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Archive for the ‘TREATMENTS’ Category

DISCO CURE IN RED & GREEN FOR CURING ALZHEIMERS

Monday, January 16th, 2012

NOW WE HAVE RED LIGHTS AND GREEN TEA AS CURE FOR ALZHEIMERS

IT MAY sound like a strange brew, but green tea and red light could provide a novel treatment for Alzheimer’s disease. Together, the two can destroy the rogue “plaques” that crowd the brains of people with the disease. The light makes it easier for the green-tea extract to get to work on the plaques.

Andrei Sommer at the University of Ulm in Germany, and colleagues, have previously used red light with a wavelength of 670 nanometres to transport cancer drugs into cells. The laser light pushes water out of the cells and when the laser is switched off, the cells “suck in” water and any other molecules, including drugs, from their surroundings.

Now, Sommer’s team have found that the same technique can be used to destroy the beta-amyloid plaques in Alzheimer’s. These plaques consist of abnormally folded peptides, and are thought to disrupt communication between nerve cells, leading to loss of memory and other symptoms.

The team bathed brain cells containing beta-amyloid in epigallocatechin gallate (EGCG) – a green-tea extract known to have beta-amyloid inhibiting properties – at the same time as stimulating the cells with red light. Beta-amyloid in the cells reduced by around 60 per cent. Shining the laser light alone onto cells reduced beta-amyloid by around 20 per cent (Photomedicine and Laser Surgery, DOI: 10.1089/pho.2011.3073).

It can be difficult getting drugs into the brain, but animal experiments show that the green-tea extract can penetrate the so-called blood-brain barrier when given orally together with red light. The light, which can penetrate tissue and bone, stimulates cell mitochondria to kick-start a process that increases the barrier’s permeability, says Sommer.

There is no reason why other drugs that attack beta-amyloid could not be delivered to the brain in the same way, he adds.

“This important research could form the basis of a potential treatment for Alzheimer’s, with or without complementary drug treatment,” says Mario Trelles, medical director of the Vilafortuny Medical Institute in Cambrils, Spain.

“The technique described could help to regulate and even stop the appearance of this disease,” he adds.

Sourced & published by Henry Sapiecha

ALZHEIMERS REVERSAL ON THE CARDS WITH INJECTION

Monday, November 7th, 2011

DOES THIS INJECTION REVERSE ALZHEIMERS?

A new study pinpoints the importance of certain soluble proteins, called cytokines, in Alzheimer’s disease. The study focuses on one of these cytokines, tumor necrosis factor-alpha(TNF), a very critical component of the brain’s immune system. Normally, TNF finely regulates the transmission of neural impulses within the brain. The authors hypothesized that elevated levels of TNF in Alzheimer’s disease interacy adversely with this regulation. To reduce elevated TNF, the authors gave patients an injection of an anti-TNF therapeutic called etanercept. Excess TNF-alpha has been documented in the cerebrospinal fluid of patients with Alzheimer’s.

The new study documents a dramatic and unprecedented therapeutic effect in an Alzheimer’s patient: improvement within minutes following delivery of perispinal etanercept, which is etanercept given by injection in the spine. Etanercept (trade name Enbrel) binds and inactivates excess TNF. Etanercept is FDA approved to treat a number of immune-mediated disorders and is used off label in the study.

The use of anti-TNF therapeutics as a new treatment choice for many diseases, such as rheumatoid arthritis and potentially even Alzheimer’s, was recently chosen as one of the top 10 health stories of 2007 by the Harvard Health Letter.

Similarly, the Neurotechnology Industry Organization has recently selected new treatment targets revealed by neuroimmunology (such as excess TNF) as one of the top 10 Neuroscience Trends of 2007. And the Dana Alliance for Brain Initiatives has chosen the pilot study using perispinal etanercept for Alzheimer’s for inclusion and discussion in their 2007 Progress Report on Brain Research.

The lead author of the study, Edward Tobinick M.D., is an assistant clinical professor of medicine at the University of California, Los Angeles and director of the Institute for Neurological Research, a private medical group in Los Angeles. Hyman Gross, M.D., clinical professor of neurology at the University of Southern California, was co-author.

