New Marker Offers Hope For More Reliable Detection Of Prostate Cancer

A new, promising marker for diagnosing prostate cancer has been discovered by Uppsala researchers with the aid of a unique method developed at the Department of Immunology, Genetics and Pathology. The study, being published this week in the journal Proceedings of the National Academy of Sciences, PNAS, can lead to more reliable diagnoses and fewer unnecessary operations.

The PSA marker used for diagnosing prostate cancer today has been criticized for false positive responses, leading to unnecessary operations. There is therefore great interest in finding new and better biomarkers.

In the limited patient material examined in our study, blood levels of so-called prostasomes seem to correlate more closely with the severity of the disease than do PSA levels, says Masood Kamali-Moghaddam, a scientist in Professor Ulf Landegren’s research team at the Department of Immunology, Genetics, and Pathology.

The team has previously developed a uniquely specific and sensitive method, called proximity ligation, for effective determination of proteins, and the method has now been adapted for detecting prostasomes.

One of the co-authors of the present study, Professor Gunnar Ronquist, showed 30 years ago that prostate cells pump out large quantities of a tiny membrane-coated particle in semen, which he named prostasomes. The hypothesis is that, in cancer, rather than winding up in semen, prostasomes are pumped out into the surrounding cancer tissue in invasive cancer. Therefore, prostasomes could be expected to occur at elevated levels in blood in cases of prostate cancer.

It has not been possible earlier to detect prostasomes in blood, but the researchers devised a unique test that requires several different antibodies to simultaneously recognize proteins on the surface of the prostasomes, and this allowed them to detect elevated levels of prostasomes in the blood of patients with prostate cancer.

“We are hopeful that this type of marker will prove valuable not only for prostate cancer but also in several other common tumor types,” says Masood Kamali- Moghaddam.

Sources: Uppsala Universitet, AlphaGalileo Foundation.

Organ Transplant Waiting Lists Can Be Artificially Inflated, Comment Organ Transplant Experts

Waiting lists for organ transplants were the topic of discussion for organ transplant experts and their views were published online first as a Viewpoint by The Lancet. They believe that such lists can be artificially inflated as not all patients requiring a transplant actually opt to receive one (and it varies depending on the organ). The Viewpoint is by Professor Rinaldo Bellomo, University of Melbourne, and Department of Intensive Care, Austin Hospital, Melbourne, Australia, and Dr Nereo Zamperetti, Department of Anesthesia and Intensive Care Medicine, San Bortolo Hospital, Vicenza, Italy, and colleagues.

Patients are marked either active or inactive on the transplantation list based on their interest in receiving the transplant.

The authors state:

“Crucially, not all the patients on waiting lists are
actually eligible for transplantation.”

They refer to an old article that was published in the Washington Post in 2008 which stated that inactive patients were a major chunk out of an approximate 100,000 patients in the USA waiting for various transplants.

Although it is expected that some patients can become temporarily inactive due to infections, moving locations, and other reasons, the Washington Post article went on to say that:

“..more than 55 percent of the patients on the list for hearts, and nearly 49 percent waiting for livers, had been inactive for more than two years. Nearly half of those waiting for kidneys had been inactive for at least a year – and nearly a third for more than two years..In some cases, evaluations of patients’ suitability for a transplant were never completed..[as in] more than 36 percent of kidney transplant candidates”.

The authors have also made a comparison of organ transplant lists with the diagnosis and treatment of diabetes. They stated that the levels of blood sugar that define diabetes have evolved over the years and gradually more and more people have become eligible for treatment with drugs.

They say:

“A waiting list shorter than the reasonable amount of transplantable organs might guarantee that every listed patient will receive a transplantation but will leave some patients without a life-saving organ that might actually be available. Thus, some inflation is inevitable and allows the option to choose the most adequate recipient for a given organ (according to size, immunological compatibility, and so on). Yet, over a certain upper threshold (seemingly exceeded in many countries), this list inflation can become unacceptable.”

