Communication is the key.: Part 2 : Direct to consumer genetics in our future daily life ?

The considerable advances of genome sequencing over the past decades have had a profound impact on our daily life and opened up new avenues for the public to have access to their genetic information and learn more about their ancestry, genealogy and other traits that make each of us unique individuals. A very large number of individual single nucleotide polymorphisms (SNPs) have been associated to diseases whereas others have no known phenotype. For example, among the SNPs mapped within ccn1(cyr61), ccn2(ctgf), ccn3(nov), ccn4(wisp-1), ccn5(wisp-2) and ccn6 (wisp-3), only mutations within ccn4 were associated to PPD (the autosomal recessive skeletal disorder Progressive Pseudorheumatoid Dysplasia). On the occasion of this JCCS special issue on the roles of hormetic responses in adaptation, and response of living species to the modifications of their environment, it appeared that it was a good time to briefly review a topic that has been the subject of passionate discussions for the past few years, that is Direct to Consumer genetic tests (DTC GT). Based on the use of DNA analysis and identification of polymorphisms, DTC GT have been developed by several companies in the USA and in countries where there was no legal obstacle for customers to have direct access to their genetic information and manage their healthcare. Problems that arose and decisions that have been taken by regulatory agencies are presented and discussed in this editorial. The « freeze » of health-oriented DTC GT in the USA neither implies the end of DNA analysis nor « fun » applications, which are not aimed at providing risks estimates for particular illnesses. As shown in the example which is discussed in this editorial, DTC GT for cosmetic applications might be considered a fun application of great interest for companies such as L’Oréal, who recently developed the Makeup Genius mobile application. Other fun applications of DTC GT are discussed but there is no doubt that nothing will stop progress and it is most probable than within a few years from now all the tensions raised about these procedures will vanish to the profit and benefit of consumers. In any case, this will only be possible through an intensive communication effort, because …communication is the key !     

探讨NTIS在ICU重症患者的预后影响

目的：观察NTIS在ICU重症患者中的发病情况,及对病情的预后。方法：2010年1月到2010年3月,收集上海交通大学附属第六人民医院重症监护病房ICU收治的患者共161例。根据甲状腺功能情况分组。记录其年龄、性别、血糖、血白蛋白、肝肾功能、电解质、白细胞、血气、心率、血压等,统计有创呼吸机的使用率、使用天数、APACHEII评分、ICU住院天数和住院期间的死亡率,分析相关的影响因素。结果：161例入住ICU的重症患者中74例伴有NTIS（45.96%）,血清游离三碘甲状腺原氨酸（FT3）水平是ICU住院时间的独立影响因素,低T3与住院期间死亡率明显相关,是主要死亡危险因子;NTIS患者较正常甲状腺患者死亡风险增加2.93倍（95%CI,1.052～8.182）。结论：低T3在重症疾病患者中发病常见,与住院期间死亡率明显相关,对于预测患者病情的严重程度和预后有重要的价值。     

Cultural Differences in the Experience of Everyday Symptoms: A Comparative Study of South Asian and European American Women

This paper describes a study of medically ambiguous symptoms in two contrasting cultural groups. The study combined a qualitative, meaning-centered approach with a structured coding system and comparative design. Thirty-six South Asian immigrants and thirty-seven European Americans participated in a semistructured health history interview designed to elicit conceptual models of medically unexplained illness. The groups reported similar symptoms, but the organization of illness episodes and explanatory models associated with these episodes differed sharply. A variety of cultural variables and processes is proposed to account for observed differences, including somatization, the role of local illness categories, and the divergent core conflicts and values associated with gender roles. It is argued that the comparative design of the study provided insights that could not have been achieved through the study of a single group.     

Pharmacologically increasing microtubule acetylation corrects stress‐exacerbated effects of organophosphates on neurons

Many veterans of the 1990‐1991 Gulf War contracted Gulf War Illness (GWI), a multisymptom disease that primarily affects the nervous system. Here, we treated cultures of human or rat neurons with diisopropyl fluorophosphate (DFP), an analog of sarin, one of the organophosphate (OP) toxicants to which the military veterans were exposed. All observed cellular defects produced by DFP were exacerbated by pretreatment with corticosterone or cortisol, which, in rat and human neurons, respectively, serves in our experiments to mimic the physical stress endured by soldiers during the war. To best mimic the disease, DFP was used below the level needed to inhibit acetylcholinesterase. We observed a diminution in the ratio of acetylated to total tubulin that was correctable by treatment with tubacin, a drug that inhibits HDAC6, the tubulin deacetylase. The reduction in microtubule acetylation was coupled with deficits in microtubule dynamics, which were correctable by HDAC6 inhibition. Deficits in mitochondrial transport and dopamine release were also improved by tubacin. Thus, various negative effects of the toxicant/stress exposures were at least partially correctable by restoring microtubule acetylation to a more normal status. Such an approach may have therapeutic benefit for individuals suffering from GWI or other neurological disorders linked to OP exposure.      

Dysbiosis in gastrointestinal pathophysiology: Role of the gut microbiome in Gulf War Illness

Gulf War Illness (GWI) has been reported in 25%–35% of veterans returned from the Gulf war. Symptoms of GWI are varied and include both neurological and gastrointestinal symptoms as well as chronic fatigue. Development of GWI has been associated with chemical exposure particularly with exposure to pyridostigmine bromide (PB) and permethrin. Recent studies have found that the pathology of GWI is connected to changes in the gut microbiota, that is the gut dysbiosis. In studies using animal models, the exposure to PB and permethrin resulted in similar changes in the gut microbiome as these found in GW veterans with GWI. Studies using animal models have also shown that phytochemicals like curcumin are beneficial in reducing the symptoms and that the extracellular vesicles (EV) released from gut bacteria and from the intestinal epithelium can both promote diseases and suppress diseases through the intercellular communication mechanisms. The intestinal epithelium cells produce EVs and these EVs of intestinal epithelium origin are found to suppress inflammatory bowel disease severity, suggesting the benefits of utilizing EV in treatments. On the contrary, EV from the plasma of septic mice enhanced the level of proinflammatory cytokines in vitro and neutrophils and macrophages in vivo, suggesting differences in the EV depending on the types of cells they were originated and/or influences of environmental changes. These studies suggest that targeting the EV that specifically have positive influences may become a new therapeutic strategy in the treatment of veterans with GWI.     

Estimating hazard ratios in cohort data with missing disease information due to death

In clinical and epidemiological studies information on the primary outcome of interest, that is, the disease status, is usually collected at a limited number of follow‐up visits. The disease status can often only be retrieved retrospectively in individuals who are alive at follow‐up, but will be missing for those who died before. Right‐censoring the death cases at the last visit (ad‐hoc analysis) yields biased hazard ratio estimates of a potential risk factor, and the bias can be substantial and occur in either direction. In this work, we investigate three different approaches that use the same likelihood contributions derived from an illness‐death multistate model in order to more adequately estimate the hazard ratio by including the death cases into the analysis: a parametric approach, a penalized likelihood approach, and an imputation‐based approach. We investigate to which extent these approaches allow for an unbiased regression analysis by evaluating their performance in simulation studies and on a real data example. In doing so, we use the full cohort with complete illness‐death data as reference and artificially induce missing information due to death by setting discrete follow‐up visits. Compared to an ad‐hoc analysis, all considered approaches provide less biased or even unbiased results, depending on the situation studied. In the real data example, the parametric approach is seen to be too restrictive, whereas the imputation‐based approach could almost reconstruct the original event history information.