12th International IACFS/ME Research and Clinical Conference:
Emerging Science and Clinical Care

A Clinician’s Review of the Conference, with Comments
October 27-30, 2016
Westin Beach Resort, Fort Lauderdale, Florida

Despite gray and blustery weather, the 12th biennial international IACFS conference was well attended by 205 professionals and 78 persons with CFS (PWCs). At least 9 foreign countries were represented. This was typical for professional attendance at the last two meetings; but patient attendance was less than half of what we experienced in the past.

My initial impression was that each scientific meeting brings out more and more new researchers, but the number of clinicians is small and probably dwindling. Another observation was that rituximab, orthostatic intolerance, post-exertional malaise, and enterovirus infections were the favored subjects this year.

Of course, the most anticipated subject for PWCs and clinicians alike was:

Treatment

Both the patient and the professional groups were treated to superb presentations by Drs. Oystein Fluge and Olav Mella of Norway, who discussed their experience with rituximab. Rituximab (Rituxan ™) is a chemotherapy drug that depletes B-cells (or CD 20 cells) in the bloodstream. It was initially developed to treat non-Hodgkins lymphoma, but has also been approved to treat moderate-to-severe rheumatoid arthritis and polyangiitis as well.

These oncologists related that in 2004 they used Rituxan to treat a patient with both lymphoma and ME/CFS. Remarkably not only did the lymphoma improve, but so did the ME/CFS! Based on that experience, in 2009 they treated 3 ME/CFS patients, all of whom experienced significant improvement.

Encouraged by these results, they designed a randomized, placebo controlled trial of 30 female subjects with ME/CFS: 15 would receive rituximab and 15 would receive placebo. Ten of the 15 treatment subjects (67%) responded, as did two of the placebo subjects! Improvement was mostly modest, but two subjects had major improvement.

Then, in 2011 they also began a study of maintenance therapy using Rituxan. This was an open label study of 29 subjects who received starting doses of Rituxan two weeks apart, then “maintenance doses” at 3, 6, 10 and 15 months. Eighteen (62%) had a clinically significant response. 11/18 responded for at least 3 years, and 5/18 have responded for 5 years. Two subjects had allergic reactions to the drug, and two developed mild neutropenia that lasted less than 5 days. Eight had a transient increase in ME/CFS symptoms, and one suffered a sustained relapse.

Drs. Fluge and Mella are now involved in a large study of 152 PWCs at 5 international centers, half of whom will receive Rituxan and half will receive placebo. We are all anxiously awaiting the results of this trial, but by agreement other treatment sites (like Hunter-Hopkins Center) will not make rituximab available until safety, efficacy, and appropriate dosing schedules are confirmed by this study.

Dr. Mella explained that B-cells produce autoantibodies and based on lab data Rituxan probably works by suppressing this autoantibody production rather than just depleting B-cells. No response was seen in the treated patients for the first 3 months, but by 6 months there was an obvious improvement in symptoms over placebo-treated subjects.

The Norwegian team has also considered other immune modulating therapies for ME/CFS including steroids, Enbrel, gammaglobulin and plasmaphoresis, but none of these has been particularly effective in previous studies. They believe, however, that another chemotherapy drug – cyclophosphamide – shows promise, although it is much more toxic than rituximab. They are currently administering cyclophosphamide to 40 subjects (15 of whom have already been treated with Rituxan). Results should be released in about 6 months (April 2017).

The Synergy Trial using low dose Ritalin (methylphenidate) and a supplement directed at improving mitochondrial function was discussed by Dr. Cindy Bateman (Bateman-Horne Center, Utah). This was a four week double blind placebo controlled trial of 128 PWCs. The active treatment was Ritalin 5-10mg twice daily plus daily KPAX, a proprietary vitamin/herbal supplement. There was only a modest difference in the response between the active drug versus placebo. PWCs who were modestly to severely ill responded best. Other than jitteriness in 4% of subjects there were no significant side effects. [Ed.: I personally think that the positive response was due to methylphenidate, which we have recommended for many years in the treatment of CFS/ME/FM.]

