The PACE trial manual for dummies by the President of SUK (the Society of Undeserved Knighthoods)

Discovered: the central nervous system lymphatic system

@ Nature, Published online 01 June 2015:

  Structural and functional features of central nervous system lymphatic vessels

 * Antoine Louveau ,  * Igor Smirnov ,  * Timothy J. Keyes ,  * Jacob D. Eccles ,  * Sherin J. Rouhani ,  * J. David Peske ,  * Noel C. Derecki ,  * David Castle ,  * James W. Mandell ,  * Kevin S. Lee ,  * Tajie H. Harris  * & Jonathan Kipnis

Nature  (2015)  doi:10.1038/nature14432       Received: 30 October 2014        Accepted: 20 March 2015      Published online: 01 June 2015

One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment1, 2, 3, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood4, 5, 6.

In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses.

These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system.

1. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction. _________________________________________

Social sciences lecturer Angela Kennedy: Psychogenic explanations for physical illnesses are almost always fatally flawed

@ amazon.co.uk:

Since the advent of "medicine" as a discrete practice, beliefs that bodily illness can somehow be caused by psychological, emotional, and behavioural "disorder" have been claimed by many in the discipline. Such beliefs became less creditable as scientific methods of detecting disease developed, with discoveries such as the physiological and anatomical abnormalities in Parkinson's disease and Multiple Sclerosis, for example, and the organisms causing syphilis and duodenal ulcers.

  Nevertheless, psychogenic explanations for illnesses still appear frequently within medical and academic literature, in "common sense" public discourses, and in medical diagnoses of patients. But how plausible are these explanations? Authors of our Own Misfortune? proposes that psychogenic explanations for physical illnesses are subject to a complex mix of confusing concepts, accompanied by certain moralistic and ideological assumptions about people and their illnesses.

  Most crucially, such explanations are also, almost always, fatally flawed, both scientifically and logically.

  Furthermore, the widespread, uncritical acceptance and use of such explanations has had serious and specific adverse effects on the people upon whom they are used.

  This is a timely, groundbreaking book about a critical theme in medicine. It provides rigorous analysis of the claims made about "mental disorder" and bodily illness, using current "medical controversies" (such as, but not limited to, Myalgic Encephalomyelitis and Chronic Fatigue Syndrome) to demonstrate the problems with and adverse effects of such claims. Authors of our Own Misfortune? is essential reading for academics, health professionals, and those directly or indirectly affected by psychogenic explanations for illness.

  Angela Kennedy is a social sciences lecturer and researcher at a number of universities in London, and author of numerous articles, papers and books in lay, professional and academic media over a 30 year career.

  Her academic research interests include: the social stratification, scapegoating and social exclusion of disadvantaged groups, and the effects of these; constructions of moral panics; and the sociology of science and medicine, including manifestations of the 'science wars'.

@ msj.sagepub.com:

Epstein–Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis

1. Michael P Pender1,–3
2. Peter A Csurhes1,4
3. Corey Smith3
4. Leone Beagley3
5. Kaye D Hooper1,2
6. Meenakshi Raj2
7. Alan Coulthard1,5
8. Scott R Burrows1,3
9. Rajiv Khanna1,3

1. ¹The University of Queensland, School of Medicine, Brisbane, Queensland, Australia
2. ²Department of Neurology, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia
3. ³QIMR Centre for Immunotherapy and Vaccine Development and Department of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
4. ⁴The University of Queensland Centre for Clinical Research, Brisbane, Queensland, Australia
5. ⁵Department of Medical Imaging, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia

Michael P. Pender, Level 9, Health Sciences Building, Royal Brisbane and Women’s Hospital, Queensland 4029, Australia. Email: m.pender@uq.edu.au

Abstract

Defective control of Epstein–Barr virus (EBV) infection by cytotoxic CD8⁺ T cells might predispose to multiple sclerosis (MS) by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. We have treated a patient with secondary progressive MS with in vitro-expanded autologous EBV-specific CD8⁺ T cells directed against viral latent proteins. This adoptive immunotherapy had no adverse effects and the patient showed clinical improvement with reduced disease activity on magnetic resonance imaging and decreased intrathecal immunoglobulin production. This is the first report of the use of EBV-specific adoptive immunotherapy to treat MS or any other autoimmune disease.

• Adoptive immunotherapy
 
• B cell
 
• CD8+ T cell
 
• Epstein–Barr virus
• multiple sclerosis
 
• treatment

• Received October 23, 2013.
• Accepted January 8, 2014.

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (http://www.uk.sagepub.com/aboutus/openaccess.htm).

Happy Birthday Champ ! We're all praying for you ! get well soon Mr. Schumacher !

autosport.com:

Michael Schumacher's family say they have been "overwhelmed" by fans' support for the seven-time Formula 1 world champion as he continues to be treated in hospital following his skiing accident.

On the German's 45th birthday on Friday, more than 200 Ferrari fans joined a silent tribute outside the University Hospital in Grenoble where Schumacher remains in a critical condition.

