The ventilatory component of the muscle metaboreflex is overstimulated in transthyretin cardiac amyloidosis patients with poor aerobic capacity.

Background: The exercise pressor reflex, i.e., metabo- and mechano-reflex, partially regulates the control of ventilation and cardiovascular function during exercise. Abnormal exercise pressor reflex response has been associated with exaggerated ventilatory drive, sympathovagal imbalance and exercise limitation in chronic heart failure patients. Whether metaboreflex is over-activated and participate to poor aerobic capacity in patients with hereditary transthyretin cardiac amyloidosis (CA-TTR) is unknown. Methods: Twenty-two CA-TTR patients (aged 76 ± 7, 68% male) with the V122I (p.Val142Ile) transthyretin underwent a thorough evaluation including heart rate variability metrics, electrochemical skin conductance (ESC), physical function cardiopulmonary exercise testing, and muscle metaboreflex assessment. Eleven control subjects were chosen for muscle metaboreflex assessment. Results: Age-matched controls (n = 11) and CA-TTR patients (n = 22) had similar metaboreflex sensitivity for heart rate, stroke volume, cardiac index and mean systemic arterial pressure. Compared with age-matched controls, metaboreflex sensitivity for systemic vascular resistance (-18.64% ± 6.91% vs 3.14% ± 23.35%) and minute-ventilation responses (-9.65% ± 14.83% vs 11.84% ± 23.1%) was markedly increased in CA-TTR patients. Values of ESC displayed positive correlations with stroke volume (r = 0.53, p = 0.011) and cardiac index (r = 0.51, p = 0.015) components of metaboreflex sensitivity, an inverse correlation with systemic vascular resistance (r = -0.55, p = 0.008) and a trend with mean arterial (r = -0.42, p = 0.052) components of metaboreflex sensitivity. Peak aerobic capacity (peak VO2%) displayed an inverse correlation with the ventilation component of metaboreflex sensitivity (r = -0.62, p = 0.015). Conclusion: Consistent with the "muscle hypothesis" in heart failure, it is proposed that deterioration of skeletal muscle function in hereditary CA-TTR patients may activate muscle metaboreflex, leading to an increase in ventilation and sensation of breathlessness, the perception of fatigue, and overall sympathetic activation.

Efficacy of two telemonitoring systems to improve glycaemic control during basal insulin initiation in patients with type 2 diabetes: The TeleDiab-2 randomized controlled trial.

TeleDiab-2 was a 13-month randomized controlled trial evaluating the efficacy and safety of two telemonitoring systems to optimize basal insulin (BI) initiation in subjects with inadequately controlled type 2 diabetes (HbA1c, 7.5%-10%). A total of 191 participants (mean age 58.7 years, mean HbA1c 8.9%) were randomized into three groups: group 1(G1, standard care, n = 63), group 2 (G2, interactive voice response system, n = 64) and group 3 (G3, Diabeo-BI app software, n = 64). The two telemonitoring systems proposed daily adjustments of BI doses, in order to facilitate the achievement of fasting blood glucose (FBG) values targeted at ~100 mg/dL. At 4 months follow-up, HbA1c reduction was significantly higher in the telemonitoring groups (G2: -1.44% and G3: -1.48% vs. G1: -0.92%; P < 0.002). Moreover, target FBG was reached by twice as many patients in the telemonitoring groups as in the control group, and insulin doses were also titrated to higher levels. No severe hypoglycaemia was observed in the telemonitoring groups and mild hypoglycaemia frequency was similar in all groups. In conclusion, both telemonitoring systems improved glycaemic control to a similar extent, without increasing hypoglycaemic episodes.

Epicardial fat accumulation is an independent marker of impaired heart rate recovery in obese patients with obstructive sleep apnea.

