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S J Marx

Publications and source records attributed to S J Marx.

At least 127 records · Page 7Linked to original sources
PubMed1986

Parathyroid mitogenic activity in plasma from patients with familial multiple endocrine neoplasia type 1.

Hyperplasia of the parathyroid glands is a central feature of familial multiple endocrine neoplasia type 1. We used cultured bovine parathyroid cells to test for mitogenic activity in plasma from patients with this disorder. Normal plasma stimulated [3H]thymidine incorporation, on the average, to the same extent as it was stimulated in a plasma-free control culture. This contrasted with the results of the tests with plasma from patients with familial multiple endocrine neoplasia type 1, in which parathyroid mitogenic activity increased 2400 percent over the control value (P less than 0.001). Plasma from these patients also stimulated the proliferation of bovine parathyroid cells in culture, whereas plasma from normal subjects inhibited it. Parathyroid mitogenic activity in plasma from the patients with familial multiple endocrine neoplasia type 1 was greater than that in plasma from patients with various other disorders, including sporadic primary hyperparathyroidism (with adenoma, hyperplasia, or cancer of the parathyroid), sporadic primary hypergastrinemia, sporadic pituitary tumor, familial hypocalciuric hypercalcemia, and multiple endocrine neoplasia type 2 (P less than 0.05). Parathyroid mitogenic activity in the plasma of patients with familial multiple endocrine neoplasia type 1 persisted for up to four years after total parathyroidectomy. The plasma also had far more mitogenic activity in cultures of parathyroid cells than did optimal concentrations of known growth factors or of any parathyroid secretagogue. This mitogenic activity had an apparent molecular weight of 50,000 to 55,000. We conclude that primary hyperparathyroidism in familial multiple endocrine neoplasia type 1 may have a humoral cause.

Adenoma↗
PubMed1986

Antibodies cytotoxic to bovine parathyroid cells in autoimmune hypoparathyroidism.

We utilized a recently developed long-term serum-free culture system for bovine parathyroid cells to detect antibodies in seven patients with autoimmune hypoparathyroidism (AHP). Antibodies were tested by indirect immunofluorescence methods and by cytotoxicity utilizing the chromium (51Cr) release technique. Seven AHP sera caused specific lysis [57 +/- 6% release of 51Cr vs. 5 +/- 1% for 56 controls (15 normal subjects and 41 patients with diverse other conditions associated with immune dysfunction)]. The least effect of any of the AHP sera on cell lysis exceeded the greatest effect of any of the control sera. Absorption of AHP sera (two cases) with bovine pituitary, thyroid, liver, or kidney cells did not affect lysis, but absorption with adrenal or parathyroid cells caused a marked decrease in specific lysis. Cytotoxicity determined by 51Cr release increased with antiserum concentration and time of incubation. Cytotoxicity was dependent on complement. Replicating parathyroid cells provide a uniform reproducible detection method for anti-parathyroid antibodies in AHP. The autoantibodies in AHP appear to be specific for tissue (parathyroid and adrenal cortex) but not for species.

Adrenal Cortex↗
PubMed1986

Analysis of the relation between alopecia and resistance to 1,25-dihydroxyvitamin D.

Alopecia is a frequent feature in hereditary resistance to (1,25(OH)2D). We sought insight into this feature by analysing data from affected members of 30 kindreds. We assessed indices of mineral metabolism in one group with normal hair compared with a group with alopecia. Hereditary resistance to 1,25(OH)2D was diagnosed at an earlier age in alopecic patients (0.9 vs 3.3 years, P less than 0.05); this reflected late presentation of metabolic bone disease in some cases with normal hair and could not be attributed to early diagnosis resulting from the striking feature of alopecia. For untreated subjects, serum concentrations of calcium and 1,25(OH)2D were similar in both groups of patients. During calciferol therapy, however, the cases with alopecia showed lower serum calcium (1.9 vs 2.4 mmol/l, P less than 0.005), but higher serum 1,25(OH)2D (2900 v 340 pg/ml, P less than 0.005). Hair status did not predict the type of defect identified with cultured skin fibroblasts but did correlate with responsiveness of 25(OH)D 24-hydroxylase to 1,25(OH)2D3 in those cells. Cells from seven of eight kindreds with alopecia showed no 24-hydroxylase response to high doses of 1,25(OH)2D3 while cells from five of six kindreds with normal hair showed a 24-hydroxylase response to high doses of 1,25(OH)2D3. We conclude that in cases with hereditary resistance to 1,25(OH)2D alopecia reflects the more severe grades of this resistance based upon earlier age at time of diagnosis, lower potential for calcaemic response to calciferols, and lower potential for 24-hydroxylase response to 1,25(OH)2D3 by cultured skin fibroblasts.

