For generations, people have consumed cranberry juice, convinced of its power to ward off urinary tract infections, though the exact mechanism of its action has not been well understood. A new study by researchers at Worcester Polytechnic Institute (WPI) reveals that the juice changes the thermodynamic properties of bacteria in the urinary tract, creating an energy barrier that prevents the microorganisms from getting close enough to latch onto cells and initiate an infection.

The study, published in the journal Colloids and Surfaces: B, was conducted by Terri Camesano, associate professor of chemical engineering at WPI, and a team of graduate students, including PhD candidate Yatao Liu. They exposed two varieties of E. coli bacteria, one with hair-like projections known as fimbriae and one without, to different concentrations of cranberry juice. Fimbriae are present on a number of virulent bacteria, including those that cause urinary tract infections, and are believed to be used by bacteria to form strong bonds with cells.

For the fimbriaed bacteria, they found that even at low concentrations, cranberry juice altered two properties that serve as indicators of the ability of bacteria to attach to cells. The first factor is called Gibbs free energy of attachment, which is a measure of the amount of energy that must be expended before a bacterium can attach to a cell. Without cranberry juice, this value was a negative number, indicating that energy would be released and attachment was highly likely. With cranberry juice the number was positive and it grew steadily as the concentration of juice increased, making attachment to urinary tract cells increasingly unlikely.

Surface free energy also rose, suggesting that the presence of cranberry juice creates an energy barrier that repels the bacteria. The researchers also placed the bacteria and urinary tract cells together in solution. Without cranberry juice, the fimbriaed bacteria attached readily to the cells. As increasing concentrations of cranberry juice were added to the solution, fewer and fewer attachments were observed.

Cranberry juice had no discernible effect on E. coli bacteria without fimbriae, suggesting that compounds in the juice may act directly on the molecular structure of the fimbriae themselves. This reinforces previous work by the WPI team that showed that exposure to cranberry juice alters the shape of the fimbriae, causing them to become compressed. Using an atomic force microscope as a minute strain gauge, the team also showed that the adhesive force exerted by bacteria on urinary tract cells declined in direct proportion to the concentration of cranberry juice in the solution.

“Our results show that, at least for urinary tract infections, cranberry juice targets the right bacteria—those that cause disease—but has no effect on non-pathogenic organisms, suggesting that cranberry juice will not disrupt bacteria that are part of the normal flora in the gut,” Camesano says. “We have also shown that this effect occurs at concentrations of cranberry juice that are comparable to levels we would expect to find in the urinary tract.”

Camesano notes that unpublished work has shown that while cranberry juice has potent effects on disease-causing bacteria, those effects are transitory. “When we takes E. coli. bacteria that have been treated with cranberry juice and place them in normal growth media, they regain the ability to adhere to urinary tract cells,” she says. “This suggests that to realize the antibacterial benefits of cranberry, one must consume cranberry juice regularly—perhaps daily.”

For those watching calories, Camesano says other recent work in her lab has shown that the effects of regular cranberry juice cocktail and diet (sugar-free) cranberry juice are identical. “That’s good news for people who do not like to consume a lot of sugary juice,” she says.

Source: Worcester Polytechnic Institute

A team of researchers at the University of California, San Diego School of Medicine has uncovered a new signaling mechanism used to activate protein kinases that are critical for the body’s inflammatory response. Their work will be published in the July 18 online edition of Science (Science Express.).

“In addition to helping explain the basic mechanisms of transmembrane receptor signaling, these results may identify a potential therapy for interfering with inflammation,” said Michael Karin, Ph.D., professor of pharmacology and pathology in UC San Diego’s Laboratory of Gene Regulation and Signal Transduction.

The tumor necrosis factor (TNF) receptor (TNFR) family codes for a large number of cell surface receptors of great biomedical importance, and its signaling mechanisms have been the subject of intense investigation during the past decade. Specific inhibitors of TNF receptor 1 (TNFR1) activation are being used in the treatment of rheumatoid arthritis, psoriasis and inflammatory bowel disease, and receptor activator of NF-κB (RANK) inhibitors were recently found to be effective in the treatment of osteoporosis and other bone loss diseases.

Now Atsushi Matsuzawa, Ph.D., and Ping-Hui Tseng, Ph.D., postdoctoral fellows in the Karin laboratory, describe how engagement of CD40, a member of the TNFR family, results in assembly of multiprotein signaling complexes at the receptor. However, according to the researchers – and contrary to previous expectations – signaling cascades that lead to activation of Jun Kinases (JNK) and p38 MAP Kinases (MAPK) are not initiated until these complexes dissociate from the receptor.

