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1.  Sickle cell disease 
Clinical Evidence  2011;2011:2402.
Introduction
Sickle cell disease causes chronic haemolytic anaemia, dactylitis, and painful acute crises. It also increases the risk of stroke, organ damage, bacterial infections, and complications of blood transfusion. In sub-Saharan Africa, up to a third of adults are carriers of the defective sickle cell gene, and 1% to 2% of babies are born with the disease.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: what are the effects of pharmaceutical and non-pharmaceutical interventions to prevent sickle cell crisis and other acute complications in people with sickle cell disease? What are the effects of pharmaceutical and non-pharmaceutical interventions to treat pain in people with sickle cell crisis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 38 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, antibiotic prophylaxis in children <5 years of age, antibiotic prophylaxis in children >5 years of age, aspirin, avoidance of cold environment, blood transfusion, codeine, corticosteroid (with narcotic analgesics), diflunisal, hydration, hydroxyurea, ibuprofen, ketorolac, limiting physical exercise, malaria chemoprophylaxis, morphine (controlled-release oral after initial intravenous bolus, repeated intravenous doses), oxygen, paracetamol, patient-controlled analgesia, pneumococcal vaccines, and rehydration.
Key Points
In sub-Saharan Africa, up to a third of adults are carriers of the defective sickle cell gene, and 1% to 2% of babies are born with the disease. Sickle cell disease causes chronic haemolytic anaemia, dactylitis, and painful acute crises. It also increases the risk of stroke, organ damage, bacterial infections, and complications of blood transfusion.
We don’t know whether avoidance of cold environments, physical exercise, or rehydration can prevent crises or complications in people with sickle cell disease. Blood transfusion (prophylactic) reduces stroke in children at increased risk of stroke, but increases the risks of iron overload, allo-immunisation, hypertensive or circulatory overload, febrile non-haemolytic reactions, allergic reactions, and haemolytic events. Penicillin prophylaxis in children <5 years of age reduces invasive pneumococcal infections regardless of pneumococcal vaccination status. We don’t know whether penicillin prophylaxis is beneficial in older children. Malaria chemoprophylaxis is considered useful in preventing malaria-induced crises, but we found few studies evaluating its benefit.Polyvalent polysaccharide pneumococcal vaccine does not reduce the incidence of pneumococcal infections in people with sickle cell disease. Pneumococcal conjugate vaccines have been reported to have protective efficacy in children <2 years of age, but this protective effect has not been shown in infants with sickle cell disease.
Hydroxyurea may reduce some complications of sickle cell disease, such as painful crises compared with placebo, but long-term effects and safety are unknown.
Morphine is widely used to treat severe pain, but we found no RCT evidence comparing it with placebo in people with sickle cell crises. Controlled-release oral morphine and patient-controlled analgesia may be as effective as repeated intravenous doses of morphine. Oral morphine increases the risk of acute chest syndrome compared with intravenous administration. High-dose corticosteroids may reduce the need for analgesia when added to intravenous morphine in people with a sickle cell crisis, but may increase the risks of adverse effects (such as infections, hypertension, and metabolic problems).
It is still unclear whether acupuncture, blood transfusion, hydration, oxygen, aspirin, codeine, diflunisal, ibuprofen, ketorolac, or paracetamol reduce pain during sickle cell crisis.
PMCID: PMC3217656  PMID: 21718552
2.  Sickle cell disease 
Clinical Evidence  2009;2009:2402.
Introduction
Sickle cell disease causes chronic haemolytic anaemia, dactylitis, and painful acute crises, and increases the risk of stroke, organ damage, bacterial infections, and complications of blood transfusion. In sub-Saharan Africa, up to a third of adults are carriers of the defective sickle cell gene, and 1-2% of babies are born with the disease.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of pharmaceutical and non-pharmaceutical interventions to prevent sickle cell crisis and other acute complications in people with sickle cell disease? What are the effects of pharmaceutical and non-pharmaceutical interventions to treat pain in people with sickle cell crisis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 38 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, antibiotic prophylaxis in children under 5 years of age, aspirin, avoidance of cold environment, blood transfusion, codeine, corticosteroid (with narcotic analgesics), diflunisal, hydration, hydroxyurea, ibuprofen, ketorolac, limiting physical exercise, malaria chemoprophylaxis, morphine (controlled-release oral after initial intravenous bolus, repeated intravenous doses), oxygen, paracetamol, patient-controlled analgesia, penicillin prophylaxis in children over 5 years of age, piracetam, pneumococcal vaccines, rehydration, and zinc sulphate.
Key Points
In sub-Saharan Africa, up to a third of adults are carriers of the defective sickle cell gene, and 1-2% of babies are born with the disease. Sickle cell disease causes chronic haemolytic anaemia, dactylitis, and painful acute crises, and increases the risk of stroke, organ damage, bacterial infections, and complications of blood transfusion.
We don’t know whether avoidance of cold environments, physical exercise, or dehydration can prevent crises or complications in people with sickle cell disease. Penicillin prophylaxis in children under 5 years of age reduces invasive pneumococcal infections regardless of pneumococcal vaccination status. We don’t know whether penicillin prophylaxis is beneficial in older children. Malaria chemoprophylaxis is considered useful in preventing malaria-induced crises, but we found few studies evaluating its benefit.
Hydroxyurea, piracetam, and zinc sulphate may reduce some complications of sickle cell disease, such as painful crises, compared with placebo, but their long-term effects and safety are unknown.
