Subretinal neovascularisation and snow banking in a case of sarcoidosis: case report.

A 49-year-old Japanese man presented with chronic granulomatous uveitis in his left eye. Later he developed macular subretinal neovascularisation. The chest x-ray showed bilateral hilar lymphadenopathy. Bronchoscopy and gallium-67 scanning were positive, PPD skin test negative, and serum angiotensin converting enzyme (ACE) levels increased. Ophthalmoscopy and fluorescein angiography of the left eye showed perivasculitis, retinochoroidal exudates, snow banking, and vitreous opacity. On these findings, the diagnosis of sarcoidosis was made. Treatment was based on topical corticosteroids, mydriatics, beta blockers, and oral carbonic anhydrase inhibitors. After 15 months the visual acuity decreased in the left eye, and a neovascular membrane was observed in the macula. Fluorescein angiography confirmed subretinal neovascularisation. Almost two years later the patient still has the neovascular membrane in his left eye.     

Effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin on the dopaminergic and cholinergic receptors as evaluated by positron emission tomography in the Rhesus monkey

Summary The effects of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (R-THBP) on the central cholinergic and dopaminergic systems in the Rhesus monkey brain were investigated by positron emission tomography (PET) with the muscarinic cholinergic receptor ligands (N-[¹¹C]methyl-benztropine) and dopaminergic receptor ligands selective for D₁ D₂, and D₃ subtypes ([¹¹C]SCH23390, N-[¹¹C]methyl-spiperone, and (+)[¹¹C]UH232, respectively). None of the doses (3, 10, and 30 mg/kg i.v.) of R-THBP used significantly affected the regional cerebral blood flow (rCBF as determined by Raichle's H₂ ¹⁵O method), and 10 mg/kg of R-THBP had little effect on the regional cerebral metabolic rate of glucose (rCMRglc) in the Rhesus monkey brain, as assessed by the graphical [¹⁸F]fluoro-deoxyglucose method. The effect of R-THBP on the muscarinic cholinergic system was dose dependent; while 3 mg/kg of R-THBP did not significantly alter the uptake ratio of N-[¹¹C]methyl-benztropine in several brain regions to that in the cerebellum, 10 and 30 mg/kg of R-THBP significantly reduced the uptake ratio in the thalamus, as well as in the frontal and temporal cortices. None of the doses (3, 10, and 30 mg/kg i.v.) of R-THBP tested affected [¹¹C]SCH23390 (dopamine D₁ receptor) binding. However, the k3 value for N-[¹¹C]methyl-spiperone (dopamine D₂ receptor) binding, which represents the association rate × B_max value, was significantly decreased in the striatum. The uptake ratio of (+)[¹¹C]UH232 (dopamine D₃ receptor) in the striatum to that in the cerebellum was also decreased by administration of R-THBP (3 and 30 mg/kg i.v.). These findings suggest that R-THBP acts on dopamine D₂ and D₃ receptors selectively without markedly affecting dopamine D₁ receptor binding. Furthermore, the changes in cholinergic and dopamine D₂ and D₃ receptors in vivo can not be attributed to a change in rCBF but may depend on the action of R-THBP.Abbreviations R-THBP 6R-L-erythro-5,6,7,8-tetrahydrobiopterin - PET positron emission tomography - rCBF regional cerebral blood flow - rCMRglc regional cerebral metabolic rate of glucose     

Role of protein kinase C in the modulation of multidrug resistance: expression of the atypical gamma isoform of protein kinase C does not confer increased resistance to doxorubicin.

Cross-resistance to anticancer drugs, termed multidrug resistance (MDR), is functionally associated with the expression of a plasma membrane, energy-dependent, drug efflux pump termed P-glycoprotein (PGP), the product of the mdr1 gene. We have shown previously that MCF-7 breast carcinoma cells transfected with the human mdr1 gene (BC-19 cells) exhibit greater MDR when stably transfected with protein kinase C alpha (PKC alpha). We now demonstrate that transfection of BC-19 cells with the gamma isoform of PKC (BC-19/PKC gamma cells), which is not normally present in BC-19 cells, does not confer increased resistance to doxorubicin, despite a 19-fold increase in PKC activity. All of the increased PKC activity is accounted for by PKC gamma and it is rapidly down-regulated by phorbol dibutyrate, within 15 min of treatment. Endogenous PKC alpha and PKC epsilon activities are not affected by phorbol dibutyrate. The cytotoxicity of doxorubicin was similar in BC-19/neo or BC-19/PKC gamma cells after either 2-hr or continuous drug exposure, and co-treatment with phorbol dibutyrate increased resistance to doxorubicin 4-fold in both cell lines. Phosphorylation of PGP was similar in both cell lines and drug accumulation was not affected by overexpression of PKC gamma. These results demonstrate that transfection of PGP-expressing cells with an atypical isoform of PKC does not confer increased MDR, and they suggest that the regulation of PGP is phenotype specific with respect to the isoform of PKC.     

