Showing papers by "Northwick Park Hospital published in 1992"

Interactions of tumor necrosis factor with granulocyte-macrophage colony-stimulating factor and other cytokines in the regulation of dendritic cell growth in vitro from early bipotent CD34+ progenitors in human bone marrow.

Abstract: Colonies of CD1a+ HLA-DR+/DQ+ CD4+ cells with the functional and some of the structural attributes of Langerhans cells are observed in human bone marrow cultures in semi-solid media and are assumed to be the progeny of an early progenitor, the dendritic/Langerhans cell CFU (CFU-DL). The cytokine-regulated growth of these cells has been studied using a chemically defined serum-free system to culture both unfractionated and highly enriched bone marrow progenitor cell populations. Although unfractionated cell growth was optimal in serum replete cultures with PHA-stimulated leukocyte-conditioned medium (PHA-LCM) suboptimal proliferation of CFU-DL was observed in serum even in the absence of PHA-LCM. No colonies were observed under serum-free conditions when granulocyte-macrophage CSF (GM-CSF), IL-3, granulocyte CSF (G-CSF), and macrophage CSF (M-CSF) were present at levels optimal for granulocyte colony-forming unit (CFU-G) and macrophage colony-forming unit (CFU-M) growth. Addition of IL-1 alpha to these cytokines stimulated a small number of CFU-DL. However, in the presence of GM-CSF and IL-3, TNF-alpha or TNF-beta (5 U/ml) were both highly effective in promoting growth up to 82% of optimal and CFU-G growth was also enhanced at these concentrations. TNF was only active during the first 3 days of culture and higher concentrations of TNF-alpha but not TNF-beta were inhibitory for both CFU-DL and CFU-G. CD34+ cell-enriched populations were also enriched for both myeloid progenitors (CFU-G + CFU-M) and CFU-DL to 36- and 48-fold, respectively, and single cell cultures of CD34+ cells yielded single colonies containing both CD1a+ dendritic cells and CD1a- macrophages. Thus dendritic/Langerhans progenitors in the bone marrow expresses CD34, have a capacity for both macrophage and dendritic cell differentiation, and depend on hemopoietic growth factors and TNF for their further development in vitro.

How common are polycystic ovaries in normal women and what is their significance for the fertility of the population

Abstract: OBJECTIVE We wished to determine the prevalence of polycystic ovaries (PCO) and relate morphological appearance to fertility. DESIGN We sent postal invitations to a random sample of women born in the years 1952–1969 from a list of a single Group Practice to attend for reproductive history questionnaire, examination, ultrasound scan of the ovaries and hormone measurements within 5 days of the onset of menstruation. SUBJECTS Of 1065 women potentially available for study, 571 (54%) replied of whom 353 (62%) agreed to participate. One hundred and ninety (18%) completed the study, 163 were deferred (57 because of current or very recent pregnancy, 106 because of inconvenience at time approached), and 18 additional women volunteered. MEASUREMENTS Prevalence of polycystic ovaries, ovarian size and morphology, menstrual history, features of androgen excess, fertility status, serum hormone levels. RESULTS The prevalence of PCO was 22% (41/190). PCO and non-PCO women were similar with respect to age, body mass index, oral contraceptive pill (OCP) usage, acne, and menstrual pattern but hirsutism (Ferrlman and Gallwey score > 7) was significantly (P= 0.006) more frequent among PCO women. Proven prior fertility was the same in PCO (56%) and non-PCO (64%) women and an equal proportion in each group had not yet tested their fertility. Of those women with previously proven fertility, self-perceived difficulty in conception occurred in similar proportions of women with and without PCO. Unresolved primary or secondary infertility (2.5–4%) was similar in both groups. Ovarian volume (each ovary separately) was larger in women with PCO irrespective of current OCP usage. Serum levels of oestradiol and FSH were similar in PCO and non-PCO women, but LH was distributed around a higher median in PCO women. Median testosterone and androstenedione levels were the same in PCO and non-PCO women. CONCLUSIONS The prevalence of polycystic ovarian morphology is high but, in this sample of women, was accompanied by minimal clinical manifestations and apparently no deleterious effects on earlier fertility. An isolated finding of polycystic ovaries may be a normal variation and should not necessarily imply altered fertility potential.