Morphine is widely used to treat severe pain, but we found no RCT evidence comparing it with placebo in people with sickle cell crises. Controlled-release oral morphine and patient-controlled analgesia may be as effective as repeated intravenous doses of morphine. Oral morphine increases the risk of acute chest syndrome compared with intravenous administration.High-dose corticosteroids may reduce the need for analgesia when added to intravenous morphine in people with a sickle cell crisis, but may increase the risks of adverse effects such as infections, hypertension, and metabolic problems.
It is still unclear whether acupuncture, blood transfusion, hydration, oxygen, aspirin, codeine, diflunisal, ibuprofen, ketorolac, or paracetamol reduce pain during sickle cell crisis.
PMCID: PMC2907800  PMID: 19445751
3.  Comparison between two pedicle screw augmentation instrumentations in adult degenerative scoliosis with osteoporosis 
Background
The operative treatment of adult degenerative scoliosis combined with osteoporosis increase following the epidemiological development. Studies have confirmed that screws in osteoporotic spines have significant lower-screw strength with more frequent screw movements within the vertebra than normal spines. Screws augmented with Polymethylmethacrylate (PMMA) or with autogenous bone can offer more powerful corrective force and significant advantages.
Methods
A retrospective analysis was conducted on 31 consecutive patients with degenerative lumbar scoliosis combined with osteoporosis who had surgery from December 2000. All had a minimum of 2-year follow-up. All patients had posterior approach surgery. 14 of them were fixed with pedicle screw by augmentation with Polymethylmethacrylate (PMMA) and the other 17 patients with autogenous bone. Age, sex and whether smoking were similar between the two groups. Surgical time, blood loss, blood transfusion, medical cost, post surgery ICU time, hospital day, length of oral pain medicines taken, Pre-and postoperative Oswestry disability index questionnaire and surgical revision were documented and compared. Preoperative, postoperative and final follow up Cobb angle, sagittal lumbar curve, correction rate, and Follow up Cobb loss were also compared.
Results
No significant differences were found between the autogenous bone group and Polymethylmethacrylate group with regards to all the targets above except for length of oral pain medicines taken and surgery cost. 2 patients were seen leakage during operation, but there is neither damage of nerve nor symptom after operation. No revision was needed.
Conclusion
Both augmentation pedicle screw with Polymethylmethacrylate (PMMA) and autogenous bone treating degenerative lumbar scoliosis combined with osteoporosis can achieve a good surgical result. Less oral pain medicines taken are the potential benefits of Polymethylmethacrylate augmentation, but that is at the cost of more medical spending.
doi:10.1186/1471-2474-12-286
PMCID: PMC3268751  PMID: 22188765
Degenerative scoliosis; Osteoporosis; Pedicle screw instrumentation augmentation; Polymethylmethacrylate; Autogenous bone
4.  Red Blood Cell Transfusion and Mortality in Trauma Patients: Risk-Stratified Analysis of an Observational Study 
PLoS Medicine  2014;11(6):e1001664.
Using a large multicentre cohort, Pablo Perel and colleagues evaluate the association of red blood cell transfusion with mortality according to the predicted risk of death for trauma patients.
Please see later in the article for the Editors' Summary
Background
Haemorrhage is a common cause of death in trauma patients. Although transfusions are extensively used in the care of bleeding trauma patients, there is uncertainty about the balance of risks and benefits and how this balance depends on the baseline risk of death. Our objective was to evaluate the association of red blood cell (RBC) transfusion with mortality according to the predicted risk of death.
Methods and Findings
A secondary analysis of the CRASH-2 trial (which originally evaluated the effect of tranexamic acid on mortality in trauma patients) was conducted. The trial included 20,127 trauma patients with significant bleeding from 274 hospitals in 40 countries. We evaluated the association of RBC transfusion with mortality in four strata of predicted risk of death: <6%, 6%–20%, 21%–50%, and >50%. For this analysis the exposure considered was RBC transfusion, and the main outcome was death from all causes at 28 days. A total of 10,227 patients (50.8%) received at least one transfusion. We found strong evidence that the association of transfusion with all-cause mortality varied according to the predicted risk of death (p-value for interaction <0.0001). Transfusion was associated with an increase in all-cause mortality among patients with <6% and 6%–20% predicted risk of death (odds ratio [OR] 5.40, 95% CI 4.08–7.13, p<0.0001, and OR 2.31, 95% CI 1.96–2.73, p<0.0001, respectively), but with a decrease in all-cause mortality in patients with >50% predicted risk of death (OR 0.59, 95% CI 0.47–0.74, p<0.0001). Transfusion was associated with an increase in fatal and non-fatal vascular events (OR 2.58, 95% CI 2.05–3.24, p<0.0001). The risk associated with RBC transfusion was significantly increased for all the predicted risk of death categories, but the relative increase was higher for those with the lowest (<6%) predicted risk of death (p-value for interaction <0.0001). As this was an observational study, the results could have been affected by different types of confounding. In addition, we could not consider haemoglobin in our analysis. In sensitivity analyses, excluding patients who died early; conducting propensity score analysis adjusting by use of platelets, fresh frozen plasma, and cryoprecipitate; and adjusting for country produced results that were similar.
Conclusions
The association of transfusion with all-cause mortality appears to vary according to the predicted risk of death. Transfusion may reduce mortality in patients at high risk of death but increase mortality in those at low risk. The effect of transfusion in low-risk patients should be further tested in a randomised trial.