The authors found that complex translocation from the cell surface receptor to the cytoplasm, which is required for JNK and p38 activation, depends on degradation of a signaling protein called TRAF3. This process can be inhibited by a class of compounds known as Smac mimics.

“As Smac mimic compounds do not interfere with the activation of NF-κB-dependent innate immunity but do prevent the induction of JNK- and p38- dependent inflammatory mediators, they may serve as the prototypes for new anti-inflammatory therapy,” said Karin, who also noted that current drugs that work by interfering with TNFR signaling exceed $5 billion a year in revenue.

Source: University of California - San Diego

A group of researchers from the University of Copenhagen and the Biocentre at the Technical University of Denmark have managed to decipher the final part of the immune system’s key codes.

The same researchers already broke the first part of the codes last autumn, and have now put together a comprehensive picture of how the immune system checks for dangers both in and outside our cells.

According to the researchers this new information, produced with the aid of artificial neural networks, means that it should be possible to predict all the immune system’s known, and also as yet unknown codes. This should in turn lead to the development of new targeted treatments, for e.g. cancer and infectious diseases.

Professor Søren Buus from the Faculty of Health Sciences at the University of Copenhagen has been at the forefront of this research project.

The body’s natural defences uses these key codes in such a way that microorganisms cannot spy on and discover its functions. It this unique protection that has so far made it difficult for scientists to decode the entire human immune system and thus develop precise immunological tools and carry out organ transplants.

Source: University of Copenhagen

After taking a fresh look at an old fossil, John Flynn, Frick Curator of Paleontology at the American Museum of Natural History, and colleagues determined that the brains of the ancestors of modern Neotropical primates were as small as those of their early fossil simian counterparts in the Old World. This means one of the hallmarks of primate biology, increased brain size, arose independently in isolated groups—the platyrrhines of the Americas and the catarrhines of Africa and Eurasia.

“Primatologists have long suspected that increased encephalization may have arisen at different points in the primate evolutionary tree, but this is the first clear demonstration of independent brain size increase in New and Old World anthropoids,” says Flynn of the paper that appeared in the Museum’s publication Novitates this June. Encephalization is the increase in brain size relative to body size. Animals with large encephalization quotients (E.Q.’s) are those with bigger brains relative to their body size in comparison to the average for an entire group. Most primates and dolphins have high E.Q.’s relative to other mammals, although some primates (especially apes and humans) have higher E.Q.’s than others. … Continue Reading »

Inhibiting a growth factor that keeps muscles from getting too big may optimize recovery of injured soldiers, researchers say.

They are studying two myostatin inhibitors in mice with limb injuries, first to see which works best and then to identify the best delivery mechanism, says Dr. Mark Hamrick, bone biologist in the Medical College of Georgia Schools of Graduate Studies and Medicine.

“Fifty to 60 percent of the injuries occurring in Iraq are to the limbs, and the average injury requires five surgeries,” Dr. Hamrick says. “Myostatin inhibitors are known to improve muscle regeneration and we have evidence that they also increase bone formation. We believe these inhibitors will result in a stronger, more rapid recovery for these soldiers and other victims of traumatic limb injuries.”

A $1.2 million grant from the Office of Naval Research to Dr. Hamrick is enabling laboratory studies of two experimental myostatin inhibitors: a decoy receptor and a binding protein, both developed by MetaMorphix, Inc. of Beltsville, Md. Both inhibitors have been shown effective in muscle regeneration, but this is the first trial that looks at their impact on bone.

Two delivery mechanisms also will be studied. “Is the best approach a single injection bolus that circulates everywhere or just localized delivery?” Dr. Hamrick says.

Study collaborators include Dr. Li Liang of the life sciences company MetaMorphix, who will oversee development of the inhibitors; Dr. Xuejun Wen, bioengineer at Clemson University in Clemson, S.C.; and David Immel, radiographic imaging expert at Savannah River National Laboratory in Aiken, S.C., who will provide three-dimensional, high-resolution computerized tomography scans of injured limbs before and after treatment.

