Posts Tagged ‘Sleep disorder’

Sleep Deprivation Death Linked Causally to the Gut

Reporter : Irina Robu, PhD

Neuroscientists at Harvard Medical School identified an unexpected link between sleep deprivation and premature death. Their findings show that the possibility that animals might be able to survive without sleep, under certain circumstances. Their study with sleep-deprived fruit flies found that death was continuously by the accumulation of reactive oxidative species in the gut. And when the flies were given antioxidant compounds that neutralized and cleared ROS from the gut, the sleep-deprived animals remained active and had normal lifespans. Extra experiments in mice confirmed that ROS accumulated in the gut when they didn’t get enough sleep.

Yet, in spite of decades of study, researchers still haven’t revealed why animals die when they don’t sleep. In attempts to answer how sleep deprivation culminates in death, most research has focused on the brain, where sleep originates. However, studies have yet to yield conclusive results. In addition to impairing cognition, sleep loss leads to dysfunction of the gastrointestinal, immune, metabolic, and circulatory systems.

The Harvard Medical School team carried out a sequence of experiments in fruit flies to search throughout the body for signs of damage caused by sleep deprivation. Fruit flies share many sleep-regulating genes with humans. To screen sleep, the investigators used infrared beams to constantly track the movement of flies housed in individual tubes. Scientist show that flies can sleep through physical shaking, so they genetically manipulated fruit flies to express a heat-sensitive protein in specific neurons, the activity of which are known to suppress sleep. When flies were housed at 29°C the protein induced neurons to remain constantly active, thus preventing the flies from sleeping.

The scientists discovered that fruit fly mortality spiked after 10 days of temperature-induced sleep deprivation and all of the flies died by around day 20 and control flies that had normal sleep lived up to approximately 40 days in the same environmental conditions. Since mortality increased around day 10, the scientists looked for markers of cell damage on that and the preceding days. They noticed that the guts of sleep-deprived flies had a dramatic build-up of ROS. The buildup of ROS in the fruit fly guts peaked around day 10 of sleep deprivation, and when deprivation was stopped, ROS levels decreased.

To find out if ROS in the gut plays a causal role in sleep deprivation-induced death, the researchers next looked at whether preventing ROS accumulation could prolong survival. They tested dozens of compounds with antioxidant properties known to neutralize ROS and identified 11 that, when given as a food supplement, allowed sleep-deprived flies to have a normal or near-normal lifespan. These compounds, such as melatonin, lipoic acid, and NAD, were particularly effective at clearing ROS from the gut. Notably, the supplements did not extend the lifespan of non-sleep-deprived flies.

The role of ROS removal in preventing death was also confirmed by experiments in which flies were genetically manipulated to overproduce antioxidant enzymes in their guts. These flies had normal to near-normal lifespans when sleep deprived, but flies that overproduced antioxidant enzymes in their nervous systems weren’t protected from sleep-deprivation-related death. While the results demonstrated that ROS build up in the gut plays a central role in causing premature death from sleep deprivation, the researchers acknowledged that many questions are still without answers. At the same time, they found that insufficient sleep is identified to restrict with the body’s hunger signaling pathways, which lead to measure the fruit fly food intake to analyze whether there were potential associations between feeding and death. They found that some sleep-deprived flies ate more throughout the day compared with non-deprived controls.

The researchers are now working to identify the biological pathways that lead to ROS accumulation in the gut and subsequent physiological disruptions.


Death Due to Sleep Deprivation Linked Causally to the Gut, and is Preventable in Flies


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  • More than 77 percent of patients in the REMfresh® Patient Reported Outcomes DURation (REMDUR) study reported achieving 6 or more hours of sleep after taking REMfresh®, the first continuous release and absorption melatonin (CRA-melatonin)
  • More than 91 percent experienced improvements in sleep onset, sleep maintenance and total sleep quality, after taking REMfresh® (CRA-melatonin)
  • Post-marketing, patient-reported outcomes data reinforces clinical trial evidence demonstrating the potential of non-prescription REMfresh®, as a new, non-prescription, drug-free hypnotic (sleep) product designed to achieve 7-hour sleep
  • New data confirms previously presented SLEEP 2017 study showing the patented Ion Powered Pump (IPP) technology in REMfresh® helps extend melatonin-targeted sleep maintenance levels in the body from 3.7 hours (with marketed immediate-release melatonin) to 6.7 hours, while mimicking the pattern of the body’s natural melatonin blood levels during the nightly sleep cycle

Real Time Coverage at SLEEP 2018 meeting, Baltimore.

Reporters: Aviva Lev-Ari, PhD, RN, and Gail S. Thornton, MA

BALTIMORE – (June 6, 2018) – A patient-reported outcomes study presented at SLEEP 2018 provides confirmatory real-world evidence of the previously peer-reviewed and presented data showing the 7-hour action of REMfresh®, a new product for sleep. REMfresh® Ion-Powered Melatoninis the first and only, continuous release and absorption melatonin (CRA-melatonin) to mimic the body’s own 7-hour Mesa Wave, the natural pattern of melatonin blood levels during a normal night’s sleep cycle. This induces sleep onset and provides lasting and restorative sleep for up to 7 hours.

