Posts Tagged ‘spinal cord injury’




Doctors Perform First FDA Approved Schwann Cell Transplant in Patient with New Spinal Cord Injury

Doctors at The Miami Project to Cure Paralysis, a Center of Excellence at the University of Miami Miller School of Medicine, performed the first-ever Food and Drug Administration approved Schwann cell transplantation in a patient with a new spinal cord injury. The procedure, performed at the University of Miami/Jackson Memorial Medical Center, is a Phase 1 clinical trial designed to evaluate the safety and feasibility of transplanting the patient’s own Schwann cells.

“This historic clinical trial represents a giant step forward in a field of medicine where each tangible step has tremendous value. This trial, and these first patients in this trial specifically, are extremely important to our mission of curing paralysis,” said neurosurgeon Barth Green, M.D., Co-Founder and Chairman of The Miami Project, and Professor and Chair of Neurological Surgery. “The Miami Project team includes hundreds of scientists, clinicians, and technicians who have joined hands to make the ‘impossible possible,’ for which this trial is a key goal and dream now being realized. This achievement reaffirms that the tens of millions of dollars and the incalculable work hours were well invested in this first of a kind human Schwann cell project.”

Led by W. Dalton Dietrich, Ph.D., Scientific Director of The Miami Project and Professor of Neurological Surgery, Neurology and Cell Biology & Anatomy, the Schwann cell clinical trial team at The Miami Project is composed of a multidisciplinary group of basic science and clinical faculty members, scientific staff, and regulatory personnel focused on advancing the trial. The transplantation procedure was conducted by the Principal Investigators of the trial, Dr. Allan Levi, M.D., Ph.D., Professor of Neurological Surgery, Orthopedic, and Rehabilitation, and James Guest, M.D., Ph.D., Associate Professor of Neurological Surgery. The patient had a neurologically complete thoracic spinal injury and received the transplantation of autologous Schwann cells about four weeks post-injury. There have been no adverse events and the team is moving forward with the trial.


This image shows a cultured Schwann cell stained for the actin cytoskeleton with phalloidin-Rd.


“a cell that forms spiral layers around a myelinated nerve fiber between two nodes of Ranvier and forms the myelin sheath consisting of the inner spiral layers from which the protoplasm has been squeezed out.”   (Source)

“As a basic scientist, the hope is always to increase knowledge and discovery,” said Dietrich. “Not every day are you able to see that translated into the clinical realm with the hopes of bettering the lives of those suffering, so this Phase I clinical trial is a vital step for the field of SCI research, and for The Miami Project team that has been working diligently on this therapeutic concept for more than a quarter of a century. This trial, when completed successfully, will lay the critical foundation for future cell-based therapies to target spinal cord injuries.”

The Miami Project clinical trial will enroll a total of eight participants with acute thoracic SCI. Newly injured patients brought to the trauma center would have to meet the stringent inclusion criteria. The participants will undergo a biopsy of a sensory nerve in one leg to obtain the tissue from which to grow their own Schwann cells. The Schwann cells are then grown in a state-of-the art culturing facility for three to five weeks to generate the number of cells necessary for transplantation, and to undergo the strict purification process. By the time the Schwann cells are surgically transplanted into the injury site, participants will be 26-42 days post-injury.

All procedures will be conducted at UM/Jackson and The Miami Project to Cure Paralysis, with colleagues at the University of Miami Miller School of Medicine. Each participant will be followed intensively for one year after receiving the transplantation surgery, and their neurologic status, medical status, pain symptoms, and muscle spasticity will be evaluated. It is expected that it could be two to three years from the time the first subject is enrolled until the final subject is one year post-transplantation. All participants will continue to be monitored for an additional four years under a separate clinical protocol. This Phase I trial is the foundation upon which The Miami Project will develop future cell transplant trials targeting different types of injuries, times post-injury, and therapeutic combinations.

Posted on January 24, 2013 By Neuroscience News Featured, Neurology (Source)




Stem cells breathe new life into paralyzed gymnast

At the Dasara Games in September of 2010, a meticulous gymnast with the ambition to achieve the same stardom as his hero Ashish Kumar, met an untimely misfortune when mistiming a somersault during a practice routine.

