Precision Medicine Approaches to Vascular Disease: JACC Focus Seminar 2/5

In this second of a 5-part Focus Seminar series, we focus on precision medicine in the context of vascular disease. The most common vascular disease worldwide is atherosclerosis, which is the primary cause of coronary artery disease, peripheral vascular disease, and a large proportion of strokes and other disorders. Atherosclerosis is a complex genetic disease that likely involves many hundreds to thousands of single nucleotide polymorphisms, each with a relatively modest effect for causing disease. Conversely, although less prevalent, there are many vascular disorders that typically involve only a single genetic change, but these changes can often have a profound effect that is sufficient to cause disease. These are termed “Mendelian vascular diseases,” which include Marfan and Loeys-Dietz syndromes. Given the very different genetic basis of atherosclerosis versus Mendelian vascular diseases, this article was divided into 2 parts to cover the most promising precision medicine approaches for these disease types.     

Calcium mobilization in liver transplantation graft with warm ischemia

The influence of warm ischemia on calcium mobilization in liver transplantation was investigated. Twenty-four porcine orthotopic liver transplantations were performed by a temporary portal arterialization technique. Swine were divided into three groups according to warm ischemia time; I (0 min,n=9), II (30 min,n=8), and III (60min,n=7). Ionized calcium was measured in arterial and hepatic venous blood, in initial perfusate, and in initial perfused blood. In group I, all the pigs survived, while in group III all succumbed. In group II, four survived and four died. Ionized calcium level in influx showed no differences, but the level in the initial perfusate in group I was significantly higher than that in group III. The level in the initial perfused blood in group I was significantly higher than levels in groups II and III. Retrospective analysis in group II showed that ionized calcium value in the initial perfused blood in the survivors was significantly higher than that in the non-survivors. A substantial amount of ionized calcium accumulated after revascularization in the graft loaded with warm ischemia, and, in group II, significantly more ionized calcium accumulated in the non-survivors.     

Self-retaining barbed suture reduces warm ischemia time during laparoscopic partial nephrectomy

Objective: To evaluate the efficacy and safety of self-retaining barbed suture in renorrhaphy during laparoscopic partial nephrectomy by comparing surgical outcomes in a prospective randomized manner.

Material and methods: From July 2014 to July 2015, a total of 60 patients with T1 renal tumor were randomized into two equal groups: self-retaining barbed suture (SRBS) and conventional absorbable polyglactin suture (non-SRBS group). All patients were treated by retroperitoneal laparoscopic partial nephrectomy. One surgeon with high volume experience performed all procedures. The patient demographics and perioperative outcomes were compared.

Results: The patient demographics and tumor characteristics were comparable. The mean tumor size and R.E.N.A.L. scores were comparable between the two groups. LPN was successfully accomplished in all patients without open conversion. The warm ischemia and renorrhaphy times were significantly shorter in the SRBS group (18.8?±?8.2 vs. 22.9?±?7.3?min, P?=?.04; 10.4?±?3.7 vs. 13.8?±?5.6?min, P?=?.01). The minor complication rate was 13.3% vs. 10.0%, which was comparable. No major complication occurred.

Conclusions: The randomized controlled trial demonstrates that SRBS for renorrhaphy during retroperitoneal laparoscopic partial nephrectomy is safe and efficient. Application of barbed suture simplifies the parenchymal repair procedure and reduces warm ischemia time in comparison with conventional suture.     

Gestational lead exposure induces developmental abnormalities and up-regulates apoptosis of fetal cerebellar cells in rats

Lead (Pb), a known environmental toxicant, adversely affects almost all organ systems. In this study, we investigated the effects of maternal lead exposure on fetal rat cerebellum. Female Sprague–Dawley rats were given lead nitrate in drinking water (0, 0.5, and 1%) for two weeks before conception, and during pregnancy. Fetuses were collected by caesarian section on gestational day 21 and observed for developmental abnormalities. The fetal cerebellar sections from control and 1% lead group were stained with cresyl violet. Immunohistochemical expressions of p53, Bax, Bcl-2, and caspase 3 were quantified by AnalySIS image analyzer (Life Science, Germany). Lead exposure induced developmental abnormalities of eyes, ear, limbs, neck and ventral abdominal wall; however, these abnormalities were commonly seen in the 1% lead-treated group. In addition, lead also caused fetal mortality and reduced body growth in both dose groups and reduced brain weight in the 1% lead-treated group. The fetal cerebella from the 1% lead-treated group showed unorganized cerebellar cortical layers, and degenerative changes in granule and Purkinje cells such as the formation of clumps of Nissl granules. An increase in Bax and caspase 3, and a decrease in Bcl-2 (p?相似文献   

Health risks and informal employment in South Africa: does formality protect health?

Background:

The association between work and health has not been well explored in the context of economically developing countries, largely due to inadequate data.

Objectives:

The objective of this study was to identify the association between informal wage work and health in South Africa using a newly available data set that includes detailed information on both employment and health.

Methods:

To explore the relationship between formality, work, and health in South Africa, data from the first (2008) wave of the National Income Dynamic Study (NIDS) were analyzed. We constructed a “formality index” which represents work arrangements on a continuum of formality to informality allowing for a more nuanced analysis of the association between wage work and health.

