Showing papers by "St Bartholomew's Hospital published in 1990"

Regulatory functions of the vascular endothelium.

Abstract: William harvey, when studying the circulation of the blood, must have recognized that "In sound and living vessels the blood remains fluid, but it coagulates in dead ones" (Ernst Brucke, 1857). Joseph Lister (1909) provided further evidence for an active role of blood vessels in maintaining the liquidity of blood. The vascular endothelium, which envelops the circulating blood in a continuous monolayer, is mainly responsible for this function. Over the past 20 years numerous other important functions have been discovered. For instance, the outer surface of the endothelial cell contains angiotensin-converting enzyme, which catalyzes the formation of the vasoconstrictor angiotensin . . .

Attitudes to chemotherapy: comparing views of patients with cancer with those of doctors, nurses, and general public.

Abstract: OBJECTIVE--To compare responses of patients with cancer with those of a matched control group, cancer specialists, general practitioners, and cancer nurses in assessing personal cost-benefit of chemotherapy DESIGN--Prospective study of consecutively recruited patients with cancer and other groups by questionnaire; half of the patients received the questionnaire again three months after starting treatment SETTING--A medical oncology ward of a London teaching hospital SUBJECTS--106 Patients with newly diagnosed solid tumours referred to the unit for consideration of treatment with cytotoxic chemotherapy, 100 of whom were able to complete the questionnaire 100 Matched controls, 315 cancer doctors (238 radiotherapists and 77 medical oncologists), 1500 randomly chosen general practitioners, and 1000 randomly chosen cancer nurses MAIN OUTCOME MEASURES--Percentage chance of cure, prolonging life, or palliation of symptoms required to make treatment worth while with two hypothetical chemotherapy treatments, with severe and mild side effects respectively RESULTS--Respondents to the questionnaire comprised 100 patients, 100 controls, 60 (78%) medical oncologists, 88 (37%) radiotherapists, 790 (53%) general practitioners, and 303 (30%) cancer nurses Most patients were willing to accept intensive chemotherapy for a very small chance of benefit The median benefit required to make the hypothetical intensive treatments worth while for patients compared with controls were: for chance of a cure (range 1 to 100%) 1% v 50%, for prolonging life (range three months to five years) 12 months v 24-60 months, and for relief of symptoms (range 1 to 100%) 10% v 75% respectively There were no significant differences in the responses of the 50 patients completing the questionnaire on a second occasion Doctors and nurses were less likely to accept radical treatment for minimal benefit compared with the patients (median scores 10-50%, 12-24 months, and 50-75%, for chance of cure, prolonging life, and relief of symptoms respectively) Significantly more patients than controls accepted treatments giving the minimal benefit for each category (cure 531 v 190%, 670 v 350%; prolonging life 421 v 100%, 530 v 250%; relief of symptoms 426 v 100%, 587 v 190% for intensive and mild treatments respectively, p less than 0001) as was the case for comparison of patients with other groups CONCLUSION--Patients with cancer are much more likely to opt for radical treatment with minimal chance of benefit than people who do not have cancer, including medical and nursing professionals This could be taken into account when discussing treatment options with patients and their relatives

Anatomic and Disease Specificity of NADH CoQ1 Reductase (Complex I) Deficiency in Parkinson's Disease

Abstract: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is thought to produce parkinsonism in humans and other primates through its inhibition of complex I The recent discovery of mitochondrial complex I deficiency in the substantia nigra of patients with Parkinson's disease has provided a remarkable link between the idiopathic disease and the action of the neurotoxin MPTP This article shows that complex I deficiency in Parkinson's disease is anatomically specific for the substantia nigra, and is not present in another neurodegenerative disorder involving the substantia nigra Evidence is also provided to show that there is no correlation between L-3,4-dihydroxyphenylalanine therapy and complex I deficiency These results suggest that complex I deficiency may be the underlying cause of dopaminergic cell death in Parkinson's disease

The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: cultured endothelial cells recycle L-citrulline to L-arginine.

