Multiple myeloma: evolving genetic events and host interactions

Multiple myeloma is a neoplasm of terminally differentiated B cells (plasma cells) in which chromosome translocations frequently place oncogenes under the control of immunoglobulin enhancers. Unlike most haematopoietic cancers, multiple myeloma often has complex chromosomal abnormalities that are reminiscent of epithelial tumours. What causes full-blown myeloma? And can our molecular understanding of this common haematological malignancy be used to develop effective preventive and treatment strategies?     

Effects of statins on human cerebral cholesterol metabolism and secretion of Alzheimer amyloid peptide

Cerebral cholesterol metabolism has been linked with production of amyloid peptide (Abeta) crucial in AD. The association between use of cholesterol-lowering drugs (statins) and AD disease is currently being intensely discussed. In this case-control study on elderly nondemented subjects, the authors provide the first evidence that statins in clinically relevant dosages indeed affect cerebral cholesterol metabolism. However, these changes were not associated with altered intrathecal secretion of Alzheimer Abeta.     

The papanicolaou smear: inadequate screening test for bacterial vaginosis during pregnancy

OBJECTIVE: Our purpose was to evaluate the ability of the Papanicolaou smear to identify bacterial vaginosis in comparison with the Amsel clinical criteria. STUDY DESIGN: We retrospectively identified 159 pregnant women screened for bacterial vaginosis with the Amsel criteria who had a contemporaneous Papanicolaou smear and negative results on screening for Chlamydia trachomatis and Neisseria gonorrhoeae. Bacterial vaginosis was identified in 45 women. We used the McNemar chi(2) test to determine discrepancies between the two screening methods for the detection of bacterial vaginosis. RESULTS: Compared with the Amsel criteria, the sensitivity and specificity of the Papanicolaou smear for yielding a diagnosis of bacterial vaginosis were 49% (95% confidence interval, 36%-64%) and 93% (95% confidence interval, 86%-97%), respectively, with a positive predictive value of 73% and a negative predictive value of 82%. The detection of bacterial vaginosis by Papanicolaou smear was significantly different from that by Amsel criteria (P =. 01). CONCLUSION: The Papanicolaou smear is not a reliable screening test for bacterial vaginosis during pregnancy.     

Sensitivity of Escherichia coli (MutT) and human (MTH1) 8-oxo-dGTPases to in vitro inhibition by the carcinogenic metals, nickel(II), copper(II), cobalt(II) and cadmium(II)

The toxicity of Ni(II), Co(II) and Cu(II) in animals, and that of Cd(II) in cultured cells, has been associated with generation of the promutagenic lesion 8-oxo-7,8-dihydroguanine (8-oxoguanine) in DNA, among other effects. One possible source of this base may be 8-oxo-7,8- dihydro-2'-deoxyguanosine-5'-triphosphate (8-oxo-dGTP), a product of oxidative damage to the nucleotide pool, from which it is incorporated into DNA. To promote such incorporation, the metals would have to inhibit specific cellular 8-oxo-dGTPases that eliminate 8-oxo-dGTP from the nucleotide pool. The present study was designed to test such inhibition in vitro on 8-oxo-dGTPases from two different species, the human MTH1 protein and Escherichia coli MutT protein. In the presence of Mg(II), the natural activator of 8-oxo-dGTPases, all four metals were found to inhibit both enzymes. For MTH1, the IC50 values (+/- SE; n = 3-4) were 17 +/- 2 microM for Cu(II), 30 +/- 8 microM for Cd(II), 376 +/- 71 microM for Co(II) and 801 +/- 97 microM for Ni(II). For MutT, they were 60 +/- 6 microM for Cd(II), 102 +/- 8 microM for Cu(II), 1461 +/- 96 microM for Ni(II) and 8788 +/- 1003 microM for Co(II). Thus, Cu(II) and Cd(II) emerged as much stronger inhibitors than Ni(II) and Co(II), and MTH1 appeared to be generally more sensitive to metal inhibition than MutT. Interestingly, in the absence of Mg(II), the activity of the enzymes could be restored by Co(II) to 73% of that with Mg(II) alone for MutT, and 34% for MTH1, the other metals being much less or non-effective. The difference in sensitivity to metal inhibition between the two enzymes may reflect the differences in the amino acid ligands, especially the cysteine ligand, outside their evolutionarily conserved Mg(II)-binding active sites, which might indicate predominantly non-competitive or uncompetitive mechanism of the inhibition. The overall results suggest that inhibition of 8-oxo- dGTPases may be involved in the mechanisms of induction of the 8- oxoguanine lesion in DNA by the metal ions studied, especially the non- redox-active Cd(II) cation.      

Localized muscular mucormycosis in a child with acute leukemia

Mucormycosis is a rare fungal infection of childhood, occurring mainly in patients with chronic illnesses such as diabetes and malignancies. The fungus seldom grows in culture and confirmation of the diagnosis depends on histologic examination of infected tissues. To date, the reported natural history of the disease has been rapid progression and a fatal outcome. Therefore, the importance of early diagnosis by tissue biopsy and early treatment with surgical debridement and systemic antifungal therapy cannot be overemphasized. The pulmonary system is the most common site for mucormycosis in patients with leukemia. We report what we believe to be the first successfully treated case of isolated muscular mucormycosis occurring in a child with biphenotypic acute leukemia. The diagnosis was made promptly by tissue examination at the time of surgical debridement. The patient was also given systemic amphotericin-B therapy.      

In utero bone marrow transplantation of fetal baboons with mismatched adult marrow: initial observations

Recent advances in prenatal diagnoses of sickle cell anemia and thalassemia permit early identification of affected fetuses. However, the only intervention possible to date is abortion of the affected fetuses. Transplantation of normal marrow into fetuses in utero could correct these life-threatening disorders, but to accomplish this techniques must be developed for fetal transplantation in man. Therefore, we have transplanted fetal baboons with mismatched adult baboon bone marrow from donors that differed at the glucose phosphate isomerase locus. Twenty-two fetuses between 60 and 160 days of gestation (term gestation is 182 days) were transplanted intraperitoneally with 10(9) marrow mononuclear cells/kg body weight using an ultrasonic technique. No immunosuppressive or preparative regimen was given prior to or after transplantation, and all fetuses tolerated the procedure well. One month after transplantation fetal blood samples were obtained to assess chimerism. Three chimeras were detected among 10 fetuses transplanted at 80 days' gestation, and no chimeras were detected in fetuses greater than 80 days' gestation at the time of transplantation. All chimeras died in utero during the third trimester of pregnancy: one of an intrauterine infection at 160 days' gestation, one at 135 days' gestation and one at 145 days' gestation. In contrast, the other 19 non-chimeric fetuses survived. These data suggest: (1) in utero fetal bone marrow transplantation is technically feasible in primates; (2) that allogeneic adult bone marrow can engraft and persist for at least 1 month in fetal baboons transplanted at 80 days of gestation; and (3) that delineation of the causes for loss of fetal chimeras should prove valuable in assessing the therapeutic potential for in utero bone marrow transplantation in man.