The sequential analysis of T lymphocyte subsets and interleukin-6 in polymyalgia rheumatica patients as predictors of disease remission and steroid withdrawal

CD4 and CD8 T lymphocyte subsets, the late T cell activation marker, HLA-DR, and serum interleukin-6 (IL-6) levels of 57 polymyalgia rheumatica (PMR) patients were followed over 2 yr to investigate whether they could be used to predict the safe withdrawal of steroid therapy. Cell phenotypes were studied by flow cytometry and IL-6 levels by ELISA. %CD8 cells were reduced below the normal range in PMR patients prior to steroid therapy. In 56% of patients, the %CD8 T lymphocytes failed to return to normal levels when quiescent disease allowed cessation of steroid therapy. Activated CD8 T cells, as detected by HLA-DR positivity, were above the normal range at the initiation of therapy and showed a negative correlation with %CD8 T cells. The serum concentration of IL-6 fluctuated over 24 months, and the correlation between IL-6 and erythrocyte sedimentation rate (ESR) seen prior to treatment was not seen at later intervals. The %CD8 T cell and serum IL-6 levels are not a good indicator of disease activity in PMR and are, therefore, unable to predict the safe withdrawal of steroids.      

High prevalence of nonsense, frame shift, and splice-site mutations in 16 patients with full-blown Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome (WAS) is a fully penetrant X-linked recessive disorder characterized by immunodeficiency, thrombocytopenia, and severe eczema. WAS is a life-threatening disease, with a poor quality of life and high mortality rate in childhood. The gene responsible for the disease has been localized to the proximal short arm of the X- chromosome and recently isolated through positional cloning and named WAS protein (WASP). We have characterized 17 WAS families. We have developed a rapid, nonradioactive screening protocol for identifying WASP gene alterations in genomic DNA. Our method allows simultaneous evaluation of single strand confirmation polymorphism and heteroduplex formation. We have identified 15 novel mutations that involve single basepair changes, or small insertions or deletions, all of which result in premature stop cordon, frame shift with secondary premature stop codon, or splice site defect. These studies document the considerable heterogeneity of the location of mutations in the WASP gene causing full-blown WAS and show the efficiency and rapidity of a screening approach for mutation identification in WAS that will be useful for carrier detection and prenatal diagnosis.     

成人脑死亡判定的循证医学指南更新——美国神经病学会质量标准分会报告

目的就如下问题对美国神经病学会1995年脑死亡判定实践标准进行更新：①符合脑死亡临床判定标准的患者神经功能能恢复吗？②确定患者神经功能永久性停止的恰当观察时间是多长？③有时可能观察到脑死亡患者的复合肢体运动,这是否错误地提示仍然保留脑功能？④何种技术手段判断呼吸停止是相对安全的？⑤是否存在新的辅助检测能准确判断患者脑死亡？方法系统回顾MEDLINE及EMBASE数据库1996年1月-2009年5月收录的文献,其研究仅限于成年人（≥18岁）。结果及建议对成年人,按照美国神经病学会于1995年确定的脑死亡判定实践标准,目前尚无判定为脑死亡患者出现神经功能恢复的报告。脑死亡患者可以存在复合的自发运动及假阳性触发呼吸机。目前还无足够的证据用以确定神经功能不可逆性停止的最短观察时间。通过氧扩散来确定呼吸停止是安全的,但目前还无足够证据确定呼吸停止检测技术的相对安全性。目前还无足够的证据确定新型辅助检测能否准确判断患者全脑功能已经停止。     

Hemoperfusion in the treatment of acute clozapine intoxication in China

BACKGROUND AND AIMS: No systematic study has focused on the characteristics and outcome of acute clozapine intoxication, although clozapine is the most widely used antipsychotic agent in China. The study reported herein examined the features of clozapine intoxication and the therapeutic effect of hemoperfusion (HP). METHODS: In a retrospective chart review, the notes of 47 patients who attempted suicide by ingesting large amounts of clozapine and were treated at the only psychiatric emergency service in Beijing were analyzed. Of the 20 unconscious patients with plasma clozapine concentrations of more than 2000 ng/mL, 14 received a combination of HP and symptomatic treatment, whereas the other 6 and the remaining 27 patients received only symptomatic treatment. Patients' psychiatric conditions and both plasma clozapine and norclozapine concentrations were closely monitored and registered. RESULTS: One patient died of pulmonary edema and subsequent heart failure, but the rest of the patients recovered without any sequelae. Patients who received HP regained consciousness significantly faster than their counterparts with the same level of clozapine plasma concentration (>2000 ng/mL) who did not receive HP. CONCLUSIONS: A combination of HP and symptomatic treatment is the best therapeutic option when plasma clozapine concentration is high.     