The authors have suggested that the criteria to be on the wait list need to be reviewed at three levels, with the first level being the national and international level. Considering that not everyone can be cured due to limited resources and that the costs involved in transplantation are very high, every country needs to decide the importance that they will give to transplantation programs and the resources that they are willing to invest in this area of medical care.

They commented:

“Every time we treat a patient, we make an allocation choice. Perhaps a reflection is needed on how much we want to help a patient who is present to survive, while overlooking the needs of the patients who are absent.”

The second level of review they suggest should be the end-stage organ disease which needs to be looked at overall, since transplantation is just a small part of the multi-faceted care required.

The authors say:

“Transplantation programmes should not lead to the misallocation of resources away from the best care of all patients affected by organ failure.”

Addressing the needs of the patients and their families, the organ transplant experts stated:

“Being listed for transplantation should be discussed with a patient only if subsequent transplantation is reasonably possible. Having strict and rigorous entry criteria would lead to short lists and, ideally, to no patients dying while on waiting lists.”

In Italy, which also happens to be the home country of one of the authors, it has been suggested that the waiting list for liver transplantation should be shorter than double the organs transplanted each year.

In Tuscany, doctors are gradually moving from compatibility to the new concept of transplantability. Compatibility is the process by which a best match for ABO blood group antigens, age, HLA etc is identified, whereas transplantability is the real probability of receiving an organ.

The authors believe that it is not justified to have a patient enter an organ transplant waiting list just because the patient has an end-stage organ failure. Patients may not always choose transplant as an option.

They say:

“Medicine (and transplantation with it) is not a means to defeat death but rather to help people live, at their best, the life they consider worth living.

(conclusion) On the data publicly available, list inflation seems to vary in extent from country to country but this inflation occurs worldwide. The size of waiting lists and the consequent mismatch between needs and resources is not a scientific or biomedical construct alone – but also a social construct. We contend that more open discussion could lead to the formulation of clear, transparent, publically available, and socially accepted criteria for inclusion. These criteria could then be transparently applied and could ensure better protection of all patients affected by end-stage disease, fairer use of resources, and the long-term success of the transplantation system itself.”

“Reflections on transplantation waiting lists”
Nereo Zamperetti MD, Prof Rinaldo Bellomo MD, Pasquale Piccinni MD, Claudio Ronco MD
The Lancet, Early Online Publication, 12 July 2011 doi:10.1016/S0140-6736(10)62343-4

Anne Hudsmith

HHS Takes Additional Steps Toward Development Of Vaccine For The Novel Influenza A (H1N1)

HHS Secretary Kathleen Sebelius announced today that the department will take important steps necessary to prepare for potential commercial-scale production of a candidate vaccine for the novel Influenza A ( H1N1). The Secretary is directing approximately $1 billion in existing funds that will be used for clinical studies that will take place over the summer and for commercial-scale production of two potential vaccine ingredients for the pre-pandemic influenza stockpile.

“Preparation and planning are critical to keep Americans safe in the face of a potential pandemic,” Secretary Sebelius said. “Our goal throughout this new H1N1 outbreak has been to stay one step ahead of the virus. An important part of this effort has been our work to develop a potential vaccine because vaccines can help prevent and control influenza virus outbreaks. The actions we are taking today will help us be prepared if a vaccine is needed.”

The funds will be used to place new orders on existing contracts with companies that hold U.S. licenses for flu vaccines. With these orders, they will produce a bulk supply of vaccine antigen and adjuvant. Antigen is the active ingredient in a vaccine that causes the human body’s immune system to develop antibodies that help fight an invading virus. Depending on the results of clinical studies, adjuvants could be added to a vaccine to improve the immune system’s response and potentially reduce the amount of antigen necessary for the body to recognize and fight a virus.

Having both antigen and adjuvant on hand provides maximum flexibility in a future immunization program, if a program is recommended. For example, if needed these ingredients could be used in vaccine to help protect health providers and other members of the critical workforce, as recommended by the National Strategy for Pandemic Influenza.

