Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies

Generalized arterial calcification of infancy (GACI) is a rare disorder caused by ENPP1 or ABCC6 variants. GACI is characterized by low pyrophosphate, arterial calcification, and high mortality during the first year of life, but the natural course and possible differences between the causative genes remain unknown. In all, 247 individual records for patients with GACI (from birth to 58.3 years of age) across 19 countries were reviewed. Overall mortality was 54.7% (13.4% in utero or stillborn), with a 50.4% probability of death before the age of 6 months (critical period). Contrary to previous publications, we found that bisphosphonate treatment had no survival benefit based on a start-time matched analysis and inconclusive results when initiated within 2 weeks of birth. Despite a similar prevalence of GACI phenotypes between ENPP1 and ABCC6 deficiencies, including arterial calcification (77.2% and 89.5%, respectively), organ calcification (65.8% and 84.2%, respectively), and cardiovascular complications (58.4% and 78.9%, respectively), mortality was higher for ENPP1 versus ABCC6 variants (40.5% versus 10.5%, respectively; p = 0.0157). Higher prevalence of rickets was reported in 70.8% of surviving affected individuals with ENPP1 compared with that of ABCC6 (11.8%; p = 0.0001). Eleven affected individuals presenting with rickets and without a GACI diagnosis, termed autosomal recessive hypophosphatemic rickets type 2 (ARHR2), all had confirmed ENPP1 variants. Approximately 70% of these patients demonstrated evidence of ectopic calcification or complications similar to those seen in individuals with GACI, which shows that ARHR2 is not a distinct condition from GACI but represents part of the spectrum of ENPP1 deficiency. Overall, this study identified an early mortality risk in GACI patients despite attempts to treat with bisphosphonates, high prevalence of rickets almost exclusive to ENPP1 deficiency, and a spectrum of heterogenous calcification and multiple organ complications with both ENPP1 and ABCC6 variants, which suggests an overlapping pathology. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.     

Bromazepam in generalized anxiety

Bromazepam was compared with placebo and with chlorprothixene in a randomized, double-blind group-comparative multicenter trial in general practice. Two hundred and forty-five patients with generalized anxiety disorder (DSM-III 1980) were treated for 2 weeks with two daily doses of bromazepam, 3 mg or chlorprothixene, 15 mg or placebo. Median reductions in Hamilton Anxiety rating were 12 (bromazepam), 10.3 (chlorprothixene) and 7.3 (placebo). The study revealed significant superiority of bromazepam over placebo (median differences 3.3, 95% confidence limits: 0.3 and 6.1) but not over chlorprothixene (median difference 1.4, 95% confidence limits –0.8 and +3.5). Significantly higher rates of tiredness, sedation and hypersomnia were found on bromazepam and chlorprothixene compared to placebo. Tolerance was rated as at least good in 85.6% on bromazepam, in 86% on chlorprothixene and in 87.8% on placebo. Neither previous psychopharmacological treatment nor presence of psychosocial stress were of perceptible influence. Bromazepam and chlorprothixene are both superior to placebo in generalized anxiety states treated in general practice, but spontaneous improvements/placebo effects are substantial.General practice The following general practitioners are gratefully acknowledged for their excellent co-operation: K. Andreasen (Grenaa), T. Andreasen (Helsingoer), C. Bjerre-Christensen (Viby J), J. Brix (Aabenraa), N.B. Caning (Stokkemarke), N. Christensen (Odense), P. Dehn-Jensen (Lyngby), J. Eggert (Langebaek), H. Fuglsang-Damgaard (Havndal), I. Fraemohs (Allingaabro), J. Gylling (Nykoebing Sjaelland), E. Halkjaer-Soerensen (Roedding), B. Hansson (Frederiksvaerk), C. Hauge (Espergaerde), S. Hede (Aalborg), G. Jensen (Copenhagen S), T. Knudsen (Arden), P. Kofod (Vejle), K. Kraen (Varde), V. Lade (Hjoerring), S. Mehlsen (Auning), J. Meyer-Christensen (Hobro), R. Michael (Langebaek), J. Munch (Oersted), L. Moeller-Hansen (Alleroed), U. Moeller (Graasten), K. Nielsen (Malling), S. Kjaerem Nielsen (Copenhagen), P.V. Nielsen (Odense), J. Peulicke (Espergaerde), O. Ravn (Roedding), C.U. Rosenberg (Aarhus), J. Rude (Goerlev), S. Spangsberg (Holbaek), H. Soegaard (Oelgod), O. Tang (Hoersholm)     

Depletion of brain norepinephrine: differential influence on anxiolyic treatment effects

