Myelostimulatory activity of recombinant human interleukin-2 in mice

In a series of studies designed to extend our understanding of interleukin-2 (IL-2) and to study the effect of biologic response modifiers on bone marrow, we observed that administering recombinant human (rH) IL-2 to normal mice resulted in an increase in the frequency of colony-forming units-culture (CFU-C) in bone marrow. In addition, rH IL-2 was able to accelerate host recovery from cyclophosphamide (CTX)- or radiation-induced bone marrow depression and peripheral blood leukopenia. Not only can rH IL-2 accelerate, in a dose-dependent manner, the return of bone marrow, peripheral blood cellularity, and CFU-C frequency to normal levels following cytoreduction by CTX or irradiation, but it also significantly increases CFU-C frequency to greater than normal levels. Furthermore, rH IL-2 can significantly prolong survival of animals receiving a lethal dose of irradiation or CTX. Thus, multiple mechanisms are responsible for the synergistic therapeutic activity associated with rH IL-2 and CTX. rH IL-2 does not act only as an immunomodulatory agent in the presence or absence of suppressor T cells, but also accelerates host recovery from cytoreductive agents, resulting in decreased leukopenia and perhaps resistances to secondary infection. Thus, rH IL-2 plus chemotherapy may increase therapeutic activity against neoplastic disease, not only by adding immune stimulation to the direct antitumor effect of the drug but also by allowing delivery of higher, more effective doses of chemotherapy.     

Five-year clinical outcomes of the first Korean-made sirolimus-eluting coronary stent with abluminal biodegradable polymer

This study evaluated the 5-year clinical outcomes of the Genoss DES, the first Korean-made sirolimus-eluting coronary stent with abluminal biodegradable polymer.We previously conducted the first-in-patient prospective, multicenter, randomized trial with a 1:1 ratio of patients using the Genoss DES and Promus Element stents; the angiographic and clinical outcomes of the Genoss DES stent were comparable to those of the Promus Element stent. The primary endpoint was major adverse cardiac events (MACE), which was a composite of death, myocardial infarction (MI), and target lesion revascularization (TLR) at 5 years.We enrolled 38 patients in the Genoss DES group and 39 in the Promus Element group. Thirty-eight patients (100%) from the Genoss DES group and 38 (97.4%) from the Promus Element group were followed up at 5 years. The rates of MACE (5.3% vs 12.8%, P = .431), death (5.3% vs 10.3%, P = .675), TLR (2.6% vs 2.6%, P = 1.000), and target vessel revascularization (TVR) (7.9% vs 2.6%, P = .358) at 5 years did not differ significantly between the groups. No TLR or target vessel revascularization was reported from years 1 to 5 after the index procedure, and no MI or stent thrombosis occurred in either group during 5 years.The biodegradable polymer Genoss DES and durable polymer Promus Element stents showed comparable low rates of MACE at the 5-year clinical follow-up.     

Is the Bladder “An Unreliable Witness” in Elderly Males with Persistent Lower Urinary Tract Symptoms?

Aim: We sought to study the usefulness of lower urinary tract symptoms and postvoid residual urine volume in the diagnosis of voiding dysfunction in elderly men. Methods: The symptoms and postvoid residual urine volume of 126 men aged 65 years or older referred for urodynamic studies were obtained. Their accuracy in the diagnosis of detrusor instability, bladder outlet obstruction and impaired detrusor contractility was quantified. Results: For the diagnosis of detrusor instability, urgency and urge incontinence with frequency and/or nocturia had a sensitivity of 73.0% and a specificity of 60.0%. For the diagnosis of bladder outlet obstruction, poor stream with frequency and/or nocturia had a sensitivity of 51.9% and a specificity of 71.6%. Using poor stream and residual urine volume of more than 50 ml occurring together, the sensitivity was 31.1% and specificity was 89.7%. For the diagnosis of impaired detrusor contractility, poor stream had a sensitivity of 44.8% and a specificity of 56.7%. With residual urine volume of more than 50 ml, a sensitivity of 96.6% and specificity of 80.4% was obtained. Conclusion: Based on our findings, we conclude that the bladder does appear to be an “ unreliable witness ” in elderly men for the diagnosis of bladder outlet obstruction, though this is less so with impaired detrusor contractility. No conclusion can be drawn for the detrusor instability as we did not use ambulatory urodynamic studies.     