This new data shows a correlative relationship between a 7-hour Mesa Wave pharmacokinetic (PK) profile and real-world evidence of improvements in sleep duration, onset, maintenance and sleep quality after taking REMfresh® (CRA-melatonin).

The post-marketing REMfresh® Patient Reported Outcomes DURation (REMDUR) study was presented at SLEEP 2018, the 32nd Annual Meeting of the Associated Professional Sleep Societies (APSS), LLC, a joint partnership of the American Academy of Sleep Medicine (AASM) and the Sleep Research Society (SRS).


Brodner and Seiden

Pictured here is David C. Brodner, M.D., and David J. Seiden, M.D., FAASM, after presenting the latest study data which found REMfresh is the first and only continuous release and absorption melatonin™ to mimic the body’s own 7-hour Mesa Wave™.


In a sample of 500 patients on REMfresh® (CRA-melatonin) responding to an online survey, 77.6 percent achieved 6 or more hours of sleep compared to 23.6 percent who slept that duration prior to taking REMfresh® (p<.0001). A vast majority of respondents also reported a major or moderate improvement in sleep onset (91.6 percent, p<.0001), sleep maintenance (94.8 percent, p<.0001) and total sleep quality (97.2 percent, p<.0001). More than three-quarters (76.6 percent) of patients indicated they take REMfresh® (CRA-melatonin) nightly. The proportion of patients reporting nightly CRA-melatonin use was significantly greater than the proportion of patients with less than nightly use (p<.0001). Most importantly, over 98 percent of patients reported they were very likely or likely to continue taking REMfresh® (CRA-melatonin) to treat their sleep complaints.

“The real-world evidence reported today in REMDUR provides further confirmation that REMfresh® represents a significant advance in the use of melatonin as a baseline therapy for treating sleep complaints,” said David C. Brodner, M.D., a leading sleep specialist who is Double Board-Certified in Otolaryngology — Head and Neck Surgery and Sleep Medicine, founder and principle Physician at the Center for Sinus, Allergy, and Sleep Wellness, in Palm Beach County, Florida, and Senior Medical Advisor for Physician’s Seal, LLC®.

“REMfresh® Ion-Powered Melatoninhas been shown to be an effective drug-free solution that is now available to the millions of Americans in need of a good night’s sleep, many of whom seek new therapies that will induce sleep and keep them asleep until the morning, without causing residual effects they’ll feel the next day. With its unique delivery system that imitates the body’s own natural sleep pattern, REMfresh® has revolutionized the role of melatonin, when delivered in the CRA form. It is no longer just a treatment for jet lag, but the CRA-melatonin found in REMfresh® has been shown to provide substantial relief to individuals having nightly sleep challenges,” said Dr. Brodner.

The scientifically advanced, patented delivery system in REMfresh® (CRA-melatonin), called Ion Powered Pump (IPP™) technology, replicates the way in which the body naturally releases and absorbs melatonin, unlike conventional melatonin sleep products. Since REMfresh® is not a drug, there is no drug hangover.

Nearly one-third of U.S. adults sleep less than the recommended seven hours daily.[1],[2] Increasing evidence suggests an association between sub-optimal sleep duration and adverse health outcomes including a higher risk of diabetes, hypertension, heart attack, stroke, obesity and depression.[3] A pooled analysis of 16 studies and over one million patients found short sleep duration corresponded with greater risk of morbidity and mortality.[4]

 REMDUR Study Design

The post-marketing REMfresh® Patient Reported Outcomes DURation (REMDUR) study was designed to obtain real-world evidence about patients’ sleep patterns, duration of sleep before and after REMfresh® (CRA-melatonin), daily REMfresh® (CRA-melatonin) use, onset of action, sleep maintenance, quality of sleep, and overall satisfaction with REMfresh® (CRA-melatonin).

Patients with sleep disturbances in the general population who received a sample of CRA-melatonin (REMfresh®) from their physicians were invited to complete a 12-question survey. Survey responses were received from 500 patients.

Confirmation of the REMAKT Clinical Study

REMDUR confirmed clinical trial findings from REMAKT (REM Absorption Kinetics Trial), a U.S.-based randomized, crossover pharmacokinetic (PK) evaluation study in healthy, non-smoking adults that compared REMfresh® (CRA-melatonin) with a market-leading, immediate-release melatonin (IR-melatonin).[5]

The study results, peer-reviewed and presented last year at SLEEP 2017, showed that melatonin levels with REMfresh® (CRA-melatonin) exceeded the targeted sleep maintenance threshold for a median of 6.7 hours, compared with 3.7 hours with the leading IR-melatonin. Conversely, the levels of the market-leading IR-melatonin formulation dramatically increased 23 times greater than the targeted levels of exogenous melatonin for sleep maintenance and had a rapid decline in serum levels that did not allow melatonin levels to be maintained beyond 4 hours.