Abstract: We have investigated the mechanism by which cultured endothelial cells generate L-arginine (L-Arg), the substrate for the biosynthesis of endothelium-derived relaxing factor. When Arg-depleted endothelial cells were incubated in Krebs' solution for 60 min, L-Arg levels were significantly (9.7-fold) elevated. The generation of L-Arg coincided with a substantial decrease (90%) in intracellular L-glutamine (L-Gln), whereas all other amino acids were virtually unaffected. Changes in calcium, pH, or oxygen tension had no effect on L-Arg generation, which was, however, prevented when the cells were incubated in culture medium containing L-Gln. L-Arg generated by endothelial cells labeled with L-[14C]Arg was derived from an unlabeled intracellular source, for the specific activity of the intracellular L-Arg pool decreased substantially (8.8-fold) over 60 min. Arg-depleted endothelial cells did not form urea or metabolize L-ornithine but converted L-citrulline (L-Cit) to L-Arg possibly via formation of L-argininosuccinic acid. Nondepleted cells stimulated with the calcium ionophore A23187 showed only a transient accumulation of L-Cit, indicating that L-Cit is recycled to L-Arg during the biosynthesis of endothelium-derived relaxing factor. The generation of L-Arg by Arg-depleted endothelial cells was partially (45%) blocked by protease inhibitors, and various Arg-containing dipeptides were rapidly cleaved to yield L-Arg. Thus, cultured endothelial cells recycle L-Cit to L-Arg and possibly liberate peptidyl L-Arg. The Arg-Cit cycle appears to be the equivalent in the endothelial cell to the formation of urea by the liver. The biosynthesis of endothelium-derived relaxing factor may, therefore, not only produce a powerful vasodilator but also relieve the endothelial cell of excess nitrogen.

Microalbuminuria in diabetes mellitus : review and recommendations for the measurement of albumin in urine

Abstract: The demonstration that microalbuminuria is predictive of overt diabetic nephropathy has created a demand for the routine measurement of urinary albumin in diabetic patients.' The first part of this report provides a brief overview of microalbuminuria in diabetes mellitus. The second defines assay performance criteria and sample handling conditions for the measurement of urinary albumin and gives recommendations for the standardization of assays and includes an assessment of selected immunochemical methods.

Ginger root--a new antiemetic. The effect of ginger root on postoperative nausea and vomiting after major gynaecological surgery.

Abstract: The effectiveness of ginger (Zingiber officinale) as an antiemetic agent was compared with placebo and metoclopramide in 60 women who had major gynaecological surgery in a double-blind, randomised study. There were statistically significantly fewer recorded incidences of nausea in the group that received ginger root compared with placebo (p less than 0.05). The number of incidences of nausea in the groups that received either ginger root or metoclopramide were similar. The administration of antiemetic after operation was significantly greater in the placebo group compared to the other two groups (p less than 0.05).

Immediate release of a nitric oxide-like factor from bovine aortic endothelial cells by Escherichia coli lipopolysaccharide

Abstract: Incubation of human washed platelets with bovine aortic endothelial cells (ECs) treated with indomethacin resulted in an inhibition of thrombin-induced platelet aggregation that was dependent on the number of ECs added. Preincubation of ECs with Escherichia coli lipopolysaccharide (LPS; 0.5-2.0 micrograms/ml) for 1 min significantly enhanced their inhibitory activity. This effect was potentiated by superoxide dismutase (60 units/ml) and reversed by oxyhemoglobin (5-10 microM), indicating that the inhibition was due to the release of endothelium-derived relaxing factor (nitric oxide). When the ECs were pretreated with NG-monomethyl-L-arginine (30-300 microM) before LPS, the antiaggregatory activity was strongly reduced. The reduction of activity by NG-monomethyl-L-arginine was reversed by L-arginine (100 microM) but not by D-arginine (100 microM). Under similar conditions, LPS also enhanced the antiaggregatory activity of ECs grown on beads. The immediate enhancement by LPS of the release of endothelium-derived relaxing factor from endothelial cells may contribute to the rapid fall in blood pressure associated with endotoxin shock in vivo.

