Forbes.com, June 29, 2010, by Peter A. Lipson  –  Over a quarter century ago, a young woman was admitted to a New York hospital with fever and agitation. She never walked out. Libby Zion died while under the care of he primary care doctor and two medical residents. The exact cause of death was never identified, but the case led to a forced examination of medical residents’ work hours. This was driven largely by Zion’s father who felt that his daughter had been killed by inexperienced, poorly supervised, and overworked resident physicians.

“You don’t need kindergarten,” he wrote in a New York Times op-ed piece, “to know that a resident working a 36-hour shift is in no condition to make any kind of judgment call — forget about life-and-death.”

It was largely thanks to Zion’s tireless work that in 1989 a bill was passed in New York State limiting resident work hours and requiring senior physicians to be physically present in the hospital. But though you might not need kindergarten to recognize this problem, you do need data. That came later.

Medical residents have traditionally worked long hours, especially in their first (“intern”) year. In fact, they used to “reside” in the hospital, and were universally young, male, and single. Now, graduating medical students are about 48% female, compared to just over 26% in 1982 (although age hasn’t changed much, which sort of surprised me).   The Libby Zion law limited resident work hours to 80 hours per week and 24 hour shifts.  During my internship in Chicago, we would typically work about 32 hours in a row on call and post-call, and call took place every fourth night,  which has long been typical for internal medicine residencies.

In 2003, the Accreditation Council on Graduate Medical Education (ACGME) instituted the first national work hour limitations for residents. These limitations looked very similar to those imposed by NY state. These work hour limitations required significant changes to how hospitals and residencies were run.  Hospitals can only support a certain number of residents, and they count on these residents and the care they provide.  Hospitals have had to reduce the number of patients cared for by residents, and has led to an increase in so-called mid-level providers (physician assistants and nurse practitioners).  And residencies had to find ways to accomplish the same or similar amount of work with the same personnel but with significant time constraints.

Many of these changes involved a more toward “shift work” and night float systems, where residents worked shifts of limited hours throughout a 24 hour day, handing off patients to the next shift.  This creates its own problems for both patients and residents.  There are concerns that shift work may lead to a disruption in continuity of care, since patients are being “handed off” potentially several times a day.  Also, residents are not supposed to be performing functions that are primarily “service” rather than educational.  During the day, residents can break away from clinical duties for educational conferences, but a 11pm-7am shift is all service.

These, and the urgent questions about the safety of both patients and residents were addressed in a comprehensive report released in 2009 by the Institute of Medicine, part of the National Academies.   While it makes sense that long sleep-free work hours might be dangerous to both patients and residents, knowing the data allows us to make proper, evidence-based decisions about these potential problems.

Resident Safety

As medical educators, we have a duty to our residents to ensure not only their education, but their well-being, at least as it relates to work. It is conceivable that long, sleepless work hours may have adverse health effects.  The 2009 IOM report summarizes some of the evidence for fatigue-related injury.  Many of this evidence is readily available through PubMed.  Needle stick injuries, for example, are a relatively common problem and there is evidence that these are related to fatigue.  There is also quite a bit of evidence that medical residents have an elevated risk for falling asleep at traffic lights and being involved in motor vehicle accidents.  And these data are not new.

Patient Safety

Data on patient safety isn’t new either.  A name that pops up again and again in this research is Charles A. Czeisler. He published a study in the New England Journal of Medicine in 2004 showing fairly convincingly that first-year residents in the ICU are at risk of committing significantly more medical errors when working extended shift vs. less onerous ones.  That’s just one good study of many.

Individual errors are inevitable, but as a phenomenon, errors can be reduced significantly, often through simple systems fixes.  One of these fixes is the implementation of reasonable resident work hours.

Denialism?

