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Biomedical subjects

J R Shapiro

Publications and source records attributed to J R Shapiro.

At least 91 records · Page 5Linked to original sources
PubMed1985

Diminished type I collagen synthesis and reduced alpha 1(I) collagen messenger RNA in cultured fibroblasts from patients with dominantly inherited (type I) osteogenesis imperfecta.

Type I osteogenesis imperfecta (OI) is characterized clinically by a moderate fracture frequency with minimal bone deformity and dominant inheritance. Previous studies of the collagenous proteins synthesized by dermal fibroblasts obtained from unrelated patients with this form of OI suggested that the biochemical basis of the disease was reduced production of type I collagen. This study was designed to determine if this biochemical finding segregated with the disease within an individual family. Dermal fibroblast strains were established from three generations of a family having the typical features of type I OI. Analysis of the collagenous proteins made in culture revealed an elevated alpha 1(III) to alpha 1(I) collagen type ratio and an elevated alpha 1(I) to alpha 2(I) collagen chain ratio. The procollagen that accumulated in the medium reflected these ratios to the same degree. Total collagen synthesis was significantly reduced in affected family members. Therefore, the most striking abnormality in affected members was a 50-75% reduction of type I collagen production. Furthermore, the ratio of the alpha 1(I)/alpha 2(I) collagen messenger RNA (mRNA), measured by dot hybridization, was one-half of the value of uninvolved family members and unrelated controls. Since the reduction in the production of type I collagen and the altered alpha 1(I)/alpha 2(I) mRNA ratio clearly segregated with affected individuals within this family, these biochemical measurements may be a useful genetic marker for type I OI.

Adult↗
PubMed1985

Correlation of ocular rigidity and blue sclerae in osteogenesis imperfecta.

A previous study of 16 patients and 16 controls had indicated that the mean ocular rigidity value was significantly lower in Osteogenesis Imperfecta (OI) patients than in normal controls (p = 0.001). These preliminary results have been confirmed in the present study of 46 patients and 53 controls where the difference in mean ocular rigidity between the patient and control group was statistically significant at the p less than 0.0001 level. Of particular interest was the inverse correlation between blueness of sclera and ocular rigidity in patients with OI. The establishment of such a relationship depended upon the availability of a larger sample size than had previously been examined.

Adolescent↗
PubMed1984

Vertebral body bone mineral content in hyperprolactinemic women.

Hyperprolactinemia with amenorrhea and galactorrhea generally has a benign clinical course without treatment. Prolonged amenorrhea due to early surgical castration or premature menopause is, however, associated with reduced bone mass and increased risk of fractures. Previous studies in hyperprolactinemic women suggested an association with decreased cortical bone density. To determine whether hyperprolactinemia is associated with reduced trabecular bone mineral, we studied 13 hyperprolactinemic women and matched normal women by quantitative computed tomographic scans of the vertebral bodies. No patient had taken bromocriptine and one patient had previously unsuccessful transsphenoidal surgery. Each patient was matched with a normal woman on the basis of race, age +/- 52 weeks, parity, exercise, tobacco use, oral contraceptive (OCP) use, and alcohol use. No subject was currently taking OCPs. Calcium, phosphorus, and protein intakes were estimated from a 3-day diet diary. The mean duration of amenorrhea was 98.9 +/- 79.7 (SD) months. The mean height, weight, serum 25-hydroxyvitamin D (25,OHD), serum 1,25 dihydroxyvitamin D [1,25(OH)2D] and daily intakes of calcium, phosphorus, and protein were not different. The bone mineral content for each patient fell within +/- SD of the mean of the normal subjects. The mean bone mineral content (mg K2HPO4 eq/ml) of the patients was 10% less than in the normal subjects (144.6 +/- 31.4 (SD) vs. 160.1 +/- 26.6, P less than 0.05). The slope of the regression of bone mineral content and age (mg K2HPO4 eq/ml X yr) was similar in patients (-2.4 +/- 1.1) and normal subjects (-2.3 +/- 1.0). We conclude that hyperprolactinemia is associated with reduced bone mineral content, but does not necessarily produce persistent acceleration of the age-related decline in bone density.

Adult↗
PubMed1983

Abnormal alpha 2-chain in type I collagen from a patient with a form of osteogenesis imperfecta.

