Circulating immune complexes in Hodgkin's disease

Levels of circulating immune complexes (CIC) were estimated in the sera of 110 patients with Hodgkin's disease (HD) and of 103 normal subjects by polyethylene glycol precipitation method. Levels of CIC were significantly elevated in HD patients compared to normal subjects with 63% of the patients showing levels above 95th percentile of the normal. Patients with symptoms showed significantly elevated levels of CIC compared to patients without symptoms. There was a good correlation between the levels of CIC and the clinical stages, the former increasing from stage I to IV. However, no such correlation was noticed with respect to the histological type of the disease. On polyacrylamide gel electrophoresis CIC of normal subjects as well as of HD patients showed a number of protein bands. But CIC of HD patients had one additional band with approximate molecular weight of 130 000 which was absent in CIC of normal subjects.     

Early-outgrowth bone marrow cells attenuate renal injury and dysfunction via an antioxidant effect in a mouse model of type 2 diabetes

Cell therapy has been extensively investigated in heart disease but less so in the kidney. We considered whether cell therapy also might be useful in diabetic kidney disease. Cognizant of the likely need for autologous cell therapy in humans, we sought to assess the efficacy of donor cells derived from both healthy and diabetic animals. Eight-week-old db/db mice were randomized to receive a single intravenous injection of PBS or 0.5 × 10(6) early-outgrowth cells (EOCs) from db/m or db/db mice. Effects were assessed 4 weeks after cell infusion. Untreated db/db mice developed mesangial matrix expansion and tubular epithelial cell apoptosis in association with increased reactive oxygen species (ROS) and overexpression of thioredoxin interacting protein (TxnIP). Without affecting blood glucose or blood pressure, EOCs not only attenuated mesangial and peritubular matrix expansion, as well as tubular apoptosis, but also diminished ROS and TxnIP overexpression in the kidney of db/db mice. EOCs derived from both diabetic db/db and nondiabetic db/m mice were equally effective in ameliorating kidney injury and oxidative stress. The similarly beneficial effects of cells from healthy and diabetic donors highlight the potential of autologous cell therapy in the related clinical setting.     

Evidence of Gene-Gene Interaction and Age-at-Diagnosis Effects in Type 1 Diabetes

The common genetic loci that independently influence the risk of type 1 diabetes have largely been determined. Their interactions with age-at-diagnosis of type 1 diabetes, sex, or the major susceptibility locus, HLA class II, remain mostly unexplored. A large collection of more than 14,866 type 1 diabetes samples (6,750 British diabetic individuals and 8,116 affected family samples of European descent) were genotyped at 38 confirmed type 1 diabetes-associated non-HLA regions and used to test for interaction of association with age-at-diagnosis, sex, and HLA class II genotypes using regression models. The alleles that confer susceptibility to type 1 diabetes at interleukin-2 (IL-2), IL2/4q27 (rs2069763) and renalase, FAD-dependent amine oxidase (RNLS)/10q23.31 (rs10509540), were associated with a lower age-at-diagnosis (P = 4.6 × 10⁻⁶ and 2.5 × 10⁻⁵, respectively). For both loci, individuals carrying the susceptible homozygous genotype were, on average, 7.2 months younger at diagnosis than those carrying the protective homozygous genotypes. In addition to protein tyrosine phosphatase nonreceptor type 22 (PTPN22), evidence of statistical interaction between HLA class II genotypes and rs3087243 at cytotoxic T-lymphocyte antigen 4 (CTLA4)/2q33.2 was obtained (P = 7.90 × 10⁻⁵). No evidence of differential risk by sex was obtained at any loci (P ≥ 0.01). Statistical interaction effects can be detected in type 1 diabetes although they provide a relatively small contribution to our understanding of the familial clustering of the disease.Knowledge of the genetic architecture of type 1 diabetes has increased recently owing to large-scale genome-wide association (GWA) studies (1–3). Estimates of the contributions of the HLA region and numerous non-HLA loci across the genome now account for a sizeable proportion of familial clustering of the disorder (4–6). However, there remains substantial familial clustering that is not explained by the known loci (likely to be in excess of 40%) (4–6). Interactions between risk loci beyond that of a multiplicative model on the odds ratio (OR) scale (or additive on the log odds scale (7)) could account for some of the “missing heritability.” In addition, the existence of differential effects according to age-at-diagnosis and sex remains relatively unexplored.The HLA region on chromosome 6p21 is the major source of familial clustering in type 1 diabetes (4). HLA-DRB1 and HLA-DQB1 are associated with ORs in excess of 10 for susceptible genotypes (or less than 0.1 for protective genotypes) (8). The risk genotype HLA-DRB1*03/HLA-DRB1*04-HLA-DQB1*0302 (referred to as DR3/DR4-DQ302) with greatest effect has been shown to have the highest frequency in the individuals with youngest onset (9). An age-at-diagnosis interaction has also been reported for HLA-DRB1*04 (10) and the HLA class I alleles HLA-A*24 and HLA-B*39 (11,12).In contrast, reports of age-at-diagnosis interaction effects at non-HLA loci are contradictory, with positive reports largely confined to studies involving small sample sets (3,13–15). Similarly, reports of gene–gene interaction of type 1 diabetes–associated regions are also mainly conflicting (16–19), we presume due to inadequate sample sizes, with most positive reports likely to be false because the false-discovery rate would be high in these underpowered studies. The only convincing gene–gene interaction reported, is between a major non-HLA locus, protein tyrosine phosphatase nonreceptor type 22 (PTPN22) and DR3/DR4-DQ302 genotypes (20–23).The incidence of childhood type 1 diabetes is similar in males and females, unlike other autoimmune diseases such as Graves disease, celiac disease, or multiple sclerosis. Despite similar frequencies of childhood type 1 diabetes by sex, there have been reports of genetic risk factors differing between males and females (22,24).Given that most studies of gene–gene interaction, age-at-diagnosis effects, and sex effects on type 1 diabetes risk have not been addressed in sufficiently well-powered studies, the Type 1 Diabetes Genetics Consortium (T1DGC) has collected more than 16,000 type 1 diabetes–affected samples and tested them for interaction effects with sex and age-at-diagnosis at 38 non-HLA type 1 diabetes–associated regions (Supplementary Table 2). Gene–gene interaction was also tested between HLA class II and the 38 non-HLA loci. With this very large sample set, the study had at least 80% power to detect effects as small as an interaction OR = 1.12 for sex and 1.19 for interactions with age-at-diagnosis or HLA. These calculations assume a multiplicative (log additive) effects model, an OR = 1.15 for association with type 1 diabetes for the test locus and a minor allele frequency of 0.2 and α = 0.0004. In contrast, with 5,000 samples, which is twice as large as any other study testing for interaction effects in type 1 diabetes published to date, the study would only be powered at 80% to detect interaction effects larger than an OR = 1.3 with sex (with the same assumptions as above). For age-at-diagnosis interaction, an OR ≥ 1.37 could be detected; for HLA interaction, an OR ≥ 1.38 could be detected (Supplementary Figs. 1–6).     

