Posted on February 17, 2022February 17, 2022 Pain Management

Mind over matter: Beating pain and painkillers

With nearly one-third of Americans suffering from chronic pain, prescription opioid painkillers have become the leading form of treatment for this debilitating condition. Unfortunately, misuse of prescription opioids can lead to serious side effects—including death by overdose. A new treatment developed by University of Utah researcher Eric Garland has shown to not only lower pain but also decrease prescription opioid misuse among chronic pain patients.

Results of a study by Garland published online Feb. 3 in the Journal of Consulting and Clinical Psychology, showed that the new treatment led to a 63 percent reduction in opioid misuse, compared to a 32 percent reduction among participants of a conventional support group. Additionally, participants in the new treatment group experienced a 22 percent reduction in pain-related impairment, which lasted for three months after the end of treatment.

The new intervention, called Mindfulness-Oriented Recovery Enhancement, or MORE, is designed to train people to respond differently to pain, stress and opioid-related cues.

MORE targets the underlying processes involved in chronic pain and opioid misuse by combining three therapeutic components: mindfulness training, reappraisal and savoring.

Mindfulness involves training the mind to increase awareness, gain control over one’s attention and regulate automatic habits.
Reappraisal is the process of reframing the meaning of a stressful or adverse event in such a way as to see it as purposeful or growth promoting.
Savoring is the process of learning to focus attention on positive events to increase one’s sensitivity to naturally rewarding experiences, such as enjoying a beautiful nature scene or experiencing a sense of connection with a loved one.

“Mental interventions can address physical problems, like pain, on both psychological and biological levels because the mind and body are interconnected,” Garland said. “Anything that happens in the brain happens in the body—so by changing brain functioning, you alter the functioning of the body.”

To test the treatment, 115 chronic pain patients were randomly assigned to eight weeks of either MORE or conventional support group therapy, and outcomes were measured through questionnaires at pre- and post-treatment, and again at a three-month follow-up. Nearly three-quarters of the group misused opioid painkillers before starting the program by taking higher doses than prescribed, using opioids to alleviate stress and anxiety or another method of unauthorized self-medication with opioids.

Among the skills taught by MORE were a daily 15-minute mindfulness practice session guided by a CD and three minutes of mindful breathing prior to taking opioid medication. This practice was intended to increase awareness of opioid craving—helping participants clarify whether opioid use was driven by urges versus a legitimate need for pain relief.

“People who are in chronic pain need relief, and opioids are medically appropriate for many individuals,” Garland said. “However, a new option is needed because existing treatments may not adequately alleviate pain while avoiding the problems that stem from chronic opioid use.”

MORE is currently being tested in a pilot brain imaging trial as a smoking cessation treatment, and there are plans to test the intervention with people suffering from mental health problems who also have alcohol addiction. Further testing on active-duty soldiers with chronic pain and a larger trial among civilians is planned. If studies continue to demonstrate positive outcomes, MORE could be prescribed by doctors as an adjunct to traditional pain management services.

Posted on February 17, 2022February 17, 2022 autoimmune conditions, Diet

Towards a treatment for gluten intolerance

Celiac disease is a severe autoimmune disorder of the intestine. It occurs when people develop sensitivity to gluten, a substance found in wheat, rye, and barley. An international research team from Italy and France has now uncovered a new molecular player in the development of gluten intolerance. Their discovery, published in The EMBO Journal, suggests potential targets for the development of therapeutic approaches for the disease.

Celiac disease can appear in people who are genetically predisposed, but it is triggered through environmental factors. When people suffering from celiac disease eat gluten, their immune system triggers a response against their body’s own cells, damaging the mucosal surface of the small intestine. About 1 in 100 people suffer from celiac disease, but the prevalence is about three times higher in patients who also suffer from cystic fibrosis. “This co-occurrence made us wonder if there is a connection between the two diseases at the molecular level,” said Luigi Maiuri of the University of Piemonte Orientale in Novara and San Raffaele Scientific Institute in Milan, Italy, who led the research together with Valeria Raia (University Federico II of Naples, Italy) and Guido Kroemer (University of Paris Descartes, France).

