Muscle sympathetic nerve activity in patients with acromegaly

Muscle sympathetic nerve activity was measured in nine acromegalic patients (age, 35 +/- 4 yr; body mass index, 28 +/- 2 kg/m2) and eight healthy subjects (age, 32 +/- 3 yr; body mass index, 25 +/- 2 kg/m2) by combining the forearm arterial-venous difference technique with the tracer method [infusion of tritiated norepinephrine (NE)]. Muscle NE release was quantified both at rest and during physiological hyperinsulinemia while maintaining euglycemia (approximately 90 mg/dL) by means of the euglycemic clamp. Arterial plasma NE was similar in the two groups at rest (197 +/- 28 and 200 +/- 27 pg/mL (-1) and slightly increased during insulin infusion. Forearm NE release was 2.33 +/- 0.55 ng x liter(-1) x min(-1) in healthy subjects and 2.67 +/- 0.61 ng x liter(-1) x min(-1) in acromegalic subjects in the basal state and increased to a similar extent during insulin infusion in both groups (3.13 +/- 0.71 and 3.32 +/- 0.75 ng x L(-1) x min(-1), P < 0.05 vs. basal), indicating a normal stimulatory effect of insulin on muscle sympathetic activity. In contrast, insulin-stimulated forearm glucose uptake was markedly lower in acromegalic patients (2.3 +/- 0.4 mg x L(-1) x min(-1)) than in control subjects (7.9 +/- 1.3 mg x L(-1) x min(-1), P < 0.001), indicating the presence of severe insulin resistance involving glucose metabolism. Our data demonstrate that patients with long-term acromegaly have normal sympathetic activity in the skeletal muscle in the basal, postabsorptive state and normal increments in NE spillover in response to the sympatho-excitatory effect of insulin. Thus, the presence of severe insulin resistance in acromegaly is not accounted for by adrenergic mechanisms

Assessment of neuroactive steroids in cerebrospinal fluid comparing acute relapse and stable disease in relapsing-remitting multiple sclerosis

Previous studies have reported an involvement of neuroactive steroids as neuroprotective and anti-inflammatory agents in neurological disorders such as multiple sclerosis (MS); an analysis of their profile during a specific clinical phase of MS is largely unknown. The pregnenolone (PREG), dehydroepiandrosterone (DHEA), and allopregnanolone (ALLO) profile was evaluated in cerebrospinal fluid (CSF) in relapsing-remitting multiple sclerosis (RR-MS) patients as well as those in patients affected by non-inflammatory neurological (control group I) and without neurological disorders (control group II). An increase of PREG and DHEA values was shown in CSF of male and female RR-MS patients compared to those observed in both control groups. The ALLO values were significantly lower in female RR-MS patients than those found in male RR-MS patients and in female without neurological disorder. During the clinical relapse, we observed female RR-MS patients showing significantly increased PREG values compared to female RR-MS patients in stable phase, while their ALLO values showed a significant decrease compared to male RR-MS patients of the same group. Male RR-MS patients with gadolinium-enhanced lesions showed PREG and DHEA values higher than those found in female RR-MS patients with gadolinium-enhanced lesions. Similary, male RR-MS patients with gadolinium-enhanced lesions showed PREG and DHEA values higher than male without gadolinium-enhanced lesions. Female RR-MS patients with gadolinium-enhanced lesions showed DHEA values higher than those found in female RR-MS patients with gadolinium-enhanced lesions. Male and female RR-MS patients with gadolinium-enhanced lesions showed ALLO values higher than those found in respective gender groups without gadolinium-enhanced lesions. ALLO values were lower in male than in female RR-MS patients without gadolinium-enhanced lesions. Considering the pharmacological properties of neuroactive steroids and the observation that neurological disorders influence their concentrations, these endogenous compounds may have an important role as prognostic factors of the disease and used as markers of MS activity such as relapses

Safety and activity of trastuzumab-containing therapies for the treatment of metastatic breast cancer: our long-term clinical experience (GOIM study).

Background: Trastuzumab is widely used as the treatment of choice for HER2-positive metastatic breast cancer (MBC). Patients and methods: Seventy patients, median age 57 years and range 31–81 years, were included in our retrospective analysis with the aim to evaluate safety and activity of trastuzumab-containing therapies. Results: We observed for first-line treatment response rate (RR) 41%, stable disease (SD) 47% and time to progression (TTP) 8 months (range 1–44). Corresponding numbers for second line were RR 23%, SD 62% and (TTP) 9 months (range 3–23) and beyond second line RR 22%, SD 78% and (TTP) 9 months (range 4–19). Overall survival was 19.2 months (3–62 months). The median cumulative dose of trastuzumab administrated was 5286 mg (464–17 940 mg). Trastuzumab was well tolerated. Median left ventricular ejection function (LVEF) at baseline was 62% and at the end of treatment was 59%. The more relevant adverse events consisted of an asymptomatic decrease in LVEF to 40% (baseline 60%) and a grade 3 symptomatic increase in bilirubin. Conclusion: Trastuzumab-containing therapies in MBC show a good safety and toxicity profile and a remarkable activity even in heavily pretreated women. Patients should benefit from continued trastuzumab therapy, as shown by the maintenance of (TTP) even beyond second-line treatment

A randomized clinical trial of lithium in multiple system atrophy.

