9-Alpha-fluorohydrocortisone in the treatment of postural hypotension in diabetic autonomic neuropathy.

A double-blind crossover study of fludrocortisone, 0,1 mg. twice daily, and placebo is reported in six diabetics with troublesome symptoms of postural hypotension due to autonomic neuropathy. During treatment with the active preparation there was an increase in the lying and tilted systolic blood pressure, a decrease in orthostatic tachycardia, and in increase in the total plasma volume and body weight, but with no change in plasma or urine osmolality; The symptoms of postural hypotension improved in four patients, while two patients with a low serum albumin developed ankle edema during treatment with fludrocortisone. It is concluded that fludrocortisone is effective in diabetics with symptomatic postural hypotesnion, but should be used with caution in patients with a low serum albumin.

A controlled trial of sorbinil, an aldose reductase inhibitor, in chronic painful diabetic neuropathy.

A double-blind, randomized, placebo-controlled cross-over trial of the aldose reductase inhibitor sorbinil was undertaken in 15 patients (age 35-68 yr) with chronic painful diabetic neuropathy. Treatment was evaluated by subjective pain responses, clinical examination, vibration perception threshold, motor and sensory nerve electrophysiology, and cardiovascular reflex tests of autonomic nerve function. Among the many measurements, only pain, tendon reflex scores, and sural sensory potential amplitude improved significantly during sorbinil administration, while scores of clinical sensory examination deteriorated. Four patients experienced an idiosyncratic reaction that rapidly recovered on discontinuing the drug. This study suggests that aldose reductase inhibitor treatment with suggests that aldose reductase inhibitor treatment with sorbinil may have an effect on symptomatic diabetic neuropathy in man.

Nerve function and metabolic control in teenage diabetics.

Peripheral somatic and autonomic nerve function have been studied in 79 teenage (16-19 yr) diabetics and 20 age- and sex-matched normal controls. Almost three-quarters of the diabetics (72%) had abnormal peripheral somatic nerve function tests, and one-third (31%) had abnormal cardiac parasympathetic tests. Both motor and sensory peripheral somatic nerve abnormalities were related to poor prevailing glycemic control (HbA1) and duration of diabetes. Thus, the 27 patients with three or more (maximum six) peripheral nerve abnormalities had significantly higher HbA1 levels (P less than 0.001) and longer duration of diabetes (P less than 0.01) than the 22 with no abnormalities. Individual peripheral somatic nerve tests almost invariably correlated only with HbA1 (median motor, P less than 0.05; peroneal motor, P less than 0.001; sural sensory, P less than 0.001) or duration of diabetes (median sensory, P less than 0.001). Sensory potential amplitude, as well as conduction velocity, was frequently reduced, implying axonal involvement. These findings suggest that abnormal peripheral and autonomic nerve function are common in young insulin-dependent diabetics and that poor metabolic control is a major determinant of the damage. DIABETES 32:142-147, February 1983.

Mononeuropathy in diabetes mellitus.

Fifty-one diabetic patients with mononeuropathies wereoneuropathy were studied to examine possible etiological factors, to determine the relationship with other diabetic complications, and to correlate with the presence and severity of background peripheral and autonomic neuropathy. The median, ulnar, and lateral popliteal nerves were most commonly affected and cranial neuropathy was relatively uncommon. When bilateral involvement of the same nerve was excluded, multiple mononeuropathies were found in only five patients. Median and ulnar mononeuropathy were gradual in onset and affected the dominant limb whereas other types of mononeuropathies were acute in onset with no predilection for either side. No consistent relationship was shown between the onset of mononeuropathy and age, sex, diabetic treatment, duration of diabetes, diabetic control, or other diabetic complications. In particular, there was no significant background peripheral and autonomic neuropathy, as assessed clinically and by objective tests, in almost one-half of the patients studied. It is concluded that diabetic mononeuropathy may occur independently of peripheral and autonomic neuropathy. It is possible, however, that a minimal degree of background damage, known to be present in all diabetic patients, may render them more susceptible than the general population to the various factors causing mononeuropathy.

