Amyloid precursor protein and amyloid beta-peptide bind to ATP synthase and regulate its activity at the surface of neural cells.

Amyloid precursor protein (APP) and amyloid beta-peptide (Abeta) have been implicated in a variety of physiological and pathological processes underlying nervous system functions. APP shares many features with adhesion molecules in that it is involved in neurite outgrowth, neuronal survival and synaptic plasticity. It is, thus, of interest to identify binding partners of APP that influence its functions. Using biochemical cross-linking techniques we have identified ATP synthase subunit alpha as a binding partner of the extracellular domain of APP and Abeta. APP and ATP synthase colocalize at the cell surface of cultured hippocampal neurons and astrocytes. ATP synthase subunit alpha reaches the cell surface via the secretory pathway and is N-glycosylated during this process. Transfection of APP-deficient neuroblastoma cells with APP results in increased surface localization of ATP synthase subunit alpha. The extracellular domain of APP and Abeta partially inhibit the extracellular generation of ATP by the ATP synthase complex. Interestingly, the binding sequence of APP and Abeta is similar in structure to the ATP synthase-binding sequence of the inhibitor of F1 (IF(1)), a naturally occurring inhibitor of the ATP synthase complex in mitochondria. In hippocampal slices, Abeta and IF(1) similarly impair both short- and long-term potentiation via a mechanism that could be suppressed by blockade of GABAergic transmission. These observations indicate that APP and Abeta regulate extracellular ATP levels in the brain, thus suggesting a novel mechanism in Abeta-mediated Alzheimer's disease pathology.

Influence of range of renal function and liver disease on predictability of creatinine clearance.

Several formulas for predicting creatinine clearance (Ccr) are used for adjusting drug dosages but limited data are available on their accuracy in patients with significant renal impairment or concurrent disease. We measured 144 Ccr in 103 patients and compared results using four predictive methods. Of nine common diseases in these patients, liver disease was associated with a large (p less than 0.02) prediction error (overprediction). After data from eight patients with liver disease were removed, there was good overall correlation between predicted and measured Ccr (r2 = 0.91 for each method) but only two of the methods (I and IV) were consistently accurate in all ranges of renal function. Methods for predicting Ccr should not be used in patients with liver disease.

Potential anticoagulant drug interactions in ambulatory patients.

Computer-generated prescription drug purchase records for ambulatory patients receiving oral anticoagulants (OAC) were studied for concomitant use of other drugs which have been reported to induce clinically significant interactions. One third of 479 patients taking OAC were exposed to a potentially interacting drug at some time during this 6-month period. The percentage of patients with drug interaction exposure correlated directly with total drug use (p less than 0.0005). There were no significant differences when interaction exposure rates were compared in the cases of single : multiple pharmacy and single : multiple physician-patient groups. Warfarin was the most common anticoagulant (greater than 95%) and barbiturates the most common interacting drug.

Electrolytic complexing of glucoheptonate and technetium-99m.

Solutions of glucoheptonate and sodium pertechnetate (Tc-99m) were subjected to electrolysis at various ampere-time products until a charge was found that consistently promoted tagging of greater than 90% efficiency. It was found that 9 coulombs (100 mA, 90 sec) consistently yielded a final product that contained less than 10% total radiochemical impurities (unbound pertechnetate and reduced, hydrolyzed technetium). Radiochemical purity of the final product was established using a two-solvent thin-layer chromatographic system with methyl-ethyl ketone and normal saline as the solvents. The tagging efficiency and stability of the tagged complex were determined with similar chromatographic analysis. It was shown that use of a 15% solution of calcium glucoheptonate resulted in a more stable product than that prepared from commercially available stannous glucoheptonate. The rapid, accurate chromatographic method for determination or radiochemical purity of the product is described. The final product is considered equal or superior to commercial Tc-99m (Sn) glucoheptonate and was produced at considerably less cost.

Limiting spectral resolution in speech for listeners with sensorineural hearing loss.