Trial registration
www.ClinicalTrials.gov NCT01746953
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Trauma—a serious injury to the body caused by violence or an accident—is a major global health problem. Every year, injuries caused by traffic collisions, falls, blows, and other traumatic events kill more than 5 million people (9% of annual global deaths). Indeed, for people between the ages of 5 and 44 years, injuries are among the top three causes of death in many countries. Trauma sometimes kills people through physical damage to the brain and other internal organs, but hemorrhage (serious uncontrolled bleeding) is responsible for 30%–40% of trauma-related deaths. Consequently, early trauma care focuses on minimizing hemorrhage (for example, by using compression to stop bleeding) and on restoring blood circulation after blood loss (health-care professionals refer to this as resuscitation). Red blood cell (RBC) transfusion is often used for the management of patients with trauma who are bleeding; other resuscitation products include isotonic saline and solutions of human blood proteins.
Why Was This Study Done?
Although RBC transfusion can save the lives of patients with trauma who are bleeding, there is considerable uncertainty regarding the balance of risks and benefits associated with this procedure. RBC transfusion, which is an expensive intervention, is associated with several potential adverse effects, including allergic reactions and infections. Moreover, blood supplies are limited, and the risks from transfusion are high in low- and middle-income countries, where most trauma-related deaths occur. In this study, which is a secondary analysis of data from a trial (CRASH-2) that evaluated the effect of tranexamic acid (which stops excessive bleeding) in patients with trauma, the researchers test the hypothesis that RBC transfusion may have a beneficial effect among patients at high risk of death following trauma but a harmful effect among those at low risk of death.
What Did the Researchers Do and Find?
The CRASH-2 trail included 20,127 patients with trauma and major bleeding treated in 274 hospitals in 40 countries. In their risk-stratified analysis, the researchers investigated the effect of RBC transfusion on CRASH-2 participants with a predicted risk of death (estimated using a validated model that included clinical variables such as heart rate and blood pressure) on admission to hospital of less than 6%, 6%–20%, 21%–50%, or more than 50%. That is, the researchers compared death rates among patients in each stratum of predicted risk of death who received a RBC transfusion with death rates among patients who did not receive a transfusion. Half the patients received at least one transfusion. Transfusion was associated with an increase in all-cause mortality at 28 days after trauma among patients with a predicted risk of death of less than 6% or of 6%–20%, but with a decrease in all-cause mortality among patients with a predicted risk of death of more than 50%. In absolute figures, compared to no transfusion, RBC transfusion was associated with 5.1 more deaths per 100 patients in the patient group with the lowest predicted risk of death but with 11.9 fewer deaths per 100 patients in the group with the highest predicted risk of death.
What Do These Findings Mean?
These findings show that RBC transfusion is associated with an increase in all-cause deaths among patients with trauma and major bleeding with a low predicted risk of death, but with a reduction in all-cause deaths among patients with a high predicted risk of death. In other words, these findings suggest that the effect of RBC transfusion on all-cause mortality may vary according to whether a patient with trauma has a high or low predicted risk of death. However, because the participants in the CRASH-2 trial were not randomly assigned to receive a RBC transfusion, it is not possible to conclude that receiving a RBC transfusion actually increased the death rate among patients with a low predicted risk of death. It might be that the patients with this level of predicted risk of death who received a transfusion shared other unknown characteristics (confounders) that were actually responsible for their increased death rate. Thus, to provide better guidance for clinicians caring for patients with trauma and hemorrhage, the hypothesis that RBC transfusion could be harmful among patients with trauma with a low predicted risk of death should be prospectively evaluated in a randomised controlled trial.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001664.
This study is further discussed in a PLOS Medicine Perspective by Druin Burch
The World Health Organization provides information on injuries and on violence and injury prevention (in several languages)
The US Centers for Disease Control and Prevention has information on injury and violence prevention and control
The National Trauma Institute, a US-based non-profit organization, provides information about hemorrhage after trauma and personal stories about surviving trauma
The UK National Health Service Choices website provides information about blood transfusion, including a personal story about transfusion after a serious road accident
The US National Heart, Lung, and Blood Institute also provides detailed information about blood transfusions
MedlinePlus provides links to further resources on injuries, bleeding, and blood transfusion (in English and Spanish)
More information in available about CRASH-2 (in several languages)
doi:10.1371/journal.pmed.1001664
PMCID: PMC4060995  PMID: 24937305
5.  An audit of fresh frozen plasma usage and effect of fresh frozen plasma on the pre–transfusion international normalized ratio 
Objective:
To audit the usage of fresh frozen plasma (FFP) and to study the effect of FFP on the pre-transfusion international normalized ratio (INR).
Materials and Methods:
Medical records of 100 consecutive patients who received FFP in our institute were retrospectively studied. FFP usage was classified as appropriate or inappropriate based on the guidelines by the National Health and Medical Research Council and The Australasian Society for Blood Transfusion. Pre-and post-transfusion INR were recorded and the effect of FFP on the pre-transfusion INR was studied in patients who appropriately received FFP. Relationship between the pre-transfusion INR and improvement in the INR per unit of FFP was studied using Pearson’s correlation.
Results:
Total 325 units were issued for the 100 patients (37 males and 63 females, mean age 33 years, range 1-65 years). Obstetrics and gynecology and medicine departments requested most units of FFP. Total 197 units (60.6%) in 67 patients were appropriately transfused and 128 units (39.4%) in 33 patients were inappropriately used. Mean improvement in the pre-transfusion INR per unit of FFP was 0.79 (median 0.53, range 0-3.5, SD 0.94). A significant improvement in the pre-transfusion INR per unit of FFP was seen in 64.9% patients. A linear relationship was noted between the pre-transfusion INR and improvement in INR per unit of FFP (r=0.89, degree of freedom 55).
