Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2)

Summary. Background: Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies against coagulation factor VIII and characterized by spontaneous hemorrhage in patients with no previous family or personal history of bleeding. Although data on several AHA cohorts have been collected, limited information is available on the optimal management of AHA. Objectives: The European Acquired Hemophilia Registry (EACH2) was established to generate a prospective, large‐scale, pan‐European database on demographics, diagnosis, underlying disorders, bleeding characteristics, treatment and outcome of AHA patients. Results: Five hundred and one (266 male, 235 female) patients from 117 centers and 13 European countries were included in the registry between 2003 and 2008. In 467 cases, hemostasis investigations and AHA diagnosis were triggered by a bleeding event. At diagnosis, patients were a median of 73.9 years. AHA was idiopathic in 51.9%; malignancy or autoimmune diseases were associated with 11.8% and 11.6% of cases. Fifty‐seven per cent of the non‐pregnancy‐related cases were male. Four hundred and seventy‐four bleeding episodes were reported at presentation, and hemostatic therapy initiated in 70.5% of patients. Delayed diagnosis significantly impacted treatment initiation in 33.5%. Four hundred and seventy‐seven patients underwent immunosuppression, and 72.6% achieved complete remission. Conclusions: Representing the largest collection of consecutive AHA cases to date, EACH2 facilitates the analysis of a variety of open questions in AHA.     

Low‐molecular‐weight heparin added to aspirin in the prevention of recurrent early‐onset pre‐eclampsia in women with inheritable thrombophilia: the FRUIT‐RCT

Summary. Background: Early‐onset hypertensive disorders (HD) of pregnancy and small‐for‐gestational age infants (SGA) are associated with placental vascular thrombosis, these often recur and are also associated with inheritable thrombophilia. Aspirin reduces the recurrence risk. Objectives: Adding low‐molecular‐weight heparin (LMWH) to aspirin at < 12 weeks gestation reduces the recurrence of HD in women with previous early‐onset HD (pre‐eclampsia, hemolysis, elevated liver enzymes and low platelets [HELLP] syndrome and eclampsia) and/or SGA, in the context of inheritable thrombophilia without antiphospholipid antibodies. Patients/methods: In a multicenter randomized control trial (RCT), 139 women included were < 12 weeks gestation. Inclusion criteria: previous delivery < 34 weeks gestation with HD and/or SGA; inheritable thrombophilia (protein C deficiency, protein S deficiency, activated protein C resistance, factor V Leiden heterozygosity and prothrombin gene G20210A mutation heterozygosity); and no antiphospholipid antibodies detected. Intervention: either daily LMWH (dalteparin, 5000 IU weight‐adjusted dosage) with aspirin 80 mg or aspirin 80 mg alone. Main outcome measures: Primary outcomes: recurrent HD onset (i) < 34 weeks gestation and (ii) irrespective of gestational age. Secondary outcomes: recurrent SGA, preterm birth, maternal/neonatal hospitalization, spontaneous abortion and individual HD. Analysis by intention‐to‐treat. Results: Low‐molecular‐weight heparin with aspirin reduced recurrent HD onset < 34 weeks gestation (risk difference [RD] 8.7%: confidence interval [CI] of RD 1.9–15.5%; P = 0.012; number needed to treat [NNT] 12). Recurrent HD irrespective of gestational age was not different between the arms. No women withdrew as a result of adverse effects. Trial Registration: http://www.isrctn.org ) (isrctn87325378). Conclusions: Adding LMWH to aspirin at < 12 weeks gestation reduces recurrent HD onset < 34 weeks gestation in women with inheritable thrombophilia and prior delivery for HD/SGA <34 weeks. However, close monitoring of the mother and fetus remains important throughout pregnancy.     

