Acetylsalicylic acid and autonomic modulation.

Loss of autonomic balance characterized by increased sympathetic activity and decreased vagal activity has been implicated as a major cardiovascular risk factor. Aspirin's cardioprotective abilities involve a multitude of physiologic processes. However, the effects of aspirin on cardiac autonomic activity are unknown. In a double-blind crossover study, 22 subjects randomly received either aspirin or placebo in the amounts of 325 mg with each meal (three times per day) over a 2.5-day period. The total amount of aspirin ingested was 2,275 mg, which resulted in plasma levels of 3.3 mg/dl. At the conclusion of each treatment, subjects were evaluated for autonomic physiology activity using standard autonomic tests. Power spectral analyses of the electrocardiograms were used to delineate autonomic function. A 2 x 4 repeated measures analysis of variance revealed significant and favorable changes in autonomic activity after the use of aspirin. Specifically, at rest high-frequency (HF) power was significantly higher (mean, 1,090 + 1,463.5 msec2) compared with the placebo (mean, 692 742 msec2) (p <0.05). Low-frequency (LF) power was significantly reduced (mean, 963 745 msec2) after aspirin compared with placebo (mean, 1,100 906 msec2). After the aspirin treatment, a significantly lower LF-to-HF power ratio (mean, 1.7 2 msec2) was noted at rest when compared with the placebo (mean, 2.5 2.7 msec2) (p <0.05). Similar significant trends were seen during the sustained isometric contraction after aspirin therapy for HF power (mean 210 2.15 msec2) compared with placebo (mean, 213 184 msec2) (p <0.05). Accordingly, the LF-to-HF power ratio was lower as well when compared to placebo treatment (mean, 2.3 3.5 msec2) (mean, 5.3 8.4 msec2) (p <0.05). No differences were found in breathing rates for hemodynamic variables between any of the protocols. The significant reduction of LF-to-HF ratio, a marker of sympathovagal balance, for both protocols appeared to be largely due to a withdrawal of LF modulation and concomitant but lesser increase in HF modulation. Favorable alterations in autonomic outflow through prostaglandin inhibition may be one of the mechanisms by which low therapeutic amounts of aspirin provide prophylactic cardioprotection.

Präder-Willi syndrome fails to alter cardiac autonomic modulation.

Twenty-six healthy subjects with a diagnosis of Präder-Willi syndrome were compared with 26 age-, gender-, and body mass index-matched controls for autonomic modulation and baroreflex sensitivity. Electrocardiograms, beat-to-beat finger blood pressures, and respiration were recorded for several minutes in the following sequence: (1) supine, (2) after transition from supine to standing, (3) sitting, (4) during a Valsalva maneuver, (5) while performing moderate exercise, and (6) during recovery from exercise while seated. All recordings were channeled and stored in a computer; analyses were carried out at a later date. Power spectral analysis (fast-Fourier transform) of heart period variability was used to assess cardiac autonomic modulation. The slope of the regression equation between heart period and blood pressure rise after the Valsalva maneuver was used as an index of baroreflex sensitivity. Analysis of variance failed to reveal significant differences in any of the autonomic and baroreflex sensitivity variables between the two groups. Because breathing patterns entrain autonomic modulation, we verified respiration and found no differences between the two groups. Therefore, findings in the current investigation indicate that cardiac autonomic modulation in patients with Präder-Willi syndrome does not differ from age and body mass index-matched subjects.

Mechanoreceptors and autonomic responses to movement in humans.

Mechanoreceptor contribution to efferent autonomic outflow is incompletely understood. To determine the effects of mechanoreceptor stimulation on autonomic reflexes, we compared autonomic responses in 34 subjects using a cross-over, counter-balanced design, in which hemodynamic, electromyographic, metabolic, and autonomic data were gathered during rest, passive, and active movement protocols. Because metaboreceptors and ventilatory responses influence autonomic outflow we verified and controlled for these influences during all protocols through comparisons of breath-by-breath gas exchange measurements. Verification of active and passive movements was made via electromyographic recordings of the moving legs. Spectral analysis of R-R variability was used to assess autonomic activity, and low to high frequency ratios were considered representative of sympathovagal balance. A repeated measures analysis of variance revealed significant modulating effects of mechanoreceptor stimulation on sympathovagal balance during passive movement upon efferent autonomic outflow (p < 0.01) independent of central command, chemoreceptor, and metaboreceptor stimulation. Furthermore, breathing frequency and volume were identical for both movement protocols. Therefore, findings in this investigation suggest that modulating influences are being exerted by mechanoreceptor stimulation on autonomic outflow to the heart.