With those attending the event wearing Ferrari red team kit, and unfolding a large Prancing Horse banner, the Schumacher family said it was in no doubt how deep the feeling of support was.

"We are overwhelmed!" said a short statement on Schumacher's official website. "The incredible sympathies shown today by the Ferrari fans outside the hospital has utterly overwhelmed us and moved us all to tears.

"We are deeply grateful for it and also for all the heart warming and heartfelt wishes for Michael to get well soon, which have reached us from all over the world."

Schumacher suffered serious head injuries in the crash last weekend, and although his condition is now stable, he remains in an induced coma following two brain operations.

The Independent: 10 best charity Christmas cards 2013, No 1. Invest in ME !!

The Independent, SALLY NEWALL Friday 15 November 2013:

It's almost time for the big festive mail-out - consider these charity cards. 100% of your money goes to the cause

1. Invest in ME

The charity ran a competition for ME patients and their carers to submit photos. We think this vibrant entry by Julie-Ann Gylaitis is a festive triumph.

£4.25 for 10
www.investinme.org

2. Artfelt

The arts programme at Sheffield Children's Hospital commissioned local artist Pete McKee to design their card this year. The result? A sweet but interesting little cartoon of McKee’s own dog Frank.  

£3.50 for 8

www.tchc.org.uk

3. RNLI

The cartoonist Giles was a keen sailor and did lots of work for the RNLI. His designs are bestsellers for the charity.  

£4.25, www.rnlishop.org.uk

4. SPANA

Everyone’s favourite desert dweller has made it onto the front of the animal charity's card. Another design features some kissing tortoises. Pucker up.

£4 for 10  www.spana.org

5. Riders for Health

Ideal for motorbike fans but actually it’s just quite a cool design. The money goes to mobilising health workers in Africa, designed by one of the charity’s volunteers.

£5 for 10 www.riders-for-health.myshopify.com

6. GOSH

This cute robin’s the work of Jacob, 6, a patient at Great Ormond Street.  

£4.50 for 10  www.shop.gosh.org

7. Child bereavement UK

Donated by artist Charlie Macksey, this dove design makes an elegant card.

£4.75 for 10 www.childbereavement.org

8. Sustrans

A nice cycling design from the charity that investing in helping people travel by foot, bike or public transport. Cyclists will like this one

£5 for 8  www.shop.sustrans.org.uk

9. Home Start

Kirstie Allsop commissioned this design for the charity. It’s by paper artist poppy chancellor and we think it makes a lovely snowflake.

£4.75 for 10, www.home-start.org.uk

10. Action medical research for children

Uninspired by many charity Christmas efforts, gallery owner Lynn Tait a gallery owner got card designers  to contribute a piece of their work exclusively to the medical research charity. This cycling Santa’s by Julie Hook.

£2.50 for six, www.action.org.uk

BIG MULTIPLE SCLEROSIS BREAKTHROUGH: first treatment to reset the immune system

Phase 1 trial safely resets patients’ immune systems, reduces attack on myelin protein

June 4, 2013 | by Marla Paul:

CHICAGO --- A phase 1 clinical trial for the first treatment to reset the immune system of multiple sclerosis (MS) patients showed the therapy was safe and dramatically reduced patients’ immune systems’ reactivity to myelin by 50 to 75 percent, according to new Northwestern Medicine research.

In MS, the immune system attacks and destroys myelin, the insulating layer that forms around nerves in the spinal cord, brain and optic nerve. When the insulation is destroyed, electrical signals can’t be effectively conducted, resulting in symptoms that range from mild limb numbness to paralysis or blindness.

“The therapy stops autoimmune responses that are already activated and prevents the activation of new autoimmune cells,” said Stephen Miller, the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine.  “Our approach leaves the function of the normal immune system intact. That’s the holy grail.”

Miller is the co-senior author of a paper on the study, which was published June 5 in the journal Science Translational Medicine. The study is a collaboration between Northwestern’s Feinberg School, University Hospital Zurich in Switzerland and University Medical Center Hamburg-Eppendorf in Germany.

The human trial is the translation of more than 30 years of preclinical research in Miller's lab.  

In the trial, the MS patients’ own specially processed white blood cells were used to stealthily deliver billions of myelin antigens into their bodies so their immune systems would recognize them as harmless and develop tolerance to them.  

Current therapies for MS suppress the entire immune system, making patients more susceptible to everyday infections and higher rates of cancer.

While the trial’s nine patients -- who were treated in Hamburg, Germany -- were too few to statistically determine the treatment’s ability to prevent the progression of MS, the study did show patients who received the highest dose of white blood cells had the greatest reduction in myelin reactivity.

The primary aim of the study was to demonstrate the treatment’s safety and tolerability. It showed the intravenous injection of up to 3 billion white blood cells with myelin antigens caused no adverse affects in MS patients. Most importantly, it did not reactivate the patients’ disease and did not affect their healthy immunity to real pathogens.

As part of the study, researchers tested patients’ immunity to tetanus because all had received tetanus shots in their lifetime. One month after the treatment, their immune responses to tetanus remained strong, showing the treatment’s immune effect was specific only to myelin.  