The natural history of sciatica associated with disc pathology. A prospective study with clinical and independent radiologic follow-up.

Abstract: The purpose of this study was to assess the natural history of sciatica due to lumbosacral nerve root compromise and to evaluate the pathomorphologic changes that accompany the natural resolution of the disease. One hundred sixty-five consecutive patients, 114 males and 51 females, with an average age of 41 years (range, 17-72) and an average duration of symptoms of 4.2 months (range, 1-72) presenting with sciatica thought to be due to lumbosacral nerve root compromise were admitted to the study. The cornerstone of treatment was the serial epidural administration of steroid and local anesthetic by the caudal route on an outpatient basis. Lumbar epidural injection or periradicular infiltration at the appropriate level, confirmed under image intensifier, was the next step before considering surgical decompression. An average of three injections (range, 0-8) was received by each patient. Patients underwent clinical examination and computed tomography. Twenty-three patients (14%) underwent surgical decompression. The remainder were clinically assessed at 1 year after presentation, and 111 were rescanned at the appropriate levels. All conservatively managed patients made a satisfactory clinical recovery: average reduction of pain on the visual analog scale was 94% (range, 45-100), and 64 (76%) of the 84 disc herniations and 7 (26%) of the 27 disc bulges showed partial or complete resolution (chi-square = 20.27, P = 0.0001). Thus a high proportion of patients with discogenic sciatica make a satisfactory recovery with aggressive conservative management, and this recovery is accompanied by resolution of disc herniations in a significant number. Only a small proportion of patients needed surgical decompression.

Graves' ophthalmopathy in relation to cigarette smoking and ethnic origin.

Abstract: Objective We aimed to study the effect of cigarette smoking on the prevalence and severity of Graves' ophthalmopathy (GO). Patients One hundred and fifty-five newly diagnosed patients with Graves' disease (GD) were diagnosed clinically and by routine biochemical methods. Twenty-five per cent (39) were of Asian origin. Methods Eye signs were classified according to the American Thyroid Association Classification. A detailed smoking questionnaire and data from hospital notes were used to calculate an index of cigarette consumption. Results Thirty-four per cent of all patients had Graves' ophthalmopathy, and the prevalence in males (26%) and females (36%) did not differ significantly. There was a prevalence of 42% among Europeans compared to 7.7% in Asians (P = 0.0002). The overall risk for Europeans for developing Graves' ophthalmopathy was 6.4 (1.78-22.7 confidence interval) times higher than for Asians. Corrected for the ethnic factor the increased risk from smoking for Europeans was 2.4 (1.12-5.18, 95% confidence interval) times higher. There was a significant dose effect (P = 0.008). Conclusions The present findings confirm an effect of cigarette smoking on Graves' ophthalmopathy and in addition show that Europeans have a substantially greater risk of developing Graves' ophthalmopathy than have Asians.

Venous leg ulcers: a prognostic index to predict time to healing.

Abstract: OBJECTIVE--To evaluate the prognostic factors in uncomplicated venous leg ulcer healing. DESIGN--Randomised parallel group controlled trial with subjects stratified by initial ulcer diameter and four months' maximum duration of follow up. SETTING--Assessment at Northwick Park Hospital vascular unit with community based treatment. PATIENTS--200 patients with clinical and objective evidence of uncomplicated venous leg ulceration and an initial ulcer diameter > 2 cm. MAIN OUTCOME MEASURE--Time to complete healing of the ulcer. RESULTS--In the presence of graduated compression healing occurred more rapidly in patients with a smaller initial ulcer area (relative risk of healing 1.92 associated with halving of ulcer area (95% confidence interval 1.58 to 2.33)), shorter duration of ulceration (relative risk 1.35 associated with halving duration (1.17 to 1.56)), younger age (relative risk 1.34 associated with 10 year decrease (1.12 to 1.59)), and no deep vein involvement (relative risk 1.8 (1.19 to 2.78)). CONCLUSION--These prognostic factors used in a simple scoring system predict time to healing.