This study is accompanied by an extensive commentary by Sue Griffin, Ph.D., director of research at the Donald W. Reynolds Institute on Aging at the University of Arkansas for Medical Sciences (UAMS) in Little Rock Arkansaw and at the Geriatric Research and Clinical Center at the VA Hospital in Little Rock, who along with Robert Mrak, M.D., chairman of pathology at University of Toledo Medical School, are editors-in-chief of the Medical Journal of Neuroinflammation.

Griffin and Mrak are pioneers in the field of neuroinflammation. Griffin published an extensive landmark study in 1989 describing the association of cytokine overexpression in the brain and Alzheimer’s disease. Her research helped pave the way for the findings of the present study. Griffin has recently been selected for membership in the Dana Alliance for Brain Initiatives, a nonprofit organization of more than 200 leading neuroscientists, including ten Nobel laureates.

“It is unprecedented that we can see cognitive and behavioral improvement in a patient with established dementia within minutes of therapeutic intervention,” said Griffin. “It is imperative that the medical and scientific communities immediately undertake to further investigate and characterize the physiologic mechanisms involved. This gives all of us in Alzheimer’s research a tremendous new clue about new avenues of research, which is so exciting and so needed in the field of Alzheimer’s. Even though this report predominantly discusses a single patient, it is of significant scientific interest because of the potential insight it may give into the processes involved in the brain dysfunction of Alzheimer’s.”

While the article discusses one patient, many other patients with mild to severe Alzheimer’s received the treatment and all have shown sustained and significently marked improvement.

The new study, entitled “Rapid cognitive improvement in Alzheimer’s disease following perispinal etanercept administration,” and the accompanying commentary, entitled “Perispinal etanercept: Potential as an Alzheimer’s therapeutic,” are available on the Web site of the Journal of Neuroinflammation (http://www.jneuroinflammation.com/content/5/1/2/abstract).

Author Hyman Gross, M.D., has no competing interests. Author Edward Tobinick, M.D. owns stock in Amgen, the manufacturer of etanercept, and has multiple issued and pending patents assigned to TACT IP LLC that describe the parenteral and perispinal use of etanercept for the treatment of Alzheimer’s disease and other neurological disorders, including, but not limited to, U.S. patents 6015557, 6177077, 6419934, 6419944, 6537549, 6982089, 7214658 and Australian patent 758523.

Sourced & published by Henry Sapiecha

ENGINEERED VIRUS TO ONLY KILL CANCER CELLS IN THE BODY

Saturday, September 3rd, 2011

New Virus Engineered

to only Kill Cancer Cells

September 1, 2011 | Filed under: Health | Posted by: G. Eden

A new virus that has been specifically engineered to kill cancer cells has been found to be a medical first because of its effectiveness. The virus has been engineered by medical researchers to target only cancer cells throughout the human body.

The virus is very special because it only attacks cancerous tumours and leaves healthy tissue fully intact.  The virus has been trialled on humans but so far the trials have only been quite small (23 people have only been trialled so far).

If the research goes to plan then the treatment could give cancer therapies a real transformation.

Viruses have been used before to kill cancer but they have always been injected direct into the tumour in order to avoid killing the healthy cells. This new virus will without doubt make the treatment much much easier and possibly more effective.

The new virus has been developed by scientists who modified the vaccinia virus. The vaccinia virus is more commonly used usually as a smallpox vaccine. The new form of this virus is known as JX-594.

The research was guided & inspired by a team of scientists from the University of Ottawa in the United States.

Sourced & published by Henry Sapiecha

WEED CAN BE A GREAT MEDICINE SAYS DOCTOR

Thursday, August 25th, 2011

The mighty Leaf that gives relief

By Margaret McCartney

Published: January 16 2010 00:04 | Last updated: January 16 2010 00:04

Cannabis and the law have a clear relationship; to take the former is to break the latter. For years, pressure has been mounting on the government to change this position. And not just for recreational reasons, but medical ones too. It is often claimed, for example, that cannabis improves the lives of multiple sclerosis sufferers.

A recent systematic review of the evidence in BMC Neurology found that cannabis did help alleviate spasticity, the uncomfortable cramp that can become constant in MS, making affected limbs hard to use. But while patients reported an improvement following treatment, objective measurements did not show any significant change.

