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.     

Rapid serodiagnosis of active pulmonary Mycobacterium tuberculosis by analysis of results from multiple antigen-specific tests

We have prospectively analyzed three antigens for serodiagnosis of tuberculosis (TB). These antigens were tuberculous glycolipid antigen, lypoarabinomannan polysaccharide antigen, and antigen 60 (A60), which was derived from purified protein derivatives. Of the 131 patients with active pulmonary TB, 57 were both smear and culture negative and 14 had chronic active pulmonary TB that remained smear positive for >12 months of chemotherapy. One hundred twenty healthy adults were controls. The percentages of patients positive in all three tests were 58.8% for smear-positive active pulmonary TB and 71.4% for chronic active pulmonary TB. When the results of the three serodiagnostic tests were evaluated in combination, the sensitivity increased to 91.5% in patients with active pulmonary TB and to 86.0% in smear- and culture-negative patients. The false-positive rate of the three-test combination was 12.5% in the healthy control groups. In conclusion, it was not possible to detect all of the antibodies against antigenic substances in the cell walls of the tuberculous bacilli in the sera of all TB patients by using available serodiagnostic tests. However, the combined use of tests with three separate antigens maximizes the effectiveness of serodiagnosis.     

Increased circulating interleukin-12 (IL-12) p40 in pulmonary sarcoidosis

In sarcoidosis, a T helper 1 (Th1) response is an essential event and the up-regulation of interleukin-12 (IL-12) has been detected in affected disease sites. In order to investigate the clinical usefulness of circulating IL-12, we measured the serum concentrations of IL-12 by ELISA and performed immunohistochemistry using specific MoAbs for IL-12 in the lungs and scalene lymph nodes of patients with sarcoidosis. The serum concentration of IL-12 p40 was detectable in all 45 patients with pulmonary sarcoidosis and 18 normal controls, whereas that of IL-12 p70 was undetectable. The serum concentrations of IL-12 p40 in pulmonary sarcoidosis were significantly higher than those of the normal controls, especially in cases with abnormal intrathoracic findings detected by chest roentogenogram. The serum concentrations of interferon-gamma (IFN-gamma) also increased compared with those of normal controls and there was a significant positive correlation between the serum concentrations of IL-12 p40 and IFN-gamma. Furthermore, serum angiotensin-converting enzyme (ACE) and lysozyme, which are known to be useful markers for disease activity in sarcoidosis, correlated well with the serum concentrations of IL-12 p40. The positive 67Ga scan group (for lung field) had significantly elevated serum IL-12 p40 levels compared with those of the negative group. No bioactivity of IL-12 p70 was detected in three sarcoid cases sera by using the IL-12 responsive cell line. Finally, the immunohistochemical approach revealed that IL-12 p40 was expressed in the epithelioid cells and macrophages of sarcoid lungs and lymph nodes. We concluded that the production of IL-12 p40 was far greater in the sera and we have demonstrated this to be a useful clinical marker for disease activity and the Th1 response in pulmonary sarcoidosis.     

Role of fibronectin-stimulated tumor cell migration in glioma invasion in vivo: clinical significance of fibronectin and fibronectin receptor expressed in human glioma tissues

In order to clarify the role of fibronectin in glioma invasion in vivo, we analyzed the relationship between fibronectin-stimulated cell migration and adhesion in 14 primary glioma cells and the expression of fibronectin and the fibronectin receptor in the corresponding tumor tissues. The tumors comprised nine glioblastomas (GB) and five anaplastic gliomas (AG) consisting of two astrocytomas, two oligoastrocytomas and one ependymoma. All glioma cells tested in the primary cell culture were found to migrate to fibronectin in a dose-dependent manner. The extent of cell migration to fibronectin was not significantly different for the GB and AG groups. On the other hand, cell adhesion to fibronectin in the AG was much stronger than that in the GB group. Immunohistochemistry demonstrated that fibronectin positively stained in the extra-cellular matrix (ECM) in eight cases and that the fibronectin receptor was positive in tumor cell membranes in 10 cases. In addition, cellular fibronectin isoforms containing ED-A and ED-B sequences were found to be immunolocalized in the tumor cells and the ECM of GB. These isoforms were also specifically expressed in tumor vessels within tumor tissues, but not in those within normal brain tissues. Cell migration tended to be expressed more strongly by glioma cells derived from tumor tissues in which fibronectin was posi-tively immunolocalized in the ECM than from tissues with negative fibronectin in the ECM. Four glioma cells derived from GB whose tumor cells did not positively stain for fibronectin receptors migrated much less extensively to fibronectin than other glioma cells whose tissues showed positive staining for the fibronectin receptor. Of these four GB, two had loss of heterozygosity in the locus of fibronectin receptor b1 gene. These results suggest that fibronectin deposited in the extracellular matrix of tumors, which can be derived from both plasma and the tumor cell itself, strongly promotes the migration of glioma cells, and that expression of the fibronectin receptor may play a critical role in the biological behavior of the tumor cells, particularly in fibronectin-stimulated cell migration in vivo.© Kluwer Academic Publishers 1998     

