Preclinical detection of Alzheimer's disease: hippocampal shape and volume predict dementia onset in the elderly.

Structural deformity of the hippocampus is characteristic of individuals with very mild and mild forms of dementia of the Alzheimer type (DAT). The purpose of this study was to determine whether a similar deformity of the hippocampus can predict the onset of dementia in nondemented elders. Using high dimensional diffeomorphic transformations of a neuroanatomical template, hippocampal volumes and surfaces were defined in 49 nondemented elders; the hippocampal surface was subsequently partitioned into three zones (i.e., lateral, superior and inferior-medial), which were proximal to the underlying CA1 subfield, CA2-4 subfields plus dentate gyrus, and subiculum, respectively. Annual clinical assessments using the Clinical Dementia Rating scale (CDR), where CDR 0 indicates no dementia and CDR 0.5 indicates very mild dementia, were then performed for a mean of 4.9 years (range 0.9-7.1 years) to monitor subjects who converted from CDR 0 to CDR 0.5. Inward variation of the lateral zone and left hippocampal volume significantly predicted conversion to CDR 0.5 in separate Cox proportional hazards models. When hippocampal surface variation and volume were included in a single model, inward variation of the lateral zone of the left hippocampal surface was selected as the only significant predictor of conversion. The pattern of hippocampal surface deformation observed in nondemented subjects who later converted to CDR 0.5 was similar to the pattern of hippocampal surface deformation previously observed to discriminate subjects with very mild DAT and nondemented subjects. These results suggest that inward deformation of the left hippocampal surface in a zone corresponding to the CA1 subfield is an early predictor of the onset of DAT in nondemented elderly subjects.

Timing Noise in SGR 1806-20.

We have phase-connected a sequence of Rossi X-Ray Timing Explorer Proportional Counter Array observations of SGR 1806-20 covering 178 days. We find that a simple secular spin-down model does not adequately fit the data. The period derivative varies gradually during the observations between 8.1x10-11 and 11.7x10-11 s s(-1) (at its highest, approximately 40% larger than the long-term trend), while the average burst rate as seen with the Burst and Transient Source Experiment drops throughout the time interval. The phase residuals give no compelling evidence for periodicity, but more closely resemble timing noise as seen in radio pulsars. The magnitude of the timing noise, however, is large relative to the noise level typically found in radio pulsars (Delta8=4.8; frequency derivative average power approximately 7x10-20 cycles(2) s(-3)). Combining these results with the noise levels measured for some anomalous X-ray pulsars, we find that all magnetar candidates have Delta(8) values larger than those expected from a simple extrapolation of the correlation found in radio pulsars. We find that the timing noise in SGR 1806-20 is greater than or equal to the levels found in some accreting systems (e.g., Vela X-1, 4U 1538-52, and 4U 1626-67), but the spin-down of SGR 1806-20 has thus far maintained coherence over 6 yr. Alternatively, an orbital model with a period Porb=733 days provides a statistically acceptable fit to the data. If the phase residuals are created by Doppler shifts from a gravitationally bound companion, then the allowed parameter space for the mass function (small) and orbital separation (large) rule out the possibility of accretion from the companion sufficient to power the persistent emission from the SGR.

A hydrophobic cluster forms early in the folding of dihydrofolate reductase.

The rapid kinetic phase that leads from unfolded species to transient folding intermediates in dihydrofolate reductase from Escherichia coli was examined by site-directed mutagenesis and by physicochemical means. The absence of this fluorescence-detected phase in the refolding of the Trp-74Phe mutant protein strongly implies that this early phase in refolding can be assigned to just one of the five Trp residues in the protein, Trp-74. In addition, water-soluble fluorescence quenching agents, iodide and cesium, have a much less significant effect on this early step in refolding than on the slower phases that lead to native and native-like conformers. These and other data imply that an important early event in the folding of dihydrofolate reductase is the formation of a hydrophobic cluster which protects Trp-74 from solvent.

Interaction of carbon and nitrogen metabolism in the productivity of maize.

Five maize (Zea mays L.) hybrids, FS854, B73 x Mo17, B84 x Mo17, B73 x B77, and P3382, grown under field conditions, were sampled at intervals during the grain-filling period. Plants were subdivided into stalks (including sheaths), leaves, and kernels. These parts were assayed for dry weight, reduced nitrogen, and extractable nonstructural carbohydrates. The duration and rates of net nitrate reduction and photosynthesis were approximated by the changes over time in the accumulation of reduced nitrogen and dry weight by the plant (total, above ground), respectively.Data on the accumulation of reduced nitrogen and dry weight by the plant show that decreases in nitrate reduction preceded (in time and extent for four of the hybrids and in extent for FS854) decreases or cessation of photosynthesis. FS854 continued to accumulate reduced nitrogen and dry matter throughout the grain-filling period.The patterns of change in stalk carbohydrate and reduced nitrogen during the early stages of ear development show the stalk serves as a storage reservoir and that these reserves were remobilized during the final stages of grain development. The marked increase and maintenance of dry weight and carbohydrate content of stalks until 34 days after anthesis, shows the capacity of the leaves to produce photosynthate through the first half of the grain-filling period exceeds the needs of the ear and/or the transport system. In contrast, stalk nitrogen content shows a slight increase up to 12 days after anthesis and decreases continually thereafter. Leaf nitrogen was lost continuously throughout grain development. The potential capacity of the plant to supply newly reduced nitrogen was inadequate to support initiation and early development of the kernels without remobilization of vegetative nitrogen. Of the two hybrids having delayed leaf senescence, FS854 with its initially higher concentration and content of reduced nitrogen in the stalk, initiated and developed a bigger ear than P3382, which had lower levels of stalk nitrogen.Three of the five hybrids had ;near linear' rates of accumulation of kernel dry weight, whereas none of the hybrids had linear rates of gain in kernel nitrogen. All hybrids had maximum or near maximum rates of gain of kernel nitrogen between 26 and 34 days after anthesis and a marked reduction (41-52%) of rates in the following sampling interval. These decreases are concurrent with decreases in rates of nitrate reduction (nitrogen accumulation) by the whole plant for four of the hybrids and with decreases in remobilization of nitrogen from the vegetation of FS854. Data for the ratio of rates of accumulation of dry weight/reduced nitrogen by the kernels versus time after anthesis, show that the accumulation of dry weight and reduced nitrogen are independent of each other. The variations in the ratio values appear best related to variations in the availability of nitrogen from the vegetation.