Academics should not remain silent on hacking : Nature News & Comment

Academics should not remain silent on hacking

The revelation that US and British spy agencies have undermined a commonly used encryption code should alarm researchers, says Charles Arthur.

Secrecy doesn’t come naturally to journalists, but sometimes it is thrust upon us. Earlier this year, there was a room in The Guardian‘s offices in London that nobody could enter alone. On a table outside by a security guard was a tidy collection of phones and other devices; nothing electronic was allowed. Inside were a coffee maker, a shredder, some paper and a few computers. All were brand new; none had ever been connected to the Internet. None ran Microsoft Windows. All were encrypted; each required two passwords, held by different people.

This is where the biggest news stories of this year lived — away from the Internet. This was where The Guardian analysed the ‘Snowden files’ (classified documents released to the press by former US National Security Agency (NSA) contractor Edward Snowden). These revealed, among other things, that the NSA and the United Kingdom’s GCHQ were running enormous efforts to crack encrypted communications online, and that they had worked to undermine the strength of encryption standards such as that used — and recommended — by the US National Institute of Standards and Technology (NIST). (The computers sadly are no more — smashed in The Guardian basement on the orders of the British government.)

NIST’s standard for random numbers used for cryptography, published in 2006, had been weakened by the NSA. Companies such as banks and financial institutions that rely on encryption to guarantee customer privacy depend on this standard. The nature of the subversions sounds abstruse: the random-number generator, the ‘Dual EC DRBG‘ standard, had been hacked by the NSA so that its output would not be as random as it should have been. That might not sound like much, but if you are trying to break an encrypted message, the knowledge that it is hundreds or thousands of times weaker than advertised is a great encouragement.

It was, to be frank, a big deal. In the world’s universities, computer scientists and mathematicians spend their careers trying to develop secure systems, and yet here was evidence of a systematic — and successful — attempt to undermine that work. Executives at companies such as Google, Yahoo, Facebook and Microsoft, which discovered that their internal networks were being tapped and their systems infiltrated, were furious. But a few isolated shouts of protest aside, the academic community has largely been silent.

That’s disappointing. Academia is where we expect to hear the free flow of ideas and opinions. Yet it has been the commercial companies that have made the most noise — because the revelations threaten trust in their businesses. Don’t academics also see the threat to open expression, and to the flow of dissident ideas from countries where people might fear that their communications are being tapped and, even if encrypted, cracked?

“Academics in cryptography and security should make themselves a promise: ‘we won’t get fooled again.’”

Some get it. Ross Anderson, a security researcher at the University of Cambridge, UK, has been highly critical and outspoken. When I spoke to him in September, soon after the NIST revelation, he called it “a wake-up call for a lot of people” and added: “This has been a 9/11 moment for the community, and it’s great that some people are beginning to wake up.”

Kenneth White, principal scientist at health-information company Social & Scientific Systems in Silver Spring, Maryland, says: “Just a year ago, such a story would have been derogated by most of my colleagues as unwarranted suspicion at best and outright paranoia at worst. But here we are.”

Anderson has an explanation for the muted response: he says that a number of British university departments have been quietly coerced by the GCHQ. The intelligence-gathering agency has a substantial budget, and ropes in academics by offering access to funds that ensures their silence on sensitive matters, Anderson says. (If that sounds like paranoia, then see above.)

I have not been able to confirm his claims, but what are the alternatives? One is that the academics are simply too busy going back over their own work looking to see if they agree with the claimed weaknesses. The other is that they simply don’t care enough.

For those who do care, White and Matthew Green, who teaches cryptography at Johns Hopkins University in Baltimore, Maryland, have embarked on an ambitious effort to clean up the mess — one that needs help.

They have created a non-profit organization called, which aims to recruit experts to provide technical assistance for security projects in the public interest, especially open-source security software. A similar effort initiated by White and Green is checking the open-source software called TrueCrypt, which is widely used to lock down hard drives during foreign travel (see

Concerns over the security of the NIST Dual EC DRBG standard were raised in 2007, but too few academics spoke out then. The events of 2013 must make them rethink. Cryptography rarely reaches the headlines, but now it has done so for all the wrong reasons. For 2014, academics working in cryptography and security should make themselves a promise: ‘We won’t get fooled again.’ And most of all, ‘We won’t go down quietly.’

Vitamin pills are a waste of money, offer no health benefits and could be harmful – study

Evidence from the study suggested that ‘supplementing the diet of well-nourished adults…has no clear benefit and might even be harmful’

Vitamin pills are a waste of money, usually offer no health benefits and could even be harmful, a group of leading scientists has said.

A study of nearly 500,000 people, carried out by academics from the University of Warwick and the Johns Hopkins School of Medicine in Baltimore, USA, has delivered a damning verdict on the claims made by the vitamin supplement industry.

Evidence from the study suggested that “supplementing the diet of well-nourished adults…has no clear benefit and might even be harmful”, despite one in three Britons taking vitamins or mineral pills.

According to The Times, scientists involved in the study, which was published in the Annals of Internal Medicine, concluded that companies selling supplements were fuelling false health anxieties to offer unnecessary cures. The industry in the UK is thought to be worth more than £650 million annually.

Researchers declared ‘case closed’ on the vitamin and mineral pills after making their conclusion based on the study of half-a-million people along with three separate research papers.

Evidence from the study suggested that

Evidence from the study suggested that “supplementing the diet of well-nourished adults…has no clear benefit and might even be harmful”, despite one in three Britons taking vitamins or mineral pills.

One of the research papers involved the retrospective study of 24 previous trials. In total 450,000 people were involved in the trials and the paper concluded that there was no beneficial effect on mortality from taking vitamins.

Another examined 6,000 elderly men and found no improvement on cognitive decline after 12 years of taking supplements, while a third saw no advantage of supplements among 1,700 men and women with heart problems over an average study of five years.

The experts said most supplements should be avoided as their use is not justified, writing: “These vitamins should not be used for chronic disease prevention. Enough is enough.”

The scientists argued that the average Western diet is sufficient to provide the necessary vitamins the body needs.