“Ananth Rao’s head crashed on to the mat and he heard a cracking sound. His spine was shattered at the cervical region (C-6, C-7), paralyzing him for life. “I’ve always been told that one must learn from mistakes,” Ananth said. “One small mistake I made has cost me so much. I lost hope completely, I thought my life was over,” said the youngster, who was operated upon after his accident at the JSS Hospital in his hometown.  Although the doctors stabilized his neck, Ananth became a bedridden quadriplegic (all four limbs paralyzed) with no control over his bowel movements and was susceptible to a number of ailments.” He was forced to drop out of Mysore Maharaja College to focus on receiving vigorous physiotherapy and standard forms of treatment. But there was little improvement in his condition.  Just over a year after his accident, doctors heard about Ananth’s condition and decided to take up his case in a bid to improve his quality of life.  With the backing of the HCG Foundation, Ananth was exposed to advanced treatment in the form of mesenchymal stem cells – connective tissue cells that can differentiate into a variety of cell types – in a bid to try to regenerate nerve cells in his spinal cord.

After two stem cell injections and 11 months of focused rehabilitation, Ananth has shown remarkable signs of improvement.

“Today, I can dream new dreams of a future where I am not dependant on anyone and I can see myself living with dignity,” said Ananth, who showed no signs of difficulty lifting his arms, holding a pen or a cup of coffee. “He had been undergoing regular treatment for a year,” said HCG chairman and CEO Dr Ajaikumar, who along with orthopaedician Dr Pramod S Chinder, took a personal interest in Ananth’s case. “He was someone who led an active life as a gymnast and I felt we should take up this challenging case to show how regeneration can happen through stem cell treatment. We are glad our efforts have finally paid off,” he said, without ruling out further improvement.” “Ananth’s case was studied in detail. Stem cells of the patient were cultured and two injections were given to him,” said Dr Chinder, who was quick to add recovery chances were case specific. “Post treatment, the patient progressed significantly, with the movements of hands and there is sensation in his legs. There is increasing evidence in the benefits of stem cell therapies and spinal cord injuries are one of the most researched. In patients, who do not have any other option of recovering from spinal cord injuries, stem cell treatment is the way to go forward,” Dr. Chinder added.


A TREATMENT FOR ALS? Neural stem cell transplants slow progression of disease

In SCIENCE & STEM CELLS, VICTORIES & SUCCESS STORIES on January 3, 2013 at 2:33 pm
A treatment for ALS?
Neural stem cell transplants slow progression of disease


“The transplanted neural stem cells help by producing factors that preserve the health and function of the host’s remaining nerve cells. They also reduce inflammation and suppress the number of disease-causing cells in the host’s spinal cord. The neural stem cells did not replace deteriorating nerve cells in the mice with ALS.  Researchers observed improved motor performance and respiratory function in the treated mice. The neural stem cell transplant also slowed the disease’s progression.

Twenty-five percent of the treated ALS mice in the study survived for one year or more — roughly three to four times longer than the untreated mice.”

Results from a meta-analysis of 11 independent amyotrophic lateral sclerosis (ALS) research studies are giving hope to the ALS community by showing, for the first time, that the fatal disease may be treatable.

Researchers say progress in treating ALS, also known as Lou Gehrig’s disease, may be made by targeting new mechanisms revealed by neural stem cell-based studies.

“This significant research will help us better understand the mechanisms underlying motor neuron diseases,” said Yang (Ted) Teng, Harvard Medical School associate professor of surgery at the Harvard-affiliated Brigham and Women’s Hospital and one of the study’s co-lead authors. Teng is also director of the Spinal Cord Injury and Stem Cell Biology Research Laboratory in the Department of Neurosurgery at Brigham and Women’s.

The research studies were conducted at Brigham and Women’s; the Harvard affiliates Children’s Hospital Boston and Veterans Affairs Boston Healthcare System; Sanford-Burnham Medical Research Institute; University of Massachusetts Medical School; Johns Hopkins University; State University of New York Upstate Medical University; and Columbia University.

“This is not a cure for ALS. But it shows the potential that mechanisms used by neural stem cells in our study have for improving an ALS patient’s quality of life and length of life,” said Yang (Ted) Teng, one of the principal investigators of Project ALS’ consortium project. File photo by Justin Ide/Harvard Staff Photographer

ALS causes nerve cells in the spinal cord to die, eventually taking away a person’s ability to move or even breathe. A decade of research conducted at multiple institutions showed, however, that when neural stem cells were transplanted into multilevels of the spinal cord of a mouse model with familial ALS, disease onset and progression slowed, motor and breathing function improved, and treated mice survived three to four times longer than untreated mice.

