Science Weekly: What are animals thinking?

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Do pets have emotions; what’s next for the Large Hadron Collider; and using YouTube to debunk myths of climate change denial

Companies and CROs Partner With Target Health


Target Health is pleased to announce part of its business model and long-term growth is to provide business to business (B2B) services to companies and CROs. Clearly, we provide Regulatory, Clinical, Biostatistical and Medical Writing services to the pharmaceutical industry with 27 approved products worldwide since 1993. We expect at least 2 more this year. However, over the past several years we have been working closely with several CROs to provide EDC and related data management and biostatistical services. We expect our first NDA submission this year using this model and we are now talking to 2 more CROs. Several pharma companies have already in-licensed Target Document and we are in the process of finalizing a deal with several others. We are cost effective and since “we know the business,“ our software provides true solutions. As a guarantee, we will always save you money.

Next week we will feature our new publication in the May edition of Applied Clinical Trials entitled : “The New eFrontier“ which addresses the challenges and opportunities of integrating electronic data capture with electronic health records.

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Research Offers Clue How Hearts Can Regenerate in Some Species

Humans can regenerate a 1) ___ but cannot replace limbs and other organs. Fish and amphibians can grow new fins or limbs, and the zebra fish, which has been adopted by researchers as a laboratory organism, can even regenerate its heart after the bottom fifth has been removed. The fish are sluggish for a while after surgery, but regrow the missing part of their 2) ___in a month. The human heart does have a limited capacity to generate new heart muscle cells with about half the cells replaced over the course of a person’s lifetime. But this regenerative capacity does not accelerate in response to a heart attack. Instead, the damaged cells are replaced by 3) ___ tissue, which does not contract. Researchers assumed that the situation is different in the zebra fish because of stem cells that could generate more heart muscle cells after injury. A recent report by Duke University offered confirmation that stem cells are the source of the repair process. 4) ___ cells are general purpose cells that generate the mature, functional cells of the body. But two independent reports in the journal Nature in March 2010, contradict the stem cell idea, reporting that the mature heart muscle cells are the principal source for regenerating the zebra fish heart. The Duke report has revised its earlier findings. The second study, from the Center for Regenerative Medicine in Barcelona, Spain, rules out stem cells, saying their contribution could be only marginal at best. The Barcelona team genetically engineered the zebra fish’s heart 5) ___ cells so that when they proliferated they would synthesize a fluorescent green protein. After cutting off the bottom of the heart and letting it regenerate, they found that all the cells in the new part of the heart glowed green, proving that existing heart muscle cells were the principal or only source of the new 6) ___. Nature’s recipe for regeneration, in this case, is to take the mature cells and walk them back in development to a stemlike state. The second step is for these stemlike heart muscle cells to grow and divide, generating replacement tissue. This contrasts with the assumption that tissues would be generated from stem cells that differentiate, or mature, into adult cells. In Nature, the muscle cells don’t go back to the 7) __ state, they just dedifferentiate a little, so we should look at how animals do it and try to imitate them. Zebra fish and mammals are separated by a long evolutionary distance and yet, surprisingly, the first step in the regeneration process, the dedifferentiation of heart muscle cells, occurs in mammals as well. In zebra fish the structure of the muscle fiber disintegrates as the cells 8) ___. The same process can be seen after injury in the hearts of mice, rats and dogs, but the cells get stuck in the second process, that of proliferating to form new tissue. All we need do is to induce the proliferation of these cells in mammals. The two reports have raised the tantalizing question of why human hearts could not complete the regeneration process. In human hearts, too, the muscle cells dedifferentiate after injury and double up their DNA, a necessary precursor to 9) ___ division. But they do not finish the process, for reasons that are so far unknown. One problem is, we don’t know how nature does it. Both approaches to the problem should be pursued in parallel: using stem cell treatments and trying to understand nature’s favored recipe for 10) ___Source: March 31, 2010, NYTimes, by Nicholas Wade

ANSWERS: 1) liver; 2) heart; 3) scar; 4) stem; 5) muscle; 6) tissue; 7) embryonic; 8) dedifferentiate; 9) cell; 10) regeneration