The REMfresh® (CRA-melatonin) studies build upon the body of evidence from prolonged-release melatonin (PR-M), marketed in Europe, which demonstrated in well-conducted, placebo-controlled studies, statistically significant improvement in sleep quality, morning alertness, sleep latency and quality of life in patients aged 55 years and older compared with placebo. REMfresh® (CRA-melatonin) was designed to overcome the challenges of absorption in the intestines, thereby extending the continual and gradual release pattern of melatonin through the night (known as the Mesa Wave, a flat-topped hill with steep sides). There was a fast time to Cmax, which is anticipated to result in improved sleep onset, while the extended median plateau time to 6.7 hours and rapid fall-off in plasma levels at the end of the Mesa Wave, may help to improve sleep maintenance and morning alertness.

Conventional melatonin products have had challenges at mimicking the profile of a Mesa Wave™. The scientific work behind REMfresh® (CRA-melatonin) sought to overcome these challenges by having the melatonin formulation in a matrix that maintains a patented, solubility-enhancing pH environment to help with the transport to the brush border of the gut and its subsequent absorption.

Designed as a hydrogel matrix tablet, REMfresh® (CRA-melatonin) provides rapid release of the melatonin from the surface of the tablet, as the hydrogel release-controlling matrix is setting up in the acidic environment (pH of 1 to 3.5) in the stomach. As the tablet moves into the higher pH (5.5 to 6.5) environment of the small-intestine, which is above the pKa of melatonin (~4.0), the acidic moiety in the tablet is designed to maintain the pH within the tablet below 4.0 for 7+ hours. The hydrogel matrix, after proper hydration, allows continuous release of the active melatonin and acidic moiety into the lumen of the intestines.

Melatonin: The Body’s Natural Sleep Ingredient

Melatonin is produced by the pineal gland in the brain and is the body’s natural sleep ingredient. Melatonin levels normally begin to rise in the mid-to late evening and remain high for the majority of the night. Levels begin to decline towards early morning, as the body’s wake cycle is triggered. As people age, melatonin levels can drop by as much as 70 percent[6] and their bodies may no longer produce enough melatonin to ensure adequate sleep.

Other available products, such as immediate-release melatonin, help initiate the onset of sleep but are usually unable to sustain prolonged sleep maintenance due to an immediate burst of melatonin, which is quickly degraded due to its relatively short half-life (60 minutes). Absorption in the lower digestive tract is limited by melatonin’s limited ability to be absorbed in a low acidity or neutral pH environment.

Importance of Sleep

Sleep is an essential part of every person’s life. The body requires a certain amount of sleep in order to properly rest, repair and renew itself. Sleep is customarily divided in four different stages, with each stage having a different effect. These four stages are:

N1, N2, deep sleep and REM sleep. The body moves among these four stages several times while asleep. If sleep is disrupted for any reason, a person’s body may not have a chance to properly restore itself, especially if it is struggling to get to the later stages, called deep sleep and REM sleep. Studies have shown that sound and sufficient sleep is important for learning, memory and a healthy immune system. A regular pattern of deep sleep and REM sleep will help a person begin the next day feeling refreshed and ready to go.

About Non-Prescription REMfresh®

REMfresh® (CRA-melatonin) is the first and only, continuous release and absorption formulation of UltraMel® melatonin (available as 2 mg and 5 mg and with a 0.5 mg anticipated in the second half of 2018). UltraMel® melatonin is a high-quality, 99 percent ultra-pure melatonin sourced from Western Europe exclusively for Physician’s Seal®.

REMfresh® (CRA-melatonin) is a dietary supplement and is regulated under the Federal Dietary Supplement Health and Education Act, which does not require pre-approval. Melatonin has been in common use for over two decades and has a well-established profile of safe use by millions of people around the world. As with all supplements, individual results may vary.

REMfresh® (CRA-melatonin) is non-habit forming and does not contain narcotics, hypnotics, barbiturates, sedatives, antihistamines, alcohol or other harsh or additive chemicals. The usual adult recommended dose is 1-2 tablets 30-60 minutes before bedtime. Follow specific dosing instructions found on the back of the box for proper use of supplements.

REMfresh® (CRA-melatonin) is available at Walmart, Rite Aid and CVS/pharmacy. In 2017 REMfresh® was ranked as  the #1 recommended brand for sleep management by sleep doctors[7].

About Physician’s Seal®

Physician’s Seal® is the innovator of REMfresh®, the first and only continuous release and absorption, 99 percent ultra-pure melatonin (CRA-melatonin) that mimics the way the body naturally releases and maintains melatonin over a 7-hour period. Physician’s Seal®, founded in 2015, is a privately held company based in Boca Raton, Florida. It is committed to bringing cutting-edge life science applications to doctors and their patients. For more information, visit www.remfresh.com and connect with us on Facebook and You Tube.