Effects of intrahippocampal injections of N-methyl-D-aspartate receptor antagonists and scopolamine on working and reference memory assessed in rats by a three-panel runway task.

In order to elucidate the roles of hippocampal N-methyl-D-aspartate-type excitatory amino acid receptors in working and reference memory in rats, the effects of intrahippocampal injections of selective and competitive N-methyl-D-aspartate receptor antagonists such as CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylic acid), 3-[(+-)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid and 2-amino-5-phosphonovaleric acid on this behavior were examined with a three-panel runway task. The results were compared with the effect of the muscarinic receptor antagonist scopolamine. In the working memory task, CGS 19755 and 3-[(+-)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid at 10 and 32 ng/side, injected bilaterally into the dorsal hippocampus before testing, produced a significant increase in the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points). This also occurred after the rats were given systemic injection of these drugs at 3.2 and 10 mg/kg. In the reference memory task, neither CGS 19755 nor 3-[(+-)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid affected the number of errors, whether given at doses up to 32 ng/side intrahippocampally or up to 10 mg/kg systemically. Working memory errors also increased significantly after intrahippocampal injections of d-2-amino-5-phosphonovaleric acid at 100 and 320 ng/side, but were not affected by I-2-amino-5-phosphonovaleric acid at doses up to 1 microgram/side. On the other hand, intrahippocampal scopolamine at 1.0 and 3.2 micrograms/side increased significantly working memory errors, without affecting reference memory errors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Surface epithelial cell damage induced by restraint and water-immersion stress in rats effects of 16,16-dimethyl prostaglandin E2 on stress-induced gastric lesions

The time-course of gastric mucosal surface epithelial cell damage and macroscopically visible lesions in response to restraint and water-immersion stress (22 degrees C) in rats was examined, and the effects on it of 16,16-dimethyl prostaglandin E2 (dmPGE2) were compared with those of papaverine, timoprazole and atropine. The stress produced surface epithelial cell damage prior to visible lesion, the former increasing in severity with time and reaching a plateau 60 min later, by which time exfoliation of surface epithelial cells was observable along the mucosal folds. In contrast, macroscopically visible lesions appeared 2 hr after stress, and severity continued to increase with time. Pretreatment injections (s.c.) of dmPGE2 (3, 30 micrograms/kg), papaverine (100 mg/kg) and atropine (1 mg/kg) protected the surface cells against stress (1 hr)-induced damage, and inhibited visible lesion formation after 4 hr stress. Timoprazole (30 mg/kg, s.c.) did not protect the surface cells, but did markedly inhibit visible lesion formation. dmPGE2, papaverine and atropine, but not timoprazole, inhibited stress-induced increases in gastric contractions. dmPGE2, timoprazole and atropine, but not papaverine, inhibited acid secretion in stress-conditions. These results indicated that stress induced damage to the gastric mucosa within 1 hr due to increased gastric contractions, and the surface epithelial cell damage developed into macroscopically visible lesions in the presence of acid, and that dmPGE2 protected the surface epithelium against stress-induced damage probably by inhibiting gastric contractions.     