Effects of ponalrestat, an aldose reductase inhibitor, on neutrophil killing of Escherichia coli and autonomic function in patients with diabetes mellitus.

In diabetic subjects, polyol pathway activity might inhibit neutrophil function and cause nerve damage. The effects of ponalrestat, an aldose reductase inhibitor, were assessed on neutrophil intracellular killing of Escherichia coli and on autonomic function in diabetic subjects in a randomized double-blind, placebo-controlled, crossover trial. We studied 31 diabetic subjects with autonomic dysfunction and 21 age- and sex-matched control subjects. During two 12-wk treatment periods, the diabetic subjects took either 600 mg of ponalrestat or matching placebo once daily. Neutrophil killing of E. coli was measured by a microbiological assay technique. Kmax by neutrophils from the diabetic subjects was lower than in the control group (Kmax of diabetic subjects 54.5 +/- 26.4 vs. control subjects 67.3 +/- 16.3, P = 0.045). Ponalrestat significantly increased bacterial killing in the diabetic subjects (Kmax of ponalrestat 75.1 +/- 16.5 vs. placebo 58.2 +/- 20.8, P = 0.003) so that there was no longer any significant difference in Kmax between the control subjects and the diabetic subjects on active treatment. Ponalrestat had no significant effect on a range of standard cardiovascular autonomic nerve function tests. We conclude that neutrophil killing of E. coli is impaired in diabetic subjects with autonomic dysfunction. This is restored to normal by ponalrestat.

Variable relationship between peripheral somatic and autonomic neuropathy in patients with different syndromes of diabetic polyneuropathy.

The relationship between abnormal peripheral nerve electrophysiology and abnormal cardiovascular autonomic function has been studied in four groups of diabetic subjects, comparable with regard to age, duration, and type of diabetes. Thirty-three had no symptoms of neuropathy, 28 had newly developed painful neuropathy, 24 had chronic painful neuropathy, and 21 had painless neuropathy with associated recurrent foot ulcers. In all three symptomatic groups, electrophysiology and autonomic function were more abnormal than in asymptomatic diabetic subjects. There was a significant overall relationship between peripheral nerve (electrophysiologic) and autonomic (cardiovascular reflex) dysfunction. However, when considered by groups, the degree of cardiovascular reflex abnormality was similar in the three symptomatic groups, whereas electrophysiology was appreciably worse in the foot ulcer group than in patients with painful neuropathy. Thus, patients with painful neuropathy had a higher ratio of autonomic (small fiber) abnormality to electrophysiologic (large fiber) abnormality. By contrast, foot ulceration was associated with the worst electrophysiologic (large fiber) abnormality. Heavier alcohol consumption and more severe retinopathy were also related to foot ulceration. In diabetic subjects with symmetrical sensory neuropathy, the relationship between large fiber and small fiber damage is not uniform. We conclude that there may be different etiologic influences on large and small fiber neuropathy in diabetic subjects and that the predominant type of fiber damage may determine the form of the presenting clinical syndrome.

Six-month treatment with sorbinil in asymptomatic diabetic neuropathy. Failure to improve abnormal nerve function.

The effect of long-term treatment with the aldose reductase inhibitor sorbinil (125 mg daily for 6 mo) was examined in 22 diabetic patients with subclinical abnormalities of nerve function. This was a placebo-controlled, double-blind crossover trial in which each of the two treatment periods lasted 6 mo. Peripheral nerve function was assessed electrophysiologically and by quantitative sensory testing; autonomic function was assessed by measurement of five cardiovascular reflexes and of mean heart rate from a 24-h ECG recording. Measurement of erythrocyte sorbitol concentrations demonstrated very significant inhibition of aldose reductase activity with sorbinil treatment, but no concomitant improvement in either peripheral or autonomic nerve function was observed.