Its sister subsidiary, IM HealthScience® (IMH) is the innovator of IBgard® and FDgard® for the dietary management of Irritable Bowel Syndrome (IBS) and Functional Dyspepsia (FD), respectively. In 2017, IMH added Fiber Choice®, a line of prebiotic fibers, to its product line via an acquisition. IMH® is a privately held company based in Boca Raton, Florida. It was founded in 2010 by a team of highly experienced pharmaceutical research and development and management executives. The company is dedicated to developing products to address overall health and wellness, including conditions with a high unmet medical need, such as digestive health. The IM HealthScience® advantage comes from developing products based on its patented, targeted-delivery technologies called Site Specific Targeting® (SST®). For more information, visit www.imhealthscience.com to learn about the company, or www.IBgard.com,  www.FDgard.com,and www.FiberChoice.com.

This information is for educational purposes only and is not meant to be a substitute for the advice of a physician or other health care professional. You should not use this information for diagnosing a health problem or disease. The company will strive to keep information current and consistent but may not be able to do so at any specific time. Generally, the most current information can be found on www.remfresh.com. Individual results may vary.

Data Presented at SLEEP 2018 Poster Session on Sleep Maintenance/Sleep Quality

Tuesday, June 5, 2018, 5-7pm

  • (Abstract 0419, Poster Board #104) Improvement in Sleep Maintenance and Sleep Quality with Ion Powered Pump Continuous Release and Absorption Melatonin: Results from a Self-Reported Patient Outcomes Study
    • David J. Seiden, M.D., FAASM, David C. Brodner, M.D., Syed M. Shah, Ph.D.

Visit Physician’s Seal® at booth 220 to learn more about REMfresh®.

The abstract is published in an online supplement of the journal, Sleep, which is available at http://www.sleepmeeting.org/docs/default-source/default-document-library/abstractbook2018.pdf?sfvrsn=2

[1] Ford, E.S., Cunningham, T.J., & Croft, J.B. (2015, May 1). Trends in Self-Reported Sleep Duration among US Adults from 1985 to 2012. Sleep, 38(5):829-832. doi: 10.5665/sleep.4684.

[2] Watson, N.F., Badr, M.S., Belenky, G., Bliwise, D.L., Buxton, G.M., Buysse, D.,…Tasali, E. (2015). Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society on the Recommended Amount of Sleep for a Healthy Adult: Methodology and Discussion. Journal of Clinical Sleep Medicine, 11(8):931-952. doi:10.1176/appi.ajp.158.11.1856.

[3] Colten, H.R., & Altevogt, B.M. (Eds). (2006). Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem.  Institute of Medicine (US) Committee on Sleep Medicine and Research. Washington, DC: National Academies Press (US). doi: https://doi.org/10.17226/11617.

[4] Cappuccio, F.P., D’Elia, L., Strazzullo, P.,&  Miller, M.A. (2010). Sleep duration and all-cause mortality: a systematic review and meta-analysis of prospective studies. Sleep, 33(5):585-592

[5] For this clinical trial, the head-to-head comparison was with the 5 mg form; a 2 mg form of the comparator was not available.

[6] Zisapel, N. (2010). Melatonin and sleep. The Open Neuroendocrinology Journal, 3: 85-95.

[7] Among primary care physicians with a certification in sleep disorders who recommended a brand of modified-release melatonin. Quintiles IMS ProVoice July-September 2017 survey.


Physician’s Seal® and REMfresh® (www.remfresh.com)

Dr. David C. Brodner, Center for Sinus, Allergy, and Sleep Wellness (http://www.brodnermd.com/sleep-hygiene.html)

Other related articles published in this Open Access Online Scientific Journal include the following:


Ultra-Pure Melatonin Product Helps Maintain Sleep for Up to 7 Hours



Sleep Science

Genetic link to sleep and mood disorders



Sleep quality, amyloid and cognitive decline



Day and Night Variation in Melatonin Level affects Plasma Membrane Redox System in Red Blood Cells



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Sleep apnea and non-invasive positive pressure breathing

Curator: Larry H Bernstein, MD, FCAP


UPDATED on 10/24/2019

Researchers identify genetic variations linked to oxygen drops during sleep

“This study highlights the advantage of using family data in searching for rare variants, which is often missed in genome-wide association studies,” said James Kiley, Ph.D., director of the Division of Lung Diseases at NHLBI. “It showed that, when guided by family linkage data, whole genome sequence analysis can identify rare variants that signal disease risks, even with a small sample. In this case, the initial discovery was done with fewer than 500 samples.”

Notably, 51 of the 57 genetic variants influence and regulate human lung fibroblast cells, a type of cell producing scar tissue in the lungs, according to study author Xiaofeng Zhu, Ph.D., professor at the Case Western Reserve University School of Medicine, Cleveland.

