Role for interleukin-1 (IL-1) in benzene-induced hematotoxicity: inhibition of conversion of pre-IL-1 alpha to mature cytokine in murine macrophages by hydroquinone and prevention of benzene-induced hematotoxicity in mice by IL-1 alpha

Chronic exposure of humans to benzene (BZ), a myelotoxin, causes aplastic anemia and acute leukemia. The stromal macrophage that produces interleukin-1 (IL-1), a cytokine essential for hematopoiesis, is a target of BZ's toxicity. Monocyte dysfunction and decreased IL-1 production have been shown to be involved in aplastic anemia in humans. Hydroquinone (HQ), a toxic bone marrow (BM) metabolite of BZ, causes time- and concentration-dependent inhibition of processing of the 34-Kd pre-interleukin-1 alpha (IL-1 alpha) to the 17-Kd mature cytokine in murine P388D1 macrophages and BM stromal macrophages, as measured by Western immunoblots of cell lysate proteins using a polyclonal rabbit antimurine IL-1 alpha antibody. HQ over a 10-fold concentration range had no effect on the lipopolysaccharide (LPS)-induced production of pre- IL-1 alpha precursor or on cell viability or DNA and protein synthesis. Stromal macrophages obtained from the femoral BM of C57Bl/6 mice exposed to BZ (600 or 800 mg/kg body weight) for 2 days were incapable of processing the 34-Kd pre-IL-1 alpha to the mature 17-Kd cytokine when stimulated in culture with LPS. Stromal macrophages from mice coadministered BZ and indomethacin, a prostaglandin H synthase (PHS) inhibitor that has been shown to prevent BZ-induced myelotoxic and genotoxic effects in mice when coadministered with benzene were able to convert the pre-IL-1 alpha to mature cytokine. Administration of recombinant murine IL-1 alpha (rMuIL-1 alpha) to mice before a dose of BZ that causes severe depression of BM cellularity completely prevents BM depression, most probably by bypassing the inability of the stromal macrophage in BZ-treated animals to process pre-IL-1 alpha to the mature cytokine.     

Analysis of a protocol for an autologous blood transfusion program for total joint replacement surgery

This retrospective study analysed an autologous blood transfusion program for total joint replacement surgery. A group of 99 patients receiving autologous blood transfusion was compared with a control group of 55 patients. One-unit phlebotomies were done 14 and 7 days before surgery. The whole blood was transfused intraoperatively. Preoperative hemoglobin values were within the normal range for all patient groups except the female autologous blood group for which the mean value was 122 +/- 11.3 g/L. Due to perioperative hemodilution, the postoperative hemoglobin values were substantially lower than preoperative values for all groups. Mean intraoperative blood loss was similar for the autologous and control groups (650 to 750 ml). No adverse reactions were associated with the autologous transfusions and 74% of the autologous group received autologous blood only. From this analysis a 3-week, three-unit preoperative collection was proposed for future use. A standardized protocol will allow logistical ease and implementation of the program for various surgical procedures.     

<Emphasis Type="Italic">TCF7L2</Emphasis>variant genotypes and type 2 diabetes risk in Brazil: significant association,but not a significant tool for risk stratification in the general population

Background  

Genetic polymorphisms of the TCF7L2 gene are strongly associated with large increments in type 2 diabetes risk in different populations worldwide. In this study, we aimed to confirm the effect of the TCF7L2 polymorphism rs7903146 on diabetes risk in a Brazilian population and to assess the use of this genetic marker in improving diabetes risk prediction in the general population.     

Direct evidence for the involvement of carbohydrate sequences in human sperm-zona pellucida binding

Several lines of evidence indicate that mammalian fertilization is initiated via a binding process that is dependent upon the recognition of oligosaccharide sequences associated with zona pellucida (ZP) glycoproteins. Here, specific chemical and enzymatic methods were employed to modify human ZP and to test their effects on sperm binding in the hemizona assay system (HZA). Periodate oxidation of human ZP under very mild conditions (10 min, 0 degrees C, 1 mM sodium m- periodate) that attacks only terminal sialic acid resulted in a 30% loss of human sperm binding in the HZA [hemizona index (HZI) = 70.2 +/- 10.9, n = 22; P < 0.05]. Periodate oxidation under mild conditions (1 h, 23 degrees C, 10 mM sodium m-periodate) caused a 40% decrease in binding (HZI = 60.8 +/- 10.3; n = 24; P< 0.01). Treatment of human ZP with neuraminidase caused a substantial increase in sperm binding to human ZP (HZI = 297 +/- 45, n = 22; P < 0.01). These findings indicate that there are sialic acid dependent binding sites coexisting with binding sites that are obscured by sialic acid. To determine the periodate sensitivity of these obscured sites, hemizona were first digested with neuraminidase and subsequently subjected to mild periodate oxidation. The combined enzymatic and chemical treatments caused a 79% decrease in sperm binding compared to control hemizona (HZI = 20.7 +/- 4.4, n = 16; P < 0.001). Human sperm-ZP interaction was also increased by digestion of human ZP with endo-beta-galactosidase (HZI = 710 +/- 232, n = 14; P < 0.01), indicating that potential binding sites for spermatozoa are also obscured by lactosaminoglycan sequences. These studies support a definitive role for the involvement of ZP-associated glycans in the binding of human spermatozoa to oocytes.      

