World AIDS Day: US women with HIV lack access to health care

As we approach World AIDS Day, 1 December 2004, it is important to remember that one in five women with HIV in the United States has no health insurance. Half of the estimated 460,000 women and men who need lifesaving antiretroviral drugs are not getting them, according to a recent report by the Institute of Medicine (IOM) of the National Academy of Sciences. 

"These figures are appalling," said Paul Volberding, MD, chairman of the HIV Medicine Association (HIVMA) Board of Directors and a member of the IOM panel that wrote the report. "We find it tragic that in the richest country in the world, so many people are not getting the care they desperately need."

Most women with HIV/AIDS who do receive care do so under publicly funded programs. Despite growing enrollment, however, funding for programs like the Ryan White CARE Act were cut in this year's budget after years of stagnation.  Medicaid, the largest provider of care for people with HIV, could face cuts in coming years because of extremely tight budgets. 

Funding cuts for AIDS programs disproportionately affect African-American women, who are more likely to be low-income and therefore dependent upon publicly funded programs.  "They are also bearing the brunt of the AIDS epidemic," said HIVMA Board Member Kimberly Smith, MD, MPH, of Chicago's Rush University Medical Center.  African-American women account for 64 percent of the 12,000 new HIV infections among women each year.

"This World AIDS Day, we would like to remind people that the epidemic in the United States is not over," Dr. Smith said.  "Access to health care must improve in this country for people with HIV/AIDS, especially African-American women."

HIVMA experts are available for interviews on access to care and other HIV/AIDS issues.  Call Steve Baragona at (703) 299-0412 to arrange an interview. 

'Lighter than air' breathing more than doubles COPD patients' exercise endurance It certainly makes sense: COPD sufferers have varying degrees of serious breathing difficulties, which keeps them from almost any kind of exercise, especially in advanced stages. So maybe "lighter than air" air would be easier to breath, reduce shortness of breath and perhaps even allow them to do some exercise with all of its physical and mental benefits.

A group of Italian researchers reports in the November issue of the Journal of Applied Physiology that while breathing a low-density mixture of 79% helium and 21% oxygen (called heliox), the length of time that 12 COPD patients could do real exercise was 9 minutes, versus only 4.2 minutes for 12 patients breathing regular air (79% nitrogen/21% oxygen). And the exercise involved wasn't trivial: The subjects cycled "until exhaustion" at a rate of 50 rpm at 80% of their maximal rate measured several days earlier while on air.

COPD: 4th leading cause of death in world and U.S., and rising

The World Health Organization estimates that chronic obstructive pulmonary disease (COPD, defined as emphysema and chronic bronchitis) as a single cause of death around the world shares fourth place with HIV/AIDS, following coronary heart disease, cerebrovascular disease and acute respiratory infection. WHO estimates that 2,740,000 people died of COPD worldwide in 2000; cigarette smoking is blamed for about 85% of cases.

According to the National Heart, Lung, and Blood Institute (NHLBI), COPD is the fourth leading cause of death in the U.S. and is projected to rise to third place for both men and women by the year 2020. NHLBI says 12.1 million Americans 25 and older were diagnosed with COPD in 2001. Estimated cost of COPD in 2002 was $32.1 billion, of which $18 billion were direct costs.

COPD is characterized by shortness of breath (dyspnea) and exercise intolerance. Among severely affected patients, especially those with emphysema, the inability to exercise or even to move small distances is mostly due to limits on "breathing out" because of limited expiratory flow, and early onset of dyspnea.

Heliox appears to positively change multitude of lung mechanics

In the current study, the more than doubling in the time COPD patients could exercise "was associated with a significant reduction in lung dynamic hyperinflation (DH) at isotime (Iso; when the patients stopped exercising during regular air breathing), as reflected by the increase in inspiratory capacity (IC) to 1.97 from 1.77 liters and a decrease in dyspnea" scoring to 6 from 8.