Lymphohistiocytic T-cell lymphoma (anaplastic large cell lymphoma CD30+/Ki-1 + with a high content of reactive histiocytes)

Abstract: We describe 13 cases of a peculiar lymphoid tumour containing very large numbers of reactive histiocytes. The tumours occurred in young patients (mean age 14.8 y) who presented with systemic symptoms and superficial lymphadenopathy. Microscopic examination revealed a diffuse effacement of lymph node structure due to the presence of histiocytes intermingled with a variable number of anaplastic large lymphoid cells. The latter, in some cases, were isolated, while in others they were arranged in clusters or were diffusely present in residual sinuses. The large anaplastic cells expressed the activation markers CD30 (Ki-1), CD25 (interleukin-2 receptor), CD70 (Ki-24) and Ki-27, as well as varying combinations of T-associated molecules. The histiocytes expressed lysozyme and the CD11b (C3bi-R), CD11c (p150, 95) CD14, CD68 (KPI) and Ber-Mac3 antigens. Double staining with the antibody Ki-67 demonstrated that the proliferating components were the CD30-positive cells and not the histiocytes. T-cell receptor beta gene rearrangements were shown in three cases tested. The patients responded well to aggressive chemotherapy and nine are still alive, eight in complete remission. It is suggested that the tumour represents a well-defined clinico-pathological entity originating from activated T-lymphocytes.

History of aspirin and its mechanism of action

Abstract: The history of Aspirin goes back many thousands of years to the early uses of decoctions or preparations of plants that contain salicylate. Salicylic acid was chemically synthesized in 1860 in Germany, and its ready supply led to even greater use as an external antiseptic, as an antipyretic, and in the treatment of rheumatism. Aspirin itself was synthesized by Felix Hoffman while working at Bayer at the turn of the century, and Hermann Dreser introduced it in 1899 when he published a report suggesting that Aspirin was a convenient way of supplying the body with the active substance salicylate. Pharmacologists have put forth many different possible modes of action of Aspirin, but the one that has gained general recognition is through inhibition of prostaglandin biosynthesis by irreversible interaction with the enzyme cyclooxygenase. This discovery in 1971 led to a veritable explosion in research, which resulted in several new, more potent Aspirin-like drugs and in an extension of the uses of Aspirin. This mode of action of Aspirin is discussed in this review as well as some of the surviving alternative hypotheses.

Consensus Document: Hawk's Cay Meeting on Therapeutic Drug Monitoring of Cyclosporine

Abstract: The optimal measurement method and clinical application of the therapeutic drug monitoring of cyclosporine remain uncertain. At a workshop held at Hawk's Cay, FL, from January 14 to January 17, 1990, 57 scientists presented their latest research findings, either in formal papers or as discussants. Lively debate and discussion followed presentation of extant and new methodologies for drug measurements as well as multicenter validation studies: applications of trough-concentration monitoring in renal, hepatic, and bone-marrow transplants as well as in autoimmune disease; and alternative pharmacokinetic approaches to guide cyclosporine therapy. The process of inducing and maintaining optimal immunosuppression to facilitate graft success is a complex and often challenging task, requiring the combined expertise of multiple disciplines. Thus, the assembly of four of the groups essential to the transplant process--clinicians, laboratory scientists, the pharmaceutical company, and the manufacturers of cyclosporine measurement kits--provided a unique opportunity to evaluate therapeutic drug monitoring issues facing the transplant field. Here we present the major conclusions reached at the meeting, brief discussions of the study data on which they are based, and a summary of unresolved problems that will require further rigorous investigations. The Consensus Document was reviewed by all the workshop participants before we submitted this final manuscript.

The c-erb B-2 proto-oncogene in human pancreatic cancer.

Abstract: The c-erb B-2 oncogene encodes a 190 kD transmembrane growth factor receptor which is closely related to the EGF receptor and has been found to be amplified and overexpressed in a number of human adenocarcinomas, particularly of the breast. We have analysed, by immunocytochemistry using the 21N antibody, expression of c-erb B-2 in a retrospective series of pancreatic adenocarcinoma, chronic pancreatitis, and examples of histologically normal pancreas. In three cases (21 per cent) of chronic pancreatitis, there were focal areas of cytoplasmic immunoreactivity in regenerating epithelium. In 15 cases (17 per cent) of pancreatic adenocarcinoma, cytoplasmic immunoreactivity was seen, while in two cases (2 per cent) strong membrane staining of tumour cells was seen which could be blocked by peptide controls. c-erb B-2 immunoreactivity was also demonstrated using a second antibody, 20N, which recognizes another peptide sequence of the c-erb B-2 protein. There was no relationship between immunoreactivity and histological subtype or grade, but there was absolute concordance between staining in primary and metastatic deposits. Since the rat homologue (neu) of the c-erb B-2 oncogene may be activated by a specific point mutation in its transmembrane region, we have analysed 23 cases from this series for mutations by polymerase chain reaction amplification and sequence-specific oligonucleotide hybridization. We were unable to identify activity mutations in this series. These data suggest that there is abnormal expression of c-erb B-2 oncogene in nearly 20 per cent of cases although mutational activation of this gene is not seen in human pancreatic adenocarcinoma.

