Fetal grafts for Parkinson’s disease: Decades in the making


In PNAS, Li et al. (1) report the pathological findings in a single patient with Parkinson’s disease (PD) who received transplantation of embryonic dopamine grafts derived from four donors placed into the right putamen 24 y before death. The patient was 59 y of age at the time of surgery and was reported to have experienced marked clinical improvement after a latency of ∼12 mo (originally reported in ref. 2). Bilateral benefits (predominantly on the left side) were noted with respect to rigidity, bradykinesia, rest tremor, and motor fluctuations, and were of sufficient magnitude that levodopa was withdrawn 32 mo following surgery. Levodopa was reinstated at 64 mo at a dose one-third of that used preoperatively and remained unchanged for the life of the patient. Still motor benefits were maintained for ∼10 y. Thereafter, the patient experienced progressive deterioration in motor function and developed a progressive dementia at year 14. At postmortem examination, the investigators reported the survival of ∼42,000 grafted dopaminergic neurons with extensive putamenal dopaminergic innervation. Approximately 11–12% of residual grafted neurons contained α-synuclein aggregates. This case suggests that the original goals of cell replacement therapy for PD, namely, survival of implanted dopamine neurons, striatal reinnervation, and clinical benefit, were met.

This is the longest postgrafting interval reported for any PD patient who has undergone a postmortem examination. It is a fascinating case that indicates that grafted fetal dopaminergic cells can survive for almost a quarter of a century and provide extensive striatal innervation. Previous reports have demonstrated similar findings at postmortem performed 18 mo (3) and 4–16 y after grafting (4⇓⇓–7); the present study suggests that these findings can endure for the life of the patient. Importantly, the authors report that fetal nigral grafting in this patient was associated with long-term motor benefit .

Bronchial epithelium in children: a key player in asthma


Abstract

Bronchial epithelium is a key element of the respiratory airways. It constitutes the interface between the environment and the host. It is a physical barrier with many chemical and immunological properties. The bronchial epithelium is abnormal in asthma, even in children. It represents a key component promoting airway inflammation and remodelling that can lead to chronic symptoms. In this review, we present an overview of bronchial epithelium and how to study it, with a specific focus on children. We report physical, chemical and immunological properties from ex vivo and in vitro studies. The responses to various deleterious agents, such as viruses or allergens, may lead to persistent abnormalities orchestrated by bronchial epithelial cells. As epithelium dysfunctions occur early in asthma, reprogramming the epithelium may represent an ambitious goal to induce asthma remission in children.

Conclusion

The bronchial epithelium is a key player in health and diseases. Acute and chronic inflammatory disorders are major healthcare problems in childhood. They require constant effort towards improving treatment and prevention. The development of the lung is a factor that may interfere with the future and natural history of these chronic airway disorders. As children are not small adults, specific research efforts should be devoted to better understand the role of the bronchial epithelium in childhood asthma. We should develop models using real epithelium obtained through less invasive methods. The key to promoting prevention at any stage of lung development will be the analysis of responses to microorganisms, allergens and pollutants. The ultimate goals are to prevent future risks of exacerbations, low lung function and the persistence of bronchial hyperresponsiveness.

Advances in pleural disease


The burden of pleural disease continues to increase internationally leading to significant healthcare costs and an urgent need for improving management. Pleural effusion is a common presentation for many pulmonary and systemic diseases, and it is estimated that each year 1.5 million people develop a pleural effusion in the USA and 200 000–250 000 in the UK [1, 2]. Despite the prevalence of pleural disease, advances in research in the field have not been equal to other fields in respiratory medicine, including much rarer conditions. By way of example, talc pleurodesis (proposed in 1935) remains the standard therapy for symptomatic malignant pleural effusion in many centres [3]; very few diseases in medicine are currently managed in the same way as they were 80 years ago.

The development of pleural medicine as a subspecialty is now justified, on the basis of the increasing choice of pleural procedures that are available to the physician and the growing number of patients presenting with pleural disease [4]. It can be argued that a specialist pleural unit is now required for optimal provision of the service, as it has been shown that specialist care significantly reduces complications [5]. This also provides the best environment for providing dedicated teaching to specialty trainees and junior staff. Although a specialist pleural centre ensures effective management for patients, standardisation of practice between centres is difficult based on the lack of high-quality research that will guide clinical practice.

