Scientists Grow a Rat Lung in the Laboratory

GoogleNews.com, Forbes.com, June 24, 2010, by Lauran Neergaard  –  WASHINGTON — It’s an early step toward one day building new lungs: Yale University researchers took apart and regrew a rat’s lung, and then transplanted it and watched it breathe.

The lung stayed in place only for an hour or two, as the scientists measured it exchanging oxygen and carbon dioxide much like a regular lung – but also spotted some problems that will take more research to fix.

Still, the work is a step in the science fiction-sounding hunt for ways to regenerate damaged lungs – although lead researcher Dr. Laura Niklason cautions that it may be 20 or 25 years before a build-a-new-organ approach is ready for people.

The work was reported online Thursday in the journal Science.

Nearly 400,000 people die of lung diseases each year in the U.S. alone, according to the American Lung Association, and lung transplants are far too rare to offer much help.

But how to replicate these spongy organs? Niklason’s team stripped an adult rat’s lung down to its basic structural support system – its scaffolding – to see if it’s possible to rebuild rather than starting completely from scratch.

First, they essentially washed away the different kinds of cells lining that lung. It gradually faded from a healthy red to a white structure of mostly collagen and other connective tissue that maintained the shape and stretchiness of the original lung, even the tubes where airways would be.

This scaffolding is like a universal donor that shouldn’t pose rejection problems, said Niklason: “Your collagen and my collagen are identical.”

The researchers put the lung scaffolding into a bioreactor, an incubator-style container designed to mimic the environment in which fetal lungs develop, with fluid pumping through them.

Then they injected a mixture of different lung cells taken from a newborn rat. In the bioreactor, those cells somehow migrated to the right spots and grew air sacs, airways and blood vessels.

In short-term implants in four different rats, engineered lungs replaced one of the animals’ native lungs and proved 95 percent as efficient at exchanging oxygen and carbon dioxide, Niklason said.

However, among the problems she spotted were small clots that formed inside the engineered lung, a sign that the new cells hadn’t grown a thick enough cover in some places.

The biggest challenge: For this approach ever to work without a person’s body rejecting the new tissue, scientists would need to use a recipient’s own cells, Niklason explained. But there isn’t a way yet to cull the kind of personalized stem cells that would be needed, meaning stem cell research must improve first, she said.

This overall approach also worked in a 2008 University of Minnesota experiment that grew a beating rat heart, and Minnesota researcher Dr. Doris Taylor welcomed the Yale lung work.

Separately in Science, a Harvard University team coated a flexible chip with layers of living lung cells, creating a laboratory tool that mimics some of the action of a breathing human lung. The goal: To replace some of the animal studies needed to test how lungs react to environmental toxins or inhaled drugs. 

From The New England Journal of Medicine

http://content.nejm.org/cgi/content/full/NEJMoa0905955

Click, above, for the full article

Stem Cells Reverse Blindness Caused by Burns

This image from an Italian study published online Wednesday, June 23, 2010 by the New England Journal of Medicine shows the eyes of three patients with alkali burns before and after successful stem cell transplants. Dozens of people blinded or injured by chemical burns had their sight restored by transplants of stem cells from their own bodies _ a stunning success for the growing cell therapy field, Italian researchers reported Wednesday. (AP Photo/New England Journal of Medicine) MANDATORY CREDIT NEW ENGLAND JOURNAL OF MEDICINE, NO SALES, EDITORIAL USE ONLY

GoogleNews.com, The Washington Post, June 24, 2010, by Alicia Chang  –  LOS ANGELES — Dozens of people who were blinded or otherwise suffered severe eye damage when they were splashed with caustic chemicals had their sight restored with transplants of their own stem cells – a stunning success for the burgeoning cell-therapy field, Italian researchers reported Wednesday.

The treatment worked completely in 82 of 107 eyes and partially in 14 others, with benefits lasting up to a decade so far. One man whose eyes were severely damaged more than 60 years ago now has near-normal vision.

