The genotype nucleophosmin mutated and FLT3‐ITD negative is characterized by high bax/bcl‐2 ratio and favourable outcome in acute myeloid leukaemia

Nucleophosmin gene (NPM1) mutations characterize acute myeloid leukaemia (AML) with normal karyotype and frequently co‐exist with FLT3 internal tandem duplications (ITD). We evaluated bcl‐2, bax, NPM1 and FLT3‐ITD in 222 AML patients. Bax/bcl‐2 ratio >0·35 and NPM1 without FLT3‐ITD were significantly associated (P = 0·0001). NPM1‐mutated (mt)/FLT3‐ITD negative patients showed a higher complete remission (CR) rate (90%, P = 0·0002) and a longer overall survival (OS, P = 0·00007). NPM1‐mt/FLT3‐ITD negative plus bax/bcl‐2 > 0·35 subset showed a very high CR rate (96%), very long OS (P = 0·00005) and disease‐free survival (P = 0·004). The favourable prognosis of NPM1‐mt/FLT3‐ITD negative patients might be explained by a higher bax/bcl‐2 ratio.     

Predictors of postoperative hematocrit and association of hematocrit with adverse outcomes for coronary artery bypass graft surgery patients with cardiopulmonary bypass

Abstract Objective: To determine predictors of low intensive care unit (ICU) admission hematocrit, and to determine if low hematocrit is associated with postoperative outcomes for coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass. Methods: We performed a retrospective study of 8417 patients who underwent CABG surgery on cardiopulmonary bypass in New York in 2007. Patients with very low ICU admission hematocrit (≤21.9%) and low ICU admission hematocrit (22.0% to 25.9%) were identified. Significant independent predictors of low and very low ICU admission hematocrit, and the independent impact of each of these states on adverse outcomes were identified. Results: A total of 1.1% had very low hematocrit and 8.3% had low hematocrit. Significant independent predictors for either low or very low hematocrit included older age, females, lower body surface area, lower ventricular function, Hispanic ethnicity, non‐Caucasian race, high creatinine, previous cardiac surgery, absence of left main disease, and emergency transfer to the operating room following catheterization or percutaneous coronary intervention. Patients with hematocrit ≤21.9% had significantly higher risk‐adjusted rates of postoperative bleeding (adjusted OR = 4.37, 95% CI [1.97, 9.68, respiratory failure (adjusted OR = 2.85, 95% CI [1.45, 5.63]), and one or more complications than patients with normal hematocrit. Patients with hematocrit between 22.0% and 25.9% also had higher complication rates. Conclusion: It is important for cardiovascular surgical teams to be aware of risk factors that predispose patients to unacceptable hematocrit values, to monitor values closely, and to treat accordingly in the operating room when low values occur. (J Card Surg 2010;25:638‐646)     

Hemagglutinin protein is a primary target of the measles virus-specific HLA-A2-restricted CD8+ T cell response during measles and after vaccination

To characterize the measles virus (MV)-specific T cell responses important for evaluation of measles vaccines, human leukocyte antigen (HLA)-A2-positive and -negative adults immunized with measles-mumps-rubella vaccine were studied. Both groups developed increases in antibody and in interferon (IFN)- gamma -producing cells in response to pooled hemagglutinin (H) and fusion peptides. HLA-A2-binding peptides were predicted for all MV-encoded proteins and confirmed by T2 cell stabilization. Twenty-nine peptides were tested, and 19 (6 from H) stimulated increased IFN- gamma secretion in a majority of vaccinees. Peptide-loaded HLA-A2 tetramers or immunoglobulin dimers documented MV-specific CD8+ T cell responses after vaccination and during measles and confirmed new A2 epitopes in H (250-259 and 516-525 aa) and matrix (M; 50-58 aa) protein and previously described epitopes in H (30-38 aa), M (211-219 aa), and nonstructural protein C (84-92 aa). No single peptide dominated the response. We conclude that H is an important stimulus for CD8+ T cell as well as for antibody responses in HLA-A2-positive individuals.     