Dermal fibroblasts in culture from a woman with a mild to moderate form of osteogenesis imperfecta synthesize two species of the pro alpha 2-chain of type I procollagen. One chain is normal. The abnormal chain has a slightly faster mobility than normal during electrophoresis in sodium dodecyl sulfate polyacrylamide gels. Analysis of cyanogen bromide peptides of the pro alpha-chain, the alpha-chain, and of the mammalian collagenase cleavage products of the pro alpha- and alpha-chains indicates that the abnormality is confined to the alpha 2(I)CB4 fragment and is consistent with loss of a short triple-helical segment. Type I collagen production was decreased, perhaps because the molecules that contained the abnormal chain were unstable, with a resultant alteration in the ratio of type III to type I collagen secreted into culture medium. Collagen fibrils in bone and skin had a normal periodicity but their diameters were 50% of control; the bone matrix was undermineralized. The structural abnormality in the alpha 2(I)-chain in this patient may affect molecular stability, intermolecular interactions, and collagen-mineral relationships that act to decrease the collagen content of tissues and affect the mineralization of bone.

Cells, Cultured↗
PubMed1983

Collagen genes and brittle bones.

The heritable diseases of connective tissue are caused by known or putative defects in the synthesis of collagens, proteoglycans, glycoproteins, or attachment proteins of the extracellular matrix. Abnormal synthesis of type I collagen has been reported in several clinical variants of osteogenesis imperfecta. Because clinical classification of these variants is limited by genetic heterogenity and variable expression, biochemical criteria should be used for precise definition of the variants. Newly recognized molecular defects in osteogenesis imperfecta include the diminished formation of type I collagen and alpha-1[I] messenger RNA; abnormal synthesis or faulty assembly of alpha-2[I]; deletion or insertion of base pairs in the gene for alpha-1[I] or alpha-2[I] and failure to secrete type I procollagen; and substitution of cysteine for glycine in the triple helix. These molecular defects are characteristic of several variants. However, the molecular lesion in most cases of severe osteogenesis imperfecta has not been identified; synthesis of type I collagen and alpha-1: alpha-2 chain ratios appears to be normal. Production of an alpha-1 trimer may represent one such lesion in severe disease.

Bone Diseases, Developmental↗
PubMed1983

Osteogenesis imperfecta and Paget's disease of bone. Biochemical and morphologic studies.

Osteogenesis imperfecta (OI) and Paget's disease of bone occurred in a patient whose brother has Paget's disease. Several other relatives have the dominant variety of OI. The familial occurrence of the two diseases is presumably due to chance and, to our knowledge, has not been previously reported. Examination of iliac crest bone biopsy specimens showed mild changes of both diseases in the proband. Electron microscopy of the bone collagen demonstrated type I collagen fibers, which are reduced in number, decreased in diameter, and stellate rather than smooth in outline. Three populations of collagen fibers were observed in the bone. The synthesis of type I collagen by dermal fibroblasts was diminished in the proband and affected relatives, but it was normal in the unaffected relatives. Since collagen fibers with a stellate outline have not been observed in OI bone, an intriguing question is the effect to the putative Paget agent (? viral) on collagen synthesis in OI.

Adult↗
PubMed1982

Hearing and middle ear function in osteogenesis imperfecta.

Fifty-five patients with osteogenesis imperfecta (OI) were studied to determine the extent to which the peripheral auditory mechanisms share in the connective tissue lesion. Ninety-two unaffected relatives and 43 control subjects were also studied. Subjects were divided into age groups younger than and older than 30 years. Hearing loss, most frequently sensorineural, occurred in 49% (younger than 30 years) and 94% (older than 30 years) of patients with OI. A sensorineural pattern of hearing loss, here considered characteristic of OI, was observed in 47% of OI subjects irrespective of age, in 42% of relatives, and 5% of controls. Middle ear analysis by tympanometry and acoustic reflex analysis indicates that, although some patients with OI have a still middle ear system similar to that seen in otosclerosis, the majority display absent acoustic reflexes and increased compliance of the middle ear with notched tympanograms suggestive of anomalous ossicular articulation. Similar findings in otherwise uninvolved relatives suggest a genetic basis for these defects.

