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Decreased serum concentrations of 1,25(OH)2D3 in patients with gout
POSTER ABSTRACTS (4.74 ± 0.15 mg/dl). As many as 3 of 15 DM patients demonstrated Sua below 3.0 mg/dl. Urinary urate excretion (Uua) of DM patients (0.270 ± 0.022 mg/kg/hr) was markedly lower than that of C (0.496 ± 0.013 mg/kg/hr), suggesting that decreased urate production is the main mechanism involved in low Sua. Three of 15 DM patients demonstrated urate clearance (Cua) under 4.0 ml/min, but Sua levels in these patients remained almost the same, suggesting that urate production had been sufficiently decreased to subtract the increment of Sua by underexcretion in these patients. After DM patients received aldose reductase inhibitor (ARI) treatment for 1 month, the decreased Uua recovered significantly. Since ARI treatment reduced conversion of glucose to sorbitol and the latter inhibited urate production, the recovery of low Sua in DM patients might be attributed to the reduction of sorbitol formation by the ARI treatment. In summery, sorbitol deposits in the tissue could be a cause of the low Sua in DM patients.
connected to an Alu sequence. The extent of deletion was at least 2.2 kb. Conclusion A large region from the middle of intron 4 beyond the known 3' flanking sequence was deleted in this germline mutation. We hypothesize that the deletion of another gene within the deleted sequence is related to the suppression of LOH.
175 D E C R E A S E D SERUM CONCENTRATIONS OF 1,25(OH)2D3 IN PATIENTS WITH GOUT Takahashi, S., Yamamoto, T., Tsutsumi, Z., Moriwaki, Y., Yamakita, J., and Higashino, K., Third Department of Internal Medicine, Hyogo College of Medicine Mukogawacho L1, Nishinomiya, Hyogo 663, Japan
Objectives Elevated levels of p185 expression have been found in a number of human adenocarcinomas, probably occurring by molecular mechanism. Also adenylosuccinate lyase (ASL) is increased in certain malignancies, like colon-rectal, breast and prostatic tumors. In order to evaluate the potentiality of ASL as tumor marker, its activity was determined in comparison with the expression of 185. Design and Methods We analyzed 16 subjects, with tubular adenoma, with tubulo-villous adenoma, and polips. P185 was determined by immunohistochemical procedure. ASL activity by HPLC method. Methods An increased expression of p185 and elevated ASL activity was observed in tubular and tubulo-villous adenomas. Conclusions Our results indicate that the elevated expression of p185 and the increased ASL activity are associated with early stages of colon neoplasia. We are stimulated to continue this study on a larger casistic and to verify the possibility of using these assays as parameters for the diagnosis of colorectal tumors.
Objectives To identify whether uric acid affects vitamin D metabolism. Design and Methods We measured the serum concentrations of 1,25(OH)2Da, 25(OH)Da, parathyroid hormone (PTH) and uric acid in 82 patients with primary gout. In addition, we administered allopurinol (200 mg/day) to patients with gout, and examined the change of serum concentration of 1,25(OH)2D3. Results The serum concentration of 1,25(OH)2Da was significantly lower (p < 0.05) in patients with gout than in control subjects. However, no differences were observed both in the serum concentrations of 25(OH)Da and PTH between the two groups. After allopurinol administration, the serum concentration of 1,25(OH)2D a rose significantly with the decrease in serum concentration of uric acid. Conclusion These results suggest that uric acid per se might directly suppresses the serum concentration of 1,25(OH)2D a in patients with gout.