Endothelin-converting enzyme 1 promotes re-sensitization of neurokinin 1 receptor-dependent neurogenic inflammation

Background and purpose:

The metalloendopeptidase endothelin-converting enzyme 1 (ECE-1) is prominently expressed in the endothelium where it converts big endothelin to endothelin-1, a vasoconstrictor peptide. Although ECE-1 is found in endosomes in endothelial cells, the role of endosomal ECE-1 is unclear. ECE-1 degrades the pro-inflammatory neuropeptide substance P (SP) in endosomes to promote recycling and re-sensitization of its neurokinin 1 (NK₁) receptor. We investigated whether ECE-1 regulates NK₁ receptor re-sensitization and the pro-inflammatory effects of SP in the endothelium.

Experimental approach:

We examined ECE-1 expression, SP trafficking and NK₁ receptor re-sensitization in human microvascular endothelial cells (HMEC-1), and investigated re-sensitization of SP-induced plasma extravasation in rats.

Key results:

HMEC-1 expressed all four ECE-1 isoforms (a-d), and fluorescent SP trafficked to early endosomes containing ECE-1b/d. The ECE-1 inhibitor SM-19712 prevented re-sensitization of SP-induced Ca²⁺ signals in HMEC-1 cells. Immunoreactive ECE-1 and NK₁ receptors co-localized in microvascular endothelial cells in the rat. SP-induced extravasation of Evans blue in the urinary bladder, skin and ears of the rat desensitized when the interval between two SP injections was 10 min, and re-sensitized after 480 min. SM-19712 inhibited this re-sensitization.

Conclusions and implications:

By degrading endocytosed SP, ECE-1 promotes the recycling and re-sensitization of NK₁ receptors in endothelial cells, and thereby induces re-sensitization of the pro-inflammatory effects of SP. Thus, ECE-1 inhibitors may ameliorate the pro-inflammatory actions of SP.     

Mechanosensitive production of reactive oxygen species in endothelial and smooth muscle cells: role in microvascular remodeling?

Changes in the hemodynamic environment (e.g., hypertension, increased blood flow/shear stress) are known to lead to vascular remodeling; however, the underlying mechanisms by which hemodynamic forces control gene expression in vascular cells are not yet completely understood. This review considers how mechanosensitive generation of reactive oxygen species (ROS) by NAD(P)H oxidases and other sources interacts with downstream signaling systems [including activation of nuclear factor kappa B (NF-kappaB) and AP-1] that modulate the phenotype of endothelial and smooth muscle cells, leading to vascular remodeling. We propose a model for an interaction between direct mechanosensitive ROS signaling and pathways activated by pressure-induced upregulation of prooxidant paracrine signaling mechanisms [local renin-angiotensin system, TNF-alpha- converting enzyme (TACE)/tumor necrosis factor alpha (TNF-alpha) system, and endothelin signaling].     

Estimation of the age at onset in spinocerebellar ataxia type 2 Cuban patients by survival analysis

Almaguer‐Mederosa LE, Falcón NS, Almira YR, Zaldivar YG, Almarales DC, Góngora EM, Herrera MP, Batallán KE, Armiñán RR, Manresa MV, Cruz GS, Laffita‐Mesa J, Cyuz TM, Chang V, Auburger G, Gispert S, Pérez LV. Estimation of the age at onset in spinocerebellar ataxia type 2 Cuban patients by survival analysis. Previous studies have investigated the close association that exists between CAG repeat number and the age at onset in SCA2 = spinocerebellar ataxia type 2. These studies have focused on affected individuals. To further characterize this association and estimate the risk of a carrier developing SCA2 at a particular age as a function of a specific CAG repeat size, we have analyzed a large group of 924 individuals, including 394 presymptomatic and 530 affected individuals with a CAG repeat length of 32–79 units. Using a Kaplan–Meier survival analysis, we obtained cumulative probability curves for disease manifestation at a particular age for each CAG repeat length in the 34–45 range. These curves were significantly different (p < 0.001) and showed small overlap. All these information may be very valuable in predictive‐testing programs, in the planning of studies for the identification of other genetic and environmental factors as modifiers of age at onset, and in the design of clinical trials for people at enlarged risk for SCA2.