Prognostic value of paroxysmal nocturnal haemoglobinuria clone presence in aplastic anaemia patients treated with combined immunosuppression: results of two‐centre prospective study

Paroxysmal nocturnal haemoglobinuria (PNH) clones are frequently detected in patients with aplastic anaemia (AA). To evaluate the prognostic role of PNH clone presence we conducted a prospective study in 125 AA patients treated with combined immunosuppressive therapy (IST). Seventy‐four patients (59%) had a PNH clone (PNH+ patients) at diagnosis, with a median clone size of 0·60% in granulocytes and 0·15% in red blood cells. The response rate at 6 months was higher in PNH+ patients than that in PNH‐ patients, both after first‐ and second‐line IST: 68% vs. 45%, P = 0·0164 and 53% vs. 13%, P = 0·0502 respectively. Moreover, 42% of PNH+ patients achieved complete remission compared with only 16% of PNH‐ patients (P = 0·0029). In multivariate logistic regression analysis, PNH clone presence (odds ratio 2·56, P = 0·0180) and baseline absolute reticulocyte count (ARC) ≥30 × 10⁹/l (odds ratio 5·19, P = 0·0011) were independent predictors of response to treatment. Stratification according to PNH positivity and ARC ≥30 × 10⁹/l showed significant distinctions for cumulative incidence of response, overall and failure‐free survival. The results of this prospective study confirmed the favourable prognostic value of PNH clone presence in the setting of IST for AA.     

Aripiprazole for the treatment of pediatric bipolar I disorder: a 30‐week,randomized, placebo‐controlled study

Objective: To evaluate the long‐term efficacy, safety, and tolerability of aripiprazole in pediatric subjects with bipolar I disorder. Methods: A randomized, double‐blind, 30‐week, placebo‐controlled study of aripiprazole (10 or 30 mg/day) in youths (10–17 years) with bipolar I disorder (manic or mixed) ± psychotic features (n = 296) was performed. After four weeks, acute treatment completers continued receiving ≤26 weeks of double‐blind treatment (n = 210). The primary outcome was Young Mania Rating Scale (YMRS) total score change. Results: Of the 210 subjects who entered the 26‐week extension phase, 32.4% completed the study (45.3% for aripiprazole 10 mg/day, 31.0% for aripiprazole 30 mg/day, and 18.8% for placebo). Both aripiprazole doses demonstrated significantly (p < 0.001) greater improvements in YMRS total score at endpoint compared with placebo in protocol‐specified last observation carried forward analyses, but not in observed case or mixed‐model repeated measures at week 30. Overall time to all‐cause discontinuation was longer for aripiprazole 10 mg/day (15.6 weeks) and aripiprazole 30 mg/day (9.5 weeks) compared with placebo (5.3 weeks; both p < 0.05 versus placebo). Both aripiprazole doses were significantly superior to placebo regarding response rates, Children’s Global Assessment of Functioning and Clinical Global Impressions‐Bipolar severity of overall and mania scores at endpoint in all analyses. Commonly reported adverse events included headache, somnolence, and extrapyramidal disorder. Conclusions: Aripiprazole 10 mg/day and 30 mg/day were superior to placebo and generally well tolerated in pediatric subjects with bipolar I disorder up to 30 weeks. Despite the benefits of treatment, completion rates were low in all treatment arms.     

Reduction of Bulimia Nervosa Symptoms After Psychostimulant Initiation in Patients With Comorbid ADHD: Five Case Reports

Studies reveal a higher occurrence of bulimia nervosa (BN) in patients with attention deficit/hyperactivity disorder (ADHD) compared to controls. Due to this high degree of comorbidity, some clinicians have used psychostimulants in this population. The goal of this article is to describe five patients with comorbid BN and ADHD and their responses to a course of psychostimulants. After medication initiation, all five patients experienced a decrease in binge/purging and an improvement in ADHD symptoms. Overall, the medications were well tolerated. Possible mechanisms underlying the relationship between ADHD and BN, and words of caution are discussed. The need for clinical trials to further evaluate the efficacy of psychostimulants in this population is warranted.     

Human pluripotent stem cell-derived functional sympathetic neurons express ACE2 and RAAS components: a framework for studying the effect of COVID-19 on sympathetic responsiveness

Clinical Autonomic Research -     

Effect of β-hydroxy-β-methylglutaryl coenzyme a reductase inhibitors and antioxidant vitamins on free radical lipid oxidation in rat liver

