The role of the endosomal/lysosomal system in amyloid-beta production and the pathophysiology of Alzheimer's disease: reexamining the spatial paradox from a lysosomal perspective

One of the hallmarks of Alzheimer's disease is the cerebral deposition of plaques composed of a 37-43 amino acid amyloid-beta (Abeta) peptide. Abeta is produced by the sequential proteolytic cleavage of an integral-membrane protein, amyloid beta-protein precursor (AbetaPP), first by beta-secretase (BACE), and then by gamma-secretase, a complex containing presenilin and Nicastrin. Although these cleavages were originally documented to occur in the endosomal/ lysosomal system, other lines of evidence suggest that the responsible proteins and activity reside in the ER or Golgi. This lack of intracellular co-localization of enzyme and substrate has been referred to as the spatial paradox of Alzheimer's disease. Here we will review the biology of the lysosome and the literature supporting the endosomal/ lysosomal production of Abeta. We will also examine some of the data supporting Abeta production in the biosynthetic compartments and demonstrate its compatibility with an endosomal/ lysosomal model. Finally, we will discuss the possible role of the acidic environment of the lysosome in the amyloidogenic process, and review the evidence for intracellular amyloidogenesis preceding amyloid plaque formation.     

Tacrolimus toxicity associated with concomitant metoclopramide therapy

Subtherapeutic tacrolimus trough concentrations were noted in a 52-year-old woman who had undergone liver transplantation. Her tacrolimus dosage was increased from 7 to 28 mg twice/day, and ketoconazole therapy was added; however, her tacrolimus concentration remained undetectable. Metoclopramide 10 mg 4 times/day was begun to control the patient's new-onset nausea and vomiting. Within 48 hours of increasing the dosage to 20 mg 4 times/day, her tacrolimus trough concentration exceeded 30 ng/ml. Signs and symptoms were suggestive of tacrolimus nephrotoxicity and neurotoxicity. According to the Naranjo scale, this adverse drug event was probably the result of improved absorption of tacrolimus secondary to metoclopramide therapy. The patient's subtherapeutic tacrolimus concentration at baseline was probably secondary to poor absorption due to impaired gastric emptying. Coadministration of metoclopramide significantly improved gastric motility and delivery of tacrolimus to the small intestine, increasing tacrolimus bioavailability, thus resulting in acute-onset tacrolimus toxicity. When tacrolimus is administered with metoclopramide in patients with gastric dysmotility, tacrolimus concentrations should be monitored closely to minimize the risk of toxicity.     

Physician-elder interaction in community family practice

OBJECTIVE: To determine whether outpatient visits by elders seeing community family physicians differ in length or content from visits by younger patients; socioemotional preferences predict visit content; and satisfaction correlates with visit content differentially across age. METHODS: In a multimethod cross-sectional study of 84 community family practices in northeastern Ohio, 3453 adult patient visits with 138 community family physicians were observed; 2362 of these patients completed self-report questionnaires. Three age groups were compared: 18 to 64, 65 to 74, and over 74 years. Length and content of the physician-patient encounter was determined using the Davis Observation Code (DOC); satisfaction was assessed using the MOS 9-item Visit Rating Scale. RESULTS: Controlling for reason for visit and demographics, visit length averaged 10.7 minutes for each group. Visit content differed significantly on 13 of 20 DOC codes between one of the older groups and the younger group; in 4 instances, content varied between the 2 older groups. Although visit content varied as predicted by socioemotional theory, no consistent patterns of association between visit content and satisfaction emerged. DISCUSSION: Older patient visits differ from those of younger patients as might be predicted by socioemotional selectivity theory; however, there was little association of visit content with patient satisfaction.     

