Posts Tagged ‘Johns Hopkins School of Medicine’

Halstedian model of cancer progression [4.1]

Writer and Curator: Larry H. Bernstein, MD, FCAP

The Halstedian model of cancer progression is attributed to the meticulous care that William Halsted, Chairman of Surgery at the founding of the Johns Hopkins Medical School who in 1894 introduced “radical mastectomy” (1-3). This would be the standard of care until the 1970s, and was made possible by his exquisite knowledge of anatomy, his sparing of tissue including debridement in all surgical procedures, his introduction of the use of cocaine into neural tissue after the introduction of antiseptic by Lister. The radical mastectomy was an extensive debilitating procedure that included the removal of the breast with all axillary lymph nodes and removal of pectoral muscles for lifesaving surgery of breast cancer. (1-6) The changes that followed were modified radical mastectomy that spares the muscles and that was followed by breast conservation surgery that leaves breast tissue behind. Then sentinel lymph node mapping was introduced with the hope of reducing the extent of axillary dissection. Finally, skin sparing mastectomy appeared in order to conserve skin and facilitate breast reconstruction. In addition, surgery was followed by radiation. (4-6)

His work was based in part on that of W. Sampson Handley, the London surgeon who believed that cancer spread outward by invasion from the original growth. (The general concept of the radical mastectomy can be traced all the way back to Lorenz Heister, a German who wrote about his ideas for mastectomy and lumpectomy in his book, Chirurgie, published in 1719.)(5)
Halsted did not believe that cancers usually spread through the bloodstream: “Although it undoubtedly occurs, I am not sure that I have observed from breast cancer, metastasis which seemed definitely to have been conveyed by way of the blood vessels.”(4)

Halsted proposed that although breast cancer begins as a local disease, it spreads in a contiguous manner away from the primary site through the lymphatic system. This proposal led to his emphasis on aggressive locoregional treatment to prevent further spread. Halsted himself suggested, “disability, ever so great, is a matter of very little importance as compared with the life of the patient.” (4) The view that surgeons at the time believed was that mastectomy was crucial to life saving treatment and it was this belief that prevented progress to other initial surgical approaches. It must be acknowledged that in Halsted’s time there was no method of grading or staging cancers, which he acknowledged. This principle, however (known as the ‘Halsted Theory’), was also critical in introducing the concept of a sentinel node in relation to breast cancer. This led to Guiliano et al. introducing lymphatic mapping for breast cancer in 1994. (5)

At the same time Halsted and Handley were developing their radical operations, another surgeon was asking, “What is it that decides which organs shall suffer in a case of disseminated cancer?” Stephen Paget, an English surgeon, concluded that cancer cells spread by way of the bloodstream to all organs in the body but were able to grow only in a few organs.(5) He drew an analogy between cancer metastasis and seeds that “are carried in all directions, but they can only live and grow if they fall on congenial soil.”  This highly sophisticated hypothesis was adopted almost a hundred years later after an understanding of metastasis became a basis for recognizing the limitations of cancer surgery, and chemotherapy was introduced for treating a systemic disease (6).

In 1971 Fisher et al. (7) commenced a randomized trial comparing the radical mastectomy with total mastectomy with or without radiotherapy. Studies such as these heralded the advent of breast conserving surgery and the acknowledgement that routine radical mastectomy may not always be the most appropriate surgical management. Today, a radical mastectomy is almost never done and the “modified radical mastectomy” is performed less frequently than before. Most women with breast cancer now have the primary tumor removed (lumpectomy), and then have radiation therapy.(4-6)

  1. The Four Founding Physicians


  1. Biographical Memoir of William Stewart Halsted 1852-1922
  2. G. MacCallum
    Presented to the NAS at the Autumn Meeting, 1935 http://nasonline.org/publications/biographical-memoirs/memoir-pdfs/halsted-w-s.pdf
  3. William Stewart Halsted – A Lecture by Dr. Peter D. OlchJ Scott Rankin, MD
    Ann Surg. 2006 Mar; 243(3): 418–425. http://dx.doi.org:/1097/01.sla.0000201546.94163.00
  1. Evolution of cancer treatments: Surgery


  1. The history of breast cancer surgery: Halsted’s radical mastectomy and beyond

Rebecca E Young
AMSJ 2013; 4(1)

  1. History of mastectomy before and after Halsted.

Ghossain A1Ghossain MA.
J Med Liban. 2009 Apr-Jun; 57(2):65-71.

  1. Breast cancer surgery: an historical narrative. Part III. From the sunset of the 19th to the dawn of the 21st century.


Sakorafas GH1Safioleas M.
Eur J Cancer Care (Engl). 2010 Mar; 19(2):145-66.

  1. Bernard Fisher reflects on a half-century’s worth of breast cancer research.

Travis K.
J Natl Cancer Inst. 2005 Nov 16; 97(22):1636-7.

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North Americans With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Genomics of Ventricular arrhythmias, A-Fib, Right Ventricular Dysplasia, Cardiomyopathy – Comprehensive Desmosome Mutation Analysis

Reporter: Aviva Lev-Ari, PhD, RN

Genomics of Ventricular arrhythmias, A-Fib, Right Ventricular Dysplasia, Cardiomyopathy – Comprehensive Desmosome Mutation Analysis in North Americans With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

A. Dénise den Haan, MD, Boon Yew Tan, MBChB, Michelle N. Zikusoka, MD, Laura Ibañez Lladó, MS, Rahul Jain, MD, Amy Daly, MS, Crystal Tichnell, MGC, Cynthia James, PhD, Nuria Amat-Alarcon, MS, Theodore Abraham, MD, Stuart D. Russell, MD,David A. Bluemke, MD, PhD, Hugh Calkins, MD, Darshan Dalal, MD, PhD and Daniel P. Judge, MD

Author Affiliations

From the Department of Medicine/Cardiology (A.D.d.H., B.Y.T., M.N.Z., L.I.L., R.J., A.D., C.T., C.J., N.A.-A., T.A., S.D.R., H.C., D.D., D.P.J.), Johns Hopkins University School of Medicine, Baltimore, Md; Department of Cardiology, Division of Heart and Lungs (A.D.d.H.), University Medical Center Utrecht, Utrecht, The Netherlands; and National Institutes of Health, Radiology and Imaging Sciences (D.A.B.), Bethesda, Md.

Correspondence to Daniel P. Judge, MD, Johns Hopkins University, Division of Cardiology, Ross 1049; 720 Rutland Avenue, Baltimore, MD 21205. E-mail djudge@jhmi.edu


Background— Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited disorder typically caused by mutations in components of the cardiac desmosome. The prevalence and significance of desmosome mutations among patients with ARVD/C in North America have not been described previously. We report comprehensive desmosome genetic analysis for 100 North Americans with clinically confirmed or suspected ARVD/C.

Methods and Results— In 82 individuals with ARVD/C and 18 people with suspected ARVD/C, DNA sequence analysis was performed on PKP2, DSG2, DSP, DSC2, and JUP. In those with ARVD/C, 52% harbored a desmosome mutation. A majority of these mutations occurred in PKP2. Notably, 3 of the individuals studied have a mutation in more than 1 gene. Patients with a desmosome mutation were more likely to have experienced ventricular tachycardia (73% versus 44%), and they presented at a younger age (33 versus 41 years) compared with those without a desmosome mutation. Men with ARVD/C were more likely than women to carry a desmosome mutation (63% versus 38%). A mutation was identified in 5 of 18 patients (28%) with suspected ARVD. In this smaller subgroup, there were no significant phenotypic differences identified between individuals with a desmosome mutation compared with those without a mutation.

Conclusions— Our study shows that in 52% of North Americans with ARVD/C a mutation in one of the cardiac desmosome genes can be identified. Compared with those without a desmosome gene mutation, individuals with a desmosome gene mutation had earlier-onset ARVD/C and were more likely to have ventricular tachycardia.


Circulation: Cardiovascular Genetics.2009; 2: 428-435

Published online before print June 3, 2009,

doi: 10.1161/ CIRCGENETICS.109.858217


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Biological Therapeutics for Asthma

Curator: Larry H Bernstein, MD, FCAP


Update on Biological Therapeutics for Asthma

Marisha L. Cook, MD, and Bruce S. Bochner, MD
Department of Medicine, Division of Allergy and Clinical Immunology
Johns Hopkins University School of Medicine, Baltimore, MD

WAO Journal 2010; 3:188–194
Difficulty in managing severe asthma has encouraged research about its pathobiology and treatment options. Novel biologic therapeutics are being developed for the treatment of asthma and are of potential use for severe refractory asthma, especially where the increased cost of such agents is more likely justified. This review summarizes currently approved (omalizumab) and investigational biologic agents for asthma, such as

  • antibodies,
  • soluble receptors,
  •  other protein-based antagonists,

and highlight recent published data on efficacy and safety of these therapies in humans. As these newer agents with highly targeted pharmacology are tested in asthma,

  • we are also poised to learn more about the role of cytokines and other molecules in the pathophysiology of asthma.

Key Words: asthma, biologic therapies, cytokines, monoclonal antibodies

Despite the well-known and fairly consistent efficacy of
drugs such as inhaled corticosteroids, leukotriene modifiers
and 2 agonists for the majority of asthmatics, as many as
10% suffer from severe disease inadequately controlled by
conventional therapy. Severe and sustained symptoms lead to
poor quality of life, disproportionate use of health care

resources, and significant adverse effects. Novel biologic therapeutics are being developed for the treatment of asthma and are of potential use for severe refractory asthma, especially where the increased cost of such agents is more likely justified.
This review will briefly summarize what is meant by “biologic therapies” and then highlight recent published data on efficacy and safety of these therapies for asthma.