Babe Ruth – Cancer Pioneer

At Babe Ruth Day at Yankee Stadium in 1947, the baseball hero of the generation stood before an admiring crowd, deep in pain and emaciated from advancing cancer, not yet aware of what ailed him. In the dugout moments before, clad in a topcoat and golf hat, he suffered a coughing spell, then, pulling himself together, walked to home plate, mentally recalling the day Lou Gehrig had made the same trip. In a broadcast heard around the world, Ruth spoke slowly and extemporaneously in a raspy voice. ”You know how bad my voice sounds,” Ruth told the roaring crowd. ”Well, it feels just as bad.” Sixteen months later, at 53, he was dead. His sports legacy has been extolled as baseball heroes of newer generations breeze past the home-run record the Babe held for 34 years, until 1961. But unknown to many, Ruth also left a legacy in the annals of medical history. In fact, he was among the first patients anywhere to receive experimental chemotherapy, and some researchers say he was the first ever to receive a combination treatment of chemotherapy and radiation for his type of cancer. For Ruth, the chemotherapy worked dramatically – but only temporarily. Nevertheless, knowledge gained from his case helped shape the combination therapy that is now standard for his disease. Shortly after his death, the nature of his disease became clear, and well publicized. Ruth suffered from a rare cancer, naso-pharyngeal, that arose in the air passages in the back of his nose and mouth. But the images of a hoarse Ruth, perpetuated in audio and videotapes on the Internet, in movies and in sports broadcasts, in addition to his well-known smoking and drinking proclivities, have contributed to the myth that Ruth had throat cancer, which is generally taken to mean cancer of the larynx, or voice box. The distinction in cancer type may be academic to fans, but to patients and the doctors who treat them, the difference is crucial. Ruth’s battle against cancer offers a rare glimpse into the many dramatic changes in medicine and attitudes toward research that have occurred in just half a century. The changes include greater accuracy in diagnosis, more effective therapy and stronger rules to inform patients about diagnoses and the consent now required from patients participating in experiments. Ruth’s health began failing in September 1946 when he sought to return to baseball as a manager. His voice became progressively hoarser. He was gripped with severe and relentless pain in his left eye. His head ached. In November, he entered French Hospital in New York City, where doctors diagnosed sinusitis, then looked at possible dental problems and pulled three teeth, without improvement. His face swelled, his left eye became shut and he lost the ability to swallow. X-rays showed a large abnormality at the base of Ruth’s skull. But several biopsies of tissues in his mouth showed nothing abnormal. Ruth’s symptoms worsened. His neck enlarged from swollen lymph nodes. His jaw hurt when he ate and he was unable to swallow. Later, Ruth was fed intravenously. Although doctors were unable to diagnose Ruth’s problem, they treated him with radiation. His hair fell out in chunks. In December, the doctors operated on Ruth and documented extensive spread of the cancer in the neck. But in the operation, surgeons had to tie off the external carotid artery because the cancer had wrapped itself around the blood vessel in his neck. The cancer also pressed on nerves that course through the neck from the brain. The pressure partly paralyzed muscles controlling his voice, accounting for his hoarseness, and making swallowing even more difficult. Now, Ruth was secluded and allowed few visitors. ”I often felt so alone that the tears would run helplessly down my cheeks,” Ruth wrote. In April 1947, every ball park in organized baseball celebrated Babe Ruth Day when Ruth, bolstered by his radiation treatments, uttered his famous hoarse words. By June, those benefits from radiation had waned. Severe pain had returned; he could not sleep. Ruth then joined the often-unaware group of anonymous patients who ushered in the modern era of anti-cancer treatment, which grew out of American research into chemical warfare agents during World War II. In 1942, researchers at Yale University tested one such agent, nitrogen mustard, in a human for the first time. But Government secrecy restrictions prevented publication until 1946, after several hundred patients had been treated. At the