Association of SULT1A1 Arg²¹³His polymorphism with male breast cancer risk: results from a multicenter study in Italy.

Male breast cancer (MBC) is rare and poorly understood. Like female breast cancer (FBC), MBCs are highly sensitive to hormonal changes, and hyperestrogenism, specifically, represents a major risk factor for MBC. MBC is considered similar to late-onset, post-menopausal estrogen/progesteron receptors positive FBC (ER+/PR+). Sulfotransferase 1A1 (SULT1A1) is an enzyme involved in the metabolism of estrogens. Recently, SULT1A1 common functional polymorphism Arg(213)His (638G>A) variant has been found to be associated with increased breast cancer (BC) risk, particularly in post-menopausal women. For this reason, we decided to explore whether SULT1A1 Arg(213)His could exert an effect on MBC development. The primary aim of this study was to evaluate the influence of the SULT1A1 Arg(213)His polymorphism on MBC risk. The secondary aim was to investigate possible associations with relevant clinical-pathologic features of MBC. A total of 394 MBC cases and 786 healthy male controls were genotyped for SULT1A1 Arg(213)His polymorphism by PCR-RFLP and high-resolution melting analysis. All MBC cases were characterized for relevant clinical-pathologic features. A significant difference in the distribution of SULT1A1 Arg(213)His genotypes was found between MBC cases and controls (P < 0.0001). The analysis of genotype-specific risk showed a significant increased MBC risk in individuals with G/A (OR 1.97, 95% CI 1.50-2.59; P < 0.0001) and A/A (OR 3.09, 95% CI 1.83-5.23; P < 0.0001) genotypes in comparison to wild-type genotype, under co-dominant model. A significant association between SULT1A1 risk genotypes and HER2 status emerged. Results indicate that SULT1A1 Arg(213)His may act as a low-penetrance risk allele for developing MBC and could be associated with a specific tumor subtype associated with HER2 overexpression.

Insulin resistance and hyperinsulinemia: No independent relation to left ventricular mass in humans.

BACKGROUND: Hyperinsulinemia and insulin resistance may contribute to the development of cardiac hypertrophy. In humans, however, the evidence is inconclusive. METHODS AND RESULTS: We studied 50 nondiabetic subjects covering a wide range of age (20 to 65 years), body mass index (BMI, 19 to 40 kg x m(-2)), and mean blood pressure (72 to 132 mm Hg). Plasma insulin concentrations and secretory rates were measured at baseline and during an oral glucose tolerance test; insulin sensitivity was measured by the insulin clamp technique. Left ventricular mass (LVM) (by 2D M-mode echocardiography) was distributed normally and was higher in obese (BMI >/=27 kg x m(-2), n=16) or hypertensive patients (blood pressure >140/90 mm Hg, n=21) (50+/-8 and 55+/-10 g x m(-2.7), respectively) than in 13 nonobese, normotensive subjects (40+/-8 g x m(-2.7), P:=0.0004). In a multivariate model adjusting for sex, age, BMI, and blood pressure, neither insulin concentrations (fasting or postglucose) nor insulin sensitivity or secretory rates were significant correlates of LVM. Systolic blood pressure (P:=0.003) and BMI (P:=0.01) were the only independent correlates of LVM. From the regression, the impact of hypertension (as a systolic pressure of 180 versus 140 mm Hg=+20%) was twice as large as that of obesity (as a BMI of 35 versus 25 kg x m(-2)=+11%), the two factors being additive. CONCLUSIONS: When adequate account is taken of body mass and blood pressure, insulin, as concentration, secretion, or action, is not an independent determinant of LVM in nondiabetic subjects.

Melatonin's growth-inhibitory effect on hepatoma AH 130 in the rat.

We tested the effects of daily melatonin treatment on the growth of the ascites hepatoma in rats, determining survival time, cell number and cell cycle phases at various stages of tumor development. Melatonin inhibited cellular proliferation, doubled mean life-time and increased survival. Thymidine incorporation in hepatoma cells from treated rats decreased significantly without changes in the apoptotic index. Flow cytometric analysis showed that melatonin slowed cell cycle progression by increasing the number of cells in phase G0G1. Thus, similar to in vitro models, melatonin's oncostatic action in vivo appears to be directed to specific cell cycle mechanisms, which remain to be elucidated.

Gemcitabine plus Epi-doxorubicin as first-line chemotherapy for bladder cancer in advanced or metastatic stage: a phase II.

