Biomedical subjects
M R Rose
Publications and source records attributed to M R Rose.
Prospects for postponing human aging.
The postponement of human aging is a long-standing aspiration in many cultures, particularly non-Western ones. Renewed interest in this goal is now being shown within the biomedical research context. This interest has probably arisen because several different approaches have yielded dramatic increases in mean and maximum life span in laboratory organisms. Among the cases where aging has been postponed in animal models are the nematode, Caenorhabditis elegans, the common lab fruit fly, Drosophila melanogaster, and the dietarily restricted rodent, both Mus and Rattus. These successes raise the question of whether similar postponement of aging might be achieved in humans. Among the broad research strategies available, five can be delineated: 1) random testing of favorite interventions; 2) searching for genes that can postpone aging among all or most species; 3) study of in vitro mammalian cell cultures; 4) study of dietarily restricted mammals; and 5) selecting mammals for postponed aging. Although all these methods could conceivably lead to the postponement of human aging, they are very different from each other with respect to their degree of uncertainty, cost, and delay.
A Darwinian function for the orbital cortex.
The relationship between evolutionary theory and human psychobiology suffers from a lack of bridging theory concerning Darwinian brain functions. This problem is addressed within the context of the theory that the human brain calculates Darwinian strategies for the long-term organization of behavior. This theory of brain function is tested using the literature of abnormal psychology, particularly phenotypes that appear to lack strategic evaluation of fitness outcomes. It is argued that sociopaths lack such "fitness-calculation", and therefore their behavior leads to reduced fitness, notwithstanding the absence of psychiatric pathology. Accidental, surgical, and congenital lesions to the orbital cortex of the frontal lobes can produce similar behavior, suggesting that the orbital cortex is the seat of strategic fitness-calculation. This bridge between Darwinian theory and brain function opens the way for formal theories of human behavior couched in terms of imminent Darwinian calculation.
A case of myopathy associated with a dystrophin gene deletion and abnormal glycogen storage.
A 30-year-old man with no family history of muscle disease presented with a progressive proximal myopathy and calf hypertrophy characteristic of Becker muscular dystrophy. A deletion of exons 45 to 48 in the dystrophin gene was confirmed by Southern blotting and multiplex polymerase chain reaction. However, muscle biopsy showed massive accumulation of glycogen, although no significant abnormality of glycolytic pathway enzymes could be demonstrated. This patient therefore has a previously undescribed myopathy associated with both Becker muscular dystrophy and a glycogen storage disorder of unknown aetiology.
Magnetic resonance imaging in tonic spasms of multiple sclerosis.
Two cases of unilateral tonic spasm are described in which high signal lesions typical of demyelination were identified on magnetic resonance imaging in the contralateral cerebral peduncle. Both cases exhibited subtle upper motoneuron signs on the side of the tonic spasms that were exacerbated immediately following an attack. In one case, functional impairment of contralateral corticospinal pathways was demonstrated by delayed central motor conduction. These cases support the view that tonic spasms in multiple sclerosis are due to lesions within the corticospinal tract.
The effect of superoxide dismutase alleles on aging in Drosophila.
The effects of superoxide dismutase on aging were tested using two different experimental approaches. In the first, replicated populations with postponed aging were compared with their controls for frequencies of electrophoretic alleles at the SOD locus. Populations with postponed aging had consistently greater frequencies of the allele coding for more active SOD protein. This allele was not part of a segregating inversion polymorphism. The second experimental approach was the extraction of SOD alleles from different natural populations followed by the construction of different SOD genotypes on hybrid genetic backgrounds. This procedure did not uncover any statistical effect of SOD genotype on longevity or fecundity. There were large effects on longevity and fecundity due to the family from which a particular SOD genotype was derived. To detect the effects of SOD genotypes on longevity with high probability would require a ten-fold increase in the number of families used.
Two-dimensional protein electrophoretic analysis of postponed aging in Drosophila.
