Hypoaldosteronism in three sibs due to 18-dehydrogenase deficiency

Three sibs all presented in the early neonatal period with a salt-losing syndrome. The salt-losing form of congenital adrenal hyperplasia was diagnosed and appropriate treatment with glucocorticosteroids, mineralocorticosteroids, and additional dietary salt started. Although early life was maintained with difficulty, with age all 3 children required decreasing amounts of replacement steroids to maintain normal plasma electrolyte balance. They were reinvestigated at the ages of 15 years and 8 years (twins), when cortisol synthesis and metabolism proved normal, but aldosterone synthesis was blocked by deficiency of 18-dehydrogenase. Rational treatment of these cases of a salt-losing syndrome in which aldosterone synthesis alone is blocked due to lack of the enzyme 18-dehydrogenase requires the administration of a mineralocorticosteroid drug only. Since deoxycorticosterone (acetate or pivalate) requires intramuscular administration, as life-long therapy oral fludrocortisone is preferable. Although fludrocortisone has glucocorticoid activity, the "hydrocortisone equivalent" effect of the small dosage used was unlikely to inhibit either pituitary corticotrophin or growth hormone production.     

Laryngeal rhabdomyosarcoma.

Laryngeal rhabdomyosarcomas are very rare, extremely malignant tumors. Approximately half of the reported cases have occurred in children. Diagnosis may be difficult, and adequate biopsy material is crucial in the identification of these lesions. Unil recently, rhabdomyosarcomas carried a dismal prognosis; however, combined treatment with surgery, irradiation, and triple chemotherapy appears to have improved the outlook. This should probably be the treatment for laryngeal rhabdomyosarcomas, and was successfully used in the case reported herein.     

Serum testosterone and the risk of prostate cancer: potential implications for testosterone therapy.

OBJECTIVE: A potential risk of testosterone replacement therapy is an increase in the incidence of prostate cancer, but it is unclear whether higher levels of serum testosterone are associated with a higher risk of prostate cancer. We prospectively evaluated serum androgen concentrations and prostate cancer risk. METHOD: Included were 794 members of the Baltimore Longitudinal Study of Aging. We estimated the rate ratio (RR) of prostate cancer by entering serial measures of serum total testosterone, dehydroepiandrosterone sulfate, sex hormone binding globulin, calculated free testosterone, and free testosterone index (FTI) into a Cox proportional hazards regression model with simple updating. RESULTS: Higher calculated free testosterone was associated with an increased age-adjusted risk of prostate cancer {RRs by quartile: 1.00, 1.52 [95% confidence interval (95% CI), 0.93-2.50], 1.16 (95% CI, 0.61-2.20), 2.59 (95% CI, 1.28-5.25); P(trend) = 0.03}, which persisted after excluding measures in men <45 years of age [RRs by quartile: 1.00, 1.33 (95% CI, 0.78-2.25), 1.26 (95% CI, 0.68-2.33), 1.89 (95% CI, 0.99-3.61); P(trend) = 0.03]. Compared to men with eugonadal FTI (> or = 0.153), men with hypogonadal FTI had a decreased risk of prostate cancer (RR, 0.51; 95% CI, 0.31-0.82). CONCLUSION: Higher levels of calculated serum free testosterone are associated with an increased risk of prostate cancer. These findings suggest that men receiving testosterone therapy should be regularly monitored for prostate cancer and underscore the need for prospective trials of testosterone therapy incorporating incidence of prostate cancer as a primary safety end point.     

Monoclonal antibody F1 binds to the kringle domain of factor XII and induces enhanced susceptibility for cleavage by kallikrein

In a previous study we have shown that monoclonal antibody F1 (MoAb F1), directed against an epitope on the heavy chain of factor XII distinct from the binding site for anionic surfaces, is able to activate factor XII in plasma (Nuijens JH, et al: J Biol Chem 264; 12941, 1989). Here, we studied in detail the mechanism underlying the activation of factor XII by MoAb F1 using purified proteins. Formation of factor XIIa was assessed by measuring its amidolytic activity towards the chromogenic substrate H-D-Pro-Phe-Arg-pNA (S-2302) in the presence of soybean trypsin inhibitor and by assessing cleavage on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Upon incubation with MoAb F1 alone, factor XII was auto-activated in a time-dependent fashion, activation being maximal after 30 hours. Factor XII incubated in the absence of MoAb F1 was hardly activated by kallikrein, whereas in the presence of MoAb F1, but not in that of a control MoAb, the rate of factor XII activation by kallikrein was promoted at least 60-fold. Maximal activation of factor XII with kallikrein in the presence of MoAb F1 was reached within 1 hour. This effect of kallikrein on the cleavage of factor XII bound to MoAb F1 was specific because the fibrinolytic enzymes plasmin, urokinase, and tissue-type plasminogen activator could not substitute for kallikrein. Also, trypsin could easily activate factor XII, but in contrast to kallikrein, this activation was independent of MoAb F1. SDS-PAGE analysis showed that the appearance of amidolytic activity correlated well with cleavage of factor XII. MoAb F1-induced activation of factor XII in this purified system was not dependent on the presence of high- molecular-weight kininogen (HK), in contrast to the activation of the contact system in plasma by MoAb F1. Experiments with deletion mutants revealed that the epitopic region for MoAb F1 on factor XII is located on the kringle domain. Thus, this study shows that binding of ligands to the kringle domain, which does not contribute to the proposed binding site for negatively charged surfaces, may induce activation of factor XII. Therefore, these findings point to the existence of multiple mechanisms of activation of factor XII.     

