Preclinical study shows that engineered T cells can selectively target the antibody-producing cells that cause autoimmune disease

June 30, 2016

University of Pennsylvania School of Medicine

With potentially major implications for the future treatment of autoimmunity and related conditions, scientists have found a way to remove the subset of antibody-making cells that cause an autoimmune disease, without harming the rest of the immune system. They studied an autoimmune disease called pemphigus vulgaris, a condition in which a patient’s own immune cells attack a protein called desmoglein-3 that normally adheres skin cells.



This is a schematic of how a “chimeric autoantibody receptor,” or CAAR, that displays fragments of the autoantigen Dsg3 helps fight an autoimmune disease called pemphigus vulgaris, a condition in which a patient’s own immune cells attack Dsg3, which normally adheres skin cells.
Credit: Christoph T. Ellebrecht, MD, Perelman School of Medicine, University of Pennsylvania



-In a study with potentially major implications for the future treatment of autoimmunity and related conditions, scientists from the Perelman School of Medicine at the University of Pennsylvania have found a way to remove the subset of antibody-making cells that cause an autoimmune disease, without harming the rest of the immune system. The autoimmune disease the team studied is called pemphigus vulgaris (PV), a condition in which a patient’s own immune cells attack a protein called desmoglein-3 (Dsg3) that normally adheres skin cells.

Current therapies for autoimmune disease, such as prednisone and rituximab, suppress large parts of the immune system, leaving patients vulnerable to potentially fatal opportunistic infections and cancers.

The Penn researchers demonstrated their new technique by successfully treating an otherwise fatal autoimmune disease in a mouse model, without apparent off-target effects, which could harm healthy tissue. The results are published in an online First Release paper in Science.

“This is a powerful strategy for targeting just autoimmune cells and sparing the good immune cells that protect us from infection,” said co-senior author Aimee S. Payne, MD, PhD, the Albert M. Kligman Associate Professor of Dermatology.

Payne and her co-senior author Michael C. Milone, MD, PhD, an assistant professor of Pathology and Laboratory Medicine, adapted the technique from the promising anti-cancer strategy by which T cells are engineered to destroy malignant cells in certain leukemias and lymphomas.

“Our study effectively opens up the application of this anti-cancer technology to the treatment of a much wider range of diseases, including autoimmunity and transplant rejection,” Milone said.

The key element in the new strategy is based on an artificial target-recognizing receptor, called a chimeric antigen receptor, or CAR, which can be engineered into patients’ T cells. In human trials, researchers remove some of patients’ T cells through a process similar to dialysis and then engineer them in a laboratory to add the gene for the CAR so that the new receptor is expressed in the T cells. The new cells are then multiplied in the lab before re-infusing them into the patient. The T cells use their CAR receptors to bind to molecules on target cells, and the act of binding triggers an internal signal that strongly activates the T cells — so that they swiftly destroy their targets.

The basic CAR T cell concept was first described in the late 1980s, principally as an anti-cancer strategy, but technical challenges delayed its translation into successful therapies. Since 2011, though, experimental CAR T cell treatments for B cell leukemias and lymphomas — cancers in which patients’ healthy B cells turn cancerous — have been successful in some patients for whom all standard therapies had failed.

B cells, which produce antibodies, can also cause autoimmunity. Payne researches autoimmunity, and a few years ago, a postdoctoral researcher in her laboratory, Christoph T. Ellebrecht, MD, took an interest in CAR T cell technology as a potential weapon against B cell-related autoimmune diseases. Soon Payne’s lab teamed up with Milone’s, which studies CAR T cell technology, in the hope of finding a powerful new way to treat these ailments.

“We thought we could adapt this technology that’s really good at killing all B cells in the body to target specifically the B cells that make antibodies that cause autoimmune disease,” said Milone.

“Targeting just the cells that cause autoimmunity has been the ultimate goal for therapy in this field,” noted Payne.

A more disease-specific receptor

In the new study, for which Ellebrecht was first author, the team took aim at pemphigus vulgaris. This condition occurs when a patient’s antibodies attack molecules that normally keep skin cells together. When left untreated, PV leads to extensive skin blistering and is almost always fatal, but in recent decades the condition has been treatable with broadly immunosuppressive drugs such as prednisone, mycophenolate mofetil, and rituximab.

To treat PV without causing broad immunosuppression, the Penn team designed an artificial CAR-type receptor that would direct patients’ T cells to attack only the B cells producing harmful anti-Dsg3 antibodies.

The team developed a “chimeric autoantibody receptor,” or CAAR, that displays fragments of the autoantigen Dsg3 — the same fragments to which PV-causing antibodies and their B cells typically bind, as Payne’s laboratory and others have shown in prior studies. The artificial receptor acts as a lure for the B cells that target Dsg3, bringing them into fatal contact with the therapeutic T cells.

Testing many variants, the team eventually found an artificial receptor design that worked well in cell culture, enabling host T cells to efficiently destroy cells producing antibodies to desmoglein, including those derived from PV patients. The engineered T cells also performed successfully in a mouse model of PV, killing desmoglein-specific B cells and preventing blistering and other manifestations of autoimmunity in the animals.

“We were able to show that the treatment killed all the Dsg3-specific B cells, a proof of concept that this approach works,” Payne said.

T cell therapies can be complicated by many factors. But in these experiments, the Penn scientists’ engineered cells maintained their potency despite the presence of anti-Dsg3 antibodies that might have swarmed their artificial receptors. In addition, there were no signs that the engineered T cells caused side effects by hitting the wrong cellular targets in the mice.

The team now plans to test their treatment in dogs, which can also develop PV and often die from the disease. “If we can use this technology to cure PV safely in dogs, it would be a breakthrough for veterinary medicine, and would hopefully pave the way for trials of this therapy in human pemphigus patients,” Payne said.

Also on the horizon for the Penn scientists are applications of CAAR T cell technology for other types of autoimmunity. The immune rejection that complicates organ transplants, and normally requires long-term immunosuppressive drug therapy, may also be treatable with CAAR T cell technology.

“If you can identify a specific marker of a B cell that you want to target, then in principle this strategy can work,” Payne said.

Other co-authors of the study include Vijay G. Bhoj, Arben Nace, Eun Jung Choi, Xuming Mao, Michael Jeffrey Cho, John T. Seykora, and George Cotsarelis, all of Penn; Giovanni Di Zenzo of the Istituto Dermopatico dell’Immacolata in Rome; and Antonio Lanzavecchia of the Institute for Research in Biomedicine in Bellinzona, Switzerland.

Story Source:

The above post is reprinted from materials provided by University of Pennsylvania School of Medicine. Note: Materials may be edited for content and length.


Source: University of Pennsylvania School of Medicine. “Treating autoimmune disease without harming normal immunity: Preclinical study shows that engineered T cells can selectively target the antibody-producing cells that cause autoimmune disease.” ScienceDaily. ScienceDaily, 30 June 2016. <>.

June 28, 2016

University of Guelph

Pipelines carrying crude oil to ports in British Columbia may spell bad news for salmon, according to a new study. Exposure to an oil sands product — diluted bitumen — impairs the swimming ability and changes the heart structures of young salmon.



Chinook swimming (stock image). Exposure to an oil sands product — diluted bitumen — impairs the swimming ability and changes the heart structures of young salmon, new research shows.
Credit: © randimal / Fotolia



Pipelines carrying crude oil to ports in British Columbia may spell bad news for salmon, according to a new University of Guelph-led study.

Exposure to an oil sands product — diluted bitumen — impairs the swimming ability and changes the heart structures of young salmon.

The research will be published in the journal Environmental Toxicology and Chemistry, and is available online now.

It’s a timely finding, says U of G post-doctoral researcher and lead author Sarah Alderman.

The National Energy Board (NEB) recently approved the controversial Trans Mountain pipeline expansion project; the federal government is expected to make a final decision by December.

The pipeline stretches from Edmonton to Burnaby B.C. The expansion would double the volume of oil sands products reaching the Pacific coast. It’s just one of several trans-Canada pipelines on the NEB’s review list.

“The Trans Mountain pipeline already carries diluted bitumen through the Fraser River Watershed and this is prime salmon habitat,” Alderman said.

Working with colleagues at Simon Fraser University and the University of British Columbia, Alderman exposed fish to small amounts of diluted bitumen for up to four weeks.

