Sympathetic Neural Adaptation to Hypocaloric Diet With or Without Exercise Training in Obese Metabolic Syndrome Subjects

OBJECTIVE

Sympathetic nervous system (SNS) overactivity contributes to the pathogenesis and target organ complications of obesity. This study was conducted to examine the effects of lifestyle interventions (weight loss alone or together with exercise) on SNS function.

RESEARCH DESIGN AND METHODS

Untreated men and women (mean age 55 ± 1 year; BMI 32.3 ± 0.5 kg/m²) who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated to either dietary weight loss (WL, n = 20), dietary weight loss and moderate-intensity aerobic exercise (WL+EX, n = 20), or no treatment (control, n = 19). Whole-body norepinephrine kinetics, muscle sympathetic nerve activity by microneurography, baroreflex sensitivity, fitness (maximal oxygen consumption), metabolic, and anthropometric measurements were made at baseline and 12 weeks.

RESULTS

Body weight decreased by −7.1 ± 0.6 and −8.4 ± 1.0 kg in the WL and WL+EX groups, respectively (both P < 0.001). Fitness increased by 19 ± 4% (P < 0.001) in the WL+EX group only. Resting SNS activity decreased similarly in the WL and WL+EX groups: norepinephrine spillover by −96 ± 30 and −101 ± 34 ng/min (both P < 0.01) and muscle sympathetic nerve activity by −12 ± 6 and −19 ± 4 bursts/100 heart beats, respectively (both P < 0.01), but remained unchanged in control subjects. Blood pressure, baroreflex sensitivity, and metabolic parameters improved significantly and similarly in the two lifestyle intervention groups.

CONCLUSIONS

The addition of moderate-intensity aerobic exercise training to a weight loss program does not confer additional benefits on resting SNS activity. This suggests that weight loss is the prime mover in sympathetic neural adaptation to a hypocaloric diet.The metabolic syndrome (MetS) is an increasingly prevalent multidimensional risk factor for cardiovascular disease and type 2 diabetes (1). Its etiology is complex and incompletely understood, but thought to involve the interplay between metabolic susceptibility, lifestyle factors, and the acquisition of excess visceral adiposity (2). Scientific studies performed over the last 2 decades strongly support the relevance of the sympathetic nervous system (SNS) in both the pathogenesis and target organ complications of MetS obesity (3).Several indexes of SNS activity, such as urinary norepinephrine excretion, norepinephrine spillover from sympathetic nerves, and postganglionic muscle sympathetic nerve activity (MSNA) are increased in subjects with MetS, even in the absence of hypertension (4–7). Among the adiposity indexes, abdominal visceral fat is most strongly associated with elevated MSNA (8). Because of the bidirectional relationship between sympathetic activation and insulin resistance, much debate has focused on their chronology. Prospective studies with 10–20 years follow-up indicate that elevated plasma norepinephrine concentration (9) and sympathetic reactivity (10) precede and predict future rise in BMI and development of insulin resistance. Although seemingly counterintuitive, sympathetic activation may be causally linked to obesity via β-adrenoceptor desensitization (11) and insulin resistance (12,13). In established obesity, metabolic, cardiovascular (baroreflex impairment), and medical conditions (obstructive sleep apnea) contribute significantly to sympathetic neural drive and further aggravate insulin resistance, hence establishing a vicious cycle (3,7). Chronic sympathetic activation is associated with an increased prevalence of preclinical cardiovascular and renal changes that are recognized predictors of adverse clinical prognosis (3,14,15).Weight loss and exercise are recommended as first-line treatments for MetS. The Diabetes Prevention Program and the Oslo Diet and Exercise Study have shown the marked clinical benefits of intensive lifestyle intervention on the resolution of the MetS (16,17). Individually, both weight loss (5) and exercise training (18,19) cause sympathoinhibition and improvement in MetS components. We have previously reported that moderate weight loss (7% of body weight) by diet alone is accompanied by reductions in whole-body norepinephrine spillover and MSNA and improvement in spontaneous cardiac baroreflex function in middle-aged MetS subjects (5). Because exercise is often added to energy restriction in the treatment of obesity, it is pertinent to clarify its additive benefits. Augmented improvements in metabolic, anthropometric, and cardiovascular parameters have been observed after combined exercise training and dietary weight loss in some (17,20,21), but not other studies (22), and there are limited data regarding their combined effect on sympathetic activity (23). Exercise training may potentially augment weight loss induced sympathoinhibition by promoting a greater loss of fat relative to lean mass (20,21), by further improvement in insulin sensitivity (24) and reduction in plasma leptin concentration (21), and by potentiation of baroreceptor sensitivity (18).The present study was conducted to 1) test the hypothesis that weight loss by combined hypocaloric diet and aerobic exercise training would be associated with greater sympathoinhibition and improvement in MetS components than hypocaloric diet alone and 2) to examine the interrelationships between reduction in sympathetic tone and concurrent changes in anthropometric, metabolic (insulin sensitivity, plasma leptin concentration), and cardiovascular parameters. A moderate-intensity bicycle riding protocol was chosen as the exercise intervention, based on an earlier study that demonstrated attenuation in whole-body and renal norepinephrine spillover rates with this regimen in healthy men (19).     

CNS 7056: A Novel Ultra-short-acting Benzodiazepine

Background: A new benzodiazepine derivative, CNS 7056, has been developed to permit a superior sedative profile to current agents, i.e., more predictable fast onset, short duration of sedative action, and rapid recovery profile. This goal has been achieved by rendering the compound susceptible to metabolism via esterases. The authors now report on the profile of CNS 7056 in vitro and in vivo.

