Equitoxicity of bolus and infusional etoposide: results of a multicenter randomised trial of the German High-Grade Non-Hodgkins Lymphoma Study Group (DSHNHL) in elderly patients with refractory or relapsing aggressive non-Hodgkin lymphoma using the CEMP regimen (cisplatinum, etoposide, mitoxantrone and prednisone)

To compare toxicity of etoposide bolus with continuous infusion and to assess the efficacy of the CEMP (cisplatinum, etoposide, mitoxantrone, prednisone) regimen, 47 patients with refractory or relapsed aggressive non-Hodgkin's lymphoma older than 60 years (n=43) or not qualifying for high-dose chemotherapy (n=4) received five four-weekly CEMP cycles. Patients were randomised to start with bolus or continuous-infusion etoposide and then received bolus and infusional etoposide in an alternating fashion. The primary objective was the comparison of differences in the course of leukocytopenia and thrombocytopenia between the two application schedules. CEMP was well tolerated with little organ and moderate haematotoxicity. There was no difference in toxicity between bolus and continuous-infusion etoposide. Complete remission rate was 44% in patients relapsing >or=1 year, 27% in patients relapsing within the first year after achieving complete remission and 5% in primary refractory patients. Median event-free and overall survivals for all patients were 3 and 10 months, respectively. The observed equitoxicity and the more challenging logistics of a 60-h infusion make bolus injection the preferred application of etoposide. As the CEMP regimen is well tolerated and efficacious in elderly patients with relapsed or refractory aggressive non-Hodgkin's lymphoma for whom more aggressive therapies are not feasible, a three-weekly modification of CEMP should be tested in combination with rituximab.     

HPV Awareness and Vaccine Acceptability in Hispanic Women Living Along the US-Mexico Border

Despite advances in prevention of cervical cancer in the US, women of Hispanic origin still bear an unequal burden in cervical cancer incidence, morbidity and mortality. Our objective was to determine the HPV vaccine knowledge and acceptability in a group of mostly Hispanic females. In this cross sectional survey, 62 % of participants heard of HPV; 34.9 % identified HPV as a cause of cervical cancer. 63 % of participants reported willingness to receive vaccine and 77 % were willing to vaccinate daughters. Those with previous abnormal PAPs were more likely to have heard of HPV and Vaccine. No other factors examined showed association with willingness to get vaccine or administer to daughters. Knowledge level remains low in this high risk population. Willingness to receive vaccine is high despite lack of access to care. Increased targeted community based education and vaccination programs may be useful in closing disparity in cervical cancer morbidity.     

JAK2V617F-positive endothelial cells contribute to clotting abnormalities in myeloproliferative neoplasms