A summary of the findings from all 11 studies was published online in December in Science Translational Medicine.

“This work sheds new light on detrimental roles played by non-neuronal cells in triggering motor neuron death, and these events should be targeted for developing more effective therapeutics to treat ALS,” Teng said.

The transplanted neural stem cells help by producing factors that preserve the health and function of the host’s remaining nerve cells. They also reduce inflammation and suppress the number of disease-causing cells in the host’s spinal cord. The neural stem cells did not replace deteriorating nerve cells in the mice with ALS.

Researchers observed improved motor performance and respiratory function in the treated mice. The neural stem cell transplant also slowed the disease’s progression. Twenty-five percent of the treated ALS mice in the study survived for one year or more — roughly three to four times longer than the untreated mice.

“This is not a cure for ALS,” said Teng, who is one of the principal investigators of Project ALS’ consortium project. “But it shows the potential that mechanisms used by neural stem cells in our study have for improving an ALS patient’s quality of life and length of life.”

To read the full story, visit the Harvard Medical School website.


In STEM CELLS IN THE NEWS on November 29, 2012 at 9:00 am

 A bone marrow harvest.

Ahead of a planned five-centre nationwide trial, the Indian Council of Medical Research (ICMR) has approved a special project at the AIIMS Trauma Centre in New Delhi where stem cell therapy will be conducted on complete paraplegics and quadriplegics to try and revive limb function.

A similar trial will be conducted at the Indian Spinal Injuries Centre (ISIC) in Vasant Kunj, south-west Delhi where 21 patients have already been registered. This project too has been approved by the ICMR. Senior ICMR scientists from the apex committee to monitor stem cell research said the five-centre trial will be coordinated from ISIC and is in the final stages of approval.  “This will be the first national ICMR trial of autologous bone marrow stem cell transplant on complete quadriplegics and paraplegics. We are finalizing the number of patients. The ISIC will be the coordinating centre. The next meeting has been scheduled for December 4,” a senior scientist said.

An autologous stem cell transplantation is a procedure in which stem cells are removed, stored and returned to the same person.  For its project, the AIIMS Trauma Centre has registered eight patients. They will be injected with stem cells from their own bone marrow to see if the damaged neurological function can be regenerated. Doctors have cautioned that earlier trials on incomplete quadriplegics and paraplegics have not suggested significant clinical improvement.

Dr. Deepak Aggarwal, associate professor of neurosurgery at the AIIMS Trauma Centre who is coordinating the study, said: “We have necessary clearances from our internal ethics committee and the national apex committee for stem cell research and therapy which has members from the ICMR and Department of Biotechnology.”

“We are trying to see if injecting patients of irreversible spinal cord injuries with stem cells from their own bone marrow, under autologous stem cell transplantation, can help regenerate neurological function,” he said.   According to Dr. Aggarwal, clinical evidence in previous international trials have not given “satisfactory results”. This is the first time that AIIMS is undertaking such a project.

At the ISIC, doctors have selected 21 complete paraplegics who are being injected with stem cells retrieved from their own bone marrow within 10-14 days of injury.  “We had done one project in 2009 to see the use of stem cell transplant in restoring limb function on spinal cord injuries, but we had only selected chronic patients where the time lapse after the injury was far more. We could not demonstrate any clinical improvement. One criticism was that the spinal cord loses its plasticity and ability to regenerate after such a long time,” Dr. H S Chhabra, medical director at ISIC, said.

In the 2009 study, where five patients were selected, the site of stem cells was the olfactory mucosa or the upper region of the nasal cavity. For the new trial at ISIC, stem cells are being retrieved from the bone marrow of patients.  At AIIMS, patients will be monitored for six months after one procedure. If there is no significant change, another procedure of extraction of stem cells and autologous transplantation will be repeated. There will be follow-ups for two years.

Of the eight patients shortlisted for the project at AIIMS, three are quadriplegics and have lost function in all four limbs. Patients were evaluated to ensure only those with “complete” loss of limb function were included, and all within six months of injury.