Conclusion:
Proportion of inappropriate FFP usage remains high. A significant improvement in INR is more likely with a high pre-transfusion INR. The improvement in INR per unit of FFP is also more with higher pre-transfusion INR.
doi:10.4103/0973-6247.67024
PMCID: PMC2937290  PMID: 20859514
Audit; effect on INR; fresh frozen plasma
6.  Glucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release 
How can cancer cells survive the consequences of cyt-c release? Huber et al provide a quantitative analysis of the protective role of enhanced glucose utilization in cancer cells and investigate the impact of cell-to-cell heterogeneity in mitochondrial bioenergetics.
How can cancer cells survive the consequences of cyt-c release? Huber et al provide a quantitative analysis of the protective role of enhanced glucose utilization in cancer cells and investigate the impact of cell-to-cell heterogeneity in mitochondrial bioenergetics.
We combine ordinary differential equations based computational modelling, single-cell microscopy and in biochemistry assays to provide the first integrated system study to portray the bioenergetic crisis in cell populations subsequent to cytochrome-c (cyt-c) release; a hallmark during chemotherapeutically induced cell death.We experimentally identified a cell-to-cell heterogeneity in the dynamics of the ATP synthase subsequent to cyt-c release, which the model explained by variations in (i) accessible cytochrome-c after release and (ii) the cell's glycolytic capacity.Our model predicted, and single-cell imaging confirmed, that high (increasing) glucose in media was able to sustain (repolarise) ΔΨm in HeLa cervical cancer and MCF-7 breast cancer cells, suggesting that they might recover from bioenergetic crisis upon elevation of glucose. However, no significant repolarisation was found in non-transformed human epithelial CRL-1807 cells. Therefore, this mechanism may provide cancer cells with a competitive advantage to evade cell death induced by anticancer drugs or other stress conditions when compared with non-transformed cells.
How can cells cope with a bioenergetic crisis? In particular, how can cancer cells survive the bioenergetic consequences of cyt-c release that are often induced by chemotherapeutic agents, and that lead to depolarisation of the mitochondrial membrane potential ΔΨm, result in loss of ionic homeostasis and induce cell death? Is there an inherent population heterogeneity that can lead to a non-synchronous response to above cell death stimuli, thereby aggravating treatment and contributing to clinical relapse? Do cancer cells have a competitive advantage to non-transformed cells in averting such a bioenergetic crisis after cyt-c release. We have investigated these questions in our study, which we regard as the first rigorous system study of single-cell bioenergetics subsequent to cyt-c release and one that bridges single-cell microscopy, in vitro analysis with ordinary differential equations (ODE) based modelling of bioenergetics pathways in the mitochondria and the cytosol.
Several laboratories have so far investigated cyt-c release experimentally (Slee et al, 1999; Atlante et al, 2000; Goldstein et al, 2000; Luetjens et al, 2001; Plas et al, 2001; Waterhouse et al, 2001; Ricci et al, 2003; Colell et al, 2007; Dussmann et al, 2003a, 2003b) and isolated mitochondria (Chinopoulos and Adam-Vizi, 2009; Kushnareva et al, 2002; Kushnareva et al, 2001). However, the cause and mechanistic of several key findings remain elusive and need a system level understanding of post-cyt-c release bioenergetic and its potential cross-talk to apoptosis signalling.
Ricci et al (2003) have identified that the cell death-inducing protease caspase-3, which get activated upon cyt-c release, can further impair mitochondrial function by cleaving and deactivating respiratory complexes I and II. We addressed the question of how such a mechanism could potentiate a bioenergetic crisis. To do so, we first assembled our ODE-based model by integrating approaches from metabolic modelling (Beard, 2005; Beard and Qian, 2007; Dash and Beard, 2008) and calibrated the model to literature data that describe bioenergetic state variables (mitochondrial membrane potential ΔΨm, mitochondrial transmembrane membrane ΔpH, respiration ratio between respiring and resting state mitochondria). By remodelling cyt-c release as observed experimentally and integrating it into our model as input, the single-cell model was able to correctly describe the kinetics of ΔΨm depolarisation and allowed its quantification. Moreover, it suggested that an additional complex I/II cleavage may further impair respiration and depolarise ΔΨm by approximately further 10%.
It was further reported that ATP synthase reversal, a change of direction in the ATP-producing enzyme that leads to pumping of protons from the mitochondrial matrix into the intramembrane space, can stabilise ΔΨm. By a remnant ΔΨm polarisation, cycling of Na+, Ca2+, K+, Cl− ions and protons across the mitochondrial and the plasma membranes is preserved, and ionic homeostasis can be maintained (Nicholls and Budd, 2000; Dussmann et al, 2003a; Chinopoulos and Adam-Vizi, 2009; Garedew et al, 2010). Our model confirmed that ATP synthase activity was reversed 10 min after onset of cyt-c release, predicted that ATP synthase reversal consumed ATP and that glycolysis was required and sufficient to provide the necessary ATP to sustain this reversal. Reverting back to our single-cell HeLa system, we confirmed the presence of ATP synthase reversal. However, reversal was only present in 20% of cells, 65% of cells showed no detectable reaction and even 15% maintained ATP synthase in forward direction.
To explain this cell-to-cell heterogeneity, we modelled that a cyt-c fraction remains accessible by respiratory complexes and for respiration subsequent to release, which we denoted as ‘respiration-accessible cyt-c'. Our model suggested that small variations in such levels can sufficiently explain the experimentally detected population heterogeneity in the direction and amount of ATP synthase proton flux (Figure 6AB). Variations in respiration-accessible cyt-c may arise from incomplete mitochondrial release. Such incomplete release has been associated with failure of cristae remodelling in the absence of the BH3-only family member BID or the intramitochondrial protein OPA1 (Frezza et al, 2006; Scorrano et al, 2002).