The Janus kinase 2 (JAK2) V₆₁₇F mutation is the primary pathogenic mutation in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Although thrombohemorrhagic incidents are the most common causes of morbidity and mortality in patients with MPNs, the events causing these clotting abnormalities remain unclear. To identify the cells responsible for the dysfunctional hemostasis, we used transgenic mice expressing JAK2V₆₁₇F in specific lineages involved in thrombosis and hemostasis. When JAK2V₆₁₇F was expressed in both hematopoietic and endothelial cells (ECs), the mice developed a significant MPN, characterized by thrombocytosis, neutrophilia, and splenomegaly. However, despite having significantly higher platelet counts than controls, these mice showed severely attenuated thrombosis following injury. Interestingly, platelet activation and aggregation in response to agonists was unaltered by JAK2V₆₁₇F expression. Subsequent bone marrow transplants revealed the contribution of both endothelial and hematopoietic compartments to the attenuated thrombosis. Furthermore, we identified a potential mechanism for this phenotype through JAK2V₆₁₇F-regulated inhibition of von Willebrand factor (VWF) function and/or secretion. JAK2V₆₁₇F⁺ mice display a condition similar to acquired von Willebrand syndrome, exhibiting significantly less high molecular weight VWF and reduced agglutination to ristocetin. These findings greatly advance our understanding of thrombohemorrhagic events in MPNs and highlight the critical role of ECs in the pathology of hematopoietic malignancies.Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders, characterized by significant increases in one or more myeloid-cell lineages. Mutations in the Janus kinase 2 (JAK2) and MPL genes are common in the majority of Philadelphia chromosome-negative (Ph⁻) MPNs, which include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). By far the most frequent mutation in MPNs is JAK2V₆₁₇F (1–4), which occurs in the highly conserved autoinhibitory JAK homology (JH) 2 domain, causing hyperactive kinase activity and hyperproliferation of myeloid progenitor cells, leading to overproduction of red blood cells (RBCs), platelets, and leukocytes. Although ET and PV have a relatively benign clinical course, patients’ life expectancy can be severely reduced by bleeding or thrombosis, the manifestations of which are significantly more common than other MPN-related complications such as myelofibrosis and acute leukemic transformation (5). The frequency and nature of thrombotic and hemorrhagic events vary greatly depending on disease phenotype and patient history. Data taken from a number of previous studies indicate that the probability of major thrombosis ranges between 8–29% (ET) and 11–39% (PV) whereas the incidence of bleeding at initial presentation is less frequent than thrombosis, ranging between 3–18% (ET) and 3–8% (PV) (6–8).A number of abnormalities that could potentially contribute to this prothrombotic phenotype have been identified in the blood and vascular cells of JAK2V₆₁₇F⁺ MPN patients. Much work has focused on defining platelet abnormalities, including increased expression of membrane proteins such as P-selectin and tissue factor (TF), which would prime platelets for activation and increase levels of platelet-activation markers and platelet factor 4 (PF4) in the plasma (9–12). Interestingly, however, aggregation studies show a decreased response to ADP and epinephrine in platelets isolated from patients with ET and PV compared with controls (10). Furthermore, no correlation has been made between severity of thrombocytosis in ET patients and increased risk of thrombosis (6, 13). In contrast, extreme thrombocytosis (platelets >1,500 × 10⁹/L) is thought to contribute to a hemorrhagic phenotype in ET patients, and is commonly attributed to the development of acquired von Willebrand syndrome (AVWS) (11, 12, 14), where the increased platelets bind to highly prothrombotic, ultralarge von Willebrand factor (VWF) multimers, removing them from the plasma (15).Recent studies suggest that leukocytosis is a potential thrombotic risk factor in young PV and ET patients, possibly through the interactions of leukocytes, especially neutrophils, with platelets and endothelial cells (ECs) (16, 17) or the production of prothrombotic molecules such as TF. Increased basal activation of neutrophils has been shown in PV and ET patients, including elevated expression of CD11b and levels of neutrophil proteases in the plasma, both of which are prothrombotic (9, 18, 19). Studies have also shown increased activation of vascular ECs in JAK2V₆₁₇F⁺ MPN patients. Increased P- and E-selectin levels in the plasma, coupled with decreased levels of nitric oxide (NO), could conceivably contribute to a prothrombotic phenotype. Furthermore, JAK2V₆₁₇F⁺ ECs have recently been reported in a subpopulation of MPN patients, and EC expression was coupled with an increased risk of thrombosis (20, 21). Taken together, previous studies describe physiological abnormalities in a number of cell types in JAK2V₆₁₇F⁺ MPN patients, all of which could contribute toward increased thrombosis and/or bleeding. However, these data are often contradictory and fail to definitively explain the mechanism/s responsible for the development of thrombohemorrhagic disease.Here, we used FF1 transgenic mice (22) to express human JAK2V₆₁₇F in specific lineages to determine which cells are responsible for the thrombohemorrhagic manifestations seen in patients with MPNs. FF1 mice were crossed with Pf4-Cre or Tie2-Cre mice to express JAK2V₆₁₇F specifically in platelets alone, or in hematopoietic cells and ECs, respectively (23–28). These models have provided us with an unparalleled opportunity to determine the specific role/s of JAK2V₆₁₇F in pathological thrombosis and hemostasis.     

The role of socioeconomic status in the susceptibility to develop systemic lupus erythematosus in Mexican patients

Clinical Rheumatology - Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disorder for which Major Histocompatibility Complex (MHC) genes are well-identified as risk factors. SLE...     

czcD gene from Bacillus megaterium and Microbacterium liquefaciens as a potential nickel–vanadium soil pollution biomarker

Metals are among the most prevalent pollutants released into the environment. For these reasons, the use of biomarkers for environmental monitoring of individuals and populations exposed to metal pollution has gained considerable attention, offering fast and sensitive detection of chemical stress in organisms. There are different metal resistance genes in bacteria that can be used as biomarkers, including cation diffusion facilitators carrying metal ions; the prototype is the cobalt–zinc–cadmium transporter (czcD). The present study reports the expression changes in the czcD gene in Bacillus megaterium and Microbacterium liquefaciens under nickel and vanadium exposure by real-time polymerase chain reaction. The nickel–vanadium-resistant strains of B. megaterium and M. liquefaciens used in this study were isolated from mine tailings in Guanajuato, Mexico. The czcD gene showed high expression under exposure to 200 ppm of Ni and 200 ppm of V during the logarithmic growth phase of M. liquefaciens in PHGII liquid media. In contrast, no changes were observed in B. megaterium during logarithmic and stationary growth, perhaps due to the gene having differential expression during the growth phases. The expression profiles obtained for czcD show the possibility of using this gene from M. liquefaciens as a biomarker of nickel and vanadium pollution in microorganisms.     