Prenatal exposure to influenza does not cause schizophrenia.

Abstract: Claims have been made that maternal infection with influenza during pregnancy is a cause of schizophrenia in the child. These assertions are based upon some apparently significant associations between the timing of influenza epidemics in the general population and birth rates of people who later suffered from schizophrenia. Such associations have not been present in studies of the 1919 and 1957 epidemics, with sample sizes larger than those on which the claims were made. More decisively, in an investigation of the subsequent psychiatric admissions of people born a few months after the 1957 epidemic, it was found that the children of 945 mothers who actually suffered from influenza during the second trimester of pregnancy were at no greater risk of developing schizophrenia than children of mothers who were not infected. In contrast to the predictions of the influenza hypothesis of 26.5 extra cases by broad diagnostic criteria and 15.8 cases by narrow criteria, the numbers observed in children of mothers exposed to influenza in the second trimester were 3 and 1 cases respectively, close to the expected rate. It is concluded that prenatal influenza and schizophrenia are unrelated.

A six year prospective study of fibrinogen and other risk factors associated with mortality in stable claudicants.

Abstract: A total of 333 patients with stable intermittent claudication at recruitment were followed up for 6 years to determine risk factors associated with subsequent mortality. Cardiovascular diseases were the underlying cause of death in 78% of the 114 patients who died. The strongest independent predictor of death during the follow-up period was the plasma fibrinogen level, an increase of 1 milligram being associated with a nearly two-fold increase in the probability of death within the next 6 years. Age, low ankle/brachial pressure index and a past history of myocardial infarction also increased the probability of death during the study period. The plasma fibrinogen level is a valuable index of those patients with stable intermittent claudication at high risk of early mortality. The results also provide further evidence for the involvement of fibrinogen in the pathogenesis of arterial disease.

The effect of nitrous oxide on laryngeal mask cuff pressure. In vitro and in vivo studies

Abstract: Summary We have studied the effect of nitrous oxide on the cuff pressure of a laryngeal mask both in vitro and in vivo. In laboratory tests, we showed that nitrous oxide and carbon dioxide diffuse across the cuff wall much more rapidly than nitrogen and oxygen. Differing partial pressures of these gases across the cuff wall therefore give rise to changes in volume and pressure within the cuff. We then studied 18 patients undergoing general anaesthesia with nitrous oxide, and found a consistent and linear increase in cuff pressure in all patients. After 30 min, the mean pressure had increased by 30 mmHg, and there was approximately 10% nitrous oxide in the cuff. It is difficult to relate these findings to pressure on pharyngeal structures, but methods of limiting the rise in intracuff pressure are discussed.

Confirmation of an association between RFLPs at the transforming growth factor-alpha locus and non-syndromic cleft lip and palate.

Abstract: Three RFLPs at the TGFA locus were studied in 60 unrelated British Caucasian subjects with non-syndromic cleft lip/palate and 60 controls. A highly significant association between the TaqI RFLP and the occurrence of clefting was found (chi 2 = 15.04, p = less than 0.001). No significant association was found with the two other RFLPs studied (BamHI and RsaI). Haplotypes derived from the three RFLPs at the TGFA locus also showed an over-representation of the C2A2B2 haplotype in cases compared to controls. Analyses of genotypes according to type of cleft and the presence or absence of a family history of clefting were also carried out. These results provide further support for the role of TGFA as a gene of major effect in the development of orofacial clefts in humans.

The mapping of a gene for craniosynostosis: evidence for linkage of the Saethre-Chotzen syndrome to distal chromosome 7p.

Abstract: Craniosynostosis or premature closure of the cranial sutures is a common abnormality occurring in about 1 in 2500 children. There is evidence of mendelian inheritance in some 20% of cases. Published reports of patients with structural alterations of the short arm of chromosome 7 have suggested that two or more genes for craniosynostosis may be situated in this region. The Saethre-Chotzen syndrome (acrocephalosyndactyly type III) is one of the most common autosomal dominant craniosynostosis syndromes. Results of molecular genetic linkage studies provide evidence for localisation of the gene responsible to distal chromosome 7p.