Building a Methodological Foundation for Impactful Urban Planetary Health Science

Anthropogenic environmental change will heavily impact cities, yet associated health risks will depend significantly on decisions made by urban leaders across a wide range of non-health sectors, including transport, energy, housing, basic urban services, and others. A subset of planetary health researchers focus on understanding the urban health impacts of global environmental change, and how these vary globally and within cities. Such researchers increasingly adopt collaborative transdisciplinary approaches to engage policy-makers, private citizens, and other actors in identifying and evaluating potential policy solutions that will reduce environmental impacts in ways that simultaneously promote health, equity, and/or local economies—in other words, maximising ‘co-benefits’. This report presents observations from a participatory workshop focused on challenges and opportunities for urban planetary health research. The workshop, held at the 16th International Conference on Urban Health (ICUH) in Xiamen, China, in November 2019, brought together 49 participants and covered topics related to collaboration, data, and research impact. It featured research projects funded by the Wellcome Trust’s Our Planet Our Health (OPOH) programme. This report aims to concisely summarise and disseminate participants’ collective contributions to current methodological practice in urban planetary health research.     

阿哌沙班VS依诺肝素用于膝关节置换术后血栓预防（ADVANCE-2）：随机双盲试验

背景依诺肝素等低分子肝素是预防大关节置换术后静脉血栓形成的首选。阿哌沙班是一种口服活性的Xa因了抑制剂，在预防大关节置换术后静脉血栓形成方面可能有效，而且相对于依诺肝素来说，出血风险较低、用法也较简便。本研究评估选择性全膝关节置换术后上述药物的有效性和安全性。方法ADVANCE．2为多中心随机双盲III期研究，选择性双侧或单侧全膝关节置换术患者通过交互式中心电话系统进行分组，随机接受阿哌沙班2．5mg每天2次口服（1528例）或依诺肝素40mg每天1次皮下注射（1529例）。随机化方案由Brist01．MyersSquibb随机中心生成，按研究中心和单侧或双侧手术分层，区组大小为4。研究者、患者、统计专家、评判者和指导委员会不知道患者分组情况。阿哌沙班于手术伤口闭合后10～12小时使用，依诺肝素于术前12小时使用；两药均持续用药10～14天，按照计划用药结束时行双侧顺行性静脉造影。土要终点是治疗期间无症状和有症状的深静脉血栓形成、非致死性肺栓塞和全因死亡的复合指标。统计学计划要求在检验阿哌沙班的优效性之前达到非劣效；非劣效检验对意向治疗患者进行分析。本研究在CliniealTrials．gov备案，备案号NCT00452530。结果接受治疗的3057例患者（阿哌沙班组1528例、依诺肝素组1529例）中，1973例符合主要有效性分析的要求。阿哌沙班组976例和依诺肝素组997例中，报告主要终点的患者分别为147例（15％）和243例（24％）[相对危险度0．62（95％可信区间d为：0．51～0．74），P〈0．0001；绝对危险度下降9.3％（5．8～12．7）1。阿哌沙班组1501例和依诺肝素组1508例中，发生大出血或临床相关非大出血的患者分别为53例（4％）和72例（5％）（P=0．09）。解读全膝关节置换术后次日上午使用阿哌沙班2．5mg每天2次，是依诺肝素40mg／天简便而更有效的口服替代措施，且不会增加出血。     

Orally active heparin and low-molecular-weight heparin

The heparins, (unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH)) given by subcutaneous or intravenous injection have been used extensively in the prevention and treatment of both venous and arterial thromboembolic disorders. The increasing use of the heparins, LMWHs in particular, in the out of hospital setting has stimulated interest in the development of orally absorbable antithrombotic agents that require little or no monitoring, and this includes the heparins. UFH or LMWH delivered orally has been shown to have an antithrombotic effect in animal thrombosis models although there is little change in plasma coagulation tests. The addition of a simple organic chemical N -(8-(2-hydroxybenzoyl)amino)caprylate (SNAC) to UFH markedly enhances its absorption. A phase II study in patients undergoing total hip replacement indicated that SNAC heparin in two different doses was as effective and safe as UFH given subcutaneously. A phase III clinical trial comparing two doses of SNAC heparin given orally with LMWH by subcutaneous injection for the prevention of venous thromboembolism in patients undergoing total hip replacement is currently underway.     

Colonic motility diagnosis based on colonic pressure

Manometry of the alimentary tract is a valuable and widely used means to evaluate and diagnose the function of the alimentary tract. However, the measurement can be inconvenient due to the invasive method used, and the many factors affecting results. Research on colonic pressure data is even more insufficient. This paper deals with colonic pressure data via an improved method ensuring that pressure data of the whole colon is available. The data is analysed based on the learning vector quantization (LVQ) method. Testing results show that this method distinguishes the normal data and the abnormal data, consistently with the original diagnoses. This method can serve as an assistant diagnosis of colonic motility and contributes to further research on colonic motility based on pressure data.