She found that salmon exposed to the highest concentration of diluted bitumen suffered a 10 per cent reduction in swimming performance.

“This may not seem like much, but to a young salmon about to head out to the ocean, it’s huge,” Alderman said.

“These fish are swimming all-out for hours each day, traveling up to 1,000 kilometres to reach the Pacific, and they need a strong heart to do this.”

The pipeline stretches from Edmonton to Burnaby B.C. The expansion would double the volume of oil sands products reaching the Pacific coast. It’s just one of several trans-Canada pipelines on the NEB’s review list.

“The Trans Mountain pipeline already carries diluted bitumen through the Fraser River Watershed and this is prime salmon habitat,” Alderman said.

Working with colleagues at Simon Fraser University and the University of British Columbia, Alderman exposed fish to small amounts of diluted bitumen for up to four weeks.

She found that salmon exposed to the highest concentration of diluted bitumen suffered a 10 per cent reduction in swimming performance.

“This may not seem like much, but to a young salmon about to head out to the ocean, it’s huge,” Alderman said.

“These fish are swimming all-out for hours each day, traveling up to 1,000 kilometres to reach the Pacific, and they need a strong heart to do this.”

The more diluted bitumen fish encounter, and the longer they are exposed to it, the greater the impact on their health and fitness, Alderman said.

“What our study really says is before you build any more pipelines through salmon habitat, you need to make sure that you’re building pipelines to the highest possible standard, that you can quickly detect any leaks in the system, and that you have rapid and thorough spill response procedures.”

Story Source:

The above post is reprinted from materials provided by University of Guelph. Note: Materials may be edited for content and length.

Journal Reference:

  1. Sarah L. Alderman, Feng Lin, Anthony P. Farrell, Christopher J. Kennedy, Todd E. Gillis. Effects of diluted bitumen exposure on juvenile sockeye salmon: From cells to performance. Environmental Toxicology and Chemistry, 2016; DOI: 10.1002/etc.3533


Source: University of Guelph. “Pipelines affect health, fitness of salmon.” ScienceDaily. ScienceDaily, 28 June 2016. <>.

June 27, 2016

University of Cambridge

The way the ocean transported heat, nutrients and carbon dioxide at the peak of the last ice age, about 20,000 years ago, is significantly different than what has previously been suggested, according to two new studies. The findings suggest that the colder ocean circulated at a very slow rate, which enabled it to store much more carbon for much longer than the modern ocean.



The world’s oceans work like a giant conveyor belt, transporting heat, nutrients and gases around the globe. In today’s oceans, warmer waters travel northwards along currents such as the Gulf Stream from the equatorial regions towards the pole, becoming saltier, colder and denser as they go, causing them to sink to the bottom. These deep waters flow into the ocean basins, eventually ending up in the Southern Ocean or the North Pacific Ocean. A complete loop can take as long as 1000 years.
Credit: © manuelbreva / Fotolia



The way the ocean transported heat, nutrients and carbon dioxide at the peak of the last ice age, about 20,000 years ago, is significantly different than what has previously been suggested, according to two new studies. The findings suggest that the colder ocean circulated at a very slow rate, which enabled it to store much more carbon for much longer than the modern ocean.

Using the information contained within the shells of tiny animals known as foraminifera, the researchers, led by the University of Cambridge, looked at the characteristics of the seawater in the Atlantic Ocean during the last ice age, including its ability to store carbon. Since atmospheric CO2 levels during the period were about a third lower than those of the pre-industrial atmosphere, the researchers were attempting to find if the extra carbon not present in the atmosphere was stored in the deep ocean instead.

They found that the deep ocean circulated at a much slower rate at the peak of the last ice age than had previously been suggested, which is one of the reasons why it was able to store much more carbon for much longer periods. That carbon was accumulated as organisms from the surface ocean died and sank into the deep ocean where their bodies dissolved, releasing carbon that was in effect ‘trapped’ there for thousands of years. Their results are reported in two separate papers in Nature Communications.

The ability to reconstruct past climate change is an important part of understanding why the climate of today behaves the way it does. It also helps to predict how the planet might respond to changes made by humans, such as the continuing emission of large quantities of CO2 into the atmosphere.

The world’s oceans work like a giant conveyor belt, transporting heat, nutrients and gases around the globe. In today’s oceans, warmer waters travel northwards along currents such as the Gulf Stream from the equatorial regions towards the pole, becoming saltier, colder and denser as they go, causing them to sink to the bottom. These deep waters flow into the ocean basins, eventually ending up in the Southern Ocean or the North Pacific Ocean. A complete loop can take as long as 1000 years.

“During the period we’re looking at, large amounts of carbon were likely transported from the surface ocean to the deep ocean by organisms as they died, sunk and dissolved,” said Emma Freeman, the lead author of one of the papers. “This process released the carbon the organisms contained into the deep ocean waters, where it was trapped for thousands of years, due to the very slow circulation.”

Freeman and her co-authors used radiocarbon dating, a technique that is more commonly used by archaeologists, in order to determine how old the water was in different parts of the ocean. Using the radiocarbon information from tiny shells of foraminifera, they found that carbon was stored in the slowly-circulating deep ocean.

In a separate study led by Jake Howe, also from Cambridge’s Department of Earth Sciences, researchers studied the neodymium isotopes contained in the foraminifera shells, a method which works like a dye tracer, and came to a similar conclusion about the amount of carbon the ocean was able to store.

“We found that during the peak of the last ice age, the deep Atlantic Ocean was filled not just with southern-sourced waters as previously thought, but with northern-sourced waters as well,” said Howe.

What was previously interpreted to be a layer of southern-sourced water in the deep Atlantic during the last ice age was in fact shown to be a mixture of slowly circulating northern- and southern-sourced waters with a large amount of carbon stored in it.

“Our research looks at a time when the world was much colder than it is now, but it’s still important for understanding the effects of changing ocean circulation,” said Freeman. “We need to understand the dynamics of the ocean in order to know how it can be affected by a changing climate.”

The research was funded in part by the Natural Environment Research Council (NERC), the Royal Society and the Isaac Newton Trust.

Story Source:

The above post is reprinted from materials provided by University of Cambridge. Note: Materials may be edited for content and length.

Journal References:

  1. Jacob N. W. Howe, Alexander M. Piotrowski, Taryn L. Noble, Stefan Mulitza, Cristiano M. Chiessi, Germain Bayon. North Atlantic Deep Water Production during the Last Glacial Maximum. Nature Communications, 2016; 7: 11765 DOI: 10.1038/ncomms11765
  2. E. Freeman, L. C. Skinner, C. Waelbroeck, D. Hodell. Radiocarbon evidence for enhanced respired carbon storage in the Atlantic at the Last Glacial Maximum. Nature Communications, 2016; 7: 11998 DOI: 10.1038/ncomms11998


Source: University of Cambridge. “Super-slow circulation allowed world’s oceans to store huge amounts of carbon during last ice age.” ScienceDaily. ScienceDaily, 27 June 2016. <>.

DIA Annual Meeting – 2016


We are in Booth 1743 this year in Philadelphia so please stop by and have a seat on our couches.


Rhododendron Fireworks Sunset at Roan – James Farley Photography


A couple weeks ago, James Farley, photographer extraordinaire, took a couple days off and traveled to Roan Mountain, on the North Carolina / Tennessee border, to capture the Rhododendrons and Flame Azaleas in peak bloom. Here are the rhododendrons. These shots are taken with his Canon 5D Mark III and 17mm Tilt-Shift lens. The Sunset photo each 5 bracketed shots merged into high dynamic range photos.