In the latest series in the European Respiratory Review, leading pleural specialists have provided reviews on the latest advances in pleural medicine. Psallidas et al. [6] provide a state-of-the-art review of malignant pleural effusion from bench-to-bedside focusing on the pathogenesis, novel treatments and future directions. Bhatnagar et al. [7] summarise the important literature relating to a number of advanced pleural interventions, including medical thoracoscopy, indwelling pleural catheters and pleural manometry. In forthcoming issues of the European Respiratory Review, benign pleural effusion, malignant pleural mesothelioma and radiological investigation of pleural disease will be covered, providing state-of-the-art advances in each area.

Research in pleural disease is now growing and large scale trials have been performed and are underway which will help answer many clinical questions. There are currently ongoing large randomised, multicentre studies aimed at: improving treatment in malignant pleural effusion and pneumothorax; understanding the pathogenesis and microbiology of pleural infection; and biomarker discovery. In parallel with clinical research, basic biological research is expected to provide much needed data on pathogenesis and mechanism, thereby suggesting novel treatments in the field. In the era of personalised medicine, translational research is anticipated to advance pleural disease through the combination of state-of-the-art laboratory research with multicentre clinical research. It is expected that the results will be applicable to everyday clinical practice.

Will 3D printers reduce aortic valve implant risks?


Due to the comparatively lower cost of production, rapid prototyping and efficiency in design, 3D printing is already making a mark at different industries such as aerospace, automotive and manufacturing of industrial equipment. However, scientists and researchers have taken 3D printing technology further by introducing it in medical sciences. Today, many bodily implants such as dental crowns, dentures, prosthetic limbs, hearing aid ear buds and even 3D bioprinted organs are being produced. The newest addition to this scene is the 3D printed aortic valve that could potentially reduce many complications, especially from transcatheter replacement of the aortic valve in patients. This will prove to be a new dimension in the application of 3D printing in the healthcare sector.

At University of Seattle, Washington, the Department of Radiology researchers are busy perfecting the technique of 3D printing models of aortic valves that could potentially help to reduce the risk factors and complications of transcatheter aortic valve replacement or TAVR. This would prove helpful for thousands of patients who are suffering from aortic stenosis. TAVR is set to become a safer alternative to more invasive and extreme surgical methods. This procedure is comparatively non invasive and involves repair of the valve without the actual removal of the damaged part from within. A replacement valve, which is fully collapsible, is delivered to the site through a catheter. This process is similar to the placement of a stent in an artery.

Even though TAVR is a relatively safe method, chances of complication occurrence still remain. One of the major problems can occur with paravalvular aortic regurgitation or PAR. This can take place when the inserted prosthetic valve does not fit correctly or due to failure of achieving the circumferential seal. It is still a difficult task to determine the exact size of prosthetic valve due to the fact that the aortic root is still a complicated area in the anatomy of humans. The aortic root can come in various sizes and shapes; hence doctors often find it difficult to determine the accurate size.

Today, transthoracic echocardiography (TTE), cardiac CT or transesophageal echocardiography (TEE) are methods used to measure the aortic valve in patients. These methods of imaging are effective only to a certain degree as the images produced are in two dimensions- thus not a hundred percent effective or accurate. The researchers at the University of Washington, however, took a hypothetical novel 3D printed aortic valve model that could be used to help physicians determine the perfect size. This would also help them to accurately predict how specific aortic valves would react to being a prosthesis of certain shape and size. Another factor it can determine is how prone to the risk of PAR a patient is in post procedural conditions.

