Germinal center B (GCB) and non-GCB cell-like diffuse large B cell lymphomas have similar outcomes following autologous haematopoietic stem cell transplantation

Patients with germinal center B cell-like (GCB) and non-GCB diffuse large B cell lymphomas (DLBCL) receiving first line therapy have distinct prognosis. We explored the differences in outcome following salvage autologous hematopoietic stem cell (HSC) transplantation between patients with GCB and non-GCB DLBCL. Forty-four patients with relapsed and 15 patients with primary refractory chemosensitive disease undergoing BEAM (BCNU [carmustine], etoposide, cytarabine, melphalan) conditioning and autologous HSC were included. Immunohistochemical analysis was performed for CD10, BCL-6, MUM1 (allowing classification into GCB and non-GCB-like DLBCL) and BCL-2. Median follow-up of survivors was 25 months; median age at the time of transplantation was 60 years (range 17–77). Thirty-two patients (54%) were classified as having GCB and 27 (46%) as having non-GCB-like DLBCL. Patients with GCB and non-GCB DLBCL did not differ in the risk of progression after HSC transplant ( P  = 0·78) or overall survival ( P  = 0·48). In multivariate analysis, only time to progression after initial treatment impacted overall survival. We conclude that patients with relapsed or primary refractory chemosensitive GCB and non-GCB-like DLBCL derive similar benefit from autologous HSC transplant.     

Relationship between international normalized ratio values,vitamin K-dependent clotting factor levels and in vivo prothrombin activation during the early and steady phases of oral anticoagulant treatment

BACKGROUND AND OBJECTIVES: In vitro studies have shown that the rate of prothrombin activation is linearly related to the concentration of factor II (FII) in the assay system, suggesting a key role of prothrombin levels in the expression of the antithrombotic activity of oral anticoagulant treatment (OAT). We investigated the in vivo relationship between prothrombin activation and vitamin K-dependent clotting factor levels during the early and steady phases of OAT in patients and in healthy volunteers. DESIGN AND METHODS: The changes in international normalizezd ratio (INR) and in the plasma levels of FVII, FX, FII, protein C (PC) and prothrombin fragment 1.2 (F1+2) induced by OAT were monitored over 9 days in 10 patients not on heparin starting warfarin after heart valve replacement (HVR) and in 9 healthy volunteers submitted to an 8-day course of warfarin treatment. FII and F1+2 plasma levels were also measured in 100 patients on stable oral anticoagulant treatment with INRs ranging from 1.2 to 6.84. RESULTS: Because HVR patients had subnormal FVII, FX and FII levels after surgery, INR values > 2.0 were attained already 24 hours after the first warfarin dose. In healthy volunteers, INR values greater than 2.0 were first observed after 72 hours. Nadir levels of FVII, PC, FX and FII were reached between 40 and 88 hours in HVR patients and between 72 and 192 hours in healthy volunteers. The FII apparent half-disappearance time (t/2) was 99 hours in HVR patients and 115 hours in healthy volunteers (p = ns). In HVR patients there was no normalization of initially elevated F1+2 levels until day 7 with an apparent t/2 of 132 hours. In healthy volunteers, a decrease to subnormal F1+2 levels was observed by day 8 of treatment (apparent t/2 = 107 hours). In both HVR patients and healthy volunteers, FII and PC levels were independent predictors of the changes in F1+2 levels (p = 0.0001). In patients on stable OAT, only FII levels were independent predictors of the variation in F1+2 levels (p = 0.0001). INTERPRETATION AND CONCLUSIONS: During the early phase of oral anticoagulant treatment in vivo prothrombin activation is a function of the balance between FII and PC levels and is not significantly prevented until nadir levels of FII are obtained. This provides an explanation for the requirement of overlapping heparin and oral anticoagulant treatment for at least 48 hours after the achievement of therapeutic INR values in patients with thromboembolic diseases. In addition, in vivo prothrombin activation is a function of FII levels rather than INR values also in patients on stable oral anticoagulant treatment.     

