Alzheimer's A beta(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells.

Alzheimer's disease (AD) is a neurodegenerative disorder involving the florid deposition of vascular and cerebral plaques composed chiefly of amyloid beta-peptide (A beta) derived from cleavage of the amyloid precursor protein (APP). Varying in length from 39 to 43 amino acids, A beta, particularly the longer A beta(42), is thought to play a significant role in AD pathogenesis. To better understand AD it is important to identify the subcellular organelles generating A beta. Studies using agents that disrupt endosomal/lysosomal function suggest that A beta is generated late in the secretory and endocytic pathways. However, much of what is known about A beta biosynthesis has been inferred by monitoring extracellular A beta levels since intracellular A beta is undetectable in most cell types. Consequently, the precise site or sites that generate A beta, or whether A beta(1-40) and A beta(1-42) are generated at the same point in the biosynthetic pathway, is not known. Using human NT2N neurons, we found that retention of APP in the endoplasmic reticulum/intermediate compartment (ER/IC) by three independent approaches eliminated production of intracellular A beta(1-40), but did not alter intracellular A beta(1-42) synthesis. These findings suggest that the ER/IC may be an important site for generating this highly amyloidogenic species of A beta.

Impact of evidence-based "clinical judgment" on the number of American adults requiring lipid-lowering therapy based on updated NHANES III data. National Health and Nutrition Examination Survey.

BACKGROUND: When the National Cholesterol Education Program Adult Treatment Panel II (ATP II) guidelines were published, National Health and Nutrition Examination Survey III data for 1988 to 1991 were used to estimate the number of Americans requiring lipid-lowering therapy based on ATP II cut points. However, the guidelines recommend using clinical judgment to determine whether to initiate drug therapy in individuals whose low-density lipoprotein cholesterol levels remain above treatment goals with diet therapy but below the initiation level for drug therapy. METHODS: We analyzed updated (1988-1994) National Health and Nutrition Examination Survey III data, based on a sample of 6796 adults aged 20 years and older, to estimate the numbers of American adults with an elevated low-density lipoprotein cholesterol level and requiring drug therapy using cut points vs clinical judgment as specified in ATP II guidelines. RESULTS: Assuming a 10% low-density lipoprotein cholesterol reduction with diet, an estimated 10.4 million American adults require drug therapy based on ATP II cut points. If we include individuals for whom the guidelines recommend clinical judgment, the estimate increases to 28.4 million. The largest increase occurs in individuals without known coronary heart disease but with 2 or more risk factors: from 5.5 to 17.5 million. These high-risk individuals have low-density lipoprotein cholesterol concentrations similar to those in patients with coronary heart disease. CONCLUSIONS: Since the ATP II guidelines were published, clinical judgment has been informed by abundant clinical trial evidence establishing the safety and benefit of lipid-lowering therapy. The large number of individuals at high risk for coronary heart disease emphasizes the need for cost-effective therapy to extend treatment to the greatest number of individuals who may benefit.

Utilization of oral hypoglycemic agents in a drug-insured U.S. population.

OBJECTIVE: Clinical trials provide information regarding the safety and efficacy of medications used to manage type 2 diabetes but do not elucidate drug effectiveness in a typical managed care environment. The aim of this study was to characterize "real-world" drug utilization patterns from both a prescriber and a patient perspective. RESEARCH DESIGN AND METHODS: We conducted a retrospective analysis of a large administrative pharmacy claims database, using data on continuously pharmacy benefit-eligible members prescribed oral hypoglycemic agents (OHAs). RESULTS: The 12-month persistence rate for the OHA cohort was low, ranging from 31% for alpha-glucosidase inhibitors to 60% for metformin; compliance rates varied between 70 and 80%. During the first 12 months of therapy, 36% of the patients remaining on therapy at 12 months had one or more therapy modifications. The mean number of therapy changes increased with the length of patient follow-up, with more than half of all patients experiencing at least one therapy change over the duration of follow-up. CONCLUSIONS: These findings document the wide variation in utilization patterns associated with pharmacological management of type 2 diabetes, suggesting that opportunity exists to optimize its pharmacological management.

