Duchenne-like muscular dystrophy in the Arabs.
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Consanguinity↗
Biomedical subjects
M Zatz
Publications and source records attributed to M Zatz.
Dystrophin immunostaining in muscles from patients with different types of muscular dystrophy: a Brazilian study.
The localization of the protein dystrophin was studied using the immunofluorescence method, in muscle biopsies from 74 patients affected by different types of muscular dystrophy and 4 normal controls. In 15 patients with limb-girdle muscular dystrophy (LGMD) the pattern was indistinguishable from normal. Among 42 Duchenne patients (DMD), 3 were totally negative and 39 showed a variable proportion (4-30%) of partially labelled fibers. With one exception 17 Becker dystrophy patients (BMD), showed a positive sarcolemmal reaction. A diffuse reaction inside the fibers, which was not observed in normal controls, was seen in the majority of DMD and also in some of the BMD patients. Based on these observations it is suggested that in DMD, a small quantity of protein is still present or there is a cross-reaction with other proteins which share some homology with dystrophin. The present results suggest that it is possible to make a differential diagnosis between DMD and BMD through dystrophin immunohistochemistry. However, to distinguish between patients with BMD and LGMD phenotypes, or DMD and outliers, complementary immunoblot studies and quantitative determination of dystrophin are necessary.
Adolescent↗
Vasoactive intestinal peptide stimulates chick pineal melatonin production and interacts with other stimulatory and inhibitory agents but does not show alpha 1-adrenergic potentiation.
Vasoactive intestinal peptide (VIP) is known to mimic the effects of beta-adrenergic receptor stimulation in the rat pineal, including marked potentiation by alpha 1-adrenergic receptor stimulation, and to cause increased melatonin synthesis. In contrast, the chick pineal does not respond to beta-adrenergic stimulation, and melatonin synthesis is inhibited by norepinephrine via an alpha 2-adrenergic receptor. The present experiments show that chick pineal cells in primary culture do, however, respond to VIP with increased melatonin production. The effect of VIP was inhibited by addition of norepinephrine or of nitrendipine or by exposing the cells to "unexpected" white light. Stimulation by VIP was enhanced by addition of forskolin or Bay K 8644 but not by alpha 1-adrenergic receptor stimulations. Although stimulation by VIP appears similar in the chick pineal to that seen in the rat pineal and other systems, "dual-receptor regulation," at least with alpha 1-adrenergic receptors, appears to be absent.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Estimate of germinal mosaicism in Duchenne muscular dystrophy.
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Creatine Kinase↗
Screening of deletions in the dystrophin gene with the cDNA probes Cf23a, Cf56a, and Cf115.
We have analysed 38 DMD patients from 34 families and 30 BMD patients from 12 families using the cDNA probes Cf23a and Cf56a, which map near the centre of the dystrophin gene, and Cf115, which is close to the 3' end of this gene. Together, probes Cf23a and Cf56a detected deletions in 50% of the DMD families and 33% of the BMD families. Probe Cf115 detected a deletion in only one DMD patient, which has not been reported before in severe X linked myopathy. Most of the DMD deletions could be detected with Cf56a while all four BMD deletions were detected with Cf23a. The pattern of deletions could not be used to predict the precise clinical course of the disease and no correlation was found between the severity of the disease and the extent of the gene deletion. A higher frequency of deletions was observed in sporadic (73%) compared with familial DMD (28%) and BMD cases (33%). This result, if confirmed in a larger sample, would have important implications for genetic counselling.
Adolescent↗
Ouabain (or salt solution lacking potassium) mimics the effects of dark pulses on the circadian pacemaker in cultured chick pineal cells.
Chick pineal cells in static culture display a persistent photosensitive circadian rhythm of melatonin production and release. Pulses of white light or darkness, in otherwise constant red light, induce phase shifts in subsequent cycles whose magnitude and direction depend on the phase at which the pulse is given. Such 'phase-dependent phase shifts' are mediated by effects on the underlying pacemaker. Here, we describe the effects of ouabain, a specific inhibitor of Na,K-ATPase, and of salt solutions lacking potassium (SS-K), which also inhibit the pump, on the melatonin rhythm. Pulses of ouabain, or of SS-K, induced phase advances and phase delays that were phase and concentration-dependent. The relationship between time of treatment and effect on the subsequent phase of the rhythm (the phase-response curve) for these treatments was essentially the same as that for pulses of darkness.
