Nonheme iron in sickle erythrocyte membranes: association with phospholipids and potential role in lipid peroxidation

Previous studies documented the abnormal association of heme and heme proteins with the sickle RBC membrane. We have now examined RBC ghosts and inside-out membranes (IOM) for the presence of nonheme iron as detected by its formation of a colored complex with ferrozine. Sickle ghosts have 33.8 +/- 18.2 nmol nonheme iron/mg membrane protein, and sickle IOM have 4.3 +/- 3.0 nmol/mg. In contrast, normal RBC ghosts and IOM have no detectable nonheme iron. The combination of heme and nonheme iron in sickle IOM averages nine times the amount of membrane- associated iron in normal IOM. Kinetics of the ferrozine reaction show that some of this nonheme iron on IOM reacts slowly and is probably in the form of ferritin, but most (72% +/- 18%) reacts rapidly and is in the form of some other biologic chelate. The latter iron compartment is removed by deferoxamine and by treatment of IOM with phospholipase D, which suggests that it represents an abnormal association of iron with polar head groups of aminophospholipids. The biologic feasibility of such a chelate was demonstrated by using an admixture of iron with model liposomes. Even in the presence of tenfold excess adenosine diphosphate, iron partitions readily into phosphatidylserine liposomes; there is no detectable association with phosphatidylcholine liposomes. To examine the bioavailability of membrane iron, we admixed membranes and t-butylhydroperoxide and found that sickle membranes show a tenfold greater peroxidation response than do normal membranes. This is not due simply to a deficiency of vitamin E, and this is profoundly inhibited by deferoxamine. Thus, while thiol oxidation in sickle membranes previously was shown to correlate with heme iron, the present data suggest that lipid peroxidation is related to nonheme iron. In control studies, we did not find this pathologic association of nonferritin, nonheme iron with IOM prepared from sickle trait, high-reticulocyte, postsplenectomy, or iron-overloaded individuals. These data provide additional support for the concept that iron decompartmentalization is a characteristic of sickle RBCs.     

Female and male partner age and menotrophin requirements influence pregnancy rates with human menopausal gonadotrophin therapy in combination with intrauterine insemination

This study analyses the influence of female and male patient age and human menopausal gonadotrophin (HMG) requirements on clinical pregnancy rates and live birth rates with ovulation stimulation using HMG in combination with intrauterine insemination (IUI). In this study, 363 consecutive HMG/IUI treatment cycles in 184 patients carried out at a university fertility centre were analysed in a retrospective fashion. The main outcomes measured were clinical pregnancy rates and live birth rates. Increased female partner age (> or = 35) and male partner age (> or = 40) were found to negatively influence pregnancy rates with HMG/ IUI therapy. In addition, this study demonstrated a critical threshold of HMG requirements beyond which pregnancy did not occur. No pregnancies occurred in treatment cycles requiring > 25 ampoules (1875 IU) of menotrophins to achieve follicular maturity, irrespective of patient age. In conclusion, female partner age, male partner age, and HMG requirements all significantly influence pregnancy rates with HMG/IUI therapy.      

The intron 4c allele of the NOS3 gene is associated with ischemic stroke in African Americans

Background  

Ischemic stroke is the most common cause of disability in North America and in addition to the generally accepted risk factors, there is increasing evidence for the potential pathophysiological role of genes. One of these genes, the endothelial nitric oxide synthase gene (NOS3) has been reported as a genetic risk factor for ischemic stroke. To independently confirm and extend the results of these previous reports, we investigated this gene as a risk factor for stroke in an ethnically diverse study population.     

Age-dependent variation of T1 and T2 relaxation times of adenocarcinoma in mice

The T1 and T2 values of adenocarcinoma EO 771 inoculated into the hind leg of mice are characterized and correlated with the histopathologic state of the tumor. Growth-dependent changes (indicated by a T1 of 630-910 msec and a T2 of 68-185 msec) can be separated into four characteristic phases. The increase in relaxation times in the early phases (A and B) is due to an increasing amount of viable tumor tissue relative to normal muscle tissue. In the later phases (C and D), a decline of the relaxation parameters is observed that is parallel to an increase in the fraction of necrotic tissue. By multiexponential analysis, two relaxation components (indicated by and, respectively) for T1 and T2 and the corresponding fractions alpha 1 and alpha 2 can be observed for both tumor and surrounding muscle tissue. A tissue criterion ("magnetic resonance fingerprint") is defined by a combination of these multiple parameters. This criterion allows separation of not only muscle and tumor tissue but also viable (early state) and necrotic (late state) tumor tissue.     