BACKGROUND: Sympathetic nervous system activation plays a pivotal role in obese patients with obstructive sleep apnea (OSA), contributing to increased cardiovascular risk. Epicardial adipose tissue (EAT) activates cardiac autonomic nervous system. Our main study objective was to investigate effects of these autonomic dysfunction factors on post-exercise heart rate recovery (HRR). METHODS: 36 patients, referred for clinical assessment of obesity (BMI > 30 kg/m2), underwent overnight polysomnography, transthoracic echocardiography and cardiopulmonary exercise testing. RESULTS: Compared to non-OSA patients, OSA patients were older and displayed reduced body weight-indexed peak VO2. Cardiac output at peak exercise was similar among groups. Peak exercise arterio-venous oxygen content difference D[a-v]O2 was lower in OSA patients. In univariate linear analysis, age, AHI, EAT thickness, peak VO2 and diabetes were associated with blunted HRR. Multiple linear regression analysis showed that increased EAT thickness, AHI and diabetes were independently associated with lower HRR. For identical AHI value and diabetes status, HRR significantly decreased by 61.7% for every 1 mm increase of EAT volume (p = 0.011). If HRR was treated as a categorical variable, EAT [odds ratio (OR) 1.78 (95% confidence interval [CI] 1.19-2.66); p = 0.005], and type 2 diabetes [OR 8.97 (95% CI 1.16-69.10); p = 0.035] were the only independent predictors of blunted HRR. CONCLUSIONS: Aerobic capacity and peak exercise D[a-v]O2 are impaired in obese OSA patients, suggesting abnormal peripheral oxygen extraction. EAT thickness is an independent marker of post-exercise HRR, which is a noninvasive marker of autonomic nerve dysfunction accompanying poor cardiovascular prognosis in obese patients.

Diabetes mellitus and obesity in the French Caribbean: A special vulnerability for women?

The objective of this study was to analyze the prevalence, awareness, treatment, and control of diabetes and its risk factors among French Caribbean adults. This cross-sectional study included 18-74-year olds (N = 2252; 56.5 percent women) who underwent a heath examination in Guadeloupe during July-December 2014. Diabetes was defined as using antidiabetic treatment, or fasting glucose ≥7 mmol/l, and glycated hemoglobin (HbA1c) ≥6.5 percent; diabetes control was defined as HbA1c < 7 percent. Multilevel logistic regression was used. Diabetes prevalence was 8.2 percent for women and 5 percent for men (age-adjusted odds ratio [aOR] for women = 2.0; 95 percent confidence interval [CI]: 1.4-2.9). The proportion of women with diabetes who were aware of it was 84.5 versus 67.3 percent in men (aOR = 2.7; 95 percent CI: 1.2-6.2). Nearly, all diagnosed participants were being treated. In less than a third of diabetics in both sexes was diabetes control obtained. Most women (55.3 percent) had a waist circumference at or above the National Cholesterol Education Program thresholds versus 14 percent of men (aOR = 9.3; 95 percent CI: 7.5-11.7), which wholly accounted for excess diabetes in women. In women, obesity and diabetes were associated with low education and income. In this French Caribbean sample, abdominal obesity and diabetes affected more women. Diabetes was rarely controlled. A comprehensive women's health policy for the prevention of abdominal obesity and diabetes is needed.

Zika virus detection in urine from patients with Guillain-Barré syndrome on Martinique, January 2016.

We report two cases of Guillain-Barré syndrome who had concomitant Zika virus viruria. This viruria persisted for longer than 15 days after symptom onset. The cases occurred on Martinique in January 2016, at the beginning of the Zika virus outbreak. Awareness of this possible neurological complication of ZikV infection is needed.

Polymorphisms in GC and NADSYN1 Genes are associated with vitamin D status and metabolic profile in Non-diabetic adults.

