Lu T.-T.,Sun Yat Sen University |
Lin X.-Q.,Guangzhou Medical University |
Zhang L.,Sun Yat Sen University |
Cai W.,Sun Yat Sen University |
And 7 more authors.
International Journal of Tuberculosis and Lung Disease | Year: 2015
OBJECTIVE: To evaluate the patterns, related factors and prognostic value of abnormal magnetic resonance angiography (MRA) in human immunodeficiency virus negative tuberculous meningitis. MATERIALS AND METHODS: We performed a prospective study in patients aged >14 years. Abnormality on MRA was correlated with clinical, laboratory and magnetic resonance imaging findings. Modified Barthel index was used to assess outcome at 6 months after inclusion. RESULTS: Of 101 patients included, MRA was abnormal in 45 (44.6%). The distribution of MRA abnormality was classified as disseminated irregular calibres of intracranial arteries with or without reduction in distant branches (29.7%, pattern 1) and localised stenosis at the base of the brain (26.7%, pattern 2). In logistic regression analysis, pattern 2 was related to stage of the disease (P= 0.002), basal exudates (P = 0.03) and infarction (P = 0.000), while pattern 1 was related to duration of disease (P = 0.050), hydrocephalus (P = 0.032) and age (P = 0.002). Pattern 1 was also correlated with infarction (P= 0.000), particularly infarction in the tubercular zone (P= 0.035) in univariate analysis. MRA abnormality was associated with paradoxical worsening (P = 0.022) and poor prognosis in univariate analysis (P= 0.035). CONCLUSION: MRA abnormality is associated with stroke and poor outcomes. Although it indicates mild vascular injury, pattern 1 MRA abnormality is nevertheless associated with infarction and needs proper intervention. © 2015 The Union.
At the Karolinska Institute in Stockholm, Fredrik Lanner is preparing to edit genes in human embryos. It’s the kind of research that sparked an international frenzy in April last year, when a Chinese team revealed that it had done the world’s first such experiments1. But Lanner doesn’t expect his work, which will explore early human development, to cause such a fuss. A year of discussion about the ethics of embryo-editing research, and perhaps simply the passage of time, seems to have blunted its controversial edge — although such work remains subject to the same ethical anxieties that surround other reproductive-biology experiments. “At least in the scientific community, I sense more support for basic-research applications,” says Lanner, who gained approval for his experiments last June. His instinct seems to be borne out by the fairly muted reaction to a 6 April report2 of an experiment to edit human embryos — only the second to be published. A team led by Yong Fan at Guangzhou Medical University in China used the gene-editing technology CRISPR–Cas9 to try to introduce a mutation that makes humans resistant to HIV infection. “I don’t think there is anything wrong with what these scientists have done,” says Sarah Chan, a bioethicist at the University of Edinburgh, UK. “This work isn’t seeking to do what is still ethically in question. It’s not seeking to create genetically modified human beings.” The ethics committee of the university-affiliated hospital that approved Fan’s work says that it has green-lighted two other embryo-editing projects; such research is ethically sound because it will lead to improvements in gene-editing technology and could help to prevent diseases, a committee spokesperson says. Last December, an international summit of scientists and ethicists declared that gene editing should not be done in human embryos that are intended for use in establishing a pregnancy — but it endorsed basic research. “People are more understanding of this research,” says Fan, who points to UK fertility regulators’ approval in February of a proposal by developmental biologist Kathy Niakan to edit genes in healthy human embryos, at the Francis Crick Institute in London. Fan’s team began its experiments in early 2014 and originally submitted the paper to Cell Stem Cell, Fan says. By the time the manuscript ended up on the desk of David Albertini, editor-in-chief of the Journal of Assisted Reproduction and Genetics, a different Guanghzou-based team had become the first to report human-embryo-editing experiments. That paper1, which tried to correct a mutation that causes a blood disease, fed into a firestorm over the ethics of modifying human reproductive cells (or ‘germline’ modification). Some researchers called for a moratorium even on