Spasticity may not be affected by cannabis; the drug may instead be treating muscle tension and discomfort. That doesn’t mean cannabis is not useful. Indeed, another review published last year in Pain Medicine found that “cannabis treatment is moderately efficacious for the treatment of chronic pain”. But it also noted that “beneficial effects may be partially (or completely) offset by potentially serious harms”.

We can hardly boast that the legitimate medicine cabinet is untainted by side-effect-free drugs. In cannabis, the most obvious side-effect is sluggishness – more commonly known as being “stoned”. This is a real problem, but it may possibly be no worse than the sedation delivered by strong analgesics  that may be prescribed or administered.

There are more worrying risks with cannabis, notably psychosis. A review in the Lancet in 2007 suggested there was a dose-related risk – the more cannabis, the greater the danger. Some studies have also indicated the risk is highest for young people, and those with a personal or family history of psychosis. So how many people are likely to be affected? A paper in Addiction last year found that the number of men who would have to stop heavy use of cannabis to prevent one case of psychosis would approach 2,800 in the 20-24 age group and 4,700 among those aged 35-39.

For many doctors and potential patients, addiction is an even bigger concern. Should it become available on prescription, cannabis would join other legitimate drugs which have dependence as a potential harm – from diazepam to morphine. The truth is that cannabis may well end up being just as useful as any of these drugs and, just like them, require careful prescription and informed consent.

Margaret McCartney is a GP in Glasgow.
margaret.mccartney@ft.com

Sourced & published by Henry Sapiecha

IS BOTOX A CURE ALL FOR MANY CONDITIONS.STUDIES SUGGEST THAT IT IS….

Thursday, August 25th, 2011

August 24, 2011 11:43 pm

Botox obtains US approval

for use as a bladder treatment

Botox, the drug best known for filling in brow wrinkles, received approval from US health regulators on Wednesday for the treatment of overactive bladders, boosting the shares of Allergan, its manufacturer.

The US Food and Drug Administration said Botox can be used by people with neurological conditions, such as spinal cord injuries or multiple sclerosis, to alleviate urinary incontinence.

Morgan Stanley analysts estimate the approval could provide Allergan with $59m in annual revenues by 2015. It could generate an additional $457m a year if, as expected, the drug is approved to treat patients with overactive bladders for non-neurological reasons.

Shares of Allergan rose 3.02 per cent to $77.90 on Wednesday.

This month, the Irish Medicines Board issued a similar approval for Botox, opening the door for its use as a bladder drug in Europe.

When injected into the bladder through a cystoscope, Botox decreases incontinence by relaxing the organ and increasing its storage capacity. The effect of the drug lasts for about nine months. Possible side-effects include urinary tract infections and problems retaining urine.

Allergan estimates that about 340,000 people in the US suffer from urinary incontinence due to neurological conditions.

David Pyott, chief executive of Allergan, said this month that he expects the company to boost its sales force to promote the drug.

Botox generates about $1.3bn in annual sales for Allergan, with half of that coming from cosmetic uses. In spite of a weak US economy, cosmetic Botox sales were up 16 per cent year on year in the the second quarter.

Allergan has said that although Botox is widely known for smoothing wrinkles, sales for therapeutic purposes will eventually outpace sales of the drug for cosmetics reasons. It has aggressively promoted the drug for various conditions.

Last year, Allergen paid $600m to settle cin court over  illegally promoting and selling Botox for unapproved uses until 2005. The company also pleaded guilty to a misdemeanour “misbranding” charge.

Botox, first approved 21 years ago for treatment of eye muscle twitches, has been a boon for Allergan and now has seven different approved uses. Doctors use the drug to treat chronic migraine headaches, muscle stiffness and severe armpit sweat.

Allergan said Botox has also been studied and evaluated for about 100 different purposes.

“It’s like an entire pipeline in one drug,” said Les Funtleyder, analyst and fund manager at Miller Tabak.

Sourced & published by Henry Sapiecha

DEPRESSION & ELECTRICAL IMPLANT IN THE BRAIN COULD BE THE ANSWER

Wednesday, July 6th, 2011

DEPRESSION CURES VIA ELECTRICAL IMPLANTS IN BRAIN

The anterior cingulate and prefrontal cortex (red) and frontal gyrus (orange) areas of the brain, which eTNS is said to activate (Image: NeuroSigma)

The World Health Organization has projected that by 2020, major depression will be the second-most significant cause for disability in the world, after heart disease. Along with psychotherapy, the disorder is usually treated using antidepressant drugs. There is often a frustrating trial-and-error period involved in finding the right drug for the right person, however, while side effects can include obesity, sexual dysfunction, and fatigue … to name a few. Los Angeles-based company NeuroSigma is now looking into an alternative drug-free therapy, that could ultimately incorporate electrodes implanted under the patient’s skin.