Improvement of BMI,body composition,and body fat distribution with lifestyle modification in Japanese Americans with impaired glucose tolerance

OBJECTIVE: To determine whether diet and endurance exercise improved adiposity-related measurements in Japanese Americans with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: This study compared the effects of an American Heart Association (AHA) step 2 diet (<30% of total calories as fat, <7% saturated fat, 55% carbohydrate, and < 200 mg cholesterol daily) plus endurance exercise for 1 h three times a week (treatment group) with an AHA step 1 diet (30% of total calories as fat, 10% saturated fat, 50% carbohydrate, and <300 mg cholesterol) plus stretching exercise three times a week (control group) on BMI, body composition (% fat), and body fat distribution at 6 and 24 months of follow-up in 64 Japanese American men and women with IGT, 58 of whom completed the study. RESULTS: At 6 months, the treatment group showed significantly greater reduction in percent, body fat (-1.4 +/- 0.4 vs. -0.3 +/- 0.3%); BMI (-1.1 +/- 0.2 vs. -0.4 +/- 0.1 kg/m(2)); subcutaneous fat by computed tomography at the abdomen (-29.3 +/- 4.2 vs. -5.7 +/- 5.9 cm(2)), thigh (-13.2 +/- 3.6 vs. -3.6 +/- 3.0 cm(2)), and thorax (-19.6 +/- 3.6 vs. -8.9 +/- 2.6 cm(2)); and skinfold thickness at the bicep (-2.0 +/- 0.6 vs. 1.1 +/- 0.6 mm) and tricep (-3.7 +/- 0.8 vs. -0.9 +/- 0.6 mm), which continued despite moving to home-based exercise for the last 18 months. CONCLUSIONS: Diet and endurance exercise improved BMI, body composition, and body fat distribution and, thus, may delay or prevent type 2 diabetes in Japanese Americans with IGT.     

Heterogeneity in older people: examining physiologic failure,age, and comorbidity

OBJECTIVES: To derive a clinically relevant age-independent physiologic failure scoring system and to use this system to examine aspects of the association of physiologic failure, age, and comorbidity with inpatient mortality. DESIGN: Retrospective, secondary analysis of a derivation and validation cohort selected from the Cleveland Health Quality Choice Coalition data set. SETTING: Thirty hospitals in greater Cleveland. PARTICIPANTS: Thirty-one thousand nine hundred seventy-six inpatients aged 50 and older discharged in 1993 with a diagnosis of congestive heart failure, pneumonia, or stroke. MEASUREMENTS: The Inpatient Physiologic Failure Score (IPFS) was developed and used to calculate physiologic failure. Forty-four candidate variables were examined for their association with inpatient mortality, and 12 were selected. A point value (2, 3, 4, or 6) based on adjusted odds ratio was assigned for an abnormal result for each of the 12 common physiologic variables. Each patient's abnormal physiology points were summed to produce a physiologic failure score (range 0-39). Comorbidity was quantified using the Patient Management Category Severity Scale. The association between mortality and increasing physiologic failure, increasing age and comorbidity, and distribution of physiologic failure with increasing age and comorbidity were examined. A threshold age was sought. Models for predicting inpatient mortality were developed. RESULTS: Twelve physiologic variables constitute the IPFS. Increasing physiologic failure, age, and comorbidity were associated with increasing mortality. Increasing physiologic failure was not associated with increasing age or comorbidity. We did not find a threshold age. The area under the receiver operating characteristic (ROC) curve for predicting inpatient mortality for IPFS was 0.730, and for comorbidity was 0.741 (not significant). The area under the ROC curve for a mortality prediction model based on age was significantly less (0.603). Accounting for patient age did not significantly improve the predictive ability of the IPFS model (area = 0.752, P <.05). The complete model best predicted mortality (0.829). CONCLUSIONS: The IPFS represents a clinically relevant method for scoring physiologic failure. Physiologic failure, age, and comorbidity are independently and differently associated with inpatient mortality. Physiology fails independent of age and comorbidity.     

The posterior superior alveolar injection technique: a report on technique variations and complications

The posterior superior alveolar (PSA) injection technique has varied over time with respect to the depth and angle of penetration, the location for deposition of anesthetic agent, and the number of injections necessary to assure adequate anesthesia to the maxillary molars. Of the standard intraoral injections, the PSA carries with it the second highest risk for anesthesia complications. With changes in armamentarium and technique, the complication rates have declined and more often are associated with anatomical considerations with respect to neurovascular compromise and/or anesthetic solution. In this study, the PSA injection technique and complication histories were investigated. Seventeen variations to the technique are reported along with 12 injection complications. A historic injection complication classification system is presented along with a management strategy based upon a review of reported provider experiences and treatment suggestions.