Nerve regeneration across cryopreserved allografts from cadaveric donors: a novel approach for peripheral nerve reconstruction

Clinical article



The use of allografts from cadaveric donors has attracted renewed interest in recent years, and pretreatment with cryopreservation and immunosuppression methods has been investigated to maximize axonal regrowth and minimize allograft rejection. The authors wanted to assess the outcome of treatments of brachial plexus stretch injuries with cryopreserved allografts from cadaveric donors in nonimmunosuppressed patients.


Ten patients with brachial plexus lesions were submitted to electromyography (EMG) testing 1 and 3 months after a traumatic event and 1 week before surgery to localize and identify the type of lesion. Intraoperative EMG recordings were performed for intraoperative monitoring to select the best surgical strategy, and postoperative EMG was used to follow up patients and determine surgical outcomes. If nerve action potentials (NAPs) were present intraoperatively, neurolysis was performed, whereas muscular/nerve neurotization was performed if NAPs were absent. Cryopreserved allografts obtained from selected cadaveric donors and provided by the tissue bank of Treviso were used for nerve reconstruction in patients who were not treated with immunosuppressive drugs.


The surgical strategy was selected according to the type and site of the nerve lesion and on the basis of IOM results: 14 cryopreserved allografts were used for 7 muscular neurotizations and for 7 nerve neurotizations, and 5 neurolysis procedures were performed. All of the patients had regained motor function at the 1- and 2-year follow-ups.


Some variables may affect functional recovery after allograft surgery, and the outcome of peripheral nerve reconstruction is more favorable when patients are carefully evaluated and selected for the surgery. The authors demonstrated that using cryopreserved allografts from cadaveric donors is a valid surgical strategy to restore function of the damaged nerve without the need for any immunosuppressive treatments. This approach offers new perspectives on procedures for extensive reconstruction of brachial and lumbosacral plexuses.

Source: JNS




We Are What We Eat, Or Are We?

Not a clinic day goes by without multiple patients asking me what they should eat, both while on treatment for their cancer and during the survivorship period. If you Google diet and cancer, you are informed that there are 207 million results.1 Such an association seems logical; we all grew up hearing the phase “you are what you eat,” a phrase attributed to French politician and gastronome Jean Anthelme Brillat-Savarin, who wrote in 1826, “Dis-moi ce que tu manges, je te dirai ce que tu es [Tell me what you eat and I will tell you what you are].”2 Despite the persistent belief for the past nearly two centuries, there remain limited, consistent data on most dietary factors and many disease, including cancers.

Studies of red meat and processed meat have been a rare example of fairly consistent results showing an association between increased intake and risk of developing colorectal cancer.3,4 In 2007, The World Cancer Fund and American Institute of Cancer Research‘s expert panel reported that there was convincing evidence that red meat and processed meat increased the risk of developing colorectal cancer.5 Their meta-analyses found that consumption of red meat led to a 1.43 (95% CI, 1.05 to 1.94) increased risk of colorectal cancer per times per week consumed and 1.29 (95% CI, 1.04 to 1.60) per 100 g/d. Similarly, consumption of processed meat was associated with a 1.21 (95% CI, 1.04 to 1.42) increased risk per 50 g/d.4 Given these consistent findings, it seems reasonable to test whether consumption of red or processed meat affected patients who already have a diagnosis of colorectal cancer.

In this issue of Journal of Clinical Oncology, McCullough et al6 report on a cohort of 2,315 subjects who developed colorectal cancer while participating in the Cancer Prevention Study-II Nutrition Cohort. They report that the quantity of red and processed red meat consumed before the diagnosis of colorectal cancer was associated with all-cause but not colorectal cancer–associated mortality. Though not statistically significant, the data suggest that this increase was due to cardiovascular-associated mortality. However, the consumption of red and processed meat after diagnosis was not associated with either end point. Curiously, those with the highest consumption of red and processed meat consistently before and after diagnosis did have an increased risk of colorectal cancer–associated mortality. This seemingly highest risk group (high intake before and after diagnosis) did not have a statistically higher risk of overall or cardiovascular-associated mortality.