As the model identified glycolysis as necessary for sustaining ATP synthase reversal, we next investigated cells cultured in a medium that contained Na-pyruvate instead of glucose and which consequently were not able to perform glycolysis. We found that such cell populations had a significantly higher fraction of cells that maintained ATP synthase in forward mode consistent with our model predictions. The common influence of respiration-accessible cyt-c and the cell's ability to perform glycolysis is summarised in Figure 7A.
Because glycolysis was able to influence ATP synthase proton pumping, which can affect ΔΨm levels, we investigating the effect of higher glucose in single cells. Our model predicted that an increase in glucose utilisation that generates higher cytosolic ATP levels is able to stabilise and repolarise ΔΨm and after release. This mechanism is independent from ATP synthase direction. For cells that have ATP synthase in reverse mode, elevated ATP leads to increased proton efflux from the matrix, cell populations that maintain ATP synthase in forward mode achieve a similar result through a reduction of proton influx at increased ATP. In both cases, the proton gradient along the inner membrane, and therefore ΔΨm, is increased as a consequence of ATP elevation. The mechanism is depicted in Figure 7B.
We confirmed our model predictions that high glucose was able to stabilise (cells maintained in high-glucose media) and/or to repolarise (cells where glucose was added subsequent to release) ΔΨm (Figure 6). While a similar recovery was also present in MCF7 breast cancer cell lines, no significant effect of elevated glucose was found in non-transformed CRL-1807 cells. In conjunction with an impairment of caspase-dependent cell death observed in many human cancers, cancer cells may use this mechanism, and this mechanism may provide cancer cells with a competitive advantage to evade cell death induced by anticancer drugs or other stress conditions when compared with non-transformed cells.
Many anticancer drugs activate caspases via the mitochondrial apoptosis pathway. Activation of this pathway triggers a concomitant bioenergetic crisis caused by the release of cytochrome-c (cyt-c). Cancer cells are able to evade these processes by altering metabolic and caspase activation pathways. In this study, we provide the first integrated system study of mitochondrial bioenergetics and apoptosis signalling and examine the role of mitochondrial cyt-c release in these events. In accordance with single-cell experiments, our model showed that loss of cyt-c decreased mitochondrial respiration by 95% and depolarised mitochondrial membrane potential ΔΨm from −142 to −88 mV, with active caspase-3 potentiating this decrease. ATP synthase was reversed under such conditions, consuming ATP and stabilising ΔΨm. However, the direction and level of ATP synthase activity showed significant heterogeneity in individual cancer cells, which the model explained by variations in (i) accessible cyt-c after release and (ii) the cell's glycolytic capacity. Our results provide a quantitative and mechanistic explanation for the protective role of enhanced glucose utilisation for cancer cells to avert the otherwise lethal bioenergetic crisis associated with apoptosis initiation.
doi:10.1038/msb.2011.2
PMCID: PMC3094064  PMID: 21364572
apoptosis; bioenergetics; cancer; ODE; single-cell imaging
7.  Influence of non-surgical risk factors on anastomotic leakage after major gastrointestinal surgery: Audit from a tertiary care teaching institute 
Context:
The occurence of anastomotic leakage after gastointestinal resection and anastomosis is associated with significant mortality and morbidity.
Aims:
There is dearth of evidence in the literature on the influence of various non-surgical factors in causing anastomotic leakage although many studies have identified their possible role.
Materials and Methods:
A retrospective audit of all the anastomotic leakages occurring between September 2009 and April 2012 in our institute was performed to identify the potential non-surgical factors that can influence anastomotic leakage. A total of 137 out of 1246 patients who developed anastmotic leak were analyzed. All the potential non-surgical causes of anastomotic leakage available in the literature were analyzed by univariate analysis and stepwise multiple logistic regression analysis was done after adjusting for the type of surgery. An intergroup comparison among the patients based on the type of surgery was also performed.
Results:
The following factors were found to be independently associated with increased risk of anastomotic leak: (1) albumin <3.5 g/dl, (2) anemia <8 g/dl, (3) hypotension (4) use of inotropes, and (5) blood transfusion. The majority of anastomotic leaks occurred after pancreatic surgeries followed by esophagectomies and occurred least after colonic resections. The risk for anastomotic leak was four times more in patients who required inotropic support in the perioperative period and three times more in patients who developed hypotension.
Conclusions:
Our study is the first retrospective audit to identify the influence of non-surgical factors for anastomotic leakage and the need for further observational studies in this direction.
doi:10.4103/2229-5151.124117
PMCID: PMC3891190  PMID: 24459621
Anastomotic leakage; non-surgical factors; major gastrointestinal surgery
8.  Early Metabolic Crisis-Related Brain Atrophy and Cognition in Traumatic Brain Injury 
Brain imaging and behavior  2013;7(3):307-315.