Biologic therapies have revolutionized the treatment of many diseases including asthma. By definition, the term “biologics” or “biologicals” include a variety of protein based therapeutics, such as antibodies, soluble receptors (eg,etanercept), recombinant protein-based receptor antagonists (eg, pitrakinra) and other related structures. Their main advantages include the duration of action and highly specific and strong binding to the target of interest; their main disadvantages are the cost and need for parenteral administration. Most biologicals in clinical use are antibodies, and their generic names contain standard nomenclature as a suffix to
indicate their origins (Fig. 1). Initially, pure murine antibodies were created with hybridoma technology, generating therapies that were 100% mouse with generic names given the suffix “momab” (eg, ibritumomab); however, immunogenicity of mouse antibodies in human subjects caused reduced efficacy and increased risk of infusion reactions including anaphylaxis and death. To reduce immunogenicity, chimeric antibodies
(“ximabs” like rituximab) were engineered. These antibodies are a marriage of murine variable regions combined with human constant regions, creating antibodies that are 80% human. These were a step forward but still had the potential for being immunogenic. Humanized monoclonal antibodies (“zumabs” such as omalizumab) go one step further, where now only the hypervariable regions of the mouse antibody are retained,
while the remaining 95% of the antibody is molecularly replaced by human sequences.

In the latest approach, fully human antibodies (“umabs” such as adalimumab) can be created by using phage display technology and molecular biology or more directly by immunizing mice that have had their immunoglobulin genes replaced with human versions. Newer artificial antibody structures such as bispecific antibodies, mix 2 separate arms with 2 different binding specificities to target 2 different types of antigens [eg, a single antibody where one arm binds interleukin (IL)-4 and the other arm binds IL-13]. Standard nomenclature for mAbs identifies their source with the last 4 or 5 letters: -omab, murine: –ximab, chimeric: -zumab, humanized: and –umab, human. The middle part of the name reflects the disease indication for which the mAb was initially intended: -lim for immune and inflammatory diseases, -cir for cardiovascular disorders, and -tu for tumors or neoplastic conditions. The first 3 or 4 letters may be chosen by the sponsor. Modified (by adding the structure of a bispecific antibody) . In general, FDA-approved mAbs have emerged between 10 and 12 years after the date that the new technologies on which they were based were reported in the scientific literature. None of these newer antibody structures have been tried in asthma, so the remainder of this review will focus on available data with standard biologicals.
Here is a listing of the key focus on biomolecules for therapeutics:

It induces the IgE isotype switch and up-regulates expression of vascular cell adhesion molecule-1 on endothelium and a variety of TH2 chemokines, thus promoting recruitment of T lymphocytes, monocytes,                 basophils, and eosinophils to sites of allergic inflammation.  A clinical trial studied the soluble recombinant human IL-4 receptor (IL-4R), Nuvance in asthma. Nuvance inhibited a decline in FEV1 during inhaled corticosteroid withdrawal and was overall well tolerated.2,3 However, in subsequent clinical trials in patients taking only beta agonist, soluble IL-4R failed to demonstrate significant clinical efficacy. A phase I randomized double blind placebo controlled study evaluated the effects of pascolizumab, a humanized anti-IL-4 antibody, in 24 patients with mild to moderate asthma. Pascolizumab was well tolerated and no serious adverse events occurred.5 However, a phase IIa clinical trial in steroid-naive, mild to moderate asthmatics, did not demonstrate clinical efficacy. Because the IL-4 targeting studies have failed to demonstrate clinical efficacy, one can justify concluding that either IL-4R is not an effective therapeutic target in asthma.


Tumor necrosis factor (TNF) is a multifunctional proinflammatory cytokine produced by inflammatory cells including monocytes, macrophages, mast cells, smooth muscle cells, and epithelial cells. TNF may initiate airway inflammation by up-regulating adhesion molecules, mucin hypersecretion, and airway remodeling, and by synergizing with TH2 cytokines. Berry et al demonstrated that severe refractory asthmatics have evidence of up-regulation of TNF as compared with healthy controls and mild asthmatics.  Entanercept was evaluated in a small, randomized, double-blind placebo-controlled crossover study in 10 patients with severe refractory asthma and elevated TNF levels, 10 patients with mild to moderate asthma, and 10 control patients. Entanercept treatment was associated with improved FEV1, asthma related quality of life, and the concentration of methacholine needed to provoke a 20% decrease in FEV1. No serious adverse reactions were noted. In another double-blind, placebo-controlled, parallel group study, 38 patients with moderate asthma on inhaled corticosteroids were treated with infliximab. Although infliximab treatment did not improve the primary end point of morning peak expiratory flow, it decreased diurnal variation of the peak expiratory flow rate and asthma exacerbations. No serious adverse events were noted. Golimumab was recently evaluated in the largest randomized, double-blind, placebo-controlled study in 309 patients with severe, uncontrolled asthma. No significant differences were observed for the change in FEV1 or exacerbations. However, several serious adverse events occurred. There is no clear role for TNF in perpetuating asthma or asthma exacerbations.


CD4 T cells are likely to be involved as a source of proinflammatory cytokines in asthma. Keliximab is a monoclonal antibody that causes a transient reduction in the number of CD4 T cells. A double blind, randomized, placebo controlled study with 22 severe oral corticosteroid dependent asthmatics patients was completed. A subset of patients received the highest dose of keliximab (3.0 mg/kg). There was significant improvement of peak expiratory flow rates in the high dose treatment arm. However, CD4 T cells remained transiently reduced 14 days postinfusion, raising safety concerns.


CD23 is a low-affinity immunoglobulin E receptor (FcRII) and is important in regulating IgE production. IDEC-152 is a chimeric monoclonal antibody directed against CD23. CD23 is expressed on

  • T and B cells,
  • neutrophils,
  • monocytes, and
  • macrophages.

CD23 is overexpressed in allergic disease and may be involved in IgE overproduction,

    • which can lead to mast cell degranulation.

A phase I dose escalating placebo-controlled study in 30 asthmatics demonstrated that

  • IDEC-152 caused a dose-dependent reduction in serum IgE concentrations.
    • No significant adverse events were reported


Airway inflammation is associated with activated CD25 T cells, IL-2, and soluble IL-2 receptors. Daclizumab is a humanized monoclonal antibody directed against the alpha subunit of the high affinity IL-2 receptor (CD25). This inhibits IL-2 binding and release of inflammatory cytokines. A randomized, double-blind, placebo-controlled, parallel group study was performed (115 patients, 88 to the treatment arm, 27 to placebo)to evaluate the efficacy of daclizumab in patients with moderate to severe asthma poorly controlled on inhaled corticosteroids. Treatment with daclizumab led to improvements in FEV1, daytime asthma symptoms, and rescue 2 agonist use,but the effects were modest.


Omalizumab is a humanized monoclonal anti-IgE antibody that binds free circulating IgE and prevents the interaction between IgE and high affinity (FcRI) and low affinity (FcRII) IgE receptors on inflammatory cells. Omalizumab also down-regulates the surface expression of FcRI on basophils, mast cells, and dendritic cells.  Omalizumab decreases free IgE levels and reduces FcRI receptor expression on mast cells and basophils. This results in decreased mast cell activation and sensitivity, leading to a reduction in eosinophil influx and activation. Anti-IgE treatment with omalizumab might result in decreased mast cell survival. Omalizumab also reduces dendritic cell FcRI receptor expression.  The primary end point in a phase III randomized prospective trial was the number of exacerbation episodes during the steroid reduction period and the stable steroid period. During the stable steroid phase, fewer omalizumab subjects than placebo subjects experienced one or more exacerbations (14.6 vs. 23.3%; P  0.009). During the steroid reduction phase, the omalizumab group had fewer subjects with exacerbations (21.3 vs. 32.3%; P  0.04). The median reduction in inhaled corticosteroid dose was significantly greater in the omalizumab group than in the placebo group (75 vs. 50%; P  0.001).  The efficacy of omalizumab was demonstrated in other clinical trials including INNOVATE.  INNOVATE was a double-blind, parallel-group study in which 419 subjects were randomized to receive omalizumab or placebo for 28 weeks. The omalizumab group had a 26% reduction in the rate of clinically significant exacerbations compared with placebo (.68 vs. .91, P  0.042).  A recent omalizumab observational study of 280 subjects demonstrates similar findings. After 6 months, they found a reduction in daily symptoms by 80%, nocturnal symptoms by 86%, asthma exacerbations by 82%, hospitalizations by 76%, unscheduled health care visits by 81%, and improvement in quality of life (Mini Asthma Quality of Life Questionnaire increased from 2.9 to 4.5 after 6 months of treatment).

Examining the effects of biologic agents provides unique and valuable insight into the pathobiology of asthma. Furthermore, it is an ideal opportunity to identify mechanisms inherent to severe refractory asthma. The development of biologic agents has been a slow and arduous process; however, a substantial amount of progress has been achieved. Although omalizumab is an expensive medical treatment, therapy may be cost effective in patients with uncontrolled severe persistent allergic asthma because the majority of the economic burden is in this population. Hopefully ongoing efforts with biologicals will lead to improved management options for our most severe asthma patients.

More information is available from the article:    World Allergy Organ J. 2010;3(6):188–194.    http://dx.doi.org/10.1097/WOX.0b013e3181e5ec5a
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922052/figure/F2/  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922052/bin/waoj-3-188-g002.gif  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922052/figure/F3/  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922052/bin/waoj-3-188-g003.gif

English: Overview of hybridoma technology and ...

English: Overview of hybridoma technology and monoclonal antibody creation (Photo credit: Wikipedia)

Mast cells are involved in allergy. Allergies ...

Mast cells are involved in allergy. Allergies such as pollen allergy are related to the antibody known as IgE. Like other antibodies, each IgE antibody is specific; one acts against oak pollen, another against ragweed. (Photo credit: Wikipedia)

Emil von Behring

Emil von Behring (Photo credit: Wikipedia)

Diagram showing the production of monoclonal a...