Several issues are worthy of consideration in interpreting the McCullough study.6 First, why did an exposure that convincingly increases the risk of developing colorectal cancer not affect the natural history of the disease once it developed?7,8 Although the exact mechanism of action for red and processed meat increasing colorectal cancer development is not known, several plausible biologic mechanisms have been proposed. Red and processed meats cooked at high temperatures contain heterocyclic amines, which are carcinogenic. A second mechanism involves endogenous formation in the gastrointestinal tract of N-nitroso compounds from the heme in red meat, many of which are carcinogenic. In addition, nitrites or nitrates added to meat for preservation could increase exogenous exposure to nitrosamines, N-nitroso compounds, and their precursors. All these proposed mechanisms lead to carcinogenic effects on the mucosa of the bowel, leading to mutational effects on those cells and potential for abnormal growth and cancer formation. The risk of recurrence for patients with nonmetastatic colorectal cancer is related to the growth of micrometastatic disease, already spread before detection and treatment of the primary lesion. Thus, local carcinogenic effects will be less significant to colorectal cancer survivors’ outside risk of forming new primary tumors. In contrast, recent studies on diet and colorectal cancer survivorship have demonstrated association with cancer recurrence, specifically as a result of high intakes of Western-pattern diet and glycemic load.9,10 Both exposures are proposed to be associated with disease recurrence by increasing insulin and insulin-like growth factors, which affect cell growth, proliferation, and metastatic potential, thereby influencing the growth of micrometastatic disease in colorectal cancer survivors.11

Another consideration in survivorship studies is what recommendations can be made to the patient at hand. When a patient is diagnosed with cancer, they want recommendations on what they can do now to help their chances of cure and/or survival. If an exposure before diagnosis is associated with an outcome, but not the exposure after diagnosis, there is not necessarily a recommendation that can be made to a patient. However, such data may suggest a factor that influenced the biology of the tumor that developed. Another question is whether more favorable or less favorable biology influenced by the exposure can be affected by what the patient does after diagnosis. One consideration could be whether a worse prognosis tumor as a result of dietary exposure should influence treatment given to the patient (ie, the factor having prognostic and predictive value). Certainly, studies of diet and lifestyle to date are far from being able to lead to such conclusions. However, it is possible such a mechanism might explain the curious finding that colorectal cancer–associated mortality was influenced by high consumption of red and processed meat both before and after diagnosis, but not in either time frame only. Specifically, patients with high consumption of red and processed meat before diagnosis should try to decrease intake after diagnosis because those who maintained high levels had a higher risk of recurrence. Such a conclusion is purely speculative on the basis of the data in this article and would need other cohorts to further clarify.

Finally, the study by McCullough et al suggests that some risk factors for colorectal cancer also increase risk for other diseases, and thus colorectal cancer patients will often have comorbidities that influence survival. Thus, the current study does remind clinicians that, although one cannot influence exposures before diagnosis, management of comorbidities is important in the care of colorectal cancer survivors to improve survival.

In conclusion, studies of host factors and cancer survival require us to consider whether the results can be of utility to our patients. First, if the exposure after diagnosis influences outcomes, one should consider whether the strength of the evidence justifies making recommendations to alter diet or lifestyle, for instance. Although a randomized controlled trial would be ideal to address this question, changing diet and lifestyle behaviors in the number of patients needed to have statistical powers remains a challenge. Because studies of diet and lifestyle in colorectal cancer survivors are all observational to date, one needs to consider potential biases and confounding. Second, it is important to understand whether an exposure affects cancer recurrence, survival, or both. Although both end points are important in survivorship care, they may have different management implications. Finally, although a message that prediagnosis diet influences outcomes may seem to have limited utility for a patient when they develop cancer, it furthers the strength of the recommendation for people to maintain a healthy diet and lifestyle throughout their life to maximize the health benefits.

Source: JCO

Exercise Alone May Help Those With Type 2 Diabetes.

Story at-a-glance

  • Engaging in a six-month moderate-intensity exercise program led to significant health improvements among people with diabetes, including decreases in fat in the abdomen, liver and around the heart, all of which is associated with an increased risk of heart disease
  • Heart disease is the number one cause of death among people with type 2 diabetes, so exercise could be potentially lifesaving for diabetics
  • Type 2 diabetes arises from faulty leptin and insulin signaling and resistance, both of which are directly related to lack of exercise and a diet high in starchy carbohydrates or sugar.
  • When you exercise for diabetes prevention or treatment, intensity is key; high-intensity interval training (HIIT) should ideally be included in your fitness program to achieve optimal results.
  • diabetes

Nearly 8 percent of the US population, or close to 26 million people, have diabetes, and another 80 million have pre-diabetes,1 which means they’re on their way to developing the full-blown version of the disease… if they don’t do something to stop it.

