Scientists Discover Why Cornea Is Transparent And Free Of Blood Vessels, Allowing Vision

Scientists at the Harvard Department of Ophthalmology's Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary (MEEI) are the first to learn why the cornea, the clear window of the eye, is free of blood vessels--a unique phenomenon that makes vision possible. The key, say the researchers, is the unexpected presence of large amounts of the protein VEGFR-3 (vascular endothelial growth factor receptor-3) on the top epithelial layer of normal healthy corneas. According to their findings, VEGFR-3 halts angiogenesis (blood vessel growth) by acting as a "sink" to bind or neutralize the growth factors sent by the body to stimulate the growth of blood vessels. The cornea has long been known to have the remarkable and unusual property of not having blood vessels, but the exact reasons for this had remained unknown.

These results, published in the July 25, 2006 issue of the Proceedings of the National Academy of Sciences and in the July 17 online edition, not only solve a profound scientific mystery, but also hold great promise for preventing and curing blinding eye disease and illnesses such as cancer, in which blood vessels grow abnormally and uncontrollably, since this phenomenon, present in the cornea normally, can be used therapeutically in other tissues.

"This is a very significant discovery," says Dr. Reza Dana, Senior Scientist at the Schepens Eye Research Institute, head of the Cornea Service at the Massachusetts Eye and Ear Infirmary, and an associate professor at Harvard Medical School, and the senior author and principal investigator of the study. "A clear cornea is essential for vision. Without the ability to maintain a blood-vessel-free cornea, our vision would be significantly impaired," he says, adding that clear, vessel-free corneas are vital to any animal that needs a high level of visual acuity to survive.

The cornea, one of only a few tissues in the body that actively keep themselves vessel-free (the other is cartilage), is the thin transparent tissue that covers the front of the eye. It is the clarity of the cornea that allows light to pass onto the retina and from there to the brain for interpretation. When the cornea is clouded by injury, infection or abnormal blood vessel growth, vision is severely impaired, if not destroyed.

Scientists have been wrestling with the "clarity" puzzle for many decades. And, while some previous studies have revealed small clues, none have pointed to one major mechanism, until this study.

In most other tissues of the body, blood vessel growth or angiogenesis occurs in response to a need for increased blood flow to heal an injured or infected area. The immune system sends in growth factors such as vascular endothelial growth factor (VEGF) to bind with a protein receptor called VEGFR-2 on blood vessels to trigger vessel growth. Three forms of VEGF--A, C, and D--bind with this receptor. Two of them, C and D also bind with VEGFR-3, which is usually found on cells lining lymphatic vessels, to stimulate the growth of lymphatic vessels.

Dana's team began to suspect the involvement of VEGFR-3 in stopping blood growth in corneas when they noticed unexpectedly that large amounts of the protein seemed to exist naturally on healthy corneal epithelium, a previously unknown location for the receptor. Dana and his team were already aware from clinical experience that the epithelium most likely played a role in suppressing blood vessel growth on the cornea, having witnessed blood vessels develop on corneas stripped of their epithelial layers.

They began to theorize that the large amounts of VEGFR-3, in this New, non-vascular location, might be attracting and sucking up all the C and D VEGF growth factors, thereby blocking them from binding with VEGFR-2. And, because this binding took place in a non-vascular setting, the growth factors were neutralized.

To test their theory, the team conducted a series of experiments.

Using corneal tissue from mice, the team did the following.

They conducted chemical analyses that demonstrated that VEFGR-3 and the gene that expressed it were indeed present on the corneal epithelium. Next, in two separate experiments, they compared corneas with and without epithelial layers that were injured. They found that only the corneas without epithelial layers developed blood vessels, implicating the role of the epithelium in suppressing blood vessel growth To further prove their theory, they added a VEGFR-3 substitute to corneas stripped of their epithelial layers and found that vessel growth continued to be suppressed, replacing the normal anti-angiogenic role of the epithelium. Finally they exposed intact corneas to an agent that blocked VEGFR-3 and found that blood vessels began to grow, formally demonstrating that the corneal epithelium is key to suppression of blood vessels and that the key mechanism is expression of VEGFR-3.

"The results from this series of tests, confirmed our belief that the presence of VEGFR-3 is the major factor in preventing blood vessel formation in the cornea," says Dana, who says that the discovery will have a far reaching impact on the development of New therapies for eye and other diseases.

"Drugs designed to manipulate the levels of this protein could heal corneas that have undergone severe trauma or help shrink tumors fed by rapidly growing abnormal blood vessels," he says. "In fact, the next step in our work is exactly this."

###

Other authors of the study include: Claus Cursiefen* +, Lu Chen*, Magali Saint-Geniez*, Pedram Hamrah*, Yiping Jin*, Saadia Rashid*, Bronislaw Pytowski**, Kris Persaud**, Yan Wu**, J. Wayne Streilein*†, Reza Dana* ++ ,

*The Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Dept. of Ophthalmology, Harvard Medical School, Boston, MA; +Dept. of Ophthalmology, Friedrich-Alexander University Erlangen-Nurnberg, Erlangen, Germany; **ImClone Systems, Inc., New York; †Dr. J. Wayne Streilein deceased March 15 th 2004.

About the Massachusetts Eye and Ear Infirmary, http://www.meei.harvard.edu./.: The Massachusetts Eye and Ear Infirmary, an independent specialty hospital, is an international center for treatment and research and a teaching hospital of Harvard Medical School.

Schepens Eye Research Institute is an affiliate of Harvard Medical School and he largest independent eye research institute in the world. For additional information, go to http://www.theschepens.org/.

Contact: Patti Jacobs
Schepens Eye Research Institute





Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Low intake of milk during pregnancy linked to decreased birth weight

A New study published in the Canadian Medical Association Journal gives expectant mothers yet another reason to drink their milk. Researchers found that women who rarely drank milk during their pregnancy gave birth to smaller babies compared to women who drank more milk.

Low birth weight affects one out of every 13 babies born each year in the United States, and it's a factor in 65 percent of infant deaths, according to the March of Dimes. This New study suggests that drinking the recommended amount of milk each day - three 8-ounce glasses -may help increase birth weight.

The Canadian researchers followed 279 women throughout their pregnancy. They found that women who limited their intake of milk to one cup or less per day consumed significantly less protein and vitamin D, and they gave birth to babies that weighed less compared to women who drank more milk.

Milk consumption and vitamin D intake from fortified milk and supplements during pregnancy were found to be each associated with infant birth weights, independently of other risk factors. Analysis of the data predicted that each cup of milk consumed daily was associated with a 41 gram increase in a baby's birth weight.




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Diagnosing Airway Disease

Jill Ohar, MD


Several presentations at this year's CHEST 2005 meeting addressed the diagnosis of airway disease. Jill Karpel, MD, Director of the Beth Thalheim Asthma Center, North Shore-Long Island Jewish Health System, presented a symposium entitled: "Do patients with asthma experience good symptom control?" The GINA Guidelines define control as:

• Minimal to no chronic symptoms;
• Infrequent exacerbations;
• No emergency visits;
• Minimal to no need for as-needed beta2-agonist;
• No limitations on activities;
• Peak expiratory flow (PEF) circadian variation of <>
• Near-normal PEF; and
• Minimal or no adverse events from medications.[1]

One of the problems with assessing asthma control is what measure should be used? Best practice is to use a composite of asthma measures: quality of life, lung function, symptom scores, exacerbation rates, and indices of inflammation. Fuhlbrigge and coworkers have shown that subjects classified as mild intermittent asthma have 2 times more symptoms than subjects classified as mild persistent asthma.[2] Furthermore, 80% of patients classified as having moderate-to-severe persistent asthma are poorly controlled. The "Asthma is American™" survey showed that 30% of asthma patients don't sleep through the night, more than 30% missed school or work because of asthma symptoms, 48% were limited in their leisure activities, and 23% required unscheduled Medical care.[3] Dolan and coworkers showed that participants in the TENOR study moved among severity categories. Furthermore, control was poor in all categories.[4] Dr. Karpel noted that 90% of asthma deaths (5000 in the United States per year) are preventable. She cited New York State healthcare data that revealed that only 72% of patients receiving inhaled corticosteroids (ICS) prescriptions filled them. More troubling is that only 30% of patients receiving ICS prescriptions used them. A study by Calhoun and coworkers[5] shows that patients characterized by symptoms, peak flow, and albuterol dose all give different estimates of asthma severity. Peak flow correlated with symptoms about 60% of the time. Dr. Karpel reaffirmed the need for use of a composite of asthma severity measures when evaluating control.

Regardless of the control or severity measure used, ICS are effective in achieving control. When ICS are withdrawn, mortality increases 20%.[6] ICS reduce sputum eosinophilia 60% and the reduction in eosinophilia is proportional to frequency of exacerbations.[7] ICS also improve airway hyperresponsiveness[8] and inflammation, as measured with exhaled nitric oxide.[9] Dr. Karpel recommended the use of the Asthma Control Test (ACT) at each visit as an asthma assessment tool. The ACT has content similar to other asthma questionnaires. Clinically meaningful cut points for interpretation of ACT scores have been published.[10] Both the CAMP and the GOAL Studies show that asthma control can be achieved.[11,12] Dr. Karpel concluded with possible reasons why treatment goals are not achieved. These include poor patient perception of control, variability of response to treatment, pharmacogenetic issues, and poor adherence to treatment regimens. Strategies to treat the patient with poorly controlled asthma include revisit their history and asthma control plan; determine specific allergen (skin testing, in vitro testing and history); search for comorbidities (gastroesophageal reflux disease, allergic rhinitis, allergic bronchopulmonary aspergillosis, chronic obstructive pulmonary disease [COPD], and alpha-1 antitrypsin deficiency); exclude conditions such as cystic fibrosis, Ig deficiency, Churg-Strauss syndrome, and chronic obstructive pulmonary disease; assess environmental control issues (asthma triggers, workplace exposures and tobacco smoke); address adherence and inhaler techniques; and assess and monitor drug therapy to optimize benefit.

Chronic Obstructive Pulmonary Disease or Asthma?
Another lecture in the airways disease track was "Is it asthma or COPD -- when to suspect the diagnosis in an adult" presented by Jill Ohar MD, Professor of Medicine, Wake Forest University Medical Center. The Dutch Hypothesis proposes that asthma, chronic bronchitis, and emphysema are different manifestations of the same disease and that the phenotype displayed by a patient is a result of a combination of genetic and environmental factors modulated by age and gender. Bronchial hyperreactivity (BHR), increased rate of decline in forced expiratory volume in 1 second (FEV1), and airway thickness are phenotypic characteristics of both asthma and COPD that have been shown to be associated with genetic sequence alterations in IL-13 and ADAM33.[13-17] BHR, the hallmark of asthma, was seen in 46% of men and 74% of women enrolled in the Lung Health Study.[18] Not only was BHR frequently associated with the presence of COPD, but also the severity of BHR was associated with the annual rate of decline in FEV1[18] and COPD mortality.[19] BHR is associated with airway thickness through Pouseilles Law, and there is a linear relationship between severity of COPD and airway thickness.[20]

Despite similarities between asthma and COPD in regard to BHR, analysis of the dose-response curves to methacholine or histamine is useful in differentiating these 2 distinct disorders. In both asthma and COPD the dose-response curves are shifted to the left, implying enhanced sensitivity to the drugs but the magnitude of this shift is greater for asthma than for COPD. Furthermore, the slope (reactivity) of the dose-response curve is greater with asthma than COPD and in asthma there may be no plateau in the curve. BHR is agent-specific. Generally, patients with asthma, not COPD, respond to eucapnic hyperventilation, and, among children with chronic airway diseases, only those with asthma respond to adenosine 5'-monophosphate.[21]

As clinicians, we tend to rely on other phenotypic characteristics to differentiate between asthma and COPD. These include response to bronchodilators and physiologic differences. Several differences exist between patients with asthma and patients with COPD in their responses to bronchodilators. Patients with asthma develop tolerance to short-acting beta agonists and they therefore should be dosed only on an as-needed basis. In patients with COPD, short-acting beta agonists are not associated with tolerance and should be dosed regularly.[22] In asthma, the use of long-acting beta agonists is associated with increased frequency of exacerbations but their use in COPD is associated with a decrease in the frequency of exacerbations. Anticholinergics have efficacy limited to acute exacerbations in asthma but are a mainstay of therapy in COPD.

Physiologic differences between asthma and COPD include abnormalities in elastic recoil and diffusion in COPD. In asthma these abnormalities do not occur. Hyperinflation that is associated with a volume dominant response to bronchodilators occurs in COPD whereas in asthma the bronchodilator response is flow dominant.[23] The hyperinflation occurs with premature closure of airways during exhalation that results in an increased residual volume that encroaches upon the vital capacity. Often patients with COPD who are not hyperinflated will become so with exertion as minute ventilation increases and time available for exhalation decreases. The diaphragms become flattened and the anterior-to-posterior diameter of the chest is increased, causing a mechanical disadvantage to breathing. The dyspnea experienced by patients with COPD is closely related to the degree of hyperinflation as measured by residual volume/total lung capacity.[24] Bronchodilators relieve this hyperinflation. The volume dominant response to bronchodilators in COPD is seen both with tiotropium[25] and fluticasone-salmeterol combination.[26] COPD subjects treated with tiotropium experienced an increase in vital capacity, and subjects treated with the fluticasone-salmeterol combination experienced an increased inspiratory capacity. Both of these changes are indicative of reduction of hyperinflation. Other differences between asthma and COPD in the response to bronchodilators are the magnitude of response as measured by FEV1 and the reproducibility of response. While both groups of patients respond to bronchodilators, the response of patients with asthma is quantitatively larger than that in COPD.[27] Furthermore, the response to bronchodilators in COPD is erratic as shown by Calverley and coworkers. Patients were evaluated for bronchodilator response on sequential visits. Roughly two thirds of patients responded to albuterol and Atrovent at every visit; however, patients shifted from visit to visit from the responder group to the nonresponder group.[28]

In summary, COPD does differ from asthma by quantity and reproducibility of bronchodilator response, slope of BHR dose-response curve, bronchodilator agent specificity, plateau of dose-response curve, and sensitivity to bronchodilator agent.