With these funds manufacturers will also prepare pilot lots of potential vaccine for use in clinical studies to determine the proper dose for a vaccine, determine if adjuvants are appropriate and ensure a vaccine is safe and effective. The U.S. government will share as much information as possible from the results of these clinical studies with the World Health Organization and the global community so that other countries can benefit from the U.S. efforts to determine dosage, safety and effectiveness.

The Biomedical Advanced Research and Development Authority (BARDA) in the HHS Office of the Assistant Secretary for Preparedness and Response established the existing contracts with these companies in 2004 as part of the National Strategy for Pandemic Influenza.

To learn more about the National Strategy for Pandemic Influenza, visit pandemicflu/plan/federal/pandemic-influenza.pdf. More about BARDA is available here. For the latest on the H1N1 flu virus, see here.

Source
HHS

Report Is First To Integrate Impact Of Multiple Environmental Stressors On Humans And Biodiversity

Multiple environmental stressors, such as agricultural runoff, pollution and invasive species, threaten rivers that serve 80 percent of the world’s population, around 5 billion people, according to researchers from The City College (CCNY) of The City University of New York (CUNY), University of Wisconsin and seven other institutions. These same stressors endanger the biodiversity of 65 percent of the world’s river habitats and put thousands of aquatic wildlife species at risk.

The findings, reported in the September 30 issue of Nature, come from the first global-scale initiative to quantify the impact of these stressors on humans and riverine biodiversity. The research team produced a series of maps documenting the impact using a computer-based framework they developed.

“We can no longer look at human water security and biodiversity threats independently,” said the corresponding author, Dr. Charles J. VГ¶rГ¶smarty, director of the CUNY Environmental CrossRoads Initiative and professor of civil engineering in The Grove School of Engineering at CCNY. “We need to link the two. The systematic framework we’ve created allows us to look at the human and biodiversity domains on an equal playing field.” The framework offers a tool for prioritizing policy and management responses to a global water crisis.

Many stressors threaten human water security and biodiversity through similar pathways, but influence water systems in distinct ways. For example, reservoirs convey few negative effects on human water supply but they significantly challenge aquatic biodiversity by impeding migration routes and changing water flow regimes.

Understanding and responding to the myriad threats to water security requires new methods to make diagnoses and to act on these findings. “As is the case with preventive medicine, our study demonstrates that diagnosing and then limiting threats at their local source, rather than through costly remedies and rehabilitation, is a more effective and sensible approach to assure global water security for both humans and aquatic biodiversity, ” notes Professor VГ¶rГ¶smarty.

“We’ve integrated maps of 23 different stressors and merged them into a single index,” said study co-leader Dr. Peter McIntyre, assistant professor of zoology, University of Wisconsin. “In the past, policymakers and researchers have been plagued by dealing with one problem at a time. A richer and more meaningful picture emerges when all threats are considered simultaneously.”

Among the stressors analyzed were the effects of pollution, dams and reservoirs, water overuse, agricultural runoff, loss of wetlands and introduction of invasive species. The authors said their findings are “conservative,” since there is insufficient information to account for additional stressors like pharmaceutical compounds and mining wastes.

High incident threat levels to human water security were found in developed and developing nations around the world. Affected areas include much of the United States, virtually all of Europe and large portions of Central Asia, the Middle East, the Indian subcontinent and eastern China.

“We uncovered a broad management principal operating at the global scale,” Professor VГ¶rГ¶smarty said. “In the industrialized world, we tend to compromise our surface waters and then try to fix problems by throwing trillions of dollars at the issues. We can afford to do that in rich countries, but poor countries can’t afford to do it.”

The researchers noted that causes of degradation of many of the developing world’s most threatened rivers bear striking similarities to those of rivers in similar condition in wealthy countries. However, going down the path of instituting highly engineered solutions practiced traditionally by industrialized nations, which emphasize treatment of the symptoms rather than protection of resources, may prove too costly for poorer countries.