Ectopic expression of rhombotin-2 causes selective expansion of CD4-CD8- lymphocytes in the thymus and T-cell tumors in transgenic mice

Although the proto-oncogene rhombotin-2 (RBTN-2) is widely expressed in most tissues, it is not expressed in T cells. We investigated the potential for overexpression of RBTN-2 to cause tumors in T cells and other tissues by constructing transgenic mice that expressed RBTN-2 under control of the metallothionein-1 promoter. Despite overexpression of RBTN-2 in all tissues, transgenic mice developed T-cell tumors only, thus indicating that tumorigenesis caused by RBTN-2 is T-cell-specific. Thymic tumors were found between 37 and 71 weeks and were invariably associated with metastasis to nonlymphoid organs. Thymuses from apparently healthy transgenic mice were also examined. In some mice there was an 10-fold increase in the CD4-CD8- thymocyte subset, yet the total number of thymocytes was the same as that in wild-type mice. Thymic homeostasis was maintained by a compensatory reduction in the CD4+CD8+ subset. The expansion of CD4-CD8- thymocytes was associated with increased expression of RBTN-2 and with increased cell proliferation. No differences were found in the proportion of thymocytes undergoing apoptosis in transgenic mice. Furthermore, RBTN-2- induced expansion of CD4-CD8- cells did not block differentiation of these cells. Thymuses with 30% CD4-CD8- cells were essentially monoclonal, indicating that all thymic immunophenotypes were derived from a single clone. Overall, our data are consistent with the following scenario: (1) RBTN-2 expression in T cells causes selective and polyclonal proliferation of CD4-CD8- thymocytes accompanied by a compensatory decrease in other thymocyte subsets; (2) a clone with growth advantage and differentiation potential is selected and populates the thymus; and (3) this clone eventually breaches homeostasis of the thymus, accompanied or followed by metastasis to other organs.     

Modulation of megakaryocytopoiesis by thrombopoietin: the c-Mpl ligand

We have further characterized the biological activities, mechanism of action, and target cell populations of recombinant human and murine thrombopoietin (rhTPO and rmTPO) in in vitro human and murine model systems. Alone, hTPO or mTPO stimulated the maturation of immature murine megakaryoblasts as measured in a single cell assay. The combination of hTPO or mTPO and interleukin-6 (IL-6) resulted in a further increase in megakaryocyte differentiation in this system. Murine TPO stimulated mouse megakaryocyte progenitor development. Human megakaryocyte progenitor development was potentiated by hTPO alone and further augmented in the presence of the early-acting cytokines (IL-3) or kit ligand/stem cell factor (KL/SCF). To further define the mechanism of action of TPO, neutralization studies were performed with antisera to IL-3, granulocyte-macrophage colony-stimulating factor (GM- CSF), IL-1 beta, and IL-11. No diminution in TPO activity was observed in the presence of these antisera. Moreover, because adhesive interactions are known to modulate hematopoiesis, we studied whether hTPO might alter such interactions between human bone marrow (BM) megakaryocytes and human BM stromal fibroblasts. No changes were observed in either megakaryocyte expression of the surface molecules lymphocyte function-associated antigen-1, very late activation antigen- 4, or intercellular adhesion molecule-1 or the adhesion of megakaryocytes to stromal fibroblasts after treatment with the growth factor. Furthermore, no induction of secretion of the cytokines IL-1 alpha, IL-1 beta, GM-CSF, IL-6, granulocyte-CSF, tumor necrosis factor- alpha, transforming growth factor-beta 1, or transforming growth factor- beta 2 by primary human BM megakaryocytes was noted after treatment of the cells with hTPO. To address whether TPO affects very primitive hematopoietic progenitors, we studied the residual cells from the BMs of mice treated with high doses of 5-fluorouracil. Although no effect of mTPO alone was noted on the viability or replication of such primitive murine progenitor populations, the triple combination of IL-3 + KL/SCF + TPO stimulated growth of megakaryocyte progenitors. These results indicate that TPO is a highly lineage-specific growth factor whose primary biological effects are likely to be direct modulation of the growth and maturation of committed megakaryocyte precursors and immature megakaryoblasts.     