Radiologic Screening
Alan Fein, MD, presented "Is radiologic screening ready for prime time?" He noted that the stethoscope was invented in 1819 and the spirometer in 1842. These still remain as useful instruments to help diagnose COPD. Dr. Fein said that much of the morbidity and mortality resultant from COPD stems from its "comorbidities." These include coronary artery disease, lung cancer, and infections. Dr. Fein stated that 50% of patients with COPD have impairment of activities of daily living. The chest radiograph in COPD is often normal and correlates poorly with the magnitude of airways obstruction. Areas of hyperlucency are difficult to evaluate on radiography and computed tomography (CT) because of the inability to determine the normal areas with which apparent hyperlucency may be compared. Dr. Fein noted that although spectacular when present, the finding of low flattened diaphragms is uncommon in mild and moderate COPD. Other classic chest radiograph findings of COPD are an increased anterior-to-posterior diameter, and increased retrosternal airspace and upper lobe enhanced lucency. Because of the relative infrequency of these classic findings, chest radiography is not a sufficient diagnostic tool in COPD.

CT scan technology provides greater accuracy than plain radiographs especially with the use of high-resolution technology. This technology still underestimates the degree of emphysema in panacinar COPD. CT scanning is good in the detection of detect small lung cancers and non-COPD-associated airway obstruction such as proximal airway obstruction, bronchiectasis, and bronchiolitis obliterans. Quantitative CT scanning, which is currently under investigation, uses a density mask to highlight areas below a defined density threshold. It can be used to measure airway thickness and airtrapping. To date, airway thickness as measured by this technique correlates well with histologic specimens. Wall area and lumen area correlate with FEV1. Furthermore, quantitative difference between inspiratory and expiratory CT scans is a measurement of airtrapping. Finally, quantitative CT scanning aids surgical decision making in lung reduction and for excision of tumors.

Scientists Discover Key to Growing New Stem Cells

Scientists at Duke University Medical Center have demonstrated they can grow human stem cells in the laboratory by blocking an enzyme that naturally triggers stem cells to mature and differentiate into specialized cells.

The discovery may enable scientists to rapidly grow stem cells and transplant them into patients with blood disorders, immune defects and select genetic diseases, said the Duke researchers.

Stem cells are the most flexible cells in the body, continually dividing into New stem cells or into specialized cells that carry out specific roles in the body. But little is known about how stem cells choose their fate. The Duke team focused on "hematopoietic" or blood stem cells.

In their study, the investigators discovered that an enzyme, aldehyde dehydrogenase (ALDH), stimulates hematopoietic stem cells to mature and transform into blood or immune cells, a process called differentiation. They inhibited this enzyme in stem cell cultures and successfully increased the number of stem cells by 3.4 fold. Moreover, they demonstrated the New stem cells were capable of fully rebuilding the blood-forming and immune systems of immune-deficient mice.

Results of the study are published on line and will be published in the August 1, 2006, issue of the Proceedings of the National Academy of Sciences.

"Our ability to treat human diseases is limited by our knowledge of how human stem cells determine their fate - that is, whether they maintain their ability to self-renew or whether they go on to become specialized cells," said John Chute, M.D., associate professor of medicine in the Duke Adult Bone Marrow and Stem Cell Transplant Program. "Unraveling the pathways that regulate self-renewal or differentiation in human stem cells can facilitate our ability to expand the growth of human stem cells for therapeutic uses."

Currently, patients who require stem cell transplants are given either bone marrow from adult donors, umbilical cord blood derived from newborn babies, or stem cells from blood. But stem cells are scarce, representing less than 0.01 percent of the bone marrow cell population. Likewise, cord blood units frequently lack sufficient numbers of stem cells to rebuild a patient's decimated immune system.

Efforts to grow human hematopoietic stem cells in the laboratory have proven extraordinarily difficult, Chute said, because growth factors in culture make stem cells rapidly differentiate. The scientists searched for ways to block a stem cell's natural propensity to differentiate without promoting uncontrolled growth.

The researchers focused on the ALDH enzyme because it is a telltale "marker" that distinguishes stem cells from other blood and immune cells. Moreover, it is known to play an essential role in the body's production of retinoic acids, which regulate cell differentiation in a variety of tissues. Yet how ALDH functions in stem cells remained unknown, Chute said.

The scientists began by analyzing how stem cells behave under normal circumstances when grown in culture. They mixed together purified human stem cells with growth factors that induce stem cells to mature and differentiate. As expected, the stem cells showed a marked decline in number as they differentiated into other types of specialized cells. By day seven, all stem cells had disappeared from culture.

The scientists then added an inhibitor of ALDH to the stem cell cultures, and they found that half of the stem cells maintained their immature and undifferentiated status. Moreover, adding the inhibitor caused a 3.4-fold increase in stem cell numbers within seven days.

Next, the scientists transplanted the cultured stem cells into immune-deficient mice to determine how the stem cells would behave. The New population of stem cells migrated to the bone marrow as expected and successfully "engrafted," or took hold in the bone marrow, where they began to produce New blood and immune cells.

"ALDH appears to play a fundamental role in the differentiation program of human hematopoietic stem cells," Chute said. "Inhibition of this enzyme facilitates the expansion of human hematopoietic stem cells in culture."

Chute said their results reveal a unique role for both ALDH and the process of retinoic acid signaling in human stem cells. Chute and colleague Donald McDonnell, Ph.D., professor of pharmacology and cancer biology, are currently testing whether they can directly block the retinoic acid receptors in stem cells and produce a comparable expansion of human stem cells.

The investigators plan to develop a clinical trial to test their approach to expand human stem cells for therapeutic purposes.

Genetic Variant Raises Risk of Prematurity in African-American Babies

By Crystal Phend, Staff Writer, MedPage Today
Reviewed by Robert Jasmer, MD; Assistant Professor of Medicine, University of California, San Francisco
August 28, 2006

Explain to interested patients that this study found having a particular genetic variant confers greater risk of premature birth because of preterm, premature rupture of the amniotic membrane.


Caution patients that while this study confirmed an association between this genetic variant and amniotic rupture for African American women, it did not look at whether it increased the risk for other ethnicities
RICHMOND, Va., Aug. 28 -- A single genetic variation may help explain why African American women have a higher risk of having premies because of early rupture of the amniotic membrane.

Presence of the genotype, called -the SERPINH1 gene -656 minor T allele, significantly raised the risk of preterm, premature rupture, (PPROM) particularly in African American women, reported Jerome F. Strauss III, M.D., Ph.D., of the Virginia Commonwealth University, and colleagues, in the Proceedings of the National Academy of Sciences.


Preterm birth is known to be two to three times more common in African American than European-American women, but socioeconomic status and access to health care do not fully explain the difference, the authors said.


When Dr. Strauss's group looked at ethnic distribution in more than 900 participants with ancestry from around the world, they found the T allele was significantly more common in African-American individuals compared with European-Americans (12.4% versus 4.1%, P<0.024).


PPROM is the leading identifiable cause of preterm birth and occurs in about 3% of all pregnancies and one-third of all preterm births. Knowledge of this genotype -- could be used to identify women who might benefit from therapeutic interventions, such as lifestyle change or Medical therapy before onset of preterm labor, the investigators wrote.


Dr. Strauss and colleagues found that the T allele of the gene, which is less common than the C allele, reduces production of a protein essential for collagen synthesis in the amnion fibroblasts therefore reducing the strength of the amnion membrane and making it more prone to rupture early in the pregnancy.


Two case-control studies by the investigators also found association of the genetic variant with preterm birth due to rupture of the amniotic membrane.


In the first, the T allele was found in 11.51% of 152 African American babies who were born prematurely due to complications involving rupture of the amniotic membrane compared to 4.05% of 174 controls born at term in normal pregnancies (P<0.0009). Furthermore, C/T allele heterozygotes were 2.68 times more likely to experience premature birth for this reason than C/C homozygotes while T/T allele homozygotes had an even greater risk (odds ratios 2.68 compared to C/T allele heterozygotes).


Likewise, the second case-control study on a separate sample of 92 premature rupture cases and 194 controls again showed a significant association between preterm, premature birth due to amniotic rupture and presence of the T allele (P<0.0076) even controlling for differences in ancestry using 29 ancestry-informative markers.


In vitro and animal tests also indicated that the T allele reduced transcription of the SERPINH1 gene compared with the C allele.


Interestingly, while the genetic variant decreased collagen in amniotic fibroblasts compared with the C allele, in vitro tests showed that it had "higher activity" in skin fibroblasts and uterine smooth muscle cells.


"Because both keloids, a fibrotic response in skin, and uterine fibroid tumors, which have a dense collagen matrix, are more prevalent in African Americans, it is intriguing to speculate that a single SNP could contribute to multiple phenotypes," Dr. Strauss and colleagues wrote.


In a related commentary, Jeremy F. Taylor, Ph.D., of the University of Missouri in Colombia, and colleagues said the study provided compelling evidence for "the first ancestry-informative mutation responsible for an increased risk of preterm premature rupture of membranes" in African-Americans.


They cautioned that the study does not answer whether the presence of the T allele is associated with increased risk of premature amniotic rupture in European-Americans.

Primary source: Proceedings of the National Academy of Sciences
Source reference:
Wang H, et al "A functional SNP in the promoter of the SERPINH1 gene increases risk of preterm premature rupture of membranes in African Americans" Proc Natl Acad Sci USA 2006.

Additional source: Proceedings of the National Academy of Sciences
Source reference:
Taylor KH, et al "Impaired chaperone compromises collagen PPROM queen" Proc Natl Acad Sci USA 2006.

75 million people suffer from chronic pain in America

Walking from Chicago to Los Angeles to raise public awareness about chronic pain, Dennis Kinch, a chronic pain survivor and inspirational speaker was hosted by Dr. Ripu Arora and the Torrance based Peninsula Pain Management Center July 12.

"I've had doctors tell me I'm just a drug addict using drugs for pain they thought didn't exist," said Kinch to a lobby filled with listeners.
“One thing I tell doctors is that if your patients say they are in pain, believe them." Kinch emphasized that chronic pain can be so bad it often drives individuals to suicide, citing a friend who recently killed himself because of the agony he lived with every day.

Kinch, himself, shared that he knew what it was like to feel suicidal about his own pain. "I'm living proof that it doesn't have to be that way anymore because with the right attitudes and understanding you can win the battle of chronic pain that 75 million Americans currently live with," said the former graphic artist.

Kinch's host, Dr. Arora, who was originally an anesthesiologist and then moved into the pain management sector of medicine, agreed: "This is a growing field of integrated pain management where we try to help the patient deal with chronic pain as it affects his or her whole life," said Dr. Arora who pointed to New technologies in the Medical field that allow better pain management than in the past.
“For example, in the spinal area we can treat small disc problems without major surgery by inserting a needle to release fluid and ease discomfort, so there are all sorts of New technologies."

Dr. Arora invited Kinch to speak at his offices because he has been providing chronic pain management service in the South Bay for over 12 years with eight years of experience in training and practice of orthopedic and general surgery. "Pain that persists despite routine Medical management will usually pose difficult problems for patients and their doctors," said Arora. "If this pain continues despite Medical care, there is an increasing probability of physical disability, psychosocial dysfunction, drug dependence and development of chronic pain," he said.

Referring to his example of small disc therapy in the spine, Arora underscored that recent advances in pain management technology along with New understanding of the anatomy and physiology of pain now make it possible to accurately diagnose and effective treat pain previously thought untreatable.

Kinch displayed a self-portrait of himself before his New treatment to underscore the pain he was going through, partly to demonstrate the emotional level of pain that is interconnected with the physical struggle. "Some patients benefit with psychological counseling for their pain and personal lives, because pain will influence your total life," said Kinch. Dr. Arora agreed, saying that many insurances now pay for psychological counseling related to chronic pain, however he said workers compensation claims often do not support psychological counseling as they take a more cynical and suspicious attitude toward 'holistic pain management.' "But the field is changing with a more holistic approach," assured Arora.

One member of the audience said his wife threatened to divorce him if he didn't get help for his pain. But Genevieve Kowalewski, another member of the audience and a client of Dr. Arora's, who is 81, said she is living proof of the positive battle against chronic pain. "My life has really improved and I'm able to do all sorts of things with the therapies I've received with Dr. Arora."

