Risk of left ventricular dysfunction in patients with probable Alzheimer's disease with APOE*4 allele

OBJECTIVE: To examine the association between the APOE genotype and cardiovascular disease in Alzheimer's disease (AD) patients. DESIGN: Case register study of 100 consecutive referrals to a Memory Clinic where type of dementia and cardiovascular comorbidity were diagnosed and APOE genotype was determined. SETTING: The Memory Clinic, University Hospital Rotterdam Dijkzigt. PARTICIPANTS: One hundred Memory Clinic patients, 59 to 91 years of age, who attended the Memory Clinic in the period between January 1994 and March 1996. MEASUREMENTS: Relative risk of cardiovascular morbidity in probable AD, based on clinical and ECG findings. RESULTS: The diagnosis of probable AD was more frequent in APOE*4 allele-carrying AD patients. When comparing homozygotes for APOE*4 with homozygotes for APOE*3, a nine-fold increase in prevalence of cardiac ischemia on ECG was found in the former. When grouping parameters of left ventricular dysfunction, the prevalence was 7.2 (95% confidence interval 1.2-42.6) times greater in probable Alzheimer patients with APOE4/4. CONCLUSIONS: In patients with probable AD, APOE*4 is associated with cardiac disease indicative of left ventricular dysfunction.     

The effects of REM sleep-inhibiting drugs in neonatal rats: evidence for a distinction between neonatal active sleep and REM sleep

Higher plant tissues produce both wax esters generated from fatty alcohols and hydrocarbons generated from fatty aldehydes. If two different reductases are responsible for the synthesis of aldehydes and alcohols, both types of reductases may be present in such tissues. To test for this possibility, pea leaves, known to produce both types of wax components, were examined. Subcellular fractionation showed that acyl-CoA reductase activities were localized mainly in the microsomal fraction. Fatty aldehyde formation was rectilinear for 30 min and subsequently decreased, whereas fatty alcohol formation remained linear for 2 h. The two activities in the microsomes were differently affected by pH; alcohol formation was optimal between pH 5 and pH 6, whereas aldehyde formation was optimal at around pH 7.5. With solubilized microsomes, protein concentration dependence of alcohol formation showed a sigmoidal pattern, possibly suggesting inhibition by hexadecanoyl-CoA at low protein concentrations. Bovine serum albumin (BSA) enhanced alcohol formation. In contrast, the aldehyde generation showed a typical protein concentration dependence, and BSA severely inhibited aldehyde generation. Phosphatidylcholine showed over twofold stimulation for alcohol formation, whereas aldehyde formation was only slightly stimulated. All of this biochemical evidence suggested the presence of two different reductases. Confirming this hypothesis, an aldehyde-generating and an alcohol-generating reductase were resolved from the solubilized microsomal proteins using Blue A agarose, gel filtration, and hexadecanoyl-CoA affinity chromatography. SDS-PAGE of the purified proteins showed that the alcohol-generating enzyme was a 58-kDa protein and the aldehyde-forming one was a 28-kDa protein. It is proposed that two different elongating systems are functionally coupled to the alcohol-generating and aldehyde-generating reductases, which in turn are coupled to the transacylase to produce wax esters and to the decarbonylase to produce hydrocarbons, respectively.     

Emphasizing conflict resolution versus conflict avoidance during schedule generation

Classical planning systems attempt to solve a planning problem by avoiding possible conflicts before the actions are put on a timeline. This is computationally very expensive and the search for all possible future conflicts may be prohibitive. A conflict resolution approach can check for immediate conflicts and try conflict resolution strategies as each activity is put on a timeline without regard for possible future conflicts. A more practical approach is to use a combination of conflict avoidance and conflict resolution based upon heuristics which limit the amount of search required when either is used. Because humans are not good at solving problems which require complex lookahead, this combined approach, with emphasis on conflict resolution, is what human schedulers actually use when they develop schedules. A system which simulates this human approach to scheduling has been developed at NASA's Goddard Space Flight Center for scheduling satellite activities. This system, which includes the Planning And Resource Reasoning (PARR) shell, allows expert schedulers to specify conflict resolution strategies as well as conflict avoidance strategies to be used during the scheduling process. PARR has been used since May 1987 to schedule the Tracking and Data Relay Satellite System services for the Earth Radiation Budget Satellite. PARR will also be used to schedule platform resources on the Explorer Platform, scheduled for launch in early 1992. This paper describes the advantages of using a combined conflict avoidance and resolution approach in a satellite scheduling system.     