“This is a roaring success,” said ophthalmologist Dr. Ivan Schwab of the University of California, Davis, who had no role in the study – the longest and largest of its kind.

Stem cell transplants offer hope to the thousands of people worldwide every year who suffer chemical burns on their corneas from heavy-duty cleansers or other substances at work or at home.

The approach would not help people with damage to the optic nerve or macular degeneration, which involves the retina. Nor would it work in people who are completely blind in both eyes, because doctors need at least some healthy tissue that they can transplant.

In the study, published online by the New England Journal of Medicine, researchers took a small number of stem cells from a patient’s healthy eye, multiplied them in the lab and placed them into the burned eye, where they were able to grow new corneal tissue to replace what had been damaged. Since the stem cells are from their own bodies, the patients do not need to take anti-rejection drugs.

Adult stem cells have been used for decades to cure blood cancers such as leukemia and diseases like sickle cell anemia. But fixing a problem like damaged eyes is a relatively new use. Researchers have been studying cell therapy for a host of other diseases, including diabetes and heart failure, with limited success.

Adult stem cells, which are found around the body, are different from embryonic stem cells, which come from human embryos and have stirred ethical concerns because removing the cells requires destroying the embryos.

Currently, people with eye burns can get an artificial cornea, a procedure that carries such complications as infection and glaucoma, or they can receive a transplant using stem cells from a cadaver, but that requires taking drugs to prevent rejection.

The Italian study involved 106 patients treated between 1998 and 2007. Most had extensive damage in one eye, and some had such limited vision that they could only sense light, count fingers or perceive hand motions. Many had been blind for years and had had unsuccessful operations to restore their vision.

The cells were taken from the limbus, the rim around the cornea, the clear window that covers the colored part of the eye. In a normal eye, stem cells in the limbus are like factories, churning out new cells to replace dead corneal cells. When an injury kills off the stem cells, scar tissue forms over the cornea, clouding vision and causing blindness.

In the Italian study, the doctors removed scar tissue over the cornea and glued the laboratory-grown stem cells over the injured eye. In cases where both eyes were damaged by burns, cells were taken from an unaffected part of the limbus.
Researchers followed the patients for an average of three years and some as long as a decade. More than three-quarters regained sight after the transplant. An additional 13 percent were considered a partial success. Though their vision improved, they still had some cloudiness in the cornea.

Patients with superficial damage were able to see within one to two months. Those with more extensive injuries took several months longer.

“They were incredibly happy. Some said it was a miracle,” said one of the study leaders, Graziella Pellegrini of the University of Modena’s Center for Regenerative Medicine in Italy. “It was not a miracle. It was simply a technique.”

The study was partly funded by the Italian government.

Researchers in the United States have been testing a different way to use self-supplied stem cells, but that work is preliminary.

One of the successful transplants in the Italian study involved a man who had severe damage in both eyes as a result of a chemical burn in 1948. Doctors grafted stem cells from a small section of his left eye to both eyes. His vision is now close to normal.

In 2008, there were 2,850 work-related chemical burns to the eyes in the United States, according to the Bureau of Labor Statistics.

Schwab of UC Davis said stem cell transplants would not help those blinded by burns in both eyes because doctors need stem cells to do the procedure.

“I don’t want to give the false hope that this will answer their prayers,” he said.

Dr. Sophie Deng, a cornea expert at the UCLA’s Jules Stein Eye Institute, said the biggest advantage was that the Italian doctors were able to expand the number of stem cells in the lab. This technique is less invasive than taking a large tissue sample from the eye and lowers the chance of an eye injury.

“The key is whether you can find a good stem cell population and expand it,” she said.

