The effects of methylmercury on Notch signaling during embryonic neural development in Drosophila melanogaster.

Methylmercury (MeHg) is a ubiquitous toxicant that targets the developing fetal nervous system. MeHg interacts with the Notch signaling pathway, a highly-conserved intercellular signaling mechanism required for normal development. Notch signaling is conveyed by activation of the genes in the enhancer of split (E(spl)) locus in Drosophila. We have previously shown that acute high doses of MeHg upregulate several E(spl) genes in Drosophila neural-derived C6 cells. Furthermore, MeHg induction of E(spl) can occur independent of the Notch receptor itself. We now show that MeHg, unlike inorganic mercury (HgCl2), preferentially upregulates E(spl)mδ and E(spl)mγ in Drosophila C6 cells. This is distinct from Delta ligand-induced Notch signaling in which no induction of E(spl)mδ is seen. MeHg is also seen to specifically upregulate E(spl)mδ in Drosophila embryos where HgCl2 showed no such effect. Additionally, treatment of embryos with MeHg caused a consistent failure in axonal outgrowth of the intersegmental nerve (ISN). This ISN phenotype was partially replicated by genetic activation of the Notch pathway, but was not replicated by increasing expression of E(spl)mδ. These data suggest a role for Notch signaling and the E(spl)mδ target gene in MeHg toxicity, however, the site of action for E(spl)mδ in this system remains to be elucidated.

Duplex scan surveillance during the first year after infrainguinal autologous vein bypass grafting surgery: costs and clinical outcomes compared with other surveillance programs.

PURPOSE: In this study we assessed the costs and clinical outcomes of duplex scan surveillance during the first year after infrainguinal autologous vein bypass grafting surgery and compared duplex scan surveillance, ankle-brachial index surveillance, and clinical follow-up. METHODS: In a clinical study, 293 patients (mean age, 70.1 years; 58.7% men) with peripheral arterial disease were observed in a duplex scan surveillance program after infrainguinal autologous vein bypass grafting surgery. Costs were calculated from the health care perspective for surveillance and subsequent interventions from 30 days to 1 year postoperatively. All costs are presented in 1995 US dollars per patient. In a simulation model, we estimated the costs and amputations of duplex scan surveillance, ankle-brachial index surveillance, and clinical follow-up conditional on the indication for surgery. The main outcome measure was the incremental cost per major amputation per patient avoided during the first postoperative year. RESULTS: Duplex scan surveillance was the least expensive ($2823) and resulted in the fewest major amputations (17 per 1000 patients examined), compared with ankle-brachial index surveillance ($5411 and 77 amputations per 1000 patients) and clinical follow-up ($5072 and 77 amputations per 1000 patients). In patients treated for critical limb ischemia, duplex scan surveillance was the least expensive ($2974) and resulted in the fewest major amputations (19 per 1000 patients). Under all surveillance programs, 13 major amputations per 1000 patients treated for intermittent claudication were performed, and clinical follow-up had the lowest costs ($1577). In a sensitivity analysis that assumed that duplex scan surveillance could have avoided six major amputations per 1000 patients treated for intermittent claudication compared with the other programs, duplex scan surveillance had an incremental cost of $80,708 per major amputation per patient avoided compared with clinical follow-up. CONCLUSION: Duplex scan surveillance is highly effective for patients treated for critical limb ischemia, leading to a reduction of major amputations and consequently to a reduction in costs compared with other surveillance programs. In patients treated for intermittent claudication, the evidence supporting duplex scan surveillance is less firm, but if duplex scan can avoid six major amputations per 1000 patients examined, the incremental costs are justified.

Salt form selection and characterization of LY333531 mesylate monohydrate.

LY333531 is a potent protein kinase C(beta) (PKC(beta)) inhibitor currently under development for the treatment of diabetic complications. Seven salts of LY333531 (hydrochloride, sulfate, mesylate, succinate, tartrate, acetate and phosphate) were evaluated during the early phase of development. Physical property screening techniques including microscopy, DSC, TGA, XRPD, hygroscopicity and solubility were utilized to narrow the selection to two salts: the mesylate and hydrochloride. Identification of the optimal salt form was based upon solubility, bioavailability, physical stability and purity. During the evaluation process three hydrated forms (anhydrate, monohydrate, and tetrahydrate) of the hydrochloride salt were identified. The mesylate salt was found to give only one, a monohydrate. Processing parameters (e.g. filtration rate, crystal form stability) demonstrated that the anhydrate was the preferred form of the hydrochloride salt. Bioavailability studies in dogs indicated that the C(max) and area under the plasma concentration vs. time curve (AUC) for LY333531 and its active metabolite, LY338522, following administration of the mesylate salt were approximately 2.6 times those obtained after the LY333531 HCl dose. This difference was presumed to be due primarily to the fact that the mesylate was five times more soluble than the hydrochloride salt in water. These factors led to selection and development of LY333531 mesylate monohydrate as the active pharmaceutical ingredient for clinical evaluation.