Combination chemotherapy with newer, more active drugs in patients with advanced and/or metastatic bladder cancer might show improved response rate and survival. Gemcitabine (GEM) and Epidoxorubicin (EPI) have demonstrated activity in this disease. In addition, experimental studies in vitro have shown that the two agents have additive-synergistic effects when used in combination. Our prior phase I dose-finding study in previously untreated patients with advanced or metastatic bladder cancer defined recommended doses for further trials of GEM 1000 mg/m2 and EPI 25 mg/m2 on days 1, 8 and 15 every 28 days. A phase II trial at this dose level was initiated in previously untreated patients to assess efficacy and toxicity. Eligible patients had measurable disease; Karnofsky performance status (PS) of > 40; no prior chemotherapy; and adequate bone marrow reserve, cardiac, hepatic and renal function. Thirty- one patients (22 males, 9 females) with median age of 64 (range 44-75) and median PS of 80 were accrued, and all were eligible. Twelve patients had T4N1-2 M0, 8 had lymph node only metastases, while 11 had visceral metastases (liver, bone, lung). A total of 181 cycles was administered (range 3-7 per patient). Major toxicities (WHO grade > or = 3) were: neutropenia in 5 patients, thrombocytopenia in 2 patients, and anemia in 2 patients. Three patients had febrile neutropenic episodes and only 3 patients required dose reduction. Grade 1-2 non-hematological toxicities included nausea/vomiting, stomatitis and alopecia. No cardiac toxicity was observed. Of the 30 response evaluable patients, 17 (57%) demonstrated a major response (3 complete and 14 partial) (95% CI: 39%-75%), 7 had stable disease (23%) and 6 progressed (20%). These preliminary results confirm the phase I observation that the combination of GEM--EPI is highly active in the treatment of advanced and metastatic bladder cancer with a favourable toxicity profile.

Melatonin as biological response modifier in cancer patients.

The neuroendocrine system modulates the immune response through neuropeptides and neurohormones, findings which point to the existence of a neuro-endocrine-immune system regulatory axis. At the same time, there is growing evidence that the pineal gland has anti-neoplastic properties, which include the action of its principal hormone, melatonin (MLT), on the immune system through the release of cytokines by activated T-cells and monocytes. The present study was carried out on 31 patients (19 males and 12 females, age range 46-73 years) with advanced solid tumors (7 gastric, 9 enteric, 8 renal, 5 bladder, 2 prostate) who either failed to respond to chemotherapy and radiotherapy or showed insignificant responses and were therefore shifted to MLT therapy (10 mg/die orally for 3 months). We obtained blood samples just before the start of MLT administration and after 30 days of therapy. Plasma was collected in EDTA tubes on ice, immediately centrifuged at 4 degrees C and stored frozen at -80 degrees C; samples were measured by immunoradiometric assays (Medgenix-Fleurus, Belgium) for tumor necrosis factor alpha (TNF), interleukin-1, 2 and 6 (IL-1, IL-2, IL-6) and interferon gamma (IFN). We used Student's paired t-test to compare each patient's cytokine circulating levels before and after MLT administration and found a significant differences (p < 0.05). After 3 months of therapy, none of our patients displayed adverse reactions to MLT or had to discontinue treatment. Nineteen patients (61%) showed disease progression. The other 12 (39%), however, achieved disease stabilization with no further growth of either the primary tumor or of secondaries; moreover, they experienced an improvement in their general well-being, in terms of Tchekmedyian's criteria, associated with a significative decrease of IL-6 circulating levels. These findings are consistent with the hypothesis that MLT modulates immune function in cancer patients by activating the cytokine system which exerts growth-inhibitory properties over a wide range of tumor cell types. Furthermore, by stimulating the cytotoxic activity of macrophages and monocytes, MLT plays a critical role in host defence against the progression of neoplasia.

Slow-releasing nicardipine in the treatment of Raynaud's phenomena without underlying diseases.

Calcium channel blockers have been used in the treatment of primary and secondary Raynaud's phenomenon (RP), and a beneficial effect was often recorded. The efficacy of slow-releasing nicardipine was assessed in a clinically homogeneous series of RP without underlying diseases in a randomized, double blind, cross-over and placebo controlled trial. Out of twenty-one selected patients (18 women and 3 men, mean age 46 +/- 12 yrs) eighteen completed the study and three dropped out, one for inadequate compliance and two due to headache. After a three-week period, slow-releasing nicardipine (20 mg two times daily) was significantly more useful than placebo: the number of RP episodes per week decreased (p less than 0.02), severity of discomfort and hand disability scores, evaluated after single RP attack, clearly improved (p less than 0.005 and p less than 0.02, respectively). According to clinical improvement, time of peak flow after postischemic reactive hyperaemia test was significantly reduced only after nicardipine (p less than 0.01). These results show that slow-releasing nicardipine is generally well tolerated and can provide effective improvement in RP patients without underlying diseases.

