Showing papers by "St Bartholomew's Hospital published in 1987"

Failure to Preserve Fertility in Patients With Hodgkin's Disease

Abstract: The hypothesis that the "down-regulated" gonad is less vulnerable to the effects of cytotoxic chemotherapy for advanced Hodgkin's disease has been investigated. Thirty men and eighteen women were randomly allocated to receive an agonist analogue of gonadotrophin-releasing hormone prior to, and for the duration of, cytotoxic chemotherapy. Buserelin (d-Ser-[TBU]6 LHRH ethylamide) was prescribed in two different dosage schedules to twenty men, and in a single dosage schedule to eight women. A standard gonadotrophin-releasing hormone test (GnRH 100 micrograms) was performed 1 week prior to and on day 1 of each cycle of chemotherapy. In all patients peak luteinizing hormone responses to GnRH were suppressed throughout treatment. The higher of the two dosage schedules used in the men caused more effective suppression of luteinizing hormone, and both regimens led to an initial suppression of peak follicle-stimulating hormone responses to GnRH, which was not maintained. At follow-up assessment up to 3 years from the completion of treatment, all men treated with buserelin were profoundly oligospermic and four of the eight women were amenorrhoeic. All ten male controls were profoundly oligospermic, and six of nine female controls were amenorrhoeic. In the dosages and schedules investigated, buserelin was ineffective in conserving fertility.

Multiple myeloma treated with high dose intravenous melphalan

Abstract: High dose melphalan (HDM, 140 mg/m2 i.v.) has been evaluated in 58 patients under 63 years with multiple myeloma. Among previously untreated patients 11/41 (27%) entered a complete remission (CR: no measurable myeloma protein and a normal bone marrow) and 21 (51%) entered a partial remission (more than 50% reduction in myeloma protein and improvement in all other features). Median duration of remission is 19 months. Two patients who had responded to previous conventional treatment entered CR after HDM. Among 15 patients who had failed on previous chemotherapy the response rate was 66% including two CRs. However, in this group all patients have relapsed within 1 year. Profound myelosuppression, moderate nausea, vomiting, mucositis and diarrhoea with reversible alopecia occurred in all patients. There were 10 deaths within 2 months of treatment mainly due to sepsis and haemorrhage. In a subsequent study, high dose methyl prednisolone (1 g/m2 daily for 5 d) has been added to HDM. Response rates are similar with 6/22 (27%) CR, 13/22 (59%) PR and 2/22 NR but there was only one early death, reflecting improvements in medical management. The high CR rate is an encouraging feature of this approach which is now to be the basis of a prospective trial sponsored by the Medical Research Council in which HDM, with and without steroids, is compared to the best available conventional therapy (the MRC VI Myelomatosis trial).

Proliferative index in breast carcinoma determined in situ by Ki67 immunostaining and its relationship to clinical and pathological variables

Abstract: Sixty cases of primary breast carcinoma have been studied using a monoclonal antibody, Ki67, which recognizes an antigen expressed by cells in G1, S, G2, and M phases of the cell cycle but not Go. A Ki67 score (positive cells/total tumour cells) was determined, and possible relationships between this index of cellular proliferation and a number of clinical and pathological parameters were investigated. There was a strong positive correlation between the Ki67 score and mitotic index (p less than 0.001), a weak negative correlation with age (p less than 0.02), and weak positive correlations with histological tumour grade (p less than 0.03), tumour necrosis (p less than 0.01), and cellular reaction (p less than 0.01). No relationship was noted between the Ki67 score and tumour size, nodal status, tumour oestrogen receptor levels, or menopausal status. The Ki67 score may prove to be an objective indicator of biological behaviour and thus be of clinical significance, particularly since it is not strongly related to other clinical and pathological parameters used in predicting outcome in breast carcinoma.

Average soft-tissue and bone models for use in radiation dosimetry

Abstract: Average tissue compositions have been derived for seven groups of soft tissues found in “Reference Man”. The analyses took into account some 40 soft tissues comprising the adult human. Different groups of soft tissues were selected to provide average tissue compositions of practical value in radiation dosimetry. In addition, as more reliable skeletal tissue data are now available, an updated tabulation is given of average bone formulations. Elemental compositions and mass and electron densities are tabulated for all of the derived systems.

Depressive disorder in primary care.

