Posted on Pain Management

Controlling cholesterol in microglia alleviates chronic pain

Inspiration for people with chronic pain

Chemotherapy can induce a painful peripheral neuropathy (CIPN), a chronic condition and common adverse effect for cancer patients undergoing treatment. Researchers at University of California San Diego School of Medicine, with colleagues elsewhere, have used a mouse model to demonstrate the pivotal role of cholesterol in CIPN, and proposed a novel therapeutic approach to reverse it.

The findings are published in the May 10, 2021, online issue of the Journal of Experimental Medicine.

The study was a collaboration between the laboratories of senior study author Yury Miller, MD, PhD, professor of medicine, and Tony Yaksh, PhD, professor of anesthesiology and pharmacology, both at UC San Diego School of Medicine. Miller studies cholesterol metabolism and cardiovascular and neuro inflammation. Yaksh specializes in neuropathic pain.

“It was truly gratifying to work at the intersection of two disciplines and identify the role cholesterol plays in activation of microglia — immune cells of the spinal cord — and regulation of chronic pain,” said first author Juliana Navia-Pelaez, PhD, a postdoctoral fellow in Miller’s lab.

“The metabolism of cellular cholesterol was already linked to neurological conditions, such as Alzheimer’s disease, but we were first to show its role and underlying mechanisms in chronic pain.”

Cholesterol is essential for brain function, both during development and in adult life. It is a major component of cell membranes, a precursor to some hormones and serves as a cellular messenger. However, excess of cholesterol is detrimental to human health; buildup of cholesterol plaques in large arteries often causes heart attacks and stroke.

The UC San Diego team found that changes in cholesterol metabolism contributed to reprogramming of microglia in a way that perpetuated chronic inflammation in the spinal cord. Genetically modified mice lacking cholesterol transporters in microglia were unable to remove excessive amounts of cholesterol, and thus experienced pain — even without chemotherapeutic intervention.

The outer membrane of these cells, which is normally fluid, became rigid with accumulated cholesterol in the form of floating solid platforms called lipid rafts. The lipid raft environment, said the authors, favors assembly and activation of cellular proteins that mediate inflammatory response, such as Toll-like receptor-4 (TLR4).

“We were surprised to find that in CIPN, enlarged lipid rafts and TLR4 assemblies persisted for days and weeks,” said Miller. “We even started calling them ‘inflammarafts’ to stress the importance of these membrane domains in neuroinflammation and pain states.”

To reverse the harmful effects of excessive cholesterol in microglia, researchers used a modified version of the apoA-I binding protein (AIBP), which hastens cholesterol removal and disrupts inflammarafts, but does not damage physiological lipid rafts. A single injection of AIBP in the spinal canal of mice reversed CIPN pain, and the therapeutic effect lasted for several weeks, without adverse effects.

“The long-lasting effect we observed with the delivery of AIBP points to a reprogramming of these immune cells that implies cholesterol plays a fundamental role in gene expression,” said Navia-Pelaez. “It might even act as a driver of epigenetic alterations in microglia and ultimately pain behavior.”

The authors said the results are part of a promising series of investigations, conducted by UC San Diego and Raft Pharmaceuticals.

“Considerable work remains to be done in terms of safety and kinetics to move this new biologic ahead for clinical trials,” said Yaksh, “but the present results are exceedingly promising as they provide a hitherto unappreciated target — inflammarafts in immune cells — for drug development in the management of chronic neuropathic pain.”

Posted on Autism

Early screening tool leads to earlier diagnosis and therapies for autism

Led by Karen Pierce, PhD, a professor in the Department of Neurosciences who with colleagues created the Get SET Early program, researchers at the UC San Diego Autism Center of Excellence (ACE) assembled a network of 203 pediatricians in the San Diego region who conducted systematic screenings of 59,411 infants or toddlers at their 12-, 18- and 24-month check-ups. CREDIT UC San Diego Health Sciences

Since it debuted in 2011, the Get SET Early program, which provides pediatricians and parents with a relatively simple process to screen for indicators of autism spectrum disorder (ASD) in children as young as age 1, has steadily grown in use and validation. Early screening and identification of ASD has been linked to more effective treatment.

