Effects of interleukin-11 on the proliferation and cell cycle status of myeloid leukemic cells

Interleukin-11 (IL-11) is a pleiotropic cytokine with effects on many different targets. Within the hematopoietic system, the effects of IL- 11 are largely manifest only through combination with other cytokines, including IL-3 and Steel factor (SF). In the present study, we addressed the question of IL-11 responsiveness within the different types of human leukemic cells, as well as the mechanism of action of IL- 11 at the cellular level. Analysis of a panel of samples from different patients with acute myeloblastic leukemia (AML) and myeloid leukemic cell lines indicated that IL-11 alone was ineffective in supporting myeloid leukemic cell growth but frequently enhanced growth supported by IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), or SF. In contrast, three acute pre-B lymphocytic leukemia (pre-B-ALL) and two acute T lymphocytic leukemia (T-ALL) lines failed to respond to IL- 11 alone or when combined with other cytokines. The growth enhancement of IL-11 among the AML patient samples was dose dependent and remarkably constant with half-efficient concentrations in the range of 0.3 to 0.4 ng/mL. The thymidine suicide studies with the patient samples revealed that 40% to 50% of the blast cells were in S-phase when exposed for 16 hours to IL-3 and this level was increased to 70% to 90% in response to either IL-11 or IL-6. Our data suggest that the latter two interleukins act synergistically with the direct mitogenic factor, IL-3, in triggering AML blast-cell proliferation. Detailed analysis with several patient samples further revealed that SF and IL- 11 both enhance IL-3-supported clonogenic growth of AML blasts and the combination of all three growth factors yields optimal growth. In contrast, IL-6 does not further enhance the effect of IL-11. These results indicate that SF and IL-11 enhance IL-3-dependent clonogenic growth through two distinct pathways, whereas IL-6 and IL-11 may trigger the same pathway.     

Hepatosplenic T-cell lymphoma: sinusal/sinusoidal localization of malignant cells expressing the T-cell receptor gamma delta

Peripheral T-cell lymphomas consist of a clinically heterogeneous group of malignant disorders whose immunophenotype usually corresponds to that of normal mature T cells. We describe and correlate the clinical, histopathologic, phenotypic, and genotypic findings in two patients with malignant lymphoma presenting with hepatosplenic disease. The morphologic pattern of lymphoma was that of a sinusal/sinusoidal infiltration in spleen, marrow, and liver. This morphologic characteristic was associated with the presence of a productive clonal rearrangement of the T-cell receptor (TCR) delta gene. Lymphoma cells expressed a CD3-TCR-gamma delta- phenotype. They were also double negative (ie, CD4-CD8-) and lacked the CD5 and CD7 antigens. In one patient, tumor progression was associated with phenotypic changes that resulted in a CD3-TCR-gamma delta- phenotype with the same delta-gene rearrangement as initially. These observations suggest the existence of a new type of peripheral T-cell lymphoma characterized by its hepatosplenic presentation, and by the sinusal/sinusoidal tropism and the TCR-gamma delta phenotype of the malignant cells.     

Recombinant human interleukin-11 stimulates multilineage hematopoietic recovery in mice after a myelosuppressive regimen of sublethal irradiation and carboplatin

Interleukin-11 (IL-11) is a novel multifunctional hematopoietic cytokine capable of stimulating cells of the myeloid, lymphoid, erythroid, and megakaryocytic lineages in vitro. We have tested the pleiotropic properties of this cytokine on the hematopoietic recovery of mice after a combined regimen of sublethal irradiation and carboplatin administration. This regimen results in severe myelosuppression, characterized by a prolonged period of thrombocytopenia and severe anemia. Administration of recombinant human IL-11 (rhIL-11; 250 micrograms/kg/d) had multilineage effects on bone marrow and spleen hematopoietic activity, increasing the number of megakaryocyte, erythroid, granulocyte, and macrophage progenitors compared with the vehicle-treated controls. This was reflected in the peripheral circulation by a reduction of both the platelet and hematocrit nadirs and a significantly reduced period of thrombocytopenia and anemia in the rhIL-11-treated mice. The results from this study support the broad spectrum of biologic activities that have been attributed to rhIL-11 in vitro and suggest that this cytokine may be an effective agent in the treatment of myelosuppression associated with cancer chemotherapy and bone marrow transplantation.     