Abstract: Since the pioneering study of psychiatric morbidity in primary care by Shepherd et al in 1966, it has become increasingly apparent that a substantial proportion (between 20% and 25%) of patients consulting their GP are suffering from some form of psychiatric disturbance (Goldberg & Blackwell, 1970; Hoeper et al, 1979). The composition of this psychiatric morbidity has been shown to be almost wholly affective in nature and largely mild in degree. In their important review Jenkins & Shepherd (1983) recently summarised the now extensive findings relating to overall minor psychiatric morbidity in primary care. However, recent collaborative studies between psychiatrists and GPs have identified that within this dilute pool of minor disorders, lurks a significant but poorly served population of patients suffering from depressive disorders which are by no means minor in degree. A number of crucial issues regarding this depression in primary care emerge which the present paper aims to review. In particular, how common is it, and how severe? How does it present and what, if any, are its special characteristics? What is the precise relationship between depressive symptoms and depressive illness presenting to the GP and what is the relationship between physical illness and depression? And finally, what is the course and outcome of depression in this setting and what are the indications for and effect of treatment?

Incidence and mechanism of neutropenia and thrombocytopenia in patients with human immunodeficiency virus infection

Abstract: The incidence of lymphopenia, thrombocytopenia and neutropenia was studied in 105 homosexual men with HIV infection. Lymphopenia was common in patients with AIDS (75%), but its incidence in PGL (24%) was not significantly different from that in asymptomatic anti-HIV positive (15%) homosexual men. Neutropenia and thrombocytopenia were found in patients with AIDS or PGL, but not in asymptomatic anti-HIV positive homosexuals. The study suggests that the neutropenia and thrombocytopenia in these patients were due to autoimmune destruction of neutrophils and platelets.

Idiopathic retroperitoneal fibrosis. A retrospective analysis of 60 cases.

Abstract: Sixty patients with idiopathic retroperitoneal fibrosis presenting between 1965 and 1984 are reviewed. Their mean age at presentation was 56 years and the male:female ratio was 3:1. The commonest presenting symptoms were flank and abdominal pain, weight loss, nausea and polyuria. Physical examination was usually normal, expect for the presence of hypertension. Anaemia and elevation of erythrocyte sedimentation rate were usually present. Proteinuria was found in less than a third of patients at presentation and significant bacteriuria was uncommon. The correct diagnosis was made or suspected in very few patients before referral. The cumulative actuarial survival rate was 86% at 1 year and 78% at 2 years. Seventeen patients died; they were significantly older and more uraemic at the time of referral than those who survived. A few patients did well with either corticosteroid therapy or ureterolysis alone. In the majority, both operation and steroid treatment were necessary. In bilateral obstruction with residual function in both kidneys, bilateral ureterolysis proved superior to unilateral operation (each followed by steroid therapy) in conserving renal function. Operation alone or steroid therapy alone should be considered in cases where steroids or surgery respectively present particular hazards. The less traumatic unilateral operation should be considered in poor risk patients and in those whose renal function is absent on one side. In many survivors, disease activity has persisted for many years. Life-long follow-up is recommended.

Improvement of abnormal lactulose/rhamnose permeability in active Crohn's disease of the small bowel by an elemental diet.

Abstract: Intestinal permeability to sugar has been used as an objective measure of small bowel integrity to assess the efficacy of an elemental diet as the sole treatment or Crohn's disease of the small bowel. Fourteen children aged 11-17 years with active small bowel Crohn's disease were given an elemental diet for six weeks. Investigations with iso-osmolar oral test solutions before and after this treatment showed that all 14 children had abnormally raised lactulose/L-rhamnose permeability ratios, which fell significantly after the elemental diet. This change coincided with marked clinical improvement, as assessed by a disease activity index score.

Mucinous carcinoma of the rectum.

Abstract: We have studied and compared 316 mucinous and 45 signet ring cell carcinomas of the rectum with 413 non-mucinous carcinomas. Mucinous carcinomas were subdivided according to the amount of mucus which was gauged subjectively as either more or less than 75% of the tumour volume. Five year survivals for non-mucinous, mucinous (less than 75%), mucinous (greater than 75%) and signet ring cell carcinoma were 62%, 60%, 53% and 13%. Mucinous carcinomas (less than 75%) were relatively well differentiated and showed an age distribution identical to their non-mucinous counterparts, but differed in their strong association with villous adenoma. Mucinous carcinomas (greater than 75%) were less well differentiated and, like signet ring cell carcinomas, occurred in younger patients and showed no special association with villous adenoma. Clinically important and independent predictive variables were found by the method of multivariate regression analysis to be number of lymph node metastases, extent of spread in continuity, character of invasive margin and peritumoural lymphocytic infiltration. After adjustment for these factors, typing of rectal cancer as mucinous, non-mucinous and signet ring cell gave no additional, clinically useful prognostic information.

