Involvement of homocysteine, homocysteine thiolactone, and paraoxonase type 1 (PON-1) in the etiology of defective human sperm function.

This study reports, for the first time, the significant (p ≤ 0.01) accumulation of homocysteine residues in low density, defective sperm suspensions isolated from patients attending an infertility clinic. This overabundance of homocysteine was not related to a deficiency in folate availability but may have been a reflection of the oxidative stress that characterizes such defective sperm populations. Direct addition of the homocysteine cyclic congener, homocysteine thiolactone, to human spermatozoa resulted in the rapid induction of mitochondrial reactive oxygen species (ROS) generation (p < 0.001), the stimulation of lipid peroxidation (p < 0.01), the promotion of tyrosine phosphorylation (p < 0.001), and the suppression of sperm motility (p < 0.001) in the absence of any significant impact on DNA integrity. The parent homocysteine molecule was less active and took 24 h to stimulate mitochondrial ROS production possibly because of the need to convert this compound to the corresponding thiolactone before it could exert a measureable biological effect. Thiolactone was also effective in suppressing the carboxymethylation of key proteins in the sperm tail, which are thought to be involved in the regulation of sperm movement. The major enzyme responsible for removing thiolactone from proteins, paraoxonase (PON-1), was shown to be a major target for alkylation by lipid aldehydes, such as 4-hydroxynonenal, generated as a consequence of oxidative stress. Exposure of human spermatozoa to such aldehydes resulted in a dose-dependent accumulation of homocysteine in spermatozoa (p < 0.03). These results suggest that one of the consequences of oxidative stress in mammalian spermatozoa is the inhibition of PON-1, which then enhances the availability of homocysteine thiolactone to interact with the epsilon-amino group of lysine residues on sperm proteins, triggering a raft of significant biological changes in these cells that ultimately compromise sperm function.

Empirical use of antisecretory drug therapy delays diagnosis of upper gastrointestinal adenocarcinoma but does not effect outcome.

BACKGROUND: Upper gastrointestinal cancer carries a poor prognosis. Although the incidence of gastric adenocarcinoma is falling, oesophageal adenocarcinoma is increasing. This has been attributed to an increasing prevalence of gastro-oesophageal reflux disease, commonly treated empirically in primary care with antisecretory drugs. Treatment has been associated with delayed diagnosis but it is unclear if this influences prognosis. AIMS: To ascertain the effect of antisecretory drugs on time to diagnosis, symptoms, tumour stage and outcome. METHODS: A retrospective cohort study of primary care records for 747 patients diagnosed with upper gastrointestinal adenocarcinoma at South Tees NHS Trust between 1991 and 2001. RESULTS: Mean time from the onset of symptoms to diagnosis was 30 weeks. Mean and median times at the primary care stage were longer than at the hospital stage for both oesophageal and gastric cancer (P < 0.0001). Patients with benign symptoms prescribed antisecretory drugs were referred later than those not on antisecretory drugs (P < 0.0001), as were patients with alarm symptoms (P = 0.0008). Prior use of antisecretory drugs delayed diagnosis by 17.6 weeks (mean) but had no effect on tumour stage at diagnosis or survival. CONCLUSION: Prior antisecretory drug therapy was associated with delayed diagnosis of upper gastrointestinal adenocarcinoma irrespective of presenting symptoms. Concerns that delays might adversely affect tumour stage or long-term survival were not substantiated.

Fibrin sealant: clinical use and the development of the University of Virginia Tissue Adhesive Center.

The utilization of fibrin sealants to augment hemostasis, seal tissues, and facilitate targeted delivery of drugs is increasing. In 1985, a hospital-based program was established to provide autologous and allogeneic cryoprecipitate that serves as a fibrin sealant when combined with bovine thrombin. To date, more than 4,000 patients have been treated with this product at our institution, with an efficacy rate greater than 90%. Collaboration among surgical services and the blood bank fostered multispecialty expertise with this product that led, in 1997, to the establishment of the University of Virginia Tissue Adhesive Center. The Tissue Adhesive Center is a multidisciplinary center whose physician director and nursing and administrative support staff facilitate basic research, laboratory investigation, and preclinical and clinical trials with collaborators throughout the university. The Tissue Adhesive Center also provides educational programs and clinical consultation, and tracks and participates in peer review of sealant use. The licensure of a commercially produced, virally inactivated, pooled-plasma fibrin sealant in May 1998 provided an alternative source of adhesive. Utilization of the commercial product surpassed use of the blood bank product in April 1999. At present, use of the commercial product is approximately 3 times that of the blood bank-produced sealant. This report reviews the clinical uses of fibrin sealant, its regulatory history, the production of fibrin sealants, the evolution of a blood bank fibrin sealant program, the development of the Tissue Adhesive Center, and the utilization of commercial and blood bank-produced sealant at our university hospital.