Dikoma Shungu and his group at Cornell (NYC) studied another supplement called NAC or N-acetyl cyteine for the treatment of ME/CFS. It is known that glutathione is reduced by about 30% in persons with ME/CFS, and tends to be lowest in persons with multiple sensitivities. Glutathione is also low in persons with major depressive disorder. The problem is that oral glutathione is not well absorbed. On the other hand, oral NAC is metabolized to glutathione and glycine in the bloodstream, so Shungu demonstrated that NAC (1800 mg daily for 4 weeks) is indeed absorbed and metabolized; he then used MR spectroscopy to prove that glutathione levels increased in the brain. [Ed.: Unfortunately he could show only minimal improvement in symptoms after taking oral glutathione, but clinically we do see a good response in many patients.]

Dr. Peter Rowe (Johns Hopkins Hospital) discussed Non-IgE Mediated Food Allergy, which he has found to be a co-morbidity in many PWCs. Persons with this type of allergy react to milk, but also to soy and sometimes egg. Exposure triggers reflux, epigastric abdominal pain, early satiety, and frequently mouth ulcers, diarrhea or constipation, and unexplained fevers. PWCs with abdominal pain or GI symptoms, therefore, might benefit from avoiding dairy, soy products, and eggs for several days to see if they have this unique food allergy!

Provocation

Considering that the symptoms of ME/CFS are exacerbated by activity or other provocations (stress, cognitive strain, orthostatic stress) several groups studied responses before and after provocation. Or as Mark Van Ness put it, “physical stress unmasks the signs and symptoms of ME/CFS.”

Dr. Jose Montoya (Stanford University) hypothesized that cytokines, adipokines, or growth factors in the blood stream of PWCs might explain many of the symptoms of ME/CFS. He exerted 24 PWCs and 24 sedentary controls on a treadmill and measured numerous cytokines before and 24 hours later. Six cytokines were different afterward in PWCs from controls: IL-1, platelet activation inhibitor (PAI-1), CD40 ligand, MIP-1a, and INF-g. It is not surprising that this represents an inflammatory pattern in PWCs.

Madison Keefe did an excellent job relating Dr. Jim Baraniuk’s study of autonomic activity in PWCs (Georgetown University, Washington DC). After stress testing, 9 of 19 PWCs developed significant Postural Orthostatic Tachycardia ( > 30 bpm on standing). Before exercise there was no difference in heart rate, sympathetic activity, parasympathetic activity. After exercise, sympathetic activity increased significantly between recumbent and standing in the study group, but not in the 11 PWCs who didn’t develop orthotachycardia after exertion or in the healthy control group. This suggests that the sympathetic nervous system may play a major role in post-exertional malaise. [Ed.: perhaps tilt testing for POTS should not be performed after treadmill testing or other exertion!]

Dane Cook (University of Wisconsin) studied the effect of exercise on cognition in PWCs and healthy controls. He used 15 women with ME/CFS and 15 female controls. After successive exercise activities, PWCs had more and more difficulty with cognitive tasks, whereas controls actually did better over time. To explain this, Cook went on to use fMRI to demonstrate brain activity. Before exercise PWCs showed a small amount of mental activity in the cingulated region. After exertion, there was activity in the inferior and superior parietal and cortical areas. This increased need for brain processing was not seen in controls.

Katarina Lien’s group (Norway) set out to study lactate production in PWCs versus healthy controls with exercise. Eighteen mild-to-moderately ill PWCs and 15 sedentary controls had their blood lactate measured every 30 seconds while exercising on two separate occasions. At any given level of exertion, PWCs always produced more lactate (which is an indication of anaerobic metabolism) . On Day 1 the lactate increased slowly but steadily with exertion in both groups, but more was produced by PWCs. On Day 2 controls produced less lactate overall, but PWCs produced more. [Ed. This confirms previous studies showing that PWCs produce more lactate (or “toxin”) during exertion than healthy individuals, which is an indication of decreased physical capacity. This same phenomenon is seen in athletes with overtraining syndrome from practicing too hard and too long. In addition to declining energy over time, such athletes report fatigue, muscle pain, cognitive difficulties, and sleep disruption. Sound familiar?!]

Peter Rowe (Johns Hopkins Hospital) discovered that neuromuscular strain can exacerbate symptoms in ME/CFS. Sixty (60) PWCs and 20 healthy controls were randomized 50:50 to either neuromuscular strain or a sham procedure for 15 minutes. The subjects were then contacted 24 hours later about their symptoms. The procedure was simple straight leg raising for 15 minutes: 61 degrees for the PWCs, and 71 degrees for controls. For the sham procedure the leg was only slightly raised on a small foam roller or towel.

