Showing papers by "Guy's and St Thomas' NHS Foundation Trust published in 2000"

Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel.

Abstract: Sexual dysfunction is highly prevalent in both sexes and adversely affects patients' quality of life and well being. Given the frequent association between sexual dysfunction and cardiovascular disease, in addition to the potential cardiac risk of sexual activity itself, a consensus panel was convened to develop recommendations for clinical management of sexual dysfunction in patients with cardiovascular disease. Based upon a review of the research and presentations by invited experts, a classification system was developed for stratification of patients into high, low, and intermediate categories of cardiac risk. The large majority of patients are in the low-risk category, which includes patients with (1) controlled hypertension; (2) mild, stable angina; (3) successful coronary revascularization; (4) a history of uncomplicated myocardial infarction (MI); (5) mild valvular disease; and (6) no symptoms and /=3 risk factors for coronary artery disease. These patients should receive further cardiologic evaluation before restratification into the low- or high-risk category. Finally, patients in the high-risk category include those with (1) unstable or refractory angina; (2) uncontrolled hypertension; (3) congestive heart failure (class III or IV); (4) very recent MI (<2 weeks); (5) high-risk arrhythmias; (6) obstructive cardiomyopathies; and (7) moderate-to-severe valvular disease. These patients should be stabilized by specific treatment for their cardiac condition before resuming sexual activity or being treated for sexual dysfunction. A simple algorithm is provided for guiding physicians in the management of sexual dysfunction in patients with varying degrees of cardiac risk.

Reliability of immunohistochemical demonstration of oestrogen receptors in routine practice: interlaboratory variance in the sensitivity of detection and evaluation of scoring systems.

Abstract: Aims —To investigate interlaboratory variance in the immunohistochemical (IHC) detection of oestrogen receptors so as to determine the rate of false negatives, which could adversely influence the decision to give adjuvant tamoxifen treatment. Methods —To ensure that similar results are obtained by different institutions, 200 laboratories from 26 countries have joined the UK national external quality assessment scheme for immunocytochemistry (NEQAS-ICC). Histological sections from breast cancers having low, medium, and high levels of oestrogen receptor expression were sent to each of the laboratories for immunohistochemical staining. The results obtained were evaluated for the sensitivity of detection, first by estimating threshold values of 1% and 10% of stained tumour cells, and second by the Quick score method, by a panel of four assessors judging individual sections independently on a single blind basis. The results were also evaluated using participants' own threshold values. Results —Over 80% of laboratories were able to demonstrate oestrogen receptor positivity on the medium and high expressing tumours, but only 37% of laboratories scored adequately on the low expressing tumour. Approximately one third of laboratories failed to register any positive staining in this tumour, while one third showed only minimal positivity. Conclusions —There is considerable interlaboratory variability, especially in relation to the detection of breast cancers with low oestrogen receptor positivity, with a false negative rate of between 30% and 60%. This variability appears to be caused by minor differences in methodology that may be rectified by fine adjustment of overall technique.

A Role for Id-1 in the Aggressive Phenotype and Steroid Hormone Response of Human Breast Cancer Cells

Abstract: The helix-loop-helix protein Id-1 inhibits the activity of basic helix-loop-helix transcription factors, and is an important regulator of cell growth and tissue-specific differentiation. We have shown (P. Y. Desprez et al., Mol. Cell. Biol., 18: 4577-4588, 1998) that ectopic expression of Id-1 inhibits differentiation and stimulates the proliferation and invasiveness of mouse mammary epithelial cells, and that there is a correlation between the levels of Id-1 protein and the aggressiveness of several human breast cancer cell lines. Here, we show that aggressive and metastatic breast cancer cells express high levels of Id-1 mRNA because of a loss of serum-dependent regulation that is mediated by a 2.2-kb region of the human Id-1 promoter. Three lines of evidence suggest that unregulated Id-1 expression may be an important regulator of the aggressive phenotype of a subset of human breast cancer cells: (a) a constitutively expressed Id-1 cDNA, when introduced into a nonaggressive breast cancer cell line (T47D), conferred a more aggressive phenotype, as measured by growth and invasiveness; (b) Id-1 was an important mediator of the effects of sex steroid hormones on T47D cell proliferation. Estrogen stimulated proliferation and induced Id-1 expression, whereas progesterone inhibited proliferation and repressed Id-1 expression. Progesterone repressed Id-1 expression, at least in part by repressing transcription. Most importantly, an antisense oligonucleotide that reduced Id-1 protein levels reduced the ability of estrogen to stimulate cell proliferation, whereas constitutive Id-1 expression rendered cells refractory to growth inhibition by progesterone; and (c) using a limited number of breast cancer biopsies, we showed that Id-1 was more frequently expressed in infiltrating carcinomas compared with ductal carcinomas in situ. Our results suggest that Id-1 can control the malignant progression of breast cancer cells, particularly that mediated by sex steroid hormones. Moreover, Id-1 has the potential to serve as a marker for aggressive breast tumors.