The pill, parity, and rheumatoid arthritis.

Abstract: The authors report on a case-control study investigating the relationship of oral contraceptive (OC) use and parity to the development of rheumatoid arthritis (RA). Women with RA were compared with 2 separate control groups women with osteoarthritis (OA) and women randomly selected from a population=based electoral register. Nulliparity was found to be a risk factor for the development of RA with age-adjusted odds ratios of 1.82 (95% confidence interval [CI] 1.09-3.03) vs the OA control group and 1.83 (95% CI 1.03-3.06) vs the population control group. Use of OCs before the age of 35 was negatively associated with RA (odds ratio 0.56 95% CI 0.29-1.12 vs the OA control group; odds ratio 0.6 95% CI 0.30-1.17 vs the population control group). Some evidence of a duration response effect was seen although the numbers were small. The 2 variables were also multiplicative with nulliparous non-OC users having a 4-fold risk of RA compared with parous OC users. These findings suggest that pregnancy and OC use have a protective effect on the development of RA although the mechanism remains unclear. (authors)

Differential expression of CD25 (interleukin-2 receptor) on lamina propria T cells and macrophages in the intestinal lesions in Crohn's disease and ulcerative colitis.

Abstract: Many interleukin-2 receptor (CD25) bearing cells can be identified by alkaline phosphatase immunohistochemistry in the diseased intestinal lamina propria of children with Crohn's disease or ulcerative colitis, but rarely in normal intestine In both diseases, the CD25+ cells are present as aggregates in the lamina propria below the epithelium, and constitute a large proportion of the lamina propria mononuclear cells In Crohn's disease, but not ulcerative colitis, CD25+ cells are abundant in the submucosa The CD25+ cells in Crohn's disease are 58-88% CD3+, CD4+, CD8-, indicating that they are T cells, whereas in ulcerative colitis the CD25+ cells are greater than 80% CD3-, CD4+, HLA-DR+, indicating that they are macrophages Thus, differential expression of CD25 on T cells and macrophages serves to distinguish the immunologic lesions in ulcerative colitis and Crohn's disease

Characterization of the sequence-specific interaction of mouse c-myb protein with DNA.

Abstract: We have examined parameters that affect sequence-specific interactions of the mouse c-myb protein with DNA oligomers containing the Myb-binding motif (CA/CGTTPu). Complexes formed between these oligomers and in vitro translated c-myb proteins were analysed by electrophoresis on non-denaturing polyacrylamide gels using the mobility-shift assay. By progressive truncation of c-myb coding sequences it was demonstrated that amino acids downstream of a region of three imperfect 51-52 residue repeats (designated R1, R2 and R3), which are located close to the amino terminus of the protein, had no qualitative or quantitative effect on the ability to interact specifically with this DNA motif. However, removal of only five amino acids of the R3 repeat completely abolished this activity. The contribution of individual DNA-binding domain repeats to this interaction was investigated by precisely deleting each individually: it was demonstrated that a combination of R2 and R3 was absolutely required for complex formation while the R1 repeat was completely dispensible. c-myb proteins showed quantitatively greater interaction with oligomers containing duplicated rather than single Myb-binding motif, in particular where these were arranged in tandem. Moreover, it was observed that c-myb protein interacted with these tandem motifs as a monomer. These findings imply that a single protein subunit straddles adjacent binding sites and the implications for c-myb activity are discussed.

The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: L-glutamine inhibits the generation of L-arginine by cultured endothelial cells.

