The immunoregulatory cytokine interleukin 6 (IL-6) directly upregulates production of human immunodeficiency virus (HIV) in acutely as well as in chronically infected cells of monocytic lineage. In addition, IL-6 synergizes with tumor necrosis factor alpha (TNF-alpha) in the induction of latent HIV expression. Unlike TNF-alpha, upregulation of viral expression induced by IL-6 alone does not occur at the transcriptional level and it is not associated with accumulation of HIV RNA. However, when IL-6 and TNF-alpha synergistically stimulate HIV production, accumulation of HIV RNA and increased transcription are observed, indicating that IL-6 affects HIV expression at multiple (transcriptional and post-transcriptional) levels.

Tumor necrosis factor a (TNF-a) is an immunoregulatory cytokine capable of inducing viral expression in cells chronically infected with the human immunodeficiency virus (HIV), such as the promonocytic line U1 and the Tlymphocytic line ACH-2. In the present study, we demonstrate an autocrine mechanism of TNF-a-mediated HIV induction.

Aim:  This observational study in patients with type 2 diabetes failing oral agent therapy with or without basal insulin was conducted to assess whether addition and self‐titration of biphasic insulin aspart 70/30 (BIAsp 30) could achieve American Association of Clinical Endocrinologists (AACE)/International Diabetes Federation (IDF) and American Diabetes Association (ADA) glycemic targets (HbA1c≤6.5 and <7%). Methods:  Enrolled patients (n = 100, HbA1c≥7.5 and ≤10%) were ≥18 years of age, had diabetes ≥12 months and had received a stable antidiabetic regimen for at least 3 months [minimum of two oral antidiabetic drugs (OADs) or at least one OAD plus once‐daily basal insulin ≤60 U]. Patients discontinued prior basal insulin and added one injection of BIAsp 30 (12 U or 70–100% of prior basal insulin dose within 15 min of dinner initiation). Patients self‐titrated their BIAsp 30 dose with investigator guidance every 3 or 4 days to achieve pre‐breakfast fasting blood glucose (FBG) of 80–110 mg/dl. At 16 weeks, a pre‐breakfast injection of 6 U of BIAsp 30 was added if week 15 HbA1c exceeded 6.5%; the added dose was titrated to achieve pre‐dinner BG of 80–110 mg/dl. After an additional 16 weeks, 3 U of pre‐lunch BIAsp 30 was added if HbA1c exceeded 6.5%. This added dose was adjusted based on 2‐h post‐lunch BG to achieve postprandial glucose of 100–140 mg/dl. Subjects achieving an HbA1c≤6.5% at 15 and 31 weeks completed the study at weeks 16 and 32 respectively. Results:  Addition of once‐daily BIAsp 30 before dinner enabled 21% of the patients to achieve AACE and IDF targets (HbA1c≤6.5%) and 41% to achieve ADA targets (HbA1c <7%). With two daily injections of BIAsp 30, these glycaemic goals were achieved by 52 and 70% of subjects. With three daily BIAsp 30 injections, 60% of patients achieved HbA1c≤6.5%, and 77% achieved HbA1c <7.0%. Conclusions:  This clinical trial demonstrates that initiation of once‐daily BIAsp 30 to type 2 diabetes patients poorly controlled on various OAD regimens was an effective treatment approach for achieving glycaemic goals. Additional patients safely achieved these goals by increasing the number of BIAsp 30 injections from one to two, and then, if uncontrolled, from two to three doses per day. Eventually, most patients previously uncontrolled on OADs with or without basal insulin were controlled by the addition and vigorous titration of BIAsp 30 to oral agent therapy.

The purpose of the present study was to quantitate insulin-mediated glucose disposal in normal glucose tolerant patients with angiographically documented coronary artery disease (CAD) and to define the pathways responsible for the insulin resistance. We studied 13 healthy, normal weight, normotensive subjects with angiographically documented CAD and 10 age-, weight-matched control subjects with an oral glucose tolerance test and a 2-h euglycaemic insulin (40 mU.m-2.min-1) clamp with tritiated glucose and indirect calorimetry. Lean body mass was measured with tritiated water. All CAD and control subjects had a normal oral glucose tolerance test. Fasting plasma insulin concentration (66 +/- 6 vs 42 +/- 6 pmol/l, p < 0.05) and area under the plasma insulin curve following glucose ingestion (498 +/- 54 vs 348 +/- 42 pmol.l-1.min-1, p < 0.001) were increased in CAD vs control subjects. Insulin-mediated whole body glucose disposal (27.8 +/- 3.9 vs 38.3 +/- 4.4 mumol.kg fat free mass (FFM)-1.min-1, p < 0.01) was significantly decreased in CAD subjects and this was entirely due to diminished non-oxidative glucose disposal (8.9 +/- 2.8 vs 20.0 +/- 3.3 mumol.kg FFM-1.min-1, p < 0.001). The magnitude of insulin resistance was positively correlated with the severity of CAD (r = 0.480, p < 0.05). In the CAD subjects basal and insulin-mediated rates of glucose and lipid oxidation were normal and insulin caused a normal suppression of hepatic glucose production. In conclusion, subjects with angiographically documented CAD are characterized by moderate-severe insulin resistance and hyperinsulinaemia and should be included in the metabolic and cardiovascular cluster of disorders that comprise the insulin resistance syndrome or "syndrome X'.

