Concern over intensive treatment for patients with Type 2 diabetes

ScienceDaily (July 26, 2011) — Doctors should be cautious about prescribing intensive glucose lowering treatment for patients with type 2 diabetes as a way of reducing heart complications, concludes a new study published online in the British Medical Journal.See Also:Health & MedicineDiabetesPersonalized MedicineHeart DiseaseCholesterolWounds and HealingToday's HealthcareReferenceDiabetes mellitus type 2Blood sugarDiabetic dietGlycemic index

French researchers found that intensive glucose lowering treatment, which is widely used for people with type 2 diabetes to reduce their heightened risk of cardiovascular disease, showed no benefit on all-cause or cardiovascular mortality.

Globally, there were an estimated 150 million adults with diabetes in 2000 and this is expected to rise to 366 million by 2030. People with type 2 diabetes are twice as likely to have cardiovascular disease than non-diabetics and are also more at risk of microvascular complications (damage to small blood vessels).

Glycaemic lowering therapies are commonly used to treat people with type 2 diabetes to prevent long term cardiovascular complications and renal and visual impairment, but previous studies have not shown clear and universal benefits of the treatment.

So a team, led by Catherine Cornu at the Louis Pradel Hospital in Bron, France, reviewed studies that looked at microvascular complications and cardiovascular events related to the intensity of glycaemic control and the quality of trials.

They analysed 13 studies involving 34,533 patients of whom 18,315 were given intensive glucose lowering treatment and 16,218 given standard treatment.

They found that intensive glucose treatment did not significantly affect all-cause mortality or cardiovascular death.

There was, however, a 15% reduction in the risk of non-fatal heart attacks, following intensive treatment and a 10% reduction in microalbuminuria -- an indication of kidney problems and heart disease -- but a more than two-fold increase in the risk of severe hypoglycaemia (dangerously low blood glucose levels).

The researchers calculated that over a five-year treatment period, 117 to 150 patients would need to be treated to avoid one heart attack, 32 to 142 to avoid one case of microalbuminuria, and 15 to 52 to avoid one severe hypoglycaemic event.

They conclude: "Intensive glucose lowering treatment of type 2 diabetes should be considered with caution and therapeutic escalation should be limited."

In an accompanying editorial, UK experts state that clinicians should consider the absolute risks and benefits of more intensive therapy carefully on an individual patient basis to determine the most sensible treatment strategy.

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New data-based strategies and treatment models can improve diabetes care for older African-Americans

ScienceDaily (July 25, 2011) — Better data are needed to evaluate access to care by minority groups at increased risk for diabetes, such as older African Americans, and to assess the benefits of new community-based treatment strategies, including greater use of health information technology and access to multilevel diabetes education teams, according to a report in Population Health Management, a peer-reviewed journal published by Mary Ann Liebert, Inc.See Also:Health & MedicineDiabetesHealth PolicyDiseases and ConditionsMental Health ResearchToday's HealthcareElder CareReferenceAthletic trainingDiabetes mellitus type 2Palliative careDiabetic diet

Older adults of racial or ethnic minority descent tend to have a higher incidence of diabetes than whites, and these populations often have less access to quality health care. Karen Fitzner, PhD, American Association of Diabetes Educators (Chicago, IL), David Dietz, MSW, MHSA, U.S. Department of Health and Human Services (Rockville, MD), and Ernest Moy, MD, MPH, Agency for Healthcare Research and Quality (Rockville, MD) identify the gaps in care for underserved older adults and describe how better use of health information technology and multilevel diabetes education teams can help fill those gaps and improve health outcomes for older African Americans with diabetes.

The authors focus on treatment models that incorporate advances in information technology such as telehealth and geo-mapping for improved data sharing, Diabetes Self-Management Education and Training (DSME/T) programs, national collaboratives, and a multilevel diabetes education team approach that relies on less-skilled team members such as community health workers, supervised and supported by a multidisciplinary team of professional health care providers to facilitate community-based diabetes care, education, and prevention.