Diagram showing the production of monoclonal antibodies via hybridoma technology (Photo credit: Wikipedia)


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Reporter: Aviva Lev-Ari, PhD, RN

Simulations Show Young Surgeons Face Special Concerns With Operating Room Distractions

Article Date: 03 Dec 2012 – 1:00 PST

A study has found that young, less-experienced surgeons made major surgical mistakes almost half the time during a “simulated” gall bladder removal when they were distracted by noises, questions, conversation or other commotion in the operating room.

In this analysis, eight out of 18, or 44 percent of surgical residents made serious errors, particularly when they were being tested in the afternoon. By comparison, only one surgeon made a mistake when there were no distractions.

Exercises such as this in what scientists call “human factors engineering” show not just that humans are fallible – we already know that – but work to identify why they make mistakes, what approaches or systems can contribute to the errors, and hopefully find ways to improve performance.

The analysis is especially important when the major mistake can be fatal.

This study, published in Archives of Surgery, was done by researchers from Oregon State University and the Oregon Health and Science University, in the first collaboration between their respective industrial engineering and general surgery faculty.

“This research clearly shows that at least with younger surgeons, distractions in the operating room can hurt you,” said Robin Feuerbacher, an assistant professor in Energy Systems Engineering at OSU-Cascades and lead author on the study. “The problem appears significant, but it may be that we can develop better ways to address the concern and help train surgeons how to deal with distractions.”

The findings do not necessarily apply to older surgeons, Feuerbacher said, and human factors research suggests that more experienced people can better perform tasks despite interruptions. But if surgery is similar to other fields of human performance, he said, older and more experienced surgeons are probably not immune to distractions and interruptions, especially under conditions of high workload or fatigue. Some of those issues will be analyzed in continued research, he said.

This study was done with second-, third- and research-year surgical residents, who are still working to perfect their surgical skills. Months were spent observing real operating room conditions so that the nature of interruptions would be realistic, although in this study the distractions were a little more frequent than usually found.

Based on these real-life scenarios, the researchers used a virtual reality simulator of a laparoscopic cholecystectomy – removing a gall bladder with minimally invasive instruments and techniques. It’s not easy, and takes significant skill and concentration.

While the young surgeons, ages 27 to 35, were trying to perform this delicate task, a cell phone would ring, followed later by a metal tray clanging to the floor. Questions would be posed about problems developing with a previous surgical patient – a necessary conversation – and someone off to the side would decide this was a great time to talk about politics, a not-so-necessary, but fairly realistic distraction.

When all this happened, the results weren’t good. Major errors, defined as things like damage to internal organs, ducts and arteries, some of which could lead to fatality, happened with regularity. 

Interrupting questions caused the most problems, followed by sidebar conversations. And for some reason, participants facing disruptions did much worse in the afternoons, even though conventional fatigue did not appear to be an issue.

“We’ve presented these findings at a surgical conference and many experienced surgeons didn’t seem too surprised by the results,” Feuerbacher said. “It appears working through interruptions is something you learn how to deal with, and in the beginning you might not deal with them very well.” 




Events that should never occur in surgery (“never events“) happen at least 4,000 times a year in the U.S. according to research from Johns Hopkins University.


The findings, published in Surgery, is the first of its kind to reveal the true extent of the prevalence of “never events” in hospitals through analysis of national malpractice claims. They observed that over 80,000 “never events” occurred between 1990 and 2010.

They estimate that at least 39 times a week a surgeon leaves foreign objects inside their patients, which includes stuff like towels or sponges. In addition surgeons performing the wrong surgery or operating on the wrong body part occurs around 20 times a week.

Marty Makary, M.D., M.P.H., an associate professor of surgery at the Johns Hopkins University School of Medicine, said:

“There are mistakes in health care that are not preventable. Infection rates will likely never get down to zero even if everyone does everything right, for example. But the events we’ve estimated are totally preventable. This study highlights that we are nowhere near where we should be and there’s a lot of work to be done.”

The researchers believe that this finding could help ensure that better systems are developed to prevent these “never events” which should never happen. 

The study examined data from the National Practitioner Data Bank which handles medical malpractice claims to calculate the total number of wrong-site-, wrong-patient and wrong-procedure surgeries.

Over 20 years. they found more than 9,744 paid malpractice claims which cost over $1.3 billion. Of whom 6.6% died, while 32.9% were permanently injured and 59.2% were temporarily injured. 

Around 4,044 never events occur annually in the U.S., according to estimates made by the research team who analyzed the rates of malpractice claims due to adverse surgical events. 

Many safety procedures have been implemented in medical centers to avoid never events, such as timeouts in the operating rooms to check if surgical plans match what the patient wants. In addition to this, an effective way of avoiding surgeries that are performed on the wrong body part is using ink to mark the site of the surgery. In order to prevent human error, Makary notes that electronic bar codes should be implemented to count sponges, towels and other surgical instruments before and after surgery. 

It is a requirement that all hospitals report the number of judgments or claims to the NPDB. Makary did note, however, that these figures could be low because sometimes items left behind after surgery are never discovered. 

Most of these events occurred among patients in their late 40s, surgeons of the same age group accounted for more than one third of the cases. More than half (62%) of the surgeons responsible for never events were found to be involved in more than one incident. 

Makary comments the importance of reporting never events to the public. He stresses that by doing so, patients will have more information about where to go for surgery as well as putting pressure on hospitals to maintain their quality of care. Hospitals should report any never events to the Join Commission, however this is often overlooked and more enforcement is necessary. 

Written by Joseph Nordqvist 
Copyright: Medical News Today 




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Breakthrough Digestive Disorders Research: Conditions affecting the Gastrointestinal Tract.

Reporter: Aviva Lev-Ari, PhD, RN


Forthcoming Electronic Book on

Metabolism and MetabolOMICS, 2013

Larry H. Bernstein, MD, FCAP and Ritu Saxena, Ph.D., Editors

Book will cover innovations in

  • Digestive Disorders GENOMICS,
  • Pharmaco-Therapy for gut infalmmation,
  • Genetic Immunology,
  • Enzymatic-therapy,
  • Bacterial infection in the gut and pharmaco-therapies
  • Cancer Biology and Therapy

of the following most common digestive disorders today

In the meantime, we are sharing the encouraging news, that is, that the symptoms of digestive disorders can be alleviated, and often completely eliminated, with the right combination of medication, dietary changes, exercise, weight loss, stress reduction and surgery.

It’s all detailed in an important new research report from Johns Hopkins — rated #1 of America’s best hospitals for 21 consecutive years 1991-2011 by U.S. News & World Report.

The 2013 Johns Hopkins Digestive Disorders White Paper

Johns Hopkins Digestive Disorders White Paper

Your Digestive Expert, H. Franklin Herlong, M.D. Adjunct Professor of MedicineJohns Hopkins University School of Medicine

The expertise you need, in language you can understand and use

In The 2013 Johns Hopkins Digestive Disorders White Paper, you will discover exciting advances and the most useful, current information to help you prevent or treat conditions affecting the digestive tract.

You’ll find a thorough overview of what the medical field knows about upper and lower digestive tract disorders (including everything from gastroesophageal reflux disease [GERD] to peptic ulcers, and irritable bowel syndrome to colorectal polyps) and conditions that affect the liver, gallbladder and pancreas.

You will learn how to prevent these diseases and, when symptoms arise, the best ways for you and your doctor to diagnose and treat them. The Johns Hopkins White Papers redefine the term “informed consumer.” In The 2013 Johns Hopkins Digestive Disorders White Paper, specialists from Johns Hopkins University School of Medicine report in depth on the latest digestive disorders prevention strategies and treatments. Thousands of Americans rely on Johns Hopkins expertise to help them manage their digestive disorders.

In The 2013 Johns Hopkins Digestive Disorders White Paper you’ll get a thorough overview of what the medical field knows about the most common digestive disorders today. You’ll find a wealth of news you can use about:

  • Celiac disease
  • Constipation
  • Crohn’s disease
  • Diarrhea
  • Diverticulosis and diverticulitis
  • Gallstones
  • Gastritis
  • GERD
  • Hiatal hernia
  • Irritable bowel syndrome
  • Ulcerative colitis
  • Ulcers

and more…

Timely Information Backed by Johns Hopkins Resources and Expertise

The symptoms of digestive disorders can be alleviated, and often completely eliminated, with the right combination of medication, dietary changes, exercise, weight loss, stress reduction and, as a last resort, surgery.

Learning as much as possible about the causes, effects and treatments for your digestive disorder is the first step toward living a fuller life with minimal discomfort and physical limitations.

The 2013 Johns Hopkins Digestive Disorders White Paper is designed to help you ensure the best outcome. Use what you learn to help you:

  • Recognize and respond to symptoms and changes as they occur.
  • Communicate effectively with your doctor, ask informed questions and understand the answers.
  • Make the right decisions, based on an understanding of the newest drugs, the latest treatments and the most promising research.
  • Take control over your condition and act out of knowledge rather than fear.

Tips for optimal digestive health

  • Maybe It’s Not “Just Heartburn”: Occasional heartburn can be treated with over-the-counter antacids. But if you have any of these symptoms, talk to your doctor to rule out more serious problems.
  • Should You Try Probiotics? Evidence is mounting that these “friendly bacteria” can help treat many digestive problems, such as IBS and Crohn’s disease. See how they work and are used, and whether they might relieve your gastrointestinal issues.
  • New Ways to Look Inside: The benefits and drawbacks of patient-friendly imaging tools including the “video pill” and virtual colonoscopy. How do state-of-the-art tools compare with established diagnostic exams?
  • Making Friends with Fiber: Getting enough dietary fiber is an easy way to prevent or treat a wide variety of digestive complaints. See which foods deliver the most fiber.
  • How to Avoid a Foodborne Illness: Follow these guidelines to choose, store, prepare and serve food in ways that minimize the health risks that result in 76 million infections and 325,000 hospitalizations annually.