The researchers said that "heliox induced a state of relative hyperventilation as reflected by the increase in minute ventilation" to 38.3 versus 35.5 liters, and minute ventilation over carbon dioxide output to 36.3 versus 33.9 at peak exercise, and by the reduction in arterial partial pressure of carbon dioxide at Iso to 44 from 48 and at peak exercise to 46 from 48.

The study, "Effect of heliox on lung dynamic hyperinflation, dyspnea, and exercise endurance capacity in COPD patients," was conducted by Paolo Palange, Gabriele Valli, Paolo Onorati, Rosa Antonucci, Patrizia Paoletti, Alessia Rosato, Felice Manfredi, and Pietro Serra from Dipartmento di Medicina Clinica, Servizio di Fisiopatologia Respiratoria, Università "La Sapienza," Rome, Italy.

Palange et al. says the "most likely explanation for our finding is that heliox improved maximal expiratory flow and maximal ventilatory capacity, as reflected by the increase in resting forced expiratory volume and by the increase in tidal volume, mean expiratory flow, and minute ventilation at peak exercise. Importantly, the improvement in maximal expiratory flow determined a significant reduction in lung dynamic hyperinflation and dyspnea, as reflected by the significant increase in inspiratory capacity (IC), inspiratory reserve volume and IC/minute ventilation, and decrease in dyspnea at Iso.

"All of these positive changes in lung mechanics allowed the patients to markedly improve exercise endurance time," they note.

And finally, "it is likely that the exercise protocol used, capable of inducing high levels of ventilation relative to subject's maximal ventilation for a prolonged period of time, has amplified the effect of heliox breathing in reducing turbulent airway resistances," the authors say. In a related observation, they believe that "the high-intensity constant work rate test utilized allowed us to clearly detect the beneficial effect of small changes in lung mechanics induced by heliox breathing on exercise capacity."

Next steps

The authors conclude that "heliox breathing, by reducing airflow limitations, lung dynamic hyperinflation and dyspnea sensation, is capable of improving high-intensity exercise endurance capacity in moderate to severe COPD patients." However, they note that "further studies are needed to verify the potential role of heliox supplementation during exercise rehabilitation programs in COPD patients."

Source
The study, "Effect of heliox on lung dynamic hyperinflation, dyspnea, and exercise endurance capacity in COPD patients," by Palange et al. appears in the November issue of the Journal of Applied Physiology, published by the American Physiological Society.

Finding could improve safety of stem cell transplants

A lipid that helps destroy potentially harmful cells during brain development shows promise for improving the safety and efficacy of stem cell transplants, say researchers at the Medical College of Georgia and University of Georgia.

When embryonic stem cells are being coaxed toward becoming brain cells that could be transplanted, that lipid, ceramide, helps eliminate cells that could later form tumors called teratomas, researchers say in the Nov. 22 issue of The Journal of Cell Biology.

“The body has amazing mechanisms to eliminate cells that are no longer wanted and that if they remain will harm the body by developing into tissues that are not meant to be,” says Dr. Erhard Bieberich, MCG biochemist and the study’s lead author. “Our studies show this particular mechanism can help stem cells safely become the cells we want them to be.”

“This is another approach to controlling differentiation and getting the cell types that you want,” says Dr. Brian G. Condie, developmental neurobiologist at UGA and MCG and senior author on the paper.

While it’s the ability of embryonic stem cells to make all types of tissue -- from brain cells to heart cells -- that has scientists worldwide exploring their potential to treat devastating diseases, their pluripotency can also be harmful if uncontrolled, says Dr. Bieberich.

Drs. Bieberich and Condie demonstrated in the Aug. 4, 2003 issue of The Journal of Cell Biology that a natural process occurs during development to eliminate excessive and potentially harmful cells. Just before neurons begin forming, there is a massive production of proteins and up-regulation of lipids. At that point, about half the cells have high levels of the protein PAR-4, half have high levels of the protein, nestin, and all have high levels of ceramide.