Edgar Miller, of the Johns Hopkins School of Medicine, said: “There are some that advocate we have many nutritional deficiencies in our diet. The truth is though we are in general overfed, our diet is completely adequate.”

He added: “These companies are marketing products to us based on perceptions of deficiencies. They make us think our diet is unhealthy, and that they can help us make up for these deficiencies and stop chronic illnesses.

“The group that needs these is very small. It’s not the general population.”

Dr Miller continued: “There’s something for everything: preventing joint pains, stopping heart disease. If you’re going to spend your money on something every month, is this really the best option?”

The NHS advised recently that other than women taking folic acid to help them conceive and the elderly and children under five benefiting from vitamin D, supplementary vitamins would be surplus to that already gained through diet, The Times said.

The Health Food Manufacturers’ Association said vitamin supplements provided people with “nutritional insurance”.

In July 2011 the Advertising Standards Agency criticised Vitabiotics Ltd for an advert headlined: ‘Advanced Nutrients For The Brain’.

They ruled that the implied claims that “recent research had shown that B vitamins could help maintain brain function and performance’ were not substantiated and were “misleading”.

Blood Test May Predict Ketamine’s Antidepressant Effect.

Researchers have identified biomarkers that they hope will eventually help predict which patients with bipolar depression will respond to subanesthetic doses of ketamine.

An experimental blood test using pharmacometabolomics found patterns, or metabolic “fingerprints,” that differ between people whose bipolar depression improved with intravenous ketamine and those who did not get better. Pharmacometabolomics uses sophisticated chemistry techniques to quantify and analyze metabolites that the body produces in response to drugs.

“This work is telling us what we should measure [in the blood],” study coauthor Irving Wainer, PhD, from the National Institute on Aging‘s Intramural Research Program in Baltimore, Maryland, toldMedscape Medical News. “Then we’ll develop the technology to predict, pretreatment, which patients will respond to ketamine treatment and find ways to individualize and optimize treatment with ketamine.”

The research findings were presented here recently at the American Society of Anesthesiologists (ASA) 2013 Annual Meeting.

Rapid Antidepressant Effect

Recent studies of this investigational use of ketamine, a glutamateN-methyl-D-aspartate (NMDA) receptor antagonist, show that many patients with treatment-refractory bipolar depression ( Biol Psychiatry, 2012;71:939-946) or other types of major depression respond rapidly to intravenous infusion of ketamine — typically in several hours.

However, 1 in 3 patients do not respond to this treatment at all, said another author of the new study, Michael Goldberg, MD, an anesthesiologist from Cooper University Health Care in Camden, New Jersey.

“It’s not ethical to put everyone [with depression] on ketamine because it has risks. Hallucinations are common and may require other medications to counteract,” Dr. Goldberg told Medscape Medical News.

Knowing before ketamine administration who would be least likely to benefit would spare them from exposure to the drug and its common dissociative side effects, he said.

Toward that end, the researchers collected blood samples from 22 patients with bipolar disorder and major depression both before and after a single intravenous infusion of 0.5 mg/kg of ketamine or a placebo; the patients then were crossed over to the alternate therapy after a 1-week drug washout.

Patients also received treatment with either lithium (n = 16) or valproate (n = 6) as a mood stabilizer and responded to this therapy, according to Dr. Goldberg. Response to ketamine was identified 230 minutes after infusion using the Montgomery-Åsberg Depression Rating Scale.

The investigators analyzed the metabolomic patterns in the blood samples using liquid chromatography/quadruple time-of-flight mass spectometry and capillary electrophoresis/laser-induced fluorescence.

They also reportedly identified the compound that ketamine breaks down into, which they called 2S, 6S hydroxynorketamine.

Quick Turnaround Test

In the group receiving comedication with lithium, patients who did not respond to ketamine treatment (“nonresponders”) had significant post-treatment differences in 18 metabolites compared with ketamine responders, according to the abstract (P values not reported).

These included significantly increased levels of the fatty acids phenyllactic acid and monoglyceride and significantly decreased levels of trimethyl-L-lysine, lysophosphatidylethanolamine, and lysophosphatidylcholine.

The same trend was seen in the patients receiving valproate, but the number of patients in this group was not large enough to determine statistical significance, Dr. Goldberg stated.

Independently of the mood stabilizer, nonresponders also reportedly had significantly higher levels of the amino acid D-serine. In their abstract, the authors suggested a difference in the activity of the enzyme serine racemase between responders and nonresponders, possibly owing to an indirect change in NMDA receptor activity.

Although most patterns observed in metabolites were of fatty acids, some were metabolites of ketamine, Nagendra Singh, PhD, said during the oral presentation of the findings. Dr. Singh, who was not a coauthor of the study, will soon be joining Cooper University Health Care as a research associate.

Of 323 metabolites analyzed, only 2 were reportedly the same between the lithium and valproate groups.

“Two different mood stabilizers had very different metabolite patterns in their fatty acids, which was very interesting,” Dr. Singh said. “This clearly demonstrates that lithium and valproate affect fatty acids differently.”

The researchers speculated that patients with bipolar depression respond to ketamine on the basis of various endogenous factors, including fatty acid metabolism and the plasma levels of endogenous compounds involved in neurotransmission.

A limitation of the study, said Dr. Wainer, is that it was not designed prospectively for pharmacometabolomics. He described the pharmacometabolomic process as “time-consuming and costly.”

Dr. Wainer said his team plans to limit future analyses to 5 or 6 metabolites.

“Our goal is to develop the technology so that there will be on-site rapid turnaround of blood test results,” he said.

Not Ready for Routine Use

Commenting on the study for Medscape Medical News, Timothy Lineberry, MD, associate professor of psychiatry at Mayo Clinic, Rochester, Minnesota, said that identifying who will benefit from and have good response to ketamine is important.

Dr. Lineberry, who was not involved with the study, said that there are not yet enough research data for physicians to routinely use ketamine in clinical practice for this off-label purpose.

“There is also a need for identifying what are the psychological markers associated with response to ketamine and the particular diagnoses that will respond to treatment,” he added.

The next patient population in which Dr. Goldberg said their research team plans to study pharmacometabolomics after ketamine infusion is those with post-traumatic stress disorder.