Rapid progression of pituitary hyperplasia in humans with primary hypothyroidism: demonstration with MR imaging.

PURPOSE: To use magnetic resonance (MR) imaging to evaluate the morphologic changes of the pituitary gland during the development of hypothyroidism. MATERIALS AND METHODS: Fourteen patients who had undergone thyroidectomy were evaluated before radioactive iodine 131 therapy. In each patient, MR imaging and measurement of serum hormone levels were performed twice: 5 weeks before 131I treatment as the "euthyroid state" with thyroid hormone supplementation and on the day of 131I treatment as the "hypothyroid state" after a 3-week depletion of thyroid hormone supplements. Nine healthy volunteers also underwent MR imaging twice at an interval of 5 weeks. Pituitary volume and the relative signal intensity ratio of the anterior pituitary to the pons were measured. The shape and signal intensity of the pituitary gland were also visually assessed. The paired Student t test was used to evaluate the significance of the data. A P value less than .05 indicated a statistically significant difference. RESULTS: The patients had significantly larger pituitary volume in the hypothyroid state than in the euthyroid state both quantitatively (P < .001) and visually. No significant differences were found in the relative signal intensity ratios of the anterior pituitary to the pons. In healthy volunteers, no significant differences in pituitary volumes or signal intensity were found between the two MR images. CONCLUSION: Rapid progression of hyperplasia of the anterior pituitary may occur with acute development of hypothyroidism.     

Pharmacokinetics and safety of Z-321, a novel specific orally active prolyl endopeptidase inhibitor, in healthy male volunteers

This study investigates the pharmacokinetics and safety profile of Z-321, (4R)-3-(indan-2-ylacetyl)-4-(1-pyrrolidinyl-carbonyl)-1,3-thiazoli dine, a novel specific orally active prolyl endopeptidase (PEP) inhibitor. Following a preliminary safety evaluation wherein 2 subjects received 3.75 and 15 mg doses and 2 other subjects received 7.5 and 30 mg doses, 16 subjects were assigned to two groups of 8 subjects each. In each group, 6 subjects were to receive active treatment, and 1 or 2 subjects were to receive placebo treatment. One group received 60 mg under fasted and fed conditions. A separate group of 8 subjects received 60 mg of Z-321 or a placebo in a bid regimen for 6 days and the morning dose on day 7. The concentrations of Z-321 and its main metabolites--R- and S-sulfoxide; RR-, SS-, and RS-indanol; and indanolsulfoxides in plasma and urine--were determined by the HPLC method. In the multiple-dose study, the cholinesterase activity was gradually increased and reached above the normal range on day 8 in 3 of 6 subjects given Z-321 and gradually returned to the normal range after completion of dosing. The elevation of plasma cholinesterase activity was considered to be an action of Z-321, but this remains to be verified. In a single-dose study at a dose of 30 mg, headache and vomiting were observed in 1 of 6 subjects. In the multiple-dose study, slight skin itching and eczema in 3 and 2 of 6 subjects, respectively, and headache in 2 of 6 subjects were observed, but all symptoms were not severe. There were no other abnormal findings in objective signs and laboratory findings, including blood pressure, heart rate, electrocardiogram, body temperature, hematology, blood chemistry, and urinalysis. The Cmax of Z-321 at 30, 60, and 120 mg in the fasting state were 63.7 +/- 23.9, 102.0 +/- 43.1, and 543.3 +/- 437.0 ng/ml (mean +/- SD), respectively, at 0.9 hours after administration, and the t1/2 was about 1.8 hours. There were no dramatic changes in the pharmacokinetics of Z-321 in the presence of food. In the multiple-dose study, there was no drug accumulation trend in plasma. These results indicate that Z-321 has acceptable pharmacodynamic and pharmacokinetics profiles for clinical use without any serious adverse events, as verified in healthy young male volunteers.