Progress in Treatments For Superbugs Impacts Patients With Lung Disease

A team of researchers from the Agency for Science, Technology and Research’s (A*STAR) Institute of Chemical and Engineering Sciences (ICES) and the National University Hospital (NUH) is working toward returning efficacy to drugs that treat respiratory system infections and antibiotic-resistant superbugs. The goal of the team is to combine drugs to combat bacteria that threaten to infect the respiratory system or agitate bacteria-linked pulmonary diseases including pneumonia, bronchiectasis, and cystic fibrosis.

Novel ways to deliver antibiotics to kill bacteria in the lungs and airways are important at a time when the population is aging and more people are expected to suffer from different kinds of respiratory infections in future, said Raymond Lin, PhD, from the Department of Laboratory Medicine at NUH, in a news release from A*STAR. The next crucial step will be to translate laboratory findings to clinical application.

The combination utilizes antibiotics and muco-active agents to kill bacteria, such as Pseudomonas aeruginosa that predominantly affects cystic fibrosis patients, in a one-two punch. First, the muco-active agents acts to disrupt bacterial cell-cell communication by disrupting the protective mucus layer, and then the antibiotic agent directly kills bacteria. According to the news release, bacteria are destroyed completely, and the overall treatment works twice as fast as current leading-edge antibiotics.

An added benefit of the treatments is their inhalable route of administration. Making the formulation inhalable and portable not only delivers a higher concentration of the drug to the lungs but also gives the added potential to be an effective out-patient treatment alternative,” said Dr. Desmond Heng, principal investigator at ICES. “Furthermore, if the disease is well- controlled in an outpatient setting with no further progression, costly hospitalization could be 1 avoided.

Importantly, this treatment scheme minimizes the chance for antibiotic resistance, a common problem of current antibiotic treatments. Moreover, the combination therapy is proposed to be effective against bacteria that have become resistant superbugs. The team at A*STAR has patented three drug formulations of three different antibiotics designed to fight against bacteria. All formulations can reduce infection by resistant bacterial strains of P. aeruginosa and Klebsiella pneumoniae to a greater extent (up to five times) than conventional antibiotics. Accordingly, small doses may be prescribed, further limiting the risk for antibacterial resistance.

    Bottom Line:

  • A team of researchers from A*STAR, ICES and NUH is working on combining drugs to combat bacteria that threaten to infect the respiratory system or agitate bacteria-linked pulmonary diseases including pneumonia, bronchiectasis, and CF
  • The combination first uses muco-active agents to disrupt bacterial cell-cell communication by breaking up the protective mucus layer, and then the antibiotic agent directly kills bacteria
  • The team at A*STAR has patented three drug formulations designed to fight against bacteria, with all capable of reducing infection by resistant bacterial strains of P. aeruginosa and Klebsiella pneumoniae to a far greater extent than conventional antibiotics

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COPD Drug Also Shows Promise For Cystic Fibrosis Patients

Data supporting a promising new treatment for CF, developed by Verona Pharma, will be presented for the first time at the 28th Annual North American Cystic Fibrosis Conference (NACFC) in Atlanta, Georgia on October 9-11, 2014.

Verona Pharma’s key molecule, RPL554, is currently being evaluated in a phase two clinical trial for the treatment of COPD (chronic obstructive pulmonary disease), but the company also believes that the therapy can treat CF as well. Cystic fibrosis is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene that results in the defective transport of ions across the membrane of epithelial cells, particularly in the lungs. RPL554 can thus activate CFTR in CF patients.

Professor John Hanrahan, Director, CF Translational Research centre at McGill University, commented, “In our experiments, RPL554 increased the activity of CFTR, ion channels on the surface of cells obtained from the lining of the airway. In cystic fibrosis patients it is the dysfunction of these ion channels, as a result of genetic mutations, that is responsible for the symptoms of the disease. We will continue to examine this effect of RPL554 in further studies. Ultimately, if found effective and safe in cystic fibrosis patients, RPL554 could emerge as a new medicine for this debilitating disease.”

