阵发性睡眠性血红蛋白尿症与血栓发生的研究进展

阵发性睡眠性血红蛋白尿症(PNH)是一种克隆性造血干细胞功能紊乱所致罕见性骨髓功能衰竭性疾病,以血管内溶血性贫血,全血细胞减少和血栓为表现。PNH虽是良性疾病,但其并发症严重影响患者生活质量和生存时间,其中最常见严重并发症是血栓。     

Suicidal ideation is associated with nighttime wakefulness in a community sample

Study ObjectivesNocturnal wakefulness is a risk factor for suicide and suicidal ideation in clinical populations. However, these results have not been demonstrated in general community samples or compared to sleep duration or sleep quality. The present study explored how the timing of wakefulness was associated with suicidal ideation for weekdays and weekends.MethodsData were collected from 888 adults aged 22–60 as part of the Sleep and Healthy Activity, Diet, Environment, and Socialization study. Suicidal ideation was measured by the Patient Health Questionnaire-9, while timing of wakefulness was estimated from the Sleep Timing Questionnaire. Binomial logistic regressions estimated the association between nocturnal (11 pm–5 am) and morning (5 am–11 am) wakefulness and suicidal ideation.ResultsNocturnal wakefulness was positively associated with suicidal ideation on weekdays (OR: 1.44 [1.28–1.64] per hour awake between 11:00 pm and 05:00 am, p < 0.0001) and weekends (OR: 1.22 [1.08–1.39], p = 0.0018). Morning wakefulness was negatively associated with suicidal ideation on weekdays (OR: 0.82 [0.72–0.92] per hour awake between 05:00 am and 11:00 am, p = 0.0008) and weekends (OR: 0.84 [0.75–0.94], p = 0.0035). These associations remained significant when adjusting for sociodemographic factors. Additionally, nocturnal wakefulness on weekdays was associated with suicidal ideation when accounting for insomnia, sleep duration, sleep quality, and chronotype (OR 1.25 [1.09–1.44] per hour awake, p = 0.002).ConclusionWakefulness at night was consistently associated with suicidal ideation. Additionally, morning wakefulness was negatively associated with suicidal ideation in some models. Although these findings are drawn from a non-clinical sample, larger longitudinal studies in the general population are needed to confirm these results.     

Inhibiting the C5-C5a receptor axis

Activation of the complement system is a major pathogenic event that drives various inflammatory responses in numerous diseases. All pathways of complement activation lead to cleavage of the C5 molecule generating the anaphylatoxin C5a and, C5b that subsequently forms the terminal complement complex (C5b-9). C5a exerts a predominant pro-inflammatory activity through interactions with the classical G-protein coupled receptor C5aR (CD88) as well as with the non-G protein coupled receptor C5L2 (GPR77), expressed on various immune and non-immune cells. C5b-9 causes cytolysis through the formation of the membrane attack complex (MAC), and sub-lytic MAC and soluble C5b-9 also possess a multitude of non-cytolytic immune functions. These two complement effectors, C5a and C5b-9, generated from C5 cleavage, are key components of the complement system responsible for propagating and/or initiating pathology in different diseases, including paroxysmal nocturnal hemoglobinuria, rheumatoid arthritis, ischemia-reperfusion injuries and neurodegenerative diseases. Thus, the C5-C5a receptor axis represents an attractive target for drug development. This review provides a comprehensive analysis of different methods of inhibiting the generation of C5a and C5b-9 as well as the signalling cascade of C5a via its receptors. These include the inhibition of C5 cleavage through targeting of C5 convertases or via the C5 molecule itself, as well as blocking the activity of C5a by neutralizing antibodies and pharmacological inhibitors, or by targeting C5a receptors per se. Examples of drugs and naturally occurring compounds used are discussed in relation to disease models and clinical trials. To date, only one such compound has thus far made it to clinical medicine: the anti-C5 antibody eculizumab, for treating paroxysmal nocturnal hemoglobinuria. However, a number of drug candidates are rapidly emerging that are currently in early-phase clinical trials. The C5-C5a axis as a target for drug development is highly promising for the treatment of currently intractable major human diseases.     

Paroxysmal nocturnal haemoglobinuria: Nature's gene therapy?

