David F. Nutting

Parathyroid Ablation in Dystrophic Hamsters: EFFECTS ON CA CONTENT AND HISTOLOGY OF HEART, DIAPHRAGM, AND RECTUS FEMORIS

Cumulative evidence indicates that there is an increased accumulation of calcium in dystrophic muscle and that this may have a pathophysiological role in the progression of the dystrophic process. The accumulation may be related to a defect of the plasma membrane. Because parathyroid hormone (PTH) stimulates calcium influx into the cytosol, the chronic effects of surgical ablation of the parathyroid glands on muscle Ca, Mg, protein synthesis, and histology, as well as plasma creatine phosphokinase (CPK), Ca, and Mg, were studied in normal and dystrophic (BIO 14.6) hamsters. Thyroparathyroidectomized (TPTX) hamsters receiving replacement doses of l-thyroxine were killed at age 90 d, 55 d after TPTX. In intact dystrophic hamsters, the Ca content in the heart was 20 times higher than in normal animals and was reduced by half in TPTX dystrophic hamsters. Similar results were observed in diaphragm and rectus femoris. No abnormalities in Mg content were observed in intact or TPTX dystrophic hamsters. Ether-extractable fat of the heart and diaphragm was reduced in dystrophic hamsters and was not modified by TPTX. Protein synthesis was enhanced in the diaphragm of dystrophic hamsters but was not changed by TPTX. The concentration of CPK in plasma was elevated in dystrophic hamsters and fell significantly after TPTX. In the latter animals, microscopic examination of the heart showed lesser signs of dystrophy, particularly in the degree of fibrosis. To determine the degree of dystrophy at the age when TPTX was performed, identical analyses were made in 35-d-old hamsters. Definitive histological signs of dystrophy were observed, and although the Ca content in heart, diaphragm, and rectus femoris was elevated, the values were lower than in 90-d-old intact and TPTX dystrophic hamsters. This indicates that chronic TPTX in dystrophic hamsters reduces, but does not arrest, the dystrophic process. In normal hamsters, a 50% reduction in plasma Ca concentration was observed 6 h after TPTX; 55 d after TPTX, however, plasma Ca was within normal limits in both normal and dystrophic hamsters. No parathyroid tissue was observed in serial sections of the trachea and adjacent tissues in TPTX animals. This suggests that in chronically TPTX hamsters fed a standard laboratory diet, plasma Ca can be maintained by mechanisms independent of parathyroid function. THE DATA INDICATE THAT IN DYSTROPHIC HAMSTERS TPTX CAUSES A MARKED REDUCTION IN: (a) muscle Ca accumulation, (b) levels of plasma CPK and, (c) intensity of histological changes in the heart. These changes were independent of the levels of plasma Ca and were not observed in normal hamsters. We conclude that PTH accentuates the dystrophic process, probably by enhancing the already increased Ca flux into muscle (apparently caused by defective sarcolemma). We postulate that normal secretion of PTH may have a deleterious effect in congenital or acquired conditions associated with altered plasma membranes.

Effect of chronic treatment with the calcium antagonist diltiazem in Duchenne muscular dystrophy.

We conducted a double-blind trial with the calcium antagonist, diltiazem (8 mg/kg/d), for 24 to 32 months in 22 boys with Duchenne muscular dystrophy, who were paired by functional activity and age. No adverse clinical or ECG effects of diltiazem were detected. In eight matched pairs, completing 28 months, manual muscle testing scores fell somewhat less in the diltiazem group (from 5.5 to 4.6) than in the placebo group (from 5.3 to 4.2), although the difference between groups was not significant (p = 0.06). The 95% confidence interval for the difference in slopes of regression lines obtained from trimonthly manual muscle tests on all subjects was markedly asymmetric in favor of the diltiazem group, but this difference was also not significant. There was less deterioration of functional activity of lower extremities in the diltiazem-treated group, when beginning and end values were analyzed (p = 0.03). However, the difference in slopes of regression lines obtained from trimonthly determinations was nonsignificant. Similarly, the beginning versus end comparisons of systolic and diastolic blood pressure showed a significantly (p < 0.05) smaller elevation of blood pressure in the diltiazem-treated group, but no difference was observed when the slopes of all values were analyzed. All other clinical and laboratory variables were unaffected by diltiazem treatment. The findings in manual muscle tests and functional activity suggest a beneficial trend with chronic diltiazem treatment in DMD.

