Clinical effectiveness and cost-consequences of selective serotonin reuptake inhibitors in the treatment of sex offenders.
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Androgen Antagonists↗
Biomedical subjects
K Browne
Publications and source records attributed to K Browne.
The quantitative risks of mesothelioma and lung cancer in relation to asbestos exposure.
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Asbestos↗
Asbestos exposure and laryngeal cancer.
OBJECTIVE: To carry out a systematic review of the evidence relating asbestos exposure to the risk of laryngeal cancer. METHOD: All identified studies of asbestos workers providing data on laryngeal disease were reviewed, together with studies of laryngeal cancers giving epidemiological or experimental evidence of associated exposures. RESULTS: Confounding due to smoking and alcohol intake, and to a lesser extent diet and socio-economic factors, creates a major difficulty over the identification of any asbestos or other occupational effect. Not only are smoking and alcohol independently associated with large increases in relative risk (RR) of laryngeal cancer, but also have a synergistic effect with each other. Few of the studies provide details of either habit. Among 24 prospective studies for which a standardized mortality ratio (SMR) was available, nine had an SMR at or below unity, and among a further 11 without an SMR for comparison, in only one was there a clear excess risk. In 17 retrospective studies, only two showed a significantly increased RR. Evidence from animal experiments, studies of associations with pleural plaques, and autopsy findings also appear negative or inconclusive. CONCLUSION: The evidence does not indicate that asbestos exposure increases the RR of laryngeal cancer.
Asbestos↗
Maintenance of sinus rhythm with oral d,l-sotalol therapy in patients with symptomatic atrial fibrillation and/or atrial flutter. d,l-Sotalol Atrial Fibrillation/Flutter Study Group.
Currently d,l-sotalol is widely used to prevent recurrence of atrial fibrillation and/or atrial flutter, although a randomized dose-response study has not previously been conducted to guide therapy for this indication. This study summarizes findings of a double-blind, placebo-controlled, multicenter, randomized trial evaluating the efficacy, safety, and dose-response relation of 3 fixed doses of d,l-sotalol (80, 120, and 160 mg twice daily) for the maintenance of sinus rhythm in 253 patients with atrial fibrillation and/or atrial flutter. All patients were in sinus rhythm at randomization. Treatment (69 patients on placebo, 59 on 80 mg, 63 on 120 mg, and 62 on 160 mg given twice daily) was continued for 12 months or until documented recurrence of symptomatic atrial fibrillation and/or flutter. Transtelephonic electrocardiographic monitoring was used to detect symptomatic recurrences. Demographic characteristics were not different in the 4 groups. Structural heart disease was present in 57% of patients. Patients with a history of heart failure were excluded. The time from randomization to symptomatic arrhythmia recurrence was significantly longer in the 2 higher d,l-sotalol dose groups than in the placebo group. The median times to recurrence were 27, 106, 229, and 175 days for the placebo, 80, 120, and 160 mg groups, respectively. There were no deaths or cases of torsade de pointes, sustained ventricular tachycardia, or ventricular fibrillation reported. Thus, d,l-sotalol appeared to be both safe and effective in maintaining sinus rhythm in patients with symptomatic atrial fibrillation and/or flutter. Further, the 120-mg twice daily dose appeared to provide the most favorable benefit and/or risk.
Anti-Arrhythmia Agents↗
Paradoxical effects of adenovirus-mediated blockade of TNF activity in murine collagen-induced arthritis.