Alopecia↗
PubMed1986

Receptor-positive hereditary resistance to 1,25-dihydroxyvitamin D: chromatography of hormone-receptor complexes on deoxyribonucleic acid-cellulose shows two classes of mutation.

We used cultured skin fibroblasts from patients with hereditary resistance to 1,25-dihydroxyvitamin D [1,25-(OH)2D] and normal hormone binding to soluble extract from cells [i.e. receptor-positive resistance to 1,25-(OH)2D] to characterize DNA binding of the receptor for 1,25-(OH)2D. Occupied receptor was generated by incubating soluble extracts from cells with [3H]1,25-(OH)2D3; occupied receptor was applied to columns of DNA-cellulose and then eluted with linear gradients of KCl. Occupied receptors of cells from other sources eluted as a single peak at 0.20-0.26 M KCl; this elution pattern was independent of tissue (skin, breast cancer, or osteosarcoma) or species (human or rat) of origin of the receptors. With cells from two kindreds in whom there was mildly decreased localization of the hormone-receptor complex to the nucleus in vitro, occupied receptor interacted abnormally with DNA-cellulose (elution at 0.09-0.13 M KCl vs. normal at 0.20-0.26 M KCl); this suggested mutation(s) that affected a DNA-binding domain of the receptor in these two kindreds. With receptor-positive cells from two other kindreds in whom there was unmeasurable hormone localization to the nucleus, the elution pattern of occupied receptors from DNA-cellulose was normal; this suggested mutation(s) which did not affect the same DNA-binding site. We conclude that our demonstration of two distinct elution profiles from DNA-cellulose reflects two independent classes of mutation, either of which can cause receptor-positive resistance to 1,25-(OH)2D.

Animals↗
PubMed1986

Secretory dysfunction in parathyroid cells from a neonate with severe primary hyperparathyroidism.

We report a patient with neonatal severe primary hyperparathyroidism whose parathyroid cells were markedly refractory to regulation by calcium in vitro. He showed life-threatening hypercalcemia (4.8-5.2 mM vs. normal of 2.1-2.7 mM). A sibling had been treated previously for an identical disorder. At age 6.5 months, four hyperplastic parathyroid glands were removed, and portions of one were immediately grafted into the forearm. Serum calcium again became elevated post-operatively and then fall to the normal range after excision of grafted parathyroid tissue. Dispersed parathyroid cells from the first operation showed no suppression of PTH secretion by 2 mM calcium; however, there was normal maximal suppressibility at 4 mM calcium with half-maximal suppression at 2.53 mM (the calcium set point). This contrasts with much lower set points previously established for suppressible cells from normal (1.02 +/- 0.10 mM, mean +/- 1 SD), from primary hyperplastic (1.10 +/- 0.14 mM), or from adenomatous (1.26 +/- 0.14 mM) parathyroid glands. The strikingly high set point may not be unique because a small number of glands previously classified as nonsuppressible (by the criterion of failing to suppress below 50% maximum at calcium concentration up to 2-3 mM) might have shown similarly high set points if tested at higher calcium concentrations. We conclude that an unusual abnormality of PTH secretory control accounts, in large part, for both the marked hypercalcemia and for its refractoriness to surgical treatment in this patient.

Calcium↗
PubMed1986

Severely deficient binding of 1,25-dihydroxyvitamin D to its receptors in a patient responsive to high doses of this hormone.