The development of paroxysmal nocturnal haemoglobinuria (PNH) requires two coincident factors: somatic mutation of the PIG-A gene in one or more haemopoietic stem cells and an abnormal, hypoplastic bone marrow environment. When both of these conditions are met, the fledgling PNH clone may flourish. This review will discuss the pathophysiology of this disease, which has recently been elucidated in some detail.     

Eculizumab Bridging before Bone Marrow Transplant for Marrow Failure Disorders Is Safe and Does Not Limit Engraftment

Paroxysmal nocturnal hemoglobinuria (PNH) often develops secondary to other bone marrow failure (BMF) disorders, especially aplastic anemia (AA). Patients with the AA/PNH syndrome may require treatment with both eculizumab to reduce intravascular hemolysis and the risk of thrombosis and allogeneic stem cell transplant for the severe BMF. There has been concern that eculizumab could adversely affect the outcomes for transplant in these patients. This is a retrospective, single-center study of severe AA (SAA)/PNH patients treated with eculizumab immediately before the start of conditioning for transplant. Metrics of engraftment and infectious outcomes are described. Eight patients with SAA/PNH and PNH-related symptoms were treated with eculizumab and then proceeded to transplant. All were successfully transplanted without adverse events related to C5 blockage before conditioning. All were also cured of their both PNH and SAA. Eculizumab is safe and efficacious in patients with PNH clones who require transplant. This is sometimes required to “bridge” patients before bone marrow transplantation and does not appear to adversely impact outcomes even when using HLA matched unrelated or haploidentical donors.     

Discovering C3 targeting therapies for paroxysmal nocturnal hemoglobinuria: Achievements and pitfalls

The treatment of paroxysmal nocturnal hemoglobinuria (PNH) was revolutionized by the introduction of the anti-C5 agent eculizumab, which resulted in sustained control of intravascular hemolysis, leading to transfusion avoidance and hemoglobin stabilization in at least half of all patients. Nevertheless, extravascular hemolysis mediated by C3 has emerged as inescapable phenomenon in PNH patients on anti-C5 treatment, frequently limiting its hematological benefit. More than 10 years ago we postulated that therapeutic interception of the complement cascade at the level of C3 should improve the clinical response in PNH. Compstatin is a 13-residue disulfide-bridged peptide binding to both human C3 and C3b, eventually disabling the formation of C3 convertases and thereby preventing complement activation via all three of its activating pathways. Several generations of compstatin analogs have been tested in vitro, and their clinical evaluation has begun in PNH and other complement-mediated diseases. Pegcetacoplan, a pegylated form of the compstatin analog POT-4, has been investigated in two phase I/II and one phase III study in PNH patients. In the phase III study, PNH patients with residual anemia already on eculizumab were randomized to receive either pegcetacoplan or eculizumab in a head-to-head comparison. At week 16, pegcetacoplan was superior to eculizumab in terms of hemoglobin change from baseline (the primary endpoint), as well as in other secondary endpoints tracking intravascular and extravascular hemolysis. Pegcetacoplan showed a good safety profile, even though breakthrough hemolysis emerged as a possible risk requiring additional attention. Here we review all the available data regarding this innovative treatment that has recently been approved for the treatment of PNH.     

Treatment for nocturnal enuresis: The current state in Japan

Nocturnal enuresis is common problem in children with a prevalence as high as 20% among children aged 5. Though nocturnal enuresis does not directly impose imminent danger to a patient's life, children with enuresis and their parents can be psychologically suffering in day‐to‐day life, including in school activities. Therefore, it is important to provide an explanation regarding the cause of nocturnal enuresis, how to approach the disorder, the course, and the outlook leading to the planned treatment. The cause of enuresis is considered to be a mismatch between nocturnal diuresis and nocturnal bladder capacity, nocturnal polyuria due to a lack of circadian change in antidiuretic hormones, and a developmental delay in the voiding mechanisms. Therefore, patients can be classified as the type associated with a large amount of urine at night (polyuria type), the type that is associated with a functionally small bladder capacity (bladder type), the type associated with both the aforementioned (mixed type), or the type that does not fall under any of these (normal type). Based on this logic, although the International Children's Continence Society has issued the standardization document, in which the enuresis alarm and desmopressin therapy are recommended as the first line treatment, a different tack has been taken in Japan, where the therapeutic strategy is plotted depending on the type of enuresis; pharmacotherapy for enuretic children aged 6 years or older includes desmopressin acetate for polyuria type, anticholinergic agents for bladder type, and a combination of these agents for mixed type.     