[Multivariate analysis of aminoacyl-tRNA synthetase activities of liver and hepatomas (author's transl)]. / Analisi multivariata delle attività aminoacil-tRNA sintetasiche del fegato e degli epatomi

Data on the aminoacyl-tRNA synthetase activities in normal liver and in three transplantable rat hepatomas, viz Yoshida's AH 130 and Morris's 5123C and 7793, were studied by means of factor analysis, a powerful technique of multivariate analysis particularly suitable foridentifying factors which theoretically may account for the pattern of interrelations between several variables. The analysis has been performed on 51 patterns of enzyme activities, covering 17 out of the 20 aminoacyl-tRNA synthetases; 80% on average of the total variability of the 17 enzyme activities may be accounted for by the first 4 factors extracted. The enzymes seem to fall into different groups, depending on their relationship with the factors thus identified. The results suggest that enzymes belonging to the same group share a common control mechanism, and are independent of the enzymes belonging to different groups, both in normal liver and in hepatomas.

[Essential monolateral hematuria: to operate or not to operate? Description of a case and review of the literature]. / Le ematurie monolaterali essenziali: operare o non operare? Descrizione di un caso e revisione della letteratura.

The case of a 31 years old female with monolateral essential hematuria is reported. Histological examination of the removed kidney showed only minute hemorrhagic spots beneath the epithelium of the calyces and the pelvis. The literature is reviewed; the benign character of this type of gross hematuria and attention for saving the kidneys was stressed.

[Echocardiographic parameters and systolic times in arterial hypertension in the elderly]. / Parametri ecocardiografici e tempi sistolici nell'ipertensione arteriosa dell'anziano.

In 40 subjects, 15 mean age 70.7 +/- 5.6 with systolic-diastolic hypertension, 15 mean age 75.5 +/- 6.8 years with systolic hypertension and 10 mean age 73.6 +/- 5.1 normotensive control group we have analyzed with M-mode 2D echocardiography and echophonocardiography the following parameters: diastolic--EDD--and systolic diameter--SD--of left ventricle, diastolic thickness of septum--SSD--and posterior wall--SPPD--of left ventricle, left ventricular ejection fraction--EF--(Theicholtr. formula), radius posterior wall thickness--R/SPPD--, left ventricular mass--LVM--(Devereux' formula), and systolic time intervals (Q-A2, LVET, PEP and PEP/LVET). The differences between groups are: systolic-diastolic hypertensive patients have increased EDD, SPPD and LVM, reduction of EF and increased PEP/LVET ratio in comparison with B and C groups; systolic hypertension doesn't increase EDD; SSD and PEP/LVET increase, while the EF remains within normal limits. In the healthy aged subjects SSD, SPPD and LVM are normal.

[Cardiovascular effects of amitriptyline in therapeutic dosages. Echocardiographic study]. / Effetti cardiovascolari dell'amitriptilina a dosaggi terapeutici. Studio ecocardiografico.

The authors studied the cardiovascular effects of amitriptyline at therapeutic plasma concentrations in 15 depressed patients (6 M. 9 F.) without cardiovascular disease both before treatment and after six months of therapy. The cardiovascular effects were evaluated by means of electrocardiographic and 2D-echocardiographic examinations in basal conditions and after hand-grip stress test. The effects of isometric hand-grip exercise (IHG) on left ventricular size and performance were studied non invasively in all patients at rest and after 3 min. of IHG at 30% of maximum contraction. Left ventricular internal diameter was measured at end-diastole and end-systole on LV echograms, and blood pressure was measured by sphygmomanometer. Our data confirmed the depressant effect of amitriptyline even on healthy myocardium, an effect that becomes manifest only at handgrip stress with a significant reduction of ejection fraction (form 70.6 to 66.4%; p < 0.001), while ECG and arterial blood pressure did not change throughout the study. This goes to show that treatment with tricyclic antidepressants always has a latent depressant effect on myocardial contractility that becomes clinically evident under stress, as well as in subjects with heart disease and in the elderly. Hence the need to monitor left ventricular function, as well as ECG and blood pressure, and to exercise great caution in prescribing tricyclic antidepressants to subjects with a history of myocardial failure.

[Effects of rehabilitation on cardiovascular autonomic function in ischemic cardiopathy]. / Effetti della riabilitazione sulla funzione autonomica cardiovascolare nella cardiopatia ischemica.