Rhododendron Fireworks Sunset at Roan – ©James Farley Photography



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Joyce Hays, Founder and Editor in Chief of On Target

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Administering AnesthesiaSource: Wikipedia Commons



Anesthesia is broken down into three main categories: general, regional, and 1) ___. All of these can be given through various methods using medicines that affect the nervous system. Think of the brain as a central computer that controls all the body’s functions and the nervous 2) ___ as a network that relays messages back and forth from the brain to different parts of the body. It does this via the spinal cord, which runs from the brain down through the backbone and contains threadlike nerves that branch out to every organ and body part. With general anesthesia, the goal is to make and keep the patient completely 3) ___ (or “asleep”) during the operation, with no sensations, feeling of pain, awareness, movement, or memory of the surgery. General anesthesia can be given through an IV (which requires a needle stick into a vein, usually in the arm) or by inhaling gases or vapors. Regional anesthesia is used when an anesthetic drug is injected near a cluster of 4) ___, numbing a larger area of the body (such as below the waist). Most people who are given regional anesthesia are deeply sedated or asleep for the procedure. Rarely, older kids or those might be at risk by being asleep may be awake or lightly sedated for this type of anesthesia. Local anesthesia is an anesthetic drug that numbs only a small, specific part of the body (for example, a hand or patch of skin). Depending on the size of the area, local anesthesia can be given as a shot, spray, or ointment. With local anesthesia, a person may be awake, sedated, or asleep. Local anesthesia is often used for minor surgeries and outpatient procedures (when patients come in for an operation and can go home that same day). If you are having surgery in a clinic or doctor’s office (such as the dentist or dermatologist), this is probably the type of anesthetic that will be used.


The type and amount of anesthesia will be specifically tailored to the patient’s needs and will depend on various factors, including: age and weight, the type and area of the surgery, allergies and current medical condition.

Common side effects are: disorientation, grogginess, confusion when waking up after surgery. Some other common side effects, which should go away fairly quickly, include:


1. Nausea or vomiting, which can usually be alleviated with anti-nausea medication

2. Chills or shakiness

3. Sore throat (if a tube was used to help with breathing)


Anesthesia today is very safe. In very rare cases, anesthesia can cause complications (such as strange heart rhythms, breathing problems, allergic reactions to medications, and even death). The risks depend on the kind of procedure, the condition of the patient, and the type of anesthesia used. Most complications can be prevented by giving the 5) ___ complete information before the surgery about things like:


1. Current and past health (including diseases or conditions such as recent or current colds, or other issues such as snoring or depression)

2. Medications (prescription and over-the-counter), supplements, or herbal remedies the patient is taking

3. Any allergies (especially to foods, medications, or latex)

4. Whether the patient is a smoker, drinks alcohol, or takes any recreational drugs

5. Any previous reactions the patient or any family member has had to anesthesia


To ensure patient safety during the surgery or procedure, it’s extremely important to answer all of the anesthesiologist’s questions as honestly and thoroughly as possible. Things that may seem harmless could affect patient reaction to the anesthesia. Doctor’s recommendations must be followed about what not to do before the surgery, like eating or drinking (usually nothing after midnight the day before) and discontinue taking herbal supplements or other medications for a certain period of time before surgery. Safety of anesthetic procedures has improved a lot over the years. Very rarely – in only one or two out of every 10,000 medical procedures involving anesthesia – a patient may become aware or 6) ___. The condition – called anesthesia awareness – means the patient can recall the surroundings or an event related to the surgery while under general anesthesia. Although it can be upsetting, patients usually do not feel pain. Certain surgeries or circumstances increase the risk of awareness during surgery because the usual dose of required anesthesia cannot be used safely. These include emergency surgeries – such as C-sections, heart surgery and trauma surgery – as well as when patients have multiple medical conditions. Physician anesthesiologists closely monitor surgeries using sophisticated equipment to ensure that, even in the rare case when awareness occurs, a patient is safe and does not feel 7) ___. A patient who has experienced anesthesia awareness during a procedure, should tell the physician anesthesiologist or health care team as soon as possible. It’s not uncommon for patients to believe they were aware during surgery, when this was not the case. A patient typically remembers the time when the anesthesia has just begun to work but has not completely taken affect, or shortly after surgery, when the anesthesia has not yet worn off, but this is not considered awareness which would take place during the procedure. Patients also are more likely to have awareness with procedures that do not involve general anesthesia. For example, you may recall all or part of your procedure if you have:


1. Intravenous, or “twilight“ sedation, often given during minor procedures such as a colonoscopy, a biopsy or a dental procedure

2. Local or regional anesthesia, such as an epidural or spinal block, or a nerve block


To reduce risk of experiencing awareness during procedures with general anesthesia, it is important to tell the physician anesthesiologist important health information, including:


1. Previous problems with anesthesia, including a history of being aware during surgery

2. All medications being taken, both prescription, over-the-counter and herbal supplements

3. Concerns about surgery, including fear of being aware during surgery


Patients who have experienced anesthesia awareness during a procedure can get counseling to help ease any feelings of confusion, stress or trauma.


As scientists learn more about the molecular mechanisms by which anesthetics cause their various effects, they will be able to design agents that are more targeted, more effective and safer, with fewer side effects. Observations of the short- and long-term effects of anesthetics on subsets of the population, such as the elderly or cancer survivors, will reveal whether certain anesthetics are better than others for members of those groups. Research on how a person’s genetic makeup influences the way he or she responds to anesthetics will enable doctors to further tailor anesthesia to individual patients.


Spinal and 8) ___ anesthesia are medicines that numb parts of the body to block pain. They are given through shots in or around the spine. Doctors who administer epidural or spinal anesthesia are anesthesiologists. First, the area of the back where the needle is inserted, is cleaned with a special solution. The area may also be numbed with a local anesthetic. Fluids will be received, through an intravenous line (IV) in a vein. You may receive medicine through the IV to help you relax or sleep lightly. For an epidural:


1. The doctor injects medicine just outside of the sac of fluid around the spinal cord. This is called the epidural space.

2. The medicine numbs, or blocks feeling, in a certain part of the body so that pain cannot be felt. The medicine begins to take effect in about 10 to 20 minutes. It works well for longer procedures. Women often have an epidural during childbirth.

3. A small tube (catheter) is often left in place. You can receive more medicine through the catheter to help control your pain during or after your procedure.


For a spinal:


1. The doctor injects medicine into the fluid of the spinal cord. This is usually done only once, so that a catheter will not need to be placed.

2. The medicine begins to take effect right away. It works well for shorter and simpler procedures.


Your pulse, blood pressure and oxygen level in your blood are checked during the procedure. After the procedure, you will have a bandage where the needle was inserted. Spinal and epidural anesthesia have fewer side effects and risks than general anesthesia (asleep and pain-free). Patients usually recover their senses much faster. Sometimes, they have to wait for the anesthetic to wear off so they can walk. Spinal anesthesia is often used for genital, urinary tract, or lower body procedures. Epidural anesthesia is often used during labor and delivery, and surgery in the pelvis and legs. Epidural and spinal anesthesia are often used when:


1. The procedure or labor is too painful without any pain medicine.

2. The procedure is in the belly, legs, or feet.

3. The body can remain in a comfortable position during the procedure.

4. You want fewer systemic side effects and a shorter recovery than you would have from general anesthesia.


With aging, the more likely it is to have surgery for a health condition such as clogged heart arteries or an arthritic knee. So it’s no surprise that more than one in 10 people who have surgery are 65 or older. Advanced age can affect the potential for surgery risks (although the patient’s medical condition type of surgery, play the major role). One concern is that the aging brain is more vulnerable to anesthesia, which prevents you from feeling pain during surgery. Two anesthesia-related surgery risks particularly in older people are:


Postoperative delirium – This temporary condition may not develop until a few days after surgery, when a patient may be confused, disoriented, have problems with memory and paying attention and is not aware of the surrounding environment. It is common, may come and go, and usually disappears after about a week.


Postoperative cognitive dysfunction (POCD) – This condition can be serious and lead to long-term 9) ___ loss and lessened ability to learn, concentrate and think. Because some of these problems are common in the elderly, the only way to determine if a patient actually suffers POCD is to conduct a mental test before surgery. Thankfully, researchers have learned about these conditions and know how to prevent or reduce the effects and anesthesia is safer today than ever before. To ensure anesthesia-related safety during surgery and decrease risk of cognitive delirium or dysfunction, plan ahead.


1. Request that a physician anesthesiologist who specializes in geriatric patients lead the anesthesia care.

2. Ask the physician to conduct a pre-surgery cognitive test – an assessment of mental function. The physician can then use that as a baseline for comparison after surgery.

3. Be sure the caregiver who spends the most time with the patient, carefully observes physical and mental activity after surgery. If anything troubling occurs, it should be reported to the physician. The physician should be consulted before taking medications after surgery that can affect the nervous system, such as drugs for anxiety, seizures, muscle spasms and difficulty falling asleep.


