol (TC) and LDL-C significantly decrased in the simvastatin (-62 mg/dL [-20%] and -72 mg/dL [-30%], respectively), CEE (-42 mg/dL [-13%] and -45 mg/dL [-18%]), and ETP (-30 mg/dL [-10%] and -26 mg/dL [-11%]) groups compared to baseline, but only simvastatin showed an effect significantly superior to diet alone. Apolipoprotein (Apo) B was decreased by simvastatin (-25%, P <.001) and by CEE (-10%, P <.05); again, simvastatin was more effective than either diet or ETP. Triglyceride concentration and VLDL-C were unmodified by treatments. HDL-C and Apo A-I significantly increased in the simvastatin group (+18% and +8%, respectively), while HDL-C was unmodified by both HRT regimens and Apo A-I was reduced by ETP treatment (-17%); lipoprotein[a] (Lp[a]) was decreased by both HRTs (-38%, P <.05, and -22%, P =.07, for CEE and ETP, respectively). Among coagulative parameters, plasminogen activator inhibitor-1 (PAI-1) was significantly reduced by CEE (-29%, P <.05) but not ETP treatment (+16%, P = not significant), while fibrinogen, antithrombin, and homocysteine were unaffected by therapy. Thus, HRT, particularly CEE, seems well tolerated and moderately effective in improving the lipid pattern and, perhaps, the coagulative/fibrinolytic balance in postmenopausal hypercholesterolemic women; it may represent a therapeutic option in slightly dyslipidemic subjects. Statins are preferred in case of more severe disease.     

Long-term outcome of neoadjuvant systemic therapy for locally advanced breast cancer in routine clinical practice

Purpose

The aim of this study is to evaluate the long-term outcome of patients with locally advanced breast cancer treated with neoadjuvant systemic chemotherapy (NST) in routine clinical practice.

Methods

Four hundred and nine patients were identified between January 1999 and December 2011. All patients received NST followed by surgery, adjuvant treatments and radiotherapy, as appropriate.

Results

At Kaplan–Meier analysis, patients with surgical stage III disease were more likely to develop distant metastasis and die from breast cancer (p < 0.001). Luminal A and luminal B/HER2-negative patients had better prognosis; moreover, patients with hormone receptor (HR)-positive tumors had a significantly longer DRFS (p < 0.0049) and OS (p < 0.0001) compared with patients with HR-negative tumors as well as patients who underwent breast-conserving surgery (DRFS and OS: p < 0.001). In multivariate analysis, HR negativity (p < 0.001 for both DRFS and OS), mastectomy (DRFS: p = 0.009; OS: p = 0.05) and stage III disease (DRFS: p < 0.001; OS: p = 0.003) were associated with shorter DRFS and OS.

Conclusions

HR negativity, mastectomy and pathological stage III disease are the variables independently associated with a worse outcome in our cohort of patients. These data are of high interest since they derive from a very heterogeneous group of patients, treated with different neoadjuvant/adjuvant regimens outside of clinical trials and with a long follow-up period.     

Platelet Activation Favours NOX2-Mediated Muscle Damage in Elite Athletes: The Role of Cocoa-Derived Polyphenols

Mechanisms of exercise-induced muscle injury with etiopathogenesis and its consequences have been described; however, the impact of different intensities of exercise on the mechanisms of muscular injury development is not well understood. The aim of this study was to exploit the relationship between platelet activation, oxidative stress and muscular injuries induced by physical exercise in elite football players compared to amateur athletes. Oxidant/antioxidant status, platelet activation and markers of muscle damage were evaluated in 23 elite football players and 23 amateur athletes. Compared to amateurs, elite football players showed lower antioxidant capacity and higher oxidative stress paralleled by increased platelet activation and muscle damage markers. Simple linear regression analysis showed that sNOX2-dp and H₂O₂, sCD40L and PDGF-bb were associated with a significant increase in muscle damage biomarkers. In vitro studies also showed that plasma obtained from elite athletes increased oxidative stress and muscle damage in human skeletal muscle myoblasts cell line compared to amateurs’ plasma, an effect blunted by the NOX2 inhibitor or by the cell treatment with cocoa-derived polyphenols. These results indicate that platelet activation increased muscular injuries induced by oxidative stress. Moreover, NOX2 inhibition and polyphenol extracts treatment positively modulates redox status and reduce exercise-induced muscular injury.     