Peripheral and autonomic nerve function in newly diagnosed diabetes mellitus.

Peripheral and autonomic nerve function was assessed in 10 newly diagnosed male diabetics (six insulin-treated and four sulfonylurea-treated) with repeated observations over the subsequent six months. There was significant impairment of motor-conduction velocity in the common peroneal nerve at diagnosis in both treatment groups, with improvement following treatment in only the insulin-treated patients. In contrast, although the blood glucose level fell in both groups, the mean level was significantly lower in the sulfonylurea-treated patients at two months and at each subsequent visit. In the autonomic function tests significant abnormality was found in the electrocardiographic R-R-interval (beat-to-beat) variation in resting heart rate in two of the insulin-treated patients and all of the sulfonylurea-treated group, with improvement in only one of the latter. One patient in the sulfonylurea-treated group also showed an abnormal response to the Valsalva maneuver (expressed as the Valsalva ratio), and this remained abnormal throughout the period of study. All other patients had normal responses to the Valsalva maneuver and sustained handgrip test. None of the patients had postural hypotension. Abnormalities in autonomic nerve function in diabetics at diagnosis have not been previously reported.

Abnormalities of ambulatory 24-hour heart rate in diabetes mellitus.

Twenty-one normal subjects and 64 diabetics with varying severity of autonomic damage underwent 24-h ambulatory EKG monitoring. No diabetics had the "sick sinus syndrome," and the frequency of arrhythmias was no higher than in the normal subjects. The diabetics had higher mean hourly heart rates, and with increasing autonomic damage there was reduction in diurnal heart rate variation. The mean waking and sleeping heart rates were higher in the diabetics. The maximum heart rates were not significantly different, but the minimum heart rates were significantly higher in the diabetics. These previously unrecognized abnormal 24-h heart rate patterns provide further evidence of damage to the heart rate-controlling mechanisms in diabetes mellitus.

Breathing, sleep, and diabetic autonomic neuropathy.

Sudden, unexplained deaths are relatively common in diabetic autonomic neuropathy. As disturbed autonomic function has been associated with sleep apnea, and sleep apnea with sudden death, we recorded breathing patterns, arterial oxygen saturation, and EEG during sleep in 8 male diabetic subjects with severe autonomic neuropathy and 8 age-matched, male diabetic subjects without autonomic neuropathy. None of the patients with autonomic neuropathy had more than 11 apneic episodes per night, and there were no significant differences between the two groups in the number of sleep apneas, the duration of individual apneic episodes, the total duration of irregular breathing during sleep, or the duration and quality of sleep. The arterial oxygen saturation when awake and the lowest arterial oxygen saturation during sleep were also similar in both groups. Thus, diabetic patients with severe autonomic neuropathy have normal breathing patterns and oxygenation during sleep, and it is unlikely that sleep apnea causes these unexpected deaths.

Heart rate variability in patients with ventricular arrhythmias: effect of antiarrhythmic drugs. Antiarrhythmic Drug Evaluation Group (ADEG).

The purpose of this study was to investigate whether heart rate variability could be reliably assessed in patients with ventricular arrhythmias and to evaluate whether it is affected by antiarrhythmic drugs. The study was based on an analysis of 239 ambulatory electrocardiographic (ECG) recordings obtained from 67 patients with frequent and complex ventricular arrhythmias enrolled in the Antiarrhythmic Drug Evaluation Group (ADEG) study. In each recording, after exclusion of premature ventricular complexes, the number of times during a 24 h period in which two consecutive sinus RR intervals differed by more than 50 ms was calculated. The total 24 h count from each recording was then used as an index of heart rate variability. This method is a reliable marker of cardiac parasympathetic activity. Recordings were analyzed at baseline (n = 56), during long-term treatment with amiodarone (n = 17), flecainide (n = 22) or propafenone (n = 17) and after washout in selected patients (n = 5). Despite the presence of a different number of arrhythmias, total 24 h counts in the same patient appeared reproducible over time (r = 0.83 between two different recordings, n = 49, p less than 0.0001). Baseline counts (median 1,698, range 26 to 13,648) were not correlated (r = 0.15) with the number of arrhythmias. The three antiarrhythmic drugs had a disparate effect on total 24 h counts: no change was observed in patients treated with amiodarone (median percent change [delta %]-8, p = NS), whereas a significant (p less than 0.025) decrease occurred in patients treated with flecainide (median delta % -56%) or propafenone (median delta % -64%).(ABSTRACT TRUNCATED AT 250 WORDS)