Responses in the literature and in doctors’ lounges have been tangential and almost intentionally obtuse.  A colleague of mine at another institution has opined that the medical profession is in a state of “institutional denialism” about the effect of long hours on safety and performance.  I don’t think that is unfair.  The evidence on this has existed for years, yet we’ve made only cosmetic adjustments to our training programs.  Even the latest ACGME rules (which take effect in July 2011) fail to address the most significant implications of the problem.  The work hour limitations they mandate will very likely help, but there is a larger systemic problem.  Medical training is lengthy and expensive.  If we’re going to cut back on hours, we need to re-evaluate whether the new hours are sufficient to meet educational needs.  If not, we are going to have to find a way to fund longer training programs and to fund the debt-ridden trainees who will spend extra years not paying their educational debt.    Quick fixes, even smart ones, aren’t going to do the trick.

The Libby Zion case that eventually led to the new work rules was over a quarter century ago.  How long will it take us to create real, comprehensive solutions?

References

Fisman, D., Harris, A., Rubin, M., Sorock, G., & Mittleman, M. (2007). Fatigue Increases the Risk of Injury From Sharp Devices in  Medical Trainees: Results From a Case‐Crossover Study•Infection Control and Hospital Epidemiology, 28 (1), 10-17 DOI: 10.1086/510569

Trinkoff, A., Le, R., Geiger‐Brown, J., & Lipscomb, J. (2007). Work Schedule, Needle Use, and Needlestick Injuries Among Registered  Nurses •Infection Control and Hospital Epidemiology, 28 (2), 156-164 DOI: 10.1086/510785

Steele, M., Ma, O., Watson, W., Thomas, H., & Muelleman, R. (1999). The Occupational Risk of Motor Vehicle Collisions for Emergency Medicine Residents Academic Emergency Medicine, 6 (10), 1050-1053 DOI: 10.1111/j.1553-2712.1999.tb01191.x

Barger LK, Cade BE, Ayas NT, Cronin JW, Rosner B, Speizer FE, Czeisler CA, & Harvard Work Hours, Health, and Safety Group (2005). Extended work shifts and the risk of motor vehicle crashes among interns. The New England journal of medicine, 352 (2), 125-34 PMID: 15647575

Landrigan CP, Rothschild JM, Cronin JW, Kaushal R, Burdick E, Katz JT, Lilly CM, Stone PH, Lockley SW, Bates DW, & Czeisler CA (2004). Effect of reducing interns’ work hours on serious medical errors in intensive care units. The New England journal of medicine, 351 (18), 1838-48 PMID: 15509817

Gaba DM, & Howard SK (2002). Patient safety: fatigue among clinicians and the safety of patients. The New England journal of medicine, 347 (16), 1249-55 PMID: 12393823

Nuckols TK, Bhattacharya J, Wolman DM, Ulmer C, & Escarce JJ (2009). Cost implications of reduced work hours and workloads for resident physicians. The New England journal of medicine, 360 (21), 2202-15 PMID: 19458365

About the author…………

Peter Lipson MD

Peter A. Lipson, MD is a practicing internist and teaching physician in Southeast Michigan. After graduating from Rush Medical College in Chicago, he completed his Internal Medicine residency at Northwestern Memorial Hospital. He currently maintains a private practice, and serves as a teaching physician at a large community hospital. He also maintains an appointment as a Clinical Assistant Professor of Medicine in the Midwestern U.S. A primary goal of his writing is to illuminate the differences between science-based medicine and everything else. His perspective as a primary care physician and his daily interaction with real patients gives him what he hopes is special insight into the current “De-lightenment” in medicine. As new media evolve, pseudo-scientific, deceptive, and immoral health practices become more and more available to patients, making his job all that much more difficult- and all that much more interesting. Disclaimer:The views in all of of Dr. Lipson’s writing are his alone. They do not represent in any way his practice, hospital, employers, or anyone else.

The New York Times, June 29, 2010, by Tara Parker-Pope  –  Does your marriage need therapy? If you’re like most people, the correct answer may well be yes, but your answer is probably no.