The evolution of non-steroidal anti-inflammatory drugs and their mechanisms of action.

Abstract: The pro-inflammatory effects of prostaglandins have been clearly demonstrated with the use of various animal models of inflammation. Furthermore, the anti-inflammatory effects and some of the side effects of aspirin and other non-steroidal anti-inflammatory agents have been shown to depend on their ability to inhibit cyclo-oxygenase. These drugs, therefore, reduce the synthesis of prostaglandins, prostacyclin and thromboxane. They do not affect leukotriene production and there is no firm evidence to suggest that they alleviate inflammation through any other mechanism. In contrast, the corticosteroids facilitate the release of lipocortin which, through inhibition of phospholipase A2 reduces arachidonic acid release. These drugs possess potent anti-inflammatory properties and attempts have been made to develop non-steroidal drugs, such as BW755C, that display similar anti-inflammatory activity through inhibition of the 2 main pathways of the arachidonic acid cascade. Administration of low dose aspirin 40 mg/day selectively inhibits production of thromboxane A2 without affecting prostacyclin. This may be because, firstly, about 60% of an administered dose of aspirin is deacylated to salicylate during first-pass metabolism and, secondly, platelets cannot regenerate cyclo-oxygenase. Thus, absorbed aspirin irreversibly affects platelet thromboxane production in the pre-systemic circulation, but the systemic plasma aspirin concentration is likely to be too low to affect prostacyclin synthesis. Studies in experimental inflammation have shown that after the administration of aspirin, the concentration of salicylate in inflammatory exudate is considerably higher than that of aspirin. In addition, a comparison of prostaglandin synthesis inhibitory potencies shows that the concentration of salicylate, but not of aspirin, at the inflammatory site is high enough to substantially inhibit prostaglandin synthesis.

GH feedback occurs through modulation of hypothalamic somatostatin under cholinergic control: studies with pyridostigmine and GHRH.

Abstract: We have studied the effect of increased cholinergic tone on the GH response to growth hormone-releasing hormone (GHRH) and on GH feedback, using pyridostigmine, an acetylcholinesterase inhibitor. In six healthy male adult volunteers 120 mg oral pyridostigmine increased basal GH secretion compared to placebo and augmented the GH response to 100 micrograms i.v. GHRH (1-29) NH2; the effect was more than the additive effect of pyridostigmine and GHRH when each was given alone. Pretreatment with 2 IU methionyl-hGH given i.v. abolished the serum GH response to GHRH given 3 h later, demonstrating a negative feedback loop of GH on the response to GHRH; this inhibited response to GHRH was restored in subjects given pyridostigmine as well as methionyl-hGH. The data demonstrate that enhanced cholinergic tone releases GH, augments the serum GH response to GHRH and unblocks the negative feedback effect of methionyl-hGH pretreatment on the GH response to GHRH. These results suggest that GH negative feedback effects on its own secretion occur predominantly through increased hypothalamic somatostatin secretion; this somatostatin secretion is under inhibitory cholinergic control.

Proliferative activity of cells in the synovium as demonstrated by a monoclonal antibody, Ki67

Abstract: The presence of proliferating cells has been sought in the synovium of rheumatoid arthritic (RA) and osteoarthritic (OA) joints using the monoclonal antibody Ki67, which marks a nuclear antigen present in all stages of the cell cycle apart from Go. Synovia were studied from 21 RA and 14 OA cases using the indirect immunoperoxidase technique. Double-staining was performed on 18 RA and 17 OA synovia with the simultaneous labelling of lysozyme (muramidase) by the immuno-alkaline phosphatase method and with Ki67 by the indirect immunoperoxidase method. Most of the RA and OA synovia showed an absence of Ki67-positive cells in the intimal cell layer. Three RA and four OA synovia showed no more than ten proliferating cells in the whole of the intimal layer examined. Similar results were obtained when double-labelling was performed. Eight RA and six OA synovia showed the presence of occasional Ki67-positive cells in the intimal layer. The total number of intimal cells was measured for each histological section, and the proliferation index calculated as the percentage of total cells in the intimal layer showing Ki67-positive staining. This varied between 0.03% and 0.0033% (between 1 : 2800 and 1 : 30 000 cells). In contrast, there were plentiful Ki67-positive cells present in the lymphocytic infiltrate and around blood vessels in the RA synovia and in the synovial infiltrate, where present, in the OA cases. The results provide further support for the suggestion that the intimal cell layer of the synovium is predominantly composed of macrophages, with some fibroblasts, and that the macrophages have not arisen locally by cell division (hyperplasia) but have migrated from the underlying synovial blood vessels.