“This is important because Mendelian Randomization analysis, a statistical approach for testing causal relationship between an exposure and an outcome, shows a potential causal relationship between how the DLC1 gene modifies fibroblasts cells and the changes in oxygen levels during sleep,” he said.



Presentation of sleep apnea

Obstructive sleep apnea is caused by a blockage of the airway.  This may occur when the soft tissue in the rear of the throat collapses and closes during sleep. Sleep apnea causes SNORING, intermittent cessation of breathing during sleep, which the person having the sleep disturbance may be unaware of.  This results in reawaking and restless sleep, and concomitantly, daytime fatigue. Obstructive sleep apnea accounts for 85% of cases. According to some studies, one in every 15 Americans is affected by this condition, and only a small percentage of them get treated.


Weight loss and diabetic control might be sufficient for some who have a mild condition.  There are also breathing exercises, and the placement of an orthodontic specially fitted mouth guard that flattens the posterior mouth during sleep.  Those who have moderate to severe sleep apnea may require assisted beathing during sleep, or surgery.  The standard treatments are CPAP (continuous positive airway pressure ) or BiPAP (Bilevel positive airway pressure), the first being most commonly used.  However, the effectiveness is influenced by body positioning during sleep.  Many patients are unable to adjust to the CPAP mask, which has to fit snugly over the mouth and nose.

TransOral Robotic Surgery (TORS) for sleep apnea

A recently introduced surgical procedure that has gained wide use is transoral robotic surgery (TORS).
The use of da Vinci® robot-assisted surgery for treatment of obstructive sleep apnea is revolutionary due to the minimally invasive nature of the procedure.  The surgeon guides the robotic arms in through the patient’s mouth, and a high-definition [3D] camera allows the surgeon to perfectly visualize areas of the mouth and throat without any open incisions.  The surgery focuses on reducing the size of the base of the tongue. Patients are assessed during an in-office examination, which includes a review of recent sleep studies, and an evaluation with a scope to identify the level and nature  of obstruction.

The sleep apnea procedure (TORS) involves the actual surgery and a 1-2 day hospital stay after the surgery. Full recovery is expected to take about three weeks. A sleep study is then conducted about three months after surgery to ensure that the procedure was successful.

About CPAP

Continuous positive airway pressure or CPAP is used both in hospitals for newborn babies or those who suffer from respiratory failure, and in the home.  The device works by increasing pressure in the airway, preventing collapse while breathing in. The CPAP machine has tubing, a setting for the pressure, and a mask that covers the mouth and nose, delivering the air pressure into the nasal passages. The right air pressure for a patient is prescribed by the sleep physician after conducting a detailed overnight study of the patient’s breathing pattern. Such a prescribed air pressure is termed as ‘titrated pressure’. The CPAP machine, set at the prescribed air pressure , blows air at the titrated pressure, maintaining the air passage open for uninterrupted breathing during sleep.

CPAP Side Effects

Nasal Congestion: Use of CPAP machines may cause nasal congestion. Some patients may experience nasal irritation or a runny nose too. This is because of the fact that the nose humidifies the air that passes through it and the air from CPAP machine dries up the nose. The body reacts by producing more mucus in the nose, which leads to nasal congestion. In some patients, there will be no mucus production and this results in dry nose, which cause nasal irritation, burning or sneezing. CPAP machines with inbuilt humidifier may help you address this problem.  Other problems are ear pressure and difficulty from a deviated nasal septum.

CPAP Alternatives

Only 23% of individuals suffering from sleep apnea succeed in getting used to CPAP. A popular alternative to this machine are the intraoral dental appliances that consist of two U-shaped plates that are joined to form a hinge. These can be custom-made by a dentist or an orthodontist.   It adjusts the lower jaw and tongue of a user, so that the air passage does not collapse while sleeping. There are lingual tabs that hold the appliance in place.

CPAP Vs. BiPAP – Difference between CPAP and BiPAP

The Continuous Positive Airway Pressure (CPAP) machine gives a predetermined level of pressure. It releases a gust of compressed air through a hose which is connected to the nose mask. The continuous air pressure is what keeps the upper airway open. Thus, air pressure prevents obstructive sleep apnea, which occurs as a result of narrowing of the air passage due to the relaxation of upper respiratory tract muscles while the patient sleeps. It assists in increasing the flow of oxygen by keeping the airway open.

The Bilevel Positive Airway Pressure (BiPAP) is a patented, non-invasive ventilation machine. As the name suggest, it delivers two levels of pressure.  Inspiratory Positive Airway Pressure (IPAP) is a high level of pressure, applied when the patient inhales. Expiratory Positive Airway Pressure (EPAP), a low level of pressure exerted during exhalation.  BiPAP is used to treat central sleep apnea and severe obstructive sleep apnea, and It is prescribed for patients who suffer from respiratory and heart diseases.
Patients using the CPAP have to exert extra force against the air flow while exhaling, whereas with the BiPAP, the airway pressure is set at high and low levels, making it more user-friendly.

