Age related skeletal muscle response to electrical stimulation.

We hypothesized that the conditioned muscles of elderly and growing organisms have different responses to electrical stimulation from that of young adult organisms. Five day old lambs, 1 year old sheep, and 8 year old elderly sheep were used for this investigation. The latissimus dorsi muscle (LDM) was partially mobilized and left in situ. Two electrodes were implanted and electrical stimulation (ES) was begun for 8 weeks; it was then stopped for 2 weeks. Biopsies were taken before ES, after 8 weeks of ES, and after the 2 week delay period. The LDM of old sheep has less fatigue resistance than the LDM of younger animals. Conditioned LDM of the lamb continued to be fatigue resistant after a 2 week delay compared with adult sheep. In all animals, lactate dehydrogenase (LDH) fraction five decreased and LDH-1 + 2 fractions increased after ES. After a 2 week delay, the data returned to baseline values only in adult animals. The percentage area occupied by mitochondria in old sheep was less after ES than in younger animals. In all animals, the mitochondrial area increased after ES and reverted to baseline values after the delay. The number of nuclei and fibers considerably increased after ES. Only in the lamb did the number of nuclei and fibers continue to be elevated after the delay. There are more changes in young skeletal muscle than in adult (1 year or 8 year old) muscle during ES, and they "remember" these properties. Elderly skeletal muscle does not convert to a fatigue resistant state as completely as adult skeletal muscle during a conventional 8 week ES protocol. It is necessary to change and prolong the ES protocol for elderly patients.

Increased prevalence of elevated urinary albumin excretion rate in type 2 diabetic patients suffering from ischemic foot lesions.

UNLABELLED: Present cross-sectional clinical study was aimed at the evaluation the prevalence of cardiovascular risk factors in Type 2-diabetics suffering from different clinical manifestations of diabetic foot lesions due to peripheral vascular disease and/or diabetic neuropathy. 1025 non-insulin-dependent (Type 2) diabetics (NIDDM) of both sexes were investigated. Patients were classified in Type II diabetes without peripheral vascular disease and foot lesions (group 0, controls), with macroangiopathic related foot lesions (group 2), with neuropathic foot lesions (group 3), and with mixed neuropathic-ischemic foot lesions (group 4). Apart from urinary albumin excretion rate (UAE), the following micro- and macroangiopathic risk factors and diseases were taken into account: Hypertension, degree of metabolic control (HbA1c), lipid concentrations, duration of diabetes, retinopathy, clinical nephropathy. RESULTS: In the total population the UAE was significantly (p < 0.01) correlated with duration of diabetes, serum creatinine, hypertension, age, lipid concentrations, HbA1c and insulin requirement. In comparison to Type II diabetic patients without peripheral vascular disease (group 0) and with neuropathic foot lesions (group 3), subjects with ischemic (group 2) and mixed neuropathic-ischemic foot lesions demonstrated an increased prevalence of pathological UAE, which was associated with a higher frequency of clinical nephropathy, retinopathy, an older age and longer duration of diabetes. It is concluded that microalbuminuria in Type 2 diabetes reflects both the existence of diabetic nephropathy and peripheral vascular disease which is often associated with the insulin resistance syndrome.

Skeletal muscle of a growing organism has a greater transformation after electrical stimulation than adult skeletal muscle.

Six adult sheep and four newborn lambs (5 days old) were implanted with stimulator leads into the latissimus dorsi muscle and connected to a Myostim 7220 pacing system (Telectronics Pacing Systems, Inc., Englewood, CO). Electrical stimulation was started immediately after the operation. After 8 weeks of electrical stimulation, contractile force (CF) in adult sheep decreased to 76-81%, and to 78-82% in lambs. After 2 weeks' delay, CF in adults was 96-98%, and only 89-93% in lambs. After a 30 min intensive stress test, unconditioned control muscle lost 39% in lambs and 43% in adults. Muscle conditioned for 8 weeks lost 7-8% CF. However, after 2 weeks' delay, CF in adult muscle lost 33%, but only 12% in lambs. After cessation of electrical stimulation, the LDH-5 and LDH-1 + 2 fractions reverted to initial levels in adults, whereas in lambs, these levels continued to follow trends established during electrical stimulation. In both adults and lambs, the percent area occupied by the mitochondria increased during electrical stimulation by 6.9% in adults and 6.5% in lambs. After electrical stimulation cessation, the percent area in adults returned to baseline levels, whereas it continued to be elevated in lambs (3.3% vs 5.1%, respectively). The transformed muscle of the lamb did not revert to baseline levels after a delay period.