CHRONIC SACRAL NEUROMODULATION IN PATIENTS WITH LOWER URINARY TRACT SYMPTOMS: RESULTS FROM A NATIONAL REGISTER

PURPOSE: The Italian Register was created in February 1997 to collect the national results of sacral neuromodulation. All Italian centers at which sacral neuromodulation is performed were invited to participate in our study. We present the results from retrospective and prospective registers. MATERIALS AND METHODS: A total of 196 patients underwent permanent implantation of sacral neuromodulation and were enrolled in the Italian register. There were 18 males and 75 females in the retrospective, and 28 males and 75 females in the prospective studies. Student's t test was used to compare paired values, and the Wilcoxon rank sum and nonparametric tests were used when necessary. RESULTS: Mean incontinent episodes daily plus or minus standard deviation for patients with detrusor instability went from 5.4 +/- 3.9 to 1.1 +/- 1.6 (median 5 and 0, respectively) at 12-month followup (p <0.001). For idiopathic retention average residual volume decreased from 277 to 108 cc (median 287 and 80, respectively), and 50% of patients stopped catheterization and another 13% catheterized once daily at 1-year after implantation. With neurogenic voiding disturbances, the results fluctuated with time from a minimum of 33% to a maximum 66% of patients who did not catheterize at 6-month followup and 12 months after implantation, respectively. At 12-month followup, 50% of patients with hyperreflexia had less than 1 incontinent episode daily. The problem was completely solved in 66% of patients in the retention group. Of patients in the urge incontinent population 39% were completely dry and 23% had less than 1 incontinent episode daily. CONCLUSIONS: Sacral neuromodulation is effective therapy for treating lower urinary tract symptoms resistant to less invasive therapy.     

美国国家骨髓库20年回顾:儿童急性白血病无关供者骨髓移植

自1987年以来,NMDP有效推动了儿童无关供者造血干细胞移植(HCT)的发展.在庆祝NMDP成立20周年之际,本文就儿童急性白血病患者移植所取得的成果和经验加以总结,目的在于进一步提高移植疗效,把握未来研究方向.     

Rituximab and immune tolerance in severe hemophilia A: a consecutive national cohort

Summary.  Background and objectives:  he management of patients with severe hemophilia A and inhibitors to factor VIII (FVIII) resistant to standard immune tolerance is challenging. There have been recent case reports of the successful use of rituximab in up to 57% of patients as part of rescue immune tolerance regimens. Because case reports and small series are prone to the potential bias of reporting good outcomes and relatively short follow up, a consecutive cohort of all patients treated in the UK with prolonged follow up was analyzed. Methods:  A national survey of all Comprehensive Care Haemophilia Cente in the UK. Results:  A total of 15 patients were reported of whom six (40%) achieved a negative inhibitor titer by Bethedsa assay. Durable responses were unusual, observed in only 14% of cases. Clinically significant responses with either a negative inhibitor or an inhibitor titer < 5 BU mL⁻¹ and no spontaneous bleeding with FVIII replacement were observed in seven (47%) cases. Concomitant use of FVIII appeared to be important. Of the 12 patients treated with rituximab and FVIII, six (50%) achieved a negative inhibitor titer and seven (58%) had a clinically beneficial response. None of the three patients treated without FVIII responded. Conclusions:  hese data suggest that the use of rituximab combined with FVIII is a potentially useful treatment for patients with inhibitors resistant to standard immune tolerance, although sustained inhibitor eradication is uncommon.     

S-allylcysteine scavenges singlet oxygen and hypochlorous acid and protects LLC-PK(1) cells of potassium dichromate-induced toxicity.