Selective Na+/H+ exchange inhibition by cariporide reduces liver fibrosis in the rat

The aim of this study was to evaluate the effect of cariporide, a selective Na(+)/H(+) exchange inhibitor, on isolated and cultured hepatic stellate cells (HSCs) and in 2 in vivo models of rat liver fibrosis. Platelet-derived growth factor (PDGF)-induced HSC proliferation, evaluated by measuring the percentage of bromodeoxyuridine-positive cells, was significantly inhibited by cariporide, with a maximal effect at 10 micromol/L. Incubation with cariporide did not inhibit PDGF-induced extracellular-regulated kinase 1/2 (ERK1/2), Akt (a downstream component of the phosphatidylinositol [PI]-3 kinase pathway), and protein kinase C (PKC) activation but reduced PDGF-induced activation of the Na(+)/H(+) exchanger, with a maximal effect at 10 micromol/L. Rats treated with dimethylnitrosamine (DMN; 10 mg/kg) for 1 and 5 weeks received a diet with or without 6 ppm cariporide. Treatment with cariporide reduced the degree of liver injury, as determined by alanine aminotransferase (ALT) values, also when administered after the induction of hepatic damage. This was associated with reduced HSC activation and proliferation and reduced collagen deposition, as determined by morphometric evaluation of alpha-smooth muscle actin (SMA)/proliferating cell nuclear antigen-positive cells and percentage of Sirius red-positive parenchyma, respectively. Moreover, cariporide was also able to reduce alpha(1)I procollagen messenger RNA (mRNA) expression. Similar effects were observed in bile duct-ligated (BDL) rats. In conclusion, selective inhibition of the Na(+)/H(+) exchanger by cariporide may represent an effective therapeutic strategy in the treatment of hepatic fibrosis.     

Comparison between QRS duration at standard ECG and signal-averaging ECG for arrhythmic risk stratification after surgical repair of tetralogy of fallot

INTRODUCTION: Surgical repair of tetralogy of Fallot is complicated by the occurrence of ventricular tachycardia (VT). Among different indexes proposed to assess prognosis of these patients, the study of QRS and repolarization provided useful information. Controversial results come from the analysis of signal-averaging ECG (SAECG). The aim of our study was to identify patients operated for tetralogy of Fallot at higher risk of sudden death by means of SAECG. METHODS AND RESULTS: Sixty-six consecutive patients, mean age 26 +/- 10 years, were studied 17.7 +/- 5.8 years after total correction for tetralogy of Fallot using standard ECG, 24-hour Holter recordings, SAECG, and echocardiography. The following variables were measured: standard QRS duration, filtered QRS duration (fQRS), high-frequency and low-amplitude signal duration (HFLA), root mean square of the mean voltage in the terminal portion of filtered QRS (RMS), left and right end-diastolic volumes, and ejection fractions. During a mean follow-up period of 7.3 +/- 3.1 years, 12 patients had episodes of sustained VT and two of them suddenly died. All patients had complete right bundle branch block. Patients with VT were characterized by a significantly longer fQRS duration at all filter settings. On the contrary, there was no difference in standard QRS duration in patients with or without VT. At a multivariate analysis, left ventricular ejection fraction and fQRS were independent predictors for VT. CONCLUSIONS: A longer fQRS duration is associated with an increased risk in developing malignant ventricular arrhythmias in asymptomatic patients after total correction of tetralogy of Fallot.     

Distinguishing visceral leishmaniasis from intolerance to pegylated interferon-alpha in a thalassemic splenectomized patient treated for chronic hepatitis C

A 37-year-old splenectomized man affected by beta-thalassemia and chronic hepatitis, recently treated with pegylated interferon-alpha (Peg-IFN), was admitted because of elevated fever lasting 3 months and unresponsiveness to broad-spectrum antibiotics. Laboratory studies showed white blood cell and platelet counts within the normal range but lower than observed before Peg-IFN treatment and an elevated erythrocyte sedimentation rate. The blood transfusion rate was reported to be increased compared with the period preceding Peg-IFN treatment. A diagnosis of visceral leishmaniasis (VL) was made after Leishmania amastigotes were identified from Giemsa-stained smears of bone marrow aspirates. Cure occurred after liposomal amphotericin B was administered. Symptoms of VL may be difficult to distinguish from the manifestations of Peg-IFN intolerance. We suggest that VL must be suspected in any immunodepressed patient with an unexplained fever and a history of exposure in an endemic area.     