Acupuncture Reduces Neuropathy Associated With Bortezomib.

Acupuncture may be able to reduce neuropathy associated with the use of bortezomib (Velcade, Millennium Pharmaceuticals, Inc.) in multiple myeloma patients, suggest new data. The results are early, but patients treated with acupuncture appeared to experience both subjective and objective improvements in symptoms.

“Acupuncture is feasible and safe for treating multiple myeloma patients with persistent and moderate pain due to bortezomib-induced peripheral neuropathy [BIPN],” said Ting Bao, MD, an assistant professor of medicine at the University of Maryland, in Baltimore. She noted that all patients appeared to have decreased pain and improved function, as evidenced by improved scores on standardized measures.

Dr. Bao presented her results here at the 10th International Conference of the Society for Integrative Oncology (SIO).

Bortezomib is an effective treatment for multiple myeloma, but its use can cause sensory neuropathy, which can limit dose and duration of treatment, she explained. “Peripheral neuropathy is one of the most common and severe toxicities, and treatment is limited to symptom management.”

Symptoms are often difficult to manage, and available treatment options frequently do not provide total relief and can cause adverse effects. Conversely, Dr. Bao pointed out, acupuncture has no side effects, and several studies have demonstrated the efficacy of acupuncture in treating peripheral neuropathy.

“As such, we hypothesized that acupuncture was a safe, feasible, and effective approach to treating BIPN, and that it works through modulating serum cytokines,” Dr. Bao said. “So as a first step in testing this hypothesis, we designed a single-arm, single-institution study.”

Safe and Feasible

For their pilot study, Dr. Bao and colleagues enrolled 27 patients with multiple myeloma who were experiencing persistent bortezomib-induced peripheral neuropathy of grade 2 or greater, despite receiving adequate medical intervention, and who were no longer using the agent.

All patients in the cohort received 10 acupuncture treatments for 10 weeks (2x/week for 2 weeks, 1x/week for 4 weeks, and then biweekly for 4 weeks), and their responses to treatment were evaluated with the Clinical Total Neuropathy Score (TNSc), the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity (FACT/GOG-Ntx) questionnaire, and the Neuropathy Pain Scale (NPS).

The TNSc was evaluated by a trained research nurse using both subjective and objective measurements. The researchers also obtained serial serum levels of proinflammatory and neurotrophic cytokines at baseline and at weeks 1, 2, 4, 8, and 14.

Dr. Bao explained that all of the patients had grade 3 to 4 neuropathy, and the median time after discontinuing bortezomib was 19 months, making spontaneous recovery not very feasible. “Neuropathy was already affecting their daily activity,” she said.

At weeks 10 and 14, TNSc, FACT/GOG-Ntx, and NPS all showed significant reduction, suggesting decreased pain, improved function, and improved objective neuropathy measurement (P-values were 0.02 and 0.03 for TNSc at weeks 10 and 14, respectively, and <.0001 for both FACT/GOG-Ntx and NPS at weeks 10 and 14).

Mechanism Unclear

However, results of nerve conduction studies did not significantly change between baseline assessment and end of study. “Fifteen patients had nerve conduction studies before and after acupuncture,” said Dr. Bao. “The majority did not show change.”

“Disappointingly, there was no correlation between symptom reduction and nerve conduction studies,” she continued. “And more disappointingly, 12 serum biomarkers did not show any significant change over time. So the mechanism remains unclear.”

Dr. Bao concluded that even though the mechanism of action still remains unclear, acupuncture is safe, feasible, and may be able to reduce pain and improve function, and that they are planning a follow-up randomized trial.

“These results were very promising, and the next step will be to look at a randomized controlled trial, and that will ultimately be the next step to see if acupuncture is effective in treating bortezomib-induced neuropathy,” said Richard Lee, MD, assistant professor of general oncology at the University of Texas MD Anderson Cancer Center in Houston.

Acupuncture may also be useful in treating other types of neuropathy, said Dr. Lee, who was approached byMedscape Medical News for an independent comment. “This is a very active area of investigation. Our group at MD Anderson, Dr. Bao’s group, and others are looking at peripheral neuropathy.”

“There are many different types of chemotherapy that can cause neuropathy, such as platinum-based agents and taxanes,” he continued. “Whether or not this type of treatment is universal for all types of chemotherapy, we don’t know. We really need further studies to investigate its use with other agents.


Shorter Sleep Duration and Poorer Sleep Quality Linked to Alzheimer’s Disease Biomarker.

Poor sleep quality may impact Alzheimer’s disease onset and progression. This is according to a new study led by researchers at the Johns Hopkins Bloomberg School of Public Health who examined the association between sleep variables and a biomarker for Alzheimer’s disease in older adults. The researchers found that reports of shorter sleep duration and poorer sleep quality were associated with a greater β-Amyloid burden, a hallmark of the disease. The results are featured online in the October issue of JAMA Neurology.

“Our study found that among older adults, reports of shorter sleep duration and poorer sleep quality were associated with higher levels of β-Amyloid measured by PET scans of the brain,” said Adam Spira, PhD, lead author of the study and an assistant professor with the Bloomberg School’s Department of Mental Health. “These results could have significant public health implications as Alzheimer’s disease is the most common cause of dementia, and approximately half of older adults have insomnia symptoms.”

Alzheimer’s disease is an irreversible, progressive brain disease that slowly destroys memory and thinking skills. According to the National Institutes of Health, as many as 5.1 million Americans may have the disease, with first symptoms appearing after age 60. Previous studies have linked disturbed sleep to cognitive impairment in older people.

In a cross-sectional study of adults from the neuro-imagining sub-study of the Baltimore Longitudinal Study of Aging with an average age of 76, the researchers examined the association between self-reported sleep variables and β-Amyloid deposition. Study participants reported sleep that ranged from more than seven hours to no more than five hours. β-Amyloid deposition was measured by the Pittsburgh compound B tracer and PET (positron emission tomography) scans of the brain. Reports of shorter sleep duration and lower sleep quality were both associated with greater Αβ buildup.