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Reporter: Aviva Lev-Ari, PhD, RN

Featured Researcher:

Prof. Beth Murinson, MD, PhD   of Technion’s Rappaport Faculty of Medicine came to Technion after being a professor at Johns Hopkins Medical School. She discusses her research in the field of Neurology and pain management.

Prof. Beth Murinson, MD, PhD, at Technion’s Rappaport Faculty of Medicine, has been a very busy person since coming to Israel in 2010 with her husband and two children. Before Technion she was an associate professor at Johns Hopkins Medical School. A neurologist who specializes in injury to the peripheral nerve, these days Murinson can be found in her laboratory and at Rambam hospital. She conducts research and works on educational projects that are designed to treat patients with acute and persistent pain; teaches medical students, both the Israeli students and those from the USA who are in TeAMS – Technion’s American medical school program; advises medical students in the USA; is an attending neurologist in the Department of Neurology at Rambam Health Care Campus and runs an outpatient clinic specializing in peripheral nerve injuries, chronic neuropathic pain and back injuries.

Murinson’s research is focused on chemotoxic and traumatic injuries to the nerve. Her two main research models address the response of growing peripheral nerve cells to exposure to a common pharmacological agent and deal with nerve injury. She is trying to determine what is the least amount of injury that will produce neuropathic pain; it is important to understand what injuries are painful and which injuries are not. Her goal is to find methodology or treatments that will help prevent induced nerve injury. There are some drugs that are widely used and taken by millions of people that have the potential to harm nerves. She also works in collaboration with the oncology group at Rambam.



“To find methodology or treatments that will help prevent induced nerve injury.”

Murinson’s academic credentials are impressive; she got an early start by graduating high school early and proceeding to receive her Bachelor’s degree in mathematics from Johns Hopkins, a Master’s from UCLA in biomathematics, and an MD/Phd (in physiology) from the University of Maryland, graduating with honors. After, she did her residency in neurology at Yale and she finished her education with a fellowship in neuroelectrophysiology back at Johns Hopkins.

It’s a wonder she found time to write a book.

Take Back Your Back is the volume to read if you are suffering from back pain. The book lets patients know everything they can do to regain control over their lives after a back injury. It provides a wealth of information on what can go wrong with the back and how patients can take charge of their own recovery.



Flaviogeranin, a new neuroprotective compound from Streptomyces sp.

Yoichi Hayakawa, Yumi Yamazaki, Maki Kurita, Takashi Kawasaki, Motoki Takagi and Kazuo Shin-ya


Cerebral ischemic disorders are one of the main causes of death. In brain ischemia, blood flow disruptions limit the supply of oxygen and glucose to neurons, initiating excitotoxic events.

Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author
The Journal of Antibiotics 63, 379-380 (July 2010) | doi:10.1038/ja.2010.49

Sarcophytolide: a new neuroprotective compound from the soft coral Sarcophyton glaucum.

F A BadriaA N GuirguisS PerovicR SteffenW E MüllerH C Schröder

Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Egypt.
Toxicology (impact factor: 3.68). 12/1998; 131(2-3):133-43.
Bioactivity-guided fractionation of an alcohol extract of the soft coral Sarcophyton glaucum collected from the intertidal areas and the fringing coral reefs near Hurghada, Red Sea, Egypt resulted in the isolation of a new lactone cembrane diterpene, sarcophytolide. The structure of this compound was deduced from its spectroscopic data and by comparison of the spectral data with those of known closely related cembrane-type compounds. In antimicrobial assays, the isolated compound exhibited a good activity towards Staphylococcus aureus, Pseudomonas aeruginosa, and Saccharomyces cerevisiae. Sarcophytolide was found to display a strong cytoprotective effect against glutamate-induced neurotoxicity in primary cortical cells from rat embryos. Preincubation of the neurons with 1 or 10 microg/ml of sarcophytolide resulted in a significant increase of the percentage of viable cells from 33 +/- 4% (treatment of the cells with glutamate only) to 44 +/- 4 and 92 +/- 6%, respectively. Administration of sarcophytolide during the post-incubation period following glutamate treatment did not prevent neuronal cell death. Pretreatment of the cells with sarcophytolide for 30 min significantly suppressed the glutamate-caused increase in the intracellular Ca2+ level ([Ca2+]i). Evidence is presented that the neuroprotective effect of sarcophytolide against glutamate may be partially due to an increased expression of the proto-oncogene bcl-2. The coral secondary metabolite, sarcophytolide, might be of interest as a potential drug for treatment of neurodegenerative disorders.

Pharmacological treatment of Alzheimer disease: From psychotropic drugs and cholinesterase inhibitors to pharmacogenomics

Cacabelos, R., et al.

Drugs Today 2000, 36(7): 415
ISSN 1699-3993
Copyright 2000 Prous Science
CCC: 1699-3993

For the past 20 years the scientific community and the pharmaceutical industry have been searching for treatments to neutralize the devastating effects of Alzheimer disease (AD). During this period important changes in the etiopathogenic concept of AD have occurred and, as a consequence, the pharmacological approach for treating AD has also changed. During the past 2 decades only 3 drugs for AD have been formally approved by the FDA, although in many countries there are several drugs which are currently used as neuroprotecting agents in dementia alone or in combination with cholinesterase inhibitors. The interest of the pharmaceutical industry has also shifted from the cholinergic hypothesis which led to the development of cholinesterase inhibitors to enhance the bioavailability of acetylcholine at the synaptic cleft to a more “molecular approach” based on new data on the pathogenic events underlying neurodegeneration in AD.

In our opinion, the pharmacological treatment of AD should rely on a better understanding of AD etiopathogenesis in order to use current drugs that protect the AD brain against deleterious events and/or to develop new drugs specifically designed to inhibit and/or regulate those factors responsible for premature neuronal death in AD. The most relevant pathogenic events in AD can be classified into 4 main categories:

  • primary events (genetic factors, neuronal apoptosis),
  • secondary events (beta-amyloid deposition in senile plaques and brain vessels, neurofibrillary tangles due to hyperphosphorylation of tau proteins, synaptic loss),
  • tertiary events (neurotransmitter deficits, neurotrophic alterations, neuroimmune dysfunction, neuroinflammatory reactions) and
  • quaternary events (excitotoxic reactions, calcium homeostasis miscarriage, free radical formation, primary and/or reactive cerebrovascular dysfunction).

All of these pathogenic events are potential targets for treatment in AD. Potential therapeutic strategies for AD treatment include palliative treatment with nonspecific neuroprotecting agents, symptomatic treatment with psychotropic drugs for noncognitive symptoms, cognitive treatment with cognition enhancers, substitutive treatment with cholinergic enhancers to improve memory deficits, multifactorial treatment using several drugs in combination and etiopathogenic treatment designed to regulate molecular factors potentially associated with AD pathogenesis.

This review discusses the conventional cholinergic enhancers (cholinesterase inhibitors, muscarinic agonists), noncholinergic strategies that have been developed with other compounds, novel combination drug strategies and future trends in drug development for AD treatment.

  • Stem-cell activation,
  • genetically manipulated cell transplantation,
  • gene therapy and
  • antisense oligonucleotide technology

constitute novel approaches for the treatment of gene-related brain damage and neuroregeneration.

The identification of an increasing number of genes associated with neuronal dysfunction along the human genome together with the influence of specific allelic associations and polymorphisms indicate that pharmacogenomics will become a preferential procedure for drug development in polygenic complex disorders. Furthermore, genetic screening of the population at risk will help to identify candidates for prevention among first-degree relatives in families with transgenerational dementia.



Dementia is a major problem of health in developed countries. Alzheimer’s disease (AD) is the main cause of dementia, accounting for 50–70% of the cases, followed by vascular dementia (30–40%) and mixed dementia (15–20%). Approximately 10–15% of direct costs in dementia are attributed to pharmacological treatment, and only 10–20% of the patients are moderate responders to conventional anti-dementia drugs, with questionable cost-effectiveness. Primary pathogenic events underlying the dementia process include genetic factors in which more than 200 different genes distributed across the human genome are involved, accompanied by progressive cerebrovascular dysfunction and diverse environmental factors. Mutations in genes directly associated with the amyloid cascade (APP, PS1, PS2) are only present in less than 5% of the AD population; however, the presence of the APOE-4 allele in the apolipoprotein E (APOE) gene represents a major risk factor for more than 40% of patients with dementia. Genotype–phenotype correlation studies and functional genomics studies have revealed the association of specific mutations in primary loci (APP, PS1, PS2) and/or APOE-related polymorphic variants with the phenotypic expression of biological traits. It is estimated that genetics accounts for 20–95% of variability in drug disposition and pharmacodynamics. Recent studies indicate that the therapeutic response in AD is genotype-specific depending upon genes associated with AD pathogenesis and/or genes responsible for drug metabolism (CYPs). In monogenic-related studies, APOE-4/4 carriers are the worst responders. In trigenic (APOE-PS1-PS2 clusters)-related studies the best responders are those patients carrying the 331222-, 341122-, 341222-, and 441112- genomic profiles. The worst responders in all genomic clusters are patients with the 441122+ genotype, indicating the powerful, deleterious effect of the APOE-4/4 genotype on therapeutics in networking activity with other AD-related genes. Cholinesterase inhibitors of current use in AD are metabolized via CYP-related enzymes. These drugs can interact with many other drugs which are substrates, inhibitors or inducers of the cytochrome P-450 system; this interaction elicits liver toxicity and other adverse drug reactions. CYP2D6-related enzymes are involved in the metabolism of more than 20% of CNS drugs. The distribution of the CYP2D6 genotypes differentiates four major categories of CYP2D6-related metabolyzer types: (a) Extensive Metabolizers (EM)(*1/*1, *1/*10)(51.61%); (b) Intermediate Metabolizers (IM) (*1/*3, *1/*4, *1/*5, *1/*6, *1/*7, *10/*10, *4/*10, *6/*10, *7/*10) (32.26%); (c) Poor Metabolizers (PM) (*4/*4, *5/*5) (9.03%); and (d) Ultra-rapid Metabolizers (UM) (*1xN/*1, *1xN/*4, Dupl) (7.10%). PMs and UMs tend to show higher transaminase activity than EMs and IMs. EMs and IMs are the best responders, and PMs and UMs are the worst responders to pharmacological treatments in AD. It seems very plausible that the pharmacogenetic response in AD depends upon the interaction of genes involved in drug metabolism and genes associated with AD pathogenesis. The establishment of clinical protocols for the practical application of pharmacogenetic strategies in AD will foster important advances in drug development, pharmacological optimization and cost-effectiveness of drugs, and personalized treatments in dementia.

