An old therapy takes new flight

Before penicillin was discovered and became the standard treatment for bacterial infections, physicians sometimes used fly larvae to treat severe, infected and chronic wounds. Maggot debridement therapy (MDT), as it is now called, has recently returned to clinical practice in the wake of increasing bacterial resistance to antibiotics. MDT is approved by the US Food and Drug Administration and can be prescribed as a drug in Europe. Exactly how MDT promotes wound healing, however, is not known; so Gwendolyn Cazander (Bronovo Hospital, The Hague, The Netherlands, and VU University Medical Center, Amsterdam, The Netherlands) and her collaborators set up a study to find out. The team hypothesized that maggot excretions and secretions (MES) influence the complement system to modulate inflammatory response in a wounded host. The complement system plays a part in innate immunity by activating the inflammatory response due to injury.

They collected MES from instar-3 larvae of Lucilia sericata (common green bottle fly) and combined it with serum samples from surgical patients. MES reduced complement activation by up to 99.99% by breaking down complement proteins C3 and C4 (Wound Rep. Reg. 20, 879–886; 2012). The scientists believe that MES could therefore prove useful in treating diseases that result from excessive complement activation.

The sins of the father

More research is showing that ancestral environmental factors can influence the physiology and behavior of descendents. This is particularly true of drug abuse. Many current studies focus on maternal influences rather than those of the father.

In a study published in Nature Neuroscience (published online 16 December 2012; doi:10.1038/nn.3280), researchers from the Perelman School of Medicine at the University of Pennsylvania (Philadelphia) and Massachusetts General Hospital (Boston) identified an heritable phenotype of cocaine resistance in the sons of drug-addicted sires.

Senior author Christopher Pierce and his team allowed male rats to self-administer cocaine for 60 days before mating them with females that had never been exposed to the drug. To eliminate any paternal behavioral influence, the pair was separated directly after mating. Next, the rats' offspring were given the opportunity to self-administer cocaine. The researchers observed a delay in acquisition and reduced maintenance of cocaine self-administration in male, but not female, progeny. Subsequent analysis of the offspring's brains revealed that those of the male rats contained elevated levels of a protein known to blunt the effects of cocaine.

These findings suggest that paternal drug use may cause the epigenetic reprogramming of the germline, thereby producing a resistance to cocaine reinforcement in male offspring.

Streamlining vaccine production using mRNA

The creation and production of vaccines has come a long way since Edward Jenner developed the first known vaccine in 1796. Jenner used cowpox, a mild relative of smallpox, to induce immunity to smallpox. Today's vaccines typically use inactivated forms, attenuated forms or purified immunogenic components of the causative pathogens as active agents. For example, influenza vaccines include hemagglutinin and neuramidase, proteins found on the surfaces of influenza virus particles, which are purified from cultures of the predominant strains of influenza in fertilized chicken eggs or in cells. This process is time-consuming and its yield is unpredictable, hindering effective management of influenza outbreaks.

Now a group of German scientists has introduced a new strategy that could revolutionize vaccine production and improve response to pandemic infections. Karl-Josef Kallen (CureVac, Tübingen) and Lothar Stitz (Friedrich-Loeffler-Institut, Riems) led the effort to create an influenza virus using mRNA encoding hemagglutinin rather than the protein itself. The mRNA vaccine successfully protected mice (even very old and very young animals), ferrets and pigs against influenza (Nat. Biotechnol. 30, 1210–1216; 2012). The vaccine can be produced rapidly and does not require refrigeration, making it a cost-effective alternative to protein-based vaccines.

Placebo-induced analgesia in rats

The placebo effect, observed in the field of pain management for many years, is marked by a measurable increase in pain relief when no actual treatment has been given. Examining the placebo effect in humans is encumbered by practical and ethical limitations, and to date, surprisingly few animal studies have focused on placebo-induced analgesia.

The reason for the lack of studies dealing with the placebo effect in animals may be a shortage of reliable models to test it. Recently, researchers at the University of Florida (Gainesville) have filled this gap by developing a rat model of conditioned analgesia in an operant pain assay (Pain 153, 2009–2016; 2012).

John Neubert and his team conditioned rats to expect morphine or saline during two training sessions. Then during a final session all rats were given saline. Approximately 30–40% of the rats that received morphine in the first two trials behaved as if they had received it during the third session as well and showed pain relief.

The authors believe this new model of placebo-induced analgesia will allow them to better understand the mechanisms underlying palliative deception and provide a foundation for developing methodologies that would be difficult to test in human studies.

Reactivation of neural ensembles

It is assumed that episodic and contextual memories are retrieved by reactivating the hippocampal and neocortical cellular networks that were established at the time of learning. It has also been shown that the brain regions that are active during learning are also engaged during testing. Now, for the first time, thanks to the work of Brian Wiltgen at the University of California (Davis), neuroscientists can determine whether the same individual neurons that encode memory are later switched on during retrieval.

In a paper published in Current Biology (23, 1–8; 2013), Wiltgen and his team examine memory retrieval using transgenic mice that express a long-lasting, activity-dependant form of green fluorescent protein. They found that neurons in the hippocampus, amygdala and neocortex that were first labeled during a context fear conditioning task (learning) were reactivated during a subsequent memory retrieval task two days later. When memory was retrieved two weeks after learning, the authors observed that reactivation was altered in the hippocampus and amygdala but remained stable in the cortex.

These findings contribute to the growing body of knowledge regarding the hippocampus' role in contextual memory formation and retrieval and introduce a new method of mapping neuronal activation during learning and testing.

Missteps in animal behavioral models of anxiety

Animal models of human disorders are often used for testing therapeutic drugs, but in some cases, the results fail to translate into clinically relevant treatments, a growing concern for biomedical research. Scientists are working hard to identify and address the causes underlying such clinical failures. Among them are Ehud Fonio (Weizmann Institute of Science, Rehovot, Israel), Yoav Benjamini and Ilan Golani (both of Tel Aviv University, Israel), who recently reported that the standard set-up used for studying chronic anxiety disorders is flawed in several ways. The typical study design measures anxiety in the wrong mouse at the wrong time, claims the group (PLoS One 7, e48414; 2012 and Nat. Methods 9, 1167–1170; 2012).

They compared anxiety-like behavior in BALB/c (a strain considered to be chronically anxious and normally used in anxiety studies) and wild-derived mice over much longer than normal experimental periods. BALB/c mice initially seemed more anxious, but after a habituation period, they calmed down and showed less anxiety than did wild-derived mice for the remainder of the experiment. Hence, the authors conclude, wild-derived mice studied for longer periods of time may be a more suitable model of chronic anxiety. Validation of this model would require extensive follow-up testing.