Kinch, who says his only medication is now the drug Neurontin, acknowledged that chronic pain sufferers have good days and bad days. He encouraged pain sufferers to graph their pain experience on a daily basis to better understand it and to share this with their doctors as a way of addressing therapies. He also pointed out that "pain tolerance" on particular days would also affect how the individuals experiences pain. "If you have a low pain tolerance day, you may find it very hard to handle pain that day," he said. He also encouraged his listeners to not give up the fight. "There are a lot of 'old school' attitudes still out there in the Medical field. One doctor who I showed my pain graph to wrote that I was obsessed with my pain and needed counseling."

Alzheimer's Disease: Researchers Move Towards Prevention

A recent study directed by Mount Sinai School of Medicine identifies a faulty molecule in the brain found in cases of mild cognitive impairment (MCI). Researchers say this faulty molecule may be responsible for the progression of MCI to mild Alzheimer's disease (AD) dementia. The study, which appeared June 10th online in the Journal Neurobiology of Aging, may lead to preventative treatments for AD.

An estimated 4.5 million Americans have Alzheimer's disease and presently there are no known cures or effective preventive strategies.

"Alzheimer's Disease is a growing health concern that affects millions of people, "says Giulio Maria Pasinetti, M.D., Ph.D., Professor of Psychiatry and Neuroscience, Director of the Neuroinflammation Research Center at Mount Sinai School of Medicine and lead author of the study. "We hope our research provides direction for preventative treatments to delay the onset of AD dementia by eliminating amyloid plaque-causing peptides in the brain."

People with AD exhibit elevated levels of beta-amyloid peptides that cause plaque buildup in the brain (the main characteristic of AD). In the earliest stages of Alzheimer's, beta-amyloid peptides are on the rise, especially in the two connected brain regions critical for memory functions-- the hippocampus and entorhinal cortex.

In this study, Dr. Pasinetti and colleagues at Mount Sinai School of Medicine in New York suggests one reason for that early increase of beta-amyloid peptides: an enzyme that breaks down beta-amyloid peptides, also referred to as an insulin-degrading enzyme (IDE), is not active in the brain in the cases at high-risk for developing AD. To assess possible changes in IDE during MCI, the investigators measured protein levels and enzymatic activity in postmortem brain tissue from 46 elderly subjects.

Implications

A loss of IDE activity has been previously shown to occur in severe AD dementia, and the current results raise the possibility that a deficit in degradation of amyloid peptides from IDE could raise levels of toxic beta-amyloid peptides even before AD dementia is diagnosed. If these results are confirmed, Mount Sinai researchers suggest that boosting IDE activity pharmacologically may reverse beta-amyloid peptide accumulation. This New finding may provide a pharmacological therapeutic angle to preventing AD dementia.

Dr. Pasinetti and colleagues also measured levels of beta-amyloid peptides in the entorhinal cortex and found that the amount of beta-amyloid was inversely correlated with IDE activity they measured in the hippocampus. These results support the idea that alterations in IDE might be causally related to beta-amyloid peptides accumulation, starting in the earliest stages of AD.

###

Mount Sinai School of Medicine

Located in Manhattan, Mount Sinai School of Medicine is internationally recognized for ground-breaking clinical and basic-science research, and innovative approaches to Medical education. Through the Mount Sinai Graduate School of Biological Sciences, Mount Sinai trains biomedical researchers with an emphasis on the rapid translation of discoveries of basic research into New techniques for fighting disease. One indication of Mount Sinai's leadership in scientific investigation is its receipt during fiscal year 2005 of $174.1 million in research support from the NIH. Mount Sinai School of Medicine also is known for unique educational programs such as the Humanities in Medicine program, which creates opportunities for liberal arts students to pursue Medical school, and instructional innovations like The Morchand Center, the nation's largest program teaching students and physicians with "standardized patients" to become not only highly skilled, but compassionate caregivers. Long dedicated to improving its community, the School extends its boundaries to work with East Harlem and surrounding communities to provide access to health care and educational programs to at risk populations.

Contact: Mount Sinai Press Office
The Mount Sinai Hospital / Mount Sinai School of Medicine





Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Teen mothers deserve a hopeful future

Too many Latina teenagers have little or no access to information about their own health and sexuality, or access to Medical care to protect themselves from unwanted pregnancy. They are having babies at a much higher rate than black and white girls, and as teenage mothers they face daunting obstacles.
As parents and as a society, we must hold both the young woman and young man responsible for an unwanted pregnancy. At the same time,we must help these young women as they struggle to finish school, work, pay the bills, and raise a child at a time when they themselves are still not finished growing up.

Teen pregnancy changes a girl`s life, but we must not allow it to end her chances for a happy and successful future.

To begin with, young girls need straightforward information about human sexuality and reproduction, and we are doing a poor Job of providing it. Just last month a group of girls at a Bronx middle school circulated a petition demanding sex education classes. We latinos must get past our embarrassment and taboos. We must talk to our teenagers about preventing pregnancy and the spread of sexually transmitted diseases by practicing abstinence, and by using condoms and birth control.

We live in a society that claims to honor the family, yet it is hard to find affordable child care and other services. Many teenage mothers drop out of high school because they cannot find adequate child care, a contributing factor in the high dropout rate among all Latinos.

As an El Diario/ La Prensa series has shown, the pressures of growing up Latina and living in paradoxical worlds lead to many struggles for these young women. In addition to a high pregnancy rate and a high dropout rate, Latinas have the highest attempted suicide rate of any adolescent group.

Teenage mothers may face the hardest struggles of all. We all bear the responsibility to help them make it.


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Simple Screening Tool Identifies Risk of BRCA Mutations

By Peggy Peck, Managing Editor, MedPage Today
Reviewed by Robert Jasmer, MD; Assistant Professor of Medicine, University of California, San Francisco
September 11, 2006

Explain to interested patients that the screening tool described in this study has not been validated by studies in other institutions.


Explain to interested patients that BRCA1/2 mutations account for only 2% to 3% of all breast cancers.

ROCKFORD, Ill., Sept. 11 -- Women who might benefit from tamoxifen chemoprevention because of an increased risk of hereditary breast cancer can be identified by a five-item assessment at a mammography clinic, suggested researchers here.

A score of eight or higher on the pedigree assessment tool had a sensitivity of 100% and a specificity of 93% for identifying women at risk for BRCA1 or BRCA 2 breast cancer susceptibility mutations, reported Kent F. Hoskins, M.D., of Saint Anthony Center for Cancer Care here, and colleagues, online in Cancer.


Moreover, the pedigree assessment tool score performed better than the Gail model, a tool that is commonly used for calculating individualized risk estimates to identify women for tamoxifen therapy, Dr. Hoskins and colleagues said. Their findings will appear in the Oct. 15 issue of the Journal.


The pedigree assessment tool system assigns arbitrary numerical values to pedigree findings. For example, a family history of breast cancer after age 50 is scored at three points, while cancer younger than 50 receives four points. The score for a Male relative with breast cancer is eight, Ashkenazi Jewish heritage adds four points and ovarian cancer at any age tallies five points.


The points are added up for both the maternal and paternal pedigrees and the woman's pedigree assessment tool score is the higher of the two scores.


Dr. Hoskins and colleagues tested the pedigree assessment tool assessment with 3,906 women who had screening mammography at a community hospital. The women had no personal history of breast cancer.


The researchers used a risk assessment model available online, known as the Frank model, that relies on prevalence data to identify women at risk for BRCA mutations, with high risk defined as a 10% or greater risk of BRCA. Using that model, 86 women were identified as a high BRCA possibility.


Dr. Hoskins then analyzed the ability of the PAT score and the Gail model to identify these same 86 women.


The tests were compared by plotting a receiver operating characteristic (ROC) curve for the pedigree assessment tool test and two Gail tests-the five year estimate and the lifetime estimate. The ideal area under the ROC curve would equal 1.0, so the test that comes closest to that ideal is the superior test.


The area under the ROC curve for pedigree assessment tool was 0.9625 versus 0.389 for the Gail 5-year estimate and 0.5861 for the Gail lifetime estimate.


The Gail model was not designed as a specific assessment for hereditary risk. But the authors said that other assessment tools designed specifically for that purpose are not suitable for use in a population-based screening setting such as a mammography clinic. The Gail model, however, works well in that setting, so it was selected as the comparator arm.


Another potential limitation was the authors' decision to use the Frank model as a gold standard against which they measured pedigree assessment tool and the Gail models. But Dr. Hoskins pointed out that the Frank model has the largest published data set, and it used the most accurate genetic testing technique. The Frank population was "most similar to our population."


The authors noted that the FDA-approved recommendation for tamoxifen chemoprevention is based on a Gail risk estimation.


But they conclude that combining the Gail model with a tool like the pedigree assessment tool would improve comprehensive breast cancer screening. It could "serve a triage function to identify women at moderate levels of risk who do not require a formal genetic evaluation, but would be candidates for chemoprevention."

Primary source: Cancer
Source reference:
Hoskins KT "Validation of a tool for identifying women at high risk for hereditary breast cancer in population-based screening" Cancer, 20006; 000:000-000


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Data Presented Indicates Escitalopram may be a Promising Future Treatment Option in Obsessive Compulsive Disorder

Data Presented Indicates Escitalopram may be a Promising Future Treatment Option in Obsessive Compulsive Disorder

PARIS, France, Sept. 19, 2006 /PRNewswire/ -- New data presented today demonstrates that escitalopram is efficacious and well tolerated in the treatment of Obsessive Compulsive Disorder (OCD) with encouraging rates of remission and relapse prevention.(1,2) Presented at a satellite symposium on the occasion of the 19th ECNP Congress in Paris, France, supported by an unrestricted educational grant from Lundbeck, the data suggests that escitalopram may be a promising future treatment option for this common and debilitating condition.

OCD is a chronic, highly debilitating disorder that is characterised by recurrent, distressing thoughts and impulses (obsessions) and/or repetitive behaviours (compulsions).(3) It is the 10th leading cause of disability of all Medical conditions in the industrialised world and affects all aspects of quality of life.(4) Although 50-60% of patients currently respond to treatment, only a minority achieve remission.(5)

"Effective treatment for OCD is vital and achieving remission should be the minimum goal of therapy to avoid relapse and achieve full patient recovery", said Prof Naomi A Fineberg, Consultant Psychiatrist and Honorary Senior Lecturer, Imperial College London and University of Hertfordshire. "These New data suggest that escitalopram is effective for acute and long-term treatment and relapse prevention in OCD and deserves to be considered as one of the first-line agents for OCD treatment."

Obsessive spectrum disorders over the life cycle - Lundbeck-supported satellite symposium

Lead investigators Prof Dan J Stein and Prof Fineberg presented findings from the first randomised controlled trial of escitalopram in the treatment of OCD.(1) The 24-week study investigated the efficacy and tolerability of escitalopram and found that:

- Both 10 and 20mg/daily escitalopram were efficacious and well-tolerated in the treatment of OCD(1)

- Compared with placebo, escitalopram 20mg/day was associated not only with lower symptoms scores mid-way through the study but also with earlier onset, increased response and increased remission rates(1)

Data from a separate randomised, double-blind, placebo-controlled relapse prevention study conducted by Stein and Fineberg was also presented and the results further demonstrated the ability of escitalopram to prevent relapse.(2) The study was designed to compare the efficacy of escitalopram with that of placebo in preventing relapse over 24 weeks in outpatients with OCD who had responded to 16 weeks prior open-label treatment with escitalopram.(2)

Results included:

- Escitalopram 10 or 20 mg/day was well tolerated and significantly reduced the risk of relapse in patients with OCD, had an anti-OCD effect during 16 weeks of open-label treatment and a significant relapse-preventing effect during continued treatment up to 24 weeks(2)

- The primary efficacy analysis showed a statistically significantly superior effect of escitalopram relative to placebo on the time to relapse of OCD, with a 52% rate of relapse in the placebo group versus a 23% rate in the escitalopram group(2)

Driving forward the optimal management of OCD

OCD was the focus of a recent consensus group review at the International Anxiety Disorders Conference (IADC) in Cape Town, South Africa in February 2006. The group, which included Stein and Fineberg reviewed the currently available scientific data on the symptomatology, diagnosis, assessment, psychobiology and treatment of OCD in order to provide an up-to-date summary of the literature and enable them to make recommendations for treating physicians.(6)

"Due to the chronic Nature of OCD and its severe impact on quality of life, it is essential that those living with the disorder receive long-term care and effective treatment," said Prof Stein, Chair, Department of Psychiatry, University of Cape Town and Director of the Medical Research Council Unit on Anxiety Disorders, University of Stellenbosch, South Africa. "This is why we felt it vital to convene a group of experts to assess the current management of OCD and to develop recommendations to improve the ongoing management of this disabling condition."

The consensus also looked at the current controversy surrounding the classification of OCD and whether it should be classified as an anxiety disorder or if classification within the group of Obsessive Compulsive Spectrum Disorders (which includes body dysmorphic disorder, pathological gambling, certain eating disorders and autism) would be more appropriate.(6,7)

The content of this release will have no influence on the Lundbeck Group's financial result for 2006.