Key words  dementia – Alzheimer’s disease – APOE – CYP2D6 – pharmacogenetics – pharmacogenomics – multifactorial treatments


Psychopharmacological Neuroprotection in Neurodegenerative Disease: Assessing the Preclinical Data

Edward C. Lauterbach; Jeff Victoroff; Kerry L. Coburn; Samuel D. Shillcutt; Suzanne M. Doonan; Mario F. Mendez


This manuscript reviews the preclinical in vitro, ex vivo, and nonhuman in vivo effects of psychopharmacological agents in clinical use on cell physiology with a view toward identifying agents with neuroprotective properties in neurodegenerative disease. These agents are routinely used in the symptomatic treatment of neurodegenerative disease. Each agent is reviewed in terms of its effects on pathogenic proteins, proteasomal function, mitochondrial viability, mitochondrial function and metabolism, mitochondrial permeability transition pore development, cellular viability, and apoptosis. Effects on the metabolism of the neurodegenerative disease pathogenic proteins alpha-synuclein, beta-amyloid, and tau, including tau phosphorylation, are particularly addressed, with application to Alzheimer’s and Parkinson’s diseases. Limitations of the current data are detailed and predictive criteria for translational clinical neuroprotection are proposed and discussed. Drugs that warrant further study for neuroprotection in neurodegenerative disease include pramipexole, thioridazine, risperidone, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, fluoxetine, buspirone, clonazepam, diphenhydramine, and melatonin. Those with multiple neuroprotective mechanisms include pramipexole, thioridazine, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, clonazepam, and melatonin. Those best viewed circumspectly in neurodegenerative disease until clinical disease course outcomes data become available, include several antipsychotics, lithium, oxcarbazepine, valproate, several tricyclic antidepressants, certain SSRIs, diazepam, and possibly diphenhydramine. A search for clinical studies of neuroprotection revealed only a single study demonstrating putatively positive results for ropinirole. An agenda for research on potentially neuroprotective agent is provided.

The most important detailed findings for each drug are briefly summarized in Table 1, Table 2, Table 3, and Table 4 (located online at http://neuro.psychiatryonline.org/cgi/content/full/22/1/8/DCI). The recently discovered TDP-43 was also considered while this project was underway, but no relevant articles were evident for this protein.

It is evident from the above that there is significant variation in degree of investigation, cell lines studied, and methodological approaches. Other limitations include the varying use of neural tissues, variance in the neuronal types studied, use of neuroblastoma lines instead of neurons, study of immature or poorly differentiated cells that may be more prone to apoptosis than more mature cells, and the infrequent characterization of effects on αSyn, tau, and Aβ. Such deficiencies in the data significantly confound the ability to draw definitive conclusions. In particular, the deficiencies in the data raise the question as to the most valid, clinically relevant, and appropriate standards of evidence to apply in determining which preclinical findings will predictably translate into clinical neuroprotection in patients with neurodegenerative diseases.

A number of concerns impact the selection of an appropriate standard of evidence. First, there are no established general criteria for judging preclinical neuroprotective data across the diversity of neurodegenerative diseases. Second, unlike clinical evidence-based medicine (EBM) standards, there do not appear to be established uniform criteria for judging the diversity of preclinical findings. From an EBM perspective, the data considered here are even less compelling than Class II or IV18 or Level C19clinical case reports since they generally do not pertain to findings in human patients. Third, there are considerable variabilities across the present preclinical findings with respect to intra- and extramodel replication, replications in neural tissue, the specific neural tissues studied, and the specific brain locus even when neurons are consistently studied. These are summarized in Table 5. Fourth, replications are still needed using the same physiological dose range, particularly because some have observed bell—shaped rather than sigmoid—shaped neuroprotective dose—response curves.20,21 Fifth, some drugs have mixed actions, simultaneously possessing some neuroprotective actions and other neurodegenerative actions. It is not yet clear whether the various actions should receive equal weight or whether one may trump others (for example, effects on apoptotic measures may be more determinative in importance than effects on more “upstream” processes such as mitochondrial potential or proteasomal function). Sixth, there is no gold-standard preclinical model but, instead, a diversity of models that each have their own select benefits and limitations. These and other factors likely contribute to the current disconnect between preclinical findings and neuroprotective clinical trial results.

Some criteria for considering neuroprotective candidate agents have been elaborated in Parkinson’s disease22 and stroke.23 In Parkinson’s disease, scientific rationale, penetration of the blood-brain barrier, safety and tolerability, and efficacy in relevant animal models of the disease or an indication of benefit in human clinical studies constitute criteria.22 In the case of FDA-approved psychotropics reviewed here, which essentially meet most of these criteria (with the exception of systematic, consistent application in relevant neurodegenerative disease models), the question then becomes: how good is the available preclinical evidence of neuroprotection? Ravina et al.22 noted that the most problematic issue in Parkinson’s disease was evaluating animal data given the many different models that were of uncertain value in predicting results in humans and noted further that a clinical trial would actually be needed to demonstrate the predictive validity of any preclinical model. Similarly, it is not possible to judge the quality of the present preclinical findings by the models used because the predictive validities of the models remain unclear. In stroke,23 potentially successful drug candidates have been considered to be inferable from preclinical data by the following criteria: (a) adequately defined dose-response relations; (b) time window studies showing a benefit period; (c) adequate physiological monitoring in unbiased, replicated, randomized, blinded animal studies; (d) lesion volume and functional outcome measures determined acutely and at longer term followup; (e) demonstration in two animal species; (f) submission of findings to a peer-reviewed journal. However, even with these criteria, Gladstone et al.24 have pointed out that translation of preclinical findings to clinical efficacy has been hampered by a lack of functional outcomes, long-term end points, permanent ischemia models, extended time windows, and selective white matter evaluation in preclinical models whereas clinical studies are plagued by insensitive outcome measures, lack of stroke subtype specificity, and inattention to the ischemic penumbra, among other concerns. Ford25 has also pointed out that a number of compounds fulfilling these stroke neuroprotectant criteria have failed to afford translational clinical neuroprotection. Analogous concerns obtain for neurodegenerative disease preclinical models and clinical methods, particularly whether putative criteria will reliably predict translation to clinical neuroprotection. Additionally, a nearly endless array of clinical variables including gender, age, pharmacogenomics, medical history, coadministered drugs, and other factors may contribute to an inability to predict clinical neuroprotection despite preclinical success. Thus, predictive criteria remain in need of development.

Reflection upon these translational issues in regard to psychotropic neuroprotection in neurodegenerative diseases first suggests the need for replication within and between specific preclinical models in specific neurons at specific loci to elucidate physiological dose-response relations that should then themselves be replicated as a first step. Additionally, other issues seem relevant to the problem of determining which candidate drugs may be most likely to effect clinical neuroprotection. We suggest preliminary neuroprotective drug selection criteria for assessing the likelihood of translational clinical neuroprotection in neurodegenerative diseases (Table 6). These criteria, including preclinical (at least two replicated neuroprotective actions at physiological doses in an established neuroprotective model, neural tissue, and disease-specific animal model in excess of the number of known neurodegenerative actions) and clinical (delayed progression on clinical markers and unexpected benign disease course not accounted for by symptomatic properties) criteria, can be evaluated over time and modified as future data indicate. Given the lack of information regarding the utility of specific preclinical paradigms in predicting clinical neuroprotective effects, it is premature to rank or weight these criteria. Rather, recent concerns26 notwithstanding and until a better study methodology is developed, we suspect that the greater the number of criteria met by a candidate drug, the greater the likelihood of demonstrating translational clinical neuroprotective efficacy in a randomized, double-blind, placebo-controlled, delayed-start or randomized-withdrawal clinical trial.27 Such trials are needed because agents deemed promising based upon preclinical data often fail to demonstrate neuroprotection in clinical trials for reasons identified in the above paragraph. At present, preclinical demonstration of replicable neuroprotective effects in neural tissues at clinically-relevant doses does not assure a positive result in a clinical trial, nor does the absence of such evidence necessarily exclude clinical neuroprotective benefits. Until such clinical findings obtain, it is impossible to identify preclinical determinants predictive of translational clinical success and ascertain whether patients are actually being helped or harmed in a neuroprotective sense by the use of these drugs.

Beyond the methodological concerns expressed above, a practical assessment of these preclinical findings is still possible. Given the relative infancy of this field of research, the present state of the literature, the limitations of the data described above, and our current ignorance of preclinical evidence predictive of successful clinical translation, there is the very real possibility of prematurely disregarding findings that may ultimately prove to be of clinical significance with further research (a “type II” error) by applying an overly stringent standard of evidence. It seems that, at the present time, the proper approach is to instead look at the preponderance of the available findings and attempt some generalizations that constitute general impressions to be tested in future research, similar to the process of developing and refining clinical diagnostic criteria. Accordingly, the following observations are drawn from looking at all of the studies, without any exclusions, except where there are clearly contradictory data. As noted, many of the findings have not yet been independently replicated in the same model despite apparent replication in a different model (Table 5). Until the state of the literature develops to the point where independent replications in the same model are routinely observed, appropriate assessment criteria must be very liberal, resulting in conclusions that can only be viewed as preliminary. Adopting this approach with its attending caveats, some preliminary observations can be gleaned from the data. Below, we first consider drugs with respect to their neuroprotective potentials, distinguishing drugs meriting further study from those that have limitations dissuading further investigation and those for which too little data are available to form any conclusions. (We also summarize neuroprotective effects by drug class in Appendix 1 and drugs by neuroprotective actions in Appendix 2 [located online at http://neuro.psychiatryonline.org/cgi/content/full/22/1/8/DCI%5D; Part 2 of this report focuses on the broader neuroprotective aspects of selected psychopharmacological classes.) Next, we assess the general properties of the various classes of psychotropics. We then consider each investigated cellular function with regard to the drugs that influence them. Finally, we detail a research agenda for drugs of interest and consider the progress made in clinical neuroprotective trials thus far, recommending a next step in their development.