Abstract: The mechanism by which L-glutamine (L-Gln) inhibits the release of endothelium-derived relaxing factor from bovine aortic cultured endothelial cells was investigated. The intracellular concentration of L-arginine (L-Arg) in Arg-depleted endothelial cells was inversely related to the level of L-Gln. Removal of L-Gln from the culture medium (usually containing L-Gln at 2 mM) abolished the inhibitory effect of the culture medium on L-Arg generation. L-Gln (0.2 and 2 mM) but not D-Gln inhibited the generation of L-Arg by both Arg-depleted and nondepleted endothelial cells. L-Gln did not interfere with the uptake of L-Arg or the metabolism of L-Arg-L-Phe to L-Arg but inhibited the formation of L-Arg from L-citrulline (L-Cit), L-Cit-L-Phe, and NG-monomethyl-L-arginine. L-Gln also inhibited the conversion of L-[14C]Cit to L-[14C]Arg by Arg-depleted endothelial cells. However, L-Gln did not inhibit the conversion of L-argininosuccinic acid to L-Arg by endothelial cell homogenates. Thus, L-Gln interferes with the conversion of L-Cit to L-Arg probably by acting on argininosuccinate synthetase rather than argininosuccinate lyase. L-Gln also inhibited the generation of L-Arg by the monocyte-macrophage cell line J774 but had no effect on the conversion of L-Cit to L-Arg by these cells. As the release of endothelium-derived relaxing factor from cultured and non-cultured endothelial cells is limited by the availability of L-Arg, endogenous L-Gln may play a regulatory role in the biosynthesis of endothelium-derived relaxing factor.

Morphological integrity of the bronchial epithelium in mild asthma.

Abstract: In severe asthma bronchial epithelial cells are damaged and detached, and it has been proposed that such damage might lead to the bronchial hyperresponsiveness that characterises asthma. To investigate the relation between airway hyperresponsiveness and epithelial damage, biopsy specimens of the bronchial mucus membrane were obtained at fibreoptic bronchoscopy from 11 patients with mild atopic asthma and airway hyperresponsiveness (provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) less than 1.0 mg/ml), and from 17 healthy non-atopic subjects who did not have airway hyperresponsiveness (PC20 methacholine greater than 8.0 mg/ml). Observers who were blind to the presence or absence of asthma examined the biopsy specimens by light and electron microscopy. Epithelial cells, intercellular spaces, and goblet cells were counted. Intercellular junctional complexes were examined, and a semiquantitative assessment was made of ciliary loss, non-parallel central ciliary filaments, and vacuoles in ciliated cells. There were no differences between the asthmatic and healthy groups in any of these measurements. These findings indicate that airway hyperresponsiveness may be present when there is no apparent change in the structure of the bronchial epithelium.

Genetic analysis of a tetracycline resistance element from Clostridium difficile and its conjugal transfer to and from Bacillus subtilis.

Abstract: Summary: A tetracycline resistance (Tcr) determinant from Clostridium difficile strain 630 was cloned into the Escherichia coli plasmid vector pUC13. The resulting plasmid pPPM20, containing an insert of 3.4 kbp, was mapped and a 1.1 kbp SacI-HindIII fragment wholly within the Tcr gene was identified. Dot-blot hybridization studies with the 1.1 kbp fragment showed that the Tcr gene belonged to hybridization class M. Tcr could be transferred between C. difficile strains and to Bacillus subtilis at a frequency of 10−7 per donor cell. The element could be returned from B. subtilis to C. difficile at a frequency of 10−8 per donor cell. This is the first demonstration of C. difficile acting as a recipient in intergeneric crosses. DNA from C. difficile transconjugants digested with EcoRV always has two hybridizing fragments of 9.5 and 11.0 kbp when probed with pPPM20. DNA from B. subtilis transconjugants digested with EcoRV produced one hybridizing band of variable size when probed with pPPM20. The behaviour of the element was reminiscent of the conjugative transposons. Therefore we compared the element to the conjugative transposon Tn916. The HincII restriction maps of the two elements differed and no hybridization was detected to oligonucleotides directed to the ends of Tn916. However, the elements do have some sequence homology, detected by hybridization analysis.