During surgery the physician anesthesiologist closely monitors the anesthesia to prevent problems. But there are things that can help re-orient you after surgery and reduce confusion or disorientation. Doctors recommend having a family member stay with a patient as they recover from any surgery. While conscious sedation is usually safe, however, if a patient is given too much of the medicine, problems with 10) ___ may occur. Therefore, a health care provider will be watching you during the whole procedure. Providers always have special equipment to help with breathing, if needed, and only certain qualified health professionals can provide conscious sedation.


NIGMS is a part of the National Institutes of Health that supports basic research to increase our understanding of biological processes and lay the foundation for advances in disease diagnosis, treatment and prevention. For more information on the Institute’s research and training programs, see . Sources:; reviewed by: Judith A. Jones, MD; Mayo Date reviewed: September 2015


ANSWERS: 1) local; 2) system; 3) unconscious; 4) nerves; 5) anesthesiologist; 6) conscious; 7) pain; 8) epidural; 9) memory; 10) breathing




Opium Poppy; Source: Wikipedia Commons



Re-enactment of the first public demonstration of general anesthesia by William T. G. Morton on October 16, 1846 in the Ether Dome at Massachusetts General Hospital, Boston. Surgeons John Collins Warren and Henry Jacob Bigelow are included in this daguerrotype by Southworth & Hawes. Source: Wikipedia Commons



The word “anesthesia“, coined by Gregory Heffely (1809-1894) in 1846 from the Greek “without“; and “sensation“), refers to the inhibition of sensation.


Attempts at producing a state of general anesthesia can be traced throughout recorded history in the writings of the ancient Sumerians, Babylonians, Assyrians, Egyptians, Greeks, Romans, Indians and Chinese. During the Middle Ages, scientists and other scholars made significant advances in science and medicine. The Renaissance saw significant advances in anatomy and surgical technique. However, despite progress, surgery remained a treatment of last resort. Largely because of the associated pain, many patients with surgical disorders chose certain death rather than undergo surgery. Although there has been a great deal of debate as to who deserves the most credit for the discovery of general anesthesia, it is basically agreed that certain scientific discoveries in the late 18th and early 19th centuries were critical to the eventual introduction and development of modern anesthetic techniques. Two “quantum leaps“ occurred in the late 19th century, which together allowed the transition to modern surgery. An appreciation of the germ theory of disease led rapidly to the development and application of antiseptic techniques in surgery. Antisepsis, which soon gave way to asepsis, reduced the overall morbidity and mortality of surgery to a far more acceptable rate than in previous eras. Concurrent with these developments were the significant advances in pharmacology and physiology which led to the development of general anesthesia and the control of pain. In the 20th century, the safety and efficacy of general anesthesia was improved by the routine use of tracheal intubation and other advanced airway management techniques. Significant advances in monitoring and new anesthetic agents with improved pharmacokinetic and pharmacodynamic characteristics also contributed to this trend. Standardized training programs for anesthesiologists and nurse anesthetists emerged during this period. The increased application of economic and business administration principles to health care in the late 20th and early 21st centuries led to the introduction of management practices such as transfer pricing to improve the efficiency of anesthetists.


The first attempts at general anesthesia were probably herbal remedies administered in prehistory. Alcohol is the oldest known sedative; it was used in ancient Mesopotamia thousands of years ago. The Sumerians are said to have cultivated and harvested the opium poppy (Papaver somniferum) in lower Mesopotamia as early as 3400 BCE, though this has been disputed. The most ancient testimony concerning the opium poppy found to date was inscribed in cuneiform script on a small white clay tablet at the end of the third millennium BCE. This tablet was discovered in 1954 during excavations at Nippur, and is currently kept at the University of Pennsylvania Museum of Archaeology and Anthropology. Deciphered by Samuel Noah Kramer and Martin Leve, it is considered to be the most ancient pharmacopoeia in existence. Some Sumerian tablets of this era have an ideogram inscribed upon them, “hul gil“, which translates to “plant of joy“, believed by some authors to refer to opium. The term gil is still used for opium in certain parts of the world. The Sumerian goddess Nidaba is often depicted with poppies growing out of her shoulders. About 2225 BCE, the Sumerian territory became a part of the Babylonian empire. Knowledge and use of the opium poppy and its euphoric effects thus passed to the Babylonians, who expanded their empire eastwards to Persia and westwards to Egypt, thereby extending its range to these civilizations. British archaeologist and cuneiformist Reginald Campbell Thompson writes that opium was known to the Assyrians in the 7th century BCE. The term “Arat Pa Pa“ occurs in the Assyrian Herbal, a collection of inscribed Assyrian tablets dated to c. 650 BCE. According to Thompson, this term is the Assyrian name for the juice of the poppy and it may be the etymological origin of the Latin “papaver“.


The ancient Egyptians had some surgical instruments, as well as crude analgesics and sedatives, including possibly an extract prepared from the mandrake fruit. The use of preparations similar to opium in surgery is recorded in the Ebers Papyrus, an Egyptian medical papyrus written in the Eighteenth dynasty. However, it is questionable whether opium itself was known in ancient Egypt. The Greek gods Hypnos (Sleep), Nyx (Night), and Thanatos (Death) were often depicted holding poppies. Prior to the introduction of opium to ancient India and China, these civilizations pioneered the use of cannabis incense and aconitum. c. 400 BCE, the Sushruta Samhita (a text from the Indian subcontinent on ayurvedic medicine and surgery) advocates the use of wine with incense of cannabis for anesthesia. By the 8th century CE, Arab traders had brought opium to India and China.


Bian Que (Chinese: c. 300 BCE) was a legendary Chinese internist and surgeon who reportedly used general anesthesia for surgical procedures. It is recorded in the Book of Master Han Fei (c. 250 BCE), the Records of the Grand Historian (c. 100 BCE), and the Book of Master Lie (c. CE 300) that Bian Que gave two men, named “Lu“ and “Chao“, a toxic drink which rendered them unconscious for three days, during which time he performed a gastrostomy upon them. Hua Tuo (Chinese: c. CE 145-220) was a Chinese surgeon of the 2nd century CE. According to the Records of Three Kingdoms (c. CE 270) and the Book of the Later Han (c. CE 430), Hua Tuo performed surgery under general anesthesia using a formula he had developed by mixing wine with a mixture of herbal extracts he called mafeisan. Hua Tuo reportedly used mafeisan to perform even major operations such as resection of gangrenous intestines. Before the surgery, he administered an oral anesthetic potion, probably dissolved in wine, in order to induce a state of unconsciousness and partial neuromuscular blockade. The exact composition of mafeisan, similar to all of Hua Tuo’s clinical knowledge, was lost when he burned his manuscripts, just before his death. The composition of the anesthetic powder was not mentioned in either the Records of Three Kingdoms or the Book of the Later Han. Because Confucian teachings regarded the body as sacred and surgery was considered a form of body mutilation, surgery was strongly discouraged in ancient China. Because of this, despite Hua Tuo’s reported success with general anesthesia, the practice of surgery in ancient China ended with his death. The name mafeisan combines ma (meaning “cannabis, hemp, numbed or tingling“), fei (meaning “boiling or bubbling“), and san (meaning “to break up or scatter“, or “medicine in powder form“). Therefore, the word mafeisan probably means something like “cannabis boil powder“. Many sinologists and scholars of traditional Chinese medicine have guessed at the composition of Hua Tuo’s mafeisan powder, but the exact components still remain unclear. His formula is believed to have contained some combination of:


1. bai zhi (Angelica dahurica),

2. cao wu (Aconitum kusnezoffii, Aconitum kusnezoffii, Kusnezoff’s monkshood, or wolfsbane root),

3. chuan xiong (Ligusticum wallichii, or Szechuan lovage),

4. dong quai (Angelica sinensis, or “female ginseng“),

5. wu tou (Aconitum carmichaelii, rhizome of Aconitum, or Chinese monkshood“),

6. yang jin hua (Flos Daturae metelis, or Datura stramonium, jimson weed, devil’s trumpet, thorn apple, locoweed, moonflower),

7. ya pu lu (Mandragora officinarum)

8. rhododendron flower, and

9. jasmine root.