There are many more cost-effective solutions, they point out. For example, engineers, can re-work dam operating rules to achieve economic benefits while simultaneously providing water releases downstream that preserve habitat and biodiversity.

With the high price tag for bringing water quality and supply in the developing countries to levels found in industrialized economies, Professor VГ¶rГ¶smarty argues that a more economical approach is called for. A strategy called integrated water resource management, which balances the needs of humans and nature, would best meet the dual challenge of establishing human water security and preserving biodiversity in the developing world.

It would be more cost effective, he contends, to ensure that river systems are not impaired in the first place. This could be accomplished through better land use management, better irrigation techniques and emphasis on protecting ecosystems. Healthy ecosystems provide many valuable, and free, services to society by providing clean water, flood control, and food supplies. The value of such freshwater services is in the trillions of dollars per year.

One of the project’s goals is to support international protocols to be used for water system protection since rivers maintain unique biotic resources and provide critical water supplies to people. An international approach is critical since more than 250 river basins cross international borders.

“It is absolutely essential to have information and tools that can be shared across nations,” Professor VГ¶rГ¶smarty stressed. “Our knowledge of these systems is progressively worsening as nations fail to invest in basic monitoring, true for both water quantity and quality. How can we craft protocols on biodiversity protection and human water security without good information?

“Monitoring the world’s fresh water would yield huge returns in terms of avoiding costly conflicts, providing food security, preserving unique life forms and a host of other valuable benefits. These benefits would cost pennies on the dollar.”

In addition to Professors VГ¶rГ¶smarty and McIntyre authors of the Nature report include Mark Gessner of the Swiss Federal Institute of Aquatic Science & Technology; David Dudgeon of the University of Hong Kong; Alex Prusevich and Stanley Glidden of the University of New Hampshire; Pamela Green of the City University of New York; Stuart Bunn of Griffith University, Australia; Caroline Sullivan of Southern Cross University, Australia; Cathy Reidy Liermann of the University of Washington; and Peter Davies of the University of Western Australia. The work was executed under the aegis and support of two elements of the Earth System Science Partnership (ESSP), which studies numerous aspects of global change science: the Global Water System Project (headquartered in Bonn) and the freshwaterBIODIVERSITAS project of DIVERSITAS, the International Programme of Biodiversity Science (Paris).

Source:
Ellis Simon
City College of New York

Smoking May Be A Risk Factor For Tuberculosis

Smoking appears to increase the risk of becoming infected with tuberculosis and the risk for the development of active disease upon infection, according to an analysis of previously published research in the February 26 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

About one-third of the world’s population is infected with the bacteria that cause tuberculosis (TB), but the organism is usually rendered inactive by the immune system, according to background information in the article. Active tuberculosis developed in approximately 8.8 million individuals in 2003 and is responsible for about 1.7 million deaths worldwide each year. “It has long been suggested that tobacco smoking may affect rates of TB morbidity and mortality,” the authors write. “This could be a result of increasing the risk of infection with TB mycobacteria, increasing the rate of active TB disease, or increasing the TB mortality rate; plausible mechanisms exist.”

Michael N. Bates, Ph.D., and colleagues at the School of Public Health, University of California, Berkeley, performed a meta-analysis of 24 previously published studies that examined the association between smoking and TB. Six of the publications dealt with the risk for TB infection, 13 with active TB disease and five with death from TB.

Across the studies, individuals who smoked had a 73 percent increased risk of becoming infected with tuberculosis and were more than twice as likely to develop active tuberculosis than those who did not smoke. This suggests that smokers are 40 to 60 percent more likely than non-smokers to develop tuberculosis disease after being infected with TB bacteria. The excess risk of death from TB associated with smoking was less than the excess risk of TB disease, suggesting that smoking does not increase the risk of death among those who already have active TB.