At ISIC, the 21 patients have been divided into three arms. The first group will be injected stem cells directly into the spinal cord, at the site of injury. For the second group, stem cells will be injected into the cerebrospinal fluid that surrounds the spinal cord.

The third arm, which will be the control arm, will not be injected with stem cells, but given other rehabilitative therapies. The functional outcome of all three groups will be compared at the end of two years.



In SCIENCE & STEM CELLS, STEM CELLS IN THE NEWS on November 22, 2012 at 8:47 am


Scientists have reversed paralysis in dogs after injecting them with cells grown from the lining of their nose.  The pets had all suffered spinal injuries which prevented them from using their back legs. The Cambridge University team is cautiously optimistic the technique could eventually have a role in the treatment of human patients.  The study is the first to test the transplant in “real-life” injuries rather than laboratory animals.

The only part of the body where nerve fibres continue to grow in adults is the olfactory system.  Found in the at the back of the nasal cavity, olfactory ensheathing cells (OEC) surround the receptor neurons that both enable us to smell and convey these signals to the brain.  The nerve cells need constant replacement which is promoted by the OECs.

For decades scientists have thought OECs might be useful in spinal cord repair. Initial trials using OECs in humans have suggested the procedure is safe.  In the study, funded by the Medical Research Council and published in Brain, the dogs had olfactory ensheathing cells from the lining of their nose removed.  These were grown and expanded for several weeks in the laboratory.

Of 34 pet dogs on the proof of concept trial, 23 had the cells transplanted into the injury site – the rest were injected with a neutral fluid.  Many of the dogs that received the transplant showed considerable improvement and were able to walk on a treadmill with the support of a harness.  None of the control group regained use of its back legs.  The research was a collaboration between the MRC’s Regenerative Medicine Centre and Cambridge University’s Veterinary School.  Professor Robin Franklin, a regeneration biologist at the Wellcome Trust-MRC Stem Cell Institute and report co-author, said: ‘Our findings are extremely exciting because they show for the first time that transplanting these types of cell into a severely damaged spinal cord can bring about significant improvement.  “We’re confident that the technique might be able to restore at least a small amount of movement in human patients with spinal cord injuries but that’s a long way from saying they might be able to regain all lost function. Prof. Franklin said, “the procedure might be used alongside drug treatments to promote nerve fibre regeneration and bioengineering to substitute damaged neural networks.”

The researchers say the transplanted cells regenerated nerve fibres across the damaged region of the spinal cord. This enabled the dogs to regain the use of their back legs and coordinate movement with their front limbs.  The new nerve connections did not occur over the long distances required to connect the brain to the spinal cord. The MRC scientists say in humans this would be vital for spinal injury patients who had lost sexual function and bowel and bladder control.

Prof Geoffrey Raisman, chair of Neural Regeneration at University College London, who discovered olfactory ensheathing cells in 1985 said: “This is not a cure for spinal cord injury in humans – that could still be a long way off. But this is the most encouraging advance for some years and is a significant step on the road towards it.”

He said the clinical benefits were still limited: “This procedure has enabled an injured dog to step with its hind legs, but the much harder range of higher functions lost in spinal cord injury – hand function, bladder function, temperature regulation, for example – are yet more complicated and still a long way away.”

Jasper, a 10-year-old dachshund, is one of the dogs which took part in the trial.

His owner May Hay told me: “Before the treatment we used to have to wheel Jasper round on a trolley because his back legs were useless. Now he whizzes around the house and garden and is able to keep up with the other dogs. It’s wonderful.”


BBC News – Nose cell transplant enables paralysed dogs to walk.


In STEM CELLS IN THE NEWS on November 12, 2012 at 8:50 pm

Xray of cervical spine

Unfortunately, there certainly is still a great deal of misinformation in the media today. While spinal cord injury stem cell treatments are going on successfully today, articles like the following are confusing.


THIS ARTICLE STATES: “For the first time, people with broken spines have recovered feeling in previously paralyzed areas after receiving injections of neural stem cells.”
THE FACT IS: This is a blatant lie (or ignorance). Spinal cord injury has been successfully treated with adult stem cells for a few years now.  The following are a few of the stories.  https://repairstemcell.wordpress.com/2011/02/07/spinal-cord-injury-and-repair-stem-cell-treatments/

Some people regain sensitivity in their extremities, some gain bladder and bowel control and some are capable of walking with a walker. The limits of improvement are yet to be seen, but this is definitely NOT even close to the first.