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Scientists discover potential stroke treatment that may extend time to prevent brain damage

ScienceDaily (July 25, 2011) — A naturally occurring substance shrank the size of stroke-induced lesions in the brains of experimental mice -- even when administered as much as 12 hours after the event, Stanford University School of Medicine researchers have shown. The substance, alpha-B-crystallin, acts as a brake on the immune system, lowering levels of inflammatory molecules whose actions are responsible for substantial brain damage above and beyond that caused by the initial oxygen deprivation of a stroke.See Also:Health & MedicineStroke PreventionHeart DiseaseElder CareMind & BrainBrain InjuryStrokeCaregivingReferenceMulti-infarct dementiaBrain damageStrokeNeurology

The finding, which will be published online July 25 in Proceedings of the National Academy of Sciences, is of great potential significance. Every year brings nearly 800,000 new stroke patients in North America. "That's one every 40 seconds," said Gary Steinberg, MD, PhD, director of Stanford's Institute for Neuro-Innovation and Translational Neurosciences and one of the study's two senior authors. Steinberg is also the Bernard and Ronni Lacroute-William Randolph Hearst Professor of Neurosurgery and the Neurosciences, and chair of neurosurgery at the medical school.

The largest single cause of severe neurological disability and the third-leading cause of death in the United States, stroke accounts for an estimated $74 billion annually in related costs, including treatment and additional assistance for the three of every four stroke patients whose ability to perform the activities of daily life is impaired. Strokes are caused by a sudden drop in the flow of blood to the brain resulting from a clot or, less often, bleeding. One of every three stroke patients is under the age of 65. In all, there are 5.4 million stroke survivors in the United States and 15 million worldwide.

The only currently approved drug for stroke -- tissue plasminogen activator, or tPA -- dissolves clots that keep oxygenated blood from reaching brain tissue. To be effective, tPA must be administered within about 4.5 hours after the stroke. But patients' brains must first be scanned to rule out the possibility that the stroke was caused by bleeding, which tPA would exacerbate, rather than by blockage.

Moreover, tPA does nothing to counter the stroke's insidious inflammatory aftershock: a flood of noxious chemicals secreted by angry immune cells that rush in to the affected area, causing significant further damage.

Alpha-B-crystallin appears to act as a sponge, sopping up those bad actors and stopping inflammation from making a bad situation worse.

Alpha-B-crystallin is a major structural protein in the eye's lens. It is also constantly made in the heart. In other tissues, including the brain, its production can be triggered by stressful events, such as oxygen deprivation or excessive heat or cold. Growing evidence suggests that alpha-B-crystallin can help curb inflammatory activity in the brain.

"The brain doesn't roll over and play dead when it's under attack," said Lawrence Steinman, MD, the other senior author of the new study, who is the George A. Zimmermann Professor of Neurology and Neurological Sciences and Pediatrics as well as chair of Stanford's interdepartmental program in immunology.

In an earlier study, published in Nature in 2007, Steinman and his colleagues found that the presence of alpha-B-crystallin could help reduce the severity of brain damage caused by multiple sclerosis, a chronic, debilitating autoimmune disease of the brain. Other studies published this year by his group have shown that alpha-B-crystallin limits the damage caused by blood-supply cutoffs to heart tissue and the retina.

It seemed logical to see if this protein could mitigate the effects of a stroke. "We made a jump from its relevance in inflammatory diseases such as multiple sclerosis," Steinberg said. "To my knowledge, nobody had looked at concentrations of alpha-B-crystallin after a stroke, either in people or in an experimental animal model before."

So, along with first authors Ahmet Arac, MD, a postdoctoral scholar in Steinberg's lab, and Steinman's former graduate student Sarah Brownell, PhD, Steinberg and Steinman turned to a standard animal model: the laboratory mouse. They found that, in mice bioengineered to lack alpha-B-crystallin, experimentally induced stroke lesions were more massive than those induced in otherwise genetically similar mice whose cells were capable of making the protein. The alpha-B-crystallin-deficient mice had worse neurological function after the stroke than did the normal mice.