Five populations of Drosophila melanogaster that had been selected for postponed aging were compared with five control populations using two-dimensional protein gel electrophoresis. The goals of the study were to identify specific proteins associated with postponed aging and to survey the population genetics of the response to selection. A total of 321 proteins were resolvable per population; these proteins were scored according to their intensity. The resulting data were analyzed using resampling, combinatoric, and maximum parsimony methods. The analysis indicated that the populations with postponed aging were different from their controls with respect to specific proteins and with respect to the variation between populations. The populations selected for postponed aging were more heterogeneous between populations than were the control populations. Maximum parsimony trees separate the selected populations, as a group, from their controls, thereby exhibiting a homoplastic pattern.
Validation of a non-invasive radioisotope method of imaging ureteric urine transport.
Measurement of ureteric function has hitherto involved the use of invasive techniques. A non-invasive, radioisotope method of imaging and displaying individual ureteric boluses has been described, a refinement of which is used in this department. Each "spindle" displayed using this technique theoretically represents an individual ureteric bolus of urine, but the technique has never been validated in the normal ureter in either the experimental model or man. A porcine model was set up to allow simultaneous measurement of ureteric bolus transmission using the radioisotope (compressed image) method and by the accepted techniques of electromyography (EMG) and urine drop counting. The timing of each urinary bolus, as recorded by the different modalities was then compared. The results from 11 studies showed a significant correlation between the radioisotope and EMG methods (mean r = 1.00, P = 0.0003). There was a constant relationship between the part of the radioisotopic image representing the rear end of the bolus and the EMG complex (mean time difference = 5.32 +/- 1.067s), thus defining that part of the image representing the peristaltic contraction wave. There was a variable relationship between the EMG and the part of the image representing the leading edge of the bolus (mean time difference = 13.36 +/- 5.23s), emphasising that bolus length is variable, being dependent on bolus volume. The radioisotope "spindle" concurs with EMG activity in the porcine ureter. The compressed image technique is thus validated as a non-invasive method of demonstrating ureteric urine transport.
Non-invasive investigation of normal individual ureteric activity in man.
This study was designed to investigate non-invasively human ureteric function between individuals and with increasing diuresis, using the radioisotope compressed image technique. Five normal males underwent fast frame renography with ureteric spindle imaging in dehydrated and hydrated states, urine production being measured in each individual for each scan. Urine flow rates and renographic parameters demonstrated that each ureter carried more urine in the hydrated state. The velocity at which individual boluses passed down the ureter was constant for each ureter and did not change with diuresis. The ureteric peristaltic rate showed wide individual variation between ureters in the same subject, but fell within what is becoming accepted as the "normal range" of < 4 urine boluses per minute. Some ureters accommodated an increase in urine flow by an increased peristaltic frequency, some showed no change and others showed a decreased frequency. In those ureters in which there was no change, or a decrease in peristaltic frequency with diuresis, the increased urine flow must have been handled by increases in bolus volume. Thus increases in ureteric urine flow in man are accommodated by changes in both peristaltic frequency and bolus size. The results are discussed in relation to previous studies which used invasive techniques.
Selection on stress resistance increases longevity in Drosophila melanogaster.
Tests for the causal involvement of specific physiological mechanisms in the control of aging require evidence that these mechanisms can be used to increase longevity or reproductive lifespan. Selection for later reproduction in Drosophila has been shown to lead to increased longevity, as well as increased resistance to starvation and desiccation stresses. Selection for increased resistance to starvation and desiccation in Drosophila melanogaster is here shown to lead to increased longevity, indicating that alleles that increase stress resistance also may increase longevity. The responses of desiccation and starvation resistance to selection are partly independent of each other, indicating a multiplicity of physiological mechanisms involved in selectively postponed aging, and thus aging in general.
Drosophila with postponed aging as a model for aging research.
Species of the genus Drosophila, commonly known as "fruitflies," are good model systems for research in aging. Drosophila are extremely well-known genetically, developmentally, and otherwise. They are also genetically analogous to mammalian species in most important respects. Previous work with Drosophila has been hampered by inbreeding depression, but more recent work using selection has created Drosophila with postponed aging that is inherited normally. Genetic transformation has also increased Drosophila life spans in some cases. Several biologic approaches have been applied to the analysis of genetically postponed aging in Drosophila: quantitative genetics, organismal physiology, and protein electrophoresis. Ultimately, these different approaches will be integrated into an overall analysis of aging in Drosophila, one that could be valuable for research with other taxa as well.