Drugs of Neuroprotective Interest

Drugs meriting further study include:

  • pramipexole,
  • thioridazine,
  • risperidone,
  • olanzapine,
  • quetiapine,
  • lithium,
  • valproate,
  • nortriptyline,
  • desipramine,
  • maprotiline,
  • fluoxetine,
  • paroxetine,
  • buspirone,
  • clonazepam,
  • diphenhydramine, and
  • melatonin.

These are drugs with at least one significant neuroprotective action and relatively negligible countervailing neurodegeneration—promoting effects, as summarized in Table 1, Table 2, and Table 3 (especially the “Comments” column summarizing the data), and particularly Table 7 (tables located online at http://neuro.psychiatryonline.org/cgi/content/full/22/1/8/DCI).

Drugs that are not recommended for further study at the present time due to more significant limiting issues (see Table 1, Table 2, and Table 3, especially “Comments” column summarizing the data). Haloperidol does not warrant further study because of tau hyperphosphorylation, reduced cell viability, and multiple proapoptotic actions, especially in hippocampus, cortex, striatum, and nigra. Fluphenazine, chlorpromazine, and clozapine, probably do not warrant further study because of multiple proapoptotic actions, and chlorpromazine inhibits tau dephosphorylation. Carbamazepine has variable neuroprotective properties. Oxcarbazepine promotes apoptosis. Clomipramine also generally promotes apoptosis. Diazepam has mixed effects on neural apoptosis, but uncouples oxidative phosphorylation, releases cytochrome c, and promotes apoptosis in a number of neuronal models, although it promoted ATP recovery and prevented cytochrome c release in a single study of ischemic hippocampal slices.

It should be emphasized that there are no convincing clinical data at present to indicate that these drugs are unsafe for clinical use due to neurodegenerative effects, only preclinical evidence to temper enthusiasm for clinical trial application as a neuroprotectant. Until such data become available, the use of these drugs continues to be guided by clinical symptomatic indications. The limiting actions described above are considered to be significant enough to likely detract from an overall neuroprotective effect, making positive findings less likely, hence our inability to recommend them at present. It must also be recognized that some of these limitations still await replication (Table 5), and that it is presently unknown precisely which neuroprotective modes of action are positively and negatively predictive of clinical neuroprotection.

Drugs for Which Limited Data Do Not Allow Recommendations

There are currently insufficient data for ropinirole, amantadine, thiothixene, aripiprazole, ziprasidone, amitriptyline, imipramine, trimipramine, doxepin, protriptyline, bupropion, sertraline, fluvoxamine, citalopram, trazodone, nefazodone, venlafaxine, duloxetine, mirtazapine, chlordiazepoxide, flurazepam, temazepam, chlorazepate, lorazepam, oxazepam, alprazolam, zolpidem, cyproheptadine, hydroxyzine, modafinil, ramelteon, benztropine, trihexyphenidyl, and biperiden.

Briefly, regarding the neuroprotective effects of psychopharmacological classes, certain generalizations are apparent (see Appendix 1 for details). There is some evidence to suggest that D2 agonists, lithium, some SSRIs, and melatonin reduce . D2 agonists, certain atypical antipsychotics and antidepressants, and melatonin suppress . Neuroleptics, lithium, certain heterocyclic antidepressants, the central benzodiazepine receptor agonist clonazepam, and melatonin inhibit . D2 agonists, atypical antipsychotics, lithium, antidepressants, the 5HT1a agonist buspirone, and melatonin inhibit , whereas the peripheral benzodiazepine receptor agonist diazepam promotes apoptosis. These, however, are gross generalizations, which are better explained in Appendix 1 and Appendix 2. Moreover, it is potentially erroneous to project neuroprotective effects upon a pharmacological class because neuroprotective properties may not relate to their currently recognized pharmacodynamic effects.

Above, we have indicated which drugs merit further study, those which cannot be recommended due to significant limiting issues, and those with inadequate data to allow assessment. Among drugs meriting further study, Table 8 discloses the various agents along with evidential weights for their various neuroprotective actions. It can be seen that drugs that inhibit apoptosis and have at least one other general antiapoptotic action (each demonstrated by a net of two or more studies supporting a neuroprotective action, without consideration of their effects on specific proteins) include pramipexole, olanzapine, lithium, desipramine, and melatonin. The remaining agents have less robust findings supporting general neuroprotective actions. Considering the effects of these drugs on proteins and at least one other neuroprotective action in a disease-specific model, the most promising drugs in Alzheimer’s disease would include olanzapine, lithium, and melatonin while drugs with less robust support in Alzheimer’s disease include pramipexole, quetiapine, valproate, and desipramine. Applying the same criteria, drugs of promise in Parkinson’s disease include pramipexole and melatonin, while drugs with less robust support in Parkinson’s disease include olanzapine, lithium, valproate, desipramine and clonazepam. Similarly, in Huntington’s disease, desipramine is the most promising, with less robust support for lithium, valproate, nortriptyline, and maprotiline. There is some support for pramipexole, olanzapine, lithium, and nortriptyline in amyotrophic lateral sclerosis. However, as we have pointed out above, it is premature to draw any clinical conclusions from these data because of the limitations we have described and because more data will be forthcoming.

Directions for Future Research

Given this inability to draw clinical conclusions, we provide the next steps that should be undertaken in developing psychotropic research to the point that results can guide the clinical application of these drugs for neuroprotection. While it is not clear what the most predictive models of clinical neuroprotection are, and what the most important neuroprotective mechanisms are, it is apparent that some drugs are further along in their preclinical research than others. It is also clear that some seemingly paradoxical neuroprotective outcomes are seen, such as modafinil’s ability to increase glutamate release and yet reduce glutamate toxicity, and paroxetine’s ability to reduce hippocampal Aβ production in Alzheimer’s disease transgenic mice despite its anticholinergic properties that would otherwise tend to increase Aβ production. These seeming contradictions point to the need to focus on research findings rather than our current limited theoretical understanding. Thus, we outline the next research steps to be taken to elaborate findings that will move us toward establishing neuroprotective drugs that can be applied by clinicians.

Apathy Treatments

It would be of interest to investigate pramipexole in normal neurons, especially dopaminergic and cholinergic neurons.

Pramipexole should be better characterized as to its effects on αSyn, Aβ, tau, and Aβ fibril and oligomer-induced reactive oxygen species formation as well as on the proteasome and on mitochondrial metabolism. It then should be investigated in clinical neuroprotection paradigms in neurodegenerative disease, particularly Parkinson’s disease.

The next step for amantadine involves investigations in neurons.


Risperidone needs more study to determine its neuroprotective potential. Its ability to reduce Complex I activity in regions of the brain, albeit not in the midbrain, indicates the need for further research as to its long-term safety in neurodegenerative diseases affecting the hippocampus, frontal lobe, and striatum, including Alzheimer’s disease, frontotemporal lobar degeneration, and Huntington’s disease. Clinical effects tend to contraindicate its use in Parkinson’s disease.

Although olanzapine should be better characterized as to its multiple neuroprotective effects (especially on the proteasome and mitochondrial permeability transition pore development), antimuscarinic and parkinsonian clinical properties argue against its application in Alzheimer’s disease and Parkinson’s disease.

Quetiapine should be better characterized as to its effects on αSyn, Aβ, tau, the proteasome, and protection against rotenone toxicity. Further studies using Aβ and initial studies using MPP+ should be carried out, with subsequent disease-modification studies in Alzheimer’s disease and Parkinson’s disease if the preceding studies indicate safety, although antihistaminic and anticholinergic clinical properties can constitute a limitation to use in Alzheimer’s disease.

Trifluoperazine, chlorpromazine, and thioridazine might be further studied in situations where inhibition of mitochondrial permeability transition pore development is of utility.

Aripiprazole and ziprasidone should be studied for their neuroprotective properties, given their low proclivities to induce extrapyramidal side effects in people with neurodegenerative disease.

Mood Stabilizers

Lithium should be studied for neuroprotection in patients with Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and cerebral ischemia. A clinical trial in Alzheimer’s disease is currently under way.

Investigation of valproate’s ability to induce mitochondrial permeability transition pore development but not mitochondrial membrane depolarization or cytochrome c release may yield information that may help develop neuroprotective mitochondrial strategies.

Valproate might be investigated in patients with Parkinson’s disease and oncological diseases for its antiapoptotic effects in the former and proapoptotic effects in microglia and the latter. Valproate’s ability to increase αSyn concentrations may be either beneficial or detrimental in Parkinson’s disease and other synucleinopathies, and further research is needed. Activated microglia appear to be of importance in neurodegenerative diseases, especially Alzheimer’s disease. Results of a recent clinical trial in Alzheimer’s disease are not yet available.


Desipramine, nortriptyline, and maprotiline should be studied in other models of Huntington’s disease. If effective, they might be tried in other neurodegenerative disease models and in depressed patients with Huntington’s disease. Nortriptyline’s effects in Huntington’s disease yeast and amyotrophic lateral sclerosis mouse models deserve replication.

