Danazol administration after gonadotrophin-releasing hormone analogue reduces rebound of uterine myomas [published erratum appears in Hum Reprod 1998 Mar;13(3):780]

We report the results of administration of danazol after suspension of gonadotrophin-releasing hormone analogue (GnRHa) therapy for uterine myomas. A total of 21 women with uterine myomas was treated with 100 mg danazol for 6 months after GnRHa therapy. Uterine volume and endocrine status were monitored monthly by ultrasound and assay of plasma gonadotrophins, oestradiol and progesterone. The results show a rebound of uterine volume about 30% less than in controls at the end of danazol therapy. Menstrual cyclicity returned after 65 +/- 3 days in 16 subjects and five patients remained amenorrhoeic. Hormone assays confirmed renewed ovarian function in the women whose menstrual periods returned. Bone mineral content was substantially reduced during GnRHa treatment but improved significantly during danazol therapy even in the women who remained amenorrhoeic. These results show the utility of danazol in prolonging the therapeutic effects of GnRHa. The mechanism by which danazol inhibits rebound of uterine volume may be due to its antiprogesterone effects on uterine myomas.      

Nucleoside analogues: 8. Some isomers of B.3839, the original 5-fluorouracil/nitrosourea molecular combination, and their effect on colon, breast and lung tumours in mice

This study describes the manipulation of secondary products arising from the synthesis of the prototypical molecular combination of 5-fluorouracil (5-FU) and chloroethylnitrosourea (CNU), B.3839, in order to investigate the effects produced by connecting the C-S-C-C-CNU chain to the 5-FU ring in different ways. The isolation of phthalimide precursors of these compounds and the transformation into CNUs is described. Anti-tumour activity of these molecular combinations against a series of experimental murine colon, lung and mammary tumours is presented. The spectrum of anti-tumour activity displayed is interesting but defies simple explanation without further detailed in vivo pharmacokinetic and metabolism studies in order to define optimal profiles for activity.     

Truncus Arteriosus With Patent Ductus Arteriosus and Normal Aortic Arch

In hearts with a common arterial trunk (truncus arteriosus), there is almost always an inverse development of the aortic arch and the ductus arteriosus. Truncus with a normal aortic arch and a patent ductus is a rare echocardiographic and surgical finding. In this report, we describe 2 neonates in whom truncus arteriosus with a normal aortic arch and a medium or large patent ductus was diagnosed by preoperative echocardiography (without catheterization) and confirmed intraoperatively.     

Characterization of antibody and selection of alternative drug therapy in hydrochlorothiazide-induced immune hemolytic anemia

The authors report the clinical and laboratory findings of a patient who had severe immune hemolytic anemia due to hydrochlorothiazide (HCTZ). In this case, the HCTZ antibody reacted not only with other thiazide and thiazide-like drugs, but also with a chemically unrelated diuretic, ethacrynic acid. These results indicate that HCTZ antibody activity is not restricted solely to the thiazides and imply that therapy with any of the reactive drugs would be contraindicated for this patient. The serologic screening for drug reactivity may be useful for selecting alternative therapy for patients with drug-induced immune hemolytic anemia.     

Nucleoside analogues. 4. Molecular combinations of anti-tumour drugs: synthesis of 5-fluorouracil seco-nucleosides with N-(2-chloroethyl)-N-nitrosourea residues by using aryl N-nitrosocarbamates

The biological study of molecular combination of anti-tumour drugs remains unexplored. Some drugs prepared earlier, seco-nucleosides with 5-fluorouracil as base and incorporating a N-(2-chloroethyl)-N-nitrosourea (CNU) residue in the linear 'sugar' moiety, have now been obtained much more readily by using aryl N-nitrosocarbamates. These include the more reactive S-oxide of the original combination, B 3839. The structure of a compound with the CNU in the 'alcohol' arm of the seco-nucleoside has been clarified. Isomeric combinations having hydroxyl groups in either the 'alcohol' or the 'aldehyde' arm, with different hydrolysis rates, have been synthesized. Results of anti-tumour testing are reported in the proceeding paper.     

Targeted gene disruption of murine CD7

CD7 is a 40 kDa type I transmembrane glycoprotein member of the Ig superfamily. CD7 is a marker of mature human T cells and NK cells, and is expressed early in their development. Cross-linking CD7 positively modulates T cell and NK cell activity as measured by calcium fluxes, expression of adhesion molecules, cytokine secretion and proliferation. CD7 associates directly with phosphoinositol 3'-kinase, and CD7 ligation induces production of D-3 phosphoinositides and tyrosine phosphorylation. Severe combined immunodeficiency has been associated with a lack of lymphocyte surface CD7. The CD7 ligand is unknown. The murine CD7 homolog is encoded by a single gene on chromosome 11. In order to characterize the role of CD7 in lymphocyte development and function we have eliminated the CD7 gene by targeted disruption. CD7- deficient mice display normal histology of thymus and spleen, normal lymphocyte populations in primary and secondary lymphoid tissues, and normal serum Ig levels. Specific antibody responses after immunization with T-dependent and T-independent antigens are equivalent in wild-type and CD7 knockout mice. CD7-deficient lymphocytes respond normally to T cell mitogenic and allogeneic stimuli, and display normal NK cell cytotoxicity.      

Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability

X-linked spinal and bulbar muscular atrophy (SBMA) is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene. Disease-associated alleles (37-66 CAGs) change in length when transmitted from parents to offspring, with a significantly greater tendency to shift size when inherited paternally. As transgenic mice carrying human AR cDNAs with 45 and 66 CAG repeats do not display repeat instability, we attempted to model trinucleotide repeat instability by generating transgenic mice with yeast artificial chromosomes (YACs) carrying AR CAG repeat expansions in their genomic context. Studies of independent lines of AR YAC transgenic mice with CAG 45 alleles reveal intergenerational instability at an overall rate of approximately 10%. We also find that the 45 CAG repeat tracts are significantly more unstable with maternal transmission and as the transmitting mother ages. Of all the CAG/CTG repeat transgenic mice produced to date the AR YAC CAG 45 mice are unstable with the smallest trinucleotide repeat mutations, suggesting that the length threshold for repeat instability in the mouse may be lowered by including the appropriate flanking human DNA sequences. By sequence-tagged site content analysis and long range mapping we determined that one unstable transgenic line has integrated an approximately 70 kb segment of the AR locus due to fragmentation of the AR YAC. Identification of the cis - acting elements that permit CAG tract instability and the trans -acting factors that modulate repeat instability in the AR YAC CAG 45 mice may provide insights into the molecular basis of trinucleotide repeat instability in humans.