Lifetime body mass index and grip strength at age 46 years: the 1970 British Cohort Study.

BACKGROUND: Ongoing rises in obesity prevalence have prompted growing concerns about potential increases in the burden of age-related musculoskeletal conditions including sarcopenia and sarcopenic obesity. This is of particular concern for future generations of older adults who have lived more of their lives in an obesogenic environment than current generations of older adults. We aimed to study longitudinal associations between body mass index (BMI) and grip strength in midlife using data from a large population-based sample, the 1970 British Cohort Study (BCS70). METHODS: BCS70 participants with valid measures of maximum grip strength at age 46 years were included in analyses [3671 males (49%) and 3876 females (51%)]. Using sex-specific linear regression models, we examined associations of (i) BMI at ages 10, 16, 30, and 46 years; (ii) body fat percentage (BF%) and waist-hip ratio at age 46 years; (iii) BMI gains between 10-16, 16-30, and 30-46; and (iv) age at onset of obesity, with grip strength. RESULTS: At age 46 years, mean (standard deviation) grip strength was 48.10 kg (8.98) in males and 29.61 kg (5.81) in females. Higher BMI at all ages was associated with stronger grip, and the scale of associations was greater in males than females from age 16 onwards (Psex interactions  < 0.01). For example, in fully adjusted models, a 1 standard deviation increase in BMI at age 16 was associated with mean differences in grip strength at age 46 years of 1.41 kg (95% confidence interval: 1.07, 1.75) in males and 0.72 kg (0.53, 0.91) in females. Higher BF% at age 46 was also associated with stronger grip in both sexes. Greater gains in BMI between ages 10 and 16 were associated with stronger grip in both sexes, but subsequent gains in BMI were only associated with stronger grip in males. Associations of greater length of exposure to obesity and stronger grip were also more consistent among males than females. For example, in fully adjusted models, mean grip strength at age 46 years of males and females who had been obese since age 10 or 16 years was 4.39 kg (1.85, 6.93) and 1.25 kg (-0.18, 2.69) higher than males and females who had never been obese, respectively. CONCLUSIONS: Higher BMI from childhood onwards is associated with stronger grip at age 46 years. This suggests that, at this age, anabolic effects of fat on muscle are outweighing the catabolic effects thought to lead to the manifestation of sarcopenic obesity later in life, especially among men. Midlife may be an optimal time to intervene to prevent sarcopenic obesity.

Displacing Sedentary Behaviour with Light Intensity Physical Activity Spontaneously Alters Habitual Macronutrient Intake and Enhances Dietary Quality in Older Females.

Displacing Sedentary Behaviour (SB) with light intensity physical activity (LIPA) is increasingly viewed as a viable means of health enhancement. It is, however, unclear whether any behavioural compensations accompany such an intervention. Therefore, the aim of this study was to identify any dietary changes that accompany SB displacement. We hypothesised that SB displacement would improve dietary quality. Thirty-five elderly females (73 ± 5 years) were randomly allocated to one of three groups: (1) sedentary behaviour fragmentation (SBF) (n = 14), (2) continuous LIPA (n = 14), or (3) control (n = 7). Habitual diet (four-day food diary) and physical behaviour (accelerometery) were assessed at weeks 0 and 8. Out of 45 nutrients examined, only glucose exhibited a group × time interaction (p = 0.03), mediated by an exclusive reduction following SBF (-31%). SBF was also the sole experimental group to increase nutrients promoting bone health (SBF: 17%, LIPA: -34%. control: 21%), whereas both experimental groups consumed more nutrients promoting anabolism (SBF: 13%, LIPA: 4%, control: -34%) (z-scores). New ambulators (n = 8) also consumed more nutrients promoting bone health (16%)/anabolism (2%) (z-scores), including significantly increased Zinc intake (p = 0.05, 29%). Displacing SB with LIPA improves dietary quality in older females. Furthermore, SB fragmentation appears advantageous for various dietary outcomes.

Body Fat Percentage, Body Mass Index, Fat Mass Index and the Ageing Bone: Their Singular and Combined Roles Linked to Physical Activity and Diet.

