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The sympathetic skin response (SSR) detects changes in the electrical potential in the skin in response to physiological and electrical stimuli and, therefore, may indicate the integrity of sympathetic cholinergic neural pathways to sweat glands. This has been evaluated in 21 patients with three forms of peripheral autonomic failure. Of these, 15 had pure autonomic failure (PAF) without additional neurological features; investigations indicated both sympathetic and parasympathetic failure. Four patients had pure cholinergic dysautonomia (PCD), with clinical and laboratory features indicating only cholinergic failure. Two siblings had dopamine-beta-hydroxylase (DBH) deficiency with only sympathetic adrenergic failure. None was on drugs affecting cholinergic function. Ten normal individuals were aged-matched with PAF patients and studied as controls. The SSR was recorded from the palmar hand and plantar foot surfaces, using previously described techniques, in response to physiological (auditory, cough and inspiratory gasp) and electrical stimuli. Nerve conduction studies excluded an associated motor or sensory neuropathy. The SSR was present in all normal individuals, and in both patients with DBH deficiency who had preserved cholinergic and sudomotor function, It was absent in all 15 PAF and all four PCD patients with impaired cholinergic function. Therefore, we conclude that the SSR reflected sympathetic cholinergic function in these three different groups with peripheral autonomic failure.
BACKGROUND: Diastolic heart failure (DHF) is reported to account for 30-50% of heart failure presentations, but its prevalence in the absence of overt coronary disease is unclear. Diastolic heart failure is usually defined by exclusion (heart failure with normal left ventricular (LV) systolic function), and few studies have sought a specific diagnosis of diastolic dysfunction. The objective of the present study was to determine the prevalence of isolated DHF and characterise LV diastolic function in patients without clinical evidence of coronary disease, who were referred for LV function assessment. METHODS: Among 938 consecutive patients referred for assessment of LV function, diastolic dysfunction was sought in patients with clinical heart failure, normal systolic function, and no valvular or coronary disease. The evaluation was based on measurement of early (E) and late (A) transmitral velocities and E wave deceleration time (DT). Pulmonary vein systolic, diastolic and atrial reversal velocities were used to differentiate pseudonormal filling in patients with normal E/A and DT. RESULTS: Normal LV systolic function was present in 331 patients (35%), of whom 53 (6%) met criteria for a clinical diagnosis of DHF. Diastolic dysfunction was confirmed by echocardiography in 38 patients (72% of clinical DHF patients), of whom 27 had impaired LV relaxation, 10 had pseudonormal filling, and one had restrictive filling. Diastolic function was normal in 13 and indeterminate in two patients. Pseudonormal or restrictive LV filling were more prevalent in patients with acute heart failure (7/20, P < 0.05). CONCLUSIONS: Carefully defined, isolated DHF is uncommon, but most of these patients demonstrate echocardiographic evidence of diastolic dysfunction.
Anoxia of the heart causes failure of contraction before any irreversible injury occurs; the mechanism by which anoxia blocks cardiac excitation-contraction coupling is unknown. Studies in whole muscle are confounded by heterogeneity; however, achieving the low oxygen tensions required to study anoxia in a single myocyte during electrophysiological recording has been a barrier in experimental design. Guided by calculations of oxygen transport, we developed a system to insulate myocytes in an open dish from oxygen by a laminar counterflowing argon column, permitting free access to the cell by microelectrodes while maintaining a PO2 less than 0.02 torr (1 torr = 133 Pa). In the absence of glucose, the amplitude of stimulated contraction of anoxic ventricular myocytes fell to zero over 2 min after a lag period attributable to the consumption of endogenous glycogen. The cytosolic calcium concentration transient, measured by indo-1 fluorescence, fell to zero simultaneously with contraction. After the twitch had failed, microinjection of caffeine around the cell still caused a large calcium release and contraction, indicating that sarcoplasmic reticular calcium stores were not depleted. Twitch failure was accompanied by shortening and then failure of the action potential; under voltage clamp, large outward currents, reversing at the resting potential, developed during contractile failure. After failure of action potential-mediated contraction, voltage-clamp depolarization, with a large command voltage to compensate for the series-resistance error due to outward currents, restored normal twitch contraction. We conclude that anoxic contractile failure in the rat myocyte is due to alteration of the action potential and the distal pathways of excitation-contraction coupling remain essentially intact.