Acoustic Impedance Tests↗
PubMed1982

Heterogeneous chemosensitivities of subpopulations of human glioma cells in culture.

Six karyotypically distinct clonal cell lines isolated from each of two freshly resected human malignant gliomas were examined for heterogeneity of morphology, in vitro growth rate, and chemosensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea and cis-diamminedichloroplatinum (II). Each clone was identified karyotypically as having come from the parent tumor. The karyotypic deviations were primarily numerical; chromosome numbers ranged from hypodiploid to near-tetraploid. Three morphological types were recognized: astrocyte-like; squamous-like; and fibroblast-like. The growth rates differed among the clones; the doubling times ranged from 48 to 84 hr in those from one tumor and from 72 to 252 hr in the other. Chemosensitivity was measured by cytotoxicity and/or colony-forming assay. In both assays and in both tumors, heterogeneity of chemosensitivity response to both drugs was demonstrated among the different clones from the same tumor. Dose-response curves from some clones differed statistically (log-probit analysis) from those of others, and when the curves were parallel, their 50% effective doses often differed. For the cytotoxicity assay, the 50% effective doses of BCNU ranged from 43 to 94 microgram/ml and for cis-diamminedichloroplatinum (II), from 29 to 340 microgram/ml. For the colony-forming assay, the 50% effective doses of 1,3-bis(2-chloroethyl)-1-nitrosourea ranged from 4.5 to 7.0 microgram/ml and for cis-diamminedichloroplatinum (II), from 0.35 to 1.40 microgram/ml. No correlation was evident between the chromosome number, morphology, growth rates, or chemosensitivities of the clones. These results identified heterogeneity of chemosensitivity among cellular subpopulations in human malignant gliomas.

Carmustine↗
PubMed1981

Low ocular rigidity in patients with osteogenesis imperfecta.

Sixteen patients with osteogenesis imperfecta (OI) have undergone a thorough eye examination. These patients had statistically significantly lower ocular rigidity measurements than a group of normal volunteers matched on age, sex, and refractive error. In addition, the corneal diameter and length of the eyeball was smaller in OI patients than that in controls. Possible correlations of low ocular rigidity with biochemical changes in scleral collagen await further investigation.

Adolescent↗
PubMed1975

Osteoporosis; evaluation of diagnosis and therapy.

Bone mineral content was determined in the radius of 29 osteoporotic patients by the photon absorption method. Mineral content was within the normal range in nine of 24 osteoporotic women. Ratios representing the bone mineral content in the proximal and distal areas of the radius did not distinguish osteoporotic subjects or patients with hyperparathyroidism from normal subjects. Ten osteoporotic women had mineral measurements during a two-year period while receiving placebo or an intake of 2,200 mg of phosphorus and 2,400 mg of calcium. No increase in radial mineral content was observed during this regimen or after adding vitamin D. We conclude that the mearurement of mineral in the radius does not always accurately reflect the overall skeletal mass in an individual patient and that prolonged therapy with high phosphorus and calcium intake did not increase the radius mineral content.

Adult↗
PubMed1975

Altered plasma half-lives of antipyrine, propylthiouracil, and methimazole in thyroid dysfunction.

In normal, nonmedicated volunteers and in patients with thyroid disorders the plasma half-lives of antipyrine, propylthiouracil, and methimazole were determined after single oral doses. The plasma half-liver plus or minus S.D. of antipyrine, propylthiouracil, and methimazole were 11.9 plus or minus 1.4 hr, 6.7 plus or minus 1.0 hr, and 9.3 plus or minus 1.4 hr, respectively, in normal volunteers, but were shortened to 7.7 plus or minus 1.2 hr, 4.3 plus or minus 0.7 hr, and 6.9 plus or minus 0.6 hr, respectively, in hyperthyroid patients. In hypothyroid patients the plasma half-lives of these drugs were prolonged to 26.4 plus or minus 4.0 hr, 24.7 plus or minus 34.5 hr, and 13.6 plus or minus 4.8 hr, respectively. Return to the euthyroid state restored plasma half-lives to or toward normal. Alterations in plasma drug half-lives during thyroid dysfunction appear to result mainly from accelerated hepatic microsomal drug metabolism in hyperthyroidism and retarded drug biotransformation during hypothyroidism.

Adult↗