Animals↗
Photoendocrine transduction in cultured chick pineal cells. III. Ouabain (or dark) pulses can block, overcome, or alter the phase response of the melatonin rhythm to light pulses.
A photoentrainment pathway, circadian pacemakers, and the apparatus for regulated melatonin production all reside within chick pineal cells. Pulses of white light (L), or darkness (D), or ouabain (Ob), in otherwise constant red light, induce phase-dependent phase shifts in the rhythm of melatonin output displayed by these cells in static culture. The phase response curves (PRCs) (which describe the relationship between the phase at which a pulse is given and the resulting phase shift) for Ob and for D are quite similar, and differ from the PRC for L pulses. Here, we describe the effects of pulses of Ob, L, and D, in combination, on subsequent phase of the melatonin rhythm. Ob pulses can block, overcome, or alter the phase response to light pulses, depending on the phases and concentrations used. Under appropriate conditions, D pulses can, like Ob, convert the phase response to a light pulse from phase delays to phase advances. Such alterations in the response to a second pulse (L) caused by a first pulse (Ob or D) implies a rapid resetting of the phase of the underlying pacemaker. The interactions of Ob, L, and D are consistent with, but do not require, the convergence of their entrainment pathways on the same oscillating component of the pacemaker.
Animals↗
Racial effect on serum creatine-kinase: implications for estimation of heterozygosity risks for females at-risk for Duchenne dystrophy.
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Adult↗
Relationship between light, calcium influx and cAMP in the acute regulation of melatonin production by cultured chick pineal cells.
Chick pineal cells in primary culture 'spontaneously' synthesize and release melatonin at 'night'. Exposing the cells to 'unexpected' white light, or to agents which retard calcium influx (nitrendipine, low external calcium), or which reduce cAMP levels (norepinephrine), acutely decreases nocturnal melatonin production. Conversely, agents which promote calcium influx (Bay K 8644) or mimic cAMP (8BrcAMP) increase nocturnal melatonin output. When these agents were used in combination, neither nitrendipine nor low external calcium reduced melatonin output in the presence of 8BrcAMP. Norepinephrine, however, did lower melatonin release in the presence of Bay K 8644. Addition of 8BrcAMP blocked the acute inhibitory effect of 'unexpected' light, but Bay K 8644 did not. Taken together with previous data, these results favor the hypothesis that both light and calcium influx acutely regulate melatonin production in the chick pineal through cAMP.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Estimate of the proportion of Duchenne muscular dystrophy with autosomal recessive inheritance.
The aim of the present report was to estimate the proportion of autosomal recessive (AR) inheritance among families with affected males diagnosed as Duchenne muscular dystrophy (DMD) in which X-linked inheritance could not be confirmed. A total of 470 families was studied: 20 with at least one affected girl with "Duchenne-like" phenotype and 450 with only affected boys. Based on the number of families with at least one affected girl and the number of patients per sibship among these pedigrees, the proportion of families with DMD inherited as an AR trait was estimated at 6.8%. It is also estimated that 2.5-4% of male isolated patients diagnosed as DMD may have the AR form, which could be one possible explanation for the inconsistent results between clinical diagnosis and dystrophin assessment in one case recently reported.
Child↗
Hypothesis: the existence of embryonic and adult isoforms of mRNA dystrophin provides an explanation for unusual clinical findings.
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Adult↗
Nocturnal rhythm of growth hormone in Duchenne patients: effect of different doses of mazindol and/or cyproheptadine.
Human growth hormone (hGH) inhibition may be beneficial for Duchenne muscular dystrophy (DMD) patients and slow the rate of progression of the disease. The purpose of the present investigation was 1) to assess, before any therapeutic trial, the natural growth hormone (GH) rhythm during physiological sleep in DMD patients and in normal control boys of comparable age; 2) to evaluate the effect of different doses of two potential GH inhibitors on nocturnal GH secretion in DMD patients receiving mazindol (1-4 mg), cyproheptadine (4-8 mg), or both drugs. The results from the present investigation showed 1) wide variability in nocturnal GH secretion before medication; 2) no correlation between nocturnal GH concentration and height, age, bone age, L-dopa provocative test, or Tanner staging; and 3) no consistent effect on GH release after mazindol, cyproheptadine therapy, or combined therapy.