Kaposi's sarcoma: advances in tumor biology and pharmacotherapy.

Kaposi's sarcoma (KS) is a highly vascularized neoplasm that primarily results in raised, highly vascularized lesions. Before the 1980s, KS was a rare disorder that occurred predominantly in elderly men of Mediterranean or Eastern European Jewish descent. With the advent of the acquired immunodeficiency syndrome (AIDS) epidemic, its occurrence has increased dramatically. It can be classified into four types: classic, African endemic, iatrogenic or drug associated, and AIDS related. Classic KS usually follows an indolent and benign clinical course that rarely requires treatment. In contrast, AIDS-KS is a fulminant disease that requires aggressive pharmacotherapy, especially when it involves visceral organs. The epidemiology, clinical presentation, pathogenesis, and management strategies of AIDS-KS are reviewed, including recent pharmacologic advances.

Factors affecting patient compliance with antihyperlipidemic medications in an HMO population.

OBJECTIVE: To identify factors that influence compliance in patients taking antihyperlipidemic medications. STUDY DESIGN: This was a retrospective cohort study in which computerized pharmacy records were used to estimate medication compliance in patients in a Health Maintenance Organization from 1993 to 1995. PATIENTS AND METHODS: Data on 772 patients on antihyperlipidemic medications were obtained from pharmacy and healthcare utilization claims and from a cross-sectional survey. The medication compliance ratio for each patient was calculated from the prescription profile. Patient compliance was modeled as a function of four clusters of determinants: patient characteristics, complexity of drug regimen, health status, and patient-provider interaction. Correlation between specific characteristics and compliance was estimated by logistic regressions. RESULTS: Approximately 37% of patients complied with at least 90% or more of their antihyperlipidemic medications. The following variables had a significant influence on compliance: female gender (odds ratio [OR], 0.64), baseline compliance (high: OR, 3.42; medium: OR, 1.86), perceived health status (SF-36 bodily pain score: OR, 1.02; SF-36 vitality score: OR, 0.97), comorbidity (OR, 0.90), and number of daily doses of antihyperlipidemic medications (OR, 0.60). CONCLUSIONS: The findings suggest that women, patients with comorbidities, patients reporting high SF-36 vitality scores, and patients with multiple doses of antihyperlipidemic medications are less likely to be compliant. Patients who self-report good compliance with previous medications are more likely to comply. This information may be used to target interventions at patients who are likely to be noncompliant with their medication regimens.

Clinical experience with endoscopic stents for treatment of common bile duct stones.

Endoscopic removal of common bile duct (CBD) stones after endoscopic sphincterotomy (EST) is now a widely accepted procedure. Surgery is usually recommended when extraction of stones after EST fails. For patients with major medical problems or who are at high surgical risk, however, endoscopic stent placement may help to prevent stone impaction and cholangitis. In this report, we describe the long-term effects and complications of biliary stent use in elderly patients with CBD stones. From August 1995 to June 1998, 19 patients with CBD stones underwent stent placement by duodenoscopy. Three of these patients underwent this procedure for temporary treatment while awaiting surgery or EST. In the remaining 16 patients (6 men and 10 women, mean age 76 +/- 10 years), invasive management carried a high risk of complications. We used a 7F straight stent for the first patient, while the remaining 15 received 7F pigtail stents. During a mean follow-up period of 34 months, two patients were lost to follow-up and two patients had migration of the stents. Three patients had acute cholangitis with stents in situ. Of these, one underwent stent exchange 8 months later, while the CBD stones were cleared either by endoscopy or surgery in the other two patients. Five patients died of nonbiliary diseases during the follow-up period. Our results show that long-term biliary stent placement is an advisable alternative therapeutic modality for high-risk and debilitated patients with CBD stones.

Prostate cancer detection, characterization, and clinical outcomes in men aged 70 years and older referred for transrectal ultrasound and prostate biopsies.