Traumatic brain injury often results in acute metabolic crisis. We recently demonstrated that this is associated with chronic brain atrophy, which is most prominent in the frontal and temporal lobes. Interestingly, the neuropsychological profile of traumatic brain injury is often characterized as ‘frontal-temporal’ in nature, suggesting a possible link between acute metabolic crisis related-brain atrophy and neurocognitive impairment in this population. While focal lesions and diffuse axonal injury have a well-established role in the neuropsychological deficits observed following traumatic brain injury, no studies to date have examined the possible contribution of acute metabolic crisis-related atrophy in the neuropsychological sequelae of traumatic brain injury. In the current study we employed positron emission tomography, magnetic resonance imaging, and neuropsychological assessments to ascertain the relationship between acute metabolic crisis related-brain atrophy and neurocognitive outcome in a sample of 14 right-handed traumatic brain injury survivors. We found that acute metabolic crisis related-atrophy in the frontal and temporal lobes was associated with poorer attention, executive functioning, and psychomotor abilities at 12 months post-injury. Furthermore, participants with gross frontal and/or temporal lobe atrophy exhibited numerous clinically significant neuropsychological deficits in contrast to participants with other patterns of brain atrophy. Our findings suggest that interventions that reduce acute metabolic crisis may lead to improved functional outcomes for traumatic brain injury survivors.
doi:10.1007/s11682-013-9231-6
PMCID: PMC4172457  PMID: 23636971
traumatic brain injury; metabolic crisis; neuropsychology; brain atrophy; neuroimaging
9.  Gender differences in severity of sickle cell diseases in non-smokers 
Pakistan Journal of Medical Sciences  2013;29(4):1050-1054.
Objective: To find out gender differences in severity of sickle cell diseases (SCDs) in non-smokers.
Methods: Three groups of SCDs patients on the basis of red blood cell (RBC) transfusions were included. Less than 10 units in their lives were kept in Group-1, Ten units of higher in Group-2 and 50 units or higher as the Third Group. Patients with a history of using one pack of cigarettes -year or above were excluded.
Results: The study included 269 patients. Mean ages of the groups were similar (28.4, 28.5, and 28.9 years, respectively). Prevalences of cases without any RBC transfusion in their lives were 7.2% and 3.7% in females and males, respectively (p<0.05). Prevalences of cases without any painful crisis were 13.8% and 6.0% in females and males, respectively (p<0.001). There was progressive increase according to mean painful crises, clubbing, chronic obstructive pulmonary disease (COPD), leg ulcers, stroke, chronic renal disease (CRD), pulmonary hypertension, and male ratio from the first towards the third groups (p<0.05, nearly for all). Mean ages of mortal cases were 29.1 and 26.2 years in females and males, respectively (p>0.05).
Conclusion: The higher painful crises per year, digital clubbing, COPD, leg ulcers, stroke, CRD, pulmonary hypertension, and male ratio of the third group, lower male ratio of patients without any RBC transfusion, lower male ratio of patients without any painful crisis, lower mean ages of male SCDs patients with mortality, and longer overall survival of females in the world could not be explained by well known strong atherosclerotic effects of smoking alone, instead it may be explained by the dominant role of male sex in life.
PMCID: PMC3817781  PMID: 24353686
Atherosclerosis; Gender differences; Sickle cell diseases; Non-smokers
10.  Current understanding of allergic transfusion reactions: incidence, pathogenesis, laboratory tests, prevention and treatment 
British Journal of Haematology  2012;160(4):434-444.
Non-haemolytic transfusion reactions are the most common type of transfusion reaction and include transfusion-related acute lung injury, transfusion-associated circulatory overload, allergic reactions, febrile reactions, post-transfusion purpura and graft-versus- host disease. Although life-threatening anaphylaxis occurs rarely, allergic reactions occur most frequently. If possible, even mild transfusion reactions should be avoided because they add to patients' existing suffering. During the last decade, several new discoveries have been made in the field of allergic diseases and transfusion medicine. First, mast cells are not the only cells that are key players in allergic diseases, particularly in the murine immune system. Second, it has been suggested that immunologically active undigested or digested food allergens in a donor's blood may be transferred to a recipient who is allergic to these antigens, causing anaphylaxis. Third, washed platelets have been shown to be effective for preventing allergic transfusion reactions, although substantial numbers of platelets are lost during washing procedures, and platelet recovery after transfusion may not be equivalent to that with unwashed platelets. This review describes allergic transfusion reactions, including the above-mentioned points, and focusses on their incidence, pathogenesis, laboratory tests, prevention and treatment.
doi:10.1111/bjh.12150
PMCID: PMC3594969  PMID: 23215650
allergic transfusion reaction; IgE; tryptase; basophil activation test; washed platelets
11.  Transfusion of red cells in hematopoietic stem cell transplantation (TRIST): study protocol for a randomized controlled trial 
Trials  2011;12:207.
Background
Insight regarding transfusion practices in Hematopoietic Stem cell Transplantation (HSCT) are lacking and the impact of red cell transfusion in this high risk group on outcomes following HSCT are not well appreciated. Red blood cell transfusion can be life-saving, however, liberal use of transfusion in critically ill patients failed to demonstrate significant clinical benefit. A large number of other observational studies have also demonstrated an association between red blood cell transfusions and increased morbidity such as infections and multi organ failure as well as increased mortality. The role of red cell transfusion on the clinical outcomes observed in patients undergoing HSCT remains poorly understood and a prospective randomized study of transfusion is required to gain insight and knowledge on best transfusion practices in this high risk population.
Methods
This report describes the design and methodological issues of a randomized pilot study evaluating red cell transfusion triggers in the setting of Hematopoietic Stem Cell Transplantation. This study has been funded by a peer review grant from the Canadian Blood Services and is registered on Clinicaltrials.gov NCT01237639.