Adolescent↗
Voltage-dependent calcium channels regulate melatonin output from cultured chick pineal cells.
Chick pineal cells maintained in primary culture display a circadian rhythm of melatonin production and release, and the nocturnal increase in melatonin output is enhanced by elevating extracellular K+. The divalent cations, Co2+, Cd2+, and Mn2+, each reduce nocturnal melatonin output. Nitrendipine and nifedipine also prevent the nocturnal rise in melatonin output, while Bay K 8644 increases it, suggesting a role for voltage-dependent Ca2+ channels in regulating melatonin output. The whole-cell patch-clamp technique was used to record from individual chick pineal cells. Under conditions designed to isolate currents through voltage-dependent Ca2+ channels, biphasic inward currents are elicited by large depolarizing commands (e.g., to 0 mV) from a holding potential of -90 mV; from a holding potential of -40 mV, only a sustained inward current is elicited by steps to 0 mV. Both components of the inward current are blocked by Co2+ or Cd2+. The sustained current is increased in amplitude by Bay K 8644 and blocked by nifedipine, while the transient current is unaffected. Since there is no evidence for vesicular release of melatonin, the "L-type" calcium channels mediating the sustained calcium current appear to be involved in the pathways regulating melatonin synthesis in chick pineal cells.
Animals↗
Does calcium influx regulate melatonin production through the circadian pacemaker in chick pineal cells? Effects of nitrendipine, Bay K 8644, Co2+, Mn2+, and low external Ca2+.
We have recently described a system, using dispersed chick pineal cells in static culture, which displays a persistent, photosensitive, circadian rhythm of melatonin production and release. Here, we describe the effects of nitrendipine (NTR) (a dihydropyridine 'antagonist' of L-type calcium channels), Bay K 8644 (BK) (a dihydropyridine calcium channel 'agonist'), cobalt and manganese ions (both inorganic calcium channel blockers), and low external calcium concentrations, on the melatonin rhythm. NTR inhibited and BK stimulated melatonin output; they were potent and effective. Co2+, Mn2+, and low external Ca2+ markedly inhibited melatonin output. These results support a role for calcium influx through voltage-dependent calcium channels (L-type) in the regulation of melatonin production. Four or 8 h pulses of white light or darkness, in otherwise constant red light, cause, in addition to acute effects, phase-dependent phase shifts of the melatonin rhythm in subsequent cycles. Such phase shifts indicate an effect on (proximal to) the pacemaker generating the rhythm. Four or 8 h pulses of NTR, BK, Co2+, or low Ca2+, however, did not appreciably alter the phase of subsequent melatonin cycles. Neither did BK interfere with phase shifts induced by light pulses. Mn2+ pulses did induce phase-dependent phase shifts, but, unlike those evoked by light or dark pulses, these were all delays. Such effects of Mn2+ in other systems have been attributed to, and are characteristic of, 'metabolic inhibitors'. On balance, the results fail to support a prominent role for calcium influx in regulating the pacemaker underlying the circadian rhythm in chick pineal cells. Rather, calcium influx appears to regulate melatonin production primarily by acting on the melatonin-synthesizing apparatus, distal to the pacemaker.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Photoendocrine transduction in cultured chick pineal cells. II. Effects of forskolin, 8-bromocyclic AMP, and 8-bromocyclic GMP on the melatonin rhythm.
We have recently described a system, using dispersed chick pineal cells in static culture, which displays a persistent, photosensitive, circadian rhythm of melatonin release, and the effects of light and darkness upon it. Here, we describe the effects of forskolin (FSK), a specific activator of adenylate cyclase, 8-bromocyclic AMP (8BrcA), an analogue of cyclic AMP, and 8-bromocyclic GMP (8BrcG), an analogue of cyclic GMP, on melatonin output by these cells. FSK stimulated melatonin output; it was potent and effective. 8BrcA, but not 8BrcG, also markedly stimulated melatonin output. These results support a role for cAMP (but not cGMP) in the regulation of melatonin production. Four hour pulses of white light or darkness, in otherwise constant red light, cause, in addition to acute effects, phase-dependent phase shifts of the melatonin rhythm in subsequent cycles. Such phase shifts indicate an effect on (proximal to) the pacemaker generating the rhythm. Four or 8 hour pulses of FSK, 8BrcA, or 8BrcG, however, did not appreciably alter the phase of subsequent melatonin cycles. Neither did they interfere with phase shifts induced by light pulses. These results fail to support a prominent role for cAMP or cGMP levels in regulating the pacemaker; nor do these cyclic nucleotides appear to mediate the prominent effects of light and dark on the pacemaker. Thus, cyclic AMP regulation of melatonin appears to occur distal to the pacemaker.
