Low, Phillip A.

AbstractNeurological and autonomic presentation in multiple system atrophy (MSA) may predict early mortality. Quantification of early autonomic failure as a mortality predictor is lacking. Early neurological and autonomic clinical features were retrospectively reviewed in 49 MSA cases (median age at onset, 56.1 years; 16 women) confirmed by autopsy at Mayo Clinic. When available, the 10‐point composite autonomic severity score derived from the autonomic reflex screen provided quantification of the degree of autonomic failure and thermoregulatory sweat test quantitated body surface anhidrosis. Symptoms at onset were autonomic in 50%, parkinsonian in 30%, and cerebellar in 20% of cases. Survival (median [95% confidence interval]) was 8.6 [6.7‐10.2] years. Survival was shorter in patients with early laboratory evidence of generalized (composite autonomic severity score ≥ 6) autonomic failure (7.0 [3.9‐9.8] vs. 9.8 [4.6‐13.8] years; P = 0.036), and early requirement of bladder catheterization (7.3 [3.1‐10.2] vs. 13.7 [8.5‐14.9] years; P = 0.003) compared with those without these clinical features. On Cox proportional analysis, prognostic indicators of shorter survival were older age at onset (hazard ratio [95% confidence interval], 1.04 [1.01‐1.08]; P = 0.03), early requirement of bladder catheterization (7.9 [1.88‐38.63]; P = 0.004), and early generalized (composite autonomic severity score ≥ 6) autonomic failure (2.8 [1.01‐9.26]; P = 0.047). Gender, phenotype, and early development of gait instability, aid‐requiring ambulation, orthostatic symptoms, neurogenic bladder, or significant anhidrosis (thermoregulatory sweat test ≥ 40%) were not indicators of shorter survival. Our data suggest that early development of severe generalized autonomic failure more than triples the risk of shorter survival in patients with MSA. © 2014 International Parkinson and Movement Disorder Society

The baroreflex plays a key role in human BP (blood pressure) regulation. Its efferent limb consists of a vagal and a sympathetic component. The Valsalva manoeuvre is widely used to quantify vagal baroreflex function [BRS_vagal (vagal baroreflex sensitivity)], but most studies have focused on the R–R interval response to BP decrement, even though the subsequent response to an increment in BP is important and different. In the present study, we sought to evaluate whether BRS_vagal can be determined from BRSvagalinc (BRS_vagal derived from the rise in BP during phases III–IV of the Valsalva manoeuvre), to assess the association between BRSvagalinc and BRSvagaldec (BRS_vagal derived from the preceeding BP decrement) and to validate BRSvagalinc as an index of autonomic function. We studied patients with severe autonomic failure (n=49, 25 female), mild autonomic failure (n=25, 11 female) and matched normal controls (n=29, 15 female). BRSvagalinc and BRSvagaldec were calculated as the regression slope of R–R interval and systolic BP during phases III–IV and the early phase II of the Valsalva manoeuvre respectively, and compared these with other autonomic indices across the groups. BRSvagalinc was calculated in all subjects and correlated highly with BRSvagaldec (r=0.72, P<0.001). BRSvagalinc also correlated significantly with BP changes during phases II and IV of the Valsalva manoeuvre and sympathetic barosensitivity. BRSvagalinc was significantly different between the groups, being highest in the controls and lowest in patients with severe autonomic failure. In conclusion, vagal BRS, determined by relating R–R interval with the BP increase following phase III, is a valuable autonomic index, provides additional information about vagal baroreflex function and reflects overall severity of autonomic failure.

ABSTRACTIntroduction: The Valsalva maneuver (VM) is used widely to quantify the sensitivity of the vagal baroreflex loop (vagal baroreflex sensitivity, BRS_v), but most studies have focused on the heart rate (HR) response to blood pressure (BP) decrement (BRS_v↓), even though the subsequent response to an increment in BP after the VM (BRS_v↑) is important and different. Methods: We evaluated recordings of HR and BP in 187 normal subjects during the VM and determined both BRS_v↑, as determined by relating HR to the BP increase after phase III and BRS_v↓. Results: BRS_v↑ was related inversely to age. In addition, BRS_v↓, age, and magnitude of phase IV were independent predictors of BRS_v↑ in a multivariate model, accounting for 47% of the variance of BRS_v↑. Conclusions: The results indicate that both BRS_v↑ and BRS_v↓ become blunted with increasing age and that these indices relate to each other. Muscle Nerve 50: 535–540, 2014

Background This study investigated the effects of a series of four hypertonic dextrose injections on the subsynovial connective tissue (SSCT) and median nerve within the carpal tunnel of a rabbit model. Methods Twenty New Zealand white rabbits were used. One forepaw carpal tunnel was randomly injected with 0.1 ml of 10 % dextrose solution. The contralateral forepaw was injected with a similar amount of saline. This injection was made once per week for 4 weeks. The animals were killed at 16 weeks after the initial injection and were evaluated by electrophysiology (EP), SSCT mechanical testing, and histology. Results Mechanical testing revealed significantly greater ultimate load and energy absorption in the dextrose injection group compared to the saline injection group ( P<0.05). Histological evaluation revealed SSCT fibrosis and thickening and edema in the median nerve bundles in the dextrose injection group. There was a prolongation in the latency of the EP test in the dextrose injection group ( P=0.08). Conclusions Previous studies had shown that one or two injections of 10 % dextrose could induce moderate SSCT fibrosis and mild EP changes without nerve histology changes. In this study, we have shown that higher doses create more severe fibrosis and, most importantly, more severe neuropathy, suggesting a dose–response effect, and confirming this as a potentially useful animal model for researching the etiology and treatment of carpal tunnel syndrome.