For a cantilever beam-column with one end built-in and the free end subjected to an oblique-eccentric arbitrary concentrated force, general formulas to produce failure were derived. The original generalized uniform solution to the oblique-eccentric buckling problem was obtained. The Secant formula and Euler's formula were proved to be specific cases in this general solution. The load ratio, F/aE, was derived as functions of the force acting direction, alpha, the slenderness ratio, L/r, as well as the eccentricity ratio, ec/r2. Material and buckling failures aspects were combined in a uniform structural failure analysis. Safe regions for the load ratio, F/aE, were visualized in the three-dimensional (F/aE)-alpha-(L/r) space with the eccentricity ratios, ec/r2, as a parameter. The column failure factor, kL, was shown to be a key index controlling both aspects of failure as well as the orientation of the second stiffest region. The angle alpha E = tan-1 (2L/pi e) for kL = pi/2 is the singular point for both strength and buckling failure, and alpha II = tan-1 (2L/3e) for KL = 0 is the upper bound of the second stiffest region. The feasible domain of the second stiffest region is bounded by alpha E and alpha II both of which are only functions of geometrical properties. The implications of these analyses for the experimental validation of cervical spine trauma are discussed.
OBJECTIVES: To characterise the clinical features of patients with suspected heart failure but preserved left ventricular systolic function to determine if they have other potential causes for their symptoms rather than being diagnosed with "diastolic heart failure." DESIGN: Prospective descriptive study. SETTING: Outpatient based direct access echocardiography service. PARTICIPANTS: 159 consecutive patients with suspected heart failure referred by general practitioners. MAIN OUTCOME MEASURES: Symptoms (including shortness of breath, ankle oedema, and paroxysmal nocturnal dyspnoea) and history of coronary heart disease and chronic pulmonary disease. Transthoracic echocardiography, body mass index, pulmonary function tests, and electrocardiography. RESULTS: 109 of 159 participants had suspected heart failure in the absence of left ventricular systolic dysfunction, valvular heart disease, or atrial fibrillation. Of these 109, 40 were either obese or very obese, 54 had a reduction in forced expiratory volume in 1 second to </=70%, and 97 had a peak expiratory flow rate </=70% of normal. Thirty one patients had a history of angina, 12 had had a myocardial infarction, and seven had undergone a coronary artery bypass graft. Only seven patients lacked a recognised explanation for their symptoms. CONCLUSIONS: For most patients with a diagnosis of heart failure but preserved left ventricular systolic function there is an alternative explanation for their symptoms-for example, obesity, lung disease, and myocardial ischaemia-and the diagnosis of diastolic heart failure is rarely needed. These alternative diagnoses should be rigorously sought and managed accordingly.
Ten patients with primary autonomic failure, followed up in a prospective clinical and laboratory study, were finally diagnosed as pure autonomic failure or multiple system atrophy with autonomic failure. Polysomnographic studies were performed in all patients. Whereas all four patients with multiple system atrophy complained of sleep related episodes suggesting REM sleep behaviour disorder (RBD) confirmed by polysomnography, RBD remained absent in the remaining six patients with pure autonomic failure. The data indicate that RBD is an important clinical feature, often heralding multiple system atrophy, but which is absent throughout the course of pure autonomic failure; its recognition can thus be useful in the prognostic evaluation of early primary autonomic failure syndromes.