In most marriages, one or both partners resist the idea of counseling. Some can’t afford it, or find it inconvenient. And many view therapy as a last resort — something only desperate couples need. Only 19 percent of currently married couples have taken part in marriage counseling; a recent study of divorcing couples found that nearly two-thirds never sought counseling before deciding to end the relationship.

“It seems like we’re even more resistant to thinking about getting help for our relationship than we are for depression or anxiety,” said Brian D. Doss, an assistant psychology professor at the University of Miami. “There’s a strong disincentive to think about your relationship as being in trouble — that’s almost admitting failure by admitting that something isn’t right.”

Marriage counseling does not always work, of course — perhaps because it is so often delayed past the point of no return. One recent study of two types of therapy found that only about half the couples reported long-lasting improvements in their marriages.

So researchers have begun looking for ways (some of them online) to reach couples before a marriage goes off the rails.

One federally financed study is tracking 217 couples taking part in an annual “marriage checkup” that essentially offers preventive care, like an annual physical or a dental exam.

“You don’t wait to see the dentist until something hurts — you go for checkups on a regular basis,” said James V. Córdova, an associate professor of psychology at Clark University in Worcester, Mass., who wrote “The Marriage Checkup” (Jason Aronson, 2009). “That’s the model we’re testing. If people were to bring their marriages in for a checkup on an annual basis, would that provide the same sort of benefit that a physical health checkup would provide?”

Although Dr. Córdova and colleagues are still tallying the data, preliminary findings show that couples who take part in the program do experience improvements in marital quality. By working with couples before they are unhappy, the checkup identifies potentially “corrosive” behaviors and helps couples make small changes in communication style before their problems spiral out of control. (Typical problems include lack of time for sex and blaming a partner for the stresses of child rearing.)

“Couples won’t go to marital therapy with just the one thing that they are struggling with,” Dr. Córdova said. “So they end up struggling in places where the fix might be simple, it’s just that they themselves are blind to it.”

Not surprisingly, some therapists are creating online self-help programs to reach couples before serious problems set in. Dr. Doss and Andrew Christensen, a psychology professor at the University of California, Los Angeles, are recruiting couples at www.OurRelationship.com to study such a program.

The online study, financed by a five-year $1.2 million grant from the National Institute of Child Health and Human Development, will deliver online therapy to 500 couples. It is based on “acceptance therapy,” which focuses on better understanding of a partner’s flaws — a technique described in “Reconcilable Differences” (Guilford Press, 2002), by Dr. Christensen and Neil S. Jacobson.

The method, formally called integrative behavioral therapy, was the subject of one of the largest and longest clinical trials of couples therapy. Over a year, 134 highly distressed married couples in Los Angeles and Seattle received 26 therapy sessions, with follow-up sessions every six months for the next five years.

Half the couples received traditional therapy that focused on better communication and problem solving, while the others took part in a similar program that included acceptance therapy. Five years after treatment, about half the marriages in both groups were significantly improved, according to the study, which appeared in the April issue of The Journal of Consulting and Clinical Psychology. Dr. Christensen says about a third of the subjects could be described as “normal, happy couples,” a significant improvement considering how distressed they were at the start. (The couples who received acceptance therapy had better results after two years, but both types of therapy were about equal by the end of the study.)

The hope is that an online version of the program could reach couples sooner, and also offer booster sessions to improve results. Even so, Dr. Christensen notes that the disadvantage of online therapy is that it won’t give couples a third party to referee their discussion.

“Nobody thinks it’s going to replace individual therapy or couples therapy,” he said. “There’s generally a sense that the intervention might be less powerful, but if it’s less powerful but is easily administered to many more people, then it’s still a very helpful treatment.”

Researchers at Brigham Young University offer an extensive online marital assessment, called Relate, for couples and individuals. The detailed questionnaire, at www.relate-institute.org, takes about 35 minutes to complete and generates a lengthy report with color-coded graphs depicting a couple’s communication and conflict style, how much effort each partner puts into the relationship, and other things. The fee is $20 to $40.

