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.

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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

OBJECTIVE The role of tracheostomy in burn patients is controversial. Previous studies, primarily in adults, suggested that severely burned patients with tracheostomies have a higher incidence of tracheostomy site infections, mortality, and pneumonia. The purpose of this study is to determine the safety and efficacy of early tracheostomy in severely burned children. DESIGN Case series study analyzing mechanical ventilation and sedation requirements before and 24 hrs after tracheostomy. SETTING Regional pediatric burn center. PATIENTS All children admitted to a regional pediatric burn center requiring tracheostomy from March 1, 1998, to October 1, 2001. METHODS Data were recorded on patients' demographics, extent of burn, presence of inhalation injury, and mortality. Mechanical ventilation variables measured pretracheostomy (pre) and posttracheostomy (post) and included mode of ventilation, ventilator settings, peak inspiratory pressures, and arterial blood gases (Pao2, Paco2, pH, and oxygen saturation). Calculated variables included compliance, Pao2:Fio2 ratio, and minute ventilation. Tracheostomy-related variables recorded included the interval to tracheostomy insertion, the duration of tracheostomy, and tracheostomy complications. MAIN RESULTS A total of 38 patients (with a mean age of 4.7 +/- 0.6 yrs and a mean total body surface area involvement of 54% +/- 4%, 63% with inhalation injury) underwent tracheostomy a mean of 3.9 +/- 0.7 days after admission. Overall mortality was 21%. There were no tracheostomy site infections, tracheostomy-related deaths, or tracheal stenoses in survivors. Peak inspiratory pressures were lower after tracheostomy (30.4 +/- 1.4 [pre] vs. 27.6 +/- 1.5 cm H2O [post]; p <.05), ventilatory volumes were higher (190 +/- 22 mL [pre] vs. 225.5 +/- 25 [post]; p <.05), compliance improved (10.5 +/- 1.4 [pre] vs. 15.1 +/- 2.3 mL/cm H2O [post]; p <.05), and the Pao2:Fio2 ratio improved (300.6 +/- 20 [pre] vs. 348.6 +/- 16 [post]). There was no difference in oxygenation, ventilation, minute ventilation, or pH after tracheostomy. CONCLUSIONS Early tracheostomy in severely burned children is safe and effective. It provides a secure airway and may result in improvement in ventilator management for these children.

Benefits of early tracheostomy in severely burned children.

From 1984 through 1989, 24 patients with 30 acute palmar burns (six were bilateral) that required skin grafting were evaluated to compare the efficacy of split-thickness versus full-thickness autografting. Sixteen of the palms had split-thickness skin grafts and 14 had full-thickness skin grafts. Normal range of motion was found in 8 of 14 palms that were treated with full-thickness skin grafts and in 4 of 16 for those that were treated with split-thickness skin grafts. Significantly fewer reconstructive surgical procedures were required in the palm burns that were treated with full-thickness skin grafts (full-thickness = 3 of 14 and split-thickness = 10 of 16). The results demonstrate improved function and decreased need for reconstructive procedures when full-thickness skin grafts are used for the treatment of deep palm burns in young pediatric patients.

A comparison of full-thickness versus split-thickness autografts for the coverage of deep palm burns in the very young pediatric patient

Predicting mortality from burns: The need for age-group specific models

Pulse oximeters have become essential devices for evaluating and monitoring patient oxygenation. The probe emits a small amount of heat into the skin in the process of signal detection. Regulations set by the Food and Drug Administration currently limit the maximum allowable temperature of an oximeter probe to 41 degrees C. As a result of the prolonged exposure of extremities to these devices, we sought to determine the actual temperature threshold for burn injury in patients. Eighteen patients undergoing surgery for removal of redundant skin (abdominoplasty, breast reduction) consented to the application of a temperature-controlled custom probe with four light-emitting diodes that had temperatures set randomly at the expected threshold for burn injury (42.5 degrees C, 43 degrees C, 43.5 degrees C, and 44 degrees C). The probe was left in place for 8 hours (or less if significant pain was noted). The sites covered by the probes were then checked for signs of injury. On the next day, the redundant skin was removed as a scheduled procedure, and histopathology was performed to detect the extent of burn injury. The study was approved by the local institutional research board. Two patients were excluded because of technical problems with the probe, one of whom had the probe turned off because of pain. The only observed sign of injury was either erythema or a superficial blister that was usually unobservable or slightly red at operation. These subtle signs of a burn were noted in one patient at 43 degrees C, four at 43.5 degrees C, and nine at 44 degrees C. No burns were noted in two patients. Minimal or no signs of injury frequently were noted by histopathology. Pulse oximeter probes are safe up to a temperature of 43 degrees C for at least 8 hours in well-perfused skin. Above that temperature, there is a risk of burn injury. Performing temperature threshold tests in redundant skin that is planned for excision is a potential method for testing the safety of devices or materials.

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Temperature threshold for burn injury: an oximeter safety study.

Infection with HIV-1, degrading the human immune system and recent advances of drug therapy to arrest HIV-1 infection, has generated considerable research interest in the area. Bonhoeffer et al. (1997) [1] , introduced a population model representing long term dynamics of HIV infection in response to available drug therapies. We consider a similar type of approximate model incorporating time delay in the process of infection on the healthy T cells which, in turn, implies inclusion of a similar delay in the process of viral replication. The model is studied both analytically and numerically. We also include a similar delay in the killing rate of infected CD4+ T cells by Cytotoxic T-Lymphocyte (CTL) and in the stimulation of CTL and analyse two resulting models numerically. The models with no time delay present have two equilibria: one where there is no infection and a non-trivial equilibrium where the infection can persist. If there is no time delay then the non-trivial equilibrium is locally asymptotically stable. Both our analytical results (for the first model) and our numerical results (for all three models) indicate that introduction of a time delay can destabilize the non-trivial equilibrium. The numerical results indicate that such destabilization occurs at realistic time delays and that there is a threshold time delay beneath which the equilibrium with infection present is locally asymptotically stable and above which this equilibrium is unstable and exhibits oscillatory solutions of increasing amplitude.

/pdf/long-term-dynamics-in-a-mathematical-model-of-hiv-1-250b1t9d9w.pdf

David G. Greenhalgh

Papers

Benefits of early tracheostomy in severely burned children.

A comparison of full-thickness versus split-thickness autografts for the coverage of deep palm burns in the very young pediatric patient

Predicting mortality from burns: The need for age-group specific models

Temperature threshold for burn injury: an oximeter safety study.

Long term dynamics in a mathematical model of HIV-1 infection with delay in different variants of the basic drug therapy model