There are several potential explanations for the association, although more research is needed to determine the mechanisms involved, the authors note. Smoking could decrease immune response or damage the function of cilia in the airways, increasing the risk for TB. “Tuberculosis control policies should in the future incorporate tobacco control as a preventive intervention,” the authors write.

“Potentially, smoking is one of the most modifiable of exposures,” they conclude. “In developing countries, where life expectancy is short, highlighting smoking as a risk factor for TB may have greater resonance than advertising its risks for cancer and cardiovascular disease.”

This study was supported by a Fogarty International Training and Research Program award, a grant from Fogarty International Center Global Tobacco Control Research and Training Program, and by the Center for Occupational and Environmental Health, University of California (Berkeley, Davis, and San Francisco). Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

American Medical Association (AMA)
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Statins Don’t Lower Risk Of Pneumonia In Elderly

Taking popular cholesterol-lowering statin drugs, such as Lipitor® (atorvastatin), does not lower the risk of pneumonia. That’s the new finding from a study of more than 3,000 Group Health patients published online on June 16 in advance of the British Medical Journal’s June 20 print issue.

“Prior research based on automated claims data had raised some hope-and maybe some hype-for statins as a way to prevent and treat infections including pneumonia,” said Sascha Dublin, MD, PhD, a physician at Group Health and assistant investigator at Group Health Center for Health Studies. “But when we used medical records to get more detailed information about patients, our findings didn’t support that approach.”

In fact, Dublin’s population-based case-control study found that pneumonia risk was, if anything, slightly higher (26%) in people using a statin than in those not using any; and this extra risk was even higher (61%) for pneumonia severe enough to require being hospitalized.

“As a doctor, I’m a fan of statins for what they’ve been proven to do: lowering cholesterol and risk of heart disease and stroke in people who’ve had either disease or are at risk for them,” said Dublin. Statins are HMG coenzyme A reductase inhibitors, which also include Zocor® (simvastatin) and Mevacor® (lovastatin). This class of medications lessens inflammation, which plays a role in infections.

“But now we and some others have found that statins may have gotten some unearned credit for health benefits that they don’t actually have, including preventing pneumonia,” Dublin said. Suggestions from prior research had led to calls for expensive randomized controlled trials of
statins to prevent or treat infection. “But our study indicates that such trials would be an ill-advised use of limited research funds at this time,” she added.

Why the discrepancy between this new study and earlier ones? “Healthy-user bias is one reason,” said Dublin. In other words, compared to people who don’t take statins, those who do may be healthier and have healthier habits that lower their risks of unrelated diseases such as pneumonia. And that’s just what she found: Study patients who were on statins were less frail or disabled and also more likely to be vaccinated against flu or pneumococcal pneumonia. They were less likely to smoke, to have dementia, or to need help with bathing or walking.

Unlike the previous research on statins and pneumonia, Dublin’s study made great efforts to control for this bias, including reviewing medical records in detail for every study subject. It confirmed that every pneumonia event was a true case of pneumonia, which prior studies rarely did. And it focused on relatively healthy elderly people. All had intact immune systems and none lived in a nursing home. She studied the same 65- to 94-year-old patients, with their records coded to protect their privacy, as in earlier Group Health research, published in The Lancet in 2008. That work showed the flu vaccine didn’t protect the elderly from pneumonia as much as had been thought.

“We did an old-fashioned ‘chart review,’” said Dublin. “By reading the text in the medical records, you catch crucial details.”

Source
Group Health

View drug information on Mevacor; Zocor.

Disruption Of Circadian Rhythm Could Lead To Diabetes

Disruption of two genes that control circadian rhythms can lead to diabetes, a researcher at UT Southwestern Medical Center has found in an animal study.

Mice with defective copies of the genes, called CLOCK and BMAL1, develop abnormalities in pancreatic cells that eventually render the cells unable to release sufficient amounts of insulin.