MRI studies have previously shown that the spinal cord has to stretch 5 to 9 cm when a person goes from bending backwards to bending all the way forward; and the spinal cord stretches about 3.5 mm by just raising the leg by 60 degrees!

The next day patients who had undergone straight leg raising reported increased fatigue, pain, lightheadedness, and poor concentration, but all controls and the 10 patients who underwent the sham procedure did not have increased symptoms. The implication here is that lying in bed, elevating the legs on a foot stool, driving, and other activities may apply neural tension and increase symptoms.

Post-Exertional Malaise

Post-Exertional Malaise (PEM) is a cardinal symptom of ME/CFS. By definition, post-exertional malaise is an exacerbation of ME/CFS symptoms occurring after physical or mental activity that was previously tolerated. These symptoms may appear immediately after the activity or after a delay, and they may last for days to weeks or more.

The symptoms of post-exertional malaise were discussed by Lily Chu (Stanford University). In a study of 144 PWCs she found that:

• post-exertional malaise symptoms include fatigue, cognitive difficulties, sleep disturbance, headache, muscle pain and flu-like symptoms
• more than 90% experience post-exertional malaise, and 10% experience emotional distress after exertion as well
• the onset of PEM is variable in 40% of PWCs, and occurs more than 24 hours after exertion in 15%
• post-exertional malaise lasts more than 3 days in 25% of PWCs
• 10% of subjects reported that PEM lasted 24 hours or less, with 90% reporting much longer
• physical and cognitive exertion trigger PEM more than emotional distress

PEM can be demonstrated objectively by obtaining cardio-pulmonary exercise testing (CPET) on two consecutive days. Healthy controls produce the same results on both tests; but PWCs perform less well the second day due to this post-exertional malaise. This was elegantly presented to us by Staci Stevens, Drs. Snell and VanNess, and Dr. Keller at the 2014 IACFS conference in San Francisco.

This year Dr. Keller presented subsets of patient responses to the 2-day CPET. In most PWCs, VO2 max (aerobic work capacity) falls by 7% or more the second day and the VO2@VAT (aerobic capacity at the Anaerobic Threshold) decreases by 12% or more. In a subset of patients with autonomic anomalies, however, the heart rate may fail to rise significantly or the systolic blood pressure fails to rise more than 10mmHg/MET. Another subset presents with ventilatory anomalies (e.g., failure to increase respiratory rate appropriately). In her pool of 97 patients who underwent 2-day CPETs:

• 34% failed to reproduce the VO2 peak
• 39% failed to reproduce the VO2 @VAT peak
• 43% demonstrated autonomic anomalies
• 47% demonstrated ventilatory anomalies, and
• 29% had normal responses on testing.

This latter group can generally exercise without experiencing significant post-exertional malaise. About 10% of them, however, still demonstrate autonomic or ventilatory anomalies.

Keller also reported that levels of CRP (C-Reactive Protein) tend to be higher in PWCs than controls, and increase with the second CPET.

Orthostatic Intolerance / Dysautonomia

In 2015 the Institute of Medicine emphasized that PWCs frequently exhibit orthostatic symptoms, especially dizziness or lightheadedness, but also more severe forms such as orthostatic hypotension, Postural Orthostatic Tachycardia Syndrome (POTS) and Neurally Mediated Hypotension (NMH).

Dr. Peter Rowe (Johns Hopkins University) provided an elegant overview of orthostatic disorders, especially Postural Orthostatic Tachycardia Syndrome (POTS) and Neurally Mediated Hypotension (NMH). In addition to pharmacological therapies he outlined many non-pharmacological therapies that help including:

• Avoid heat, including hot showers and hot tubs
• Avoid prolonged sitting or standing
• Avoid high carbohydrate meals (which increase blood flow to the gut)
• Avoid diuretics, vasodilators (e.g. alcohol, nitroglycerin, some BP meds), and alpha-blockers
  (more BP meds, Viagra and other ED meds)
• Raise the head of your bed by 10-15 degrees
• Wear compression garments (waste high > thigh high > knee support hose)
• Wear body shaping garments (such as Spanx)
• Wear an abdominal binder
• Avoid sleeping too long (leads to dehydration)
• Certain body positions help (such as crossing the legs, squatting, knee-chest sitting, or clenching the fists)

He also recommended reducing stress (relaxation or meditation techniques, counseling), exercising as able, controlling pain, avoiding hypoglycemia, and avoiding beta-agonists (such as albuterol for asthma) because they all stimulate catecholamines and exacerbate symptoms.

