Seeing red: Arterial spin labeling shows increased blood flow to key areas
of the brain after patients took a new Parkinson’s drug. Red indicates the
areas that saw the biggest increase across many different patients.
Credit: Kevin Black

Finding effective drug dosages using MRI could accelerate drug development

MIT Technology Review, December 13, 2010, by Veronique Greenwood  —  Even the most promising drug will fail if it never reaches its target. So before starting large clinical trials, pharmaceutical companies must determine, among other things, the precise dosage to use, a process that can be expensive and time-consuming. Scientists investigating a drug for Parkinson’s disease have now shown how an MRI scan can quickly determine the optimal dosage for drugs that act on the brain.

The most precise way to track drugs as they move through the body is a PET (positron emission tomography) scan, in which a drug is a radioactively tagged, injected into the body, and tracked with a scanner. But PET scans have several drawbacks, notes Kevin Black, associate professor of psychiatry at Washington University in St. Louis, Missouri, who led the new research, published in the December issue of The Journal of Neuroscience. PET scanners, and PET scans, are very costly. And because they expose subjects to radioactivity, multiple PET scans can pose a health risk. As an alternative to PET scans, drug companies sometimes spend months to years assessing optimal dosages via clinical measures such as mood questionnaires or tests of patients’ manual dexterity.

The Washington University study, funded by Synosia Therapeutics, is the first to track a drug’s effect with an MRI technique called arterial spin labeling (ASL). Using this approach, the researchers determined the optimal dosage of the Parkinson’s drug noninvasively, without injections or radioactivity, in four months.

The researchers focused the MRI machine on subjects’ neck arteries to tag water molecules in the blood by changing their magnetic properties. These water molecules were visible in subsequent scans, providing a picture of arterial blood flow to particular parts of the brain.

The researchers took scans before and after the administration of different doses of the drug. When they compared the shots, Black and colleagues could see immediately which areas of the brain implicated in Parkinson’s showed increased blood flow, owing to the action of the drug. This allowed them to identify the most effective dosage for further testing.

Using ASL to accelerate the move to large trials will interest drug companies as a cost-cutting measure, says the University of Pennsylvania’s John Detre, a neurologist who developed ASL in the early 1990s and was not involved in the new research. “A key go/no-go decision in drug development early on is whether the drug is getting into the brain and doing what you think it’s doing,” he says. “This study is a fantastic proof of principle.”

ASL doesn’t have the specificity of PET scans, which can track the way drugs act at a molecular level, says Luis Hernandez of the University of Michigan’s MRI Research Facility. “But if you want to know if the drug is changing the part of the brain it should be reaching,” he remarks, “then this works well.”

An obvious target for ASL is antidepressants, which take two to six weeks or longer to show a clinical effect. With ASL, it is possible to see very quickly whether the drug is affecting the brain—an indication that it could be effective in alleviating depression. Detre adds that the technique could see more use in other areas of drug development: “You might be able to use this one technique to look at the effects of a very broad range of drugs on the brain.”

Clostridium difficile

GoogleNews.com, FORBES.com, December 13, 2010, by Lauran Neergaard, WASHINGTON — A superbug named C-diff is on the rise, a germ that so ravages some people’s intestines that repeated tries of the strongest, most expensive antibiotic can’t conquer their disabling diarrhea.

Now a small but growing number of doctors are trying a last-ditch treatment: Using good bacteria to fight off the bad by transplanting stool from a healthy person into the sick person’s colon.

Yes, there’s a yuck factor. But reports of several dozen cases in a medical journal and at a meeting of the nation’s gastroenterologists this fall suggest that with no more inconvenience than a colonoscopy, people who have suffered C-diff for months, or longer, can rapidly improve.

“This is the ultimate probiotic,” says Dr. Lawrence Brandt of New York’s Montefiore Medical Center, who has performed 17 of the procedures.

Yet it’s much more complex: An entire bacterial neighborhood is transplanted, almost like an organ transplant minus the anti-rejection drugs, says Dr. Alexander Khoruts of the University of Minnesota. He took a genetic fingerprint of the gut bacteria in a woman left emaciated after eight months of severe C-diff. Not only did the diarrhea disappear after a fecal transplant, but that normal bacteria mirroring her husband’s – the donor – quickly took root in her recovering intestine.

Here’s the caution: Fecal transplants haven’t been studied in the way that science requires to prove they work – by comparing similar patients given either a transplant or more intense antibiotics. History is full of failed treatments that doctors thought promising until they were put to a real test.

“There’s very good reason to think this fecal transplantation, or bacteriotherapy, might work, but it needs to be proven before everybody starts to do it,” stresses Dr. Lawrence Schiller, a gastroenterologist with the Baylor Health Care system in Dallas. He followed reports on the treatment at the American College of Gastroenterology’s recent meeting, but hasn’t joined the fledgling trend.