To test out the hypothesis, the team of researchers conducted an experiment which involved testing the effectiveness of 3D printed aortic root models. Eight patients were identified by lead author and resident of radiology Dr. Beth Ripley during the course of the experiment. These patients have all experienced post TAVR PAR. Then these patients were matched with eight similar patients in terms of sex, age and implanted valve size. This new set of patients did not undergo the PAR complication after they had undergone TAVR. Those who assisted Dr. Ripley were Michael K. Cheezum, Tatiana Kelil, Marcelo F. Di Carli, Alexandra Goncalves, Mike Steigner, Frank J. Rybicki, Ron Blankstein and Dimitrios Mitsouras. Their research paper documented the findings of their experiment and results, which was published in the Journal of Cardiovascular Computed Tomography.

Curbs on free speech are growing tighter. It is time to speak out


IN A sense, this is a golden age for free speech. Your smartphone can call up newspapers from the other side of world in seconds. More than a billion tweets, Facebook posts and blog updates are published every single day. Anyone with access to the internet can be a publisher, and anyone who can reach Wikipedia enters a digital haven where America’s First Amendment reigns.

However, watchdogs report that speaking out is becoming more dangerous—and they are right. As our report shows, curbs on free speech have grown tighter. Without the contest of ideas, the world is timid and ignorant.

Free speech is under attack in three ways. First, repression by governments has increased. Several countries have reimposed cold-war controls or introduced new ones. After the collapse of the Soviet Union, Russia enjoyed a free-for-all of vigorous debate. Under Vladimir Putin, the muzzle has tightened again. All the main television-news outlets are now controlled by the state or by Mr Putin’s cronies. Journalists who ask awkward questions are no longer likely to be sent to labour camps, but several have been murdered.

China’s leader, Xi Jinping, ordered a crackdown after he took over in 2012, toughening up censorship of social media, arresting hundreds of dissidents and replacing liberal debate in universities with extra Marxism. In the Middle East the overthrow of despots during the Arab spring let people speak freely for the first time in generations. This has lasted in Tunisia, but Syria and Libya are more dangerous for journalists than they were before the uprisings; and Egypt is ruled by a man who says, with a straight face: “Don’t listen to anyone but me.”

Words, sticks and stones

Second, a worrying number of non-state actors are enforcing censorship by assassination. Reporters in Mexico who investigate crime or corruption are often murdered, and sometimes tortured first. Jihadists slaughter those they think have insulted their faith. When authors and artists say anything that might be deemed disrespectful of Islam, they take risks. Secular bloggers in Bangladesh are hacked to death in the street (see article); French cartoonists are gunned down in their offices. The jihadists hurt Muslims more than any others, not least by making it harder for them to have an honest discussion about how to organise their societies.

Third, the idea has spread that people and groups have a right not to be offended. This may sound innocuous. Politeness is a virtue, after all. But if I have a right not to be offended, that means someone must police what you say about me, or about the things I hold dear, such as my ethnic group, religion, or even political beliefs. Since offence is subjective, the power to police it is both vast and arbitrary.

Nevertheless, many students in America and Europe believe that someone should exercise it. Some retreat into the absolutism of identity politics, arguing that men have no right to speak about feminism nor whites to speak about slavery. Others have blocked thoughtful, well-known speakers, such as Condoleezza Rice and Ayaan Hirsi Ali, from being heard on campus (see article).

Concern for the victims of discrimination is laudable. And student protest is often, in itself, an act of free speech. But university is a place where students are supposed to learn how to think. That mission is impossible if uncomfortable ideas are off-limits. And protest can easily stray into preciousness: the University of California, for example, suggests that it is a racist “micro-aggression” to say that “America is a land of opportunity”, because it could be taken to imply that those who do not succeed have only themselves to blame.

The inconvenient truth

Intolerance among Western liberals also has wholly unintended consequences. Even despots know that locking up mouthy but non-violent dissidents is disreputable. Nearly all countries have laws that protect freedom of speech. So authoritarians are always looking out for respectable-sounding excuses to trample on it. National security is one. Russia recently sentenced Vadim Tyumentsev, a blogger, to five years in prison for promoting “extremism”, after he criticised Russian policy in Ukraine. “Hate speech” is another. China locks up campaigners for Tibetan independence for “inciting ethnic hatred”; Saudi Arabia flogs blasphemers; Indians can be jailed for up to three years for promoting disharmony “on grounds of religion, race…caste…or any other ground whatsoever”.