Among newer treatments for NMH and POTS are desmopressin (DDAVP) and ivabradine (Corlanor ™). DDAVP causes the kidneys to retain water and therefore increase blood volume, which can rapidly reduce tachycardia and symptoms in POTS (Coffin sore throat, Heart Rhythm 2012). Ivabradine selectively inhibits the cardiac pacemaker and decreases heart rate. It is FDA-approved to treat heart failure, but works well to reduce heart rate in POTS without having to use a beta-blocker.

Central Nervous System / Neuro Biologic Function

Ben Natelson’s group in New York City studied neurobiologic features in 44 PWCs and 17 healthy controls. Each group was divided into those with psychiatric issues such as depression and anxiety, versus those without psychiatric issues. They then underwent cranial MRI, lumbar puncture, and studies of cerebral blood flow. In brief summary, 80% of the PWCs had an abnormal MRI, typically T2 weighted high intensity spots, while only 20% of controls had an abnormality. 26-30% of PWCs had elevated protein or white blood cells in the cerebrospinal fluid; ventricular lactate levels were higher; and glutathione levels were lower. Cerebral blood flow was lower in some regions of the brain in PWCs. There were no differences between patients with psychiatric issues or with no psychiatric issues, once again pointing out that this illness is in the brain, not just “in the head.” Natelson hypothesizes that neuroinflammation due to cytokine release in the brain is probably responsible for these findings.

Genetics

“SNP” (pronounced “snip”) stands for Single Nucleotide Polymorphism. It means that some people will have one base at a certain position in their genes, and other people will have a different base at that position. The two forms of SNPs are called “alleles.” For example, look at the bases in two short gene sequences:

5’ ATTGTTTTGTTAAGT 3’
5’ ATTGTTTCGTTAAGT 3’

In one segment T ( thymine ) is the 8th nucleotide, but in the second segment C ( cytosine) is the 8th nucleotide. The substitution of C in the gene sequence is due to a mutation and is known as a SNP.

At any rate, geneticists at Nova University found 3 SNPs distinguish PWCs from healthy controls, and all of those SNPs involve genes that code for a subunit of NADH. NADH generated by the citric acid cycle is in turn used by the oxidative phosphorylation pathway to generate energy-rich adenosine triphosphate (or ATP).

Pediatrics

Sarah Knight (Melbourne AU) discussed the functional impact of ME/CFS on children and adolescents, half of whom attended school less than 20% of the time. Her study compared the cognitive abilities of 25 adolescents with ME/CFS to 23 healthy controls after cognitive exertion. Even before provocation, PWCs showed decreased processing speed, memory, attention, and verbal learning. After cognitive exertion these PWCs reported slower processing speed, more difficulty with sustained attention and working memory, and subjective fatigue. Thus, clinicians and school staff need to be aware that adolescents with ME/CFS have cognitive issues both before and after mental exertion.

Peter Rowe (Johns Hopkins Hospital, Baltimore) studied range of motion in 55 adolescents and young adults with ME/CFS. As described in the Journal of Pediatrics 2014; 165: 360-366, many had limitations in ankle dorsiflexion, straight leg raising, knee bending, prone press-ups, and spinal issues. 60% of these subjects underwent regular physical therapy, and 93% underwent some physical therapy – mostly manual therapy as opposed to just exercise. The median time to achieve marked improvement in range of motion was 7 months, but improvement in range of motion was also associated with general functional improvement.

Infectious Diseases / Microbiomes

Dr. John Chia spent over 3 hours discussing Enterovirus infections. Enteroviruses are so-named because they mostly affect the stomach and intestines. They include coxsackie viruses, echoviruses, and polio. Not only can enteroviruses (EVs) trigger ME/CFS, but Chia believes they may be the ultimate causative agent.