BACKGROUND: Our aim was to assess the associations between vitamin D (vitD) status, metabolic profile and polymorphisms in genes involved in the transport (Group-Component: GC) and the hydroxylation (NAD synthetase 1: NADSYN1) of 25 hydroxyvitamin D (25(OH)D) in non-diabetic individuals. METHODS: We conducted a cross-sectional study with 323 individuals recruited from the Health Center of Guadeloupe, France. The rs2282679 T > G and rs2298849 T > C in GC and rs12785878 G > T in NADSYN1 were genotyped. RESULTS: Mean age was 46(range 18-86) years. 57% of participants had vitD insufficiency, 8% had vitD deficiency, 61% were overweight and 58% had dyslipidemia. A higher frequency of overweight was noted in women carrying rs2298849T allele v CC carriers (71% v 50%; P = 0.035). The rs2282679G allele was associated with increased risks of vitD deficiency and vitD insufficiency (OR =3.53, P = 0.008, OR = 2.34, P = 0.02 respectively). The rs2298849 TT genotype was associated with vitD deficiency and overweight (OR =3.4, P = 0.004 and OR = 1.76, P = 0.04 respectively) and the rs12785878 GG genotype with vitD insufficiency and dyslipidemia (OR = 1.80, P = 0.01 and OR = 1.72, P = 0.03 respectively). Based on the number of risk alleles for rs2282679 and rs12785878 combined, a genotype score of 3 (vs. 0-1) was associated with a 5.5 ng/mL average reduction in serum 25(OH)D levels (P = 0.001). CONCLUSIONS: The GC and NADSYN1 genes are associated with the vitamin D status and might contribute to dyslipidemia and overweight independently of 25(OH)D levels.

Normotensive incidentally discovered pheochromocytomas display specific biochemical, cellular, and molecular characteristics.

CONTEXT: A number of incidentally discovered pheochromocytomas are not associated with hypertension. The characteristics of normotensive incidentally discovered pheochromocytomas (NIPs) are poorly known. OBJECTIVE: The purpose of this work was to assess the clinical, hormonal, histological, and molecular features of NIPs. DESIGN: This was a retrospective cohort recruited from 2001 to 2011 in 2 tertiary care medical departments. PATIENTS AND METHODS: Clinical, biological, and radiological investigations performed in 96 consecutive patients with sporadic unilateral pheochromocytomas were examined; 47 patients had overt pheochromocytomas responsible for hypertension. Among the patients with incidental pheochromocytomas, 28 had hypertension and 21 were normotensive (NIPs). A total of 62 tumors were examined to determine the Pheochromocytoma of the Adrenal Gland Scale Score, and 29 were studied for the expression of 16 genes involved in chromaffin cell function. RESULTS: Tumor size and metaiodobenzylguanidine (MIBG) scintigraphy results were similar for hypertensive pheochromocytomas (HPs) and NIPs. Patients with NIPs displayed reduced summed levels of urinary catecholamines and metanephrines and, more specifically, reduced levels of adrenaline and metadrenaline compared with those of patients with HPs (P < .001). Urinary metanephrines had 98% diagnostic sensitivity in patients with HPs and only 75% in patients with NIPs (P < .01). Tumor diameter positively correlated with the total amount of urinary concentrations of metanephrines in patients with HPs (P < .001) but not in patients with NIPs. NIPs displayed global decreased chromaffin gene expression (reaching significance for 5 of them) and 2 corresponding proteins (phenylethanolamine N-methyltransferase and secretogranin II) and a significant increase in the cellularity, mitotic activity, and presence of atypical mitosis (P < .05). CONCLUSIONS: NIPs differ from pheochromocytomas responsible for hypertension and display features of altered chromaffin differentiation. These tumors may be misdiagnosed with the use of the usual biological diagnostic tools.

PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy.

Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting with syndromic insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a mutational hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85α, p55α, and p50α regulatory subunits of class IA phosphatidylinositol 3 kinases (PI3Ks), which are known to play a key role in insulin signaling. Functional data from fibroblasts derived from individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling. Our findings extend the genetic causes of severe insulin-resistance syndromes and provide important information with respect to the function of PIK3R1 in normal development and its role in human diseases, including growth delay, Rieger anomaly and other ocular affections, insulin resistance, diabetes, paucity of fat, and ovarian cysts.

Remedial actions for the physical inactivity of hospitalized patients with type 2 diabetes.

