Biomedical subjects
Publications and source records attributed to J Müller.
A diploid yeast strain heterozygous at the canavanine locus was subjected to long-term gamma exposure in continuous chemostat cultures. Radiation induces canavanine resistance presumably by mitotic recombination. The efficiency of this process increased with lower dose rate. Experiments using a split-dose protocol showed that radiation possibly induces a recombinogenic activity.
The response of critical immunological parameters in seven athletes to the sustained physical stress of marathon running was assessed. Variables analysed were the responsiveness of lymphocytes (measured as mitogenic response to concanavalin A), the numbers of lymphocytes, their subsets, and leukocyte numbers. In addition, blood levels of cortisol, epinephrine, and norepinephrine were determined. After the run, lymphocyte responsiveness was severely depressed to 1-70% of the resting values, even though the lymphocyte counts did not change. Leukocyte counts were elevated 2.8-fold. No dramatic changes were found within the lymphocyte subsets, although an increase in pan T-cells and the helper/inducer subset 2 d after the run was significant. In addition, the numbers of B-cells decreased significantly. No change was observed within the suppressor/cytotoxic subset. Cortisol increased 2.1-fold, epinephrine 3.2-fold and norepinephrine 2.7-fold. All these parameters returned to baseline values within 2 d. These data were compared with data obtained during and after spaceflight. We conclude that prolonged physical stress of marathon running induces changes in immunological responsiveness that are strikingly similar to those arising from the stress of spaceflight.
The authors discuss the international campaign of doctors in opposition to nuclear warfare, "the ultimate scourge of mankind", and give their impressions of the seventh international IPPNW congress held in Moscow from May 29 to June 1, 1987.
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Sixteen patients with 18 attacks of distal ulcerative colitis were treated randomly with either 0.5 mg topically administered beclomethasone dipropionate (BDP) or 5 mg betamethasone phosphate (BMT). The effect of the steroid enemas on adrenocortical function was examined by ACTH tests, which were performed before and 20 days after treatment. At completion of the trial, a marked suppression of the adrenocortical function was found in seven of eight patients treated for nine attacks with BMT but not in any patients in the BDP group (P less than 0.01). The mean posttreatment basal and stimulated plasma cortisol levels in the BMT group were significantly lower as compared with the BDP group. The overall therapeutic response assessed by score systems was comparable in the two treatment groups. It is concluded that, in the topical treatment of ulcerative colitis, BDP is preferable to BMT because it exerts an equal anti-inflammatory action without affecting adrenocortical function.
Autophagic vacuoles (AVs) in adrenal parenchymal cells of the outer part of the zona fasciculata were investigated by means of electron microscopic morphometry in 40 adult male Sprague Dawley rats. Four test groups and four control groups received twice daily subcutaneous injections of ACTH (12.5 U/kg body weight) or physiological saline, respectively, for 3, 6, 9 and 12 days. At 12 days the total dry weight of the adrenals was increased in ACTH-treated animals from 17.2 to 71.0 mg (about fourfold) and the average volume of zona fasciculata cells from 1,500 to 5,100 microns3 (about threefold). The relatively larger increase in total mass reflects mitotic activity in the growing adrenal tissue. The calculated growth rate of total tissue expressed as the percentage increase in dry weight per day was 12% at day 3 and decreased to 4.6% at day 12 of ACTH stimulation. During the time interval investigated the cytoplasmic volume fraction of autophagic vacuoles was significantly reduced from 10 X 10(-5) in controls to 1 X 10(-5) in ACTH-treated animals (p less than 0.001). Assuming a half-life for AVs of 7.9 min (Papadopoulos and Pfeifer 1986), autophagic degradation of cytoplasm can be calculated as 1.3%/day in controls, but only 0.15%/day in ACTH-treated animals. Thus growth of 1.15%/day can be attributed to inhibition of autophagic degradation. Although this is only part of total growth, it is evident from the present results that anticatabolic growth induction is utilized nearly to its maximum in adrenocortical fasciculata cells under the influence of ACTH.
Whereas cytochrome P-45011 beta has been recently shown to catalyze the two-step conversion of corticosterone to aldosterone in the bovine and porcine adrenal cortex, the identity of the enzyme involved in the two final steps of aldosterone biosynthesis in the rat adrenal cortex is as yet unknown. Mitochondria from capsular adrenals of sodium-deficient, potassium-replete rats converted corticosterone to 18-hydroxycorticosterone and aldosterone at markedly higher rates than mitochondria from capsular adrenals of sodium-replete, potassium-deficient rats. However, the same preparations exhibited no difference in the 11 beta-hydroxylase activity, i.e. the conversion of deoxycorticosterone to corticosterone. Only mitochondria of zona glomerulosa from rats with stimulated aldosterone biosynthesis contained a 49K protein which showed a strong cross-reactivity with a monoclonal antibody raised against purified bovine cytochrome P-45011 beta. By contrast, a crossreactive protein with a molecular weight of 51K was found in mitochondria of zona fasciculata and in mitochondria of zona glomerulosa from rats with a suppressed aldosterone biosynthesis. These findings indicate the existence of two different forms of cytochrome P-45011 beta in the rat adrenal cortex, with only one of them, i.e. the 49K form, being capable of catalyzing the two final steps of aldosterone biosynthesis in situ.