Others have suggested the potion may have also contained hashish, bhang, shang-luh, or opium. Victor H. Mair wrote that mafei “appears to be a transcription of some Indo-European word related to “morphine“.“ Some authors believe that Hua Tuo may have discovered surgical analgesia by acupuncture, and that mafeisan either had nothing to do with or was simply an adjunct to his strategy for anesthesia. Many physicians have attempted to re-create the same formulation based on historical records but none have achieved the same clinical efficacy as Hua Tuo’s. In any event, Hua Tuo’s formula did not appear to be effective for major operations.


Other substances used from antiquity for anesthetic purposes include extracts of juniper and coca. Arabic and Persian physicians may have utilized oral as well as inhaled anesthetics. Ferdowsi (940-1020) was a Persian poet who lived in the Abbasid Caliphate. In Shahnameh, his national epic poem, Ferdowsi described a caesarean section performed on Rudaba. A special wine prepared by a Zoroastrian priest was used as an anesthetic for this operation. Although Shahnameh is fictional, the passage nevertheless supports the idea that general anesthesia had at least been described in ancient Persia, even if not successfully implemented. In 1000, Abu al-Qasim al-Zahrawi (936-1013) and Ibn Sina (980-1037), Arab physicians, described the use of inhaled anesthesia using the “soporific sponge“, a sponge imbued with aromatics and narcotics, which was to be placed under a patient’s nose during surgical operations. Opium made its way from Asia Minor to all parts of Europe between the 10th and 13th centuries.


Throughout 1200 – 1500 CE in England, a potion called dwale was used as an anesthetic. This mixture contained bile, opium, lettuce, bryony, and hemlock. Surgeons roused them by rubbing vinegar and salt on their cheekbones. One can find records of dwale in numerous literary sources, including Shakespeare’s Hamlet, and the John Keats poem Ode to a Nightingale. In the 13th century, we have the first prescription of the “spongia soporifica“ – a sponge soaked in the juices of unripe mulberry, flax, mandragora leaves, ivy, lettuce seeds, lapathum, and hemlock with hyoscyamus. After treatment and/or storage, the sponge could be heated and the vapors inhaled with anesthetic effect. Aureolus Theophrastus Bombastus von Hohenheim (1493-1541), better known as Paracelsus, discovered the analgesic properties of diethyl ether around 1525. It was first synthesized in 1540 by Valerius Cordus, who noted some of its medicinal properties. He called it oleum dulce vitrioli, a name that reflects the fact that it is synthesized by distilling a mixture of ethanol and sulfuric acid (known at that time as oil of vitriol). August Sigmund Frobenius gave the name Spiritus Vini AEthereus to the substance in 1730. Joseph Priestley (1733-1804) was an English polymath who discovered nitrous oxide, nitric oxide, ammonia, hydrogen chloride and (along with Carl Wilhelm Scheele and Antoine Lavoisier) oxygen. Beginning in 1775, Priestley published his research in Experiments and Observations on Different Kinds of Air, a six-volume work. The recent discoveries about these and other gases stimulated a great deal of interest in the European scientific community. Thomas Beddoes (1760-1808) was an English philosopher, physician and teacher of medicine, and like his older colleague Priestley, was also a member of the Lunar Society of Birmingham. With an eye toward making further advances in this new science as well as offering treatment for diseases previously thought to be untreatable (such as asthma and tuberculosis), Beddoes founded the Pneumatic Institution for inhalation gas therapy in 1798 at Dowry Square in Clifton, Bristol. Beddoes employed chemist and physicist Humphry Davy(1778-1829) as superintendent of the institute, and engineer James Watt (1736-1819) to help manufacture the gases. Other members of the Lunar Society such as Erasmus Darwin and Josiah Wedgwood were also actively involved with the institute. During the course of his research at the Pneumatic Institution, Davy discovered the anesthetic properties of nitrous oxide. Davy, who coined the term “laughing gas“ for nitrous oxide, published his findings the following year in the now-classic treatise: Researches, chemical and philosophical-chiefly concerning nitrous oxide or dephlogisticated nitrous air, and its respiration. Davy was not a physician, and he never administered nitrous oxide during a surgical procedure. He was however the first to document the analgesic effects of nitrous oxide, as well as its potential benefits in relieving pain during surgery:


“As nitrous oxide in its extensive operation appears capable of destroying physical pain, it may probably be used with advantage during surgical operations in which no great effusion of blood takes place.“


Hanaoka Seishu (1760-1835) of Osaka was a Japanese surgeon of the Edo period with a knowledge of Chinese herbal medicine, as well as Western surgical techniques he had learned through Rangaku (literally “Dutch learning“, and by extension “Western learning“). Beginning in about 1785, Hanaoka embarked on a quest to re-create a compound that would have pharmacologic properties similar to Hua Tuo’s mafeisan. After years of research and experimentation, he finally developed a formula which he named tsusensan (also known as mafutsu-san). Like that of Hua Tuo, this compound was composed of extracts of several different plants, including:2 parts bai zhi (Angelica dahurica)


2 parts cao wu (Aconitum sp.monkshood or wolfsbane);

2 parts chuan ban xia (Pinellia ternata);

2 parts chuan xiong (Ligusticum wallichiiCnidium rhizomeCnidium officinale or Szechuan lovage);

2 parts dong quai (Angelica sinensis or female ginseng);

1 part tian nan xing (Arisaema rhizomatum or cobra lily)

8 parts yang jin hua (Datura stramoniumKorean morning glorythorn applejimson weeddevil’s trumpetstinkweed, or locoweed).


Five of these seven ingredients were thought to be elements of Hua Tuo’s anesthetic potion, 1600 years earlier. Some sources claim that Angelica archangelica (often referred to as garden angelica, holy ghost, or wild celery) was also an ingredient. The active ingredients in tsusensan are scopolamine, hyoscyamine, atropine, aconitine and angelicotoxin. When consumed in sufficient quantity, tsusensan produces a state of general anesthesia and skeletal muscle paralysis. Shutei Nakagawa (1773-1850), a close friend of Hanaoka, wrote a small pamphlet entitled “Mayaku-ko“ (“narcotic powder“) in 1796. Although the original manuscript was lost in a fire in 1867, this brochure described the current state of Hanaoka’s research on general anesthesia. On 13 October 1804, Hanaoka performed a partial mastectomy for breast cancer on a 60-year-old woman named Kan Aiya, using tsusensan as a general anesthetic. This is generally regarded today as the first reliable documentation of an operation to be performed under general anesthesia. Hanaoka went on to perform many operations using tsusensan, including resection of malignant tumors, extraction of bladder stones, and extremity amputations. Before his death in 1835, Hanaoka performed more than 150 operations for breast cancer. Friedrich Serturner (1783-1841) first isolated morphine from opium in 1804; he named it morphine after Morpheus, the Greek god of dreams. Henry Hill Hickman (1800-1830) experimented with the use of carbon dioxide as an anesthetic in the 1820s. He would make the animal insensible, effectively via almost suffocating it with carbon dioxide, then determine the effects of the gas by amputating one of its limbs. In 1824, Hickman submitted the results of his research to the Royal Society in a short treatise entitled Letter on suspended animation: with the view of ascertaining its probable utility in surgical operations on human subjects. The response was an 1826 article in The Lancet titled ‘Surgical Humbug’ that ruthlessly criticized his work. Hickman died four years later at age 30. Though he was unappreciated at the time of his death, his work has since been positively reappraised and he is now recognized as one of the fathers of anesthesia.


By the late 1830s, Humphry Davy’s experiments had become widely publicized within academic circles in the northeastern United States. Wandering lecturers would hold public gatherings, referred to as “ether frolics“, where members of the audience were encouraged to inhale diethyl ether or nitrous oxide to demonstrate the mind-altering properties of these agents while providing much entertainment to onlookers. Four notable men participated in these events and witnessed the use of ether in this manner. They were William Edward Clarke (1819-1898), Crawford W. Long(1815-1878), Horace Wells (1815-1848), and William T. G. Morton (1819-1868). While attending undergraduate school in Rochester, New York in 1839, classmates Clarke and Morton apparently experimented with ether with some regularity. In January 1842, by now a medical student at Berkshire Medical College, Clarke administered ether to a Miss Hobbie, while Elijah Pope performed a dental extraction. In so doing, he became the first to administer an inhaled anesthetic to facilitate the performance of a surgical procedure. Clarke apparently thought little of his accomplishment, and chose neither to publish nor to pursue this technique any further. This event is not even mentioned in Clarke’s biography. Crawford W. Long was a physician and pharmacist practicing in Jefferson, Georgia in the mid-19th century. During his time as a student at the University of Pennsylvania School of Medicine in the late 1830s, he had observed and probably participated in the ether frolics that had become popular at that time. At these gatherings, Long observed that some participants experienced bumps and bruises, but afterward had no recall of what had happened. He postulated that that diethyl ether produced pharmacologic effects similar to those of nitrous oxide. On 30 March 1842, he administered diethyl ether by inhalation to a man named James Venable, in order to remove a tumor from the man’s neck. Long later removed a second tumor from Venable, again under ether anesthesia. He went on to employ ether as a general anesthetic for limb amputations and parturition. Long however did not publish his experience until 1849, thereby denying himself much of the credit he deserved.