THIS ARTICLE STATES:  “The cells, acquired from donated fetal brain tissue…”

THE FACT IS:  While these are not embryonic stem cells (a fetus starts at 7 weeks so they are technically ‘adult’ or non-embryonic stem cells), the back lash from the religious right on the use of fetal brain tissue, donated or not, is going to be extreme.  There should be no risk of cysts and tumors as these cells are already differentiated but let’s wait and see.


THE ARTICLE STATES:  “The patients also received a temporary course of immunosuppressive drugs to limit rejection of the cells.”

THE FACT IS:  Donated (or allogenic) stem cells carry the risk of graft versus-host disease (GVHD) or rejection so the immune system must be suppressed.  When you are dealing with illness or in this case, spinal cord injury, lowering the immune system with immunosuppressive drugs carries inherent risks.


I will take a position of cautious optimism and wait and see the results.  So the only question remaining to be asked is:  Autologous (from the aprient) stem cells carry none of these risks.  Why were they not used?



In VICTORIES & SUCCESS STORIES on February 9, 2011 at 9:40 am



Spinal Cord Injury and Adult Stem Cell Treatments

In VICTORIES & SUCCESS STORIES on February 7, 2011 at 11:42 pm

Recently, two New Zealand “experts” in the field of spinal cord injuries weighed in on stem cell treatments.  One of them,  Dr Richard Acland, Christchurch’s Burwood Hospital director of the spinal injuries unit, told TV ONE’s Breakfast today that he has concerns about stem cell treatments and their ability to help SCI patents recover.  The other, “Spinal Cord Society president Noela Vallis said the procedure has been carried out overseas on well over 100 people with few negative side-effects and varying degrees of improvement for each patient.”  via

Well done Noela!  It is obvious to me that you are familiar with and have based your optimism on these articles…and it is further obvious that Dr Acland has never seen any of them:


REGENERATING THE CENTRAL NERVOUS SYSTEM  https://repairstemcell.wordpress.com/2011/10/17/regenerating-the-central-nervous-system/

Stepping Towards A Paralysis Cure, A Tale Of Two Supermen Stem Cells Cure 23 Year Old Male of Paralysis – C6…-C7 injury

Paraplegic – Adult Stem Cell Success Stories – Laura Dominguez


Successful Stem Cell Treatment of Spinal Cord Injury in Dogs

Spinal Cord Injury Patient Wins…and Loses


Adult Stem Cell Grafts Help Paralyzed Heal

Medical hope as paralysed dog cured by stem cell therapy – mirror.co.ukhttps://repairstemcell.wordpress.com/2009/10/08/medical-hope-as-paralysed-dog-cured-by-stem-cell-therapy-mirror-co-uk/

Major the Roseville police dog gets stem cell treatment – http://blogs.citypages.com/blotter/2011/01/major_police_dog_stem_cell.php

Or email me at dsgrano@gmail.com

Geron’s Stem Cell Trial

In BUSINESS OF STEM CELLS on November 3, 2009 at 11:07 am

[For more articles on the long, sordid and somewhat pathetic history of Geron’s embryonic stem cell clinical trial to treat spinal cord injury, click here]

Spinal Cord Injury

Geron Corporation’s Stem Cell Trial

Monday November 2, 2009

Geron Corporation is a company based in Menlo Park, CA and the first biotech company in the USA to be granted permission for a clinical trial of regenerative medicine using embryonic stem cells, in humans. While permission was granted in January 2009, the trials were put on hold until last Friday (October 30, 2009) when the latest round of preclinical trials using animals revealed some side effects that warranted further investigation.

According to the Geron News Release, test animals receiving the treatment, GRNOPC1, developed a higher number of cysts at the area of spinal cord injury than in previous studies. However, the FDA has agreed to allow the studies to continue, since the cysts appear to be non-proliferative, confined to the injury site, and not associated with any serious adverse effects or SUSARS.

GRNOPC1 consists of human embryonic stem cell (hESC)-derived oligodendrocyte progenitor cells (OPCs). Oligodendrocytes are cells of the nervous system that produce the myelin shealth, which insultates the axons of nerve cells. Injection with the cells was shown to enhance remyelination of the spinal cord in adult rats. Demyelination after spinal cord injury contributes to loss of neural function. Rats treated with GRNOPC1 seven days after injury exhibited substantially better recovery and improved locomotor ability.