Cystic fibrosis is characterized by the build-up of thick and sticky mucus in the patients’ lungs and intestine. It is caused by mutations of the gene coding for cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is an ion transport protein that plays an important role in keeping mucus fluid – when it fails, the mucus clogs up. Moreover, CFTR malfunction triggers a number of additional reactions in the lungs and other organs including intestine by activation of the immune system. These effects are very similar to the responses triggered by gluten in celiac patients. Maiuri, Kroemer and their colleagues took a closer look at the molecular underpinnings of these similarities.

Gluten is difficult to digest, so that relatively long protein parts – peptides – enter the intestine. Using human intestinal cell lines that are sensitive to gluten, the researchers found that one specific peptide, P31-43, directly binds to CFTR and impairs its function. This interaction triggers cellular stress and inflammation, suggesting that CFTR plays a central role in mediating gluten sensitivity in celiac patients.

Moreover, the interaction between P31-43 and CFTR can be inhibited by a potentiator of CFTR, called VX-770. When intestinal cells or tissue samples collected from celiac disease patients were pre-incubated with VX-770 before being exposed to P31-43, the peptide did not elicit an immune reaction. Thus, VX-770 protects gluten-sensitive epithelial cells from the detrimental effect of gluten. In addition, the researchers found that VX-770 could protect gluten-sensitive mice from gluten-induced intestinal symptoms.

There is, as yet, no cure for celiac disease; the only therapeutic strategy is to keep a strict diet. However, the current study is a promising step towards the development of a treatment. It suggests that CFTR potentiators, which have been developed to treat cystic fibrosis, may also be explored as a starting point for the development of a remedy for celiac disease.

Posted on February 17, 2022February 17, 2022 Diabetes

Composition of gut microbiome predicts the onset of type 2 diabetes

Microbiota transfer therapy for autism: Multi-omic approaches and lessons learned

The international research group utilised targeted machine learning techniques to discover if specific signals in the gut microbiome composition were associated with increased risk of developing type 2 diabetes.

They identified six bacterial groups from family Lachnospiraceae and its close relatives which were associated with an increased risk of developing type 2 diabetes during the follow-up.

– People from Eastern and Western Finland are known to have both genetic and lifestyle differences, which are also reflected in their health. Despite these differences, the microbes identified in the research were robustly associated with incident disease throughout Finland, explains one of the two main authors of the research article, Postdoctoral Researcher Matti Ruuskanen from the University of Turku.

– These bacterial species have been also previously linked with prevalent type 2 diabetes and several other metabolic diseases, such as fatty liver disease. They also seem to be at least partly linked with the quality of diet, says the other main author, Postdoctoral Researcher Pande Erawijantari.

The results of this study support previous notions on links between adult-onset diabetes, dietary habits, and metabolic diseases, likely modulated by the gut microbiome.

Risk Factors Help Predict Disease Occurrence

The prevalence of type 2 diabetes is still increasing around the world. The disease has major impacts on quality of life, and it is recognised as a serious and costly public health concern. Prevention and treatment of adult-onset diabetes are thus highly important research topics.

– One viable strategy in preventing the development of the disease would be to identify the early signs of type 2 diabetes to undertake preventative measures, such as lifestyle modification, says Matti Ruuskanen.

Previous research has identified several risk factors for type 2 diabetes, such as genetics, lifestyle, and environmental factors. Moreover, changes in gut microbiome composition have also been associated with type 2 diabetes, but previous studies have mostly reported differences between healthy volunteers and those already diagnosed with the disease.

– The results of this study help us better understand the risk factors of type 2 diabetes and could aid in the development of more effective treatments in the future, envisions Pande Erawijantari.

The analysis was conducted by studying fecal samples collected from a large, representative, and unique Finnish population cohort, FINRISK 2002. Extensive health data from over 5,000 participants was collected during sampling, and the incidence of disease was tracked for nearly 16 years through electronic health records. This enabled the identification of microbial biomarkers which predicted the incidence of type 2 diabetes in participants who were healthy at the baseline examination.

Posted on February 17, 2022February 17, 2022 Multiple Sclerosis

Multiple sclerosis: Study with twins untangles environmental and genetic influences

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and the most common cause of neurological impairment in young adults. In MS, the patient’s own immune system attacks the brain and spinal cord, resulting in cumulative neurological deficits such as damaged sight, sensory disturbances, motor deficits (e.g. limiting the ability to walk) as well as cognitive impairment. Although the cause of MS is still unclear, a variety of genetic risk factors and environmental influences have already been linked to the disease.