Nucleolus-associated J chains in myeloma cells: clinical significance

Bone marrow aspirates from 20 patients with multiple myeloma (MM), 4 with smoldering multiple myeloma (S-MM), 1 with idiopathic Bence Jones proteinuria (I-BJP), and 6 with primary macroglobulinemia (PMG) were examined for nucleolus-associated J chain. The incidence of nucleolar J chain-positive (J+) cells among nucleolated cells producing M-component was measured. This incidence (94.0-100%) in terminal MM was significantly higher than that (0-58.0%) in non-terminal MM. Judging from a low incidence in the remission phase, chemotherapy might cause a selective elimination of less differentiated myeloma cells with J+ nucleoli and might have some effect on J chain synthesis. The incidence of nucleolar J+ cells was very low in S-MM. The IgM cells in PMG, where J chain is present in a disulfide-linked form, had no or few J+ nucleoli. No correlation between the incidence of nucleolar J+ cells among nucleolated plasma cells and the percentage of nucleolated cells or that of J+ cells was found. Large J+ nucleoli seemed to be another morphological feature indicating anaplastic myeloma cells. A high incidence of nucleolar J+ cells may be one of the indicators for progressive disease.     

Binding of lysozyme to lipopolysaccharide suppresses tumor necrosis factor production in vivo.

Endotoxin (lipopolysaccharide [LPS]) released during gram-negative bacterial infection induces varieties of cytokines which directly and/or indirectly cause shock, disseminated intravascular coagulation, and death. We previously showed that lysozyme (LZM) was an LPS-binding protein and inhibited various immunomodulating activities of LPS. In this study, we examined the effect of LZM on the LPS-triggered septic shock model induced by carrageenan treatment and assessed by tumor necrosis factor production. The data presented in this report strongly suggest that LZM-LPS complex formation completely abrogates tumor necrosis factor production and the mortality caused by LPS and that LZM may be useful for the treatment of endotoxin shock.     

Antibody dependent cell mediated cytotoxicity on human cervical carcinoma cell line, ME-180, with human monoclonal antibody.

A human monoclonal antibody (MCA), CLN-IgG, showed cytotoxic effect in vitro against the cervical carcinoma cell line, ME-180, by antibody dependent cell-mediated cytotoxicity (ADCC). To determine which fractions of cells in peripheral blood lymphocyte (PBL) mediate ADCC, PBL were separated with nylon wool column and sheep red blood cells (SRBC). Both adherent cells (monocyte) and non-T, non-B cells showed cytotoxicity by ADCC. Human non-T, non-B cells showed higher cytotoxic activity against ME-180 cells than monocytes. Furthermore murine effector cells were less effective in ADCC than human effector cells with human MCA.     

Coexistence of cerebral aneurysm and angiographically occult AVM in the occipital lobe; a case report]

The authors report a case of an 8-year-old boy with coexistent aneurysm and arteriovenous malformation (AVM) at the periphery of the left middle cerebral artery. The patient was referred to our hospital because of intracerebral hematoma in the occipital lobe. Angiography revealed an aneurysm at the periphery of the left middle cerebral artery. A small AVM was found, adjacent to the aneurysm, by histological examination of the aneurysm and surrounding tissue resected by surgery. The patient was discharged uneventfully 17 days after surgery. The association of intracranial aneurysm with AVM is reported to be seen in 1.4% of patients with intracranial aneurysms, and 6.4% to 16.7% of patients with an intracranial AVM. Three hypotheses have been proposed in order to explain the association of an aneurysm with AVM: (1) Congenital multiple disorders of vascular development, (2) Hemodynamic stress resulting from the presence of an AVM, (3) Coincidence without any causal relationship between them. The coexistence of the two vascular lesions, adjacent to each other at the peripheral cerebral arteries is rare. Only 7 cases have been reported in the literature. Four of the 8 cases including ours were children, and 6 of the 8 cases were thought to have had a hemorrhage from the AVM. It is likely that the coexistence of the two lesions in our patient is of congenital origin, because the influence of hemodynamic stress from the AVM seemed little and coexistence of the lesions as found in our case is more frequently seen in childhood.     

Lugol-combined endoscopic detection of minute malignant lesions of the thoracic esophagus.

Early-stage esophageal carcinomas, particularly cases of intraepithelial carcinoma and mucosal carcinoma, are extremely difficult to detect because the patients have no particular complaints, and findings on the x-rays are nil. At present, endoscopic examination is the only tool of any value for discerning such lesions. Lugol-combined endoscopy with biopsy has proven to be most effective for detecting the presence and spread of small malignant lesions of the esophagus. Studies were conducted on the diagnostic features of one intraepithelial, five mucosal and 29 submucosal carcinomas of the esophagus, detected through the use of Lugol-combined endoscopy.