About Lundbeck

H. Lundbeck A/S is an international pharmaceutical company engaged in the research and development, production, marketing and sale of drugs for the treatment of psychiatric and neurological disorders. In 2005, the company's revenue was DKK 9.1 billion (approximately EUR 1.2 billion). The number of employees is approx. 5,000. For further information, visit http://www.lundbeck.com/

Notes to Editors:

OCD affects between 2-3% of the general population(6) and is associated with significant functional disability and economic costs.(1) OCD has a number of manifestations but involves having both obsessions and compulsions. A common obsession is around dirt, germs and contamination. As compulsions are acts performed repeatedly in hopes of obtaining relief from obsessions, those with OCD may wash compulsively to the point that their hands become raw and inflamed.

- Up to 2/3 of individuals with OCD suffer from co-morbid depression at some time during their illness(8)

- Symptomatology often starts as early as childhood or adolescence and affects a majority of the patients for their whole life, requiring long-time care and treatment(9)

- OCD affects men and women equally(3)

- OCD often goes unrecognised. On average, people with OCD see three to four doctors and spend 9 years seeking treatment before they receive a correct diagnosis. Studies find that it takes an average of 17 years from the time OCD begins for people to obtain appropriate treatment(10)

References

1. Stein DJ, Tonnoir B, Andersen EW, Fineberg NA. Escitalopram in the treatment of obsessive-compulsive disorder. 159th Annual Meeting American Psychiatric Association, May 2006, Toronto

2. Fineberg NA, Lemming O, Stein DJ, Tonnoir B. Escitalopram in relapse prevention in patients with obsessive-compulsive disorder. 159th Annual Meeting American Psychiatric Association, May 2006, Toronto

3. Obsessive Compulsive Disorder. National Institute of Mental Health (NIMH). Last accessed on 23.08.06 from http://www.nimh.nih.gov/Publicat/ocdfacts.cfm

4. Eisen JL, Mancebo MA, Pinto A, Coles ME, Pagano ME, Stout R, et al. Impact of obsessive-compulsive disorder on quality of life. Comprehensive Psychiatry 2006; 47 (4); 270-5.

5. Ballenger JC. Remission rates in patients with anxiety disorders treated with paroxetine. J Clin Psychiatry. 2004 Dec; 65(12):1696-707

6. Stein DJ et al, "The Cape Town Consensus Statement," International Anxiety Disorders Conference, Cape Town, South Africa, February 2006.

7. Bartz JA, Hollander E. Is obsessive compulsive disorder an anxiety disorder? Prog Neuropsychopharmacol Biol Psychiatry 2006 May; 30(3): 338-52

8. Fineberg NA, Johansen T, Chamberlain SR. Depression within OCD: from neurobiology and clinical responses toward endophenotypes. University of Hertfordshire, Hatfield, UK.

9. Hollander E. Anxiety and OC spectrum disorders. Mount Sinai School of Medicine, New York USA.

10. About OCD. Obsessive Compulsive Foundation. Last accessed on 23.08.06 from http://www.ocfoundation.org/what-is-ocd.html

H Lundbeck A/S
CONTACT: For more information, or to arrange an interview with Prof
Stein or Prof Fineberg, please contact: Sven Schellberg, Group Medical
Marketing Manager, H.Lundbeck A/S,.: Tel +45-36-43-43-25, Mobile:
+45-30-83-43-25, E-mail: svsc@lundbeck.com; Paul Gittins, Ruder Finn UK Ltd,
Tel: +44(0)207-462-8922, Mobile: +44-7958-533-462, Email:
pgittins@ruderfinn.co.uk




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

FDA Approves Antipsychotic Drug for Irritability in Autistic Children

ROCKVILLE, Md., Oct. 9 -- The FDA has approved Risperdal (risperidone), an adult antipsychotic agent, for symptomatic treatment of irritability in autistic children and adolescents.
Risperdal, marketed by Janssen, is the first drug approved for this indication. Aggression, deliberate self-injury, and temper tantrums were the behaviors identified for Risperdal treatment.

Steven Galson, M.D., director of the FDA's Center for Drug Evaluation and Research, characterized the approval as part of an FDA initiative to encourage the "development of appropriate pediatric labeling for adult drugs," once the drugs have demonstrated an appropriate risk-benefit profile when tested in children.

Risperdal has been approved since 1993 for the short-term treatment of adults with schizophrenia, and since 2003 for the short-term treatment of adults with acute manic or mixed episodes associated with extreme mood swings.

The product's effectiveness in the symptomatic treatment of irritability associated with pediatric autistic disorders was established in two eight-week, placebo-controlled trials in 156 patients ages five to 16, 90% of them five to 12.

The results, which were evaluated using two assessment scales, showed that children taking Risperdal achieved significantly improved scores for certain behavioral symptoms of autism compared with children on placebo. The most common side effects of the use of Risperdal included drowsiness, constipation, fatigue, and weight gain.


Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Woman crosses disability barrier

Sunday, October 08, 2006
By NANCY H. GONTER
ngonter@repub.com
NORTHAMPTON - Claudia Moore O'Brien's apron is more than just something that holds everything she needs when her hands are busy with her crutches.

The apron, featured in her New children's book "My Mom's Apron," illustrates how people can handle any problem they are dealt.

"The reason I wrote it is I wanted to give people ideas that if something in your life is difficult, like your hands are filled with crutches, you try to find other ways to do things," Moore O'Brien told a group of third-graders recently after she read her book to them at R.K. Finn Ryan Road School.

Advertisement






"My Mom's Apron," the first book for Moore O'Brien, who is a graphic designer, tells about her own experience of being a single mother with a disability raising a small daughter. That daughter, Olivia Caraher, is now 15 and a 10th-grader at Northampton High School.

The book tells how Moore O'Brien used an apron that once belonged to a friend who was a waitress and had lots of pockets, to hold all the things she needed, such as the telephone, biscuits for the dog, Zelly, and even the feather duster.

Moore O'Brien, 54, had polio when she was 5. It left her with one leg that is very weak and has a brace on it. She uses both crutches and a wheelchair, and told children that she has different-colored crutches and wheelchairs, including blue and red chairs.

She made it clear to children that there are few things she can't do because of her disability. She explained how she can take airplanes and will go to California next week. She also plays tennis and skis downhill using a special ski.

Pupils who heard Moore O'Brien read her book said they thought it was cool she wrote a book and they were amazed by some of the things she can do.

"I thought it was a good book. It was cool because she did it about her and how she had an apron and used it to hold the things she needed," said Brenna L. Gompper, 8, a third-grader.

Fellow third-grader Raven J. Cerina, also 8, said he liked the apron because it could hold anything. He was impressed that Moore O'Brien could participate in sports.

"That sort of amazed me. I never knew that," he said.

Moore O'Brien's book is available through her Web site www.artvandelayart.com for $6 and will soon be at local bookstores.



Saludos Cordiales
Dr. José Manuel Ferrer Guerra

FDA Adds Brain Bleed Warning to Avastin (bevacizumab) Label

ROCKVILLE, Md., Sept. 26 -- The FDA has alerted physicians to a New label change for the anti-angiogenic colorectal-cancer drug Avastin (bevacizumab) that cites rare cases of a reversible posterior leukoencephalopathy syndrome.
The brain-capillary leak syndrome has been reported or confirmed in less than 0.1% of the estimated 60,000 cancer patients treated with Avastin, said Genentech, which markets Avastin.

The warning about reversible posterior leukoencephalopathy was added to the Adverse Reactions and Dosage and Administration sections of the Avastin label.

The FDA also added information about nasal septum perforation to the Adverse Events, Other Serious Adverse Events section of the label. In a letter to clinicians, Genentech said there have been seven cases of nasal septum perforation reported in post market surveillance.

Reversible posterior leukoencephalopathy syndrome is associated with hypertension, fluid retention, and the cytotoxic effects of the immunosuppressive drugs on the vascular endothelium.

J. Leonard Lichtenfeld, M.D., deputy Medical director of the American Cancer Society in Atlanta, said this not the first time that the anti-angiogenic agent has been linked with bleeding problems. He noted, for example, the perforated colon has been reported in Avastin colorectal cancer studies.

"This is exactly the reason that post marketing surveillance is so important for all drugs and especially for chemotherapy drugs," Dr. Lichtenfeld said.

Avastin, he said, "typically is given to patients with advanced disease and aggressive tumors," a patient population that is compromised by disease and thus at higher risk for side-effects.

Reversible posterior leukoencephalopathy usually presents with "headache, seizure, visual disturbance, and altered mental function, and is characterized by reversibility upon control of hypertension or other instigating factors," according to the Genentech letter to clinicians.

Although mild to severe hypertension is usually present with the syndrome, it is not necessary for a diagnosis of reversible posterior leukoencephalopathy. The onset of symptoms has been reported to occur within 16 hours to one year of initiation of Avastin treatment.

Magnetic resonance imaging studies are needed to confirm diagnosis.

Avastin should be stopped in patients who develop symptoms of reversible posterior leukoencephalopathy and, if necessary, hypertension treatment should be initiated.

Symptoms "usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae," according to Genentech.

Finally, the company said it is not known whether Avastin can safely be reinitiated in patients who developed reversible posterior leukoencephalopathy syndrome.

The company said it began reviewing safety data for Avastin after the brain leak syndrome was described in two letters were published in a March issue of the New England Journal of Medicine.




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Novartis Hepatitis B Drug Sebivo Gets Swiss Approval

BASEL -(Dow Jones)- Pharmaceutical company Novartis AG (NVS) Thursday said its hepatitis B drug Sebivo has been cleared by Swiss health authorities.

Sebivo, or telbivudine, a New treatment for patients with chronic hepatitis B shown to deliver more rapid and profound viral suppression than lamivudine, has received approval in Switzerland. This important approval provides access to an innovative New therapy for Swiss patients but also supports expanded regulatory submissions. More than 100 countries worldwide look to the approval of a medicine in the company's home country to serve as a reference for local regulatory reviews.

A single pill taken orally once daily with or without food, Sebivo has been shown to effectively suppress replication of the hepatitis B virus.

Approximately 350 million people worldwide are living with chronic hepatitis B, a virus that affects the liver and is estimated to be 50 to 100 times more infectious than human immunodeficiency virus, or HIV. Hepatitis B virus can cause chronic lifelong infection, which can lead to several liver conditions - including cirrhosis, cancer or organ failure - and death. Hepatitis B is the second most common cause of cancer after smoking, with 1.2 million people estimated to die annually from hepatitis B-related chronic liver disease.

Applications for approval were filed with the US Food and Drug Administration in late 2005 as well as with the European Medicines Agency and the Chinese health authority in the first quarter of 2006. A different trademark for telbivudine in the US is currently under discussion.

The approval of Sebivo is based primarily on one-year data from the GLOBE study, the largest worldwide registration trial ever conducted in patients with chronic hepatitis B. This two-year Phase III clinical trial compared Sebivo with lamivudine in the treatment of 1,367 adults with chronic hepatitis B at 112 clinical centers in 20 countries.

Results from GLOBE indicate that Sebivo produces significantly greater viral suppression on a number of virologic markers compared to lamivudine after one year in both chronic hepatitis B e-antigen positive and negative patients. Two-year data from the GLOBE study is planned to be presented at the American Association for the Study of Liver Disease meeting in Boston Oct 30.

Sebivo is being developed in collaboration between Idenix Pharmaceuticals Inc (IDIX) and Novartis Pharma AG under a development and commercialization arrangement established in May 2003, along with another hepatitis B clinical product candidate, valtorcitabine. The collaboration arrangement further provides that Idenix and Novartis will co-promote Sebivo and valtorcitabine and other product candidates that Novartis has licensed, upon successful development and approval, in the US, France, Germany, Italy, Spain and the UK.

Novartis holds the exclusive license to commercialize Sebivo and valtorcitabine in the rest of the world. In March 2006, Novartis expanded its collaboration with Idenix to include valopicitabine for the treatment of chronic hepatitis C.

Company Web Site: http://www.novartis.com

-Zurich Bureau, Dow Jones Newswires; +41 43 443 8040; zurichdjnews@dowjones.com

(END) Dow Jones Newswires

September 21, 2006 01:43 ET (05:43 GMT)



Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Pfizer's Anti-Smoking Pill Champix Approved in Europe

- More Than 1.2 Million Europeans Die of Smoking-Related Diseases Each Year; WHO Estimates the Annual Financial Burden of Smoking in Europe at $165 Billion (euro 130 Billion) by 2010

NEW YORK, September 29, 2006 /PRNewswire-FirstCall/ -- Pfizer Inc said today that the European Commission has approved Champix(R) (varenicline), a novel pill for smoking cessation in adults. In addition, because smokers often need considerable support to quit successfully, Champix will be available with a patient support plan which smokers can customize to address their individual behavioral triggers as they try to quit smoking.

Smoking is a chronic relapsing Medical condition that typically involves a physical and psychological addiction to nicotine. In Europe alone, more than 1.2 million people die each year from smoking-related diseases. In addition to the human toll, there is a significant social and economic cost associated with smoking. By 2010, the World Health Organization predicts the annual global cost of tobacco-related illness will be approximately $500 billion, with Europe accounting for up to $165 billion of this sum. While most smokers recognize the significant health risks associated with smoking, research shows that without adequate behavioral therapy and environmental support, most smokers relapse within a few days of trying to quit and few are able to remain quit.