Hormone replacement therapy and cardiovascular disease.

Abstract: Oestrogen alone probably confers a degree of protection against ischaemic heart disease and stroke and is appropriate for women requiring hormone replacement therapy (HRT) who have undergone hysterectomy. However, the cardiovascular effects of the progestogens used with oestrogen in the much larger number of women who have not undergone hysterectomy are unknown. Some widely used progestogens have adverse effects on lipoprotein levels and may raise blood pressure. The antithrombin III level may be involved in determining the response to oestrogen in different settings. The indications for HRT and the effects of different formulations on cardiovascular disease constitute one of the most pressing but complex issues in present-day medical practice. These questions can only be satisfactorily answered by the randomised controlled trials that should have been initiated several years ago and the feasibility of which is only now being investigated.

Sport and the overtraining syndrome: Immunological aspects

Abstract: Acute exercise of varying severity and corresponding levels of long term competition and training have been found to affect various components of the immune system including lymphocyte subsets, immunoglobulin levels, the mononuclear phagocytic system, polymorphonuclear leukocytes and cytokines, especially IL-1, IL-2, IL-6 and TNF. A tentative trend may be discerned whereby light to moderate exercise may increase immune responsiveness but high-level competition sport, especially if it involves extensive endurance training, may lead to a degree of immunosuppression. Such immune malfunction may be a component of the overtraining syndrome, in which recurrent infections during periods of maximum training or competition stress may form part of the syndrome. Evidence is presented that such overworked muscle may fail to supply adequate glutamine for normal lymphocyte function. Principles of an overtraining treatment strategy are suggested.

Cobalamin and folate: recent developments.

Abstract: Introduction New concepts in this field continue to develop at the clinical level,within the laboratory and in the realm of basic research. The appreciation that the anaesthetic gas nitrous oxide (N20) specifically inactivates the cobalamin dependent enzyme, methionine synthetase, and produces megaloblastic anaemia in man, has made it possible to perform extensive animal studies on cobalamin-folate interrelations, and to test the methylfolate trap hypothesis in a meaningful way. This has led to the development of alternative ideas as to how cobalamin regulates folate metabolism, based on a large body of data obtained from study of animals in which cobalamin was inactivated. Cobalamin neuropathy, too, has been explored in greater depth than has been possible hitherto. On the diagnostic side, considerable claims have been made for the measurement of serum methylmalonic acid as an indicator of cobalamin deficiency.

The Northwick Park ‘Functional’ Psychosis Study: diagnosis and outcome

Abstract: Three hundred and twenty-six consecutively admitted patients with functional psychotic illnesses to which no diagnostic classification had been applied were followed up after 2.5 years. They were examined in social, clinical and psychological terms and the CATEGO programme and DSM-III criteria were applied to data concerning the index episode to derive diagnostic classifications. The deterioration in occupational functioning and the hospital careers of patients with diagnostic classifications of schizophrenia were worse than those in the other groups and positive and negative features were also more severe in patients with a classification of schizophrenia. By contrast, no differences in psychological test performance were found between the groups based upon diagnostic classification. Impaired psychological test performance was found and it was strongly related to concurrent mental state abnormalities, particularly negative symptoms. It is concluded that the diagnostic classifications used were of limited value in predicting outcome in functional psychosis.

Gemfibrozil reduces plasma prothrombin fragment F1 + 2 concentration, a marker of coagulability, in patients with coronary heart disease.

