Adding Glucagon to Artificial Pancreas May Cut Hypoglycemia

Possible reduction in hypoglycemia in pooled small outpatient studies

 Using both a glucagon and insulin pump integrated with continuous glucose monitoring could reduce nighttime hypoglycemia in type 1 diabetes, a combined analysis of two small outpatient studies suggested.

Overnight use of the dual-hormone system was associated with less time spent in the hypoglycemic range under 72 mg/dL, at 1.0% compared with 3.1% with the single-hormone system and 5.1% with conventional insulin pump therapy, Ahmad Haidar, PhD, of McGill University in Montreal, and colleagues found.

The difference was almost entirely accounted for during the first half of the night, the time when glucagon was administered, whereas insulin delivery was otherwise similar between the two artificial pancreas systems.

Those were the findings from two randomized open-label crossover trials, one with 21 adults and seven children in a home setting using Medtronic pumps and sensors for two nights per intervention and the other with 33 children in a camp setting using Dexcom sensors and Roche pumps for 3 nights per intervention.

Combined analysis was reported here at the American Diabetes Association annual meeting, along with simultaneous publication of the pediatric camp study online inLancet Diabetes and Endocrinology.

The two artificial pancreas systems yielded similar overall glucose levels, both averaging 122 mg/dL compared with 140 mg/dL with conventional pump therapy.

Time spent at night in the hyperglycemic range over 144 mg/dL was 21% with the dual system, 23% with the single-hormone system, and 48% with conventional pump therapy.

The difference in nocturnal hypoglycemia was not significant in the pediatric study on its own, given the higher bar for statistical significance with multiple looks.

That study used a research-level set-up, with the kids’ continuous glucose monitors reading out to a sensor set outside the camp tent every 10 minutes, which was then entered manually by study staff into a tablet computer to run a dosing algorithm for the artificial pancreas systems that was then used to manually deliver the medications via remote control.

The researchers suggested that their findings warrant larger, longer studies with the goal of a fully integrated system.

Such a system would be more complex and more expensive, Jessica R. Castle, MD, of the Oregon Health & Science University in Portland, cautioned in an editorial accompanying the Lancet paper.

“Many advancements are needed to make a dual-hormonal automated system commercially viable,” she wrote, “including the approval of a stable glucagon formulation, a dual-chamber pump for combined storage and delivery of insulin and glucagon, and preferably a specialized infusion set that allows for combined delivery through a single insertion site.

“Despite these hurdles, the ongoing development of dual-hormonal systems is needed. Until a truly ultra-rapid insulin is available, an insulin-only system will be suboptimal, particularly in situations where insulin needs drop rapidly, such as during exercise.”

Having a hard time focusing? Research identifies complex of neurons crucial to controlling attention

Our ability to pay attention to certain things while ignoring distractions determines how good we are at a given task, whether it is driving a car or doing brain surgery. A research team at McGill University has for the first time convincingly identified a network of neurons in a particular area of the brain, the lateral prefrontal cortex, that interact with one another to promptly filter visual information while at the same time ignoring distractions. It’s a discovery with potentially far reaching implications for people who suffer from diseases such as autism, ADHD and schizophrenia.


The researchers recorded brain activity in macaques as they moved their eyes to look at objects being displayed on a while ignoring visual . These recorded signals were then input into a decoder running on a which mimicked the kinds of computations performed by the brain as it focuses. With some startling results.

“The decoder was able to predict very consistently and within a few milliseconds where the macaques were covertly focusing attention even before they looked in that direction,” says Julio Martinez-Trujillo, of McGill’s Department of Physiology and the lead author of the paper. “We were also able to predict whether the monkey would be distracted by some intrusive stimulus even before the onset of that distraction.”

But what was even more interesting was that the researchers were able to manipulate the computer’s ability to “focus” by subtly manipulating the neuronal activity that had been recorded and input into the machine. In effect, by manipulating the interactions of the neurons, the researchers were able to induce “focused” and “distracted” states in the computer.

“This suggests that we are tapping into the mechanisms responsible for the quality of the attentional focus, and might shed light into the reasons why this process fails in certain neurological diseases such as ADHD, autism and ,” says Sébastien Tremblay, a doctoral student at McGill University and the first author of the paper which was published in the current edition of Neuron. “Being able to extract and read the neuronal code from higher-level areas of the brain could also lead to important breakthroughs in the emerging field of neural prosthetics, where people who are paralysed use their thoughts to control objects in their environment.”

Doctors behind ADHD study question drug treatment.

The co-authors of a 20-year-old study promoting the use of prescription drugs to combat the effects of attention deficit hyperactivity disorder (ADHD) are now claiming the report may have overstated medication’s benefits.

According to a report in the New York Times, at least two co-authors of the highly influential study – called the Multimodal Treatment Study of Children With ADHD – have come forward to express concern that the original report also downplayed the benefits of behavioral therapy.

“There was lost opportunity to give kids the advantage of both and develop more resources in schools to support the child — that value was dismissed,” said co-author Dr. Gene Arnold, a child psychiatrist and professor at Ohio State University.

“I hope it didn’t do irreparable damage,” added a second co-author, Dr. Lilly Hechtman of Montreal’s McGill University. “The people who pay the price in the end is the kids. That’s the biggest tragedy in all of this.”

The report originally claimed that not only was medication like Adderall and Ritalin more effective than therapy, but also that combining the two treatments offered little to no benefit to the patient. Even a 2001 report that showed a combination of medication and therapy effectively treating ADHD symptoms by 12 percent over medication only (68 – 56 percent) labeled the results“small by conventional standards.”

Boosted by marketing from pharmaceuticals, prescriptions for ADHD drugs have skyrocketed since the early 1990s, alongside a significant rise in the diagnosis of ADHD in general.