New England Journal of Medicine:http://www.nejm.org

NEJM.org, by Rebecca Smith-Bindman MD, June 24, 2010  –  Ms. C., a 59-year-old schoolteacher, awoke on September 8, 2009, with facial paralysis. In a local emergency room, she underwent computed tomographic (CT) and magnetic resonance imaging (MRI) brain scanning. The scans were normal, Bell’s palsy was diagnosed, and the symptoms resolved over the next few weeks. Two weeks later, Ms. C. began losing her hair in a band-like distribution, and the following week she awoke with vertigo and confusion and returned to the emergency room, where repeat CT and MRI scans were normal. Fatigue, malaise, memory loss, and confusion began soon thereafter and have continued, making it difficult for her to work. Review of the first CT scan revealed that she had received a radiation dose to her brain of 6 Gy — approximately 100 times the dose from the average brain CT scan, 10 times the dose from the average brain-perfusion scan, and 3 times the daily dose of radiation treatment for brain cancer. Ms. C. is now a plaintiff in both a federal class-action lawsuit against a CT-scanner manufacturer and a state medical malpractice lawsuit. More than 378 patients in the United States have been identified as having received brain-perfusion scans with similar radiation overdoses, and the Food and Drug Administration (FDA) has issued a national advisory that hospitals should carefully check their CT protocols.

Radiation doses from CT scans are 100 to 500 times those from conventional radiography, depending on what part of the body is imaged. CT-machine manufacturers compete, in part, on the basis of image quality, which is directly associated with radiation dose (see figure).1 Technical advances such as increased imaging speed have led to new CT scanning techniques that have also boosted doses. For example, the brain-perfusion scan undergone by Ms. C. uses sophisticated techniques for assessing regional blood flow and, even when done correctly, delivers a dose 10 times that of a routine brain CT. Although such imaging techniques may have a role in diagnosis, there are few evidence-based guidelines regarding their appropriate use, and institutional use varies widely, reflecting physicians’ preferences and manufacturers’ promotion of these capabilities, rather than scientific evidence of improved clinical outcomes. Ms. C. not only received an accidental radiation overdose but also underwent a high-dose brain-perfusion CT when a much-lower-dose, routine head CT would have sufficed.

Computed Tomography (CT) of the Chest — Routine (Left) versus Low Dose (Right).

The surveillance of small pulmonary nodules is a common indication for chest CT, and several protocols can be used for these studies. Routine chest CT (Panel A) is associated with a radiation dose to the patient that is 10 times that of low-dose chest CT (Panel B) (dose-length product, 938 mGy per centimeter vs. 88 mGy per centimeter; effective dose, 15.9 mSv vs. 1.5 mSv) — yet each shows the small pulmonary nodule equally well (Panels A and B, arrows). The pulmonary parenchyma and upper abdomen are better visualized on the higher-dose routine scan (Panels A and C, respectively) than the low-dose scan (Panels B and D, respectively), but these areas are irrelevant to follow-up of a small pulmonary nodule. A recent survey of radiologists who perform chest CT showed that low-dose CT was not routinely used for examinations performed solely for the purpose of nodule follow-up and that most radiologists were unaware of the CT settings used for initial versus follow-up CT.1 Standardization of CT protocols could result in substantial reduction in patients’ radiation doses without loss of diagnostic accuracy. Images courtesy of Dr. Michael J. Flynn, Department of Radiology, Henry Ford Health Systems.
Although it has not been shown directly that CT increases cancer risk, radiation is a known carcinogen, and extensive epidemiologic and biologic evidence links ionizing-radiation exposure with cancer. The National Research Council (NRC) has concluded that patients exposed to radiation in the range provided by a single CT scan have an increased cancer risk,2 although uncertainty remains about the magnitude of the risk. My colleagues and I calculated the actual radiation doses delivered by commonly performed CT studies and quantified the associated cancer risks using the NRC’s models.3 We found that the risk of cancer from a single CT scan could be as high as 1 in 80 — unacceptably high, given the capacity to reduce these doses.