C-diff, formally named Clostridium difficile, has become a menace in the nation’s hospitals, and can spread outside of them, too. Some patients suffer just mild diarrhea, but others, especially older adults weakened by previous illness, can develop a more severe condition called colitis. There aren’t precise counts but some government estimates suggest C-diff may be responsible for as many as 15,000 deaths a year.

Up to a third of patients experience a second infection, and some go on to suffer recurrent bouts. Those worst-case patients are put on increasingly strong doses of the powerful antibiotic vancomycin for weeks, even months, at a time, treatments that Brandt says can cost $2,500 or more with each try.

But because antibiotics kill good germs as well as bad ones, the C-diff can bounce back inside a colon now depleted of the hundreds of species of bacteria that are supposed to live there.

“They’re caught in this cycle of treatment and re-treatment,” says Minnesota’s Khoruts, who has performed 21 fecal transplants since discovering how normal bacteria took over in his first patient in 2008. He’s now begun more detailed before-and-after mapping of patients to try to identify whether particular good bacteria are key.

Fecal transplants aren’t new – the first was reported in 1958, and they’ve been performed occasionally ever since. But of 170 cases described in medical journals since then, about a third were published this year, suggesting increased interest as the C-diff problem grows, says Montefiore’s Brandt.

Doctors who perform fecal transplants agree that more rigorous research is needed – without it, there’s no way to know if only the supposed successes, and not the failures are being written up. Brandt is planning a pilot study.

“I used to say this was just a measure of how desperate patients and their doctors were. There came a time when there was nothing else to do,” says Dr. Christina Surawicz of the University of Washington’s Harborview Medical Center, before performing her 16th procedure last week.

How are they done? There’s no one method. Brandt insists on a list of tests to make sure the donor doesn’t have diseases such as hepatitis or HIV, or intestinal parasites. Then the donor, usually a close relative, brings in a fresh stool sample that Brandt liquifies and essentially drips into the patient’s colon during a routine colonoscopy.

Insurance companies don’t specifically cover fecal transplants, but they do pay for colonoscopies for C-diff patients, Brandt says. The donor’s testing can run to several hundred dollars. If insurance does not cover it, the patients pay.

One of Brandt’s patients suffered recurrent bouts of C-diff for about 18 months before finding the option. “You start to feel like a leper, quite honestly,” says Ruth, a New York woman who asked that her last name not be used. She says she’s felt great for two years since getting treated, although “I will tell you I have not taken another antibiotic.”

Clostridium Difficile
(C. difficile, C. diff)

Clostridium Difficile (C. diff) Colitis Overview

Clostridium difficile (or C. difficile, C. diff) colitis is a common infection of the colon that is typically associated with the use of antibiotics. It is, therefore, also called antibiotic-associated colitis. Another common name for this condition is pseudomembranous colitis.

Clostridium is a family of bacteria containing several members. Some of the other well known bacteria in this group include Clostridium botulinum and Clostridium tetani, which are the causes of botulism and tetanus, respectively.

There are typically two forms of Clostridium difficile; one is the inactive or non-infectious form, called the spore, and the other is the active and infectious form. The spore form can survive in the environment for a long time, whereas the active form cannot.

Clostridium difficile colonize the intestinal tract by the oral route (mouth), following the disruption of the balance of normal colonic bacteria (normal flora), which is usually due to the use of antibiotics. Although C. diff spores may reside in the active form in the colon of some individuals (carrier state), they can also be ingested in this form (fecal-oral transmission).

After being shed in the stool, C. diff may be found residing in many places, especially in hospitals, nursing homes, and other health care facilities.

The common locations of the C. diff include:

furniture,

bathroom floors,

stethoscopes,

bedpans,

telephones,

fingernails,

floors,

diaper pails,

jewelry (rings),

infant’s rooms,

toilet seats, and

other objects commonly used by patients and health care professionals.

From Medscape Medical News

Medscape.com, by Mark  Crane, December 11, 2010 — It has long been known that disruptive behavior by healthcare professionals undermines a culture of safety, team collaboration, and communication flow. A new study shows that it also has a direct effect on a hospital’s financial health.

It may be impossible to specifically quantify the economic consequences of physicians and others who “act out,” intimidate and bully colleagues, or just are not good team players. The study, by Alan H. Rosenstein, MD, medical director of Physician Wellness Services of Minneapolis, Minnesota, in the Journal of Healthcare Risk Management, estimates the financial risk of disruptive behavior in terms of staff recruitment and retention, malpractice lawsuits, and “no pay for adverse events” reimbursement policies of many insurers.