176 A GERMLINE PARTIAL DELETION OF A D E N I N E PHOSPHORIBOSYLTRANSFERASE GENE PRESUMABLY RELATED TO THE SUPPRESSION OF LOSS OF HETEROZYGOSITY IN SOMATIC CELLS Atsuo Taniguchi, Masayuki Hakoda, Shin Totokawa, Hisashi Yamanaka, Chihiro Terai, Naoyuki Kamatani and Sadao Kashiwazaki Institute of Rheumatology, Tokyo Women's Medical College, KS BLDG, 9-12 Wakamatsu-cho, Shinjuku-ku, Tokyo 162, Japan Objectives We have reported three individuals with heterozygous APRT deficiency caused by a gross genomic alteration (APRT*Qdel) in whom loss of heterozygosity (LOH) was not observed (Hakoda et al. Hum Genet. in press). In this study, we attempted to define this mutation at the molecular level. Design and Methods Using DNA from a compound heterozygote (APRT*Qdel/APRT*QO) and sequence-discriminating endonucleases, we broadly estimated the extent of deletion and devised an inverse-PCR method. Results In APRT~Qdel gene, exons 1-4 were intact but the normal sequence was interrupted within the intron 4 and was CLINICAL BIOCHEMISTRY, VOLUME 30, APRIL 1997
177
IMMUNOHISTOCHEMICAL ANALYSIS OF P185 A N D ASL ACTIVITY IN TRANSFORMED H U M A N TISSUES L. Terzuoli, B. Frosi, B. Porcelli, F. Carlucci, C. Minacci*, R. Vernillo**, L. Baldi, A. Tabucchi, E. Marinello, Institute of Biochemistry and Enzymology, *Institute of Patologic Anatomy, **Institute of General Surgery, University of Siena, Italy
178 PURINE-MEDIATED APOPTOSIS L.F. Thompson, Oklahoma Medical Research Foundation, Oklahoma City, OK Objectives In this Workshop presentation, the mechanisms by which purine nucleosides and nucleoside derivatives mediate apoptosis of lymphoid cells will be discussed. Early work by tGzaki et al. showed that adenosine and deoxyadenosine induced apoptosis of murine thymocytes. This effect could be duplicated by adenosine receptor agonists and other cAMP elevating agents such as forskolin (McConkey, et al.). More recently, Lalli and colleagues demonstrated that dibutyryl-cAMP caused a cell cycle block and apoptosis in cultured murine thymic lobes. Benveniste et al. demonstrated that deoxyadenosine, in the presence of an adenosine deaminase inhibitor, initiated apoptosis of cultured murine thymocyte suspensions. In this case, the apoptosis was mediated by a p53-dependent pathway. S-adenosylhomocysteine, which may accumulate in adenosine deaminase deficiency, has recently been shown by Ratter et al. to be a physiological modulator of Fas-mediated cell death. All of these experimental systems suggest that pathologic elevations in adenosine or deoxyadenosine may be deleterious for normal T cell development and raise the possibility that purine nucleosides may also play a role in the apoptosis which is a normal component of thymocyte differentiation. Contributions from Workshop Participants will be solicited. 285
connected to an Alu sequence. The extent of deletion was at least 2.2 kb. Conclusion A large region from the middle of intron 4 beyond the known 3' flanking sequence was deleted in this germline mutation. We hypothesize that the deletion of another gene within the deleted sequence is related to the suppression of LOH.
175 D E C R E A S E D SERUM CONCENTRATIONS OF 1,25(OH)2D3 IN PATIENTS WITH GOUT Takahashi, S., Yamamoto, T., Tsutsumi, Z., Moriwaki, Y., Yamakita, J., and Higashino, K., Third Department of Internal Medicine, Hyogo College of Medicine Mukogawacho L1, Nishinomiya, Hyogo 663, Japan
Objectives Elevated levels of p185 expression have been found in a number of human adenocarcinomas, probably occurring by molecular mechanism. Also adenylosuccinate lyase (ASL) is increased in certain malignancies, like colon-rectal, breast and prostatic tumors. In order to evaluate the potentiality of ASL as tumor marker, its activity was determined in comparison with the expression of 185. Design and Methods We analyzed 16 subjects, with tubular adenoma, with tubulo-villous adenoma, and polips. P185 was determined by immunohistochemical procedure. ASL activity by HPLC method. Methods An increased expression of p185 and elevated ASL activity was observed in tubular and tubulo-villous adenomas. Conclusions Our results indicate that the elevated expression of p185 and the increased ASL activity are associated with early stages of colon neoplasia. We are stimulated to continue this study on a larger casistic and to verify the possibility of using these assays as parameters for the diagnosis of colorectal tumors.
