Assessment of bone quality with trabecular bone score in type 2 diabetes mellitus: A study from the FRISBEE cohort.

OBJECTIVE: The purpose of our study was to compare bone mineral density (BMD) and trabecular bone score (TBS) values between patients with type 2 diabetes (T2D) and control subjects with similar FRAX scores in order to evaluate TBS as an additional tool for assessing fracture risk in diabetic subjects. METHODS: A cross-sectional analysis was performed using BMD results from 260 subjects participating in the FRISBEE study (Fracture RISk Brussels Epidemiological Enquiry), an ongoing prospective epidemiological study in a population-based cohort (Brussels, Belgium) of 3560 postmenopausal women aged 60-85 years. TBS measurement was possible in 1108 subjects from the FRISBEE cohort. Among these 1108 subjects, 65 had known T2D at inclusion. For each diabetic case we selected 3 controls from our database. (n = 195). Diabetic subjects and controls were matched for age and baseline FRAX score for major osteoporotic fractures. RESULTS: BMD (g/cm2 ) tended to be higher in T2D than in control subjects, significantly so at the total hip 0.90 ± 0.13 versus 0.87 ± 0.12 (P = 0.015). On the contrary, TBS was significantly lower in the T2D group (mean = 1.19 ± 0.17) compared with the control group (mean = 1.27 ± 0.13) (P = 0.005). Mean TBS remained significantly lower in T2D (1.22 ± 0.17) compared with the control group (1.27 ± 0.13) (P = 0.02) after adjustment for body mass index. CONCLUSION: Our data suggest that TBS complements BMD at the total hip, in demonstrating the "diabetes-associated bone disease".

The discovery of IDX21437: Design, synthesis and antiviral evaluation of 2'-α-chloro-2'-ß-C-methyl branched uridine pronucleotides as potent liver-targeted HCV polymerase inhibitors.

Herein we describe the discovery of IDX21437 35b, a novel RPd-aminoacid-based phosphoramidate prodrug of 2'-α-chloro-2'-ß-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected RP diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection.

Discovery and structural diversity of the hepatitis C virus NS3/4A serine protease inhibitor series leading to clinical candidate IDX320.

Exploration of the P2 region by mimicking the proline motif found in BILN2061 resulted in the discovery of two series of potent HCV NS3/4A protease inhibitors. X-ray crystal structure of the ligand in contact with the NS3/4A protein and modulation of the quinoline heterocyclic region by structure based design and modeling allowed for the optimization of enzyme potency and cellular activity. This research led to the selection of clinical candidate IDX320 having good genotype coverage and pharmacokinetic properties in various species.

Structure-based design of a novel series of azetidine inhibitors of the hepatitis C virus NS3/4A serine protease.

Structural homology between thrombin inhibitors and the early tetrapeptide HCV protease inhibitor led to the bioisosteric replacement of the P2 proline by a 2,4-disubstituted azetidine within the macrocyclic ß-strand mimic. Molecular modeling guided the design of the series. This approach was validated by the excellent activity and selectivity in biochemical and cell based assays of this novel series and confirmed by the co-crystal structure of the inhibitor with the NS3/4A protein (PDB code: 4TYD).

Cardiovascular autonomic control during short-term thermoneutral and cool head-out immersion.