A 1.6-yr-old Hispanic boy with sparse hair, muscle weakness, severe growth retardation, and rickets was found to have hypocalcemia, secondary hyperparathyroidism, and high circulating 1,25-dihydroxyvitamin D [1,25-(OH)2D] levels. One year of treatment with a high dose of 1,25-(OH)2D3 (20 micrograms, orally, daily) resulted in marked subjective and radiological improvement; there was a parallel improvement in serum calcium, phosphorus, PTH, alkaline phosphatase, and osteocalcin concentrations. Soluble extracts from cultured skin fibroblasts did not bind [3H]1,25-(OH)2D3 using standard methods. To evaluate the possibility of receptors with abnormally low affinity, we tested for binding with [3H]1,25-(OH)2D3 concentrations higher than those usually used. In one experiment, there was a suggestion of low affinity binding. Hormone receptors with abnormally low affinity for 1,25-(OH)2D may explain this patients resistance to 1,25-(OH)2D. Therapy to maintain extremely high serum 1,25-(OH)2D3 concentrations markedly improved mineral homoeostasis, but did not affect the hair disorder.

Calcitriol↗
PubMed1986

Multiple endocrine neoplasia type I: assessment of laboratory tests to screen for the gene in a large kindred.

We measured multiple components of serum or plasma in 221 members of a kindred with familial multiple endocrine neoplasia type 1 (FMEN1). The kindred showed typical features of FMEN1; the FMEN1 gene could be traced through 7 generations with 74 members identifiable as gene carriers. Between family screening in 1981 and completion of our study in 1985, we identified 16 previously unscreened members as carriers of the FMEN1 gene. The earliest age at diagnosis of FMEN1 was 17. The tests with the greatest yield of abnormal results among carriers of the FMEN1 gene were albumin-adjusted calcium, PTH, gastrin, and (in females) prolactin. The following tests provided little or no use in identifying carriers: prolactin (in males), pancreatic polypeptide, glucagon, glicentin, insulin, growth hormone, motilin, and somatostatin. Primary hyperparathyroidism was the commonest expression of the FMEN1 gene; the gene penetrance for this trait increased from near 0% before age 15 to near 100% after age 40. It appeared prior to development of serious morbidity from hypergastrinemia or hyperprolactinemia. All 42 co-operating members who were alive and expressing the FMEN1 gene in 1984 showed active or treated primary hyperparathyroidism. Primary hypergastrinemia had a prevalence below half of that for primary hyperparathyroidism at all ages and was not diagnosed in the absence of primary hyperparathyroidism. Primary hyperprolactinemia was still less prevalent than primary hypergastrinemia. It was limited almost exclusively to females.

Adolescent↗
PubMed1985

Low affinity of the receptor for 1 alpha,25-dihydroxyvitamin D3 in the marmoset, a New World monkey.

Circulating levels of 1,25-dihydroxyvitamin D are 10-fold higher in the marmoset, a New World monkey, than in man; to assess hormone receptors, we evaluated interactions of 1,25-dihydroxyvitamin D3 with virus-transformed lymphocytes. Soluble extracts of transformed lymphocytes from humans showed hormone binding with affinity and capacity similar to that of receptors for 1,25-dihydroxyvitamin D from other human tissues. However, soluble extracts of transformed lymphocytes from the marmoset showed a strikingly lower affinity for 1,25-dihydroxyvitamin D (Kd 2.2 vs 0.27 nM in marmoset vs human) and a mildly lower binding capacity (6.9 vs 16 fmol/mg protein). A defective receptor for 1,25-dihydroxyvitamin D3 could account for resistance of target tissues to this hormone in the marmoset.

Animals↗
PubMed1985

Radioimmunoassay for the middle region of human parathyroid hormone: comparison of two radioiodinated synthetic peptides.

Two synthetic peptides were evaluated to develop radioligands for midregion-specific radioimmunoassay (RIA) of human parathyroid hormone (hPTH). Both contained the 44-68 sequence of hPTH (no tyrosine residues); one contained a tyrosine residue added to the amino-terminus, (Tyr43)hPTH(43-68). The purified radioligands showed similar chemical properties (stability to storage, efficient phase separation with dextran-coated charcoal, low adsorption to glassware). Both radioligands were tested using three anti-PTH sera of proven clinical utility. While each of these midregion-directed antisera showed unique specificity, they all reacted with high affinity with both radioligands and none of them discriminated significantly between the two synthetic midregion peptides. 125I-(Tyr43)hPTH(43-68) gave RIAs that were 15-50% more sensitive to hPTH(1-84) and the unlabelled synthetic midregion peptides than RIAs using 125I-hPTH(44-68) with all three antisera examined. 125I-(Tyr43)hPTH(43-68) was more susceptible than 125I-hPTH(44-68) to degradation from plasma or serum; this susceptibility was reduced by the peptidase inhibitor aprotinin (500 KIU/ml). Simultaneous RIAs of a series of patient plasmas using either of the two radioligands with antiserum NG5/5 produced indistinguishable discrimination between samples (r = 0.984). Analysis of data on the relation of serum calcium and hPTH midregion immunoreactivity showed a useful separation hyperparathyroidism, primary hypoparathyroidism and secondary hypoparathyroidism.