Rationale: Previous studies have demonstrated that anxiolytic-like anticonflict effects can be produced by either (1) acute administration of traditional anti-anxiety compounds (benzodiazepines or barbiturates) or (2) chronic administration of tricyclic (TCA) or monoamine oxidase inhibitor (MAOI) antidepressants. Objective: The present study determined the effects of noradrenergic neuronal depletion on these distinct anticonflict treatments. Methods: After 3 weeks of training in a repeated measures drink suppression conflict paradigm, water-restricted rats consumed 11–14 ml water/session (unpunished responding) and accepted 25–40 shocks/session (punished responding) during control (i.e., non-drug) 10-min test sessions. The noradrenergic neurotoxin DSP4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride; 65 mg/kg, IP] or its vehicle (saline; 1 ml/kg) was administered after 3 weeks of conflict testing. Conflict behavior was then evaluated for 8 weeks post-treatment. In separate groups of DSP4- and vehicle-pretreated subjects, the effects of acute administration (10-min pretreatment) of phenobarbital (5–40 mg/kg) or alprazolam (0.3–2.5 mg/kg) were determined. In a third experiment, the effects of chronic treatment with the TCA desipramine (DMI; 5 mg/kg, twice daily for 8 weeks) or the non-selective MAOI phenelzine (4.0 mg/kg, twice daily for 8 weeks) on conflict behavior were determined in additional groups of DSP4- or vehicle-pretreated subjects. Results: DSP4 treatment produced a modest yet statistically significant decrease in punished responding (i.e., anxiogenic-like effect) relative to vehicle controls. DSP4 pretreatment did not alter the anticonflict effects of acute alprazolam or phenobarbital treatment. In contrast, DSP4 treatment completely abolished the anticonflict effects produced by chronic DMI or chronic phenelzine treatment. Conclusions: Thus, noradrenergic neuronal integrity appears to be required for the anxiolytic-like effects of chronic antidepressant treatment, but not for the anxiolytic-like effects of acute treatment with barbiturates and benzodiazepines. Received: 6 August 1998/Final version: 16 October 1998     

Different patterns of spleen involvement in systemic and malignant mastocytosis

Summary Three cases of splenic involvement in three different types of generalized mastocytosis (systemic mast cell disease) are reported. The macroscopic, histological and ultrastructural modifications of the spleen are described. Each case exhibited a different morphological pattern. Giemsa staining, fluorescence after acridine orange staining and naphthol ASD chloracetate esterase reaction are shown to be valuable for diagnosis. By comparison, immunohistochemistry seemed not to be very useful, because no specific antigens are expressed. These findings are compared to previously published cases. Their value for the diagnosis and the prognosis are discussed.     

Multiple mononeuropathy as the initial presentation of systemic lupus erythematosus — nerve biopsy and response to plasma exchange

Summary A total of 15 patients affected by idiopathic dystonia (7 with generalized and 8 with focal or segmental dystonia) were subjected to therapy with bromocriptine at low doses, pimozide and trihexyphenidyl. The symptoms were evaluated by giving a progressive score in relation to the intensity of the dystonic symptom to each of the body segments involved by the dystonia. Bromocriptine did not significantly modify the dystonia. Pimozide showed a slight nonsignificant improvement of the dystonic symptoms. Trihexyphenidyl was effective in the generalized dystonias, in agreement with previous reports in the literature. The variation in the pharmacological results could be due to the diversity of the dystonic syndromes, which comprise cases that are different in age at onset, site of dystonic symptoms, and evolution.

---

Zusammenfassung Fünfzehn von idiopathischer — und zwar 7 von generalisierter und 8 von fokaler und segmentarischer — Dystonie befallenen Patienten unterzogen sich verschiedenen pharmakologischen Behandlungen mit kleinen Mengen Bromocriptine, Pymozide und Triesifenidile. Die Symptome wurden durch eine fortlaufende Punktzahl bezeichnet, so daß deren Schätzung von der Intensität des Symptoms Dystonie in jedem einzelnen befallenen Körperteil abhing. Die Dystonien wurden durch Bromocriptine nicht bedeutend geändert.Pymozide führte zu einer geringeren, doch unbedeutenden, Besserung der dystonischen Symptome.Triesifenidile wirkte auf die generalisierten Dystonien, in Übereinstimmung mit einigen Literaturangaben.Die Veränderlichkeit der pharmakologischen Ergebnisse wurde auf die Verschiedenheit der dystonischen Syndrome zurückgeführt, unter denen man Fälle versammelt, die sich durch Anfangsalter, Sitz der dystonischen Symptome und Entwicklungsart voneinander unterscheiden.

