Assessment of motor skill task performance with a task progress-weighted error measure.

A quantitative measure has been developed for the assessment and skill ordering of target-cued motor control and coordination task performances. It is similar to the classical root mean square error (RMSE) measure but modified with task progress weighting that attenuates with target proximity to its destination and amplifies as data sampling occurrences accumulate prior to task completion. The measure has the same mathematical form whether the task design is of the tracing type or of the tracking type, and thus can be used in cross task type comparisons. The new measure is applied to a few simple hypothetical task performances in order to illustrate some of its properties, and then applied to actual experimental data from a tracing task and a tracking task to demonstrate its use.

Quantification of manual force control and tremor.

Isometric impulse frequencies associated with active tremor and force regulation were examined in 10 patients with idiopathic Parkinson's disease (PD) and in 10 older adults (OAs) who performed an isometric tracing task. The authors decoupled and analyzed the data to determine whether PD-related tremor in the thumb and in the index finger during isometric force control are related and whether PD impairs the performance of volitional force control beyond the errors contributed by tremor. After decoupling, there were clear and robust differences in PD patients' control of isometric force that could not be attributed to action-tremor error. Those errors, which occurred in the absence of movement, suggest impairment in coordinated recruitment and derecruitment of motor units during a fine-motor task.

Multiphasic models of survival: analysis of mortality rate change regions and the issue of finite species lifespan.

Recent large-scale experimental population studies have allowed us to probe the dynamics of survival in the "oldest old" of a small number of biological species. The results of these studies add strong support to the validity of a multiphasic survival/mortality model for population survival as has been previously proposed by a number of investigators. In this paper we briefly review some of the problems with the Gompertz survival model, and the issue of locating the region in which the mortality rate might change. We derive some rigorous formulae for bounding the mortality rate change regions and compare the predictions to the available experimental data. We demonstrate that the mortality cut point parameter appears to be directly related to topological properties of the species survival curve, in particular, the inflection time. We conclude by addressing some of the pitfalls of using a mortality cut point model and propose an alternative formulation for a mortality model involving multiphasic mortality dynamics and incorporating a nonspecified upperbound on species lifespan.

Estimating parametric survival model parameters in gerontological aging studies: methodological problems and insights.

Studies of the biology of aging (both experimental and evolutionary) frequently involve the estimation of parameters arising in various multi-parameter survival models such as the Gompertz or Weibull distribution. Standard parameter estimation methodologies, such as maximum likelihood estimation (MLE) or nonlinear regression (NLR), require knowledge of the actual life spans or their explicit algebraic equivalents in order to provide reliable parameter estimates. Many fundamental biological discussions and conclusions are highly dependent upon accurate estimates of these survival parameters (this has historically been the case in the study of genetic and environmental effects on longevity and the evolutionary biology of aging). In this article, we examine some of the issues arising in the estimation of gerontologic survival model parameters. We not only address issues of accuracy when the original life-span data are unknown, we consider the accuracy of the estimates even when the exact life spans are known. We examine these issues as applied to known experimental data on diet restriction and we fit the frequently used, two-parameter Gompertzian survival distribution to these experimental data. Consequences of methodological misuse are demonstrated and subsequently related to the values of the final parameter estimates and their associated errors. These results generalize to other multiparametric distributions such as the Weibull, Makeham, and logistic survival distributions.

A gerontological distance metric for analysis of survival dynamics.

A metric for quantifying a gerontological mapping 'distance' or displacement consistent with the historical concept of velocity of aging and with the more recent concept of acceleration of aging, is introduced using the paradigm of a simple linear dynamics system of elementary physics. This analysis is extended to recent analytical methods utilizing intrinsic or internal time scaling so that biological or gerontological similarity can be distinguished from chronological age similarity, not only among various intraspecies populations but also among interspecies populations which may not even have the same underlying mechanisms of senescence or survival distributions. Illustrative examples are provided and discussed. Also, applications involving the comparison of an individual from one population to an individual from another population, when both can be assessed with respect to their respective group properties, are considered.