“These findings are important in part because sleep disturbances can be treated in older people. To the degree that poor sleep promotes the development of Alzheimer’s disease, treatments for poor sleep or efforts to maintain healthy sleep patterns may help prevent or slow the progression of Alzheimer disease,” said Spira.  He added that the findings cannot demonstrate a causal link between poor sleep and Alzheimer’s disease, and that longitudinal studies with objective sleep measures are needed to further examine whether poor sleep contributes to or accelerates Alzheimer’s disease.

Deal done over HeLa cell line.

Deborah Lacks wanted answers. In 1974, she asked a leading medical geneticist to tell her about HeLa cells, a tissue-culture cell line derived from the cancer that had killed her mother Henrietta in 1951. The researcher, who was collecting blood from the Lacks family to map HeLa genes, autographed a medical textbook he had written and said that everything she needed to know lay within its dense pages.

It would be more than 30 years before the family got a better explanation.

Now the director of the US National Institutes of Health (NIH), Francis Collins, is trying to make up for decades of slights. Over the past four months, he has met Lacks family members to answer questions and to discuss what should be done with genome data from their matriarch’s cell line.

“We wanted to get a better understanding of what information was going to be out there about Henrietta, and what information was going to be out there about us,” says Henrietta’s grandson David Lacks Jr. (Deborah Lacks died in 2009.) On 7 August, Collins announced that the family has endorsed case-by-case release of the information, subject to approval by a committee that will include family members .

The consensual approach is a sea change from the dismissive treatment of the past, says Rebecca Skloot, the journalist who recounted the scene between Deborah Lacks and the researcher in her 2010 book The Immortal Life of Henrietta Lacks. “It was the first time in the very long history of HeLa cells that any scientists have sat down and devoted complete attention to explaining to the family what was going on,” she says (see ‘The Lacks legacy‘).

The agreement allows the publication of a US government-funded HeLa genome sequence as well as the re-release of data that were pulled from public view soon after publication in March because of the family’s concerns. Nature’s News team learned of the negotiations last month but agreed to delay coverage so as not to impede the talks. Brokered during meetings at Johns Hopkins School of Medicine in Baltimore, Maryland, the deal rekindles debates over consent and ownership of tissues, and data that arise from their study, at a time when the NIH is updating such rules.

The HeLa cell line was established in 1951 from a biopsy of a cervical tumour taken from Henrietta Lacks, a working-class African-American woman living near Baltimore. The cells were taken without the knowledge or permission of her or her family, and they became the first human cells to grow well in a lab. They contributed to the development of a polio vaccine, the discovery of human telo­merase and countless other advances. A PubMed search for ‘HeLa’ turns up more than 75,000 papers. “My lab is growing HeLa cells today,” Collins told Nature in an interview on the NIH campus in Bethesda, Maryland. “We’re using them for all kinds of gene-expression experiments, as is almost every molecular-biology lab.”

On 11 March, weeks before Collins drove to Baltimore to meet the Lacks family for the first time, a team led by Lars Steinmetz at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, published a paper called ‘The genomic and transcriptomic landscape of a HeLa cell line’ (J. J. M. Landry et al. Genes Genomes Genet.; 2013). News coverage (see noted the link to Henrietta Lacks, but not privacy concerns.

Skloot, in a later article for The New York Times, made clear that family members were unhappy that — yet again — they had not been consulted. “I think it’s private information,” Henrietta’s granddaughter Jeri Lacks-Whye told Nature. “I look at it as though these are my grandmother’s medical records that are just out there for the world to see.” The EMBL team removed the data from public access, and hoped that a solution could be reached.

As the controversy erupted, Nature was preparing to publish an even more detailed sequence of the HeLa genome, according to senior author Jay Shendure, a genome scientist at the University of Washington in Seattle. His team, funded by the NIH, started decoding HeLa DNA in 2011, as part of an effort to develop new sequencing techniques. They also hoped that the genome would be useful for other researchers, a motivation shared by the EMBL team. They submitted their paper to Nature in November 2012.

The paper’s reviewers did not raise privacy concerns before recommending it for publication; nor did Nature, Shendure says. He considered contacting the Lacks family before publication, and restricting access. “Figuring out how to reach out to the family was very much on the table when events overtook us.”

After Skloot’s article on the EMBL paper came out in March, Collins learned about Shendure’s NIH-funded project. He saw an opportunity. He was already at work reforming the rules that govern research on human subjects. “It looked as if this was a moment to get everybody in the same room,” he says.

And so, on the evening of 8 April, Collins met a group of Henrietta Lacks’ children and grandchildren for dinner and discussion at the Johns Hopkins campus. Along with Collins was his chief adviser and two mediators from the university. Skloot phoned in to the meeting, which was to be the first of three.

Collins says that family members told him how unsettling it had been to learn about HeLa cells decades after Lacks died. They peppered Collins with questions about genetic sequencing and how Lacks’ cells had been used. “I felt like I was taking ‘Biology 101’,” says Lacks-Whye. Collins told them that Shendure’s team might have identified the genetic change that made their grandmother’s tumour so aggressive and HeLa cells so prolific. The NIH later put the family in touch with experts in clinical genetics who told them what health information could be gleaned from the genome, and the NIH offered to help family members have their own genomes sequenced and interpreted.

Collins says that he did not pressure the family to agree to the release of the HeLa genome data; he was open to leaving the NIH-funded work unpublished. But he told the family that it would be impossible to keep the data locked away. NIH researchers had calculated that 400 genomes’ worth of HeLa data are already publicly available in piecemeal form — parts of projects such as the Encyclopedia of DNA Elements — and that scientists in thousands of labs around the world could easily and cheaply sequence the cell line themselves.

Some Lacks family members raised the possibility of financial compensation, Collins says. Directly paying the family was not on the table, but he and his advisers tried to think of other ways the family could benefit, such as patenting a genetic test for cancer based on HeLa-cell mutations. They could not think of any. But they could at least reassure the family that others would not make a quick buck from their grandmother’s genome, because the US Supreme Court had this year ruled that unmodified genes could not be patented. Lacks-Whye says that the family does not want to dwell on money — and that her father has often said he “feels compensated by knowing what his mother has been doing for the world”.