Hyperparathyroidism associated with thyroid pathology

BACKGROUND: The pathological association between thyroid and parathyroid gland disease is here discussed. The multiphase analyzer has revealed a new type of subclinical primary hyperparathyroidism (HPP) and the role of surgery in these cases is not clear. METHODS: This is a prospective study of all cases of thyroid disease in association with parathyroid disease treated surgically in our Institute from July 1999 to June 2001. RESULTS: Of the 221 thyroidectomies carried out, 29 patients had an elevated preoperative serum level of parathyroid hormone (PTH). An ultrasonography examination was performed on all patients and a preoperative scanning with 99Tc-MIBI on 11 of 29 patients. We examined intraoperatively 19 cases of HPP (14 parathyroid adenoma, 5 hyperplasia). In 10 cases we observed a normal size of the parathyroid gland and we did not perform a parathyroidectomy. CONCLUSIONS: All patients with elevated serum parathyroid hormone and serum calcium levels before thyroidectomy should be considered candidates also for surgery to the parathyroid glands. The pathological association between thyroid and parathyroid gland diseases is not rare. We must conduct an accurate neck exploration in all these cases.     

Effects of type-I and -II interferons on 90K antigen expression in ovarian carcinoma cells

Antigen 90K is produced by several tumor-cell lines and by patients with cancer. Its function has not yet been clarified, although recent reports suggest that it plays a role in the tumor—host relationship—for example by stimulation of natural killer and lymphokine-activated killer-cell activity. Previous studies have indicated that 90K expression may be under the influence of interferon-α. Here, we provide evidence that both interferon-α and -γ can enhance the secretion of 90K and augment the level of specific mRNA expression in 3 ovarian carcinoma cell lines (OVCAR-3, HTB-77 and SKOV-6). However, interferon-γ leads to depletion of cellular 90K whereas interferon-α increases both secreted and cellular 90K levels. In equimolar concentrations, Interferon-α was always superior to interferon-γ in augmenting 90K protein or mRNA levels. Combinations of TNF with interferon-γ were highly synergistic both in reducing cell proliferation and in increasing 90K secretion and mRNA expression. This synergism was seen to a lesser extent with interferon-α.     

Bronchial hyperresponsiveness in adults with seasonal and perennial rhinitis: is there a link for asthma and rhinitis?

Epidemiological studies have shown that asthma and rhinitis often coexist in the same patients and the prevalence of asthma is greater in patients with rhinitis. The aim of this study was to evaluate the differences in bronchial reactivity in subjects with seasonal and perennial rhinitis. We enrolled 128 subjects with seasonal or perennial allergic rhinitis divided into three groups: A with perennial rhinitis and allergy to Dermatophagoides Pteronissynus; B with seasonal rhinitis and allergy to Graminae and Parietaria, who underwent methacholine challenge test (MCHt) during the exposure period (fron March until May); C with seasonal rhinitis and allergy to Graminae and Parietaria, who underwent MCHt during the non exposure period (from June until February). The PC20 mean values of group A (1774.8 ± 20.7) and group B (1740.7 ± 38.8) were not significantly different, but significantly lower than those of group C (3010.0 ± 56.9) (p=0.001). The subjects with group A were positive to the MCHt in 54.54%, against 29.28% of group B and 11.62% of group C (p=0.007). The results show differences in the degree of bronchial responsiveness. The dose-response curves documented a lower value of PC20 in the group with perennial rhinitis and a statistically significant difference of bronchial hyperresponsiveness prevalence between the three groups (p=0.007).     