Estrogen replacement, vascular distensibility, and blood pressures in postmenopausal women.

The pathogenesis of blood pressure (BP) rise in aging women remains unexplained, and one of the many incriminating factors may include abnormalities in arteriolar resistance vessels. The aim of this study was to determine the effects of unopposed estrogen on arteriolar distensibility, baroreceptor sensitivity (BRS), BP changes, and rate-pressure product (RPP). We tested the hypotheses that estrogen replacement therapy (ERT) enhances arteriolar distensibility and ameliorates BRS, which leads to decreases in BP and RPP. Postmenopausal women participated in a single-blind crossover study; the participants of this study, after baseline measurements, were randomly assigned to receive estrogen (ERT) or a drug-free treatment with a 6-wk washout period between treatments. The single-blind design was instituted because subjects become unblinded due to physiological changes (i.e., fluid shifts, weight gain, and secretory changes) associated with estrogen intake. However, investigators and technicians involved in data collection and analyses remained blind. After each treatment, subjects performed identical autonomic tests, during which electrocardiograms, beat-by-beat BPs, and respiration were recorded. The area under the dicrotic notch of the BP wave was used as an index of arteriolar distensibility. The magnitude of the reflex bradycardia after a precipitous rise in BP was used to determine BRS. Power spectral analysis of heart rate variability was used to assess autonomic activity. BPs were recorded from resistance vessels in the finger using a beat-by-beat photoplethysmographic device. RPP, a noninvasive marker of myocardial oxygen consumption, was calculated. Repeated-measures analyses of variance revealed a significantly enhanced arteriolar distensibility and BRS after ERT (P < 0.05). A trend of a lower sympathovagal balance at rest was observed after ERT, however, this trend did not reach statistical significance (P = 0.061) compared with the other treatments. The above autonomic changes produced significantly lower systolic and diastolic BP changes and RPPs (P < 0.05) at rest and during isometric exercise. We conclude that short-term unopposed ERT favorably enhances arteriolar distensibility, BRS, and hemodynamic parameters in postmenopausal women. These findings have clinical implications in the goals for treating cardiovascular risk factors in aging women.

A length of stay study of the dually entitled Medicare and Medicaid population: challenges for managed competition.

Length of stay (LOS) differences were not observed between the dually entitled and other Medicare stroke patients when complexity of disease was considered. LOS for dually entitled heart failure patients was 33.2 percent longer than other Medicare heart failures and were equally likely to be in the extreme DRG subclass. Patients with extreme heart failure stayed 15.5 days longer than those with mild heart failure. LOS differences (+4.5 days) were observed between the dually entitled and other Medicare heart failures when complexity of disease was considered. Within these two DRGs, incremental health care needs for dually entitled equalled 10 percent of the hospital's total Medicare days associated with stroke and heart failure.

Slope of serial glomerular filtration rate and the progression of diabetic glomerular disease.

Glomerular function was evaluated longitudinally over a 24- to 48-month period in 18 patients with diabetic glomerular disease (DGD) manifested by proteinuria. GFR was determined by iothalamate clearance at 4-month intervals. The patients were divided into two groups: Group 1 (N = 9) had subnephrotic proteinuria and an initially normal GFR of 91 +/- 8 mL/min. Group 2 (N = 9) had nephrotic-range proteinuria, and initial GFR was reduced to 53 +/- 5 mL/min. Serial GFR fluctuated over time in Group 1, but no trend towards hypofiltration was evident. In contrast, GFR declined linearly in Group 2 at 1.1 +/- 0.3 mL/min per month. The transglomerular sieving of uncharged dextrans of graded size was analyzed and initially revealed a uniform reduction in glomerular pore density and an enhancement of shuntlike pores. Pore density was initially reduced by 80% and declined further after 24 months in nephrotic Group 2; corresponding pore density in subnephrotic Group 1 was reduced by half but remained constant. Renal biopsy of four members of Group 1 revealed a 22% prevalence of global glomerulosclerosis. Remaining open glomeruli exhibited hypertrophy, excessive extracellular matrix, and deformation of epithelial podocytes. The latter abnormality appeared to be the predominant determinant of lowered ultrafiltration capacity. It was inferred that trials of therapy to attenuate the progression of DGD should be initiated at a functional level similar to that in subnephrotic Group 1. Because GFR is unlikely to decline over a 2- to 4-yr period, it is suggested that such trials be extended for longer periods. Alternatively, morphometric analysis of serial renal biopsies may shorten the time needed to demonstrate effective renoprotection in DGD.

Contractures in neuromuscular disease.