Yet no professional or governmental organization is responsible for collecting, monitoring, or reporting patients’ CT-dose information. The FDA approves CT scanners, but because it has no authority to oversee the way CT tests are used in clinical practice, it collects only limited data on routine doses. Radiologists and other medical specialists determine how CT tests are performed. Studies have consistently shown that physicians know little about radiation doses or cancer risks from medical imaging. Furthermore, although the general principle is that doses should be “as low as reasonably achievable” (referred to as ALARA), there are no guidelines to indicate what doses are reasonable or achievable for most types of CT. Finally, CT technologists receive no consistent education about what doses are excessive and, in many U.S. states, are not certified. The overdose received by Ms. C. was displayed on the CT console during scanning, but the technologist did not recognize it as abnormal.

In February 2010, the FDA launched an initiative to reduce unnecessary radiation from medical imaging (www.fda.gov/Radiation-EmittingProducts/RadiationSafety/RadiationDoseReduction/UCM199904). Ultimately, the agency will probably require manufacturers to incorporate safeguards against overdosing into equipment design, require dose information to be recorded in a standard fashion for inclusion in medical records, and develop tools for patients to track their imaging history. Notably absent from the initiative are plans to standardize, monitor, or regulate how imaging equipment is used. Recognizing the importance of developing evidence-based criteria for appropriate imaging use and the importance of generating diagnostic reference levels of radiation (or target radiation doses), but lacking the authority to undertake these tasks, the FDA has encouraged professional organizations to take the lead in these areas.

Also in February, the Committee on Energy and Commerce of the U.S. House of Representatives held a hearing on medical radiation, soliciting stakeholder testimony and opening the door to possible federal legislative oversight. Following the precedent of the Mammography Quality Standards Act of 1992, which is widely believed to have improved the quality of mammography, Congress could grant the FDA jurisdiction over CT and other procedures that deliver radiation.

Given the importance of CT to clinical care, as well as its potential for causing radiation poisoning (when errors are made) and cancer (even when protocols are followed), we must take steps to make it as safe as possible. The first step is to lower the doses for each scan. Evidence suggests the radiation dose from CT could be reduced by 50% or more without reducing diagnostic accuracy.4 Although several individuals, groups such as the Alliance for Radiation Safety in Pediatric Imaging (with its Image Gently campaign), and manufacturers are trying to reduce doses, no organization has responsibility for standardizing the conduct of examinations. And no specific interventions have been shown to reduce the doses that patients routinely receive. Several studies have shown that the doses used in clinical practice not only are higher than commonly reported but also vary substantially within and among facilities.3 CT protocols and techniques must be optimized and standardized, by means of an organized, systems-based approach, to minimize the risk of errors attributable to physicians’ independent decisions about which of thousands of protocols to use. We need to establish diagnostic reference levels, on the basis of clinically relevant outcomes and safety, not the creation of the greatest-quality images, if such quality does not improve outcomes. These standards could be adopted as measures of quality of care by organizations such as the National Quality Forum and National Committee for Quality Assurance.

Facilities must then monitor delivered doses and compare them with the benchmarks. Many European quality-assurance programs have been performing these tasks for over a decade, and average doses have been reduced considerably. Monitoring U.S. patients’ exposure would lead to an awareness of radiation associated with imaging and to reductions in average and extreme doses. If given a legislative mandate, the FDA could take the lead in creating standards and assessing compliance. Facilities that could not meet the standards should not be certified to conduct CT.

In addition, technologists and physicians must be educated regarding the importance of minimizing doses, and comprehensible dose information must be displayed wherever diagnostic studies are done. Furthermore, the default CT settings should generate the lowest doses that will yield the essential diagnostic information. The dose from each CT examination should be documented in the patient’s medical record and tracked over time. The Medical Imaging and Technology Alliance has agreed to begin reporting dose information in a consistent fashion for all new CT scanners by the end of 2010. If this information were available for all existing scanners, it would greatly facilitate the tracking of patients’ radiation doses.