In the end, the family decided that it wanted the data to be available under a restricted-access system similar to the NIH dbGaP database, which links individuals’ genetic make-up to traits and diseases. Researchers would apply for permission to acquire the data and agree to use them for biomedical research only, and would not contact Lacks family members. A committee that includes family members will handle requests, and papers that use the data will recognize Henrietta Lacks and her kin. The first of these papers, the NIH-funded paper, is published in this issue..

In discussing HeLa cells and the agreement forged with the family, Collins and others often use the word “unique”. No other human sample matches the cell line for ubiquity, notoriety or celebrity (Oprah Winfrey is producing a film based on the story). The NIH does not see the deal with the family as a guide to handling other human samples. “It’s not going to be a precedent,” says Collins’ chief adviser Kathy Hudson.

But it will probably inform other cases, she adds. The US government is redrafting rules that govern the relationship between federally funded researchers and participants. New rules aim to give subjects greater say in how their tissues and personal data are used. “Going forward, I’m very much of the mind that the most appropriate way to show respect for persons is to ask,” Collins says. “Ask people, ‘Are you comfortable having this specimen used for future genomic research for a broad range of biomedical applications?’ — if they say no, no means no.”

As for the myriad other tissues out there that were obtained without consent, Collins says that it would slow science too much to ban their use. Laura Rodriguez, a policy official at the NIH who works on guidelines for genome sequencing, says that there is a low risk of donors of such samples being identified. But in January, researchers working on a genomics project showed that it is possible to identify anonymous participants — and their families — by cross-referencing their genomes with genealogy DNA databases.

Hank Greely, a biotechnology lawyer at Stanford University in California who has advised the EMBL group, says the HeLa agreement is a “good solution”, but applying it to other unconsented cell lines and data would be unwieldy and impractical. “The one thing we really should be doing is making sure every­thing we collect from here into the future is acceptable.”

Lacks-Whye has similar advice. Researchers can make major breakthroughs, she says, while still respecting the wishes of patients and their families. “Have them involved,” she says. “That’s not only for HeLa sequences, but anybody who participates in research.”



Psychedelic Drugs No Risk to Mental Health, Possibly Beneficial.

Using classic psychedelic drugs does not raise the risk for mental health problems; on the contrary, it may offer some protection, new research suggests.

Among 130,152 representative US adults, including 21,967 reported psychedelic drug users, researchers found no significant link between lifetime use of lysergic acid diethylamide (LSD), psilocybin, mescaline, or peyote and an increased rate of mental health problems.

Rather, in several cases, psychedelic drug use was associated with a lower rate of mental health problems, Teri S. Krebs, PhD, and Pål-Ørjan Johansen, PhD, of the Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, report.

The findings were published online August 19 in PLoS One.

Lower Rates of Distress

“We were not particularly surprised. Overall, there is a lack of evidence that psychedelics cause lasting mental health problems,” Dr. Krebs told Medscape Medical News.

More than 30 million Americans have used LSD, psilocybin, or mescaline at some time in their lives. Some case reports of mental illness in people who had used psychedelics fueled some concern of a link. But there are “many potential biases of relying on individual anecdotes,” Dr. Krebs said. “In particular, mental illness is rather common, and symptoms often appear in the early 20s, which is the same time that people often first use psychedelics.”

In the current population study, after adjusting for other risk factors, there was no link between psychedelic drug use and a range of mental health outcomes, including serious psychologic distress, mental health treatment, symptoms of 8 psychiatric disorders (panic disorder, major depressive episode, mania, social phobia, general anxiety disorder, agoraphobia, posttraumatic stress disorder, and nonaffective psychosis), and 7 specific symptoms of nonaffective psychosis.

In fact, lifetime use of psilocybin or mescaline and past-year use of LSD were associated with lower rates of serious psychologic distress. Lifetime use of LSD was also significantly associated with a lower rate of outpatient mental health treatment and psychiatric medicine prescription.

“We cannot exclude the possibility that use of psychedelics might have a negative effect on mental health for some individuals or groups, perhaps counterbalanced at a population level by a positive effect on mental health in others,” the authors note. Nevertheless, “recent clinical trials have also failed to find any evidence of any lasting harmful effects of psychedelics.”

Less Harmful

“This is an important analysis,” Matthew W. Johnson, PhD, of the Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, in Baltimore, Maryland, who was not involved in the study, told Medscape Medical News.

“Although there is evidence suggesting beneficial effects of psychedelics in well-controlled clinical research, that does not address the occurrence of psychiatric adverse effects in the population. It is very interesting to know that these drugs are not associated with adverse mental health outcomes at the population level,” Dr. Johnson said.

“However, as the authors note, it is certainly possible that individual recreational users experience harms. This analysis would just suggest that this may be limited in scope, and possibly offset by some individuals also receiving benefit at the population level,” he added.

This study “chimes very much with what we know already about psychedelics — that they are essentially much less harmful than other illicit substances,” Mark Bolstridge, BSc, MRCPsych, Centre for Neuropsychopharmacology, Imperial College London, United Kingdom, told Medscape Medical News.

“Having personally worked in mental health and trained in psychiatry, I am yet to see any individual suffering from significant mental health problems as a result of using psychedelics. Alcohol, amphetamines, and cannabis, yes, but never psychedelics,” said Dr. Bolstridge, who was not involved in the study.

Dr. Krebs noted that “psychedelics interact with a specific type of serotonin receptor in the brain and may stimulate the formation of new connections and patterns. They generally seem to open an individual to an awareness of new perspectives and opportunities for action. People often report deeply personally and spiritually meaningful experiences with psychedelics,” she said.

Researchers at Imperial College London have found that healthy adults recall memories much more vividly while under the influence of psilocybin, and functional magnetic resonance imaging (fMRI) data reveal a neurobiological basis for this effect, as reported by Medscape Medical News.

Their research also shows that psilocybin has potential in the treatment of depression, anxiety, and possibly cluster headaches.

Debunking Myths

“We know categorically that psychedelics taken in a controlled clinical environment with appropriate support almost certainly never lead to any recurring or enduring mental health problems,” Dr. Bolstridge said.