Force enhancement of skeletal muscle used for dynamic cardiomyoplasty and as a skeletal muscle ventricle.

Some patients with pre end-stage congestive heart disease do not receive a significant hemodynamic benefit from dynamic cardiomyoplasty because, during prolonged preoperative immobilization, their latissimus dorsi muscle (LDM) becomes extremely weak. It is the authors' hypothesis that the local administration of an anabolic steroid into an electrically stimulated LDM will produce a thicker and stronger muscle with significant resistance to fatigue. The electrical stimulation training protocol of sheep continued for 8 weeks. For localized anabolic steroid administration an osmotic pump was placed in a subcutaneous pocket and the catheter was introduced into the LDM. The contractile force of electrically stimulated and unstimulated control muscle was studied. Control data were calculated as 100% and all other data were corrected to control. After 4 weeks there was no decrease in contractile force. The change seen was from 88 to 100% with different preloads (10, 15, and 20 g/kg) and amplitudes of impulses (5 and 10 V). After 8 weeks, the LDM was more powerful than before electrical stimulation, with a change of 97-133%. Usually after 8 weeks of electrical stimulation alone, contractile force decreases to 70-75%. During a fatigue test (30 min, 100 bursts per minute, 10-25 Hz, ripple frequency, 10 V impulse amplitude) after 4 and 8 weeks of our protocol, the LDM lost only 12% of its initial force, whereas control muscle lost 40%. Thus local anabolic steroid administration makes the LDM stronger and more useful for cardiomyoplasty.

Cardioversion, defibrillation, and overdrive pacing of ventricular arrhythmias: the effect of moricizine in dogs with sustained monomorphic ventricular tachycardia.

The purpose of this investigation is to define whether the antiarrhythmic drug moricizine has beneficial or adverse effects on currently used antitachycardia and antifibrillatory devices. These studies were performed in a dog model of sustained monomorphic ventricular tachycardia (VT). In 11 dogs, the left anterior descending artery and all surrounding epicardial collateral feeder vessels were ligated. Defibrillator patches were implanted and the dogs were allowed to recover. After a 7-day recovery period, effective refractory period (ERP), end diastolic threshold (EDT), VT induction, and VT and ventricular fibrillation (VF) termination data were collected before and after moricizine infusion (2 mg/kg). In this experimental model, moricizine caused the following electrophysiological changes: a prolongation of the ERP from 173 +/- 14 to 182 +/- 15 (P < 0.02) with no significant effect on the EDT for pacing; a prolongation of the VT cycle length from 175 +/- 18 to 201 +/- 23 msec (P < 0.003); an increased cycle length required for overdrive pacing from 136 +/- 20 to 157 +/- 22 msec (P < 0.01); no effect on the energy required to cardiovert VT; an increase in the defibrillation threshold from 7.5 +/- 4 to 9.4 +/- 4 joules (P < 0.006) and; in 5 of the 8 dogs with VT, the VT could be initiated with somewhat less aggressive stimulation. Significant beneficial electrophysiological physiological effects were noted on the VT cycle length, including a proportionately prolonged overdrive pacing cycle length for VT termination.(ABSTRACT TRUNCATED AT 250 WORDS)

Iontophoretic transmyocardial drug delivery. A novel approach to antiarrhythmic drug therapy.