Phase I trial of interleukin-2 after unmodified HLA-matched sibling bone marrow transplantation for children with acute leukemia

Allogeneic bone marrow transplantation (BMT) for advanced acute leukemia is associated with a high risk of relapse. It is postulated that interleukin-2 (IL-2) administered after BMT might induce or amplify a graft-versus-leukemia effect and thereby reduce the relapse rate. To identify an IL-2 regimen for testing this hypothesis, a phase I trial of IL-2 (Roche) was performed in children in complete remission (CR) without active graft-versus-host disease (GVHD) off immunosuppressive agents after unmodified allogeneic matched-sibling BMT for acute leukemia beyond first remission. Beginning a median of 68 days after BMT, 17 patients received escalating doses of induction IL-2 (0.9, 3.0, or 6.0 x 10(6) IU/m2/d representing levels I, II, and III) for 5 days by continuous intravenous infusion (CIV). After 6 days of rest, they received maintenance IL-2 (0.9 x 10(6) IU/m2/d) for 10 days by CIV infusion. Levels I and II were well-tolerated, but, of 6 patients at level III, 1 developed pulmonary infiltrates, 1 developed hypotension (both resolved), and 1 died of bacterial sepsis and acute respiratory distress syndrome. Grade II acute GVHD developed in 1 patient at level I and 1 at level III. The maximum tolerated dose of induction IL-2 was level II. IL-2 induced lymphocytosis, with an increase in CD56+ and CD8+ cells. Ten patients remain in CR at 5+ to 67+ months. Thus, a regimen of IL-2 has been identified that did not induce a high incidence of acute GVHD when administered to children after unmodified allogeneic BMT. Its clinical activity will be assessed in a phase II trial.     

Functional classification of aortic regurgitation using cardiac computed tomography: comparison with surgical inspection

In patients with aortic regurgitation (AR), a precise preoperative assessment of aortic valve (AV) pathology is important if AV repair or sparing operation is an alternative option. The aim of this study was to assess the diagnostic accuracy of computed tomography (CT) for evaluating the AR mechanism compared with surgical inspection. 59 patients with AR who underwent AV surgery and preoperative cardiac CT were evaluated. AR mechanism was classified into type 1 (aortic dilatation or cusp perforation), type 2 (prolapsed cusp) and type 3 (cusp retraction). Agreement between CT and surgical inspection was obtained. Correlation between aortic regurgitant orifice (ARO) and imaging parameters were evaluated. On surgical inspection, type 1 AR was noted in 22 patients, type 2 in 16 and type 3 in 21. Agreement regarding the AR mechanism on CT was excellent (intra-class correlation coefficient, 0.81). At the patient level, the Cohen’s κ value for CT findings with surgical inspection was of 0.89. At the cusp level, moderate agreement was noted between CT and surgical inspection. In the per-cusp analysis, CT had a sensitivity of 72.6%, specificity of 85.1%, positive predictive value of 73.8% and negative predictive value of 84.3% for the detection of aortic cusp abnormality. The diameter, perimeter and area of aortic annulus had moderate correlation with ARO (r?=?0.54–0.66, P?<?0.001). CT-derived classification of AR mechanism showed excellent agreement with surgical inspection.     

Do Fructose-Containing Sugars Lead to Adverse Health Consequences? Results of Recent Systematic Reviews and Meta-analyses

Sugars have replaced fat as the dominant public health nutrition concern. A fructose-centric view of cardiometabolic disease has emerged whereby fructose-containing sugars are thought to have deleterious effects on body weight, fasting and postprandial blood lipids, glycemia, blood pressure, uric acid, and markers of nonalcoholic fatty liver disease. Long-term prospective cohort studies have not supported these associations when assessing the relation between total fructose-containing sugars at any amount of intake and incident cardiometabolic disease. Conversely, a consistent signal for harm has been reported for sugary beverages when comparing the highest with the lowest intakes. These associations, however, do not hold at moderate intakes, which are more reflective of real-world intakes, are subject to important collinearity effects, and have small risk estimates with modest population-attributable risk fractions. Higher-level evidence from controlled feeding trials shows that fructose-containing sugars in either liquid or solid form have adverse cardiometabolic effects only when they supplement diets with excess calories compared with the same diets without the excess calories. In the absence of harm when fructose-containing sugars are exchanged for other sources of carbohydrate under energy-matched conditions, excess calories appear to be the dominant consideration. Like with the earlier fat story, it is difficult to separate the contribution of fructose-containing sugars from that of other sources of excess calories in the epidemic of obesity and cardiometabolic disease. Attention needs to remain focused on reducing the overconsumption of all caloric foods associated with obesity and cardiometabolic disease, including sugary beverages and foods, and promoting greater physical activity.     

Robotic-assisted mesh pelvic closure for prevention of small bowel descent after surgery for recurrent rectal cancer

Techniques in Coloproctology -