The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.

/pdf/apoptosis-a-review-of-programmed-cell-death-ly0ozrc0t6.pdf

Apoptosis: A Review of Programmed Cell Death

A precise definition of the basic reproduction number, Ro, is presented for a general compartmental disease transmission model based on a system of ordinary dierential equations. It is shown that, if Ro 1, then it is unstable. Thus,Ro is a threshold parameter for the model. An analysis of the local centre manifold yields a simple criterion for the existence and stability of super- and sub-threshold endemic equilibria for Ro near one. This criterion, together with the definition of Ro, is illustrated by treatment, multigroup, staged progression, multistrain and vectorhost models and can be applied to more complex models. The results are significant for disease control.

/pdf/reproduction-numbers-and-sub-threshold-endemic-equilibria-4b4f32pm0g.pdf

Reproduction numbers and sub-threshold endemic equilibria for compartmental models of disease transmission

Many models for the spread of infectious diseases in populations have been analyzed mathematically and applied to specific diseases. Threshold theorems involving the basic reproduction number $R_{0}$, the contact number $\sigma$, and the replacement number $R$ are reviewed for the classic SIR epidemic and endemic models. Similar results with new expressions for $R_{0}$ are obtained for MSEIR and SEIR endemic models with either continuous age or age groups. Values of $R_{0}$ and $\sigma$ are estimated for various diseases including measles in Niger and pertussis in the United States. Previous models with age structure, heterogeneity, and spatial structure are surveyed.

https://epubs.siam.org/doi/pdf/10.1137/S0036144500371907

The Mathematics of Infectious Diseases

Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Having a uniform standard for diagnosing and classifying AKI would enhance our ability to manage these patients. Future clinical and translational research in AKI will require collaborative networks of investigators drawn from various disciplines, dissemination of information via multidisciplinary joint conferences and publications, and improved translation of knowledge from pre-clinical research. We describe an initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI. Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a two day conference in Amsterdam, The Netherlands, in September 2005 and were assigned to one of three workgroups. Each group's discussions formed the basis for draft recommendations that were later refined and improved during discussion with the larger group. Dissenting opinions were also noted. The final draft recommendations were circulated to all participants and subsequently agreed upon as the consensus recommendations for this report. Participating societies endorsed the recommendations and agreed to help disseminate the results. The term AKI is proposed to represent the entire spectrum of acute renal failure. Diagnostic criteria for AKI are proposed based on acute alterations in serum creatinine or urine output. A staging system for AKI which reflects quantitative changes in serum creatinine and urine output has been developed. We describe the formation of a multidisciplinary collaborative network focused on AKI. We have proposed uniform standards for diagnosing and classifying AKI which will need to be validated in future studies. The Acute Kidney Injury Network offers a mechanism for proceeding with efforts to improve patient outcomes.

Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury

Secret History: Return of the Black Death Channel 4, 7-8pm In 1348 the Black Death swept through London, killing people within days of the appearance of their first symptoms. Exactly how many died, and why, has long been a mystery. This Secret History documentary follows experts as they pick through the evidence and reveal why the plague killed on such a scale. And they ask, what might be coming next?