Myostatin is primarily produced by muscle cells. Females tend to produce more myostatin receptors, which helps explain why men tend to have greater muscle mass. Dr. Hamrick’s lab also has found the receptor on bone-derived stem cells – needed to help repair an injury – and others have found it in healing fractures. “When you take it away, the healed callus that forms at the fracture site has more bone in it,” says Dr. Hamrick. “Myostatin also increases fibrosis and scarring within tissue so part of what you are doing is blocking that.”

Bone and muscle healing typically go hand in hand. Muscle provides blood, growth factors and potentially stem cells for a healing callus. It’s not yet known how well bones reciprocate. “If you can improve muscle healing, you can improve bone healing,” Dr. Hamrick says. “Young people have a tremendous potential to heal that can be improved with better approaches to preventing infection and to healing soft tissue and bone in an integrated manner.”

Researchers hope to move to clinical trials in two to three years, Dr. Hamrick says. “If we find the primary role of myostatin is very early in the healing process and see a big jump in expression early in a fracture callus, it may be that a single injection bolus immediately after injury is the best time for treatment rather than continued treatment over a period of time.”

Myostatin is most highly expressed during development, but adults have some as well, so blocking it still facilitates muscle growth and development, primarily in response to exercise. Myostatin expression also tends to rise following an injury, apparently to control proliferation of new and regenerating cells, Dr. Hamrick says. Although there is no FDA-approved myostatin inhibitor, body builders often take supplements that claim to reduce myostatin function and help build muscle.

A whole spectrum of naturally occurring genetic variations likely result in minor alterations in myostatin signaling that could help explain why some people are more muscular than others, Dr. Hamrick notes. In a separate study funded by the National Institutes of Health, he is using a genetically engineered ‘mighty mouse,’ which is missing the myostatin gene, to find the best way to optimize bone growth and help young people avoid osteoporosis. German researchers reported in 2004 in the New England Journal of Medicine the case of a child whose muscles already were bulging as a newborn apparently because of a dysfunctional myostatin gene.

Source: Medical College of Georgia

Children born after a frozen, thawed embryo has been replaced in the womb have higher birth weight than those born where fresh embryos were used, Danish scientists reported to the 24th annual conference of the European Society of Human Reproduction and Embryology today (Tuesday 8 July). The mothers had longer pregnancies, and the children did not show an increased risk of congenital malformations, said Dr. Anja Pinborg, from the Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

The scientists studied all the 1267 children born in Denmark between 1995 and 2006 after frozen embryo replacement (FER). The children were divided into three groups; those born after cryo-preserved IVF (878), those born after cryo-preserved ICSI (310), and 79 where the method of creation of the embryos was unknown. During the same period 17857 children were born after IVF/ICSI treatment using fresh embryos, and these children were used as controls. Data on the children’s outcomes, including congenital malformations, were obtained from Danish national registries.

Freezing embryos allows couples to have several cycles of IVF/ICSI from the same egg collection. The embryos are subsequently thawed and replaced three to five days after ovulation in exactly the same way as fresh embryos are used. The technique helps to reduce the number of times ovaries are stimulated and eggs collected.

The scientists found similar rates of multiple pregnancies in the FER groups (ICSI 11.7% and IVF 14.2%), but in the fresh embryo groups the rates were considerably higher (ICSI 24.8% and IVF 27.3%). Maternal age was significantly higher in the FER group. Pregnancy duration was significantly longer for these mothers, and birth weight was also higher – about 200 grams – in the FER group. The proportion of low birth weight FER children significantly lower, as was the percentage of pre-term births.

“Additionally there were significantly fewer children admitted to a neonatal intensive care unit in the FER group,” said Dr. Pinborg, “although, when limited to single births, this difference disappeared. Most encouragingly, we found no increased risk of congenital malformations in the FER group; the rate in this group was 7.1% compared to 8.8% where fresh embryos had been used.”

Concerns had previously been raised about the effect of freezing and thawing of embryos, but this study has laid them to rest, the scientists say. “Up till now the data has been extremely limited,” said Dr. Pinborg. “There is only one other large birth register study – from Sweden – which shows similar results to ours. Our findings are of particular importance for Scandinavian countries, where single elective embryo transfer is regarded as the gold standard. This has meant that the use of FER has been rising steadily over the past few years. We wanted to be sure that the procedure had no deleterious effect on the offspring,” said Dr. Pinborg.

“The findings are reassuring, although we still lack sub-analyses regarding malformations and neurological sequelae of the FER. But if our results continue to be positive, FER can be accepted as a completely safe procedure, which can be used even more frequently than it is currently,” she said.