It has been found that S-allylcysteine (SAC), a garlic-derived compound, has in vivo and in vitro antioxidant properties. In addition, it is known that SAC is able to scavenge different reactive oxygen or nitrogen species including superoxide anion (O(2)(-)), hydrogen peroxide (H(2)O(2)), hydroxyl radical (OH()), and peroxynitrite anion (ONOO(-)) although the IC(5O) values for each reactive species has not been calculated and the potential ability of SAC to scavenge singlet oxygen ((1)O(2)) and hypochlorous acid (HOCl) has not been explored. The purposes of this work was (a) to explore the potential ability of SAC to scavenge (1)O(2) and HOCl, (b) to further characterize the O(2)(-), H(2)O(2), OH(), and ONOO(-) scavenging ability of SAC by measuring the IC(50) values using in vitro assays, and (c) to explore the potential ability of SAC to ameliorate the potassium dichromate (K(2)Cr(2)O(7))-induced cytotoxicity in LLC-PK1 cells in which oxidative stress is involved. The scavenging activity was compared against the following reference compounds: N-acetylcysteine for O(2)(-), sodium pyruvate for H(2)O(2), dimethylthiourea for OH(), lipoic acid and glutathione for (1)O(2), lipoic acid for HOCl, and penicillamine for ONOO(-). It was found that SAC was able to scavenge concentration-dependently all the species assayed with the following IC(5O) (mean+/-SEM, mM): O(2)(-) (14.49+/-1.67), H(2)O(2) (68+/-1.92), OH() (0.68+/-0.06), (1)O(2) (1.93+/-0.27), HOCl (2.86+/-0.15), and ONOO(-) (0.80+/-0.05). When the ability of SAC to scavenge these species was compared to those of the reference compounds it was found that the efficacy of SAC (a) to scavenge O(2)(-), H(2)O(2), OH(), and ONOO(-) was lower, (b) to scavenge HOCl was similar, and (c) to scavenge (1)O(2) was higher. In addition, it was found that SAC was able to prevent K(2)Cr(2)O(7)-induced toxicity in LLC-PK1 cells in culture. It was showed for the first time that SAC is able to scavenge (1)O(2) and HOCl and to ameliorate the K(2)Cr(2)O(7)-induced toxicity.     

Can anaerobic threshold be used as an end-point for therapeutic trials in heart failure?: Lessons from a multicentre randomized placebo-controlled trial

‘Anaerobic threshold’ (AT), proposed as a non-invasiveindex of exercise tolerance, independent of patient motivation,is considered more reliable than exercise duration in assessingthe effect of drug therapy in chronic heart failure (CHF). However,inter-observer variation in patients may be more difficult thanin normal subjects. In a multicentre study, 85 patients from10 centres performed a total of 331 bicycle maximal tests (rampprotocols, 10 watts. min^–1) with respiratory gas analysisby different systems. A central committee reviewed all the tests.Percentages of AT determination ranged from 34% to 71% dependingon the method used. Apart from the respiratory exchange ratio(RER=1) method, which yielded the lowest rate of determination.and the crossing point (when RER=1), which yielded the highestrate, 71%, other methods of determination, such as carbon dioxide(42%), minute ventilation (52%) or ventilatory equivalents plottedvs time (57%), did not dtffer in the rate of AT determination. Thus, even among trained physicians, AT determination was notreliable. The crossing point may nevertheless be a valuableindex from a pragmatic standpoint, although it occurs afterthe actual AT Peak oxygen uptake should remain the main end-pointin assessment of exercise capacity.     

Risk factors for urinary incontinence among postmenopausal Mexican women

Introduction and hypothesis

Previous studies of racial/ethnic variation in urinary incontinence (UI) suggest that population-specific studies of UI risk factors are needed to develop appropriate public health recommendations. We assessed UI risk factors among postmenopausal Mexican women enrolled in the Mexican Teachers’ Cohort.

Methods

We conducted a cross-sectional study among 15,296 postmenopausal women who completed the 2008 questionnaire. UI cases were women who reported experiencing UI during menopause. Self-reported potential UI risk factors included age, reproductive variables, smoking status, adiposity, and several health conditions. We estimated multivariate-adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) for UI using multivariable logistic regression.

Results

Among these postmenopausal women, the prevalence of UI was 14 %. Odds of UI were higher among women with ≥4 children vs nulliparous women (OR 1.43, 95 % CI 1.04–1.96) or body mass index (BMI) ≥30 vs <22 kg/m² (OR 2.00, 95 % CI: 1.55–2.57). Age at first birth <20 vs 20–24 years, past or current vs never smoking, larger waist-to-hip ratio, and history of asthma, high blood pressure, or diabetes were also associated with higher odds of UI (OR 1.2–1.3). We found a trend of lower odds of UI with older age.

Conclusions

Our data suggest that information about UI and UI prevention strategies might be particularly useful for Mexican postmenopausal women with 4 or more children or higher BMI. Further studies with longitudinal UI data, in addition to data on UI severity and subtype, are needed to provide more specific information about UI risk factors to Mexican women.