Chia patiently went through case studies of EV- related acute gastritis, acute diffuse enteritis, epidemic appendicitis and intussusceptions, Hand-Foot-Mouth Disease , herpangina, Leukocytoclastic Vasculitis, acalculous cholecystitis, pelvic abscesses, and encephalitis. In the latter, EV is thought to travel directly from the stomach to the brain by tracking along the vagus nerve. Chia pointed out that while antibodies to coxsackie virus or echovirus may be present, the best way to make a diagnosis is staining for VP1 (enterovirus capsular protein) in stomach biopsies or other tissue samples. Unfortunately, there is no good treatment, but some PWCs with evidence of EV infection have improved after treatment with an herbal preparation called oxymatrine.

Ludovic Giloteaux ( Cornell ) had the (unenviable) job of studying bacteria and viral microbiomes in the feces of PWCs. One major finding was increased lipopolysaccarhide (LPS), a compound that may seep into the bloodstream of PWCs who have “leaky gut,” or loose junctions between gut endothelial cells. Elevated levels of caudovirale viruses in PWCs lead to inflammation and leaky gut. He pointed out that microbes in the gut can synthesize hormones and neurotransmitters (such as norepinephrine, serotonin, dopamine, and GABA) as well as inflammatory molecules like cytokines and prostaglandins. Giloteaux also noted that beneficial butyrate-producing bacteria are deficient in PWCs and in persons with irritable bowel syndrome; and there is much less bacterial diversity in patients compared to healthy controls.

DeMeirLeir ( Belgium ) also reported that lipopolysaccharide derived from gut bacteria is elevated in ME/CFS and may play an important role in the pathophysiology (cause) of the disorder. Elevated levels of sCD14 in the blood is a surrogate marker for increased LPS.

Markers / Cytokines

Wouldn’t it be wonderful if we had a test (or marker) for ME/CFS?!

Kenny DeMeirLeir ( Belgium ) sought such markers in 140 PWCs compared to 140 healthy controls. When four markers were present, they identified the majority of PWCs with good selectivity and specificity. These were soluble CD14, IL8, CD3/CD57+ lymphocytes, and prostaglandin E2. DeMeirLeir justified these results by pointing out that sCD14 is typically elevated in ME/CFS and is also a surrogate marker for lipopolysaccharide (LPS) in the gut, which has also been noted in PWCs. IL8 induces neutrophils and is an indicator of inflammation. PGE2 is derived from phospholipids, which are generally increased in inflammation, infection, and cancer. Low CD3/CD57 cells (that is, natural killer cells) are also typical of ME/CFS and indicate immunodysfunction.

Cytokines are chemicals that are generated by active lymphocytes when they detect “an invader.” Some indicate infection or inflammation, and others are anti-inflammatory in nature. Because cytokines can cause the flu-like or viral symptoms of ME/CFS, they have long been implicated in the disorder.

Jose Montoya (Stanford) divided 192 PWCs into three groups based on the severity of their illness. He then measured numerous cytokines in the blood stream and concluded that two cytokines ( TGF-beta and resistin) were unique in the PWCs, and 17 cytokines correlated with severity.

CDC MCAM Study

Dr. Elizabeth Unger introduced the ongoing Multisite Clinical Assessment of ME/CFS (MCAM) to the audience, and then various group leaders described results of the program so far. Although ME/CFS is recognized worldwide, there has been no consensus on what definition to use, the proper examination of patients, and how to confirm the presence of such subjective symptoms as fatigue, pain, sleep disruptuion, post-exertional malaise, cognitive problems, dizziness, etc. The CDC has recruited 7 expert medical groups from around the US to submit historical and physical data over 400 PWCs. In addition, studies of cognition, exercise ability, blood and salivary tests have been obtained. A methods paper has been accepted for publication already, and future papers will discuss patient characteristics and symptoms.

So far, the subjects are remarkably similar across the research groups with respect to age, male-to-female ratio, weight, marital status, education, disability (75.4%), and age at diagnosis (38 years). Standardized questionnaires were used to measure illness domains of ME/CFS, and found that fatigue, post-exertional malaise, and unrefreshing sleep were the most frequently reported symptoms. Special surveys (SF-36 and MFI-20 subscale scores) of ME/CFS patients document profound impairment in this illness, but show that emotional functioning and mental health are remarkably preserved despite this debilitating illness. Physically, lymphadenopathy (glands), sore throat, abdominal pain, light or sound sensitivity, and alcohol intolerance were the most consistent complaints, although headache, sinus problems, diarrhea, depression, shortness of breath, chills, feverishness, unsteadiness, dizziness, and bladder problems were also common.