The present study evaluated thyroid hormone indices of patients with acute renal failure without other systemic illnesses (n = 12), as compared to patients with critical illnesses in the presence (n = 16) and absence (n = 6) of acute renal failure. Abnormalities in the group with acute renal failure alone included decreased serum levels of total T4 and T3, and elevated levels of free rT3. Serum levels of free T4 by equilibrium dialysis and the enzyme immunoassay, T3 uptake ratios, TSH and total rT3 were normal. These findings are consistent with the presence of decreased binding of T4 and rT3 to their serum carrier proteins. Critically ill patients with acute renal failure differed in that they had lower total T4 and T3 levels and elevated T3 uptake ratio values. As in the group with acute renal failure alone, total rT3 levels were normal and free rT3 values were elevated. The group with critical illness alone differed only in that the total rT3 concentrations were elevated in all patients. The alterations of thyroid hormone indices in acute renal failure are similar to those of other nonthyroidal illnesses with the exception of the normal total rT3 levels. This suggests that the failing kidney or the metabolic consequences of uremia specifically affect rT3 metabolism.
In canine veterinary medicine, both acute and chronic renal failure occur relatively frequently, from a variety of causes similar to those in man. However, the normal dog has a very high protein catabolic rate and high endogenous kidney function, and, therefore, requires frequent and highly efficient dialysis, for maintenance during renal failure. We have developed techniques to support the uremic dog with hemodialysis. An experimentally anephric dog, and two dogs with clinically occurring acute renal failure (caused by ethylene glycol intoxication and heat stroke) have been supported with frequent use of hollow fiber dialyzers, using a carotid artery to jugular vein shunt. Patency of shunts was maintained by administration of oral aspirin. A very high urea and creatinine generation rate necessitated daily dialysis during much of the clinical course of renal failure. The experimentally anuric animal was supported for 35 days. The ethylene glycol-induced renal failure animal was euthanized on the 21st day, and the heat stress-induced renal failure animal recovered sufficient intrinsic renal function after 16 days of dialysis for maintenance of life without dialysis.
BACKGROUND: Muscle zinc deficit may be important in cardiac failure pathogenesis. We studied whether Zn deficit is present in dilated (DCM) and hypertrophic (HCM) cardiomyopathies with chronic cardiac failure. The aim was to find out whether it might be a diagnostic and prognostic marker. METHODS: Zn and Cu values were measured in plasma, urine and red blood cells by flame atomic absorption spectrophotometer in normal subjects, in 15 patients with DCM and in 11 patients with HCM in chronic cardiac failure. RESULTS: There is a statistically important increase of zincuria as well as low plasmatic and erythrocytic zinc in DCM; low plasmatic and erythrocytic zinc was found in HCM. CONCLUSIONS: It is likely that chronic cardiac failure, by atrial natriuretic peptide activation, increases zincuria and involves a secondary loss of plasmatic and erythrocytic zinc. Primitive or secondary zinc deficit causes marked structural and functional myocardial cell impairment. Hypozinchemia from increased zincuria seems to represent an important diagnostic and prognostic marker in chronic failured cardiomyopathies. Dilated cardiomyopathy, particularly in elder subjects, may be considered as a primitive or a secondary Zn-deficit myocardial disease. In the essay, the possible pathogenetic mechanisms underlying hypozinchemia and determining functional and structural myocardial cell changes are discussed. The main consequence of present results is pharmacological Zn administration as a new pathogenetic therapy in chronic failured cardiomyopathies.
