Lack of c-kit (CD117) expression in CD30+ lymphomas and lymphomatoid papulosis.

c-Kit receptor (CD117) is expressed by erythroid, megakaryocytic, and myeloid precursors and mature mast cells and has been reported to be expressed in CD30+ lymphomas such as Hodgkin's disease and anaplastic large-cell lymphoma. Imatinib mesylate, a well-established inhibitor of bcr-abl tyrosine kinase, and currently used for the treatment of patients with chronic myeloid leukemia, also inhibits c-kit receptor kinase activity. In view of the possible use of imatinib as experimental therapy for patients with c-kit-positive tumors, we assessed c-kit expression in CD30+ cell lines and lymphomas. The cell lines were assessed using multiple methods (RT-PCR, flow cytometry, and Western blot). c-Kit expression was also immunohistochemically assessed in 168 CD30+ lymphomas including 87 classical Hodgkin's disease, 63 anaplastic large-cell lymphoma, and 15 cutaneous anaplastic large-cell lymphoma. We also studied 18 cases of lymphomatoid papulosis, a CD30+ lesion closely related to cutaneous anaplastic large-cell lymphoma. Neither c-kit mRNA nor protein was detected in any of the cell lines assessed. Furthermore, treatment with imatinib did not inhibit proliferation of cell lines in vitro. Using immunohistochemistry, only one of 183 (0.5%) lesions was positive for c-kit, the positive case being an ALK-negative anaplastic large-cell lymphoma. Our data demonstrate that expression of c-kit receptor is exceedingly rare among CD30+ lymphomas and lymphomatoid papulosis, suggesting that c-kit receptor is unlikely to be an appropriate target for therapeutic options such as imatinib in patients with these tumors.     

Interleukin-6 and flow-mediated dilatation as markers of increased vascular inflammation in women receiving hormone therapy

OBJECTIVE: The lack of a beneficial long-term cardiovascular effect of hormone therapy and the early incidence of cardiovascular adverse events observed in recent randomized studies have been related to a heightened inflammatory effect of hormone therapy. DESIGN: We evaluated the effect of different postmenopause therapies on inflammatory markers and endothelial function in 205 postmenopausal women before and after therapy. RESULTS: all postmenopausal women, estrogens alone increased plasma levels of C-reactive protein (CRP) but decreased all other markers of inflammation including interleukin-6 (IL-6) (CRP: +75% +/- 11%, intracellular adhesion molecule: -21% +/- 4%, vascular cell adhesion molecule: -15% +/- 6%, E-selectin: -18% +/- 4%, s-thrombomodulin -10.5% +/- 3.7%, IL-6 -14% +/- 6%; percent changes, P < 0.01 compared with baseline). Raloxifene and tibolone did not significantly affect the overall inflammatory milieu. In a minority of patients, estrogen-progestogen associations and tibolone increased IL-6 levels and induced unfavorable changes on inflammation markers (CRP: +93% +/- 8%, intracellular adhesion molecule: -3% +/- 2%, vascular cell adhesion molecule: -5% +/- 2%, E-selectin: +6% +/- 2%, s-thrombomodulin: +5% +/- 2%, IL-6: +12% +/- 4%; percent changes compared with baseline). Patients with increased IL-6 levels were older and had a longer time since menopause. In all patients except those with increased IL-6 levels, hormone therapy improved endothelial function, whereas tibolone and raloxifene did not significantly change endothelial function compared with baseline. A worsening of endothelial function was detected in patients with increased IL-6 levels during therapy. CONCLUSIONS: Postmenopausal hormone therapy is associated with decreased vascular inflammation; however, in patients with a longer time since menopause, postmenopause hormone therapy may increase inflammation and worsen endothelial function. These unfavorable vascular effects may be detected by an elevation in IL-6 levels and by a lack of improvement in endothelial function.     

