Regional uptake of iodine-125-metaiodobenzylguanidine in the rat heart

Regional uptake of iodine- 125-metaiodobenzylguanidine ([¹²⁵I]MIBG) was evaluated in normal (n=12) and reserpinized (n=12) rat hearts. At 15 min and 1, 3 and 6 h after injection of [¹²⁵I]MIBG, tissue activities were calculated for the right ventricular myocardium (RV), the whole left ventricular myocardium (whole LV), the epicardial layer of the left ventricular myocardium (Ep LV), the endocardial layer of the left ventricular myocardium (En LV), the basal segment of the left ventricular myocardium and the apical segment of the left ventricular myocardium. The uptake of [¹²⁵I]MIBG at 6 h after injection in the normal rat heart was higher in RV than in whole LV (0.45 ± 0.09% vs 0.30 ± 0.06% kg dose/g), and in Ep LV than in En LV (0.32 ± 0.07% vs 0.25 ± 0.05%). In the reserpinized rat heart, the difference in the uptake between Ep LV and En LV was smaller. This suggests that the difference in the regional [¹²⁵I] MIBG uptake might reflect different intravesicular uptake in the layers of the heart. To our knowledge, the low uptake in the endocardial layer was a new finding which seems to indicate a difference in innervation between the epicardial and endocardial layers of the left ventricle in the rat heart. Autoradiographic study also showed the low uptake of [¹²⁵I] MIBG in the endocardial layer, while homogeneous perfusion was observed with thallium-201, supporting the tissue uptake study. Thus, the endocardial and epicardial layers of the left ventricle in the rat heart were considered to be differently innervated.     

Ultrastructural effects of granulocyte colony stimulating factor (G-CSF) and macrophage colony stimulating factor (M-CSF) on rat neutrophils and monocytes

Human granulocyte colony stimulating factor (G-CSF) and macrophage colony stimulating factor (M-CSF) were administered intravenously to rats, and their effects on neutrophils and monocytes were examined by electron microscopy. G-CSF increased the number of cytoplasmic granules in neutrophils. It also enhanced maturation of the nuclear shape in the neutrophils, while chromatin condensation and peroxidase distribution remained immature. M-CSF induced proliferation of monocytes in peripheral blood and bone marrow, but did not affect morphology or distribution of peroxidase reactivity. This study was presented at the 25th Annual Meeting of the Clinical Electron Microscopy Society of Japan, Matsumoto, September 28–30, 1993.     

Drug delivery system using microspheres that contain tacrolimus in porcine small bowel transplantation

Rejection remains a major barrier to successful bowel transplantation, in spite of improved immunosuppressive techniques. Therefore, new, more effective, immunosuppressants, with fewer side effects, are needed. Biodegradable microspheres containing tacrolimus (FK506) were used in an experimental porcine small bowel transplantation. Twenty pigs underwent transplantation and were divided into four groups according to the immunosuppressive regimen. Group A (n=5): no immunosuppression; group B (n=6): 0.2 mg/kg per day of FK506; group C (n=3): 1.0 mg/kg per day of FK506; group D (n=6): 0.04 mg/kg per day of FK506 contained in biodegradable microspheres. Rejection was diagnosed macroscopically by endoscopic examination and histologically by biopsy specimen analysis. The mean survival time and standard deviation (SD) were 8.8±3.5, 11.0±1.4, 9.7±2.5 and 28.6±22.5 days for groups A, B, C, and D, respectively, with a statistically significant difference found between group D, on the one hand, and groups A, B and C, on the other. The mean trough blood concentration of FK506 was 10.5±2.2, 27.9±6.0 and 10.5±3.5 ng/ml in groups B, C and D, respectively. In groups A and B, all pigs died of rejection, without infection. In group C, all died of infection, without rejection. In contrast, none of the pigs in group D developed rejection or infection. Our results clearly show that the drug delivery system using biodegradable microspheres that contain FK506 is effective for controlling rejection with fewer side effects in the porcine small bowel transplantation.     