According to new data from the Centers for Disease Control and Prevention, 15 percent of high-school-age children have been diagnosed with the disorder, with roughly 3.5 million currently taking medication. These numbers stand in stark contrast to the 600,000 or so children diagnosed with ADHD in 1990.

“The numbers make it look like an epidemic. Well, it’s not. It’s preposterous,” Keith Conners, a psychologist and professor emeritus at Duke University, said to the Times earlier in December.“This is a concoction to justify the giving out of medication at unprecedented and unjustifiable levels.”

One of the reasons medication has been used so often to treat the disorder is that, at the cost of $200 a year, it’s significantly cheaper than therapy, which can run up to $1,000 a year or more and isn’t covered as comprehensively by insurance companies. While medication can be helpful, it also has its consequences – potential addiction, anxiety, depression, insomnia and, in some cases, suicidal tendencies and hallucinations.

Behavioral therapy, meanwhile, focuses on developing a child’s long-term academic and social skills. According to psychologist Ruth Hughes of the advocacy group Children and Adults With Attention-Deficit/Hyperactivity Disorder, medication may make a child ready to learn important skills, but it still requires someone to teach them.

Now, new studies are suggesting that the effects of medication begin to decrease once a child grows older, suggesting it’s extremely difficult to calculate how a child will react as they reach young adulthood. Some researchers pin the blame on the fact that many children stop taking the pills, while others say it demonstrates the inability of a medication-only approach to conclusively treat the disorder.

“My belief based on the science is that symptom reduction is a good thing, but adding skill-building is a better thing,” Stephen Hinshaw, a psychologist at the University of California, Berkeley, said to the Times. “If you don’t provide skills-based training, you’re doing the kid a disservice. I wish we had had a fairer test.”

Women’s breasts age faster than the rest of their body.

Breasts typically age more quickly than the rest of the female body. So suggests a system that may be the most accurate way yet of identifying a person’s age from a blood or tissue sample.

As we age, the pattern of chemical markings on our DNA changes. Each gene becomes more or less methylated, that is, they have methyl chemical groups added or removed. This generally increases or decreases gene expression. The whole process is known as epigenetics.

The question "how old are you?" just became a lot harder to answer <i>(Image: REX/Cultura)</i>

Steve Horvath at the University of California, Los Angeles, and his colleagues have used these changes to estimate a person’s age. To do so, they first performed a detailed statistical analysis of methylation patterns in 7844 healthy tissue samples from 51 different types of tissue. The tissue covered a range of ages – from fetuses to people 101 years old.

Universal ageing

The analysis allowed the team to weed out methylation patterns that varied between tissues, leaving just those that are common to all tissues. This enabled them to identify a subset of 353 specific regions of the genome that became either more or less methylated with age in almost all types of tissue.

By measuring the total amount of methylation in these regions, the team was able to create an algorithm that identified the age of the tissue.

The team validated the algorithm against thousands more samples of known age. Horvath says the method is twice as accurate as the next best method of ageing tissue, which is based on the length of telomeres – tips of chromosomes that “burn down” with age like candle wicks. He says that his method has a 96 per cent chance of accurately identifying someone’s age to within 3.6 years compared with around 53 per cent for telomeres.

“What’s unique about this study is the idea that there’s a signature of ageing common across tissues in spite of the significant tissue specificity of DNA methylation patterns,” comments Moshe Szyf, who studies methylation at McGill University in Montreal, Canada. “The data point to the possibility that DNA methylation signatures could be used as robust markers of biological ageing.”

Young at heart

Horvath says that, remarkably, their analysis shows that some parts of the body age at different rates. When they used their algorithm on healthy breast tissue from a group of women of average age 46, for example, it churned out a result that was on average two to three years older than the woman’s actual age. Whereas in two groups aged 55 and 60 across both sexes, heart tissue appeared nine years younger than true age.

If it is known where the sample comes from, it is still possible to accurately predict age after some straightforward adjustment, says Horvath. However, in general, the algorithm is most accurate for samples from people under 30 years of age. “The older one gets, the less accurate it becomes,” he says.

Horvath thinks that breast tissue ages more quickly because of its constant exposure to hormones. Heart tissue may remain younger, by contrast, because it is constantly regenerated by stem cells.

Cancerous tissue also appeared to age prematurely, coming out at 36 years older than the person’s actual age on average across 20 cancers from 20 different organs.

Because ageing is a risk factor for all cancers, Horvath suggests that the premature ageing of breast tissue might explain why it is the most common cancer in women. “It could be so prevalent because that part of the female body is older,” he says.

Blood work

Because the method also works on blood it might have the potential to be used forensically, to reveal the age of a murder suspect, suggests Horvath. It might also be used to diagnose cancer, by revealing accelerated ageing in tissue biopsies.

“The data raises questions about whether these DNA methylation changes play a causal role in ageing and, if so, whether epigenetic interventions could reverse these and therefore slow down ageing,” says Szyf. “The chemical robustness of DNA methylation and the ability to accurately measure it make it a very attractive tool to study ageing, which could well be superior to measuring telomere length, which is the current practice.”

Horvath says that further studies comparing telomere and epigenetic ageingcould be useful, and hopes the two can be complementary. He also says that the software for his algorithm is openly available so that other researchers can try validating it on their own tissue samples.

Journal reference: Genome Biology, DOI: 10.1186/gb-2013-14-10r115

Florbetapir Approved: Now How Do We Use It?

April 19, 2012 — Florbetapir (Amyvid, Eli Lilly/Avid Radiopharmaceuticals), a new agent to detect beta-amyloid plaques in living patients with possible Alzheimer’s disease (AD), has just been approved by the US Food and Drug Administration (FDA). The question now is how this imaging option will be used in practice.

Although they are for the most part enthusiastically awaiting access to this new agent, expected to be available by June, many neurologists are also striking a cautionary note. Cost, availability, the need for expert interpretation of scans using the florbetapir tracer, and what it really means for a diagnosis of AD are a few of the concerns being raised.