That something is the silver lining to this major public health epidemic, as research clearly shows lifestyle changes are extremely effective at not only preventing type 2 diabetes but also reversing it if you’ve already been diagnosed.

Among them, exercise has recently made headlines for making major improvements in diabetics’ health.

Exercise Improves Diabetics’ Health – Even Without Other Lifestyle Changes

In a new study of people with diabetes, engaging in a six-month moderate-intensity exercise program led to significant health improvements.2 Specifically, they had decreases in fat in the abdomen, liver and around the heart, all of which is associated with an increased risk of heart disease.

In case you aren’t aware, heart disease is the number one cause of death among people with type 2 diabetes. It’s estimated that at least 65 percent of those with diabetes die from some form of heart disease or stroke.3

While the exercise program didn’t lead to direct changes in heart function, the reductions in dangerous visceral fat around key organs – as well as reductions in pericardial fat, which is the second layer of fat around the heart – will undoubtedly improve heart health among this at-risk population. The study’s lead author noted:4

“ … reduction of liver fat content and visceral fat volume by physical exercise are very important to reverse the adverse effects of lipid accumulation elsewhere, such as the heart and arterial vessel wall.”

Also noteworthy about the study was the relatively small amount of exercise needed to prompt such beneficial changes. The participants exercised between 3.5 and 6 hours a week (and ended the program with a 12-day trekking expedition), which is a reasonable goal for most people.

Further, the benefits were gained from exercise alone; no other lifestyle or dietary changes were made, which shows just how powerful staying active can be in improving your health — even if you’ve already been diagnosed with a potentially chronic disease.

Why Exercise Has Been Called the ‘Silver Bullet’ in Diabetes Treatment

When diagnosed with type 2 diabetes, many believe their fate has been sealed and all they can do now is “control” it. This is far from the truth. You can essentially “cure” yourself of this disease and permanently control it. Exercise can be one of your secret weapons to doing so.

The amazing thing about exercise is that it exerts its effects very quickly. There are long-term benefits, too, of course, but you’ll also get acute, nearly instantaneous benefits as well. This should be excellent motivation to those of you who are procrastinating on your exercise program, as you don’t have to exercise for a year or six months to experience benefits!

Research published in Medicine & Science in Sports & Exercise found, for example, that one single session of moderate exercise can improve the way your body regulates glucose and reduces the spikes in blood sugar that occur after a meal (elevations in these spikes, known as postprandial glucose, or PPG, are associated with type 2 diabetes, heart disease, and death).5

When you exercise for diabetes prevention or treatment, intensity is key. A slow walk around the block, while better than watching TV on the couch, is not likely to cut it (although if you’re morbidly obese and very out of shape this is a good way to start). Instead, high-intensity interval training (HIIT), which is a core component of my Peak Fitness program, should ideally be included in your fitness program to achieve optimal results. This technique uses short bursts of intense activity followed by a longer period of recovery, and the cycle is then repeated multiple times. All you need is about 20 minutes of HIIT two or three times a week for maximum benefits. HIIT can significantly improve your insulin sensitivity, especially if you’re on a low-processed-food, low-sugar/low-grain diet as well.

If You Want to Reverse Diabetes, Diet and Exercise Changes Are Essential

Exercise is vital if you have diabetes, but even though physical activity alone is likely to give your health a boost, you should not rely on it as your sole treatment strategy. Type 2 diabetics need to address the root of the problem, which is insulin and leptin resistance—caused by faulty leptin and insulin signaling, which is directly attributable to not only lack of exercise but also the food you eat. The truth of the matter is that type 2 diabetes is a fully preventable condition and it’s also close to 100% reversible, provided you take the proper steps to heal your body.

In one study, for instance, researchers randomly assigned diabetic participants, who were also overweight or obese, to an intensive program of diet and exercise, in which they were urged to cut calories down to 1,200-1,800 calories per day and engage in nearly three hours of physical exercise per week.6

After one year, 11.5 percent of the program participants no longer needed medication to keep their blood sugar levels below the diabetes threshold – in other words, they were no longer diabetic. For comparison, only 2 percent of the non-intervention group experienced any significant improvement in their condition. Again, type 2 diabetes arises from faulty leptin signaling and insulin resistance, both of which are directly diet- and exercise-related. It is NOT a disease of blood sugar.

