Biomedical subjects
Publications and source records attributed to G Stevens.
An unusual case of Merkel cell carcinoma is presented in which the time course to development of nodal and haematogenous metastases was protracted and the predominant site of metastatic disease was small bowel.
Tyrosinase-positive oculocutaneous albinism (ty-pos OCA) is an autosomal recessive disorder of the melanin pigmentary system. South African ty-pos OCA individuals occur with two distinct phenotypes, with or without darkly pigmented patches (ephelides, or dendritic freckles) on exposed areas of the skin. These phenotypes are concordant within families, suggesting that there may be more than one mutation at the ty-pos OCA locus. Linkage studies carried out in 41 families have shown linkage between markers in the Prader-Willi/Angelman syndrome (PWS/AS) region on chromosome 15q11-q13 and ty-pos OCA. Analysis showed no obligatory crossovers between the alleles at the D15S12 locus and ty-pos OCA, suggesting that the D15S12 locus is very close to or part of the disease locus, which is postulated to be the human homologue, P, of the mouse pink-eyed dilution gene, p. Unlike caucasoid "ty-pos OCA" individuals, negroid ty-pos OCA individuals do not show any evidence of locus heterogeneity. Studies of allelic association between the polymorphic alleles detected at the D15S12 locus and ephelus status suggest that there was a single major mutation giving rise to ty-pos OCA without ephelides. There may, however, be two major mutations causing ty-pos OCA with ephelides, one associated with D15S12 allele 1 and the other associated with D15S12 allele 2. The two loci, GABRA5 and D15S24, flanking D15S12, are both hypervariable, and many different haplotypes were observed with the alleles at the three loci on both ty-pos OCA-associated chromosomes and "normal" chromosomes.(ABSTRACT TRUNCATED AT 250 WORDS)
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The locus for Tyrosinase-Positive Oculocutaneous Albinism (ty-pos OCA) has not yet been localised. The search for the ty-pos OCA locus has included a search for linkage to candidate pigment loci and a candidate chromosomal region, as well as a random search using highly polymorphic markers in 42 families, including 271 individuals of whom 79 are affected. The lod scores for the tyrosinase (TYR) locus (11q14-q21), homologous to the albino locus, c, in the mouse and the CAS2/TRP1 locus (9p22-pter), homologous to the brown locus, b, in the mouse were -5.89 and -7.22, respectively, at a recombination fraction of theta = 0.01, thus excluding them from being the ty-pos OCA locus. In the candidate chromosomal region, 11p, four loci (probes) were tested, SAA (pSAA82), CALC (pHC36), HBB (Gamma-globin haplotype) and an AC repeat polymorphism at the Wilm's Tumour locus (WT1). A portion of 11p was excluded with the following lod scores: pSAA82 lod = -2.05 at theta = 0.10; pHC36 lod = -3.87 at theta = 0.05; gamma-globin haplotype lod = -2.80 at theta = 0.10; and WT1 lod = -2.34 at theta = 0.10. Thirty-three polymorphic markers randomly distributed on 13 different chromosomes were all excluded from close linkage to ty-pos OCA.
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Oocytes were recovered by laparoscopic aspiration from 3- to 8-week-old calves treated with follicle-stimulating hormone (FSH) followed by human chorionic gonadotropin (hCG) to induce follicular growth and oocyte maturation in vivo. Most of the recovered oocytes either had resumed meiotic maturation at the time of aspiration or were competent to undergo maturation during subsequent culture in vitro. Oocytes matured in vivo following FSH and hCG treatment underwent in vitro fertilization (70%) at rates not significantly different from those of control oocytes recovered from adult cow ovaries at abattoirs and matured in vitro (75%). Calf oocytes that were immature at aspiration exhibited lower fertilization rates after in vitro maturation (36%) but their rate of development to morulae and blastocysts did not differ from that of mature oocytes at aspiration. A total of 91% of the zygotes produced from calf oocytes developed to morula and 27% to blastocyst stages during 6 days of culture. The proportion developing to morulae was significantly higher (P<0.05) than that observed for zygotes resulting from in vitro maturation and fertilization of oocytes recovered from cow ovaries obtained at an abattoir and processed concomitantly (59% to morulae and 18% to blastocysts). Morulae or blastocysts developed from oocytes from 5 to 6-week-old calves, when transferred to synchronized recipient heifers, resulted in 2 confirmed pregnancies, one of which produced a single full-term live calf. The ability to produce embryos from oocytes recovered from newborn or prepubertal calves offers the potential for markedly reducing the generation interval in cattle, thereby substantially accelerating the rate of genetic gain that can be achieved through embryo transfer.