Differing patterns of cardiac parasympathetic activity and their evolution in selected patients with a first myocardial infarction.

OBJECTIVES: The purpose of the study was to compare cardiac parasympathetic activity during the early and convalescent phases of acute anterior and inferior myocardial infarction. BACKGROUND: Previous studies have shown that cardiac parasympathetic activity may vary with the site of infarction and that recovery may occur after infarction. METHODS: Cardiac parasympathetic activity was measured from 24-h electrocardiograms by counting the number of times that successive RR intervals (counts) differed by > 50 ms. Recordings began within 12 h of admission and at 7, 42 and 140 days after acute myocardial infarction in 20 patients (mean age 57 +/- 7.9 years). All patients were treated with streptokinase, aspirin and oral beta-adrenergic blocking agents. RESULTS: For the entire group, mean total 24-h RR counts increased from 592 (range 78 to 3,812) at 48 h to 648 (range 109 to 5,473) at 7 days, 1,145 (range 162 to 6,268) at 42 days and 1,958 (range 344 to 9,632) at 140 days. Patients with anterior infarction had significantly lower counts (mean 277, range 78 to 2,708; n = 11) compared with those with inferior infarction (mean 2,172, range 897 to 3,812; n = 9) at 48 h (p < 0.05). There was no significant difference in counts between patients with anterior (mean 1,051, range 212 to 6,268) and inferior (mean 1,321, range 162 to 3,265) infarction after 42 or after 140 days (anterior: mean 1,655, range 344 to 9,632; inferior: mean 2,588, range 1,700 to 5,767). CONCLUSIONS: These data suggest that after anterior myocardial infarction there is impaired cardiac parasympathetic function that improves within 6 weeks, whereas in inferior infarction there is relative preservation of cardiac parasympathetic function.

Nonhomologous synapsis and reduced crossing over in a heterozygous paracentric inversion in Saccharomyces cerevisiae.

Homologous chromosome synapsis ("homosynapsis") and crossing over are well-conserved aspects of meiotic chromosome behavior. The long-standing assumption that these two processes are causally related has been challenged recently by observations in Saccharomyces cerevisiae of significant levels of crossing over (1) between small sequences at nonhomologous locations and (2) in mutants where synapsis is abnormal or absent. In order to avoid problems of local sequence effects and of mutation pleiotropy, we have perturbed synapsis by making a set of isogenic strains that are heterozygous and homozygous for a large chromosomal paracentric inversion covering a well marked genetic interval and then measured recombination. We find that reciprocal recombination in the marked interval in heterozygotes is reduced variably across the interval, on average to approximately 55% of that in the homozygotes, and that positive interference still modulates crossing over. Cytologically, stable synapsis across the interval is apparently heterologous rather than homologous, consistent with the interpretation that stable homosynapsis is required to initiate or consummate a large fraction of the crossing over observed in wild-type strains. When crossing over does occur in heterozygotes, dicentric and acentric chromosomes are formed and can be visualized and quantitated on blots though not demonstrated in viable spores. We find that there is no loss of dicentric chromosomes during the two meiotic divisions and that the acentric chromosome is recovered at only 1/3 to 1/2 of the expected level.

