ANTIBIOTICS GIVE RISE TO NEW COMMUNITIES OF HARMFUL BACTERIA

Most people have taken an antibiotic to treat a bacterial infection. Now researchers from the University of North Carolina at Chapel Hill and the University of San Diego, La Jolla, reveal that the way we often think about antibiotics -- as straightforward killing machines -- needs to be revised.

 The work, led by Elizabeth Shank, an assistant professor of biology in the UNC-Chapel Hill College of Arts and Sciences as well as microbiology and immunology in the UNC-Chapel Hill School of Medicine, and Rachel Bleich, a graduate student in the UNC-Chapel Hill Eshelman School of Pharmacy, not only adds a new dimension to how we treat infections, but also might change our understanding of why bacteria produce antibiotics in the first place.

"For a long time we've thought that bacteria make antibiotics for the same reasons that we love them -- because they kill other bacteria," said Shank, whose work appears in the February 23 Early Edition of the Proceedings of the National Academy of Sciences. "However, we've also known that antibiotics can sometimes have pesky side-effects, like stimulating biofilm formation."

Shank and her team now show that this side-effect -- the production of biofilms -- is not a side-effect after all, suggesting that bacteria may have evolved to produce antibiotics in order to produce biofilms and not only for their killing abilities.

Biofilms are communities of bacteria that form on surfaces, a phenomenon dentists usually refer to as plaque. Biofilms are everywhere. In many cases, biofilms can be beneficial, such as when they protect plant roots from pathogens. But they can also harm, for instance when they form on medical catheters or feeding tubes in patients, causing disease.

"It was never that surprising that many bacteria form biofilms in response to antibiotics: it helps them survive an attack. But it's always been thought that this was a general stress response, a kind of non-specific side-effect of antibiotics. Our findings indicate that this isn't true. We've discovered an antibiotic that very specifically activates biofilm formation, and does so in a way that has nothing to do with its ability to kill."

Shank and her team previously reported that the soil bacterium Bacillus cereus could stimulate the bacterium Bacillus subtilis to form a biofilm in response to an unknown secreted signal. B. subtilis is found in soil and the gastrointestinal tract of humans.

Using imaging mass spectrometry, they subsequently identified the signaling compound that induced biofilm production as thiocillin, a member of a class of antibiotics called thiazolyl peptide antibiotics, which are produced by a range of bacteria.

At that point, Shank and her colleagues knew thiocillin had two very specific and different functions, but they didn't know why -- and wanted to know how it worked. That's when they modified thiocillin's structure in a way that eliminated thiocillin's antibiotic activity, but did not halt biofilm production.

"That suggests that antibiotics can independently and simultaneously induce potentially dangerous biofilm formation in other bacteria and that these activities may be acting through specific signaling pathways," said Shank. "It has generated further discussion about the evolution of antibiotic activity, and the fact that some antibiotics being used therapeutically may induce biofilm formation in a strong and specific way, which has broad implications for human health."

The Rapid Rise Of Stem Cell Research For Nerve Pain

Today's post from consultqd.clevelandclinic.org (see link below) takes a rather complex look at developments in stem cell research for neuropathic pain and concludes that significant progress is being made. It's still at the rodent-lab-testing stage but seems much closer to a successful outcome than many studies that we read about. The article is not particularly easy reading for the layman but you can get the gist of what's being discussed. Yet again, this is evidence of the spin-off potential of the current 'war on opioids', which seems to have shaken up the pharmaceutical industry research departments, to the point where they are seriously investigating new possibilities in anticipation of draconian laws restricting opioid distribution. Interesting article.

Stem Cell Therapy for Neuropathic Pain: New Findings Show Promise
Animal studies demonstrate effectiveness  Consult QD Aug. 10, 2016

Stem cell research at Cleveland Clinic could pave the way for an entirely new approach to chronic pain treatment that reduces medicine’s current reliance on opioid therapy for intractable pain. The modality also shows promise as a tool to reverse opioid tolerance (OT) and opioid-induced hyperalgesia (OIH), particularly problematic side effects of opioid therapy. Jianguo Cheng, MD, PhD, and his colleagues at Cleveland Clinic have developed patented methods of attenuating opioid tolerance.