OBJECTIVES: To evaluate the diagnostic findings and treatment options chosen in men aged 70 years and older referred for prostate biopsy. METHODS: Age, prostate-specific antigen (PSA), biopsy pathology, clinical stage, treatment pursued, and treatment outcome were analyzed in 210 men age 70 years and older referred for transrectal ultrasound and prostate biopsies. All patients were followed for a mean of 46.9 months (range 28 to 63). RESULTS: Cancer was found in 120 (56.8%) of the patients. The cancer detection rate was significantly higher (81.0%) in patients aged 80 years and older than those younger than 80 years. Cancer patients aged 80 years and older had a higher rate of poorly differentiated cancer (64.7%) compared with the 70 to 74-year-olds (33.3%) and 75 to 79-year-olds (32.1%). The patients aged 80 years and older also had a larger proportion of high-stage cancer. The patients younger than 80 years had a significantly higher incidence of stable/falling PSA with treatment compared with the older patients. Of the 210 patients, 41 (19.4%) died within 5 years of the diagnostic procedure; 3 died of prostate cancer. The death rate was not significantly different among the three age groups evaluated. None of the patients aged 80 years and older died of prostate cancer. CONCLUSIONS: Patients aged 80 years and older who are diagnosed with prostate cancer are less likely to respond well to treatment and usually die of unrelated causes. Aggressive diagnosis, staging, and treatment in octogenarians should be guided by the patients' symptoms, overall health, and personal preferences.

Locally application of amphetamine into the ventral tegmental area enhances dopamine release in the nucleus accumbens and the medial prefrontal cortex through noradrenergic neurotransmission.

The effects and mechanisms of locally applied d-amphetamine (AMPH) into the ventral tegmental area (VTA) on extracellular dopamine (DA) concentrations in both the nucleus accumbens (N ACC) and the medial prefrontal cortex (mPFC) were investigated. A solution containing either, 0, 100, 500 or 1000 microM AMPH was infused, using a 1-ml Hamilton syringe, into the VTA of chloral hydrate-anesthetized rats for 100 min through a microdialysis probe. Infusion of AMPH into the VTA dose-dependently increased extracellular DA in the N ACC and in the mPFC. The introductory rate of AMPH application through the dialysis probe into the VTA was estimated simultaneously. Local infusion of either a selective alpha adrenoceptor antagonist (phentolamine, 1 and 10 microM) or a selective beta adrenoceptor antagonist (alprenolol, 1 and 10 nM) dose-dependently blunted the intra-VTA AMPH-induced extracellular DA increase in the N ACC. Further, local infusion of phentolamine (0.1 and 1 microM) and alprenolol (1 and 10 nM) appreciably and dose-dependently reduced the effects of AMPH on the DA increase in the mPFC. These results suggest that intra-VTA AMPH can enhance DA release in the N ACC and in the mPFC by activating noradrenergic neurotransmission in the VTA.

A critical evaluation of the methodology of the literature on medication compliance.

OBJECTIVE: To develop a simple evaluation tool to assess methodologic rigor of the literature on patient compliance with medications, and to apply the tool to a sample of the literature. METHODS: A computerized search of the MEDLINE database (January 1980-December 1996) was performed. All English-language articles on compliance with medications were identified, using the MeSH terms patient-compliance and drug-therapy. A 10% sample was then randomly selected for review. Methodologic rigor was assessed on eight standards: study design, specification of patient sample, power analysis, specification of disease, specification of therapeutic regimen, duration of follow-up, definition of compliance, and compliance measurement. The raw scores of the eight standards were then combined in three summary scores, standardized from 0 to 100: study design, disease-related features, and compliance issues. RESULTS: Seventy-two articles from 719 identified were reviewed. The majority of the research articles were descriptive (63.9%), and patients in these studies were selected mainly from a convenience sample (41.7%). Just nine studies were multicenter studies, and three employed power analysis. The compliance definition was replicable in 41.7% of the studies. In 22 articles neither the compliance measure nor the criteria were stated. One-quarter of the studies (18) used a nonvalidated measure of compliance. Only two studies reached a score of 6 in the compliance measure, and eight studies used two different measures of compliance simultaneously. The median values in the summary scores were: study design 8.3, disease 42.9, compliance issues 50. CONCLUSIONS: The quality of the compliance research was generally poor. These low scores reflect very important shortcomings in the methodology. Such oversights make it difficult for the reader to critically assess the validity of the conclusions.