On 10 December 1844, Gardner Quincy Colton held a public demonstration of nitrous oxide in Hartford, Connecticut. One of the participants, Samuel A. Cooley, sustained a significant injury to his leg while under the influence of nitrous oxide without noticing the injury. Horace Wells, a Connecticut dentist present in the audience that day, immediately seized upon the significance of this apparent analgesic effect of nitrous oxide. The following day, Wells underwent a painless dental extraction while under the influence of nitrous oxide administered by Colton. Wells then began to administer nitrous oxide to his patients, successfully performing several dental extractions over the next couple of weeks. William T. G. Morton, another New England dentist, was a former student and then-current business partner of Wells. He was also a former acquaintance and classmate of William Edward Clarke (the two had attended undergraduate school together in Rochester, New York). Morton arranged for Wells to demonstrate his technique for dental extraction under nitrous oxide general anesthesia at Massachusetts General Hospital, in conjunction with the prominent surgeon John Collins Warren. This demonstration, which took place on 20 January 1845, ended in failure when the patient cried out in pain in the middle of the operation. On 30 September 1846, Morton administered diethyl ether to Eben Frost, a music teacher from Boston, for a dental extraction. Two weeks later, Morton became the first to publicly demonstrate the use of diethyl ether as a general anesthetic at Massachusetts General Hospital, in what is known today as the Ether Dome. On 16 October 1846, John Collins Warren removed a tumor from the neck of a local printer, Edward Gilbert Abbott. Upon completion of the procedure, Warren reportedly quipped, “Gentlemen, this is no humbug.“ News of this event rapidly traveled around the world. Robert Liston performed the first amputation in December of that year. Morton published his experience soon after. Harvard University professor Charles Thomas Jackson (1805-1880) later claimed that Morton stole his idea; Morton disagreed and a lifelong dispute began. For many years, Morton was credited as being the pioneer of general anesthesia in the Western hemisphere, despite the fact that his demonstration occurred four years after Long’s initial experience. Long later petitioned William Crosby Dawson (1798-1856), a United States Senator from Georgia at that time, to support his claim on the floor of the United States Senate as the first to use ether anesthesia.


In 1847, Scottish obstetrician James Young Simpson (1811-1870) of Edinburgh was the first to use chloroform as a general anesthetic. The use of chloroform anesthesia expanded rapidly thereafter in Europe. Chloroform began to replace ether as an anesthetic in the United States at the beginning of the 20th century. It was soon abandoned in favor of ether when its hepatic and cardiac toxicity, especially its tendency to cause potentially fatal cardiac dysrhythmias, became apparent. In 1871, the German surgeon Friedrich Trendelenburg (1844-1924) published a paper describing the first successful elective human tracheotomy to be performed for the purpose of administration of general anesthesia. In 1880, the Scottish surgeon William Macewen (1848-1924) reported on his use of orotracheal intubation as an alternative to tracheotomy to allow a patient with glottic edema to breathe, as well as in the setting of general anesthesia with chloroform. All previous observations of the glottis and larynx (including those of Manuel Garc?a, Wilhelm Hack and Macewen) had been performed under indirect vision (using mirrors) until 23 April 1895, when Alfred Kirstein (1863-1922) of Germany first described direct visualization of the vocal cords. Kirstein performed the first direct laryngoscopy in Berlin, using an esophagoscope he had modified for this purpose; he called this device an autoscope. The death of Emperor Frederick III (1831-1888) may have motivated Kirstein to develop the autoscope.


The 20th century saw the transformation of the practices of tracheotomy, endoscopy and non-surgical tracheal intubation from rarely employed procedures to essential components of the practices of anesthesia, critical care medicine, emergency medicine, gastroenterology, pulmonology and surgery. In 1902, Hermann Emil Fischer (1852-1919) and Joseph von Mering (1849-1908) discovered that diethylbarbituric acid was an effective hypnotic agent. Also called barbital or Veronal (the trade name assigned to it by Bayer Pharmaceuticals), this new drug became the first commercially marketed barbiturate; it was used as a treatment for insomnia from 1903 until the mid-1950s. Until 1913, oral and maxillofacial surgery was performed by mask inhalation anesthesia, topical application of local anesthetics to the mucosa, rectal anesthesia, or intravenous anesthesia. While otherwise effective, these techniques did not protect the airway from obstruction and also exposed patients to the risk of pulmonary aspiration of blood and mucus into the tracheobronchial tree. In 1913, Chevalier Jackson (1865-1958) was the first to report a high rate of success for the use of direct laryngoscopy as a means to intubate the trachea. Jackson introduced a new laryngoscope blade that had a light source at the distal tip, rather than the proximal light source used by Kirstein. This new blade incorporated a component that the operator could slide out to allow room for passage of an endotracheal tube or bronchoscope. Also in 1913, Henry H. Janeway (1873-1921) published results he had achieved using a laryngoscope he had recently developed. An American anesthesiologist practicing at Bellevue Hospital in New York City, Janeway was of the opinion that direct intratracheal insufflation of volatile anesthetics would provide improved conditions for otolaryngologic surgery. With this in mind, he developed a laryngoscope designed for the sole purpose of tracheal intubation. Similar to Jackson’s device, Janeway’s instrument incorporated a distal light source. Unique however was the inclusion of batteries within the handle, a central notch in the blade for maintaining the tracheal tube in the midline of the oropharynx during intubation and a slight curve to the distal tip of the blade to help guide the tube through the glottis. The success of this design led to its subsequent use in other types of surgery. Janeway was thus instrumental in popularizing the widespread use of direct laryngoscopy and tracheal intubation in the practice of anesthesiology.


Sodium thiopental, the first intravenous anesthetic, was synthesized in 1934 by Ernest H. Volwiler (1893-1992) and Donalee L. Tabern (1900-1974), working for Abbott Laboratories. It was first used in humans on 8 March 1934 by Ralph M. Waters in an investigation of its properties, which were short-term anesthesia and surprisingly little analgesia. Three months later, John Silas Lundy started a clinical trial of thiopental at the Mayo Clinic at the request of Abbott Laboratories. Volwiler and Tabern were awarded U.S. Patent No. 2,153,729 in 1939 for the discovery of thiopental, and they were inducted into the National Inventors Hall of Fame in 1986. In 1939, the search for a synthetic substitute for atropine culminated serendipitously in the discovery of meperidine, the first opiate with a structure altogether different from that of morphine. This was followed in 1947 by the widespread introduction of methadone, another structurally unrelated compound with pharmacological properties similar to those of morphine. After World War I, further advances were made in the field of intratracheal anesthesia. Among these were those made by Sir Ivan Whiteside Magill (1888-1986). Working at the Queen’s Hospital for Facial and Jaw Injuries in Sidcup with plastic surgeon Sir Harold Gillies (1882-1960) and anesthetist, E. Stanley Rowbotham (1890-1979), Magill developed the technique of awake blind nasotracheal intubation. Magill devised a new type of angulated forceps (the Magill forceps) that are still used today to facilitate nasotracheal intubation in a manner that is little changed from Magill’s original technique. Other devices invented by Magill include the Magill laryngoscope blade, as well as several apparatuses for the administration of volatile anesthetic agents. The Magill curve of an endotracheal tube is also named for Magill.