Amino Acid Sequence↗
PubMed1985

Primary hyperparathyroidism in familial multiple endocrine neoplasia type I. Long-term follow-up of serum calcium levels after parathyroidectomy.

Serum calcium levels were analyzed after one or more explorations for primary hyperparathyroidism in familial multiple endocrine neoplasia type I. These data covered all 85 operations (performed in many hospitals) on 61 of 62 members from 14 kindreds. After 61 initial operations, there were high rates of persistent or recurrent hypercalcemia (54 percent) and chronic hypocalcemia (10 percent). These rates contrast with lower postoperative rates of hypercalcemia (4 to 16 percent) or chronic hypocalcemia (1 to 8 percent) in large series of primary hyperparathyroidism. Persistent or recurrent hypercalcemia after initial exploration decreased only modestly in patients who underwent surgery after 1975 versus before 1975 (46 versus 63 percent). The rate for long-term remission of hypercalcemia after initial parathyroidectomy was higher after a diagnosis of parathyroid hyperplasia was made (as opposed to adenoma) (57 versus 30 percent, p less than 0.05) and after removal of three or more glands (as opposed to removal of two and a half or less) (70 versus 34 percent, p less than 0.01). Following 24 reoperations, there were also high rates of persistent or recurrent hypercalcemia (46 percent) and chronic hypocalcemia (25 percent). After surgery in unselected patients with primary hyperparathyroidism, recurrent hypercalcemia (as opposed to persistent hypercalcemia) is distinctly uncommon; however, it was frequent in familial multiple endocrine neoplasia type I, with total recurrences increasing from 21 percent at five years to 41 percent at 10 years in patients who showed a normocalcemic interval after surgery. The data indicate that the occurrence of persistent or recurrent hypercalcemia after parathyroidectomy in familial multiple endocrine neoplasia type I remains frequent. Although recurrent hypercalcemia may be characteristic of the response to any technique of parathyroidectomy in familial multiple endocrine neoplasia type I and not preventable, persistent hypercalcemia can be decreased by preoperative recognition of the specific familial cause, involvement of an experienced surgical team, and histologic confirmation of the identification of three or more parathyroid glands.

Actuarial Analysis↗
PubMed1985

Familial hypocalciuric hypercalcemia. Mild expression of the gene in heterozygotes and severe expression in homozygotes.

Autosomal dominant familial hypocalciuric hypercalcemia was found in a kindred with neonatal severe primary hyperparathyroidism, previously judged to be an autosomal recessive trait. Mild hypercalcemia was documented in eight members representing three generations. Mild hypercalcemia was documented at an age as early as one week. In seven adults presumed to be heterozygotes, urinary calcium levels were in the same range as for familial hypocalciuric hypercalcemia. An additional adult member (who previously underwent parathyroidectomy for neonatal severe primary hyperparathyroidism) showed an abnormality in renal clearance of calcium and sodium characteristic of combined familial hypocalciuric hypercalcemia and surgical hypoparathyroidism. Parathyroidectomy in three hypercalcemic members did not cause normocalcemia. Unlike other kindreds with familial hypocalciuric hypercalcemia in whom hypercalcemia is consistent over time and moderate in heterozygotes, this kindred was characterized by heterozygotes showing hypercalcemia that was intermittent and mild. The consanguineous parents of the two previously described severely affected neonates were judged to be heterozygotes for familial hypocalciuric hypercalcemia. In conclusion, (1) a gene presenting as familial hypocalciuric hypercalcemia can be expressed as hypercalcemia that is intermittent and very mild in heterozygotes; (2) such a gene can cause neonatal severe primary hyperparathyroidism in homozygotes.

Adolescent↗
PubMed1985

Parathyroid gland morphology in nonparathyroid hormone-mediated hypercalcemia.

