Impaired radial artery compliance in normotensive subjects with familial hypercholesterolemia

Hypercholesterolemia impairs arteriolar dilatation, but whether the vascular abnormalities accompanying this condition include large artery function is unknown. We addressed this issue in 13 normotensive subjects with familial hypercholesterolemia (serum cholesterol 401.6 \ub1 16.9 mg/dl, mean \ub1 S.E., FHC) and no evidence of atherosclerotic lesions, in whom radial artery (RA) diameter and blood pressure (BP) were measured beat to beat by an echotracking and a Finapres device, respectively. RA compliance (RAG) was derived from the diameter/BP relationship and expressed over the systo-diastolic BP range, both at baseline and after a 12-min brachial artery occlusion. RAC was expressed also as the area under the RAC/BP curve divided for pulse BP. Measurements included maximal forearm blood flow (plethysmography) and minimal forearm vascular resistance (FVR) which were obtained from the values following the 12-min brachial arterial occlusion. Data were collected before and after 6- and 24-month lipid lowering treatment (simvastatin 40 mg/day). Ten age-matched normotensive normocholesterolemic healthy subjects (N) served as controls. Compared to N, baseline RAC was strikingly reduced in FHC (-53.5%, P < 0.01). After ischemia RAC increased significantly and markedly in N (+38.7, P < 0.01), while only a modest and non-significant increase was observed in FHC. Minimal FVR was markedly higher in FHC than in N (3.5 \ub1 0.9 vs 1.6 \ub1 0.1 units, P < 0.01). In FHC (7 subjects) RAC remained unchanged after 6 months of lipid lowering treatment, but increased markedly (+55.2%, P < 0.05) when treatment was prolonged to 24 months. Lipid lowering treatment also reduced minimal FVR, the effect being significant bath after 6 and after 24 months. No changes in RAC and minimal FVR were seen after 6 months in controls. Thus, in subjects with a marked increase in serum cholesterol due to FHC, not only arteriolar dilatation, but also RAC and distensibility are markedly impaired. This impairment can be favourably affected by an effective lipid lowering treatment of long duration

Sex differences in the associations between L-arginine pathway metabolites, skeletal muscle mass and function, and their responses to resistance exercise, in old age

This work was supported by the Biotechnology and Biological Sciences Research Council (BB/J015911/1) and was registered at clinicaltrials.gov (ClinicalTrials. gov Identifier: NCT02843009). Supplementary email included with articlePeer reviewedPostprin

Breakthroughs in medicinal chemistry: New targets and mechanisms, new drugs, new hopes–2

[No abstract available][Not available

Breakthroughs in medicinal chemistry: New targets and mechanisms, new drugs, new hopes-3

[No abstract available]Funding: The APC was sponsored by MDPI

Pulse pressure is independently associated with sensorimotor peripheral neuropathy in patients with type-2 Diabetes

Background:The mechanisms responsible for the onset and progression of sensorimotor peripheral neuropathy (SMPN )in type-2 diabetes remain largely unknown.Although a link between hypertension and SMPN has been observed, it is not clear which blood pressure component ( i.e. systolic,SBP;diastolic,DBP;or pulse pressure,PP )is primarily involved. Aim:To determine the relationship between different blood pressure components and parameters of nerve function in type 2 diabetes. Methods: In 55 consecutive ambulatory patients with stable type 2 diabetes ( age 62.6+-8.0 years, mean+-SD) we measured clinic blood pressure and 10 neurophysiologic parameters: motor nerves conduction velocity ( median,ulnar,posterior tibial and peroneal nerve ),sensory amplitude, and latency ( median,ulnar and sural nerve ). Results:Univariate analysis showed that age,diabetes duration, SBP and PP were negatively correlated with nerve function.Regression analysis showed that, after correcting for age, duration of diabetes, glycated haemoglobin, body mass index, microalbuminuria, and SBP, PP was independently and negatively associated with nerve conduction velocity ( median, P= 0.011; ulnar, P= 0.001; peroneal, P= 0.006; and posterior tibial , P= 0.005 and signal amplitude ( ulnar, P =0.027; sural, P =0.055 ) and positively associated with signal latency ( median,P =0.083; sural, P=0.021 ). SBP was negatively associated with signal amplitude ( median, P= 0.012 ) and positively associated with latency ( ulnar, P= 0.018 ). By contrast, DBP failed to show any significant correlation with nerve function. Conclusion: PP is strongly associated with neurophysiologic parameters of nerve function in patients with type 2 diabetes. This relationship is independent of traditional risk factors and other BP components