The researchers found cells that inherited PAR-4 died when partnered with ceramide. Fortunately, the nestin-bearing cells are most likely to become neurons while the PAR-4 cells, should they survive, could contribute to brain malformation.

In this new paper, they took their findings in mouse embryonic stem cells and also looked at an approved line of human embryonic stem cells available through the National Institutes of Health Embryonic Stem Cell Registry.

They found as the cells differentiated in culture, those containing PAR-4 have yet another bad dance card.

“We have discovered that particular cells derived from embryonic stem cells that express PAR-4 also cause teratoma formation,” says Dr. Bieberich of the mostly benign growths comprised of multiple types of tissue, typically none of which belong in the tissue where they are found.

They found PAR-4-expressing cells also express Oct-4, a transcription factor that controls a cell’s ability to develop into all three basic types of tissue: mesoderm, ectoderm and endoderm.  “If Oct-4 is expressed, the cells are still pluripotent, which is good if you want to grow all those kinds of embryonic layers,” says Dr. Bieberich. “But if you transplant them, you are at risk of forming teratomas.”

However, at least in the culture dish, when they added PAR-4’s lethal dance partner, ceramide, to the mix, PAR-4- and Oct-4-expressing cells again died before they could do harm.

The ceramide analogue, N-oleoyl serinol, or S18, also increased the proportion of nestin-containing cells in cell cultures and grafts.

Drs. Bieberich and Condie were quick to note that in their studies, they intentionally left PAR-4- and Oct-4-bearing cells in the mix to see if they could eliminate them.

“There already are ways to grow stem cells, purify them in cell culture and get a pure population of stem cells that you can transplant,” says Dr. Condie. “You want to make those cells differentiate into a particular cell type that is no longer able to form teratomas,” Dr. Bieberich says of this purification. “Having said that, that may not always be absolute.”

“What we are trying to do is find ways that can be combined with those methods currently being used to further reduce the chances of teratoma formation and make stem cells extremely safe,” Dr. Condie says. “This is something that you want to have zero doubt about.”

The next step is to look at an intact mouse embryo to see if the identical processes are at work.

The researchers’ work was funded by the NIH’s National Institute of Neurological Disorders and Stroke. Staff members of Dr. Bieberich’s lab, Dr. Jeane Silva, research coordinator; Dr. Guanghu Wang, research associate; and Kannan Krishnamurthy, graduate student; contributed to this work and co-author the publication. Testosterone deficiency found in one-third of diabetic men Low testosterone production appears to be a common complication of type 2 diabetes in men, affecting 1 out of 3 diabetic patients, a new study has shown.

Moreover, results of the investigation show that this condition, known clinically as hypogonadism, is caused not by a defect in the testes, where testosterone is produced, but by improper functioning of the pituitary gland, which controls production of testosterone, or of the hypothalamus, the region of the brain that controls the pituitary.

"This starts a whole new story on the crucial complications of type 2 diabetes," said Paresh Dandona, M.D., senior author on the study and director of the Division of Endocrinology, Diabetes and Metabolism at the University at Buffalo and Kaleida Health, where the study was conducted.

Results of the study appear in the November issue of Journal of Clinical Endocrinology and Metabolism.

Sandeep Dhindsa, M.D., UB assistant professor of medicine and first author on the study, said the findings are important because hypogonadism has not been recognized as a complication of type 2 diabetes, and the high prevalence of 30 percent was unexpected.

"The surprisingly high prevalence of low testosterone levels was associated with lower levels of pituitary hormones called gonadotrophins, suggesting that the primary defect in these patients was either in the pituitary or higher up in the hypothalamus," he said. "Since gonadotrophins drive the testes to produce testosterone, this finding gives us an insight into the pathogenesis of this complication of type 2 diabetes."

Earlier studies, including those conducted by this research group, found that diabetic subjects with erectile dysfunction and low testosterone levels often have low levels of pituitary hormones. However, conclusions from prior studies have been fraught with problems with testosterone assays, Dhindsa noted.