“These results indicate that disruption of the daily clock may contribute to diabetes by impairing the pancreas’ ability to deliver insulin,” said Dr. Joseph Takahashi, an investigator with the Howard Hughes Medical Institute at UT Southwestern and co-senior author of the study, which appeared in the journal Nature. Dr. Takahashi, who recently joined UT Southwestern as chairman of neuroscience, performed the research with colleagues when he was at Northwestern University.

Circadian rhythms are cyclical patterns in biological activities, such as sleeping, eating, body temperature and hormone production.

The mammalian CLOCK gene, which Dr. Takahashi discovered in 1997, operates in many tissues of the body to regulate circadian rhythms. The gene codes for a protein called a transcription factor, which binds to other genes and controls whether they become active. BMAL1 also codes for a transcription factor that works together with the CLOCK protein.

The researchers examined pancreatic islet beta cells, which secrete insulin when blood sugar levels increase. They genetically engineered some mice to have defective CLOCK genes and some to also lack the BMAL1 gene. The mice also were engineered to contain a bioluminescent molecule that allowed the researchers to detect the circadian clock in pancreatic cells as a fluctuating glow.

Normal islet cells glowed in a 24-hour rhythm, while cells with defective CLOCK genes showed nearly flat rhythms. Cells from different organs exhibited different circadian rhythm patterns, indicating that each organ controls its own internal clocks.

Further study showed that the islet cells in the mutant animals created normal amounts of insulin, but the CLOCK mutant cells were defective in releasing the hormone.

Mice with defective CLOCK genes were prone to obesity and other signs of metabolic syndrome and liver dysfunction. Young mice lacking the BMAL1 gene only in their pancreas, however, had normal body weight and composition, and their behavior followed normal circadian patterns, although their blood sugar levels were abnormally high, the researchers found.

“This finding indicates that disruption of clock genes only in the pancreas, and not the rest of the body clock, can produce early signs of diabetes,” Dr. Takahashi said “These studies are important because they show a direct link between the clock in pancreatic beta-cells and glucose regulation. This should aid our understanding of the causes of glucose abnormalities.”

Researchers from Northwestern University led the study, with participation from researchers at the University of Chicago; the University of Wisconsin, Madison; Washington University School of Medicine, St. Louis; and GeneGo Inc.

The study was funded by the National Institutes of Health, the Chicago Biomedical Consortium Searle Funds and the Juvenile Diabetes Research Foundation.

Source:

UT Southwestern Medical Center

Dalmatian Bladder Stones Caused By Gene That Regulates Uric Acid In Humans

A gene mutation in Dalmatian dogs causing high levels of uric acid that can lead to bladder stones has been identified by a team of researchers in the
School of Veterinary Medicine at the University of California, Davis.

The discovery equips dog breeders with the tools to eliminate the harmful trait from the Dalmatian breed, and yields clues to the cause of similar
problems in humans. The findings are published November 7 in the open-access journal PLoS Genetics.

All mammals excrete waste products in their urine, but only humans, great apes and Dalmatian dogs produce elevated levels of uric acid in their urine
and blood. Other dog breeds do not usually produce uric acid.

In humans, this can result in kidney stones, hypertension and gout, a painful inflammation of the joints. In Dalmatians, high uric acid levels result
in the formation of bladder stones that often have to be removed surgically.

“This defect has been reported for nearly a century and was probably unintentionally introduced as breeders worked to select more distinctive
spotting patterns,” said veterinary geneticist and lead author Danika Bannasch. The gene responsible, however, has remained elusive until now.

“This trait can now be removed from the breed by crossing Dalmatians with the normal offspring of the original Dalmatian-pointer breeding that
occurred in the early 1970s,” Bannasch said. “The result is a healthy dog that looks like a Dalmatian, maintains the Dalmatian breed
characteristics and is genetically almost identical.”

The researchers collected DNA and urine samples from hundreds of dogs to identify the gene responsible for high levels of uric acid.
Genetic analysis of dogs that are a cross between pointers and Dalmatians revealed that gene to be SLC2A9, a gene that recently has been reported to
be important in regulating uric acid levels in humans. DNA analysis showed that mutations in the SLC2A9 gene were responsible for the elevated uric
acid in the Dalmatians.