Defective intracellular antioxidant enzyme production in type 1 diabetic patients with nephropathy

Abstract: There is an individual susceptibility to diabetic nephropathy, and oxidative stress is believed to play an important role in the pathogenesis of diabetic complications. Active oxygen species induce antioxidant enzyme expression in tissues, an effect considered to be a defensive mechanism. To test whether altered intracellular antioxidant enzyme production might explain the predisposition to diabetic nephropathy, we studied the effect of long-term (12 weeks) exposure to normal (5 mmol/l) or high (22 mmol/l) glucose concentrations on fibroblast antioxidant enzyme gene expression and protein activity in type 1 diabetic patients with and without nephropathy, nondiabetic nephropathic patients, and nondiabetic control subjects. Under conditions of normal glucose concentration in the culture media, CuZnSuperoxide-dismutase, MnSuperoxide-dismutase, catalase, and glutathione-peroxidase activity and mRNA expression were not different among the four groups. Under high-glucose conditions, CuZnSuperoxide-dismutase mRNA and activity increased similarly in all groups (P < 0.001 vs. basal), whereas MnSuperoxide-dismutase did not change. In contrast, catalase mRNA and activity as well as glutathione-peroxidase mRNA and activity increased in fibroblasts from type 1 diabetic patients without nephropathy (P < 0.001), in fibroblasts from nondiabetic nephropathic patients (P < 0.001), and in fibroblasts from nondiabetic control subjects (P < 0.001), but not in fibroblasts from type 1 diabetic patients with nephropathy. Exposure to high glucose concentrations significantly increased lipid peroxidation in cells, higher levels being found in cells from diabetic patients with nephropathy (P < 0.001). These data, while confirming that exposure to high glucose concentrations induces an antioxidant defense in skin fibroblasts from normal subjects, demonstrate a failure of this defensive mechanism in cells from type 1 diabetic patients with nephropathy, whereas skin fibroblasts from diabetic patients without complications or from nondiabetic nephropathic patients have an intact antioxidant response to glucose-induced oxidative stress.

Antifibrinolytics for heavy menstrual bleeding.