BACKGROUND: Antiarrhythmic drugs often fail to achieve therapeutic effects without toxic systemic levels. Direct transport of drugs into the myocardium may circumvent this problem and may also provide new insights into antiarrhythmic drug effect on arrhythmogenic tissues. In a canine model, procainamide (PA) was delivered iontophoretically using pulsed current synchronized with the ventricular depolarization via an implantable defibrillator patch electrode that was modified to contain a 3.6-ml chamber. Myocardial tissue concentrations of PA were evaluated in 7-day myocardial infarcts (n = 16) that were exposed to 10 minutes of iontophoretic PA delivery and compared with passive diffusion (n = 5) and intravenous (n = 16) PA. These dogs were followed for 3 hours. The infarcted tissue PA levels were compared with normal myocardium. Coronary and systemic blood levels of PA, effective refractory period (ERP), diastolic threshold, and efficacy of ventricular tachycardia (VT) suppression were evaluated throughout the follow-up period. METHODS AND RESULTS: Three hours after 10 minutes of iontophoretic, passive, and intravenous PA, the epicardial layer concentration in the center of the infarcted zone was 840 +/- 853 micrograms/g, 93 +/- 90 micrograms/g, and 15 +/- 8 micrograms/g of tissue, respectively. In the endocardial layer, the PA concentrations with iontophoresis were 38 +/- 57 micrograms/g and were significantly higher than those achieved with either passive diffusion 38 +/- (4 +/- 2 micrograms/g) or with intravenous delivery (11 +/- 5 micrograms/g) (p less than 0.05). Epicardial tissue PA concentrations 3 hours after iontophoresis, passive diffusion, and intravenous PA in the normally perfused tissues were 14 +/- 13 micrograms/g, 3 +/- 2 micrograms/g, and 16 +/- 8 micrograms/g of PA, respectively. Venous blood levels were 2 +/- 3 micrograms/ml 3 hours after iontophoresis, 1 +/- 1 microgram/ml 3 hours after passive PA delivery, and 11 +/- 7 micrograms/ml with intravenous administration (p less than 0.05 intravenous versus passive and iontophoresis). Iontophoretic delivery of PA resulted in 22 +/- 29 msec ERP prolongation intramurally in the infarcted zone with no significant normal tissue ERP prolongation. Passive delivery of PA produced no significant changes in ERP. After intravenous infusion, the ERP in the infarcted zone increased by 35 +/- 29 msec and 13 +/- 12 msec in the normal tissue. Sustained monomorphic VT was induced in 20 animals. In one of these animals, only nonsustained VT could be induced at baseline; however, after intravenous PA, VT could be induced and remained inducible throughout the 3-hour follow-up period. In the iontophoretic delivery group, PA suppressed VT in all of the animals, with termination time ranging from 20 seconds to 7 minutes. In three cases, sustained monomorphic VT could be reinduced, two after 60 minutes and one after 120 minutes. However, in seven dogs, VT could not be induced during the 3-hour follow-up period. None of the dogs in which PA was delivered iontophoretically into the infarcted myocardium developed VT that was not induced before delivery of the drug. Intravenous PA administration resulted in VT suppression in one of 10 dogs. In two dogs, VT could not be induced before intravenous infusion of PA. However, after intravenous PA, VT could be induced. Immunohistochemical mapping of the PA within the infarcted tissue revealed transmural PA distribution. CONCLUSIONS: These data show that 1) the delivery of high transmural concentrations of PA directly into infarcted myocardium is both feasible and effective...

Increased prevalence of proliferative retinopathy and cardiovascular autonomic dysfunction in IDDM patients with proteinuria.