Oxidative stress is present in the diabetic state. Our work has focused on its presence in peripheral nerves. Antioxidant enzymes are reduced in peripheral nerves and are further reduced in diabetic nerves. That lipid peroxidation will cause neuropathy is supported by evidence of the development of neuropathy de novo when normal nerves are rendered α-tocopherol deficient and by the augmentation of the conduction deficit in diabetic nerves subjected to this insult. Oxidative stress appears to be primarily due to the processes of nerve ischemia and hyperglycemia auto-oxidation. The indexes of oxidative stress include an increase in nerve, dorsal root, and sympathetic ganglia lipid hydroperoxides and conjugated dienes. The most reliable and sensitive index, however, is a reduction in reduced glutathione. Experimental diabetic neuropathy results in myelinopathy of dorsal roots and a vacuolar neuropathy of dorsal root ganglion. The vacuoles are mitochondrial; we posit that lipid peroxidation causes mitochondrial DNA mutations that increase reduced oxygen species, causing further damage to mitochondrial respiratory chain and function and resulting in a sensory neuropathy, α-lipoic acid is a potent antioxidant that prevents lipid peroxidation in vitro and in vivo. We evaluated the efficacy of the drug in doses of 20, 50, and 100 mg/kg administered intraperitoneally in preventing the biochemical, electrophysiological, and nerve blood flow deficits in the peripheral nerves of experimental diabetic neuropathy, α-lipoic acid dose- and time-dependently prevented the deficits in nerve conduction and nerve blood flow and biochemical abnormalities (reductions in reduced glutathione and lipid peroxidation). The nerve blood flow deficit was 50% (P &lt; 0.001). Supplementation dose-dependently prevented the deficit; at the highest concentration, nerve blood flow was not different from that of control nerves. Digital nerve conduction underwent a dose-dependent improvement at 1 month (P &lt; 0.05). By 3 months, all treated groups had lost their deficit. The antioxidant drug is potentially efficacious for human diabetic sensory neuropathy.

We previously reported the presence of endoneurial hypoxia, ischemia, impairment of the blood-nerve barrier, and reduction of norepinephrine and 6-ketoprostaglandin F1α in chronic streptozocin-induced diabetic neuropathy (SDN) and interpreted these findings as suggesting the involvement of oxygen free radicals (OFRs) but did not directly measure indices of OFR activity. In this study, we report on sciatic nerve conjugated dienes, hydroperoxides, norepinephrine, and malondialdehyde in SDN at 1, 4, and 12 mo in male Sprague-Dawley rats. Severe hyperglycemia was present throughout in diabetic rats. Conjugated dienes were consistently increased at all time points, hydroperoxides were consistently reduced, and malondialdehyde was not significantly different in diabetes compared with controls. These findings are consistent with increased OFR activity in experimental diabetes. It is necessary to monitor several indices of OFR activity in a metabolically active tissue such as the peripheral nerve.

PurposeAutoantibodies are implicated in the pathogenesis of cardiovascular diseases and cardiac arrhythmias. In this pilot study, we tested the hypothesis that autoantibodies are present in patients with postural orthostatic tachycardia syndrome (POTS).Experimental designSeven control subjects (6 F:1 M, average age 36.1 years) and ten patients with the diagnosis of POTS (7 F: 3 M, average age 35.1 years) provided informed consent and 30 mL of venous blood. Human heart membrane proteins were resolved by 2DE and immunoblotted against purified IgGs from controls and patients.ResultsEighteen protein spots immunoreactive specifically against patient IgGs were detected and they were excised from gels, trypsin‐digested, and analyzed by nanoLC‐electrospray MS/MS. Forty unique proteins were identified and these include proteins that are associated with cardiac hypertrophy (mimecan, myozenin), cardiac remodeling (periostin), cardiomyopathy (desmin, desmoplakin), cell survival (laminin), structural integrity (filamin), chaperone proteins (crystalline, HSP70), mitochondrial enzymes, and channel proteins. Ingenuity Pathway Analysis showed multiple pathways were involved including those that regulate energy metabolism, redox, fibrosis, cardiac hypertrophy, and degeneration.Conclusions and clinical relevanceAutoantibodies are present in patients with POTS. These autoantibodies cross‐react with a wide range of cardiac proteins and may induce alterations in cardiac function. Autoimmune pathogenetic mechanisms should be further explored in these patients.