Expression of human cationic trypsinogen (PRSS1) in murine acinar cells promotes pancreatitis and apoptotic cell death.

Hereditary pancreatitis (HP) is an autosomal dominant disease that displays the features of both acute and chronic pancreatitis. Mutations in human cationic trypsinogen (PRSS1) are associated with HP and have provided some insight into the pathogenesis of pancreatitis, but mechanisms responsible for the initiation of pancreatitis have not been elucidated and the role of apoptosis and necrosis has been much debated. However, it has been generally accepted that trypsinogen, prematurely activated within the pancreatic acinar cell, has a major role in the initiation process. Functional studies of HP have been limited by the absence of an experimental system that authentically mimics disease development. We therefore developed a novel transgenic murine model system using wild-type (WT) human PRSS1 or two HP-associated mutants (R122H and N29I) to determine whether expression of human cationic trypsinogen in murine acinar cells promotes pancreatitis. The rat elastase promoter was used to target transgene expression to pancreatic acinar cells in three transgenic strains that were generated: Tg(Ela-PRSS1)NV, Tg(Ela-PRSS1*R122H)NV and Tg(Ela-PRSS1*N29I)NV. Mice were analysed histologically, immunohistochemically and biochemically. We found that transgene expression is restricted to pancreatic acinar cells and transgenic PRSS1 proteins are targeted to the pancreatic secretory pathway. Animals from all transgenic strains developed pancreatitis characterised by acinar cell vacuolisation, inflammatory infiltrates and fibrosis. Transgenic animals also developed more severe pancreatitis upon treatment with low-dose cerulein than controls, displaying significantly higher scores for oedema, inflammation and overall histopathology. Expression of PRSS1, WT or mutant, in acinar cells increased apoptosis in pancreatic tissues and isolated acinar cells. Moreover, studies of isolated acinar cells demonstrated that transgene expression promotes apoptosis rather than necrosis. We therefore conclude that expression of WT or mutant human PRSS1 in murine acinar cells induces apoptosis and is sufficient to promote spontaneous pancreatitis, which is enhanced in response to cellular insult.

A review of functional status measures for workers with upper extremity disorders.

In order to identify functional status measures for epidemiological studies among workers with mild to moderate disorders of the neck and upper extremity, a literature search was conducted for the years 1966 to 2001. Inclusion criteria were: (1) relevance to neck and upper extremity; (2) assessment among workers; and (3) relevance to mild to moderate disorders. Of 13 instruments reviewed, six measures were tested among workers. The three best measures, depending on the purpose of research, included the standardised Nordic Musculoskeletal Questionnaire, the Upper Extremity Questionnaire, and the Neck and Upper Limb Instrument. Development of a functional protocol is regarded as a realistic enhancement for research of neck and upper extremity disorders in the workplace. For research and clinical practice, measures of functional status, sensitive enough to measure the subtle conditions in mild to moderate disorders, may provide prognostic information about the risk of developing musculoskeletal disorders in apparently healthy patients. Appropriate use of functional status questionnaires is imperative for a meaningful portrayal of health.

A simple method for orienting silk and other flexible fibres in transmission electron microscopy specimens.

When microstructures are characterized by transmission electron microscopy (TEM), the interpretation of results is facilitated if the material can be sectioned in defined orientations. In the case of fibres, it is especially useful if transverse and longitudinal sections can be obtained reliably. Here we describe a procedure for orienting spider silk and other flexible fibres for TEM investigation. Prior to embedding in epoxy resin, the silk is wound around a notched support made from polyester film. No glue is required. After the silk and its supporting film have been embedded and the resin has been cured the film can be peeled away to reveal nearly perfectly orientated silk threads. Both transverse and longitudinal sections can then be cut with a microtome. The method can be extended to obtain sections at any intermediate orientation.

Economic assessment of troglitazone as an adjunct to sulfonylurea therapy in the treatment of type 2 diabetes.