“All in all, I think the [new] paper is an important addition to the scientific literature, and it can only help in dispelling the myths surrounding these much maligned substances and in reinforcing the case for continued investigations into how these fascinating compounds work in the brain,” Dr. Bolstridge said.

“In particular, [it can help in] attempting to determine whether they can prove effective in helping those patients incapacitated by ongoing mental health problems and who are little helped by conventional psychiatric treatments,” he added.

Dr. Krebs said clinical trials looking at the potential benefits of psilocybin in alcoholism and smoking cessation are also under way. Last year, she and Dr. Johansen published a meta-analysis of randomized controlled trials of LSD in alcoholism, which provided evidence for a beneficial effect of LSD for treating alcohol dependency.



Cocoa, Even With Few Flavonoids, Boosts Cognition.

Drinking cocoa, whether rich in flavonoids or not, appears to boost the effect of blood flow on neuronal activity in the brain, known as neurovascular coupling (NVC).

A new study shows not only that drinking flavonoid-rich or flavonoid-poor cocoa improves NVC but also that higher NVC is associated with better cognitive performance and greater cerebral white matter structural integrity in elderly patients with vascular risk factors.

As researchers search for ways to detect dementia at the earliest possible stage, the study results could pave the way for using NVC as a biomarker for vascular function in those at high risk for dementia, said lead author Farzaneh A. Sorond, MD, PhD, Department of Neurology, Stroke Division, Brigham and Women’s Hospital, Boston, Massachusetts.

“Our study shows that NVC is modifiable and can be enhanced with cocoa consumption,” said Dr. Sorond.

Tight Correlation

The double-blind proof-of-concept study included 60 community-dwelling participants, mean age 72.9 years. About 90% of the participants were hypertensive, but with well-controlled blood pressure, and half had diabetes mellitus type 2 with reasonably good control. Three quarters were overweight or obese.

Participants were randomly assigned to 2 cups a day of cocoa rich in flavonoids (609 mg per serving) or cocoa with little flavonoids (13 mg per serving). Diets were adjusted to incorporate the cocoa, each cup of which contained 100 calories. Participants were also asked to abstain from eating chocolate.

Researchers measured cerebral blood flow in these participants using transcranial Doppler ultrasonography. Among other things, they documented changes in the middle cerebral artery and blood flow velocity at rest and in response to cognitive tasks (NVC).

The study showed that NVC was tightly correlated with cognition; scores for Trail making Test B, a test of executive function, were significantly better in those with intact NVC (89 seconds vs 167 seconds; P = .002). Participants with intact NVC also had significantly better performance on the 2-Back Task, a test for both attention and memory (82% vs 75%; P = .02).

“The higher you increase your blood flow during a cognitive task, the better your cognitive performance,” commented Dr. Sorond, adding that this is something that has never been shown before.

NVC was also correlated with cerebral white matter structural integrity. Higher NVC was associated with overall less white matter macro- and micro-structural damage. In general, those with intact NVC had a greater volume of normal white matter and smaller volume of white matter hyperintensities, higher fractional anisotropy, and lower mean diffusivity in the normal white matter and WMH.

Therapeutic Target

These results suggest that NVC could be an important therapeutic target. But before NVC can be considered a biomarker, it has to be shown to be changeable, and the clinical importance of the modification must be shown.

To that end, the study authors opted to use cocoa. They could have chosen many other potential modifiers but chose cocoa because the literature has shown the beneficial effects of cocoa on brain health and also because it’s something that many people enjoy, said Dr. Sorond.

The study found that blood pressure, blood flow, and change in NVC were not significantly different between the 2 cocoa groups. In the combined cocoa groups, 30-day blood pressures were not significantly different from baseline (P > .5).

In contrast, response to cocoa differed significantly depending on NVC status. Cocoa had a significant effect on NVC in those with impaired (<5%) coupling at baseline. Of those with impaired NVC, 89% responded to 30 days of cocoa consumption and increased NVC compared with only 36% of those with intact NVC (P = .0002). In those with impaired baseline coupling, cocoa consumption was associated with an 8.3% (P < .0001) increase in NVC at 30 days.

The effect of cocoa consumption on Trail B scores was also significantly dependent on NVC status.

The authors were surprised at the lack of effect of flavonoids because previous research had indicated a dose-response with respect to cognitive performance. It could be something other than flavonoids in the cocoa, possibly caffeine, that improves NVC, or it could be that the 13 mg in the low-flavonoid cocoa group was enough to have an effect.

“I think there are effects of flavonol on brain blood flow no matter how low it is,” said Dr. Sorond, adding that perhaps only a tiny amount is needed to activate an enzyme or some other trigger.

It’s important to identify the component or mechanism, whatever it is, because just telling patients to drink cocoa could be risky, said Dr. Sorond. “Patients with diabetes or hypertension really don’t need the extra sugar, extra calories, and extra fat that come with it.”

Dr. Sorond thinks NVC could be measured in high-risk patients seen in the clinic. “I think this could be an easy, in-clinic quick test of vascular brain function that pertains to cognitive performance.”

The ideal next step would be to carry out a larger study in patients with mild cognitive impairment that includes more detailed cognitive profiles and more control groups. “We need a cocoa arm; we need a caffeine arm; we need maybe other arms, to make sure that we understand this, and maybe look at some of the metabolites in the blood as a result of cocoa consumption that correlates with these things,” said Dr. Sorond.

Remarkable First Step

In an accompanying editorial, Paul B. Rosenberg, MD, associate professor of psychiatry and behavioral sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, and Can Ozan Tan, PhD, Harvard Medical School, Boston, write that in many ways, the study represents a “remarkable first step.”

For one thing, it demonstrates the practical utility of a simple, inexpensive, and noninvasive technique for measuring NVC that has several advantages over functional MRI and other means of measuring blood brain flow during cognitive tasks.

In demonstrating a link between NVC and cerebral white matter structural integrity, the study provides an important validation for the association between vascular and cognitive function, according to Dr. Rosenberg.