In an eight-week clinical trial conducted last June, researchers at UCLA externally stimulated the cranial trigeminal nerve of patients who suffered from depression. This was accomplished by attaching two electrodes to the skin of each subject’s forehead, which were in turn attached to a mobile phone-sized stimulating device. The external Trigeminal Nerve Stimulation (eTNS) process reportedly resulted in a 70 percent reduction in symptom severity during the trial, and a subsequent 80 percent remission rate, with none of the side effects associated with antidepressants.

The technology is licensed exclusively to NeuroSigma.

Last month, findings were presented on four more subjects from those trials, including functional neuroimaging PET data. It was determined that even brief exposure to eTNS increased blood flow to regions of the brain associated with depression and mood regulation. “These findings of a potential mechanism of action support our original hypothesis that electrical stimulation of the trigeminal nerves, located in facial skin tissue, can provide a very safe and effective means to send signals to key structures deep in the brain, thus providing a high-bandwidth pathway to the brain without current penetrating directly through the skull” said UCLA‘s Dr. Ian Cook.

A twenty-subject, double-blind second phase of the trials began this February, and should wrap up late this year.

NeuroSigma is meanwhile continuing development of eTNS, while also working on a version of the system that would utilize implantable subcutaneous electrodes. Known as sTNS, patients who responded well to eTNS could choose to switch over to it. The technology could also possibly be used to treat epilepsy and post-traumatic stress disorder.

Sourced & published by Henry Sapiecha

MS MULTIPLE SCLEROSIS TREATMENT HAS DRAMATIC RESULTS SAYS ITALIAN DOCTOR

Monday, June 20th, 2011

MS TREATMENT RESULTS ENCOURAGING SAYS ITALIAN DOCTOR

An Italian doctor has been getting dramatic results with a new type of treatment for Multiple Sclerosis, or MS, which affects up to 2.5 million people worldwide. In an initial study, Dr. Paolo Zamboni took 65 patients with relapsing-remitting MS, performed a simple operation to unblock restricted bloodflow out of the brain – and two years after the surgery, 73% of the patients had no symptoms. Dr. Zamboni’s thinking could turn the current understanding of MS on its head, and offer many sufferers a complete cure.

Multiple sclerosis, or MS, has long been regarded as a life sentence of debilitating nerve degeneration. More common in females, the disease affects an estimated 2.5 million people around the world, causing physical and mental disabilities that can gradually destroy a patient’s quality of life.

It’s generally accepted that there’s no cure for MS, only treatments that mitigate the symptoms – but a new way of looking at the disease has opened the door to a simple treatment that is causing radical improvements in a small sample of sufferers.

Italian Dr. Paolo Zamboni has put forward the idea that many types of MS are actually caused by a blockage of the pathways that remove excess iron from the brain – and by simply clearing out a couple of major veins to reopen the blood flow, the root cause of the disease can be eliminated.

Dr. Zamboni’s revelations came as part of a very personal mission – to cure his wife as she began a downward spiral after diagnosis. Reading everything he could on the subject, Dr. Zamboni found a number of century-old sources citing excess iron as a possible cause of MS. It happened to dovetail with some research he had been doing previously on how a buildup of iron can damage blood vessels in the legs – could it be that a buildup of iron was somehow damaging blood vessels in the brain?

He immediately took to the ultrasound machine to see if the idea had any merit – and made a staggering discovery. More than 90% of people with MS have some sort of malformation or blockage in the veins that drain blood from the brain. Including, as it turned out, his wife.

He formed a hypothesis on how this could lead to MS: iron builds up in the brain, blocking and damaging these crucial blood vessels. As the vessels rupture, they allow both the iron itself, and immune cells from the bloodstream, to cross the blood-brain barrier into the cerebro-spinal fluid. Once the immune cells have direct access to the immune system, they begin to attack the myelin sheathing of the cerebral nerves – Multiple Sclerosis develops.