Australian researchers are using the same assessment, along with a DVD and telephone education program called Couple Care, found at www.couplecare.info, to reach families in remote areas who don’t have access to traditional therapy. The Utah and Australia researchers have begun a randomized, controlled trial of about 300 couples to determine the effectiveness of the approach.

Preliminary data show that couples reported improvement, but Kim Halford, a professor of clinical psychology at the University of Queensland, St. Lucia, in Australia, said more study of long-term effects was needed.

Dr. Halford notes that as more couples meet through Web dating services, the appeal of online couples counseling may increase. “If information technology is integral to how you began your relationship,” he said, “then if therapy is required it’s not surprising that they would look to online technology.”


A version of this article appeared in print on June 29, 2010, on page D1 of the New York edition.

Oscar’s surgery was performed by Noel Fitzpatrick, neuro-orthopedic surgeon

GoogleNews.com, June 28, 2010, by Ryan Morrison  –  “Without this surgery he wouldn’t be here, it’s as simple as that,” Kate Allan, whose cat Oscar is recovering from an operation at the  veterinarian hospital.

Oscar is making headlines as this was no routine operation – he is the first bionic cat.

While snoozing in a maize field in Jersey, Oscar had his back paws sliced off by a combine harvester. Oscar’s other owner, Mike Nolan, was at home when a passer-by knocked on his door to ask if he owned a black cat.  Mr. Nolan said it was horrible: “Complete panic at that point, [Oscar was] covered in blood, bits of flesh, it was very gruesome.”

Oscar in the corn field before his accident

“It was very traumatic, I was convinced we were going to have to put him down at this point.”. Peter Haworth was the vet Mr. Nolan saw at New Era Veterinary Hospital in Jersey, he was able to clean and dress Oscar’s wounds.

Mr. Nolan said: “Peter was able to stabilize him, got painkillers going and he was comfortable within minutes of getting into the vets, on a strong painkiller I imagine.” The vet then suggested Oscar’s owners approach Noel Fitzpatrick, a veterinary surgeon from Surrey, who had been doing pioneering work on prosthetics. The next stage in Oscar’s road to fame then involved a lot of communication between England and Jersey with x-rays and pictures being sent back and forth.

Mr. Nolan said: “Peter e-mailed Noel, they had a lot of communication, Noel then contacted us to let us know what his processes would be. “It was very much a three way communication time, a lot of e-mails, pictures and x-rays flying around and Noel pretty quickly decided Oscar was a good patient.”

Two weeks later he was flown to the UK where he was measured for the implants and finally to have surgery.

The new feet are custom-made implants that “peg” the ankle to the foot. They are bioengineered to mimic the way deer antler bone grows through the skin. Ms Allan said the chances of her cat surviving without this operation would have been nil. Ms Allan said: “The fact that Oscar was such a young cat, he was only two and a half when it happened made him an ideal patient for this surgery.

“Oscar is a very chilled cat, he is very laid back, he takes things well which led to the surgeons in Surrey describing him as a very suitable candidate for this kind of surgery.” Oscar had to be transported to the UK from Jersey by air cargo and the whole journey meant him spending up to eight hours in his box.

Mr. Nolan said he felt for Oscar: “It was a little traumatic for us but I would imagine it was a lot more traumatic for him, a lot of noises and a lot of things going on he wasn’t aware of.” And for his owners one of the worst parts of the process was the uncertainty as it had never been done before.

We were in the hands of the surgeons. “Right the way along they said ‘we’d do everything we can but we’ve never done it before’, there were no guarantees. “We really trusted Noel for the work he was doing and we went with it.” For his owners the decision whether to go through with the surgery or not was down to how it would affect Oscar’s life going forward. Mr. Nolan said: “We would never have gone through with it if there was doubt about his quality of life going forward. “As he is at the moment we’re told he is running around, he has taken to his new feet really well. He is jumping about, walking as a cat should, eating, sleeping – it’s phenomenal really.” They were both really impressed with the quality of care Oscar has been given.