Key High‐efficiency Practices of Emergency Department Providers: A Mixed‐methods Study

Objective

The objective of this study was to determine specific provider practices associated with high provider efficiency in community emergency departments (EDs).

Methods

A mixed‐methods study design was utilized to identify key behaviors associated with efficiency. Stage 1 was a convenience sample of 16 participants (ED medical directors, nurses, advanced practice providers, and physicians) identified provider efficiency behaviors during semistructured interviews. Ninety‐nine behaviors were identified and distilled by a group of three ED clinicians into 18 themes. Stage 2 was an observational study of 35 providers was performed in four (30,000‐ to 55,000‐visit) community EDs during two 4‐hour periods and recorded in minute‐by‐minute observation logs. In Stage 3, each behavior or practice from Stage 1 was assigned a score within each observation period. Behaviors were tested for association with provider efficiency (relative value units/hour) using linear univariate generalized estimating equations with an identity link, clustered on ED site.

Results

Five ED provider practices were found to be positively associated with efficiency: average patient load, using name of team member, conversations with health care team, visits to patient rooms, and running the board. Two behaviors, “inefficiency practices,” demonstrated significant negative correlations: non–work‐related tasks and documentation on patients no longer in the ED.

Conclusions

Average patient load, running the board, conversations with team member, and using names of team members are associated with enhanced provider productivity. Identification of behaviors associated with efficiency can be utilized by medical directors, clinicians, and trainees to improve personal efficiency or counsel team members.

     

Hypertension in a Brazilian Urban Slum Population

Low- and middle-income countries account for the majority of hypertension disease burden. However, little is known about the distribution of this illness within subpopulations of these countries, particularly among those who live in urban informal settlements. A cross-sectional hypertension survey was conducted in 2003 among 5649 adult residents of a slum settlement in the city of Salvador, Brazil. Hypertension was defined as either an elevated arterial systolic (≥140 mmHg) or diastolic (≥90 mmHg) blood pressure. Sex-specific multivariable models of systolic blood pressure were constructed to identify factors associated with elevated blood pressure. The prevalence of hypertension in the population 18 years and older was 21 % (1162/5649). Men had 1.2 times the risk of hypertension compared with women (95 % confidence intervals (CI), 1.05, 1.36). Increasing age and lack of any schooling, particularly for women, were also significantly associated with elevated blood pressure (p < 0.05). There was also a direct association between men who were black and an elevated blood pressure. Among those who were hypertensive, 65.5 % were aware of their condition, and only 36.3 % of those aware were actively using anti-hypertensive medications. Men were less likely to be aware of their diagnosis or to use medications (p < 0.01 for both) than women. The prevalence of hypertension in this slum community was lower than reported frequencies in the non-slum population of Brazil and Salvador, yet both disease awareness and treatment frequency were low. Further research on hypertension and other chronic non-communicable diseases in slum populations is urgently needed to guide prevention and treatment efforts in this growing population.     

Polymorphonuclear granulocytes in rheumatic tissue destruction VIII. Considerations on the inflammatory cartilage destruction in chronic arthritides in comparison with liver injuries by PMN's

Inflammatory cartilage destruction in chronic arthritides is usually regarded as the process owing to chondrocytic chondrolysis or ingrowth of pannus tissue. Besides these two mechanisms a third one-cartilage degradation directly mediated by polymorphonuclear granulocytes (PMN's) of the synovial fluid-seems to be underestimated. There is growing evidence that PMN's are involved in several non-bacterial organ destructions (e.g., alcoholic hepatitis); thus, two case reports are presented demonstrating cartilage destruction by PMN's via the synovial fluid. It is shown by light and electron microscopy that in florid rheumatoid arthritis, PMN's from the inflamed synovial fluid can gain access to the cartilaginous surface. The adherence of PMN's to the superficial matrix, eventually mediated by immunocomplexes, may activate these cells with the subsequent secretion of destructive enzymes as well as reactive oxygen species. Cartilage degradation may be the consequence. From the morphological findings it is deduced that this mechanism may have important implications for inflammatory cartilage loss.     