Methods: The affinity of CNS 7056 and its carboxylic acid metabolite, CNS 7054, for benzodiazepine receptors and their selectivity profiles were evaluated using radioligand binding. The activity of CNS 7056 and midazolam at subtypes ([alpha]1[beta]2[gamma]2, [alpha]2[beta]2[gamma]2, [alpha]3[beta]2[gamma]2, [alpha]5[beta]2[gamma]2) of the [gamma]-aminobutyric acid type A (GABAA) receptor was evaluated using the whole cell patch clamp technique. The activity of CNS 7056 at brain benzodiazepine receptors in vivo was measured in rats using extracellular electrophysiology in the substantia nigra pars reticulata. The sedative profile was measured in rodents using the loss of righting reflex test.

Results: CNS 7056 bound to brain benzodiazepine sites with high affinity. The carboxylic acid metabolite, CNS 7054, showed around 300 times lower affinity. CNS 7056 and CNS 7054 (10 [mu]m) showed no affinity for a range of other receptors. CNS 7056 enhanced GABA currents in cells stably transfected with subtypes of the GABAA receptor. CNS 7056, like midazolam and other classic benzodiazepines, did not show clear selectivity between subtypes of the GABAA receptor. CNS 7056 (intravenous) caused a dose-dependent inhibition of substantia nigra pars reticulata neuronal firing and recovery to baseline firing rates was reached rapidly. CNS 7056 (intravenous) induced loss of the righting reflex in rodents. The duration of loss of righting reflex was short (< 10 min) and was inhibited by pretreatment with flumazenil.     

The discard of deceased donor kidneys in the UK

It is essential to minimize the unnecessary discard of procured deceased donor kidneys, but information on discard rates and the extent to which discard can be avoided are limited. Analysis of the UK Transplant Registry revealed that the discard rate of procured deceased donor kidneys has increased from 5% in 2002‐3 to 12% in 2011‐12. A national offering system for hard‐to‐place kidneys was introduced in the UK in 2006 (the Declined Kidney Scheme), but just 13% of kidneys that were subsequently discarded until 2012 were offered through the scheme. In order to examine the appropriateness of discard, 20 consecutive discarded kidneys from 13 deceased donors were assessed to determine if surgeons agreed with the decision that they were not implantable. Donors had a median (range) age of 67 (31–80) yr. Kidneys had been offered to a median of 3 (1–12) centers before discard. Four (20%) of the discarded kidneys were thought to be usable, and nine (45%) were possibly usable. As a result of these findings, major changes to the UK deceased donor kidney offering system have been implemented, including simultaneous offering and broader entry criteria for hard‐to‐place kidneys. Organizational changes are necessary to improve utilization of deceased donor kidneys.     

A prospective randomised controlled trial to assess the efficacy of dynamic stabilisation of the lumbar spine with the Wallis ligament

Purpose

This prospective randomised control study is to demonstrate whether or not there is a clinical benefit from inserting a Wallis implant on the functional recovery of patients who have undergone lumbar decompression surgery.

Method

Sixty consecutive patients with an average age of 58 years (34–81) who were selected for primary lumbosacral decompression were randomly assigned into two groups with equal number of patients, decompression alone or decompression with Wallis implant. The patients had an average follow-up of 40 months. Patients were assessed by visual analogue scale (VAS) (Boonstra et al., Int J Rehabil Res 31:165–169, 2008; Price et al., Pain 17:45–56, 1983) pain score for back and leg pain, and the Oswestry Disability Index questionnaire (ODI) (Smeets et al., Arthritis Care Res (Hoboken) 63:S158–S173, 2011).

Results

The results in both the groups did not reveal a significant difference in the clinical outcome assessment of back pain score or ODI. With the Wilcoxon two-sample test, no difference in median values was achieved (p value 0.0787 for ODI and p value 0.1926 for back pain). The average ODI in the Wallis group dropped from 50.93 to 29.11. The average VAS for the Wallis group back pain dropped from 7.79 to 4.22.

Conclusion

The Wallis implant is a safe medical device. This study revealed a reduction in pain and functional disability in patients treated with decompression surgery for lumbar stenosis, with or without Wallis. The Wallis group improved more, but it was not statistically significant. The risk of complications is lower than other interspinous devices [18, 19].     

The use of fat grafting and platelet‐rich plasma for wound healing: A review of the current evidence

Fat grafting is becoming a common procedure in regenerative medicine because of its high content of growth factors and adipose derived stem cells (ADSCs) and the ease of harvest, safety, and low cost. The high concentration of ADSCs found in fat has the potential to differentiate into a wide range of wound‐healing cells including fibroblasts and keratinocytes as well as demonstrating proangiogenic qualities. This suggests that fat could play an important role in wound healing. However retention rates of fat grafts are highly variable due in part to inconsistent vascularisation of the transplanted fat. Furthermore, conditions such as diabetes, which have a high prevalence of chronic wounds, reduce the potency and regenerative potential of ADSCs. Platelet‐rich plasma (PRP) is an autologous blood product rich in growth factors, cell adhesion molecules, and cytokines. It has been hypothesised that PRP may have a positive effect on the survival and retention of fat grafts because of improved proliferation and differentiations of ADSCs, reduced inflammation, and improved vascularisation. There is also increasing interest in a possible synergistic effect that PRP may have on the healing potential of fat, although the evidence for this is very limited. In this review, we evaluate the evidence in both in vitro and animal studies on the mechanistic relationship between fat and PRP and how this translates to a benefit in wound healing. We also discuss future directions for both research and clinical practice on how to enhance the regenerative potential of the combination of PRP and fat.