Medscape Medical News polled experts in the field of AD to see how they view the approval and how they see this diagnostic tool may fit into their clinical practice.

Diagnostic Dilemmas

Florbetapir is a diagnostic agent tagged with a radioisotope, fluorine-18. Used with positron emission tomography (PET), it binds to amyloid plaques in the brain. Approved by the FDA on April 9, florbetapir is 1 of 3 imaging agents in various stages of development; others are florbetaben (Bayer/Piramal Imaging SA) and flutemetamol (GE Healthcare). All are reported to detect amyloid deposition in the living brain.


Although the presence of amyloid on the scan doesn’t necessarily mean the patient has AD, a scan showing little amyloid deposition, “is inconsistent with a neuropathological diagnosis,” of AD, a press release from the company at the time of approval notes. The statement added that the safety and effectiveness of florbetapir have not been established for predicting development of dementia or other neurologic conditions, or for monitoring responses to therapies.

Still, the use of florbetapir may clear up some diagnostic dilemmas, said Sandra Black, MD, professor, Department of Medicine, Division of Neurology, University of Toronto, Ontario, Canada. “It might help in situations where you’re not quite sure what’s going on — when you don’t know whether this is aphasia due to AD or a frontal temporal dementia-type thing.”

Pedro Rosa-Neto, MD, assistant professor, neurology, neurosurgery and psychiatry, McGill University, Montreal, Quebec, Canada, felt that the new tracer could be informative in the investigation of patients with early onset or atypical presentations of dementia to rule out AD, and in cases of rapidly progressive dementia.

“Rapidly progressive Alzheimer’s disease is a highly neglected condition, frequently misdiagnosed as Creutzfeldt-Jakob disease,” Dr. Rosa-Neto noted. For these selected cases, he sees PET using florbetapir adding to the information gained from the clinical history, various magnetic resonance imaging (MRI) modalities, including fluid-attenuated inversion recovery and diffusion-weighted imaging, cerebrospinal fluid sampling, and neuropsychological and genetic evaluations.

Although the tracer could be of assistance in patients with dementia in whom it’s unclear whether amyloid is a cause of cognitive deterioration, it would not be as useful an addition in cases where all clinical, cognitive, and imaging findings strongly point to the presence of AD, said Liana Apostolova, MD, Alzheimer’s Disease Research Center, University of California, Los Angeles.

“While the test could be useful to confirm that presumption, dementia specialists can already diagnose AD under these circumstances with high sensitivity,” she said. “This is when I might say, ‘I’m pretty certain what’s going on at this point; I don’t need to subject the patient to this expensive diagnostic procedure.”

Role in Mild Cognitive Impairment?

Some clinicians agreed that there is a place for the new biomarker in patients with mild cognitive impairment (MCI). Ronald Petersen, MD, PhD, director, Alzheimer’s Disease Research Center, Mayo Clinic, Rochester, Minnesota, credited with developing the concept of MCI, said the tracer “will be helpful” to see whether amyloid can explain memory problems experienced by these patients. “It will not make the diagnosis, but it will help the clinician sort out the cause of the symptoms.”

Dr. Petersen pointed out that many patients with MCI — perhaps up to 40% — don’t have AD as the underlying cause of their cognitive problems.

For Steven T. DeKosky, MD, vice president and dean, University of Virginia School of Medicine, Charlottesville, the new biomarker “seems like a reasonably accurate detector” of whether MCI is AD in development or whether it relates to some other cause.

Other physicians said they wanted to avoid using the new tracer in cases of MCI.

“Although I think a positive amyloid imaging study would increase the likelihood that the person will decline, that is not known for certain,” said David Knopman, MD, Department of Neurology, also at Mayo Clinic Rochester, Minnesota. “So, I would definitely not do an amyloid scan routinely.”

Doctors stressed that a positive scan does not necessarily mean an asymptomatic patient will develop AD. “Many cognitively normal elderly will show amyloid deposition in their brains as the disease is believed to have an asymptomatic stage that lasts up to 20 years,” pointed out Dr. Apostolova.

“I don’t think we know enough about the prognostic factors of a positive amyloid scan,” said Adam S. Fleisher MD, director of brain imaging, Banner Alzheimer Institute, Phoenix, Arizona, during a Web-based debate on the role of neuroimaging in the diagnosis of AD earlier this year.

On the other hand, a negative scan may not mean a patient is out of the woods because there could be another explanation for their cognitive problems, such as vascular dementia.

“We will have to be very careful using amyloid imaging and making sure patients understand that a negative scan is not necessarily a cause to celebrate,” said James B. Brewer, MD, PhD, associate professor, radiology and neurosciences, Human Memory Laboratory, University of California at San Diego, who also participated in the Webinar.

Possible other causes of cognitive decline could include stroke, thyroid problems, drug interactions, chronic alcoholism, and vitamin deficiencies. Psychiatric disorders such as depression can masquerade as dementia as well.

The Alzheimer’s Association acknowledged that FDA approval of florbetapir is a “double-edged sword,” although it supports the move.

…the fact that all of the potential uses of this product are not crystal clear tempers our enthusiasm.

In a statement, the Association said that although the approval will expand the clinical and research opportunities for amyloid imaging, “the fact that all of the potential uses of this product are not crystal clear tempers our enthusiasm.” Additional research is needed to clarify the role of florbetapir-PET imaging in Alzheimer’s, it added.

Worried Well

Physicians weighing in agreed that amyloid measurements alone are not enough — that other imaging tests, including MRI, should also be part of the diagnostic equation. Many talked about the “multi-modal use” of this and other emerging amyloid biomarkers.

And, as Dr. Brewer pointed out, the new amyloid tracer does not measure tau, which some experts believe plays a crucial role in AD. Another agent under development by researchers at the University of California, Los Angeles, called FDDNP, images both tau and amyloid on PET.