Results
In 3 Canadian centres, 100 patients undergoing Hematopoietic Stem Cell Transplantation will be randomized to either a restrictive (target hemoglobin of 70-90 g/L) or liberal (target hemoglobin of 90-110 g/L) red cell transfusion strategy, based daily hemoglobin values up to 100 days post-transplant. The study will stratify participants by centre and type of transplant. The primary goal is to demonstrate study feasibility and we will collect clinical outcomes on 1) Transfusion Requirements, 2) Transplant Related Mortality, 3) Maximum grade of acute Graft versus Host Disease, 4) Veno-occlusive Disease, 5) Serious Infections, 6) Bearman Toxicity Score, 7) Bleeding, 8) Quality of Life, 9) Number of Hospitalizations and 10) Number of Intensive Care Unit (ICU) Admissions.
Conclusion
Upon completion, this pilot trial will provide preliminary insight into red cell transfusion practice and its influence in hematopoietic stem cell transplant outcomes. The results of this trial will inform the conduct of a larger study.
doi:10.1186/1745-6215-12-207
PMCID: PMC3187728  PMID: 21936907
Hematopoietic Stem Cell Transplant; Red cell transfusion; Erythrocyte; Triggers; Randomized Clinical Trial; Pilot
12.  Dengue haemorrhagic fever or dengue shock syndrome in children 
Clinical Evidence  2009;2009:0917.
Introduction
Dengue haemorrhagic fever and dengue shock syndrome are major causes of hospital admission and mortality in children. Up to 5% of people with dengue haemorrhagic fever die of the infection, depending on availability of appropriate supportive care.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of supportive treatments for dengue haemorrhagic fever or dengue shock syndrome in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 13 systematic reviews or RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding blood component transfusion to standard intravenous fluids; adding carbazochrome sodium sulfonate, corticosteroids, or intravenous immunoglobulin to standard intravenous fluids; adding recombinant-activated factor VII to blood component transfusion; colloids; crystalloids; and intravenous fluids.
Key Points
Infection with the dengue virus, transmitted by mosquito, ranges from asymptomatic or undifferentiated febrile illness to fatal haemorrhagic fever, and affects up to 100 million people a year worldwide. Dengue haemorrhagic fever is characterised by: a sudden onset of high fever; haemorrhages in the skin, gastrointestinal tract, and mucosa; and low platelet counts. Plasma leakage results in fluid in the abdomen and lungs. It typically occurs in children under 15 years.Severe dengue haemorrhagic fever is called dengue shock syndrome.Dengue haemorrhagic fever and dengue shock syndrome are major causes of hospital admission and mortality in children. Up to 5% of people with dengue haemorrhagic fever die of the infection, depending on availability of appropriate supportive care.
Intravenous fluids are the standard treatment to expand plasma volume and are likely to be beneficial, but studies to demonstrate their effectiveness would be unethical. Crystalloids seem as effective as colloids in children with moderately severe dengue shock syndrome, although we don't know whether they are beneficial in severe dengue shock syndrome.There is consensus that blood component transfusion (fresh frozen plasma, packed red blood cells, or platelets) should be added to intravenous fluids in children with coagulopathy or bleeding. The optimal time for beginning transfusion is unclear.
We don't know whether adding carbazochrome sodium sulfonate (AC-17), corticosteroids, intravenous immunoglobulin, or recombinant activated factor VII to standard intravenous fluids reduces the risks of shock, pleural effusion, or mortality. We also don't know whether adding recombinant activated factor VII toblood component transfusion reduces the risk of bleeding episodes, shock, or mortality.
PMCID: PMC2907812  PMID: 19445771
13.  Assessment of Impact of Training in Improving Knowledge of Blood Transfusion among Clinicians 
Summary
Background
Blood is a precious resource that needs to be prescribed, handled, stored and transfused as per guidelines to ensure recipient safety. The present study aims to assess the basic knowledge of clinicians pertaining to safe transfusion practice, impart relevant training, and assess the impact of such training programs.
Methods
A total of 25 fresh bachelor of medicine and bachelor of surgery graduates were enrolled for the study. The participants were given a pre-assessment questionnaire related to the entire transfusion chain followed by interactive training of the participants and post-training re-assessment.
Results
The mean score in the pre-training assessment was 51% while in the post-training assessment the mean score was 85.4%; the difference was statistically significant. There were significant differences in knowledge pertaining to storage temperature, shelf life of red cells and platelets, alternate group choice for fresh frozen plasma, and documentation of transfusion reaction. The participants had inadequate knowledge pertaining to cross-match procedure and management of transfusion reactions.
Conclusion
The study assessed the knowledge and awareness of clinicians regarding blood transfusion practice. Mandatory training and inclusion of transfusion medicine as a subject at undergraduate level can help in improving transfusion practice and ensuring recipient safety.
doi:10.1159/000362896
PMCID: PMC4086763  PMID: 25053936
Blood safety; Blood transfusion; Knowledge, training and awareness
14.  2008 Emily Cooley Memorial Lecture Lessons Learned from Pediatric Transfusion Medicine Clinical Trials … A Little Child Shall Lead Them 
Transfusion  2009;49(9):1996-2004.
Background
Many clinical practices in transfusion medicine are controversial and/or lack definitive guidelines established by sound clinical trials. Although recommendations based on results of clinical trials performed using infants and children may not always be applied directly to adults — and vice versa — lessons learned from pediatric trials can be useful when critically assessing the design/results/conclusions of adult trials.
Methods
Four randomized clinical trials (RCTs) studying pediatric patients were critically reviewed. They addressed two RBC transfusion issues: (1) transfusion guidelines by which RBC transfusions are “triggered” by liberal (high pretransfusion patient hematocrit levels) versus being “triggered” by restricted (low pretransfusion hematocrit levels); and (2) transfusion of fresh RBCs (≤7 days storage) versus RBCs (up to 42 days storage).