He named the problem Chronic Cerebro-Spinal Venous Insufficiency, or CCSVI.

Zamboni immediately scheduled his wife for a simple operation to unblock the veins – a catheter was threaded up through blood vessels in the groin area, all the way up to the effected area, and then a small balloon was inflated to clear out the blockage. It’s a standard and relatively risk-free operation – and the results were immediate. In the three years since the surgery, Dr. Zamboni’s wife has not had an attack.

Widening out his study, Dr. Zamboni then tried the same operation on a group of 65 MS-sufferers, identifying blood drainage blockages in the brain and unblocking them – and more than 73% of the patients are completely free of the symptoms of MS, two years after the operation.

In some cases, a balloon is not enough to fully open the vein channel, which collapses either as soon as the balloon is removed, or sometime later. In these cases, a metal stent can easily be used, which remains in place holding the vein open permanently.

Dr. Zamboni’s lucky find is yet to be accepted by the medical community, which is traditionally slow to accept revolutionary ideas. Still, most agree that while further study needs to be undertaken before this is looked upon as a cure for MS, the results thus far have been very positive.

Naturally, support groups for MS sufferers are buzzing with the news that a simple operation could free patients from what they have always been told would be a lifelong affliction, and further studies are being undertaken by researchers around the world hoping to confirm the link between CCSVI and MS, and open the door for the treatment to become available for sufferers worldwide.

It’s certainly a very exciting find for MS sufferers, as it represents a possible complete cure, as opposed to an ongoing treatment of symptoms. We wish Dr. Zamboni and the various teams looking further into this issue the best of luck.

Via The Globe and Mail.

Sourced & published by Henry Sapiecha

NASAL SPRAY VACCINE COULD BE THE FIX FOR TYPE 1 DIABETES

Monday, June 20th, 2011

A nasal spray vaccine currently being trialed in Australia could prevent the development of type 1 diabetes.


Previous research showed that the nasal vaccine was successful in preventing the disease in mice, and now the results of a study involving 52 adults with early type 1 diabetes has provided encouraging evidence that it could also be effective in preventing the disease humans.

Type 1 diabetes occurs when the body’s immune system attacks and kills the insulin-producing beta cells in the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose, which can result in heart disease, stroke, kidney failure, blindness and premature death if left untreated, with the most common treatment being the daily injection of insulin.

Although the 52 participants in the study had early type 1 diabetes and had evidence of immunity to insulin-producing beta cells in the pancreas, they were not yet at the stage of requiring insulin injections. For the study, the participants were given either the nasal vaccine or a placebo for 12 months.

When administered through the nasal passages, the insulin vaccine stimulates the immune system present in the mucosal linings and works to desensitize the whole immune system to insulin so that the immune system’s white blood cells are prevented from attacking insulin in the beta cells.

“The results showed that the vaccine allowed the immune system to restore immune tolerance to insulin,” said Professor Len Harrison of the Walter and Eliza Hall Institute in Melbourne, Australia. “When subsequently given insulin by injection, the participants who had received the nasal insulin vaccine were found to be desensitized to insulin.”

The researchers from the Walter and Eliza Hall Institute and the Royal Melbourne Hospital say the results of the study indicate they are on the right track to finding a vaccine for type 1 diabetes and the same approach could also be adapted to other autoimmune diseases.

“The nasal vaccine approach, if shown to be successful in human type 1 diabetes, could also be tested with different vaccines for the prevention of other autoimmune diseases such as rheumatoid arthritis and multiple sclerosis,” added Professor Harrison.

The Type 1 Diabetes Prevention Trial, which was previously known as the intranasal insulin trial, INIT II), began in 2006 and is now halfway through the testing phase. Following the encouraging results of the study, hopes are high a nasal vaccine for type 1 diabetes could be available in as little as two years.

Details of the research was published in the April 2011 issue of the journal Diabetes.

Sourced & published by Henry Sapiecha

PANCREATIC CANCER HAS NOW GOT AN ENEMY

Saturday, May 21st, 2011

Associated Press

FDA expands Pfizer drug

approval for rare cancer

Associated Press, 05.20.11, 06:23 PM EDT

WASHINGTON — The Food and Drug Administration said Friday it expanded approval of a Pfizer drug to treat a rare form of pancreatic cancer.

