To develop a management strategy (rehabilitation programme) for postsurgical erectile dysfunction (ED) among men experiencing ED associated with treatment of prostate, bladder or rectal cancer that is suitable for use in a UK NHS healthcare context.
PubMed literature searches of ED management together with a survey of 13 experts in the management of ED from across the UK were conducted.
Data from 37 articles and completed questionnaires were collated. The results discussed in this study demonstrate improved objective and subjective clinical outcomes for physical parameters, sexual satisfaction, and rates of both spontaneous erections and those associated with ED treatment strategies.
Based on the literature and survey analysis, recommendations are proposed for the standardisation of management strategies employed for postsurgical ED.
Low levels of testosterone are manifested by erectile dysfunction, reduced sexual desire, and loss of morning erections with increasing numbers of men are being diagnosed and require treatment. The prevalence rates of testosterone deficiency vary according to different studies but may be as high as 40% in populations of patients with type 2 diabetes. There is increasing evidence that testosterone deficiency is associated with increased cardiovascular and all-cause mortality. Screening for low testosterone is recommended in a number of high risk groups including those with type 2 diabetes and metabolic syndrome. There are recent data to suggest that testosterone replacement therapy may reduce cardiovascular mortality as well as improving multiple surrogate markers for cardiovascular events. Specific clinical trials of testosterone replacement therapy are needed in selected populations but in the meantime we must treat patients based on the best current evidence.
To determine differences in the rates of growth, endocrine and calcium related abnormalities in the various thalassemia syndromes in North America with current therapy.
Medical history, physical examinations and blood and urine collections were obtained from patients with all thalassemia syndromes age 6 years and older in the Thalassemia Clinical Research Network.
361 subjects, 49% male, mean age 23.2 years (range 6.1 to 75 years) were studied. Approximately 25% of children and adults, regardless of the thalassemia syndrome, had short stature. Overall growth in children was mildly affected. Final height was close to midparental height (z = -0.73 ± 1.24). Patients with beta thalassemia major (TM) had higher rates of hypogonadism, multiple endocrinopathies, worse hyperglycemia, subclinical hypoparathyroidism and hypercalciuria. Hypogonadism remained the most frequent endocrinopathy and was frequently under-treated. 12.8% of the subjects had 25 vitamin D concentrations less than 27nmol/L and 82% less than 75nmol/L, regardless of the thalassemia syndrome. Adolescents had lower 25 vitamin D levels than children and adults.
Compared to patients with other thalassemia syndromes, those with beta TM suffer from higher rates of multiple endocrinopathies, abnormal calcium metabolism and hypercalciuria. Vitamin D abnormalities are high among adolescents.
To assess the level of activity and toxicity of gefitinib (ZD1839, Iressa™) in a population of patients with locally recurrent and/or metastatic head and neck cancer. Patients were recruited into an expanded access programme through the multidisciplinary head and neck clinics at the Royal Marsden and St George's Hospitals. Patients were required to have received at least one course of standard systemic chemotherapy or radiation therapy, or be medically unfit for chemotherapy. Patients were commenced on single-agent gefitinib at a dose of 500 mg day−1. Clinical, symptomatic and radiological response, time to progression (TTP), survival and toxicity were recorded. A total of 47 patients were enrolled (35 male and 12 female) with a median age of 62 years (range 18–93 years). The observed clinical response rate was 8% with a disease control rate (complete response, partial response, stable disease) of 36%. In all, 34% of patients experienced an improvement in their symptoms. The median TTP and survival were 2.6 and 4.3 months, respectively. Acneiform folliculitis was the most frequent toxicity observed (76%) but the majority of cases were grade 1 or 2. Only four patients experienced grade 3 toxicity of any type (all cases of folliculitis). Gefitinib was well tolerated and yielded symptomatic improvement in one-third of patients. However, this agent appeared to possess limited antitumour activity in this group of patients with head and neck cancer in whom the objective response rate, median TTP and survival were all lower than has been reported in a previous study.
gefitinib; head and neck cancer'; palliation
We have previously shown that the systemic exposure to inhaled fluticasone propionate (FP) is reduced in asthmatics compared with healthy subjects. We have now compared its pharmacokinetics in patients suffering from chronic obstructive pulmonary disease (COPD, n = 10) and matched healthy subjects (n = 13).