time, a team headed by Dr. Richard Lewisohn, a surgeon at Mount Sinai Hospital in New York City, was experimenting with an anti-cancer drug, teropterin, in mice. There were different teropterins, all extracted from brewers’ yeast, and their effects on mice varied widely with the preparation. Over the violent objections of Dr. Lewisohn’s team members, who believed the substance was not ready for tests in people, Ruth began receiving daily injections of teropterin on June 29. (A closely related drug, methotrexate, is now widely used in treating cancer and other diseases.) Ruth said he knew teropterin had rarely been used on humans and ”asked no questions,” and probably signed no formal consent, as is required today, before receiving injections for six weeks. Ruth knew the risk: The drug could help or hurt. The drug had dramatic effects. His pain waned; his spirit improved. Able to eat again, he began regaining some of the 80 pounds he had lost. By August, the enlarged lymph nodes in his neck had completely disappeared. In September, Dr. Lewisohn reported Ruth’s case, without using his name, at a scientific meeting in St. Louis. But word leaked that Ruth had received the novel therapy. Citing success on an unidentified famous figure, The Wall Street Journal’s lead story of Sept. 11, 1947, suggested scientists were on the verge of a cure for cancer. The Babe Ruth trials clearly exemplify just how much has changed in a half century. Whether Ruth was even fully aware that he had cancer is open to question. On June 13, 1948, Ruth participated in the 25th anniversary of Yankee Stadium, wearing his old No. 3 Yankee uniform and telling misty-eyed fans how glad he was to be with his old pals again. A few days later, Ruth entered Memorial Hospital (now Memorial Sloan-Kettering Cancer Center) in Manhattan. His wife, Claire, wrote that she believed the Babe never knew he had cancerOn Aug. 16, Ruth died of pneumonia. An autopsy showed the cancer that began in the nose and mouth had spread widely through his body. Ruth apparently never received teropterin again. Mount Sinai has no records on Ruth or the research, a spokesman said. Memorial Hospital’s news release emphasized that Ruth ”received no special drug or chemical in the attempt to control his tumor.” Much later, Ruth’s cancer became an issue when a team of specialists at the University of California at San Francisco discussed a patient with naso-pharyngeal cancer. A pathologist, Dr. Harvey Z. Klein, said that while in training he had learned of Ruth’s diagnosis. ”That created a great stir because virtually everyone else in the room said Ruth died of laryngeal cancer,” said Dr. Jeffrey H. Spiegel, a specialist in head and neck surgery at the center. In San Francisco, Dr. Mark I. Singer, the chief of head and neck surgery at Mount Zion Hospital, was puzzled because the eye pain and headache Ruth had experienced typified cancer in the back of the nose much more than cancer of the vocal cords. A colleague, Dr. Nadim B. Bikhazi, was asked to ascertain the cause of Ruth’s death and found it in microfilm of New York Times articles, which described the autopsy findings. Dr. Bikhazi then received permission from Ruth’s daughter, Julia Ruth Stevens, to examine the autopsy report. The crucial finding, Dr. Bikhazi said in an interview in San Francisco, was that no cancer was found in the larynx. Much has been made of Ruth’s heavy drinking, smoking and use of snuff and his habits’ links to his cancer. Those links would hold for cancer of the larynx, but the case for naso-pharyngeal cancer is far less clear-cut. The links between these two types of cancer and tobacco are controversial, in part because of the rarity of the cancers. While there is no evidence that tobacco killed him, Dr. Bikhazi said it probably played a part. Today, doctors can diagnose naso-pharyngeal cancer quicker and less painfully than in Ruth’s time. A nose bleed, lump in the neck and hearing loss in one ear are clues to the diagnosis of naso-pharyngeal cancer. Because Ruth was in the most advanced stage of the cancer, his case would still be difficult to treat today. These days, about 40% of patients with advanced naso-pharyngeal cancer survive at least five years. Although the types and amounts of medications, and timing of their delivery, are not precisely given for naso-pharyngeal cancer today, Dr. Spiegel said, ”Ruth was the first person to get treated almost the right way.” Source; The New York Times, by Lawrence K. Altman MD

