The impact of human single nucleotide polymorphisms on Bacillus Calmette-Guérin responses

The influence of genetic variability on human immune responses has major implications for the understanding of disease mechanisms and host-pathogen interactions. Bacillus Calmette-Guérin (BCG) vaccine, which is given globally to protect against tuberculosis, has high variability in its protective efficacy against mycobacteria and its beneficial off-target (heterologous) effects. Single nucleotide polymorphisms (SNPs) are major cause of genetic variation and have been strongly associated with susceptibility to tuberculosis and outcomes following BCG immunotherapy for cancer. This review discusses the contribution of SNPs to the variability in mycobacterial-specific and off-target BCG responses, and the implications for this on development of novel TB vaccines and strategies to harness the beneficial off-target effects of BCG.     

Zinc inhibits aflatoxin B1-induced cytotoxicity and genotoxicity in human hepatocytes (HepG2 cells)

Aflatoxin B1 (AFB1) has strong carcinogenicity. Consumption of AFB1-contaminated agricultural products and the occurrence of hepatocellular carcinoma have received widespread attention. The aim of this paper was to investigate whether zinc supplementation could inhibit AFB1-induced cytotoxicity and genotoxicity in HepG2 cells and the mechanism of this inhibition. Our data suggest that zinc sources can relieve a certain degree of AFB1-induced cytotoxicity and genotoxicity by protecting against apoptotic body formation and DNA strand breaks, affecting S phase cell cycle arrest, reducing 8-OHdG formation, inhibiting global DNA hypomethylation and regulating gene expression in antioxidation, zinc-association and apoptosis processes. Consequently, zinc stabilizes the integrity of DNA and improves cell survival.These data provides new insights into the protective role of zinc in alleviating AFB1-induced cytotoxicity and mediating epigenetic changes in hepatocytes, demonstrating that zinc sources have detoxification properties in mycotoxin-induced toxicity.     

Vaccination with virus-like particles containing H5 antigens from three H5N1 clades protects chickens from H5N1 and H5N8 influenza viruses

Highly pathogenic avian influenza (HPAI) viruses, especially H5N1 strains, represent a public health threat and cause widespread morbidity and mortality in domestic poultry. Recombinant virus-like particles (VLPs) represent a promising novel vaccine approach to control avian influenza including HPAI strains. Influenza VLPs contain viral hemagglutinin (HA), which can be expressed in cell culture within highly immunogenic VLPs that morphologically and antigenically resemble influenza virions, except VLPs are non-infectious. Here we describe a recombinant VLP containing HA proteins derived from three distinct clades of H5N1 viruses as an experimental, broadly protective H5 avian influenza vaccine. A baculovirus vector was configured to co-express the H5 genes from recent H5N1 HPAI isolates A/chicken/Germany/2014 (clade 2.3.4.4), A/chicken/West Java/Subang/29/2007 (clade 2.1.3) and A/chicken/Egypt/121/2012 (clade 2.2.1). Co-expression of these genes in Sf9 cells along with influenza neuraminidase (NA) and retrovirus gag genes resulted in production of triple-clade H555 VLPs that exhibited hemagglutination activity and morphologically resembled influenza virions. Vaccination of chickens with these VLPs resulted in induction of serum antibody responses and efficient protection against experimental challenges with three different viruses including the recent U.S. H5N8 HPAI isolate. We conclude that these novel triple-clade VLPs represent a feasible strategy for simultaneously evoking protective antibodies against multiple variants of H5 influenza virus.     

Schizophrenia: the illness that made us human

Any hypotheses concerning the origins of humans must explain many things. Among these are: 1, the growth in brain size around two million years ago; 2, the presence of subcutaneous fat; 3, the near absence of change or cultural progress for around 2 million years after the brain grew in size; 4, the cultural explosion which began somewhere between fifty thousand and one hundred thousand years ago with the emergence of art, music, religion and warfare; 5, the further cultural explosion around ten thousand to fifteen thousand years ago which developed with the emergence of agriculture and which has continued since.Since the brain, like subcutaneous fat, is particularly rich in lipids, and since the microconnections of the brain are substantially lipid in nature, it is suggested that changes in lipid metabolism are what differentiated humans from the great apes. The growth in brain size and in the quality of subcutaneous adipose tissue may have occurred because of changes in the proteins which regulate the rate of delivery of fatty acids to tissues, notably lipoprotein lipases and fatty acid binding proteins. The creativity which occurred one hundred thousand years ago may have resulted from changes in phospholipid-synthesizing, -remodelling and -degrading enzymes which largely determine the microconnectivity of neurons.Family studies and adoption studies indicate that schizophrenia in a family member is associated with an increased risk of the illness in other family members. It is also associated with an increased risk of schizotypy, manic-depression, dyslexia, sociopathy and psychopathy. On the other hand it is also an indication of an increased likelihood of high creativity, leadership qualities, achievements in many fields, high musical skills and an intense interest in religion.I propose that the characteristics which entered the human race about one hundred thousand years ago and which ended around two million years of cultural near-stagnation are precisely those shown by the families of people with schizophrenia. I propose that these features are caused by variations in phospholipid biochemistry which are responsible both for schizophrenia and for our humanity. This would help to explain why schizophrenia is present to approximately the same degree in all races. It is the illness which made us human prior to the separation of the races.     

