Effect of aerobic training on the host systemic milieu in patients with solid tumours: an exploratory correlative study.

BACKGROUND: Few studies have investigated the effects of exercise on modulation of host factors in cancer patients. We investigated the efficacy of chronic aerobic training on multiple host-related effector pathways in patients with solid tumours. PATIENTS AND METHODS: Paired peripheral blood samples were obtained from 44 patients with solid tumours receiving cytotoxic therapy and synthetic erythropoietin (usual care; n=21) or usual care plus supervised aerobic training (n=23) for 12 weeks. Samples were characterised for changes in immune, cytokine and angiogenic factors, and metabolic intermediates. Aerobic training consisted of three supervised cycle ergometry sessions per week at 60% to 100% of peak oxygen consumption (VO2peak), 30-45 min per session, for 12 weeks following a nonlinear prescription. RESULTS: The between-group delta change in cardiopulmonary function was +4.1 ml kg (-1) min(-1), favouring aerobic training (P<0.05). Significant pre-post between-group differences for five cytokine and angiogenic factors (HGF, IL-4, macrophage inflammatory protein-1ß (MIP-1ß), vascular endothelial growth factor (VEGF), and TNF-α) also favour the aerobic training group (P's<0.05). These reductions occurred in conjunction with nonsignificant group differences for T lymphocytes CD4(+), CD8(+), and CD8(+)/CD45RA (P<0.10). For these factors, circulating concentrations generally increased from baseline to week 12 in the aerobic training group compared with decreases or no change in the usual care group. No significant changes in any metabolic intermediates were observed. CONCLUSIONS: Aerobic training alters host availability of select immune-inflammatory effectors in patients with solid tumours; larger confirmatory studies in more homogenous samples are warranted.

Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss.

AIMS/HYPOTHESIS: Insulin resistance (IR) improves with weight loss, but this response is heterogeneous. We hypothesised that metabolomic profiling would identify biomarkers predicting changes in IR with weight loss. METHODS: Targeted mass spectrometry-based profiling of 60 metabolites, plus biochemical assays of NEFA, ß-hydroxybutyrate, ketones, insulin and glucose were performed in baseline and 6 month plasma samples from 500 participants who had lost ≥4 kg during Phase I of the Weight Loss Maintenance (WLM) trial. Homeostatic model assessment of insulin resistance (HOMA-IR) and change in HOMA-IR with weight loss (∆HOMA-IR) were calculated. Principal components analysis (PCA) and mixed models adjusted for race, sex, baseline weight, and amount of weight loss were used; findings were validated in an independent cohort of patients (n = 22). RESULTS: Mean weight loss was 8.67 ± 4.28 kg; mean ∆HOMA-IR was -0.80 ± 1.73, range -28.9 to 4.82). Baseline PCA-derived factor 3 (branched chain amino acids [BCAAs] and associated catabolites) correlated with baseline HOMA-IR (r = 0.50, p < 0.0001) and independently associated with ∆HOMA-IR (p < 0.0001). ∆HOMA-IR increased in a linear fashion with increasing baseline factor 3 quartiles. Amount of weight loss was only modestly correlated with ∆HOMA-IR (r = 0.24). These findings were validated in the independent cohort, with a factor composed of BCAAs and related metabolites predicting ∆HOMA-IR (p = 0.007). CONCLUSIONS/INTERPRETATION: A cluster of metabolites comprising BCAAs and related analytes predicts improvement in HOMA-IR independent of the amount of weight lost. These results may help identify individuals most likely to benefit from moderate weight loss and elucidate novel mechanisms of IR in obesity.

Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men.