The aim of our study was to test the safety and tolerability of lithium in multiple system atrophy (MSA). The study was randomized, placebo-controlled, and double-blind. The primary endpoint of the study was safety and tolerability. An interim analysis, performed 1 year after the first patient was randomized, showed a higher proportion of trial abandon (P < 0.01) and a higher number of adverse events (P < 0.02) in the lithium group. The trial was stopped by the Data Monitoring Committee. Overall, lithium was not well tolerated, and we do not encourage future studies with lithium in MSA patients

Growth hormone- and pressure overload-induced cardiac hypertrophy evoke different responses to ischemia-reperfusion and mechanical stretch.

Objective. To compare the molecular, histological, and functional characteristics of growth hormone (GH)- and pressure overload-induced cardiac hypertrophy, and their responses to ischemia-reperfusion and mechanical stretch. Design. Four groups of male Wistar rats were studied: aortic banding (n = 24, AB) or sham (n = 24, controls) for 10 weeks, and GH treatment (n = 24; 3.5 mg/kg/day, GH) or placebo (n = 24, controls) for 4 weeks. At 13 weeks, the rats were randomly subjected to: (i) assessment of basal left ventricular mRNA expression of sarcoplasmic reticulum calcium-ATPase (SERCA-2), phospholamban (PLB), and Na+-Ca2+ exchanger (NCX) and collagen volume fraction (CVF) (Protocol A, 8 rats in each group); (ii) left ventricular no-flow ischemia with simultaneous evaluation of intracellular Ca2+ handling and ATP, phosphocreatine (PCr) and inorganic phosphate (Pi) content (Protocol B, 12 rats in each group),- or (iii) left ventricular mechanical stretch for 40 min with assessment of tumor necrosis-alpha (TNF-alpha) mRNA (Protocol C, 4 rats in each group). Protocol B and C were carried out in a Langendorff apparatus. Results. In Protocol A. no difference was found as to myocardial mRNA content of Ca2+ regulating proteins and CVF in GH animals vs controls. In contrast. in the AB group, myocardial mRNA expression of SERCA-2 and PLB was downregulated while that of NCX and CVF were increased vs. controls (p < 0.05). In Protocol B, recovery of left ventricular function was significantly decreased in AB vs GH goups and controls and this was associated with 1.6-fold increase in intracellular Ca2+ overload during reperfusion (p < 0.05). Baseline ATP content was similar in the four study groups, whereas PCr and Pi was lower in AB vs GH rats and controls. However, the time courses of high-energy phosphate metabolic changes did not differ during ischemia and reperfusion in the four study groups. In Protocol C, no detectable TNF-alpha mRNA level was found in the left ventricular myocardium of GH treated rats and controls at baseline, while a modest expression was noted in AB animals. Mechanical stretch resulted in de novo myocardial TNF-a mRNA expression in GH group and controls, which was dramatically increased in AB animals (approximate to 5-fold above baseline, p < 0.001). Conclusions. The data show that cardiac hypertrophy activated by short-term GH treatment confers cardioprotection compared with pressure overload with regard to molecular and histological characteristics, and responses to ischemia-reperfusion and mechanical stretch

Comparative proteomics of soluble factors secreted by human breast adipose tissue from tumor and normal breast

