Fatty acid oxidation in the pathogenesis of Alzheimer's disease

Alzheimer's disease (AD) is the most common dementing illness of the elderly and is a mounting public health problem. Pharmacoepidemiological data, analytical data from human tissue and body fluids, and mechanistic data mostly from murine models all have implicated oxidation products of two fatty acids, arachidonic acid (AA) and docosahexaenoic acid (DHA), in the pathogenesis of neurodegeneration. Here we review the biochemistry of AA and DHA oxidation, both enzyme-catalyzed and free radical mediated, and summarize those studies that have investigated these oxidation products as effectors of neurodegeneration and biomarkers of AD. Given the evolving appreciation for toxicity associated with current pharmaceuticals used to block AA and DHA oxidation, we close by speculating on likely areas of future research directed at suppressing this facet of neurodegeneration. If successful, these interventions are unlikely to cure AD, but may check its explosive growth and hopefully reduce its incidence and prevalence in the elderly.     

Oarside and nonoarside knee extensor strength measures and their relationship to rowing ergometer performance

Laterality difference in strength characterize some sports and occupations. The purposes of this study were to compare oarside and nonoarside knee extensor strength of intercollegiate rowers and to determine the relationship between joint-specific strength measures and rowing ergometer performance. Fifteen light-weight sweep oarsmen performed concentric-eccentric cycles with a five-second pause between muscle actions through the range of 90 degrees to 10 degrees flexion at angular velocities of 160 and 200 degrees /sec. Although the oarside knee extensors produced greater peak and average torques in seven of eight comparisons, only the peak torque during oarside concentric muscle actions at 160 degrees /sec angular velocity was significantly greater (p < 0.05), i.e., about six percent. Correlations between rowing ergometer scores and strength measurements were low (r = -0.26 to -0.43) and nonsignificant (p > 0.05). A tendency may exist for light-weight sweep rowers to develop greater strength in the oarside knee extensors. Unilateral and joint-specific tests may provide valuable comparative information to guide rehabilitation and training; however, these tests of knee extensor strength are poorly related to and should not be used as the only predictors of readiness to return to activity and rowing performance. J Orthop Sports Phys Ther 1991;14(5):213-219.     

The survival motor neuron protein in spinal muscular atrophy

The 38 kDa survival motor neuron (SMN) protein is encoded by two ubiquitously expressed genes: telomeric SMN (SMN(T)) and centromeric SMN (SMN(C)). Mutations in SMN(T), but not SMN(C), cause proximal spinal muscular atrophy (SMA), an autosomal recessive disorder that results in loss of motor neurons. SMN is found in the cytoplasm and nucleus. The nuclear form is located in structures termed gems. Using a panel of anti-SMN antibodies, we demonstrate that the SMN protein is expressed from both the SMN(T) and SMN(C) genes. Western blot analysis of fibroblasts from SMA patients with various clinical severities of SMA showed a moderate reduction in the amount of SMN protein, particularly in type I (most severe) patients. Immunocytochemical analysis of SMA patient fibroblasts indicates a significant reduction in the number of gems in type I SMA patients and a correlation of the number of gems with clinical severity. This correlation to phenotype using primary fibroblasts may serve as a useful diagnostic tool in an easily accessible tissue. SMN is expressed at high levels in brain, kidney and liver, moderate levels in skeletal and cardiac muscle, and low levels in fibroblasts and lymphocytes. In SMA patients, the SMN level was moderately reduced in muscle and lymphoblasts. In contrast, SMN was expressed at high levels in spinal cord from normals and non- SMA disease controls, but was reduced 100-fold in spinal cord from type I patients. The marked reduction of SMN in type I SMA spinal cords is consistent with the features of this motor neuron disease. We suggest that disruption of SMN(T) in type I patients results in loss of SMN from motor neurons, resulting in the degeneration of these neurons.      

A field comparison of seven diagnostic techniques for human trypanosomiasis in the Luangwa Valley, Zambia

One serological and six parasitological techniques for diagnosing human trypanosomiasis were compared with regard to sensitivity, specificity, positive and negative predictive values, and practicality in field application in the Luangwa Valley of Zambia. Seven (0.64%) trypanosomiasis cases were diagnosed parasitologically in a survey of 1093 people from 19 villages. The indirect fluorescent antibody test (IFAT) was more sensitive but less specific than the parasitological techniques, detecting 71% of the confirmed cases in the first round of testing. Rat inoculation, the Giemsa stained thick film and miniature anion-exchange/centrifugation (mAEC) were all more sensitive than wet blood film examination, microhaematocrit centrifugation and wet film examination of the buffy coat after microhaematocrit centrifugation. The comparison indicated that the most effective, practical combination of techniques for survey in the Luangwa Valley was IFAT screening followed by examination of seropositive patients by rat inoculation and the mAEC (or stained thick film) in parallel format. Calculation of positive and negative predictive values showed that trypanosomiasis point prevalence measured in this way would still be underestimated by approximately 60%, indicating the need to improve IFAT specificity and parasitological sensitivity. Although only one of the seven patients diagnosed in the survey presented with signs and symptoms indicating possible trypanosomiasis, no evidence of a population of "healthy carriers" was found.     

Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: results from a randomized trial.