Dopamine D2 Receptors in Addiction-Like Reward Dysfunction and Compulsive Eating In Obese Rats

Both obesity and drug addiction have been linked to a dysfunction in the brain’s reward system. In both cases overconsumption can trigger a gradual increase in the reward threshold-requiring more and more palatable high fat food or reinforcing drug to satisfy the craving over time. According to an article published online in Nature Neuroscience (28 March 2010), some of the same brain mechanisms that fuel drug addiction in humans accompany the emergence of compulsive eating behaviors and the development of obesity in animals. When rats were given access to varying levels of high-fat foods, it was found unrestricted availability alone can trigger addiction-like responses in the brain, leading to compulsive eating behaviors and the onset of obesity. The study was conducted in three groups of male rats over a 40-day period. Throughout the study, feeding behaviors of each group were observed noting caloric intake, weight gain, and brain response. Each day, the three groups had unlimited access to standard lab food. In addition, two of the groups also had access to high-fat, cafeteria style foods for short (one-hour) or long (18-23 hours) periods. After 40 days, all groups were denied access to the high-fat foods. Results showed that as the rats became obese, the levels of D2DR in the brain’s reward circuit decreased. This drop in D2DR is similar to that previously seen in humans addicted to drugs like cocaine or heroin. The results support the notion that type 2 dopamine receptors (D2DR)-brain receptors that have been shown to play a key role in addiction also play a key role in the rats’ heightened response to food. Study results also suggest that environmental factors, such as increased or unlimited access to high-fat food options, can contribute to the problem of obesity.

Impaired Brain Connections Traced to Schizophrenia Mutation

Scientists have suspected such a brain connectivity disturbance in schizophrenia for more than a century. Although the disorder is thought to be 70% heritable, its genetics are quite complex. Neuroimaging studies in schizophrenia patients have found abnormal connections between the brain’s prefrontal cortex, the executive hub, and the hippocampus, the memory hub, linked to impaired working memory. It was also known that a mutation in the suspect site on chromosome 22, called 22q11.2, boosts schizophrenia risk 30-fold and also causes other abnormalities. Although accounting for only a small portion of cases, this tiny missing section of genetic material, called a microdeletion, has repeatedly turned up in genetic studies of schizophrenia and is an indisputable risk factor. Still, the mutation’s link to the disturbed connectivity and working memory deficit eluded detection. According to an article published in Nature (1 April 2010), the strongest known recurrent genetic cause of schizophrenia impairs communications between the brain’s decision-making and memory hubs, resulting in working memory deficits. To explore the mutation’s effects on brain circuitry, the study engineered a line of mice expressing the same missing segment of genetic material as the patients. Strikingly, like their human counterparts with schizophrenia, these animals turned out to have difficulty with working memory tasks – holding information in mind from moment to moment. Successful performance of such tasks depends on good connections in a circuit linking the prefrontal cortex and the hippocampus. To measure such functional connections, the study monitored signals emitted by single neurons implanted in the two distant brain structures while mice performed a working memory task in a T-maze. Results showed that the more in-sync the neurons from the two areas fired, the better the functional connections between the two structures – and the better the mice performed the task. Moreover, the better the synchrony to start with, the quicker the animals learned the task. The more synchrony improved, the better they performed. As suspected, the mice with the chromosome 22 mutation faltered on all counts — showing much worse synchrony, learning and performance levels than control mice.

Songbird Genome Analysis Reveals New Insights into Vocal Behavior – A Genomic Achievement That’s for the Birds and for Humans