A double-blind, randomized, cross-over study design was used. Plasma FP and serum cortisol were measured for 12 h after subjects received hydrofluoroalkane FP 1000 µg day−1 inhaled (via an MDI and spacer) for 7 days and following a single 1000-µg intravenous dose.
The pharmacokinetics differed in the two groups. After inhalation, geometric least square means were significantly lower in the COPD group for the plasma AUC (1961 vs 2996 pg ml−1 h−1 for COPD and controls, respectively; P = 0.03) and the Cmax (235 vs 421 pg ml−1 for COPD and controls, respectively; P = 0.03). Suppression of serum cortisol concentration over 12 h was greater in healthy controls. Weighted mean serum cortisol concentration (nmol l−1) in healthy subjects and COPD was 93 and 170, respectively (P = 0.03). The intravenous pharmacokinetic parameters for FP were comparable in the two groups, resulting in similar suppression of serum cortisol.
We conclude that the altered pharmacokinetics of inhaled fluticasone propionate in COPD caused less hypothalamic–pituitary–adrenal suppression than in healthy controls. This is further evidence that the systemic effects of inhaled corticosteroids should be assessed in patients and not healthy subjects.
adrenal; COPD; inhaled corticosteroids; pharmacokinetics
Previous studies showed that conotruncal heart malformations can arise with the increase or decrease in α1 connexin function in neural crest cells. To elucidate the possible basis for the quantitative requirement for α1 connexin gap junctions in cardiac development, a neural crest outgrowth culture system was used to examine migration of neural crest cells derived from CMV43 transgenic embryos overexpressing α1 connexins, and from α1 connexin knockout (KO) mice and FC transgenic mice expressing a dominant-negative α1 connexin fusion protein. These studies showed that the migration rate of cardiac neural crest was increased in the CMV43 embryos, but decreased in the FC transgenic and α1 connexin KO embryos. Migration changes occurred in step with connexin gene or transgene dosage in the homozygous vs. hemizygous α1 connexin KO and CMV43 embryos, respectively. Dye coupling analysis in neural crest cells in the outgrowth cultures and also in the living embryos showed an elevation of gap junction communication in the CMV43 transgenic mice, while a reduction was observed in the FC transgenic and α1 connexin KO mice. Further analysis using oleamide to downregulate gap junction communication in nontransgenic outgrowth cultures showed that this independent method of reducing gap junction communication in cardiac crest cells also resulted in a reduction in the rate of crest migration. To determine the possible relevance of these findings to neural crest migration in vivo, a lacZ transgene was used to visualize the distribution of cardiac neural crest cells in the outflow tract. These studies showed more lacZ-positive cells in the outflow septum in the CMV43 transgenic mice, while a reduction was observed in the α1 connexin KO mice. Surprisingly, this was accompanied by cell proliferation changes, not in the cardiac neural crest cells, but in the myocardium— an elevation in the CMV43 mice vs. a reduction in the α1 connexin KO mice. The latter observation suggests that cardiac neural crest cells may have a role in modulating growth and development of non–neural crest– derived tissues. Overall, these findings suggest that gap junction communication mediated by α1 connexins plays an important role in cardiac neural crest migration. Furthermore, they indicate that cardiac neural crest perturbation is the likely underlying cause for heart defects in mice with the gain or loss of α1 connexin function.
