Genetic polymorphism of cytochrome P450 1A1 (Cyp1A1) and glutathione transferases (M1, T1 and P1) among Africans.

The co-ordinate expression and regulation of the drug metabolising enzymes, cytochrome P4501A1 (CYPlAl) and glutathione transferases (GSTM1, GSTT1 and GSTP1), and their metabolic balance in the cells of target organs may determine whether exposure to carcinogens results in cancer. Besides showing variability in activity due to induction and inhibition, these enzymes also exhibit genetic polymorphism that alter enzyme levels and activity. We determined frequencies of common allelic variants of CYP1A1 and glutathione (M1, T1 and P1) among Tanzanians, South African Venda and Zimbabweans using PCR/restriction fragment length polymorphism techniques. The CYP1A1 Val462 mutant variant was found at a frequency of 1.3% among 114 subjects. The GSTM1*0 genotype was found at a frequency of 29% and 33% among Tanzanian psychiatric patients and healthy volunteers, respectively. Similarly, the GSTT1*0 polymorphism was present with a frequency of 25% in both the psychiatric patients and healthy controls. The frequency of GSTP1 Val105 variant was 16%, 12% and 21% among Tanzanians, South African Venda and Zimbabweans, respectively. We conclude here that CYP1A1 Val462 polymorphism is very rare among Africans. This is the first report of the GSTP1 Val105 variant frequency in African populations. We show here that there are no differences in frequencies of the variant alleles for CYP1A1, GSTM1, GSTT1 and GSTP1 in the three African populations.     

Influenza A (H1N1) vs non-H1N1 ARDS: Analysis of clinical course

Purpose

The purpose of the study is to compare H1N1-induced acute respiratory distress syndrome (ARDS) with ARDS due to other causes of severe community-acquired pneumonia focusing on pulmonary function.

Materials and methods

This is a retrospective data analysis of adult ARDS patients between January 2009 and December 2010 in an ARDS referral center. Patient characteristics, severity of illness scores, modalities, and duration of extracorporeal lung support were evaluated as well as intensive care unit stay and survival. Parameters of mechanical ventilation and pulmonary function were analyzed on day of admission and over the consecutive 10 days using a nonparametric analysis of longitudinal data in a 2-factorial design. In a logistic regression analysis, risk factors for extracorporeal lung support were investigated.

Results

Twenty-one patients with H1N1-ARDS and 41 with non-H1N1-ARDS were identified. Gas exchange was more severely impaired in patients with H1N1-ARDS over course of time. Extracorporeal membrane oxygenation was more frequently needed in H1N1-ARDS. Despite significantly prolonged weaning off extracorporeal lung support and intensive care unit stay in H1N1 patients, the proportion of survivors did not differ significantly. Only Sepsis-Related Organ Failure Assessment score could be identified as an independent predictor of extracorporeal lung support.

Conclusions

Clinical course of H1N1-ARDS is substantially different from non-H1N1-ARDS. Affected patients may require extensive therapy including extracorporeal lung support in ARDS referral centers.     

Effect of OATP1B1 (SLCO1B1) variant alleles on the pharmacokinetics of pitavastatin in healthy volunteers

BACKGROUND: Pitavastatin is a potent, newly developed 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor for the treatment of hyperlipidemia. We characterized the effects of organic anion transporting polypeptide 1 B 1 (OATP 1 B 1) alleles *1a, *1b, and *15 on the pharmacokinetics of pitavastatin. METHODS: Twenty-four healthy Korean volunteers who had previously participated in a pharmacokinetic study of pitavastatin (single oral dose, 1--8 mg) were further investigated. Subjects were grouped according to OATP 1 B 1 genotype. Dose-normalized area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) values were analyzed, because different dosages were administered to subjects, whereas the pharmacokinetics showed linear characteristics. RESULTS: Dose-normalized pitavastatin AUCs for *1b/*1b (group 1), *1a/*1a or *1a/*1b (group 2), and *1a/*15 or *1b/*15 (group 3) were 38.8+/-13.3, 54.4 +/-12.4, and 68.1+/-6.3 ng.h.mL(-1).mg(-1) (mean+/-SD), respectively, with significant differences between all 3 groups (P=.008) and between subjects carrying and those not carrying the *15 allele (P = .004). Dose-normalized pitavastatin C(max) values were 13.2+/- 3.3, 18.2+/-5.7, and 29.4+/- 9.6 ng.mL(-1).mg(-1) in groups 1, 2, and 3, respectively, and also showed significant differences (P=.003) in a manner similar to that shown by AUC. No significant differences were found between the genotype groups in terms of dose-normalized AUC or C(max) values of pitavastatin lactone. CONCLUSION: OATP 1 B 1 variant haplotypes were found to have a significant effect on the pharmacokinetics of pitavastatin. These results suggest that the *15 allele is associated with decreased pitavastatin uptake from blood into hepatocytes and that OATP 1 B 1 genetic polymorphisms have no effect on the pharmacokinetics of pitavastatin lactone.     