The percentage of subjects with contractures, mean maximal loss of range, and relative contracture indices are reported in 230 patients, with 11 diseases seen in a neuromuscular disease clinic during a five-year period. The highest percentage of contractures occurred in patients with Duchenne muscular dystrophy. The number of contractures was significantly greater (p less than .001) (1) in the lower than in the upper extremities; (2) in diseases considered myopathic than in those considered neuropathic; (3) in diseases that are X-linked than in those that are not; and (4) in rapidly progressive than in slowly progressive diseases.

Laryngeal diversion in the treatment of intractable aspiration in motor neuron disease.

Motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) often causes bulbar palsy with subsequent aspiration. Laryngeal diversion procedures are not commonly mentioned in the literature. However, they are viable but infrequently used surgical treatment options that have several advantages over a routine tracheostomy. We report a case of a 67-year-old man with MND/ALS and severe aspiration. He underwent a laryngeal diversion procedure with complete relief of signs and symptoms of aspiration. Laryngeal diversion, unlike tracheostomy, completely eliminates the possibility of aspiration as well as the need for suctioning. The primary disadvantage is complete loss of phonation. These procedures appear worthy of trial in patients with MND/ALS, and may ultimately be the preferred treatment in this setting.

Dysphagia following stroke: quantitative evaluation of pharyngeal transit times.

Forty stroke subjects referred for dysphagia and studied by videofluoroscopy were compared with 16 individuals with no known pharyngeal swallowing difficulty. Kinematic pharyngeal transit time was defined as the time from the first movement of the bolus posteriorly resulting in a complete swallow to the return of the epiglottis to its original position. The mean transit time was 1.00 second for the comparative group and 6.15 seconds for the stroke group (p less than 0.001). Other component transit times are described and were all significantly prolonged for the stroke group. There was no significant difference in transit times between right-sided and left-sided lesions except for the segmental interval from onset of bolus movement to arrival at the valleculae, which was significant at p = 0.05. Measurement of transit times using the method described in this study requires equipment available in most hospitals. These measurements may be used in the evaluation of dysphagia in various pathologic disorders, in following the progress of patients with dysphagia, and in evaluating the effects of remedial therapies.

Evaluation of phrenic nerve and pulmonary function in hereditary motor and sensory neuropathy, type I.

Phrenic nerve and diaphragmatic dysfunction has been assumed to be the cause of respiratory failure in hereditary motor and sensory neuropathy, type 1 (HMSN I). In order to determine the relationship between phrenic nerve and pulmonary function in this disease, 25 patients underwent a 4-step evaluation process consisting of: (1) bilateral phrenic nerve conduction study; (2) median, peroneal, and tibial motor conduction studies; (3) measurement of forced vital capacity (FVC) and maximal inspiratory and expiratory pressures (MIP, MEP); and (4) pulmonary-focused history and physical. Phrenic nerve motor latency was abnormally prolonged in 22 of the 23 (96%) subjects when a response was obtained. All had slowed velocity or absent peripheral motor conduction responses. Vital capacity was abnormally reduced in 6 of the 25 (24%) subjects. Eight (32%) had an abnormally reduced MIP, while 19 (76%) had an abnormally reduced MEP. Only 2 (8%) subjects had clinical evidence of pulmonary dysfunction. None of the dependent variables (FVC, MIP, MEP, peripheral nerve conduction, or clinical examination) correlated with phrenic nerve latencies. Although phrenic nerve latencies are markedly prolonged in HMSN I, these values are not useful in predicting respiratory dysfunction.

Fast and slow skeletal muscles: effect of ethanol on contractility of muscles from mice.

We examined in vitro the effect of ethanol at four concentrations (0g%, 0.1g%, 0.2g%, and 0.4g%) on contractile parameters of 40 fast extensor digitorum longus (EDL) and 40 slow soleus muscles from healthy mice at 35C. Preparations were curarized to avoid the possible effect of ethanol on the terminal axons or skeletal neuromuscular junction. Contractile parameters measured included: (1) twitch and tetanic tension; (2) rate of tension development; (3) time to peak tension and half relaxation for twitch; (4) time to first evidence of relaxation in the tetanus; and (5) maximum rate of relaxation. The three lower concentrations of ethanol had no significant effect on muscle contractility; however, the 0.4g% dose reduced EDL twitch tension by 9%. High doses of ethanol (2.5g%) reduced the tetanic tension produced by the EDL and soleus muscles 31% and 26%, respectively. Ethanol at 2.5g% also reduced the twitch tension of the EDL and soleus by 50% and 38%, respectively. The data suggested that the 0.4g% is the highest dose of ethanol that should be used to dilute drugs in a solution that will bathe directly stimulated curarized muscle without confounding effects. In addition, it is highly unlikely that a direct effect of ethanol on muscle contractility in humans is related to an impairment in driving.