Source: European Society for Human Reproduction and Embryology

Alterations in a molecular brain pathway activated by marijuana may contribute to the cognitive symptoms of schizophrenia, according to a report in the July issue of Archives of General Psychiatry, one of the JAMA/Archives journals.

Expression of the cannabinoid 1 receptor (CB1R), the site of action of the main chemical ingredient of marijuana, is significantly reduced in the brains of individuals with schizophrenia. Activation of CB1R impairs signaling by gamma-aminobutyric acid (GABA), an important neurotransmitter essential for core cognitive processes such as working memory. The use of marijuana in individuals with schizophrenia appears to worsen this deficit in GABA synthesis.

Since reduced GABA is known to be present in schizophrenia, these findings suggest possible new drug targets that could help to improve function in people with the mental illness, University of Pittsburgh School of Medicine researchers report.

“Heavy marijuana use, particularly in adolescence, appears to be associated with an increased risk for the later development of schizophrenia, and the course of illness is worse for people with schizophrenia who use marijuana,” said David A. Lewis, M.D., corresponding author of the study and UPMC Endowed Professor in Translational Neuroscience, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine. “We wanted to understand the biological mechanisms that could explain these observations, and with this study, I believe that we can narrow down at least part of the ‘why’ to CB1R, the receptor for both tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana, and the brains own cannabinoid chemical messengers.”

Dr. Lewis and his colleagues examined specimens of brain tissue collected after death from 23 people with schizophrenia and 23 normal comparison subjects matched for a number of factors, including age and sex. The researchers evaluated levels of CB1R messenger RNA and protein, and also measured levels of glutamic acid decarboxylase (GAD-67), an enzyme that makes GABA, and cholecystokinin (CCK), a neuropeptide released from GABA neurons that, among other actions, regulates the production of the brain’s own cannabinoids.

“CB1R levels were significantly 15 percent lower in the subjects with schizophrenia,” Dr. Lewis said. “We measured these biochemical messengers using three techniques, and each time got the same answer – less CB1R in people with schizophrenia.” This reduction, he noted, appears to be the brain’s way of compensating for lower levels of GABA, and the use of marijuana defeats this compensation.

“These findings may provide insight into the biological basis of why cannabis use worsens schizophrenia, and, as a result, identify a novel target for new drug development that could improve treatments available for schizophrenia,” said Dr. Lewis.

Source: University of Pittsburgh Schools of the Health Sciences

Reduced Cortical Cannabinoid 1 Receptor Messenger RNA and Protein Expression in Schizophrenia. Stephen M. Eggan; Takanori Hashimoto; David A. Lewis. Arch Gen Psychiatry. 2008;65(7):772-784.

With unprecedented levels of obesity across the Western world, and incidence of associated heart disease, cancer and diabetes rising, there is a major drive to find new treatments. Scientists from Germany have recently discovered that extracts of a traditional herbal remedy derived from Tabebuia impetiginosa can act to delay the absorption of dietary fat in animal models. They believe that the extract could be incorporated into a food supplement which may not only reduce obesity, but also lessen the risk of development of type 2 diabetes and coronary heart disease. Dr Nils Roos from the Max Rubner Institute will present the results on Monday 7th July at the Society for Experimental Biology’s Annual Meeting in Marseille.

Dr Roos and his team have shown that Tabebuia extract can reduce levels of triglycerides, a breakdown product of fat, in rats after they have been fed a fatty meal. “This result shows the extract may have a potential use in treating obesity,” he observes. “However, as coronary heart disease and diabetes have also been shown to be associated with higher triglyceride levels after eating, we believe a food-supplement based on Tabebuia could reduce the incidence of these diseases as well. What is more, as obesity in developing countries is also on the increase, such extracts, taken as a capsule or added to food, may be a cheaper alternative for the rural population to pharmaceuticals.”

Although it is clear that Tabebuia extract can act to inhibit the absorption of dietary fat, the scientists have not yet identified the exact compounds within the extract that are responsible for the effects. “The actual substances involved are probably even more active than the extract,” says Dr Roos. “We are currently in the process of identifying these compounds, and will then test long-term efficiacy and safety in miniature pigs whose physiology is closer to that of humans than rat physiology is, before moving onto human trials. At this point, we hope to be able to develop the extract, either as a food supplement or in a medicinal context.”

Source: Society for Experimental Biology