A rare case of allergic granulomatous angitis (Churg Strauss syndrome) with positive anti-glomerular basement membrane (GBM) antibody in serum]

A 33-year-old man with a 6-month history of rhinitis and bronchial asthma was referred to our hospital with polyarthralgia, severe anemia, hypoxemia, mononeuropathy multiplex, and renal insufficiency with hematuria. Marked eosinophilia was observed in his sputum, peripheral blood, and bronchoalveolar lavage fluid (BALF). In addition, his sputum contained many hemosiderin-laden macrophages, indicative of pulmonary hemorrhage. His chest roentgenogram on admission showed diffuse ground grass appearance. High resolution computed tomography (HRCT) demonstrated diffuse high density areas throughout the lung fields and characteristic irregularity and enlargement of the peripheral pulmonary arteries. His general condition rapidly deteriorated, but dramatically improved with oral steroid administration, and his major symptoms disappeared within a few days. Examination of the biopsied lung tissue revealed unequivocal evidence of pulmonary angitis with marked eosinophilic infiltration and perivascular granulomas. Bone marrow biopsy showed hyperplasia of eosinophilic leukocytes in contrast to the low cellularity. Suppression of erythroid hemopoiesis was thought to be the primary cause for his rapidly progressive anemia. Serum anti-GBM antibody titer returned to within the normal range soon after the initiation of steroid therapy.     

A HhaI/BstUI polymorphism in a novel gene at human chromosome 11p15.5

We found a HhaI/BstUI polymorphism in the 3′ untranslated region of a novel gene which was localized to 11p15.5. This region is one of prominent imprinting domains and contains multiple imprinted genes, such as H19, IGF2 , KVLQT1, and p57 ^KIP2 , which suggests that regional factors might contribute to the imprinting. This polymorphism will be useful in the allelic analysis of expression and methylation of the novel gene. Received: July 24, 1998 / Accepted: July 29, 1998     

Transgenic expression of mutant peroxisome proliferator-activated receptor gamma in liver precipitates fasting-induced steatosis but protects against high-fat diet-induced steatosis in mice

Steatosis is one of the most common liver diseases and is associated with the metabolic syndrome. A line of evidence suggests that peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma are involved in its pathogenesis. Hepatic overexpression of PPARgamma1 in mice provokes steatosis, whereas liver-specific PPARgamma disruption ameliorates steatosis in ob/ob mice, suggesting that hepatic PPARgamma functions as an aggravator of steatosis. In contrast, PPARalpha-null mice are susceptible to steatosis because of reduced hepatic fatty acid oxidation. PPARgamma with mutations in its C-terminal ligand-binding domain (L468A/E471A mutant PPARgamma1) have been reported as a constitutive repressor of both PPARalpha and PPARgamma activities in vitro. To elucidate the effect of co-suppression of PPARalpha and PPARgamma on steatosis, we generated mutant PPARgamma transgenic mice (Liver mt PPARgamma Tg) under the control of liver-specific human serum amyloid P component promoter. In the liver of transgenic mice, PPARalpha and PPARgamma agonist-induced augmentation of the expression of downstream target genes of PPARalpha and PPARgamma, respectively, was significantly attenuated, suggesting PPARalpha and PPARgamma co-suppression in vivo. Suppression of PPARalpha and PPARgamma target genes was also observed in the fasted and high-fat-fed conditions. Liver mt PPARgamma Tg were susceptible to fasting-induced steatosis while being protected against high-fat diet-induced steatosis. The opposite hepatic outcomes in Liver mt PPARgamma Tg as a result of fasting and high-fat feeding may indicate distinct roles of PPARalpha and PPARgamma in 2 different types of nutritionally provoked steatosis.     

Evaluation of molecular targeted cancer drug by changes in tumor marker doubling times

Background  

We evaluated the usefulness of tumor marker doubling time (DT) as an efficacy indicator of a molecular targeted anticancer agent.     

Downregulation of leptin by free fatty acids in rat adipocytes: effects of triacsin C, palmitate, and 2-bromopalmitate

Free fatty acid (FFA) has been reported to decrease leptin mRNA levels in 3T3-L1 adipocytes. When using this cell line, it is difficult to determine the protein levels because a very small amount of leptin is secreted into the medium. The effect of FFA on leptin secretion from adipocytes has not yet been determined. In addition, in vivo studies have failed to demonstrate a FFA-induced decrease in plasma leptin levels. To clarify the effect of FFA on leptin production, we investigated the leptin protein level in the medium and the mRNA level in primary cultured rat adipocytes treated with triacsin C, which is a potent inhibitor of acyl-coenzyme A (CoA) synthetase, palmitate, and 2-bromopalmitate. Triacsin C (0 to 5 x 10(-5) mol/L) decreased leptin concentrations in the culture medium in a dose-dependent manner. Leptin mRNA levels were decreased to 10% of the control in the presence of triacsin C. The concentration of triacsin C needed to suppress leptin production was similar to the Ki value (approximately 10(-5) mol/L) for inhibition of acyl-CoA synthetase. Both palmitate and 2-bromopalmitate decreased leptin concentra-tions but did not affect the triacsin C-induced decrease in leptin additively. In conclusion, both protein and mRNA levels of leptin were decreased by triacsin C and FFA in primary cultured rat adipocytes. Our findings suggest that FFA is involved in the regulation of leptin production in adipocytes.     

Pathophysiogical role of leptin in lifestyle-related diseases. Studies with transgenic skinny mice overexpressing leptin

Leptin is a major adipocyte-derived hormone that is involved in the regulation of food intake and energy expenditure. Plasma leptin concentrations are elevated in obese subjects, suggesting its pathophysiological role in obesity-related lifestyle-related diseases. We have recently succeeded in the generation of transgenic skinny mice overexpressing leptin. They exhibit increased glucose metabolism and insulin sensitivity accompanied by a significant increase in insulin signaling for glucose utilization in the skeletal muscle and liver. They also show blood pressure elevation through the sympathetic activation. Introduction of the lethal yellow agouti (A(y)) allele into transgenic skinny mice results in late-onset obesity and diabetes with blood pressure elevation similar to those found in nontransgenic agouti mice (A(y)/+ mice). After caloric restriction, blood pressure elevation is reversed but insulin resistance still remains in A(y)/+ mice in parallel with a reduction of plasma leptin concentrations. By contrast, blood pressure elevation is sustained but insulin resistance is reversed in transgenic mice overexpressing leptin with the A(y) allele (Tg/+:A(y)/+ mice), which remain hyperleptinemic. Collectively, our data suggest the pathophysiologic and therapeutic implication of leptin in obesity-related insulin resistance and hypertension.