"Champix provides a unique and New treatment that was specifically designed to help people stop smoking," said Dr. Michael Berelowitz, Pfizer Worldwide Medical. "Most smokers do not continue to smoke out of choice, but because they are addicted to nicotine in tobacco. Prior research has shown that the combination of behavior counseling and drug therapy is often more effective and cost-effective as health interventions than attempting to quit unaided. To meet these needs Pfizer will go beyond offering a New treatment by also providing customized behavioral support through a program designed to help smokers in the quit process."

Discovered and developed by Pfizer, Champix is specifically designed as an aid to smoking cessation. It is believed to work by reducing the severity of the smoker's urge to smoke and alleviating many withdrawal symptoms from nicotine. Moreover, if a person smokes a cigarette while receiving treatment, the medicine has the potential to diminish the sense of satisfaction associated with smoking.

Many European governments have instituted tobacco control policy changes that help create a more supportive environment for smokers who want to quit. These policies include bans on tobacco advertising and sponsorship, stronger public health warning labels, and smoking bans in all workplaces, including restaurants, bars and pubs. Comprehensive workplace smoking bans have already been approved in Ireland, Italy, Malta, Norway, England, Scotland, Belgium and Lithuania. Similar policies are being considered in France, Germany and other countries.

"Public health campaigns have increased people's understanding of the harmful health effects of smoking so that smokers are educated and more motivated to quit. In addition, more smokers are trying to quit today as a result of smoke-free policies in Europe and they need our support," said Professor Bertrand Dautzenberg, Service of Pneumology and Intensive Care, Hospital Pitie-Salpetriere, Paris. "With Champix's approval, healthcare professionals and smokers have a New treatment advance to help address this challenging addiction."

The approval of Champix(R) (varenicline) was based on a comprehensive clinical trial program including four pivotal trials involving approximately 4,000 cigarette smokers. Subjects on average had smoked about 21 cigarettes per day for an average of approximately 25 years. In two identically designed studies, patients receiving a 12-week course of varenicline therapy (1 mg twice daily) had nearly four times the odds of quitting versus those taking placebo and had nearly twice the odds of quitting versus those patients taking bupropion SR (150 mg twice daily), at the end of the 12-week course of therapy. Patients in these studies were also provided with educational materials and received brief smoking-cessation counseling at each clinic visit. Patients were followed for an additional 40 weeks without treatment. After one year, approximately one-in-five patients who received the 12-week course of varenicline remained smoke-free. For those patients who quit at the end of 12 weeks with varenicline, a separate study showed that an additional course of 12 weeks treatment with varenicline resulted in a greater likelihood of long-term success in quitting smoking.

In trials, varenicline was generally well tolerated, with overall discontinuation rates similar to placebo (11.4% for varenicline vs. 9.7% for placebo). The most common side effects included nausea, abnormal dreams, headache, insomnia, constipation, gas and vomiting.

This medication, varenicline, received U.S. Food and Drug Administration approval as an aid to smoking cessation treatment in May 2006 (with tradename Chantix(TM) (varenicline) in the United States).

CONTACT: Shreya Prudlo, +1-212-733-4889, or Oliver Stohlmann, Europe,+43-664-3350485, both for Pfizer Inc

Web site: http://www.pfizer.com/

Company News On-Call: Pfizer's press releases are available through PR Newswire's Company News On-Call service on PRN's Web Site. Visit http://www.prnewswire.com/comp/688250.html /

Ticker Symbol: (:PFE)

Terms and conditions of use apply
Copyright © 2006 PR Newswire Association LLC. All rights reserved.
A United Business Media Company



Saludos Cordiales
Dr. José Manuel Ferrer Guerra

A Raw Egg in the Eye Is No Joke

By Neil Osterweil, Senior Associate Editor, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.
September 21, 2006

Explain to patients that thrown raw eggs, or most other thrown objects for that matter, can result in severe damage to the eye, including the possibility of permanent loss of vision, or blindness.
LIVERPOOL, England, Sept. 21 -- Throwing a raw egg is a prank gone bad all too often, warned emergency physicians here who cited blunt ocular trauma.
Hurling eggs at passersby has become something of a ritual among teens and young adults here on Halloween, and outraged emergency room physicians reported seeing 13 patients with blunt ocular trauma as a result.


Eight of the 13 patients had major injuries, four had permanent complications, and one suffered severe, irreversible visual loss, wrote Jon Durian, M.D., of the St. Paul's Eye Unit at the Royal Liverpool University Hospital, and colleagues, in the October issue of Emergency Medicine Journal.


"As anyone who has woken up on 1 November each year and looked out at the chaos left in the wake of the previous night's activities can attest, Halloween and so-called mischief night (the night before) is now becoming an annual excuse for anti-social behavior ranging from mild annoyance to the sheer dangerous," the authors wrote.


"One particular prank that seems to be becoming more common is the practice of throwing raw eggs either at buildings or at innocent passersby," they added. "Aside from the dry-cleaning bills, a raw egg can lead to severe ocular injury due to its weight and size, as has been reported previously."


The authors conducted a prospective study of all egg-induced ocular injuries seen in their department over 14 months.


They divided the eye injuries into minor, intermediate, and major categories. Minor injuries included hematoma of the eyelid, subconjunctival hemorrhage or corneal abrasion. Intermediate injuries included those resulting in a transient rise in intraocular pressure (IOP) or traumatic uveitis.


Major injuries included hyphema, commotio retinae (edema around the macula due to the force of the injury; a risk factor for retinal tears), retinal detachment, globe breach, or long-lasting sequelae.


Although the rate of ocular trauma was small (13 out 18,651 cases), the majority of the episodes resulted in major injuries, the authors reported.


Twelve of the 13 patients were men. The average age was 27.9 years. All had been hit in the eye with raw eggs thrown by strangers, and all had injuries to one eye only (nine left eyes and four right eyes).


The authors found that on initial examination, only one patient had 20/20 visual acuity, seven presented with 20/30 and the remainder had 20/60 or worse (one of these five patients was densely amblyopic, with acuity of only 20/200 before presentation).


All of the patients had closed globe injuries, but only three were minor, consisting of corneal abrasions, subconjunctival hemorrhage, and a simple lid hematoma. These patients were give antibiotics and were discharged.


Two patients had intermediate injuries. One, the patient with amblyopia, presented with corneal abrasion and traumatic uveitis in the amblyopic eye. This patient was treated with steroids and antibiotics, and his injuries had settled after one week of follow-up. The second intermediate injury was a case of subconjunctival hemorrhage with traumatic uveitis that again settled after appropriate treatment.


The remaining eight injuries were classified as major. Five of these patients had combinations of commotio retinae, rise in intraocular pressure, and hyphema, all of which settled after appropriate treatment.


Of the remaining three patients with major injuries, one had subconjunctival hemorrhage and corneal abrasions, as well as marked commotio of the macula region. On electrodiagnostic testing at two months, he was found to have to permanent damage to the middle and outer retinal layers of the macula corresponding to the photoreceptor layer. On discharge, his vision remained poor, at 20/300.


The second patient, who had been hit in the eye with an egg thrown from a passing car, presented with pain and mildly reduced vision. He was found on examination to have a subconjunctival hemorrhage, hyphema, mild vitreous haemorrhage, and extensive commotio retinae involving the macula, although no retinal breaks were seen. He subsequently suffered a marked vitreous hemorrhage leading to a large retinal tear requiring vitrectomy, cryotherapy, and gas endo-tamponnade.


At three months, the patient developed a macula on retinal detachment requiring additional vitreoretinal surgery. This patient was eventually discharged with 20/20 vision, but only after six months of treatment.


The last case was that of a 22-year-old man who presented immediately after being hit in the eye with an egg with a visual acuity of 20/60. On examination, he was seen to have a large corneal abrasion, small hyphema with secondary rise in intraocular pressure (31 mm Hg), and extensive inferior commotio retinae with some peripheral retinal hemorrhages.


He was subsequently found to have inferior angle recession, putting him at enhanced risk for glaucoma, although a little more than a month later his vision had improved to 20/30, and his intraocular pressure had normalized.


"Obviously, you cannot educate people against throwing objects at each other; you rely on their common sense," the authors wrote. "However, the recent advertising stunt by a leading supermarket in re-branding their eggs as 'mischief eggs' must at least be considered to be irresponsible and at worst almost incitement to this type of assault. The medical community should expect those with most access to the nation's conscience -- advertisers, retailers and TV program makers -- to act in a responsible manner against these and other easily preventable injuries."

Primary source: Emergency Medicine Journal
Source reference:
Stewart RMK et al. "'Here's egg in your eye': a prospective study of blunt ocular trauma resulting from thrown eggs." Emerg Med J 2006;23:756-758.



Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Scientists Discover Why Cornea Is Transparent And Free Of Blood Vessels, Allowing Vision

Scientists at the Harvard Department of Ophthalmology's Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary (MEEI) are the first to learn why the cornea, the clear window of the eye, is free of blood vessels--a unique phenomenon that makes vision possible. The key, say the researchers, is the unexpected presence of large amounts of the protein VEGFR-3 (vascular endothelial growth factor receptor-3) on the top epithelial layer of normal healthy corneas. According to their findings, VEGFR-3 halts angiogenesis (blood vessel growth) by acting as a "sink" to bind or neutralize the growth factors sent by the body to stimulate the growth of blood vessels. The cornea has long been known to have the remarkable and unusual property of not having blood vessels, but the exact reasons for this had remained unknown.

These results, published in the July 25, 2006 issue of the Proceedings of the National Academy of Sciences and in the July 17 online edition, not only solve a profound scientific mystery, but also hold great promise for preventing and curing blinding eye disease and illnesses such as cancer, in which blood vessels grow abnormally and uncontrollably, since this phenomenon, present in the cornea normally, can be used therapeutically in other tissues.

"This is a very significant discovery," says Dr. Reza Dana, Senior Scientist at the Schepens Eye Research Institute, head of the Cornea Service at the Massachusetts Eye and Ear Infirmary, and an associate professor at Harvard Medical School, and the senior author and principal investigator of the study. "A clear cornea is essential for vision. Without the ability to maintain a blood-vessel-free cornea, our vision would be significantly impaired," he says, adding that clear, vessel-free corneas are vital to any animal that needs a high level of visual acuity to survive.

The cornea, one of only a few tissues in the body that actively keep themselves vessel-free (the other is cartilage), is the thin transparent tissue that covers the front of the eye. It is the clarity of the cornea that allows light to pass onto the retina and from there to the brain for interpretation. When the cornea is clouded by injury, infection or abnormal blood vessel growth, vision is severely impaired, if not destroyed.

Scientists have been wrestling with the "clarity" puzzle for many decades. And, while some previous studies have revealed small clues, none have pointed to one major mechanism, until this study.

In most other tissues of the body, blood vessel growth or angiogenesis occurs in response to a need for increased blood flow to heal an injured or infected area. The immune system sends in growth factors such as vascular endothelial growth factor (VEGF) to bind with a protein receptor called VEGFR-2 on blood vessels to trigger vessel growth. Three forms of VEGF--A, C, and D--bind with this receptor. Two of them, C and D also bind with VEGFR-3, which is usually found on cells lining lymphatic vessels, to stimulate the growth of lymphatic vessels.

Dana's team began to suspect the involvement of VEGFR-3 in stopping blood growth in corneas when they noticed unexpectedly that large amounts of the protein seemed to exist naturally on healthy corneal epithelium, a previously unknown location for the receptor. Dana and his team were already aware from clinical experience that the epithelium most likely played a role in suppressing blood vessel growth on the cornea, having witnessed blood vessels develop on corneas stripped of their epithelial layers.

They began to theorize that the large amounts of VEGFR-3, in this New, non-vascular location, might be attracting and sucking up all the C and D VEGF growth factors, thereby blocking them from binding with VEGFR-2. And, because this binding took place in a non-vascular setting, the growth factors were neutralized.

To test their theory, the team conducted a series of experiments.

Using corneal tissue from mice, the team did the following.

They conducted chemical analyses that demonstrated that VEFGR-3 and the gene that expressed it were indeed present on the corneal epithelium. Next, in two separate experiments, they compared corneas with and without epithelial layers that were injured. They found that only the corneas without epithelial layers developed blood vessels, implicating the role of the epithelium in suppressing blood vessel growth To further prove their theory, they added a VEGFR-3 substitute to corneas stripped of their epithelial layers and found that vessel growth continued to be suppressed, replacing the normal anti-angiogenic role of the epithelium. Finally they exposed intact corneas to an agent that blocked VEGFR-3 and found that blood vessels began to grow, formally demonstrating that the corneal epithelium is key to suppression of blood vessels and that the key mechanism is expression of VEGFR-3.

"The results from this series of tests, confirmed our belief that the presence of VEGFR-3 is the major factor in preventing blood vessel formation in the cornea," says Dana, who says that the discovery will have a far reaching impact on the development of New therapies for eye and other diseases.

"Drugs designed to manipulate the levels of this protein could heal corneas that have undergone severe trauma or help shrink tumors fed by rapidly growing abnormal blood vessels," he says. "In fact, the next step in our work is exactly this."

###

Other authors of the study include: Claus Cursiefen* +, Lu Chen*, Magali Saint-Geniez*, Pedram Hamrah*, Yiping Jin*, Saadia Rashid*, Bronislaw Pytowski**, Kris Persaud**, Yan Wu**, J. Wayne Streilein*†, Reza Dana* ++ ,

*The Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Dept. of Ophthalmology, Harvard Medical School, Boston, MA; +Dept. of Ophthalmology, Friedrich-Alexander University Erlangen-Nurnberg, Erlangen, Germany; **ImClone Systems, Inc., New York; †Dr. J. Wayne Streilein deceased March 15 th 2004.

