Pioglitazone improves aortic wall elasticity in a rat model of elastocalcinotic arteriosclerosis

Specific treatment of age-related aortic wall arteriosclerosis and stiffening is lacking. Because ligands for peroxisome proliferator-activated receptor gamma have beneficial effects on the arterial wall in atherosclerosis, via an antiinflammatory mechanism, we investigated whether long-term pioglitazone (Pio) treatment protects against another form of vascular wall disease, arteriosclerosis. We evaluated, in a rat model of elastocalcinotic arteriosclerosis (hypervitaminosis D and nicotine [VDN]), whether Pio (3 mg . kg(-1) per day for 1.5 month PO) attenuated arteriosclerosis and its consequences: aortic wall rigidity, increased aortic pulse pressure, and left ventricular hypertrophy. In VDN rats, medial calcification was associated with monocyte/macrophage infiltration and induction of tumor necrosis factor alpha and interleukin 1beta. Pio increased nuclear peroxisome proliferator-activated receptor gamma immunostaining in the aortic wall, decreased tumor necrosis factor alpha (P <0.05 versus VDN Pio-), tended to decrease interleukin 1beta mRNA expression (P =0.08 versus VDN Pio-), blunted aortic wall calcification (271+/-69, P <0.05 versus VDN Pio- 562+/-87 micromol . g(-1) dry weight) and prevented fragmentation of elastic fibers (segments per 10,000 microm2: 8.4+/-0.3; P <0.05 versus VDN Pio- 10.5+/-0.6). Pio reduced aortic wall stiffness (elastic modulus/wall stress: 4.8+/-0.6; P <0.05 versus VDN Pio- 10.0+/-1.6), aortic pulse pressure (30+/-2 mm Hg; P <0.05 versus VDN Pio- 39+/-4) and left ventricular hypertrophy (1.58+/-0.05 g . kg(-1); P <0.05 versus VDN Pio- 1.76+/-0.06). In conclusion, long-term Pio treatment attenuates aortic wall elastocalcinosis and, thus, lowers aortic wall stiffness, aortic pulse pressure, and left ventricular hypertrophy.     

Exploration of left ventricular relaxation using gamma-angiography in 70 hypertensive subjects. Practical consequences and implications

This study was performed to evaluate the incidence ant the practical consequences of left ventricular diastolic dysfunction in hypertensive. In 70 mild to moderate hypertensive subjects group [systolic 161 +/- 16 and diastolic blood pressure 104 +/- 9 mmHg 18 women, 52 men, 51 +/- 7 years old] and in a 15 normal subjects control group, the peak filling rate (PFR) and the time to peak filling rate (TPFR) were measured with the time/activity curve of the rest equilibrium blood pool scintigraphy. The ejection fraction and the stress test were normal in all patients [EF 0.66 +/- 0.05, ranging from 0.59 to 0.88]. The PFR was not significantly different in the hypertensive group but 59/70 patients [84 p. 100] showed an individual value lower than the theoretical age and heart rate expected value. The TPFR was not significantly different (183 +/- 33 ms-vs 180, p = ns). In a Holter-defined sub-group of patients (n = 22) exhibiting a high prevalence of supra-ventricular premature beats or a paroxysmal atrial fibrillation, the PFR was significantly slower than in the total hypertensive group [1.92 +/- 0.33 EDV/s-1, p = 0.02]. Early indices of diastolic function give some instantaneous information on left ventricular filling. Determining the exact significance of individual values of PFR and TPFR requires a better knowledge of physiologic and pathologic determinants of LV filling.     

The impact of an insulin sensitizer, troglitazone, on glucose metabolism in African Americans at risk for type 2 diabetes mellitus: a placebo-controlled, 24-month randomized study

African Americans (AA) have greater prevalence of type 2 diabetes mellitus (DM), and nondiabetic AA have demonstrated increased insulin resistance when compared with Caucasian Americans (CA). The objective of this study was to examine the impact of chronic use of an insulin sensitizer on glucose metabolism in normal glucose tolerant AA at risk for DM (previous gestational diabetes mellitus [GDM] or first-degree relative with DM). Forty-nine high-risk AA received 200 mg/d troglitazone (TRO) versus 81 age-, weight-, and body mass index (BMI)-matched high-risk AA who received placebo (PLA) for 24 months. Yearly anthropometric measurements, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIVGTT) were performed. Biochemical parameters were monitored quarterly. There was no significant change in anthropometric measurements over 24 months in TRO versus PLA. There were no significant differences in serum glucose, insulin, or C-peptide incremental area under the curve (AUC) in TRO versus PLA at baseline or 24 months for OGTT and FSIVGTT. The insulin sensitivity (S(I)) for TRO and PLA increased from baseline to 24 months by 17% and 16%, respectively. The TRO demonstrated a 26% increase in insulin/glucose ratio versus 1% increase in the PLA at 24 months. The disposition index (DI) increased 33% from baseline in TRO versus 21% increase in PLA. Modest improvement in glucose metabolism was seen in TRO when compared with PLA. TRO was well tolerated without significant reported adverse events. Based on our current data, the treatment of normal glucose tolerant high-risk AA with thiazolidinedione (TZD) may be beneficial to "reset" and protect glucose metabolism by improving insulin responses. Because of the potential drug-related risks associated with use of TZD and the proven positive impact of diet and exercise in prevention of DM, studies of longer duration with examination of other potentially beneficial parameters, such as cardiovascular indices and inflammatory markers will be necessary to justify the cost in the nondiabetic population.     