The effect of total body irradiation and bone marrow transplantation during childhood and adolescence on growth and endocrine function.

Abstract: Seventeen children (11 M, 6 F) with acute leukaemia and myeloproliferative disorders were investigated for growth and endocrine dysfunction. All had undergone bone marrow transplantation prepared with cyclophosphamide and single fraction total body irradiation (900-1000 cGy) between 1.5 and 3.8 (mean 2.2) years previously. The majority of children exhibited growth failure, which was of multiple aetiology. Ten patients, of whom eight had had previous prophylactic cranial irradiation, had evidence of growth hormone deficiency based on the reduced growth hormone response to insulin induced hypoglycaemia. Three patients had evidence of hypothalamic damage as shown by their growth hormone response to 200 micrograms GHRH (1-29) NH2 intravenously. Gonadal failure was common, assessed clinically, and biochemically by basal gonadotrophin and sex steroid concentrations. All four girls of adolescent age (10.6-14.1 years) had ovarian failure requiring sex steroid replacement. Of the eight boys of adolescent age (12.3-18.3 years), two had testicular failure requiring sex steroid supplements. Both of these had had previous testicular irradiation. Five others had compensated gonadal failure, and one had normal Leydig cell function. Abnormalities of the TSH response to TRH occurred in 10 patients but only three had overt hypothyroidism. Unlike growth hormone deficiency, gonadal and thyroid dysfunction showed no correlation with previous cranial radiotherapy.

Uptake of iodine-123 MIBG by pheochromocytomas, paragangliomas, and neuroblastomas: a histopathological comparison.

Abstract: The percentage uptake of [123I]metaiodobenzylguanidine (MIBG) by tumors of the paraganglion system is compared with the number of neurosecretory granules (assessed by both light and electron microscopy) in the subsequently resected tumors in six patients. Iodine-123 MIBG was injected intravenously; the tumor uptake of [123I]MIBG varied between 0.001% and 0.14% of the injected dose per gram of tumor tissue at 22 hr. The number of neurosecretory granules in tissue sections was scored on a scale of I-III. A direct proportional correlation was found between the percentage uptake of [123I]MIBG by the tumor and the number of neurosecretory granules in the tissue sections but not with plasma or urinary catecholamines. This technique for imaging reflects the storage status of the tumor better than plasma and urinary catecholamine measurements.

Novel chimaeric protein expressed in Philadelphia positive acute lymphoblastic leukaemia.

Abstract: Cytogenic changes are becoming increasingly important in understanding the pathogenesis of human malignancies. The t(9;22) (q34;q11) translocation is one of the most consistent and generates the Philadelphia chromosome (Ph1) (ref. 1) in chronic myeloid leukaemia (CML); it has also been observed in some acute lymphoblastic leukaemias (ALL) (ref. 2). In CML the breakpoints occur on chromosome 22 in the region designated bcr (ref. 3) and result in the expression of a bcr-abl fusion product of relative molecular mass (MT) 210,000 (210K) with associated in vitro tyrosine kinase activity (P210bcr-abl). In some cases of Ph1-positive ALL, a novel abl-related protein (P190all-abl) of 190K has been shown to have tyrosine kinase activity. In this report we demonstrate that the P190all-abl protein has a bcr determinant from the amino-terminal region, but is lacking a bcr determinant normally found in the P210bcr-abl near the bcr-abl junction. The chimaeric nature of the P190all-abl was confirmed by sequential immunoprecipitation with antisera against abl and bcr peptides.

The use of rats associated with a human faecal flora as a model for studying the effects of diet on the human gut microflora.

