The A-chain of insulin is a hot-spot for CD4+ T cell epitopes in human type 1 diabetes.

Type 1 diabetes (T1D) is caused by T cell-mediated destruction of the pancreatic insulin-producing beta cells. While the role of CD4(+) T cells in the pathogenesis of T1D is accepted widely, the epitopes recognized by pathogenic human CD4(+) T cells remain poorly defined. None the less, responses to the N-terminal region of the insulin A-chain have been described. Human CD4(+) T cells from the pancreatic lymph nodes of subjects with T1D respond to the first 15 amino acids of the insulin A-chain. We identified a human leucocyte antigen-DR4-restricted epitope comprising the first 13 amino acids of the insulin A-chain (A1-13), dependent upon generation of a vicinal disulphide bond between adjacent cysteines (A6-A7). Here we describe the analysis of a CD4(+) T cell clone, isolated from a subject with T1D, which recognizes a new HLR-DR4-restricted epitope (KRGIVEQCCTSICS) that overlaps the insulin A1-13 epitope. This is a novel epitope, because the clone responds to proinsulin but not to insulin, T cell recognition requires the last two residues of the C-peptide (Lys, Arg) and recognition does not depend upon a vicinal disulphide bond between the A6 and A7 cysteines. The finding of a further CD4(+) T cell epitope in the N-terminal A-chain region of human insulin underscores the importance of this region as a target of CD4(+) T cell responses in human T1D.

A fatal case of phlegmonous colitis in chronic hepatitis C receiving combination interferon and ribavirin therapy.

Phlegmonous colitis is an acute suppurative infection of the large bowel that is rarely described, rapidly fatal and often escapes clinical attention. Patients with chronic hepatic diseases appear to be predisposed to this condition. We report a novel case of fatal phlegmonous colitis in a cirrhotic patient receiving combination pegylated interferon and ribavirin for chronic hepatitis C, highlighting the importance of early recognition of this aggressive infectious entity.

PU.1 cooperates with IRF4 and IRF8 to suppress pre-B-cell leukemia.

The Ets family transcription factor PU.1 and the interferon regulatory factor (IRF)4 and IRF8 regulate gene expression by binding to composite DNA sequences known as Ets/interferon consensus elements. Although all three factors are expressed from the onset of B-cell development, single deficiency of these factors in B-cell progenitors only mildly impacts on bone marrow B lymphopoiesis. Here we tested whether PU.1 cooperates with IRF factors in regulating early B-cell development. Lack of PU.1 and IRF4 resulted in a partial block in development the pre-B-cell stage. The combined deletion of PU.1 and IRF8 reduced recirculating B-cell numbers. Strikingly, all PU.1/IRF4 and ~50% of PU.1/IRF8 double deficient mice developed pre-B-cell acute lymphoblastic leukemia (B-ALL) associated with reduced expression of the established B-lineage tumor suppressor genes, Ikaros and Spi-B. These genes are directly regulated by PU.1/IRF4/IRF8, and restoration of Ikaros or Spi-B expression inhibited leukemic cell growth. In summary, we demonstrate that PU.1, IRF4 and IRF8 cooperate to regulate early B-cell development and to prevent pre-B-ALL formation.

[Synthesis and biological activity of tyrosine protein kinase inhibitors].

Four classes of 25 tyrosine protein kinase (TPK) inhibitors were designed and synthesized. Compounds 1-10 were tested to inhibit TPK of HL-60 leukemia cell using 32P-ATP method, and some of them exhibit evident inhibitory activities. Their structure-activity relationship is similar to that of TPK inhibitors reported in literatures. Compounds 11-25 were tested to inhibit TPK of normal rat spleen cell using ELISA method and their SAR is different from that using 32P-ATP method.

[Dot-ELISA in the diagnosis of neurocysticercosis].

The dot-enzyme-linked immunosorbent assay was used to detect Cysticercus cellulosae antibodies in sera of patients with neurocysticercosis. Among 108 confirmed cases of neurocysticercosis 81.6-96.1% showed positive reactions. Two out of 54 normal control sera reacted at a serum dilution of 1:20, but none at a 1:40 (range 40-640). No cross reactions were observed with sera from cases of paragonimiasis and clonorchiasis, but it did occur to some extent with sera from cases of echinococcosis and cerebrovascular diseases. The results indicated that the dot-ELISA was sensitive, specific and economic for the diagnosis of neurocysticercosis.

Development and validation of a disease-specific quality of life questionnaire for gastro-oesophageal reflux disease: the GERD-QOL questionnaire.

BACKGROUND: A simple and meaningful health-related quality of life (HRQoL) questionnaire for gastro-oesophageal reflux disease (GERD) patients is lacking. AIM: To develop and validate a disease-specific HRQoL instrument (GERD-QOL) for GERD patients. METHODS: An 18-item questionnaire was generated to measure the impact of GERD on sleep, exercise, diet, need for medication, sex life, work, social activity and psychological well-being. GERD patients were invited to complete the GERD-QOL, a visual analogue scale (VAS) and a validated Chinese generic QoL (SF-36) questionnaire before and after esomeprazole treatment. Factor analysis was performed for item selection and psychometric properties were measured. An English version was developed by a forward-backward translation process. RESULTS: A final 16-item GERD-QOL questionnaire was developed. The items were grouped into four subscales (Daily activity, Treatment effect, Diet, and Psychological well-being) after factor analysis. GERD-QOL had good item-internal consistency (Cronbach's alpha: 0.64-0.88), high test-retest reliability (intraclass correlation coefficient: 0.73-0.94, P < 0.001). Its subscale scores were correlated with SF-36 and VAS, which demonstrated high construct validity (P < 0.001). Discriminant validity was verified by correlating GERD-QOL scores with symptom severity (P < 0.001). Responsiveness after esomeprazole treatment was significant (paired-t-test P < 0.001). An English version of GERD-QOL was developed. CONCLUSION: The instrument, GERD-QOL, is valid and reliable.

Milk clotting activity in bovine fetal abomasa.

Abomasa (vells) were removed from 30 fetal calves at each of the 6th, 7th, 8th, and 9th mo of development. Milk clotting enzymes were exhaustively extracted in 10% NaCl solutions from the dried abomasal tissue. Total enzyme activity at each stage of fetal development was compared with that from abomasa of 3 to 5-day-old milk-fed calves. Enzyme activity was present in the abomasa of bovine fetuses as early as the 6th mo of development and increased as the fetuses approached full term. Average activity recovered from fetal vells at the 6th, 7th, 8th, and 9th mo of development represented 2, 7, 12, and 31% of the activity per vell, and 8, 14, 22, and 38% of the activity per unit vell weight, of that recovered from high quality calf vells. Diffusion patterns on casein-agar gels produced by bovine fetal extracts differed from those produced by commercial calf rennet extract or porcine pepsin.