A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides

Mycosis fungoides is a T-cell lymphoma that arises in the skin and progresses at highly variable rates. Nonradomized studies have suggested that early aggressive therapy may improve the prognosis in this usually fatal disease. We studied 103 patients with mycosis fungoides, who, after complete staging, were randomly assigned to receive either combination therapy, consisting of 3000 cGy of electron-beam radiation to the skin combined with parenteral chemotherapy with cyclophosphamide, doxorubicin, etoposide, and vincristine (n = 52) or sequential topical treatment (n = 51). The prognostic factors were well balanced in the two groups. Combined therapy produced considerable toxicity: 12 patients required hospitalization for fever and transient neutropenia, 5 had congestive heart failure, and 2 were later found to have acute nonlymphocytic leukemia. Patients receiving combined therapy had a significantly higher rate of complete response, documented by biopsy, than patients receiving conservative therapy (38 percent vs. 18 percent; P = 0.032). After a median follow-up of 75 months, however, there was no significant difference between the treatment groups in disease-free or overall survival. We conclude that early aggressive therapy with radiation and chemotherapy does not improve the prognosis for patients with mycosis fungoides as compared with conservative treatment beginning with sequential topical therapies.     

Insulin-dependent diabetes mellitus and the major histocompatibility complex peptide transporters TAP1 and TAP2: no association in a population with a high disease incidence

Abstract: Although many studies have established an association between insulin-dependent diabetes mellitus (IDDM) and the class II region of the human major histocompatibility complex (MHC), it has been difficult to assign susceptibility to a single locus. Recently, two antigen-processing genes, TAP1 and TAP2 , have been identified within the region. Previous studies have reached conflicting conclusions as to the role of these genes in IDDM; it is uncertain whether an increased frequency of the allele TAP2A and a concomitant decrease in TAP2B are independent disease associations or secondary to linkage disequilibrium (LD) between TAP2A and HLA-DR3 . To further investigate this question, we have characterized TAP1 and TAP2 alleles in 129 IDDM patients from Sardinia, a population with limited genetic heterogeneity and a high disease incidence. When compared to 90 random controls, the only significant difference was a decrease in the minor allele TAP2C in patients. However, when HLA-DR and - DQ matched controls were compared, this difference disappeared. Further analysis suggested that TAP2C was in LD with HLA-DRB1*1401 and subtypes of HLA-DRB1*11 , alleles which were not observed in the IDDM population. LD was also observed between other TAP and HLA-DR alleles, in particular between TAP2A and HLA-DR3 in both patients and controls. Our data supports the conclusion that there is no primary association between TAP2 alleles and IDDM, and that previously reported associations may be due to LD with other class II loci.     

Females experiencing sexual and drug vulnerabilities are at elevated risk for HIV infection among youth who use injection drugs

OBJECTIVES: To compare sociodemographic, drug-related, and sexual risk variables between young (13-24 years of age) and older (> or =25 years of age) injection drug users (IDUs); and to determine HIV prevalence and associated risk factors for HIV infection among young IDUs. METHODS: Data were collected through the Vancouver Injection Drug Users Study (VIDUS). To date, over 1400 Vancouver area IDUs have been enrolled and observed during follow-up. Sociodemographic, drug-related, and sexual risk variables were compared between younger and older IDUs using nonparametric methods. Mantel-Haenszel and logistic regression methods were used to compare HIV-positive and HIV-negative female youth. RESULTS: Younger injectors (N = 232) were more likely to be female; work in the sex trade; report condom use; inject heroin daily; smoke crack cocaine daily; and need help injecting. HIV prevalence at baseline among the youth was 10%. HIV prevalence was associated with female gender; history of sexual abuse; engaging in survival sex; injecting heroin daily; injecting speedballs (a mixture of heroin and cocaine) daily; and having numerous lifetime sexual partners. CONCLUSION: Our data show that HIV positivity among young IDUs is concentrated among females engaged in dual sexual and drug-related risk exposure categories. Over half the HIV-positive youth were Aboriginal (a classification used by the federal government in Canada to include native peoples of all ethnic groups). Targeted interventions that take into account sexual and drug risk for young female and Aboriginal peoples are urgently needed.     

Mapping of gene loci in the Q13–Q15 region of chromosome 12

The gene loci CDK4, GLI, CHOP and MDM2 have been mapped to the q13–q15 region of chromosome 12. Using fluorescencein situ hybridization onto simultaneously DAPI-banded metaphase chromosomes and interphase nuclei, we have more precisely mapped and ordered these loci, together with a number of Genethon microsatellite markers. GLI and CHOP localize to 12q13.3–14.1, CDK4 to 12q14 and MDM2 to 12q14.3–q15, and the gene order is cen-GLI/CHOP-CDK4-MDM2. The Genethon microsatellites D12S80 and D12S83 flank MDM2.     