All doctors also emphasized the importance of patient counseling before ordering an amyloid test.

“You have to have a good understanding of how that’s going to influence discussions with the patient, and your treatment and prognostic decision-making,” said Dr. Fleisher. He added that the test results could be quite anxiety provoking for a patient.

Doctors who spoke to Medscape Medical News also expressed a concern about “direct to patient” advertising and about “worried well” patients asking for this test. Many called for caution about using this new biomarker in cognitively normal patients who are anxious about their amyloid status.

The Alzheimer’s Association, too, warns of “less than scrupulous” imaging operators who make unrealistic promises to such patients about the value of florbetapir imaging. It recommends that the test be accessible only in the context of a complete evaluation of medical/neurologic status and with appropriate expert consultation.

Cost Issues

Cost may be a significant issue in determining whom to scan using this new biomarker, doctors agreed. The price tag for the radioactive compound alone appears to be in the neighborhood of $1600, said Dr. Apostolova.

“Then there will be the added cost of getting the PET scan which in most places will be between $1000 and $1500. So I think we are looking at a cost of about $2500 to $3000 per scan here.”

Because the tracer will be costly, “we have to use it with caution and only when it’s really necessary,’ said Dr. Apostolova, “Is it going to tell me anything beyond what I already know?”

As for insurance coverage, Dr. Petersen said that it’s unclear at this time who will pay for this new agent when it becomes available in June. Dr. Knopman commented that that “to start with, no insurer will pay for it.” The agent is also not currently eligible for coverage by the Centers for Medicare and Medicaid Services (CMS) because of its specific policy on reimbursement for PET procedures.

During a press conference after approval of the agent, Stephanie Prodouz, manager of Eli Lilly Bio-Medicines Communications, said that, “Although Amyvid will not be eligible for coverage, it’s important to note that Lilly is working with a broad group of stakeholders to explore and collaborate with CMS to find a new policy for PET coverage.”

Treatment Lacking

Although there is palpable excitement among some neurologists about the diagnostic possibilities of this new tracer, their enthusiasm is also tempered by the lack of available AD treatments.

“From a scientific viewpoint, the development of amyloid imaging was huge [but] the commercial availability is less so, unless it can be tied to finding better therapeutics,” said Dr. Knopman. “Until there are better therapeutics for AD, amyloid imaging does not change the landscape in clinical practice.”

Until there are better therapeutics for AD, amyloid imaging does not change the landscape in clinical practice.

But new treatments are on the horizon, according to Marwan Sabbagh, MD, director, Banner Sun Health Research institute, Sun City, Arizona. “Later this year, you will see 2 large immunotherapy studies — bapineuzumab and solanezumab — reporting their data to the world on their phase 3 trials, so the game changing elements here are perfectly timed in anticipation of these potential disease modifying agents.”

Bapineuzumab and solanezumab are both monoclonal antibodies that bind to and clear beta amyloid. Dr. Sabbagh is an investigator on both trials and serves on the steering committee for the bapineuzumab study.

Still, it’s unclear what role the amyloid plays and whether clearing it will result in any change in cognitive status. However, if safe and effective treatments become available, “that changes the whole ball game,” commented Dr. Brewer.

Dr. Apostolova agreed. “If we can find an agent that can halt the disease progression, before symptoms occur, this [florbetapir] will become the single most useful diagnostic and prognostic test out there,” she added.

For his part, Dr. DeKosky said that if an effective AD drug were available, the amyloid test could be used not necessarily to rule out AD but to determine that the cognitive impairment a patient experiences is indeed AD, so that drug could be administered.

Still, even in the absence of more effective amyloid treatments, many doctors felt that the test could nevertheless be useful. For example, said Dr. Brewer, it provides physicians with an opportunity to educate patients, help them manage risk factors and perhaps get them enrolled in a clinical trial.

As well, said Dr. Apostolova, the test results may spur patients to make necessary work-related arrangements or put their personal affairs in order. “Knowledge is power,” she said.

Clinical Studies

According to Eli Lilly, the information on scans using the new tracer correlates highly with what is seen on autopsy. In a study that used the majority interpretation of 5 readers, there were 96% sensitivity and 100% specificity in patients who underwent scanning within a year of death.

Dr. Black called this autopsy correlation research “elegant.” “It showed that indeed they were really picking up the amyloid” prior to death in these patients, she said.

The clinical studies also showed that the new diagnostic tracer appears to be very safe. The most common adverse reactions reported in these trials were headache (1.8%), musculoskeletal pain (0.8%), fatigue (0.6%), nausea (0.6%), anxiety (0.4%), back pain (0.4%), increased blood pressure (0.4%), claustrophobia (0.4%), feeling cold (0.4%), insomnia (0.4%), and neck pain (0.4%).

The studies are outlined in more detail in the product prescribing information.

But although the new imaging agent is safe and promises to be helpful diagnostically, training of interpreters will be key. Florbetapir was approved only with the proviso that Eli Lilly improve education initiatives for readers of the images. In January 2011, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted 13 to 3 against recommending approval for the tracer, but in a second unofficial vote, the committee voted 16 to 0 in favor of approval if the company would agree to structured training for those reading the scans.

“There was a fear that radiologists would not know how to interpret the scans, as well as a concern about what would be an appropriate use of this agent,” said Dr. Black.

After working with the FDA and nuclear medicine experts, Eli Lilly developed both an online and an in-person training program for physicians. According to the company, images should be interpreted only by readers who have successfully completed a training course. The company cautions that errors may occur in the estimation of plaque density during image interpretation.

“This is a new kid on the block; it’s a new technique” that requires training, commented Dr. Apostolova, who carries out imaging research. “It’s not the case that one day, all of a sudden, one’s brain’s tissue becomes full of amyloid. It’s a slow protracted continuous build up.”