proof-of-principle research in non-viable embryos. Albertini, a reproductive biologist at the University of Kansas Medical Center in Kansas City, felt that it was important to publish Fan’s paper to educate scientists and clinicians. He says that the manuscript went through two rounds of review over eight months — twice as long as is normal for the journal — and that he urged the researchers to discuss the ethical issues surrounding germline editing in the paper. Fan’s paper should help to reassure international observers about the legitimacy of human-embryo-editing research in China, says Robin Lovell-Badge, a developmental biologist at the Crick. More such embryo-editing papers are likely to be published, he adds. “I know that there are papers floating around in review,” he says.“I’d much rather everything was out in the open.” (Fan says that his team is now focusing on improving the efficiency of CRISPR using human stem cells). Research involving the editing of human embryos will begin soon elsewhere in the world, if it hasn’t done so privately already. In a Cell paper published on 7 April3, Lanner’s team analysed gene expression in 88 early human embryos and is using those data to identify genes to disrupt in embryos using CRISPR–Cas9. Lanner will discuss the work at a meeting on human gene editing organized by the US National Academy of Sciences and National Academy of Medicine this month in Paris. He says that the experiments could begin in the coming months. Evan Snyder, a stem-cell scientist at the Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California, says that he doesn’t know of anyone in the United States conducting human embryo editing. But he thinks that US scientists will inevitably take on such research, although federal funding of research on human embryos and germline modification is prohibited. It is important for such research to go forward, Snyder adds, to determine whether technical hurdles would prevent clinical applications. Norms for conducting and publishing human-embryo-editing work are still taking shape. Snyder says that whenever possible, researchers should use alternatives, such as embryos of non-human primates. And when it is not, they should use only surplus embryos that would ordinarily be discarded from in vitro fertilization clinics. Both Chinese teams used non-viable embryos, but Lovell-Badge says experiments in normal embryos are also important: to see, for instance, whether CRISPR–Cas9 is more or less effective in such cells. Some scientists contend that gene-editing experiments designed to probe human development, such as those planned by Lanner and Niakan, are more valuable than experiments that are intended to lay the groundwork for creating genetically modified humans. “At the moment, there seems little point in pursuing long-term clinical goals when there’s so much not known about the technique with human embryos,” says Lovell-Badge. But Chan thinks there should be ethical latitude for both kinds of research to proceed. “We should give the public the credit for being able to understand the difference between research into genetically modified embryos and genetically modifying human beings,” she says. “I think it’s a good thing if the hubbub dies down a bit.”
Researchers in China have edited the genes of human embryos to make cells resistant to HIV infection. It’s the second reported case of using molecular scissors called CRISPR/Cas9 to alter genes in human embryos. In the new work, published April 6 in the Journal of Assisted Reproduction and Genetics, the researchers snipped a gene called CCR5 to introduce a mutation that prevents HIV from entering cells. Just as in the first report, the researchers used embryos that have three copies of each chromosome and would not grow into a baby if implanted in a uterus. Few embryos in the study were altered in the desired way. Even embryos that contained the intended HIV-blocking mutation in one copy of CCR5 either had normal DNA or an unintended mutation in other copies of the gene. The study “demonstrates that significant technical issues remain to be addressed,” Yong Fan of Guangzhou Medical University and colleagues conclude. “Germline editing” — genetic modification of human cells, including embryos, eggs and sperm, that can be passed to future generations — has been controversial. Because these embryos are not viable, the gene alteration would not be considered germline editing according to guidelines issued after an international summit in December.