Rapamycin inhibits PAI-1 expression and reduces interstitial fibrosis and glomerulosclerosis in chronic allograft nephropathy

BACKGROUND: Chronic allograft nephropathy (CAN) is characterized by deposition of extracellular matrix (ECM) in all renal compartments. PAI-1 seems to play a pivotal role in ECM turnover in CAN. Rapamycin has been shown to improve long-term graft survival in patients with CAN. The aim of the study was to evaluate the molecular mechanisms underlying the beneficial effects of rapamycin on CAN progression at glomerular and tubulointerstitial level. METHODS: After a biopsy-proven CAN diagnosis (T0), 18 patients on calcineurin inhibitors (CNI) were randomly assigned in a 2:1 ratio to continue CNI (6 patients) or to receive rapamycin (RAPA; 12 patients). After 2 years of treatment (T24), all patients underwent a second renal biopsy. Morphometric analysis was conducted at T0 and at T24. PAI-1 expression was evaluated at T0 and T24 by immunohistochemistry. We evaluated the effect of rapamycin on PAI-1 gene expression in cultured proximal tubular cells incubated with CD40L or thrombin, two potential CAN pathogenic mediators. RESULTS: The RAPA group showed a significant regression of glomerulosclerotic lesions and only a 26% increase in interstitial fibrosis after 2 years compared to baseline, whereas the CNI group showed progression of glomerulosclerosis and 112% increase in fibrosis. Glomerular and tubulointerstitial PAI-1 expression was reduced compared to the baseline in the RAPA group, while they were unchanged in the CNI group. In vitro data showed that rapamycin significantly reduced PAI-1 gene expression induced by both CD40L and thrombin in proximal tubular epithelial cells. CONCLUSIONS: These data suggest that rapamycin may modulate ECM deposition in CAN reducing PAI-1 expression.     

Correlation of epidermal nerve fiber density with pain-related evoked potentials in HIV neuropathy

HIV associated sensory neuropathy is a common neurological disorder with reported prevalence of 53%. When only small fibers are involved, the diagnosis of neuropathy remains difficult since standard nerve conduction studies generally are unremarkable. We assessed a method to identify small-fiber neuropathy using electrically evoked pain-related potentials and correlated the electrophysiological results with intraepidermal nerve fiber density in patients with HIV associated sensory neuropathy. Nineteen HIV positive patients were investigated for clinically diagnosed peripheral neuropathy with Neuropathy Symptoms Score (NSS)  3 and Neuropathy Disability Score (NDS)  5. Nine healthy HIV negative control subjects were recruited. We performed standard nerve conduction testing, electrically evoked pain-related potentials and skin biopsy in all participants. Pain-related evoked potentials revealed abnormalities in all HIV positive neuropathy patients, while standard nerve conduction testing was abnormal in eight patients only. Pain-related evoked potential latencies and amplitudes strongly correlated with intraepidermal nerve fiber density. The method of pain-related evoked potential conduction appears to be a sensitive, fast, non-invasive technique for the detection of small-fiber neuropathy and may prove to become a valuable diagnostic asset.     

Single amino acid substitution in aquaporin 11 causes renal failure

A screen of recessive mutations generated by the chemical mutagen n-ethyl-n-nitrosourea (ENU) mapped a new mutant locus (5772SB) termed sudden juvenile death syndrome (sjds) to chromosome 7 in mice. These mutant mice, which exhibit severe proximal tubule injury and formation of giant vacuoles in the renal cortex, die from renal failure, a phenotype that resembles aquaporin 11 (Aqp11) knockout mice. In this report, the ENU-induced single-nucleotide variant (sjds mutation) is identified. To determine whether this variant, which causes an amino acid substitution (Cys227Ser) in the predicted E-loop region of aquaporin 11, is responsible for the sjds lethal renal phenotype, Aqp11-/sjds compound heterozygous mice were generated from Aqp11 +/sjds and Aqp11 +/- intercrosses. The compound heterozygous Aqp11 -/sjds offspring exhibited a lethal renal phenotype (renal failure by 2 wk), similar to the Aqp11 sjds/sjds and Aqp11-/- phenotypes. These results demonstrate that the identified mutation causes renal failure in Aqp11 sjds/sjds mutant mice, providing a model for better understanding of the structure and function of aquaporin 11 in renal physiology.