Biomedical subjects
Publications and source records attributed to M Albani.
We report on a child in whom severe nutritional vitamin B12 deficiency was exacerbated by a genetic impairment of the folate cycle, causing reduced CSF concentrations of the methyl group donor 5-methyltetrahydrofolate. Some patients with vitamin B12 deficiency may benefit from high dose folic acid supplementation, even if plasma concentrations are high.
At the age of five years a male child started to develop a progressive rigid spine, torsion scoliosis, and flexion contractures of his elbows, knees, hips, and ankles owing to severe proximal and distal muscle weakness. He had three muscle biopsies from three different muscles at ages 7, 11, and 14 years, respectively. Myopathologically, these muscle tissues contained numerous inclusions which, at the ultrastructural level, turned out to be reducing bodies and cytoplasmic bodies, often in close spatial proximity. Similar histological inclusions, although not further identified by histochemistry and electron microscopy, were seen in his maternal grandmother's biopsied muscle tissue who had developed weakness of the legs and hands after the age of 50 years. The patient's parents were healthy, but the mother's quadriceps muscle showed an increased spectrum of muscle fibre diameters. Our patient, thus, had a neuromuscular disorder, perhaps familial, presenting as a mixed congenital myopathy, i.e., reducing body myopathy with cytoplasmic bodies, of which the morphological lesions could be consistently documented over several years in his different limb muscles. While other mixed congenital myopathies had shown cores and rods, both related to sarcomeres and thus possibly morphogenetically related, cytoplasmic bodies thought to be related to Z-bands and reducing bodies dissimilar to any muscle fibre constituent do not share any common denominator. Therefore, we suggest that this neuromuscular disorder may be a unique mixed congenital myopathy, either sporadic or genetic. In the latter case, the transmission pattern suggested X-linked recessive inheritance, but an autosomal-dominant transmission with variable penetrance could not be ruled out.
OBJECTIVE: To locate the exact site of the primary lesion in the neuromuscular system in acutely ischaemic extremities. DESIGN: Experimental study. SETTING: University hospital, Greece. ANIMALS: 22 adult rats. INTERVENTIONS: Isometric tensions of extensor digitorum longus muscles were recorded before ischaemia and every 5 minutes after the arterial occlusions by indirect stimulation. When no contractile activity was elicited, the muscle was stimulated directly and recordings made every 5 minutes. The sciatic nerve function was checked by recordings of nerve conduction velocity. Specimens from the muscles were examined under electron microscopy. MAIN OUTCOME MEASURES: Muscle contractile properties, conduction velocity, and electron microscopic appearance. RESULTS: After a period of about 50 minutes neuromuscular function under indirect stimulation in the ischaemic limbs was lost, whilst under direct stimulation the extensor digitorum longus muscles and the sciatic nerves still functioned. Electron microscopic study showed distinct alterations at the neuromuscular junctions. CONCLUSIONS: The response of the neuromuscular system to acute ischaemia indicated that the neuromuscular junction is probably the site most susceptible to acute ischaemia.
The purpose of the present study was to investigate the immediate and 48-hr post-exercise effects of eccentric contraction-biased exercise on the contractile properties of the soleus muscle in situ. Adult male Wistar rats were categorised into sedentary control rats (n = 10), rats studied immediately (n = 10), and rats studied 48 hours after the exercise (n = 10). The exercise protocol consisted of a 90-min intermittent downhill running (-16 degrees, 16 m/min) on a motor-driven treadmill. The contractile properties of the soleus muscle were recorded following i.p. chloral hydrate anaesthesia. Isometric twitch force (Pt), time-to-peak tension (TPT), half-relaxation time (1/2 RT), and tetanic force at stimulation frequencies of 40, 80, and 100 Hz were recorded. A low-frequency muscle fatigue protocol (stimulation at 4 Hz for 5 min) was applied to test for fatigability. The main findings indicated that Pt generation dropped both immediately and 48 hr after the exercise, while tetanic force was partially restored after 48 hr. Exercise-induced E-C coupling failure and contractile machinery disorganisation due to muscle injury are put forward as the main force reduction causes.