Ms Allan said: “We really believe he has had such amazing medical care throughout, both at New Era here and at Fitzpatrick referrals in England they treat him really well. “For instance he has three of his own rooms, he goes for walks on the lead, they treat him as part of the family, he goes out and about and so on.” There are pros and cons to Oscar being from Jersey but the biggest issue is that his owners can’t just bring him home early. Ms Allan said they’re leaving him in England for now: “The fact that he is from Jersey has its pros and cons. He’s still in England at the moment because he is going through full rehabilitation.

Oscar is recov­er­ing well in the UK

“If we lived in England we would be able to bring him back and forth because he could come home now but he still needs treatment.

“We have to decide if we want to put him through the trauma of flying or going on the boat regularly and at this stage probably not.”

When Oscar finally returns home to Jersey his owners have said that they will be watching him much more carefully.

Ms Allan said: “I think he will be more restricted when he comes back. The feet don’t have sensitivity in them but we will be able to take him outside and for walks and so on.

“But also we would be a bit cautious about him going to the fields with the combine harvesters anyway.”

Mr. Allan said: “Peter [their vet] has told us that following all the traumatic things that have happened to him he may not want to go out, he might be happier indoors.”

After everything that has happened, his owners wanted to thank the passer by who found Oscar in the field and everyone else involved.

Ms Allan said: “We would like to thank the passer by on her bicycle, we still don’t know who she was. Without her coming to knock on our door he wouldn’t be here.

“There have been a lucky series of events in this story so we would like to thank everybody involved.”

The Bionic Vet is on BBC 1 at 2245 BST on Wednesday 30 June 2010.

Forbes.com, June 28, 2010  –  NEW YORK — A drug candidate used to restore a steady heartbeat received a recommendation for approval in Europe, according to Merck and Co. and Cardiome Pharma Corp.

The companies said Friday the Committee for Medicinal Products for Human Use said Brinavess should be approved as a treatment for recent onset atrial fibrillation in adults. Atrial fibrillation is a condition that causes the upper chambers of the heart to beat rapidly and ineffectively.

The recommendation improves the chances that European Union regulators will approve Brinavess for sale in the 27 EU countries, along with Norway and Iceland. Regulators will complete a review of the drug later this year.

Brinavess, or vernakalant, is delivered by infusion. Merck ( MRKnews people ) and Cardiome are also working on an oral version of the drug. The companies have also applied for U.S. approval of the infusion form of the drug.

Separately, Merck said the committee made a decision on its drug candidate Sycrest. The committee recommended that Sycrest be approved as a treatment for treating moderate to severe episodes associated with bipolar disorder in adults. However the committee did not recommend approval of Sycrest, or asenapine, as a treatment for schizophrenia.

Merck is headquartered in Whitehouse Station, N.J., and Cardiome is based in Vancouver, British Columbia.

Feeling a little blah these days? Maybe it’s time to start a green-tea habit.

New research suggests that drinking this sky-high-in-antioxidants green brew may help ensure that you never feel down in the dumps.

Amazing Tea Trend
In a study involving more than a thousand elderly adults in Japan, those who reported drinking 4 or more cups of green tea a day were also 44 percent less likely to experience depression — mild or severe. More research is needed to confirm a causal effect, but we already know that green tea is tops for many other health reasons. So you have every reason to sip away while the jury deliberates.

Amino Acids Have the Edge
In the study, coffee and other types of teas didn’t seem to have the same emotional benefit as green tea. So what gives? It’s not entirely clear yet, but researchers suspect a type of amino acid — called theanine — found in high levels in green tea might play a role. In animal research this compound seems to help increase the brain’s supply of two mood-boosting chemicals: serotonin and dopamine. And as a refresher, here are a few more reasons that drinking green tea is so great for you:

The recipe for green iced tea is very simple. You can use agave syrup, Splenda, or some other sweetener aside from granulated sugar to make it healthier.

Iced Green Tea

8 cups of cold water
1 1/4 – 1 1/2 cups of granulated sugar (or Splenda or about 3/4 c of agave syrup)
6-8 bags of green tea.

