Three hundred and seventy-six subjects with advanced Parkinson's disease participated in a prospective, double-blind placebo-controlled study of the dopamine agonist pergolide mesylate as an adjunct to Sinemet. At 6 months, patients randomized to pergolide had a statistically significant improvement in total Parkinson's score, scores of activities of daily living, motor function, number of "off" hours, Hoehn and Yahr stage, and numerous parameters of parkinsonian function including bradykinesia, rigidity, gait, and dexterity. This benefit was obtained with the addition of a mean dose of 2.94 mg of pergolide, which permitted a 24.7% reduction in dose of levodopa. Adverse reactions were, for the most part, mild, reversible, and not of major clinical significance. No significant cardiac or electrocardiographic abnormalities were detected. This study demonstrates that pergolide mesylate, as an adjunct to levodopa, is an effective antiparkinsonian agent that provides clinical improvement while permitting a reduction in levodopa dose.
The kinetic properties of human erythrocyte pyruvate kinase vary depending on whether Mg2+ or Mn2+ is used as the essential divalent cation. In the Mg2+-activated system catalytic activity is dependent on MgADP but not on the concentrations of uncomplexed Mg2+ or ADP. The Mn2+activated reaction is dependent on both free Mn2+ and Mn-ADP, but not on uncomplexed ADP. Free P-enolpyruvate, rather than P-enolpyruvate complexed with metal, appears to be the preferred substrate. The velocity profile for P-enolpyruvate in the Mg2+-activated system is sigmoid (Hill's = 1.78) and the addition of low concentrations of fructose-1,6-P shifts the profile to a hyperbola ( = 0.92). In the Mn2+activated reaction a single hyperbolic curve is obtained with or without fructose-1,6-P ( = 0.95). Hill plots for free Mg2+ and free Mn2+ show slopes of 1.2 and 1.7, respectively. At Xyruvate kinase (EC 2.7.1.40) catalyzes the conversion of P-enolpyruvate1 and ADP to pyruvate and ATP; the reaction requires both monovalent and divalent cations (Boyer et al., 1943). Cationic cofactors are required by many enzymes and apparently play a significant role in metabolic regulation (Wyatt, 1964;Bygrave, 1967). The observations that the cation specificity of glutamine synthetase changes from Mg2+ to Mn2+ on adenylylation (Kingdon et al., 1967;Shapiro and Ginsburg, 1968), that Escherichia coli ADP: glucose synthetase has markedly different kinetics depending on whether Mg2+ or Mn2+ serves as cofactor (Centner and Preiss, 1968) and that yeast phosphofructokinase shows a dependence on both uncomplexed and complexed Mg- (Mavis and Stellwagen, 1970) indicate the importance of specific cation effects.A recent estimate of intracellular concentrations of free Mg2+ (Rose, 1968) in the human erythrocyte suggests that substantial amounts of ATP and ADP exist in the uncomplexed form, emphasizing the need to examine the effects of both free and bound ligands on red cell enzyme catalysis. The present communication describes the kinetic differences between Mg2+ and Mn2+ activation of a pyruvate kinase isolated from human erythrocytes.Experimental Section Methods Materials. DPNH, Na2ADP, trisodium P-enolpyruvate, and crystalline rabbit muscle pyruvate kinase, lactate det From the
Stone Dow, Oregon's first neurologist, died on February 24, 1995, at the age of 87 years following a long illness. Dow had a long and productive life and, despite his illness, continued to work until a few weeks before his death. He was an internationally known investigator who made impor¬ tant contributions to our understanding of the cerebel¬ lum, epilepsy, and multiple sclerosis.A 1929 graduate of Linfield College (McMinnville, Ore), Dow received his master's, doctorate, and medical degrees from the University of Oregon Medi¬ cal School (Portland), now Oregon Health Sciences University. As a medical student, Dow was introduced to histological techniques by anatomist Olaf Larsell, with whom he carried out research on the innervation of the human lung published in January 1933 in the American Journal of Anatomy. Under Larsell's tutelage, he developed his lifelong interest in the cerebellum. Obtaining pregnant bats from a church belfry in Port¬ land, he described the embryologie characteristics of the bat cerebellum. In 1935 he wrote his PhD thesis on the neural pathways connecting the flocculus and paraflocculus to the vestibular nuclei.Following his internship in medicine, Dow be¬ came a fellow in the laboratory of John Fulton at Yale University (New Haven, Conn). There he met wellknown neuroscientists Earl Walker,
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