Evolution of senescence: late survival sacrificed for reproduction.
In so far as it is associated with declining fertility and increasing mortality, senescence is directly detrimental to reproductive success. Natural selection should therefore act in the direction of postponing or eliminating senescence from the life history. The widespread occurrence of senescence is explained by observing that (i) the force of natural selection is generally weaker at late ages than at early ages, and (ii) the acquisition of greater longevity usually involves some cost. Two convergent theories are the 'antagonistic pleiotropy' theory, based in population genetics, and the 'disposable soma' theory, based in physiological ecology. The antagonistic pleiotropy theory proposes that certain alleles that are favoured because of beneficial early effects also have deleterious later effects. The disposable soma theory suggests that because of the competing demands of reproduction less effort is invested in the maintenance of somatic tissues than is necessary for indefinite survival.
Quantitative genetics of postponed aging in Drosophila melanogaster. I. Analysis of outbred populations.
Selection has been used to create replicated outbred stocks of Drosophila melanogaster with increased longevity, increased later fecundity, and increased levels of physiological performance at later ages. The present study analyzed the quantitative transmission patterns of such stocks, employing extensive replication in numbers of stocks, individuals, and assayed characters. The populations used derived from five lines with postponed aging and five control lines, all created in 1980 from the same founding base population. The following characters were studied: early 24-hr fecundity, early ovary weight, early female starvation resistance, early male starvation resistance, female longevity and male longevity. Numerous crosses were performed to test for non-Mendelian inheritance, average dominance, maternal effects, sex-linkage and between-line heterogeneity. There was only slight evidence for any of these phenomena arising reproducibly in the characters studied. These findings suggest the value of this set of stocks for studies of the physiological basis of postponed aging.
Quantitative genetics of postponed aging in Drosophila melanogaster. II. Analysis of selected lines.
Quantitative genetic analyses of Drosophila melanogaster stocks with postponed aging have suffered from the problem of a lack of certainty concerning patterns of allelic differentiation. The present experiments were designed to alleviate this difficulty by selecting for enhanced levels of characters known to be related to postponed aging. Selection successfully increased the degree of differentiation of postponed aging stocks with respect to starvation resistance and fecundity, but persistent additive genetic variance suggested that selection did not result in fixation of alleles. The artificially selected stocks were subjected to crosses to test for patterns of dominance and maternal effects. There was little evidence for these effects in the inheritance of the characters underlying postponed aging, even with the increased differentiation of the selected stocks.
The relationship between a diagnosis of antisocial personality and hostility: development of an Antisocial Hostility scale.
An antisocial hostility scale was developed by correlating items of the Buss-Durkee Hostility Inventory with a diagnosis of antisocial personality (ASP) as determined by a computerized version of the DSM-III. Fifty-two male volunteers for drug-related studies at the Addiction Research Center were used for a preliminary test development sample. The scale developed thereby was related significantly to a diagnosis of antisocial personality in a cross-validation sample of 28 drug abusers. A final scale was developed by obtaining correlations between ASP and Buss-Durkee items using the subjects from both of these preliminary samples. Items that comprise the scale were predominantly behaviorally oriented hostility items covered by the Assault scale rather than affective items such as those in the Resentment scale. In a 122 cross-validation sample the scale was related significantly to a diagnosis of antisocial personality. The study confirms the generality of the criterion of overt aggression as a condition for meeting DSM-III criteria for antisocial personality.
Excretion of iodine-123-hippuran, technetium-99m-red blood cells, and technetium-99m-macroaggregated albumin into breast milk.
The amount of radioactivity excreted in breast milk following three different nuclear medicine procedures on twelve nursing mothers has been measured. Some of this information has already been incorporated into the latest guidelines on suspension of feeding after maternal radiopharmaceutical administration. The overall radiation dose that the patients' babies would have sustained had breast feeding not been interrupted has been estimated as an effective dose equivalent. A model has been developed to describe the relationship between clearance of activity from the milk, time between expressions, and the fraction of milk expressed. Some simple guidance is given on calculation of suitable interruption times for any individual mother from counts on her milk samples.