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).     

Ultrastructure of capillary permeability in human brain tumor: primary meningeal malignant melanoma

The tumor vessels of a primary meningeal malignant melanoma were studied by electron microscopy. There were numerous endothelial fenestrae and basal lamina abnormalities in the intrinsic tumor capillaries. They resembled the tumor vessels found in nonglial tumors, but were distinctly different from those seen in glial tumors with nonfenestrated capillaries. These findings were anticipated because leptomeninges have fenestrated capillaries.     

Synthesis, pharmacological activity and biopharmaceutical characteristics of alpha,2-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetates

The pro-drugs of alpha,2-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid(I) with a potent anti-inflammatory activity were synthesized in order to reduce its gastrointestinal side effects. Various esters synthesized were evaluated for their anti-inflammatory activity and ulcerogenicity. Among the compounds maintaining a potent activity of I, N,N-dimethylcarbamoylmethyl alpha,2-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetate (II-18) showed excellent biopharmaceutical characteristics. The ulcerogenic effect of II-18 on the rat gastric mucosa was about 3 times less than that of I. It was suggested that II-18 may be an useful biolabile pro-drug for I among the compounds tested.     

The effect of wedged insoles on the thrust of osteoarthritic knees

Summary. We describe a method of quantifying the lateral/medial thrust of the knee which occurs in the early phase of walking. We have used this method to evaluate the effects of wedged insoles on the lateral and medial thrust for normal knees and knees with unicompartment osteoarthritis (OA). A laterally elevated (valgus) insole decreased the lateral thrust of both normal and osteoarthritic knees. A medially elevated (varus) insole increased the lateral thrust. In 50 symptomatic knees with medial compartment OA, decreasing the lateral thrust with a valgus insole reduced pain on walking in 27. Patients whose pain was reduced by valgus insoles tended to have earlier OA and to have a significantly greater reduction in the lateral thrust than in the 23 remaining unaffected knees. A varus insole was effective in decreasing the medial thrust and reducing pain in all ten knees with lateral compartment OA. We recommend the use of valgus insoles for patients with painful early medial compartment OA and the use of varus insoles for lateral compartment OA.

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Résumé. Les auteurs présentent une méthode d’évaluation quantitative, avec mesure par un accéléromètre, des écarts internes ou externes qui se font au niveau du genou dans la première phase du pas. Ils ont étudié les effets dynamiques et l’utilité clinique des semelles à coin valgisant ou varisant pour les genous atteints d’arthrose unicompartimentale. Une semelle à coin externe (valgisante) diminue l’écart externe ou augmente l’écart interne que subit le genou normal ou arthrosique. L’effet est inverse pour une semelle à coin interne. Sur 50 genoux atteints d’arthrose interne avec écart externe, la semelle à coin valgisant diminue les douleurs à la marche dans 27 cas et est inefficace dans 23 cas. Les genoux pour lesquels les semelles valgisantes sont efficaces ont une réduction significative de l’écart externe par rapport à ceux pour lesquels ces semelles sont inefficaces. La semelle valgisante est plus efficace en cas d’arthrose du genou débutante qu’en cas d’arthrose évoluée. La semelle varisante est active pour les 10 genoux avec arthrose compartimentale externe et écart interne.

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Accepted: 28 February 1996     

Desmoid tumor of the abdominal wall preoperatively suspected as urachal tumor: a case report]

A case of desmoid tumor of the abdominal wall which was preoperatively suspected as urachal tumor is presented. The patient was a 56-year-old man, who was referred to our clinic for further examination of the mass detected incidentally in the ventral region of the urinary bladder by computed tomography. Ultrasonography showed that the mass had a heterogenous and hypoechogenic content. An urachal tumor was suspected and surgery was performed to remove the tumor. During the operation we found that the tumor was completely separated from the urinary bladder and that it had originated from the left rectus abdominal muscle. The pathological diagnosis was desmoid tumor of the abdominal wall. Since urachal tumor has no characteristic findings on the imaging examinations, it is difficult to differentiate desmoid tumor of the lower abdominal wall from urachal tumor, preoperatively.     

Mucosal interleukin-1β production and acid secretion in enlarged fold gastritis

Background : We have previously shown that eradication of Helicobacter pylori increases acid secretion in H. pylori -associated enlarged fold gastritis.
Aim : To investigate whether locally produced interleukin-1β is possibly involved in the inhibition of acid secretion in H. pylori gastritis.
Methods : IL-1β release from the gastric body mucosa was determined by short-term culture of biopsy specimens in 13 patients with enlarged fold gastritis (all H. pylori -positive), five H. pylori -positive and 10 H. pylori -negative patients without enlarged folds. The acid-inhibitory effect of locally produced IL-1β was examined by [¹⁴C]-aminopyrine uptake assay using isolated rabbit gastric glands.
Results : IL-1β release was significantly greater in patients with enlarged fold gastritis, significantly correlated with both basal and tetragastrin-stimulated acid outputs in the H. pylori -positive patients ( r  = −0.591 and r  = −0.641, respectively; P  < 0.01), and significantly decreased with concomitant increases in acid secretions after eradication of H. pylori . [¹⁴C]-aminopyrine uptake was inhibited by IL-1β in a dose-dependent manner.
Conclusions : Increased production of IL-1β caused by H. pylori infection is possibly involved in the inhibition of acid secretion in enlarged fold gastritis.     

Induction and activation of the aryl hydrocarbon receptor by IL-4 in B cells

It is widely known that IL-4 and IL-13 act on various kinds of cells, including B cells, resulting in enhancement of proliferation, class switching to IgE and expression of several surface proteins. These functions are important for the recognition of the various antigens in B cells and are known to be involved in the pathogenesis of allergic diseases. However, it has not been known whether IL-4/IL-13 is involved in the metabolism of various kinds of xenobiotics including 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD), and it remains undetermined whether TCDD, an environmental pollutant, influences IgE production in B cells, exaggerating allergic reactions. We identified IL-4- or IL-13-inducible genes in a human Burkitt lymphoma cell line, DND-39, using microarray technology, in which the AHR gene was included. The AHR gene product, the aryl hydrocarbon receptor (AhR), was induced by IL-4 in both mouse and human B cells in a STAT6-dependent manner. IL-4 alone had the ability to translocate the induced AhR to the nuclei. TCDD, a ligand for AhR, rapidly degraded the induced AhR by the proteasomal pathway, although IL-4-activated AhR sustained its expression. AhR activated by IL-4 caused expression of a xenobiotic-metabolizing gene, CYP1A1, and TCDD synergistically acted on the induction of this gene by IL-4. However, the induction of AhR had no effect on IgE synthesis or CD23 expression. These results indicate that the metabolism of xenobiotics would be a novel biological function of IL-4 and IL-13 in B cells, whereas TCDD is not involved in IgE synthesis in B cells.