A spectrum of antibody (IgG. IgG1, IgM) response in mice infected with trichinella spiralis treated with L-mimosine

The purpose of this study was to demonstrate the anti-inflammatory effects of L-mimosine on chronic inflammation, by investigating its effect on the immunological response of BALB/c mice infected with the nematode parasite Trichinella spiralis. Specific anti-parasite immunoglobulins (IgG, IgG1 and IgM) were detected by the ELISA method in the serum of both the treated and the untreated animals at different periods of time for 60 days post infection. Two groups consisting of 18 mice each were used. The mice were 6 weeks of age. Both groups were infected with 220 larvae (L1-T. spiralis) per os: one group was administered an intraperitoneal injection of L-mimosine (200 &mgr;g/100 ml/dose) for 27 days (the first injection started 7 days before infection) and the second group was administered an intraperitoneal injection of saline solution (100 &mgr;l/dose). Parasite specific IgG, IgG1 and IgM levels were determined in the sera of infected, untreated mice. The levels of IgG and IgG1 were increased following infection and remained elevated throughout the experimental period, while IgM was significantly decreased on the 50th day post-infection. These levels were found to be lower in the L-mimosine treated infected mice, compared to the untreated mice. The inhibition started from day 10 and continued until day 60. In healthy animals, the production of immunoglobulins was not measurable. Non-infected animals treated with L-mimosine also showed no detectable anti-parasite specific immunoglobulins.     

A mutant form of the Wilms' tumor suppressor gene WT1 observed in Denys-Drash syndrome interferes with glomerular capillary development

The Wilms' tumor suppressor gene WT1 encodes a zinc finger protein that is required for urogenital development. In the kidney, WT1 is most highly expressed in glomerular epithelial cells or podocytes, which are an essential component of the filtering system. Human subjects heterozygous for point mutations in the WT1 gene develop renal failure because of the formation of scar tissue within glomeruli. The relationship between WT1 expression in podocytes during development and glomerular scarring is not well understood. In this study, transgenic mice that expressed a mutant form of WT1 in podocytes were derived. The capillaries within transgenic glomeruli were dilated, indicating that WT1 might regulate the expression of growth factors that affect capillary development. Platelet endothelial cell adhesion molecule-1 expression was greatly reduced on glomerular endothelial cells of transgenic kidneys. These results suggest that WT1 controls the expression of growth factors that regulate glomerular capillary development and that abnormal capillary development might lead to glomerular disease.     

Changes of topoisomerase IIalpha expression in breast tumors after neoadjuvant chemotherapy predicts relapse-free survival.

PURPOSE: To assess the value of changes in the expression of topoisomerase IIalpha (TopoII) and the proto-oncogene erbB-2 (HER-2) as predictors of relapse-free survival in women with operable breast cancer treated with anthracycline-based neoadjuvant chemotherapy. PATIENTS AND METHODS: Seventy-seven patients with primary breast cancer who had undergone neoadjuvant anthracycline-based chemotherapy were included in the present study. TopoII and HER-2 were measured by immunohistochemistry in prechemotherapy and postchemotherapy (at the time of surgery) tumor specimens, and the value of their changes as predictors of relapse-free survival were evaluated by Kaplan-Meier and Cox proportional hazard regression analyses. RESULTS: Neoadjuvant chemotherapy resulted in a significant reduction in the percentage of cells expressing TopoII (P < 0.0001). No significant change was observed for HER-2. TopoII and HER-2 expression before chemotherapy predicted tumor response to treatment. Changes in TopoII expression after chemotherapy were strongly associated with a poor relapse-free survival (P < 0.0001) in a Cox multivariate analysis adjusted for other clinicopathologic prognostic factors. CONCLUSION: Changes in TopoII expression after anthracycline-based neoadjuvant chemotherapy is an independent predictor of a poor relapse-free survival in patients with breast cancer. Tumor cells displaying an increased TopoII expression after treatment may be responsible for relapses, and may, therefore, define a group of patients with anthracycline-resistant breast cancer.