The first hospital anesthesia department was established at the Massachusetts General Hospital in 1936, under the leadership of Henry K. Beecher(1904-1976). Sir Robert Reynolds Macintosh (1897-1989) achieved significant advances in techniques for tracheal intubation when he introduced his new curved laryngoscope blade in 1943. The Macintosh blade remains to this day the most widely used laryngoscope blade for orotracheal intubation. In 1949, Macintosh published a case report describing the novel use of a gum elastic urinary catheter as an endotracheal tube introducer to facilitate difficult tracheal intubation. Inspired by Macintosh’s report, P. Hex Venn (who was at that time the anesthetic advisor to the British firm Eschmann Bros. & Walsh, Ltd.) set about developing an endotracheal tube introducer based on this concept. Venn’s design was accepted in March 1973, and what became known as the Eschmann endotracheal tube introducer went into production later that year. The material of Venn’s design was different from that of a gum elastic bougie in that it had two layers: a core of tube woven from polyester threads and an outer resin layer. This provided more stiffness but maintained the flexibility and the slippery surface. Other differences were the length (the new introducer was 60 cm (24 in), which is much longer than the gum elastic bougie) and the presence of a 35? curved tip, permitting it to be steered around obstacles.


Many new intravenous and inhalational anesthetics were developed and brought into clinical use during the second half of the 20th century. Paul Janssen (1926-2003), the founder of Janssen Pharmaceutica, is credited with the development of over 80 pharmaceutical compounds. Janssen synthesized nearly all of the butyrophenone class of antipsychotic agents, beginning with haloperidol (1958) and droperidol (1961). These agents were rapidly integrated into the practice of anesthesia. In 1960, Janssen’s team synthesized fentanyl, the first of the piperidinone-derived opioids. Fentanyl was followed by sufentanil (1974), alfentanil (1976), carfentanil (1976), and lofentanil (1980). Janssen and his team also developed etomidate (1964), a potent intravenous anesthetic induction agent.


The concept of using a fiberoptic endoscope for tracheal intubation was introduced by Peter Murphy, an English anesthetist, in 1967. By the mid-1980s, the flexible fiberoptic bronchoscope had become an indispensable instrument within the pulmonology and anesthesia communities. The “digital revolution“ of the 21st century has brought newer technology to the art and science of tracheal intubation. Several manufacturers have developed video laryngoscopes which employ digital technology such as the complementary metal-oxide semiconductor active pixel sensor (CMOS APS) to generate a view of the glottis so that the trachea may be intubated. The Glidescope video laryngoscope is one example of such a device. Xenon has been used as a general anesthetic. Although it is expensive, pneumatically close breathing system anesthesia machines (stepahan akzent x color trolly) that can deliver xenon are available on the world market, because of a completely closed breathing system. Recycling of xenon have made it economically viable. Several countries: Russia, Ukraine, Moldavia, Kazakhstan, Kyrghistan, the EU, USA and Japan, have been using Xenon for the last 5 years and more. Xenon therapy is also used for stress, insomnia, psychosomatic disorders, cardiovascular diseases, strokes, pain syndromes, drug and alcohol addiction.


Manufactured Stem Cells to Advance Clinical Research


The NIH has developed a clinical-grade stem cell line, which has the potential to accelerate the advance of new medical applications and cell-based therapies for millions of people suffering from such ailments as Alzheimer’s disease, Parkinson’s disease, spinal cord injury, diabetes, and muscular dystrophy. The stem cells were developed by isolating human umbilical cord blood cells following a healthy birth, and coaxing them back into a pluripotent state, or one in which they have the potential to develop into any cell type in the body. Cells developed in this manner are called induced pluripotent stem cells (iPSCs). With NIH support, these cells are being manufactured by Lonza, Walkersville, Maryland, and described in a publication in Stem Cell Reports (2015;5:647-659). These clinical-grade stem cells are different from the more common laboratory-grade cells – those used in most scientific publications – because unlike laboratory-grade stem cells, clinical-grade stem cells can be used for clinical applications in humans. The distinctive feature of this cell line is that it was developed under current good manufacturing practices (cGMP), a set of stringent regulations enforced by the U.S. Food and Drug Administration which ensures each batch of cells produced will meet quality and safety standards required for potential clinical use. The NIH Common Fund’s Regenerative Medicine program supported the manufacturing of this cell line. The NIH Common Fund encourages collaboration and supports a series of exceptionally high-impact, trans-NIH programs. Common Fund programs are designed to pursue major opportunities and gaps in biomedical research that no single NIH Institute could tackle alone, but that the agency as a whole can address to make the biggest impact possible on the progress of medical research.


Significant progress with stem cell therapy in mice is already underway. Researchers have reversed diabetic conditions in mice using iPSC-generated insulin-producing cells and have partially restored limb function in mice with spinal cord injuries. Translating these studies into humans is the next challenge, and by making clinical-grade stem cells available, NIH hopes to speed up the development of new stem cell therapies for patients.


The clinical-grade stem cells, as well as research-grade cells cultured from the same cell line, are available for order and will be stored and distributed by the National Institute of Neurological Disorders and Stroke (NINDS) Human Cell and Data Repository (NHCDR)that is supported through a NINDS grant to RUCDR Infinite Biologics at Rutgers University, Piscataway, New Jersey. RUCDR also distributes laboratory-grade cell lines made by the NIH Regenerative Medicine Program. Laboratory-grade cells can be used for research that lays the foundation for eventual use of clinical-grade cells, such as determining the conditions necessary to guide the iPSCs to become specific cell types like neurons, insulin-producing beta-cells, or heart cells.


The Regenerative Medicine Program supported the manufacturing of the clinical-grade stem cell line as part of its mission to serve as a national resource for stem cell science to accelerate the development of new medical applications and cell-based therapies. Another avenue through which the Regenerative Medicine Program is fulfilling its mission is through the Stem Cell Translation Laboratory (SCTL) that is funded by the Common Fund and administered by the NIH’s National Center for Advancing Translational Sciences (NCATS). The aim of the SCTL is to remove barriers that currently impede the therapeutic application of iPSCs, which include the lack of highly reproducible and well-defined procedures required to generate, characterize and differentiate patient-specific iPSCs in a safe fashion for pre-clinical and clinical use. In parallel to developing an integrated stem cell research program within NCATS, the SCTL will soon be soliciting collaborations from the research community in order to address the most pressing impediments towards stem cell therapies.


Association Between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack


In China, there are approximately 3 million new strokes every year, and approximately 30% of them are minor ischemic strokes. TIA is even more common with an estimated 23.9 million occurring in 2010, based on a Chinese national survey. Understanding the relationship between CYP2C19 variants and clinical effect of clopidogrel (Plavix; Bristol-Myers Squibb Co. and Sanofi SA) is critically important to optimize treatment for patients with minor stroke or TIA.


The Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial showed that the combination of clopidogrel with aspirin compared with aspirin alone reduced the risk of stroke among patients with transient ischemic attack (TIA) or minor ischemic stroke who can be treated within 24 hours after the onset of symptoms. Clopidogrel, in combination with aspirin, has become a recommended treatment option for patients with TIA or acute minor stroke. Clopidogrel requires conversion to an active metabolite by hepatic cytochrome p450 (CYP) isoenzymes to exert an antiplatelet effect, and polymorphisms of the CYP2C19 gene (OMIM 124020) have been identified as strong predictors of clopidogrel nonresponsiveness. In the clinical setting the association between CYP2C19 loss-of-function alleles (especially the most common *2 and *3 variants) and clinical efficacy of clopidogrel has been studied extensively with discordant results and Very limited data are available addressing the effect of CYP2C19 variants on clopidogrel efficacy in stroke, especially in Asian populations, in which the rates of stroke incidence and mortality are higher compared with white populations. The prevalence of CYP2C19 loss-of-function variants is also high in Asian populations.


As a result, a study published online in JAMA (23 June 2016) examined the efficacy and safety of dual therapy of clopidogrel and aspirin compared with aspirin alone according to genotype status among patients in the trial. For the study, Three CYP2C19 major alleles (*2, *3, *17) were genotyped among 2933 Chinese patients from 73 sites who were enrolled in the CHANCE trial conducted from January 2, 2010, to March 20, 2012.


For the study, patients with acute minor ischemic stroke or transient ischemic attack in the trial were randomized to treatment with clopidogrel combined with aspirin or to aspirin alone. The primary efficacy outcome was new stroke. The secondary efficacy outcome was a composite of new composite vascular events (ischemic stroke, hemorrhagic stroke, myocardial infarction, or vascular death). Bleeding was the safety outcome.