AIMS/HYPOTHESIS: Insulin resistance (IR) is associated with obesity, but can also develop in individuals with normal body weight. We employed comprehensive profiling methods to identify metabolic events associated with IR, while controlling for obesity. METHODS: We selected 263 non-obese (BMI approximately 24 kg/m2) Asian-Indian and Chinese men from a large cross-sectional study carried out in Singapore. Individuals taking medication for diabetes or hyperlipidaemia were excluded. Participants were separated into lower and upper tertiles of IR based on HOMA indices of < or =1.06 or > or =1.93, respectively. MS-based metabolic profiling of acylcarnitines, amino acids and organic acids was combined with hormonal and cytokine profiling in all participants. RESULTS: After controlling for BMI, commonly accepted risk factors for IR, including circulating fatty acids and inflammatory cytokines, did not discriminate the upper and lower quartiles of insulin sensitivity in either Asian- Indian or Chinese men. Instead, IR was correlated with increased levels of alanine, proline, valine, leucine/isoleucine, phenylalanine, tyrosine, glutamate/glutamine and ornithine, and a cluster of branched-chain and related amino acids identified by principal components analysis. These changes were not due to increased protein intake by individuals in the upper quartile of IR. Increased abdominal adiposity and leptin, and decreased adiponectin and IGF-binding protein 1 were also correlated with IR. CONCLUSIONS/INTERPRETATION: These findings demonstrate that perturbations in amino acid homeostasis, but not inflammatory markers or NEFAs, are associated with IR in individuals of relatively low body mass.

Long-term changes in neurotrophic factor expression in distal nerve stump following denervation and reinnervation with motor or sensory nerve.

Several factors have been proposed to account for poor motor recovery after prolonged denervation, including motor neuron cell death and incomplete or poor regeneration of motor fibers into the muscle. Both may result from failure of the muscle and the distal motor nerve stump to continue expression of neurotrophic factors following delayed muscle reinnervation. This study investigated whether regenerating motor or sensory axons modulate distal nerve neurotrophic factor expression. We found that transected distal tibial nerve up-regulated brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) mRNA, down-regulated neurotrophin-3 and ciliary neurotrophic factor mRNA, and that although these levels returned to normal with regeneration, the chronically denervated distal nerve stump continued to express these neurotrophic factors for at least 6 months following injury. A sensory nerve (the cutaneous saphenous nerve) sutured to distal tibial nerve lowered injury-induced BDNF and GDNF mRNA levels in distal stump, but repair with a mixed nerve (peroneal, containing muscle and cutaneous axons) was more effective. Repair with sensory or mixed nerves did not affect nerve growth factor or neurotrophin-3 expression. Thus, distal nerve contributed to a neurotrophic environment for nerve regeneration for at least 6 months, and sensory nerve repair helped normalize distal nerve neurotrophic factor mRNA expression following denervation. Furthermore, as BDNF and GDNF levels in distal stump increased following denervation and returned to control levels following reinnervation, their levels serve as markers for the status of regeneration by either motor or sensory nerve.

Review of data describing outcomes that are used to assess changes in quality of life after reduction mammaplasty.

Although plastic surgeons have empirically "known" of the benefits of reduction mammaplasty for their patients, a paucity of outcome studies have been reported. For this study, an attempt to perform a meta-analysis of outcomes in reduction mammaplasty was undertaken. A computer literature search was performed of the MEDLINE database for the period between 1966 and September of 1997 for the Medical Subject Headings mammaplasty and outcome measures. Reference lists were used for additional reports. No trials were identified that met the criteria for meta-analysis. Seventeen publications met less restrictive review criteria that evaluated quality-of-life outcome measures. A systematic evaluation of patient-focused outcome measures demonstrated that consistent improvement in physical symptoms was found across most studies, as was a high degree of patient satisfaction (78 to 95 percent very or moderately satisfied), and some have shown improvement in body image and psychological well-being. However, although this review does identify consistent improvements in patient quality of life after reduction mammaplasty, inconsistencies among study designs do not allow formal meta-analysis.

Improved functional recovery of denervated skeletal muscle after temporary sensory nerve innervation.