The threat to free speech on Western campuses is very different from that faced by atheists in Afghanistan or democrats in China. But when progressive thinkers agree that offensive words should be censored, it helps authoritarian regimes to justify their own much harsher restrictions and intolerant religious groups their violence. When human-rights campaigners object to what is happening under oppressive regimes, despots can point out that liberal democracies such as France and Spain also criminalise those who “glorify” or “defend” terrorism, and that many Western countries make it a crime to insult a religion or to incite racial hatred.

One strongman who has enjoyed tweaking the West for hypocrisy is Recep Tayyip Erdogan, president of Turkey. At home, he will tolerate no insults to his person, faith or policies. Abroad, he demands the same courtesy—and in Germany he has found it. In March a German comedian recited a satirical poem about him “shagging goats and oppressing minorities” (only the more serious charge is true). Mr Erdogan invoked an old, neglected German law against insulting foreign heads of state. Amazingly, Angela Merkel, the German chancellor, has let the prosecution proceed. Even more amazingly, nine other European countries still have similar laws, and 13 bar insults against their own head of state.

Opinion polls reveal that in many countries support for free speech is lukewarm and conditional. If words are upsetting, people would rather the government or some other authority made the speaker shut up. A group of Islamic countries are lobbying to make insulting religion a crime under international law. They have every reason to expect that they will succeed.

So it is worth spelling out why free expression is the bedrock of all liberties. Free speech is the best defence against bad government. Politicians who err (that is, all of them) should be subjected to unfettered criticism. Those who hear it may respond to it; those who silence it may never find out how their policies misfired. As Amartya Sen, a Nobel laureate, has pointed out, no democracy with a free press ever endured famine.

In all areas of life, free debate sorts good ideas from bad ones. Science cannot develop unless old certainties are queried. Taboos are the enemy of understanding. When China’s government orders economists to offer optimistic forecasts, it guarantees that its own policymaking will be ill-informed. When American social-science faculties hire only left-wing professors, their research deserves to be taken less seriously.

The law should recognise the right to free speech as nearly absolute. Exceptions should be rare. Child pornography should be banned, since its production involves harm to children. States need to keep some things secret: free speech does not mean the right to publish nuclear launch codes. But in most areas where campaigners are calling for enforced civility (or worse, deference) they should be resisted.

Blasphemy laws are an anachronism. A religion should be open to debate. Laws against hate speech are unworkably subjective and widely abused. Banning words or arguments which one group finds offensive does not lead to social harmony. On the contrary, it gives everyone an incentive to take offence—a fact that opportunistic politicians with ethnic-based support are quick to exploit.

Incitement to violence should be banned. However, it should be narrowly defined as instances when the speaker intends to goad those who agree with him to commit violence, and when his words are likely to have an immediate effect. Shouting “Let’s kill the Jews” to an angry mob outside a synagogue qualifies. Drunkenly posting “I wish all the Jews were dead” on an obscure Facebook page probably does not. Saying something offensive about a group whose members then start a riot certainly does not count. They should have responded with words, or by ignoring the fool who insulted them.

In volatile countries, such as Rwanda and Burundi, words that incite violence will differ from those that would do so in a stable democracy. But the principles remain the same. The police should deal with serious and imminent threats, not arrest every bigot with a laptop or a megaphone. (The governments of Rwanda and Burundi, alas, show no such restraint.)

Areopagitica online

Facebook, Twitter and other digital giants should, as private organisations, be free to decide what they allow to be published on their platforms. By the same logic, a private university should be free, as far as the law is concerned, to enforce a speech code on its students. If you don’t like a Christian college’s rules against swearing, pornography and expressing disbelief in God, you can go somewhere else. However, any public college, and any college that aspires to help students grow intellectually, should aim to expose them to challenging ideas. The world outside campus will often offend them; they must learn to fight back using peaceful protests, rhetoric and reason.

These are good rules for everyone. Never try to silence views with which you disagree. Answer objectionable speech with more speech. Win the argument without resorting to force. And grow a tougher hide.