Geron expects re-initiation of the clinical trial in late 2010. Since the treatment must be applied shortly after injury, anyone wanting to participate in a clinical trial must agree to injections within 7 to 14 days of spinal injury…

via Geron Corporation’s Stem Cell Trial.

Adult Stem Cell Grafts Help Paralyzed Heal

In VICTORIES & SUCCESS STORIES on October 21, 2009 at 4:43 am

Wayne State Study Shows Adult Stem Cell Grafts Help Paralyzed

A new study by a Wayne State University School of Medicine researcher details the outcome of adult stem cell grafts in spinal cord injuries and how the procedure led to increased mobility and quality of life for patients.

Spinal cord injury
A severe spinal cord injury often causes loss of feeling and paralysis, the loss of movement and voluntary control over the muscles in the body. Spinal cord damage also causes loss of reflex function below the point of injury interrupting bodily functions such as breathing, bowel control, and bladder control. In the event of a spinal injury prompt medical attention can help to minimize further spinal cord damage.
Associate Professor Jean Peduzzi-Nelson of the Department of Anatomy and Cell Biology conducted the study, “Olfactory Mucosal Autografts and Rehabilitation for Chronic Traumatic Spinal Cord Injury,” which was published online in the journal Neurorehabilitation and Neural Repair.
The process involves the use of adult stem-like progenitor cells in the patient’s own nasal tissue. The use of a person’s own stem cells, Peduzzi-Nelson said, lessens the problems of rejection, tumor formation and disease transmission.

Spinal Cord Injury
In the study, 20 patients with severe chronic spinal cord injuries received a treatment combination of partial scar removal, transplantation of nasal tissue containing stem cells to the site of the spinal cord injury and rehabilitation. All of the patients had total paralysis below the level of their spinal cord injury before the treatment.
“This may be the first clinical study of patients with severe, chronic spinal cord injury to report considerable functional improvement in some patients with a combination treatment,” Peduzzi-Nelson said. “Normally, in people with spinal cord injuries that happened more than 18 months ago, there is little improvement.”
The injuries in the study patients were 18 months to 15 years old. The patients, ages 19 to 37, had no use of their legs before the treatment. One paraplegic treated almost three years after the injury now ambulates with two crutches and knee braces. Ten other patients ambulate with physical assistance and walkers (with and without braces). One 31-year-old male tetriplegic patient uses a walker without the help of knee braces or physical assistance. When the stem cell transplant and scar removal process was combined with an advanced form of rehabilitative training that employs brain-initiated weight-bearing movement, 13 patients improved in the standard measures used to assess functional independence and walking capabilities.

“We concluded that olfactory mucosal autograft is feasible, relatively safe and possibly beneficial in people with chronic spinal cord injury when combined with post-operative rehabilitation,” Peduzzi-Nelson said. “There are clear indications of efficacy based on neurological, functional and electrophysiological testing that justify moving forward to a larger, controlled clinical trial. In patients who are willing to commit to lots of intense rehabilitation, this combination treatment holds promise to improve their condition.”
Peduzzi-Nelson noted that there are many sources of stem cells in the body, including bone marrow, fat and the brain, but that the olfactory mucosa is the only suitable tissue that can be easily obtained with minimally invasive procedures.
Spinal Cord Injury
The stem-like progenitor cells in the olfactory mucosa are special because they normally form new neurons more rapidly than cells from any other place in the adult nervous system. When such cells are transplanted into chick embryos, she said, the cells can form mature cells of the heart, trunk muscles, liver, brain and spinal cord. This suggests that olfactory stem-like progenitor cells are very immature and capable of forming a variety of cell types.
  • The partial scar removal and tissue transplantation procedures were performed in Portugal. The rehabilitation of patients took place in Italy and Portugal.
  • “Many patients in the Detroit area have had this procedure,” she said. “Along with some colleagues, I have sent questionnaires to these local patients to find out whether or not there are any side-effects or functional improvement.”
  • Peduzzi-Nelson said that she and Jay Meythaler, M.D., chairman of the Department of Physical Medicine and Rehabilitation, along with other colleagues, are seeking FDA approval to perform the procedure in the United States.
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