Hormonal alterations of the sensitivity of amino acid transport to growth hormone in muscle of young rats.

Summary The ability of growth hormone in vitro to stimulate amino acid and sugar uptake by diaphragm muscle from normal rats declines from age 15 days to age 30 days. In 15-day-old intact rats, as in older, hypophysectomized rats, GH has a biphasic effect on amino acid transport: a transient stimulatory phase, followed by a period of refractoriness to stimulation by additional GH. It appears that after age 15 days the refractoriness phase becomes progressively dominant. GH actions are not affected by prolactin or by adrenalectomy. However, during midlactation, exogenous glucocorti-coid may reduce refractoriness, thus enhancing the response to additional GH.

Octreotide Enhances Positive Calcium Balance in Duchenne Muscular Dystrophy

ABSTRACT: Although receptors for somatostatin are found in bone cells, the effect of somatostatin analogs on calcium metabolism is unknown. The authors studied, in a metabolic ward, the effect of octreotide (a long‐acting somatostatin analog) and a placebo in two 6‐day calcium balance periods in 8 children with Duchenne muscular dystrophy. As expected, octreotide (2 &mgr;g/kg, subcutaneously, every 8 hours) reduced serum growth hormone and somatomedin (IGF‐1) to levels found in growth hormone deflciency. Octreotide enhanced calcium retention by 30% (96 mg daily [P < 0.04]) in 7 boys for whom complete data (diet, urine, and fecal calcium) were available. In 6 children with urinary calcium excretion (UCa) greater than 50 mg daily, octreotide markedly lowered UCa, from 114 ± 23 mg daily to 61 ± 9 mg daily (P < 0.03). Calcium retention occurred in patients with or without initial hypercalciuria, but the higher the basal UCa, the greater was the inhibition by octreotide (r = 0.79; P < 0.03). Inactive, nonambulatory patients had a more pronounced response of UCa to octreotide (P < 0.02). Octreotide caused a mild, nonsignificant reduction in fecal calcium, with no major changes in serum calcium, phosphorus, parathyroid hormone, urinary excretion of sodium and potassium, or in creatinine clearance. Based on the current observations and the presence of receptors for somatostatin in bone cells, this hormone may have, at least on a short‐term basis, an anabolic effect on calcium, perhaps favoring its deposition in bone.

Cyclosporine and Duchenne muscular dystrophy

meningeal and cerebral involvement. The subacute meningitis and brainstem parenchymal disease preceded multisystem disease, including bilateral chorioretinitis, by several months. A biopsy of the meninges was not done, so we could only assume that his brainstem and meningeal disease was due to WG. After consultation with Dr. Anthony Fauci a t the NIH, this patient was treated with cyclophosphamide/prednisone and made an excellent clinical recovery. We believe our report is the first showing reversal of meningeal disease in WG with immunosuppressive therapy. Our patient has had no recurrence of his granulomatous disease although he has persistent mild neurologic findings and is blind in one eye. He ultimately developed a seizure disorder, but sophisticated imaging studies, not available in the mid-l970s, revealed no new disease.

Parathyroid Hormone in Muscular Dystrophy

Fifty years ago, Houssay showed that pituitary ablation ameliorates the hyperglycemia of pancreatectomized dogs.1 This approach was later applied to human diseases, such as diabetes mellitus and cancer. A conclusion of those studies is that under certain circumstances, hormones secreted in normal amounts may be deleterious in human disease. In this presentation we will discuss the role that normally functioning parathyroid glands may have in muscular dystrophy.