Efficacy of istradefylline for gait disorders with freezing of gait in Parkinson’s disease: A single-arm,open-label,prospective, multicenter study

Background: Gait disorders are common in Parkinson’s disease patients who respond poorly to dopaminergic treatment. Blockade of adenosine A_2A receptors is expected to improve gait disorders. Istradefylline is a first-in-class selective adenosine A_2A receptor antagonist with benefits for motor complications associated with Parkinson’s disease.

Research design and methods: This multicenter, open-label, single-group, prospective interventional study evaluated changes in total gait-related scores of the Part II/III Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Freezing of Gait Questionnaire (FOG-Q) in 31 Parkinson’s disease patients treated with istradefylline. Gait analysis by portable gait rhythmogram was performed.

Results: MDS-UPDRS Part III gait-related total scores significantly decreased at Weeks 4–12 from baseline with significant improvements in gait, freezing of gait, and postural stability. Significant decreases in MDS-UPDRS Part II total scores and individual item scores at Week 12 indicated improved daily living activities. At Week 12, there were significant improvements in FOG-Q, new FOG-Q, and overall movement per 48 h measured by portable gait rhythmogram. Adverse events occurred in 7/31 patients.

Conclusions: Istradefylline improved gait disorders in Parkinson’s disease patients complicated with freezing of gait, improving their quality of life. No unexpected adverse drug reactions were identified.

Trial registration: UMIN-CTR (UMIN000020288).     

Cardiocirculatory disturbances after surgery of carcinoma of the thoracic esophagus

From 1976 to 1985, 277 cases of carcinoma of the esophagus were resected in the Second Department of Surgery, Tohoku University School of Medicine. Postoperative cardiocirculatory disturbances occurred in 114 cases (41.2%), arrhythmia being the disturbance most frequently observed (86.8%). Low cardiac output syndrome occurred in 8 cases and myocardial infarction occurred in 3 cases. The majority of the cases were treated successfully, but 5 patients died within one month after operation. Causes of death were as follows: myocardial infarction, constrictive pericarditis, cardiac tamponade, non-occlusive mesenteric ischemia and acute cardiac failure. Postoperative arrhythmia occurred mainly up to the third postoperative day. Low cardiac output syndrome occurred just after operation or on the first postoperative day. All cases of myocardial infarction occurred on the first postoperative day. The rate of occurrence of cardiocirculatory disturbances in aged patients (greater than or equal to 70) was significantly higher than other group (less than or equal to 69), (56.7%:38.1%, p less than 0.05). The rate of occurrence of cardiocirculatory disturbances in patients who had a history of hypertension or in patients with abnormal preoperative electrocardiographic findings were relatively higher than those in patients who had no history of hypertension or in patients with no abnormal preoperative electrocardiographic findings. The rate of occurrence of cardiocirculatory disturbances in patients who had undergone total resection of the thoracic esophagus was significantly higher than that in patients who had undergone partial resection of the thoracic esophagus (42.8%:23.8%, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Grading score system: A method for evaluation of the degree of senescence in Senescence Accelerated Mouse (SAM)

For evaluation of the degree of senescence in SAM-P, accelerated senescence prone mouse, formerly called SAM or prone series or P-series, consisting of SAM-P/1, SAM-P/2, SAM-P/3 and SAM-P/4 corresponding to P-1, P-2, P-3 and P-4 series, respectively, in the previous reports, and in SAM-R, accelerated senescence resistant mouse, formerly called resistant series or R-series, consisting of SAM-R/1, SAM-R/2 and SAM-R/3 corresponding to R-1, R-2 and R-3 series, respectively, in the previous reports, the grading score system was adopted. The items to be examined in this system include 11 categories selected from the clinical signs and gross lesions considered to be associated with the aging process. The degree of the senescence in each category was graded from 0 to 4 according to the detailed criteria devised in our laboratory. After 8 months of age each mouse was examined every 4 months, and some of the mice were examined after 2 months of age.In almost all categories, the grading score and incidence began to increase from 4 or 6 months of age and continued to increase with advancing age in both SAM-P and SAM-R. The increase, however, was more marked in SAM-P than in SAM-R. The slow but steady increase in the SAM-R levelled out at 24 months of age and was comparable to that of 12 months of age in SAM-P. In both SAM-P/1 at 8 months of age and SAM-R/2 at 12 months of age, there was a significant reverse correlation between total score of this grading score system and length of residual life after examination.Systematic and extensive studies using the grading score system showed that if the validity of the system is, based on “irreversibility” and “universality” of the changes in     