The researchers also found that supplying synthetic alpha-B-crystallin to the deficient mice reduced brain-lesion sizes after a stroke, even when the substance was administered 12 hours after the stroke was induced. And they saw elevated alpha-B-crystallin levels in blood plasma from both human patients and mice after a stroke. (The human samples were obtained from study co-author Gregory Albers, MD, the Coy Foundation Professor of Neurology and Neurological Sciences and the director of the Stanford Stroke Center).

"In younger patients, the larger the stroke, the higher the concentration of alpha-B-crystallin," said Steinberg. Interestingly, increased alpha-B-crystallin levels were not detected in plasma from patients over the age of 80, whose strokes typically have worse consequences than those affecting younger patients.

Finally, the investigators demonstrated that alpha-B-crystallin-treated mice produce fewer inflammatory immune-signaling molecules and more anti-inflammatory ones than untreated mice.

At the doses given to the mice in this study, alpha-B-crystallin appeared to be nontoxic. "This is a naturally occurring molecule the body is already producing, although maybe just not enough of it," said Steinberg. "We're just supplementing it." If further studies by other labs and in other models confirm and extend the findings, alpha-B-crystallin may be an excellent candidate for clinical trials in stroke, Steinman and Steinberg both said.

"This is the first demonstration of an efficacious brain-protecting agent that targets the inflammatory aspect of stroke in a novel way, and it can be given at quite a delay," said Thomas Carmichael, MD, PhD, professor and vice chair of neurology at the David Geffen School of Medicine at UCLA. Carmichael, a stroke expert, did not participate in the study but is familiar with its methodology and results. "Tissue plasminogen activator has a fairly narrow risk-to-benefit ratio. The longer you wait, the more likely it is to stimulate a hemorrhage."

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Bioengineers identify the cellular mechanisms of traumatic brain injury; New hope for treatment of TBI in veterans wounded by explosions

ScienceDaily (July 22, 2011) — Bioengineers at Harvard have identified, for the very first time, the mechanism for diffuse axonal injury and explained why cerebral vasospasm is more common in blast-induced brain injuries than in brain injuries typically suffered by civilians.See Also:Health & MedicineNervous SystemBrain TumorPsychology ResearchMind & BrainBrain InjuryNeuroscienceDisorders and SyndromesReferenceCerebral contusionHead injuryBrain damageTraumatic brain injury

The research addresses two major aspects of traumatic brain injury (TBI), with significant implications for the medical treatment of soldiers wounded by explosions.

Two papers, published in the journals Proceedings of the National Academy of Sciences (PNAS) and PLoS ONE, provide the most comprehensive explanation to date of how mechanical forces can be translated into subtly disastrous physiological changes within the brain's neurons and vasculature.

"These results have been a long time coming," says principal investigator Kevin Kit Parker, a Professor of Bioengineering at Harvard's School of Engineering and Applied Sciences (SEAS) and a major in the U.S. Army. "So many young men and women are returning from military service with brain injuries, and we just don't know how to help them."

When the brain encounters a jarring force, such as an exploding roadside bomb, the delicate tissue slams against the skull. The result, if the patient survives, can be a temporary concussion, a more dangerous hemorrhage, or long-term TBI, which can even lead to the early onset of Parkinson's or Alzheimer's diseases.

Inspired by Parker's own military experience, the Disease Biophysics Group (based at SEAS and at the Wyss Institute for Biologically Inspired Engineering at Harvard) has taken up the cause. Using cutting-edge tissue engineering techniques -- essentially creating a living brain on a chip -- biologists, physicists, engineers, and materials scientists collaborate to study brain injury and potential targets for treatment.

Now, researchers in his group have identified the cellular mechanism that initiates diffuse axonal injury, offering urgently needed direction for research in therapeutic treatments.

Their studies show that integrins, receptor proteins embedded in the cell membrane, provide the crucial link between external forces and internal physiological changes.

Integrins connect the structural components within the cell (such as actin and other cytoskeletal proteins) with the extracellular matrix that binds cells together into tissue. Collectively, this network of structural and signaling components is referred to as the focal adhesion complex.

Parker's research has demonstrated that the forces unleashed by an explosion physically disrupt the structure of the focal adhesion complex, setting off a chain reaction of destructive molecular signals within the nerve cells of the brain.