Cost-effectiveness and cost-utility of combination therapy in early rheumatoid arthritis: randomized comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone. COBRA Trial Group. Combinatietherapie Bij Reumatoïde Artritis.

OBJECTIVE: Assessment of the cost-effectiveness and cost-utility of early intervention in rheumatoid arthritis (RA) patients, with combined step-down prednisolone, methotrexate and sulphasalazine, compared to sulphasalazine alone. METHODS: Multicentre 56 week randomized double-blind trial with full economic analysis of direct costs and utility analysis with rating scale and standard gamble measurement techniques. RESULTS: The combined-treatment group included 76 patients and the sulphasalazine group 78 patients. The mean total costs per patient in the first 56 weeks of follow-up were $5519 for combined treatment and $6511 for treatment with sulphasalazine alone (P = 0.37). Out-patient care, in-patient care and non-health care each contributed about one-third to the total costs. The combined-treatment group appeared to generate savings in the length of hospital stay for RA, non-protocol drugs and costs of home help, but comparisons were not statistically significant. Protocol drugs and monitoring were slightly more expensive in the combined-treatment group. Clinical, radiographic and functional outcomes significantly favoured combined treatment at week 28 (radiography also at week 56). Utility scores also favoured combined treatment. CONCLUSION: Combined treatment is cost-effective due to enhanced efficacy at lower or equal direct costs.

Cost-effectiveness of dynamic graciloplasty in patients with fecal incontinence.

PURPOSE: This study evaluates the cost-effectiveness of dynamic graciloplasty for intractable fecal incontinence. PATIENTS AND METHODS: The costs and effects of dynamic graciloplasty were measured in a prospective, longitudinal study and in a clinical trial. Forty-three patients with intractable fecal incontinence were evaluated before and after dynamic graciloplasty. Costs were obtained from the hospital information system and from patient-oriented questionnaires. We compared the costs of a dynamic graciloplasty with the costs of a colostomy. Colostomy costs were evaluated using a group of seven patients who had a stoma in place for incontinence for several years. Sensitivity analyses were included. RESULTS: Total direct costs of lifelong dynamic graciloplasty were $31,733 (United States dollars), costs of lifelong conventional treatment were $12,180 (United States), and costs of colostomy, including lifelong stoma care, were $71,576 (United States). The clinical success rate of dynamic graciloplasty was 74 percent. Quality of life after successful dynamic graciloplasty was better than with conventional treatment. CONCLUSION: We found that dynamic graciloplasty was more expensive than conventional treatment but resulted in a significantly higher quality of life. Stoma treatment was the least attractive alternative regarding both costs and effects. The Dutch Health Insurance Executive Board recommended reimbursement for the dynamic graciloplasty procedure.

Do retrospective and prospective quality of life assessments differ for pancreas-kidney transplant recipients?

The literature indicates that chronically ill patients have a remarkable capacity to adapt to their illness. For example, they will generally report a better quality of life (QoL) than individuals in the general population who are asked to imagine themselves as chronically ill and to rate their QoL. The present study further explores this phenomenon in type I diabetic transplant recipients with end-stage renal disease. In a prospective, longitudinal study, we assessed the QoL in 22 patients, both before and after they received a combined pancreas-kidney transplant. After transplantation, the patients were also asked to assess their pretransplant QoL by rating it on a 10-point scale. What we found was that prior to transplantation, QoL was prospectively given a mean rating of 5.23; this score increased to 7 after a successful transplant procedure. During follow-up assessments 5, 12, and 18 months after successful transplantation, patients retrospectively scored their pretransplant QoL as 3.27, 3.14, and 3.05, respectively. We conclude that when type I diabetic patients with end-stage renal disease undergo a transplant procedure to improve their health status, they re-evaluate their pretransplant QoL, and this retrospective assessment is significantly lower than their prospective one when transplantation is successful.

