Oral weekly ibandronate prevents bone loss in postmenopausal women

OBJECTIVES: To investigate the efficacy, safety, and dose-response of once-weekly oral ibandronate in the prevention of postmenopausal bone loss. DESIGN: This was a multi-centre, placebo-controlled, double-blind, randomized, 24-month phase II/III dose-finding study. SETTING: Primary care units in 14 osteoporosis centres. SUBJECTS: A total of 630 women were stratified into four strata according to time since menopause (TSM, 1-3 vs. >3 years) and baseline bone mineral density (BMD; normal: T-score > or =1 vs. osteopenic: -2.5 < or = T-score < or = 1) of the lumbar spine. INTERVENTIONS: Within each stratum women were further randomized to receive once-weekly ibandronate (5, 10, or 20 mg week-1) or placebo for 24 months. MAIN OUTCOME MEASURES: Efficacy parameters were the relative changes from baseline in spine (L1-4) and hip BMD, and biochemical markers of bone turnover (serum and urinary C-telopeptide of collagen type I (CTx), osteocalcin, and alkaline phosphatase) measured by dual energy X-ray absorptiometry and enzyme immunoassays, respectively. RESULTS: Once-weekly therapy with ibandronate induced dose-dependent increases in spine and hip BMD. At month 24, differences between the relative changes in spine and hip BMD induced by 20 mg ibandronate and placebo was 4.0 and 2.7%, respectively. Similar or more pronounced differences were seen in osteopenic women of TSM 1-3 years (5.3 and 3.5%) and of TSM >3 years (3.5 and 2.9%), respectively. A dose-dependent suppression of all biochemical markers of bone turnover was observed with significant decreases in the 20 mg dose groups of all strata at month 24. The overall safety results indicated that once-weekly oral ibandronate was well-tolerated at all three doses. CONCLUSION: Once-weekly oral therapy with 20 mg ibandronate provides an effective and safe therapy for the prevention of postmenopausal bone loss.     

Interaction between beta-adrenergic receptor stimulation and nitric oxide release on tissue perfusion and metabolism

Nitric oxide (NO) may be an important modulator of sympathetic tone. We used im and sc microdialysis in humans to characterize the interaction of NO synthase inhibition and adrenoreceptor stimulation on tissue perfusion, metabolism, and norepinephrine release. Microdialysis probes were perfused with L- or D-nitro-L-arginine-methyl-ester (100 micromol/L) followed by incremental doses of isoproterenol, epinephrine, or nitroprusside. Blood flow was estimated based on the ethanol dilution technique. In muscle, the increase in blood flow with isoproterenol was abolished by L-NAME. The ethanol ratio was 0.03 +/- 0.011 with D-NAME and 0.075 +/- 0.014 with L-NAME during isoproterenol treatment (1 micromol/L). The effect was less pronounced in adipose tissue. The vasodilatory effect of nitroprusside was similar with D- and L-NAME. L-NAME augmented isoproterenol- and epinephrine-induced glycerol release. Dialysate glycerol during 1 micromol/L isoproterenol was 47 +/- 6.7 micromol/L with D-NAME and 72 +/- 15 micromol/L with L-NAME. In skeletal muscle, dialysate norepinephrine during 1 micromol/L isoproterenol treatment was 0.73 +/- 0.17 and 1.3 +/- 0.15 nmol/L with D- and L-NAME, respectively. We conclude that NO synthase inhibition attenuates beta(2)-adrenoreceptor-mediated vasodilation and enhances beta-adrenoreceptor-mediated lipolysis. These effects are in part mediated through an increase in interstitial norepinephrine concentrations. The data are consistent with the idea that in humans, NO is important in modulating and ameliorating sympathetic effects in peripheral tissues.     

Bound leptin and sympathetic outflow in nonobese men

Leptin exists in a free form and a receptor-bound form. Protein-bound rather than free leptin levels may be associated with regulation of muscle sympathetic nerve activity (MSNA). We determined MSNA and bound leptin concentrations in 25 men [age, 29 +/- 6 yr, body mass index (BMI), 24 +/- 3 kg/m(2)]. Baroreflex sensitivity was measured using phenylephrine and nitroprusside infusions. We measured bound leptin in patients with central (multiple system atrophy, n = 8; age, 59 +/- 8 yr; BMI, 23 +/- 2 kg/m(2)) and peripheral autonomic failure (pure autonomic failure, n = 4; age, 71 +/- 10 yr; BMI, 25 +/- 3 kg/m(2)). MSNA was correlated with protein-bound leptin concentrations (r(2) = 0.35; P < 0.01) but not with free leptin levels (r(2) = 0.09). MSNA at baseline was 15 +/- 2 bursts x minutes(-1) in subjects with lower and 24 +/- 3 bursts x minutes(-1) in subjects with higher bound leptin concentrations (P < 0.05). Blood pressure as well as baroreflex regulation of heart rate and MSNA was similar in both groups. Phenylephrine and nitroprusside responses were similar. Patients with multiple system atrophy and autonomic failure featured similar bound leptin levels. We conclude that protein-bound rather than free leptin levels are correlated with basal sympathetic outflow in normotensive, nonobese men. This relationship cannot be explained by a direct central nervous effect of protein-bound leptin. Instead, protein-bound leptin may increase sympathetic vasomotor tone indirectly via a baroreflex mechanism.     