Abstract: The activities of four bacterial biotransformation enzymes (beta-glucosidase, beta-glucuronidase, nitrate reductase and nitroreductase) were measured in the caecal contents of conventional flora rats or germ-free rats contaminated with a mixed, human faecal flora and compared with activities present in a fresh human stool preparation. Both the conventional flora rats and the rats inoculated with a human flora exhibited an enzyme profile generally similar to that of human faeces, although the conventional rat flora exhibited negligible nitrate reductase activity. The enzyme profile remained essentially unaltered in both human flora preparations following supplementation of the diet with pectin, whereas the conventional rat flora responded to this plant cell wall carbohydrate with a significant increase in nitrate reductase activity. The results demonstrate that enzymic activities of the human faecal microflora can be simulated in rats associated with a mixed population of human intestinal bacteria.

Growth hormone pretreatment in man blocks the response to growth hormone-releasing hormone; evidence for a direct effect of growth hormone.

Abstract: SUMMARY The effect of pretreatment with biosynthetic methionyl human GH (hGH) on the GH response to GHRH has been studied in normal subjects. Eight volunteers were given either 4IU hGH or placebo s.c. 12-hourly for 72 h before a GHRH test, or a single s.c. dose of 4 IU hGH 12 h before a GHRH test. Somatomedin-C (Sm-C) levels at the time of the GHRH tests were significantly elevated after treatment with hGH compared to placebo, and the GH response to GHRH was significantly attenuated. A further six subjects were given 2 IU hGH or placebo i.v., and i.v. GHRH 3 h later; there was no rise in Sm-C for the 5 h of the study after either treatment; nevertheless, the response to GHRH was completely abolished by pretreatment with hGH. These results demonstrate that GH can regulate its own secretion independently of changes in Sm-C levels, through a mechanism other than the inhibition of GHRH release. The attenuated response to GHRH in the presence of elevated Sm-C levels may be related to Sm-C, or be a more direct effect of the recently elevated GH levels.

Restriction endonuclease DNA analysis of Clostridium difficile.

Abstract: HindIII restriction enzyme digests of genomic DNA from nine distinct strains of Clostridium difficile were undertaken, and the results were related to those of a previously established typing method based on [35S]methionine-labeled protein profiles. Each of the typed strains identified by its protein profile could also be distinguished by its unique DNA digestion pattern. Analysis of strains isolated from 10 patients during a hospital outbreak of antibiotic-associated colitis revealed identical DNA profiles, confirming a single strain as the source of cross-infection. Characterization of isolates from worldwide sources revealed similar digestion patterns within the same strain type. Restriction endonuclease DNA analysis provides a sensitive and useful technique for studying the epidemiology of C. difficile.

Hormonal regulation of acid phosphatase release by osteoclasts disaggregated from neonatal rat bone.

Abstract: Osteoclasts disaggregated from neonatal rat long bones and incubated on plastic or glass substrates were found to release a considerable proportion of tartrate-resistant acid phosphatase into culture supernatants. Enzyme release was detectable in the supernatant medium of cultures containing as few as ten cells after 1 hr of incubation and proceeded in a linear manner for the ensuing 6 hr. Calcitonin (1 pg/ml) and cytochalasin B (5 micrograms/ml) inhibited release into the supernatant, suggesting that release represents enzyme secretion. Prostaglandin E1 induced transient inhibition followed by recovery; parathyroid hormone and 1,25(OH)2 vitamin D3 were without influence. Acid phosphatase release in these cultures shows a pattern of hormone responsiveness that coincides with the effects of these hormones on bone resorption by isolated osteoclasts. The extent of acid phosphatase release and its regulation by calciotropic hormones imply a central role for acid hydrolase secretion in osteoclastic bone resorption. The experimental system described in this study may facilitate analysis of the pharmacological hormonal and cellular regulation of osteoclastic function.

Fluorophotometric measurements of tear turnover rate in normal healthy persons: evidence for a circadian rhythm.

Abstract: The determination of tear turnover rate in a total of 16 normal healthy volunteers is described. A continuous reading fluorophotometer is used to measure the fluorescence resulting from the instillation of 1 microliter of 2 per cent fluorescein into the eye. A mean (+/- s.d.) turnover rate of 14.9 +/- 5.6 per cent per minute is found, in agreement with previously reported values. Morning and afternoon measurements on the same subject show that morning tear turnover rates are significantly higher than those in the afternoon (p less than 0.01), suggesting a circadian rhythm in tear flow. It is also concluded that use of a 10 per cent fluorescein solution can lead to a significant underestimation of tear turnover rates and that any resulting errors are likely to be larger for light coloured irises.