The study demonstrates that NVC “hangs together” as a measure of vascular function, which could be used in studies targeting vascular interventions, said Dr. Rosenberg in an interview with Medscape Medical News. In this way, he added, the study is “promising for the development of new treatments for vascular dementia.”

The study suggests that the vascular effects of cocoa are not due to its flavonol content, noted Dr. Rosenberg.”It could be a placebo effect.”

Dr. Rosenberg pointed out several strengths of the study, including its relatively large size for a pilot study and its “well-chosen” measures.

Among its weaknesses are that it’s not a placebo-controlled study and the hypothesis that flavonoid-rich cocoa would work better than flavonoid-poor cocoa didn’t pan out. The study may also not have been long enough, said Dr. Rosenberg. “It’s nice to see a drug work for 30 days, but you really need a longer study.”

The study didn’t include patients with mild cognitive impairment who are at risk of developing dementia, which Dr. Rosenberg sees as another weakness. “It’s one thing to show an effect in cognitively healthy older people; it’s a very different thing to show an effect in people who have a brain disease,” he said.

The Alzheimer’s Association also sees weaknesses in the study. Not only is it a very small and very preliminary study, but it was also not well designed as a test of an intervention or therapy because it didn’t include a control group for comparison with the group that drank cocoa, said Maria Carrillo, PhD, Alzheimer’s Association vice president of medical and scientific relations.

Further, said Dr. Carrillo, it didn’t appear that other factors that could possibly affect brain blood flow and/or cognition were controlled for, tracked, or accounted for in the study.

“There is no information on what else the 18 people with impaired cerebral blood flow did during the trial that might have improved their cerebral blood flow or cognitive performance: exercise, for example. A well-designed intervention trial anticipates, tracks, and accounts for these possible confounding factors to help ensure the credibility of the findings.”

Source: Neurology


Women are more vulnerable to infections.

Public-health officials discount role of sex in people’s response to flu and other infections.

Sabra Klein came to the annual meeting of the Society for the Study of Reproduction this week armed with a message that might seem obvious to scientists who obsess over sex: men and women are different. But it is a fact often overlooked by health researchers, says Klein, an immunologist at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland.


Her research on influenza viruses in mice, presented at the meeting in Montreal, Canada, helps explain why women are more susceptible to death and disease from infectious pathogens — and the reason is intimately linked with reproduction. “She’s one of the people that really gets the bigger picture as far as why do we see these patterns,” says Marlene Zuk, an evolutionary biologist at the University of Minnesota, Twin Cities, in St. Paul.

Women generally suffer more severe flu symptoms than men, for example, despite the fact that they tend to have fewer viruses during an infection. To Klein, this suggests that women quickly mount a substantial immune-system attack to clear infections — and suffer the consequences of the inflammatory responses that flood their systems. “This is where females run into trouble,” Klein says.

She and her collaborators have found this disparity in mice infected with flu viruses1. But when the researchers castrated the males and removed the ovaries from the females, the difference disappeared as the males became more sensitive to infection.

But testes are not simply protective. Klein found that giving the neutered females the female sex hormones oestrogen and progesterone actually protected them from disease.

For females, infections appear to throw these cycling sex hormones out of whack. They elongate the oestrus cycle in non-neutered female mice — stretching the part of the cycle associated with the lowest amounts of oestrogen from 4-5 days to 8-9 days.

Researchers have long known that immunological cells have receptors for sex hormones, and that autoimmune disease strikes women more frequently than men. Nevertheless, Klein says that her work should have implications for current public-health practices.

Women, who are often less likely than men to get vaccinated against flu, should be encouraged to do so, she says. And researchers may want to examine whether hormone-replacement therapies and contraceptive drugs have unintended — possibly positive — effects on some types of infectious disease.

But most importantly, Klein says, medical studies should take sex differences into account. Many epidemiological studies do not break down results by sex, a practice that she has found can obscure crucial trends2. And clinical trials have traditionally worked around the female oestrus cycle, because it can interfere with results.

To Zuk, Klein has provided a voice of reason here. “Why is it viewed as interference when you have interaction with the endocrine system or some other aspect of the reproductive system?” she asks.

“The age-old answer we get is that funding is tight and if we’re going to compare sexes, we’ll have to double the groups,” says Klein. But on the basis of her work, she says, “I don’t know that that’s actually true”.

Source Nature


Loa loa: neglected neurology and nematodes.

In the early 1990s, efforts to eradicate river blindness came up against an unexpected problem: a rare parasitic worm that seemed to cause serious neurological adverse events in patients treated with the anti-filarial drug ivermectin. David Holmes reports on how the battle against the worm might finally be turning.


There are neglected tropical diseases, and then there is loiasis: a rare filariasis that is caused by the nematode worm Loa loa. Loiasis has come increasingly to light as a result of the serious adverse neurological events that very rarely arise in patients infected with L loa when they undergo treatment for another neglected tropical disease, onchoceriasis, a filarial disease more commonly known as river blindness. Confused? You wouldn’t be alone, but a small group of researchers have been slowly unravelling the L loa enigma.

As early as 1991, reports were starting to emerge of severe adverse neurological events in a handful of patients treated with ivermectin in areas of Cameroon and the Democratic Republic of Congo (DRC) where loiasis and onchoceriasis are co-endemic. Although the incidence of serious adverse events (SAEs) is low (22 out of 17 877 people in Cameroon treated with ivermectin in a study published in The Lancet), about 9% of these events are neurological. According to Farrah Mateen, a neurologist by training who now specialises in international health at Johns Hopkins University in Baltimore, MD, USA, “the range of symptoms that have been reported is pretty impressive”. They include cases of coma, some of which result in encephalopathy, parkinsonism, or death. The first signs, which appear after about 12 h, usually include fatigue and generalised athralgia, but can also include mutism and incontinence. After a day or so, more severe disorders of consciousness start to manifest.