Cost of stroke in The Netherlands from a societal perspective.

BACKGROUND AND PURPOSE: Cerebrovascular disorders are associated with a high level of morbidity and mortality and call for considerable resources. The objective of this study was to determine from a societal perspective the medical consumption (direct costs) and productivity losses (indirect costs) caused by cerebrovascular disorders in the Netherlands. METHODS: This study can be characterized as a cost-of-illness study based on prevalence data. All data gathered refer to 1993. Cerebrovascular disorders are defined according to the International Classification of Diseases, 9th Revision (ICD-9) classification. Data from medical registrations and national statistics have been analyzed. For both direct and indirect costs, volume and cost components are presented. To test the likelihood of the assumptions, a sensitivity analysis was performed. RESULTS: The cost of cerebrovascular disorders in the Netherlands in 1993 amounted to 2.5 billion Dutch guilders, of which 1.9 billion were spent on medical consumption. It was found that direct costs are generated mainly by the long-term care of inpatients (nursing homes and hospitals). The productivity losses were relatively low in comparison with other diseases, probably due to the fact that most patients with cerebrovascular disorders are elderly. CONCLUSIONS: More than 3% of the Dutch annual healthcare budget is spent on patients suffering from cerebrovascular disorders. Costs in the future may be influenced by, among other things, demographic changes, new therapies, and cost-reduction programs introduced by the government.

From biomedical to biopsychosocial. Being scientific in the human domain.

In an era of managed care that encourages shortened patient encounters, large group practices that limit a consistent primary care physician, and a reliance upon self-report inventories, it is easy to lose the essence of the doctor-patient relationship. Important information seems limited to that which can be entered into a database field. Fortunately, Dr. George L. Engel continues to remind us that it is the dyad of patient and physician that forms the substrate whereby meaningful data can be observed and obtained from a suffering individual. This special article emphasizes the importance of the medical interview not only as a human encounter but also as a rigorous instrument to better understand the patient and help explain the data that the patient presents. Subjective experiences such as sadness, grief, and fear are not soft signs but essential elements of a patient history. Dr. Engel is an internist with psychoanalytic training whose impact upon consultation-liaison psychiatry has been immense. His seminal paper on the biopsychosocial model became an organizing principle for psychiatric education in medical settings. It is the challenge--yet the reward--of the physician to empathically make meaningful connections between the patient's life history and presenting problems to diagnose the difficulties with which the patient presents. This essay demonstrates the rigor involved in such a task.

Comparison before and after transplantation of pancreas-kidney and pancreas-kidney with loss of pancreas--a prospective controlled quality of life study.

The aim of combined pancreas-kidney transplantation (PKT) in type I diabetic patients with end-stage nephropathy is to restore both functions. Quality of life (QoL) is supposed to improve as a result of this combined transplantation. The objectives of this study are to evaluate QoL before and after PKT and to compare the results with patients in whom the pancreas graft failed soon after the transplantation (PKT-P). The trial is a prospective controlled multicenter study. The control group consists of patients before transplantation and patients who received a PKT in whom the pancreas rejected or thrombosed soon after the transplantation. (PKT-P). A standardized home-based interview is done during dialysis, and repeated 5, 12, and 18 months after transplantation in both groups by the same interviewer. The interview consisted of disease-specific questions (RSCL), general questionnaires (NHP I and II, ABS), the Visual Analogue Scale, a specific questionnaire (Anxiety), and evaluative questions about social support and transplantation. Patients in whom the PKT is successful (n=17) improve significantly or show a strong tendency toward improvement on many aspects of quality of life. Patients in whom the pancreas failed (n=5) still demonstrate improvement, although this is not statistically significant in most cases. Intergroup comparison shows that PKT patients are less anxious, suffer of less itching, have better average daily living conditions, have no diet restrictions, and have a better [correction of have and] global quality of life.

Medical technology assessment: economic evaluation of new technologies.

Growing expenditures in health care made it necessary to find control mechanisms to evaluate expenditure. Medical technology assessment is becoming a valuable tool to assist policymakers in controlling new medical technologies. This review deals with the increasing importance of economic evaluation as part of medical technology assessment and describes various techniques by which an economic evaluation can be performed.

Anal dynamic graciloplasty in the treatment of intractable fecal incontinence.