METHODS: Twenty patients with uncomplicated myocardial infarction randomized in two groups (group 1 and 2) of ten patients were investigated. Only group 1 trained four months according to a protocol of rehabilitation, whereas patients of group 2 followed their usual activity (control group). The autonomic cardiovascular function was estimated by Ewing's tests, that evaluate the variations of heart rate and blood pressure during deep breathing. RESULTS: Our data showed an increase of parasympathetic tone in group 1 (Valsalva ratio 1.55 +/- 0.28 vs 1.36 +/- 0.28, p < 0.01; variation in heart rate during deep breathing 17.3 +/- 4.6 vs 13.3 +/- 4.2). The sympathetic activity tests showed no significant difference after training. On the other hand, group 2 showed no significant difference in sympathetic and parasympathetic activity. CONCLUSIONS: In patients with uncomplicated myocardial infarction physical training increases the parasympathetic activity; as shown in the literature, such an increase can have clinical and prognostic importance, since improves cardiac performance and reduces the risk of sudden death from arrhythmic events.

Changes in autonomic regulation and ventricular repolarization induced by subclinical hyperthyroidism.

UNLABELLED: The aim of the present study was to evaluate the effect of subclinical hyperthyroidism (SHT) on cardiovascular autonomic function and ventricular repolarization. METHODS: Thirty subjects (25 females; mean age 49.6 ± 9.8 years) with SHT, as judged by reduced TSH serum levels and normal free T4 and T3 serum levels, and 30 age and sex-matched control subjects underwent standard 12-lead ECG, and 24h ambulatory ECG monitoring. The dispersion of the QT interval, an index of inhomogeneity of repolarization, and the heart rate variability (HRV), a measure of cardiac autonomic modulation, were studied. RESULTS: Patients with SHT showed higher QT dispersion (p<0.001) and lower HRV measures (0.01>p<0.001) than controls. In SHT patients, QT dispersion was inversely related to HRV (r=-0.47, p<0.01). CONCLUSION: The results of the present study demonstrated that SHT is associated with a sympathovagal imbalance, characterized by increased sympathetic activity in the presence of diminished vagal tone, and with an increased inhomogeneity of ventricular recovery times. The assessment of HRV and QT dispersion in patients with SHT may represent a useful tool in monitoring the cardiovascular risk of this condition.

Thyroid hormones and the cardiovascular system: pathophysiology and interventions.

Thyroid dysfunction, however mild, can significantly affect the cardiovascular (CV) system. The effects of thyroid hormones may be viewed as genomic and non-genomic, with the former occurring over a longer time scale and both affecting structural and functional proteins in CV tissue. As the interplay between thyroid function and the CV system becomes elucidated, particularly in the context of a system biology approach, the heart failure phenotype is better understood. Symptomatology is related to disturbance in inotropic and chronotropic function. Moreover, biochemical changes reflected by thyroid function testing with the non-thyroidal illness syndrome can prognosticate and guide therapy in heart failure. In addition, empiric treatment with thyroid hormone analogues or T3 represent emergent and highly controversial interventions.

Acute respiratory distress syndrome in an adult patient with a myelodysplastic disorder.

A 58-year-old man was diagnosed to have refractory anaemia with excessive blasts. After 3 1/2 years of relative control on periodic blood transfusions, the patient developed an acute leukaemia. Although the blastic crisis was not extreme (WBC counts less than 100 X 10(9)/l), a severe, intractable respiratory distress syndrome set in and brought the patient to the exitus in a few days. Overt signs of septic shock were absent, as was evidence of any other known cause of adult respiratory distress. Acute pulmonary failure can be the cause of death in leukaemic patients even in the absence of overwhelming sepsis or hyperleucocytosis.

[Echocardiographic study of left ventricular function in 2 different procedures]. / Studio ecocardiografico della funzione ventricolare sinistra in due diverse strategie emodialitiche.

Four patients on regular dialysis were studied by echocardiographic method during ultrafiltration sequential dialysis performed according to two different protocols: procedure 1: ultrafiltration alone (1 hour) followed by diffusive dialysis (3 hours); procedure 2: dialysis (3 hours) followed by ultrafiltration alone (1 hour). Blood pressure, heart rate, cardiac output, stroke volume, systolic and diastolic dimension of the left ventricle, systolic and diastolic volumes of the left ventricle, ejection fraction, shortening fraction and total peripheral vascular resistance index were measured. During ultrafiltration there is an increase of the total peripheral vascular resistance index. Myocardial contractility improves only during dialysis. Physiographic and therapeutic implications are discussed.