Dr. Jan-Anders Karlsson, CEO of Verona Pharma, noted, “We will now seek to build on these findings by testing the activity of RPL554 in patients with this orphan disease. We are currently focused on progressing RPL554 in phase 2 clinical trials for COPD, initially positioning it as a novel treatment for acute exacerbations of the disease. We are also building a broader franchise around this drug to maximize its value, both to patients and to investors. We are therefore exploring the potential of the drug in different diseases as well as in the multi- blockbuster markets for COPD and asthma maintenance therapy. The results outlined in this NACFC presentation suggest another tangible opportunity for us to explore.”

    Bottom Line:

  • Verona Pharma’s key molecule, RPL554, is currently being evaluated in a phase two clinical trial 3 for the treatment of COPD (chronic obstructive pulmonary disease) and appears to be a promising new treatment for CF
  • Where CF is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, RPL554 increases the activity of CFTR and can thus activate CFTR in CF patients
  • Verona intends to explore the potential of this drug in different diseases; they presented this finding for the first time at the NACFC in Atlanta, Georgia this October

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Molecular Hydrogen Can Protect Patients Against Pulmonary Hypertension

New research suggests oral administration of the antioxidant molecular hydrogen via hydrogen water may offer therapeutic value to patients with Pulmonary Hypertension.

Pulmonary hypertension (PH) is a condition caused by increased pressure in the pulmonary arteries. In advanced cases, its symptoms (shortness of breath, tiredness, chest pain) worsen and may limit all physical activity. The most-used therapies rely on vasodilators of several kinds. However, traditional treatments have failed to block the progress of disease effectively.

In patients with PH, there is a significant increase in reactive oxygen species (ROS), a condition named Oxidative Stress. Their accumulation can seriously damage cells, for which treatment with antioxidants has proven effective. However, since high doses of nonselective antioxidants (i.e., antioxidants that bind multiple receptors in several different areas in the body) can have detrimental effects (e.g. hemorrhage), selective antioxidants like molecular hydrogen (H2) are found to be a safer and more efficient therapy for PH patients. H2 selectively reduces two 4 specific ROS (hydroxyl radicals and peroxynitrite) without impacting what is now described as physiological ROS (e.g. ROS found to be beneficial and necessary for cells’ survival).

In this study, the team found that H2 prevented the development of PH and reversed RV hypertrophy (thickened muscle around the heart’s right lower chamber). Accordingly with previous studies, the therapeutic effect of H2 was related to its antioxidant and anti- inflammatory activities. Additionally, though both H2 delivery methods (intraperitoneal injection and oral administration) were equally effective, the authors proposed using oral administration in the treatment of Pulmonary Hypertension since it proves less expensive and offers a longer-release time.

    Bottom Line:

  • Research shows oral administration of molecular hydrogen (H2) is effective in treating Pulmonary Hypertension (PH)
  • (PH) is a condition caused by increased pressure in the pulmonary arteries that results in debilitating symptoms of chest pain, fatigue, and shortness of breath
  • In the study, H2 was found to prevent the development of PH and actually reverse RV hypertrophy

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By Distracting Antibodies, Pseudomonas Can Cause Bronchiectasis

One of the obstacles that pharmaceutical companies and researchers face in the development of new therapeutics is bacterial mutation. Some medications take, on average, a decade of testing and rigorous filing for regulatory approval, only to be met with evolved and tougher strains of bacteria that will only be sensitive to a new formulation. A team of scientists from the University of Birmingham in England recently discovered a new bacterial defense mechanism that may offer them the ability to neutralize antibodies and use them to their advantage in order to advance new medications.

A Pseudomonas infection can be difficult to treat and can inflict significant lung damage, especially in people with impaired airway clearance such as cystic fibrosis and bronchiectasis. Bronchiectasis can result from a prolonged, poorly managed infection, and it manifests as a persistent cough, accompanied by shortness of breath and chest pain. A respiratory infection from Pseudomonas aeruginosa is a serious concern among individuals with cystic fibrosis (CF), as well.

In this study, researchers analyzed blood samples from bronchiectasis patients with an active Pseudomonas infection and reduced lung function. They found elevated levels of IgG2 in the patients’ systems, which rendered the immune system useless against the bacteria. These specific antibodies attached themselves to sugar chains along the bacteria’s surface, “distracting” bactericidal complement proteins and helping preserve the bacteria. This discovery of antibodies having more affinity to bacterial sugar chains prompts many questions in the research and development of antibiotics, vaccines, and immunotherapy.