This study took a multi-analytical approach including group differences, correlations and unit-weighed directional z-score comparisons to identify the key mediators of bone health. A total of 190 participants (18⁻80 years) were categorized by body fat%, body mass index (BMI) and fat mass index (FMI) to examine the effect of differing obesity criteria on bone characteristics. A subset of 50 healthy-eating middle-to-older aged adults (44⁻80 years) was randomly selected to examine any added impact of lifestyle and inflammatory profiles. Diet was assessed using a 3-day food diary, bone mineral density (BMD) and content (BMC) by dual energy x-ray absorptiometry in the lumbar, thoracic, (upper and lower) appendicular and pelvic areas. Physical activity was assessed using the Baecke questionnaire, and endocrine profiling was assessed using multiplex luminometry. Obesity, classed via BMI, positively affected 20 out of 22 BMC- and BMD-related outcome measures, whereas FMI was associated with 14 outcome measures and adiposity only modulated nine out of 22 BMC- and BMD-related outcome measures. Whilst bivariate correlations only linked vitamin A and relative protein intake with BMD, the Z-score composite summary presented a significantly different overall dietary quality between healthy and osteopenic individuals. In addition, bivariate correlations from the subset revealed daily energy intake, sport-based physical activity and BMI positive mediators of seven out of 10 BMD sites with age and body fat% shown to be negative mediators of bone characteristics. In conclusion, whilst BMI is a good indicator of bone characteristics, high body fat% should also be the focus of osteoporosis risk with ageing. Interestingly, high BMI in conjunction with moderate to vigorous activity supplemented with an optimal diet (quality and quantity) are identified as positive modulators of bone heath.

Transseptal left ventricular lead placement using snare technique.

BACKGROUND: Coronary sinus (CS) lead placement for cardiac resynchronization therapy has a failure rate of ∼5-10%. Here we describe a way of implanting an endocardial left ventricular (LV) lead via a transseptal puncture (TSP), using a GooseNeck snare and active fixation lead. METHODS: Three male patients (67-83 years) with failed or extracted epicardial LV leads implanted via the CS had an endocardial LV lead implanted. TSP was performed via a femoral vein. The active fixation pacing lead was advanced to the right atrium from a subclavian vein. A GooseNeck snare was passed via the TSP sheath and used to grasp the tip of the pacing lead. The sheath, GooseNeck snare, and pacing lead tip were then passed to the left atrium by sliding the system up the TSP guidewire and across the interatrial septum before deflecting the lead to permit implantation in the left ventricle. RESULTS: Successful implantation was performed in all patients with an LV implant time of 25-55 minutes. CONCLUSION: The use of a GooseNeck snare via a deflectable transseptal sheath represents a reliable alternative method for endocardial LV lead placement in patients with failed CS LV lead implantation.

Engineered zinc finger protein-mediated VEGF-a activation restores deficient VEGF-a in sensory neurons in experimental diabetes.

OBJECTIVE: The objectives of the study were to evaluate retrograde axonal transport of vascular endothelial growth factor A (VEGF-A) protein to sensory neurons after intramuscular administration of an engineered zinc finger protein activator of endogenous VEGF-A (VZ+434) in an experimental model of diabetes, and to characterize the VEGF-A target neurons. RESEARCH DESIGN AND METHODS: We compared the expression of VEGF-A in lumbar (L)4/5 dorsal root ganglia (DRG) of control rats and VZ+434-treated and untreated streptozotocin (STZ)-induced diabetic rats. In addition, axonal transport of VEGF-A, activation of signal transduction pathways in the DRG, and mechanical sensitivity were assessed. RESULTS: VEGF-A immunoreactivity (IR) was detected in small- to medium-diameter neurons in DRG of control rats. Fewer VEGF-A-IR neurons were observed in DRG from STZ-induced diabetic rats; this decrease was confirmed and quantified by Western blotting. VZ+434 administration resulted in a significant increase in VEGF-A protein expression in ipsilateral DRG, 24 h after injection. VEGF-A was axonally transported to the DRG via the sciatic nerve. VZ+434 administration resulted in significant activation of AKT in the ipsilateral DRG by 48 h that was sustained for 1 week after injection. VZ+434 protected against mechanical allodynia 8 weeks after STZ injection. CONCLUSIONS: Intramuscular administration of VZ+434 increases VEGF-A protein levels in L4/5 DRG, correcting the deficit observed after induction of diabetes, and protects against mechanical allodynia. Elevated VEGF-A levels result from retrograde axonal transport and are associated with altered signal transduction, via the phosphatidylinositol 3'-kinase pathway. These data support a neuroprotective role for VEGF-A in the therapeutic actions of VZ+434 and suggest a mechanism by which VEGF-A exerts this activity.