BACKGROUND: Moderately cold head-out water immersion stimulates both baro- and cold-receptors, and triggers complex and contradictory effects on the cardiovascular system and its autonomic nervous control. OBJECTIVES: To assess the effects of water immersion and cold on cardiovascular status and related autonomic nervous activity. METHODS: Hemodynamic variables and indexes of autonomic nervous activity (analysis of heart rate and blood pressure variability) were evaluated in 12 healthy subjects during 3 exposures of 20 min each in the upright position, i.e., in air (AIR, 24-25 degrees C), and during head-out water immersion at 35-36 degrees C (WIn) and 26-27 degrees C (WIc). RESULTS: Plasma noradrenaline, systolic and diastolic blood pressure, and total peripheral resistances were reduced during WIn compared to AIR (263.9 +/- 39.4 vs. 492.5 +/- 35.7 pg x ml(-1), 116.5 +/- 3.7 and 65.4 +/- 1.7 mmHg vs. 140.8 +/- 4.7 and 89.8 +/- 2.8 mmHg, 14.1 +/- 1.0 vs. 16.3 +/- 0.9 mmHg x L(-1) x min, respectively) while they were increased during WIc (530.8 +/- 84.7 pg ml(-1), 148.0 +/- 7.0 mmHg, 80.8 +/- 3.0 mmHg, and 25.8 +/- 1.9 mmHg x L(-1) x min, respectively). The blood pressure variability was reduced to the same extent during WIc and Win compared to AIR. Heart rate decreased during WIn (67.8 +/- 2.7 vs. 81.2 +/- 2.7 bpm during AIR), in parallel with an increased cardiac parasympathetic activity. This pattern was strengthened during WIc (55.3 +/- 2.2 bpm). CONCLUSIONS: Thermoneutral WI lowered sympathetic activity and arterial tone, while moderate whole-body skin cooling triggered vascular sympathetic activation. Conversely, both WI and cold triggered cardiac parasympathetic activation, highlighting a complex autonomic control of the cardiovascular system.

Conditions of autonomic reciprocal interplay versus autonomic co-activation: effects on non-linear heart rate dynamics.

The present study was aimed at investigating the autonomic nervous system influences on the fractal organization of human heart rate during sympathovagal interactions, with special emphasize on the short-term fractal organization in heart rate variability (HRV), as assessed by the scaling exponent (alpha(1)) of the detrended fluctuation analysis. Linear and non-linear HRV analyses were used to study the sympathetic and vagal modulation of heart rate in ten healthy men (mean +/- SEM; age 26 +/- 1 years) during conditions of 1) increased sympathetic activity and vagal withdrawal (head-up tilt), 2) decreased sympathetic activity and increased vagal outflow (thermoneutral upright head-out water immersion, WIn), and 3) simultaneous activation of the two arms of the autonomic nervous activity (upright head-out immersion in cold water, WIc). Hemodynamic and linear HRV results were consistent with previous reports during similar physiological conditions. alpha(1) increased significantly during head-up tilt (from 0.71 +/- 0.13 supine to 0.90 +/- 0.15 upright) and WIn (0.86 +/- 0.10) and was significantly decreased during WIc (0.61 +/- 0.15). Thus, alpha(1) increased when the cardiac autonomic interplay was altered in a reciprocal fashion, whatever the direction of the balance change. Conversely, alpha(1) decreased during the concomitant activation of both vagal and sympathetic activities. The results of linear analysis were necessary to precisely define the direction of change in autonomic control revealed by an increase in alpha(1), while the direction of change in alpha(1) indicated whether an increased vagal activity is coupled with a decreased or increased sympathetic activation. Using both linear and non-linear analysis of HRV may increase the understanding of changes in cardiac autonomic status.

Side-effects of L-dopa on venous tone in Parkinson's disease: a leg-weighing assessment.

In the present study, the effects of L-dopa treatment on cardiovascular variables and peripheral venous tone were assessed in 13 patients with Parkinson's disease (PD) with Hoehn and Yahr stages 1-4. Patients were investigated once with their regular treatment and once after 12 h of interruption of L-dopa treatment. L-Dopa intake significantly reduced systolic and diastolic blood pressure, heart rate and plasma noradrenaline and adrenaline in both the supine and upright (60 degrees ) positions. A significant reduction in stroke volume and cardiac output was also seen with L-dopa. The vascular status of the legs was assessed through thigh compression during leg weighing, a new technique developed in our laboratory. Healthy subjects were used to demonstrate that this technique provided reproducible results, consistent with those provided by strain gauge plethysmography of the calf. When using this technique in patients with PD, L-dopa caused a significant lowering of vascular tone in the lower limbs as shown, in particular, by an increase in venous distensibility. Combined with the results of the orthostatic tilting, these findings support that the treatment-linked lowering of plasma noradrenaline in patients with PD was concomitant with a significant reduction in blood pressure, heart rate and vascular tone in the lower limbs. These pharmacological side-effects contributed to reduce venous return and arterial blood pressure which, together with a lowered heart rate, worsened the haemodynamic status.