Objectives To identify whether uric acid affects vitamin D metabolism. Design and Methods We measured the serum concentrations of 1,25(OH)2Da, 25(OH)Da, parathyroid hormone (PTH) and uric acid in 82 patients with primary gout. In addition, we administered allopurinol (200 mg/day) to patients with gout, and examined the change of serum concentration of 1,25(OH)2D3. Results The serum concentration of 1,25(OH)2Da was significantly lower (p < 0.05) in patients with gout than in control subjects. However, no differences were observed both in the serum concentrations of 25(OH)Da and PTH between the two groups. After allopurinol administration, the serum concentration of 1,25(OH)2D a rose significantly with the decrease in serum concentration of uric acid. Conclusion These results suggest that uric acid per se might directly suppresses the serum concentration of 1,25(OH)2D a in patients with gout.
176 A GERMLINE PARTIAL DELETION OF A D E N I N E PHOSPHORIBOSYLTRANSFERASE GENE PRESUMABLY RELATED TO THE SUPPRESSION OF LOSS OF HETEROZYGOSITY IN SOMATIC CELLS Atsuo Taniguchi, Masayuki Hakoda, Shin Totokawa, Hisashi Yamanaka, Chihiro Terai, Naoyuki Kamatani and Sadao Kashiwazaki Institute of Rheumatology, Tokyo Women's Medical College, KS BLDG, 9-12 Wakamatsu-cho, Shinjuku-ku, Tokyo 162, Japan Objectives We have reported three individuals with heterozygous APRT deficiency caused by a gross genomic alteration (APRT*Qdel) in whom loss of heterozygosity (LOH) was not observed (Hakoda et al. Hum Genet. in press). In this study, we attempted to define this mutation at the molecular level. Design and Methods Using DNA from a compound heterozygote (APRT*Qdel/APRT*QO) and sequence-discriminating endonucleases, we broadly estimated the extent of deletion and devised an inverse-PCR method. Results In APRT~Qdel gene, exons 1-4 were intact but the normal sequence was interrupted within the intron 4 and was CLINICAL BIOCHEMISTRY, VOLUME 30, APRIL 1997
177
IMMUNOHISTOCHEMICAL ANALYSIS OF P185 A N D ASL ACTIVITY IN TRANSFORMED H U M A N TISSUES L. Terzuoli, B. Frosi, B. Porcelli, F. Carlucci, C. Minacci*, R. Vernillo**, L. Baldi, A. Tabucchi, E. Marinello, Institute of Biochemistry and Enzymology, *Institute of Patologic Anatomy, **Institute of General Surgery, University of Siena, Italy
178 PURINE-MEDIATED APOPTOSIS L.F. Thompson, Oklahoma Medical Research Foundation, Oklahoma City, OK Objectives In this Workshop presentation, the mechanisms by which purine nucleosides and nucleoside derivatives mediate apoptosis of lymphoid cells will be discussed. Early work by tGzaki et al. showed that adenosine and deoxyadenosine induced apoptosis of murine thymocytes. This effect could be duplicated by adenosine receptor agonists and other cAMP elevating agents such as forskolin (McConkey, et al.). More recently, Lalli and colleagues demonstrated that dibutyryl-cAMP caused a cell cycle block and apoptosis in cultured murine thymic lobes. Benveniste et al. demonstrated that deoxyadenosine, in the presence of an adenosine deaminase inhibitor, initiated apoptosis of cultured murine thymocyte suspensions. In this case, the apoptosis was mediated by a p53-dependent pathway. S-adenosylhomocysteine, which may accumulate in adenosine deaminase deficiency, has recently been shown by Ratter et al. to be a physiological modulator of Fas-mediated cell death. All of these experimental systems suggest that pathologic elevations in adenosine or deoxyadenosine may be deleterious for normal T cell development and raise the possibility that purine nucleosides may also play a role in the apoptosis which is a normal component of thymocyte differentiation. Contributions from Workshop Participants will be solicited. 285