TGI Friday! Our weekly round-up of recently published research abstracts and related items | 7 March 2014

From Pentagon Report, October 2013

Subgrouping Chronic Fatigue Syndrome patients by genetic and immune profiling

Jose Montoya; Ian Valencia; Holden Maecker; Michael Mindrinos; Rosemary Fernandez
– Stanford University

Abstract

We have a cohort of 200 untreated CFS cases and 400 matched controls that will undergo two novel tests (CyTOF-phosphoflow and HLA Typing through a breakthrough method discovered at Stanford) in order to help enhance our understanding of CFS and contribute to the elucidation of the pathogenesis of the disease.

For CyTOF testing, we are exploring the immune responses by a novel flow cytometer that detects individual cell traits with time-of-flight mass spectrometry (CyTOF). We have completed the CyTOF phenotyping, phospho-flow panel, and gating schemes for testing. Also, the flow cytometry preparation robotics for CyTOF was optimized and antibodies were conjugated. The testing is ongoing and we hope to continue testing as permitted.

For HLA typing testing, we are determining the human leukocyte antigens (HLA) types using a novel method that combines long-range polymerase chain reaction (PCR) with very high-throughput, multiplexed Illumina paired-end sequencing of genes permitting direct haplotyping. We have identified the DNA PAXgene tubes that will be used for testing. Also, we have identified the best possible conditions to amplify all the HLA gene of interest, namely for the class I genes HLA-A, -B, -C and for the class II genes: HLA DQA, DQB, DRB DPA and DPB.

Lastly, we achieved the goal of robust and highly reproducible amplification of each.

In summary, for CyTOF testing we finalized the Phospho-CyTOF panel and have begun testing samples. To date we have tested 54 samples. These samples will continue to be tested for Year 2. The data is being received; no analysis has been done yet. The data will be analyzed by our statistical team.

For HLA typing testing, all the DNA PAXgenes have been identified and separated into different batches. To date, two plates have been run and are currently being analyzed. To date we have tested 180 samples Year 1 has allowed us to ready the logistics and to begin CyTOF and HLA Typing testing.


From the Journal of the American Heart Association, 26 February 2014

Original Research: Vascular Medicine

Autoimmune Basis for Postural Tachycardia Syndrome

Hongliang Li, MD, PhD; Xichun Yu, MD; Campbell Liles, BS; Muneer Khan, MD; Megan Vanderlinde‐Wood, MD; Allison Galloway, MD; Caitlin Zillner, BS; Alexandria Benbrook, BS; Sean Reim, BS; Daniel Collier, BS; Michael A. Hill, PhD; Satish R. Raj, MD; Luis E. Okamoto, MD; Madeleine W. Cunningham, PhD; Christopher E. Aston, PhD; David C. Kem,
MD
1) Endocrinology and Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center & Veterans Affairs Medical Center, Oklahoma City, OK (H.L., X.Y., C.L., M.K., M.V.W., A.G., C.Z., A.B., S.R., D.C., D.C.K.)
2) Heart Rhythm Institute, University of Oklahoma Health Sciences Center & Veterans Affairs Medical Center, Oklahoma City, OK (H.L., X.Y., D.C.K.)
3) Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK (M.W.C.)
4Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK (C.E.A.)
5Department of Medical Pharmacology and Physiology, Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO (M.A.H.)
6) Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University, Nashville, TN (S.R.R., L.E.O.)
7) Department of Pharmacology, Vanderbilt University, Nashville, TN (S.R.R.)
Correspondence to:
David C. Kem, MD, Heart Rhythm Institute, University of Oklahoma Health Sciences Center, TCH 6E103, 1200 Everett Dr, Oklahoma City, OK 73104. E‐mail: david-kem@ouhsc.edu

Abstract

BACKGROUND

Patients with postural tachycardia syndrome (POTS) have exaggerated orthostatic tachycardia often following a viral illness, suggesting autoimmunity may play a pathophysiological role in POTS. We tested the hypothesis that they harbor functional autoantibodies to
adrenergic receptors (AR).

