Involuntary movement disorders

Excluding surgical procedures, this article focuses on clinical pharmacotherapeutic approaches to treatment of parkinsonism and tremor, chorea, dystonia, tic, and tardive dyskinesia.     

Theory and measurement of ocular chromatic aberration

We have determined the transverse chromatic aberration of the human eye by measuring the apparent offset of a two-color vernier viewed foveally through a displaced, pinhole aperture. For the same subjects, we also determined the longitudinal chromatic aberration for foveal viewing by the method of best focus. In both cases, the results were closely predicted by a simple, reduced-eye optical-model for which transverse and longitudinal chromatic aberration are directly proportional, with the constant of proportionally being the amount of displacement of the pinhole from the visual axis. Further measurements revealed that the natural pupil was closely centered on the visual axis for two subjects and slightly displaced in the temporal direction for three other subjects. One implication of these results is that, although the eye has substantial chromatic aberration, the pupil is positioned so as to minimize the transverse component of the aberration for central vision, thereby optimizing foveal image quality for polychromatic objects.     

In vitro and in vivo cholera toxin production by classical and El Tor isolates of Vibrio cholerae

A comparative study was carried out on the in vitro production of cholera toxin by 19 Vibrio cholerae El Tor isolates from patients with cholera in South Africa, one El Tor isolate from a patient in Malawi (a country approximately 1000 km north-northeast of South Africa), 6 El Tor and 12 classical type isolates from patients in Bangladesh, and 5 culture collection classical strains. Identical phage types and indistinguishable toxigenicities among the South African and Malawi V. cholerae, representing isolations obtained over a 10-year period, indicated that essentially a single strain was involved in the cholera of these regions. Similarly, phage typing and toxin profiles indicated that the 12 classical and 6 El Tor V. cholerae cultures in Bangladesh, all isolated in November 1983, represented just two strains. As assessed by titrations in Y-1 mouse adrenal and Chinese hamster ovary cell lines, the general order of toxigenicities was Bangladesh and culture collection classical greater than Bangladesh El Tor greater than southern African El Tor. The African isolates consistently gave rise to very low titers. Their relative reluctance to produce the toxin in vitro compared with the culture collection classical strains, particularly strain 569B, was confirmed by rocket electrophoresis. In somewhat of a contrast, maximum in vivo titers in rice water stools from cholera patients in South Africa and from both classical and El Tor type cholera patients in Bangladesh were essentially equal. It is postulated that under the continuous culture conditions that occur in vivo, cholera toxin concentrations can accumulate to a maximum level, depending on the rate of purging by the diarrheal fluid rather than the toxigenicity of the infecting stain. The relevance of these findings to the relative severities of classical and El Tor types of cholera is discussed.     

Metabolism of ingested U and Ra

The literature on metabolism of U and Ra for man relevant to deriving drinking water standards has been reviewed and summarized. Radium is well understood, but significant gaps remain in our knowledge about U metabolism. Limits should be based on an equilibrium model where a constant relationship between intake and organ burden is established, using the best and most likely metabolic parameters. For the skeleton we conclude that the best estimate of skeletal burden expressed in days equivalent intake are 25 days for 226Ra, 10 days for 228Ra, and 0.3 days for 224Ra. For long-lived isotopes of U, we chose 11 days, with a range between 1 and 35 days. The committee believes that intake of natural U in water should be limited by considerations of toxicity to the kidney, and we believe that the metabolic model of Spoor and Hursh with a modified gastrointestinal (GI) absorption (1.4%) should be used to infer kidney content. Our review and analysis of the world literature leads us to believe the average human GI absorption of U is most likely 1-2% and is probably reasonably independent of age or the mass of U ingested. Using a safety factor of 50-150, the committee recommends a limit of U in water of 100 micrograms/l in order to limit toxic effects in the kidney. One hundred micrograms/liter is equivalent to 67 pCi/l of long-lived alpha-emitting natural U isotopes. Further research into the distribution of U in the human body is desirable, especially at natural levels in kidney and skeleton, the time-dependent pharmacokinetics of U in animals, the GI absorption of U in man from water and food, toxicological and U distribution studies in animals under conditions of chronic oral U intake, and metabolic model error propagation.     

Proteomic analysis of mitochondria-to-nucleus retrograde response in human cancer

All tumors examined to date contain mutations in mitochondrial DNA (mtDNA). In addition, depletion of mtDNA is reported in a variety of tumors. Mitochondrial dysfunction resulting from changes in mtDNA invokes mitochondria-to-nucleus retrograde response in human cells. To identify proteins involved in retrograde response and their potential role in tumorigenesis, we carried out a comparative proteomic analysis using a cell line in which the mitochondrial genome was completely depleted (rho(0) cells lacking all mtDNA-encoded protein subunits), a cybrid cell line in which mtDNA was restored, and the parental cell line. Our comparative proteomic approach revealed marked changes in the cellular proteome and led us to identify quantitative changes in expression of several proteins. We found that subunits of complex I and complex III, molecular chaperones, and a protein involved in cell cycle control were downregulated and Inosine 5'-monophosphate dehydrogenase type 2 (IMPDH2) involved in nucleotide biosynthesis was upregulated in rho(0) cells. Our findings demonstrate that the expression of proteins is restored to wild type level by transfer of wild type mitochondria to rho(0) cells, suggesting that these proteins play key roles in retrograde response. To determine a potential role for identified retrograde responsive proteins in tumorigenesis, we analyzed the expression of UQCRC1 gene (encoding ubiquinol cytochrome-c reductase core protein I) in breast and ovarian tumors. We found that (1) UQCRC1 was highly expressed in breast (74%) and ovarian tumors (34%) and (2) the expression positively correlated with cytochrome c-oxidase (COXII) encoded by mtDNA. Our study opens an avenue for identification of retrograde proteins as potential tumor suppressors or oncogenes involved in carcinogenesis.     

The effect of ECS upon spontaneous alternation in rats

Rats were given two pairs of unreinforced trials in a Y-maze with one hour between trials of a pair. It was found that ECS given immediately after the first trial of a pair did not reduce the rat's tendency to alternate on the second trial, although ECS was shown to impair passive avoidance learning in the same apparatus. It is argued that spontaneous alternation involves a kind of memory, and that these results show that this memory is not affected by ECS. This conclusion is discussed in relation to the hypothesis that ECS produces retrograde amnesia.