The chromatin structure of the interleukin-2 (IL-2) gene was probed by DNase I treatment of isolated nuclei. The 5' region of the IL-2 gene contains three regions of hypersensitivity to DNase I. When peripheral blood T cells or Jurkat T cells are stimulated with mitogens, IL-2 message is induced, and the promoter region of the IL-2 gene develops an additional hypersensitive site. This suggests that a DNA sequence close to the transcriptional start site is involved in the transduction of the extracellular signal. Such a conclusion is further supported by DNA transfection experiments. A short segment of DNA, which includes the region of induced hypersensitivity, confers inducibility on the linked chloramphenicol acetyltransferase gene in transiently transfected Jurkat cells. In addition, cells of nonhematopoietic origins exhibit a strikingly different chromatin pattern of IL-2, suggesting a role during differentiation for some of the hypersensitive sites.Activation of T lymphocytes by mitogens or antigens leads to secretion of the growth factor interleukin-2 (IL-2) (14,27,30,32,34). This factor interacts with the IL-2 receptor on the surface of activated T cells, and such an interaction is required for progression of these cells through the cell cycle (3). T cells thus proliferate in part via an autocrine mechanism. Subsequent to the induction phase, IL-2 expression appears to be specifically down modulated (6). Consequently, the magnitude of the initial pulse of IL-2 synthesis determines to a large degree the magnitude of the proliferative stimulus. Several agents which interfere with IL-2 production, such as cyclosporin A (CsA) (7, 22) and glucocorticoids (12), have powerful immunosuppressive actions. These agents most likely prevent the expansion of clones of antigen-specific T lymphocytes. The effects of glucocorticoids are broad, whereas the dramatic immunosuppressive effects of CsA are based largely on the inhibition of IL-2 production and give some insight into the critical role of IL-2 regulation in governing the immune response.The IL-2 gene product has been purified (28, 32), both cDNA and genomic clones for IL-2 have been identified, and the complete structure of the gene is known (11,18,19,37 Normal peripheral blood T cells also require two signals for activation; namely, antigens (or mitogens) and macrophages (3,26,29,38). Macrophages probably exert their effect through the IL-1 factor (5, 29). The mitogen PHA is thought to substitute for the signal normally provided by antigen, and PMA is probably a substitute for IL-1 or macrophages or both.Despite such extensive knowledge about the structure and function of the IL-2 gene and the signals leading to its activation in both normal T cells as well as in model cell lines, very little is known about the intracellular events that result in transcriptional activation or the determinants for its tissue-specific expression. Therefore, we set out to study the regulation of the IL-2 gene at the DNA level. We approached this in two ways: first by probing the chr...

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SummaryInterferon "), (IFN-v), a lymphokine that exerts multiple immunoregulatory effects, has been found to be elevated in the plasma, cerebrospinal fluid, and lymph nodes of human immunoddldency virus (HIV)-infected individuals and has shown variable effects on HIV replication in acutely infected cells. In the present study, we have demonstrated that IFN-v is a potent modulator of HIV expression in persistently infected U1 promonocytic cells in which virus production is characterized by a constitutive state of relative latency. Direct stimulation of U1 cells with IFN-'), (10-1,000 U/m1) activated HIV expression, as measured by reverse transcriptase (RT) activity in the culture supernatant and increased levels of cell-associated viral protein and mRNAs. These effects on virus expression were not accounted for by the induction of endogenous TNF-cr secretion, as previously described in U1 cells stimulated with phorbol myristate acetate (PMA). At the ultrastructural level, the stimulatory activity of IFN-v was correlated with HIV particle production in intracytoplasmic vacuoles along with the differentiation of U1 into macrophage-like cells. Furthermore, costimulation of U1 cells with IFN-v and PMA significantly increased the accumulation of vacuole-associated HIV concomitant with decreasing membrane-associated particles and RT activity production, as compared with cells stimulated with PMA alone. No evidence of spontaneous secretion of intracellular vacuole-associated virus was obtained by kinetic analysis of the RT activity released in the supernatants throughout the culture period unless cells were deliberately disrupted, These findings suggest that vacuole-associated virions likely represent a relatively stable intracellular reservoir of HIV, as previously described in primary macrophages infected in vitro or in infected macrophages in the brains of patients with acquired immune deficiency syndrome. The reduced levels of RT activity observed in the culture supernatants of U1 cells stimulated with PMA in the presence of IFN-3' were not indicative of a suppressive effect of IFN-3' on PMA-induced expression of HIV proteins and mRNAs, either directly or mediated by the release of IFN-od/3. This study suggests that IFN-3' may play an important role as an inducer of HIV expression in infected mononuclear phagocytes.