The agency said it cleared Sutent to treat cancerous tumors of the pancreas that cannot be surgically removed, or have spread to other parts of the body. Such tumors are slow-growing and rare, affecting less than 1,000 U.S. patients each year, according to an FDA estimate.

Earlier this month the FDA approved Novartis ( NVS news people )’ Afinitor for the same disease.

Sutent is a pill-based drug that blocks molecules involved in the growth and spread of tumors. It is already approved as a treatment for kidney cancer and for tumors of the stomach, esophagus, and bowels that do not respond to other treatment. The drug was first cleared by the FDA in 2006.

The FDA approved the drug based on a study of 171 patients in which those taking Sutent lived about five months longer without their disease spreading than patients taking a placebo.

Side effects with the drug include diarrhea, nausea, vomiting, fatigue, high blood pressure, energy loss, stomach pain and changes in hair color.

Sourced & published by Henry Sapiecha

PARALYSED PEOPLE GET ELECTRICAL IMPLANT TO WALK AGAIN

Friday, May 20th, 2011

Paralysed man stands again

after electrical implant

May 20, 2011 – 1:21PM


After Rob Summers was paralysed below the chest in a car accident in 2006, his doctors told him he would never stand again. They were wrong.

Despite intensive physical therapy for three years, Mr Summers’s condition had not improved. So in 2009, doctors implanted an electrical stimulator on to the lining of his spinal cord to try waking up his damaged nervous system.

Within days, Mr Summers, 25, stood without help. Months later, he wiggled his toes, moved his knees, ankles and hips and was able to take a few steps on a treadmill.

Walking again ... Rob SummersA few steps … Rob Summers. Photo: AFP / Courtesy of Rob Summers

“It was the most incredible feeling,” said Mr Summers, of Portland, Oregon. “After not being able to move for four years, I thought things could finally change.”

Still, despite his renewed optimism, Mr Summers cannot stand when he is not in a therapy session with the stimulator turned on, and he normally gets around in a wheelchair. Doctors are limiting his use of the device to several hours at a time.

His case is described in a paper published today in the journal Lancet. The research was paid for by the US National Institutes of Health and the Christopher and Dana Reeve Foundation.

Building up his strength ... Rob Summers.Building up his strength … Rob Summers. Photo: AFP / Courtesy of Rob Summers

For years, certain people with incomplete spinal cord injuries, who have some control of their limbs, have experienced some improvement after experiments to stimulate their muscles electrically. But such progress had not been seen before in someone with a complete spinal cord injury.

“This is not a cure, but it could lead to improved functionality in some patients,” said Gregoire Courtine, head of experimental neurorehabilitation at the University of Zurich. He was not connected to Mr Summers’s case.

He cautioned that Mr Summers’s recovery so far had not make any difference to his daily life and that more research was needed to help paralysed people regain enough mobility to make a difference in their normal routines.

Before the accident ... Rob Summers.Before the accident … Rob Summers. Photo: AFP / Courtesy of Rob Summers

The electrical stimulator surgeons implanted on to Mr Summers’s spinal cord is usually used to relieve pain and can cost up to $US20,000.

Mr Summers’s doctors implanted it lower than normal, on to the very bottom of his vertebrae.

“The stimulator sends a general signal to the spinal cord to walk or stand,” said Susan Harkema, rehabilitation research director at the Kentucky Spinal Cord Injury Research Centre in Louisville and the Lancet study’s lead author.

Dr Harkema and her colleagues were surprised that Mr Summers was able to move his legs voluntarily. “That tells us we can access the circuitry of the nervous system, which opens up a whole new avenue for us to address paralysis,” Dr Harkema said. She said prescribing drugs might also speed recovery.

John McDonald, director of the International Centre for Spinal Cord Injury at Kennedy Krieger Institute in Baltimore, said the strategy could be adopted rapidly for the 10 to 15 per cent of paralysed patients who might benefit. He was not connected to the Summers case.

“There is no question we will do this for our patients,” Dr McDonald said.

He added that, since the electrical stimulators were already approved for pain relief, it should not be difficult to study them to help some patients regain movement.

For now, Mr Summers does about two hours a day of physical therapy.

“My ultimate goal is to walk and run again,” he said. “I believe anything is possible and that I will get out of my wheelchair one day.”

AP  Sourced & published by Henry Sapiecha


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