A new treatment satisfaction measure for asthmatics: a validation study.

The Patient Satisfaction with Asthma Medication (PSAM) questionnaire was developed because no treatment satisfaction questionnaire could be identified that was comprehensive yet brief enough for use in clinical trials. Adult moderate asthmatics residing in Canada using an inhaled medication (either salmeterol, formoterol, or albuterol) self-administered the questionnaire, which also included the Asthma Quality of Life Questionnaire (AQLQ). A total of 53 asthmatics (70% female, 45% married, mean age: 47 years) completed the questionnaire. Using variable clustering, four PSAM scales were identified: Inhaler Properties, Comparison with Other Medications, Overall Perception of Medication, and Relief. Internal-consistency reliability provided evidence of reliability and lack of redundancy (Cronbach's Alpha: 0.82-0.88). Test-retest reliability was acceptable (ICC values at or near 0.70). As expected, interscale PSAM correlations were moderate to high; correlations between the PSAM and the AQLQ were low to moderate. To assess known groups validity, respondents were categorized by self-reported degree of asthma control: 'very well controlled', 'somewhat controlled', and 'not well controlled'. Significant between-groups differences were found on all PSAM scales except Inhaler Properties. Patients categorized as 'very well controlled' tended to report highest PSAM scale scores. The PSAM questionnaire demonstrated reliability and validity in moderate asthmatics. Responsiveness should be assessed in future, prospective studies.

Computer-assisted design of an implantable, intrathoracic artificial lung.

A semiempirical mathematical model of convective oxygen transport is used to design a new, low pressure loss, implantable artificial lung that could be used as a bridge to lung transplantation in patients with advanced respiratory failure. The mass transfer and flow friction relations pertinent to the design of a cross-flow hollow fiber membrane lung are described. The artificial lung is designed to transfer over 200 ml/min of oxygen at blood flow rates up to 5 L/min. A compact design and a blood-side pressure loss of < 15 mm Hg allows the device to be implanted in the left chest without the need for a prosthetic blood pump. Surgical implantation of the artificial lung would require the creation of inflow and outflow anastomoses. Oxygen would be supplied via an external source. Blood properties, operating conditions, and empirically determined mass transfer and flow properties are all specified and input into a computer program that numerically solves the design equations. Computer-generated values for the device frontal area, blood path length, and fiber surface area are thereby obtained. The use of this computer-assisted design minimizes the need for extensive trial-and-error testing of prototype devices. Results from in vitro tests of a prototype implantable lung indicate that the mathematical model we describe is an accurate and useful tool in the design of hollow fiber artificial lungs.

Transforming growth factor-alpha antisense vectors can inhibit glioma cell growth.

The effects of transforming growth factor-alpha (TGF-alpha) on cell growth were studied in human glioma U251 cells transfected with antisense TGF-alpha vectors (pcDNAI.neo). Several antisense clones showed a marked decrease in growth rate in serum-free medium but not in medium containing 10% FBS, compared with those of parental cells and clones from sense or vector transfectants. Antisense clones also produced fewer and smaller colonies in anchorage-independent growth assays. Moreover, there was a reduction in TGF-alpha expression in these antisense clones at both the protein and mRNA levels, as determined by enzyme linked immuno-sorbent assay and reverse transcriptase polymerase chain reaction analysis. A U251 clone transfected by TGF-alpha antisense in a different vector (pMT/Ep) also showed a marked suppression in cell growth and TGF-alpha mRNA level. Finally, transfected clones with either vector system, showed decreased tumorigenicity in nude mice. In summary, a strong correlation between the inhibition of glioma cell growth and TGF-alpha expression was obtained from two different plasmid vectors, indicating that the expression of TGF-alpha could be specifically and effectively down-regulated by TGF-alpha antisense vector, which in turn led to growth inhibition. These studies suggests that TGF-alpha plays an essential role in controlling human glioma cell proliferation and may serve as a potential target for treatment of malignant glioma.