CONTEXT: Cardiac troponins I (cTnI) and T (cTnT) are useful for assessing prognosis in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI). However, the use of cardiac troponins for predicting benefit of an invasive vs conservative strategy in this patient population is not clear. OBJECTIVE: To prospectively test whether an early invasive strategy provides greater benefit than a conservative strategy in acute coronary syndrome patients with elevated baseline troponin levels. DESIGN: Prospective, randomized trial conducted from December 1997 to June 2000. SETTING: One hundred sixty-nine community and tertiary care hospitals in 9 countries. PARTICIPANTS: A total of 2220 patients with acute coronary syndrome were enrolled. Baseline troponin level data were available for analysis in 1821, and 1780 completed the 6-month follow-up. INTERVENTIONS: Patients were randomly assigned to receive (1) an early invasive strategy of coronary angiography between 4 and 48 hours after randomization and revascularization when feasible based on coronary anatomy (n = 1114) or (2) a conservative strategy of medical treatment and, if stable, predischarge exercise tolerance testing (n = 1106). Conservative strategy patients underwent coronary angiography and revascularization only if they manifested recurrent ischemia at rest or on provocative testing. MAIN OUTCOME MEASURE: Composite end point of death, MI, or rehospitalization for acute coronary syndrome at 6 months. RESULTS: Patients with a cTnI level of 0.1 ng/mL or more (n = 1087) experienced a significant reduction in the primary end point with the invasive vs conservative strategy (15.3% vs 25.0%; odds ratio [OR], 0.54; 95% confidence interval [CI], 0.40-0.73). Patients with cTnI levels of less than 0.1 ng/mL had no detectable benefit from early invasive management (16.0% vs 12.4%; OR, 1.4; 95% CI, 0.89-2.05; P<.001 for interaction). The benefit of invasive vs conservative management through 30 days was evident even among patients with low-level (0.1-0.4 ng/mL) cTnI elevation (4.4% vs 16.5%; OR, 0.24; 95% CI, 0.08-0.69). Directionally similar results were observed with cTnT. CONCLUSION: In patients with clinically documented acute coronary syndrome who are treated with glycoprotein IIb/IIIa inhibitors, even small elevations in cTnI and cTnT identify high-risk patients who derive a large clinical benefit from an early invasive strategy.     

The spectrin-ankyrin skeleton controls CD45 surface display and interleukin-2 production

With T cell receptor stimulation, intracellular pools of CD45 and spectrin move to the surface. These processes are coupled. In both peripheral lymphocytes and Jurkat T cells, betaI spectrin and ankyrin associate with CD45. In Jurkat T cells, betaI spectrin peptides suppress surface recruitment of CD45 and CD3 and abrogate T cell activation. Other glycoproteins such as CD43 are not altered by the spectrin peptides. Spectrin's effects are mediated by ankyrin, which binds directly to the cytoplasmic domain of CD45 (K(d) = 4.3 +/- 3.0 nM). These data reveal a novel and unexpected contribution of the spectrin-ankyrin skeleton to the control of T lymphocyte function.     

A phase I safety, pharmacological and biological study of the farnesyl protein transferase inhibitor, tipifarnib and capecitabine in advanced solid tumors.

BACKGROUND: To evaluate the toxicity and pharmacological and biological properties of the farnesyl protein transferase (FPTase) inhibitor, tipifarnib (R115777, ZARNESTRAtrade mark) and capecitabine administered for 14 days every 3 weeks. PATIENTS AND METHODS: Patients with advanced cancers received twice daily tipifarnib (100-500 mg) and capecitabine (1000-1125 mg/m(2)) for 14 days every 3 weeks. Pharmacokinetics of tipifarnib, capecitabine and 5-fluorouracil (5-FU) were determined. Peripheral blood mononuclear cells were analyzed for farnesylation of the HDJ2 chaperone protein and FPTase activity. RESULTS: Forty-one patients received 185 courses of treatment. Diarrhea and palmar-plantar erythrodysesthesia were dose limiting at 300 mg tipifarnib/1125 mg/m(2) capecitabine b.i.d. When the capecitabine dose was fixed at 1000 mg/m(2) b.i.d., neutropenia was dose limiting at 400 and 500 mg b.i.d. of tipifarnib. Capecitabine did not affect the pharmacology of tipifarnib at 100-300 mg b.i.d., although tipifarnib significantly increased the C(max) of 5-FU at 400 mg b.i.d. HDJ2 farnesylation and FPTase activity decreased between 200 and 400 mg b.i.d. doses of tipifarnib, without a dose-response relationship. Five patients demonstrated partial remissions and 11 patients maintained prolonged stable disease. CONCLUSIONS: Tipifarnib and capecitabine are well tolerated at 300 mg/1000 mg/m(2) b.i.d., respectively, resulting in biologically relevant plasma concentrations and antitumor activity. The recommended dose for further disease-focused studies is 300 mg b.i.d. tipifarnib and 1000 mg/m(2) b.i.d. capecitabine, given for 14 days every 3 weeks.     

Exclusion of the stomatin, α-adducin and β-adducin loci in a large kindred with dehydrated hereditary stomatocytosis

Defects in stomatin, α-and β-adducin have been implicated in erythrocyte disorders of cation permeability. We performed linkage analysis of the genetic loci for these proteins in a large kindred with xerocytosis (dehydrated hereditary stomatocytosis). Using polymerase chain reaction-based genotyping techniques, all three loci are excluded as disease gene candidates. Am. J. Hematol. 60:72–74, 1999. © 1999 Wiley-Liss, Inc.     

Clinical implications of depression in rheumatoid arthritis

The clinical implications of depression in the context of rheumatoid arthritis are described. An overview of the diagnostic criteria for depression is provided, with specific focus on major depression and the associated subtypes. The neurobiological literature on major depression is briefly reviewed and the implications of the depression literature for the care of persons with rheumatoid arthritis are discussed.