Tumor progression depends on the tumor-stroma interaction. In the breast, adipose tissue is the predominant stromal type. We have previously demonstrated that conditioned media (CMs) from explants of human adipose tissue of tumor breasts (hATT) increase proliferation and migration of breast cancer epithelial cells when compared to human adipose tissue from normal breasts (hATN). In this work, we aim to identify specific proteins and molecular/biological pathways associated with the secretion profile of hATT and hATN explants. hATT-CMs and hATN-CMs were separated by SDS-PAGE and analyzed by means of two-dimensional nano-liquid chromatography-mass spectrometry. The data was analyzed using ProteoIQ and FunRich software. In addition, 42 cytokines from hATTCMs and hATN-CMs were assayed by a protein antibody assay. Compared to hATNCMs, hATT-CMs showed greater protein diversity. We found that hATT-CMs presented a greater amount of proteins related to complement system activity, metabolism and immune system, as well as proteins involved in a variety of biological processes such as signal transduction and cell communication. Specifically, apolipoprotein AI and AII, complement component 3, and vimentin and desmin were significantly increased in hATT-CMs versus hATN-CMs. Moreover, a multivariate discriminant analysis of the cytokines detected by the array showed that IL-6, MCP-2 and GRO cytokines were sufficient and necessary to differentiate hATT-CMs from hATN-CMs. This analysis also showed that the levels of these three cytokines, taken together, correlated with stage and histological grade of the tumor in the hATT-CMs group, and with body mass index in the hATN-CMs group.Fil: Fletcher, Sabrina Johanna. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Hapon, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Callegari, E.. University Of South Dakota; Estados UnidosFil: Crosbie, M. L.. Complejo Médico Policial "Churruca Visca"; ArgentinaFil: Santiso, N.. Complejo Médico Policial "Churruca Visca"; ArgentinaFil: Ursino, A.. Complejo Médico Policial "Churruca Visca"; ArgentinaFil: Amato, A. R.. Complejo Médico Policial "Churruca Visca"; ArgentinaFil: Gutiérrez, A.. Complejo Médico Policial "Churruca Visca"; ArgentinaFil: Sacca, Paula Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Dreszman, R.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Pérez, A.. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Matemática; ArgentinaFil: Caron, Ruben Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Calvo, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Pistone Creydt, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentin

Analysis of the ATR-Chk1 and ATM-Chk2 pathways in male breast cancer revealed the prognostic significance of ATR expression

The ATR-Chk1 and ATM-Chk2 pathways are central in DNA damage repair (DDR) and their over-activation may confer aggressive molecular features, being an adaptive response to endogenous DNA damage and oncogene-induced replication stress. Herein we investigated the ATR-Chk1 and ATM-Chk2 signalings in male breast cancer (MBC). The expression of DDR kinases (pATR, pATM, pChk1, pChk2, and pWee1) and DNA damage markers (pRPA32 and γ-H2AX) was evaluated by immunohistochemistry in 289 MBC samples to assess their association. Survival analyses were carried out in 112 patients. Survival curves were estimated with the Kaplan-Meier method and compared by log-rank test. Cox proportional regression models were generated to identify variables impacting survival outcomes. The expression of pATR conferred poorer survival outcomes (log rank p = 0.013, p = 0.007 and p = 0.010 for overall, 15- and 10-year survival, respectively). Multivariate Cox models of 10-year survival and overall indicated that pATR expression, alone or combined with pChk2, was an independent predictor of adverse outcomes (10-year survival: pATR: HR 2.74, 95% CI: 1.23–6.10; pATR/pChk2: HR 2.92, 95% CI: 1.35–6.33; overall survival: pATR: HR 2.58, 95% CI: 1.20–5.53; pATR/pChk2: HR 2.89, 95% CI: 1.37–6.12). Overall, the ATR/ATM-initiated molecular cascade seems to be active in a fraction of MBC patients and may represent a negative prognostic factor

Treatment of Type 2 Diabetes and Outcomes in Patients With Heart Failure: A Nested Case–Control Study From the U.K. General Practice Research Database

OBJECTIVE - Diabetes and heart failure commonly coexist, and prior studies have suggested better outcomes with met formin than other antidiabetic agents. We designed this study to determine whether this association reflects a beneficial effect of metformin or a harmful effect of other agents. RESEARCH DESIGN AND METHODS - We performed a case-control study nested within the U.K. General Practice Research Database cohort in which diagnoses were assigned by each patient's primary care physician. Case subjects were patients 35 years or older, newly diagnosed with both heart failure and diabetes after January 1988, and who died prior to October 2007. Control subjects were matched to case subjects based on age, sex, clinic site, calendar year, and duration of follow-up. Analyses were adjusted for comorbidities, A1C, renal function, and BMI. RESULTS - The duration of concurrent diabetes and heart failure was 2.8 years (SD 2.6) in our 1,633 case subjects and 1,633 control subjects (mean age 78 years, 53% male). Compared with patients who were not exposed to antidiabetic drugs, the current use of metformin monotherapy (adjusted odds ratio 0.65 [0.48-0.87]) or metformin with or without other agents (0.72 [0.59-0.90]) was associated with lower mortality; however, use of other antidiabetic drugs or insulin was not associated with all-cause mortality. Conversely, the use of ACE inhibitors/angiotensin receptor blockers (0.55 [0.45-0.68]) and beta-blockers (0.76 [0.61-0.95]) were associated with reduced mortality. CONCLUSIONS - Our results confirm the benefits of trial-proven anti-failure therapies in patients with diabetes and support the use of metformin-based strategies to lower glucose