CD80 (B7-1) and CD86 (B7-2) genes and genetic susceptibility to coeliac disease.

The role of the costimulatory molecules B7-1 (CD80) and B7-2 (CD86) in T-cell activation makes them good candidates for coeliac disease susceptibility genes. We conducted a genetic linkage study of the CD80/86 gene region in the general Finnish population and in a local subisolate. No linkage was found in either population.     

Dermofat grafts to the extraconal orbital space.

Dermofat grafts were placed in the upper or lower lid sulci in 35 subjects, aged from 11 to 59 years, to improve the cosmesis of volume deficient sockets or prevent tissue adhesion. Volume enhancement and cosmetic improvement were achieved in 31 patients, in whom useful vision was present in 13/22 after previous trauma, in 4/4 with facial clefting, and in 3/3 with orbital or facial fat atrophy. Grafts were used successfully in nine patients to prevent scar formation after division of adhesions between the eyelids or levator muscle and the orbital margins. A reduction of the bulk of upper-lid grafts was required in three cases; histopathology of the excised fat showed relatively minor degrees of inflammation, atrophy, and fibrosis.     

Nasopharyngeal intracavitary brachytherapy: the controversy of T2b disease

BACKGROUND: Locally persistent nasopharyngeal carcinoma (NPC) carries an increased risk of local failure if additional treatment is not given. It has been shown that intracavitary brachytherapy is effective in the treatment of patients with T1 and T2a NPC, although its role in the treatment of T2b disease had remained uncertain. The objectives of the current study were to evaluate the outcomes of patients with T2b, locally persistent NPC who were treated with high-dose-rate (HDR) intracavitary brachytherapy and to explore whether routine brachytherapy boost could improve the local control of patients who had T2b NPC at initial diagnosis. METHODS: Thirty-four patients with locally persistent NPC who were treated during 1992-2000 with HDR intracavitary brachytherapy were analyzed retrospectively. All patients had T2b disease at initial diagnosis. They were treated with HDR intracavitary brachytherapy at doses of 22.5-24.0 grays (Gy) in 3 weekly sessions. To compare the efficacy of brachytherapy, another 403 consecutive patients with nonmetastatic T2b NPC who were treated with curative intent by external radiotherapy (ERT) during the same period were evaluated. RESULTS: An improvement in the 5-year actuarial local failure-free survival rate (brachytherapy group vs. ERT group: 96.9% vs. 81.5%; P = 0.024), the disease-specific survival rate (84.5% vs. 68.1%; P = 0.021), and the overall survival rate (78.3% vs. 63.1%; P = 0.034) was demonstrated in the group that had locally persistent NPC who were salvaged with brachytherapy. In assessing local control, the addition of brachytherapy was just short of statistical significance on multivariate analysis (P = 0.054). The complication rates were comparable between the brachytherapy group and the ERT group. CONCLUSIONS: The results suggested that patients with T2b NPC who have locally persistent disease can be salvaged effectively with brachytherapy. Their local control was even better than that achieved by patients who had clinical remission of local disease at the completion of ERT. Furthermore, it is possible that routine brachytherapy boost, after the completion of ERT, may improve local control in patients who have T2b disease at initial diagnosis. However, its exact benefit can be elucidated only by prospective, randomized studies.     

Small bowel cyclooxygenase 2 (COX-2) expression in patients with IgA nephropathy

BACKGROUND: Clinical manifestation of IgA nephropathy (IgAN) strikingly occurs after respiratory tract infections. An intestinal inflammation has also been described. We hypothesized that the intestinal inflammation should manifest itself as an increase in inflammatory cells and mucosal cyclooxygenase 2 (COX-2) expression. METHODS: By using immunohistochemistry, we determined the phenotype and quantity of inflammatory cells in duodenal biopsy specimens from 17 IgAN patients. Control material comprised 18 patients undergoing gastroscopy because of dyspepsia. RESULTS: All the biopsy specimens disclosed normal villous architecture. In IgAN, CD3(+) cells and COX-2-positive cells were significantly increased and J chain-producing plasma cells were significantly decreased. CD3(+) cells coexpressed COX-2 protein and COX-2-positive cells also expressed CD45RO antigen. The number of lymphocytes correlated significantly with serum IgA and COX-2-expression with serum IgA and the degree of hematuria. COX-2-positive subepithelial fibroblasts were a conspicuous finding in IgAN. In CD68(+) and CD15(+) cells, a significant increase was seen. Many of these cells also expressed COX-2 protein. CD15(+) positivity correlated significantly with proteinuria in IgAN. CONCLUSION: Our results indicate that small bowel inflammation in IgAN shows itself as an increased number of mucosal inflammatory cells. However, polymeric IgA production is significantly decreased. An increased mucosal COX-2 expression suggests activation of the inflammatory cells and the degree of inflammation significantly correlates with serum IgA and the amount of proteinuria and hematuria. Subepithelial fibroblasts seem also to be involved in the inflammatory reaction.     