Seizure duration and latency of hypermotor manifestations distinguish frontal from extrafrontal onset in sleep‐related hypermotor epilepsy

Sleep‐related hypermotor epilepsy (SHE) is an epilepsy syndrome that is characterized by the occurrence of sleep‐related hypermotor seizures of variable complexity and duration. Seizures usually arise in the frontal lobe, but extrafrontal seizure onset zones are well described. To identify clinically relevant ictal features of SHE that could distinguish a frontal from an extrafrontal onset zone, we conducted a retrospective analysis of seizure characteristics in 58 patients with drug‐resistant SHE (43 frontal and 15 extrafrontal) who underwent video‐stereo‐electroencephalographic recordings and became seizure‐free after epilepsy surgery. We found that the mean duration of electrographic seizures and clinically observable ictal manifestations were significantly shorter in frontal SHE compared to extrafrontal SHE. The mean latency between electrographic seizure onset and the onset of hypermotor manifestations was also shorter in frontal SHE. Accordingly, a latency > 5 seconds between the first video‐detectable movement (eg, eye opening or a minor motor event) and the onset of hypermotor manifestations yielded a sensitivity of 75% and a specificity of 90% for an extrafrontal onset, thereby indicating that specific ictal features in SHE can provide clinically useful clues to increase diagnostic accuracy in this syndrome.     

Polygraphic findings of 47 cases with respiratory inhibition after crying

Abstract

Objective: To report the polygraphic findings of infants with respiratory inhibition after crying (RIAC).

Methods: We screened for RIAC among infants with a gestational age ≥36 weeks using our established method with cranial ultrasonography, SpO₂ monitoring and polygraphy. RIAC is defined as central apnea that occurred immediately after crying with a decrease in SpO₂ to <60%, followed by repeated irregular respiration and apnea as the respiration gradually recovered. The subjects were infants with RIAC for whom we could study the polygraphic findings in detail.

Results: Forty-seven RIAC cases were included in the present analysis. The frequency of RIAC was 2.1 (1.2–7.0) times per 24?h. The maximum duration of respiratory inhibition was 78.0 (52.6–109.0) s. The maximum duration of SpO₂ <60% during RIAC was 39.0 (9.8–93.2) s. The minimum SpO₂ value during RIAC was 53.0% (42.2–58.0%). The minimum heart rate during RIAC was 103.0 (79.1–127.1) bpm.

Conclusions: RIAC is observed among healthy infants, and they experience repeated prolonged hypoxemia.     

每日小剂量他达拉非治疗骨盆骨折尿道断裂后勃起功能障碍的疗效观察

目的:评价每日小剂量他达拉非治疗骨盆骨折尿道断裂(PFUD)后勃起功能障碍(ED)的疗效。方法:2008年1月至2011年12月共有46例骨盆骨折尿道断裂后ED患者纳入观察。患者年龄25～51(33.9±7.2)岁,受伤时间3～72(19.6±12.7)个月。所有患者自诉受伤前的性功能正常。患者在未服用5型磷酸二酯酶抑制剂的情况下进行夜间勃起周径和硬度测量(NPTR)。根据NPTR检测结果将患者分为有夜间勃起异常组和无夜间勃起组。对所有患者给予每晚他达拉非10 mg治疗3个月,采用IIEF-5评分、性生活日记问题2和问题3评价治疗效果。结果:38例(82.6%)患者完成检查和治疗,8例失访。NPTR检测证实夜间勃起异常26例(68.4%),无夜间勃起12例(31.6%)。他达拉非治疗3个月后,夜间勃起异常组患者IIEF-5改善明显高于无夜间勃起组(P<0.05),夜间勃起异常组患者对SEP2和SEP3回答"是"的比例明显高于无夜间勃起组(76.9%vs41.7%,65.4%vs 25.0%,P<0.05)。结论:每日小剂量他达拉非可有效改善PFUD后ED患者的勃起功能,有夜间勃起的患者治疗效果更明显。