Day: 08/02/2010

Marijuana Time Warp

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People who smoke pot can feel lost in time—for some, it’s part of the draw. Now researchers may have figured out one reason why cannabinoids, the psychoactive compounds in marijuana and hashish, make people feel this way; they disrupt the body’s internal clock.

Sleeping, eating, and other activities are all part of a 24-hour physiological cycle known as the circadian rhythm. This internal clock is controlled by neurons in a region of the brain called the suprachiasmatic nucleus (SCN). The SCN normally uses light to reset the clock. That’s what happens when you travel from one time zone to another. But absent any sensory input, SCN neurons will still maintain a circadian rhythm: People and animals kept in total darkness continue to eat and sleep at the usual times.

Several years ago, researchers discovered that SCN neurons possess receptors for cannabinoids. In the new study, a team led by Yale University circadian biologist Anthony van den Pol tried to figure out what role these receptors play.

The researchers housed 42 mice in total darkness for 2 weeks to synchronize their internal clocks. In this environment the animals cycled through active and inactive phases lasting about 12 hours each. After 2 weeks, the researchers shined a light into some of the cages shortly after the mice had entered their active phase. Because mice are nocturnal, they became active about 2 hours later in the day than did mice not exposed to light, a phenomenon called “phase delay.” But mice given brain injections of cannabinoids before light exposure exhibited much less of a phase delay; they became active only 1 hour later than did animals not exposed to light.

The researchers then looked at the SCN cells themselves. When they added cannabinoids to mouse SCN cells in a petri dish, the cells fired about 50% more frequently. This increased activity likely mucks up the circadian rhythm in a live mouse, the researchers reported online this week in The Journal of Neuroscience.

The team believes cannabinoids may have a similar effect in humans. People tend to lose track of time when they smoke pot, van den Pol says. That may be because the cannabinoids in the drug cause their SCN neurons to fire erratically, he says, disrupting their internal clock.

Joseph Bass, a circadian researcher at Northwestern University in Evanston, Illinois, says the work supports the idea that addictive substances can impact the body’s circadian rhythm. Anecdotally, this may seem obvious, but until recently studies of addictive substances focused only on the brain’s reward system. Evidence that molecules can impact both the reward system and the circadian system is just emerging, Bass says.

Island Monkeys Give Clues to Origins of HIV’s Ancestor

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VIENNA—Thousands of years ago, a piece of West Africa separated from the mainland and formed the island of Bioko. The monkeys that inhabit the island may be crucial to unraveling the puzzling origins of the AIDS epidemic in humans, according to a study presented here last week at the 18th International AIDS Conference.

Scientists have argued about the origin of the AIDS epidemic since it surfaced in 1981, but this much is widely accepted today: Sometime around 1931, HIV-1, the main virus driving the epidemic, likely entered humans from chimpanzees, which are infected with a related virus called SIVcpz. The chimp virus, in turn, is a blend of SIVs from two different monkey species.

Less clear is when the monkey viruses moved into chimpanzees. Last year, one prominent investigator in the origin field, evolutionary biologist Michael Worobey of the University of Arizona in Tucson, found evidence that the monkey-to-chimp jump occurred sometime between 1266 and 1685. Worobey and his team used changes in the RNA of these SIVs to calculate their age. These so-called molecular clocks depend on how they’re calibrated, however, and not everyone was convinced.

Skeptics, including virologist Preston Marx of the Tulane National Primate Research Center in Covington, Louisiana, suspected the leap from monkeys to chimps occurred tens of thousands of years earlier. SIVs and SIVcpz are found everywhere from East to West Africa, and Marx reasoned that it “was just not possible” for the viruses to have spread so widely in 500 years. So he came up with a new way to calibrate the molecular clock that relied on Bioko’s known separation date from the mainland, and he recruited Worobey to help him analyze the data.

Marx and his team collected samples of SIV in dead monkeys on Bioko, which were killed for bushmeat. The researchers isolated SIVs from four different species on the island. One species, the Bioko drill (Mandrillus leucophaeus poensis), has a mainland counterpart that also harbors SIV. The fact that the virus was in both drills and that the island separated from the mainland 12,000 years ago provided a precise way to calibrate the molecular clock, and comparisons of the SIVs confirmed Marx’s suspicion that the jump into chimpanzees must have occurred much earlier than Worobey’s previous estimates.

As it turned out, the SIV from the drills closely matches SIV from red-capped mangabeys, one of the two contributors to SIVcpz. So an ancestor of this drill could have infected chimpanzees. According to Marx’s analysis, a virus related to the Bioko drill’s SIV infected chimpanzees at least 22,000 years ago.

Worobey’s earlier studies did not date the origin of SIV itself but suggested that it was “relatively young.” Others have argued that the SIVs emerged millions of years ago. The new analysis of all four monkey species suggests that, at a minimum, the SIVs are 76,000 years old—although Marx suspects that they evolved far earlier. This longer history of primates harboring the viruses may explain why SIVs cause no harm in the African monkeys they infect, Marx noted: The hosts have had more time to evolve appropriate immune responses or cellular changes that make them less vulnerable to the viruses. (Recent reports strongly indicate that SIVcpz can cause AIDS in chimpanzees.)

“The data are excellent,” says Simon Wain-Hobson, a virologist at the Pasteur Institute in Paris who has been involved in origin studies since the start of the AIDS epidemic. But he cautions that the SIV on the island may have been introduced recently, upending Marx and Worobey’s clock calibration. “The jury is out,” says Wain-Hobson, noting that he is not ready to discard the substantial evidence from other molecular-clock analyses that SIVcpz is younger.

Paul Sharp, an evolutionary biologist at the University of Edinburgh in the United Kingdom who first described the SIVs that led to SIVcpz, has more confidence that the new findings will hold up to scrutiny. “Molecular-clock analyses have suggested that the SIVs arose within the last few thousand years,” he says. “These Bioko viruses are clear evidence that the SIVs must  be   much older than that.”

Cubicin (daptomycin): Drug Safety Communication – Risk of Eosinophilic Pneumonia

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MedWatch logo MedWatch - The FDA Safety Information and Adverse Event Reporting Program

Cubicin (daptomycin): Drug Safety Communication – Risk of Eosinophilic Pneumonia

AUDIENCE: Infectious Disease, Pulmonology

ISSUE:  FDA notified healthcare professionals and patients about the potential for developing eosinophilic pneumonia during treatment with Cubicin (daptomycin), an intravenous antibacterial drug indicated for use in treatment of serious skin infections and bloodstream infections. Eosinophilic pneumonia is a rare but serious condition where a type of white blood cell (eosinophil) fills the lungs. Symptoms of eosinophilic pneumonia include fever, cough, shortness of breath, and difficulty breathing. Eosinophilic pneumonia may lead to progressive respiratory failure and is potentially fatal if not quickly recognized and appropriately managed.

BACKGROUND: FDA has reviewed published case reports of Cubicin-associated eosinophilic pneumonia and conducted a review of post-marketing adverse event reports from the FDA’s Adverse Event Reporting System. FDA’s review identified 7 cases of eosinophilic pneumonia between 2004 and 2010 that were most likely associated with Cubicin. Based on these reviews, FDA determined that eosinophilic pneumonia can be associated with Cubicin use and requested that the manufacturer of Cubicin include this information in the Warnings and Precautions and Adverse Reactions, Post-Marketing Experience sections of the drug label.

RECOMMENDATION: Healthcare professionals should closely monitor patients being treated with Cubicin for eosinophilic pneumonia. Patients receiving Cubicin should immediately contact their healthcare professional if they develop a new or worsening fever, cough, shortness of breath, or difficulty breathing.