At this meeting Dr. Gudrun Lange reported results of the cognitive studies (using CogState computerized neuropsychiatric testing). She reported decreased reaction time, poor learning (especially after mental or physical effort), reduced information processing speed, and difficulty with decision making. Processing speed was the foremost neurocognitive deficit in ME/CFS.

Dr. Dane Cook reported that cardio-pulmonary exercise testing has confirmed that PWCs have a reduced aerobic work capacity, peak heart rate, earlier onset of anaerobic threshold, and maximum watts produced, compared to control. Blood lactate was lower in PWCs at peak.

Saliva was collected four times during the first hour upon awakening. Dr. Sally Lin reported that the mean cortisol and alpha-amylase levels were the same in patients and controls, but more PWCs had a change of more than 50% in their cortisol levels. Post-exertional malaise was associated with a minimal change in cortisol levels.

Troy Querec discussed how NK Cell Activity was measured (data incomplete) and Dr. Rajeevan reported that samples of saliva and blood will be saved in a biorepository.

Evaluation of the surveys used will be helpful in developing recommendations for use as outcome measures; physical findings combined with biologic (laboratory) data may be helpful in subgrouping patients; and the biorepository can be accessed by the CDC and reputable researchers for future studies.

[Ed.: We are honored to be one of the seven expert clinics chosen for this study, and proud of over 50 of our patients who have participated in this study over the past 5 years! Thank you!! The study is funded through 2017, but may continue even longer.]

Metabolism

In the earliest years of CFIDS research blood and urine tests suggested that the Krebs Cycle (or Citric Acid Cycle) in mitochondria was not functioning well. ATP (the cellular source of energy) is produced by the mitochondria, and ATP is known to be deficient in PWCs. Subsequently Dr. Paul Cheney and I encouraged patients to supplement with Krebs Cycle intermediates such as B12, folate, magnesium, malate, ketoglutarate, succinate, and B6 or P6P (pyridoxine 6 phosphate). Drs. Fluge and Mella have resurrected this hypothesis, suggesting that autoantibodies are adversely affecting the mitochondrial Citric Acid Cycle. Using known data about this cycle and then applying reason, they suggest that there is a blockage between pyruvate and acetyl-coenzyme A in the mitochondria due to the pyruvate dehydrogenase complex. They hope to test this hypothesis by administering P6P and other supplements to PWCs.

Metabolic studies from Stanford show that Krebs Cycle intermediates are reduced in ME/CFS. Naviaux has hypothesized that reduced levels of sphingolipids, phospholipids, purines, riboflavin, branched chain amino acids, and amino acids (in female patients) suggest that ME/CFS is a hypometabolic state (like hibernation or dauer). Other metabolic studies at Cornell University also suggest that ME/CFS is a hypometabolic state.

Miscellaneous

Years ago, Paul Cheney and I studied the neurological exam in PWCs, concluding that balance, tandem stance, and the Romberg exam (feet slightly apart, arms outstretched, eyes closed) were abnormal in about 85% of patients, but less than 15% of healthy controls. Kunihisa Miwa (Japan) reported similar studies performed in his clinic. He determined that imbalance / dysequilibrium was present in 29% of his patients. 10/35 had a positive Romberg test (toppled over), and 100% of these experienced postural swaying . 25/35 did not have a positive Romberg, and 20% of them had postural swaying. 40% of the patients with a positive Romberg were unable to stand 10 minutes, and 20% were unable to sit for that period of time; whereas the negative Romberg group was able to even balance on one leg or tandem walk without difficulty. Miwa concluded that PWCs with a positive Romberg test complain of more orthostatic intolerance (imbalance, dizziness) and difficulty standing or sitting for prolonged periods. Thus the Romberg test may be a sign of more severe illness.

______________________________________________________________

Charles W. Lapp, MD, Director
Hunter-Hopkins Center, P.A., Charlotte, North Carolina
November 13, 2016

The above information reflects the personal opinions of the author only, and is not meant to be an exact or exhaustive review of the IACFS conference. The author would appreciate comments or corrections.

This material is copyrighted, but may be reprinted with permission of the author and with appropriate credit. Contact drlapp@drlapp.net. (© 2016)

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