Interplay of peripheral neuropathy and hypertension in Type- 2 diabetes of short duration

Our understanding of the IGF-I system has increased dramatically in recent yr due in part to the advances in molecular and cellular biology. Not only can we now measure circulating levels of the members of this axis in order to address the possibly pathophysiological changes, but genetic alterations can now be identified as the underlying cause of specific clinical situations. In normal children, circulating levels of IGF-I and the IGF binding proteins (IGFBPs) change throughout development and in some cases are gender dependent. Children and adolescents with a variety of illnesses and metabolic disorders have altered circulating IGF-I and IGFBP levels. Hence, in children or adolescents with exogenous obesity, anorexia nervosa, coeliac disease, leukaemia and other types of cancer, as well as in cases of GH deficiency, this axis can be altered. These data may help us to understand the physiology and pathophysiology of this system, but the clinical or diagnostic utility of these measurements is still largely debated. Indeed, in most of the above mentioned illnesses, circulating IGF and IGFBP levels overlap with normal values. Furthermore, these measurements do not provide data concerning levels of these factors at target tissues or of local synthesis and autocrine-paracrine effects. However, measurements of IGF-I and its binding proteins, as well as GH and its binding proteins, can help us to focus our analysis of patients suspected to have genetic abnormalities on the GH receptor, IGF-I, its receptor, IGFALS, or intracellular signalling proteins such as STAT5b or ERK. Possibly, the most clear clinical utility of circulating IGF-I measurements in children is in cases of GH deficiency or insensitivity or under GH treatment. However, the fact there are cases of children with non-detectable levels of circulating IGF-I that yet normal height and growth velocity, or with non-detectable levels of GH yet normal growth and IGF-I levels, raises many questions. Furthermore, circulating IGF-I levels may be within the normal control levels and the child may have a pathological growth pattern. Hence, just how useful are these measurements? Another clinically important question pertains to GH treatment in patients, such as in the Turner Syndrome, where supraphysiological levels of serum IGF-I are reached in order to induce growth. The interpretation and clinical utility of measurements of circulating IGF-I and its BPs are currently being widely discussed. As our knowledge of this system increases, with the identification of new members of this family and its intracellular mechanisms of action, as well as new genetic alterations in patients, the interpretation of laboratory results will also improve and help to better our diagnostic capability

Predictors of impaired blood pressure homeostasis during acute and sustained orthostasis in patients with type 2 diabetes

Aim. Sympathetic failure with acute postural hypotension is a common feature of advanced autonomic neuropathy in type 2 diabetes. It is unknown, however, whether: a) the presence of sympathetic autonomic neuropathy is also a powerful predictor of postural blood pressure changes during sustained orthostasis and b) other factors affecting baroreceptor and neuro-hormonal control might play a role. Methods. Systolic blood pressure (SBP) was measured during supine rest and after 2, 5, and 20 min of active orthostasis in 45 males with type 2 diabetes (age 56.4 +/- 8.2 years, mean +/- SD) and different degrees of autonomic neuropathy (absence of neuropathy, n=26, parasympathetic neuropathy, n=9, and sympathetic neuropathy, n=10). Eight healthy subjects (50.1 +/- 11.6 years) served as controls. A multiple backward regression analysis was performed to identify independent predictors of SBP changes during orthostasis. The regression model included presence/absence of sympathetic autonomic neuropathy, age, diabetes duration, presence/absence of hypertension, baseline SBP and neuro-hormonal parameters (plasma adrenaline, noradrenaline, plasma renin activity, and aldosterone). Results. Sympathetic autonomic neuropathy (P=0.005), baseline SBP (P=0.001), and adrenaline (P=0.003) independently predicted SBP changes after 2 min (R-2=0.64); sympathetic autonomic neuropathy (P < 0.001), baseline adrenaline (P=0.008), and plasma renin activity (P=0.006) predicted SBP changes after 5 min (R-2=0.58); whereas sympathetic autonomic neuropathy (P < 0.001) and baseline SBP (P < 0.001) predicted SBP changes after 20 min orthostasis (R-2=0.65). Conclusion. The presence of sympathetic autonomic neuropathy and higher supine SBP values remain strong and independent predictors of SBP fall not only during the acute transition from supine to standing position but also during sustained orthostasis in type 2 diabetes. Lower baseline plasma adrenaline concentrations and plasma renin activity are also involved, though to a lesser extent, in the genesis of this haemodynamic response