OBJECTIVE: To assess the economic efficiency of adding troglitazone to sulfonylurea therapy to improve glycemic control. BACKGROUND: Despite the high prevalence of type 2 diabetes, existing treatment strategies often fail. New oral agents give a wider segment of the population with type 2 diabetes hope of achieving near-normal blood-glucose levels. Troglitazone, a novel chemical entity, is one promising new agent. METHODS: We conducted an economic analysis based on glycemic-control data from a randomized clinical trial comparing troglitazone with placebo, each added to glyburide. A patient simulation model was used to translate these data to long-term outcomes associated with diabetes. Patients had poorly controlled type 2 diabetes mellitus despite glyburide therapy. Risk functions of developing and progressing through nephropathy, retinopathy, neuropathy, hypoglycemia, and macrovascular disease were developed from the Diabetes Control and Complications Trial and large epidemiologic studies. Cost estimates were based on data from 5 states, all payor databases, surveys, and literature. The main outcomes of the model were cost-consequences, number of patients developing each type of complication, mean time to development of the complication, cost per life-year gained (LYG), and cost per quality-adjusted life-year. RESULTS: The model predicts that for every 1000 patients treated with troglitazone, the improved glycemic control could mean that 95 to 140 fewer patients would experience one of the most severe diabetic complications (eg, blindness, end-stage renal disease, amputation), which may increase life expectancy by 2.0 years. These benefits are obtained at an additional $2100 per LYG (undiscounted). The ratio remains <$50,000 per LYG for most variations in input. CONCLUSIONS: The clinical trial demonstrated that troglitazone + glyburide improves glycemic control compared with glyburide alone. Based on these results, the model estimates fewer diabetic complications at a cost well below accepted cost-effective thresholds.

The NURSE Center: A peer mentor-tutor project for disadvantaged nursing students in Appalachia.

To assist disadvantaged Appalachian nursing students, a grant-supported peer mentor-tutor project was initiated in a regional university. Located in the NURSE Center (Nursing Undergraduate Resource for Successful Education), the goals of the project were to improve participants'academic achievement, increase retention, encourage timely academic progression, and improve NCLEX-RN passing rates. The authors describe the project, the first year of operation, and future directions.

Transdifferentiation of mature cortical cells to functional abscission cells in bean

Abscission explants of bean (Phaseolus vulgaris L.) were treated with ethylene to induce cell separation at the primary abscission zone. After several days of further incubation of the remaining petiole in endogenously produced ethylene, the distal two-thirds of the petiole became senescent, and the remaining (proximal) portion stayed green. Cell-to-cell separation (secondary abscission) takes place precisely at the interface between the senescing yellow and the enlarging green cells. The expression of the abscission-associated isoform of beta-1,4-glucanhydrolase, the activation of the Golgi apparatus, and enhanced vesicle formation occurred only in the enlarging cortical cells on the green side. These changes were indistinguishable from those that occur in normal abscission cells and confirm the conversion of the cortical cells to abscission-type cells. Secondary abscission cells were also induced by applying auxin to the exposed primary abscission surface after the pulvinus was shed, provided ethylene was added. Then, the orientation of development of green and yellow tissue was reversed; the distal tissue remained green and the proximal tissue yellowed. Nevertheless, separation still occurred at the junction between green and yellow cells and, again, it was one to two cell layers of the green side that enlarged and separated from their senescing neighbors. Evaluation of Feulgen-stained tissue establishes that, although nuclear changes occur, the conversion of the cortical cell to an abscission zone cell is a true transdifferentiation event, occurring in the absence of cell division.

Effect of antidepressant therapy on health care utilization and costs in primary care.