Genetic predisposition alone does not lead to MS

Studies in recent years have clearly shown that genetic risk variants are a necessary condition for developing multiple sclerosis. “Based on our study, we were able to show that about half of the composition of our immune system is determined by genetics,” says Florian Ingelfinger, a PhD candidate at the UZH Institute of Experimental Immunology. The study by the team led by immunologist Burkhard Becher, professor at the Institute of Experimental Immunology at UZH, and the research groups of Lisa Ann Gerdes and Eduardo Beltrán of the Institute of Clinical Neuroimmunology at the LMU Klinikum, shows that these genetic influences, while always present in MS patients, are not on their own sufficient to trigger multiple sclerosis. In the study, 61 pairs of monozygotic twins where one twin is affected by MS whereas the co-twin is healthy were examined. From a genetic point of view, the twins were thus identical. “Although the healthy twins also had the maximum genetic risk for MS, they showed no clinical signs of the disease,” says Lisa Ann Gerdes.

Twin study eliminates genetic influences

Thanks to this globally unique cohort of identical twins, the researchers were able to exclude genetic influences by comparing twins with and without multiple sclerosis. “We are exploring the central question of how the immune system of two genetically identical individuals leads to significant inflammation and massive nerve damage in one case, and no damage at all in the other,” explains Burkhard Becher. Using identical twins enabled the international team of scientists to rule out the genetic influence and specifically track the immune system changes that were ultimately responsible for triggering MS in one twin.

Cutting-edge single-cell technologies and artificial intelligence

The researchers harness state-of-the-art technologies to describe the immune profiles of the twin pairs in rich detail. “We use a combination of mass cytometry and the latest methods in genetics paired with machine learning to not only identify characteristic proteins in the immune cells of the sick twin in each case, but also to decode the totality of all the genes that are switched on in these cells,” Florian Ingelfinger explains. Eduardo Beltrán, an expert in single-cell genomics, adds: “This ensures that we obtain as much information as currently technically possible from these valuable samples.” The team uses a variety of tailored algorithms based on artificial intelligence to extract relevant insights from this immense dataset.

An error in the communication of immune cells

“Surprisingly, we found the biggest differences in the immune profiles of MS affected twins in to be in the cytokine receptors, i.e. the way immune cells communicate with one another. The cytokine network is like the language of the immune system,” says Ingelfinger. The researchers found that increased sensitivity to certain cytokines leads to greater activation of T cells in the blood of patients with multiple sclerosis. These T cells are more likely to migrate into the central nervous system of patients and cause damage there. The identified cells were found to have the characteristics of recently activated cells, which were in the process of developing into fully functional T cells. “We may have discovered the cellular big bang of MS here – precursor cells that give rise to disease-causing T cells,” says Becher.

Important foundation for understanding the influence of genetics and environment on MS

“The findings of this study are particularly valuable in comparison to previous studies of MS which do not control for genetic predisposition,” says Burkhard Becher. “We are thus able to find out which part of the immune dysfunction in MS is influenced by genetic components and which by environmental factors. This is of fundamental importance in understanding the development of the disease.” The participating twins were recruited for the study at the LMU Klinikum. “This unique opportunity to unravel the influence of genetics and environment in multiple sclerosis is entirely thanks to our patients who agreed to join the study,” said Lisa Ann Gerdes.

Posted on February 17, 2022February 17, 2022 Patient Talk

Placenta may hold clues for early autism diagnosis and intervention

Loss of placental hormone linked to brain and social behavior changes

New UC Davis MIND Institute research has identified a novel human gene linked to fetal brain development and autism . The discovery also links the gene to the mother’s early prenatal vitamin use and placental oxygen levels.

In a study published Feb. 16 in Genome Biology, the researchers used genomic sequencing to find a DNA methylation signature in the placenta of newborns eventually diagnosed with autism. This signature mark was linked to early fetal neurodevelopment.

“By taking an unbiased approach to investigating placental DNA methylation differences, we discovered a novel gene in a poorly mapped region of the genome associated with autism, ” said Janine LaSalle, lead author on the study and professor of microbiology and immunology at UC Davis Health.

Autism is a complex neurological condition linked to genetic and environmental factors. The U.S. Centers for Disease Control and Prevention (CDC) estimates that one in 44 children are diagnosed with autism. It is much more prevalent in males than females.

Why studying the placenta is important

The placenta supports fetal development in the uterus. It regulates oxygen supply and metabolism and provides hormones and neurotransmitters critical for the fetus’ developing brain.