Inside the neuron, integrins normally mediate the activation of the proteins RhoA and Rho kinase (ROCK). When the focal adhesion complex is disturbed, the Rho-ROCK signaling pathway goes haywire: it directs the motor protein actin to retract the cell's arm-like axons, disconnecting the neurons from each other and collapsing the cellular networks that constitute the brain.

"Our research has shown that abrupt mechanical forces, such as those from a blast wave and transduced by integrins, can result in neural injury," says Matthew A. Hemphill, who with Borna Dabiri (S.B. '07) and Sylvain Gabriele, is a lead author of the paper in PLoS One. Dabiri and Hemphill are currently graduate students at SEAS, and Gabriele is a former postdoctoral fellow in Parker's lab.

Adds Dabiri: "Encouragingly, we also found that treating the neural tissue with HA-1077, which is a ROCK inhibitor, within the first 10 minutes of injury, reduced the number of focal swellings. We think that further study of ROCK inhibition could lead to viable treatments within the near future."

A second direction of research in Parker's lab has solved another mystery in TBI, explaining why cerebral vasospasm, a dangerous remodeling of the brain's blood vessels, occurs more commonly in TBI caused by explosions than in other types of brain trauma.

"Until now, other researchers looking at TBI focused on ion channels and membrane poration, and it was generally accepted that cerebralvasospasm was only caused by hemorrhaging. It turns out that it's much morecomplicated than that," says Patrick W. Alford, a former postdoctoral fellow in Parker's lab and lead author of the paper in PNAS. "Integrins and Rho-ROCK signaling appear to be players in both diffuse axonal injury and cerebral vasospasm."

As reported in PNAS, the forces exerted on arteries are different during an explosive blast than during blunt force trauma. Subarachnoid hemorrhage, which can occur in very severe head injuries, is known to cause vasospasm, but Parker's new research shows that the unique force of an explosion can also cause vasospasm by itself.

The blast from an explosion creates a surge in blood pressure, which stretches the walls of the blood vessels in the brain. To study this, Parker's team of bioengineers built artificial arteries, made of living vascular cells, and used a specialized machine to rapidly stretch them, simulating an explosion. While this stretching did not overtly damage the cellular structure, it did cause an immediate hypersensitivity to the protein endothelin-1.

Endothelin-1 is known to stimulate vascular cells to absorb calcium ions, which affect actin -- the same protein involved in the retraction of axons.

In the 24 hours following the simulated blast, the vascular tissues hypercontract and undergo a complete phenotypic switch, disrupting the overall function of the tissue. Both of these behaviors are characteristic of cerebral vasospasm.

Most importantly, as in the neural tissue, the Rho-ROCK signaling pathway plays an important role in the behavior of actin and the cells' contraction. Parker's team found that inhibition of Rho soon after the injury can mitigate the harmful effects of the blast on the brain's vascular system.

"We have established a toe-hold as we try to climb up on top of this problem," says Parker. "In many ways, this work is just the beginning."

Parker's coauthors on the paper in PLoS One are Hemphill, currently at the University of Mons in Belgium; Dabiri, who beganworking in Parker's lab as an undergraduate; Gabriele, who is now at the University of Mons; Lucas Kerscher, a visiting student; Christian Franck, formerly a postdoctoral fellow at SEAS and now at Brown University; Josue A. Goss, a staff engineer at SEAS; and Alford, who is now at the University ofMinnesota.

Parker's coauthors on the paper in PNAS are Alford; Dabiri; Goss; Hemphill; and Mark D. Brigham, a graduate student at SEAS.

The Disease Biophysics Group received financial support from the Defense Advanced Research Projects Agency (DARPA) Preventing Violent Explosive Neurologic Trauma (PREVENT) Program, the Department of Defense, and the Harvard School of Engineering and Applied Sciences (SEAS).

The researchers also gratefully acknowledge the use of facilities at the Harvard Center for Nanoscale Systems, a member of the National Nanotechnology Infrastructure Network (NNIN), which is funded by the National Science Foundation (NSF).

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