"A large portion of testosterone in the blood is bound to proteins, but a small portion is unbound and largely determines the amount of testosterone that is available to the tissues," said Dhindsa. "This active portion is called free testosterone. Assays to accurately determine it are delicate, tedious and time-consuming.

"This investigation set out to determine, in a prospective fashion, the prevalence of low total testosterone, accurately measure free testosterone in male patients with type 2 diabetes and to attempt to determine the seat of the problem in those with low free testosterone."

The study involved 103 consecutive males with type 2 diabetes who were referred to the Diabetes-Endocrinology of Western New York for treatment. None of the men had been diagnosed previously with low testosterone levels.

The researchers collected fasting blood samples from the participants and analyzed them for testosterone levels and for hormones associated with testosterone production. They also measured cholesterol and glucose levels, and a blood marker for how well glucose was controlled during previous months, called hemoglobin A1c. Data on height, weight and diabetic complications, including erectile dysfunction, neuropathy, retinopathy and coronary artery disease, were recorded.

Results showed that nearly one-third of the men had hypogonadism. Although obesity is associated with hypogonadism and is prevalent among type 2 diabetics, only 10-15 percent of the variation in low free testosterone levels could be attributable to body mass index, Dhindsa said. More than 30 percent of lean patients also were hypogonadal.

"Equally important, most of the men who had low testosterone levels also had lower levels of gonadotrophins, as compared to men with normal testosterone levels," he noted. "Furthermore, the gonadotrophin concentration in the blood correlated positively with free testosterone levels, supporting the notion that the cause of the defect is in the pituitary or hypothalamus."

The high prevalence of low testosterone in diabetic men is concerning, said Dhindsa, because in addition to lowered libido and erectile dysfunction, the condition is associated with loss of muscle tone, increase in abdominal fat, loss of bone density, and can affect mood and cognition.

"Further studies will help us determine why type 2 diabetic patients are more prone to developing hypogonadism," he said. "While obesity may explain part of the high prevalence of hypogonadism, it is likely that other factors associated with type 2 diabetes also contribute significantly. This area is clearly ripe for further investigation."

Additional researchers on the study were Sathyavani Prabhakar, M.D., UB clinical assistant instructor of medicine, Manak Sethi, M.D., research assistant, Arindam Bandyopadhyay, M.D., UB clinical assistant professor of medicine, and Ajay Chaudhuri, M.D., UB assistant professor of medicine. Brain researchers to develop new class of drugs to repair psychiatric disorders

“Smart” drugs capable of targeting specific brain cells to control psychiatric disorders such as autism and schizophrenia may be ready for early clinical trials within three years, with the launch of a $1.5 million project to take place at the Brain Research Centre (BRC), a partnership of the University of British Columbia and Vancouver Coastal Health Research Institute (VCHRI).

The new drugs would be the first significant change in decades to medications used to treat psychiatric disorders, says neuroscientist and team leader Yu Tian Wang, a UBC professor of Medicine and BRC member.

“We’re designing a whole new generation of medications that will work only on brain cells in areas that need to be repaired,” says Wang. “This new type of drug will correct abnormal brain functions in a targeted way, so patients don’t experience the side effects found in existing medications that affect the whole brain.”

One of only three investigations funded in NeuroScience Canada’s new Brain Repair Program, the project brings together five researchers from across Canada, including three investigators from the BRC at UBC Hospital.

Healthy brain functioning relies on a balance between the chemical messengers that stimulate brain cell activity (excitatory neurotransmitters) and those that diminish activity (inhibitory neurotransmitters.)

When balance is disrupted, the flow of information among brain cells in certain areas becomes confused. The result is impairments in perception, thought and behaviour seen in patients with brain disorders ranging from autism to major psychoses including schizophrenia and depression.

Using sophisticated equipment to view, study and manipulate brain messaging at the cellular level, the team will test their design of a type of drug that can fine-tune communication between brain cells and bring excitatory and inhibitory activity into a healthy balance.