Collagen-induced arthritis (CIA) is an experimental model of arthritis widely used to dissect the pathogenesis of human rheumatoid arthritis and to identify potential therapeutic targets. Among these, TNF-alpha has been recognized to play an important role. Here we investigate the feasibility and therapeutic efficacy of prolonged blockade of TNF-alpha activity through the adenovirus-mediated gene delivery of a dimeric chimeric human p55 TNFR-IgG fusion protein and compare it to protein therapy in established CIA. A single i.v. administration of the replication-deficient adenovirus yielded microgram serum levels of the chimeric fusion protein and ameliorated CIA for 10 days. Subsequently, benefit was lost and a rebound to greater inflammatory activity was observed despite the continual presence of bioactive TNFR fusion protein. A similar trend was also observed in mice injected directly with comparable amounts of a human TNFR-IgG fusion protein, whereas the administration of a control adenovirus-encoding beta-galactosidase or of a control human IgG1 protein did not significantly affect the disease course. The mechanisms of the rebound of CIA were investigated, and augmented Ab response to collagen type II and TNFR were identified as potential causes. Our results confirm the feasibility of adenovirus-mediated gene delivery of cytokine inhibitors in animal models of autoimmune diseases for investigational purposes and highlight the importance of prolonged studies. Further investigations are needed to optimize ways of exploiting the potential of adenoviral gene therapy in RA.
Abatacept↗
Efficient adenoviral infection with IkappaB alpha reveals that macrophage tumor necrosis factor alpha production in rheumatoid arthritis is NF-kappaB dependent.
Tumor necrosis factor (TNF) alpha has been shown to be a major therapeutic target in rheumatoid arthritis with the success of anti-TNFalpha antibody clinical trials. Although signaling pathways leading to TNFalpha expression have been studied in some detail, there is evidence for considerable differences between individual cell types. This prompted us to investigate the intracellular signaling pathways that result in increased TNFalpha synthesis from macrophages in the diseased synovial joint tissue. Using an adenoviral system in vitro we report the successful delivery of genes to more than 95% of normal human macrophages. This permitted us to show, by using adenoviral transfer of IkappaB alpha, the natural inhibitor of NF-kappaB, that induction of TNFalpha in normal human macrophages by lipopolysaccharide, but not by some other stimuli, was inhibited by 80%. Furthermore the spontaneous production of TNFalpha from human rheumatoid joint cell cultures was inhibited by 75%, indicating that the NF-kappaB pathway is an essential step for TNFalpha synthesis in synovial macrophages and demonstrating that NF-kappaB should be an effective therapeutic target in this disease.
Adenoviridae↗
Real-time measurement of skin radiation during cardiac catheterization.
A novel skin dose monitor was used to measure radiation incident on maximal X-ray exposed skin during 135 diagnostic and 65 interventional coronary procedures. For the diagnostic studies (n = 135), mean skin dose was 180 +/- 64 mGy; for PTCA (n = 35), it was 1021 +/- 674 mGy, single stents (n = 25) 1529 +/- 601 mGy, and multiple stents with rotational atherectomy (n = 5) 2496 +/- 1028 mGy. The dose independently increased with more cine runs, more fluoroscopy, and greater patient weight. Physicians should consider the potential for adverse radiation exposure when planning coronary interventional cases and deciding on the X-ray mode and angles used.
Angioplasty, Balloon, Coronary↗
Local gene therapy with CTLA4-immunoglobulin fusion protein in experimental allergic encephalomyelitis.
It has been reported previously that the induction phase of experimental allergic encephalomyelitis (EAE) is highly sensitive to systemic blockade of stimulation via MHC class II molecules and co-stimulation via the CD28:CD80/CD86 pathways. In contrast, the effector phases of EAE were relatively unaffected by similar treatments using MHC class II antigen (Ag)-specific mAb and cytotoxic T lymphocyte antigen (CTLA)4-Ig fusion proteins in some studies. This has been attributed to different sensitivities of effector cell function or the poor penetrance of inhibitory proteins into the central nervous system (CNS). To examine this question further, MHC class II Ag-specific mAb and CTLA4-Ig were delivered directly into the CNS following EAE induction, and both were found to inhibit disease. While it was found that systemic administration of mouse CTLA4-Ig could also inhibit the progression of effector immune responses when administered shortly before or during clinical disease, these were significantly more active when delivered directly into the CNS, which probably involved an action on both CD28 ligands, CD80 and CD86. Although mouse CTLA4-human Ig was therapeutically less efficient than mouse CTLA4-mouse Ig protein, probably due to the enhanced immunogenicity and lower functional activity, gene delivery of CTLA4-human Ig into the CNS using a non-replicating adenoviral vector was more effective than a single injection of CTLA4-human Ig protein. Gene delivery significantly ameliorated the development of EAE, without necessarily inhibiting unrelated peripheral immune responsiveness. Local gene delivery of CTLA4-Ig may thus be an important target for immunotherapy of human autoimmune conditions such as multiple sclerosis.