Serum, urine and tissue biochemical findings were studied in 21 cases of fulminant Wilson's disease with respect to the value of a recently described biochemical index based on serum alkaline phosphatase and total serum bilirubin levels, and these cases were compared with 193 other cases of fulminant liver failure. Serum bilirubin, alkaline phosphatase and AST levels found in fulminant Wilson's disease were significantly different from those found in other cases of fulminant liver failure, but differentiation from other causes of fulminant liver failure on the basis of these biochemical parameters was not possible. The alkaline phosphatase/bilirubin and aspartate AST/bilirubin ratios derived from the above parameters were also significantly lower in fulminant Wilson's disease than in other categories of fulminant liver failure, but distinction between diagnostic categories on this basis was not possible. When ratios that correctly identified all cases of fulminant Wilson's disease were selected, 59/190 (31%) and 84/190 (44%) cases of non-Wilsonian fulminant liver failure would erroneously be assigned a diagnosis of fulminant Wilson's disease, by alkaline phosphatase/bilirubin and AST/bilirubin ratios, respectively. A low alkaline phosphatase-to-bilirubin ratio (< 0.57) in any category of fulminant liver failure suggested a significantly worse prognosis than in cases with higher ratios (chi 2, Yates' corrected = 5.37, p = 0.02). In the Wilson's disease group, serum and hepatic copper and ceruloplasmin concentrations were normal in 4/21, 2/15 and 2/19, respectively, whereas urinary copper level was elevated in 18/18 and was the most valuable test in diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND: Our patient experienced acute renal failure but not fulminant hepatic failure from acetaminophen toxicity. OBJECTIVE: To review the clinical and laboratory characteristics of similar cases of acetaminophen nephrotoxicity. METHODS: A MEDLINE search and medical record search at two large teaching hospitals. RESULTS: We reviewed our index case, a patient at Jackson Memorial Hospital, and 34 additional patients with acetaminophen nephrotoxicity reported in the literature. Oliguria was present in 23 of 31 patients. There was no difference in peak serum creatinine levels between patients treated with N-acetylcysteine and those not treated. The onset of acute renal failure was from 2-5 days after overdose, and peak serum creatinine levels occurred 3-16 days (average 7.3 days) after overdose. Thirteen patients required hemodialysis; all but one were oliguric. Renal failure was spontaneously reversible in all patients. CONCLUSION: Although uncommon, it is possible to have acute renal failure due to acetaminophen toxicity in the absence of fulminant hepatic failure.
Cardiac function improvement seen with hemofiltration may be attributable to "cardiac depressant factor(s)" removal. The authors have attempted "factor" isolation. Initial 12 hr hemofiltrate was obtained from: 4 patients with acute congestive heart failure (cardiac index: 2.02 +/- 0.48) and acute renal failure (blood urea nitrogen [BUN] 97.7 +/- 32.7; serum creatinine [SCr] 6.2 +/- 3.4 mg%) (Group I); 8 patients with chronic congestive heart failure (CI: 2.69 +/- 1.3) and mild renal failure (BUN 48.8 +/- 31.4; SCr 3.5 +/- 2.4 mg%) (Group II); and 8 patients with end-stage renal disease and no congestive heart failure (Group III). Crude samples were passed through C18Sep-Pak, and eluted with methanol/water mixtures, and 50% methanol samples were fractionated by high pressure liquid chromatography. Inotropic response was studied by injecting samples (in Krebs-Hensleit buffer) into a Langendorff rat heart preparation. The effect of pH, acetate, salts, and adding propranolol on the inotropic response also was tested. Myocardial depression followed all vehicle and preparatory elements: 0.1 M HCl (-47%); 0.08 M acetic acid (-75%); Na acetate (-25%); 0.1 M NaHCO3 (-11%); Na citrate (-84%); and Na glutarate (-14%). Group I had biphasic responses, the positive inotropism accorded to catecholamines, whereas negative inotropism was equal in each patient (-40.3%). Group II had a biphasic response with negative (-15%) inotropism noted. Group III was weakly biphasic. The data indicate there was myocardial depressive activity, most pronounced in Groups I and II, after method interference was corrected.