Autologous fibrin sealant reduces pain after tonsillectomy.

OBJECTIVES/HYPOTHESIS: Pain is a major cause of morbidity after tonsillectomy. Although various efforts have been made to reduce pain, the use of oral analgesics, which can have adverse side effects, remains the standard of care. It is hypothesized that fibrin sealant, used to achieve hemostasis and enhance healing in many surgical procedures, might help decrease pain after this operation. STUDY DESIGN: A prospective, randomized, blinded study was performed on 20 children aged 5 to 17 years who were undergoing tonsillectomy, to evaluate the efficacy of FIBRIN SEALANT in reducing postoperative pain. METHODS: All patients pre-donated 40 mL of blood from which autologous concentrated fibrinogen was prepared by cryoprecipitation. In the fibrin sealant group, fibrinogen and topical bovine thrombin were sprayed onto the surgical site to form fibrin sealant at the conclusion of tonsillectomy. The 10 patients in the control group (C) received no fibrin sealant. Patients rated their level of pain immediately after surgery and at regular intervals for 3 days after surgery using the Wong-Baker Faces Pain Rating Scale (1-6). Emesis, postoperative bleeding, medications, and adverse events were also evaluated. RESULTS: At 7.00 P.M. on postoperative day (POD) 0, the mean +/- SD fibrin sealant group pain score (2.9+/-0.41 units) was significantly lower than for the C group (4.1+/-0.43 units; P < or = .05). There was also a trend in favor of less pain in the fibrin sealant group at 7:00 P.M. on POD 1, with a mean of 3.5+/-0.43 units versus 2.4+/-0.48 units for C (P = .15). The odds of a patient in C experiencing emesis were 8.16 times higher, (P < or = .05) than for patients in the fibrin sealant group. CONCLUSIONS: Fibrin sealant significantly reduced pain the evening after pediatric tonsillectomy and also decreased the chance of experiencing emesis. Thus fibrin sealant may be clinically useful as an adjunct to tonsillectomy.

Intrathoracic fibrin sealant application using computed tomography fluoroscopy.

Persistent intrathoracic airspace and bronchopleural fistula remain a problem following lung resection or in patients with severe bullous disease experiencing a spontaneous pneumothorax. Although fibrin sealant has been used successfully to manage such air-leaks, precise nonoperative intrathoracic application is difficult. This report describes a novel technique using computed tomography fluoroscopy for catheter-directed FS application through a previously placed thoracostomy tube. Continuous computed tomography-fluoroscopy images allowed real-time catheter manipulation for precise placement of fibrin sealant.

Long-term prescribing of proton pump inhibitors in general practice.

BACKGROUND: Proton pump inhibitors (PPIs) constitute the largest sector of the National Health Service (NHS) community drugs bill (238 m Pounds; 5.6%). Little is known of the long-term prescribing component of this. AIM: To study the extent, the reasons for, and the cost implications of the long-term prescription of PPIs in general practice. METHOD: Subjects on long-term therapy were identified by searches of computerized and paper records from three practices, comprising 21 GPs with 46,650 patients, representing a population cross section in north-east England. RESULTS: Two hundred and nine (0.45%) patients were on long-term PPIs (range between practices = 0.3% to 0.55%): 87% were on omeprazole, 13% lansoprazole; average age = 60 years (male = 56 years, female = 64 years; range = 14 to 91 years); male to female ratio = 47:53. The main indications were 'reflux' (39%), 'oesophagitis' (17%), non-specified 'dyspepsia' (24%), 'peptic ulcer' (8%). During the study year, 1952 prescriptions (28-day courses) were issued: a mean of nine per patient (range = 1 to 8). Sixteen per cent of patients requested fewer than six prescriptions, 27% requested between six and nine prescriptions, and only 21% requested sufficient prescriptions for the entire year. The average cost was 3707 Pounds per general practitioner per annum, or 320,000 Pounds for the district, representing 40% of the total PPI bill. CONCLUSION: Of the total population, 0.45% were prescribed long-term PPIs; most for symptom relief. The long-term component comprised 40% of all PPI costs estimated at 100 million Pounds per annum for the United Kingdom. Most patients took their treatment only intermittently. More research is needed into strategies for rationalization of long-term PPI therapy. For most patients, doctors can advise on-demand rather than regular once-daily therapy.

Factors influencing compliance in long-term proton pump inhibitor therapy in general practice.