Cell size, projection path, and localization of estrogen-sensitive neurons in the rat ventromedial hypothalamus

Antidromic action potentials were recorded in and around the ventromedial nucleus of the hypothalamus (VMN) of the ovariectomized female rat following stimulation of the central gray matter of the mesencephalon (CG). The animals had either the lateral or caudal trajectory of the VMN efferent disrupted by a small knife cut. Changes in the polarity, peak-to-peak amplitude, and the duration of the initial positive deflection of the antidromic action potentials were recorded for each response as the recording electrode was advanced at 10-micron intervals from the point of detection of the potential until its deterioration. Seventy-four recordings in which potentials exceeded 2 mV at the maxima were subjected to further analysis. The mean spatial spread of the extracellular antidromic action potentials, which was measured by moving the recording electrode at 10-micron intervals, was significantly larger in responses in 17 animals bearing the posterior knife cut (n = 41) than those in 15 animals with the lateral knife cut (n = 33). Mean peak-to-peak amplitude was also significantly greater in responses from the posterior-cut animals than in those from the lateral-cut ones. In the former, action potentials were completed with a shorter time lapse than the latter. In the posterior-cut animals, estrogen treatment of the ovariectomized rats significantly lowered antidromic activation thresholds and shortened absolute refractory periods for CG stimulation. Estrogen had no detectable effect on the excitability of cells that survived the lateral cut. Histological analyses located antidromically driven cells in the posterior-cut animals in the rostral extremity of the VMN and the adjacent retrochiasmatic area; those in the lateral-cut animals were scattered in and around the VMN, caudad to the former. These results suggest that rostral VMN neurons with large soma and laterally projecting axons are responsible for estrogen-dependent autonomic, neuroendocrine, and behavioral functions, such as reproduction and feeding.     

Impairment of cardiac beta-adrenoceptor cellular signaling by decreased expression of G(s alpha) in septic rabbits

BACKGROUND: Abnormalities in the beta-adrenergic control of cardiac function play a role in the pathogenesis of several disease states. Because circulatory failure in patients with septic shock is known to be less responsive to catecholamines, we investigated whether the beta-adrenoceptor-linked signal transduction mechanisms are altered in the heart of a septic animal model METHODS: Rabbits were rendered endotoxemic by an intravenous injection of 100 microg/kg Escherichia coli lipopolysaccharide. Three and 6 h later, the myocardial tissues were used for the experiments. RESULTS: The positive inotropic response to isoproterenol was significantly impaired in papillary muscles isolated from septic rabbits compared with those from controls. The impaired inotropic responsiveness to isoproterenol was not prevented by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine, indicating no involvement of nitric oxide overproduction. Adenylate cyclase activity stimulated with isoproterenol and 5'-guanylyl imidodiphosphate was markedly reduced in septic myocardium. The contractile and adenylate cyclase responses to colforsin daropate, a direct adenylate cyclase activator, were unaffected by sepsis. Radioligand binding experiments with (-)[125I]iodocyanopindolol revealed no significant alteration in myocardial beta-adrenoceptor density or affinity in sepsis. Determination of cardiac G(s alpha) level by Western blotting showed a reduction of approximately 50% in sepsis. The relative content of G(s alpha) messenger RNA in septic myocardium also was reduced from the control level by about 50%, as determined by Northern blot analysis. Little change was found in protein and messenger RNA levels of G(s alpha) in septic myocardium. CONCLUSIONS: Impairment of myocardial functional responsiveness to beta-adrenoceptor stimulation appears in the early stage of sepsis. The impaired response to beta-adrenoceptor stimulation in the heart in this pathologic state may result in part from a decreased level of G(s alpha) protein which occurs at the level of gene expression.