The purpose of the present cross-sectional clinical study was to evaluate the prevalence of retinopathy in Type 1 diabetic patients without nephropathy and with different degrees of nephropathy. In addition we investigated the association between retinopathy, nephropathy, and other variables, and studied the importance of cardiovascular autonomic dysfunction to these conditions. 76 Type 1 diabetic patients were investigated. All patients were initially selected on the basis of body weight, and 47 proteinuric patients were further selected for age, diabetes duration and the duration of insulin treatment (see Table 1). Proteinuric diabetic patients were categorized by degree of nephropathy, i.e. for incipient nephropathy (proteinuria of less than 0.5 g/day), for overt nephropathy (proteinuria of more than 0.5 g/day), and for renal failure (serum creatinine of more than 103 mumol/l). Retinopathy was assessed by ophthalmoscopy. Cardiovascular autonomic dysfunction (CAD) was assessed by heart rate variations, 30:15 ratios, the Valsalva maneuver, and systolic blood pressure fall upon standing. Our findings revealed increased prevalence of retinopathy in patients with more advanced stages of nephropathy. CAD abnormalities exhibited increased prevalence among proteinuric patients. Our data clearly revealed differences between proteinuric and non-proteinuric patients. In both proteinuric and non-proteinuric patients there were found correlations of retinopathy with diabetes duration, and only in proteinurics was retinopathy correlated with kidney function, systolic blood pressure and CAD findings. In patients in identical stages of nephropathy, increased prevalence of CAD abnormalities was shown in patients suffering from proliferative retinopathy. Thus our data suggest that CAD abnormalities might be related in some way to both the proliferative retinopathy and to diabetic nephropathy.

The effect of antihypertensive treatment on kidney function in insulin-dependent (type I) diabetics with renal failure.

Diabetic nephropathy is the dominant cause of hypertension in insulin-dependent diabetics, and long-term rigid antihypertensive treatment inhibits the progression of nephropathy, probably even when there is renal insufficiency. In our clinical study 14 insulin-dependent diabetics with diabetic nephropathy and renal failure (glomerular filtration rate [GFR] 0.39 +/- 0.12 ml/sec) underwent rigid blood pressure treatment. Antihypertensive therapy included furosemide, propranolol, dihydralazine and nifedipine. The whole group showed a lowering in mean blood pressures from 150.1 +/- 2.3/91.3 +/- 1.4 mm Hg to 139.8 +/- 3.1/86.5 +/- 2.0 mm Hg (p less than 0.01). During the observation period the mean decline in glomerular filtration rate decreased from -0.022 +/- 0.003 ml/sec per month to -0.010 +/- 0.007 ml/sec per month. In 10 out of 14 patients with very advanced nephropathy the further decline of GFR halted markedly. Thus, vigorous blood pressure control is able to postpone endstage renal disease even in advanced diabetic nephropathy.

Importance of cardiovascular autonomic dysfunction in IDDM subjects with diabetic nephropathy.

Diabetic nephropathy (DNP) is associated with increased cardiovascular mortality. This may be contributed to by associated cardiovascular autonomic dysfunction (CAD). The aim of this study was to investigate the prevalence of CAD in patients with insulin-dependent diabetes mellitus (IDDM) at different stages of DNP. We studied patients with incipient DNP (group 1, n = 10), overt DNP (group 2, n = 20), renal insufficiency (group 3, n = 27), and end-stage renal failure (group 4, n = 12) and compared them with 30 IDDM patients without clinical signs of DNP (group 5) and with 17 nondiabetic controls (group 6). All groups were matched for age and diabetic groups were matched for duration of diabetes. Assessments of CAD included beat-to-beat variation during forced respiration, heart-rate response to standing, heart-rate response to Valsalva maneuver, basal heart rate, and blood pressure response to standing. Clinical evaluation included assessment of the history and an examination for peripheral polyneuropathy. We found mean impairment of heart-rate variation during respiration, in response to Valsalva maneuver, and in heart-rate response to standing in all diabetic groups compared with nondiabetic controls (P less than .01). Heart-rate responses differed significantly between patients with renal insufficiency (groups 3 and 4) and with other patient groups (group 5; P less than .01). CAD was shown to be more prevalent in patients with DNP, more so as DNP progresses. To some extent, it is already present in the early stages of DNP. CAD may be a contributory factor for increased cardiovascular mortality in patients with DNP.(ABSTRACT TRUNCATED AT 250 WORDS)

[Visceral diabetic polyneuropathy - quantitative determination of respiratory cardiac arrhythmia]. / Untersuchungen zur viszeralen diabetischen Polyneuropathie - quantitative Bestimmung der respiratorischen Herzarrhythmie.