Increased risk of tuberculosis with human T-lymphotropic virus-1 infection: a case-control study

OBJECTIVES: To investigate whether infection with human T-lymphotropic virus type 1 (HTLV-1) increases the risk of tuberculosis. DESIGN: A case-control study. SETTING: City of Salvador, Brazil. PARTICIPANTS: A total of 375 patients with tuberculosis (cases) and 378 individuals without tuberculosis (controls), matched by age and sex. MAIN OUTCOME MEASURE: Tuberculosis of lung or lymph node. MAIN EXPOSURE: Human HTLV-1 infection. RESULTS: The prevalence of HTLV-1 infection was 4.27% (16/375) in patients with tuberculosis and 1.32% (5/378) in controls, resulting in a crude odds ratio of 3.31 (95% CI, 1.20-9.13) and an adjusted odds ratio of 3.01 (95% CI, 1.06-8.58). CONCLUSION: HTLV-1 infection is associated with a first diagnosis of tuberculosis. This may have implications for tuberculosis control in places with high prevalence of HTLV-1.     

Small volume hypertonic resuscitation of circulatory shock

Small volume hypertonic resuscitation is a relatively new conceptual approach to shock therapy. It was originally based on the idea that a relatively large blood volume expansion could be obtained by administering a relatively small volume of fluid, taking advantage of osmosis. It was soon realized that the physiological vasodilator property of hypertonicity was a useful byproduct of small volume resuscitation in that it induced reperfusion of previously ischemic territories, even though such an effect encroached upon the malefic effects of the ischemia-reperfusion process. Subsequent research disclosed a number of previously unsuspected properties of hypertonic resuscitation, amongst them the correction of endothelial and red cell edema with significant consequences in terms of capillary blood flow. A whole set of actions of hypertonicity upon the immune system are being gradually uncovered, but the full implication of these observations with regard to the clinical scenario are still under study. Small volume resuscitation for shock is in current clinical use in some parts of the world, in spite of objections raised concerning its safety under conditions of uncontrolled bleeding. These objections stem mainly from experimental studies, but there are few signs that they may be of real clinical significance. This review attempts to cover the earlier and the more recent developments in this field.     

Lack of optimal T-cell reactivity against the hepatitis C virus is associated with the development of fibrosis/cirrhosis during chronic hepatitis

Chronic hepatitis C virus (HCV) infection develops in 85% of exposed individuals and 20% develop cirrhosis. However, the pathogenesis of this process is not well-understood. The objective of this study was to determine whether HCV-reactive T cells play a role in the process of development of cirrhosis during chronic HCV infection. We analyzed 21 human leukocyte antigen (HLA)-A2 patients with chronic HCV infection (9 with histology of inflammation and 12 with histology of fibrosis/cirrhosis). The frequency of CD8(+) T cells reactive to 12 HCV-derived epitopes was determined by an interferon-gamma enzyme-linked immunospot (ELISPOT) assay. The frequency of CD4(+) Th1 and Th2 cells reactive to the HCV core antigen was determined by interferon-gamma and interleukin-5 ELISPOT assays, respectively. Patients with histology of inflammation showed a significantly higher CD8(+) T-cell response to five HCV-derived epitopes (YLLPRRGPRL [core], CINGVCWTV [NS3], LLCPAGHAV [NS3], ILAGYGAGV [NS4B], and GLQDCTMLV [NS5B]) as compared with patients with histology of fibrosis/cirrhosis. Also, patients with histology of inflammation showed a significantly higher CD4(+) Th1 response to the HCV core antigen as compared to patients with histology of fibrosis/cirrhosis. These results indicate that a lack of an optimal T-cell response to HCV is associated with the development of cirrhosis during chronic HCV infection.     

Bone marrow-derived mesenchymal stem cells in repair of the injured lung

We sought to determine whether an intact bone marrow is essential to lung repair following bleomycin-induced lung injury in mice, and the mechanisms of any protective effects conferred by bone marrow-derived mesenchymal stem cell (BMDMSC) transfer. We found that myelosupression increased susceptibility to bleomycin injury and that BMDMSC transfer was protective. Protection was associated with the differentiation of engrafted BMDMSC into specific and distinct lung cell phenotypes, with an increase in circulating levels of G-CSF and GM-CSF (known for their ability to promote the mobilization of endogenous stem cells) and with a decrease in inflammatory cytokines. In vitro, cells from injured, but not from normal, mouse lung produced soluble factors that caused BMDMSC to proliferate and migrate toward the injured lung. We conclude that bone marrow stem cells are important in the repair of bleomycin-injured lung and that transfer of mesenchymal stem cells protects against the injury. BMDMSC localize to the injured lung and assume lung cell phenotypes, but protection from injury and fibrosis also involves suppression of inflammation and triggering production of reparative growth factors.