About the Massachusetts Eye and Ear Infirmary, http://www.meei.harvard.edu./.: The Massachusetts Eye and Ear Infirmary, an independent specialty hospital, is an international center for treatment and research and a teaching hospital of Harvard Medical School.

Schepens Eye Research Institute is an affiliate of Harvard Medical School and he largest independent eye research institute in the world. For additional information, go to http://www.theschepens.org/.

Contact: Patti Jacobs
Schepens Eye Research Institute





Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Therapeutic Approach to Gastroesophageal Reflux Disease and Acid-Mediated Conditions

Brooks D. Cash, MD, FACP


Introduction

Gastroesophageal reflux disease (GERD) and other gastric acid-mediated disease are the most common clinical problems seen in a typical gastroenterology practice. By extension, these conditions are also commonly encountered in the primary care arena. The prevalence of GERD in the population is estimated to be between 15% and 20%. It is widely accepted that GERD and other acid-mediated conditions, such as peptic ulcer disease, are important sources of morbidity and even mortality in a subset of patients and, if unrecognized or ineffectively treated, are associated with significant impairments in quality of life.[1] Acid-suppression therapy is the basis for effective treatment of these disorders. In 2005, clinicians have an impressive array of acid-suppressing medications from which to choose. Since their introduction in the early 1990s, the proton-pump inhibitors (PPIs) have become the agents of choice for the treatment of acid-mediated disorders for many practicing clinicians and knowledgeable patients, and have become one of the most frequently prescribed classes of medications worldwide.

During this year's meeting of the American College of Gastroenterology (ACG), multiple studies directed at therapeutic approaches for GERD and other acid-mediated conditions were presented. This report discusses many of these topical issues.

Erosive Esophagitis and Barrett's Esophagus
The classic symptoms of heartburn and regurgitation make GERD relatively simple to recognize and treat in the majority of cases. Because of its prevalence, however, complications arising from GERD, such as erosive esophagitis (EE), bleeding, peptic stricture, Barrett's esophagus (BE), and esophageal adenocarcinoma underscore the importance of aggressive acid suppression in the subset of patients prone to complicated disease. Therapy for EE may be conceptualized as 2-pronged, much like that of inflammatory bowel disease. The primary objective is to provide symptom relief and mucosal healing. The second objective is to maintain this healing and thus prevent the development of additional complications. Previous studies have demonstrated the superiority of PPIs over placebo and histamine type-2 receptor antagonists (H2RAs) for both of these treatment goals. During this year's ACG meeting, Comer and colleagues[2] added to that body of evidence with their report on the effects of pantoprazole 40 mg daily vs ranitidine 150 mg twice daily for the maintenance of symptom relief in patients with a history of EE. In this analysis, the degree of both daytime and nighttime symptom control in 175 patients treated with pantoprazole was found to be superior to that in 176 patients treated with ranitidine. This finding is especially important in light of published data linking nighttime GERD symptoms to a greater probability of complicated disease.[3] In this pooled analysis, approximately 90% of patients treated with the PPI were free from daytime and nighttime GERD symptoms more than 70% of the time, and 75% were free from symptoms more than 90% of the time. Corresponding values for ranitidine were approximately 62% and 36%, respectively.

Several investigators also offered data on BE that deserve additional evaluation. In one of these reports, 61 patients with BE managed on long-term PPI therapy were followed longitudinally for periods of up to 16 years for a total of 853 patient-years of follow-up.[4] Most of these patients were on omeprazole or esomeprazole either daily or twice daily. All patients underwent surveillance upper endoscopies in accordance with societal guidelines during the study period. Only 5 patients developed a worsening of their GERD-related disease. One patient developed low-grade esophageal dysplasia which could not be found on subsequent sampling, and 4 patients experienced recurrent Los Angeles class B or C EE, which responded to more aggressive PPI dosing. No patients developed adenocarcinoma of the esophagus during follow-up. However, there were several instances of gastric fundic gland polyposis, and 1 patient developed a gastric adenoma with high-grade dysplasia that was resected completely. This study is too small to establish a causal relationship with PPIs and these gastric lesions, but additional reports such as this one would be helpful in that regard. These concerns notwithstanding, however, PPI therapy in patients with BE appears to be very well tolerated and may be an important aspect of care in the prevention of more worrisome disease in such patients. Two other related abstracts also merit discussion because they suggest that chronic PPI therapy in GERD patients may be protective in terms of risk reduction for the development of esophageal adenocarcinoma. The first of these reports was a case series examining the effects of lifestyle revisions (weight loss, abstinence from caffeine, etc) and high doses of PPIs (160-360 mg daily), and documents regression of BE in 5 patients so treated.[5] The second of these reports is a retrospective review of the Veterans' Affairs Database for the period 1998-2004.[6] Of the 80,784 patients with an ICD-9 code of GERD, 55,875 (69.2%) were prescribed PPI therapy. Esophageal cancer (cell type not specified) was diagnosed in 223 (0.3%). In their multivariate analysis to determine which confounders might be associated with GERD and esophageal carcinoma, these investigators identified a protective effect linked to PPI use. Patients prescribed PPIs were nearly 50% less likely to develop esophageal cancer than those not prescribed PPI therapy (odds ratio [OR] 0.52; 95% confidence interval [CI], 0.40-0.70; P < .0001). Obviously, these reports are limited with respect to the population studied (overwhelmingly male and white) and the lack of data regarding other diagnoses, such as BE as well as PPI dose and duration, but they are hypothesis-generating and may be signals that aggressive acid suppression in patients with GERD may have additional benefits above and beyond just symptom control.

Endoscopy-Negative Reflux Disease

The PPIs, given their demonstrated efficacy and safety, are now considered to be the prescription agents of choice for patients with chronic uncomplicated and complicated GERD. PPIs have repeatedly been shown to be superior to other acid-suppressing agents for both healing and symptom relief in patients with EE. Patients with EE, however, represent the minority of individuals with GERD symptoms. The larger population of patients -- those with typical GERD symptoms and the absence of endoscopic changes of the esophagus -- have what has been termed nonerosive reflux disease (NERD) or endoscopy-negative reflux disease (ENRD). Highly effective therapies for patients with ENRD remain elusive. PPIs significantly reduce symptoms in only 50% to 60% of such patients. Historically these patients are treated with increasing doses of PPIs and may go on to other therapies, such as smooth-muscle relaxants, promotility agents, tricyclic antidepressants, or perhaps surgical/endoscopic treatments. One of the reasons for the diminished response to acid suppression is that there may be other factors besides acid that are responsible for the symptoms of heartburn and regurgitation in patients with ENRD. ENRD may actually be a heterogeneous condition comprising patients with acid reflux, nonacid reflux, and functional gastrointestinal syndromes. New technologies, such as the implantable wireless pH probe and esophageal impedance, have allowed clinicians to get a more complete picture of what is happening inside the esophagus. In particular, much of the data being derived from impedance, which allows clinicians to "see" a fluid reflux episode manifested by increased electrical conduction (decreased "impedance") along a series of spaced electrodes in the catheter, has led to the hypothesis of a "hypersensitive" esophagus in which the volume of the refluxed fluid bolus is thought to be as important as the pH of the fluid as a cause of symptoms. At this year's ACG meeting, Mittal and colleagues[7] relied on the older technologies of the Bernstein acid perfusion test and 24-hour pH monitoring to underscore the observation that not all GERD patients are the same. These investigators selected 28 patients with "classic" symptoms of heartburn and regurgitation and studied them with acid perfusion (Bernstein testing) and 24-hour pH testing. Only 46% (13/28) had a positive Bernstein test. Of the 75% of GERD patients reporting symptoms during pH monitoring, 8 were in the Bernstein-positive group whereas 13 were among those patients who had negative Bernstein tests. It is interesting that both groups of patients reporting symptoms during pH monitoring had similar symptom severity scores.

In another report, investigators studied 98 patients with the chronic GERD symptoms of heartburn and regurgitation who failed to respond to therapeutic doses of PPI administered for at least 8 weeks.[8] Approximately 75% used daily PPIs whereas 25% of patients used a twice-daily dose. In addition to heartburn and regurgitation, these patients also complained of belching (79%), dyspepsia (58%-72%), bloating (66%), excessive postprandial fullness (65%), chest pain (62%), hoarseness (47%), cough (45%), and nausea (43%). In descending order, heartburn, belching and upper abdominal discomfort, bloating, and chest pain were the most bothersome symptoms to these PPI nonresponders. In a related report,[9] investigators conducted a 4-week randomized, parallel-group, open-label trial of tegaserod,* a partial serotonin type-4 receptor agonist currently approved for use in patients with chronic constipation and irritable bowel syndrome with constipation. Forty-one patients were randomized to treatment with PPI plus tegaserod (6 mg twice daily) or PPI alone in a 2:1 allocation, and changes were measured both within treatment groups and between treatment groups. At the end of the trial there was significant symptom improvement noted in the PPI-plus-tegaserod group compared with in the PPI-alone group. Not only were the symptoms of heartburn and regurgitation reduced, but improvements were also noted in bloating and nausea (P < .05 for all comparisons) and a global symptom index score (P < .0002). No serious adverse events were reported. Although these data are very preliminary, this may represent an attractive approach in the management of this challenging group of patients.

Acid Suppression in Special Circumstances

Acid suppression is being increasingly used in special clinical circumstances, and data supporting these applications continue to accumulate. One of these circumstances is in patients with sleep disturbances, largely due to increasing awareness and recognition of the effects of GERD on sleep. However, it is becoming clear that typical GERD symptoms may not always declare themselves in patients with disturbed sleep. In one study presented during these meeting proceedings,[10] 81 patients with chronic sleep complaints underwent 2 separate polysomnographic sleep evaluations accompanied by distal pH monitoring. None of these patients had complaints of heartburn or regurgitation. As a result of physiologic testing, 26% of these patients were diagnosed with acid reflux, defined in this study as an intraesophageal pH < 4 for more than 30 seconds. Moreover, 25% of those with acid reflux had at least 1 episode that lasted more than 5 minutes. In fact, the average duration of each reflux episode was more than 30 minutes, and perhaps most important, 94% of all recorded reflux events were associated with an arousal or an awakening, suggesting a causal relationship. O'Connor and colleagues[11] found similar prevalence values in their examination of the quality of life (QOL) in patients with obstructive sleep apnea and GERD. Among 168 patients with obstructive sleep apnea, 24% reported moderate-to-severe daytime GERD symptoms and 31% reported moderate-to-severe nighttime symptoms. Not surprisingly, obstructive sleep apnea patients had lower QOL scores than the general US population, and the addition of GERD symptoms resulted in even lower QOL scores. The effects of acid suppression on sleep in this group of patients remains to be seen, but studies such as these continue to add to the body of evidence supporting a role for GERD in disordered sleep, and it may become advisable to evaluate such patients with objective techniques such as pH monitoring because typical GERD symptoms may not always be present.

The only PPI with a US Food and Drug Administration approval for Zollinger-Ellison syndrome (ZES) is pantoprazole. However, it appears that esomeprazole* is also effective at controlling acid output in patients with ZES, as demonstrated by Pisegna and colleagues.[12] In their report, 19 patients with ZES and 2 with idiopathic gastric acid hypersecretion were switched from their previous PPI and placed on varying doses of esomeprazole titrated to suppressed basal acid output and symptom control, measured after the switch and then again at 3 and 6 months. At 6 months, 95% of patients had controlled acid output, with the majority of these taking esomeprazole 40 mg twice daily. Adverse events were rare and manageable without PPI cessation.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are well recognized as a leading cause of peptic ulcer disease, and gastrointestinal complications from NSAIDs are a significant source of morbidity and mortality. Multiple approaches have been developed to minimize these risks, including the substitution of cyclooxygenase (COX)-2 selective NSAIDs or the coadministration of misoprostol or acid-suppressing agents such as PPIs. Misoprostol is associated with crampy abdominal pain and diarrhea, and there are multiple unanswered questions regarding the safety of the COX-2 NSAIDs. PN 100* is a novel combination tablet that contains 15 mg of lansoprazole and 500 mg of enteric-coated naproxen. When administered twice daily to patients for 14 days, PN 100 was associated with significantly less incidence of gastric erosions or ulcers than either enteric-coated naproxen (500 mg twice daily) alone or enteric-coated naproxen plus lansoprazole (500 mg twice daily and 15 mg every morning, respectively).[13] There were no peptic ulcer complications reported. This study did not report on clinical symptoms such as dyspepsia and is limited by its small size, its endoscopic rather than clinical outcomes, and the unequal doses of PPI in the comparison groups -- but it does support future investigations with this combination medication and possibly others.