In related news, clinical stage biotechnology company GlycoMimetics, Inc. develops drugs that mimic the molecular structure of carbohydrates involved in important biological processes. Their leading pipeline treatment for this infection is GMI-1051 – formulated to target specific virulence factors that determine the bacteria’s growth and resistance, In studies that involved animal models, this treatment was able to enhance the body’s immunity, clearance of the bacteria, and odds of survival compared to treatment based solely on use of antibiotics.

    Bottom Line:

  • In seeking to combat bacterial mutation, scientists discovered a new bacterial defense mechanism that may lead to the formulation of new medications.
  • They found elevated levels of IgG2 antibodies in bronchiectasis patients with Pseudomonas infection and reduced lung function
  • These antibodies attach themselves to sugar chains along the bacteria’s surface, “distracting” bactericidal complement proteins and rendering the immune system useless against the bacteria

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Antimicrobial CSA-13 Proven Effective Against Psuedomonas Aeruginosa Biofilm

N8 Respiratory LLC, an emerging respiratory therapeutics company focused on treatment of chronic cystic fibrosis pulmonary infections, announced new results from a preclinical study demonstrating its lead compound CSA-13's efficacy as an antimicrobial peptide mimic against Pseudomonas aeruginosa. The study will be presented as a poster at the North American Cystic Fibrosis Conference (NACFC) in Atlanta, GA.

The study measured efficacy and the MIC of CSA-13 and tobramycin when combined with standard and tobramycin-resistant strains of P. aeruginosa. Sputum of cystic fibrosis patients was also added to each treatment to determine the impact of biofilm on each treatment. Results showed that the minimum inhibitory concentration (MIC) of CSA-13 was unchanged in the presence of sputum from CF patients, while the MIC of tobramycin (the most common antibiotic for pulmonary P. aeruginosa infections) increased significantly in the presence of sputum from CF patients. CSA-13's MIC also remained unchanged whether tested in a tobramycin susceptible, or a tobramycin resistant strain.

"This is an encouraging study, as it demonstrates the ability of CSA-13 to remain effective even in the presence of sputum from a cystic fibrosis patient," said Paul B. Savage, MD, Department of Chemistry and Biochemistry, Brigham Young University. "Further, it confirms previous findings that the compound may continue to be effective even in antibiotic-resistant strains of P. aeruginosa."

    Bottom Line:

  • N8 Respiratory LLC announced results from a preclinical study demonstrating CSA-13's effectiveness as an antimicrobial peptide mimic against Pseudomonas aeruginosa
  • The study measured efficacy of CSA-13 and tobramycin when combined with standard and tobramycin-resistant strains of P. aeruginosa and analyzed the sputum of cystic fibrosis patients to determine the impact of biofilm on each treatment
  • Successful findings were presented at the NACFC in Atlanta, Georgia this October

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Tannic Acid May Help CF Patients Recover From Bacterial Lung Infections

From an early age, the lungs of individuals with cystic fibrosis (CF) are colonised and infected by bacteria, a common example of which being Staphylococcus aureus (S. aureus). Researchers from the University of Pennsylvania and the Howard Hughes Medical Institute previously showed that an enzyme called Sphingomyelin phosphodiesterase C (SMaseC) produced by the S. aureus bacterium may harm the health of CF patients. Now, they have discovered an inhibitor for this pathogenic bacterial enzyme.

Scientists saw that the SMaseC enzyme suppresses CFTR channel activity in these experimentally modified frog oocytes, and also in a human lung cell line. The problems originating from genetic defects in CFTR channels are likely made greater if the enzyme reduces the function of the CFTR channel even further. SMaseC also suppresses a type of voltage-gated potassium channel, known as the Kv1.3 channel, in immune cells. Suppression of these potassium channels is known to weaken host immunity, which would make it more difficult for the CF patients to recover from lung infections.