Compliance with sulfonylureas in a health maintenance organization: a pharmacy record-based study.

OBJECTIVE: To determine which factors affect compliance with sulfonylureas in a population served by a health maintenance organization in Southern California. METHODS: Retrospective analysis of pharmacy records and healthcare utilization data for two years (April 1993-March 1995), and a survey mailed to patients. Patients treated with sulfonylureas were selected for analysis on the basis of their prescription profile. Compliance was measured from the pharmacy records as the proportion of days the patient was in possession of the prescribed medications. Patient compliance with sulfonylureas was modeled as a function of four clusters of determinants: patient-related attributes, drug regimen characteristics and complexity, health status and disease-related variables, and characteristics of the interaction with healthcare providers. RESULTS: 786 patients were identified for analysis (49.1% women, mean age 59 y). The mean compliance rate was 83% +/- 22% SD. Compliance was significantly positively related with age and self-reported level of medication-taking compliance at baseline. Factors shown to have an inverse relationship with compliance were treatment complexity, perception of general health, and being a newly treated patient (adjusted R2 for the final model = 0.148). CONCLUSIONS: Our results suggest that factors found to be associated with noncompliant behavior (e.g., being a newly treated patient, self-reported compliance, regimen complexity) can be assessed by physicians and pharmacists as a routine practice.

Characteristics of US adults with the metabolic syndrome and therapeutic implications.

BACKGROUND: The third Adult Treatment Panel (ATP III) of the National Cholesterol Education Program defines clinical criteria for diagnosis of the metabolic syndrome, which increases cardiovascular risk and is a target for therapy. AIM: We analysed the third National Health and Nutrition Examination Survey (NHANES III; 1988-94) to determine how many US adults meet these criteria and are recommended for lipid-modifying drug therapy by ATP III. METHODS: NHANES III data were used to estimate the number of individuals with the metabolic syndrome and the number recommended for treatment by ATP III, based on 1990 census data. RESULTS: An estimated 36.3 million (23%) US adults have the metabolic syndrome. Of these, 84% met the criterion for obesity, 76% for blood pressure, 75% for HDL-C, 74% for triglycerides and 41% for glucose. Most (54%) are in the higher risk categories of ATP III, yet only 39% overall are recommended for drug therapy by ATP III cutpoints; of these, most will achieve LDL-C targets with reductions of 35-40%. Of the 15.3 million individuals with the metabolic syndrome and triglycerides > or = 2.26 mmol/l (200 mg/dl), non-HDL-C is above ATP III recommendations in 11.6 million. CONCLUSIONS: Of the large number of Americans with the metabolic syndrome, ATP III recommends drug therapy for only a minority, because LDL-C typically is not substantially elevated. Instead, high triglycerides and low HDL-C are more common; clinical trial data are needed to determine whether optimal therapy should focus on reductions in LDL-C or on comprehensive improvements to the lipid profile.

Expression and analysis of presenilin 1 in a human neuronal system: localization in cell bodies and dendrites.

Mutations in the recently identified presenilin 1 gene on chromosome 14 cause early onset familial Alzheimer disease (FAD). Herein we describe the expression and analysis of the protein coded by presenilin 1 (PS1) in NT2N neurons, a human neuronal model system. PS1 was expressed using recombinant Semliki Forest virions and detected by introduced antigenic tags or antisera to PS1-derived peptides. Immunoprecipitation revealed two major PS1 bands of approximately 43 and 50 kDa, neither of which were N-glycosylated or O-glycosylated. Immunoreactive PS1 was detected in cell bodies and dendrites of NT2N neurons but not in axons or on the cell surface. PS1 was also detected in BHK cells, where it was also intracellular and colocalized with calnexin, a marker for the rough endoplasmic reticulum. A mutant form of PS1 linked to FAD did not differ from the wild-type protein at the light microscopic level. The model system described here will enable studies of the function of PS1 in human neurons and the role of mutant PS1 in FAD.