"Tissue" transglutaminase in AIDS

Apoptosis or programmed cell death (PCD) is an active process of cellular self-destruction, essential for embryonic development and maintenance of homeostasis of multicellular organisms. Programmed cell death induction can serve as a defence mechanism of the host against intracellular microbes. Virus infections trigger host cell apoptosis, which can either limit virus production or contribute directly to viral pathogenesis.Several independent laboratories have identified "tissue" transglutaminase (tTG) as a potentially important player of the cell death program(s). This gene is specifically expressed in cells dying during mammalian development as well as in those undergoing apoptosis in various patho-physiological and experimental settings [Eur. J. Cell Biol. 56 (1991) 170; Piacentini, M., Davies, P.J.A., Fesus, L., 1994. Tissue transglutaminase in cells undergoing apoptosis. In: Tomei, L.D., Cope, F.O. (Eds.), Apoptosis II: The molecular basis of apoptosis in disease. Cold Spring Harbor Lab. Press, pp. 143-165.]. This chapter reviews recent studies concerning the expression and the possible role of "tissue" transglutaminase (tTG) in apoptotic cells; particular emphasis is given to its expression in the cell death pathways associated with HIV infection in the immune system.We propose here that the induction of the tTG gene in cells of the immune system, as well as the detection of the isodipeptide epsilon(gamma-glutamyl)lysine in plasma, are useful markers of apoptosis and might make it possible to monitor disease progression in HIV-infected individuals.     

Serological analysis of B6.C-H-2bm12 (I-A mutant)

The B6.C-H-2bm12 has been examined serologically with a new set of reagents and several complementation studies were performed to determine the extent of the mutation. The results show that: (a) the mutation has also affected the site(s) bound by xenogeneic anti-Ia antibodies; (b) the IJb region was not affected; (c) complementation studies with stains bearing a, b, d, k and s haplotypes did not complement bm12 for the expression of the lost I-Ab specificities, suggesting a structural (rather than regulatory) gene alteration in bm12; (d) H-2 haplotypes b and bm12 could complement d to establish the Ia.22 specificity, indicating that Ia-1 and Ae are separate genes in the I-A subregion. In addition, an antibody to the gained specificity on bm12 is described.     

The enigma of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic cholestatic disease characterized by a striking predominance in female patients (with most cases diagnosed between ages 40 and 60 yr) as well as serum auto-antibodies to mitochondrial antigens, elevated serum immunoglobulin M, progressive destruction of intrahepatic bile ducts, and, ultimately, liver cirrhosis and failure (1). The precise mechanisms leading to selective destruction of biliary epithelial cells lining intrahepatic bile ducts are still unknown, although numerous immunomediated pathways have been proposed. Genetic background appears to be important in determining susceptibility to the disease (2), but no clear association with alleles in the major histocompatibility complex has been identified. Molecular mimicry either by infections (3) or xenobiotics (4) has been proposed to be capable of breaking tolerance in genetically predisposed individuals, thus leading to onset of PBC. This article describes and discusses the available data regarding the immunomediated pathogenesis of PBC (with particular attention to auto-antibodies and autoreactive T-cells) and presents the recent evidence indicating a role for either xenobiotic chemicals or novel infectious agents in the induction of the disease.     

Platelet-activating factor receptor deficiency delays elimination of adult worms but reduces fecundity in Strongyloides venezuelensis-infected mice

We describe the parasitological kinetics and histopathological and immunological alterations in platelet-activating factor receptor-deficient (PAFR(-/-)) and wild-type mice after a single Strongyloides venezuelensis infection (subcutaneous inoculation of 500 L3 larvae). There was no difference in the numbers of worms that reached and became established in the small intestines of PAFR(-/-) and wild-type mice. However, at 12 days after infection, significantly more worms were recovered from PAFR(-/-) mice. Although PAFR(-/-) infected mice showed a delay in elimination of adult worms, worms established in the small intestine of these mice produced a significantly lower number of eggs due to a reduction in worm fecundity. There were also significant reductions in the number of circulating and tissue eosinophils and tumor necrosis factor levels in the small intestines of PAFR(-/-) mice infected for 7 days compared to the number and level in wild-type mice. Histological analysis confirmed the reduced inflammatory process and revealed that the PAFR(-/-) mice had a smaller number of goblet cells. The concentrations of the type 2 cytokines interleukin-4 (IL-4), IL-5, and IL-10 were lower in small intestine homogenates and in supernatants of antigen-stimulated lymphocytes from spleens or mesenteric lymph nodes of PAFR(-/-) mice than in the corresponding preparations from wild-type mice. Thus, in S. venezuelensis-infected PAFR(-/-) mice, decreased intestinal inflammation is associated with enhanced worm survival but decreased fecundity. We suggest that although a Th2-predominant inflammatory response decreases worm survival, the worm may use factors produced during this response to facilitate egg output and reproduction. PAFR-mediated responses appear to modulate these host-derived signals that are important for worm fecundity.