Animal studies by Dr. Cheng and his colleagues have demonstrated the effectiveness of mesenchymal stem cell (MSC) transplantation in reducing hyperalgesia due to nerve injury. The group’s work has shown MSC transplantation’s effectiveness in reducing pain induced by sciatic nerve injury in rats and mice. MSC transplantation significantly reduced pain sensitivity evaluated by foot withdrawal thresholds in animals in response to thermal or mechanical stimulation. These cells produced immune modulatory and anti-inflammatory effects, promoted sensory nerve repair, and showed strong analgesic properties that could provide a safer and more effective alternative to current treatment modalities, in the management of neuropathic pain, says Dr. Cheng, Professor of Anesthesiology and Director of the Cleveland Clinic Multidisciplinary Pain Medicine Fellowship Program.

Pain medicine researchers are searching for an alternative to opioid therapy because neuropathic pain often does not respond to morphine and other opioids. Opioid analgesics can also lead to a variety of complications, ranging from itching and constipation to dependence, addiction, respiratory depression and death.

About 30 percent of neuropathy cases are caused by nerve damage associated with diabetes. However, hundreds of diseases are linked to neuropathic pain. Sources of neuropathic pain include alcoholism, amputation (which can result in phantom pain), some chemotherapy drugs (for example, Cisplatin®, Paclitaxel®, Vincristine®), radiation therapy, complex regional pain syndrome type II, trigeminal neuralgia, shingles, spinal stenosis, and central nervous system disorders, such as Parkinson disease and multiple sclerosis.

Recent research by Dr. Cheng and his group has yielded new discoveries that bode well for MSC transplantation as a potential future treatment modality. One investigation compared the analgesic effects of MSC derived from bone marrow with MSC derived from adipose tissue. Adipose-derived cells were found to be as efficacious as bone marrow-derived cells in reducing neuropathic pain in rats. The finding suggests that stem cell therapy could offer a practical option because stem cells from adipose tissue are relatively easy to obtain.

Recent investigations by Dr. Cheng and his colleagues comparing the analgesic effectiveness of intrathecal versus intravenous methods of MSC transplantation show both methods to be equally effective. The finding has important implications because intravenous transplantation of MSC could offer a safer and more expeditious route of delivery than intrathecal transplantation.

“We originally thought that stem cells would have to be introduced intrathecally in order to reduce pain, and that stem cells introduced intravenously would pass through the lungs and fail to produce analgesia,” says Dr. Cheng. “The finding that intravenous transplantation is as effective as intrathecal transplantation is encouraging.”

Dr. Cheng’s group has also discovered that MSCs can be found in the area surrounding the injured nerve following MSC transplantation. “For reasons we do not yet fully understand, these cells have the ability to migrate to the injury site to promote repair of the injured nerve fibers,” Dr. Cheng says. “The cells can sense the injury’s location and travel to it.”

Although many questions must be answered before it can be known whether stem cell therapy is safe and effective for humans, some small patient studies show potential, Dr. Cheng says. According to one observational study in Australia, MSC transplantation reduced pain in patients suffering from trigeminal neuralgia, a particularly difficult condition to treat. “Though the findings are preliminary, the study provides some evidence that what we have learned in the laboratory can be translated to clinical use,” Dr. Cheng says.

Dr. Cheng’s team has achieved analgesia with MSC transplantation from rats to mice, providing early evidence that stem cells’ anti-inflammatory and immuno-modulatory properties can be transferred between species. An important pre-clinical study will be to see whether the transplantation of human stem cells to animals also can produce analgesic and anti-tolerance effects, Dr. Cheng says.

Dr. Cheng’s team presented research at the 2016 annual meeting of the American Academy of Pain Medicine showing MSC’s potential to reverse opioid tolerance and opioid-induced hyperalgesia, problems that can compromise the safety and efficacy of opioid therapy. Intravenous transplantation of bone marrow-derived MSC significantly attenuated OT and OIH in animals whether the transplantation was performed seven days before or 14 days after the initiation of daily morphine injections. These data demonstrate that MSC transplantation can not only prevent the development of OT and OIH but can also reverse it.

https://consultqd.clevelandclinic.org/2016/08/stem-cell-therapy-neuropathic-pain-new-findings-show-promise/?utm_campaign=crowdfire&utm_content=crowdfire&utm_medium=social&utm_source=twitter