Laser surgery of Neurofibromatosis 1 (NF 1)

Over six years of experience, the technique of treating NF 1 by laser surgery has been developed and has become a standardized treatment protocol. Whole-body therapy is undertaken over several sessions, during which a distinctive LPLL technique is applied to radically remove every NF fibroma, success being assured by nothing less than total extirpation of the tumors present. Either the argon or the carbon dioxide laser is employed, depending on the stage of the tumors. In 58 sessions of approximately 150 laser hours 21 patients have been treated. There have been no recurrences. A radically removed tumor diminishes the total number of programmed tumors by one. This is the basis underlying the therapy described. Psychosocial care of NF 1 patients remains a factor of great importance. In itself, however, it is not sufficient to achieve emotional recovery and physicocosmetic well-being.     

ABCA1, ABCG1, and SR-BI: Transit of HDL-associated sphingosine-1-phosphate

Sphingosine-1-phosphate (S1P) is a zwitterionic lysophospholipid generated by the sphingosine kinase-catalyzed phosphorylation of sphingosine. A number of the biological effects of S1P are mediated by its binding to five specific G protein-coupled receptors located on the cell surface or intracellular targets. However, the synthesis and secretion of S1P require release out of cells for binding with receptors by certain transporters and carriers. High-density lipoprotein (HDL) is an important carrier of S1P in the blood, but the mechanism by which it does so is unclear. This review discusses the mechanism how S1P is transported, and focuses particularly on how the formation of HDL-associated S1P (HDL-S1P) is mediated by certain transporters and carriers. A hypothesis that the ATP-binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor class B memberI (SR-BI) play pivotal roles in HDL-S1P formation is also described.     

色素失禁症11例临床特征分析

【目的】探讨色素失禁症患儿临床特征,提高对该病的认识。【方法】对本院2004年1月至2013年12月收治的色素失禁症11例患儿临床特点进行分析。【结果】11例患儿中10例为女性,1例男性,2例为双胞胎早产儿。11例均有皮肤受累,神经系统受累发生惊厥2例,眼部受累2例。6例外周血嗜酸性粒细胞数比例明显升高,4例行皮肤活检,病理结果疱内有大量嗜酸性细胞支持诊断,1例核转录因子κB必需调节器（NEMO）基因缺失。【结论】色素失禁症是一种少见的 X连锁的显性遗传病,新生儿期皮肤损害显著,可累及多系统,眼部及神经系统病变严重,应得到早期诊断;皮肤病理和染色体的基因分析是确诊方法,应对患儿进行定期随访。     

A novel role of sphingosine 1-phosphate receptor S1pr1 in mouse thrombopoiesis

Millions of platelets are produced each hour by bone marrow (BM) megakaryocytes (MKs). MKs extend transendothelial proplatelet (PP) extensions into BM sinusoids and shed new platelets into the blood. The mechanisms that control platelet generation remain incompletely understood. Using conditional mutants and intravital multiphoton microscopy, we show here that the lipid mediator sphingosine 1-phosphate (S1P) serves as a critical directional cue guiding the elongation of megakaryocytic PP extensions from the interstitium into BM sinusoids and triggering the subsequent shedding of PPs into the blood. Correspondingly, mice lacking the S1P receptor S1pr1 develop severe thrombocytopenia caused by both formation of aberrant extravascular PPs and defective intravascular PP shedding. In contrast, activation of S1pr1 signaling leads to the prompt release of new platelets into the circulating blood. Collectively, our findings uncover a novel function of the S1P–S1pr1 axis as master regulator of efficient thrombopoiesis and might raise new therapeutic options for patients with thrombocytopenia.Billions of anucleated platelets circulate in mammalian blood to prevent blood loss in case of tissue injury. The lifespan of platelets is short (4–6 d in mice and 5–9 d in humans; Leeksma and Cohen, 1955; Robinson et al., 2000); as a consequence, several million platelets have to be produced every hour to maintain their physiological blood counts and to avoid the risk of bleeding. In mammals, platelets are generated in BM from megakaryocytes (MKs), polyploid, terminally differentiated myeloid cells with a typical morphology and diameters of up to 100 µm.The production of platelets from MKs involves several sequential developmental and maturation steps. MKs develop from hematopoietic stem and progenitor cells, which give rise to an increasingly restricted lineage culminating in the formation of megakaryocytic precursors that generate MKs. During their differentiation and maturation, MKs localize to the perivascular niche, where they interact with sinusoidal BM endothelial cells (Avecilla et al., 2004; Patel et al., 2005a). Once they have settled in the perivascular microenvironment, mature MKs form dynamic transendothelial pseudopods, which extend into the lumen of BM sinusoids. These intravascular pseudopodial extensions, termed proplatelets (PPs), continue to elongate and become tapered into multiple platelet-size beads connected to each other and with their maternal MKs by thin cytoplasmic bridges (Italiano et al., 1999; Patel et al., 2005a). The release of platelets, the final step of platelet formation, then occurs within the blood, where new platelets are shed as fragments from the tips of intravascular PPs (Stenberg and Levin, 1989; Choi et al., 1995; Italiano et al., 1999; Junt et al., 2007).MKs are a rare cell population, constituting <0.01% of all BM cells. This contrasts with the high demand of platelet production, implying that the differentiation of MKs (termed megakaryocytopoiesis) and the subsequent assembly and release of platelets by MKs (termed thrombopoiesis) are highly efficient and tightly controlled processes. Among the factors that modulate megakaryocytopoiesis, thrombopoietin (TPO) is the major regulator of MK expansion from hematopoietic stem and progenitor cells, whereas chemokines, including stromal-derived factor-1 (SDF-1), primarily initiate the relocation of maturing MKs to the perivascular microenvironment (Avecilla et al., 2004). In contrast, the molecular pathways that control the final steps of thrombopoiesis, particularly the guidance signals that direct megakaryocytic pseudopodial extensions into the vascular lumen and trigger the intravascular release of new platelets, are entirely unknown.The bioactive sphingolipid sphingosine 1-phosphate (S1P) and the receptors responsive to this mediator regulate important biological functions of various hematopoietic cell types (Spiegel and Milstien, 2003, 2011; Schwab et al., 2005; Massberg et al., 2007), including cell migration in the BM compartment (Ishii et al., 2009; Allende et al., 2010). Here we report that S1P and the MK S1P receptor S1pr1 receptor are indispensable for normal BM thrombopoiesis. Using mouse mutants and by multiphoton intravital microscopy (MP-IVM), we demonstrate that a transendothelial S1P gradient navigates megakaryocytic PP extensions into the lumen of BM sinusoids. In the blood, PP extensions are exposed to high S1P concentrations, which initiate the subsequent shedding of platelets into the circulation. Both processes involve the S1P receptor S1pr1, triggering activation of the Gi/Rac GTPase signaling. Correspondingly, lack of S1pr1 on MKs, but not of other S1P receptors, results in severe thrombocytopenia. Thus, we have identified the S1P–S1pr1 pathway as a key nodal point integrating guidance cues that navigate directional PP elongation and enabling the final step of thrombopoiesis, the shedding of new platelets into the blood stream.     