Abstract: Background Heavy menstrual bleeding (HMB) is an important cause of ill health in women. Medical therapy with the avoidance of possibly unnecessary surgery is an attractive treatment option. A wide variety of medications are available to reduce heavy menstrual bleeding but there is considerable variation in practice and uncertainty about the most appropriate therapy. Plasminogen activators are a group of enzymes that cause fibrinolysis (the dissolution of clots). An increase in the levels of plasminogen activators has been found in the endometrium of women with heavy menstrual bleeding compared to those with normal menstrual loss. Plasminogen activator inhibitors (antifibrinolytic agents) have therefore been promoted as a treatment for heavy menstrual bleeding. There has been a reluctance to prescribe tranexamic acid due to possible side effects of the drugs such as an increased risk of thrombogenic disease (deep venous thrombosis). Long term studies in Sweden however have shown that the rate of incidence of thromobosis in women treated with tranexamic acid is comparable with the spontaneous frequency of thrombosis in women. Objectives To determine the effectiveness of antifibrinolytics in achieving a reduction in heavy menstrual bleeding. Search strategy We searched the Cochrane Menstrual Disorders & Subfertility Group trials register (searched 6 April 2004) the Cochrane Central Register of Controlled Trials (CENTRAL)(The Cochrane Library Issue 1 2004) MEDLINE (1966 to April 2004) EMBASE (1985 to April 2004) and reference lists of articles. We also contacted manufacturers and researchers in the field. Selection criteria Randomised controlled trials in women of reproductive age treated with antifibrinolytic agents versus placebo no treatment or any other medical (non-surgical) therapy for regular heavy menstrual bleeding within either the primary family planning or specialist clinic settings. Women with post menopausal bleeding intermenstrual bleeding iatrogenic or pathological causes of heavy menstrual bleeding were excluded. Data collections and analysis Fifteen eligible trials were assessed by three reviewers and eight of these did not meet with the inclusion criteria. Of the seven remaining trials four of these could be included within the meta- analysis. The remaining three trials had a crossover design and despite contacting the authors and appropriate companies we were unable to extract the results in a format suitable to include these within the meta-analysis. However the results are included within the text of the review for discussion. Main results Antifibrinolytic therapy compared to placebo shoed a significant reduction in mean blood loss (weighted mean difference (WMD) -94.0 95% confidence interval (CI) -151.4 to -36.5]) and significant change in mean reduction of blood loss (WMD -110.2 95% CI -146.5 to -73.8]). This objective improvement was not mirrored by a patient perceived improvement in monthly menstrual blood loss relative risk (RR) 2.5 95% CI 0.9 to 7.3) in the one study which recorded this outcome (Edlund 1995). Antifibrinolytic agents were compared on only three other medical (non-surgical) therapies mefenamic acid norethisterone administered in the luteal phase and ethamsylate. In all instances there was a significant reduction in mean blood loss (WMD -73.0 95% CI -123.4 to -22.6; WMD -111.0 95% CI -178.5 to -43.5; and WMD -100 95% CI - 143.9 to -56.1 respectively) and a strong although non-significant trend in favour of tranexamic acid in the participants perception of an improvement in menstrual blood loss. There were no significant differences in the frequency of reported side effects with tranexamic acid when compared to oral luteal phase progestogens (RR 0.4 95% CI 0.1 to 1.2) or withdrawal from treatment because of adverse events when compared with NSAIDs and ethamsylate when these treatments were used for heavy menstrual bleeding. Change in the quality of life measures flooding and leakage and sex life were significantly improved in the tranexamic acid group when compared to the oral progestagen group. These findings are based in most cases on only one trial. Authors conclusions Antifibrinolytic therapy causes a greater reduction in objective measurements of heavy menstrual bleeding when compared to placebo or other medical therapies (NSAIDS oral luteal phase progestagens and ethamsylate). This treatment is not associated with an increase in side effects compared to placebo NSAIDS oral luteal phase progestagens or ethamsylate. Flooding and leakage and sex life is significantly improved after tranexamic acid therapy when compared with oral luteal progestogens but no other measures of quality of life were assessed. No study has used resource cost as an outcome. There are no data available within randomised controlled trials which record the frequency of thromboembolic events. (authors)

A hypothetical scheme for the brainstem control of vertical gaze.

Abstract: Objectives: To develop a hypothetical scheme to account for clinical disorders of vertical gaze based on recent insights gained from experimental studies. Methods: The authors critically reviewed reports of anatomy, physiology, and effects of pharmacologic inactivation of midbrain nuclei. Results: Vertical saccades are generated by burst neurons lying in the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF). Each burst neuron projects to motoneurons in a manner such that the eyes are tightly coordinated (yoked) during vertical saccades. Saccadic innervation from riMLF is unilateral to depressor muscles but bilateral to elevator muscles, with axons crossing within the oculomotor nucleus. Thus, riMLF lesions cause conjugate saccadic palsies that are usually either complete or selectively downward. Each riMLF contains burst neurons for both up and down saccades, but only for ipsilateral torsional saccades. Therefore, unilateral riMLF lesions can be detected at the bedside if torsional quick phases are absent during ipsidirectional head rotations in roll. The interstitial nucleus of Cajal (INC) is important for holding the eye in eccentric gaze after a vertical saccade and coordinating eye–head movements in roll. Bilateral INC lesions limit the range of vertical gaze. The posterior commissure (PC) is the route by which INC projects to ocular motoneurons. Inactivation of PC causes vertical gaze-evoked nystagmus, but destructive lesions cause a more profound defect of vertical gaze, probably due to involvement of the nucleus of the PC. Vestibular signals originating from each of the vertical labyrinthine canals ascend to the midbrain through several distinct pathways; normal vestibular function is best tested by rotating the patient’s head in the planes of these canals. Conclusions: Predictions of a current scheme to account for vertical gaze palsy can be tested at the bedside with systematic examination of each functional class of eye movements.