neural crest; gap junction; connexin 43; oleamide; cardiac
BACKGROUND--Metered dose inhalers for the treatment of asthma use chlorofluorocarbons as propellants. These face an international ban due to their effect on the ozone layer. Salmeterol has been reformulated using the non-chlorinated propellant Glaxo inhalation grade HFA134a. METHODS--The safety, tolerability and systemic pharmacodynamic activity of the salmeterol/HFA134a inhaler, the current salmeterol inhaler, and placebo (HFA134a) were compared in 12 healthy volunteers in a double blind, randomised crossover study using a cumulative dosing design. RESULTS--Safety and tolerability were similar and the response was related to the dose over the range used (50-400 micrograms) with both salmeterol inhalers. The salmeterol/HFA134a inhaler showed no differences from the current inhaler for pulse rate, blood pressure, tremor, QTc interval, and plasma glucose levels. The salmeterol/HFA134a inhaler had significantly less effect on plasma potassium levels. CONCLUSIONS--In healthy volunteers the salmeterol/HFA134a inhaler is at least as safe and well tolerated as the current salmeterol inhaler, and has similar systemic pharmacodynamic activity.
Retinoids play a critical role in cardiac morphogenesis. To examine the effects of excessive retinoid signaling on myocardial development, transgenic mice that overexpress a constitutively active retinoic acid receptor (RAR) controlled by either the alpha- or beta-myosin heavy chain (MyHC) promoter were generated. Animals carrying the alpha-MyHC-RAR transgene expressed RARs in embryonic atria and in adult atria and ventricles, but developed no signs of either malformations or disease. In contrast, beta-MyHC-RAR animals, where expression was activated in fetal ventricles, developed a dilated cardiomyopathy that varied in severity with transgene copy number. Characteristic postmortem lesions included biventricular chamber dilation and left atrial thrombosis; the incidence and severity of these lesions increased with increasing copy number. Transcript analyses showed that molecular markers of hypertrophy, alpha-skeletal actin, atrial natriuretic factor and beta-MyHC, were upregulated. Cardiac performance of transgenic hearts was evaluated using the isolated perfused working heart model as well as in vivo, by transthoracic M-mode echocardiography. Both analyses showed moderate to severe impairment of left ventricular function and reduced cardiac contractility. Thus, expression of a constitutively active RAR in developing atria and/ or in postnatal ventricles is relatively benign, while ventricular expression during gestation can lead to significant cardiac dysfunction.
This point of view compares the issue of informed patient consent primarily as it operates in Australia and the United Kingdom. It affords an overview, also, of the applicable law in the United States and Canada. It particularly focuses on the legal test to be applied to patient consent as established in the Bolam case in the United Kingdom. The case, following its approval by the House of Lords, holds that the negligent standard in patient consent situations is to be determined, in cases of dispute, in accordance with standards as viewed by a proper body of competent medical practitioners. By contrast, the law in the United States is premised on the notion of the fundamental right of patients to determine what should or should not be done with their own bodies. In Australia the Bolam test has been rejected by the High Court of Australia following earlier decisions in the State Supreme Courts. The Australian courts did not accept that the setting of standards by the medical profession was an acceptable way of determining the entitlements of a patient who has suffered harm. The author places this discussion in the context of greater community awareness of medical procedures, the heightened accountability of professionals and the increasing practice of having a substantial patient input into medical decisions. He also suggests that the differing social and professional attitudes to authority and fundamental rights to be found between Australia and the United Kingdom have influenced the outcome of the cases in the higher courts of both countries. He suggests that the Bolam test is an illustration of the tendency of authority in the United Kingdom to believe that 'Nanny know best'.
There is evidence from in vitro systems that the extent of neuronal loss in acute central nervous system ischaemia can be reduced by manoeuvres which restrict availability of glucose to the ischaemic area. Experiments were designed to test whether hypoglycaemia induced with insulin is associated with improved behavioural outcome in a recovery model of stroke. Rats learned a maze task as a test of working memory, believed to be subserved by the hippocampus, and then had a period of cerebral ischaemia, followed by reperfusion. After an interval of 14 days they were tested on the same maze, where lesioned animals had very significant (p less than 0.0001) impairment of working memory, whereas lesioned and treated (2.0 u/kg-1 insulin, minimum single plasma glucose value: 3.1 mmol/l-1) animals were indistinguishable from control animals. It is concluded that a striking degree of protection can be obtained with levels of mild hypoglycaemia which may be acceptable and practicable for use in humans.