Localization of the plasma membrane Ca(2+)-ATPase isoform PMCA3 in rat cerebellum, choroid plexus and hippocampus.

mRNA encoding rat plasma membrane Ca(2+)-ATPase isoform PMCA3 was localized in the granule cell layer of the cerebellum and in choroid plexus by in situ hybridization with an 35S-labelled oligodeoxynucleotide probe. In order to examine whether this isoform is expressed as a protein in brain, polyclonal antibodies were raised against a peptide corresponding to a C-terminal 18 amino acid sequence of PMCA3 which had been conjugated to bovine serum albumin. Using immunoblot analysis with affinity-purified antibodies, PMCA3 protein was found in rat brain microsomes and cultured neurons. The translated protein had an observed molecular mass of approximately 135 kDa, as predicted from molecular cloning studies. The pattern of localization of PMCA3 in brain using anti-peptide antibodies was consistent with findings from in situ hybridization. PMCA3-like immunoreactive sites were found in the granule cell and molecular layers of rat cerebellum and in choroid plexus, and the pattern of staining suggests that immunoreactive sites are associated with granule cell processes. This conclusion was supported by the finding that growth-associated protein-43, a protein known to be present in axons and nerve terminals, had a pattern of distribution similar to PMCA3 in the molecular layer of cerebellum. Very low levels of PMCA3-like immunoreactivity were associated with Purkinje cell soma or processes, consistent with the low levels of PMCA3 mRNA found in these neurons. PMCA3-like immunoreactivity was lower in hippocampus than in cerebellum; hippocampal CA1 region immunoreactivity was primarily associated with dendritic fields rather than with pyramidal cell bodies. The results demonstrate that a PMCA3-like protein is expressed in neurons of rat brain and is localized primarily in cell processes.

How square is the survival curve of a given species?

An investigator-independent parameter, the prolate rectangularity index kappa for describing the so-called rectangularity of biological population survival curves, is introduced, developed, and applied to realworld survival datasets. This new rectangularity parameter is constructed using an intrinsic time scaling that places the intrinsic inflection point time at a value of unity so that species populations may be compared independently of their extrinsic life span distributions. The analytical expressions for the prolate rectangularity index of the theoretical Gompertz and Weibull continuous models are obtained, as are numerical values of this index for discrete experimental population survival data sets from two dissimilar species with orders of magnitude difference in extrinsic life span range. The values of the parameter are also compared for populations of a single species having differing dietary regimens, and for human demographic populations at decade intervals in extrinsic chronological time during the current century. It is found that scaling time, using the survival inflection point, appreciably collapses extrinsic survival profile dispersion among similar populations and allows a more meaningful comparison of profiles among dissimilar populations. Using this method of scaling, demographic populations within the United States are seen to have rectangularity parameter values that have been slowly drifting during this century toward values indicating a higher degree of rectangularity. In recent decades, however, the trend appears to be stabilizing with kappa values indicating no approach towards the theoretical maximum rectangularity. This apparent submaximal stabilization of kappa supports a hypothesis of no genetically pre-determined maximum life span in human populations. Or, if such a maximum exists, we are not currently near it.

Intrinsic time scaling in survival analysis: application to biological populations.

A method of dimensionless time-scaling based on extrinsic expectation of life at birth but intrinsic to a system generating a survival distribution is introduced. Such scaling allows the survival fraction function and its associated mortality function to serve as Green's functions for their generalized equivalents, i.e., a "population" function and a "death" function. The analytical mechanics of utilizing these concepts are formulated, applied to the classical Gompertz and Weibull survival models, and discussed with respect to biological relevance.

The plasma membrane Ca(2+)-ATPase mRNA isoform PMCA 4 is expressed at high levels in neurons of rat piriform cortex and neocortex.

Ca2+ transport mediated by the plasma membrane Ca(2+)-ATPase (PMCA) serves an important role in regulation of cytosolic-free Ca2+ in a variety of cells. Isoform PMCA4 mRNA distribution in rat brain was studied by in situ hybridization using 33P-labeled antisense oligodeoxynucleotide probes. Very high levels of hybridization were found in piriform cortex with high levels in amygdaloid nucleus and laminae 2 and 6 of cerebral cortex. Significantly lower levels were found in hypothalamic nuclei and very low or undetectable levels were found in cerebellum, habenula, olfactory bulb, thalamus, choroid plexus of the third and fourth ventricles and in CA1 and CA3 cells of the hippocampus. These results suggest that PMCA4 is not a housekeeping form of the Ca(2+)-ATPase.

Calibration of 14C-plastic standards for quantitative autoradiography with 33P.

Probes labeled with 33P have potential for widespread use in in situ hybridization because they are better able to detect relatively scarce mRNAs compared with probes labeled with 35S, but the relatively short half-life of 33P is a disadvantage when it is used as a radioactivity standard for quantitative autoradiography. To determine if plastic sections containing 14C can be used as standards for quantitative autoradiography with 33P, we co-exposed 33P-labeled liver paste sections and 14C-plastic standards to Hyperfilm beta max. The autoradiographic response of Hyperfilm beta max to these isotopes was almost identical. Second-order polynomial equations obtained from analysis of film relative optical density and radioactivity permitted derivation of tissue-equivalent radioactivity from the film optical densities produced by the 14C standards for 1-14-day exposures. These results validate the use of plastic 14C standards for quantifying 33P used in contact film autoradiography.