Analysis of genetic and phenotypic heterogeneity in juvenile polyposis.

Abstract: Background—Juvenile polyposis syndrome (JPS) is characterised by gastrointestinal (GI) hamartomatous polyposis and an increased risk of GI malignancy. Juvenile polyps also occur in the Cowden (CS), Bannayan-Ruvalcaba-Riley (BRRS) and Gorlin (GS) syndromes. Diagnosing JPS can be problematic because it relies on exclusion of CS, BRRS, and GS. Germline mutations in the PTCH, PTEN and DPC4 (SMAD4) genes can cause GS, CS/BRRS, and JPS, respectively. Aims—To examine the contribution of mutations in PTCH, PTEN, and DPC4 (SMAD4) to JPS. Methods—Forty seven individuals from 15 families and nine apparently sporadic cases with JPS were screened for germline mutations in DPC4, PTEN, and PTCH. Results—No patient had a mutation in PTEN or PTCH. Five diVerent germline mutations were detected in DPC4; three of these were deletions, one a single base substitution creating a stop codon, and one a missense change. None of these patients had distinguishing clinical features. Conclusions—Mutations in PTEN and PTCH are unlikely to cause juvenile polyposis in the absence of clinical features indicative of CS, BRRS, or GS. A proportion of JPS patients harbour DPC4 mutations (21% in this study) but there remains uncharacterised genetic heterogeneity in JPS. (Gut 2000;46:656‐660)

The Exon 13 Duplication in the BRCA1 Gene Is a Founder Mutation Present in Geographically Diverse Populations

Abstract: Recently, a 6-kb duplication of exon 13, which creates a frameshift in the coding sequence of the BRCA1 gene, has been described in three unrelated U.S. families of European ancestry and in one Portuguese family. Here, our goal was to estimate the frequency and geographic diversity of carriers of this duplication. To do this, a collaborative screening study was set up that involved 39 institutions from 19 countries and included 3,580 unrelated individuals with a family history of the disease and 934 early-onset breast and/or ovarian cancer cases. A total of 11 additional families carrying this mutation were identified in Australia (1), Belgium (1), Canada (1), Great Britain (6), and the United States (2). Haplotyping showed that they are likely to derive from a common ancestor, possibly of northern British origin. Our results demonstrate that it is strongly advisable, for laboratories carrying out screening either in English-speaking countries or in countries with historical links with Britain, to include within their BRCA1 screening protocols the polymerase chain reaction–based assay described in this report.

Transmission of IgA and IgG monoclonal antibodies to mucosal fluids following intranasal or parenteral delivery.

Abstract: Background: The efficacy by which passive antibodies can reach the lungs could be important for the outcome of immunotherapy of respiratory pulmonary infections. We examined how tra

Diversity in epilepsy and a newly recognized benign childhood syndrome.

Abstract: Epilepsy affects 1 to 2% of the population in developed countries.1 Epilepsy is not a single disorder but rather a label for many heterogeneous syndromes characterized by underlying etiology, age at onset, seizure type, EEG patterns, and prognosis.2,3⇓ Accurate diagnosis of each syndrome is necessary for both evaluation and treatment. A prime example of this heterogeneity is the class of idiopathic disorders with age-related onset. One of the best known and most common of these is benign rolandic epilepsy (BRE). The recognition of this heterogeneity within the epilepsies has been formalized in the International League Against Epilepsy’s (ILAE) classification of the epilepsies.2 This system is under revision to reflect advances in our understanding of the epilepsies and to include new syndromes as they become …

Endomysial antibody production is not related to histological damage after in vitro gluten challenge.