Individuals with sarcoidosis were evaluated for preferential usage of T cells with the gamma delta-positive (+) type of T cell antigen receptor. Compared with normal subjects (n = 19), the group with sarcoidosis had increased numbers of CD3+ alpha beta-negative (-) T cells in the blood (normal, 58 +/- 12 cells/microliters; sarcoid, 192 +/- 45 cells/microliters, P less than 0.05) and in the epithelial lining fluid of the lung (normal, 78 14 cells/microliters; sarcoid, 240 +/- 60 cells/microliters, P less than 0.04) and a concomitant elevated number of blood and lung CD3+ gamma delta+ T cells, owing to a striking increase in the number of CD3+ gamma delta+ T cells in a subgroup (7 of 20) of sarcoid individuals. The elevated numbers of sarcoid blood gamma delta+ T lymphocytes were mostly Ti gamma A+ and delta TCS1-, a pattern also seen in normal individuals, consistent with the majority of gamma delta+ T cells expressing one gamma-chain variable region, V gamma 9. The observation of an increase in the total gamma delta+ T cell numbers in a sarcoid subgroup suggests that various specific stimuli may trigger the expansion of different T cell subpopulations within different groups of individuals with sarcoidosis.
To evaluate the concept that biases in the usage of T cell antigen receptor beta variable (V) regions may be manifested in T lymphocytes that accumulate in nonmalignant, T cell-mediated human disorders, a V beta 8-specific antibody (anti-Ti3A, 5REX9H5) was used to evaluate lung and blood T cells in pulmonary sarcoidosis, a chronic granulomatous disorder of unknown etiology. Whereas normal patients had less than 5% Ti3A+ lung (n = 7) and/or blood (n = 9) lymphocytes, strikingly, a subgroup (8 of 21) with active pulmonary sarcoidosis had greater than 7% Ti3A+ lung and/or blood T cells and a higher proportion of Ti3A+ lymphocytes in the lung compared with blood. Dual-color flow cytometry demonstrated compartmentalization of Ti3A+ CD4+ lymphocytes to lung and Ti3A+ CD8+ lymphocytes to blood. Analysis with a 32P-labeled V beta 8 probe revealed that sarcoid lung T lymphocytes contained higher amounts of V beta 8+ mRNA than autologous blood T cells. However, Southern analysis of sarcoid lung and blood T cell DNA demonstrated no evidence of clonal rearrangements of V beta 8 genes. These observations demonstrate a clear bias toward the use of at least one V beta region in sarcoidosis, and suggests T cells accumulate secondary to external selective pressure, rather than in a random polyclonal fashion or by clonal expansion of one or few T cell clones.
Current concepts of the pathogenesis of sarcoidosis suggest that the expanded numbers of activated T-helper/inducer cells at sites of disease activity result, at least in part, from their proliferation in the local milieu. Normal clonal proliferation of T cells involves activation and expression of the IL 2 receptor (IL 2R) gene. Thus, knowing that IL 2R mRNA transcripts are relatively long lived, we hypothesized that sarcoid blood T cells may contain IL 2R mRNA transcripts and express functional surface IL 2R, although the cells are probably activated elsewhere. Northern analysis using a 32P-labeled cDNA probe for the IL 2R p55 protein demonstrated that blood T cells of patients with active sarcoidosis, but not of normal patients, express 3.5- and 1.5-kb IL 2R mRNA transcripts, the same as those observed in normal T cells activated in vitro. Consistent with this, using flow cytometry and an MAb directed against the IL 2R p55 protein (2A3), we observed detectable levels of IL 2R surface protein on increased numbers of blood T cells of active sarcoidosis patients (4.7 +/- 0.9%) compared with blood T cells of normal patients (0.9 +/- 0.2%). Importantly, when the sarcoid blood T cells were exposed to IL 2 in vitro, they proliferated at a rate greater than that of normal blood T cells under the same conditions, suggesting that the IL 2R spontaneously expressed by sarcoid blood T cells were functionally active. In the context of the known compartmentalization of spontaneous IL 2 production and T cell proliferation at sites of disease in active pulmonary sarcoidosis, these IL 2R positive blood T cells would probably have a proliferative advantage if they trafficked to sites of active sarcoidosis, such as the lower respiratory tract.