METHODS AND RESULTS

Fourteen POTS patients (7 each from 2 institutions) and 10 healthy subjects were examined for α1AR
autoantibody‐mediated contractility using a perfused rat cremaster arteriole assay. A receptor‐transfected cell‐based assay was used to detect the presence of β1AR and β2AR autoantibodies. Data were normalized and expressed as a percentage of baseline.

The sera of all 14 POTS patients demonstrated significant arteriolar contractile activity (69±3% compared to 91±1% of baseline for healthy controls, P<0.001) when coexisting β2AR dilative activity was blocked; and this was suppressed by α1AR blockade with prazosin. POTS sera acted as a partial α1AR antagonist significantly shifting phenylephrine contractility curves to the right. All POTS sera increased β1AR activation (130±3% of baseline, P<0.01) and a subset had increased β2AR activity versus healthy subjects. POTS sera shifted isoproterenol cAMP response curves to the left, consistent with enhanced β1AR and β2AR agonist activity. Autoantibody‐positive POTS sera demonstrated specific binding to β1AR, β2AR, and α1AR in transfected cells. CONCLUSIONS POTS patients have elevated α1AR autoantibodies exerting a partial peripheral antagonist effect resulting in a compensatory sympathoneural activation of α1AR for vasoconstriction and concurrent βAR‐mediated tachycardia. Coexisting β1AR and β2AR agonistic autoantibodies facilitate this tachycardia. These findings may explain the increased standing plasma norepinephrine and excessive tachycardia observed in many POTS patients.


From the Indian Journal of Medical Research, January 2014. Download full paper.

Role of gut pathogens in development of irritable bowel syndrome

Madhusudan Grover
Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, USA

Abstract

Acute infectious gastroenteritis is one of the most commonly identifiable risk factors for the development of irritable bowel syndrome (IBS). A number of bacterial, viral and parasitic pathogens have been found to be associated with the development of IBS and other functional gastrointestinal (GI) disorders.

Epidemiological studies have identified demographic and acute enteritis-related risk factors for the development of post-infectious-IBS (PI-IBS). Immune dysregulation, alterations in barrier function, serotonergic and mast cell activation have been identified as potential pathophysiological mechanisms.

Additionally, variations in host genes involved in barrier function, antigen presentation and cytokine response have been associated with PI-IBS development. However, it is unknown whether specific pathogens have unique effects on long-term alterations in gut physiology or different pathogens converge to cause common alterations resulting in similar phenotype.

The role of microbial virulence and pathogenicity factors in development of PI-IBS is also largely unknown. Additionally, alterations in host gut sensation, motility,
secretion, and barrier function in PI-IBS need to be elucidated.

Finally, both GI infections and antibiotics used to treat these infections can cause long-term alterations in host commensal microbiota. It is plausible that alteration in the commensal microbiome persists in a subset of patients predisposing them to
develop PI-IBS.


From Frontiers in Phsysiology, 10.3389/fphys.2014.00109 Download full paper

Exercise Physiology: Perspective Article

Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS): The essence of objective assessment, accurate diagnosis, and acknowledging biological and clinical subgroups.

Frank N. Twisk
ME-de-patiënten Foundation, Netherlands

Abstract

Myalgic Encephalomyelitis (ME) was identified as a new clinical entity in 1959 and has been acknowledged as a disease of th central nervous system/neurological disease by the World Health
Organisation since 1969.

Cognitive impairment, (muscle) weakness, circulatory disturbances, marked variability of symptoms, and, above all, post-exertional malaise: a long-lasting increase of symptoms after minor exertion, are distinctive symptoms of ME.

Chronic Fatigue Syndrome (CFS) was introduced in 1988 and was redefined into clinically evaluated, unexplained (persistent or relapsing) chronic fatigue, accompanied by at least four out of a list of eight symptoms, e.g. headaches and unrefreshing sleep, in 1994.

Although the labels are used interchangeably, ME and CFS define distinct diagnostic entities. Post-exertional malaise and cognitive deficits e.g. are not mandatory for the diagnosis CFS, while obligatory for the diagnosis ME. “Fatigue” is not obligatory for the diagnosis ME. Since fatigue and other symptoms are subjective and ambiguous, research has been hampered. Despite this and other methodological issues, research has observed specific abnormalities in ME/CFS repetitively, e.g. immunological abnormalities, oxidative and nitrosative.


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