Once you understand that, the remedy becomes clear: To reverse the disease, you need to recover your body’s insulin and leptin sensitivities. The ONLY way to accomplish this is through proper diet and exercise, as detailed in my free Nutrition Plan. Bariatric surgery, which is being increasingly recommended as a diabetes treatment, will NOT do the trick, and there is NO drug that can correct leptin signaling and insulin resistance, either.

Why What You Eat Can Make or Break Your Health and Cause Diabetes

Let’s review the mechanics of insulin and leptin resistance

  • Leptin is a hormone produced in your fat cells. One of leptin’s primary roles is regulating your appetite and body weight. It tells your brain when to eat, how much to eat, and most importantly, when to stop eating. And leptin tells your brain what to do with the energy it has. Leptin is largely responsible for the accuracy of insulin signaling and whether or not you become insulin resistant.
  • Insulin—Sugars and grains raise your blood sugar. When this happens, insulin is released to direct the extra energy into storage. A small amount is stored as a starch-like substance called glycogen, but the majority is stored as your main backup energy supply—fat. Insulin’s major role is not to lower your blood sugar, but rather to store the extra energy for future times of need. Insulin’s effect of lowering your blood sugar is merely a “side effect” of this energy storage process.

As you can see, these two hormones work in tandem, creating either a health-damaging or health-promoting cycle, depending on what you eat. If you consume loads of sugars and grains, your blood sugar spikes will lead to increased insulin, which leads to increased fat storage. The extra fat then produces more leptin. The problem arises when your leptin levels become chronically elevated.

At this point, you become leptin resistant—your body can no longer “hear” the hormonal signals telling your brain you’re full and should stop eating. As your fat stores increase, your weight goes up, and insulin resistance sets in. Now your body has become “deaf” to the signals from both hormones (leptin and insulin), and disease follows; one of which is diabetes.

Are You Ready to Send Your Diabetes Packing?

Adhering to the following guidelines can help you do at least three things that are essential for successfully treating type 2 diabetes: recover your insulin/leptin sensitivity, normalize your weight, and normalize your blood pressure:

  • Severely limit or eliminate sugar and grains in your diet, especially fructose which is far more detrimental to your health than any other type of sugar. Following my Nutrition Plan will help you do this without too much fuss. Avoid excessive protein as your body will convert that to sugar in your liver, which will sabotage your ability to control insulin resistance. Excess protein may even be more damaging to your health than excess carbs.
  • Exercise regularly. As mentioned, exercise is an absolutely essential factor and, without it, you’re unlikely to get this devastating disease under control. It is one of the fastest and most powerful ways to lower your insulin and leptin resistance. If you’re unsure of how to get started, I recommend reviewing my Peak Fitness program for tips and guidelines.
  • Avoid trans fats.
  • Get plenty of omega-3 fats from a high-quality, animal-based source, such as krill oil.
  • Optimize your vitamin D levels. Recent studies have revealed that getting enough vitamin D can have a powerful effect on normalizing your blood pressure and that low vitamin D levels may increase your risk of heart disease.
  • Optimize your gut flora. Your gut is a living ecosystem, full of both good bacteria and opportunistic strains that can cause trouble. Multiple studies have shown that obese people have different intestinal bacteria than lean people. When the microbes in your gut exist in proper balance, your immune system will be stronger and the better your body will function overall. Fortunately, optimizing your gut flora is relatively easy. You can reseed your body with beneficial bacteria by eating fermented foods (such as fermented vegetables, natto, raw organic cheese, or raw milk kefir) or by taking a high-quality probiotic supplement.
  • Address any underlying emotional issues and/or stress. Non-invasive tools like the Emotional Freedom Technique (EFT) can be helpful and effective.
  • Get enough high-quality sleep every night.
  • Monitor your fasting insulin level. This is every bit as important as your fasting blood sugar. You’ll want your fasting insulin level to be between 2 and 4. The higher your level, the worse your insulin sensitivity is.

Diabetes is a condition that is personally close to me, as most of my paternal relatives (my dad included), have, or have died from, diabetes. But my personal experience with diabetes and subsequent review of the literature has made it very clear to me that virtually every case of type 2 diabetes is reversible. If you’ve been diagnosed with type 2 diabetes or pre-diabetes, today can be the day that you take control of your health and start the journey to cure yourself of this disease.


Researchers turn off Down’s syndrome genes.

Silencing extra chromosome in cell cultures could lead to new treatments for the disorder.