The human safety study sets the stage for a phase 2 trial to see if the new treatment can prevent the progression of MS in humans. Scientists are currently trying to raise $1.5 million to launch the trial, which has already been approved in Switzerland. Miller’s preclinical research demonstrated the treatment stopped the progression of relapsing-remitting MS in mice.

“In the phase 2 trial we want to treat patients as early as possible in the disease before they have paralysis due to myelin damage.” Miller said.  “Once the myelin is destroyed, it’s hard to repair that.”

In the trial, patients’ white blood cells were filtered out, specially processed and coupled with myelin antigens by a complex GMP manufacturing process developed by the study co-senior authors, Roland Martin, Mireia Sospedra, and Andreas Lutterotti and their team at the University Medical Center Hamburg-Eppendorf. Then billions of these dead cells secretly carrying the myelin antigens were injected intravenously into the patients. The cells entered the spleen, which filters the blood and helps the body dispose of aging and dying blood cells. During this process, the immune cells start to recognize myelin as a harmless and immune tolerance quickly develops. This was confirmed in the patients by immune assays developed and carried out by the research team in Hamburg.

This therapy, with further testing, may be useful for treating not only MS but also a host of other autoimmune and allergic diseases simply by switching the antigens attached to the cells. Previously published preclinical research by Miller showed the therapy’s effectiveness for type 1 diabetes and airway allergy (asthma) and peanut allergy.

The MS human trial relates directly to Miller’s recently published research in mice in which he used nanoparticles -- rather than a patient’s white blood cells -- to deliver the myelin antigen. Using a patient’s white blood cells is a costly and labor-intensive procedure. Miller’s study showed the nanoparticles, which are potentially cheaper and more accessible to a general population, could be as effective as the white blood cells as delivery vehicles.  This nanoparticle technology has been licensed to Cour Pharmaceutical Development Company and is in preclinical development.

Miller’s research represents several pillars of Northwestern’s Strategic Plan by discovering new ways to treat disease in the biomedical sciences and translating those discoveries into ideas and products that make the world a better place for everyone.

The research was supported by the German Federal Ministry for Education and Research and the Cumming Foundation.

University of Zurich: It is relatively certain that MS is an autoimmune disease in which the body’s own defense cells attack the myelin in the brain and spinal cord

healthcanal.com, 27/02/2012: Damaged myelin in the brain and spinal cord does not cause the autoimmune disease Multiple sclerosis (MS), neuroimmunologists from the University of Zurich have now demonstrated in collaboration with researchers from Berlin, Leipzig, Mainz and Munich.

In the current issue of Nature Neuroscience, they therefore rule out a popular hypothesis on the origins of MS. The scientists are now primarily looking for the cause of the development of MS in the immune system instead of the central nervous system.

Millions of adults suffer from the incurable disease multiple sclerosis (MS). It is relatively certain that MS is an autoimmune disease in which the body’s own defense cells attack the myelin in the brain and spinal cord. Myelin enwraps the nerve cells and is important for their function of transmitting stimuli as electrical signals. There are numerous unconfirmed hypotheses on the development of MS, one of which has now been refuted by the neuroimmunologists in their current research: The death of oligodendrocytes, as the cells that produce the myelin sheath are called, does not trigger MS.

Neurodegenerative hypothesis obsolete
With their research, the scientists disprove the so-called “neurodegenerative hypothesis”, which was based on observations that certain patients exhibited characteristic myelin damage without a discernable immune attack. In the popular hypothesis, the scientists assume that MS-triggering myelin damage occurs without the involvement of the immune system. In this scenario, the immune response against myelin would be the result – and not the cause – of this pathogenic process.

The aim of the research project was to confirm or disprove this hypothesis based on a new mouse model. Using genetic tricks, they induced myelin defects without alerting the immune defense. “At the beginning of our study, we found myelin damage that strongly resembled the previous observations in MS patients,” explains Burkhard Becher, a professor at the University of Zurich. “However, not once were we able to observe an MS-like autoimmune disease.” In order to ascertain whether an active immune defense causes the disease based on a combination of an infection and myelin damage, the researchers conducted a variety of further experiments – without success. “We were unable to detect an MS-like disease – no matter how intensely we stimulated the immune system," says Ari Waisman, a professor from the University Medical Center Mainz. “We therefore consider the neurodegenerative hypothesis obsolete.”

Focus on immune system
The teams involved in the study want to continue researching the cause and origins of MS. “In light of these and other new findings, research on the pathogenesis of MS is bound to concentrate less on the brain and more on the immune system in future,” says Professor Thorsten Buch from the Technischen Universität München.

Literature:
Giuseppe Locatelli, Simone Wörtge, Thorsten Buch, Barbara Ingold, Friederike Frommer, Bettina Sobottka, Martin Krueger, Khalad Karram, Claudia Bühlmann, Ingo Bechmann, Frank L. Heppner, Ari Waisman and Burkhard Becher. Primary oligodendrocyte death does not elicit anti-CNS immunity. Nature Neuroscience. 26 February, 2012. Doi: 10.1038/nn.3062

University of Zurich