New Alström syndrome phenotypes based on the evaluation of 182 cases

BACKGROUND: Alstr?m syndrome is a recessively inherited genetic disorder characterized by congenital retinal dystrophy that leads to blindness, hearing impairment, childhood obesity, insulin resistance, and type 2 diabetes mellitus. We provide new details on cardiologic, hepatic, gastrointestinal, urologic, pulmonary, and neurobehavioral phenotypes in Alstr?m syndrome and describe the histopathologic findings in 5 individuals. METHODS: We obtained data on 182 patients from clinical examinations, medical record reviews, standardized questionnaires, and personal interviews with physicians and parents. RESULTS: Dilated cardiomyopathy occurred in 60% of patients. Age at onset was either during infancy, often before vision disturbances were noted, or in adolescence or adulthood. There is a risk of recurrence of infantile cardiomyopathy. Hyperinsulinemia (92%) developed in early childhood and progressed to type 2 diabetes mellitus in 82% of those older than 16 years. Hypertriglyceridemia (54%) precipitated pancreatitis in 8 patients. Urologic dysfunction and gastrointestinal disturbances occurred in 48% and 35% of patients, respectively. Fifty-three percent of patients had persistent pulmonary symptoms. Neurologic symptoms in 20% of patients included clonic tic and absence seizures. Developmental motor or language delays were observed in 46% of patients. Fibrotic infiltrations of multiple organs, that is, kidney, heart, liver, lung, urinary bladder, gonads, and pancreas, were observed. CONCLUSIONS: The wide-ranging and complex spectrum of phenotypes reported herein broadens those previously described for Alstr?m syndrome. These findings will aid physicians in making an early and accurate diagnosis and will help effect appropriate monitoring and treatment.     

Protein kinase C epsilon regulates tumor necrosis factor-alpha-induced stannin gene expression

Stannin (Snn) is a highly conserved vertebrate protein that has been closely linked to trimethyltin (TMT) toxicity. We have previously demonstrated that Snn is required for TMT-induced cell death. Others have shown that TMT exposure results in tumor necrosis factor-alpha (TNFalpha) production and that TNFalpha treatment induces Snn gene expression in human umbilical vein endothelial cells (HUVECs). In this study, we investigated a signaling mechanism by which Snn gene expression is regulated by TMT and demonstrated that TNFalpha stimulates Snn gene expression in a protein kinase C epsilon-dependent manner in HUVECs in response to TMT exposure. Supporting this, we show that TMT-induced toxicity is significantly blocked by pretreatment with an anti-TNFalpha antibody in HUVECs. Using a quantitative real-time polymerase chain reaction assay, we also show that the level of Snn gene expression is significantly increased in HUVECs in response to either TMT or TNFalpha treatment. This TNFalpha-induced Snn gene expression is blocked when HUVECs were pretreated with bisindolylmaleimide I, an inhibitor of protein kinase C (PKC). In contrast, when HUVECs were treated with phorbol 12-myristate 13-acetate, a PKC activator, we observed a significant increase in Snn gene expression. Using isotype-specific siRNA against PKC, we further show that knockdown of PKC epsilon, but not PKC delta or PKC zeta, significantly blocked TNFalpha-induced Snn gene expression. Together, these results indicate that TNFalpha-induced, PKC epsilon-dependent Snn expression may be a critical factor in TMT-induced cytotoxicity.     

Pulmonary toxicity,hepatic, and extrahepatic metabolism of 2-methylnaphthalene in mice

Male mice ($\text{C57BL}\text{6J}$) were injected once ip with 0.1, 1, 100, 200, 400, 600, 800, or 1000 mg/kg of 2-methylnaphthalene dissolved in corn oil. After 24 hr, the animals were killed and the lungs, livers, and kidneys were prepared for light microscopy. In addition, some lungs were subjected to scanning and transmission electron microscopy. A dose of 200 mg/kg produced a bronchiolar necrosis which affected the nonciliated bronchiolar (Clara) cell; the parenchymal cells remained unaffected. At higher doses of 2-methylnaphthalene (800 mg/kg), in addition to the damaged Clara cell, severe damage to the upper respiratory tract was noted. No liver or kidney pathology was detected by light microscopy in animals treated with the highest dose. No cellular damage was noted in any organ at doses less than 200 mg/kg. Forty-eight hours after a dose of 200–1000 mg/kg of 2-methylnaphthalene, less pulmonary damage was detected by light microscopy. The metabolism of 2-methylnaphthalene was investigated in hepatic, pulmonary, and renal microsomes from $\text{C57BL}\text{6J}$ mice. Lung and liver microsomes produced three isomeric dihydrodiols of 2-methylnaphthalene as well as other monohydroxylated metabolites. Only trace amounts of these metabolites were produced by the kidney.