Existing anti-psychotic drugs adjust communication on cell surfaces throughout the brain. Balance is restored in affected areas, however, the drugs may cause imbalance in normal, unaffected areas, leading to negative side effects. Side effects can range from sluggishness, insomnia and anxiety to severe psychoses, and limit prolonged use of these medications.

The new generation of “smart” drugs will target only the cells where communication balance is impaired, leaving healthy areas of the brain unaffected.

Wang estimates the new type of drug could be available to patients within five to 10 years.

Brain and nervous system disorders affect one in five Canadians and are among the leading causes of death in this country and are the leading cause of disability. Health Canada has estimated the economic burden of these disorders at $22.7 billion and costs are expected to rise significantly as the population ages.

Other team members are: (in alphabetical order) Assistant Prof. Alaa El-Husseini, UBC Dept. of Psychiatry and BRC; Associate Prof. Stephen Ferguson, University of Western Ontario; Assistant Prof. Ridha Joober, McGill University; Professor Anthony Phillips, UBC Dept. of Psychiatry and BRC.

Note to editors: Moving and still colour images of brain cell-to-brain cell communication are available.

The Brain Research Centre, located at UBC Hospital, comprises more than 160 investigators with multidisciplinary expertise in neuroscience research ranging from the test tube, to the bedside, to industrial spin-offs.

NeuroScience Canada’s Brain Repair Program is an $8-million program that has received major support from the Canadian Institutes of Health Research (CIHR) to support Canada’s world-class neuroscience researchers. Further information about the NeuroScience Canada awards may be found at www.neurosciencecanada.ca.

NeuroScience Canada was founded in1988 and uses private, corporate and government funding to support research on mechanisms that protect and repair the brain and nervous system.

CIHR is the Government of Canada’s agency for health research.

VCHRI is a joint venture between UBC and Vancouver Coastal Health that promotes development of new researchers and research activity.

Patients' own stem cells used to cure incontinence Austrian researchers are successfully treating incontinent women with the patient's own muscle-derived stem cells. The findings of the first clinical study of its kind were presented today at the annual meeting of the Radiological Society of North America (RSNA).

"Urinary incontinence is a major problem for women, and for an increasing number of men," said Ferdinand Frauscher, M.D., associate professor of radiology at the Medical University of Innsbruck and the head of uroradiology at University Hospital. "We believe we have developed a long-lasting and effective treatment that is especially promising because it is generated from the patient's own body."

The stem cells are removed from a patient's arm, cultured in a lab for six weeks, and then injected into the wall of the urethra and into the sphincter muscle. The result is increased muscle mass and contractility of the sphincter and a thicker urethra. Many patients have no urinary leakage within 24 hours after the 15- to 20-minute outpatient procedure.

Stress incontinence affects nearly 15 million people – primarily women – around the world. It occurs when the urethra narrows or becomes otherwise abnormal, or when the sphincter muscles that help open and close the urethra become weak or diminished, causing urine leakage when an individual exercises, coughs, sneezes, laughs or lifts heavy objects.

Twenty females, ages 36 to 84, who were experiencing minor to severe stress incontinence participated in the research. Muscle-derived stem cells were removed from each patient's arm and cultured, or grown, using a patented technique that yielded 50 million new muscle cells (myoblasts) and 50 million connective tissue cells (fibroblasts) after six weeks. When implanted into the patient under general or local anesthetia, the new stem cells began to replicate the existing cells nearby. One year after the procedure, 18 of the study's 20 patients remain continent.

"These are very intelligent cells," Dr. Frauscher said. "Not only do they stay where they are injected, but also they quickly form new muscle tissue and when the muscle mass reaches the appropriate size, the cell growth ceases automatically."

Since the stem cells must be in contact with urethra and sphincter tissue for the procedure to work, a major factor in the success of this treatment was the development of transurethral three-dimensional ultrasound. "With real-time ultrasound, we are able to see exactly where the new cells must be placed," Dr. Frauscher said.