Endoscopic Approaches to GERD

Emerging data on plication, an endoscopic therapy for GERD, were presented during this year's ACG meeting. In the first of 2 studies, investigators reported follow-up data on patients who underwent plication with the EndoCinch (Bard; Billerica, Massachusetts) device between 1998 and 1999.[14] Prior to plication, all patients had mild GERD symptoms that required, and were responsive to, daily PPI therapy. Compared with 6 months post procedure at which point 69% of patients were off all PPI therapy, only 17% remained free of PPIs at 6 years. One patient from the original cohort of 13 had proceeded to fundoplication. Whereas larger studies are needed, this report highlights the importance of prolonged follow-up after these procedures. Prolonged treatment effects with another plication device, the Plicator(NDO Surgical; Mansfield, Massachusetts), were also reported during these meeting proceedings.[15] At 3 years post procedure, 60% of patients who were previously dependent on daily PPIs no longer required this therapy for their GERD symptoms. The fact that in the previous 24 months 20% of patients had noted an increasing need for GERD medications, however, is concerning in light of the previously mentioned 6-year data with the other plication device. It may be that these approaches, while still being refined, have a finite lifespan in terms of symptom relief. These data, in patients whose symptoms were previously completely controlled with medications, should make clinicians and patients seriously consider whether to pursue plication therapy at this time.

Concluding Remarks

We continue to gain important insights regarding the optimization of existing therapies and the development of new approaches to both uncomplicated and complicated GERD as well as other acid-mediated conditions. On the basis of data presented during this year's ACG meeting, the clinical evidence supporting the primary role of PPIs in patients with GERD symptoms or EE secondary to GERD appears to be incontrovertible. Although very preliminary, there is some evidence that aggressive acid suppression with PPI therapy may alter the natural course of preneoplastic conditions such as BE, but these data should be considered cautiously, with a view toward much larger and longer prospective studies. Clinical features that are unique to ENRD, and the reasons for nonresponsiveness to typical GERD therapy in this setting, are slowly being worked out. New approaches using non-acid-suppressing medications such as tegaserod in these patients are being reported and may hold some promise if future studies bear out these preliminary results. PPIs have also been shown to have a role in other acid-mediated conditions, such as ZES and peptic ulcer disease prophylaxis. New delivery methods promise to make these therapies more amenable to affected patients. Finally, the long-term effects of gastric plication on GERD symptoms do not appear to be especially promising, and further refinements in this technology are needed before it will become a viable alternative therapy for GERD.

*The US Food and Drug Administration has not approved this medication for this use.




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

FDA Releases New Data Suggesting Birth Defects Tied to Lamictal

ROCKVILLE, Md., Sept. 29, 2006--New information suggests that babies exposed to Lamictal during the first three months of pregnancy may have a higher chance of being born with a cleft lip or cleft palate. Babies born with cleft lip or cleft palate have a gap in the upper lip or roof of the mouth.

If you take Lamictal and are pregnant or are thinking of becoming pregnant, talk with your doctor. Lamictal is used for seizures or bipolar disorder, serious conditions that need treatment even during pregnancy. Do not start or stop using Lamictal without talking to your doctor.

More research is needed to be sure about this possibly increased chance of cleft lip or cleft palate in babies born to mothers who take Lamictal.

Please see the attachments for more information.

Contact: 1-888-INFO-FDA (1-888-463-6332) -- main FDA Phone Number (for general inquiries)



Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Evaluation of Patients With Symptoms of Gastroesophageal Reflux -- Role of Reflux Monitoring

Philip O. Katz, MD


Introduction

Gastroesophageal reflux disease (GERD) is a common problem in gastroenterologic practice. In the vast majority of clinical scenarios, the diagnosis is suspected on the basis of patient history and a therapeutic trial of antisecretory therapy initiated to confirm the relationship between the presenting symptoms and acid. Patients who fail to respond to therapy or have complicated disease or unusual symptoms require further evaluation. In many cases, prolonged monitoring either for acid reflux (measurement of pH) or nonacid reflux may be required to determine whether the symptoms are indeed due to GERD. In addition, an endoscopic evaluation may be needed to assess for the presence or absence of mucosal disease.

Two New technologies recently available for prolonged reflux monitoring are the wireless pH monitoring system (Bravo; Medtronic; Minneapolis, Minnesota) and multichannel intraluminal impedance (Sleuth; Sandhill Scientific, Inc.; Highlands Ranch, Colorado). Wireless pH monitoring, which uses a "telemetry capsule"-based monitoring system, allows sampling for 48 hours and can be placed such that no catheter is required. This advancement in patient comfort and acceptance has progressed our knowledge of GERD and our ability to determine the relationship between acid and symptoms. Multichannel intraluminal impedance technology (MII/pH) has allowed us to characterize a bolus independent of the presence of acid. This combined MII/pH monitoring allows us to assess the patient for the presence of acid or nonacid (pH > 4) reflux using a single catheter. This so-called "nonacid reflux" has been a source of controversy because it has been difficult to determine whether refluxate with a pH > 4 is responsible for symptoms. During this year's meeting of the American College of Gastroenterology, several studies addressed the use of these technologies in the evaluation of patients with suspected GERD and are the focus of this report.

Catheter-Based Reflux Monitoring

Utility in the Diagnosis of Refractory GERD Symptoms?
Maqbool and colleagues[1] evaluated combined MII/pH monitoring to assess the clinical utility of this technology in patients with refractory GERD symptoms. In this prospective study involving 42 patients, 15 with atypical symptoms (hoarseness, throat clearing, sore throat, cough, chest pain, and globus) and 27 with predominantly typical symptoms (heartburn and regurgitation) on twice-daily proton-pump inhibitor therapy (PPI) were evaluated. MII/pH monitoring was performed by placing the catheter transnasally such that the impedance measuring segments were 3, 5, 7, 9, 15, and 17 cm above the lower esophageal sphincter (LES), with a simultaneous pH sensor at 5 cm above the LES. The study authors reviewed the tracings for the presence of distal and proximal reflux events. They found that all patients with purely atypical symptoms (n = 15) had a normal MII/pH study. In contrast, 9 of 27 (33%) with typical symptoms had abnormal MII/pH findings (P < .02). The predominant symptom in this latter group was regurgitation (7 of 9; 78%). Although not part of the original study, the investigators commented that 5 of 9 patients with abnormal MII/pH studies, 4 of whom had regurgitation, underwent surgical fundoplication and had complete symptom resolution in the early postoperative period. Their conclusion that MII/pH monitoring is rarely useful in patients with atypical symptoms refractory to aggressive acid suppression is similar to other preliminary observations.[2] However, the findings in patients with typical symptoms, particularly regurgitation, suggest the usefulness of this New technology in this patient population. Surgical success in a small group of patients with nonacid reflux and a positive symptom association were reported in another preliminary study.[3]

Evaluation of Gastroesophageal Reflux After Fundoplication

A small study by Kaul and Krauze[4] attempted to characterize the frequency and composition of gastroesophageal reflux after fundoplication in children using impedance technology (MII/pH). The authors performed 24 studies in children ranging from age 10 months to 11.5 years. The catheter was placed after endoscopy under general anesthesia and position verified by chest x-ray. They found: a trend towards a decrease in total number of reflux episodes after fundoplication; that gas reflux was more frequent than liquid reflux; and that few patients had evidence of esophagitis, including by microscopic examination. The study authors concluded that this technology was tolerated by the children and would provide useful results if reflux monitoring was required.

GERD in Patients With Pulmonary Symptoms

Ferguson and colleagues[5] presented the results of a study assessing the utility of MII/pH technology in patients with pulmonary diseases and complaints. The study involved 17 patients with pulmonary diseases/complaints as follows: idiopathic pulmonary fibrosis (n = 6), chronic obstructive pulmonary disease (n = 5), chronic cough (n = 3), and 1 patient each with restrictive bronchiolitis, asthma, and pulmonary hypertension. Overall, 10 of 17 (58%) patients had evidence of abnormal reflux, with 6 of 17 demonstrating normal pH testing but abnormal nonacid reflux. Four of 17 had abnormal acid reflux (2 on twice-daily PPI therapy and 2 off acid-suppressing therapy). Although no therapy was given to patients with nonacid reflux, nor any outcomes reported, the utility of pH testing with impedance in assessing this patient population for nonacid reflux was confirmed, and the frequency of nonacid reflux was found to be similar to that reported in earlier studies.[2,3]

Symptomatology Among GERD Patients on PPI Therapy
Jazrawi and colleagues[6] retrospectively evaluated 30 patients who had undergone MII/pH monitoring while on PPI therapy. They calculated the symptom association probability (positive if greater than 95%) and the symptom index (positive if greater than 50%), 2 ways of documenting the relationship between symptoms and reflux, with the goal of determining whether one strategy was more helpful in patient assessment. Their findings were similar to those discussed above, in that heartburn, regurgitation, and cough were the symptoms most likely to have a positive symptom association probability. Most important, however, the authors found a poor concordance for the symptom association probability and symptom index for both acidic and nonacidic reflux (33.3% and 42.8%, respectively). These study findings underscore that although MII/pH technology can detect nonacid reflux, correlating the presence of nonacid reflux and symptoms remains a clinical challenge using the current measures of symptom association probability and index.

Frequencies of Acid and Nonacid Reflux After Treatment

A small study by Vela and Richter[7] presented preliminary data on the use of MII/pH technology to assess the efficacy of pharmacologic interventions in patients with GERD. Six patients underwent separate 24-hour ambulatory MII/pH studies, the first after 2 weeks of baclofen* (gamma aminobutyric acid receptor type B agonist that inhibits transient LES relaxations) 20 mg 3 times per day, and the second after 2 weeks of therapy with esomeprazole 40 mg once daily. Adequate technical tracings were available for all 12 studies, and revealed that a similar number of reflux episodes were detected regardless of therapeutic intervention, with reflux on baclofen being predominantly acid and on esomeprazole being predominantly nonacid. This study reinforces the potential utility of baclofen-like drugs in the treatment of reflux, particularly postprandial symptoms in patients on acid-suppression therapy. Drugs with a better safety profile are awaited.

Wireless pH Monitoring

Concordance of Data Between First and Second 24-Hour Recording Periods
A group from the Mayo Clinic in Scottsdale, Arizona,[8] assessed intrasession variability and reproducibility of wireless pH studies in patients who had the capsule placed while either sedated or unsedated. Eighty-seven patients were studied, with approximately half comprising each group. The study authors evaluated the concordance of data between the two 24-hour periods in sedated vs unsedated patients, assessing intergroup differences in pH parameters. Overall, 85 of 87 (98%) of patients completed the full 48-hour study period. Significant correlations were found between the two 24-hour recording periods for both groups; however, variability was higher and correlations (reproducibility) lower in the sedated group compared with the unsedated group. Although these differences were not statistically significant, additional study is required to determine the optimal approach to placement of this device.

Does Wireless pH Capsule Placement Affect Esophageal Motor Function?

In a very straightforward study, Zhang and colleagues[9] evaluated the effect of the attachment of the wireless pH capsule on esophageal motility. Ten subjects were evaluated with a solid-state manometry assembly with 36 circumferential sensors spaced 1 cm apart, positioned to record from the hypopharynx to the stomach. Manometry studies were performed before and 12 or more hours after capsule placement. Two barium-swallow studies were also performed in 6 subjects under fluoroscopy, synchronized with manometric recordings. Overall, there was no change in basal LES pressure, LES relaxation, or peristaltic function. It is interesting to note that there was a noticeable 1.5-cm high pressure focus during peristalsis at the location of the capsule during fluoroscopy. Additionally, 5 of the 10 subjects reported foreign-body sensation and/or chest pain. Although the median pressure at the attachment site was increased in the 5 subjects with symptoms, it did not reach statistical significance compared with those without symptoms. These findings suggest that this short area of increased peristaltic amplitude may have a bearing on the genesis of symptoms in patients while the capsule is in place.

pH Testing in Patients With Noncardiac Chest Pain

Persistent noncardiac chest pain in patients on PPI therapy remains a clinical challenge. The optimal evaluation of these patients has still not been determined, and what additional diagnostic information pH monitoring may offer in this population remains to be assessed. Achem and colleagues[10] reviewed their experience with prolonged pH testing in a large cohort of patients with noncardiac chest pain. One hundred and thirty patients were evaluated, 80 of whom were on PPI therapy, with 59 agreeing to pH monitoring. In the group evaluated on PPI therapy, only 5 of 59 (8.4%) had continued acid reflux. Perhaps of equal interest, only 18 of 59 (30.5%) subjects studied while off PPI therapy had abnormal pH studies.

Findings from this retrospective observational study reinforce that the presence of abnormal gastroesophageal reflux in patients with noncardiac chest pain may not be as frequent as reported, and that an important minority of patients on PPI therapy continue to reflux acid. Most important, careful evaluation of these patients is required to make an accurate diagnosis of reflux.

Concluding Remarks

Our approach to the evaluation of patients with symptoms suspected to be due to GERD despite PPI therapy continues to evolve. As MII/pH technology has been studied further, we have come to understand that an important minority of patients continue to have nonacid reflux and symptoms associated with these events. It is possible that a select group of patients, probably those with regurgitation as the primary symptom, have a clear relationship between symptoms and reflux. The association of nonacid reflux with atypical symptoms, including chest pain and ear-nose-throat symptoms, remains a subject of debate, and requires additional study. Further developments in prolonged monitoring with capsule-based technology promise to add much to our understanding and management of this difficult patient group. We await these enhancements and the future research in this difficult patient group.

*The US Food and Drug Administration has not approved this medication for this use.