Growth factors in chronic myelogenous leukemia

Transforming growth factors (TGFs) are implicated in malignancy, therefore qualitative and quantitative differences of these growth factors in chronic myelogenous leukemia (CML) in chronic phase has been investigated in this report. Induction of anchorage independent growth of BALB/c 3T3 and NRK-49F fibroblasts was used as an assay to detect TGF-beta activity in sera, serum free leukocyte and stromal conditioned medium of CML patients as well as normal subjects. The data shows that enhanced levels of transforming growth factor (type beta like activity) are detectable in the sera of chronic myelogenous leukemia patients. We believe that the enhanced levels of TGF-beta type activity may have a role in myeloid hyperplasia characteristic of CML patients in chronic phase of the disease.     

Abrogation of human chronic myeloid leukemia cells insensitivity to adriamycin and mitoxanthrone cytotoxicity by quinidine

The inherent, insensitive nature of human chronic myeloid leukemia (CML) cells to antiproliferative effects of adriamycin (ADR) disallows its utility in the clinics. Efforts were directed towards sensitizing CML cells to ADR and mitoxanthrone (MITO) cytotoxicity by employing quinidine, an antiarhythmic agent. Inhibition of radiolabeled thymidine incorporation into DNA was used as a measure of drug activity. A dose-dependent inhibition of DNA biosynthesis was observed with increasing concentrations of ADR (0.1 to 100 micrograms/ml), MITO (0.05 to 5 micrograms/ml) and quinidine (0.1 to 50 mumol/l). When the CML cells were exposed to quinidine and ADR/MITO simultaneously, the observed enhancement in the antiproliferative activity of the anticancer drug was markedly less as compared to the inhibition of DNA synthesis observed in CML cells pretreated with quinidine for 1 h prior to exposure to the cytotoxic drugs. Pretreatment of CML cells with quinidine resulted in a significantly (p less than 0.001) increased synergistic inhibition of DNA biosynthesis which was completely irreversible. Results highlight the utility of quinidine as a drug response modulator in a schedule-dependent manner to potentiate the cytotoxicity of ADR and MITO and warrants further studies into a possible role of quinidine to increase the chemotherapeutic efficacy of antineoplastic drugs in the clinics.     

Pattern of subtypes of acute lymphoblastic leukemia in India

Leukemic cells from 124 acute lymphoblastic leukemia (ALL) and 31 chronic lymphatic leukemia (CLL) were examined for sheep erythrocyte receptor (E), surface immunoglobulin (SIg) and their reactivity with a panel of monoclonal antibodies recognizing specific surface antigens including pan-T, Common ALL and Ia antigens. In acute lymphatic leukemia, 33% of patients reveal T-cell receptor associated with higher age group, mediastinal mass and high WBC count. Common ALL was predominant between 2 and 9-yr age group. Among chronic lymphatic leukemia, 2 patients were found to be T-CLL while 29 revealed presence of SIg. Ia antigen was detected in 44.4% of ALL and 64% fo CLL patients. The pattern of surface marker observed in our series may be related to our life style, socio-economic and environmental factors.