Abatacept↗
Granzyme B (GraB) autonomously crosses the cell membrane and perforin initiates apoptosis and GraB nuclear localization.
Granzyme B (GraB) induces apoptosis in the presence of perforin. Perforin polymerizes in the cell membrane to form a nonspecific ion pore, but it is not known where GraB acts to initiate the events that ultimately lead to apoptosis. It has been hypothesized that GraB enters the target cell through a perforin channel and then initiates apoptosis by cleaving and activating members of the ICE/Ced-3 family of cell death proteases. To determine if GraB can enter the cell, we treated YAC-1 or HeLa cells with FITC-labeled GraB and measured intracellular fluorescence with a high sensitivity CCD camera and image analyzer. GraB was internalized and found diffusely dispersed in the cell cytoplasm within 10 min. Uptake was inhibited at low temperature (4 degrees C) and by pretreatment with metabolic inhibitors, NaF and DNP, or cytochalasin B, a drug that both blocks microfilament formation, and FITC-GraB remained on the cell membrane localized in patches. With the simultaneous addition of perforin and FITC-GraB, no significant increase in cytoplasmic fluorescence was observed over that found in cells treated only with FITC-GraB. However, FITC-GraB was now detected in the nucleus of apoptotic cells labeling apoptotic bodies and localized areas within and along the nuclear membrane. The ability of GraB to enter cells in the absence of perforin was reexamined using anti-GraB antibody immunogold staining of ultrathin cryosections of cells incubated with GraB. Within 15 min, gold particles were detected both on the plasma membrane and in the cytoplasm of cells with some gold staining adjacent to the nuclear envelope but not in the nucleus. Cells internalizing GraB in the absence of perforin appeared morphologically normal by Hoechst staining and electron microscopy. GraB directly microinjected into the cytoplasm of B16 melanoma cells induced transient plasma membrane blebbing and nuclear coarsening but the cells did not become frankly apoptotic unless perforin was added. We conclude that GraB can enter cells autonomously but that perforin initiates the apoptotic process and the entry of GraB into the nucleus.
Animals↗
Malignant mesothelioma in south east England: clinicopathological experience of 272 cases.
BACKGROUND: Malignant mesothelioma is a rare pleural tumour associated with asbestos exposure. The proportion of malignant mesothelioma unrelated to asbestos exposure, and any differentiating features between exposed and unexposed cases, are not well described. This study describes occupational, clinical, and pathological features in a large cohort of cases of malignant mesothelioma from south east England. METHODS: All 272 cases from this region were studied, either in life or after death when necropsy examination suggested malignant mesothelioma. Detailed information was gathered regarding the occupational history, clinical course, and mode of death. Necropsies were performed in 98% of cases. Lung tissue was examined histologically to confirm the diagnosis, subtype of tumour, presence or absence of asbestosis and asbestos bodies. RESULTS: Exposure to asbestos was documented in 87% of cases, while in the remainder, no asbestos exposure was found nor were asbestos bodies seen; 94.5% were pleural, 5.1% peritoneal, and 0.4% pericardial. Right sided tumours were more common than left sided tumours (ratio 1.6:1). Patients usually presented with breathlessness and chest pain, but 33% presented with pleural effusion in the absence of chest pain. The mean (SD) time from first exposure to asbestos to symptoms was 40 (12) years with a median (interquartile range (IQR) survival of 14 (12.5) months. The median (IQR) survival time in sarcomatous, epithelial, and mixed cell type malignant mesothelioma was 9.4 (10) months, 12.5 (18) months, and 11 (14) months, respectively, and was significantly greater in cases detected by chance. Clinical features were similar in asbestos related and non-asbestos related malignant mesothelioma. CONCLUSIONS: In south east England most cases of malignant mesothelioma are associated with asbestos exposure. Clinical features do not differentiate between asbestos related and non-asbestos related disease.