Medscape

www.ccmjournal.org April 2015 • Volume 43 • Number 4 In this issue of Critical Care Medicine, Jeschke et al (1) from the Inflammation and the Host Response to Injury Glue Grant have reexamined their data and have concluded that there is a “cutoff” burn size for mortality, sepsis, infection, and multiple organ failure of approximately 60% total body surface area (TBSA) burn for children (< 16 yr) and 40% TBSA for adults from 16 to 65 years. They conclude that burns larger than these designated sizes are high risk for morbidity and mortality, even in highly specialized centers. I commend the authors for gleaming data from the extensive work of the “Glue Grant.” The ultimate goal of the project was to prospectively collect data from five large burn hospitals and link these data to gene expression and protein production. The goal of linking molecular and cellular signaling to clinical outcome is an excellent and important one. This article, however, simply collects clinical data with the goal to predict a “cutoff” for a marked increase in mortality (as the primary goal) and infection, sepsis, and multiple organ failure as a secondary goal. Although this goal is laudable, there are several issues that must be considered prior to making any conclusions about their study. The first question that one must ask is what does this cutoff burn size mean? Does it mean that one does not need to worry about smaller burns in that age group? Or is it just statistical analysis that indicates that the complication rate may go up significantly at a designated burn size? Clearly, children with burns of less than 60% TBSA get very sick and die, and the same is true for adults with less than 40% TBSA burns. As a matter of fact, it is the child with a relatively small burn who often surprises less experienced physicians with severe infections or sepsis. One would hate to have physicians outside of burn centers “feel comfortable” with children or adults with relatively small burns and miss a potentially life-threatening septic episode. One must agree, however, that the larger the burn, the harder it is to avoid sepsis and mortality, but one should monitor all large burns closely. The second question to be asked is—does a burn size change how you might treat a patient? Would one treat a 45% burn differently than a 70% burn? One must still aggressively excise and cover the wound, monitor for infection, and be aggressive with nutritional support. Although the treatment might be a little easier in a smaller burn, the treatment is still the same. The third concern is the surprisingly low number of patients enrolled in the study. In five centers, there were only 573 patients enrolled or 72 patients per year. There were only 226 pediatric and 324 adult patients. These limited numbers of patients make using the data less reliable compared to the current national databases such as the National Burn Registry of the American Burn Association (2, 3). The same Galveston group was able to collect data from almost twice the number of pediatric burn patients (4) and found the same result (which is not surprising since most of the patients in this study were from the same population). Most disappointing is the surprisingly low number of elderly patients (> 65 yr). They were only able to obtain consent from 23 elderly patients. As the elderly population is increasing, finding some type of predictor for mortality might be helpful. It is not clear why so few elderly were entered. Finally, the most important problem with this study, and all attempts to predict mortality, is selection bias. All of the patients included in this study had to be greater than 20% TBSA, be admitted in less than 4 days, and require some form of surgical intervention. Since, in the United States, the vast majority of burns admitted to hospitals are less than 10% TBSA and probably 85% are less than 20% TBSA. Eliminating these patients from any analysis must influence the results. Considering that the combined burn centers involved in the Glue Grant probably admit well over 1,000 patients per year, the low number included in the study is very disappointing. It would be helpful to know how many eligible patients failed to consent to the study. It must always be considered that any survival study of burns admitted to a burn center has bias since the patients must survive to make it to the tertiary referral area. Many people die before making it to a burn center. Expanding the inclusion to 4 days makes that bias more pronounced. The authors admit that Galveston patients dominate the pediatric data, which creates another obvious bias. Galveston admits predominantly children with extensive burns from Mexico. The children have to survive to make it to their facility and when they do, their outcomes are superb. Should that data be used for prediction of all pediatric burns in the United States when very few of the U.S. population are represented? It seems that it should not. Again, I commend the authors for being involved in a very important study, and this article provides statistically significant results, but the clinical relevance is not clear. Burn surgeons will treat patients with all burn sizes with the same degree of alacrity.