Tolerogenic dendritic cells induce antigen-specific hyporesponsiveness in insulin- and glutamic acid decarboxylase 65-autoreactive T lymphocytes from type 1 diabetic patients

Tolerogenic dendritic cells (tDC) constitute a promising therapy for autoimmune diseases, since they can anergize T lymphocytes recognizing self-antigens. Patients with type 1 diabetes mellitus (T1D) have autoreactive T cells against pancreatic islet antigens (insulin, glutamic acid decarboxylase 65 -GAD65-). We aimed to determine the ability of tDC derived from T1D patients to inactivate their insulin- and GAD65-reactive T cells. CD14 + monocytes and CD4 + CD45RA- effector/memory lymphocytes were isolated from 25 patients. Monocyte-derived DC were generated in the absence (control, cDC) or presence of IL-10 and TGF-β1 (tDC), and loaded with insulin or GAD65. DC were cultured with T lymphocytes (primary culture), and cell proliferation and cytokine secretion were determined. These lymphocytes were rechallenged with insulin-, GAD65- or candidin-pulsed cDC (secondary culture) to assess whether tDC rendered T cells hyporesponsive to further stimulation. In the primary cultures, tDC induced significant lower lymphocyte proliferation and IL-2 and IFN-γ secretion than cDC; in contrast, tDC induced higher IL-10 production. Lymphocytes from 60% of patients proliferated specifically against insulin or GAD65 (group 1), whereas 40% did not (group 2). Most patients from group 1 had controlled glycemia. The secondary cultures showed tolerance induction to insulin or GAD65 in 14 and 10 patients, respectively. A high percentage of these patients (70–80%) belonged to group 1. Importantly, tDC induced antigen-specific T-cell hyporesponsiveness, since the responses against unrelated antigens were unaffected. These results suggest that tDC therapy against multiple antigens might be useful in a subset of T1D patients.     

General anesthesia type does not influence serum levels of neutrophil gelatinase-associated lipocalin during the perioperative period in video laparoscopic bariatric surgery

OBJECTIVES:

Video laparoscopic bariatric surgery is the preferred surgical technique for treating morbid obesity. However, pneumoperitoneum can pose risks to the kidneys by causing a decrease in renal blood flow. Furthermore, as in other surgical procedures, laparoscopic bariatric surgery triggers an acute inflammatory response. Neutrophil gelatinase-associated lipocalin is an early and accurate biomarker of renal injury, as well as of the inflammatory response. Anesthetic drugs could offer some protection for the kidneys and could attenuate the acute inflammatory response from surgical trauma. The objective of this study was to compare the effects of two types of anesthetics, propofol and sevoflurane, on the serum levels of neutrophil gelatinase-associated lipocalin during the perioperative period in laparoscopic bariatric surgery.

METHODS:

Sixty-four patients scheduled for laparoscopic bariatric surgery were randomized into two anesthesia groups and were administered either total intravenous anesthesia (propofol) or inhalation anesthesia (sevoflurane). In the perioperative period, blood samples were collected at three time points (before anesthesia, 6 hours after pneumoperitoneum and 24 hours after pneumoperitoneum) and urine output was measured for 24 hours. Acute kidney injuries were evaluated by examining both the clinical and laboratory parameters during the postoperative period. The differences between the groups were compared using non-parametric tests. ReBEC (http://www.ensaiosclinicos.gov.br/rg/recruiting/): RBR-8wt2fy

RESULTS:

None of the patients developed an acute kidney injury during the study and no significant differences were found between the serum neutrophil gelatinase-associated lipocalin levels of the groups during the perioperative period.

CONCLUSION:

The choice of anesthetic drug, either propofol or sevoflurane, did not affect the serum levels of neutrophil gelatinase-associated lipocalin during the perioperative period in laparoscopic bariatric surgery.