Abstract: The effects of gemfibrozil on several indices of haemostatic activity were explored in male patients with coronary heart disease (CHD). Sixty-three of 71 patients completed a crossover study in which gemfibrozil 1,200 mg/day and matching placebo were each taken in randomised order for 2 months in a double-blind manner, separated by a 2-month washout period. Serum cholesterol decreased by an average (95% confidence interval) of 12 (9 to 15)% and non-fasting triglyceride concentration by 43 (34 to 51)% during active treatment. Plasma prothrombin fragment F1 + 2 concentration, a marker of the in vivo rate of generation of thrombin, was 25 (12 to 37)% lower on average while on gemfibrozil than during the placebo phase. Factor VII coagulant activity (VIIc) and antigen concentration, and fibrinopeptide A concentration were not influenced by gemfibrozil in the group overall. However, the VIIc response appeared to be dependent upon the untreated cholesterol level. Hypercholesterolaemic men (cholesterol greater than 6.5 mmol/l) experienced a significant reduction in VIIc averaging 6% of standard during active therapy. Other effects of gemfibrozil were a 5 (2 to 9)% increase in plasma fibrinogen by a gravimetric method, an 11 (8 to 13)% increase in platelet count, and a 6 (2 to 10)% reduction in white cell count. The reduced incidence of CHD following gemfibrozil therapy in hyperlipidaemic patients may arise in part through a reduction in procoagulant activity and thus the risk of an occlusive coronary thrombosis.

Apparent cleidocranial dysplasia associated with abnormalities of 8q22 in three individuals.

Abstract: Cleidocranial dysplasia is an autosomal dominant, generalised skeletal disorder characterised by variable clavicular hypoplasia, frontal bossing, multiple Wormian bones, and delayed eruption of the teeth. The gene locus for this syndrome has not yet been assigned. Three individuals with manifestations of cleidocranial dysplasia associated with rearrangements of chromosome 8q22 are described. The evidence presented suggests that the gene for cleidocranial dysplasia may be located on chromosome 8q in humans in a region showing homology to mouse chromosome 3.

Anaphylactoid reaction to propofol

Abstract: Summary A case of an anaphylactoid reaction following the induction of anaesthesia is reported. Subsequent intradermal testing suggested propofol to be the causative agent.

Hypothesis: Age-associated Changes in Gait Represent, in Part, a Tendency towards Parkinsonism

Abstract: In 144 healthy, active, asymptomatic volunteers (aged 30-88 years), age explained 33% of the variance in free walking speed. This could not be ascribed simply to differences in physique at maturity, since height had a more important effect on speed (p less than 0.0001) than did leg length (p less than 0.01). Multiple linear regression was used to fit models for speed, by selection from four sets of variables: common physical, body sway, functional anatomy of spine and lower limbs, and psychometric. The best model (which included age) explained little more of the variance (41%) than did age alone. Moreover, incorporation of age into the alternative model, built in its absence, still contributed significantly (p less than 0.0001) to the variance explained. The effect of age on gait appeared to be complex, with an increment in double support time disproportionate to the reduction in speed. We formulate by exclusion, the hypothesis that age-associated changes in gait represent, in part, a tendency towards parkinsonism.

Cerebral edema following acute sodium valproate overdose.

Abstract: We report a case of cerebral edema resulting from acute sodium valproate poisoning. This was associated with abnormalities of liver and renal function, hypocalcaemia and generalized muscle spasms.

Plasma fibrinogen and factor VII as risk factors for cardiovascular disease.

Abstract: The importance of the thrombotic component of coronary heart disease is increasingly recognised, and in particular the role of the coagulation system in this process. The Northwick Park Heart study was the first major prospective study to identify both fibrinogen and factor VIIc as risk factors, as powerful as total cholesterol in predicting ischaemic events. Since then, a number of epidemiological studies have confirmed the importance of fibrinogen, not just in CHD but in stroke as well. A variety of environmental factors are known to influence levels of factor VII and fibrinogen and therefore support their role in the development of coronary thrombosis. Both are known to increase with age and body weight and are relatively elevated in diabetes. Fibrinogen is strongly related to smoking habit and a substantial proportion of the IHD risk associated with smoking is mediated through this relationship. There is a dose response effect between number of cigarettes smoked and level of fibrinogen and an inverse relationship with time since cessation of the habit. Factor VII is known to correlate with total cholesterol level, and there is a relationship between dietary variability of fat intake and factor VII, which is likely to play an important role in the risk of CHD. The case for using either anticoagulation or anti platelet agents in secondary prevention of myocardial infarction is now clear, but there are still uncertainties in primary prevention which relate to the ideal dose intensity of either aspirin or anti-coagulation and the type of patient most likely to benefit. The ongoing Thrombosis Prevention Trial identifies middle-aged males at high risk of a myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)