Frequent ongoing T-cell receptor rearrangements in childhood B- precursor acute lymphoblastic leukemia: implications for monitoring minimal residual disease

Crosslineage T-cell receptor delta (TCR delta) rearrangements are widely used as tumor markers for the follow up of minimal residual disease in childhood B-precursor acute lymphoblastic leukemia (ALL) by polymerase chain reaction (PCR). The major drawback of this approach is the risk of false-negative results due to clonal evolution. We investigated the stability of V delta 2D delta 3 rearrangements in a group of 56 childhood B-precursor ALL patients by PCR and Southern blot analysis. At the PCR level, V delta 2D delta 3-to-J alpha rearranged subclones (one pathway for secondary TCR delta recombination) were demonstrated in 85.2% of V delta 2D delta 3-positive patients tested, which showed that small subclones are present in the large majority of patients despite apparently monoclonal TCR delta Southern blot patterns. Sequence analysis of V delta 2D delta 3J alpha rearrangements showed a biased J alpha gene usage, with HAPO5 and J alpha F in 26 of 32 and 6 of 32 clones, respectively. Comparison of V delta 2D delta 3 rearrangement status between diagnosis and first relapse showed differences in seven of eight patients studied. In contrast, from first relapse onward, no clonal changes were observed in six patients studied. To investigate the occurrence of crosslineage TCR delta rearrangements in normal B and T cells, fluorescence-activated cell sorter-sorted peripheral blood CD19+/CD3- and CD19-/CD3+ cell populations from three healthy donors were analyzed. V delta 2D delta 3 rearrangements were detected at low frequencies in both B and T cells, which suggests that V delta 2-to-D delta 3 joining also occurs during normal B-cell differentiation. A model for crosslineage TCR delta rearrangements in B-precursor ALL is deduced that explains the observed clonal changes between diagnosis and relapse and is compatible with multistep leukemogenesis of B-precursor ALL.     

Use of porcine factor VIII in the treatment of patients with acquired hemophilia

Data have been collected from 47 centers in Europe and North America on the treatment with porcine factor VIII concentrate of 74 acute bleeding episodes in 65 patients with acquired hemophilia. The median initial anti-human factor VIII auto-antibody inhibitor level was 38 Bethesda unit (BU)/mL (range 1.2 to 1,024) whereas that against porcine was 1 BU/mL (range 0 to 15). The mean initial dose of porcine factor VIII infused was 84 IU/kg, which increased the plasma factor VIII:C activity by 0.85 IU/mL. Therapy was continued for a mean of 8.5 days during which time the average number of infusions was 11. Objective clinical responses were rated as good or excellent in 78% of recipients. Side effects were uncommon; only one patient experienced a severe anaphylactic reaction necessitating the discontinuation of porcine FVIII therapy. After therapy, no increase in the median level of anti- human FVIII or anti-porcine antibody was noted in the group as a whole, although 13 patients showed individual increases in either anti-human or anti-porcine antibody levels or both of more than 10 BU/mL. Of the 7 patients who subsequently rebled, 5 were successfully re-treated and 2 did not respond to further porcine factor VIII treatment. Porcine factor VIII is safe and clinically effective treatment for bleeding episodes associated with acquired hemophilia and should be considered as first-line therapy for patients whose acquired anti-factor VIII:C antibody cross-reacts with porcine factor VIII:C at low levels.     

Osteoprotegerin: A novel biomarker for inflammatory bowel disease and gastrointestinal carcinoma

Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor superfamily of proteins. Although initial data illustrated the key role that OPG plays in bone turnover, numerous recent reports indicate that OPG is also an important factor in inflammatory pathways and tumor cell survival. OPG contributes directly to inflammatory processes and has been evaluated as a novel non‐invasive biomarker of gut inflammation. Furthermore, OPG affects cell turn‐over, differentiation, death, and survival via extracellular pathways, correlating with worse prognosis in inflammatory bowel diseases and several gastrointestinal carcinomas. It is now clear that OPG has multiple functions and characteristics. This review gives an overview of OPG, highlights its roles in different extracellular pathways, and outlines how OPG could be used as a novel non‐invasive biological marker in inflammatory bowel diseases and gastrointestinal carcinomas.     

Association of TAP1/TAP2 gene polymorphism with inflammatory urogenital diseases combined with joint diseases

AIM: To study association of TAP1/TAP2 gene polymorphism with urogenital infections combined with joint lesions. MATERIALS AND METHODS: Of 139 patients examined 45 ones had inflammation caused by Chlamydia trachomatis (17 had joint disease), 42 had Mycoplasma hominis infection (joint lesions in 17 cases). Method of amplification was used on the basis of specific primers (ARMS). RESULTS: Patients infected with C. trachomatis significantly more frequently had allele TAP1-02011 and TAP2-0201 (RR = 18.5, p < 0.01 and RR = 4.61, p < 0.05, respectively). Joint lesion in patients with chlamydial infection was associated with allele TAP1-02011 (RR = 11.92, p < 0.05). In mycoplasmosis association with joint lesions there is a significant link of joint syndrome with heterogeneous combination threonine/alanine in gene TAP2 position 565 (RR = 4.22, p < 0.05). CONCLUSION: The findings can be used for predicting the joint syndrome development in patients with urogenital infection.     

Experimental Investigation of the Pharmacokinetics of Nibentan

Pharmaceutical Chemistry Journal -     

Gene Probe Analysis in an Informative Family with Multiple Endocrine Neoplasia Syndrome Type 2A (MEN 2A). Improvement in Carrier Risk Estimation

Gene probe analysis of the MEN 2A locus on chromosome 10 hasbeen undertaken using the markers TB10.163, RBP 3 and TB14.34in a large kindred with familial medullary thyroid carcinomas,with or without phaeochromocytomas or primary hyperparathyroidism.A maximum LOD score of 2.97 gave strong evidence of close linkagewith zero recombination. For 12 members of the family so far not known to be affectedby any form of the disease the estimated risk of carrying thegene has been considerably decreased in all but one, whose riskhas been greatly increased.