In 100 insulin-dependent diabetics, the degree of the respiratory cardiac arrhythmia as a measure of the participation of the N. vagus in the polyneuropathy is determined by means of the triggered cross-correlation function. The impairment of the respiratory cardiac arrhythmia shows statistical relations to the electroneurographic changes of somatic nerves, to the duration of diabetes and to the occurrence of microangiopathies.

[Diabetic polyneuropathy. 4. Synopsis of electroneurographic findings in diabetics]. / Die diabetische Polyneuropathie 4. Mitteilung: Synopsis elektroneurographischer Befunde bei Diabetikern.

Sensory conduction velocity of the median nerve, motor conduction velocity of both median and tibial nerves, and corresponding distal laterncies are sufficient parameters to establish the diagnosis of polyneuropathy almost with certainty. Considering these six parameters yielded in detection of peripheral nerve dysfunction in 22% of diabetic patients who were free from clinical signs of polyneuropathy. Electroneurographical findings in 340 out of 677 patients with diabetes mellitus were interpreted as evidence of segmental demyelination. Within this group there was the majority of patients with clinical signs of polyneuropathy and with subclinical signs of peripheral nerve dysfunction. There existed a positive correlation between signs of nerve dysfunction with angiopathy, age and duration of the disease. A second group consisting of 243 diabetics with signs of incipient segmental demyelination with or without signs of axonaal degeneration mainly included juvenile patients with a short duration of the disease and with a low frequency of angiopathy.

[Diabetic polyneuropathy. 3. Electroneurographic findings in diabetics and their relationships to age and duration of diabetes]. / Die diabetische Polyneuropathie. 3. Mitteilung: Elektroneurographische Befunde bei Diabetikern und ihre Beziehung zum Lebensalter und zur Diabetesdauer.

Nerve conduction velocities were determined in patients with diabetes mellitus: motor conduction of the median nerve in 778 patients, sensory conduction of the median nerve in 680 patients and motor conduction of the tibial nerve in 745 patients. In 40.9% out of 778 patients at least one of the three nerve conduction velocities were found within pathological ranges. 30.4% of 227 patients below 19 years of age in whom the duration of the disease did not exceed four years exhibited at least one delayed nerve conduction velocity. Clinical signs of polyneuropathy in children and in adolescents below 19 years of age are rare (0.6%). In contrast delayed nerve conduction velocities were found in 29.4%. Metabolic disturbance of peripheral nerve function is assumed to be responsible in these patients, for angiopathy in children and adolescents is very rare too.

[The diabetic polyneuropathy. I. Relation between impaired function in peripheral nerves and clinical findings]. / Die diabetische Polyneuropathie. 1. Mitteilung: Beziehungen zwischen Funktionsstörungen am peripheren Nerven und klinischen Befunden.

789 patients with diabetes mellitus were studied by clinical and electroneurographical investigation. Motor and sensory conduction velocities of the median nerve and motor conduction velocity of the tibial nerve were determined. 86.1% of the patients suffered from juvenile diabetes, and 13.9% from maturity onset diabetes. Average duration of the disease was 9.5 years, average age of the patients was 26.7 years. Clinical signs of polyneuropathy were found in 19.1%. In 40.9% of the patients at least one of 3 conduction velocities was found to be delayed. Patients with clinical signs of polyneuropathy exhibited delayed nerve conduction velocities and delayed distal latencies. Diagnosis of polyneuropathy almost with certainty is possible by determining the three nerve conduction velocities and the three corresponding distal latencies. 22% of patients without clinical signs of polyneuropathy exhibited electroneurographical signs of impaired peripheral nerve function. Heredity, body weight, lipid metabolism, actual metabolic balance, and treatment were found to be without any significant influence on nerve conduction velocity.

[The diabetic polyneuropathy. II. Polyneuropathy, angiopathy and nerve conduction velocity]. / Die diabetische Polyneuropathies. 2. Mitteilung: Polyneuropathie, Angiopathie und Nervenleitgeschwindigkeit.