Tibialis anterior (ta) muscle biopsies before and after elective abdominal aortic aneurysm (AAA) repair operation were obtained, in order to observe possible changes after the aortic declamping reperfusion. Open muscle biopsies were taken from each of eight patients (60-75 years old) which were processed for enzyme histochemistry, and for transmission electron microscopy (EM). Morphometric analysis was applied to estimate the number and the area of muscle fibres of each fibre type. Rectus abdominis muscle biopsies were served as controls. Before the operation the predominant elements found were the presence of atrophic muscle fibres, fibre size diversity, localised cellular reactions, increased extent of connective tissue, disappearance, in many cases, of the mosaic pattern, predominance of type I and oxidative fibres, and existence of fibres with core-like structures in the sarcoplasm. Type I fibres consisted of 66.95 +/- 9% of all muscle fibres, the mean cross sectional area of which was 3,372.8 +/- 1,016 microm(2) and of type II fibres was 3,786.5 +/- 6,046 microm(2). After the aortic clamping was performed mitochondrial swelling was found, as well as disorganisation of sarcomeres. After declamping of the aorta, there were also severe edema, local fibre necrosis, and adhesion of leucocytes, whereas muscle fibre areas became 3,935.18 micro 531 microm(2) for type I and 5,804 +/- 1,075 microm(2) for type II. The short ischemic period during aortic clamping and the subsequent reperfusion resulted mainly in ultrastructural changes.
BACKGROUND: Patients with end-stage renal disease on haemodialysis (HD) have limited work capacity. Many structural and functional alterations in skeletal muscles contribute to this disability. METHODS: To evaluate the effects of exercise training on uraemic myopathy, seven HD patients (mean age 44.1+/-17.2 years) were studied. Open muscle biopsies were taken from their vastus lateralis muscle before and after a 6-month exercise rehabilitation programme and examined by routine light- and transmission electron-microscopy. Histochemical stainings of frozen sections were performed and morphometric analysis was also applied to estimate the proportion of each fibre type and the muscle fibre area. Spiroergometric and neurophysiological testing and peak extension forces of the lower limbs were measured before and after exercise training. RESULTS: All patients showed impaired exercise capacity, which was associated with marked muscular atrophy (mean area 2548+/-463 microm2) and reduction in muscle strength and nerve conduction velocity. All types of fibres were atrophied, but type II were more affected. The ultrastructural study showed severe degenerative changes in skeletal muscle fibres, mitochondria, and capillaries. Exercise training had an impressive effect on muscular atrophy; in particular the proportion of type II fibres increased by 51% and mean muscle fibre area by 29%. Favourable changes were also seen on the structure and number of capillaries and mitochondria. These results were confirmed by a 48% increase in VO2 peak and a 29% in exercise time, as well as an improvement in the peak muscle strength of the lower limbs and in nerve conduction velocity. CONCLUSIONS: Skeletal muscle atrophy in HD patients contribute to their poor exercise tolerance. The application of an exercise training rehabilitation programme improved muscle atrophy markedly, and therefore had beneficial effects in overall work performance.
Administration of exogenous levedopa triggers locomotion in young rats prior to the onset of quadripedal movement. The same substance decreases locomotion in adult animals. The ontogenetic development of the response to levodopa was investigated in rats. Intraperitoneal injection of levodopa (150 micrograms/kg body weight) caused characteristic "crawling" or "swimming-like" locomotion patterns in 5- to 6-day-old animals. Noradrenergic mechanisms may be involved in this behavior. In 18- to 20-day-old rats, levodopa caused excessive locomotor activity, including running, jumping, and wall climbing. This effect can be attributed to the activation of postsynaptic dopaminergic receptors that are already present during the early stages of life. At 25-30 days of age, levodopa-induced motor activity was decreased in comparison with that of the 18- to 20-day-old rats, possibly due to changing patterns of D1/D2-dopamine receptor subtype interactions. In contrast to observations in younger rats, the same dose of levodopa suppressed motor activity in 60- to 75-day-old rats. The presence of functional dopamine autoreceptors at this age may account for the change.
Plasma membrane fluidity of intact peripheral blood lymphocytes (PBL) of phenytoin-treated nonepileptic patients and phenytoin-treated CD4+ lymphoid cells H9 and K37 was determined by fluorescence anisotropy measurements. Anisotropy values of the membrane probe 6-(9-anthroyloxy) stearic acid were decreased in all cell types as compared with controls, indicating increased plasma membrane fluidity of phenytoin-treated cells. Specific binding of 125I-labeled vasoactive intestinal peptide (VIP) to its cellular receptor CD4 on PBL was decreased in PBL of phenytoin-treated patients as compared with untreated, healthy subjects. Adsorption of a different ligand to the CD4 receptor on PBL, the human immunodeficiency virus type 1 (HIV-1), was likewise abolished to PBL of phenytoin-treated patients and phenytoin-treated CD4+ H9 and K37 cells, as assessed by indirect immunofluorescence. Subsequent HIV-1 infection of phenytoin-treated H9 and K37 cells was reduced as measured by indirect immunofluorescence and p24 antigen production. These data indicate that CD4 receptor availability for VIP and HIV-1 was reduced in phenytoin-treated cells. Using the DNA-specific dye Hoechst 33258, we examined cell cycle phase distributions of HIV-1 adsorbing and nonadsorbing H9 cells, as separated by flow cytometry. The majority of HIV-1 adsorbing cells were found to be in the G2/M phase, while nonadsorbing cells were mainly in the G0/G1 phase, during which plasma membrane fluidity is supposed to be increased. This study indicates that plasma membrane fluidization by phenytoin may serve to disrupt CD4 receptor function and emphasizes the impact of plasma membrane properties on HIV-1 adsorption and infection.