开道散合扶正和胃合剂治疗上消化道癌性狭窄疗效观察

目的：观察开道散合扶正和胃合剂治疗上消化道癌性狭窄的临床疗效。方法：对40例患者采用口服开道散、扶正和胃合剂联合胃镜下癌灶内注射5-氟脲嘧啶注射液及鸦胆子乳剂方法治疗上消化道癌性狭窄。结果：治疗后无瘤灶消失病例,34例患者肿瘤缩小达50％以上,完全缓解0例,部分缓解34例,稳定4例,进展2例,有效率为85．0％。治疗后患者吞咽困难有了较明显的改善,显效7例,有效31例,无效2例,总有效率95．0％。治疗后所有患者的卡氏评分均有所升高,与治疗前比较,差异有显著性意义（P〈0．05）,提示治疗后患者的生活质量有所改善。结论：开道散合扶正和胃合剂治疗上消化道癌性狭窄疗效满意,能使实体瘤缩小、吞咽困难改善、生活质量提高。     

Hymenoptera-venom-induced upregulation of the basophil activation marker ecto-nucleotide pyrophosphatase/phosphodiesterase 3 in sensitized individuals

BACKGROUND: Bee and wasp venoms are potent allergens capable of inducing severe clinical reactions. To detect immediate-type hypersensitivity to these allergens, a rapid in vitro test was developed that relies on the upregulation of ecto-nucleotide pyrophosphatase/phosphodiesterase 3 (E-NPP3) on activated basophils. METHODS: Blood basophils of 13 healthy donors and 22 patients allergic to bee or wasp venom were analyzed for E-NPP3 (CD203c) expression using monoclonal antibody 97A6. Basophils were analyzed by flow cytometry after activation with anti-IgE antibody or allergen. Venom-induced E-NPP3 upregulation on basophils was compared with diagnostic parameters, including skin tests and assessment of specific IgE. In selected samples, the increase in E-NPP3 expression on activated basophils was compared with histamine release and CD63 upregulation. RESULTS: In 20/22 patients sensitized to wasp or bee venom, E-NPP3 expression on basophils was upregulated in response to activation by allergen or anti-IgE. The maximum increase in E-NPP3 expression (above ten times of baseline) was achieved after 15 min of stimulation with 1 microg/ml of allergen or anti-IgE antibody. Sensitized individuals who failed to upregulate E-NPP3 in response to IgE receptor cross-linking also failed to induce histamine release and CD63 upregulation. CONCLUSIONS: Flow cytometric determination of hymenoptera-venom-induced upregulation of E-NPP3 is a novel in vitro test to identify sensitized individuals.     

Enzymic modification of a tyrosine residue to a stable free radical in ribonucleotide reductase.

Protein B2, a subunit of ribonucleotide reductase from Escherichia coli, contains in its active form a tyrosyl free radical as part of the polypeptide chain and a dimeric iron center that stabilizes the radical. The enzyme depends on this radical for its catalytic activity. Treatment with hydroxyurea scavenges the radical without disturbing the iron center and, thereby, results in an inactive form of the subunit, B2/HU. A second inactive form, apoB2, lacking both the radical and the iron center, is obtained by treatment of B2 with 8-hydroxyquinoline. Here we describe an enzyme activity in extracts from E. coli that transforms the catalytically inactive B2/HU form into the active B2 subunit by regeneration of the tyrosyl radical. This reaction requires the presence of oxygen, dithiothreitol, and Mg2+ and does not proceed through apoB2. Under anaerobic conditions, we obtained evidence for a second activity in the bacterial extract that destroys the free radical and transforms B2 into B2/HU. We suggest that this novel type of protein modification is functionally related to the synthesis of deoxyribonucleotides and DNA.     

Human MSH2 binds to trinucleotide repeat DNA structures associated with neurodegenerative diseases

The expansion of trinucleotide repeat sequences is associated with several neurodegenerative diseases. The mechanism of this expansion is unknown but may involve slipped-strand structures where adjacent rather than perfect complementary sequences of a trinucleotide repeat become paired. Here, we have studied the interaction of the human mismatch repair protein MSH2 with slipped-strand structures formed from a triplet repeat sequence in order to address the possible role of MSH2 in trinucleotide expansion. Genomic clones of the myotonic dystrophy locus containing disease-relevant lengths of (CTG)n x (CAG)n triplet repeats were examined. We have constructed two types of slipped-strand structures by annealing complementary strands of DNA containing: (i) equal numbers of trinucleotide repeats (homoduplex slipped structures or S-DNA) or (ii) different numbers of repeats (heteroduplex slipped intermediates or SI-DNA). SI-DNAs having an excess of either CTG or CAG repeats were structurally distinct and could be separated electrophoretically and studied individually. Using a band-shift assay, the MSH2 was shown to bind to both S-DNA and SI-DNA in a structure- specific manner. The affinity of MSH2 increased with the length of the repeat sequence. Furthermore, MSH2 bound preferentially to looped-out CAG repeat sequences, implicating a strand asymmetry in MSH2 recognition. Our results are consistent with the idea that MSH2 may participate in trinucleotide repeat expansion via its role in repair and/or recombination.