DMC1 functions in a Saccharomyces cerevisiae meiotic pathway that is largely independent of the RAD51 pathway.

Meiotic recombination in the yeast Saccharomyces cerevisiae requires two similar recA-like proteins, Dmc1p and Rad51p. A screen for dominant meiotic mutants provided DMC1-G126D, a dominant allele mutated in the conserved ATP-binding site (specifically, the A-loop motif) that confers a null phenotype. A recessive null allele, dmc1-K69E, was isolated as an intragenic suppressor of DMC1-G126D. Dmc1-K69Ep, unlike Dmc1p, does not interact homotypically in a two-hybrid assay, although it does interact with other fusion proteins identified by two-hybrid screen with Dmc1p. Dmc1p, unlike Rad51p, does not interact in the two-hybrid assay with Rad52p or Rad54p. However, Dmc1p does interact with Tid1p, a Rad54p homologue, with Tid4p, a Rad16p homologue, and with other fusion proteins that do not interact with Rad51p, suggesting that Dmc1p and Rad51p function in separate, though possibly overlapping, recombinational repair complexes. Epistasis analysis suggests that DMC1 and RAD51 function in separate pathways responsible for meiotic recombination. Taken together, our results are consistent with a requirement for DMC1 for meiosis-specific entry of DNA double-strand break ends into chromatin. Interestingly, the pattern on CHEF gels of chromosome fragments that result from meiotic DNA double-strand break formation is different in DMC1 mutant strains from that seen in rad50S strains.

Chronic and remitting painful diabetic polyneuropathy. Correlations with clinical features and subsequent changes in neurophysiology.

Twenty-nine diabetic patients (19 men, 10 women) aged 19-71 yr with newly developed painful polyneuropathy were studied prospectively for 12-18 mo. Pain remitted completely in 16 patients within 12 mo, but continued in the other 13 patients. At presentation, no differences were found in the type or prevalence of symptoms or neurophysiological measurements (electrophysiology and cardiovascular autonomic function tests) between the patients whose pain remitted and those whose pain continued. Most electrophysiological measurements improved slightly in remitting patients but deteriorated slightly in those whose pain continued to reveal a significant difference (P less than .05) between the groups on final review. Similarly, abnormal autonomic nerve function improved slightly when pain remitted but worsened or persisted in patients whose pain continued, again revealing a significant difference between the groups (P less than .05) on final review. We also observed that pain remission usually occurred if the onset of symptoms shortly followed some sudden metabolic change (e.g., rapid improvement in glycemic control, ketoacidosis, anorexia nervosa) when the duration of diabetes was relatively short or when considerable weight loss preceded the onset of pain. We suggest that remitting and chronic painful diabetic polyneuropathy have distinctive clinical features at presentation and detectable neurophysiological differences during their symptomatic evolution.

Decreased skin wrinkling in diabetes mellitus.

Skin wrinkling, which may be dependent on peripheral autonomic innervation, was assessed in 100 normal and 42 diabetic subjects using a temperature-controlled water bath with immersion of the hands for 30 min. Markedly decreased skin wrinkling was observed in diabetic subjects and in manual workers, but did not correlate with cardiovascular tests of autonomic function, control, type or duration of diabetes, or diabetic complications. The cause of decreased skin wrinkling in people with diabetes is unexplained.

Provocation of postural hypotension by nitroglycerin in diabetic autonomic neuropathy?

The effect of nitroglycerin on heart rate and systolic blood pressure was compared in 5 normal subjects, 12 diabetic subjects without autonomic neuropathy, and 5 diabetic subjects with autonomic neuropathy. The magnitude and time course of the increase in heart rate and the decrease in systolic blood pressure after nitroglycerin were similar in the normal and diabetic subjects without autonomic neuropathy, whereas a lesser increase in heart rate and a greater decrease in systolic blood pressure occurred in the diabetic subjects with autonomic neuropathy. It is therefore suggested that caution should be exercised when prescribing vasodilator drugs in diabetic patients, particularly those with autonomic neuropathy.