We studied the effects of two inhibitors of β-hydroxy-β-methylglutaryl coenzyme A reductase, simvastatin and lovastatin, on the lag phase of ascorbate-dependent lipid oxidation in rat liver. Oxidizability of liver biological membranes significantly increased in intact animals and rats with induced hypercholesterolemia after peroral administration of these statins. The lag phase of ascorbate-dependent lipid oxidation in liver biomembranes decreased by 2.1 times in hypercholesterolemic rats. In animals of the lovastatin group this parameter decreased by 4.4 times compared to the control. In intact rats receiving simvastatin, the lag phase of oxidation in biomembranes from the liver decreased practically by 2 times. At the same time, in animals receiving simvastatin in combination with antioxidant vitamins (vitamins E and C, provitamin A) and selenium, the period of induction of oxidation increased by 3.3 times. Our results indicate that β-hydroxy-β-methylglutaryl coenzyme A reductase inhibitors produce a prooxidant effect on the liver, which can be prevented by administration of antioxidant agents. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 4, pp. 390–393, April, 2007     

Autoimmunity, spontaneous tumourigenesis, and IL-15 insufficiency in mice with a targeted disruption of the tumour suppressor gene Fus1

The Fus1 gene resides in the critical 3p21.3 human chromosomal region deleted in lung and breast cancers. Recently, the tumour suppressor properties of Fus1 were confirmed experimentally by intra-tumoural administration of Fus1 that suppressed experimental lung metastasis in mice. We generated Fus1-deficient mice that were viable, fertile, and demonstrated a complex immunological phenotype. Animals with a disrupted Fus1 gene developed signs of autoimmune disease, such as vasculitis, glomerulonephritis, anaemia, circulating autoantibodies, and showed an increased frequency of spontaneous vascular tumours. Preliminary analysis of immune cell populations revealed a consistent defect in NK cell maturation in Fus1 null mice that correlated with changes in the expression of IL-15. Injection of IL-15 into Fus1 knockout mice completely rescued the NK cell maturation defect. Based on these results, we propose the hypothesis that Fus1 deficiency affects NK cell maturation through the reduction of IL-15 production but does not directly alter their developmental capacity. Since acquired immunity was not affected in Fus1-deficient animals, we suggest a relationship between the Fus1 protein and the regulation of innate immunity via IL-15 production. The increased frequency of spontaneous cancers and the development of an autoimmune syndrome in Fus1 null mice imply that these mice could serve as a model for studying molecular mechanisms of anti-tumour immunity and autoimmunity.     

Sequential parallel comparison design with binary and time‐to‐event outcomes

Sequential parallel comparison design (SPCD) has been proposed to increase the likelihood of success of clinical trials especially trials with possibly high placebo effect. Sequential parallel comparison design is conducted with 2 stages. Participants are randomized between active therapy and placebo in stage 1. Then, stage 1 placebo nonresponders are rerandomized between active therapy and placebo. Data from the 2 stages are pooled to yield a single P value. We consider SPCD with binary and with time‐to‐event outcomes. For time‐to‐event outcomes, response is defined as a favorable event prior to the end of follow‐up for a given stage of SPCD. We show that for these cases, the usual test statistics from stages 1 and 2 are asymptotically normal and uncorrelated under the null hypothesis, leading to a straightforward combined testing procedure. In addition, we show that the estimators of the treatment effects from the 2 stages are asymptotically normal and uncorrelated under the null and alternative hypothesis, yielding confidence interval procedures with correct coverage. Simulations and real data analysis demonstrate the utility of the binary and time‐to‐event SPCD.     

Mechanistic study of 1,1-dimethylhydrazine transformation over Pt/SiO2 catalyst

Catalytic oxidation of 1,1-dimethylhydrazine (UDMH) with molecular oxygen over Pt/SiO₂ was studied by in situ FTIR spectroscopy coupled with online MS monitoring of the gas phase. An unusual two-step oxidation process was detected in experiments with the pulse UDMH feeding: initial UDMH oxidation over a fresh platinum surface quickly terminates due to the blockage of active sites; a time-separated second oxidation step corresponds to combustion of the surface residue. This residue consists of C N nitrile groups formed via decomposition of the products of non-oxidative UDMH conversion, such as dimethylamine. The two-step oxidation picture is observed over a broad range of reaction temperatures and oxygen to UDMH ratios.

Unusual two-step oxidation process of 1,1-dimethylhydrazine on Pt/SiO₂ catalyst.     

Molecular characterization of a high A2 beta thalassemia by direct sequencing of single strand enriched amplified genomic DNA

Two families, one of Anglo-Saxon-Dutch descent, and the other, West Indian black, have an atypical beta thalassemia characterized by an unusually high level of Hb A2 in the heterozygous state. Restriction endonuclease mapping showed a deletion of about 1.35 kilobase (kb) in the 5' region of the beta globin gene. Direct sequencing of a specific region of genomic DNA amplified by a new modification of the polymerase chain reaction defined the deletion to be 1,393 base pairs (bp) and to be the same in both families. The deletion extends from 485 bp 5' to the mRNA CAP site to the middle of the second intervening sequence. This deletion, together with three others previously described that remove the 5' end of the beta gene but leave the delta gene intact, are all associated with unusually high levels of Hb A2 in the heterozygous state.