Results:

We found that formality of employment was significantly associated with health in South Africa, but that the protective effect of formality in employment on health was largely derived from the higher levels of income earned through more formal types of employment. Nevertheless, we did find that the association between informality and poor health was significantly greater for women in wage employment than for males.     

Heavy chain diseases

Heavy chain diseases (HCDs) are rare B-cell lymphoplasma-cell proliferative disorders characterized by production of truncated monoclonal immunoglobulin heavy chains without associated light chains. HCDs involving the three main immunoglobulin classes have been described; alpha-HCD is the most common and has the most uniform presentation, gamma- and mu-HCDs have variable clinical presentations and histopathologic features. HCDs can be thought of as variant types of non-Hodgkin lymphoma: alpha-HCD presents as an extranodal marginal-zone lymphoma of mucosa-associated lymph-node tissue, gamma-HCD as lymphoplasmacytoid non-Hodgkin lymphoma, and mu-HCD as small lymphocytic non-Hodgkin lymphoma or chronic lymphocytic leukemia. Diagnosis of HCD requires documentation of a deleted immunoglobulin heavy chain without a bound light chain in the serum or urine. Prognosis is variable, and no standardized effective treatment programs are available except for alpha-HCD, which in its early stage may respond to antibiotics.     

Hepatic venous outflow obstruction after right lateral sector living-donor liver transplantation,treated by insertion of an expandable metallic stent

Hepatic venous outflow obstruction is a relatively uncommon but important and devastating complication occurring after liver transplantation. Recently, right lateral sector liver grafts have sometimes been used in living-donor liver transplantation (LDLT), but, to our knowledge, early hepatic venous outflow obstruction has never been reported in right lateral sector LDLT. A 58-year-old woman was diagnosed with liver cirrhosis and hepatocellular carcinoma and underwent right lateral sector LDLT. Postoperatively, she developed liver dysfunction. Doppler ultrasound examination revealed flat waveforms and low-flow velocity in the right hepatic vein (RHV). A computed tomography (CT) scan revealed a ventrally distorted RHV due to hypertrophy of the liver graft. Hepatic venous obstruction was suspected and a hepatic venogram was performed. The venogram revealed stenosis of the RHV due to the distortion of the vein. We performed percutaneous transfemoral balloon dilatation, but this was not effective. We then inserted an expandable metallic stent (EMS) into the RHV. After the EMS placement, the condition of the patient improved. Venogram and CT data suggested that the obstruction of the RHV developed because of distortion of the RHV to the ventral side during liver regeneration.     

Skeletal muscle stem cells do not transdifferentiate into cardiomyocytes after cardiac grafting

Skeletal muscle cell-derived grafts in the heart may benefit myocardial performance after infarction. Several studies have suggested that skeletal muscle stem cells (satellite cells) from adult muscle undergo transdifferentiation into cardiomyocytes after grafting into the heart, but expression of cardiac markers in graft cells has not been rigorously confirmed. To determine the fate of satellite cell-derived grafts in the heart, adult rat satellite cells were tagged in vitro with bromodeoxyuridine (BrdU) and grafted into normal hearts of syngeneic rats. At 4 and 12 weeks the graft cells formed multinucleated, cross-striated myofibers that expressed fast skeletal myosin heavy chain (MHC), thus indicating a mature skeletal muscle phenotype. Double staining for the BrdU tag and cardiac-specific markers was employed to identify transdifferentiation. Aside from four questionable cells, none of the 11 grafts examined expressed alpha-MHC, cardiac troponin I, or atrial natriuretic peptide. At 4 weeks, grafts expressed beta -MHC, a hallmark of slow twitch myofibers. By 12 weeks, however, the myofibers had atrophied and downregulated beta-MHC. Grafts never expressed the intercalated disk proteins N-cadherin or connexin43, hence electromechanical coupling did not occur. In conclusion, satellite cells differentiate into mature skeletal muscle and do not express cardiac-specific genes after grafting into the heart. Thus, transdifferentiation into cardiomyocytes did not occur.     

慢性重型肝炎患者血清肝细胞生长因子浓度变化的动态观察

研究慢性病毒性肝炎患者血清中肝细胞生长因子(HGF)的浓度变化与病情的关系,用ELISA法检测19例慢性乙型重型肝炎患者(慢重肝)血清中的HGF浓度的动态变化,并比较生存患者和死亡患者的HGF变化,结果:1.慢重肝患者血清HGF浓度变化与血清TBil的变化相一致,生存患者HGF在达到一个峰值后随血清TBil的降低而降低;死亡患者的HGF则进行性升高,在死亡前达最高值。2.生存患者的HGF峰值浓度为(5.214±1.657)μg/L,TBil为(236±109)μmol/L,PTA为(48.26±10.15)％;而死亡患者分别为(7.521±2.152)μg/L、(412±128).μmol/L、(30.09±14.28)％,均有显著性的差异。HGF在慢重肝患者血清中有较明显的升高,而且与TBil的变化有相关性,动态观察血清HGF的变化可作为判断病情的指标之一。