Hand skin blood flow in diabetic patients with autonomic neuropathy and microangiopathy.

OBJECTIVE: To determine whether changes in hand skin blood flow in diabetic men could be demonstrated with liquid crystal contact thermography and to assess the relative effects of autonomic neuropathy and microangiopathy on these changes. RESEARCH DESIGN AND METHODS: Thirty-four diabetic and 12 age-matched nondiabetic men comprised the study. The diabetic men were categorized according to standard cardiovascular autonomic function tests and the presence or absence of background or proliferative retinopathy and/or proteinuria. Bilateral hand thermograms were measured at rest and after immersion of the right hand in ice-cold water. RESULTS: Diabetic men with definite or severe autonomic neuropathy (n = 13) had a high frequency of anisothermal baseline thermograms (77 vs. 25% in nondiabetic subjects, P less than 0.05). After ice-cold water immersion, right-hand recovery was abnormally slow (514 +/- 157 arbitrary U, area under the curve) compared with nondiabetic men (685 +/- 135 arbitrary U, P less than 0.01). Diabetic men with proliferative retinopathy (n = 8) all had definite or severe autonomic neuropathy and showed the same abnormalities. Diabetic men with nor or early autonomic changes showed normal thermographic patterns. CONCLUSIONS: These results are consistent with increased palmar arteriovenous shunt blood flow or capillary closure in the hands of diabetic patients with definite or severe autonomic neuropathy. They indicate that thermoregulatory reflex changes in hand skin blood flow are controlled by the autonomic nervous system. It is possible, however, that diabetic microangiopathy, associated with the presence of proliferative retinopathy, also independently affects hand skin blood flow.

The value of cardiovascular autonomic function tests: 10 years experience in diabetes.

Five simple, noninvasive cardiovascular reflex tests have been used to assess autonomic function in one center over the past 10 yr. Seven hundred seventy-four diabetic subjects were tested for diagnostic and research purposes. In 543 subjects completing all five tests, abnormalities of heart rate tests occurred in 40%, while abnormal blood pressure tests occurred in less than 20%. Their results were grouped as normal (39%), early (15%), definite (18%), and severe (22%) involvement. Six percent had an atypical pattern of results. Two hundred thirty-seven diabetic subjects had the tests repeated greater than or equal to 3 mo apart: 26% worsened, 71% were unchanged, and only 3% improved. The worsening followed a sequential pattern with first heart rate and later additional blood pressure abnormalities. Comparison between a single test (heart rate response to deep breathing) and the full battery in 360 subjects showed that one test alone does not distinguish the degree or severity of autonomic damage. These tests provide a useful framework to assess autonomic neuropathy simply, quickly, and noninvasively.

Relationship of skin thickness to duration of diabetes, glycemic control, and diabetic complications in male IDDM patients.

Skin thickness is primarily determined by collagen content and is increased in insulin-dependent diabetes mellitus (IDDM). We measured skin thickness in 66 IDDM patients aged 24-38 yr and investigated whether it correlated with long-term glycemic control and the presence of certain diabetic complications. With univariate analysis, skin thickness was increased and significantly related to duration of diabetes (P less than .001), previous glycemic control (P less than .001), retinopathy (P less than .001), cheiroarthropathy (P less than .001), and vibration-perception threshold (P less than .05). There was a negative correlation between forced expiratory volume at 1 s (P less than .05) and vital capacity (P less than .05) with duration of diabetes. Neither skin thickness nor ankle arteriomedial wall calcification correlated with abnormal autonomic function tests. When corrected for duration of diabetes, there was a weak correlation between skin thickness and glycemic control (P less than .05) but no correlation with retinopathy, cheiroarthropathy, and vibration-perception threshold. This study confirms that there are widespread connective tissue changes in diabetes mellitus, although the biochemistry needs further elucidation.