Occasionally, patients with other causes of hypercalcemia undergo parathyroidectomy for suspected primary hyperparathyroidism. We studied the parathyroid glands from 12 persons with nonparathyroid hypercalcemia. Glands from these individuals were similar to normal glands in size and fat:parenchymal ratio, showing neither atrophy nor hyperplasia. A distinctive histologic feature, also seen in hyperparathyroid hypercalcemia, is the presence of pale, vacuolated cells arranged in a trabecular pattern. Recognition of normal parathyroid parenchymal weight and the nonspecific nature of these vacuolated cells is necessary to prevent false-positive diagnoses of parathyroid hyperplasia. For glands which have not been weighted, parenchymal cross-sectional area can only be used as a rough index of parenchymal weight.

Adult↗
PubMed1985

Parathymic parathyroid: CT, US, and angiographic findings.

Six patients with primary hyperparathyroidism caused by an undescended parathymic adenoma are described. All glands were anterior to the common carotid artery at the level of the hyoid bone. Blood supply was from the superior thyroid artery, and venous drainage was into the superior thyroid vein. Ultrasound (one of five) and computed tomography (two of six) were rarely positive, but glands can be detected with both modalities if the examination is carried high enough. Glands within the carotid sheath are generally lower in the neck and have a blood supply from the inferior thyroid artery with drainage into the vertebral veins.

Adenoma↗
PubMed1985

Vitamin D-dependent rickets type II. Defective induction of 25-hydroxyvitamin D3-24-hydroxylase by 1,25-dihydroxyvitamin D3 in cultured skin fibroblasts.

UNLABELLED: 1,25(OH)2D3 induces 25(OH)D3-24-hydroxylase (24-OHase) in cultured skin fibroblasts from normal subjects. We evaluated 24-OHase induction by 1,25(OH)2D3 in skin fibroblasts from 10 normal subjects and from four unrelated patients with hereditary resistance to 1,25(OH)2D or vitamin D-dependent rickets type II (DD II). Fibroblasts were preincubated with varying concentrations of 1,25(OH)2D3 for 15 h and were then incubated with 0.5 microM [3H]25(OH)D3 at 37 degrees C for 30 min; lipid extracts of the cells were analyzed for [3H]24,25(OH)2D3 by high performance liquid chromatography and periodate oxidation. Apparent maximal [3H]24,25(OH)2D3 production in normal cell lines was 9 pmol/10(6) cells per 30 min and occurred after induction with 10(-8) M 1,25(OH)2D3. 24-OHase induction was detectable in normal fibroblasts at approximately 3 X 10(-10) M 1,25(OH)2D3. [3H]24,25(OH)2D3 formation after exposure to 1,25(OH)2D3 was abnormal in fibroblasts from all four patients with DD II. In fibroblasts from two patients with DD II, [3H]24,25(OH)2D3 formation was unmeasurable (below 0.2 pmol/10(6) cells per 30 min) at 1,25(OH)2D3 concentrations up to 10(-6) M. Fibroblasts from the other two patients with DD II required far higher than normal concentrations of 1,25(OH)2D3 for detectable [3H]24,25(OH)2D3 induction. In one, [3H]24,25(OH)2D3 production reached 2.9 pmol/10(6) cells per 30 min at 10(-6) M 1,25(OH)2D3 (30% normal maximum at 10(-6) M 1,25(OH)2D3). In the other, [3H]24,25(OH)2D3 production achieved normal levels, 7.3 pmol/10(6) cells per 30 min after 10(-6) M 1,25(OH)2D3. The two patients whose cells had a detectable 24-OHase induction by 1,25(OH)2D3 showed a calcemic response to high doses of calciferols in vivo. Our current observations correlate with these two patients' responsiveness to calciferols in vivo and suggest that their target organ defects can be partially or completely overcome with extremely high concentrations of 1,25(OH)2D3. The two patients whose cells showed no detectable 24-OHase induction in vitro failed to show a calcemic response to high doses of calciferols in vivo. IN CONCLUSION: (a) the measurement of 24-OHase induction by 1,25(OH)2D3 in cultured skin fibroblasts is a sensitive in vitro test for defective genes in the 1,25(OH)2D effector pathway. (b) This assay provides a useful tool for characterizing the target tissue defects in DD II and predicting response to calciferol therapy.

Alopecia↗