Long-term proton pump inhibitor (PPI) prescribing in general practice is common, but only a minority of patients request their prescriptions regularly. This study determined factors linked with compliance using questionnaires and diary cards. The chief factors determining whether or not patients took their PPIs were the presence or severity of symptoms and the desire to remain in personal control, together with a fear of side-effects and lack of knowledge about the drugs. As most such prescribing is for uncomplicated gastro-oesophageal reflux disease, on-demand therapy should now be formally advocated.

Co-prescription of H2 receptor blockers and proton pump inhibitors with warfarin in general practice.

Acid-suppressing drugs and anticoagulants are used increasingly in general practice. Warfarin is potentiated by some acid-suppressing drugs, notably cimetidine and omeprazole, through interference of the cytochrome P450 system. This study aimed to ascertain the extent of co-prescribing of warfarin and acid-suppressing drugs in general practice. We conducted a retrospective survey of the records of all patients prescribed acid-suppressing drugs over a 2-year period to ascertain those who had also taken warfarin; we also made a cross-sectional survey of all patients on warfarin to ascertain those who had taken acid-suppressing drugs. From a general practice population of 45 574 patients in northern England, 3423 (7.5%) had been prescribed acid-suppressing drugs during the previous 24 months. Of 274 patients who had been on warfarin, 44 (16.1%) had also taken acid-suppressing drugs (26 H2 receptor blockers and 18 proton-pump inhibitors). The commonest reasons for anticoagulation were thrombo-embolic disease (40.9%), atrial fibrillation (36.4%), valvular heart disease (18.2%), and surgical prophylaxis (4.5%). The indications for concurrent acid-suppressing drugs were: 'dyspepsia' 38.6%, reflux 22.7%, oesophagitis 13.6%, duodenal ulcer 13.6%, gastric ulcer 4.5%, unknown 6.8%. There have been no studies from primary care to evaluate the possible clinical effects of the concomitant use of acid-suppressing drugs and warfarin; some fluctuations in coagulation control, particularly in patients taking the combinations intermittently, may be due to this.

Irritable bowel syndrome, gastro-oesophageal reflux, and bronchial hyper-responsiveness in the general population.

BACKGROUND: Associations have been shown between irritable bowel syndrome (IBS) and gastro-oesophageal reflux, between gastro-oesophageal reflux and asthma, and more recently between IBS and bronchial hyper-responsiveness (BHR). AIMS: To explore the inter-relations between these conditions. SUBJECTS: A randomly selected community sample of 4432 adults. METHODS: A validated postal symptom questionnaire investigating the associations between IBS, gastro-oesophageal reflux symptoms, and symptomatic BHR. RESULTS: 3169 questionnaires (71.7% response) returned by 1451 men and 1718 women were analysed. One year prevalences, in men and women respectively, of IBS were 10.5% and 22.9%, of dyspepsia 26.3% and 25. 25%, of gastro-oesophageal reflux symptoms 29.4% and 28.2%, of BHR 13.2% and 14.6%, and of chronic bronchitis 8.3% and 4.9%. Logistic regression showed independent associations between IBS and BHR, gastro-oesophageal reflux symptoms, and dyspepsia. There was no significant independent association between IBS and chronic bronchitis. In men and women the odds ratio with 95% confidence interval (CI) for IBS and gastro-oesophageal reflux symptoms was 2.6 (2.1-3.1; p<0.001) and for IBS and BHR 2.1 (1.7-2.7; p<0.001). These associations held on stratifying for sex and consultation behaviour. IBS, gastro-oesophageal reflux symptoms, and bronchial hyper-responsiveness occurred more frequently together than expected, 2.5% (95% CI 2.41-2.57) of the sample having all three conditions compared with an expected prevalence of 0.7% (95% CI 0.66-0.71). The conditions were independently associated with each other. CONCLUSIONS: These observations may indicate the presence of an underlying disorder producing symptoms in gastrointestinal and respiratory systems.

Two protein-tyrosine phosphatases inactivate the osmotic stress response pathway in yeast by targeting the mitogen-activated protein kinase, Hog1.

Protein phosphatases inactivate mitogen-activated protein kinase (MAPK) signaling pathways by dephosphorylating components of the MAPK cascade. Two genes encoding protein-tyrosine phosphatases, PTP2, and a new phosphatase, PTP3, have been isolated in a genetic selection for negative regulators of an osmotic stress response pathway called HOG, for high osmolarity glycerol, in budding yeast. PTP2 and PTP3 were isolated as multicopy suppressors of a severe growth defect due to hyperactivation of the HOG pathway. Phosphatase activity is required for suppression since mutation of the catalytic Cys residue in Ptp2 and Ptp3, destroys suppressor function and biochemical activity. The substrate of these phosphatases is likely to be the MAPK, Hog1. Catalytically inactive Ptp2 and Ptp3 coprecipitate with Hog1 from yeast extracts. In addition, strains lacking PTP2 and PTP3 do not dephosphorylate Hog1-phosphotyrosine as well as wild type. The latter suggests that PTP2 and PTP3 play a role in adaptation. Consistent with this role, osmotic stress induces expression of PTP2 and PTP3 transcripts in a Hog1-dependent manner. Thus Ptp2 and Ptp3 likely act in a negative feedback loop to inactivate Hog1.