Osteosarcomatosis

A review of the 690 cases of osteosarcoma in the radiographic file of the Armed Forces Institute of Pathology revealed 29 cases of "osteosarcomatosis" (multiple skeletal sites of osteosarcoma). Fifteen of these patients were 18 years old and under and manifested rapidly appearing, usually symmetric, sclerotic metaphyseal lesions. The remaining 14 patients were more than 18 years old and had fewer, asymmetric sclerotic lesions. In most patients (28 of 29), a radiographically dominant skeletal tumor was seen. Pulmonary metastases occurred in the majority of patients and were detected at the same time as the bone lesions. These 29 patients were studied with regard to demographic data and skeletal distribution and radiographic appearance of their lesions. As a result of the findings, a metastatic origin from a primary dominant osteosarcoma is favored over a multifocal origin as the basis for osteosarcomatosis. Osteosarcomatosis is more commonly encountered in the mature skeleton than has been previously recognized.     

CLINICO-EPIDEMIOLOGICAL ALGORITHM FOR PREDICTING SYSTEMIC ARTERIAL HYPERTENSION AT HIGH ALTITUDE THROUGH MATHEMATICAL MODELLING

A population based hybrid design combining element of cohort and cross-sectional approach was used to develop a simple clinical algorithm to predict individual probability of developing hypertension (systolic BP > 140 mm Hg and/or diastolic BP > 90 mmHg). 3615 soldiers initially normotensive at the time of induction into high altitude, were studied by systematic random sampling. Multiple logistic regression analysis showed a high significant association between hypertension and age, body mass index (BMI), tobacco smoking and alcohol consumption. Using the constant/coefficient values obtained from the logistic model and the receiver operating characteristics (ROC) curve analysis, the following predictive rule was developed – To the age in years, add (BMIx 3.86); also add 5.53 if he is a smoker; and add 19.81 if he consumes alcohol. If the total exceeds 142, the individual is at high risk of developing hypertension. This algorithm carries a sensitivity of 68.2% and specificity of 78.5%.KEY WORDS: Hypertension, High altitude     

α-葡萄糖苷酶抑制剂治疗2型糖尿病的系统评价

目的评价α-葡萄糖苷酶抑制剂治疗2型糖尿病患者的效果。方法检索Cochrane图书馆、MEDLINE、EMBASE、CurrentContents、LILACS在研试验数据库,主题为α-葡萄糖苷酶抑制剂的综述的参考文献,并联系纳入试验的专家与实施者。最近检索日期为2003年月12月(CurrentContents)和2003年4月(其他数据库)。纳入α-葡萄糖苷酶抑制剂单一疗法与其它干预比较,治疗2型糖尿病疗程至少12周的随机对照试验,并且试验至少包括以下结局之一:病死率、患病率、生活质量、血糖控制、血脂、胰岛素水平、体重、不良事件。两名评价者独立阅读所有摘要,评价质量并提取数据,分歧通过协商解决或由第三位评价者裁决。由一位统计学家在对提取数据输入数据库时进行检查。我们尽量联系所有作者以核实数据。结果共纳入41个试验、8130例受试者,其中30个针对阿卡波糖,7个针对米格列醇,1个针对优格列波糖,还有3个为不同α-葡萄糖苷酶抑制剂间的比较。绝大多数研究疗程为24周,仅有2个研究超过1年。与安慰剂相比,阿卡波糖血糖控制效果更好:糖化血红蛋白–0.8%[95%CI(–0.9,–0.7)],空腹血糖–1.1mmol/L[95%CI(–1.4,–0.9)],负荷血糖–2.3mmol/L[95%CI(–2.7,–1.9)],阿卡波糖对糖化血红蛋白的作用呈非剂量依赖。我们发现其可降低负荷胰岛素,但对血脂和体重未见临床相关的作用。不良反应主要来自胃肠道且与剂量相关。相对于磺脲,阿卡波糖将空腹和负荷胰岛素水平分别降低至–24.8pmol/L[95%CI(–43.3,–6.3)]和–133.2pmol/L[95%CI(–184.5,–81.8)],但阿卡波糖引起的不良反应更多。结论关于α-葡萄糖苷酶抑制剂是否影响2型糖尿病患者的病死率和患病率仍不清楚。相反,其对血糖控制或胰岛素水平作用明显,对血脂和体重的作用差异无统计学意义。α-葡萄糖苷酶抑制剂更长疗程的效果仍不确定。阿卡波糖剂量超过50mg(TID)时不能进一步影响糖化血红蛋白水平,不良反应反而更多,与磺脲相比,α-葡萄糖苷酶抑制剂降低了空腹和负荷胰岛素水平,但在血糖控制和不良反应方面存在不利影响。