The insertion of one gene can muzzle the extra copy of chromosome 21 that causes Down’s syndrome, according to a study published today inNature1. The method could help researchers to identify the cellular pathways behind the disorder’s symptoms, and to design targeted treatments.


“It’s a strategy that can be applied in multiple ways, and I think can be useful right now,” says Jeanne Lawrence, a cell biologist at the University of Massachusetts Medical School in Worcester, and the lead author of the study.

Lawrence and her team devised an approach to mimic the natural process that silences one of the two X chromosomes carried by all female mammals. Both chromosomes contain a gene called XIST(the X-inactivation gene), which, when activated, produces an RNA molecule that coats the surface of a chromosome like a blanket, blocking other genes from being expressed. In female mammals, one copy of the XIST gene is activated — silencing the X chromosome on which it resides.

Lawrence’s team spliced the XIST gene into one of the three copies of chromosome 21 in cells from a person with Down’s syndrome. The team also inserted a genetic ‘switch’ that allowed them to turn on XIST by dosing the cells with the antibiotic doxycycline. Doing so dampened expression of individual genes along chromosome 21 that are thought to contribute to the pervasive developmental problems that comprise Down’s syndrome.

First steps

The experiment used induced pluripotent stem cells, which can develop into many different types of mature cells, so the researchers hope that one day they will be able to study the effects of Down’s syndrome in different organs and tissue types. That work could lead to treatments that address degenerative symptoms of Down’s syndrome, such as the tendency of people with the disorder to develop early dementia.

“The idea of shutting off a whole chromosome is extremely interesting” in Down’s syndrome research, says stem-cell researcher Nissim Benvenisty of Hebrew University in Jerusalem. He anticipates future studies that split altered cells into two batches — one with the extra chromosome 21 turned on, and one with it off — to compare how they function and respond to treatments.

Researchers have previously removed the extra chromosome in cells from people with Down’s syndrome using a different type of genetic modification2. That technique relied on the fact that induced pluripotent stem cells that carry the third copy of chromosome 21 occasionally boot it out naturally — but “it’s a pain in the neck”, says Mitchell Weiss, a stem-cell researcher at the Children’s Hospital of Philadelphia in Pennsylvania. “You can’t control it.”

However, Weiss says that the latest method has its own drawbacks: turning on XIST may not block all gene expression in the extra chromosome, and that could muddle experimental results.

Still, Weiss thinks that the approach could yield fresh treatments for Down’s syndrome — and prove useful for studying other chromosome disorders such as Patau syndrome, a developmental disorder caused by a third copy of chromosome 13.

Source: Nature


EU Okays Afatinib for NSCLC, Filgrastim and Defibrotide.

The European Committee for Medicinal Products for Human Use (CHMP) has recommended that the targeted agent afatinib (Giotrif, Boehringer Ingelheim) be approved for use in nonsmall-cell lung cancer (NSCLC) that tests positive for EGFRmutations.

Afatinib was recently approved for this indication in the United States under the trade name Gilotrif.

This is the third drug to target EGFR mutations in NSCLC; it joins erlotinib (Tarceva) and gefitinib (Iressa). Both are available in most countries in the world, with one notable exception — gefitinib is not available in the United States.

About 10% to 15% of NSCLC is positive for EGFR mutations in Western populations; in Asian populations, the incidence is higher.

Filgrastim Biosimilar

The CHMP also recommended approval for the growth factor filgrastim (Grastofil, Apotex) for the treatment of neutropenia, which is a biosimilar to Neupogen (Amgen). “Studies have shown Grastofil to have a comparable quality, safety, and efficacy profile to Neupogen,” the committee noted.

Filgrastim is a granulocyte colony-stimulating factor that regulates the production and release of functional neutrophils from the bone marrow. It is used in cancer patients to counteract the myelosuppressive effects of chemotherapy by reducing the duration of neutropenia and the incidence of febrile neutropenia.

Change of Mind on Defibrotide

In addition, in its July meeting, the CHMP recommended the approval of defibrotide (Defitelio, Gentium) for use in the treatment of severe hepatic veno-occlusive disease, also known as sinusoidal obstructive syndrome, related to hematopoietic stem cell transplantation. The product has orphan drug status for this indication.

The CHMP issued a negative opinion on this product in March 2012. But at the request of the company, the committee re-examined its stance. After that re-examination, it issued a positive opinion for the very narrow indication of severe veno-occlusive disease.