Stem cells are unspecialized cells capable of renewing themselves through cell division. Scientists believe that adult stem cells are located in small numbers throughout the tissues of the human body, where they quietly reside until activated by disease or injury and begin dividing. In addition to repairing body tissue, stem cells can be induced to become cells for specialized functions of the body.

Dr. Frauscher said the cost of the stem cell procedure was comparable to two popular treatments for incontinence: the long-term purchase and use of absorbents, such as adult diapers, and collagen injections, which show improvement during the first six months but often result in symptoms returning after a year. Dr. Frauscher also said the stem cell treatment appears to be more successful with women at this time. For men, incontinence is often caused by prostate surgery, which may result in scar tissue formation, where the stem cells do not grow very well. In men without scar tissue stem cell therapy seems to work as well as in women, Dr. Frauscher said.

Co-authors of the Austrian study are Andrea Klauser, M.D., Dieter Zur Nedden, M.D., Leo Pallwein, M.D., Rainer Marksteiner, Ph.D., Hannes Strasser, M.D., and Georg Bartsch, M.D.

Brain imaging with MRI could replace lie detector When people lie, they use different parts of their brains than when they tell the truth, and these brain changes can be measured by functional magnetic resonance imaging (fMRI), according to a study presented today at the annual meeting of the Radiological Society of North America. The results suggest that fMRI may one day prove a more accurate lie detector than the polygraph.

"There may be unique areas in the brain involved in deception that can be measured with fMRI," said lead author Scott H. Faro, M.D. "We were able to create consistent and robust brain activation related to a real-life deception process." Dr. Faro is professor and vice-chairman of radiology and director of the Functional Brain Imaging Center and Clinical MRI at Temple University School of Medicine in Philadelphia.

The researchers created a relevant situation for 11 normal volunteers. Six of the volunteers were asked to shoot a toy gun with blank bullets and then to lie about their participation. The non-shooters were asked to tell the truth about the situation. The researchers examined the individuals with fMRI, while simultaneously administering a polygraph exam. The polygraph measured three physiologic responses: respiration, blood pressure and galvanic skin conductance, or the skin's ability to conduct electricity, which increases when an individual perspires.

The volunteers were asked questions that pertained to the situation, along with unrelated control questions. In all cases, the polygraph and fMRI accurately distinguished truthful responses from deceptive ones. fMRI showed activation in several areas of the brain during the deception process. These areas were located in the frontal (medial inferior and pre-central), temporal (hippocampus and middle temporal), and limbic (anterior and posterior cingulate) lobes. During a truthful response, the fMRI showed activation in the frontal lobe (inferior and medial), temporal lobe (inferior) and cingulate gyrus.

Overall, there were regional differences in activation between deceptive and truthful conditions. Furthermore, there were more areas of the brain activated during the deception process compared to the truth-telling condition.

Dr. Faro's study is the first to use polygraph correlation and a modified version of positive control questioning techniques in conjunction with fMRI. It is also the first to involve a real-life stimulus. "I believe this is a vital approach to understand this very complex type of cognitive behavior," Dr. Faro said. "The real-life stimulus is critical if this technique is to be developed into a practical test of deception."

Because physiologic responses can vary among individuals and, in some cases, can be regulated, the polygraph is not considered a wholly reliable means of lie detection. According to Dr. Faro, it is too early to tell if fMRI can be "fooled" in the same manner.

However, these results are promising in that they suggest a consistency in brain patterns that might be beyond conscious control.

"We have just begun to understand the potential of fMRI in studying deceptive behavior," Dr. Faro said. "We plan to investigate the potential of fMRI both as a stand-alone test and as a supplement to the polygraph with the goal of creating the most accurate test for deception."

Dr. Faro's co-authors on this paper were Feroze Mohamed, Ph.D., Nathan Gordon, M.S., Steve Platek, Ph.D, Mike Williams, Ph.D., and Harris Ahmad, M.D.