Psychoses in patients with Parkinson's disease; their frequency, phenomenology, and clinical correlates]

The frequency, phenomenology, and risk factors of hallucinations and delusions were investigated in 64 consecutive inpatients with Parkinson's disease. Fifty patients were admitted to our hospital with symptoms related to Parkinson's disease: psychiatric problems 27 (psychosis 22; anxiety 2; depression 2; mania 1): motor symptoms, 20 (wearing-off 5; akinesia 4; freezing 4; postural instability 4; dyskinesia 2; tremor 2; dystonia 1), and sensory symptoms, 3. Fourteen patients were admitted with other medical problems (pneumonia 4; cerebral infarction 3; bone fracture 3; lumbago 2; seizure 1; cat bite 1). Totally 49 patients had psychiatric problems. Psychosis was present in 43 patients, dementia in 10, depression in 8, mania in 1, anxiety in 10, agitation in 6, stereotypy in 2, and hypersexuality in 2. Of the 43 patients with psychoses, 40 presented with visual hallucinations, 18 with auditory hallucinations, and 23 with delusions. To determine what the clinical correlates with the severity of psychosis were, we divided the patients into 3 groups: the severe group, 22 patients admitted because of psychotic symptoms; the mild group, 21 patients admitted because of problems other than psychosis but presenting psychotic symptoms; and the control group, 21 patients who had no psychotic symptoms. Incidences of auditory hallucinations and delusions were higher in the severe group as compared to the mild group. Patients in the severe group had higher Hoehn-Yahr stages, lower Mini-Mental State Examination scores, decreased H/M ratios of cardiac 123I-MIBG uptake, and lower frequencies of background activity on electroencephalograms. There were no differences in age at admission, age at onset of Parkinson's disease, duration of illness, amounts of levodopa and dopamine agonists received, Hamilton's depression rating scores, and brain MR findings, including atrophy and ischemic changes. Emergence of psychotic symptoms in parkinsonian patients appears to be clearly associated with impaired cognitive function. Therefore, it may be associated with the disease process itself. Terms such as dopaminomimetic or levodopa-induced psychosis may not be appropriate when describing psychosis in Parkinson's disease.     

Suppression of adjuvant-induced arthritic bone destruction by cyclooxygenase-2 selective agents with and without inhibitory potency against carbonic anhydrase II.

In vitro assays revealed that COX-2 inhibitors with CA II inhibitory potency suppressed both differentiation and activity of osteoclasts, whereas that without the potency reduced only osteoclast differentiation. However, all COX-2 inhibitors similarly suppressed bone destruction in adjuvant-induced arthritic rats, indicating that suppression of osteoclast differentiation is more effective than that of osteoclast activity for the treatment. INTRODUCTION: Cyclooxygenase (COX)-2 and carbonic anhydrase II (CA II) are known to play important roles in the differentiation of osteoclasts and the activity of mature osteoclasts, respectively. Because several COX-2 selective agents were recently found to possess an inhibitory potency against CA II, this study compared the bone sparing effects of COX-2 selective agents with and without the CA II inhibitory potency. MATERIALS AND METHODS: Osteoclast differentiation was determined by the mouse co-culture system of osteoblasts and bone marrow cells, and mature osteoclast activity was measured by the pit area on a dentine slice resorbed by osteoclasts generated and isolated from bone marrow cells. In vivo effects on arthritic bone destruction were determined by radiological and histological analyses of hind-paws of adjuvant-induced arthritic (AIA) rats. RESULTS: CA II was expressed predominantly in mature osteoclasts, but not in the precursors. CA II activity was inhibited by sulfonamide-type COX-2 selective agents celecoxib and JTE-522 similarly to a CA II inhibitor acetazolamide, but not by a methylsulfone-type COX-2 inhibitor rofecoxib. In vitro assays clearly revealed that celecoxib and JTE-522 suppressed both differentiation and activity of osteoclasts, whereas rofecoxib and acetazolamide suppressed only osteoclast differentiation and activation, respectively. However, bone destruction in AIA rats was potently and similarly suppressed by all COX-2 selective agents whether with or without CA II inhibitory potency, although only moderately by acetazolamide. CONCLUSIONS: Suppression of osteoclast differentiation by COX-2 inhibition is more effective than suppression of mature osteoclast activity by CA II inhibition for the treatment of arthritic bone destruction.     