A new study, published in the April 26, 2021 issue of the Journal of Pediatrics, by researchers at University of California San Diego School of Medicine, further bolsters these findings.

Led by Karen Pierce, PhD, a professor in the Department of Neurosciences who with colleagues created the Get SET Early program, researchers at the UC San Diego Autism Center of Excellence (ACE) assembled a network of 203 pediatricians in the San Diego region who conducted systematic screenings of 59,411 infants or toddlers at their 12-, 18- and 24-month check-ups.

Parents completed a validated questionnaire about their child’s use of eye contact, words, gestures and other forms of age-appropriate communication, using either a paper form or an iPad. The final question on the screening tool: “Do you have any concerns about your child’s development?” (Yes or No).

Digital screens automatically scored patients as pass or fail. Pediatricians were asked to indicate whether they were referring toddlers who failed a screening for further evaluation and if not, why not.

Overall, 897 children failed the initial screening and received further evaluation at ACE. Within this cohort, 403 received a subsequent diagnosis of ASD. Approximately 60 percent of these children were assessed at their 12-month well baby visits, and received a comprehensive evaluation, diagnosis and treatment referral by age 15 months.

“There is extensive evidence that early therapy can have a positive impact on the developing brain,” said Pierce, who is co-director of ACE. “The opportunity to diagnose and thus begin treatment for autism around a child’s first birthday has enormous potential to change outcomes for children affected with the disorder. These toddlers, as part of the Get SET Early program began treatment roughly three years earlier than the national average of 52 months.”

But the study also revealed some surprising findings: Participating pediatricians referred only 39 percent of toddlers who had failed a screening for additional evaluation.

“Data from the iPads indicated the lack of referral follow-through was because pediatricians thought that the results of the screen were wrong,” said Pierce. “But if a parent noted that they were concerned by checking ‘yes’ on the last question, the referral rate increased to 70 percent.

“These findings underscore the importance of parent participation and input when seeking to detect the earliest signs of ASD or other development delays in young children. If you are a parent and have even minor concerns about how your child is developing, you must speak up. Don’t wait. Your voice carries weight.”

ASD is now estimated to affect one in every 54 children born in the United States. Multiple studies, including research conducted by Pierce and colleagues have found that simple parent checklists performed as early as a child’s first birthday can identify symptoms of ASD. Early diagnoses have been found to be highly stable as early as 14 months.

Pierce said the Get SET Early program, which has expanded to other cities and states with funding from the National Institute of Mental Health, can be adopted by any pediatric office, at virtually no cost.

Posted on Diabetes

The enzyme that could help 700 million people worldwide

3D illustration of kidney disease which now affects 10 per cent of the world’s population due to a spike in obesity, leading to diabetes CREDIT University of South Australia

University of South Australia researchers have identified an enzyme that may help to curb chronic kidney disease, which affects approximately 700 million people worldwide.

This enzyme, NEDD4-2, is critical for kidney health, says UniSA Centre for Cancer Biology scientist Dr Jantina Manning in a new paper published this month in Cell Death & Disease.

The early career researcher and her colleagues, including 2020 SA Scientist of the Year Professor Sharad Kumar, have shown in an animal study the correlation between a high salt diet, low levels of NEDD4-2 and advanced kidney disease.

While a high salt diet can exacerbate some forms of kidney disease, until now, researchers did not realise that NEDD4-2 plays a role in promoting this salt-induced kidney damage.

“We now know that both a high sodium diet and low NEDD4-2 levels promote renal disease progression, even in the absence of high blood pressure, which normally goes hand in hand with increased sodium,” says Dr Manning.

NEDD4-2 regulates the pathway required for sodium reabsorption in the kidneys to ensure correct levels of salt are maintained. If the NEDD4-2 protein is reduced or inhibited, increased salt absorption can result in kidney damage.

Even people on a low salt diet can get kidney damage if they have low levels of NEDD4-2 due to genetic variations or mutations in the gene.

Prof Kumar says the long-term goal is to develop a drug that can increase NEDD4-2 levels in people with chronic kidney disease (CKD).