Cell repopulation and overall treatment time

Abstract: Prolongation of the overall treatment time in radiotherapy, especially of squamous cell carcinomas of the head and neck, decreases the chances of cure. This is most likely because of the proliferation of surviving clonogenic tumor cells between dose fractions. Between the 3rd and 7th week of conventional radiotherapy of head and neck cancers, on average 0.5 to 0.7 Gy are lost per day by repopulation. As this represents an average value, repopulation may be even more efficient in subgroups of faster tumors. There is little information on repopulation rates during the first 2 weeks of radiotherapy. Prolongation of the overall treatment time in radiotherapy helps to avoid severe side effects from acutely responding tissues, especially oral mucosa. This sparing effect of increasing overall treatment time is mainly caused by the regeneration of mucosal stem cells and transit cells. This repopulation is slow in the first 2 weeks and accelerates dramatically thereafter. The nature of the trigger for acceleration is not known but seems to be related to a critical threshold of acute tissue hypoplasia and the development of the inflammatory reaction of the connective tissue. It is not known whether accelerated tumor repopulation is stimulated by the same or a similar mechanism as the normal epithelium. During accelerated repopulation the oral mucosa is able to compensate a considerably higher proportion of the daily dose fraction than the tumor. These factors have to be taken into account when treatment strategies are designed to cope with the problem of accelerated repopulation.

Trends in admissions for hip fracture in England and Wales, 1968-85.

Abstract: should be provided in all cases. The high incidence of patients seeking advice from the general practitioner or district nurse after their return home was worrying and is not a problem of which we are aware in our normal practice. Complications perceived by patients may not necessarily be regarded as complications by a surgeon but, nevertheless, we were unhappy to discover potential infection rates of around 15% after inguinal hernia and varicose vein surgery. Patients having this type of surgery remain in hospital for only a day or so. Inflammatory and infective sequelae are likely to have resolved and may be forgotten by the patient by the time of the surgical outpatient review at two or three months. We intend to survey our patients treated locallv to see if the trend can be confirmed. Transient testicular swelling in three patients after inguinal hernia repair was attributable to one surgeon whose practice was probably to overtighten the internal inguinal ring. Personal technique has been modified. An unexpected finding highlighting the cost of waiting lists was that 13 patients (11 5%) awaiting routine elective surgery claimed that they were unable to work. Though patients rated the scheme highly, the scheme was not without difficulties. Nevertheless, the apparent success of the scheme challenges the traditional approach of initial assessment, operation, and follow up being performed by the same surgical team. Problems might be expected in matters of contentious management and certainly some patients had slightly different operations from those recommended by the referring surgeon. The preoperative ward round must therefore be conducted with the importance and the duration of the outpatient consultation. When complications occur they are best dealt with by the operating surgeon and may not be appreciated when review is carried out elsewhere. Patients were generally allocated for transfer to Wroughton by availability and geographical clustering rather than by the nature of the operation and expected duration of the procedure. Problems were therefore encountered with the content and duration of some operating lists. It is crucial for the efficient use of theatre time and the appropriate allocation of surgical staff that case selection should be made by the operating consultant surgeon and not by administrative personnel. Selection of patients with regard to their fitness for an anaesthetic before transfer is important to spare patients disappointment and a wasted journey. Four patients in our series were returned home without an operation despite prior assessment at the review clinic. An ideal scheme should include advice from the anaesthetic department of the receiving hospital of local criteria and thresholds for deferring operation in the presence of conditions such as hypertension or glycosuria. With regard to overall surgical performance it is not possible to get something for nothing. The rate limiting step in surgical performance in this military hospital is operating time rather than bed space, and as a result of operating on 112 patients from another region the same number of local NHS patients in Wiltshire were deferred. From the operating team's point of view there was no training benefit. The type of routine, repetitive surgery transferred was that which will inevitably be found at low priority on all surgical waiting lists and which we see regularly from day to day. The hospital gained because the Crewe Health Authority contributed £36 per patient per day based on recovery of minimal costs. This amount might seem to undersell the services offered but compared favourably with the existing arrangements of non-sponsorship of local NHS patients. If similar financial arrangements were to be negotiated with health authorities in the local area then there would be no reason to receive elective surgical patients from far away.