It also proposes a 10-point process to reduce those effects and curtail negative conduct that can damage patient satisfaction and a hospital’s reputation.

“The joint commission states that nearly 70% of sentinel events can be traced back to an error in communication,” Dr. Rosenstein told Medscape Medical News. “There is a strong correlation between bad behavior and bad things happening. People who are intimidated are reluctant to speak up when they see something about to go wrong. The essential information flow is broken when nurses are afraid to call a physician who routinely verbally abuses them.

“Addressing disruptive behaviors as one of the human factor issues affecting healthcare delivery should be a key component of all risk management programs,” he said. “These behaviors are more widespread than many thought, often because the health professional acting out under stressful conditions doesn’t understand the downstream effect his actions have on others.”

Dr. Rosenstein defines disruptive behavior as “any any inappropriate behavior, confrontation, or conflict, ranging from verbal abuse (yelling, intimidation, condescending, berating, disrespectful, abusive behaviors) to physical or sexual harassment, that can negatively affect work relationships, communication efficiency, information transfer, and the process and outcomes of care.” Although the data have shown that usually only 3% to 5% of the medical staff is truly disruptive, these individuals can have a profound effect on the entire organization.

Nurse Retention

The survey showed that more than 80% of respondents had witnessed disruptive behavior by physicians, and more than one third knew of a nurse who had left the hospital because of it.

“The direct costs of recruiting a new nurse can range between $60,000 and $100,000,” in addition to the indirect costs of orientation, training, and the time needed to get a newly hired nurse up to speed.

“More than 90% of respondents stated that as a result of a disruptive incident, they were stressed or intimidated, or lost their ability to focus and concentrate, which led to significant gaps in communication, collaboration, and information transfer,” the author notes.

In addition: “More than 70% of the respondents saw a direct linkage between disruptive behaviors and compromises in patient quality and the occurrence of medical errors, more than 50% felt there were compromises in patient safety, and 25% felt there was a linkage to patient mortality. Fifteen percent of the respondents stated that they were aware of a specific adverse event that could be attributed to a disruptive episode.”

Adverse Events

Many insurers are refusing additional payments to cover the expense of preventable adverse events, including those following disruptive behaviors. The author and colleagues conducted a multihospital study, looking at the frequency of selected adverse events and their effect on hospital lengths of stay, cost, and patient mortality.

“While not all adverse events are directly caused by bad behavior, there’s strong anecdotal evidence that many are due to the communication breakdown, and the costs are quite high,” Dr. Rosenstein said.

For example, the cost of an adverse drug event ranges from $2000 to $5800 per hospitalization, and an increase in length of hospital stay of 2.2 to 4.6 days. An estimated 1.5 million preventable drug events occur each year, and 1 of every 10 patients suffers as a result.

Likewise, the costs of a hospital-acquired infection averages between $20,000 and $38,000 in additional costs of care. An estimated 1.7 million infections and 99,000 deaths occur each year related to hospital infections.

Malpractice Liability, State Fines, and Accreditation

Negligence claims are often precipitated by exposures related to poor communication, dissatisfaction, and adverse events. “Several studies have shown a strong correlation among provider communication, patient dissatisfaction, physician incident reports and the likelihood of being sued,” Dr. Rosenstein writes. The average cost of a medical error–based claim was $521,560, according to a 2006 study in the New England Journal of Medicine.

In addition, states are imposing fines for organizational mistakes. In 2009, California fined 7 hospitals for harm caused to patients from avoidable mistakes. The fines range from $25,000 to $100,000 per hospital. Since 2007, the state has issued 134 fines to 90 hospitals, totaling $4.225 million.

Regarding accreditation, the joint commission issued a standard in January 2008 requiring hospitals to confront “disruptive” medical staff members. Hospitals must implement a code-of-conduct policy and provide education to address disruptive behavior, or they could face accreditation problems.

Ways to Address Disruptive Behaviors

Dr. Rosenstein calls on hospitals to be more proactive in addressing negative behaviors by first trying a remedial approach instead of a confrontational or punitive legal one.

“Many doctors don’t recognize that they are acting in a disruptive manner and may not be aware of the negative impact it has on staff relationships and outcomes of care,” Dr. Rosenstein said. “We’re suggesting that early intervention by friends, family, or colleagues can help physicians recognize the extent of the problem before it causes an adverse event.”

Virginia Hood, MD, a nephrologist in Burlington, Vermont, and president-elect of the American College of Physicians, agrees that hospital staff and administration need better ways to deal with disruptive behavior before it becomes a legal case.