Relationship of sleep apnea syndrome to other complicating conditions

Macular edema

Sixteen of 22 obese diabetics of an apneic cohort had severe and six had moderate obstructive sleep apnea syndrome.  The cohort had an average of 44.6 + 21.9 apneic or hypopneic events per hour averaging 23.3 + 5.9 seconds, with oxygen saturation of 73.5 + 9.5% (normal 94%).  The patients had retinopathy manifesting multiple nerve-fiber layer infarcts, at least 3 in each eye, and more than 6 infarcts in most eyes, with microvascular leakage and macular edema.  This finding was rare among the cohort without sleep apnea.

Laparoscopic surgery has been associated with ventilator complications, contingent on cardiac and respiratory comorbidities, and body habitus., particularly morbidly obese patients receiving general anesthesia. The EZ PAP positive airway pressure system is an easily used, disposable device that delivers CPAP air flow from an oxygen flow meter, and has been predicted to improve oxygenation, reducxe CO2 retention, and lower the risk of respiratory complications postoperatively.  Patients in the EZ PAP group demonstrated improvement in ventilator effort in the first few hours postoperatively, but the measured benefit did not exceed 4 hours.  Interventions must be aimed at improvement for longer periods.

Sleep apnea is well documented to negatively affect neurocognitive and neuropsychiatric functioning, including memory, attention, mood, and anxiety.  It has been identified as a risk for developing Alzheimer’s disease, and TBI (traumatic brain injury) is a risk factor for developing dementia, expetially in those with the apolipoprotein epsilon 4 allele.  The majority of sleep apnea are male and TBI is common in veterans of combat,  the increased incidence of sleep disordered breathing in TBI patients (SDB in TBI in 50-70% of patients) is of interest to the Department of Veterans Affairs.  A recent review by O’Hara et al. found that sleep apnea interacted with APOE ε4 and carried increased risk for poor cognitive performance.  Moreover, SNPs within the APOE gene (rs157580, rs405509, rs769455, and rs7412) all showed associations with OSA in children, with age and BMI as covariates.  This suggests that the interaction between TBI, OSA, and APOE genotype is quite complex.  Studies indicate that CPAP/BiPAP can be effective in reducing the sleep apnea and the cognitive sequelae.  The question is raised as  to whether the treatment of OSA might only target APOE ε4 carriers, but it is important to recognize that chronic pulmonary disease that increases hypoxia would factor in.

Treatment of Obstructive Sleep Apnea Reduces the Risk of Atrial Fibrillation Recurrence After Catheter Ablation

Objectives The aim of this study was to examine the effect of continuous positive airway pressure (CPAP) therapy on atrial fibrillation (AF) recurrence in patients with obstructive sleep apnea (OSA) undergoing pulmonary vein isolation (PVI).
Background OSA is a predictor of AF recurrence following PVI, but the impact of CPAP therapy on PVI outcome in patients with OSA is unknown.
Methods Among 426 patients who underwent PVI between 2007 and 2010, 62 patients had a polysomnography-confirmed diagnosis of OSA. While 32 patients were “CPAP users” the remaining 30 patients were “CPAP nonusers.” The recurrence of any atrial tachyarrhythmia, use of antiarrhythmic drugs, and need for repeat ablations were compared between the groups during a follow-up period of 12 months. Additionally, the outcome of patients with OSA was compared to a group of patients from the same PVI cohort without OSA.
Results CPAP therapy resulted in higher AF-free survival rate (71.9% vs. 36.7%; p = 0.01) and AF-free survival off antiarrhythmic drugs or repeat ablation following PVI (65.6% vs. 33.3%; p = 0.02). AF recurrence rate of CPAP-treated patients was similar to a group of patients without OSA (HR: 0.7, p = 0.46). AF recurrence following PVI in CPAP nonuser patients was significantly higher (HR: 2.4, p < 0.02) and similar to that of OSA patients managed medically without ablation (HR: 2.1, p = 0.68).
Conclusions CPAP is an important therapy in OSA patients undergoing PVI that improves arrhythmia free survival.
Comment: . The current study extends similar benefits to those undergoing catheter ablation to those undergoing elective cardioversion of atrial fibrillation with a better long term success when OSA patients are treated with CPAP.
J Am Coll Cardiol. 2013;62(4):300-305.   http://dx.doi.org/10.1016/j.jacc.2013.03.052  


A putative relationship between OSA and diabetic macular edema associated with optic nerve fiber layer infarcts.
Unver YB, Yavuz GSA, Stafford CA, Sinclair SH.
The  Open Sleep Journal 2009;2:11-19.       1874-6209/09

EZ-PAP in the postoperative period: a pilot study.
Talley HC, Twiss K, Wilkinson S, et al.
J Anesth Clin Res 2012; 3:8

Continuous positive airway pressure devices for the treatment of obstructive sleep apnea-hypopnea syndrome: a systematic review and economic analysis.
McDaid C,  Griffin S, Weatherly H, Duree K, et al.
High Technology Assessment 2009; 13(4):1-136

Sleep apnea, apolipoprotein epsilon 4 allele, and TBI: Mechanism for cognitive dysfunction and development of dementia.
O’Hara R, Luzon A, Hubbard J, Zeitzer JM.
J Rehab Res Develop  2009; 46(6):837-850.