Can we really predict morbidity and mortality in burn patients

An age-dependent population dynamical model with a small parameter

In this issue, Dr. Bollero and colleagues have written a comprehensive summary of their treatment of acute traumatic wounds with negative pressure therapy (NPT). The authors have impressive results with very difficult wounds. They attribute much of their success to the use of NPT. They also suggest that the use of NPT has allowed for a more simplified approach to very complex wounds. In the past, flaps were the main strategy for treating these wounds but now, they simply use NPT and then they usually just need to apply skin grafts over the mostly healed wounds. The authors reveal commendable results but I must make a few comments. Being an older clinician, I lived in the ancient times ‘‘BV’’ (before vacuum therapy) and was forced to use older strategies to treat these complicated wounds. The surprising thing was that in the past (and for some of us currently) these wounds actually did heal without the use of NPT. I have lived through the days of enthusiasm for recombinant growth factors, cellular biologics and gene therapy to see that the current preferred treatment for chronic wounds is now NPT. I have been constantly hearing from my colleagues that they utilize NPT and after a few weeks, miraculously, granulation tissue develops that will accept a skin graft. I have to think to myself, however, that granulation tissue also appears with simple saline-soaked dressings! So why have the V.A.C. (KCI) and other systems become so popular? My guess is that the main reason for this enthusiasm is that NPT is easier for the clinician. In the past, the doctor (usually the medical student or intern) or the nurse would have to perform dressing changes two to three times a day. With NPT a specialized nurse only has to apply the treatment every few days. The doctor or nurse does not even have to look at the wound anymore. As these authors state, NPT does not replace debridement but after that is achieved, NPT takes over. Weeks later, the wound is ready for a graft. In this way, I guess the authors are correct; their work is easier, but is NPT really better than other treatments? If you can excuse my cynicism, I will provide an honest critique of Dr. Bollero’s paper. I hope the authors excuse my comments, which have been incited by years of reading the literature on NPT. The authors have performed a retrospective review of an assortment of wounds in 82 patients. The wound types varied from traumatic wounds to various types of chronic wounds. While it is never really clearly stated, I believe that this paper is only reviewing the traumatic wounds. It is a shame that the authors did not include the other half of their patients in this publication, but I guess those results would be reported elsewhere. Even with restricting this paper to trauma patients, the authors include a wide variation in the types of wounds. Included in their analysis are one burn patient and one necrotizing soft tissue infection. Most burns do not require NPT for treatment and necrotizing infections clearly need aggressive debridement before any coverage. In addition, eight patients (around 10%) required amputation; so how did these patients figure in the efficacy of NPT? Another comment has to be challenged. The authors state in the Methods that ‘‘pain was reported to be well-tolerated at dressing changes. In fact, no pharmacological sedation or anaesthesia was required.’’ Later in the results, the authors state that ‘‘continuous negative pressure was better tolerated than intermittent mode.’’ I guess that there was some discomfort. One final comment has to be made, the authors state that ‘‘NPT was started the day after primary surgery for a better bleeding control . . . .’’ I hope that NPT is not a substitute for adequate bleeding control. As a matter of fact, our institution has had a case of significant blood loss that was attributed to the NPT device ‘‘sucking’’ the blood into the bucket, with no one noticing the amount of hemorrhage. Let me get down to the real meat of the paper. Did the use of NPT really improve the wound care of these patients? The authors were able to cover the wounds with skin grafts in 66% of the cases. The number of flaps was reduced compared with the numbers performed in the past. But why did the numbers of flaps go down? It would seem to me that the real reason is surgeon preference. I suspect that in the past, plastic surgeons were comfortable with performing flaps and preferred to perform flaps rather than wait for the wound to granulate. I suspect that if they had treated the wounds conservatively they would have had similar outcomes compared with the current caregivers. The current paper suggests that NPT leads to a better outcome but the ultimate outcome at a mean follow-up of 265 days was good in only 76% of cases. I wonder what the outcome at 9 months was before NPT. So, I guess that I can agree with the statement that NPT ‘‘is at least as fast as with the modern advanced wound dressing . . . .’’ What I really want, however, is for someone to perform a real prospective, blinded, randomized clinical trial to determine whether NPT is better than conventional therapy. Until then, my cynicism will persist.

Negative pressure therapy, a panacea or not?

Corynebacterium parvum impairs wound healing

American Burn Association Past President Palmer Q. Bessey, MD, orchestrated a Burn Workforce Conference in Washington, DC in February, 2014, with the goal of evaluating the workforce needs for doctors, nurses, and occupational/physical therapists. This report summarizes the issues related to the need for training future surgeons to manage burn patients. General surgery and plastic surgery residents currently have minimal requirements for burn experience during their training. The respective Boards, however, do require knowledge in the management of burn care. The number of surgeons entering burn fellowships is limited to approximately 10 per year and there are only a handful of burn fellowship programs to train future burn surgeons. A survey sent to burn surgeons revealed that the current workforce is aging and needs to a constant supply of new physicians. It is clear that there is a need to formalize burn fellowships and it was felt that the American Burn Association should be responsible for accreditation of those fellowships.

David G. Greenhalgh

Papers

Can we really predict morbidity and mortality in burn patients

An age-dependent population dynamical model with a small parameter

Negative pressure therapy, a panacea or not?

Corynebacterium parvum impairs wound healing

Building the Burn Physician Workforce for the 21st Century: Report From February 2014 Burns Workforce Conference