The zebra finch (Taeniopygia guttata), which derives its name from the black-and-white stripes on the male finch’s throat, serves as a valuable model for studying human speech, communication and neurological disorders. The finch is the first songbird – and the second bird, after the chicken – to have its genome sequenced. According to an article published online in Nature (1 April 2010), an international research consortium has identified more than 800 genes that appear to play a role in the male zebra finch’s ability to learn elaborate songs from his father. The team also found evidence that song behavior engages complex gene regulatory networks within the brain of the songbird. These networks that rely on parts of the genome that were once considered junk. A major reason it was decided to study the zebra finch genome was the male bird’s ability to learn complex songs from its father. At first, a fledgling finch makes seemingly random sounds, much like the babble of human babies. With practice, the young bird eventually learns to imitate its father’s song. Once the bird has mastered the family song, he will sing it for the rest of his life and pass it on to the next generation. This ability to communicate through learned vocalization is lacking in chickens and female zebra finches. Though female finches do perceive and remember songs, their inability to learn songs may be due to differences in their hormone status and chromosomal differences that affect the brain. In addition to male songbirds, other animals that communicate through learned vocalizations include other songbirds, parrots, hummingbirds, bats, whales and humans. The chicken and zebra finch genomes are similar in many ways. Both have about 1 billion DNA base pairs – roughly one-third the size of a human genome. However, some genes associated with vocal behavior have undergone accelerated evolution in the finch. For example, a disproportionately high number of ion channel genes was found among the 49 genes in the finch genome that are suppressed, or turned off, in response to song. Ion channels allow the movement of ions (electrically charged particles) across cell membranes. Human ion channel genes have been shown to play key roles in many aspects of behavior, neurological function and disease. Consequently, the researchers suspect that the evolution of this group of genes in songbirds may be essential for learned vocalization. The study also identified portions of the genome crucial to regulating the activity of genes involved in song behavior. While many parts of the genome are engaged during vocal communication, one surprising finding was the extensive involvement of non-protein coding ribonucleic acids (ncRNAs). Protein-coding components make up just a small fraction of the genomes of humans and other animals. It was once thought that the non-coding part of the genome was not essential, amounting to biological junk. Recently, researchers have begun to amass evidence that many parts of the non-coding regions serve important biological functions. Analysis of the zebra finch genome sequence suggested that ncRNAs, which have been proposed to contribute to the evolution of greater complexity in humans and other animals, may be a driving force behind learned vocal communication. Story Landis, Ph.D., director of the National Institute of Neurological Disorders and Stroke (NINDS), stated that “these findings will transform scientific research on the songbird system.“ He added that “although scientists understand much about how songbirds acquire and modify their vocal patterns, the availability of the genome sequence will allow insight into the molecular underpinnings of this natural behavior which could lead to better understanding of learning and memory, neural development and adaptation, and speech and hearing disorders.”

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Medical Department Policy Update-Prospective CMS Leadership

It may be hard to believe, but now that health insurance reform has been signed into law, the hard work is only beginning. The implementation of the new law will fall in substantial measure to the Center for Medicare and Medicaid Services (CMS), the entity responsible for administering the Medicare and Medicaid programs and consequently the largest purchaser of health care services in the nation. Astonishingly, the CMS has been without a permanent leader since 2006 when Dr. Mark McClellan stepped down. Recent reports suggest that President Obama will nominate Dr. Donald Berwick, a Harvard Pediatrics & Public Health Professor who additionally leads the Cambridge Massachusetts based Institute for Healthcare Improvement, a non-profit organization dedicated to improving healthcare worldwide through innovative system change, as the next leader of the CMS. Given the rancor surrounding the passage of the health care bill it is encouraging how well news of this appointment has been received. Dr. Berwick is broadly respected, and in addition seems to be genuinely liked across the healthcare community. Dr. Berwick approach is on patient-centered quality care to be achieved through system redesign. His policy options will likely extend well beyond simply raising revenues and rationing services. We anticipate that this mindset will be respectful and welcoming to genuine innovation across the spectrum of care so long as these demonstrate value and the potential to improve quality, specifically including the quality of the patient experience. His appointment requires confirmation, which will subject Dr. Berwick to both scrutiny and potential discomfort since the hearings will provide a forum to revisit health reform with all the associated acrimony of the past year’s debate. We at Target Health wish him well. His credentials, experience, and approach are well suited to the difficult tasks ahead, and our country needs wise and experienced health care leadership during this time of transformation.

By Mark Horn MD, MPH, Chief Medical Officer at Target Health Inc.


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