To try and counteract the effects of the enzyme, the researchers went on to test a collection of over 2,000 approved drugs and natural products in a chemical library. They found that tannic acid -- a readily available and inexpensive natural product that has been used to treat disease as far back as 1850 -- stopped SMaseC from having a negative effect on both the CFTR and the Kv1.3 channels. "We hope to test whether the application of the SMaseC inhibitor tannic acid, in conjunction with effective antibiotic treatment and supportive measures, will provide a significant therapeutic improvement over current treatments for cystic fibrosis," Dr. Zhe Lu, the senior author, says. His team is also working hard to understand the exact mechanism by which tannic acid counters the negative actions of SMaseC.

    Bottom Line:

  • Researchers, having previously shown that an enzyme called SMaseC produced by the S. aureus 9 bacterium may harm the health of CF patients, have now discovered SMaseC's inhibitor
  • Working with frog eggs and human lung cells, scientists found that SMaseC suppresses CFTR channel activity and a potassium channel called Kv1.3 that negatively affects the immune system
  • Upon discovery that tannic acid stopped SMaseC from having a negative effect on both the CFTR and the Kv1.3 channels, scientists are now working on how tannic acid can help treat CF

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Is CF Patient Lung Function Higher in US than UK? YES!

Young adults and children with cystic fibrosis in the United States have better lung function than those who live in the United Kingdom, despite the fact that both countries have well-developed healthcare systems. Differences in lung function may be a result of differences in healthcare structure, according to the authors of “Children and Young Adults in the USA Have Better Lung Function Compared with the UK,” which was published in the journal BMJ Thorax.

“At this stage there is a lot more work to do to identify the cause of the differences,” stated Dr. Diana Bilton, Chair of the UK Cystic Fibrosis Registry steering committee, in a news report. “It is important that we all look at our practice... check whether we are using the medicines already available in the best way. We also need to look at how we deliver care.”

Dr. Bilton’s comments were fueled by an analysis of 2010 data from the US and the UK involving cystic fibrosis patients aged six to twenty-five years. Lung function was 3.31% higher in US patients, which may be a result of medication and routine medical practices.

In the United States, it is common for patients to be treated only at specialist centers, whereas in the United Kingdom, patients generally see a specialist once a year and see a pediatrician, rather than a cystic fibrosis expert, in the interim. “Comparing clinical outcomes between countries can be informative where clear differences in care models and treatment approaches occur and it is important that we learn from other countries,” stated Janet Allen, Director of Research and Care at the Cystic Fibrosis Trust.

On top of frequent specialized care, American patients receive different therapies than those in the United Kingdom. Chronic pulmonary therapies and chronic macrolide antibiotics are used more often in the United States, and the use of hypertonic saline and rhDNase is most strikingly different.

Although the data was from 2010, which allows time for changes in healthcare that may have evened out the imbalanced lung function by the current year, the report identifies the potential 10 need for more aggressive treatment of cystic fibrosis in the United Kingdom.

    Bottom Line:

  • Young adults and children with CF in the U.S. have better lung function than those who live in the UK
  • Differences in lung function may be a result of differences in healthcare structure
  • On an observational note, findings were based on analysis from four years ago, from 2010 data gathered from the US and the UK; constructive changes may have already been made

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New Orphan Drug Targeting F508delta Mutation Being Developed By ProQR Therapeutics

ProQR Therapeutics B.V., a biopharmaceutical company based in Leiden, Netherlands and founded in 2012, is developing RNA-based therapeutics for the treatment of genetic disorders. They recently announced their stock market listing, raising approximately $98 million toward the development of their new drugs.

ProQR Therapeutics’ lead candidate is QR-010, a RNA-based oligonucleotide for the treatment of Cystic Fibrosis (CF). Per the European Medicines Agency’s (EMA) website, QR-010: “ QR010.... is an ‘anti-sense oligonucleotide’, a very short piece of synthesized RNA (a type of genetic material involved in the production of proteins). This anti-sense RNA specifically attaches to the ‘sense’ RNA with the F508delta mutation which is responsible for the production of the abnormal CFTR protein in cystic fibrosis. As a result, the anti-sense RNA is expected to induce the repair of the genetic RNA abnormality, leading to the production of a fully functional CFTR protein.”