OBJECTIVE: Physical inactivity is often suspected in hospitalized patients with type 2 diabetes but has yet to be quantified. RESEARCH DESIGN AND METHODS: We measured the level of physical activity of 36 hospitalized (H) and 36 free-living nonhospitalized (NH) type 2 diabetic subjects with actimeters (SenseWear Arm-Band). RESULTS: The number of steps (H: 4,381 +/- 3,742 steps/24 h, NH: 7,220 +/- 4,763 steps/24 h; P < 0.01), duration of physical activity (H: 45 +/- 57 min/24 h, NH: 148 +/- 116 min/24 h; P < 0.005), and physical activity expenditure (H: 287 +/- 390 kcal/24 h, NH: 1,035 +/- 1,006 kcal/24 h; P < 0.005) were two- to threefold lower in the hospitalized patients. Simple advice enabled us to increase their recorded levels of physical activity by approximately 50% (P < 0.005), and a further 50% (P < 0.05) was obtained by the use of a pedometer. CONCLUSIONS: The physical inactivity of hospitalized patients with type 2 diabetes is significant and remediable, although the advice given must take into account the existence of sensory neuropathy and silent myocardial ischemia.

Usefulness of adrenal scintigraphy in the follow-up of adrenocortical incidentalomas: a prospective multicenter study.

OBJECTIVES: Prognostic factors for progression of benign adrenocortical adenomas (AI) remain poorly known. We assessed the usefulness of (131)I-6-beta-iodomethylnorcholesterol scintigraphy (IMS) to predict the occurrence of adrenal hyperfunction or mass enlargement. DESIGN: Fifty-one consecutive inpatients with unilateral AI and normal 24-h urinary free cortisol (UFC) were enrolled in a multicenter observational prospective study to investigate the relationship between the scintigraphic pattern and the progression of biological abnormalities of the hypothalamo-pituitary-adrenal axis or tumor size. RESULTS: Biochemically defined 'subclinical' Cushing's syndrome (SCS) was found at baseline in 47% of patients. Unilateral uptake (UU) was significantly associated with SCS (P<0.05). During the follow-up (4.3+/-1.6-year): 53% of patients showed unchanged hormonal evaluation, 29% displayed intermittent SCS and 18% showed definitive hormonal progression of SCS but without overt biochemical hypercortisolism. UU was associated with persistence of SCS and hormonal progression (P<0.01). In multivariate analysis, UU and impaired 1 mg dexamethasone suppression were independently associated with hormonal progression. Three patients with UU developed clinical CS despite persistently normal UFC. Tumor size increased in 10% patients and was not associated with any scintigraphic pattern. CONCLUSION: Evolution of SCS toward overt biochemical CS in patients with AI is a rare event during a 4-year follow-up. UU is predictive for the occurrence of SCS, its persistence and progression within the spectrum of SCS. Further studies aiming to establish the clinical consequences of SCS are needed to recommend IMS as a complementary evaluation in patients with AI and biochemical SCS.

Body composition of obese subjects by air displacement plethysmography: The influence of hydration.

OBJECTIVE: We investigated whether air displacement plethysmography (ADP) could detect small changes in body composition of obese subjects with alterations in hydration. RESEARCH METHODS AND PROCEDURES: Ten obese subjects (mean BMI, 39.3 +/- 2.8 kg/m2) entered the ADP chamber without and with oil (1, 2, or 4 liters), water (1, 2, or 4 liters), or mixed (1 liter oil + 1 liter water or 2 liters oil + 2 liters water) loads. Real and measured changes in body composition were compared by regression analysis and Bland-Altman procedures. RESULTS: The ADP-measured changes in volume did not differ from the real values and were strongly correlated with them (r = 0.98). In all cases, loads of differing composition and similar volume led to different values of fat, fat-free mass, and percentage fat. Water was detected as increased fat-free mass only with loads of > or =2 liters, most of the water being falsely detected as increased fat mass. The observed changes were correlated with the real ones for fat mass (r = 0.68; p < 0.0001), fat-free mass (r = 0.66; p < 0.0001), and percentage fat (r = 0.61; p < 0.0001), but fat mass changes were overestimated by approximately 1 kg, and fat-free mass changes were underestimated by approximately 1 kg. This underestimation increased with the highest water loads, as shown by the Bland-Altman plot (r = -0.27; p < 0.05). Percentage fat changes were overestimated by 0.8% (p < 0.001); the magnitude of the error was correlated with the weight of the water load (r = 0.62; p < 0.0001). DISCUSSION: ADP accurately measures changes in body volume, discriminating small changes in body composition. It overestimates changes in adiposity, as most of the increased hydration is detected as an enlarged fat mass.