“We are now testing different strategies to make sure this protein is maintained at a normal level all the time for overall kidney health,” Prof Kumar says.

“In diabetic nephropathy – a common cause of kidney disease – levels of NEDD4-2 are severely reduced. This is the case even when salt is not a factor.”

The study also revealed a surprising finding: that the high salt diet induced kidney disease is not always due to high blood pressure.

“In a lot of cases, kidney disease is exacerbated by hypertension, so we wanted to investigate that link in our study. In fact, we found the complete opposite – that a high salt diet caused excessive water loss and low blood pressure. This is significant because it means that kidney disease can also happen in people who don’t have high blood pressure,” Dr Manning says.

A 2020 Lancet paper estimated that about 700 million people – or 10 per cent of the world’s population – suffer from chronic kidney disease, which represents a 29 per cent increase in the past 30 years.

The huge spike in CKD is mainly attributed to a global obesity epidemic in recent decades, leading to diabetes, one of the leading causes of chronic kidney disease along with high blood pressure.

World Health Organization statistics reveal a 300 per cent increase in diabetes between 1980 and 2014, making it one of the top 10 causes of death worldwide and showing the gravity of the problem facing scientists trying to tackle kidney disease.

“Obesity and lifestyle are two main factors driving chronic kidney disease but there are other things at play as well,” says Dr Manning. “Acute kidney injuries, drugs taken for other conditions, high blood pressure and a genetic predisposition can also cause it.”

Posted on Pain Management

One in five adults experience chronic pain

Don't let the pain destroy you
Don’t let the pain destroy you


Chronic pain is among the most common chronic conditions in the United States, but estimates of its prevalence and impact vary widely. In 2019, the National Center for Health Statistics of the Centers for Disease Control and Prevention added a new set of questions relating to pain to its National Health Interview Survey (NHIS), a large household-based annual survey that offers valuable insights into the health statuses of U.S. adults nationwide. In an article published in Pain, researchers from Brigham and Women’s Hospital and Mass Eye and Ear report that 50.2 million (20.5 percent) U.S. adults experience chronic pain based on analysis of the new NHIS data. They estimated the total value of lost productivity due to chronic pain to be nearly $300 billion annually.

“Chronic pain is a serious condition that affects millions of Americans,” said corresponding author R. Jason Yong, MD, MBA, medical director of the Pain Management Center at the Brigham and associate chief of pain in the Department of Anesthesiology, Perioperative, and Pain Medicine. “Other studies have touched on this fact, but data from pain clinics, hospitals and other providers tends to only provide information on people seeking out medical attention. Having the NHIS data to validate previous studies is incredibly impactful.”

The authors found that respondents with chronic pain reported missing significantly more workdays compared to those without chronic pain (10.3 days versus 2.8). They used these figures to quantify the total economic impact of chronic pain on Americans, which they estimated to be $79.9 billion in lost wages. Those with chronic pain also reported more limitations to their engagement in social activities and activities of daily living. Back, hip, knee and foot pain were the most common sources of pain reported, and physical therapy and massage therapy were most commonly sought as treatments.

“The impetus for our study arose from the day-to-day clinical finding that many of our chronic sinusitis patients also reported headache, migraine and other forms of chronic pain,” said senior author Neil Bhattacharyya, MD, MA, FACS, professor of Otolaryngology–Head and Neck Surgery at Mass Eye and Ear. “We decided to look at the bigger picture of chronic pain, and we were somewhat surprised at the large-scale presence of chronic pain in the US.”

The 2019 NHIS included data from 31,997 adults across the nation. When the data was first published in May, investigators decided to focus their initial analysis on ascertaining national estimates of prevalence and impact, but plan to conduct further analysis of other questions included in the survey. This may reveal more specific trends related to pain and its treatment across the U.S., especially regarding opioid use.

“Given the overall scale and impact of pain on Americans, we see that a multimodal, multidisciplinary approach to treating pain is even more important than what we have been emphasizing over the past few decades,” Yong said. “Pain medicine is relatively young as a field, and it encompasses specialties including emergency medicine, anesthesia, psychiatry, neurology, physiatry and radiology. We need all of the tools in our armamentarium to treat patients suffering from chronic pain.”