789 patients with diabetes mellitus were studied by clinical and electroneurographical examination. Motor conduction velocity of the median and the tibial nerve and sensory conduction of the median nerve were determined. 81.1% of the patients we suffering from diabetes which began in childhood or adolescence, 13.9% were suffering from maturity onset diabetes. Average duration of the disease was 9.5 years, average age was 26.7 years. Clinical signs of polyneuropathy were found in 19.1%. Typical findings were pain and paraesthesia, lack or abolition of triceps surae reflexes, impaired pallaesthesia on lower extremities. 48.3% of 151 patients with clinical signs of polyneuropathy were suffering from combined angiopathy, 32.5% from microangiopathy, 7.9% from macroangiopathy. Severity of complicating retinopathy and macroangio,athy were found to be correlated with polyneuropathy. 58.2% of 323 diabetics with at least one delayed nerve conduction velocity exhibited signs of angiopathy. In nearly 30% of children and adolescents after comparatively short duration of the disease at least one conduction velocity was delayed. In diabetic children and adolescents metabolic disturbances are assumed to cause peripheral nerve dysfunction.

Structural properties of pyruvate carboxylases from chicken liver and other sources.

Varieties of pyruvate carboxylase [pyruvate: CO2 ligase (ADP-forming), EC 6.4.1.1] obtained from the livers of several species of vertebrates, including humans, all show the same basic structure. They are composed of large polypeptide chains of molecular weights ranging from 1.2 to 1.3 X 10(5) for the different varieties of the enzyme. The native form of the enzyme appears to be a tetramer with a molecular weight of about 5 X 10(5). In the case of pyruvate carboxylase from chicken liver each polypeptide chain contains a biotin moiety, thus supporting the thesis that the tetramer contains four identical polypeptide chains. Pyruvate carboxylase from yeast appears to be basically similar to those from the vertebrate species and has a tetrameric structure. Each protomer contains a single polypeptide chain with a molecular weitht of 1.25 X 10(5). In contrast, pyruvate carboxylase from two bacterial species, Pseudomonas citronellolis and Axotobacter vinelandii, appears to be a dimer with a molecular weight (2.5 X 10(5)) about half that of the animal and yeast species. As a further difference, each of the protomers of the bacterial enzymes contain two polypeptides of 6.5 and 5.4 X 10(5) molecular weight in case of the Pseudomonas enzyme. The larger of the two polypeptides contains the biotin moiety. The functional units of the bacterial enzyme thus appear to contain two polypeptides while that of the liver and yeast enzymes is made up of a single chain. Neither of these arrangements corresponds with those of other biotin enzymes whose structure has been extensively studied (acetyl-CoA carboxylases from liver or Excherichia coli, and transcarboxylase from Propionibacterium).

Plant epicuticular lipids: alteration by herbicidal carbamates.

The effect of several carbamates and trichloroacetic acid on the biosynthesis of epicuticular lipids from leaves of pea (Pisum sativum) was tested by chemical and visual methods. The carbamates tested included S-(2,3-dichloroallyl) diisopropylthiocarbamate (diallate), N-(3-chlorophenyl) isopropylcarbamate (chloropropham), S-ethyl dipropylthiocarbamate, and 2-chloroallyl diethyldithiocarbamate. Diallate reduced epicuticular lipids by 50% when the plants were root-treated and by 80% when vapor-treated. These results were supported by scanning electron microscopy and carbon replica techniques with transmission electron microscopy. The ratio of wax lipid components in the diallate-treated plants remained unchanged, with the exception of the primary alcohols, which were reduced. Diallate appears to interfere with the biosynthesis of a precursor to the elongation-decarboxylation pathway of lipid synthesis. N-(3-Chlorophenyl)isopropylcarbamate had no significant effect on total amounts of extractable epicuticular lipids, nor did it alter the structure of the wax formation on the leaves. The scanning electron microscopy micrographs indicated that S-ethyl dipropylthiocarbamate significantly reduced wax formation on pea leaves. 2-Chloroallyl diethyldithiocarbamate altered the structure of the wax formations, but not the total amount of wax (scanning electron microscopy). Trichloroacetic acid had little effect on wax deposition compared to diallate or S-ethyl dipropylthiocarbamate (scanning electron microscopy). The implication of the effect of the carbamates on epicuticular lipids and penetration of subsequent topically applied chemicals is discussed.