Adult↗
Poloxamer-188 as an adjunct to primary percutaneous transluminal coronary angioplasty for acute myocardial infarction.
Poloxamer-188 is a surfactant polymer with antithrombotic and hemorheologic properties that make it potentially useful as an adjunct to acute reperfusion strategies. Animal studies and early human studies have documented poloxamer-188 to be effective at improving myocardial salvage when used as an adjunct to intravenous thrombolytic therapy for acute myocardial infarction. The current trial was a prospective pilot study involving 150 patients who were randomized in a 2:1 fashion to a poloxamer-188 infusion for 48-hours versus placebo. The poloxamer-188 infusion was well tolerated subjectively. The only clinically significant laboratory abnormality noted was an elevation in the serum creatinine above 2.0 g/dl in 12% (n = 12) of the 98 poloxamer-188 treated patients versus 1 of the 52 (2%) of the placebo treated patients (p = 0.048). Clinical end points including reinfarction (1% vs 4%), cardiogenic shock (7% vs 6%), and death (9% vs 4%) were statistically similar in the poloxamer-188 and placebo groups, respectively (p = NS). Using quantitative nuclear techniques, final infarct size and myocardial salvage were statistically similar in the poloxamer-188 and placebo groups. Mean left ventricular ejection fractions 1 week post after infarction were 51% +/- 12% in the poloxamer-188 group and 52% +/- 13% in the placebo group (p = NS). Final infarct size, was not altered by the poloxamer- 188 infusion; however, it was significantly correlated with normal perfusion (Thrombolysis in Myocardial Infarction grade 3 flow) in the infarct vessel after angioplasty. This study documented poloxamer-188 to be ineffective as an adjunct to primary angioplasty for acute myocardial infarction and resulted in azotemia in 12% of the patients.
Aged↗
Mesothelioma in a community in the north of England.
OBJECTIVES: To find the numbers of mesotheliomas in Calderdale over the period 1966-94 and determine their relation to asbestos exposure, pathology, and mineral fibre burden within the lungs of affected subjects. METHODS: Cases were entered into the study if the subject has been diagnosed with mesothelioma after postmortem and histopathological examinations. Occupational data were obtained mainly from the case records of the Cape Asbestos medical officer, hospital, and medical practitioner and from death certificates. Analyses of the mineral fibres were performed with transmission electron microscopy and energy dispersive x ray spectrometry. RESULTS: 73 mesotheliomas were diagnosed from 1966 to 1994. Forty four were associated with exposure at the Acre Mill factory, which manufactured asbestos products. Concentrations of amphibole asbestos fibres were found to be raised above controls in 31 out of 32 cases associated with Acre Mill exposure, in 10 out of 12 other cases exposed to asbestos and eight out of 17 cases not exposed to asbestos. CONCLUSIONS: There was a high number of mesotheliomas in Calderdale. More than half of the cases were associated with occupation at the Acre Mill factory and were associated with exposure to amphibole asbestos, predominantly crocidolite. No cases associated with neighbourhood exposure to asbestos were identified.
Adult↗
Asbestos-related bilateral diffuse pleural thickening: natural history of radiographic and lung function abnormalities.
Sixty-four subjects with asbestos-related diffuse pleural thickening attending the London Medical Boarding Centre for Respiratory Diseases (formerly, the Central Pneumoconiosis Panel) were studied to investigate symptomatology, lung function, and radiographic change over an average period of 8 to 9 yr. Chest pain was a common symptom, occurring in over half of the subjects. Approximately one-third of the subjects had a history of pleurisy or pleural effusion. Full long function, available in all cases, showed a highly significant decrement (p < 0.001) compared with predicted values in all variables except gas transfer coefficient (Kco) at initial presentation, consistent with a restrictive ventilatory defect. Longitudinal lung function, available over a mean period of 8.9 yr in 36 subjects, showed a significant decrement above that predicted in FEV1 and FVC only (p < 0.05). Decreases in other parameters were observed, although statistical significance was not achieved. Radiographic score increased with time but there was no correlation between change in lung function and increasing radiographic score, probably reflecting the initial severity of the disease in subjects studied. These observations confirm an initial decrement in lung function in diffuse pleural thickening which is followed by comparatively little change over time.
