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Robert P. Martin

ABSTRACT

The Koenig colour reaction, as modified by Oertel, may be used for detection and quantification of testosterone acetate and epitestosterone as well as for androst-4-ene-3,17-dione and testosterone.

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C Brachet, E Boros, S Tenoutasse, W Lissens, G Andry, P Martin, P Bergmann and C Heinrichs

Objective

Familial hypocalciuric hypercalcaemia (FHH) is clinically characterized by mild to moderate parathyroid hormone (PTH)-dependent hypercalcaemia, autosomal dominant pattern of inheritance, and normal to frankly reduced urinary calcium excretion in spite of a high serum calcium (clearance (Ca)/clearance (Cr)<0.01). FHH has a benign course and should be differentiated from primary hyperparathyroidism. It is usually caused by a heterozygous loss-of-function mutation in the calcium-sensing receptor gene (CASR).

Design

We report the case of a 16-year-old patient with hypercalcaemia and a mixed family history of parathyroid adenoma and mild hypercalcaemia. Serum calcium was 14 mg/dl with a serum iPTH of 253 pg/ml.

Results

A neck 99mTc-sesta MIBI tomoscintigraphy showed a definite hyperactivity in the left upper quadrant. A surgical four-gland exploration confirmed a single parathyroid adenoma. After surgical resection of a left superior parathyroid adenoma, the patient's hypercalcemia improved but did not normalize, returning to a level typical of FHH. An inactivating mutation in exon 4 of the CASR gene, predicting a p.Glu297Lys amino acid substitution was found.

Conclusions

Thus, this 16-year old patient presented with the association of FHH and a single parathyroid adenoma. The young age of the patient and the association of parathyroid adenoma and FHH in his grandmother argue for a causal link between CASR mutation and parathyroid adenoma in this family. This case contributes to illustrate the expanding clinical spectrum of CASR loss-of-function mutations.

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Martin Rodbell, Michael C. Lin, Yoram Salomon, Constantine Londos, James P. Harwood, Bruce R. Martin, Marc Rendell and Mones Berman

I. INTRODUCTION

The living system is constantly struggling against thermodynamic equilibration. In large measure, it does so through specific control mechanisms integrated within a complex of interconnecting circuits. These control mechanisms can be likened to information processing systems in that they contain components for signal detection and discrimination, coupling or transduction, amplification, and for translation into chemical signals that can be processed by other linked information processing systems.

Monod, Wyman & Changeux (1965) formulated the now classical concept of allosteric regulation which describes how informational processing may occur in molecular terms. Several variants of the original concept have been developed to account for the diverse properties of allosteric enzyme systems (Koshland, 1969). Basic to all allosteric mechanisms is the flexibility of the proteins comprising these systems. Flexibility allows a protein molecule to change its shape in response to

1) In modified form given as The Jacobeus lecture by invitation of

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D J Handelsman, B B Yeap, L Flicker, S Martin, G A Wittert and Lam P Ly

Aim

The age-specific population profiles in men of circulating testosterone and its two bioactive metabolites dihydrotestosterone (DHT) and estradiol (E2) across the adult lifespan and its determinants are not well described.

Objective

Our objective was to deduce smoothed age-specific centiles of circulating testosterone, DHT, and E2 in men using pooled data from population-based studies in three Australian cities from liquid chromatography–mass spectrometry steroid measurements in a single laboratory.

Design, setting, and participants

We pooled data of 10 904 serum samples (serum testosterone, DHT, E2, age, height, and weight) from observational population-based studies in three major cities across Australia.

Main outcome measures

Age-specific smoothed centiles for serum testosterone, DHT, and E2 in men aged 35–100 years were deduced by large sample data analysis methods.

Results

We found that serum testosterone, DHT, and E2 decline gradually from ages 35 onwards with a more marked decline after 80 years of age. Higher weight, BMI, and body surface area as well as shorter stature are associated with reduced serum testosterone, DHT, and E2.

Conclusions

Among Australian men, there is a gradual progressive population-wide decline in androgen status during male aging until the age of 80 years after which there is a more marked decline. Obesity and short stature are associated with reduced androgen status. Research into the age-related decline in androgen status should focus on the progressive accumulation of age-related comorbidities to better inform optimal clinical trial design.

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Daniel P. Stites, Joseph Caldwell, Martin C. Carr and H. Hugh Fudenberg

ABSTRACT

We have reviewed selected aspects of recent findings in the ontogeny of immunity in man. For obvious reasons, constraints placed on experimental work with human subjects, albeit deceased foetuses, limit the work to in vitro studies. Nevertheless, a number of novel and important concepts have emerged. First, as in lower animals, lymphoid development of the foetal thymus in general precedes the development of immunocompetence in peripheral lymphoid tissues. A striking exception to this rule is the finding of cells in early foetal liver which respond to allogeneic cells in the mixed lymphocyte culture some weeks before lymphoid organization of the thymus. In addition, the response of foetal cells to allogeneic cells in the mixed lymphocyte reaction (MLR) precedes the response to phytohaemagglutinin (PHA), a stimulant with relative T cell specificity. The use of markers for T cells to map the emergence of this class of lymphocytes correlates well with various functional attributes of T cells in in vitro culture systems. B cells emerge first in foetal liver at about 9 weeks' gestation, but formation of immunoglobulin by the foetus occurs at very low levels until after birth. There is a suggestion that progression from IgM to IgA synthesis occurs during human foetal lymphoid development. Taken as a whole, these data suggest a rather remarkable and perhaps unexpected degree of cellular and potential humoral immunocompetence at early stages of foetal development in man.