In a big pot, pour in cold water and sugar. Turn on the heat, and stir the sugar until the water becomes translucent again. Cover the pot of sugar water, and allow the mixture to boil. Meanwhile, place the green tea bags in a large container (with a lid) that can handle hot water and quick temperature changes. Once the water boils, turn off the heat, and immediately pour the sugar water into the large container. Cover the container (with the lid or foil), and allow the tea to sit or steep and cool for 10 minutes. Then place the container in the refrigerator, or pour yourself a glass with a bunch of ice!

References:  Green tea consumption is associated with depressive symptoms in the elderly. Niu, K. et al., American Journal of Clinical Nutrition 2009 Dec;90(6):1615-1622.

It’s summer! And nothing says it better than fabulous, refreshing iced tea. But don’t just settle for the plain ol’ bag of green tea. Go for a custom brew. This pitcher has a special infusion chamber that lets you mix loose teas, fruits, herbs — whatever you fancy. Create your own house blend, like lemon-thyme-green or lime-mint-green. Mmmm, mmmm — delish!

  

Science Weekly: End of the world news

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The BBC’s David Shukman, the Guardian’s hack day, mobile phone masts and cancer, and patenting genes

New Readers

ON TARGET welcomes our new readers who met us this month at the annual meeting of the Drug Information Association (DIA) in Washington and at BioMed in Israel. ON TARGET has been published continually since 1995 and there are now over 3,200 loyal readers who receive ON TARGET by request only. Readers are from Industry, Government, Academia and those who just want to read something interesting each week. The mailing list is never shared with anyone and is housed in a secure environment with the Target Health IT Department.

For more information about Target Health contact Warren Pearlson (212-681-2100 ext 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health website at: www.targethealth.com

Easier Way to Synthesize New Drugs Could Have a Big Impact on Pharma Business

Some drugs may be more effective the longer they last inside the 1) ___. To prevent such drugs from being broken down too rapidly, pharmaceutical manufacturers often attach a fluorine-containing structure called a trifluoromethyl (CF3) group. However, the processes now used require harsh reaction conditions or only work in a small number of cases, limiting their usefulness for synthesizing new drug candidates for testing. Now, MIT chemists have designed a new way to attach a CF3 group to certain compounds, which they believe could allow pharmaceutical companies to create and test new drugs much faster and potentially reduce the cost of drug discovery. The new synthesis, reported in the June 25 issue of Science, could have an immediate impact. MIT Chemistry Professor Stephen Buchwald, who led the research team, says achieving the synthesis has been a long-standing challenge for 2) ___. The CF3 group  is a component of several commonly used drugs, including the antidepressant Prozac, arthritis medication Celebrex and Januvia, used to treat diabetes symptoms. When foreign compounds such as drugs enter the body, they get sent to the 3) ___, where they are broken down and shipped on to the kidneys for excretion. However, CF3 groups are hard for the body to break down because they contain three fluorine atoms. Fluorine is not really a component of things we eat, so the body does not know what to do with it. CF3 groups are also a common component of agricultural chemicals such as pesticides. To add a CF3 group to organic (carbon-containing) molecules, chemists often use hydrogen fluoride under conditions that might produce undesired reactions among the many structural components found in complex molecules like 4) ___ or agrochemicals. With the new reaction, the CF3 group can be added at a much later stage of the overall drug synthesis. The reaction can also be used with a broad range of starting materials, giving drug developers much more flexibility in designing new compounds. Chemists have been trying to find a widely applicable catalytic method to attach CF3 to aryl compounds (compounds containing one or more six-carbon rings) for a couple of decades. Some have achieved different parts of the reaction, but none successfully put all the pieces together to arrive at a method that is applicable for a wide range of different aryl 5) ___. The major challenge has been finding a suitable catalyst (a molecule that speeds up a reaction) to transfer the CF3 entity from another source to the carbon ring. CF3- tends to be unstable when detached from other molecules, so the catalyst must act quickly to transfer the CF3 group before it decomposes. The MIT team chose to use a catalyst built from palladium, a silvery-white metal commonly used in catalytic converters. The MIT team is not the first to try palladium catalysis for this reaction, but the key to their success was the use of a ligand called BrettPhos, which they had previously developed for other purposes. A ligand is a 6) ___ that binds to the metal to stabilize it and hasten the reaction. Coming up with a useful reaction required much testing of different combinations of palladium, ligand, CF3 source, temperature and other factors. Everything had to match up. During the reaction, a CF3 group is transferred from a silicon carrier to the palladium, displacing a chlorine atom. Subsequently, the aryl-CF3 unit is released and the catalytic cycle begins anew. The researchers tried the synthesis with a variety of aryl compounds and achieved yields ranging from 70 to 94% of the trifluoromethylated products. In its current state, the process is too expensive for manufacturing use. For drug discovery, however, it may lower overall 7) ___ because it streamlines the entire synthesis process. For discovery chemistry, the price of the metal is much less important. All of the reaction components are commercially available, so pharmaceutical and other companies will immediately be able to use this method. “This versatile new methodology is directly applicable to drug development,“ says John Schwab, a program director at the National Institute of Health’s National Institute of General Medical Sciences, which partially funded the research. “This is a terrific example of how U.S. healthcare consumers are benefiting from their investment in NIH and in basic, 8) ___ research.“ 