Fluoxetine has inhibited neural stem cell apoptosis, hippocampal apoptosis in newborn mice and rats and serotonin-induced apoptosis. Although it has some proapoptotic properties, fluoxetine should be studied further as a neuroprotectant in Alzheimer’s disease.

Paroxetine should be studied further for neuroprotective properties, especially in regard to reductions in Aβ and hyperphosphorylated tau.

Anxiolytics and Hypnotics

Buspirone has inhibited apoptosis in several neuronal models and now deserves study in regard to other related characteristics. If further studies indicate safety, studies in patients with neurodegenerative disease should then be undertaken.

Which types of GABA-A agonists protect against Aβ neurotoxicity and which do not requires clarification.

Clonazepam should be studied further for its restorative properties in Complex I deficiency, and should be better characterized in regard to apoptotic effects in neuronal models, especially on frontal lobe apoptosis in mature animals. If favorable results are forthcoming, it might then be tried in patients with neurodegenerative disease, especially Parkinson’s disease, although its association with falls in the elderly is a limitation.

Diphenhydramine should be further characterized in inflammatory, malignant, hypoxic, and other models where histamine plays a role.

Melatonin might now be investigated in patients with Alzheimer’s disease and in those with Parkinson’s disease.

Comprehensive Strategies

Deficiencies detailed in Table 5 deserve to be addressed in future studies. Validation of Table 6 translational predictive criteria awaits investigation. The relative predictive weightings of the various criteria also await outcome studies.

Combination therapies of psychotropics with differing profiles of neuroprotective actions may yield greater clinical impact than monotherapies. These varying profiles are depicted in Table 8. For example, across neurodegenerative diseases, the combination of lithium and melatonin might provide neuroprotective synergies, as might pramipexole, olanzapine, lithium, and nortriptyline in amyotrophic lateral sclerosis, lithium, and desipramine in Huntington’s disease, and pramipexole, lithium, desipramine, and melatonin in Alzheimer’s disease (Table 8). In Alzheimer’s disease, lithium and melatonin together might synergize efficacy at Aβ, hyperphosphorylated tau, reactive oxygen species, transition pore development, and apoptosis, with lithium perhaps improving ubiquitylation. In Parkinson’s disease, this combination plus pramipexole may synergize benefits to reactive oxygen species, transition pore, and apoptosis, with lithium perhaps improving ubiquitylation and pramipexole and melatonin perhaps synergizing efficacy on αSyn. It should be remembered, however, that some combination therapies, applied in cancer chemotherapy, have sometimes resulted in a reduced efficacy of all drugs and an increase in side-effects.28 Animal trials of proposed combinations would be a first step in evaluating their safety and efficacy.

Progress Thus Far: Clinical Trials

So far, some preliminary progress has been made in identifying the clinical neuroprotective properties of some of these agents. A search performed on October 9, 2007 using the search terms “randomized clinical trial AND (neuroprotection OR disease-modifying OR disease-modification OR disease modifying OR disease modification) for each drug revealed only one clinical neuroprotection study (ropinirole versus -dopa), and two studies evaluating glutathione reductase and a gamma interferon, relevant to disease progression, but without evaluating actual indices of clinical neuroprotection. A 6-18F-fluorodopa PET study of 186 patients with Parkinson’s disease randomized to either ropinirole or -dopa revealed a significant one third reduction in the rate of loss of dopamine terminals in subjects treated with ropinirole.29 A study of valproate plus placebo versus valproate plus melatonin in patients with epilepsy demonstrated a significant increase in glutathione reductase in the melatonin group, but no clinical indices of actual neuroprotection were evaluated in that study.30 A study in patients with relapsing-remitting multiple sclerosis identified a relationship between sertraline treatment of depression and attenuation of proinflammatory cytokine IFN-gamma, but again, actual indices of clinical neuroprotection were not assessed.31 In addition to the findings of the search, the CALM-Parkinson’s disease study involving the dopamine agonist pramipexole in Parkinson’s disease found faster progression (or at least less improvement on total UPDRS score) but slower dopamine transporter signal loss than with -dopa over 46 months,32 although the study has been criticized for lack of a placebo, group heterogeneity, and confounding influences on dopamine transporters. In contrast, a 2-year study of ropinirole found no significant difference in fluorodopa uptake compared to -dopa treatment (−13% versus −18%).33

A search of clinical trials (www.clinicaltrials.gov) on October 9, 2007 using the terms (neuroprotection OR disease-modifying OR disease-modification OR disease modifying OR disease modification) and neurodegenerative diseases revealed only a few studies in progress. These included pramipexole in amyotrophic lateral sclerosis, early versus delayed pramipexole in Parkinson’s disease, and valproate in spinal muscular atrophy. Since that time, as of February 1, 2009, additional studies have been registered. In Alzheimer’s disease, these include a short-term study of CSF tau epitopes with lithium, brain volume and clinical progression with valproate, and hippocampal volume, brain volume, and clinical progression with escitalopram. In frontotemporal dementia, there is a single study of CSF and brain volume with quetiapine versus D-amphetamine. In Huntington’s disease, there is a study of CSF BDNF levels with lithium versus valproate. In dementia with Lewy bodies and Parkinson’s disease dementia (PDD), there is a study of clinical progression with ramelteon. In Parkinson’s disease, there is a study of striatal dopamine transporter by β-CIT SPECT with pramipexole versus -dopa while an 8 year study of disability with pramipexole has been terminated. Only the spinal muscular atrophy and dementia with Lewy bodies/PDD studies employ clinical neuroprotective designs (delayed-start paradigm), and the validity of biomarker correlates, particularly dopamine transporter measures in Parkinson’s disease, continues to be studied.

The discussion above relies on multiple investigative approaches using a number of different psychotropics in a variety of models and a diversity of cell lines. A major caveat is that preclinical results do not necessarily translate into clinical realities. For example, favorable preclinical findings for the neuroprotectant minocycline exist in Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, stroke, spinal cord injury, and MS models, but a recent phase III trial in patients with amyotrophic lateral sclerosis was halted because of a 25% faster rate of neurological progression with the active drug than with placebo.34 Nevertheless, some generalizations seem possible at this stage. The considerations above are offered in hopes of stimulating the identification and development of pharmaceuticals that are useful both for symptomatic improvement and for long-term neuroprotection in neurodegenerative disease. Pursuit of the directions for research suggested above may contribute to that development.


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Reporter: Aviva Lev-Ari, PhD, RN


According to The 2012 Johns Hopkins Heart Attack Prevention White Paper by Heart Experts

Roger S. Blumenthal, M.D. 

Director, Johns Hopkins Ciccarone Center for the Prevention of Heart Disease

Professor of Medicine, Johns Hopkins University School of Medicine


Simeon Margolis, M.D., Ph.D.

Professor of Medicine and Biological Chemistry

Johns Hopkins University School of Medicine


The death rate from heart attacks has been declining steadily for many years, in large part because people are receiving better medical care. Yet too many men and women are not taking the steps that could help protect them.

It’s easier than you think. But you’d be amazed how many people ignore the #1 tool for preventing a heart attack:

What really triggers a heart attack?

What you need to know sooner rather than later.

See who’s most likely to have a heart attack. You’ll learn the most common risk factors and how to minimize them. You’ll also learn the importance of primary prevention if you haven’t been diagnosed with coronary heart disease (CHD) or suffered a heart attack.

Discover the changes that take place in the coronary arteries leading up to a heart attack.

Learn what happens during a heart attack, and how the steps you take during the first hour can affect survival.

Find out why a yearly flu shot can protect your heart. You’ll learn about the importance of taming inflammation.

Learn what your waist measurement can reveal about the health of your heart.

But this is only the beginning. Learn about the standard screening tests, and the newer, potentially better alternatives being developed.

The heart-mind connection: How cognitive behavior therapy (CBT) may help ward off a heart attack

Evidence linking the flu vaccine to lower heart attack risk.

Angina: A critical warning of heart disease that should never be ignored.

Latest thinking on how ministrokes (TIAs) lead to heart attack.

Explore new technologies that are now available to assess the health of your coronary arteries. See how the tests are done and how they compare to traditional methods of predicting future heart attacks.

You will feel far better prepared to have an intelligent conversation with your doctor about the issues that concern you most.

How great is your risk?

A close look at the factors that set the stage for heart attack.

Simply, clearly and accurately, the specialists at Johns Hopkins explain the major risk factors that lead to heart attack.

You will take a close look at the different types of lipids. Understand cholesterol’s role in your body… the difference between “good” HDL and “bad” LDL cholesterol… why reducing cholesterol levels can help prevent coronary heart disease and heart attacks… how triglycerides differ from the other lipids.

You will see how inflammation and C-reactive protein are associated with risk of heart disease and heart attack. Examine the role of blood clots and coronary artery spasms in triggering heart attacks.

You will learn which risk factors (like age and family history) can’t be changed, although knowing about them can motivate you to take the preventive steps that can LOWER your risk of heart attack.

More important you will learn which risk factors are within your control. You’ll be able to set clear, practical goals for yourself with guidance from Johns Hopkins specialists. And you’ll discover what to do if you have risk factors like high blood pressure, abdominal obesity or metabolic syndrome working against you.

Learn the MOST IMPORTANT STEPS After a Heart Attack —

Steps That Could SAVE YOUR LIFE

A special feature in The 2012 Johns Hopkins Heart Attack Prevention White Paper details essential steps you should take if you experience the warning signs of a heart attack.

Let us assure you, there is no more powerful motivator to get your cholesterol, your blood pressure and your weight under control than the threat of undergoing a heart attack sometime in the future.

This is just one of many reasons to order your own copy of The 2012 Johns Hopkins Heart Attack Prevention White Paper and start putting it to good use right away.

Direct to you from Johns Hopkins Medicine

Since 1889, Johns Hopkins researchers have advanced the development of science and medicine, quickly transferring new knowledge from the research laboratory to the patient’s bedside. The School of Medicine is the largest recipient of biomedical research funds from the National Institutes of Health, and in 2003, Johns Hopkins University’s own Peter Agre, M.D., won the Nobel Prize in chemistry.