Although humans also carry the SLC2A9 gene, scientists have not yet identified the exact mechanism that causes humans and great apes to have elevated
uric acid levels. The recent identification of the responsible gene mutation in dogs may help scientists better understand the related problem in
humans.

The study was partially supported by a fellowship from the Morris Animal Foundation and the National Institute of Diabetes and Digestive and Kidney
Diseases within the National Institutes of Health.

By Dec. 1, the Veterinary Genetics Laboratory in UC DavisВ№ School of Veterinary Medicine will begin offering DNA testing for the mutation in dogs to
allow breeders to eliminate the trait. Information on the testing program will be available online at vgl.ucdavis.edu/.

“Mutations in the SLC2A9 Gene Cause Hyperuricosuria and Hyperuricemia in the Dog.”
Bannasch D, Safra N, Young A, Karmi N, Schaible RS, et al. (2008)
PLoS Genet 4(11): e1000246. doi:10.1371/journal.pgen.1000246
Click here to view article online.

About PLoS Genetics

PLoS Genetics reflects the full breadth and interdisciplinary nature of genetics and genomics research by publishing
outstanding original contributions in all areas of biology. All works published in PLoS Genetics are open access. Everything is immediately and freely
available online throughout the world subject only to the condition that the original authorship and source are properly attributed. Copyright is
retained by the authors. The Public Library of Science uses the Creative Commons Attribution License.

PLoS Genetics

About the Public Library of Science

The Public Library of Science (PLoS) is a non-profit organization of scientists and physicians committed to making the world’s scientific and medical
literature a freely available public resource.

Public Library of Science

Treatment For Severe Respiratory Failure From Conditions Like Swine Flu Is Better When ECMO Is Part Of Treatment Than With Conventional Ventilation

Patients with severe acute respiratory failure (ARF) should be referred for
treatment using extracorporeal membrane `oxygenation (ECMO), rather than
using conventional ventilator management, to improve their chances of
survival without disability. ECMO would be cost-effective in the UK and
other countries with similar health care costs. These are the conclusions of
an Article published Online First and in a forthcoming edition of The
Lancet, Dr Giles Peek, Department of Cardiothoracic Surgery and
Extracorporeal Membrane Oxygenation, Glenfield Hospital, Leicester, UK,
Professor Miranda Mugford, University of East Anglia, UK, and Professor
Diana Elbourne of the London School of Hygiene and Tropical Medicine, UK,
and colleagues. ECMO has already been a vital tool for battling swine flu
and will be essential during the northern hemisphere winter when cases could
rise dramatically again.

Severe ARF causes high mortality in adults despite improvements in
ventilation techniques and other treatments (eg, steroids, inhaled nitric
oxide). Conventional management is by intermittent positive-pressure
ventilation where oxygen-enriched air is blown into the lungs at high
pressure, this in turn causes oxygen toxicity and pressure injury to the
lung tissue on top of the underlying lung disease, delaying or preventing
recovery. ECMO is an alternative which uses heart-lung bypass technology to
provide gas exchange outside the body, allowing time for the lung treatment
and recovery. Heparin is also given to prevent the blood clotting when it
passes through the ECMO system. In this study, the authors compared
treatment by a specialised ECMO team with care from specialist intensive
care unit teams using conventional ventilation, and also assessed the
cost-effectiveness of referral for ECMO care. In this UK-based randomised
controlled trial, 180 adults were randomly assigned to receive continued
conventional management (90) or ECMO (90). Eligible patients were aged 18-65
years and had severe but potentially reversible respiratory failure. The
primary outcome was death or severe disability at 6 months after
randomisation. Data about resource use and economic outcomes
(quality-adjusted life-years [QALYs]) were collected.