OBJECTIVES: To examine the effects of drug treatment on laboratory exercise tests in relation to measures of daily activity in patients with chronic heart failure. SETTING: University teaching hospital. SUBJECTS: 18 patients with mild to moderate chronic heart failure (New York Heart Association functional class II-III) and 10 age matched healthy controls. METHODS: Assessments were made before and after 12 weeks of vasodilator drug treatment. Exercise capacity was measured during two different types of treadmill exercise, one using a ramp protocol and the other a fixed work load. Corridor walk tests at three self selected speeds were also undertaken and measures of customary activity assessed from pedometer scores. RESULTS: Exercise times were significantly increased from baseline (P < 0.01) with both treadmill protocols after 12 weeks of drug treatment, with a positive correlation between the duration of treadmill exercise for both protocols (r = 0.69, P < 0.01). Corridor walk tests of 100 m at a self selected slow speed also improved (P < 0.02) but these did not correlate with the changes in treadmill exercise time. The pedometer scores of the patients with heart failure were greatly reduced compared with those of the controls (258 (45) x 10(2) v 619 (67) x 10(2) steps/week, P < 0.001) and after 12 weeks of treatment were unchanged (261 (42) x 10(2) steps/week). CONCLUSIONS: These data confirm the need to use different exercise protocols when assessing the benefits of drug treatment in patients with chronic heart failure. Treatments that seem effective with conventional laboratory based exercise tests may not improve daily activities. This may reflect a failure of apparently successful treatment and should be considered when interpreting clinical trials.
BACKGROUND: Preclinical and preliminary clinical data have suggested that tumor necrosis factor-alpha (TNFalpha) may play a role in the evolution and progression of heart failure and that inhibition of TNFalpha may favorably modify the course of the disease. We evaluated the efficacy and safety of infliximab, a chimeric monoclonal antibody to TNFalpha, in patients with moderate-to-severe heart failure. METHODS AND RESULTS: One hundred fifty patients with stable New York Heart Association class III or IV heart failure and left ventricular ejection fraction <or=35% were randomly assigned to receive placebo (n=49), infliximab 5 mg/kg (n=50), or infliximab 10 mg/kg (n=51) at 0, 2, and 6 weeks after randomization and were followed-up prospectively for 28 weeks. Neither dose of infliximab improved clinical status at 14 weeks, the primary endpoint of the study, despite suppression of inflammatory markers (C-reactive protein and interleukin-6) and a modest increase in ejection fraction in the patients receiving 5 mg/kg (P=0.013). Furthermore, after 28 weeks, 13, 10, and 20 patients were hospitalized for any reason in the placebo, 5 mg/kg infliximab, and 10 mg/kg infliximab groups, respectively. The combined risk of death from any cause or hospitalization for heart failure through 28 weeks was increased in the patients randomized to 10 mg/kg infliximab (hazard ratio 2.84, 95% confidence interval 1.01 to 7.97; nominal P=0.043). CONCLUSIONS: Short-term TNFalpha antagonism with infliximab did not improve and high doses (10 mg/kg) adversely affected the clinical condition of patients with moderate-to-severe chronic heart failure.
The function of atrial natriuretic peptide (ANP) is claimed to be control of salt and water homeostasis, and thus, the hormone may be involved in the pathogenesis of certain diseases with impaired volume regulation. We, therefore, studied plasma ANP concentration in dogs with chronic renal failure, congestive heart failure, and hyperadrenocorticism. Dogs with chronic renal failure had twofold higher plasma ANP concentration (16.2 +/- 5.8 fmol/ml), compared with healthy dogs (8.3 +/- 3.5 fmol/ml). An even more distinct increase (sixfold) of plasma ANP concentration was found in dogs with congestive heart failure (52.9 +/- 29.7 fmol/ml). In contrast, dogs with hyperadrenocorticism did not have high ANP plasma concentration (5.5 +/- 2.0 fmol/ml). High-performance liquid chromatographic analysis of plasma from dogs with congestive heart failure indicated that, in addition to the normal circulating form of ANP (99-126), the unprocessed precursor ANP (1-126) is detectable in the circulation. These qualitative and quantitative alterations of plasma ANP concentration in dogs further suggest involvement of this peptide in the development and/or maintenance of diseases associated with impaired volume regulation.