A 17-year-old girl with type II glycogen storage disease (Pompe's) developed severe right-heart failure as a result of pulmonary hypertension due to, predominantly nocturnal, hypoventilation. At night the partial pressure of oxygen was only 30-50 mmHg, pCO2 70-100 mmHg. After persistent nightly intermittent positive pressure ventilation blood gases as well as electrocardiographic and echocardiographic findings have now--after 12 months--become normal and the patient has been completely restored to a normal life. This case demonstrates that life expectancy and quality of patients with chronic forms of Pompe's disease (and probably also with other chronic neuromuscular diseases) can be markedly improved by nightly artificial ventilation which reduces nocturnal hypoventilation and resulting pulmonary hypertension.
Plasma membrane fluidity of intact nonmuscle cells from patients with myotonic dystrophy (MyD) was determined by fluorescence anisotropy measurements. Anisotropy values of the probe diphenylhexatriene were decreased in patient mononuclear cells (0.163 +/- 0.017, n = 13) versus controls (0.181 +/- 0.013, n = 13, P less than 0.01) and in patient platelets (0.087 +/- 0.017, n = 9) versus controls (0.137 +/- 0.015, n = 9, P less than 0.001) indicating increased plasma membrane fluidity in patient nonmuscle cells. Vasopressin plasma concentrations were increased in patients (7.4 +/- 2.1 pg/ml, n = 12) versus controls (4.5 +/- 1.4 pg/ml, n = 22, P less than 0.0005), whereas serum osmolality was normal. These data are compatible with a decreased vasopressin sensitivity in MyD patients. Specific binding of 125I-labelled vasoactive intestinal peptide (VIP) was decreased in patient mononuclear cells (2.9 +/- 0.9%/10(6) cells, n = 8) versus controls (5.2 +/- 1.6%/10(6) cells, n = 9, P less than 0.005) and receptor affinity for VIP was decreased in patient mononuclear cells (Kd = 0.26 +/- 0.05 nM, n = 8) versus controls (Kd = 0.19 +/- 0.02 nM, n = 9, P less than 0.005). In nonmuscle cells of MyD patients, increased membrane fluidity correlated with decreased receptor availability. This might explain the various endocrine defects described in MyD patients.
Sera from Duchenne muscular dystrophy (DMD) patients showed a membrane fluidizing effect on DMD and control lymphocytes. To look for the cause of this membrane fluidizing effect, human lymphocytes from healthy subjects were incubated in sera and in different serum fractions from DMD patients and healthy control subjects, and membrane fluidity was determined by steady state fluorescence polarization of the probe diphenyl hexatriene. DMD sera and total DMD lipoproteins showed a similar membrane fluidizing effect (p less than 0.02) after incubation, whereas lipoprotein deficient serum did not show any effect on membrane fluidity. Control and DMD HDL showed a membrane fluidizing effect, the fluidizing effect of DMD HDL being slightly higher as compared to control HDL. Control LDL and DMD LDL showed a membrane rigidifying effect, the rigidifying effect of DMD LDL being significantly lower as compared to control LDL (p less than 0.02). These data demonstrate that the membrane fluidizing effect of DMD serum is lipoprotein associated, LDL being the most important mediator of this effect.
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Changes in motor unit organisation following nerve injury in adult and neonatal rats were compared. Motor units were studied in extensor digitorum longus muscles reinnervated after nerve injury in either neonatal or adult rats. The force developed by individual motor units was measured by stimulating ventral root filaments. After nerve section in adult rats the distribution of motor unit force was restored to normal but this did not occur following nerve crush in neonatal animals. Thus following nerve injury during the neonatal period the muscles were not only permanently weaker, but the distribution of motor unit sizes was also abnormal. Muscle fibres belonging to a single motor unit were identified histologically by the glycogen depletion method, and their fibre type and cross-sectional area measured. Although all the fibres of the same unit became histochemically homogeneous, they showed greater variation in size than normal units, suggesting that factors other than the influence of the axons control the size of muscle fibres.