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R.P. WILLIG, S.L. KAPLAN, N. MARTIN, W.D. ODELL and M.M. GRUMBACH

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R. K. Bartholomeusz, N. W. Bruce, C. E. Martin and P. E. Hartmann

ABSTRACT

Daily blood samples were taken from 6, chronically cannulated, fully conscious rats to measure plasma progesterone levels throughout gestation. Progesterone levels in individual rats fluctuated by up to 28 ng/ml per day, but tended to be consistently higher or lower than the group mean. The accuracy of predicting progesterone levels in individual rats from previous values was examined.

Progesterone levels on day 7 of gestation were negatively correlated with foetal weights near term. There was little indication that high progesterone levels at any stage of gestation lead to increased foetal or placental weights. Progesterone levels on day 17 were positively correlated with the number of corpora lutea but there was little relationship between progesterone and either the number or total mass of the placentas.

Serial blood samples taken from a second group of 6 rats at 2 hourly intervals showed that the time between the major fall in progesterone levels to below 12 ng/ml and the onset of parturition was relatively constant (varying by only 8 h) despite a 29 h range in the total length of gestation.

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Kenneth H. Hupart, Charles R. DeFesi, Claire P. Katz, Lawrence E. Shapiro and Martin I. Surks

Abstract.

Rats bearing the Walker 256 carcinoma have decreased pituitary nuclear T3 but normal pituitary TSH content and response to experimental hypothyroidism. To elucidate further the role of T3 receptor occupancy and biological response in the tumor-bearing rat model of nonthyroidal disease, we measured the concentration of T3 nuclear receptors, rTSH and rGH and β-TSH mRNA and GH mRNA in the anterior pituitary of euthyroid rats bearing the Walker 256 carcinoma. The abundance of T3 nuclear receptors was decreased in tumorbearing rats and was associated with a decrease in mRNA content for β-TSH and GH. α-tubulin mRNA was decreased to a comparable degree. The pituitary content of rTSH and rGH was, however, the same as in control animals. Since tumor rats have normal regulation of TSH secretion by thyroid hormone, the present findings suggest that TSH secretion in T rats is maintained by a lower T3 nuclear receptor occupancy than in controls. The decrease in β-TSH mRNA may precede a decrease in TSH synthesis and changes in pituitary TSH stores. Since the decrease in GH mRNA was comparable to the decrease in α-tubulin mRNA, it does not appear to be specifically related to decreased T3 nuclear receptor occupancy. We conclude that, in the tumor-bearing rat model of nonthyroidal disease, decreases in β-TSH mRNA occur despite a decreased T3 receptor occupancy. Both thyroid-dependent and thyroid-independent factors may be involved in regulating β-TSH mRNA.

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C. E. Martin, M. H. Cake, P. E. Hartmann and I. F. Cook

ABSTRACT

The concentration of total corticosteroids, corticosteroid binding globulin (CBG) and progesterone were determined in maternal and foetal/neonatal plasma from rats on days 5, 4, 3, 2, 1 before birth and days 0, 1, and 4 after birth. In addition free corticosteroids and adrenal weight/unit body weight were measured on the foetuses/neonates and the foetuses, respectively. Although the concentration of maternal total corticosteroids and CBG ranged from 53.0 ± 12.5 to 31.0 ± 13.1 μg/100 ml (x̄ ± sem) and 26.6 ± 2.2 to 45.1 ± 0.9 μg corticosteroid bound/100 ml plasma, respectively, the changes in the concentration of these constituents were not related to the initiation of either parturition or lactation. The concentration of total corticosteroids in foetal plasma increased significanly (P < 0.05) from day 5 (14.6 μg/100 ml) to reach peak concentrations (44.9 μg/100 ml) on day 3 before birth and then decreased to low levels (7.7 μg/100 ml) at birth.

The pattern of change in foetal adrenal weight/unit body weight closely followed the pattern of change in the concentration of total corticosteroids in foetal plasma during the last 5 days of gestation. There was a significant (P < 0.05) daily decrease in the concentration of CBG in the foetuses from 4 days before until 1 day before birth, which resulted in a significant (P < 0.01) increase from 3.08 to 5.94 μg/100 ml of free corticosteroids in the foetal plasma between day 2 and day 1 before birth, respectively. This peak corresponded with a significant fall (P < 0.02) in the maternal progesterone (measured by protein binding assay) from 2.57 μg/100 ml to 0.62 μg/100 ml between day 2 and day 1 before birth. Foetal progesterone (measured by radioimmunoassay) showed the same changes as maternal progesterone but was between 25–50 % of that in maternal plasma. These findings suggest that the changes in foetal free corticosteroids and maternal progesterone are important in the initiation of parturition in the rat.