Prolonged muscle denervation results in poor functional recovery after nerve repair. The possible protective effect of temporary sensory innervation of denervated muscle, prior to motor nerve repair, has been examined in the rat. Soleus and gastrocnemius muscles were denervated by cutting the tibial nerve, and the peroneal nerve was then sutured to the transected distal tibial nerve stump either immediately or after two, four or six months. In half of the animals with delayed repair, the saphenous (sensory) nerve was temporarily attached to the distal nerve stump. Muscles were evaluated three months after the peroneal-to-tibial union, and were compared with each other, with unoperated control muscles and with untreated denervated muscles. After four to six months of sensory "protection", gastrocnemius muscles weighed significantly more than unprotected muscles, and both gastrocnemius and soleus muscles exhibited better preservation of their structure, with less fiber atrophy and connective tissue hyperplasia. The maximum compound action potentials were significantly larger in gastrocnemius and soleus muscles following sensory protection, irrespective of the delay in motor nerve union. Isometric force, although less than in control animals and in those with immediate nerve repair, remained reasonably constant after sensory protection, while in unprotected muscles there was a progressive and significant decline as the period of denervation lengthened. We interpret these results as showing that, although incapable of forming excitable neuromuscular junctions, sensory nerves can nevertheless exert powerful trophic effects on denervated muscle fibers. We propose that these findings indicate a useful strategy for improving the outcome of peripheral nerve surgery.

Peripheral nerve and neuromuscular allotransplantation: current status.

Some major peripheral nerve deficits in otherwise salvageable extremities are unreconstructable with autogenous nerve grafts because of their limited availability. Peripheral nerve allotransplantation has been attempted experimentally and clinically for more than a century. It is only since the advent of the immunophyllin-immunosuppressive agents (Cyclosporin A and FK506) that nerve regeneration across allografts has been comparable to that observed across autografts. Experimental studies have demonstrated excellent regeneration through nerve allografts with recipient CsA and FK506 immunosuppression given continuously and for limited periods. This permitted the development of a clinical trial. To date, seven patients received major nerve reconstructions with nerve allografts under temporary immunosuppression; six have had sensory recovery; three motor recovery; and one no recovery due to rejection. The experimental and clinical work will be reviewed and relevance to composite tissue allotransplantation discussed.

Preservation of denervated muscle by sensory protection in rats.

The goal of this study was to determine whether sensory motor nerve crossover could alter post-denervation atrophy of skeletal muscle. Sixty adult Lewis rats were divided into three groups: 1) unilateral transection of the tibial nerve alone; 2) unilateral transection of the tibial nerve with immediate repair; and 3) unilateral tibial and sural nerve transections with repair of the proximal sural nerve (sensory) to the distal tibial nerve (motor). The unoperated hind legs acted as positive controls. At 1 and 2 months postoperatively, posterior compartment musculature was harvested, weighed, then fixed and stained for histologic analysis. One month postoperatively, mean muscle weight in Group 1 animals (transection alone) was 23.0 +/- 2.6 percent of the control side; for Group 2 animals (motor-motor repair) was 40.9 +/- 42 percent; and for the sensory-protected Group 3 animals (sensory-motor repair) was 26.7 +/- 2.8 percent of controls (n = 15 per group). Two months postoperatively, the mean weights were 14.5 +/- 0.9 percent, 58.8 +/- 7.3 percent, and 21.1 +/- 3.1 percent of controls for Groups 1, 2, and 3, respectively (n = 5 per group). Differences between groups were statistically significant. Histologic analysis of Group 1 specimens revealed generalized atrophy of all muscle fibers. In Group 2, specimens showed evidence of reinnervation and less atrophy. Group 3 specimens demonstrated an atrophic pattern with islands of non-atrophic fibers scattered throughout. Sensory protection was thus shown to have significant effect on post-denervation atrophy in rat skeletal muscle.

Long-segment nerve allograft regeneration in the sheep model: experimental study and review of the literature.

Experimental work in the field of nerve allotransplantation has dealt with the feasibility of nerve allografts reconstructing nerve gaps. In the majority of studies, the nerve gap studied has been short, and some degree of regeneration has been achieved, even in the untreated allograft. To better approximate clinical nerve-allograft reconstruction, a series of long-segment (8-cm) nerve allografts were performed in the ovine model. Twenty outbred ewes were randomized into two experimental groups with four experimental conditions. Animals received nerve allografts treated under one of the following conditions: fresh nerve autograft, fresh nerve allograft, cold-preserved nerve autograft, or cold-preserved nerve allograft. The nerve grafts were examined and compared at 6 and 10 months, using histological, morphometric, and electro-physiologic analyses. The results of the study demonstrated that, while excellent regeneration occurred across the nerve autograft, the long nerve allograft could not support axonal elongation. Similarly, cold nerve preservation did not enhance regeneration. The sheep animal model allows for investigation of the long nerve gap and may be beneficial in a better correlation of experimental nerve transplantation with clinical conditions.