Patients will fall on a continuum, with some having minimal amyloid binding and others moderate or severe amounts, she added. “The last ones would be the easiest to call, but there will be many intermediate cases where we have to decide on a threshold that we will be using to call a scan positive versus calling it negative.”

Not Straightforward

The lack of familiarity in reading scans could pose “a big problem” for clinicians since “it’s not straightforward,” commented Dr. Petersen.

Dr. Knopman agreed, saying he’s “very concerned” about the scan interpretation issues. “I am dubious that radiologists who don’t do a lot of them will misinterpret them,” he said. “Even after nuclear medicine physicians have taken the course provided by Lilly, if they have low instances of contact with the test, they are likely to make mistakes in interpretation.”

He added that he’s particularly worried about the risk for overdiagnosis of Alzheimer’s, especially when the amyloid imaging is not interpreted in light of the clinical history.

“For example, up to 30% of cognitively normal people over age 70 years are expected to have a ‘positive’ scan,” he said. “I’m worried that a normalperson will hear that their amyloid scan shows ‘Alzheimer’s disease’ and will conclude that they have the disease and are at imminent risk of losing their memories. In fact, an abnormal amyloid scan should be interpreted as showing amyloidosis, not Alzheimer’s.”

Dr. Black said her “hunch” is that florbetapir will be more likely to be used in specialty memory clinics that have access to experts who can properly interpret the scans than in general family practices.

Longer Half-Life

One of the advantages of the new agent is its versatility. Florbetapir has a half-life of almost 2 hours, compared to a half-life of 20 minutes for the currently available amyloid imaging agent, carbon 11–labeled Pittsburgh compound B (C-PiB).

The discovery of PiB was truly ground-breaking and set the stage for the current series of amyloid tracers now hitting the market, said Dr. DeKosky, who led the clinical trials of PiB.

“PiB was 7 years ahead of all these others,” he said. “We were able to find a way to non-invasively detect amyloid in living people harmlessly, and then several people found a way to develop different compounds. They are all to be congratulated, but the first one is always the one for which there’s romance,” he says wryly.

But because even florbetapir still loses over half of its radioactivity every 2 hours, it must be distributed in a timely fashion from a radiopharmacy to an imaging center. To address this problem, Siemens PETNET Solutions, a subsidiary of Siemens Medical Solutions USA Inc, announced last week a manufacturing and distribution agreement with Eli Lilly.

Beginning in June, Siemens will supply florbetapir to imaging centers in limited US markets. By the end of the year, the company anticipates having 25 manufacturing centers and co-located radiopharmacies offering the compound.

Dr. Apostolova pointed out that to administer florbetapir, a center must also have a PET scanner. In addition to the manufacturing and distribution of florbetapir, Siemens announced its new Biograph mCT PET/CT (computed tomography) scanner, and related software.

Many neurologists said they have faith that the distribution network used by Lilly/Avid will make the agent widely available to clinicians.

“Now we have PET scanners everywhere, which we didn’t have maybe 7 or 8 years ago,” Dr. Black noted. “And now we have an 18-fluorine compound and there are others that should be emerging soon.”

This widening and promising landscape, she said, “is very exciting.”


Everything in moderation: excessive nerve cell pruning leads to disease.

Mechanism meant to maintain efficiency of brain network involved in neurodegenerative disease

Scientists at the Montreal Neurological Institute and Hospital-The Neuro, McGill University, have made important discoveries about a cellular process that occurs during normal brain development and may play an important role in neurodegenerative diseases. The study’s findings, published in Cell Reports, a leading scientific journal, point to new pathways and targets for novel therapies for Alzheimer’s, Parkinson’s, ALS and other neurodegenerative diseases that affect millions of people world-wide.

Research into neurodegenerative disease has traditionally concentrated on the death of nerve cell bodies. However, it is now certain that in most cases that nerve cell body death represents the final event of an extended disease process. Studies have shown that protecting cell bodies from death has no impact on disease progression whereas blocking preceding axon breakdown has a significant benefit.  The new study by researchers at The Neuro shifts the focus to the loss or degeneration of axons, the nerve-cell ‘branches’ that receive and distribute neurochemical signals among neurons.

During early development, axons are pruned to ensure normal growth of the nervous system. Emerging evidence suggests that this pruning process becomes reactivated in neurodegenerative disease, leading to the aberrant loss of axons and dendrites. Axonal pruning in development is significantly influenced by proteins called caspases. “The idea that caspases are even involved in axonal degeneration during development is very recent” said Dr. Philip Barker, a principal investigator at The Neuro and senior author of the study.

Dr. Barker and his colleagues show that the activity of certain ’executioner’ caspases (caspase-3 and caspase-9) induce axonal degeneration and that their action is suppressed by a protein termed XIAP (X-linked inhibitor of apoptosis). “We found that caspase-3- and -9 play crucial roles in axonal degeneration and that their activities are regulated by XIAP. XIAP acts as a brake on caspase activity and must be removed for degeneration to proceed” added Dr. Barker.

This balancing act between caspases and XIAP ensure that caspases do not cause unnecessary or excessive destruction. However, this balance may shift during neurodegenerative disease. “If we understand the pathways that regulate XIAP levels, we may be able to develop therapies that reduce caspase-dependent degeneration during neurodegenerative disease”.

Kidney Failure a Possible Risk of Prostate Cancer Hormone Treatment.

Hormone therapy for prostate cancer may dramatically increase a man’s risk of kidney failure, according to a new study.

Use of androgen deprivation therapy was tied to a 250 percent increase in a man’s chances of suffering acute kidney injury, Canadian researchers found in a review of more than 10,000 men receiving treatment for early stage prostate cancer.

The study appears in the July 17 issue of the Journal of the American Medical Association.

Androgen deprivation therapy uses medication or surgery to reduce the amount of male hormones in a man’s body, which can then cause prostate cancer cells to shrink or grow more slowly.