Association of plasma somatostatin with disease severity and progression in patients with autosomal dominant polycystic kidney disease

Background

Somatostatin (SST) inhibits intracellular cyclic adenosine monophosphate (cAMP) production and thus may modify cyst formation in autosomal dominant polycystic kidney disease (ADPKD). We investigated whether endogenous plasma SST concentration is associated with disease severity and progression in patients with ADPKD, and whether plasma SST concentrations change during treatment with a vasopressin V2 receptor antagonist or SST analogue.

Methods

In this observational study, fasting concentrations of SST were measured in 127 ADPKD patients (diagnosed upon the revised Ravine criteria) by ELISA. cAMP was measured in 24?h urine by Radio Immuno Assay. Kidney function was measured (mGFR) as ¹²⁵I-iothalamate clearance, and total kidney volume was measured by MRI volumetry and adjusted for height (htTKV). Disease progression was expressed as annual change in mGFR and htTKV. Additionally, baseline versus follow-up SST concentrations were compared in ADPKD patients during vasopressin V2 receptor antagonist (tolvaptan) (n?=?27) or SST analogue (lanreotide) treatment (n?=?25).

Results

In 127 ADPKD patients, 41?±?11?years, 44% female, eGFR 73?±?32?ml/min/1.73m², mGFR 75?±?32?ml/min/1.73m² and htTKV 826 (521–1297) ml/m, SST concentration was 48.5 (34.3–77.8) pg/ml. At baseline, SST was associated with urinary cAMP, mGFR and htTKV (p?=?0.02, p?=?0.004 and p?=?0.02, respectively), but these associations lost significance after adjustment for age and sex or protein intake (p?=?0.09, p?=?0.06 and p?=?0.15 respectively). Baseline SST was not associated with annual change in mGFR, or htTKV during follow-up (st. β?=???0.02, p?=?0.87 and st. β?=???0.07, p?=?0.54 respectively). During treatment with tolvaptan SST levels remained stable 38.2 (23.8–70.7) pg/mL vs. 39.8 (31.2–58.5) pg/mL, p?=?0.85), whereas SST levels decreased significantly during treatment with lanreotide (42.5 (33.2–55.0) pg/ml vs. 29.3 (24.8–37.6), p?=?0.008).

Conclusions

Fasting plasma SST concentration is not associated with disease severity or progression in patients with ADPKD. Treatment with lanreotide caused a decrease in SST concentration. These data suggest that plasma SST cannot be used as a biomarker to assess prognosis in ADPKD, but leave the possibility open that change in SST concentration during lanreotide treatment may reflect therapy efficacy.

     

Bone metabolism and risk of secondary hyperparathyroidism 12 months after gastric banding in obese pre-menopausal women

OBJECTIVE: To evaluate, during the first postoperative year in obese pre-menopausal women, the effects of laparoscopic gastric banding on calcium and vitamin D metabolism, the potential modifications of bone mineral content and bone mineral density, and the risk of development of secondary hyperparathyroidism. SUBJECTS: Thirty-one obese pre-menopausal women aged between 25 and 52 y with a mean body mass index (BMI) of 43.6 kg/m(2), scheduled for gastric banding were included. Patients with renal, hepatic, metabolic and bone disease were excluded. METHODS: Body composition and bone mineral density (BMD) were measured at baseline, 6 and 12 months after gastric banding using dual-energy X-ray absorptiometry. Serum calcium, phosphate, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, bilirubin, urea, creatinine, uric acid, proteins, parathormone, vitamin D(3), IGF-1, IGF-BP3 and telopeptide, as well as urinary telopeptide, were measured at baseline and 1, 3, 6, 9 and 12 months after surgery. RESULTS: After 1 y vitamin D3 remained stable and PTH decreased by 12%, but the difference was not significant. Serum telopeptide C increased significantly by 100% (P<0.001). There was an initial drop of the IGF-BP3 during the first 6 months (P<0.05), but the reduction was no longer significant after 1 y. The BMD of cortical bone (femoral neck) decreased significantly and showed a trend of a positive correlation with the increase of telopeptides (P<0.06). The BMD of trabecular bone, at the lumbar spine, increased proportionally to the reduction of hip circumference and of body fat. CONCLUSION: There is no evidence of secondary hyperparathyroidism 1 y after gastric banding. Nevertheless biochemical bone markers show a negative remodelling balance, characterized by an increase of bone resorption. The serum telopeptide seems to be a reliable parameter, not affected by weight loss, to follow up bone turnover after gastroplasty.     

