MA’AT analysis has been applied to methyl β-d-ribofuranoside (3) and methyl 2-deoxy-β-d-erythro-pentofuranoside (4) to demonstrate the ability of this new experimental method to determine multi-state conformational equilibria in solution. Density functional theory (DFT) was used to obtain parameterized equations for >20 NMR spin-coupling constants sensitive to furanose ring conformation in 3 and 4, and these equations were used in conjunction with experimental spin-couplings to produce unbiased MA’AT models of ring pseudorotation. These models describe two-state north–south conformational exchange consistent with results obtained from traditional treatments of more limited sets of NMR spin-couplings (e.g., PSEUROT). While PSEUROT, MA’AT, and aqueous molecular dynamics models yielded similar two-state models, MA’AT analysis gives more reliable results since significantly more experimental observables are employed compared to PSEUROT, and no assumptions are needed to render the fitting tractable. MA’AT models indicate a roughly equal distribution of north and south ring conformers of 4 in aqueous (2H2O) solution compared to ∼80% north forms for 3. Librational motion about the mean pseudorotation phase angles P of the preferred north and south conformers of 3 in solution is more constrained than that for 4. The greater rigidity of the β-ribo ring may be caused by synergistic stereoelectronic effects and/or noncovalent (e.g., hydrogen-bonding) interactions in solution that preferentially stabilize north forms of 3. MA’AT analysis of oligonucleotides and other furanose ring-containing biomolecules promises to improve current experimental models of sugar ring behavior in solution and help reveal context effects on ring conformation in more complex biologically important systems.

Background: A recent consensus statement introduced the term “ET plus”. Although investigators have quantified the prevalence of ET plus in cross-sectional studies, patients with ET plus have not been tracked longitudinally; hence, there is no understanding of its stability over time.Methods: We present prospective, longitudinal phenotypic data on an ET cohort that was followed regularly at 18-month intervals (T1, T2, T3, T4) for up to 64 months. We assigned an ET or ET plus diagnosis to each case at each time interval.Results: There were 201 participants at baseline. The proportion with ET plus increased from 58.7% at baseline to 72.1% at T4 (p = 0.046). Of 172 (85.6%) who received a diagnosis of ET plus at one or more time intervals, the diagnosis was unstable (e.g., with reversion) in 62 (36.0%). We also assessed the stability of the clinical features of ET plus. Rest tremor was the most unstable clinical feature of ET plus; it was present in 59 participants, among whom it reverted from present to absent in 23 (39.0%). By contrast, for “memory impairment” (i.e., either mild cognitive impairment or dementia), the proportion who reverted from present to absent was only 21.3%.Conclusion: These data support our two a priori hypotheses: (1) the prevalence of ET plus would increase progressively, as it likely represents a more advanced stage of ET, and (2) the ET plus diagnosis would not be stable over time, as cases would fluctuate with respect to their phenotypic features and their assigned diagnoses.

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Background: Essential tremor (ET) is a progressive neurological disease whose natural history is one of progressive increase in tremor severity over time; surprisingly though, there are no published videotape diaries that visually and tangibly portray this progression over time. Phenomenology: Progressive, stepwise increase in limb tremor severity over a ten-tofifteen-year period in three patients with ET. Educational value: We hope that this brief visual diary will serve as a useful teaching tool for students, primary care physicians, and neurologists to "see with their own eyes" the extent of change that can occur in the ETs.

BackgroundFew longitudinal studies assess the progression of essential tremor (ET). One unexplored issue is whether tremor severity increases across time at a uniform rate. That is, does the observed rate of change in tremor severity within a particular patient remain constant or vary across time? This question of intra-individual differences is particularly important since it reflects a primary patient concern–will the nature of change I have seen to date be what I can expect in the future?MethodsET cases were enrolled in a prospective, longitudinal study. We selected 35 cases and assessed tremor severity via Bain and Findley ratings of Archimedes spirals assigned by a senior movement disorders neurologist. After reviewing both the change in spiral scores and the rate of change in scores, we identified five mutually exclusive patterns of severity change. We calculated the prevalence of each category using two complementary sets of classification criteria.ResultsLength of follow-up was 4.5 to 16.0 years, mean=10.2 years. Mean baseline tremor severity score was 4.6, SD=1.6. Depending upon the classification criteria used, the tremor scores of one-third to one-half of cases did not increase in a uniform fashion but were better described as demonstrating jumps and/or reversals in scores across time.ConclusionsWe document the nature of changes in ET tremor severity scores across a ten-year period via expert ratings of Archimedes spiral drawings. Such natural history data are valuable to patients and clinicians who hope to better understand and predict the likely course of ET symptoms.