Interatrial septum thickness and difficulty with transseptal puncture during redo catheter ablation of atrial fibrillation.

BACKGROUND: Patients undergoing catheter ablation for atrial fibrillation (AF) frequently require redo procedures, but there are no data reporting interatrial septum thickness (IAS) and difficulty during repeat transseptal puncture (TSP). METHODS: Patients undergoing two separate AF ablation procedures had preprocedural fossa ovalis (FO) thickness measured using transesophageal echocardiography (TEE). "Difficult" TSP was defined by two observers as requiring excessive force, or conversion to TEE guidance. RESULTS: The study comprised 42 patients (37 male) with mean+/-SD age 55+/-9 years. Mean FO thickness was significantly greater at the time of redo TSP (2.2+/-1.6 mm vs 2.6+/-1.5 mm at redo, P=0.03); however, this finding was limited to those who underwent initial dual transseptal sheath procedures, FO thickness 2.0+/-1.5 mm and 2.5+/-1.4 mm for TEE 1 and 2, respectively (P=0.048). There was a trend for more frequent difficult redo TSP procedures, 7/42 (17%; 95% confidence interval [CI] 8-31) redo, versus 4/42 (10%; 95% CI 3-23) first TSP. On univariate analysis, FO thickness was not predictive of TSP difficulty; the only predictor of difficult redo TSP was diabetes. CONCLUSIONS: IAS thickness at the FO increased following catheter ablation of AF, yet on subgroup analysis this was limited to initial procedures utilizing dual transseptal sheaths. There was a trend toward more frequent difficulty during redo TSP, yet this was not associated with FO thickening. Diabetes may predispose to difficulty during redo TSP; this finding requires confirmation in a larger study population.

Thioredoxin interacting protein is increased in sensory neurons in experimental diabetes.

Diabetic neuropathy is a major complication of diabetes and has multifactoral aetiology. The exact cause of damage is unknown although high glucose and oxidative stress are known to contribute significantly. In order to identify molecular targets of the disease and possibly new therapeutic targets, we previously examined the effect of diabetes on dorsal root ganglia (DRG) neurons using Affymetrix gene chip arrays. A number of individual genes and groups of genes were found to be dysregulated; the most significant of these was thioredoxin interacting protein (Txnip). This gene was found to have increased expression in DRG from diabetic rats with all durations of diabetes examined, including those that preceded the onset of functional changes such as decreased nerve conduction velocity. Increased Txnip expression therefore represents an early change in diabetic neuropathy that could, at least in part, be responsible for causing the initial functional deficits. This study confirmed the changes in Txnip expression at the mRNA and protein levels and identified the cell types responsible for the change. Furthermore we investigated the mechanism of diabetes-induced Txnip gene induction. Neither the antioxidant dexlipotam (R-lipoic acid) nor the p38 MAP kinase inhibitor SB239063 could prevent increases in Txnip expression despite reducing oxidative stress. However, treatment of rats with insulin prevented diabetes-induced increases in Txnip gene expression. These results indicate another mechanism by which diabetes may cause oxidative damage in peripheral nerve, and may represent a novel target for therapeutic intervention.

Gene transfer of an engineered transcription factor promoting expression of VEGF-A protects against experimental diabetic neuropathy.

Peripheral neuropathy is a common, irreversible complication of diabetes. We investigated whether gene transfer of an engineered zinc finger protein transcription factor (ZFP-TF) designed to upregulate expression of the endogenous vascular endothelial growth factor (VEGF)-A gene could protect against experimental diabetic neuropathy. ZFP-TF-driven activation of the endogenous gene results in expression of all of the VEGF-A isoforms, a fact that may be of significance for recapitulation of the proper biological responses stimulated by this potent neuroprotective growth factor. We show here that this engineered ZFP-TF activates VEGF-A in appropriate cells in culture and that the secreted VEGF-A protein induced by the ZFP protects neuroblastoma cell lines from a serum starvation insult in vitro. Importantly, single and repeat intramuscular injections of formulated plasmid DNA encoding the VEGF-A-activating ZFP-TF resulted in protection of both sensory and motor nerve conduction velocities in a streptozotocin-induced rat model of diabetes. These data suggest that VEGF-A-activating ZFP-TFs may ultimately be of clinical utility in the treatment of this disease.