Appendicular lean tissue mass and the prevalence of sarcopenia among healthy women.

Studies indicate that deficient skeletal muscle mass or sarcopenia is a major cause of disability and morbidity among the elderly. In part, due to the lack of generally applicable normal values, there is still insufficient epidemiologic data available on the frequency and severity of sarcopenia in health and under various disease-related conditions. The objectives of the present study were to (1) characterize the age- and menopause-related variations in appendicular lean tissue mass (LTM(A)), (2) provide young-normal means and estimate the age-specific prevalence of sarcopenia among healthy women. A total of 754 healthy women were included in the study of cross-sectional design. LTM(A) was estimated by dual-energy x-ray absorptiometry (DEXA). Physical characteristics and menopausal status were also registered. LTM(A) as well as height showed significant negative correlation with age with Pearson's r values of -0.43 and -0.06, respectively (P <.05). Trend of finding lower mean values with advancing age remained even when LTM(A) was adjusted for height(2) (ht(2)). Menopause did not seem to have any influence on LTM(A). Young-normal means were obtained from 216 premenopausal women aged 18 to 39 years. Prevalence rates of sarcopenia in healthy women were determined with reference to a cut-off line corresponding to LTM(A) or LTM(A)/ht(2) less than young-normal mean 2 SD and were found to be 40.2% and 12.3%, respectively, among the healthy elderly (>70 years of age). Results of the present study provide further evidence that sarcopenia exists even among otherwise healthy women with increasing age-specific prevalence. Further studies are needed (1) to estimate the prevalence of sarcopenia under various health and disease-related conditions with reference to the hereby given cut-off values and (2) to find therapeutic strategies with beneficial effects in conserving skeletal muscle mass.     

Biomolecules Regulating Defense Mechanism in Plants

There are two types of defense mechanism in plants which are regulated by biomolecules. Physical defense is the corporeal barrier developed in the form of leaf surface wax, thorns, trichomes, cell wall thickness, lignification and secondary metabolites as toxins. Chemical mechanism includes emission of biomolecules such as proteins, secondary metabolites and volatile compounds in response to attack by herbivores and insects. Among proteins, storage proteins, tuber proteins and extracellular proteins take part in defense mechanism. Storage proteins include albumins, lectins, vicilins, glycine-rich proteins and proteinase inhibitors which play crucial role in defense against microorganisms and insect pests. Tuber proteins include patatins, ocatins and tarins which have antimicrobial activity against various phytopathogens. Plant extracellular proteins include pathogenesis-related proteins (PR) which have glucanases activity and chitinase activity against cell wall of microorganisms. The secondary metabolites such as phytoanticipins and phytoalexins have defense against microorganisms, insects and herbivorous animals. Volatile compounds include terpenes, terpenoids, fatty acid derivatives, phenylpropanoids, benzenoids, and sulfur- and nitrogen-containing volatile compounds. They are released by plants to repel or attack specific plant pathogens. Since these biomolecules have array of mechanisms to fight against plant pathogens, they can be utilized for reduction of environment pollution, human health and agriculture problems.

     

Orthostatic tolerance is difficult to predict in recurrent syncope patients

Objectives  

We tested the hypothesis that detailed anthropometric and hemodynamic measurements predict orthostatic tolerance in neurally mediated syncope patients. In addition, we tested whether orthostatic tolerance is related to syncope frequency in real life.     

The effect of oral calcitonin on cartilage turnover and surface erosion in an ovariectomized rat model

OBJECTIVE: To investigate whether oral calcitonin treatment influences the increases in type II collagen (CII) degradation and related surface erosions of articular cartilage in ovariectomized rats. METHODS: Fifty rats were randomly allocated into 1 of the 5 following intervention groups: sham-operated, ovariectomy, ovariectomy plus subcutaneously implanted 17beta-estradiol pellet, ovariectomy plus 2 mg/kg salmon calcitonin plus 50 mg/kg 5CNAC (carrier), or ovariectomy plus 50 mg/kg 5CNAC. Each treatment was administered for 9 weeks after the ovariectomy. Blood samples for biochemical marker analysis were collected from fasting animals at baseline, on day 3, and after 1, 2, 4, 6, and 9 weeks. CII degradation was quantified by specific immunoassay, and the changes in severity scores of articular cartilage erosions were visualized and scored in histologic sections of the knees. RESULTS: Ovariectomy resulted in a marked increase in serum levels of C-telopeptide of type II collagen (CTX-II) (P < 0.001), which could be effectively reversed by 17beta-estradiol supplementation. Oral administration of calcitonin elicited similar decreases in serum levels of CTX-II (P < 0.001). Histologic scoring of cartilage erosion showed significantly less cartilage erosion in calcitonin-treated ovariectomized rats versus control ovariectomized rats that were untreated or treated with 5CNAC alone. (P < 0.01). CONCLUSION: The in vivo effects of calcitonin in rats suggest that calcitonin is able to counteract CII degradation and the accompanying structural disintegration of articular cartilage promoted by estrogen deficiency. Clinical assessment of the chondroprotective potential of calcitonin in postmenopausal women seems warranted.