     

捕获再捕获法估计吸毒人群基数的数据模型研究

目的建立捕获-再捕获法估计吸毒人群基数的分析数据模型.方法收集和分析戒毒所登记资料,确定捕获期和捕获间隔期,建立捕获-再捕获法使用的分析数据模型,以估计当地吸毒人群基数.结果获得建立捕获-再捕获法使用的分析数据模型的方法.结论按照统一的方法建立数据分析模型是运用捕获-再捕获法对吸毒人群基数进行估计的关键.     

系统性红斑狼疮HLA-DM基因与环境危险因素研究

目的探索HLA-DM基因及其与环境危险因素的交互作用对系统性红斑狼疮(SLE)发病的影响.方法采取病例对照研究,用PCR-RFLP的方法确定HLA-DM的基因型,用非条件logistic模型分析SLE的危险因素,用广义线性模型分析环境与基因的交互作用.结果共检测到3种DMA与4种DMB等位基因,其分布在SLE组与正常对照组分布一致.logistic模型分析显示SLE的环境危险因素有5个(潮湿、精神刺激、日晒、刀豆、扁桃体感染),女性个人婚育史因素有3个(出生时母亲的年龄、月经初潮年龄、流产次数).广义线性模型分析提示HLA-DMB*0102与扁桃体感染的交互项效应达到显著水平.结论有多个环境危险因素与SLE的发病有关,HLA-DM基因的遗传多态性对SLE发病及活动性没有独立作用,但HLA-DM基因与某些环境因素存在交互作用.     

孕妇广泛焦虑障碍和血浆DA、NE、5-HT的相关研究

目的 :探讨分娩前孕妇广泛性焦虑障碍与血浆 5 - HT、DA、NE的关系。方法 :首先用心理卫生量表 (SAS、SDS、HAMA、HAMD)筛查孕妇中存在广泛性焦虑和抑郁共病共 4 6例。研究组血浆中五羟色胺 (5 - HT4 6例 )、去甲肾上腺素 (NE4 6例 )、多巴胺 (DA4 5例 )和正常对照组 (5 - HT、DA、NE各 2 0例 )由苏州大学生化工程研究所采用高效液相色谱仪、电化学检测器进行测定。结果 :分娩前孕妇广泛性焦虑障碍血浆 5 - HT、DA、NE和对照组未见明显差异。讨论 :我们在产前经 SAS、HAMA检测发现产前孕妇广泛性焦虑障碍有 74例。我们选择了资料完整诊断明确的产前广泛性焦虑进行了血浆 5 - HT、NE、DA测定结果发现与对照组没有明显差异 ,这说明孕妇在临床上焦虑症状明显 ,但体内血浆神经介质极不稳定 ,神经介质变化在人体内较为复杂 ,使两者没有变化 ,提示孕妇广泛性焦虑障碍患者存在外周交感神经兴奋性增高 ,血浆 5 - HT、NE、DA浓度不能鉴别焦虑症。以上观点还需进一步研究。在妇产科广泛焦虑障碍这一疾病 ,应引起产科医师注意。     

帕罗西汀与阿普唑仑治疗广泛性焦虑症的疗效比较

目的探讨帕罗西汀治疗广泛性焦虑症的临床疗效及安全性。方法将60例符合CCMD-3广泛性焦虑诊断标准患者随机分配至帕罗西汀组和阿普唑仑组,各30例,治疗6周。采用SAS、HAMA和TESS评定疗效及不良反应。结果帕罗西汀与阿普唑仑对广泛性焦虑症均有显著疗效,两组间无显著性差异((P>0.05),帕罗西汀副作用明显少于阿普唑仑((P<0.01)。结论帕罗西汀治疗广泛性焦虑症安全有效,副作用少。     

GROUNDHOG DAY: CAUSE AND EFFECT AND THE PRIMARY IMPORTANCE OF THE FINITE POPULATION INDUCED BY RANDOMIZATION

The logical structure that enables randomized clinical trials to establish cause and effect is reviewed. Statisticians have a major role to define this structure clearly and to help clinicians apply statistical inference in ways directly related to their trials. Scientific importance of establishing limited cause and effect should be accented rather than inferences to generalized populations beyond the scope of a trial's actual random sampling. Authors of clinical reports should clearly define the randomization-induced populations to which their inferences apply. Careful attention to identifying this population of inference can lead to resolution of some issues commonly debated in the analysis of clinical trials. If formal inferences to generalized populations are attempted, these populations should also be carefully described, the assumed random sampling process should be carefully defined, and appropriate methods should be used that correspond with the assumed random sampling process.