Six-month cardiovascular changes in cyclosporine-treated recipients of corneal grafts: serial baroreflex responses.

Loss of autonomic cardiovascular homoeostasis is often suspected in hypertension that has developed after organ transplantation. We serially assessed autonomic cardiovascular control in eight patients in generally good condition who needed cyclosporine (CyA) treatment because of high risk of rejection in corneal transplantation. To this aim, we investigated the patients, before and while they were receiving CyA, for 1 week and at 1, 3 and 6 months. For each period, spontaneous baroreflex, blood pressure, heart rate and variability were assessed, as well as neuro-hormonal indicators, while the patients were in both supine and 60 degrees upright positions. After 1 week of treatment, patients showed increases in systolic, diastolic and pulse blood pressures (P<0.05) that were concomitant with a transient decrease in plasma noradrenaline (P<0.05), which, thereafter, resumed the range of baseline values for 6 months. After patients had received CyA treatment for 1 month, the total power of systolic blood pressure variability and its low-frequency component remained higher than before treatment (P<0.05). At 3 and 6 months, heart rate was decreased (P<0.001) when high-frequency power of RR variability and plasma atrial natriuretic peptide were increased (P<0.05). As plasma noradrenaline never exceeded the baseline range, the hypertensive effect of CyA was not likely to have resulted from sympathetic activation. Rather, the increase in systolic blood pressure variability, its low-frequency component and the pattern of pulse pressure changes, pointed to a direct vascular effect of CyA. The maintenance of a normal cardiac baroreflex function during 6 months of CyA treatment might be pivotal to the adaptive responses towards direct CyA effects.

Decrease in heart rate variability with overtraining: assessment by the Poincaré plot analysis.

Numerous symptoms have been associated with the overtraining syndrome (OT), including changes in autonomic function. Heart rate variability (HRV) provides non-invasive data about the autonomic regulation of heart rate in real-life conditions. The aims of the study were to: (i) characterize the HRV profile of seven athletes (OA) diagnosed as suffering of OT, compared with eight healthy sedentary (C) and eight trained (T) subjects during supine rest and 60 degrees upright, and (ii) compare the traditional time- and frequency-domain analysis assessment of HRV with the non-linear Poincaré plot analysis. In the latter each R-R interval is plotted as a function of the previous one, and the standard deviations of the instantaneous (SD1) and long-term R-R interval variability are calculated. Total power was higher in T than in C and OA both in supine (1158 +/- 1137, 6092 +/- 3554 and 2970 +/- 2947 ms2 for C, T and OA, respectively) and in upright (640 +/- 499, 1814 +/- 806 and 1092 +/- 712 ms2 for C, T and OA, respectively; P<0.05) positions. In supine position, indicators of parasympathetic activity to the sinus node were higher in T compared with C and OA (high-frequency power: 419.1 +/- 381.2, 1105.3 +/- 781.4 and 463.7 +/- 715.8 ms2 for C, T and OA, respectively; P<0.05; SD1: 29.5 +/- 18.5, 75.2 +/- 17.2 and 37.6 +/- 27.5 for C, T and OA, respectively; P<0.05). OA had a marked predominance of sympathetic activity regardless of the position (LF/HF were 0.47 +/- 0.35, 0.47 +/- 0.50 and 3.96 +/- 5.71 in supine position for C, T and OA, respectively, and 2.09 +/- 2.17, 7.22 +/- 6.82 and 12.04 +/- 10.36 in upright position for C, T and OA, respectively). The changes in HRV indexes induced by the upright posture were greater in T than in OA. The shape of the Poincaré plots allowed the distinction between the three groups, with wide and narrow shapes in T and OA, respectively, compared with C. As Poincaré plot parameters are easy to compute and associated with the 'width' of the scatter gram, they corroborate the traditional time- and frequency-domain analysis. We suggest that they could be used to indicate fatigue and/or prevent OT.