English: The Cycle of Obstructive Sleep Apnea ...

English: The Cycle of Obstructive Sleep Apnea – OSA (Photo credit: Wikipedia)

English: This is my own machine of which I too...

English: This is my own machine of which I took the picture. (Photo credit: Wikipedia)

Young Innovator Develops bCPAP to Save Babies ...

Young Innovator Develops bCPAP to Save Babies Lives (Photo credit: USAID_IMAGES)

English: Medical report showing the duration a...

English: Medical report showing the duration and frequency of sleep apnea of a test subject. Duration and frequencies are sorted by the sleeper’s position in bed. Français : Analyse de la durée et du nombre d’apnées en fonction de la position du dormeur. (Photo credit: Wikipedia)

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How Might Sleep Apnea Lead to Serious Health Concerns like Cardiac and Cancer?

Author: Larry H Bernstein, MD, FCAP


3.3.16   How Might Sleep Apnea Lead to Serious Health Concerns like Cardiac and Cancer?, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 2: CRISPR for Gene Editing and DNA Repair

UPDATED on 7/23/2019

Israel-led research team develops AI-based model to detect sleep apnea | The Times of Israel


What is the link between sleep apnea and cardiovascular disease and is the treatment of obstructive sleep apnea (OSA) by continuous positive airway pressure in patients (CPAP) with heart failure to improve left ventricular systolic function sufficient?  There are statistics incicating the benefit of CPAP and improvement of LVSF in those patients on CPAP with CHF.  But that observation does not get at why the patients benefit, or whether the OSA is sufficient.  Don’t expect a randomized clinical trial of any design to be brought to bear on the subject, considering the ethical issues involved.  We’ll return to that in a moment.
In a recent study researchers in Spain followed thousands of patients at sleep clinics and found that those with the most severe forms of sleep apnea had a 65 percent greater risk of developing cancer of any kind. The second study, of about 1,500 government workers in Wisconsin, showed that those with the most disordered sleep had five times the rate of dying from cancer as people without the sleep disorder (apnea not specified). Both research teams only looked at cancer diagnoses and outcomes in general.  If I lump the two studies, assuming that all patients with the most disordered sleep had OSA and were on CPAP, what does this tell us?  The heart and lung function together as a cardiopulmonary oxygenation unit!  A problem disrupting oxygenation, such as autonomically controlled sleep disruption or, oronasal obstruction (ASSOCIATED WITH SNORING), would be expected to have an effect on alertness during the day, predisposition to CHF from strain on the CP circulation as well as ventilatory impairment and peripheral oxygenation.  It appears that an association with ANY cancer, unspecified, is a long reach.
In both studies the researchers ruled out the possibility that the usual risk factors for cancer, like
  1. age
  2. smoking
  3. alcohol use
  4. physical activity
  5. weight
The association between cancer and disordered breathing at night remained
  • even after they adjusted for confounding variables.
This led to the conclusion that cancer might be linked to (intermittent) lack of oxygen supply interrupting aerobic cell activity over long periods of time.  The conclusion is drawn that from two associations
  • the research on positive outcome from CPAP in OSA and
  • a possible link between breathing and cardiac and cancer clearly
demonstrates the importance of regular breathing exercises (other wise known as ‘Pranayama’ in India) as part of our every day life.
This answers the first observation I posed. That is, the use of CPAP, while enormously important, is not sufficient.  Regular breathing exercises would seem to be helpful, although not a standard part of current treatment. This would be especially important if the movement of the abdominal muscles and diaphragm were synchronized with the expansion of the nthorax for maximum air flow.  This observation is familiar from working with a certified exercise physiologist.   The other part of this is an optimum time for walking and carrying out basic muscle and flexibility exercises several times a week, which has been shown repeatedly by studies on health benefits.
It is not my place to raise some questions about the way the studies were carried out.  The patients who have sleep apnea would be expected to have an increased body mass index (BMI), and while not sarcopenic, more likely to have excess body fat, abdominal distribution in males, and hip distribution in females, amd more importantly, unseen fat in the abdominal peritoneum.  This is related to type 2 diabetes with a metabolic syndrome, a separate indicator of CVD risk.   The metabolic syndrome involves TNF-alpha (once also known as cachexin), IL-1, IL-6, C-reactive protein, and in the case of fat signaling, adipokines, as well as insulin resistance and, as a result, some counter-regulatory secretion of glucocorticosteroids.  This metabolic picture would result in the following:
  1. impaired glucose utilization
  2. some excess and uncompensated gluconeogenesis
  3. the impaired lactate reentry at the end of glycolysis
  4. an effect on allosteric PFK
Features 1-4 look like what Warburg called a Pasteur Effect, not at the clellular level, but in the whole individual.   While obesity and type 2 diabetes are occuring in the young and adolescent population, the consequences might not be seen until years later.  The consequences could be in a middle aged person falling asleep at a meeting, or a series of automabile accidents related to falling asleep at the wheel.
At a time that clinical laboratory measurements are so accurate, and
  • the associations between type 2 diabetes,
  • measurement of wt/ht^2,
  • arm strength,
  • skin fold thickness,