ProQR Therapeutics plans on filing an FDA Investigational New Drug (IND) application by the end of 2014 with a Phase Ib clinical trial to follow. ProQR Therapeutics is targeting the DF508 CF mutation, which is the most prevalent mutation comprising about 70% of all CF patients.

In August 2014, Cystic Fibrosis Foundation Therapeutics (CFFT), a subsidiary of the Cystic Fibrosis Foundation (CFF), entered into an agreement with ProQR Therapeutics to provide up to $3 million to support the clinical development of QR-010.

    Bottom Line:

  • ProQR Therapeutics is developing a new orphan drug called QR010
  • ProQR Therapeutics plans to schedule a Phase Ib clinical trial in a few months

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Using Aerobika OPEP Effectively Treats Bronchiectasis, Cystic Fibrosis, and COPD

A recent study conducted at the Robarts Research Institute at Western University in London, UK, demonstrated the effectiveness of the drug-free Aerobika device for the treatment of chronic obstructive pulmonary disease (COPD), cystic fibrosis )CF) and bronchiectasis after three weeks of use every day. The device was developed and commercialized by Monaghan Medical Corporation and is used by many leading hospitals in the United States.

The study demonstrated that patients using Aerobika daily for three weeks increased mucus clearance, decreased cough frequency and breathlessness, and enhanced exercise tolerance. In addition, the scientists also discovered that the device induces an overall increase in the quality of life without side effects, as reported by the patients themselves who tested the device.

The researchers assessed Aerobika’s effectiveness through the Pulmonary Function Test, Six Minute Walk Test, the St. George’s Respiratory Questionnaire (SGRQ), the Patient Evaluation Questionnaire (PEQ), and Hyperpolarized Helium-3 Magnetic Resonance Lung Imaging (3He MRI). The results of the study corroborate a different study conducted by Trudell Medical International (TMI), which revealed the safety and effectiveness of Aerobika for the treatment of COPD.

The Aerobika Oscillating Positive Expiratory Pressure (OPEP) device is a treatment that does not require any drugs, but uses a proprietary pressure-oscillation dynamic, which is able to offer intermittent resistance, as well as positive pressure and oscillations at the same time. With these movements and pressure, the device releases and clears mucus, unclogging the airways. The device was recently granted the Gold medal at the Medical Design Excellence Awards (MDEA), a contest that recognizes innovative medical devices that are able to improve patients’ care and quality of life.

    Bottom Line:

  • The Aerobika Oscillating Positive Expiratory Pressure (OPEP) device is an effective treatment for airway clearance that does not require any drugs
  • The device uses a proprietary pressure-oscillation dynamic, which is able to offer intermittent resistance, as well as positive pressure and oscillations all at the same time
  • The study demonstrated that patients using Aerobika daily for three weeks increased mucus clearance, decreased cough frequency and breathlessness, enhanced exercise tolerance, and had an overall increase in the quality of life without any side effects

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Device For Cystic Fibrosis Care Is Improved Using Open Design and 3D Printing

A collaborative design effort to create a dispensing device for medicines used to treat the genetic disease cystic fibrosis (CF) was spearheaded by researchers in the UK. The team – from Sheffield Hallam University, the University of Sheffield and the CF unit at Northern General Hospital – enlisted the aid of patients in the design of the new dispenser, which aim to overcome some of the barriers to treatment with Creon, an enzyme preparation that is used to help CF patients digest food.

Creon (pancrelipase), and other such pancreatic enzymes, are taken in capsule form alongside meals and mixes with food in the stomach, helping individuals with CF to extract the vital nutrients and energy they need. At the moment, Creon capsules are supplied in a large pot somewhat reminiscent of a hockey puck. The container is big, bulky and rattles, which may not be a problem when eating at home but is not desirable when dining out, particularly as several capsules may need to be taken each meal. Patients sometimes transfer the capsules to other more discreet containers such as Altoids tins, but these do not help them keep track of the many pills that need to be taken every day, which can be more than a dozen in some cases.

“Creon use outside the home was identified as a vital issue, with novel Creon dispensers suggested as a potential solution,” according to the researchers, led by designer Matt Dexter, who presented their work as a poster at the 37th European Cystic Fibrosis Conference in Gothenburg, Sweden, in June.