This paper is not about the medical condition of AIDS. Nor is it about the history of the condition since it was first reported in Atlanta, Georgia in 1981. It looks rather, at the catalogue of legislative and other legal responses to the spread of AIDS. The paper analyses the AIDS condition in its historical context. The hysteria accompanying the outbreak of AIDS is contrasted with the similar hysteria associated with other previous epidemics experienced in Australia over the past two centuries. The paper categorises the responses of lawmakers to the condition, according to the approach taken; from 'full blast', through 'moderate heat' to 'low key' or an attempt to avoid or minimise legal intervention. It is suggested that the appropriate response should depend upon such factors as the present magnitude of the condition, its likely future course, the availability of cures and protections against its spread and objectives being sought by intervention. Unless these factors are taken into account gross over-reaction can occur, causing social disruption and much personal injustice.
Low-dose dopamine or a placebo was given to six healthy mongrel dogs, each receiving tobramycin at 2.0 mg/kg on consecutive days in a randomized crossover fashion. Dopamine increased the total and renal clearances and elimination rate constant of tobramycin by 12.5, 20, and 25.9%, respectively, suggesting that low-dose dopamine increases the clearance of tobramycin in dogs primarily through renal mechanisms.
The editorial in the September 1982 issue of this journal and many articles before and since have addressed the problem of informed consent. Is it possible? Is it a useful concept? Is there anything new to be said about it? In this article the basic rationale of the rule (patient autonomy) is explained and the extent of the rule explored. Various exceptions have been offered by the law and an attempt is made to catalogue the chief of these. A number of specially vulnerable groups are then identified, the most important, and vexed, being children. How can informed consent be secured in the case of young patients? Finally, a few problems are mentioned in an attempt to get this subject back to reality. The appeal to the principle primum non nocere may be medical paternalism in disguise. Informed consent is the competing principle that reminds us of the primacy of human autonomy. A pointer is given to the future: even the use of sound recordings to explain medical procedures and to activate informed consent so that it may become a reality and not just a lawyer's myth, should be considered.
GR 20263 is a new broad-spectrum injectable cephalosporin which is stable to most beta-lactamases. Its in vitro activities were of the same order as those of cefotaxime against most gram-negative bacteria, were clearly inferior to cefotaxime against Staphylococcus aureus, but were significantly more active against Pseudomonas aeruginosa. Against the 25 strains used, GR 20263 was significantly more active than any of the other agents tested: piperacillin, azlocillin, gentamicin, amikacin, and carbenicillin. GR 20263 protected mice against experimental infections with P. aeruginosa more effectively than other beta-lactam antibiotics; its general effectiveness in this test was comparable with gentamicin. Studies on human volunteers showed that it produces high, long-lasting blood levels, with much of the antibiotic being recovered in the urine. Intramuscular and intravenous injections were well tolerated by the volunteers, and there were no untoward side effects.
1 Ciclazindol, like mazindol, produced a significant concentration-dependent increase in glucose-uptake into human skeletal muscle in both the presence and absence of insulin. 2 Methysergide, which inhibits the action of fenfluramine on glucose-uptake into skeletal muscle, did not influence the effect of mazindol.