OBJECTIVE: Four groups of patients receiving different antidepressant drugs in a primary care setting were compared in terms of duration of antidepressant therapy and health and mental health care utilization and costs. METHODS: A retrospective analysis of the medical and pharmacy claims of an employed population and their families was conducted. A total of 1,242 patients with a diagnosis of depression were included in the analyses. The four antidepressant cohorts were fluoxetine (N = 799), trazodone (N = 89), the tricyclics amitriptyline and imipramine (N = 104), and the secondary amine tricyclics desipramine and nortriptyline (N = 250). The primary outcome measures were total health care charges, total charges for mental health services, and the pattern of antidepressant use. Secondary measures included charges for outpatient care and pharmacy and the number of outpatient visits. Data analysis involved use of two-stage multivariate regression modeling known as sample selection models. RESULTS: Patients taking fluoxetine achieved higher rates of continuous use for at least six months compared with those taking the other drugs. After selection bias due to observed and unobserved characteristics and other confounding variables was adjusted for, no significant differences were found between drug cohorts in total medical charges. CONCLUSIONS: Improvements in the process of care at no apparent increase in total charges appear possible through appropriate medication therapy.

Model of complications of NIDDM. I. Model construction and assumptions.

OBJECTIVE: To develop a model of NIDDM for analyzing prevention strategies for NIDDM. RESEARCH DESIGN AND METHODS: A Markov type model with Monte Carlo techniques was used. Age, sex, and ethnicity of cohort was based on U.S. data. Incidence rates of complications were also based on community and population studies. RESULTS: Nonproliferative retinopathy, proliferative retinopathy, and macular edema are predicted in 79, 19, and 52%, respectively, of people with NIDDM; 19% are predicted to develop legal blindness. Microalbuminuria, gross proteinuria, and end-stage renal disease related to diabetes are predicted in 53, 40, and 17%, respectively. Symptomatic sensorimotor neuropathy and lower-extremity amputation are predicted in 31 and 17%, respectively. Cardiovascular disease is predicted in 39%. Higher rates of complications (1.1-3.0x) are predicted in minority populations. Predicted average life expectancy is 17 years after diagnosis. CONCLUSIONS: A probabilistic model of NIDDM predicts the vascular complications of NIDDM in a cohort representative of the incident cases of diabetes in the U.S. before age 75 years. Predictions of complications and mortality are consistent with the known epidemiology of NIDDM. The model is suitable for evaluating the effect of preventive interventions on the natural history of NIDDM.

Model of complications of NIDDM. II. Analysis of the health benefits and cost-effectiveness of treating NIDDM with the goal of normoglycemia.

OBJECTIVE: To analyze the health benefits and economics of treating NIDDM with the goal of normoglycemia. RESEARCH DESIGN AND METHODS: Incidence-based simulation model of NIDDM was used. Hazard rates for complications were adjusted for glycemia using risk gradients from the Diabetes Control and Complications Trial. Treatment costs were estimated from national survey data and clinical trials. Incremental costs and benefits were expressed in present value dollars (3% discount rate). Life-years were adjusted for quality of life, yielding quality-adjusted life-years (QALYs). RESULTS: Comprehensive treatment of NIDDM that maintains an HbA1c value of 7.2% is predicted to reduce the cumulative incidence of blindness, end-stage renal disease, and lower-extremity amputation by 72, 87, and 67%, respectively. Cardiovascular disease risk increased by 3% (no effect of treating glycemia is assumed). Life expectancy increased 1.39 years. The cost of treating hyperglycemia increased by almost twofold, which is partially offset by reductions in the cost of complications. The estimated incremental cost/QALY gained is $16,002. Treatment is more cost-effective for those with longer glycemic exposure (earlier onset of diabetes), minorities, and those with higher HbA1c under standard care. CONCLUSIONS: The incremental effectiveness of treating NIDDM with the goal of normoglycemia is estimated to be approximately $16,000/QALY gained, which is in the range of interventions that are generally considered cost-effective.

Economic value of gemcitabine in non-small cell lung cancer.