It is a therapy usually reserved for advanced cases of prostate cancer, said study co-author Laurent Azoulay, a pharmacoepidemiologist at Jewish General Hospital‘s Lady Davis Institute, in Montreal. Previous research already has linked androgen deprivation therapy to a possible increased risk of heart attack.

These new findings tying hormone therapy to acute kidney injury — a rapid loss of kidney function with a 50 percent mortality rate — should prompt doctors to think twice before using androgen deprivation therapy to treat prostate cancer patients at little risk of dying from the disease, said Azoulay, also an assistant professor in McGill University‘s department of oncology.

“There is a big debate over who should receive androgen deprivation therapy, and the timing of use,” he said. “In patients whose prostate cancer has spread, the benefits outweigh the risk, but now there’s this jump to using [androgen deprivation therapy] in patients who would not typically die from prostate cancer. In that subgroup of patients, the risks might outweigh the benefit.”

Dr. Durado Brooks, director of prostate and colorectal cancers for the American Cancer Society, called the Canadian study “intriguing.”

“They did find what would appear to be a fairly strong association between androgen deprivation treatment and acute kidney injury,” Brooks said. “This is something that men and their clinicians need to be aware of and watching out for if they choose to go with androgen deprivation therapy as part of their treatment plan for prostate cancer.”

However, Brooks also noted that the study relied on past medical data and did not involve current prostate cancer patients compared against a control group.

“These results are suggestive that an association may exist, but they are not definitive,” Brooks said. “There will need to be other research looking at this.”

For the new study, the research team identified 10,250 men who had been diagnosed with nonmetastatic (not spreading) prostate cancer between 1997 and 2008, using patient data maintained by the United Kingdom. Researchers then tracked whether each patient had been hospitalized with acute kidney injury, and whether their kidney failure occurred during or after the hormone treatment.

Prostate cancer patients who received androgen deprivation therapy were 2.5 times more likely to suffer kidney failure, the study found. Their risk of acute kidney injury particularly increased if they received a combined androgen blockade, a therapy that uses different hormone-suppression methods to drastically decrease male and female hormone levels in the body.

Both male and female hormones play a large role in kidney function, Azoulay said, which could explain why androgen deprivation therapy can cause such drastic damage to the organ.

“Testosterone and estrogen have been shown to play an important role in renal [kidney] function,” he said. “It seems that testosterone has vessel-dilating effects, and estrogen has a protective effect against renal injury.”



Can science explain why I’m a pessimist?

_68637051_624_compMany of us categorise ourselves as either optimist or pessimist, but what can science tell us about how we got that way and can we change, asks Michael Mosley.

Debbie and Trudi are identical twins.

They have much in common, except that Trudi is cheerful and optimistic while Debbie is prone to bouts of profound depression.

It is likely that her depression was triggered by a major life event, though the twins have different views as to what that event might have been.

By studying a group of identical twins like Debbie and Trudi, Prof Tim Spector, based at St Thomas’ hospital in London, has been trying to answer fundamental questions about how our personality is formed. Why are some people more positive about life than others?

Spector has been able to identify a handful of genes which are switched on in one twin and not the other.

Twin studies suggest that, when it comes to personality, about half the differences between us are because of genetic factors. But Spector points out that throughout our lives, in response to environmental factors, our genes are constantly being dialled up and down as with a dimmer switch, a process known as epigenetics.

With twins like Trudi and Debbie they have found changes in just five genes in the brain’s hippocampus which they believe have triggered depression in Debbie.

Spector, who describes himself as an optimist, hopes that this research will lead to improved treatments for depression and anxiety.

“We used to say,” he told me, “that we can’t change our genes. We now know there are these mini mechanisms that can switch them on and off. We’re regaining control, if you like, of our genes.”

Even more surprising is research which has identified changes in the activity of genes caused by the presence or absence of maternal love.

  • Michael Mosley presents The Truth about Personality on BBC Two at 21:00 GMT on Wednesday 10 July
  • He explores what science can tell us about optimism and pessimism and whether we can change our outlook

Prof Michael Meaney, from McGill University in Canada, is investigating ways to measure how many glucocorticoid receptors are activated in someone’s brain.

The number of active glucocorticoid receptors is an indicator of that person’s ability to withstand stress. It may also be a measure of how well mothered they were at a young age – reflecting how anxious and stressed their mothers were, and how this impacted on the amount of affection they received in their early years.

I am one of a small handful of people who have done their test and had the results. I haven’t told my mother yet.

I see myself as being more at the pessimistic end of the spectrum but would like to change, so I went to visit psychologist and neuroscientist Prof Elaine Fox at her laboratory at Essex University.

Fox is interested in how our “affective mindset”, the way we view the world, shapes us. As well as using questionnaires she and her team look for specific patterns of brain activity.

They began by measuring the levels of electrical activity on the two sides of my brain with an electroencephalograph. It turns out I have more electrical activity in my right frontal cortex than my left. This, Fox explains, is associated with people who are prone to higher levels of pessimism and anxiety.

Then I did another test, designed to measure my “negative bias”. Still wired up I was asked to press a button whenever I saw dots flashing in a particular pattern behind faces being displayed on a computer screen. I was asked not to focus on the faces, just on the dots.

“Sometimes,” Fox says afterwards, “there was an angry face near the dots, sometimes a happy face. Your response time to the dots was faster when they appeared near the angry face.