ANSWERS: 1) body; 2) chemists; 3) liver; 4) pharmaceuticals; 5) compounds; 6) molecule; 7) costs; 8) biomedical

Source: MIT: Journal Reference: Eun Jin Cho, Todd D. Senecal, Tom Kinzel, Yong Zhang, Donald A. Watson, Stephen L. Buchwald. The Palladium-Catalyzed Trifluoromethylation of Aryl Chlorides. Science, 2010; 328 (5986): 1679-1681 DOI: 10.1126/science.1190524

Lupus

Four main types of lupus exist: systemic lupus erythematosus, discoid lupus erythematosus, drug-induced lupus erythematosus and neonatal lupus erythematosus. Of these, systemic lupus erythematosus (SLE) is the most common and serious form of lupus. The history of SLE can be divided into three periods: classical, neoclassical, and modern.

The classical period began when the disease was first recognized in the Middle Ages and when a description of the dermatological manifestation of the disorder was recorded.  The term lupus (Latin for wolf) is attributed to 12th-century physician Rogerius, who used it to describe erosive facial lesions that were reminiscent of a wolf’s bite, and the classic malar rash, that resembled a wolf’s scratch. The first published illustrations of lupus erythematosus were included in von Hebra’s text, Atlas of Skin Diseases, published in 1856.

The neoclassical period was heralded by Moric Kaposi’s recognition in 1872 of the systemic manifestations of the disease. Kaposi wrote, “… experience has shown that lupus erythematosus (“erythematosus” is Latin for red) … may be attended by altogether more severe pathological changes … and even dangerous constitutional symptoms may be intimately associated with the process in question, and that death may result from conditions which must be considered to arise from the local malady.“ Kaposi proposed that there were two types of lupus erythematosus; the discoid form and a disseminated form. Furthermore, he enumerated various symptoms and signs which characterized the disseminated form including (1) subcutaneous nodules, (2) arthritis with synovial hypertrophy of both small and large joints, (3) lymphadenopathy, (4) fever, (5) weight loss, (6) anemia, and (7) central nervous system involvement. The existence of a systemic form of lupus was firmly established by the work of Osler in Baltimore and Jadassohn in Vienna in 1904.

The modern period began in 1948 with the discovery of the LE cell by Hargraves and colleagues. The investigators observed these cells in the bone marrow of patients with acute disseminated lupus erythematosus and postulated that the cell “… is the result of … phagocytosis of free nuclear material with a resulting round vacuole containing this partially digested and lysed nuclear material …“ This discovery ushered in the present era of the application of immunology to the study of lupus erythematosus. 

