The nutritional management of type 3c (pancreatogenic) diabetes in chronic pancreatitis.

Type 3c diabetes mellitus (T3cDM), also known as pancreatogenic diabetes, refers to diabetes caused by disease of the exocrine pancreas. T3cDM is not commonly recognised by clinicians and frequently it is misclassified as T1DM, or more commonly, T2DM. T3cDM can be difficult to distinguish from T1DM and T2DM, and it often co-exists with the latter. The aim of this review is to describe T3cDM, along with its complications, diagnosis and management. We focus on the nutritional implications of T3cDM for those with chronic pancreatitis, and provide a practical guide to the nutritional management of this condition.

Product quality control testing for the oral polio vaccine.

A brief overview regarding the quality control testing of the Sabin oral polio vaccine is provided. Product testing procedures and specifications are established through product license agreements between the vaccine manufacturer and the FDA Center for Biologics Evaluation and Research. The manufacture and testing of ORIMUNE is a multi-stage process that is closely monitored by the FDA following explicit protocols and requires extensive quality control testing at various stages.

CD8+ T cell-mediated suppression of HIV long terminal repeat-driven gene expression is not associated with improved clinical status.

OBJECTIVES: To determine the associations between the suppression of HIV-1 long terminal repeat (LTR)-mediated gene expression by CD8+ T-cell supernatants and clinical correlates of well-being, including CD4+ and CD8+ T-cell counts, beta-chemokine production and clinical stage of disease. METHODS: Culture supernatants of activated CD8+ T cells derived from a panel of HIV-1-infected subjects were assessed for their ability to suppress HIV-1 LTR-mediated chloramphenicol acetyl transferase (CAT) expression. The percentage suppression of gene expression was correlated with CD4+ and CD8+ T-cell counts and clinical stage of infection. Some individuals within this group were followed at 2-3 month intervals over time to assess the consistency of the suppression. Selected CD8+ T-cell culture supernatants of diverse suppressive ability were screened for the levels of the beta-chemokines macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta and RANTES. RESULTS: The ability of CD8+ T cells of HIV-1 infected subjects to suppress HIV-1 LTR-mediated gene expression did not show a dependence upon high CD4+ T-cell counts or on the clinical stage or duration of infection. The ability to suppress gene expression did show a relationship with higher CD8+ T-cell counts and correlated with the levels of beta-chemokines in the culture supernatants. In contrast, strong suppression was mediated by CD8+ T-cell supernatants from some subjects with very low CD8+ T-cell counts and relatively low chemokine levels. CONCLUSIONS: Although the suppression of gene expression by CD8+ T-cell culture supernatants showed statistical correlation with beta-chemokine levels and with higher CD8+ T-cell count, no correlation could be found with correlates of clinical well-being.

Biochemical correlates of responsiveness and collateral sensitivity of some methotrexate-resistant murine tumors to the lipophilic antifolate, metoprine.

The M5076 murine "ovarian" tumor which is naturally refractive to methotrexate was found to be highly responsive to the lipophilic antifolate, metoprine. M5076 cells were markedly deficient in mediated entry of methotrexate. This was in contrast to the L1210 leukemia, a tumor highly responsive to methotrexate but poorly responsive to metoprine. Two L1210 leukemia sublines, with acquired resistance to methotrexate by virtue of a deficiency in mediated entry of drug similar to that seen for M5076 cells, were found to be collaterally sensitive to metoprine. The insensitivity to methotrexate of the M5076 tumor and the two L1210 sublines is associated with low saturability (high Km) and reduced capacity (low Vmax) for mediated influx of drug. 5-Methyltetrahydrofolate, the major circulating folate in blood but not metoprine, shares this mediated route for entry. Therefore, a relatively low level of accumulation of this natural folate in these methotrexate-resistant tumors, in the face of a metoprine-induced blockade at the level of dihydrofolate reductase, probably accounts for the high sensitivity of these tumors to this lipophilic agent. Evidence for this notion was derived during transport and growth experiments in vitro using 5-formyltetrahydrofolate as a model folate coenzyme. The value for influx Vmax of this folate compound in a transport-deficient methotrexate-resistant subline compared to the parental L1210 was reduced to the same extent as that shown for methotrexate. Growth of this resistant L1210 subline showed a greater requirement for this model compound than did the parental line. Also, the concentration necessary for 50% inhibition by metoprine in the presence of this reduced folate was lower in the resistant subline. Inhibition of each cell line by metoprine, on the other hand, was the same when folic acid was used as the folate source. The implications of these findings for the use of lipophilic antifolates as alternative therapy for some methotrexate-resistant tumors are discussed.

Relative frequency and kinetic properties of transport-defective phenotypes among methotrexate-resistant L1210 clonal cell lines derived in vivo.

Information was sought on the relative extent to which transport-defective, methotrexate-resistant phenotypes emerge among the total subpopulation of resistant phenotypes during therapeutic challenge of leukemic cells in vivo. A number of monoclonal methotrexate-resistant sublines of the L1210 leukemia were derived during methotrexate therapy of leukemic mice and biochemically characterized. Of the total number of 14 sublines derived, five exhibited altered [3H]methotrexate transport alone, five exhibited increased dihydrofolate reductase content alone (2- to 18-fold), and four showed alterations in both of these properties. Methotrexate binding and substrate turnover rate for dihydrofolate reductase appeared to be unchanged in any of the resistant sublines. The relative resistance of each subline was accounted for by the biochemical alterations observed. Among the transport-defective sublines, one subcategory showed a 3- to 4-fold reduction in apparent influx Vmax for [3H]methotrexate, a second category showed both a 5-fold reduction in influx Vmax and a 3-fold increase in the apparent influx Km, and one subline showed only a 2-fold increase in Km. Otherwise, Michaelis-Menten saturation kinetics for influx was observed in each case and in the case of the parental line and the other resistant sublines. None of the resistant sublines exhibited altered efflux of [3H]methotrexate. Steady-state levels measured for intracellular exchangeable (osmotically active) fractions of drug accurately reflected the values for specific kinetic parameters determined for each sensitive and resistant cell line. These studies show that transport-defective phenotypes represent a major category of methotrexate-resistant cell types which emerge initially from leukemic cell populations under therapy in mice. Based on considerations discussed here, it is reasonable to assume that a similar relative occurrence of this phenotype would result during methotrexate therapy of leukemia patients.