Although cost considerations traditionally have not been important in cancer treatment decision making, there is increasing concern worldwide about the economic impact of therapeutic alternatives in the field of oncology. In particular, there is greater pressure for pharmaceutical companies to assess the economic value of new products. We have investigated and compared the clinical outcomes and corresponding cost savings of a novel nucleoside analog, gemcitabine, with other chemotherapy options in three different health care settings: Germany, the United States, and Spain. To date, most of the work with gemcitabine has been done in non-small cell lung cancer. Most non-small cell lung cancer patients present with advanced disease that is unsuitable for surgery and, in many cases, unsuitable for potentially curative chemotherapy. Chemotherapy for the majority of patients is therefore administered with palliative intent. For this reason, the comparative agents chosen for the economic models were palliative treatments (cisplatin/etoposide and ifosfamide/etoposide). As is customary with oncolytics, gemcitabine was investigated first as a single agent in noncomparative trials. Since data were not available from a comparator trial, we estimated comparative data from the literature sources and expert opinion (German and Spanish cost models) and from retrospective chart reviews (US cost model). In all three models, the efficacy was assumed to be equal, so a cost-minimization approach was used. Gemcitabine monotherapy showed cost savings compared with both cisplatin/etoposide and ifosfamide/etoposide in all treatment settings. The majority of these savings were due to differences in hospitalization for drug administration, and the incidence and treatment of nausea and vomiting and febrile neutropenia.

Economic value of gemcitabine compared to cisplatin and etoposide in non-small cell lung cancer.

Although chemotherapy costs have not been highlighted traditionally, there is increasing pressure to demonstrate the value of new treatments within the health care budget. Pharmaceutical companies are assessing the economic value of their products before launch. Gemcitabine is a nucleoside analogue developed for use in solid tumours. The purpose of this model was to investigate the clinical outcomes and potential cost savings for gemcitabine used as monotherapy compared to cisplatin and etoposide combination therapy in late stage non-small cell lung cancer (NSCLC), in a palliative (as opposed to aggressive) chemotherapy setting. Gemcitabine treatment data were taken from a large NSCLC study and data from retrospective chart reviews identified through the National Oncology Data Base. The model population and effectiveness of the two regimens were judged to be similar, except for baseline performance status. If drug costs were not included, the probability distribution resulting from the simulation showed median cost savings per cycle ranging from $US 1504 to $US 7425, with a medium value of $US 2154. The model suggested that gemcitabine would result in cost savings per cycle more than 90% of the time. Outpatient versus inpatient drug administrations accounted for the majority of potential cost savings. Most of the remaining cost savings were attributable to the difference in febrile neutropenia and antiemetic use. This economic model showed susbstantial savings if gemcitabine was used instead of cisplatin and etoposide combination therapy in the United States' community care setting. Some savings would be realized even if the location of treatment for both regimens was mostly outpatient. Assessment of the product's economic value before launch has assisted in our understanding of the potential areas of cost savings for gemcitabine and has guided us in the design of prospective randomized studies which included pharmacoeconomic endpoints.

Valuation of medical resource units collected in health economic studies.

This paper reviews the issues that are critical for the valuation of medical resources in the context of health economic studies. There are several points to consider when undertaking the valuation of medical resources. The perspective of the analysis should be established before determining the valuation process. Future costs should be discounted to present values, and time and effort spent in assigning a monetary value to a medical resource should be proportional to its importance in the analysis. Prices vary considerably based on location of the service and the severity of the illness episode. Because of the wide variability in pricing data, sensitivity analysis is an important component of validation of study results. A variety of data sources have been applied to the valuation of medical resources. Several types of data are reviewed in this paper, including claims data, national survey data, administrative data, and marketing research data. Valuation of medical resources collected in clinical trials is complex because of the lack of standardization of the data sources. A national pricing data source for health economic valuation would greatly facilitate study analysis and make comparisons between results more meaningful.

Thrombolysis in acute myocardial infarction following prolonged cardiopulmonary resuscitation.