Verification of a free vascularized nerve graft model in the rat with application to the peripheral nerve allograft.

We report a vascularized sciatic nerve graft in the rat, based upon the femoral popliteal superior muscular artery pedicle. The pedicle may be raised from the common femoral artery via the popliteal artery, with accompanying venous drainage to the femoral vein. We have characterized two vessels: the middle tibial artery to the posterior tibial nerve and the arteria comitas nervus peroneus to the peroneal nerve. Plastic monomer and Evans blue labeled albumin injections established the anatomic model. The graft was reliably perfused at the time of isolation and 24 hours post-transplantation. The model was used to evaluate regeneration across allogeneic (ACI to Lewis, n = 12) versus syngeneic (Lewis to Lewis, n = 6) nerve grafts. Electrophysiologic and histomorphometric assessments demonstrated that the vascularized immunosuppressed allograft was similar to the vascularized syngeneic graft. Both were superior to the vascularized allograft without immunosuppression.

The peripheral nerve allograft in the primate immunosuppressed with Cyclosporin A: I. Histologic and electrophysiologic assessment.

Nerve regeneration across peripheral nerve allografts and control autografts in primates immunosuppressed with Cyclosporin A was quantitatively evaluated by electrophysiologic and histologic methods. Twelve cynomolgus monkeys received 3-cm autografts and allografts in contralateral ulnar nerves. They were immunosuppressed with Cyclosporin A at 25 mg/kg per day or placebo vehicle. Morphometric analysis of nerve graft and distal nerve segments was assessed at 1 year after engraftment. Quantitative electrophysiologic studies were performed percutaneously at 6 and 12 months, and compound action potentials were measured directly across the nerve grafts at 1 year. Excellent regeneration was seen across autografts and allografts in Cyclosporin A-treated and placebo-treated recipients.

The peripheral nerve allograft in the primate immunosuppressed with Cyclosporin A: II. Functional evaluation of reinnervated muscle.

Isometric contractile function was evaluated in primates receiving peripheral nerve allografts and autografts. Twelve adult male cynomolgus monkeys received both sural nerve allografts and autografts to the ulnar nerve in opposite forearms. Half the animals received Cyclosporin A (CsA) immunosuppression (25 mg/kg per day); the remaining animals received placebo. One year following nerve engraftment, isometric contractile muscle function was evaluated in reinnervated abductor digiti quinti and intact abductor pollicis brevis muscles. Maximal twitch tension (Pt), tetanic tension (P(o)), time to peak tension (tpt), rate of rise of twitch tension (DP/dt), and muscle fatigue were evaluated at optimal muscle length (L(o)). All reinnervated muscles distal to nerve autografts and allografts in both Cyclosporin A-immunosuppressed and placebo-treated animals generated equivalent maximal twitch tension, tetanic tension, and time to peak tension, with no significant difference between groups (p > 0.05 by ANOVA). There was a tendency toward increased muscle fatiguability in Cyclosporin A-treated animals (p > 0.05). However, the rate of rise of twitch tension was significantly faster in the reinnervated and intact muscles of Cyclosporin A-treated primates (p < 0.05). Evidence of excellent functional reinnervation across nerve allografts and autografts similar to that seen in histologic and electrophysiologic studies was noted. Cyclosporin A immunosuppression did not significantly enhance recovery of muscle function distal to nerve allografts in this model.

Walking track analysis: a long-term assessment of peripheral nerve recovery.

Functional recovery following sciatic, tibial, and peroneal nerve injury was assessed over a 1-year period using walking track analysis in the rat. Internal neurolysis did not affect nerve function. Crush injury induced a temporary, but complete, loss of function that recovered to control levels by 4 weeks. Nerve transection resulted in complete loss of function without any evidence of recovery. After nerve repair, functional recovery occurred, reaching near-optimal recovery by 12 weeks. The degree of functional recovery varied with the specific nerve involved. The sciatic nerve recovered 41 percent of function, whereas the tibial nerve recovered 54 percent of function. The peroneal nerve exhibited the highest degree of recovery, achieving functional levels similar to control values. Assessment of neural regeneration using walking track analysis appears to be a valuable addition to the traditional methods of histology and electrophysiology.