BACKGROUND: In patients with intractable fecal incontinence, conventional treatment is not always successful. Dynamic graciloplasty (transposition of the gracilis muscle to the anus with the implantation of stimulating electrodes) was developed to provide such patients with functional neosphincters. We evaluated the clinical results of this new surgical approach and the effects on quality of life. METHODS: We treated 52 patients with dynamic graciloplasty. The clinical results of treatment were evaluated in an interview, by anal manometry, and by enema testing. The degree of continence was scored. To assess quality of life, four questionnaires were administered (parts 1 and 2 of the Nottingham Health Profile, the State-Trait Anxiety Inventory, and the Self-rating Depression scale). RESULTS: Among the 52 patients, 38 (73 percent) were continent after a median follow-up of 2.1 years. At 52 weeks the patients' condition had improved with respect to the median frequency of defecation (from five to two times per 24 hours, P < 0.001), the median time defecation could be postponed (from 9 seconds to 19 minutes, P = 0.012), and the median time an enema could be retained (from 0 to 180 seconds, P = 0.005). Patients in whom the technique was successful became less anxious than those in whom it failed (P = 0.002) and improved with regard to effectiveness in their occupations, ability to perform tasks around the home, personal relationships, sexual function, and social life (P = 0.01). They also became less isolated socially (P = 0.05). CONCLUSIONS: Dynamic graciloplasty is a safe and reliable technique in patients with severe incontinence and may result in a better quality of life.

[Ambulatory surgery in the Netherlands]. / Ambulante Chirurgie in den Niederlanden.

Day care treatment is encouraged in the Netherlands on the one hand by the government and on the other hand by the request of the patients. There is a continuous shift from clinical to day care cases and through diversification, f.i. 24-hour admittance and short stay, one will be able to further reduce the number of expensive long stay hospital beds.

Effect of impurities on estradiol crystallization in a sustained-release implant.

During the development of a silicone rubber implant for the delivery of estradiol 17-beta some batches of implants made from a certain lot of commercial estradiol inexplicably developed surface crystals of estradiol after several days of storage. An impurity profile was obtained for 28 lots of estradiol by a newly developed HPLC method. One or more impurities may have had a role in the spontaneous crystal growth on the surface of the implants, because the one lot of estradiol that initially had surface crystals on aging produced acceptable implants after multiple recrystallizations. Attempts to isolate suspected impurities for characterization were unsuccessful. During the manufacture of the implants, temperatures sufficient to melt the estradiol (mp, 173-179 degrees C) were used. It was expected that, upon implant cooling, melted impure estradiol would form a thermodynamically more active (i.e., noncrystalline) physical form. This metastable form could have migrated to the implant surface, where ambient conditions favored crystallization. Because melted estradiol of a higher purity tended to crystallize more readily, it was less likely to form a glass upon cooling. The phenomenon of surface crystallization was limited to one lot of estradiol with the highest level of impurities. Data from differential scanning calorimetry studies supported this conclusion.

How much longer must medicine's science be bound by a seventeenth century world view?

The exclusion of nonmaterial human phenomena mandated by medical science's continuing allegiance to a 17th century scientific world view has constituted a major obstacle to medicine's scientific maturation as a human discipline. But 20th century conceptual changes even in physics (not to mention the influence of the theory of evolution) now renders that exclusion untenable and in effect legitimizes efforts to devise scientific means appropriate for the human domain. Practical as well as theoretical issues involved in such an undertaking are discussed within the framework of a 20th century scientific world view as represented by the biopsychosocial model, a counterpart to the traditional biomedical model.

Volume and outcome of organ transplantation.

In general, technically demanding medical procedures are associated with better outcomes when they are carried out in institutions and by physicians with higher volumes of practice. This paper examines the evidence for a volume-outcome relationship in the case of organ transplantation. Although few studies have been done on this subject, existing evidence is consistent with improved outcomes at higher volumes. Therefore, evidence supports policies that regionalize transplantation services.

On looking inward and being scientific. A tribute to Arthur H. Schmale, MD.

Paradoxically, Schmale's greatest contribution remains hardly known even to his admirers. That has been his challenge to the tradition disallowing introspection and dialogue as scientific instrumentalities. There can be no more appropriate tribute to Schmale at 65 than to call attention to how he has gone about refining everyday observation, introspection, and dialogue for scientific use. In so doing he reestablishes the ancient triad introspection-observation-dialogue as the basic scientific method of clinical study.