Finally, the number of CT scans performed should be reduced. CT use has meant more accurate and earlier diagnoses. Yet the threshold for use is so low that many tests now obtained are unlikely to enhance the patient’s health or clinical decision making. Ironically, technical improvements have led to increases in the identification of incidental (and almost certainly irrelevant) findings that result in follow-up CT for surveillance. Currently, each year in the United States, approximately 10% of the population undergoes a CT scan, with a total of 75 million scans conducted; moreover, the use of CT continues to grow by more than 10% annually.5 The profitability of the technology contributes to the increasing ownership of CT machines by nonradiologists, which almost certainly increases their use through self-referral. We need to have frank discussions about the risks, benefits, and costs of CT, and we need more research to determine which exams lead to improved patient outcomes and strategies for limiting the use of exams that are unlikely to do so.

Consensus is growing that we must ensure that patients undergoing CT receive the minimum radiation dose possible to produce a medical benefit. CT has transformed the practice of medicine. It is time to put systems in place to ensure that it is as safe as possible.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.


Source Information

From the Departments of Radiology and Biomedical Imaging, Epidemiology and Biostatistics, and Obstetrics, Gynecology, and Reproductive Sciences, University of California at San Francisco, San Francisco.

This article (10.1056/NEJMp1002530) was published on June 23, 2010, at NEJM.org.

References

  1. 1.       Eisenberg RL, Bankier AA, Boiselle PM. Compliance with Fleischner Society guidelines for management of small lung nodules: a survey of 834 radiologists. Radiology 2010;255:218-224. [Free Full Text]
  2. 2.       Board of Radiation Effects Research Division on Earth and Life Sciences. Health risks from exposure to low levels of ionizing radiation: BEIR VII phase 2. Washington, DC: National Academy Press, 2006.
  3. 3.       Smith-Bindman R, Lipson J, Marcus R, et al. Radiation dose associated with common computed tomography examinations and the associated lifetime attributable risk of cancer. Arch Intern Med 2009;169:2078-2086. [Free Full Text]
  4. 4.       Catalano C, Francone M, Ascarelli A, Mangia M, Iacucci I, Passariello R. Optimizing radiation dose and image quality. Eur Radiol 2007;17:Suppl 6:F26-F32. [CrossRef][Medline]

Medicare Payment Advisory Commission. Healthcare spending and the Medicare program: a data book. June 2009. (Accessed June 10, 2010, at http://www.medpac.gov/documents/Jun09DataBookEntireReport.pdf.)

WorldHealth.net, June 24, 2010  –  In examining health records on 53,000 Norwegian residents, segmented from the second Nor-Trøndelag Health Study (HUNT 2), Norwegian University of Science and Technology (NTNU) researchers have found that maintaining a sense of humor not only keeps people healthy, but helps to increase their longevity.  Sven Svebak and colleagues evaluated people’s sense of humor with three questions that reveal a person’s ability to understand humor and to think in a humorous way, finding that mortality was reduced by about 20% in subjects with high scores compared to people with low scores. In addition, subjects with the highest scores were twice as likely to survive the 7-year long follow-up period, as compared to those with the lowest scores. Svebak  concludes that: “There is reason to believe that sense of humor continues to have a positive effect on mental health and social life, even after people have become retirees, although the positive effect on life expectancy could not be shown after the age of 75. At that point, genetics and biological aging are of greater importance.”

Svebak, S., Romundstad, S., Holmen, J. A 7-year prospective study of sense of humor and mortality in an adult county population: The HUNT-2 study. The International Journal of Psychiatry in Medicine, 40, 125-146.

Am J Clin Nutr (June 2, 2010). doi:10.3945/ajcn.2010.29413

© 2010 American Society for Clinical Nutrition

Kimberly A Skarupski, Christine Tangney, Hong Li, Bichun Ouyang, Denis A Evans and Martha Clare Morris

1 From the Section of Nutrition and Nutritional Epidemiology (KAS, CT, HL, BO, and MCM), Rush Institute for Healthy Aging (KAS and DAE), the Department of Internal Medicine (KAS, DAE, and MCM), the Department of Clinical Nutrition (CT), Rush Alzheimer’s Disease Center (DAE), and the Department of Neurological Sciences (DAE), Rush University Medical Center, Chicago, IL.