Immunohistochemical, histochemical, and morphometrical studies of six gastric carcinoid tumors and their possible precursor lesions in gastric mucosa are reported. All tumors, presenting successively at our institute, occurred in the corpus mucosa of 45- to 78-year-old patients. Two neoplasms had already metastasized. Three tumors contained gastrin- and/or serotonin-positive cells. Two groups of carcinoids, one with atrophic gastritis type A [AGA (four cases)], and one without AGA (two cases) were discerned. Only cases with AGA showed antral G cell hyperplasia consistently as well as fundic endocrine cell proliferation and sometimes multifocal tumors. This confirms previous reports that hypergastrinemia might be a predisposing condition for the development of gastric carcinoids in AGA. Fundic endocrine cell increase, verified by quantitative methods, was either diffuse or nodular. Diffuse endocrine cell hyperplasia comprised G, EC, and ECl cells. The observation that endocrine cell nodules comprised a similar mixture of endocrine cells, sometimes communicating with glands of pseudopyloric metaplasia and proving to be reversible in one case, provides evidence that these nodules are hyperplastic, but finally may lead to gastric carcinoid tumors in AGA. Size less than 150 micron, basal location, and mixed hormone content may be helpful criteria for the distinction of hyperplastic endocrine cell nodules from small carcinoid tumors.
Based on evidence from morphological and histochemical studies and from clinical experience, the following hypotheses are proposed: carcinoma-in-situ (CIS) germ cells are malignant gonocytes; these CIS gonocytes have some capacity to regress into more primitive, totipotent embryonic cells which can give rise to all types of nonseminomatous germ cell tumours; the tumour germ cells of classical seminomas are malignant gonocytes derived from CIS gonocytes which have lost their ability to regress into totipotent embryonic cells; the ability of CIS gonocytes to regress into totipotent embryonic cells decreases with age, whereas the capacity to form classical seminoma cells is preserved; the transformation of CIS gonocytes into invasive tumours is dependent on factors such as gonadotrophins and/or testicular steroids; the pathogenesis of classical and spermatocytic seminoma are unrelated. As a consequence of these hypotheses an alternative nomenclature for carcinoma-in-situ, seminoma and dysgerminoma is suggested.
The spermatocytic seminoma has clinical and histological characteristics which differ from those of other germ cell tumours of the testis. Classical seminomas and teratomas are believed to originate from intratubular carcinoma-in-situ (CIS), which is almost invariably found adjacent to these neoplasms. In addition, DNA analysis of these tumours and the surrounding CIS has shown both to have an aneuploid distribution. In order to throw light on the origin of the spermatocytic seminoma, we have examined the testicular tissue adjacent to fifteen spermatocytic seminomas for the presence of CIS and assessed the DNA content of the tumour cells densitometrically. In twelve specimens seminiferous tubules were present adjacent to the tumour, and in none of these cases was CIS seen. Nuclear DNA measurements were possible in eleven tumours and in five cases the distribution was diploid, in three cases tetraploid, and only in three cases aneuploid. Therefore, we suggest that the spermatocytic seminoma has a different cell of origin from that of other germ cell tumours of the testis.
Germ cell neoplasia detected at the preinvasive stage of carcinoma-in-situ (CIS) can be cured by orchidectomy or by localized irradiation of the testis. Therefore, screening for carcinoma-in-situ of the testis has been applied to groups of individuals known to have an increased risk of testicular cancer. A high (5.5%) incidence of CIS was found in the contralateral testis of men with a unilateral cancer of the testis. An increased incidence of CIS was also found among men with a history of cryptorchidism. We recommend routine screening for CIS of the testis in both groups of men. The role of screening for CIS among subfertile men remains to be elucidated.
Carcinoma-in-situ (CIS) of the testis progresses to invasive cancer within 5 years in 50% of cases, and therefore requires therapeutic intervention. CIS is probably eradicated by intensive cancer chemotherapy but this is too toxic for the management of non-invasive disease. Eight patients with unilateral testicular cancer and contralateral CIS received localized irradiation (20 Gy in ten fractions of 2 Gy) to the remaining testis: after 3 months the CIS cells had disappeared and 'Sertoli-cell-only' tubules were found. LH and FSH levels were elevated but testosterone levels remained fairly constant. Localized irradiation should be considered as the treatment of CIS in the contralateral testis of testicular tumour patients unless chemotherapy is indicated for the primary tumour. Unilateral orchidectomy is recommended for unilateral CIS associated with infertility or testicular maldescent. Localized testicular irradiation should now be considered for bilateral disease. Patients with the androgen insensitivity syndrome should normally be treated with bilateral orchidectomy, but irradiation may be useful in selected cases.
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Sertoli cells were studied using stereological methods in testes obtained from five children who were stillborn, and 31 individuals between 3 months and 40 years of age, who had suffered from sudden, unexpected death. The mean nuclear volume of the Sertoli cells, the numerical density of Sertoli cells, and the total number of Sertoli cells per individual were determined by point- and profile-counting of 0.5 micron sections. The nuclear volume of Sertoli cells increased from a median of 120 microns3 (range 53-130) during the period of 3 months to 10 years to 210 microns3 (170-260) in adults (greater than 25 years). The numerical density of Sertoli cells decreased from a median of 1200 X 10(6)/cm3 (870-1400) during childhood (3 months to 10 years) to 140 X 10(6)/cm3 (110-260) in adults (greater than 25 years). The total number of Sertoli cells per individual increased significantly from a median of 260 X 10(6) (130-520) during the late foetal period to 1500 X 10(6) (850-2900) in individuals from 3 months to 10 years of age. A further increase was found during puberty as the number of Sertoli cells in adults (greater than 25 years) was 3700 X 10(6) (2500-5600). These results indicate that significant qualitative and quantitative changes in the population of Sertoli cells take place after birth.
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