Urinary incontinence in the elderly: relation to cognitive and motor function

Urinary incontinence is a common problem in older subjects, very often wrongfully accepted as a normal part of the aging process. A total of 520 subjects (208 males and 312 females; mean age 74.8 +/- 11.8 years), from both private- and nursing-home dwelling populations, were included in this study aimed to estimate the incidence of urinary incontinence and identify factors associated with condition, in aged subjects. The incidence and type of urinary incontinence (stress, urge or mixed incontinence) were assessed by structured questionnaires and diagnosis was confirmed by a seven-day consecutive voiding diary. Assessment of physical, cognitive and emotional functions was performed on each subject using the Mini Mental State Examination (MMSE), Instrumental Activities of Daily Living Scale (IADL), Tinetti Scale (gait), Tinetti Scale (balance) and Geriatric Depression Scale (GDS) instruments. In the total population sample the incidence of urinary incontinence was 47.9%. The incontinence cases were classified, according to the different types, as: stress incontinence (males: 3.4%; females: 8.7%; males+females: 6.5%); urge incontinence (males: 27.4%; females: 31.4%; males+females: 29.8%); mixed incontinence (males: 20.2%; females: 5.8%; males+females: 11.5%). In the total population sample, no significant relationship was found between age and prevalence of urinary incontinence. In the elderly female group, age significantly correlated in a direct manner with urge incontinence (P<0.01) and inversely with stress incontinence (P<0.001). Only in the male sex group age significantly correlated with mixed incontinence (P<0.005). Multiple linear regression analysis showed that the dependent variable 'incontinence' could be predicted by MMSE (P<0.001) in the male sex group and by the Tinetti Scale (gait) (P<0.001) in the female sex group.     

Increased IGF-I : IGFBP-3 ratio in patients with hepatocellular carcinoma

BACKGROUND: The development of hepatocellular carcinoma in liver cirrhosis is associated with altered synthesis and secretion of several growth factors. AIM: The aim of this prospective study was to investigate the potential implication of IGF-I and its major binding protein (IGFBP-3) in the development of hepatocellular carcinoma. PATIENTS AND METHODS: IGF-I and IGFBP-3 were measured in 150 healthy subjects, 40 patients with liver cirrhosis and 63 with liver cirrhosis and untreated hepatocellular carcinoma. The ratio between IGF-I and IGFBP-3 was also calculated. RESULTS: Serum IGF-I (70 +/- 10 and 65 +/- 7 vs. 185 +/- 6.4 microg/l, P < 0.001) and IGFBP-3 levels (1225 +/- 113 and 984 +/- 67 vs. 3017 +/ -80 microg/l, P < 0.001) were lower in patients with liver cirrhosis, without or with hepatocellular carcinoma, than in controls. Age was negatively correlated with IGF-I levels in patients with liver cirrhosis (r = -0.6; P = 0.0002) as well as in controls (r = -0.8, P < 0.0001), but not in patients with hepatocellular carcinoma (r = -0.2; P = 0.2). Additionally, in patients with liver cirrhosis (r = -0.54; P = 0.0003) and more weakly in those with hepatocellular carcinoma (r = -0.24; P = 0.04) IGF-I levels were negatively correlated with liver failure measured according with Child class. Despite patients with class C hepatocellular carcinoma being older than those in the same functional class with cirrhosis (64 +/- 2 vs. 57 +/- 12 years, P < 0.01), they had a significantly increased IGF-I : IGFBP-3 ratio (0.18 +/- 0.05 vs. 0.41 +/- 0.09, P = 0.04), due mostly to increased IGF-I levels (27.1 +/- 5.6 vs. 42 +/- 6.2 microg/l) as IGFBP-3 levels were similar to patients with cirrhosis (734 +/- 81 vs. 679 +/- 83 microg/l). CONCLUSIONS: Hepatocellular carcinoma is associated with a higher IGF-I : IGFBP-3 ratio than that found in patients with liver cirrhosis and a similar degree of liver failure.