Gene therapy of hepatocellular carcinoma in vitro and in vivo in nude mice by adenoviral transfer of the Escherichia coli purine nucleoside phosphorylase gene

Expression of viral or bacterial enzymes in tumor cells to convert nontoxic prodrugs into highly toxic metabolites is an attractive gene-therapeutic approach for the treatment of hepatocellular carcinoma (HCC). The Escherichia coli purine nucleoside phosphorylase (PNP) converts purine analogs into freely diffusible metabolites, which are highly toxic to dividing and nondividing cells. We investigated the antitumor effects of PNP in the human HCC cell lines, HepG2, Hep3B, and HuH-7, and performed a comparison with herpes simplex thymidine kinase (TK). The genes for PNP, TK, and enhanced green fluorescent protein (EGFP) were delivered to HCC cells by identical adenoviral vectors. Fludarabine and ganciclovir (GCV) served as prodrugs for PNP and TK, respectively. Expression of PNP highly sensitized HCC cells to fludarabine treatment. Fludarabine concentrations between 0.5 and 1 microg/mL killed 100% of the cells expressing PNP with no detectable toxicity in control cells expressing EGFP. Expression of PNP in as few as 10% of HCC cells induced efficient killing of most bystander cells. Expression of TK followed by GCV treatment produced a potent growth inhibition but failed to kill all TK-expressing HCC cells. More importantly, the TK system exhibited a lower degree of bystander effect. Adenoviral delivery of PNP followed by fludarabine administration prevented subcutaneous and intrahepatic tumor formation in nude mice and was also effective for the treatment of established tumors. These results demonstrate the potential of the PNP/fludarabine system for the treatment of HCC.     

Diagnostic value of intraoperative swabs of heart valves in infective endocarditis

BACKGROUND AND AIM OF THE STUDY: Intraoperative swabs of heart valves are obtained regularly from patients undergoing heart valve surgery for infective endocarditis (IE) in order to confirm the preoperative diagnosis and to adjust the antibiotic regimen. The study aim was to assess the diagnostic value of intraoperative swabs of heart valves in IE. METHODS: A total of 83 patients was referred for surgical treatment of active IE between October 1994 and May 1999. Preoperatively, microorganisms were isolated using a minimum of two positive blood cultures; results were compared with those obtained from intraoperative heart valve swab cultures. RESULTS: Preoperatively, 73 patients (88%) had a positive blood culture, and 10 (12%) had culture-negative endocarditis. The intraoperative swab confirmed the preoperative diagnosis in 31 cases (37%). Bacteria were isolated in three of the ten patients with preoperative culture-negative IE. Despite positive histopathological findings in seven patients, no microorganisms were cultured either pre- or intraoperatively. Among the remaining 42 patients (51%) with active IE, 25 valve cultures were sterile and 17 valve swabs were presumed to be contaminated. CONCLUSION: In patients with active IE in whom the causative agent could be isolated and identified before surgery, intraoperative valve swabs did not contribute further to patient management. In isolating contaminants, the risk of inappropriate modification of the antibiotic regimen is imminent. The diagnostic validity in culture-negative IE appears negligible.     

High-dose chemoradiotherapy and autologous blood stem cell transplantation in multiple myeloma: results of a phase II trial involving 63 patients

Sixty-three patients with high tumor mass multiple myeloma were treated with high-dose chemotherapy and total body irradiation supported by autologous blood stem cell transplantation. After high-dose therapy, they were monitored for a median of 44 months. Seven patients died early from toxicity. All the other patients, including those whose disease was resistant to previous therapies, showed a tumor mass reduction. At 6 months postengraftment, 40 (71%) of the surviving patients had minimal residual disease and 11 (20%) were in apparent complete remission. During follow-up, 25 out of the 63 (39%) patients relapsed and 16 of these died; 31 (49%) had a sustained remission. The median overall and event-free survival times after transplantation were 59 and 43 months, respectively. The initial serum beta 2-microglobulin value (> or < 2.8 mg/L) and length of previous therapy (> or < 6 courses of chemotherapy) were the only significant prognostic factors. In all surviving patients, blood stem cell autograft provided satisfactory and sustained haematopoietic reconstitution most often within 15 days. High dose chemoradiotherapy followed by autologous blood stem cell transplantation is thus an important therapeutic option for young patients with aggressive multiple myeloma.