Among 2933 patients, 1948 (66.4%) were men, with a mean age of 62.4 years. Overall, 1207 patients (41.2%) were noncarriers and 1726 patients (58.8%) were carriers of loss-of-function alleles (*2, *3). After day 90 follow-up, clopidogrel-aspirin reduced the rate of new stroke in the noncarriers but not in the carriers of the loss-of-function alleles (P?=?.02 for interaction; events among noncarriers, 41 (6.7%) with clopidogrel-aspirin vs 74 (12.4%) with aspirin; hazard ratio [HR], 0.51; events among carriers, 80 (9.4%) with clopidogrel-aspirin vs 94 (10.8%) with aspirin; HR, 0.93. Similar results were observed for the secondary composite efficacy outcome (noncarriers: 41 (6.7%) with clopidogrel-aspirin vs 75 (12.5%) with aspirin; HR, 0.50; carriers: 80 (9.4%) with clopidogrel-aspirin vs 95 (10.9%) with aspirin; HR, 0.92; P?=?.02 for interaction). The effect of treatment assignment on bleeding did not vary significantly between the carriers and the noncarriers of the loss-of-function alleles (2.3% for carriers and 2.5% for noncarriers in the clopidogrel-aspirin group vs 1.4% for carriers and 1.7% for noncarriers in the aspirin only group; P?=?.78 for interaction).


According to the authors, among patients with minor ischemic stroke or transient ischemic attack, the use of clopidogrel plus aspirin compared with aspirin alone reduced the risk of a new stroke only in the subgroup of patients who were not carriers of the CYP2C19 loss-of-function alleles. These findings support a role of CYP2C19 genotype in the efficacy of this treatment.


Brexit Means that EMA Must Leave Canary Wharf for New Digs


There will be a regulatory impact on the pharmaceutical industry as a result of Thursday’s vote by the U.K. to leave the European Union. The first is that the European Medicines Agency (EMA), with more than 600 employees and headquartered at Canary Wharf in London, will now have to leave and find a new home even though it moved into its new building just two years ago. Apparently, Italy, Sweden and Denmark have all expressed interest in taking over as host country. Another impact will be on the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) in that it will have to decide if it wants to continue to work alongside EMA, or whether, like the US FDA, will develop its own drug regulatory system. For example, MHRA and EMA currently work closely on facility inspections.


EU Directive 2001/83/EC, which governs medicinal products, requires the UK to implement relevant legislation into national law. Currently, this is done by reference to the European Communities Act of 1972 and through the implementation of the Human Medicines Regulation of 2012. These laws will remain in place unless the UK government decides to change them. One possible solution would be for the MHRA to function like Switzerland’s Swissmedic, where medical products are independently authorized but work with EMA under mutual recognition and sharing agreements. Alternatively, the MHRA could function like Norway, Iceland and Liechtenstein, which are outside the EU, but work with EMA.


Time will tell.


Editor’s note: Here’s hoping that a second, more thoughtful, vote will be taken, in which the previous UK- EU status will remain in place. Global issues, like climate change will be more difficult to address without strong unity among nations.


Mushrooms Stuffed & Baked with Spinach, Tofutti & Parmesan


These were so good, they literally disappeared, the minute I took them out of the oven. ©Joyce Hays, Target Health Inc.


A delicious appetizer with icy white wine, or as a veggie side dish or as a colorful and tasty part of brunch. Not to mention, low calorie. ©Joyce Hays, Target Health Inc.





2 square boxes of fresh baby portabella or white mushrooms

1 container of Tofutti (soy cream cheese)

1 box frozen chopped spinach, thawed, squeezed to drain with paper towels

5 fresh garlic cloves, sliced not squeezed

2 stalks scallion, sliced up to half of the green section

1 teaspoon turmeric

4 Tablespoons truffle oil (white or black)

1 Tablespoon black mustard seeds, toasted

1 cup freshly grated Parmesan cheese

Instead of salt, use two long pieces of anchovy, sliced (in jar or can)

Pinch black pepper

2 Pinches chili flakes

1 squeeze of fresh lemon (the juice), amounting to 1/2 to 1 teaspoon

(Optional) use panko, only if the mixture is too thin and liquidy.

2/3 cup fresh cilantro, chopped

3 Tablespoons white wine (whatever white wine is opened in fridge)

1 or 2 Tablespoons butter



A plethora of healthy, tasty ingredients. ©Joyce Hays, Target Health Inc.





1 Heat oven to 350?F.

Wipe mushrooms to clean with paper towel.

Remove stems from mushroom caps, slice and set aside, to be used later.

Chop everything that needs chopping. Do it all at the same time.



Wipe mushrooms clean. Pull or cut the stems out, so they’re ready to be stuffed. ©Joyce Hays, Target Health Inc.



Chopping cilantro, garlic, scallions, mushroom stems. ©Joyce Hays, Target Health Inc.



In a small frying pan, over medium heat, saute the garlic, scallions, sliced mushroom stems, mustard seeds in a tiny bit of truffle oil. Remove from heat when garlic is golden and mustard seeds have popped (use a cover, so they don’t pop out of the pan).



Starting the saut? process. ©Joyce Hays, Target Health Inc.



Just added the scallions. ©Joyce Hays, Target Health Inc.



In large mixing bowl or food processor: (use the beaters on a slow speed) and mix Tofutti, lemon juice, spinach, 1/2 cup of the Parmesan cheese, the anchovy pieces, pepper, all the spices, the rest of the truffle oil, cilantro, then the warm garlic mixture, until well blended. Add the wine and combine that.



Making the spinach stuffing. ©Joyce Hays, Target Health Inc.



If the mixture seems too thin and liquid-y, add some panko slowly and stir it in, until the mixture is just right to stuff into the mushrooms. Try to use as little Panko as possible.

Use a tiny size spoon and stuff the mixture into the mushroom caps, mounding slightly, the way you would stuff a deviled egg.

Cover a baking sheet with parchment paper and place the mushrooms on the baking sheet.



Stuff the mushrooms with the spinach mixture. ©Joyce Hays, Target Health Inc.



In a small bowl, mix the remaining 1/2 cup Parmesan cheese, with 1 or 2 Tablespoons butter and a sprinkling of panko. Sprinkle this crumb mixture over the filled mushroom caps, pressing lightly.



I used a measuring cup to mix the crumb topping in. ©Joyce Hays, Target Health Inc.



Bake anywhere from 10 to 20 minutes or until thoroughly heated. Wait for the mushrooms to get golden brown on top, then remove from oven.

Each oven is different, so keep your eye on the mushrooms. If the mushrooms are oozing melty cheese and slightly browned, they’re done.

Remove from oven and cool just slightly. Serve right away. These stuffed mushrooms are much better nice and warm, so plan to bake them just before serving.



Here’s one serving of the stuffed mushroom appetizer that we’re having with icy Sauvignon Blanc. ©Joyce Hays, Target Health Inc.



Just out of the oven ©Joyce Hays, Target Health Inc.



This is such a worthwhile investment of time, because you won’t spend much of it, and yet, you will get such delicious results with this mushroom appetizer or veggie side dish, that goes with just about anything. They’re also, a fabulous snack and/or serve for brunch with eggs. Just mushrooms, soy cream cheese and spinach, is all it takes.



Chilled, Cloudy Bay, Sauvignon Blanc from New Zealand ©Joyce Hays, Target Health Inc.



I’ve mentioned how much we love going to the MetOpera for the whole season with their exquisite sounds, the dark mystery, the large scale drama, the sheer beauty of everything. Well, this weekend we went to Greenwich Village, specifically, The Minetta Lane Theater on winding Minetta Lane. This old historic section of New York City is always quaint and charming. As we followed the curve of narrow, cobbled Minetta Lane, it was delightful to pull up to a theater, equally quaint and charming. We had been looking forward to “Himself and Nora,“ a story with music of the great Irish writer, James Joyce and his muse (his wife after 27 years), the lovely Nora. We enjoyed this as much as any production at the MetOpera, and this is one reason why we love the Big Apple so much; there’s so much to love. From the majestic to the charming. What’s your mood? There’s literally a smorgasbord of culture to pick from.


We recommend, Himself and Nora, highly. The acting and singing are amazing. Talent is everywhere. This little theater, like many off-Broadway groups, serves as a lab for Broadway and beyond. We’ve seen many shows that start as experiments in downtown theaters, and end up on the Great White Way.




From Our Table to Yours !


Bon Appetit!


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