Researchers from Guangzhou Medical University said they used a gene-editing technique known as CRISPR to artificially induce a mutation in human cells and make them resistant to HIV, the virus that causes AIDS. Their paper, which appeared last week in the Journal of Assisted Reproduction and Genetics, is only the world's second published account of gene editing in human embryos. Critics said the study—intended as a proof-of-principle exercise—was unnecessary and lacked medical justification, and strongly cautioned against the broader ethical implications of the slippery slope of human genome modification. "This paper doesn't look like it offers much more than anecdotal evidence that (CRISPR) works in human embryos, which we already knew," George Daley, a stem-cell biologist at Children's Hospital Boston, told the prominent science journal Nature. It demonstrated that "the science is going forward before there's been the general consensus after deliberation that such an approach is medically warranted", he added. Tetsuya Ishii, a bioethicist at Japan's Hokkaido University, denounced the research as "just playing with human embryos", Nature said. In a statement issued by the hospital where they carried out their research, the Guangzhou team brushed aside such concerns, focusing instead on the "incalculable" size of the future market for disease treatments. "The assessments of those outside the field are not authoritative, and the research environment will continue to evolve," they said. "For us what is most important is that we diligently complete our research and stick to the path we believe in, acquiring independent intellectual property rights... so that we do not have to defer to others." Such perseverance, they said will ensure "our own position in the international community", adding: "The future market for the treatment of diseases through gene editing is incalculable." Speaking to China's state-run Global Times newspaper, the paper's lead author Fan Yong said: "It is the pioneers that will make the rules in this field." Han Bin, the director of China's National Center for Gene Research, told the paper—which often takes a nationalistic tone—that the technology's potential therapeutic benefits for all diseases caused by inherited variation, including cancer, should outweigh any qualms. Instead of following other countries' ethical stances, China should formulate its own standards and regulations, the Global Times cited him as saying. China is quickly cementing a reputation as a leader in the fields of genetic research and cloning, showing a willingness to forge ahead even as others hesitate over ethical issues. The world's biggest cloning factory is under construction in the northern port of Tianjin, with plans to churn out everything from pets to premium beef cattle. The chief executive of Boyalife Group, the Chinese firm behind it, told AFP his company had technology advanced enough to replicate humans. The head of its South Korean partner has been quoted as saying it preferred mainland locations to avoid bioethics laws elsewhere that would ban the use of human eggs. The Guangzhou Medical University study used flawed embryos not viable for fertility treatment, and had been approved by the university's ethics committee. Four out of the 26 embryos were successfully modified, while a number exhibited unexpected mutations. All of them were destroyed three days later. "The purpose of this study was to evaluate the technology and establish principles for the introduction of precise genetic modifications in early human embryos," the Journal of Assisted Reproduction and Genetics paper read. The legality of human embryo research varies by country, and there is no international consensus on what ought to be allowed. In the US, the influential National Institutes of Health are banned from funding such studies, while Britain's independent fertility regulator only issued its first licence for human embryo modification research in February, for a study on infertility and miscarriages.
Guan W.-J.,Guangzhou Medical University |
Gao Y.-H.,Zhengzhou University |
Xu G.,Guangzhou First Peoples Hospital |
Lin Z.-Y.,Guangzhou Medical University |
And 6 more authors.
Respirology | Year: 2015
Background and objective The triplet of airway infection, inflammation and bronchial wall destruction associated with excessive matrix metalloproteinases (MMP) release and imbalance of tissue inhibitor metalloproteinase-1 (TIMP-1) is implicated in bronchiectasis. We sought to determine the associations between sputum MMP (MMP-8, MMP-9) and TIMP-1 and the severity of bronchiectasis; the utility of MMP in predicting risks of future bronchiectasis exacerbations (BE); and the changes in MMP levels during BE. Methods We recruited 102 patients with stable bronchiectasis and 22 healthy subjects. For bronchiectasis patients, baseline measurements consisted of sputum inflammation and MMP measurements, bacterial culture, spirometry and chest high-resolution computed tomography (HRCT). Bronchiectasis patients were followed up for 1 year to determine the frequency of BE. Changes in MMP levels during BE were assessed in 36 bronchiectasis patients. Results Sputum MMP-8, MMP-9 and MMP-9/TIMP-1 ratio in bronchiectasis patients were significantly increased compared with healthy subjects. MMP-8 and MMP-9 levels, but not TIMP-1, were positively correlated with clinical measures, including HRCT scores, spirometry and Bronchiectasis Severity Index. Seventy-nine bronchiectasis patients were included in survival analyses of BE. Lower levels of baseline MMP-9 were associated with reduced risks of and a longer time to the first BE during follow-up. MMP-8 and MMP-9, but not TIMP-1 or MMP-9/TIMP-1 ratio, were significantly heightened during BE. Conclusions Sputum MMP might be useful biomarkers for the assessment of bronchiectasis severity and the prediction of future risks of BE. Our results provide the rationales for the future clinical application of MMP inhibitors. © 2015 Asian Pacific Society of Respirology.