The White Papers give Johns Hopkins an effective, affordable way to extend new knowledge to the widest possible audience, benefiting countless men and women with serious medical concerns.

When it comes to the health of your heart, you should insist on knowing where your information comes from. Check the credentials of the experts who advise you before you decide whether they are worthy of your trust.

The 2012 Johns Hopkins Heart Attack Prevention White Paper draws on the vast resources and experience of The Johns Hopkins Hospital and the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease. It gives Johns Hopkins specialists a forum to explore the combination of lifestyle adjustments and medical therapies that can slow the progression of heart disease and decrease your risk of heart attack or stroke.

Prepared by two of the most respected experts in the field

You can trust what you read in The 2012 Johns Hopkins Heart Attack Prevention White Paper. Coauthor Roger S. Blumenthal, M.D., is Professor of Medicine in the Division of Cardiology at The Johns Hopkins Hospital and the Director of the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease. His interests include the development of new strategies to manage coronary heart disease risk factors and the noninvasive detection of coronary atherosclerosis.

Co-author Simeon Margolis, M.D., Ph.D., is Professor of Medicine and Biological Chemistry at the Johns Hopkins University School of Medicine and the medical editor of The Johns Hopkins newsletter, Health After 50.

Their impeccable credentials and reputations ensure that what you read is responsible, practical and useful in your quest for a healthier heart.

You can also be sure that it reflects the latest scientific research and clinical findings.

The expertise you need, in clear, plain English you can understand and use every day

The 2012 Johns Hopkins Heart Attack Prevention White Paper brings you the latest news you can use. It’s designed with YOU in mind, the busy person who has no time, money or energy to waste on old or inaccurate information, or heart attack “prevention strategies” that are really just myths or hype.

Drug-free steps to take RIGHT NOW to lower your risk of a heart attack

The right lifestyle changes can go a long way toward bringing down high blood pressure and cholesterol levels. These simple changes may be enough to let you avoid medication altogether. But if not, making a few well-chosen adjustments in your habits can boost the effectiveness of the medications you take, perhaps even reducing the dosage you require.

How to protect against heart attacks with fiber. Find out if you are getting the recommended daily amount.

What new research reveals about calcium supplements and your risk of coronary heart disease.

What about soy? Antioxidants? Limiting your sodium? Boosting your potassium intake? Learn effective ways to get your risk factors under control through the food choices you make every day.


What counts as “exercise?”

Do you have to break a sweat before it’s good for your heart?

You’ve heard it before: regular exercise can raise HDL cholesterol, control your weight, improve the work capacity of your heart, reduce your blood pressure and blood glucose and relieve stress.

So why is it so difficult to get up off the couch and get moving?

You’ll learn how often to exercise. Whether short bursts of activity can offer the same protection as longer exercise periods when it comes to reducing risk of coronary heart disease.

And you will read how to exercise safely — a must-see if you are concerned about having a heart attack or cardiac arrest during physical activity.

“Alcohol to protect my heart? I’ll drink to that!”

Should you? Will drinking alcoholic beverages really lower your risk of heart attack, as the headlines proclaim? The 2012 Johns Hopkins Heart Attack Prevention White Paper looks at how a small amount of alcohol can help raise “good” HDL cholesterol. Discover what the research says is “enough” alcohol to reduce your risk of heart attack, and what’s “too much.”

See your heart’s health in a whole new way

Because solid, authoritative medical research stands behind the recommendations of Johns Hopkins Medicine, each White Paper includes highlights of new studies that are relevant to you.

When you have The 2012 Johns Hopkins Heart Attack Prevention White Paper, you have the power to affect your health care as never before. Use what you learn to:

Recognize and respond to symptoms and significant changes in your heart health as they occur.

Make conscious, deliberate choices in what you eat and drink and do, based on what is known to lower the risk of cardiovascular disease.

Communicate effectively with your doctor. A helpful glossary takes the mystery out of “medical-speak.” Words like ischemia and ejection fraction will lose their power to intimidate or confuse you.

You will be better equipped to ask informed questions and to understand the answers.

Make the right decisions, based on a better understanding of the newest drugs, the latest surgical techniques and the most promising research.

Take control over your condition and act out of knowledge, rather than fear.


Who will benefit from this timely intelligence?

The fact that you are reading this suggests that you’re not willing to leave your fate in others’ hands. You want to know more. You need to know more. And you’re willing to seek out the best and most current information so you can raise important issues with your own doctors.

The 2012 Johns Hopkins Heart Attack Prevention White Paper will prove valuable to you if any of the following criteria describe your personal situation.

You are being treated for high cholesterol or high blood pressure or have other cardiovascular risk factors such as diabetes, smoking, obesity or a sedentary lifestyle.

You have a family history of heart disease and want to break the pattern.

You want to reduce the likelihood of needing bypass surgery or other invasive procedures.

You have already had a heart attack and want to avoid a second one.

You realize that first heart attacks often prove fatal to women because the early warning signs — which are different from men’s — may be misunderstood or ignored.

You live with or care for someone with cardiovascular risk factors and want to do everything possible to prevent a heart attack.


The specialists at Johns Hopkins created The 2012 Johns Hopkins Heart Attack Prevention White Paper to serve as your first line of defense against a heart attack. Special Bonus: Place your order today and we will include a free gift that could, literally, save your life.


The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease takes a comprehensive approach to the management of heart health. In the FREE Special Report that you can download when you pay now for The 2012 Johns Hopkins Heart Attack Prevention White Paper, the experts share practical, specific advice on how you can slow the progression of cardiovascular disease and decrease your future risk of heart attack, stroke, bypass surgery or angioplasty.

What you need to know is yours free in Tested, Proven Ways To Save Your Heart. It’s our gift to you, when you order and pay by credit card… yours to keep and use even if you decide to return The 2012 Johns Hopkins Heart Attack Prevention White Paper for any reason.



FREE Heart Attack Prevention Special Report: 

Tested, Proven Ways To Save Your Heart

Heart Attack Prevention Strategies

The #1 Way to Prevent a Heart Attack 

The importance of smoking cessation cannot be underestimated.

Walking Your Way to a Healthier Heart 

Johns Hopkins specialists outline the best ways for starting a walking program to maximize your heart health.

Action Plan When a Heart Attack Strikes 

The crucial symptoms to look out for (which can often be different in men and inAs you wi women) and what to do and NOT do if you or a loved one starts to show the telltale signs.

Cholesterol Busting Foods

The latest research on stanols, sterols, soy, fiber, and more.

A Drink a Day for Heart Health?

Moderate alcohol intake has been suggested as a way to ward off heart attack. This special report discusses the pros and cons.


You’ll get BOTH — The 2012 Johns Hopkins Heart Attack Prevention White Paper mailed to you and your free Special Report as an instant electronic download, all for only $19.95 plus shipping and handling.

YOUR FREE GIFT shows you how to walk your way to a healthier heart. Yes, you’ve heard it again and again: Walking is a good way to protect your heart. Everyone knows how to do it. It doesn’t cost anything, and you don’t need special equipment other than the right shoes.

Do you know what a group of men did to lower their risk of coronary heart disease by 18 percent? Tested, Proven Ways to Save Your Heart reveals their winning walking approach that yielded big benefits. You will also discover:

A safe way to get started, and what’s “enough” exercise to give you the heart protection you’re after.

Is faster better? How to set a healthy pace for maximum cardiovascular benefit, and warning signs that you’re pushing too hard.

How to determine your “target” heart rate zone so your walks give you significant cardiovascular benefits.

The walking style that boosts your calorie burning by up to 10 percent.

How to make your walking plan work with the weather and your lifestyle.

Cool-down stretches that keep you from feeling sore afterward.


And so much more!

But walking is just the beginning. Your free copy of Tested, Proven Ways To Save Your Heart gives you a truly effective way to conquer your heart’s worst enemy. Despite everything the public has been taught for the last 40 years about the dangers of tobacco, cigarette smoking is responsible for about 440,000 premature deaths each year in the United States.

Smoking, or living with a smoker, can undermine your best efforts to achieve a healthy heart. Only 5 to 10 percent of people successfully quit on their own, which is why the information in this free gift is so essential. Based on vast clinical experience and knowledge of the full range of medications and techniques to help you quit, Johns Hopkins doctors give you tools that raise your chances of quitting for good.

Learn the three things that, if used in combination, give you a far greater likelihood of kicking the habit.

The latest scientific thinking on nicotine replacement gum, skin patches, nasal sprays and inhalers.

Who’s a candidate for the medications that can help reduce cravings and withdrawal symptoms.

Tips for people who have tried (perhaps many times) before without lasting success.

Why avoiding alcohol can help you avoid cigarettes…


and so much more…

The sooner you take steps to reduce your heart attack risk, the better. Prevention remains your most powerful medicine. But knowing how to respond in an emergency-whether it involves you or someone you are with-can be crucial to survival.

When heart attack strikes…

be prepared with a fast and appropriate response.

As you will learn in your free copy of Tested, Proven Ways To Save Your Heart, what you do and what you don’t do during the first crucial minutes and hours following a heart attack can make all the difference in the outcome.

Did you know that a third of all people having a heart attack never experience any chest pain at all? Your Johns Hopkins-designed “Action Plan When a Heart Attack Strikes” alerts you to the range of warning signs, including the less common ones that are more likely to occur in women.

At what point should you call an ambulance? When are you better off driving the person to the hospital instead of waiting for the ambulance to arrive? What information must the emergency personnel have right away? How do you handle the person in denial, who insists, “You’re overreacting” or “There’s nothing wrong?”

I hope you never need to use this information at all. But you’ll be much better prepared to respond calmly and effectively when you have your free gift, Tested, Proven Ways To Save Your Heart, on hand.




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