In fact, the overarching aim of the project was to discuss a variety of different CF-oriented ‘products’ that might be made in this way, but an improved dispenser for Creon was the most popular choice to take forward by those participating in the effort. Others under consideration included a treatment cabinet designed to hold all the treatment paraphernalia required for managing CF.

Various design ideas for the device were tossed about, and one – inspired by Pez candy dispensers – was taken through to multiple prototype stages and constructed using a MakerBot 3D printer. The prototypes were road-tested by the CF community and opinions were shared, allowing for various refinements to the design to be made.

All told, more than 500 people from across the world participated in the project, which eventually yielded a discreet, rattle-free dispenser that fits easily into a pocket or handbag, and delivers one capsule per push. In time, the design will also incorporate an electronic dose counter to help patients and healthcare professionals monitor adherence to treatment. And of course the dispenser is open-source, so the files are freely available on Thingiverse to download.

    Bottom Line:

  • A new CF-oriented device was collaboratively created and tested on more than 500 people
  • The design is a rattle-free pancreatic enzyme dispenser for discreet use when out among other people
  • It was made using a 3D printer and is an open design, meaning it available for free download

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Join A Yoga Class And Laugh Your Worries Away

In 2008, Lainie Diamond was living in New York and was wondering where her laughter went. She discovered a yoga instructor named Vishwa Prakash who wasn't teaching the typical stretching and stances most people associate with the ancient exercise system for body and mind. He was teaching how to laugh, regardless of if students were in the mood.

Laughter yoga is an exercise routine founded in 1995 by an Indian physician, Dr. Madan Kataria. Prakash studied under Kataria and began offering laughter yoga classes in New York. Diamond joined Prakash's free class and- can you guess? Yes, soon she too wanted to help others find their laughter and became a certified laughter yoga instructor.

At its core, Diamond said, laughter yoga teaches people how to breathe. "We hear the phrase, 'Just breathe,' all the time," she said. "Breathing is very important for the body." As a professional singer, Diamond was already familiar with a variety of breathing techniques to help her achieve long notes. Through laughter yoga, she discovered the therapeutic value of breathing. "Music is my vocation and laughter is my life," she said. "Breathing can be healing. Laughter helps oxygenate your body and can change your brain chemistry. "

A report by the Mayo Clinic suggests that giggles and guffaws have a number of short- and long- term benefits. Laughter, according to the clinic, enhances the intake of oxygen, which in turn stimulates the body's heart, lungs and muscles and increases endorphins released by the brain. Laughter is said to sooth tension by stimulating blood circulation.

Whereas negative thoughts result in chemical reactions that can increase stress and decrease immunity, laughter creates positive thoughts that result in release of neuropeptides, which are a type of chemical transmitter, to fight stress and illness, the clinic reported. Other benefits of laughter can include pain relief, better coping skills and an antidote for depression and anxiety.

"The body doesn't know a real laugh from a fake laugh," Diamond said. "One of our laugher yoga mottos is, 'Fake it 'til you make it.' " Just going through the motions with various "deep ho- ho-hos and ha-ha-has" can help oxygenate the body, she said. But, laughter yoga isn't all laughs. Those who take (the class) are able to express laughter, anger and forgiveness through breathing exercises."

The participants in her class are often seen moving around, sometimes hugging themselves while laughing silently or out loud. It may look funny, however, Diamond said they are learning breathing techniques and activating various muscles. Another benefit of laughter, Diamond said, is that it can serve as glue bonding people together socially. "The effects of laughter yoga can be life-changing for people and affects their careers, their family life and their relationships," Diamond said.

    Bottom Line:

  • Laughter yoga is an exercise routine that teaches people how to breathe using laughter
  • The Mayo Clinic reports that laughter enhances the intake of oxygen, soothes tension by stimulating blood circulation, and creates positive thoughts that result in release of neuropeptides to fight stress and illness
  • Because the body doesn't know a real laugh from a fake one, even just going through the motions with various "deep ho-ho-hos and ha-ha-has" can help oxygenate your body and change your brain chemistry for the good

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