1例甲型H1N1流感合并肺部感染的护理

甲型H1N1流感是一种新的甲型流感病毒引起的急性呼吸道传染病, 通常表现为流感样症状,包括发热、咳嗽、咽痛、咳痰、流涕、鼻塞、头痛、全身酸痛、乏力.     

骨髓增生异常综合征患者GSTT1、GSTM1基因分布频率和NQO1基因多态性分析

目的探讨谷胱甘肽S转移酶（GST）基因T1、M1（GSTY1、GSTM1）和苯醌氧化还原酶基因（NQO1C609T）多态性与骨髓增生异常综合征（MDS）易感性及MDS染色体核型异常的关系。方法用多重PCR方法检测52例MDS患者和241名与患者无血缘关系的正常人GSTF1和GSTM1基因型，用PCR-限制性片段长度多态性（RFLP）方法分析NQO1C609T基因型。结果与正常人对照组相比，MDS患者GSTT1和GSTM1无效型（nu11）比例明显增高（P值均〈0．01），其比值比（OR）分别为2．873（95％可信区间：1．491～5．537）和3．591（95％可信区间：1．717～7．508）。染色体核型正常的MDS患者GSTT1无效型比例较正常人对照组显著增高（OR=5．336，P〈0．01），而GSTM1无效型比例与正常人对照组比较差异无统计学意义染色体核型异常的MDS患者GSTM1无效型比例较正常人对照组显著增高（OR=3．740，P〈0．01），而GSTT1无效型比例与正常人对照组比较差异无统计学意义MDS患者的NQI1C609T各基因型与正常人对照组差异无统计学意义。结论GSTT1和GSTM1基因无效型可能与MDS发生相关，对判断MDS患者是否出现染色体核型异常有一定意义。     

Comparative pharmacophore modeling of organic anion transporting polypeptides: a meta-analysis of rat Oatp1a1 and human OATP1B1

The organic anion transporting polypeptides OATPs are key membrane transporters for which crystal structures are not currently available. They transport a diverse array of xenobiotics and are expressed at the interface of hepatocytes, renal tubular cells, enterocytes, and the choroid plexus. To aid the understanding of the key molecular features for substrate-transporter interactions, pharmacophore models were produced for the two OATPs that have been most extensively studied, namely rat Oatp1a1 and human OATP1B1. Literature data from Chinese hamster ovary, HeLa, human embryonic kidney 293 cells, and Xenopus laevis oocytes were used to construct pharmacophores for each individual transporter which were later merged to show similarities across cell lines for the same transporter. Additionally, meta-pharmacophores were generated from the combined datasets of each cell system used with the same transporter. The pharmacophores for each transporter consisted of hydrogen bond acceptor and hydrophobic features. There was good agreement between the merged and meta-pharmacophores containing two hydrogen bond acceptors and two or three hydrophobic features for Oatp1a1 and OATP1B1. External test sets were used to validate the individual pharmacophores. The meta-pharmacophores were also used to make predictions for molecules not included in the models and provided new molecular insight into the key features for these OATP transporters. This approach can be extended to other transporters for which limited data are available.