The contribution of platelet-activating factor to allergen-induced eosinophil infiltration and bronchial hyperresponsiveness

Platelet-activating factor (PAF) is an ether-linked phospholipid having a range of biological properties of relevance to our understanding of the pathogenesis of bronchial asthma and related allergic diseases. In particular the ability of PAF to induce eosinophil activation and recruitment has received considerable attention. Since in experimental animals PAF and allergen-induced eosinophil infiltration are dependent upon platelet activation, it is suggested that platelet activation may be an important component of the allergic process. The ability of PAF antagonists to inhibit various aspects of the allergic response has been demonstrated in a number of animal models but not all of them have been extended into man. Based on a paper presented at the Third International Conference on Platelet-Activating Factor and Structurally Related Alkyl Ether Lipids, Tokyo, Japan, May 1989.     

A note on computing environments and network reliability

Interest has increased during recent years in using microcomputers for implementation of network reliability algorithms. There are indications that some implementations suffer severe restrictions imposed by such a computing environment, whereas some other results indicate otherwise. This brief note attempts to clarify the apparently contradictory conclusions that would be naturally drawn from recent papers that treat this subject.     

Activating mutations for the met tyrosine kinase receptor in human cancer

Recently, mutations in the Met tyrosine kinase receptor have been identified in both hereditary and sporadic forms of papillary renal carcinoma. We have introduced the corresponding mutations into the met cDNA and examined the effect of each mutation in biochemical and biological assays. We find that the Met mutants exhibit increased levels of tyrosine phosphorylation and enhanced kinase activity toward an exogenous substrate when compared with wild-type Met. Moreover, NIH 3T3 cells expressing mutant Met molecules form foci in vitro and are tumorigenic in nude mice. Enzymatic and biological differences were evident among the various mutants examined, and the somatic mutations were generally more active than those of germ-line origin. A strong correlation between the enzymatic and biological activity of the mutants was observed, indicating that tumorigenesis by Met is quantitatively related to its level of activation. These results demonstrate that the Met mutants originally identified in human papillary renal carcinoma are oncogenic and thus are likely to play a determinant role in this disease, and these results raise the possibility that activating Met mutations also may contribute to other human malignancies.     

Inactivation of 4-oxalocrotonate tautomerase by 2-oxo-3-pentynoate

The compound, 2-oxo-3-pentynoate, has been synthesized and tested as an inhibitor of the enzyme 4-oxalocrotonate tautomerase. The enzyme is rapidly and irreversibly inactivated by the acetylenic product analogue in a time-dependent fashion. The enzyme displays saturation kinetics and is protected from inactivation by the presence of substrate. These observations are consistent with inactivation taking place at the active site. Partial reactivation ( approximately 18%) occurs by incubating the inactivated enzyme with 10 mM hydroxylamine (pH 7.3). The partition ratio, determined to be approximately 0.4, suggests that the inactivation of 4-OT by 2-oxo-3-pentynoate shows half-of-the-sites stoichiometry. The same phenomenon is observed in the inactivation of 4-OT by 3-bromopyruvate and can be explained by examination of the crystal structure. Mass spectral analysis shows that a single residue is modified on the enzyme which has been localized to the nine residue amino-terminal fragment Pro-1 to Glu-9. It can be reasonably concluded that Pro-1 is the site of covalent attachment. Inactivation of 4-OT can occur by either a Michael addition of 4-OT to C-4 of 2-oxo-3-pentynoate or by the enzyme-catalyzed rearrangement of 2-oxo-3-pentynoate to an allene derivative which alkylates Pro-1. These results provide the foundation for the use of 2-oxo-3-pentynoate in future mechanistic studies and as a ligand in an inactivated 4-OT complex that can be studied by X-ray crystallography. Finally, 2-oxo-3-pentynoate is an acetylene analogue of a variety of 2-oxo acids and as such may have general utility as an inhibitor of reactions that bind and process these compounds.     

GeneTree: comparing gene and species phylogenies using reconciled trees

SUMMARY: GeneTree is a program for comparing gene and species trees using reconciled trees. The program can compute the cost of embedding a gene tree within a species tree, visually display the location and number of gene duplications and losses, and search for optimal species trees. AVAILABILITY: The program is free and is available at ((http://taxonomy.zoology.gla.ac. uk/rod/genetree/genetree.html)).