Degeneration of the inferior olive in spinocerebellar ataxia 6 may depend on disease duration: Report of two autopsy cases and statistical analysis of autopsy cases reported to date

This report concerns a clinicopathological study of two autopsied patients with spinocerebellar ataxia 6 (SCA6), and a statistical analysis between neuronal loss of the inferior olive and disease duration of 15 SCA6 autopsy cases reported to date, including the two cases reported in this study. Cases 1 and 2 came from independent Japanese families. Case 1 developed gait disturbance at age 35 years and died at age 78 years; she had a CAG‐repeat expansion of the SCA6 gene (25/13). Case 2 presented with gait disturbance at age 68 years and died at age 78 years; he had an expanded CAG‐repeat of the SCA6 gene (22/13). Neuropathological examination of both cases disclosed not only neuronal loss of the Purkinje cells and inferior olive, but also some unnoticed features, including cactus‐like expansion of the dendrite of Purkinje cells and relative preservation of Golgi cells in the granular layer of the cerebellum. Exploratory statistical analysis between 11 SCA6 autopsy cases with neuronal loss in the inferior olive (average disease duration: 27 years) and four SCA6 autopsy cases without neuronal loss in the olive (average disease duration: 14.5 years) was investigated by Kaplan–Meier estimates of survival and log–rank test, retrospectively. Kaplan–Meier estimates of survival revealed an obvious difference between the two groups. Survival of 10 years after the disease onset was 90.9% in the former 11 SCA6 autopsy cases, but was 50% in the latter four SCA6 autopsy cases. Furthermore, a log–rank test on the two groups disclosed a significant difference (P = 0.0450). We postulate that the neuronal loss of the inferior olive in SCA6 may depend on disease duration.     

Extreme hyperbilirubinemia induced by endoscopic injection sclerotherapy in a patient with esophageal varices and thalassemia: Report of a case

We describe herein the case of a 57-year-old man with thalassemia who developed acute liver failure after undergoing endoscopic injection sclerotherapy (EIS) to control hemorrhage from a ruptured esophageal varix. The patient, who had been comfirmed as having liver cirrhosis due to chronic hepatitis C with thalassemia in 1989, was admitted to our department to undergo EIS for esophageal varices, at which time his serum total bilirubin level was 5.5 mg/dl. As a small amount of hematemesis occurred just after a percutaneous transhepatic portography was performed, emergency EIS was carried out, following which the serum total bilirubin level markedly increased, mainly with a direct fraction, until it reached 70 mg/dl. The patient eventually died from acute liver failure with extreme hyperbilrubinemia on the 27th day after experiencing hematemesis despite all treatment. This unfortunate case demonstrates that sclerotherapy could be an inappropriate method of treatment for patients with hemolytic disease.     

Attenuation of conducted vasodilatation in rat mesenteric arteries during hypertension: role of inwardly rectifying potassium channels

The present study was designed to elucidate whether the conduction of vasomotor responses mediated by endothelium-derived hyperpolarizing factor (EDHF) in rat mesenteric arteries is altered during hypertension. Iontophoresed acetylcholine (ACh; 500 ms) caused EDHF-mediated hyperpolarization and vasodilatation at the local site and these responses spread through the endothelium to remote sites in 12-week-old Wistar-Kyoto rats (WKY). Conducted responses were significantly attenuated in age-matched spontaneously hypertensive rats (SHR) although the rate of decay with distance did not change. Inhibition of inwardly rectifying potassium (Kir) channels (30 μ m barium) eliminated the difference between WKY and SHR by attenuating conducted responses in WKY but not SHR. At the local site, barium (30 μ m ) significantly reduced the duration but not the amplitude of ACh-induced hyperpolarization in WKY only. Barium had no effect when the iontophoretic stimulus was reduced to 350 ms. After blockade of EDHF in SHR, ACh elicited a depolarization which our indirect data suggest spreads along the vessel in the endothelium. Messenger RNA expression of Kir2.0 genes did not differ between the strains nor did the amplitude of K⁺-induced hyperpolarization, which was abolished by disruption of the endothelium. Immunohistochemistry revealed a decrease in connexin (Cx)37 but not Cx40 or Cx43 protein in endothelial cells of SHR compared to WKY. Results suggest that conduction of EDHF-mediated responses in WKY, but not in SHR, is facilitated by activation of Kir channels at the site of ACh application and not by differences in endothelial connexin expression. Lack of Kir channel involvement in hypertension may result from reduction in the duration of the hyperpolarization due to the development of ACh-mediated depolarization, rather than to any difference in Kir subunit expression or function.     

Weight loss in Parkinson’s disease

Journal of Neurology - Weight loss is frequent in patients with Parkinson’s disease (PD). Reduced energy intake and/or increased energy expenditure have been postulated as the cause....