are common measures of fitness, they don’t appear to have any place in these studies. If that is the case, then how is it possible to make sense of a relationship between SEVERITY of sleep disturbance and health outcome.

English: The Cycle of Obstructive Sleep Apnea ...

English: The Cycle of Obstructive Sleep Apnea – OSA (Photo credit: Wikipedia)

English: The graph shows the correlation betwe...

English: The graph shows the correlation between body mass index (BMI) and percent body fat (%BF) for men in NCHS’ NHANES III 1994 data. The body fat percent shown uses the method from Romero-Corral et al. to convert NHANES BIA to %BF (June 2008). “Accuracy of body mass index in diagnosing obesity in the adult general population”. International Journal of Obesity 32 (6) : 959–956. DOI:10.1038/ijo.2008.11. PMID 18283284. (Photo credit: Wikipedia)

English: Body mass index, BMI, body size, body...

English: Body mass index, BMI, body size, body weight, mortality Italiano: indice di massa corporea, IMC, altezza corporea, peso corporeo, mortalità (Photo credit: Wikipedia)

Italiano: biometria, epidemiologia, rischio, p...

Italiano: biometria, epidemiologia, rischio, peso corporeo umano, mortalità, indice di massa corporea, IMC, body mass index, BMI, prospective studies collaboration (Photo credit: Wikipedia)

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English: The illustration shows the major sign...

English: The illustration shows the major signs and symptoms of heart failure. (Photo credit: Wikipedia)

Link between sleep apnea and cardiovascular disease is an established fact and one recent study further supported that treatment of obstructive sleep apnea by continuous positive airway pressure in patients (CPAP) with heart failure would improve left ventricular systolic function.

In a recent study researchers in Spain followed thousands of patients at sleep clinics and found that those with the most severe forms of sleep apnea had a 65 percent greater risk of developing cancer of any kind. The second study, of about 1,500 government workers in Wisconsin, showed that those with the most breathing abnormalities at night had five times the rate of dying from cancer as people without the sleep disorder. Both research teams only looked at cancer diagnosesand outcomes in general, without focusing on any specific type of cancer.

CPAP user Svenska: CPAP-brukare

CPAP user Svenska: CPAP-brukare (Photo credit: Wikipedia)

In both studies the researchers ruled out the possibility that the usual risk factors for cancer, like age, smoking, alcohol use, physical activity and weight, could have played a role. The association between cancer and disordered breathing at night remained even after they adjusted these and other variables.

They are of the opinion that cancer linked to possible lack of oxygen or anaerobic cell activity over long periods of time, therefore, it’s possible poor breathing fails to oxygenate the cells sufficiently.

Instructor de Kundalini yoga practicando Pranayama

Instructor de Kundalini yoga practicando Pranayama (Photo credit: Wikipedia)

Thus I personlly believe that the research on positive outcome on possible link between breathing and cardiac and cancer clearly demonstrates the importance of regular breathing exercises (other wise known as ‘Pranayama’ in India) as part of our every day life.





Curator: Dr. V.S. Karra, Ph.D.

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Main health effects of sleep deprivation (See ...

Main health effects of sleep deprivation (See Wikipedia:Sleep deprivation). Model: Mikael Häggström. To discuss image, please see Template talk:Häggström diagrams (Photo credit: Wikipedia)

Reporter: Venkat Karra, Ph.D.

Sleep may influence weight by affecting hormones, glucose metabolism and inflammation, say scientists. A new study has found that sleeping more than nine hours a night appears to suppress genetic factors that lead to weight gain. In contrast, getting too little sleep seems to have the opposite effect. Adding a few hours sleep to your night may prevent you from gaining weight. These new findings reveal a complex interaction between sleep and genetic factors linked to body weight.

The study found heritability of body mass index (BMI) — a measurement relating weight and height — was twice as high for short than for long sleepers.

Thus sleep well and stay healthy.



Sleep Duration and Body Mass Index in Twins: A Gene-Environment Interaction

by Nathaniel F. Watson, MD, MSc; Kathryn Paige Harden, PhD; Dedra Buchwald, MD; Michael V. Vitiello, PhD; Allan I. Pack, MB ChB, PhD; David S. Weigle, MD; Jack Goldberg, PhD

Sleep, Volume 35/ Issue 05 / Tuesday, May 01, 2012

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