The researchers found that 68 of the 90 patients (75%) assigned to
consideration of ECMO actually received it. Of those referred for
consideration of ECMO, 63% survived to 6 months without disability compared
to 47% of those who were assigned to conventional management. This is
equivalent to 1 extra survivor without disability for every 6 patients
treated. Consideration of ECMO treatment led to a gain of 0.03 QALYs at
6-month follow-up. Use of modelling, making assumptions about life
expectancy, costs and quality of life after 6 months, predicted that the
cost per QALY of ECMO referral as ВЈ19,252. The cost per case was twice that
for conventional treatment, but the cost-effectiveness was still well within
the range regarded as cost-effective by health technology assessment
organisations such as the UK’s National Institute for Health and Clinical
Excellence (NICE).

The authors say: “This study shows a significant improvement in survival
without severe disability at 6 months in patients transferred to a
specialist centre for consideration for ECMO treatment compared with
continued conventional ventilation.”

They conclude: “The cost-effectiveness of ECMO would be improved if costs of
both transport and provision of the technique could be reduced…We are
confident that ECMO is a clinically effective treatment for acute
respiratory distress syndrome, which also promises to be cost effective in
comparison with other techniques competing for health resources.”

Dr Peek adds*: “Swine flu causes a viral pneumonia which can result in
severe respiratory failure in young adults, we have already used ECMO during
the first wave of the pandemic with good effect and we are expecting ECMO to
prove an invaluable weapon in the fight against the winter resurgence of the
infection, as has already been seen during the Australasian winter.”

In an accompanying Comment, Dr Joseph B Zwischenberger, University of
Kentucky College of Medicine, Lexington, KY, USA, and James E Lynch, ECMO
programme director, University of Texas Medical Branch, Galveston, TX, USA,
conclude: “The CESAR group should be congratulated on completion of such a
complex and large trial. The debate that will surround this study reflects
the difficulty of this type of research in the critically ill patient. This
study will likely provide ammunition for both those in favour and those
against the use of ECMO in the adult population.”

Source
The Lancet

KAI Pharmaceuticals Announces Advancement Of KAI-4169 Clinical Program Into A Phase 2 Trial

KAI Pharmaceuticals, Inc., a privately held drug discovery and development company, announced enrollment of the first patients in a Phase 2 study of KAI-4169, a novel pharmaceutical agent being tested for the treatment of secondary hyperparathyroidism (SHPT), which is a frequent and serious complication of end-stage renal disease (ESRD). The Phase 2 study is a double-blind, randomized, placebo-controlled, multiple ascending dose study to assess the safety, tolerability and efficacy of multiple intravenous (IV) doses of KAI-4169 administered during hemodialysis in patients with SHPT.

Results obtained in the study will be used to select the appropriate dosing regimen for further development of KAI-4169 for the chronic management of SHPT in ESRD patients. Previous Phase 1 data demonstrated that single IV doses of KAI-4169 were safe and well-tolerated and resulted in sustained reductions in serum levels of parathyroid hormone (PTH) in both healthy male subjects and ESRD patients with SHPT.

“The KAI-4169 program continues to advance as planned, and we expect to report data from the Phase 2 study in the second half of this year,” commented Steven James, President and CEO of KAI. “The results to date have been encouraging in these hard-to-treat patients. The unmet medical need is compelling – elevated PTH exacerbates mineral imbalances (particularly calcium and phosphorus) in ESRD patients, and is linked to severe pathological effects such as osteodystrophy, vascular calcification, and increased risk for cardiovascular events, all of which contribute to morbidity and mortality in these patients.”

About Secondary Hyperparathyroidism

SHPT develops early in chronic kidney disease (CKD) and worsens as renal function declines and progresses to ESRD. SHPT, which affects the vast majority of patients with ESRD, is associated with bone disease (high-turnover renal osteodystrophy) and cardiovascular disease (vascular calcification) and can lead to significant morbidity. In the U.S., there are roughly 350,000 and eight million patients with ESRD and CKD, respectively.

Source:

KAI Pharmaceuticals