Transitions of latency time and oscillation phase on parameter surfaces from models of intracellular calcium ion dynamics.

The dynamics of two classical elementary compartmental models stimulating intracellular calcium ion oscillatory behavior are examined in terms of parameter surfaces. It has been found that, along certain lines of instability on surfaces defined by model parameters, the highly non-linear nature of these models produces sharp transitions in the latency time which determines the phase of oscillations once they commence. This sensitivity to initial conditions in deterministic models, along with the stochastic variance inevitably present in actual biological systems, illustrates how two seemingly identical cells activated by identical synchronous stimulation can exhibit oscillatory responses which are out of phase with respect to each other.

Selection of oligonucleotide probes for detection of mRNA isoforms.

In this article we discuss strategies for selecting oligonucleotides to target isoform-specific mRNAs, drawing on our experience with isotopically labeled oligonucleotides for ISH of Na,K-ATPase mRNA alpha- and beta-subunit isoforms. Oligonucleotide probes based on one of these isoforms have a high probability of forming nonspecific hybrids with related isoform mRNAs. The design and selection of isoform-specific ISH and how their nucleotide structure influences hybridization are reviewed, as well as basic principles in identifying and evaluating candidate probes. Controls such as Tm analysis and GC content are evaluated. For distinguishing among multiple isoforms of gene families, choose lowest possible homology between isoforms consistent with other factors that influence probe performance.

Plasma membrane Ca(2+)-ATPase isoforms: distribution of mRNAs in rat brain by in situ hybridization.

Several mRNAs which encode for isoforms of the plasma membrane Ca(2+)-transport ATPase (PMCA) are present in adult rat brain. Using in situ hybridization with antisense oligonucleotide probes we found complex patterns of specific hybridization for three isoforms (PMCA1-3). Each rat brain region studied exhibited a distinct pattern of expression of isoforms. PMCA1 mRNA, which is widely distributed in rat tissues, was highest in CA1 pyramidal cells of hippocampus and very low in hypothalamic nuclei, cerebellum and choroid plexus. PMCA2 mRNA was highest in Purkinje cells of cerebellum and low in caudate-putamen, hypothalamic nuclei, habenula and choroid plexus. The highest levels of PMCA3 mRNA were found in habenula and choroid plexus. The PMCA1-3 isoforms appeared to be expressed primarily in neurons since hybridization was detected neither in white matter nor in regions rich in astrocytes. In different regions, different levels of expression of each PMCA mRNA may underlie specialized requirements for calcium homeostasis in specific neurons.

Psychophysiological parameters of migraine and muscle-contraction headaches.

Previous headache studies have been unable to verify the presumed presence of headache. Attempting to correct this design fault, the present study assessed four psychophysiological measures (frontalis EMG, temporal BVP, temporal and finger skin temperature) and salient subjective measures in 13 migraineurs, eight muscle-contraction headache sufferers, and 13 age-matched normals. All subjects submitted to two 30-minute sessions of quiet monitoring, and for the headache subjects, one of the sessions was headache active. A bogus, but convincing preliminary "assessment" revealed insufficient headache activity in the headache active session, forcing subjects to reschedule that session in the future when a strong headache was present. A parallel manipulation was employed with the normal subjects. A MANOVA failed to discriminate within- or between-group differences on the psychophysiological measures. Self-reported pain was uncorrelated with the psychophysiological indices. These results cast further doubt on the validity of the psychophysiological measures employed in this study, the same ones routinely endorsed by headache researchers and therapists. We discuss problems of recruitment, compliance, and attrition in basic headache research.

Progressive versus self-control relaxation to reduce spontaneous bleeding in hemophiliacs.

Motivated by previous reports of relaxation successes with hemophiliacs, we sought to isolate the value of relaxation strategies. The effects of progressive and self-control relaxation on spontaneous bleeding and collateral symptoms were tested with seven hemophiliacs in a combined multiple-baseline partial-crossover design. Following 6 or 12 weeks of training in either or both relaxation methods, there was no strong evidence that the treatment affected bleeding or perceived pain in these subjects. These disappointing results were obtained despite within-session physiological evidence of relaxation induction and self- and spouse reports of faithful relaxation practice. The present results failed to replicate previous findings, cast doubt on the stress theory of spontaneous bleeding, and recommend further research to clarify the role of psychological interventions for hemophiliacs.