Selective reinnervation: a comparison of recovery following microsuture and conduit nerve repair.

Selective reinnervation was studied by comparing the regeneration across a conventional neurorraphy versus a conduit nerve repair. Lewis rats underwent right sciatic nerve transection followed by one of four different nerve repairs (n = 8/group). In groups I and II a conventional neurorraphy was performed and in groups III and IV the proximal and distal stumps were coapted by use of a silicone conduit with an interstump gap of 5 mm. The proximal and distal stumps in groups I and III were aligned anatomically correct and the proximal stump was rotated 180 degrees in groups II and IV (i.e. proximal peroneal nerve opposite the distal tibial nerve and the proximal tibial nerve opposite the distal peroneal nerve). By 14 weeks, there was an equivalent, but incomplete return in sciatic function index (SFI) in groups I, III, and IV as measured by walking track analysis. However, the SFI became unmeasurable by 6 weeks in all group II animals. At 14 weeks, the percent innervation of the tibialis anterior and medial gastronemius muscles by the peroneal and tibial nerves respectively was estimated by selective compound muscle action potential amplitude recordings. When fascicular alignment was reversed, there was greater tibial (P = 0.02) and lesser peroneal (P = 0.005) innervation of the gastrocnemius muscle in the conduit (group IV) versus the neurorraphy (group II) group. This suggests that the gastrocnemius muscle may be selectively reinnervated by the tibial nerve. However, there was no evidence of selective reinnervation of the tibialis anterior muscle. Despite these differences, the functional recovery in both conduit repair groups (III and IV) was equivalent to a correctly aligned microsuture repair (group I) and superior to that in the incorrectly aligned microsuture repair (group II).

Inter- and intraobserver reliability of walking-track analysis used to assess sciatic nerve function in rats.

The inter- and intraobserver reliability of the walking-track analysis of sciatic nerve function in the rat was assessed. Twenty-five walking tracks were assessed on three different occasions by four observers. Whereas the interobserver reliability was found to be excellent (r = 0.92), the intraobserver reliability was only satisfactory (r = 0.53 to r = 0.76). Walking-track analysis provides a noninvasive technique to assess function recovery in the rat, with excellent intraobserver reliability demonstrated. The lower intraobserver reliability suggests limitations to this new measurement technique.

The sensory potential of free flap donor sites.

Microneurovascular techniques make transfer of innervated soft tissue a reality. The present study investigated the sensory potential of four such donor sites: volar wrist, dorsal hand, dorsal foot, and great toe. Normal moving and static two-point discrimination values for these areas are reported. A sensory reeducation protocol demonstrated that even these normal values may be improved with training. This suggests that the full potential of transferred innervated soft tissue may best be achieved by incorporating sensory reeducation routinely in the postoperative rehabilitation program.

Self-evaluation of walking-track measurement using a Sciatic Function Index.

Recovery of function is of prime importance after peripheral nerve injury and repair. This paper describes a method of obtaining and measuring walking-tracks and generating a Sciatic Function Index (SFI) to quantify functional sciatic nerve recovery in the rat. The reader is provided with a series of walking-tracks to measure, analyze and compare to those analyzed by experienced observers.

Functional evaluation of complete sciatic, peroneal, and posterior tibial nerve lesions in the rat.

Quantification of peripheral nerve regeneration in animal studies of nerve injury and repair by histologic, morphologic, and electrophysiologic parameters has been controversial because such studies may not necessarily correlate with actual nerve function. This study modifies the previously described sciatic functional index (SFI), tibial functional index (TFI), and peroneal functional index (PFI) based on multiple linear regression analysis of factors derived from measurements of walking tracks in rats with defined nerve injuries. The factors that contributed to these formulas were print-length factor (PLF), toe-spread factor (TSF), and intermediary toe-spread factor (ITF). It was shown that animals with selective nerve injuries gave walking tracks that were consistent, predictable, and based on known neuromuscular deficits. The new formula for sciatic functional index was compared with previously described indices. The sciatic functional index, tibial functional index, and peroneal functional index offer the peripheral nerve investigator a noninvasive quantitative assessment of hindlimb motor function in the rat with selective hindlimb nerve injury.