Aged↗
Child sexual abuse prevention: what offenders tell us.
Ninety-one child sex offenders were interviewed about the methods they used to target children, the age range of their victims, how they selected children and maintained them as victims, and what suggestions they had for preventing child sexual abuse. Offenders were selected from treatment programs, probation, special hospitals, and prisons. They were interviewed using a semi-structured questionnaire. Results indicate that offenders gained access to children through caretaking, such as babysitting; targeted children by using bribes, gifts and games; used force, anger, threats, and bribes to ensure their continuing compliance; and systematically desensitized children through touch, talk about sex, and persuasion. Nearly half the offenders had no bad feelings about sexually abusing children. The implications for prevention programs are discussed.
Adolescent↗
Preventing child maltreatment through community nursing.
The role of community nurses, such as health visitors, in the prevention of child abuse and neglect by home visits is reviewed. The paper evaluates the potential of community nurses for predicting and identifying families at high risk for child maltreatment in order to support them through the promotion of positive parental knowledge, attitudes, skills and behaviour. The success of health visitor interventions to prevent family problems is also evaluated. The review concludes that accurate prediction of child-maltreating families requires more than one screening procedure to reduce the number of false alarms, and suggests that health visitors might be trained in the objective assessment of parent-child interaction. Few health visitor interventions were deemed a success, indicating that greater support and training is required for community nurses if they are to be used to prevent child abuse and neglect. However, recent changes in the community nursing services and the purchaser-provider split in health care has reduced this possibility.
Adolescent↗
Opinions on the traumatizing effects of child sexual abuse: evidence for consensus.
The aim of the study was to investigate peoples' views of characteristics associated with child sexual abuse (CSA) and place them in order of severity for subsequent trauma. Clinically relevant characteristics of CSA were presented in the form of a questionnaire to a sample of professionals working with CSA, a sample of student nonprofessionals and a sample of patients with eating disorders including a high proportion of CSA victims. A significant consensus existed across the three samples in the ranked order of characteristics from most to least severe for perceived adverse long-term outcome. Respondent sex, social class, or past sexual abuse experience had no significant effect on this concordance. The findings of this study have shown that professional, nonprofessional, and psychiatric patients opinions on CSA severity are consistent and coincide with clinical observations and empirical evidence. It is argued that a shared consensus on traumatic effects of CSA characteristics is important for the therapeutic process and may prove useful as a guideline for the assessment of severity in CSA cases.
Adolescent↗
Asbestos fibers in parenteral medication.
The adequacy of current regulations for the control of particulate matter in injectable medicines has been brought into question by a recent television program which reported that asbestos fibers had been found in a number of such preparations. The fibers were identified as chrysotile, which occurs very widely as a secondary mineral in rocks, and is almost ubiquitous among minerals derived from natural erosion. Fibers are found in almost all drinking water and air samples unrelated to any contamination of fiber resulting from industrial exploitation. Because of this, even extreme laboratory precautions may fail to eliminate every fine fiber. A normal person living in an urban environment inhales about 10(5) asbestos fibers daily and ingests 10(10). There is evidence that a small proportion of these fibers regularly enters the circulation, and some fibers may be excreted in the urine. Elimination also occurs because retained chrysotile fibers fragment and disappear relatively quickly from human tissues, probably through macrophage action. Fiber length and dose are also important in disease causation. Established evidence on fiber length, durability, and quantitative exposure required for disease production does not indicate that the fibers reported to have been found in parenteral preparations constitute any hazard.
Asbestos↗