“The placenta is an often misunderstood and overlooked tissue, despite its importance in regulating and thereby reflecting events critical to brain development in utero. It is like a time capsule for finding things that happened in utero. For decades, hospital births have thrown away placentae despite this tissue being a gold mine for finding molecular clues to child outcomes,” LaSalle said.

During pregnancy, the fetus might experience oxidative stress, an imbalance of free radicals and antioxidants in the body. This is common in normal brain development. However, in some cases, exposure to environmental factors such as air pollution and pesticides can lead to excessive oxidative stress. This state can lead to cell and tissue damage or delayed neurodevelopment.

“Oxidative stress is normal. But excessive oxidative stress may come from environmental exposures linked to autismsuch as air pollution, pesticides, maternal obesity and inflammation,” LaSalle said.

The epigenome is a set of chemical compounds and proteins that tell the DNA what to do. These compounds attach to DNA and modify its function. One such compound is CH₃ (known as the methyl group) which leads to DNA methylation. The neonatal epigenome can reflect past interactions between genetic and environmental factors during early development. It may also influence future health outcomes.

The placenta is a promising tissue for identifying DNA methylation changes at genes that also function in the fetal brain. This study examined the association of autism with placental DNA methylation.

Finding factors in mother’s placenta that might predict autism

The researchers studied the development of 204 children born to mothers enrolled in the MARBLES and EARLI studies. These mothers had at least one older child with autism and were considered with higher probability of having another child with autism m. When these children were born, the mothers’ placentae were preserved for future analysis.

At 36 months, the children got diagnostic and developmental assessments. Based on these tests, the researchers grouped the children under “typically developing” (TD), “with autism ” and “non-typical development” (Non-TD).

The researchers also extracted and quantified the DNA from the placenta tissues. They divided the placenta samples into discovery, replication and specificity replication groups.

For the discovery group, they split and sequenced 92 samples (46 ASD, 46 TD) from the MARBLES study using whole-genome bisulfite sequencing (WGBS) and whole-genome sequencing (WGS). To determine if differential methylation was reproducible in a different population, the replication group included WGBS data from 16 ASD and 31 TD samples from the EARLI study.

The specificity replication group had 21 autism , 13 Non-TD and 31 TD placenta samples from the MARBLES study. The researchers used these samples to determine if methylation changes were specific to autism .

Finally, they performed whole genome sequencing on 41 ASD and 37 TD MARBLES children.

Placenta to reveal insights into genes related to autism

The researchers identified a block of differential methylation in autism at 22q13.33, a region in chromosome 22 not previously linked to autisk . They located and characterized a novel gene known as LOC105373085 within that region and renamed it NHIP (neuronal hypoxia inducible, placenta associated).

To understand the function of this gene, they detected the levels of NHIP expression in human cell lines and brain tissue. They tested the responsiveness of NHIP to hypoxia, a state of low oxygen levels in the tissues. The researchers found that NHIP is a gene that gets turned on in neurons following hypoxia and regulates other gene pathways with functions in neuronal development and response to oxidative stress. Higher NHIP levels increased the cell division in an embryonic cell line.

This is important because in the placenta, hypoxia triggers placental cell division to make further contact with maternal blood vessels to supply enough oxygen for the developing brain.

“We found that the NHIP gene is active in the brain, responsive to oxidative stress, and influences expression of other known genes associated with autism,” LaSalle said. “In most pregnancies, the placenta experiences some inevitable levels of stress. We think that NHIP is there to buffer the effects of excessive oxidative stress.”

Prenatal vitamins and autism

Another remarkable finding from the study was the role prenatal vitamins play in regulating the work of NHIP. Prenatal vitamins are high in folic acid and can reduce oxidative stress.

Prenatal vitamins use during the first month of pregnancy showed a significant protective effect among individuals with genetic differences at 22q13.33 NHIP region. Taking prenatal vitamins in the first month of pregnancy seems to provide essential metabolic elements to counteract the genetic inheritance of reduced NHIP responsiveness to oxidative stress.

“In line with previous studies, we found that taking a prenatal vitamin is essential when planning a pregnancy,” said LaSalle. “Findings from our study provide key insights that may help in identifying newborns more likely to develop autism and getting them into an earlier intervention or just knowing to watch them sooner.”

The researchers pointed out that these results will require further replication before being used diagnostically.