The mechanism of action of defibrotide has not been fully elucidated, the committee notes in its summary. The drug increases the breakdown of blood clots, and it might also protect cells lining the blood vessels, it notes. The most common adverse events are hemorrhage, hypotension, and coagulopathy.


How to Regrow a Head.

A single gene switch makes worms regenerate their whole bodies from their tails

Knocking out a single gene can switch on a worm’s ability to regenerate parts of its body, even enabling it to grow a new head. The fact that such a simple manipulation can restore healing abilities provides new insight into how the stem cells involved in this process are marshaled in animals.


Some animals, such as salamanders and newts, can regenerate entire body parts, and mice can regrow toes if left with enough nail (see ‘How nails regenerate lost fingertips’). Yet other species, including humans, merely produce scar tissue after an amputation. A trio of studies published on Nature’s website today offers new clues as to what is behind these differences.

All three studies looked at Wnt genes, which code for a series of enzymes that relay information from outside the cell to the nucleus, eventually producing proteins called β-catenins, which regulate gene expression. Wnt genes occur in all animals, but the studies looked at their roles in planarian flatworms. Some planarians can completely regenerate from small body parts such as their tails, whereas other flatworm species have more limited regenerative abilities.

Flatworm, heal thyself
Scientists already knew that the Wnt genes are expressed in a gradient along the worms’ bodies—from high at the tail to low at the head—and suspected that the genes were involved in directing stem cells during healing. In the latest studies, researchers wanted to find out if a lack of Wnt gene expression was responsible for the poorer regenerative abilities in particular worm species.

When these species are sliced apart at a point more than halfway to their tail ends, they can regenerate a tail from the head piece, but the tail section is unable to form a new head. However, if the wound is closer to the head—not more than about one-third of the way from it—then both parts will fully regenerate.

To explain the disparity, Jochen Rink, a molecular biologist at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, sliced a worm called Dendrocoelum lacteum at different positions along its body. He and his team then sequenced RNA from the various wounds. The researchers found that, in wounds that did regrow heads, genes coding for a series of enzymes involved in the Wnt pathway had their expression turned up. But in the pieces that couldn’t regrow, the Wnt genes “didn’t even twitch”, Rink says.

In the second study, developmental biologists Phillip Newmark of the University of Illinois at Urbana-Champaign and James Sikes (now at the University of San Francisco in California) found similar roles for Wnt genes in a different species of worm, called Procotyla fluviatilis.

But perhaps most surprisingly, both teams found that by suppressing a gene that regulated Wnt function in their flatworms, they could get chunks of the normally non-regenerative tissue to grow fully functional heads.

“This is a fantastic advert for our field,” says Aziz Aboobaker, a biologist who studies planarian worms at the University of Oxford, UK, but was not involved in any of the studies. “Here’s a scenario where these animals don’t regenerate a brain, and then by knocking out just one gene, it’s possible to rescue that.”

Heady stuff
In the third study Yoshihiko Umesono, now at the University of Tokushima in Japan, and colleagues found that in the flatworm Phagocata kawakatsui, another signaling cascade—the extracellular signal-related kinase (ERK) pathway—had apreviously unsuspected role in regeneration.

In an e-mail to Nature, Umesono suggests that the effects of ERK proteins and Wnt proteins counteract each other. If the Wnt pathway dominates then it signals tail growth, but if ERK suppresses its influence then heads can form.

Because Wnt and ERK proteins are present in all animals, Rink suggests that regenerative capacity could exist in many species, but might be in a latent state because it is silenced. Once the silencing is removed, regeneration could reappear, he thinks.

“Sure, that’s a possibility,” says Aboobaker. But he thinks that the implications are broader than just worms regrowing heads.

“What’s happening here is that cells are reading their position in the body and then rebuilding the requisite structures,” Aboobaker says. “That’s also what happens when cells from your liver or kidney replace themselves—if we can understand those processes better, that’s useful.”


How Math Helped Forecast Hurricane Sandy.

Many early forecasts for Hurricane Sandy last year predicted that the system would fizzle over the Atlantic. Yet a model developed by researchers at the European Center for Medium-Range Forecasts showed a more alarming scenario: the storm would instead turn west to threaten the Eastern Seaboard. The model’s refined predictions pinpointed the hurricane’s landfall around the New Jersey area in time to allow residents to seek higher ground. The key to the more accurate forecast involved mathematical mastery of the storm’s chaotic behavior.