10 quotes on optimism and pessimism

  • “A pessimist sees difficulty in every opportunity. An optimist sees the opportunity in every difficulty” – Winston Churchill
  • “The man who is a pessimist before 48 knows too much; if he is an optimist after it, he knows too little” – Mark Twain
  • “The point of living, and of being an optimist, is to be foolish enough to believe that the best is yet to come” – Peter Ustinov
  • “Blessed is he who expects nothing, for he shall never be disappointed” – Alexander Pope
  • “A pessimist is a person who has had to listen to too many optimists” – Don Marquis
  • “An optimist may see a light where there is none, but why must the pessimist always run to blow it out?” Rene Descartes
  • “The basis of optimism is sheer terror” Oscar Wilde
  • “No pessimist ever discovered the secret of the stars, or sailed to an uncharted land, or opened a new doorway for the human spirit” – Helen Keller
  • “I’m a pessimist because of intelligence, but an optimist because of will” Antonio Gramsci
  • “I like pessimists. They’re always the ones who bring lifejackets for the boat” – Lisa Kleypas

Source: Goodreads, Brainyquote, Jimpoz

“The reason you were faster is because your attention had already been drawn to the angry face, even though you may not have been aware of that.”

The tests confirmed I have a fundamentally negative bias. To counter this, Elaine suggested I try a short course of CBM (cognitive bias modification) and mindfulness meditation.

Being a pessimist, constantly on the lookout for things that can go wrong, leads to increased stress and anxiety. And it’s more than just a state of mind. It’s powerfully connected to your health.

In one study, which started in 1975, scientists asked more than a thousand inhabitants of the town of Oxford, Ohio, to fill in a questionnaire about jobs, health, family and attitudes towards growing older.

Decades later Prof Becca Levy of Yale University tracked down what had happened. When Levy went through the death records she found that those who had felt the most optimistic about growing older had lived, on average, around seven and a half years longer than those who were more pessimistic.

It was a striking finding and took into account other possible explanations, such as the fact that people who were more pessimistic may have been influenced by prior sickness or depression.

Similar results emerged from a study of nuns done by Deborah Danner and others at the University of Kentucky. They looked at the diaries of 180 Catholic nuns, written when they had entered their nunneries in the 1930s.

They then rigorously scored these diaries for optimistic or pessimistic outlook. Nuns who live in a closed community are a good group to study because they live in the same environment for most of their lives, eating the same foods and having similar experiences.

When the researchers traced what had happened to the nuns they discovered that those who expressed the most positive emotions about life when they were in their early 20s lived up to 10 years longer than those who expressed the least.

As for me, after seven weeks of doing mindfulness meditation and CBM I felt much calmer and returned to Prof Fox’s lab for more tests. The results were extremely encouraging.

It seems that even later in life you can change your outlook. Even for the pessimists, that should be worth celebrating.

Source: BBC


Dietary and Supplemental Calcium Intake and Cardiovascular Disease MortalityThe National Institutes of Health–AARP Diet and Health Study.

Importance  Calcium intake has been promoted because of its proposed benefit on bone health, particularly among the older population. However, concerns have been raised about the potential adverse effect of high calcium intake on cardiovascular health.

Objective  To investigate whether intake of dietary and supplemental calcium is associated with mortality from total cardiovascular disease (CVD), heart disease, and cerebrovascular diseases.

Design and Setting  Prospective study from 1995 through 1996 in California, Florida, Louisiana, New Jersey, North Carolina, and Pennsylvania and the 2 metropolitan areas of Atlanta, Georgia, and Detroit, Michigan.

Participants  A total of 388 229 men and women aged 50 to 71 years from the National Institutes of Health–AARP Diet and Health Study.

Main Outcome Measures  Dietary and supplemental calcium intake was assessed at baseline (1995-1996). Supplemental calcium intake included calcium from multivitamins and individual calcium supplements. Cardiovascular disease deaths were ascertained using the National Death Index. Multivariate Cox proportional hazards regression models adjusted for demographic, lifestyle, and dietary variables were used to estimate relative risks (RRs) and 95% CIs.

Results  During a mean of 12 years of follow-up, 7904 and 3874 CVD deaths in men and women, respectively, were identified. Supplements containing calcium were used by 51% of men and 70% of women. In men, supplemental calcium intake was associated with an elevated risk of CVD death (RR>1000 vs 0 mg/d, 1.20; 95% CI, 1.05-1.36), more specifically with heart disease death (RR, 1.19; 95% CI, 1.03-1.37) but not significantly with cerebrovascular disease death (RR, 1.14; 95% CI, 0.81-1.61). In women, supplemental calcium intake was not associated with CVD death (RR, 1.06; 95% CI, 0.96-1.18), heart disease death (1.05; 0.93-1.18), or cerebrovascular disease death (1.08; 0.87-1.33). Dietary calcium intake was unrelated to CVD death in either men or women.

Conclusions and Relevance  Our findings suggest that high intake of supplemental calcium is associated with an excess risk of CVD death in men but not in women. Additional studies are needed to investigate the effect of supplemental calcium use beyond bone health.

Source: JAMA


Researchers assess multiple vitamin D doses in healthy breast-fed infants.

Researchers in Canada suggest that vitamin D supplementation of 1,600 IU per day increased plasma 25-hydroxyvitamin D concentrations to at least 75 nmol/L among 97.5% of infants aged 3 months. However, this dosage also increased concentrations associated with hypocalcemia, according to data.

The literature has established that vitamin D supplementation for infants is required to support healthy bone mineral accretion. However, conflicting recommendations for this patient population have led to further research.

“We have generated strong support using evidence-based dose response studies that the 400 IU dosage is quite satisfactory and that this is recommended now by the Institute of Medicine, Health Canada, Canadian Pediatric Society and the American Academy of Pediatrics,” researcher Hope Weiler, RD, PhD, of the School of Dietetics and Human Nutrition at McGill University in Quebec, said during a media telebriefing. “We also know that the higher dose recommended by the Canadian Pediatrics Society was well received by our infants and did generate a nice response in 25-hydroxyvitamin D, and the upper limits of 1,000 IU and 1,200 IU would be suitable as safety markers across the first year of life.”