2 Supported by grants AG11101 and AG13170 from the NIH/NIA.

3 Address correspondence to KA Skarupski, Section of Nutrition and Nutritional Epidemiology, Rush University Medical Center, Oak Park Professional Office Building, Suite 4700, 610 South Maple Avenue, Oak Park, IL 60304. E-mail: kimberly_skarupski@rush.edu.

ABSTRACT

Background: B-vitamin deficiencies have been associated with depression; however, there is very little prospective evidence from population-based studies of older adults.

Objective: We examined whether dietary intakes of vitamins B-6, folate, or vitamin B-12 were predictive of depressive symptoms over an average of 7.2 y in a community-based population of older adults.

Design: The study sample consisted of 3503 adults from the Chicago Health and Aging project, an ongoing, population-based, biracial (59% African American) study in adults aged 65 y. Dietary assessment was made by food-frequency questionnaire. Incident depression was measured by the presence of 4 depressive symptoms from the 10-item version of the Center for Epidemiologic Studies Depression scale.

Results: The logistic regression models, which used generalized estimating equations, showed that higher total intakes, which included supplementation, of vitamins B-6 and B-12 were associated with a decreased likelihood of incident depression for up to 12 y of follow-up, after adjustment for age, sex, race, education, income, and antidepressant medication use. For example, each 10 additional milligrams of vitamin B-6 and 10 additional micrograms of vitamin B-12 were associated with 2% lower odds of depressive symptoms per year. There was no association between depressive symptoms and food intakes of these vitamins or folate. These associations remained after adjustment for smoking, alcohol use, widowhood, caregiving status, cognitive function, physical disability, and medical conditions.

Conclusion: Our results support the hypotheses that high total intakes of vitamins B-6 and B-12 are protective of depressive symptoms over time in community-residing older adults.

Copyright © 2010 by the American Society for Nutrition

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GoogleNews.com, June 24, 2010  –  Merck said Thursday that the U.S. Food and Drug Administration approved its inhaled asthma treatment Dulera.

Dulera is a fixed-dose inhaled aerosol combination of a corticosteroid with a beta2-agonist, intended for treatment of asthma patients 12 and older. Merck said it expects the drug to be in pharmacies by the end of July.

Reuters reports that similar asthma treatments include GlaxoSmithKline’s Advair and AstraZeneca’s Symbicort.

Merck & Co. said Thursday it received marketing approval for its asthma treatment Dulera, but the drug will come with a serious warning that it can increase risk of death.

The Food and Drug Administration cleared Dulera, which comes in an inhaler, for use in patients 12 and older, the company said.

Dulera, which combines two types of medication, is meant only for patients with poorly controlled asthma. That’s because of the slight risk that one component _ formoterol fumarate, part of the drug class called long-acting beta agonists _ could cause asthma-related death. These drugs relax muscles around stressed airways, which could keep patients from noticing dangerous inflammation building up in their airways.

The FDA is mandating that Dulera carry its strongest warning, in a black box in the detailed package insert, as is required for four asthma medicines in the same class: Advair, Symbicort, Foradil and Serevent.

Earlier this month, the agency strengthened rules it announced in February for all long-acting beta agonists, or LABAs. Besides carrying the warning about risk of death, these drugs are to be used along with an inhaled corticosteroid. Also, patients should use LABAs only until asthma control is achieved and maintained, then gradually stop using them.

Dulera’s second component is an inhaled corticosteroid, mometasone furoate, for reducing airway inflammation. That drug is sold under the brand name Asmanex as an allergy treatment. It was developed by Schering-Plough Corp., which Merck bought last November.

Merck said Dulera should be available around the country by the end of July, in two strengths.