Thrombolytic therapy was administered to a 64-year-old man with an acute anterolateral myocardial infarction who had received cardiopulmonary resuscitation (CPR) for 24 minutes. At the time of thrombolytic therapy, the patient was alert and without clinical or radiographic evidence of injury. The patient developed a retroperitoneal hematoma related to femoral line placement, as well as subcutaneous bruising of the anterior chest wall; both were self-limited. No long- term morbidity developed, and the myocardial infarction was aborted. The use of thrombolytic therapy for patients with acute myocardial infarction who have received CPR is reviewed. In the absence of clinical or radiographic evidence of trauma from CPR, patients with acute myocardial infarction should not be excluded from receiving thrombolytic therapy solely because of having had CPR or the duration of CPR.

A comparison of 1- and 2-cell ova production by F2 50% Meishan versus F1 White line gilts.

The objective of this study was to compare recovery of pronuclear and 2-cell ova from F2 50% Meishan (MX) gilts versus F1 White line (L42) gilts. Sexually mature MX and L42 gilts were allocated across 2 treatments: Super (MX:n=9; L42:n=10) and Control (MX:n=6; L42:n=5) in a 2 x 2 factorial experiment. Allyl trenbolone (AT) was used to synchronize estrus in all gilts. Super gilts were given pregnant mare serum gonadotropin (PMSG: 1250 IU) at 24 h after AT withdrawal. Eighty-five hours after PMSG administration, all Super gilts received 750 IU of human chorionic gonadotropin (hCG). Super gilts which exhibited estrus within 24 h of hCG administration (MX-Super: n=6; L42-Super: n=5) and all Control gilts were bred naturally to Line 3 boars at 12 and 24 hours after the onset of estrus. Ova were recovered from Super gilts between 60 and 64 h after hCG and Control gilts at 48 h after the onset of estrus. All 1- and 2-cell ova were centrifuged at 15000 x g and observed using differential interference contrast microscopy. The mean ovulation rate was greater (P<0.05) for both MX-Super and L42-Super gilts in comparison to their respective Control groups. No differences were detected in the mean ovulation rate (P>0.38) or the mean number of 1- and 2-cell ova recovered (P>0.50) between MX-Super and L42-Super gilts. The proportion of 1- and 2-cell ova which exhibited visible pronuclei or nuclei was also similar among MX-SUPER and L42-SUPER gilts. This study demonstrates that MX gilts respond/perform comparably to L42 gilts with respect to estrus synchronization, superovulation, ova yield, and the ease of visibility of pronuclei or nuclei in the ova.

Clinical economics: a method for prospective health resource data collection.

Information about the economic benefit of new drugs is becoming increasingly important for formulary considerations, reimbursement policies and related considerations. Although economic benefits of drugs have been analysed and reported, the economic benefits of drugs have rarely been examined in the course of randomised therapeutic trials. We designed a modular survey instrument, the Resource Utilisation Survey (RUS), to collect economic outcomes in prospective trials. A pilot test of the RUS was conducted using clinical trial methods in a study of nizatidine versus placebo in preventing ulcers induced by nonsteroidal anti-inflammatory drugs. The purpose of the pilot study was to evaluate the RUS instrument and corresponding study design issues in clinical trials for either acute or chronic diseases. With the lessons learned from the pilot study, the RUS has been used successfully in other ongoing clinical trials.

Further similarities of endogenous pyrogen and leukocytic endogenous mediator.

The release of endogenous pyrogen (EP) from rabbit peritoneal granulocytes was measured with a three-point log dose-response curve. Release of EP was inhibited when the cells were incubated in media containing potassium or calcium. Measurements of leukocytic endogenous mediator (LEM) activity, i.e., lowering of plasma iron and zinc and increases in blood neutrophils, were made on the same supernatant media. When EP release was inhibited there was a similar inhibition of LEM activity. These results indicate a similarity between the release of pyrogenic and LEM activities. Together with previous purification studies, the results suggest that EP and LEM are similar and may be identical factors.