Weather forecasts are calculated with computers that solve equations involving variables such as wind speed, pressure, temperature, air density and humidity. If the earth somehow possessed just one weather system, our fist shaking at forecasts could end. Instead, of course, the planet harbors many systems that intermix across boundaries and scales, making forecasting a tangled problem.

In the case of Sandy, forecasters monitored a higher-order variable called potential vorticity, a measure of a weather system’s swirl, to help predict the storm’s future development. A crucial ingredient for Sandy’s devastating landfall proved to be an enhancement of this swirl measure caused by a trough of low-pressure air that was thousands of miles away in the northeastern Pacific when the tropical depressionfirst formed. As Sandy moved north from the Caribbean, the distant trough traveled east across the U.S. on what turned out to be a collision course. On October 29 Sandy’s warm, moist air began to rise as it approached the trough’s cooler air, whipping up stronger winds. As the two weather systems coiled around each other, Sandy surged in strength and curved toward the nation’s northeastern shoreline, just as the European researchers had foreseen. The ultimate accuracy of the group’s forecasts about a week before Sandy’s landfall can be attributed to the success of its model in predicting and capturing the interaction between these weather systems.

The step-by-step quantification of this stormy choreography was accomplished solely through the careful application of mathematics. By predicting Sandy’s landfall, in a very real sense, the European team’s math helped to save American lives.


Better asthma drugs on way.


Asthma inhalers could soon become much more effective, thanks to a clever new way of making the particles they deliver invented by a Melbourne chemical engineer and his team.

Current puffer designs and typical size ranges of particles mean a large portion of the medication propelled into a patient’s throat remains there. Only a fraction reaches the lungs.


But Monash University lecturer Dr Meng Wai Woo and his team have now developed a method of making ultra-fine particles, which will make drug delivery much more consistent and efficient. The new method, known as anti-solvent vapour precipitation, uses ethanol to dehydrate droplets, and results in super-small particles of uniform size.

“Ultrafine uniform particles will ensure that fewer drug particles get stuck in the throat while more can reach the lower regions of the lungs,” said Dr Woo. “Because we can now make the small particles more uniform, it means the inhalers will work better.”

The team’s work results in particles smaller than a micron (thousandth of a millimetre) in diameter – much smaller than those produced by conventional dehydrating mechanisms, which are limited by the size of the atomised droplet.

The team’s discovery was unveiled at the 18th International Drying Symposium in Xiamen, China, last year. It is likely to excite a lot of interest among pharmaceutical companies. Infusion devices and metered dose inhalers account for around $US20 billion in worldwide sales each year, with the key development aim being to balance improved efficiency against the cost of manufacture.

“From a drug manufacturer’s perspective, this new approach can maintain the uniformity of the particle and yet potentially maintain commercially viable production rate,” said Dr Woo.

Investigations into using ethanol as a means of producing ultrafine particles began in 2011, as part of Dr Woo’s ongoing research into manufacturing processes in the dairy industry.

Attempting to produce lactose crystals, his team decided to reject the traditional hot air drying method and use nitrogen laced with ethanol vapour as an alternative dehydrating agent.

To their surprise, the result was not the crystals they expected, but hundreds of very tiny, very uniform lactose particles. Further testing showed that the amount of alcohol absorbed into the initial droplets was a key variable in influencing the outcome.

Dr Woo’s method means that the pharmaceutical industry can now potentially deliver critical medicines via the airway direct into the lungs with much greater accuracy.

Assisted by a grant from the Australian Research Council, the Monash team is now testing its method on another dairy product – whey – researching the ultrafine particle delivery of protein-based medicines. They are also building a demonstration unit to showcase the anti-solvent vapour precipitation process, which will be completed later this year.

Dr Woo is one of 12 early-career scientists unveiling their research to the public for the first time thanks to Fresh Science, a national program sponsored by the Australian Government through the Inspiring Australia initiative.



Sudden decline in male testosterone may cause Parkinson’s disease.

The results of a new study by neurological researchers at Rush University Medical Center show that a sudden decrease of testosterone, the male sex hormone, may cause Parkinson’s like symptoms in male mice. The findings were recently published in the Journal of Biological Chemistry.

One of the major roadblocks for discovering drugs against Parkinson’s disease is the unavailability of a reliable animal model for this disease.