8-Bromo Cyclic Adenosine Monophosphate↗
Two mechanisms of photoendocrine transduction in cultured chick pineal cells: pertussis toxin blocks the acute but not the phase-shifting effects of light on the melatonin rhythm.
We have recently described a system, using dispersed chick pineal cells in static culture, which displays a persistent, photosensitive, circadian rhythm of melatonin release. Light has two apparent effects on this melatonin rhythm: the first is an acute inhibition of melatonin output, the second is entrainment of the underlying pacemaker. These two effects could be mediated by the same or different mechanisms. Pertussis toxin, which acts to block the function of transducin and certain other G-proteins, blocked the acute effects of light on chick pineal cells, but not the ability of light pulses to induce phase-dependent phase shifts of the rhythm. There must, therefore, be at least two mechanistic pathways by which light affects chick pineal melatonin production. Transducin or other pertussis toxin-sensitive G-proteins would appear to be involved in the acute effects of light on the melatonin-synthesizing apparatus, but not in the effects of light on the circadian pacemaker which generates the melatonin rhythm. Some plausible pertussis toxin-sensitive mechanisms are discussed.
Animals↗
Norepinephrine, acting via adenylate cyclase, inhibits melatonin output but does not phase-shift the pacemaker in cultured chick pineal cells.
We have recently described a system, using dispersed chick pineal cells in static culture, which displays a persistent, photosensitive, circadian rhythm of melatonin release, and the effects of light upon it. Here we describe the effects of norepinephrine (NE) on melatonin output by these cells. NE inhibited nocturnal melatonin release; it was potent and effective. Pertussis toxin, forskolin, or 8-Br-cAMP blocked or circumvented inhibition by NE, suggesting the involvement of adenylate cyclase. Four hour pulses of NE caused acute suppression of melatonin output, but did not affect the phase of subsequent cycles in constant red light. These results indicate that NE affects melatonin production by mechanisms acting distal to the pacemaker which generates the melatonin rhythm. Insofar as adenylate cyclase appears to be involved in the action of NE, it might be involved in the regulation of melatonin output by the pacemaker, but is not implicated in regulation of the pacemaker by light.
8-Bromo Cyclic Adenosine Monophosphate↗
Photoendocrine transduction in cultured chick pineal cells: effects of light, dark, and potassium on the melatonin rhythm.
Several laboratories have demonstrated the persistence of photosensitive rhythms related to melatonin secretion in cultured chick pineals. We describe here a system using dispersed chick pineal cells in static culture, which displays a rhythm of melatonin release for at least two weeks under cyclic lighting conditions, and for at least 4 cycles under constant red light. Using a rapid and specific extraction assay for the [14C]melatonin formed (from [14C]tryptophan) and secreted by these cells, we have examined the effects of perturbations (light, dark, and potassium) on the amplitude, period, and phase of the melatonin rhythm. The period in constant red light was close to 20 h, but in constant white light (or 12:12 cycles) it was closer to 24 h. Four-hour pulses of white light (in otherwise constant red light) caused an acute fall in melatonin output, and phase-dependent phase shifts of the rhythm relative to controls. Pulses of darkness (in otherwise constant red light) tended to increase melatonin output, and caused phase-dependent phase shifts. Elevated potassium concentrations increased melatonin output and the amplitude of the rhythm, but did not change the period. Four-hour pulses of low (5.4 mM) potassium (in otherwise constant high potassium) mimicked the acute effect of light, reducing melatonin output, but did not induce appreciable phase shifts. Changes in membrane potential appear more likely to be involved in the regulation of melatonin output (and thus be regulated by the pacemaker) than to be involved in regulation of the pacemaker which generates the melatonin rhythm.
Animals↗