What chance a caring management culture?

Management of the NHS is necessary and vital to effective delivery of health services. It is not a process that can be avoided, whoever does it. New Labour needs effective managers in the NHS if they are to bring about the changes they want to see. Manager bashing, which New Labour is showing signs of continuing, is counter productive and encourages a climate of threat for managers which subsequently translates into bad management practice with its inevitable consequences for service quality and productivity. The NHS badly needs a positive long-term strategy of serious investment in individual and organizational development. It is a question of balanced investment between the long-term management capability of the NHS and immediate patient care. The major issues of rationing, priorities and the balance between health and health services will always be part of the difficult national and local management task. Some move by politicians in the direction of open recognition of these difficulties and the burden they place on the skill, will and courage of managers could go a long way to building a caring management culture.

From paradigms lost to paradigms regained? The MILTON approach to health care reform.

Proposes the MILTON model of health care policy and management as a framework within which debates about the future reform of the UK National Health Service may be conducted. Reviews the economic, political, social and technological forces which have shaped health care policy and management. Suggests that, at the macrolevel, the paradigm has changed from one based on assessment of needs to one based on securing value for money. At the microlevel, there have been equally profound changes in the nature and availability of work. A theme common to both levels is that of rapid and continuous change. Claims the MILTON model offers a way for the protagonists in the health care debate to locate their arguments about policies of health care provision and the implications for the management of work in a changing world in four planes of the model. The benefits are that the differing positions may be seen more clearly and, arguably more important, that a wider range of options is appreciated when, all too often in the past, arguments have become polarized on a single plane.

Healthy working and performance management. A discussion of the approach and a report on a survey of NHS organizations.

Achieving high performance in an organization is a complex business. Most approaches are too piecemeal, unidimensional or iatrogenic. Healthy working is an approach to managing performance that attempts to overcome these problems by aiming, in a holistic manner, to harmonize those factors which affect, either separately or jointly, individual physical, mental and emotional health and individual and organizational performance. The approach is based on a set of values and a series of steps. The first step has to be establishing an information base-line--the four key indicators. A survey was undertaken by PBS to establish the availability and usefulness of data in NHS organizations; summarizes some of the issues raised. Although a worryingly small number keep useful data or produce useful information, much can be done in making critical links if available data is fully used.

Beyond the business plan.

Acknowledges that business planning in the NHS frequently disappoints. Reasons for this are found in the tendency for managers to view the production of a plan as an end rather than a means. A further difficulty resides in the perception managers have of their world. Argues that marketing is the most appropriate paradigm for understanding and structuring this world at present. However, an adaptive cognitive style is necessary to allow constant reframing within the dominant paradigm or even reframing of the paradigm itself. In adopting these approaches, the probability of achieving competitive advantage is heightened. If they are ignored, however, it is likely that training and development techniques, however sophisticated, will have little lasting impact.

Positioning the human resource business using service level agreements.

Explores the introduction and development of Service Level Agreements (SLAs) in relation to Human Resource Departments. Considers approaches to SLAs and highlights four dimensions necessary for the completion of an SLA. Stresses that Human Resource Specialists should have a thorough understanding of how directorates and other departments relate to one another to provide added value in terms of contribution to the organizational outcomes. Suggests the idea of adding value is an integral part of the SLA process which ensures that it operates as a means to an end and does not become an end in itself. Examines the degree of devolved freedom given to a department to seek work or sell its products outside its Trust/Unit. Scrutinizes the format of SLAs and concludes that the benefits of SLAs for users of Human Resource Departments and the benefits to the Human Resource Departments are similar.

Managing people: the breakfast menu.

Discusses an exploratory study of the impact of NHS reforms on the management of staff. Argues that "management" has moved from a view that staff should be provided with a secure and comfortable working environment to "labour" being viewed simply as a factor of production. The result seems to be an unprecedented sense of alienation among significant numbers of NHS staff. Proposes possible ways forward. The first focuses on the "means", accepting that the "ends" of the NHS will, for the foreseeable future, be dominated by the market. The second examines more closely the market-driven, business "end" or purpose and challenges the unitary view of the NHS Trust as a coherent business entity. Beyond these short- to medium-term responses, concludes that a return to a somewhat more flexible and less hard-edged human resources philosophy is a longer-term investment as the labour market tightens and skilled staff become scarcer in the later 1990s.