“While scientists use different toxins and a number of complex genetic approaches to model Parkinson’s disease in mice, we have found that the sudden drop in the levels of testosterone following castration is sufficient to cause persistent Parkinson’s like pathology and symptoms in male mice,” said Dr. Kalipada Pahan, lead author of the study and the Floyd A. Davis endowed professor of neurology at Rush. “We found that the supplementation of testosterone in the form of 5-alpha dihydrotestosterone (DHT) pellets reverses Parkinson’s pathology in male mice.”

“In men, testosterone levels are intimately coupled to many disease processes,” said Pahan. Typically, in healthy males, testosterone level is the maximum in the mid-30s, which then drop about one percent each year. However, testosterone levels may dip drastically due to stress or sudden turn of other life events, which may make somebody more vulnerable to Parkinson’s disease.

“Therefore, preservation of testosterone in males may be an important step to become resistant to Parkinson’s disease,” said Pahan.

Understanding how the disease works is important to developing effective drugs that protect the brain and stop the progression of Parkinson’s disease. Nitric oxide is an important molecule for our brain and the body.

“However, when nitric oxide is produced within the brain in excess by a protein called inducible nitric oxide synthase, neurons start dying,” said Pahan.

“This study has become more fascinating than we thought,” said Pahan. “After castration, levels of inducible nitric oxide synthase (iNOS) and nitric oxide go up in the brain dramatically. Interestingly, castration does not cause Parkinson’s like symptoms in male mice deficient in iNOS gene, indicating that loss of testosterone causes symptoms via increased nitric oxide production.”

“Further research must be conducted to see how we could potentially target testosterone levels in human males in order to find a viable treatment,” said Pahan.S



Migraine associated with brain artery defect..

The network of arteries supplying blood flow to the brain is more likely to be incomplete in people who suffer migraine, a new study by researchers in the Perelman School of Medicine at the University of Pennsylvania reports. Variations in arterial anatomy lead to asymmetries in cerebral blood flow that might contribute to the process triggering migraines.

The arterial supply of blood to the brain is protected by a series of connections between the major arteries, termed the “circle of Willis” after the English physician who first described it in the 17th century. People with migraine, particularly migraine with aura, are more likely to be missing components of the circle of Willis.


Migraine affects an estimated 28 million Americans, causing significant disability. Experts once believed that migraine was caused by dilation of blood vessels in the head, while more recently it has been attributed to abnormal neuronal signals. In this study, appearing in PLOS ONE, researchers suggest that blood vessels play a different role than previously suspected: structural alterations of the blood supply to the brain may increase susceptibility to changes in cerebral blood flow, contributing to the abnormal neuronal activity that starts migraine.

“People with migraine actually have differences in the structure of their blood vessels; this is something you are born with,” said the study’s lead author, Brett Cucchiara, MD, Associate Professor of Neurology. “These differences seem to be associated with changes in blood flow in the brain, and it’s possible that these changes may trigger migraine, which may explain why some people, for instance, notice that dehydration triggers their headaches.”

In a study of 170 people from three groups—a control group with no headaches, those who had migraine with aura, and those who had migraine without aura—the team found that an incomplete circle of Willis was more common in people with migraine with aura (73 percent) and migraine without aura (67 percent), compared to a headache-free control group (51 percent). The team used magnetic resonance angiography to examine blood vessel structure and a noninvasive magnetic resonance imaging method pioneered at the University of Pennsylvania, called Arterial spin labeling (ASL), to measure changes in cerebral blood flow.

“Abnormalities in both the circle of Willis and blood flow were most prominent in the back of the brain, where the visual cortex is located. This may help explain why the most common migraine auras consist of visual symptoms such as seeing distortions, spots, or wavy lines,” said the study’s senior author, John Detre, MD, Professor of Neurology and Radiology.

Both migraine and incomplete circle of Willis are common, and the observed association is likely one of many factors that contribute to migraine in any individual. The researchers suggest that at some point diagnostic tests of circle of Willis integrity and function could help pinpoint this contributing factor in an individual patient. Treatment strategies might then be personalized and tested in specific subgroups.

In addition to Dr. Cucchiara and Dr. Detre, the research team at Penn includes Scott Kasner, MD, Ritobrato Datta, PhD, Geoffrey Aguirre, MD, PhD from Neurology, and Ronald Wolf, MD, PhD, from Radiology. Radiologists Lidia Nagae, MD, from the Children’s Hospital of Philadelphia, and Quan Zhang, PhD, from Tianjin Medical University in Tianjin, China, contributed to the study.