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Any Age Is Okay for Adjuvant Chemotherapy for Early Lung Cancer

By Peggy Peck, Managing Editor, MedPage Today
Reviewed by Robert Jasmer, MD; Assistant Professor of Medicine, University of California, San Francisco

June 03, 2006

ATLANTA, June 3 — Older age is no barrier to platinum-based adjuvant chemotherapy for early-stage non-small-cell lung cancer (NSCLC), researchers reported here.

And even when elderly patients can't tolerate maximum doses of chemotherapy, they still derive a substantial survival benefit, said Carmela Pepe, M.D., of Princess Margaret Hospital in Toronto in a presentation at the American Society of Clinical Oncology meeting here.

"At five years, the survival rate for patients over age 65 who had adjuvant chemotherapy with Navelbine (vinorelbine) and Platinol (cisplatin) was 66%, versus 46% for same-age patients who had only surgery," she said.

The difference was significant (P=0.04), which was not the case for patients under age 65 in whom the 70% survival for patients who had adjuvant chemotherapy was not significantly greater than the 58% five-year survival posted by surgery patients (P=0.14).

Disease-specific survival at five years was 73% for older patients who had chemotherapy following surgery versus 56% for those who had surgery alone (P=0.13). In younger patients disease-specific survival was significantly better for younger patients with adjuvant chemotherapy-72% versus 60% (P=0.05).

Her study was a retrospective review of the toxicity and survival benefits for 327 patients ages 65 or younger and 155 patients older than 65, who were enrolled in the National Cancer Institute of Canada Clinical Trials Group and Integroup Study JBR-10.


Baseline prognostic factors were similar among the two age groups, with the exception of histology. The older patients were more likely to have andenocarcinomas, while the younger patients were more likely to have squamous-cell carcinomas.


There were no significant differences in toxicities, she said, except for myalgias and mood alteration, which was observed more frequently in the younger patients.


But no older patient completed the full 16-dose Navelbine regimen and only 31.8% received the recommended eight doses of Platinol, which was significant P=0.014 for Navelbine and 0.006 for Platinol, compared with younger patients.


So it followed that the dose intensity was significantly less among the older patients-13.2 for younger patients versus 10.0 for older patients taking Navelbine (P=0.0004) and 18.0 versus 14.1 for those taking Platinol (P=0.001), she said.


She said older patients were more likely to refuse treatments and they were also more likely to "have co-morbidities that caused them to stop treatment."


But the study showed, she said, "that even a little bit of chemotherapy is very beneficial in these patients."


Thoracic surgeon Yolanda L. Colson, M.D., of Brigham and Women's Hospital in Boston said Dr. Pepe's results confirm "that we shouldn't make treatment decisions based on age alone."


Dr. Colson moderated an ASCO press briefing where Dr. Pepe discussed her results.

Primary source: American Society of Clinical Oncology
Source reference:


Pepe C et al "Adjuvant chemotherapy in elderly patients: an analysis of National Cancer Institute of Canada Clinical Trials Group and Intergroup BR.10" Abstract 7009.




Saludos Cordiales
Dr. José Manuel Ferrer Guerra

Evaluation of Patients With Symptoms of Gastroesophageal Reflux -- Role of Reflux Monitoring

Philip O. Katz, MD


Introduction
Gastroesophageal reflux disease (GERD) is a common problem in gastroenterologic practice. In the vast majority of clinical scenarios, the diagnosis is suspected on the basis of patient history and a therapeutic trial of antisecretory therapy initiated to confirm the relationship between the presenting symptoms and acid. Patients who fail to respond to therapy or have complicated disease or unusual symptoms require further evaluation. In many cases, prolonged monitoring either for acid reflux (measurement of pH) or nonacid reflux may be required to determine whether the symptoms are indeed due to GERD. In addition, an endoscopic evaluation may be needed to assess for the presence or absence of mucosal disease.

Two New technologies recently available for prolonged reflux monitoring are the wireless pH monitoring system (Bravo; Medtronic; Minneapolis, Minnesota) and multichannel intraluminal impedance (Sleuth; Sandhill Scientific, Inc.; Highlands Ranch, Colorado). Wireless pH monitoring, which uses a "telemetry capsule"-based monitoring system, allows sampling for 48 hours and can be placed such that no catheter is required. This advancement in patient comfort and acceptance has progressed our knowledge of GERD and our ability to determine the relationship between acid and symptoms. Multichannel intraluminal impedance technology (MII/pH) has allowed us to characterize a bolus independent of the presence of acid. This combined MII/pH monitoring allows us to assess the patient for the presence of acid or nonacid (pH > 4) reflux using a single catheter. This so-called "nonacid reflux" has been a source of controversy because it has been difficult to determine whether refluxate with a pH > 4 is responsible for symptoms. During this year's meeting of the American College of Gastroenterology, several studies addressed the use of these technologies in the evaluation of patients with suspected GERD and are the focus of this report.

Catheter-Based Reflux Monitoring
Utility in the Diagnosis of Refractory GERD Symptoms?
Maqbool and colleagues[1] evaluated combined MII/pH monitoring to assess the clinical utility of this technology in patients with refractory GERD symptoms. In this prospective study involving 42 patients, 15 with atypical symptoms (hoarseness, throat clearing, sore throat, cough, chest pain, and globus) and 27 with predominantly typical symptoms (heartburn and regurgitation) on twice-daily proton-pump inhibitor therapy (PPI) were evaluated. MII/pH monitoring was performed by placing the catheter transnasally such that the impedance measuring segments were 3, 5, 7, 9, 15, and 17 cm above the lower esophageal sphincter (LES), with a simultaneous pH sensor at 5 cm above the LES. The study authors reviewed the tracings for the presence of distal and proximal reflux events. They found that all patients with purely atypical symptoms (n = 15) had a normal MII/pH study. In contrast, 9 of 27 (33%) with typical symptoms had abnormal MII/pH findings (P < .02). The predominant symptom in this latter group was regurgitation (7 of 9; 78%). Although not part of the original study, the investigators commented that 5 of 9 patients with abnormal MII/pH studies, 4 of whom had regurgitation, underwent surgical fundoplication and had complete symptom resolution in the early postoperative period. Their conclusion that MII/pH monitoring is rarely useful in patients with atypical symptoms refractory to aggressive acid suppression is similar to other preliminary observations.[2] However, the findings in patients with typical symptoms, particularly regurgitation, suggest the usefulness of this New technology in this patient population. Surgical success in a small group of patients with nonacid reflux and a positive symptom association were reported in another preliminary study.[3]

Evaluation of Gastroesophageal Reflux After Fundoplication
A small study by Kaul and Krauze[4] attempted to characterize the frequency and composition of gastroesophageal reflux after fundoplication in children using impedance technology (MII/pH). The authors performed 24 studies in children ranging from age 10 months to 11.5 years. The catheter was placed after endoscopy under general anesthesia and position verified by chest x-ray. They found: a trend towards a decrease in total number of reflux episodes after fundoplication; that gas reflux was more frequent than liquid reflux; and that few patients had evidence of esophagitis, including by microscopic examination. The study authors concluded that this technology was tolerated by the children and would provide useful results if reflux monitoring was required.

GERD in Patients With Pulmonary Symptoms
Ferguson and colleagues[5] presented the results of a study assessing the utility of MII/pH technology in patients with pulmonary diseases and complaints. The study involved 17 patients with pulmonary diseases/complaints as follows: idiopathic pulmonary fibrosis (n = 6), chronic obstructive pulmonary disease (n = 5), chronic cough (n = 3), and 1 patient each with restrictive bronchiolitis, asthma, and pulmonary hypertension. Overall, 10 of 17 (58%) patients had evidence of abnormal reflux, with 6 of 17 demonstrating normal pH testing but abnormal nonacid reflux. Four of 17 had abnormal acid reflux (2 on twice-daily PPI therapy and 2 off acid-suppressing therapy). Although no therapy was given to patients with nonacid reflux, nor any outcomes reported, the utility of pH testing with impedance in assessing this patient population for nonacid reflux was confirmed, and the frequency of nonacid reflux was found to be similar to that reported in earlier studies.[2,3]

Symptomatology Among GERD Patients on PPI Therapy
Jazrawi and colleagues[6] retrospectively evaluated 30 patients who had undergone MII/pH monitoring while on PPI therapy. They calculated the symptom association probability (positive if greater than 95%) and the symptom index (positive if greater than 50%), 2 ways of documenting the relationship between symptoms and reflux, with the goal of determining whether one strategy was more helpful in patient assessment. Their findings were similar to those discussed above, in that heartburn, regurgitation, and cough were the symptoms most likely to have a positive symptom association probability. Most important, however, the authors found a poor concordance for the symptom association probability and symptom index for both acidic and nonacidic reflux (33.3% and 42.8%, respectively). These study findings underscore that although MII/pH technology can detect nonacid reflux, correlating the presence of nonacid reflux and symptoms remains a clinical challenge using the current measures of symptom association probability and index.

Frequencies of Acid and Nonacid Reflux After Treatment
A small study by Vela and Richter[7] presented preliminary data on the use of MII/pH technology to assess the efficacy of pharmacologic interventions in patients with GERD. Six patients underwent separate 24-hour ambulatory MII/pH studies, the first after 2 weeks of baclofen* (gamma aminobutyric acid receptor type B agonist that inhibits transient LES relaxations) 20 mg 3 times per day, and the second after 2 weeks of therapy with esomeprazole 40 mg once daily. Adequate technical tracings were available for all 12 studies, and revealed that a similar number of reflux episodes were detected regardless of therapeutic intervention, with reflux on baclofen being predominantly acid and on esomeprazole being predominantly nonacid. This study reinforces the potential utility of baclofen-like drugs in the treatment of reflux, particularly postprandial symptoms in patients on acid-suppression therapy. Drugs with a better safety profile are awaited.

Wireless pH Monitoring
Concordance of Data Between First and Second 24-Hour Recording Periods
A group from the Mayo Clinic in Scottsdale, Arizona,[8] assessed intrasession variability and reproducibility of wireless pH studies in patients who had the capsule placed while either sedated or unsedated. Eighty-seven patients were studied, with approximately half comprising each group. The study authors evaluated the concordance of data between the two 24-hour periods in sedated vs unsedated patients, assessing intergroup differences in pH parameters. Overall, 85 of 87 (98%) of patients completed the full 48-hour study period. Significant correlations were found between the two 24-hour recording periods for both groups; however, variability was higher and correlations (reproducibility) lower in the sedated group compared with the unsedated group. Although these differences were not statistically significant, additional study is required to determine the optimal approach to placement of this device.

Does Wireless pH Capsule Placement Affect Esophageal Motor Function?
In a very straightforward study, Zhang and colleagues[9] evaluated the effect of the attachment of the wireless pH capsule on esophageal motility. Ten subjects were evaluated with a solid-state manometry assembly with 36 circumferential sensors spaced 1 cm apart, positioned to record from the hypopharynx to the stomach. Manometry studies were performed before and 12 or more hours after capsule placement. Two barium-swallow studies were also performed in 6 subjects under fluoroscopy, synchronized with manometric recordings. Overall, there was no change in basal LES pressure, LES relaxation, or peristaltic function. It is interesting to note that there was a noticeable 1.5-cm high pressure focus during peristalsis at the location of the capsule during fluoroscopy. Additionally, 5 of the 10 subjects reported foreign-body sensation and/or chest pain. Although the median pressure at the attachment site was increased in the 5 subjects with symptoms, it did not reach statistical significance compared with those without symptoms. These findings suggest that this short area of increased peristaltic amplitude may have a bearing on the genesis of symptoms in patients while the capsule is in place.

pH Testing in Patients With Noncardiac Chest Pain
Persistent noncardiac chest pain in patients on PPI therapy remains a clinical challenge. The optimal evaluation of these patients has still not been determined, and what additional diagnostic information pH monitoring may offer in this population remains to be assessed. Achem and colleagues[10] reviewed their experience with prolonged pH testing in a large cohort of patients with noncardiac chest pain. One hundred and thirty patients were evaluated, 80 of whom were on PPI therapy, with 59 agreeing to pH monitoring. In the group evaluated on PPI therapy, only 5 of 59 (8.4%) had continued acid reflux. Perhaps of equal interest, only 18 of 59 (30.5%) subjects studied while off PPI therapy had abnormal pH studies.

Findings from this retrospective observational study reinforce that the presence of abnormal gastroesophageal reflux in patients with noncardiac chest pain may not be as frequent as reported, and that an important minority of patients on PPI therapy continue to reflux acid. Most important, careful evaluation of these patients is required to make an accurate diagnosis of reflux.

Concluding Remarks
Our approach to the evaluation of patients with symptoms suspected to be due to GERD despite PPI therapy continues to evolve. As MII/pH technology has been studied further, we have come to understand that an important minority of patients continue to have nonacid reflux and symptoms associated with these events. It is possible that a select group of patients, probably those with regurgitation as the primary symptom, have a clear relationship between symptoms and reflux. The association of nonacid reflux with atypical symptoms, including chest pain and ear-nose-throat symptoms, remains a subject of debate, and requires additional study. Further developments in prolonged monitoring with capsule-based technology promise to add much to our understanding and management of this difficult patient group. We await these enhancements and the future research in this difficult patient group.

*The US Food and Drug Administration has not approved this medication for this use.




Saludos Cordiales
Dr. José Manuel Ferrer Guerra