According to a 1955 review by the eminent Belgian neurologist Ludo van Bogaert, the first case report of a L loa worm, extracted from a woman’s eye, was published in 1770 by a French surgeon at San Domingo in the Caribbean. van Bogaert argued, rather presciently as it turns out, that the neurological manifestations of L loa were a subject “of some importance in view of the increasing availability of highly potent anti-filarial drugs”, but the filariasis was nevertheless considered largely benign until, in the late 1980s and early 1990s, the first cases of SAEs began to be described in regions that were co-endemic for L loa and Onchocerca volvulus, and where ivermectin treatment for O volvulus was ongoing.

In 1995, a coalition led by the World Bank and WHO set out to eradicate onchoceriasis by rolling out the African Programme for Onchoceriasis Control. The programme works by creating a community-based distribution network for the broad-spectrum antiparasitic drug ivermectin, which when delivered as a one-time dose (150 μg/kg) kills and protects against theO volvulus parasite that causes onchoceriasis. About 90 million people were treated last year through the programme in the 12 countries of subsaharan Africa where onchoceriasis persists; ivermectin will be donated indefinitely through the Mectizan Donation Program until the disease is eradicated. Now, as the programme moves from control towards an end game of elimination, and therefore into increasingly remote areas where populations have until now remained untreated, it has become increasingly important to look at the problems caused by L loa, explains Adrian Hopkins, Director of the MDP. “In the past there was the justification for ivermectin treatment because onchoceriasis definitely shortens life, so taking the risk was justified in areas with very high levels of onchoceriasis. But if we talk about eradication then we’re talking about treating in areas where there is a very low prevalence of onchoceriasis, so we have to make sure we’ve got as much information as we can”, he says.

Michel Boussinesq, Director of Research at the Institut de Recherche pour le Developpement in Montpellier, France, has worked for over 20 years on the epidemiology of onchocerciasis and ivermectin-based control strategies, and was one of the first to look into the relationship between L loa and ivermectin SAEs. “The first studies were done in the early 1990s, and our first task was to demonstrate that there was a relationship between the SAEs and L loa”, he says. Boussinesq was part of the team that published the Lancet study that established that the risk of developing marked or serious reactions to ivermectin was significantly higher when the filarial load exceeded 8000 microfilariae per mL of blood, and was very high for loads of more than 50 000 microfilariae per mL.

“The threshold of risk is assumed to be about 30 000 microfilariae per mL of blood, and the proportion of people with such high loads in the most endemic villages is probably 5% max”, says Boussinesq. “So the proportion of people with high loads who are at risk is fairly high, but only a small proportion of these people develop an SAE: it’s not that everyone with a level of above 30 000 will develop a SAE, so there must be some other cofactors”.

Two of the biggest challenges facing investigators have been the rarity of cases, and the fact that almost all cases occur in extremely remote areas of the bush, so gathering information is difficult. But there are enough data to establish the general pattern of how most symptoms manifest, explains Hopkins. “It goes through a process: patients become disorientated and confused, and this can take place over a number of hours or half a day, progressing to a coma”, he explains.

Unpicking the pathogenesis, however, has been a tortuous process. “There have been two approaches”, says Charles Mackenzie, a Professor of Pathology at Michigan State University, MI, USA. “One is to try to see what went wrong by doing autopsies on patients. And then because the parasite is also found in mandrils and in baboons, which was understood many years ago by Brian Duke in Cameroon, the MDP assisted in setting up a programme to look at what happened in those infected animals after treatment in parasitologically similar situations of very high parasitic loads”, he explains.

The leading hypothesis that has emerged from these studies is that the sudden die off of L loa in patients treated with ivermectin can, in patients with a high parasitic load, trigger an immunological response. But the paucity of data means the jury is still out on the pathology. Indeed, Joseph Kamgno, Director of the Center for Research on Filariasis and Other Tropical Diseases (CRFilMT) at Yaounde in Cameroon, described a case in DRC in which a patient infected with L loadeveloped encephalopathy without any ivermectin treatment. “The mechanism is quite unclear”, says Kamgno.

Together with maintaining a very active surveillance programme to try to detect and report as many cases as possible, Kamgno’s group have also devised local guidelines for the supportive care that should be given to patients who become comatose. “One of the problems we have is that, sometimes, with patients that go comatose, a lot of people look for traditional remedies first, and particularly in the DRC the hospital has always been the last place to go if you have a coma, which means you get patients 3 or 4 days later, often with bed sores already well established. And patients often die from septicaemia through bed sores”, says Hopkins. “So part of the strategy is ensuring that the population understands what has to be done, and that if a patient gets confused or starts going comatose that they’re transferred to a centre set up specially for the management of these patients”.

The management itself is not complicated, consisting of supportive care, and provided patients have been well cared for, they should wake up over a period of 3 or 4 days. But what happens to the patients after they wake up is slightly more mysterious. “Initially we thought that when patients woke up, we didn’t think there were any real sequelae to that episode, but we need to do more research on that because it does seem to be that there might be a problem”, says Hopkins. “There are one or two teachers who say they can’t concentrate to go back to teaching, but we don’t have an awful lot of information on that”. Bringing some neurological evaluation to bear on the situation is something that Mateen is hoping to get started on soon, to try to see whether she can follow up some of those people who have reported SAEs. “Some of the basic questions are still unanswered”, she notes. “Did they survive? What’s their neurological situation? Are they cognitively intact? And there are a lot of other research issues: normative cognitive data are still being established in many of these regions”.

Meanwhile, researchers are trying to tackle L loa from other directions. The Gates Foundation has funded a project to test the feasibility of using automatic counting techniques to test people in the field, to identify patients who have high levels of the L loa parasite and exclude them from ivermectin treatment. Others are looking for alternatives to ivermectin that could be used to treat onchoceriasis in areas where L loa is endemic. A group led by Mark Taylor at the Liverpool School of Tropical Medicine, UK, are looking at targeting Wolbachia spp, bacterial symbionts of some filarial parasites that are present in onchoceriasis and lymphatic filariasis but not in loiasis. Killing the symbionts eventually kills off the O volvulusfilaria while leaving the L loa unharmed, although the treatment must be taken daily for 6 weeks, so isn’t yet amenable to large-scale treatment. But with the “host of research going on at the moment looking at the disease from every different angle”, Hopkins says, Loa loa looks like it might not be quite so neglected after all.

Source: Lancet