Two other immunologic markers were recognized in the 1950s as being associated with lupus: the biologic false-positive test for syphilis12 and the immunofluorescent test for antinuclear antibodies. Medical historians have theorized that people with porphyria (a disease that shares many symptoms with SLE) generated folklore stories of vampires and werewolves, due to the photosensitivity, scarring, hair growth, and porphyrin brownish-red stained teeth in severe recessive forms of porphyria (or combinations of the disorder, known as dual, homozygous, or compound heterozygous porphyrias). 

Useful medication for the disease was first found in 1894, when quinine was first reported as an effective therapy. Four years later, the use of salicylates in conjunction with quinine was noted to be of still greater benefit. This was the best available treatment until the middle of the twentieth century, when the treatment of systemic lupus was revolutionized by the discovery of the efficacy of adrenocorticotrophic hormone and cortisone by Hench. Corticosteroids have been the primary therapy for almost all patients with systemic lupus. Antimalarials have been used principally for patients with skin and joint involvement on the one hand and cytotoxic/immunosuppressive drugs have been used for patients with glomerulonephritis, systemic vasculitis, and other severe life-threatening manifestations on the other.

Two other major advances in the modern era have been the development of animal models of lupus and the recognition of the role of genetic predisposition to the development of lupus. The familial occurrence of systemic lupus was first noted by Leonhardt in 1954 and later studies by Arnett and Shulman at Johns Hopkins. Subsequently, familial aggregation of lupus, the concordance of lupus in monozygotic twin pairs, and the association of genetic markers with lupus have been described.

Folate Promotes Healing In Spinal Cord Injuries

Nearly 11,000 Americans experience a spinal cord injury each year. The effects of spinal cord injury vary with the extent of the injury, with severe injuries resulting in complete paralysis below the injury site. Folate, a B vitamin, occurs naturally in leafy green vegetables and other foods. The synthetic form, folic acid, is used to supplement cereal grains in the United States. The vitamin is important for the formation of the brain and spinal cord in the early embryo. The U. S. Public Health Service recommends that all women of childbearing age consume 400 micrograms of folic acid each day to reduce their risk of having a child with a neural tube defect, a birth defect of the brain and spinal cord. According to an article published in the Journal of Clinical Investigation (2010;120:1603-1616), the vitamin folate appears to promote healing in damaged rat spinal cord tissue by triggering a change in DNA. The study showed that the healing effects of the vitamin increased with the dosage, until regrowth of the damaged tissue reached a maximum level. After this threshold was reached, regrowth declined progressively with increasing doses until it reached the level seen in the absence of the vitamin. Specifically, folate stimulated a process known as DNA methylation, a natural biochemical process in which chemical compounds known as methyl groups are attached to DNA. The study results suggest that a greater understanding of the chemical sequences associated with folate metabolism and DNA methylation may lead to new techniques to promote healing of damaged spinal cords and other nervous system injuries. The research is at an early stage and additional studies are needed to determine what role folate might play in the treatment of human beings with spinal cord injury. Because of folate’s role in fetal spinal cord development, the study sought to determine if the vitamin could promote healing in damaged adult nervous system tissue. In a previous study, the researchers showed that folate could enhance the regrowth of axons, or nerve fibers, in rats with spinal cord injuries. To understand how folate helps repair damaged axons, the authors undertook additional observations. They found that injured nerve tissue began producing surface receptors for folate. Folate fits into the receptors, like a key fits into a lock, and then is absorbed into the nerve cell. After folate was absorbed into injured nervous system tissue, the nerve cells began producing enzymes that attach methyl groups to DNA. Chemically blocking folate from binding to the nerve cells, or blocking the methylation enzymes, hindered the nerve healing process. The study also tested the methylation of spinal cord DNA at various doses of folate and found that, like the regrowth of axons, DNA methylation peaked at a dose of 80 micrograms folate per kilogram of body weight.

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