A retrospective study was undertaken of factors affecting survival in 129 patients with cerebral metastases from malignant melanoma referred to the Department of Radiation Oncology from June 1982 to January 1990. Their ages ranged from 19 to 83 years and the time interval from diagnosis of the primary tumour to development of cerebral metastases ranged from one month to 17 years. Cerebral metastases were apparently solitary in 59 (46%) and multiple in 70 (54%) patients respectively. Craniotomy with resection of tumour was performed in 49 patients, of whom 24 had a solitary cerebral metastasis as the only evidence of disease. Most patients (94%) received a course of radiotherapy. Median survival of the whole group after detection of cerebral metastases was 5 months (range less than 1-87+). Univariate analysis indicated that a solitary cerebral metastasis, absence of extracranial disease and tumour resection predicted improved survival, but only surgical intervention was of independent prognostic significance in a multivariate analysis. The effect of cranial irradiation on survival could not be assessed, but the dose of radiation did not influence survival. Of the 10 patients who survived for more than 2 years, eight had total resection of a solitary cerebral metastasis.
A retrospective study was undertaken in 1990 of 188 patients with the diagnosis of non small cell carcinoma of the lung referred to the Department of Radiation Oncology in 1984. Most patients (178/188) received a course of radiotherapy. This was definitive in 23, palliative in 148 (primary site in 113, metastases in 16, primary plus metastases in 19) and postoperative in 7. This report is a 5 year followup of the 171 patients treated by radiation alone, to assess factors that influence survival. Tumour histology was 50% squamous, 23% adenocarcinoma, 16% large cell and 4% unspecified, non small cell carcinoma. In 8% no histological diagnosis was obtained. The most common symptoms were cough (44%), dyspnoea (43%), chest pain (37%), haemoptysis (33%) and systemic symptoms (36%). Tumour stage (TNM) was assessed retrospectively as I(5%), II(8%), IIIA(18%), IIIB(22%) and IV(28%). A subgroup of 31 cases (18%) of uncertain staging (I-III) was analysed separately and in 2 cases (1%) no staging information was available. Palliative intent of treatment and poorer performance status were related significantly to increasing stage of disease. The effects of palliative treatment were recorded in 79 cases; in 71 there was a reduction in symptoms. The median survival from diagnosis was 8 months (range < 1-72). Using univariate and multivariate analyses, significant and independent prognostic factors for improved survival were good performance status, absence of systemic symptoms, lower tumour stage and curative intent of treatment (higher radiation dose). However the 5-year survival was only 2%. Long-term survival was associated predominantly with early stage disease but not with the type or intent of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Tyrosinase-positive oculocutaneous albinism (ty-pos OCA), an autosomal recessive disorder of the melanin biosynthetic pathway, is the most common type of albinism occurring worldwide. In southern African Bantu-speaking negroids it has an overall prevalence of about 1/3,900. Since the basic biochemical defect is unknown, a linkage study with candidate loci, candidate chromosomal regions, and random loci was undertaken. The ty-pos OCA locus was found to be linked to two arbitrary loci, D15S10 and D15S13, in the Prader-Willi/Angelman chromosomal region on chromosome 15q11.2-q12. The pink-eyed dilute locus, p, on mouse chromosome 7, maps close to a region of homology on human chromosome 15q, and we postulate that the ty-pos OCA and p loci are homologous.
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Fifty-six patients with bilateral sight-threatening noninfectious intermediate or posterior uveitis participated in a randomized double-masked study of the use of cyclosporine vs prednisolone in their treatment. Applying the end-point definitions, visual acuity or vitreal haze improved in only 13 of 28 (46%) patients in each group. The macular edema resolved in seven of 15 patients of the cyclosporine-treated group, and in ten of 16 patients of the prednisolone-treated group (P = .376). Patients whose therapies failed both cyclosporine and prednisolone trials were treated with both drugs, which resulted in additional patient improvements. Secondary effects were observed in both therapeutic alternatives, the most notable being alterations in serum creatinine concentration and hypertension with the dosage of cyclosporine used.