Consonant recognition was measured as a function of the degree of spectral resolution of the speech stimulus in normally hearing listeners and listeners with moderate sensorineural hearing loss. Previous work (Turner, Souza, and Forget, 1995) has shown that listeners with sensorineural hearing loss could recognize consonants as well as listeners with normal hearing when speech was processed to have only one channel of spectral resolution. The hypothesis tested in the present experiment was that when speech was limited to a small number of spectral channels, both normally hearing and hearing-impaired listeners would continue to perform similarly. As the stimuli were presented with finer degrees of spectral resolution, and the poorer-than-normal spectral resolving abilities of the hearing-impaired listeners became a limiting factor, one would predict that the performance of the hearing-impaired listeners would then become poorer than the normally hearing listeners. Previous research on the frequency-resolution abilities of listeners with mild-to-moderate hearing loss suggests that these listeners have critical bandwidths three to four times larger than do listeners with normal hearing. In the present experiment, speech stimuli were processed to have 1, 2, 4, or 8 channels of spectral information. Results for the 1-channel speech condition were consistent with the previous study in that both groups of listeners performed similarly. However, the hearing-impaired listeners performed more poorly than the normally hearing listeners for all other conditions, including the 2-channel speech condition. These results would appear to contradict the original hypothesis, in that listeners with moderate sensorineural hearing loss would be expected to have at least 2 channels of frequency resolution. One possibility is that the frequency resolution of hearing-impaired listeners may be much poorer than previously estimated; however, a subsequent filtered speech experiment did not support this explanation. The present results do indicate that although listeners with hearing loss are able to use the temporal-envelope information of a single channel in a normal fashion, when given the opportunity to combine information across more than one channel, they show deficient performance.

Pediatric asthma quality of life questionnaire: validation in children from Singapore.

"Quality of Life" is a multidimensional measure encompassing the physical, emotional and social functioning of the child. The asthma specific questionnaire contains 23 questions (items) in three areas (domains) of activity, symptoms and emotions. The objective of the present study was to validate the Paediatric Asthma Quality of Life Questionnaire "PAQLQ"(copyright 1991 McMaster University). If the questionnaire is valid, a change in the child's asthma will be accompanied by a change in the "Quality of Life" questionnaire score. The questionnaire was administered twice over four weeks and the child's asthma status was assessed concurrently. Two groups were thus identified; Group A = unchanged asthma, Group B = changed asthma. Forty-seven children, aged 7 to 14 years, completed the study. Reliability of the questionnaire shows an intraclass-correlation coefficient of only 0.71. Cross-sectional construct validity was demonstrated by a significant correlation between the whole questionnaire and the clinical asthma score (p<0.001) but not in the separate domains. Longitudinal construct validity was also demonstrated by the significant correlation between change in the total questionnaire score, but not separate domains, with change in the child's asthma score (p<0.05). Responsiveness was shown by a significant difference in the magnitude of the change in the questionnaire score between the two groups (p<0.001), but again not in the separate domains. It was concluded that the questionnaire was validated as a whole but not in as convincing a manner, as has been done by others, and we are therefore in a position to advise caution in its application in our population.

Sugars and polyols inhibit fibrillogenesis of type I collagen by disrupting hydrogen-bonded water bridges between the helices.

To better understand the mechanism of collagen fibrillogenesis, we studied how various sugars and polyols affect the formation and stability of collagen fibers. We combined traditional fiber assembly assays with direct measurement of the interaction between collagen triple helices in fibers by osmotic stress and X-ray diffraction. We found that the effects of sugars and polyols were highly specific with respect to small structural differences between these solutes. For example, 1,2-propane diol only weakly inhibited the fiber assembly and practically did not affect the interaction between collagen helices in fibers. At the same concentration, 1,3-propane diol eliminated the attraction between collagen helices and strongly suppressed fibrillogenesis. The two diols have the same atomic composition and differ only by the position of one of their hydroxyls. Still, their ability to inhibit fiber assembly differs by more than an order of magnitude, as judged by protein solubility. We argue that this is because collagen fibrillogenesis requires formation of hydrogen-bonded water clusters bridging recognition sites on the opposing helices. The ability of various sugars and polyols to inhibit the fiber assembly and to destabilize existing fibers is determined by how efficiently these solutes can compete with water for crucial hydrogen bonds and, thus, disrupt the water bridges. The effect of a sugar or a polyol appears to be strongly dependent on the specific stereochemistry of the solute hydroxyls that defines the preferred hydrogen-bonding pattern of the solute.