“An outburst can be triggered by exhaustion and undue stress. The people who yell and scream need assistance,” she says. “If it’s an isolated case, a senior person should take them aside in a nonconfrontational way and help resolve what’s going on, and educate the doctor that his behavior can’t be repeated regardless of the stress.”

Dr. Hood emphasized that any hospital committee must make sure “the complaint isn’t mischievous, some political game that goes on in hospitals. You need a good organizational structure to be set up to investigate the complaint, counsel the disruptor, and protect patient safety.”

Dr. Rosenstein’s study calls for a greater organizational commitment by enacting policies that specifically identify impermissible actions and providing resources, including sensitivity training, to address the problem.

Incident reporting must be consistent. “All complaints should be channeled to one committee and reviewed by a multidisciplinary group to avoid personal bias or potential conflicts of interest regarding the individuals involved. The committee should be responsible for directing the complaint to the appropriate party and ensuring that follow-up action is taken.”

Dr. Rosenstein recommends a range of programs, including assertiveness training, team collaboration training, cockpit management, and pit crew management, that “can help individuals gain the confidence to speak up immediately without fear of intimidation or retaliation.”

Only those with experience in conflict management and dispute resolution should intervene in situations of disruptive behavior, Dr. Rosenstein concludes. “For some individuals, particularly first-time offenders, the act of bringing the event to their attention will help them recognize the consequences of their behaviors, and the behaviors do not recur. Other individuals require a more comprehensive approach and in-depth training in stress or anger management or, in some cases, individualized therapy.”

The author has disclosed no relevant financial relationships.

From WebMD Health News

WebMD.com, December 13, 2010, by Daniel J. DeNoon — Redheads may feel pain more sharply, but the facts don’t support their reputation for excessive bleeding during or after surgery.

That’s the conclusion of four Welsh surgeons who searched the medical and anecdotal literature for evidence to support the belief that surgery poses extra problems for people with red hair.

“It would seem that the reputation of people with red hair for having increased [surgical] risk is without any basis in fact and should only be used as an excuse of last resort by surgeons,” Andrew L. Cunningham of Morriston Hospital in Swansea, Wales, and colleagues conclude in the Christmas issue of BMJ.

Up to 2% of the world population and up to 6% of those in the Northern Hemisphere have red hair and fair skin. It’s due to an inherited mutation that causes loss of function in the gene responsible for black-brown hair and skin color.

Redheads are at increased risk of skin cancer. There’s also some evidence that they have a lower pain threshold and respond less well to anesthetics such as lidocaine.

Because red-haired people reportedly bruise more easily than others, it’s been supposed that they are also more likely to bleed during or soon after surgery. But Cunningham and colleagues could find no evidence linking red hair to coagulation problems or bleeding tendencies.

There has also been a rumor that redheads are prone to hernias. For this the researchers found no basis in fact.

“Despite sporadic reports to the contrary, the clinical implications of red hair … remain questionable,” they conclude.

SOURCE:

Cunningham, A. BMJ, published online Dec. 10, 2010.

The Voyager 1 spacecraft, currently hurling through space at 38,000 mph — and nearing the edge of the solar system.  Credit: NASA

The event is a major milestone in Voyager 1’s passage through the heliosheath, the turbulent outer shell of the sun’s sphere of influence, and the spacecraft’s upcoming departure from our solar system.

OUTER SPACE – NASA says the long-running Voyager 1 spacecraft hurtling toward the edge of the solar system has reached another milestone.

Since 2004, the unmanned probe has been exploring a region of space where the solar wind — charged particles streaming from the sun — slows abruptly and crashes into the thin gas between stars. NASA said Monday that recent readings show the solar wind has slowed to zero, meaning the spacecraft is getting ever closer to the solar system’s edge.

“The solar wind has turned the corner,” said Ed Stone, Voyager project scientist based at the California Institute of Technology in Pasadena, Calif. “Voyager 1 is getting close to interstellar space.”

The event is a major milestone in Voyager 1’s passage through the heliosheath, the turbulent outer shell  of the sun’s sphere of influence, and the spacecraft’s upcoming departure from our solar system.

It’ll take about four more years before Voyager 1 completely exits the solar system and enters interstellar space, however, NASA scientists said the speed of the solar wind hit zero in June, when Voyager 1 was 10.6 billion miles from the sun.

Voyager 1 and its twin Voyager 2 were launched in 1977 to explore the giant planets and have kept on going. Voyager 2 is about 8.8 billion miles from the sun, traveling a different path at a different speed.

Voyager 1 is traveling faster, at a speed of about 38,000 mph, compared to Voyager 2’s velocity of 35,000 mph. In the next few years, scientists expect Voyager 2 to encounter the same kind of phenomenon as Voyager 1.