The clinical courses of 17 JNCL patients were analyzed retrospectively with the use of a simple, disease-specific scoring system. The mean observation period was 14 years (range 8-18 years). Scores of 0 (maximal dysfunction) to 3 (normal function) were assigned to each patient's vision, intellect, language, motor function, and epilepsy for each year of observation. The lapse of medians and ranges of all patients' scores were established from age 3 to 20 years. This scoring system allowed quantitative description of an individual course in context of the wide natural variability of the disease. Patients with seizures starting before the age of 10 years tended to have intractable epilepsy, to receive multiple antiepileptic drug therapies, and to have poor courses including problems not related to epilepsy. One patient had a course clearly outside the usual variability of JNCL and is thought to represent a genetic variant.
Sudden infant death syndrome (SIDS) remains the predominant cause of postneonatal mortality. Epidemiological studies have led to the definition of populations with an increased risk for SIDS: subsequent siblings of SIDS victims, infants with near miss for SID episodes, prematurely born infants with perinatal risk factors, and infants of drug dependent mothers. Furthermore, a variety of additional although rarely independent factors regarding both mothers and infants have been found to be associated with an increased risk for SIDS. Despite of this, the majority of infants still dying from SIDS do not belong to one or more of these risk groups and even within a group considered to be at increased risk it is impossible so far to identify individual infants at highest risk on the basis of an infant's history and clinical data. Therefore, different methods have been applied during the last several years in order to detect functional abnormalities of cardiorespiratory control during sleep with the aim of obtaining more specific and sensitive predictors of subsequent severe apnoea and SIDS. In an attempt to evaluate the predictive power of these various methods the present article reviews their results in relation to the follow up data of the infants under study. The results of the meanwhile innumerous studies were found to be at variance and often controversial. At the present time, none of these tests may be looked at as virtually improving our ability to predict the risk for prolonged apnoea and SIDS. One of the reasons for this may be the lack of standardisation of the particular methods with respect to both definition of study groups and conditions of testing infants. Since all of these tests have mainly been performed in infants of epidemiological risk groups, the definition of which is an indispensable prerequisite for the evaluation of both the indication and the results of such tests, an updated survey of the more recent epidemiological studies is given as an introduction.
Studying the development of transcutaneous blood gas levels (tcpO2 and tcpCO2) and the sleep apnea profile in relation to sleep states in normal preterm infants between 36 and 52 weeks postconceptual age we found a dynamic increase in tcpO2 during regular breathing (without apnea) and a steady decrease in tcpCO2 during both regular and periodic breathing. The mean tcpO2 of periodic breathing, however, persistently remained well below the corresponding level found during regular breathing. It is suggested that in normal preterm infants there is a continued maturational adjustment of autonomic respiratory control up to 3 months post term and, furthermore, that periodic breathing may persistently be associated with a relative hypoxemia.
Peripheral neuropathy marked by reduced nerve conduction velocities was found in four unrelated children, between the ages of 15 months and 9 years, whose autopsies revealed Leigh's subacute necrotizing encephalomyelopathy. Sural nerve biopsies disclosed primary demyelination and remyelination, as well as loss of myelinated and unmyelinated axons. The use of morphometric and electron microscopic studies shows that these techniques may reveal peripheral neuropathy in Leigh's disease more often than light microscopic methods alone.
Since 1981, 96 infants considered at increased risk of SIDS underwent home monitoring for prolonged sleep apnea: 23 infants after a near miss for SIDS event, 28 siblings of a SIDS victim and 45 infants with a variety of perinatal risk factors. For a total of 65 infants the course of home monitor surveillance was completed by September 1984 with a duration ranging from 6 to 15 month: 26% (4/15) of the near miss for SIDS group, 23% (3/13) of the SIDS siblings and 13% (5/37) of the perinatal risk cases developed more than one prolonged apneic episode with additional symptoms requiring vigorous intervention by parents. Two infants of the perinatal risk group became SIDS victims: despite an apnea alarm after 15 seconds the parents were unable to resuscitate their infant in one case, the other died from SIDS about 4 month after monitoring was discontinued because of an uneventful course and normal polygraphic sleep recordings The large number of prolonged apneas requiring intervention and the two SIDS cases (3% of the total study group) indicate a considerably increased risk of prolonged life-threatening sleep apnea and SIDS in the population monitored.