The rate and early pattern of development of radiation-induced renal damage has been determined in the mouse by measuring reductions in both haematocrit and excretion of 51Cr-EDTA, and increases in both urination frequency and urine volume. Kidneys of CBA mice were irradiated bilaterally with 2 fractions of X-rays, one week apart. Renal function was determined immediately prior to irradiation and at 3-4 weekly intervals to 22 weeks post-irradiation. Onset of damage was detected as early as 3-6 weeks using the urination frequency assay. This was confirmed by estimating the volume of urine excreted. A significant fall in haematocrit was not detected until 6-9 weeks post-treatment and a fall in isotope clearance was not detected significantly until 12 weeks. This early detection of damage was consistent with reports using both mouse and other species. The time at which damage was detected first was independent of radiation dose for the frequency and haematocrit assays. For 51Cr-EDTA clearance, there was the suggestion of earlier functional loss for the higher doses. Following the onset of damage, a steady, dose-dependent decline in renal function was measured by all assays. The latency period is defined as the time required to reach a given level of functional damage. This time decreased with increasing radiation dose, to a minimum value set by the time of onset of damage, which varied from 3 to 12 weeks, depending on the assay used. The differences in response measured prior to 12 weeks post-irradiation represent the first occasion on which a dissociation between these 3 assays has been detected.(ABSTRACT TRUNCATED AT 250 WORDS)
In two pilot studies, 55 patients with symptomatic metastases from malignant melanoma were treated with irradiation and concurrent cisplatin. In the first group, cisplatin was given as a continuous intravenous infusion of 20 mg/m2 per day on days 1-5 and 22-26, with irradiation on days 2, 5, 9, 16, 23 and 26. The second group received 20 mg cisplatin over 24 h commencing 1 h before each fraction of irradiation on days 1, 4, 8, 11, 15 and 18. The first series of 28 patients had 30 lesions treated. Nine (30%) of these lesions responded completely and 10 (33%) achieved partial response for an overall response rate of 63% (95% confidence interval 44-80%). Survival was not evaluated in this group. The second group was comprised of 27 patients, with one irradiated lesion each. 1 patient achieved a complete response and 13 (48%) a partial response for an overall response rate of 52% (32-71%). Median survival was 21 weeks (16-31 weeks). Treatment was well tolerated with nausea and vomiting being the most common toxicity. Synchronous cisplatin infusion with radiotherapy achieves high response rates in metastatic melanoma. Whether it is superior to radiotherapy alone will require evaluation in a randomised trial.
Fanconi's syndrome with phosphopenic rickets is described in a 2-year-old girl who had been treated for an embryonal sarcoma with multiagent chemotherapy including high-dose ifosfamide. The radiological and biochemical signs of rickets disappeared after treatment with 25-OH vitamin D3 and phosphorus supplements. Monitoring of tubular function in children during and after treatment with ifosfamide is mandatory.
Bradykinin was found to bind to specific high-affinity sites in cultured cortical astrocytes from rat brain, and this binding appeared to be specific for the B2 bradykinin receptor subtype. Nonlinear regression analysis of saturation experiments using a computer programme revealed a single KD of 16.6 +/- 2.6 nM and a Bmax of 352.2 +/- 30.7 fmol/mg of protein. These results indicate that astrocytes possess bradykinin receptors and that these are predominantly of the B2 subtype.
O-2A progenitor cells, the precursors of oligodendrocytes in the central nervous system (CNS), probably originate in the subventricular germinal zones of the developing CNS, and subsequently migrate away from there to populate the rest of the CNS with oligodendrocytes. We are trying to understand how the O-2A progenitor cells interact with their changing environment as they migrate, and how this influences each stage of their development into mature, myelinating oligodendrocytes. In this article we summarize evidence that platelet-derived growth factor (PDGF) is important for stimulating O-2A progenitor cell proliferation in vivo, and describe our efforts to map the distribution of PDGF and its receptors in the developing rat CNS by in situ hybridization and immunohistochemistry. These studies suggest that, in the CNS, PDGF alpha-receptor subunits may be restricted to O-2A lineage cells that have started to migrate away from the subventricular zones towards their final destinations. Many neurons express the A and/or B chains of PDGF, and astrocytes express the A chain, but it is not yet clear which of these cell types might be the major source of PDGF for O-2A lineage cells in vivo. O-2A progenitor cells can be purified and maintained in a proliferating state in vitro by culturing in the presence of PDGF and bFGF. Under these conditions, the POU transcription factor SCIP/Tst-1 is expressed at a high level; when oligodendrocyte differentiation is initiated by withdrawing the growth factors, SCIP/Tst-1 mRNA is rapidly down-regulated, followed by a decline in SCIP/Tst-1 protein and sequential activation of myelin-specific genes.(ABSTRACT TRUNCATED AT 250 WORDS)
Pregnant CD-1 mice were injected with diethylstilboestrol (10 micrograms/kg body weight) in 0.1 ml maize oil, or maize oil alone, on Day 16 of gestation. Six experimental and 6 control female progeny were killed daily from birth until Day 7 and uterine tissues were examined by light microscopy. In-utero exposure to diethylstilboestrol resulted in hypertrophy of luminal epithelial cells and premature formation of uterine glands. The initial sign of uterine gland formation was invagination of the uterine surface epithelial cell layer into the underlying connective tissue stroma. A temporal difference occurred between control animals and those exposed to diethylstilboestrol: uterine gland formation first occurred in experimental progeny on Day 4, but not until Day 5 in control progeny. Uterine glands which extended deep into the connective tissue stroma to the myometrium were present in diethylstilboestrol-treated progeny by Day 7, but remained in the superficial endometrial connective tissue stroma in control animals. The results indicate that prenatal exposure of mice to diethylstilboestrol causes uterine epithelial cell hypertrophy at birth and the premature formation of uterine glands during the first week of neonatal uterine development.