Pathobiology of pulmonary hypertension: Impact on clinical management

Our previous studies showed how analysis of pulmonary vascular changes on lung biopsy tissue and on angiography added to the hemodynamic assessment of pulmonary vascular resistance in predicting the success of a surgical repair. Both the potential for heightened vasoreactivity in the early postoperative period and for reversibility of pulmonary vascular disease at later follow-up were correlated with qualitative and quantitative evaluation of arterial changes. The ability of continuous intravenous prostacylin to arrest progression and even induce regression of structurally advanced pulmonary vascular disease in some cases has led to rethinking how pathological material can be useful in clinical decision making. The presence of occlusive changes and particularly plexiform lesions was thought to represent irreversible disease, but the observation that ongoing cellular proliferation and connective tissue synthesis occurs even in advanced lesions thought to represent end stage ‘burnt-out’ lesions, led to re-evaluation of the potential of biologically reversing the disease process. Our laboratory has used clinical material, cultured cells, and studies in experimental animals to gain new insights into some of the mechanisms which lead to the progression of vascular changes, and has used this information in strategies aimed at arresting progression and, more recently, inducing regression of pulmonary hypertension and associated vascular lesions. Specifically, we have focused on the increased activity of an endogenous vascular elastase (EVE) and expression of the glycoproteins tenascin and fibronectin in the pathobiology of pulmonary hypertension. This report will first review our studies in children with congenital heart defects, assessment of reversibility of pulmonary hypertension, and then discuss more recent work addressing cellular and molecular mechanisms aimed at developing newer therapeutic strategies. Copyright © 2000 by W.B. Saunders Company     

Radiofrequency lesioning techniques in the management of chronic pain

Radiofrequency lesioning is used in pain management as a means of denervating a painful structure by generating a thermal lesion within a sensory nerve or sensory pathway of the CNS. Radiofrequency lesioning apparatus uses a radiofrequency source to apply a current to an insulated needle with an exposed tip. A radiofrequency current applied to the needle causes a zone of heating around the uninsulated part of the needle. The tissue is heated not the needle, therefore the needle has to be placed adjacent and parallel to a nerve rather than perpendicular to it. Data from randomized trials or large open series support the use of radiofrequency lesioning in lumbar facet arthropathy, cervical facet arthropathy, trigeminal neuralgia, unilateral cancer pain (e.g. mesothelioma), segmental cancer pain, discogenic low back pain, and sympathetically mediated pain. The safety of percutaneous radiofrequency lesioning compares favourably with many of the techniques it has supplanted. However possible complications include unintentional nerve injury and peripheral and central neuropathic pain.     

miR-128真核表达载体的构建及功能的初步研究

目的构建miR-128真核表达载体,研究其在神经胶质瘤细胞株U343表达及对U343细胞增殖的影响。方法以人神经胶质瘤细胞株U343的DNA为模板扩增miR-128-1和miR-128-2的前体序列,将人miR-128-1(hsamiR128-1)和人miR-128-2(hsa-miR128-2)基因克隆到真核表达载体pCR3.1,将pCR3.1-miR-128-1(p-128-1)和pCR3.1-miR-128-2(p-128-2)表达载体瞬时转染U343细胞,采用Northern印迹检测成熟的miR-128表达。将U343细胞接种96孔板,MTT法检测过表达miR-128对细胞增殖的影响。结果p-128-1和p-128-2表达载体经酶切及测序鉴定正确;二者转染细胞后,反转录-聚合酶链反应(RT-PCR)扩增结果显示,其能有效表达miR-128的前体;Northern印迹结果均能产生成熟态的miR-128。MTT检测结果在无血清培养和维甲酸处理的情况下,细胞的增殖能力明显下降。结论成功构建了p-128-1和p-128-2的真核表达载体,转染神经胶质瘤细胞后能有效表达,miR-128基因过表达能抑制U343细胞的增殖。