Analysis of human muscle contractility with a microcomputer-controlled stimulus and data acquisition system.

This report describes and assesses a technique to indirectly stimulate and quantify the human in vivo muscle response for clinical use. A method has been developed to isolate, stimulate, and record the flexor function of the first dorsal interosseus and first volar interosseus at the metacarpophalangeal (MCP) joint by stimulation of the ulnar nerve at the wrist. A microprocessor-based data acquisition and analysis system was built to deliver the electric stimulus and convert the muscle action potential (M-wave) and force measurements into digital form for analysis. To evaluate the technique, the twitch, paired twitch, and tetanic contractions were analyzed in 81 normal subjects. The tension developed by the youngest subjects (14 to 19 years old) was significantly less than the tension developed by subjects in the three older groups (20 to 34 years, 35 to 50 years, and 50 to 65 years); the tensions in the older groups were not significantly different from each other. Only minor gender differences were noted. This indicates that it is necessary to use age-group controls when looking for evidence of a muscle contractile abnormality in patients with neuromuscular disorders. posttetanic potentiation of the twitch was observed in all healthy subjects, and there was no evidence of an age or gender influence. The posttetanic increase in twitch tension was not associated with a prolongation of the twitch contraction time.

In vivo quantification of muscle contractility in humans: healthy subjects and patients with myotonic muscular dystrophy.

The purpose of this study was to use direct in vivo contractility measurements to assess muscle function in patients with myotonic muscular dystrophy (MMD). The tetanic and twitch responses and several time parameters of muscle contraction were obtained from nine MMD subjects and nine able-bodied, age-matched controls. After a routine nerve conduction study, in vivo contractility measurements were obtained by stimulating the ulnar nerve at the wrist and recording the isometric flexor function of the intrinsic muscles at the metacarpophalangeal joint of the index finger. A series of single stimuli, paired stimuli, and fused tetanic stimulations were generated during a 20-minute experimental protocol. A stable tetanus was produced at 50Hz for 1.2 seconds. M-wave and contractile data were recorded at 1,000Hz by digitization of the analog signal and storage by the microcomputer. The MMD patients were weaker than controls (p less than .05), as shown by the 39% reduction in tetanic tension and 57% reduction in twitch tension. The MMD patients also had a significant impairment in relaxing their muscles as shown by the 1,100% increase in half-relaxation time after contraction, even though there was no evidence of repetitive firing after cessation of stimulus. These data show that MMD patients exhibit failure of sarcolemmal activation, altered excitation-contraction coupling mechanisms, and failure of the contractile machinery. The myotonia is due in part, to some defect in the contractile machinery; it is not solely due to failure of sarcolemmal activation.

Atrial natriuretic peptide and response to changing plasma volume in diabetic nephropathy.

We evaluated the renal and hormonal responses to volume expansion induced by water immersion in subjects with diabetic nephropathy (n = 12) and in healthy control subjects (n = 9). Immersion induced similar average increments in sodium excretion (+/- 223 vs. 176 mumol/min) and comparable decrements in renovascular resistance (RVR; -15 vs. -16 U). However, whereas the control subjects responded uniformly, the response among diabetic subjects was highly variable, with a subset of patients exhibiting paradoxical antinatriuresis and vasoconstriction. Immersion was associated with marked elevation of atrial natriuretic peptide (ANP) in plasma of diabetic versus control subjects (61 +/- 9 vs. 19 +/- 2 pM, respectively; P less than 0.001). Yet for each picomolar increment in plasma ANP during immersion, the corresponding increases in urinary excretion of cyclic guanosine monophosphate (26 vs. 279 pmol/min) and sodium (9 vs. 47 mumol/min) and the reciprocal lowering of RVR (0.7 vs. 1.9 U) were blunted in the diabetic versus control group. Volume contraction in the postimmersion period was associated with disproportionate antinatriuresis and renal vasoconstriction in the diabetic group, despite a persistent elevation of ANP (29 +/- 2 vs. 16 +/- 2 pM, P less than 0.01). We propose that renal insensitivity to ANP in diabetic nephropathy could contribute to altered vasoreactivity and abnormal excretory responsiveness to changing plasma volume. Blunted natriuresis in response to ANP release and enhanced sodium retention during volume contraction could account for the expanded extracellular fluid volume that has consistently been reported to accompany the development of diabetic nephropathy.