The polymorphic 43Thr bcl-2 protein confers relative resistance to autoimmunity: an analytical evaluation.

We have found a novel polymorphic (Ala43Thr; ACC-->GCC) bcl-2 allele in a Japanese population. An in vitro expression study with a mouse IL-7-dependent pre-B cell line has revealed that inhibition of the programmed cell death function of 43Thr bcl-2 protein is suppressed compared with that of normal 43Ala bcl-2 protein. Since bcl-2 expression in B-lymphoid cells elicits autoimmune disease in mice, we have investigated the possibility of whether a bcl-2 polymorphism has a different susceptibility to autoimmune disease. To evaluate the clinical impact of this polymorphism, the frequency of bcl-2 polymorphism was investigated in 221 children with insulin-dependent diabetes mellitus (IDDM), 237 adults with autoimmune disease (105 with rheumatoid arthritis, 57 with systemic lupus erythematosus, 55 with Sjögren's syndrome, and 20 others), and 290 healthy Japanese children and adults. The frequency of the 43Thr bcl-2 allele, either homozygous or heterozygous, was 14.5% in normal controls, 6.8% (P<0.01) in children with IDDM, and 8.0% (P<0.025) in adults with autoimmune disease. These results suggest that the 43Thr allele of bcl-2 confers resistance to autoimmune disease. The different anti-apoptotic function resulting from the different expression of bcl-2 protein in lymphocytes seems to be associated with the development of autoimmune disease, indicating that the bcl-2 gene affects human autoimmune disease.

Molecular cloning, tissue distribution, and chromosomal localization of human cationic amino acid transporter 2 (HCAT2).

Human cationic amino acid transporter 2 (HCAT2) was isolated from a human intestine cDNA library. The nucleotide sequence of the coding region predicts a 658-amino-acid protein with a calculated molecular weight of 71,669. As 91% of the residues are identical with those of the mouse cationic amino acid transporter 2 (MCAT2), HCAT2 seems to be a human counterpart of MCAT2. We found no isoform as was present in MCAT2. In Northern blot analysis, a single (9.0 kb) HCAT2 mRNA transcript was present in various human tissues. The highest level of expression was observed in skeletal muscle and the lowest level in the kidney. Hydropathy plots indicated that the translated protein is predicted to have 14 transmembrane domains with three potential N-glycosylation sites. Two patients with lysinuric protein intolerance (MIM No. 222700) were analyzed for HCAT2 cDNA but no mutation was detected. The HCAT2 gene was assigned to human chromosome 8p21.3-p22.

Correction of ornithine transcarbamylase deficiency in adult spf(ash) mice and in OTC-deficient human hepatocytes with recombinant adenoviruses bearing the CAG promoter.

Ornithine transcarbamylase (OTC) deficiency, the most common and severe inborn error of the urea cycle in humans, remains without adequate treatment, and mortality rates are high. Adenoviral vectors provide an efficient system for gene delivery, but there are problems, including toxicity. Efficient promoters that reduce the amount of vector required for treatment need to be developed. We constructed two recombinant adenoviral vectors, AdexCAGhOTC and AdexSR alpha hOTC, which harbor the human OTC gene under transcriptional control of CAG (a modified chicken beta-actin promoter with CMV-IE enhancer) and SR alpha (the SV40 early promoter with the R segment and part of the US segment of the HTLV-1 LTR), respectively. Each was tested in adult spf(ash) mice, an animal model of human OTC deficiency, and in primary human hepatocytes with OTC deficiency. Spf(ash) mice have a pronounced orotic aciduria as seen in humans. A complete recovery of hepatic OTC activity with minimal tissue damage was observed in these animals following the intravenous administration of AdexCAGhOTC alone. Western blot analysis confirmed hepatic OTC expression and normalization of orotic aciduria was evident for 60 days. Enzyme activities of primary human hepatocytes infected with AdexCAGhOTC were 10-40 times higher than those with AdexSR alpha hOTC. Thus, the adenoviral vector with an efficient promoter such as CAG, can be given further consideration for possible gene therapy in humans with OTC deficiency.

CT's capability in detecting advanced gastric cancer.

Upper GI series and CT scans of 23 patients with advanced gastric cancer were reviewed and correlated to determine CT's capability in detecting gastric tumors. The CT images of the gastric carcinomas revealed either a mass or thickening of the wall. These abnormalities were present in 78% of the cases whereas CT demonstrated a "mass" in 52%. The most difficult site for CT diagnosis of gastric cancer was the antrum. Diagnostic accuracy of CT in evaluating tumor invasion of adjacent structures is reportedly high. However, in the present study this was not necessarily true. In 4 of 5 patients whose gastric tumors proved unresectable, CT failed to reveal adjacent invasion. This suggests that CT is not always reliable in predicting surgical resectability.

Normal or benign gastric wall thickening demonstrated by computed tomography.

Using a fourth generation computed tomography (CT) scanner, the gastric wall was easily demonstrated. On review of CT images of the upper abdomen, thick gastric walls were observed in numerous patients without gastric pathology. Administration of dilute Gastrografin and gas producing agent expanded the gastric wall and resolved the problem. With large gastric rugae and with gastric ulcers, thick gastric walls are also observed, presenting a problem in CT interpretation. The approach described in this report proved helpful in resolving these cases.

Linear nevus sebaceus syndrome. Report of a case with Lennox-Gastaut syndrome following infantile spasms.

We report what we believe to be the first known case of linear nevus sebaceus syndrome with infantile spasms followed by Lennox-Gastaut syndrome. The EEG revealed hemihypsarrhythmia and then asymmetrical slow spike-wave complexes. A pneumoencephalogram showed dilation and distortion of the lateral ventricle ipsilateral to the facial nevus on the left side. A computerized tomographic scan disclosed low density in the left parietotemporal region, a feature not reported previously. The findings indicated extensive lateralized cerebral lesions.

Primary intracranial sarcomas: radiological diagnosis with emphasis on arteriography.

The radiological manifestations of primary intracranial sarcomas may be non-specific and they vary widely according to their histological variations. Reticulum cell sarcomas, however, can be included in the differential diagnosis with a high degree of reliability when one observes a hypovascular mass with arterial encasement and deep medullary veins. Tumor vessels and tumor stains supplied by dilated feeding arteries suggest the possibility of a sarcoma of the brain or of the meninges in infants. Nine reticulum cell sarcomas, four undifferentiated sarcomas, and one fibrosarcoma are presented here with their radiological manifestations, especially on angiography.

Angiographic diagnosis of fourth ventricle tumors.

Twelve primary fourth ventricle tumors and 22 medulloblastomas occupying mainly the fourth ventricle were analyzed, with emphasis on the differential diagnosis, vascularity, and some unusual findings. Though both types of tumor often have identical manifestations, the correct diagnosis can be made in most cases by careful evaluation of the posterior inferior cerebellar artery, particularly the choroidal and nodular branches. Unusual findings in primary fourth ventricle tumors mimicking tumors of the pons and medulla oblongata are described, and possible explanations for these findings are discussed. The results of this study underscore the importance of angiotomography in the diagnosis of tumors of the fourth ventricle.

Angiographic demonstration of a calcified splenic hamartoma.

A case of hamartoma of the spleen is reported. Radiographic examination revealed a mass containing innumerable calcifications in the left upper quadrant. Angiography demonstrated an avascular mass. The authors believe that such calcification and avascularity are late manifestations of a slowly-growing splenic tumor which may well be hypervascular if examined earlier.