Repeated automatic versus ambulatory blood pressure measurement: the effects of age and sex in a normal ageing population

OBJECTIVES: To study blood pressure adaptation in relation to age and sex. In a subsample, laboratory blood pressure measurements were compared with ambulatory daytime blood pressure measurements to determine the degree of agreement between the two methods. The night-time blood pressure reduction was analysed as a function of blood pressure status, age and sex. DESIGN: A cross-sectional study in 469 healthy volunteers, aged 23-82 years, stratified for age, sex and educational level. METHODS: Laboratory blood pressure was measured automatically (Dinamap 8100) five times during a 20 min recording session. Cardiovascular events in the medical history were identified in order to treat the cardiovascular event-free group separately in subsequent analyses. Within 3 weeks after laboratory blood pressure measurement, ambulatory blood pressure was measured for 24 h in 135 volunteers from the main study. RESULTS: Both diastolic and systolic blood pressure varied markedly in a single measurement session as a function of age, independent of mean pressure level. After 15 min no further blood pressure decrease was observed. On the basis of the average of the final two blood pressure measurements, 18.8% of the subjects were in the hypertensive range (WHO/ISH guidelines). Ambulatory blood pressure measurements were in accord with earlier findings and correlated 0.74 and 0.73 with laboratory diastolic and systolic blood pressure, respectively, but weighted kappa values indicated only moderate agreement (0.42 and 0.51). Women showed a more profound reduction in cnight-time blood pressure than did men. CONCLUSIONS: There is a substantial change in blood pressure during a single measurement session which is greater in older age groups. The moderate agreement between the two methods of blood pressure measurement supports the notion that blood pressure measured in a single session has limited generalizability to average daytime levels in a population sample.     

Functional interaction of the gp80 and gp130IL-6 receptors in human B cell malignancies

IL-6, or cytokines of the IL-6 family using gp130 as transducer chain receptor, have been suggested to play a role in certain B lymphoid neoplasia. The presence of cell membrane gp80 and gp130 IL-6 receptors was studied in 98 patients with various leukaemia and non-Hodgkin's malignant lymphoma using flow cytofluorometry and immunohistology. Except neoplasia of immature B cells which expressed neither of the receptors, the majority of B cell tumours expressed one or both of them, mantle cell lymphoma being found to express the highest density of receptors. Using IL-6-dependent XG myeloma cell lines and mAb recog-nizing various gp80 and gp130 functional epitopes, it has been shown that IL-6 activation leads to a modified expression of some epitopes. In particular, the decrease or the dis-appearance of a gp130 epitope called A1 signed gp130 dimerization which is the first step of the gp130 activation pathway. Gp80 and gp130 epitope analysis was achieved in 17 of the patients. In four, an epitope phenotype compatible with a cytokine-induced activation was found. The cells of five B-CLL patients which expressed both gp80 and gp130 receptors were incubated with IL-6 to induce activation. In three of the cases they were found to rearrange their receptors in activated forms but not in the two others, showing that cells able to be activated or not can be found. These results confirm that gp130 signalling might play an important role in the pathogenesis of certain B cell neoplasia.     

Neuroendocrine mechanisms regulating growth hormone and prolactin secretion during lactation

The maternal plasma concentrations of GH and PRL increase dramatically upon the initiation of lactation in the rat. In light of the fact that these two hormones have evolved from one common precursor, we sought to determine if the neuroendocrine mechanisms regulating their concomitant increase during lactation are common or if they are functionally distinct. To evaluate this, lactating rats were passively immunized with antiserum raised against GHRH and then monitored for changes in GH and PRL secretion in response to suckling. On day 9 or 10 postpartum, pups were removed from their mothers at 0800 h. At 1100 h mothers were injected with normal rabbit serum (NRS) or GHRH antiserum (GHRH-ab). At 1400 h a control blood sample was drawn. Pups were then returned to their mothers, with subsequent blood samples drawn over the next 60 min. Plasma concentrations of GH significantly increased to 12.3 +/- 1.0 ng/ml (mean +/- SEM) in NRS-treated females after the return of the pups. In contrast, there was no change in GH concentrations in the females treated with the GHRH-ab. Plasma PRL concentrations rose approximately 200 ng/ml in both the NRS-treated animals and the GHRH-ab-treated ones. Body weight gains of the pups during the 60-min period of lactation were similar in both groups. These results suggest that the neuroendocrine mechanisms regulating the increases in GH and PRL during lactation are distinct and that GHRH is the hypothalamic factor responsible for the increase in GH. Furthermore, these results suggest that acutely interrupting the increase in GH secretion that occurs during lactation does not compromise nursing behavior and performance.