According to data from a double blind, randomized study published in JAMA, Weiler and colleagues investigated the efficacy of various dosages of vitamin D supplements in supporting plasma 25-(OH)D concentrations in healthy, breast-fed infants (n=132) aged 1 month. The patients were randomly assigned to oral cholecalciferol (vitamin D3) supplements of 400 IU per day (n=39), 800 IU per day (n=39), 1,200 IU per day (n=38) or 1,600 IU per day (n=16), and they were followed for 11 months.

According to 3-month data, 55% (95% CI, 38-72) of infants in the 400-IU group demonstrated a 25-(OH)D concentration of at least 75 nmol/L vs. 81% (95% CI, 65-91) in the 800-IU group, 92% (95% CI, 77-98) in the 1,200-IU group and 100% in the 1,600-IU group. Due to elevations in 25-(OH)D concentrations, the 1,600 IU dosage was discontinued, researchers wrote. Moreover, the concentration did not continue in 97.5% of the infants at age 12 months in any of the groups.

Further data indicate that all dosages established 25-(OH)D concentrations of at least 50 nmol/L among 97% (95% CI, 94-100) of the infants at 3 months. This continued in 98% (95% CI, 94-100) at 12 months, the researchers wrote.

“Future studies should be larger and, hopefully, be able to detect early, as well as [determine], long-term benefits to bone. We may also consider other health benefits such as the immune system. Our future studies should consider other populations,” Weiler said. “We should also consider those at higher risk for deficiency, whether it’s due to geographic location where a mother’s exposure to sunshine is limited or the infant is born with vitamin D deficiency.”

In an accompanying editorial, Steven A. Abrams, MD, of the department of pediatrics at the US Department of Agriculture/Agricultural Research Service Children’s Nutrition Research Center at Baylor College of Medicine and Texas Children’s Hospital in Houston, said the study did not answer the question of what the target should be for plasma 25-(OH)D concentrations.

“Of importance, higher vitamin D dosages in this study did not lead to improved bone outcomes as reflected by DXA results for bone mineral content,” Abrams wrote.

He suggested that higher vitamin D intake and target plasma 25-(OH)D concentrations should be tested in clinical trials with markedly defined outcomes and precise safety monitoring.


Weiler H. JAMA. Theme Issue on Child Health: New research on the optimal dosing and possible adverse effects of different levels of vitamin D supplementation, important for bone health, for infants. Presented at: the JAMA Network 2013 Media Briefing; April 30, 2013; New York.

Disclosure: Abrams reports payment for lectures’/speakers’ bureaus from Mead-Johnson Nutrition and Abbott Nutrition and grants to his institution from Mead-Johnson Nutrition. Gallo reports travel support from CIHR Human Development Child and Youth Health and the American Society for Bone and Mineral Research. Sharma reports consulting fees for analyses prepared for Rodd and Weiler. Jones reports being cofounder and scientific advisory board member for Cytochroma Inc., and for receiving payment for speakers’ bureaus from Genzyme/Sanofi.





  • I  think it’s a helpful study in terms of the fact that they had different groups of newborn children treated with vitamin D with 400 IU being the recommended dose up to 12 months according to the Institute of Medicine and Endocrine Society guidelines. It was a well-designed study and relevant because vitamin D is a very hot topic right now due to the deficiencies in children and adults.

I agree with the editorial. This group of patients was a mostly white group with relatively high socioeconomic status. In the group that was administered 400 IU per day, researchers found that those infants reached 25(OH)D level of at least 20 ng/mL. That is a big debate. The IOM thinks 25(OH)D levels of 20 ng/mL are adequate for most, and I think a lot of endocrinologists and the Endocrine Society says most people need a level of 30 ng/mL.

This study shows that infants who were administered up to 400 IU per day reached a level of at least 20 ng/mL by 3 months. The whole group did not attain the level of 30 ng/mL, which again is what some endocrinologists think is an optimal level. To achieve a level of 30 ng/mL, perhaps 400 IU is not enough per day for some infants (especially those with darker skin pigmentation or at higher risk for deficiencies).

In addition to looking at the levels or how much vitamin D is needed to achieve a level of 20 ng/mL or 30 ng/mL, they also looked at the bone mineral content but found no significant difference in the groups. I think the editorial comment summed up this point. In treating infants with higher doses of vitamin D corresponding to higher serum levels above 30 ng/mL; does that confer other benefits? There are many early studies now looking at the relationship between vitamin D and asthma, food allergies, incidence of type 1 diabetes and autoimmune disease.

The important point Abrams raises is that we need more long-term studies to see if there is a skeletal benefit in terms of having a higher vitamin D level which would correspond to having a higher dose of vitamin D administered.

  • Dominique Noё Long, MD
  • Instructor of pediatric endocrinology
    The Johns Hopkins Children’s Center
    Baltimore, Md.



  • The strengths and usefulness of the study are the quantification of serum 25-OH vitamin D levels with various doses of vitamin D supplementation. The currently recommended dose of vitamin D, 400 IU daily, was chosen because historically this dose has proven to prevent rickets, which as pediatric endocrinologists, is our main objective. Therefore this study helps provide information in the ongoing debate regarding the optimal serum level of 25(OH) D. Interestingly, all doses of cholecalciferol increased serum levels of 25(OH) D to >50 nmol/L. Higher doses of cholecalciferol correlated with higher levels of 25(OH) D, however no group sustained >97.5% of infants to vitamin D levels >75 nmol/L. No one truly knows the ideal serum level of vitamin D, but this study suggests that >50 nmol/L was sufficient in this patient population. This study also provides information on the safety of higher doses of vitamin D supplementation. It may be harder to extrapolate in the darker-skin pigmented population who may need more vs. the white population. It’s just another piece to the puzzle of the debate on vitamin D.
  • Janet Crane, MD
  • Clinical research fellow in pediatric endocrinology
    The Johns Hopkins Children’s Center
    Baltimore, Md.