Abstract: Objective To determine whether in vitro induction of endomysial antibodies is an in vitro marker of coeliac toxicity. Design To determine whether in vitro endomysial antibodies induced by gliadin incubation correlate with histological damage induced by in vitro gliadin challenge. Methods Small-bowel organ cultures from seven patients with treated coeliac disease were incubated in an organ culture system with gliadin; histological damage was morphometrically evaluated and endomysial antibodies were measured in the organ culture supernatant by indirect immunofluorescence. Results Although incubation with gliadin caused histological damage, there was no detectable production of endomysial antibody. Conclusions In vitro, endomysial antibody induction cannot be used as a marker of coeliac toxicity. Endomysial antibodies are not necessary for generating the histological lesion of coeliac disease.

Morphologic preservation and variability of human donor retina.

Abstract: PURPOSE: To facilitate studies of human retina and utilization of human retinal tissue for treatment of retinal diseases, we studied morphologic preservation in postmortem human retina. METHODS: Morphology of retinas from thirty-one human eyes was examined using light and electron microscopy. The inner and outer retina, rod and cone photoreceptor cells, and central and peripheral retina were compared with regard to morphologic preservation. Possible factors affecting survival were analyzed. RESULTS: The earliest postmortem change was vacuolation of the nerve fiber layer within a few hours postmortem, followed by vacuolation and cytoplasmic swelling of the inner retina. As compared with the inner retina, outer retinal structure was better preserved, i.e., the photoreceptor cells maintained better morphology. Rod cell morphology was better preserved than cone cell morphology, with good preservation of the rod outer segment disc membranes and the inner segment mitochondrial membranes. Thus, well-preserved rod photoreceptor cells were evident in specimens at least 48-hours postmortem. Peripheral retina was better preserved than the central retina including the fovea and perifovea. Factors affecting anatomical integrity included the total time postmortem and, more importantly, the time between death and enucleation. Other factors, including age and sex, did not appear to affect morphological preservation in the present study. CONCLUSIONS: Human retina postmortem remained morphologically intact for a relatively long period of time, with differential preservation among different geographic areas and cell types. This morphologic evidence is consistent with previous findings of functional preservation (e.g. , photoresponses) in such tissue. This study may shed some light on understanding of human retina and its utilization for retinal transplantation.

Balloon pulmonary valvuloplasty in carcinoid syndrome

Abstract: Half of all patients with carcinoid syndrome develop cardiac involvement. Patients who have cardiac involvement have a significantly worse prognosis than those without, and death can occur directly as a result of cardiac involvement. A case of carcinoid syndrome in a 38 year old woman with lesions in the liver, who presented with right sided valvar abnormalities, a dilated right ventricle, and right ventricular pressure overload, is presented. In order to palliate the patient's symptoms and to decrease right sided pressures before major abdominal surgery, balloon pulmonary valvuloplasty was performed at the time of cardiac catheterisation. This resulted in a reduction in the pulmonary gradient and right ventricular pressure. Following the procedure, the patient's symptoms were completely relieved. She went on to laparotomy where the lesions in the liver were excised without complication.

Effects of electrobrightening on the fit surface of cobalt-chromium RPD frameworks

Abstract: Purpose: The purpose of this study was to compare 3 different electrobrightening techniques and 3 electrolytic solutions in their effects upon the fit surface of cast cobalt-chromium frameworks. Materials and Methods: Fifty cast cobalt-chromium frameworks, which were subsequently divided into batches of 10, were prepared according to a standard protocol. Three electrobrightening techniques were tested initially using a single brand of electrolyte (Croform) and a batch of 10 frameworks per technique. The loss of metal by weight was determined from the fit surface of each casting. The least corrosive technique of these 3 was used again0 with 2 other brands of electrolyte (Nobilium and E501) in a repetition of the protocol. The fit surfaces of 8 random samples cut from each batch of electrobrightened castings were viewed by scanning electron microscope (SEM). Results: Statistical analysis applying a one-way analysis of variance and Bonferroni's multiple comparison of means test demonstrated that one immersion of the framework for 10 minutes at 1 amp when used in conjunction with Nobilium electrolyte removed the least metal (P = 0.001). The SEM study suggested that the Nobilium electrolyte also produced the smoothest surface. Conclusion: Electrobrightening techniques affect the amount of metal removed, and the electrolytic solution used influences the resultant surface.