Results
Findings established by primary outcomes generally were firm (eg, fewer RBC transfusions were given to infants/children managed by restricted guidelines; transfusing small volumes of RBCs stored up to 42 days to preterm infants diminished allogeneic donor exposures and were equally efficacious and safe as fresh RBCs stored ≤7 days). Findings based on secondary outcomes, subset and post hoc analyses were inconsistent (eg, clinical outcomes were equivalent following liberal or restricted transfusions in only two of three RCTs; in the third, more neurological problems were found in neonates given restricted transfusions).
Conclusions
Clinical practices should be based on data pertaining to the primary outcomes of RCTs, as trials are designed and statistically powered to address these issues. Clinical practices suggested by analysis of secondary outcomes, subsets of patients and post hoc analyses, should be applied cautiously until studied further — ideally, as primary outcomes in subsequent RCTs.
doi:10.1111/j.1537-2995.2009.02267.x
PMCID: PMC2750829  PMID: 19527476
15.  ABO Antibody Titers are not Predictive of Hemolytic Reactions Due to Plasma Incompatible Platelet Transfusions 
Transfusion  2012;52(10):2087-2093.
Background
The overall risk of hemolytic transfusion reactions from plasma (minor) incompatible platelet transfusions and the role of a critical anti-A or anti-B titer in predicting/preventing these reactions has not been clearly established.
Methods
We evaluated all apheresis platelet (AP) transfusions for three months. Using the gel titer method, we determined the anti-A and/or the anti-B IgG titer for all incompatible APs. Reported febrile transfusion reactions and hemolytic transfusion reactions (HTRs) were recorded; transfusions were not prospectively evaluated by the study team. A post-transfusion DAT and eluate were performed after a reported febrile or hemolytic reaction for patients who received plasma incompatible APs.
Results
647of 4,288 AP transfusions (15.1%) were plasma incompatible. Group O APs (N = 278) had significantly higher anti-A and anti-B titers than group A or B APs (p<0.0001). No group A or B APs had a titer >128 (0/342). For group O APs, 73 had titers ≥256 (26.3%), and 27 had titers ≥512 (9.7%). No HTRs were reported to any plasma incompatible AP transfusion during the study period. Two plasma incompatible AP transfusions were associated with fever/chills and positive DATs, of which one had a positive eluate. The incidence of a DAT and eluate positive febrile transfusion reaction in the plasma incompatible AP population is 0.15% (95% CI 0.0–0.86%).
Conclusion
A critical anti-A or B titer is not sufficient to predict the risk of hemolysis in patients receiving plasma incompatible APs, although underreporting of reactions to the blood bank may limit the generalizability of this study.
doi:10.1111/j.1537-2995.2012.03574.x
PMCID: PMC3360137  PMID: 22339320
platelet; apheresis; ABO; antibody titer; transfusion; incompatible; febrile transfusion reaction; hemolysis
16.  Erythropoietin: current status. 
Understanding the regulation of red blood cell production has been greatly enhanced by the cloning and expression of the gene for human erythropoietin (Epo) and its receptor. The availability of recombinant human erythropoietin (rhEpo) for administration to patients has ushered in a new era in molecular medicine. Intravenous or subcutaneous administration of rhEpo can reliably cure the anemia of chronic renal failure and may be effective in the treatment of anemias secondary to chronic inflammation, malignancy, and marrow suppression from chemotherapy. In addition, rhEpo therapy will probably play a prominent role in transfusion medicine, both in preparing patients for auto-transfusions as well as in minimizing red cell transfusion requirements in the post-operative period.
PMCID: PMC2589359  PMID: 2293499
17.  What is the best strategy for the prevention of transfusion-transmitted malaria in sub-Saharan African countries where malaria is endemic? 
Malaria Journal  2013;12:465.
The transmission of malaria by blood transfusion was one of the first recorded incidents of transfusion-transmitted infections (TTIs). Although the World Health Organization (WHO) recommends that blood for transfusion should be screened for TTIs, malaria screening is not performed in most malaria-endemic countries in sub-Saharan Africa (SSA). The transfusion of infected red blood cells may lead to severe post-transfusion clinical manifestations of malaria, which could be rapidly fatal. Ensuring that blood supply in endemic countries is free from malaria is highly problematical, as most of the donors may potentially harbour low levels of malaria parasites. Pre-transfusion screening within endemic settings has been identified as a cost-effective option for prevention of transfusion-transmitted malaria (TTM). But currently, there is no screening method that is practical, affordable and suitably sensitive for use by blood banks in SSA. Even if this method was available, rejection of malaria-positive donors would considerably jeopardize the blood supply and increase morbidity and mortality, especially among pregnant women and children who top the scale of blood transfusion users in SSA. In this context, the systematic prophylaxis of recipients with anti-malarials could constitute a good alternative, as it prevents any deferral of donor units as well as the occurrence of TTM. With the on-going programme, namely the Affordable Medicine Facility - Malaria, there is an increase in the availability of low-priced artemisinin-based combination therapy that can be used for systematic prophylaxis. It appears nonetheless an urgent need to conduct cost-benefit studies in order to evaluate each of the TTM preventive methods. This approach could permit the design and implementation of an evidence-based measure of TTM prevention in SSA, advocating thereby its widespread use in the region.
doi:10.1186/1475-2875-12-465
PMCID: PMC3877868  PMID: 24373501
Malaria; Blood transfusion; Transfusion-transmitted malaria; Sub-Saharan Africa
18.  The role of the Data and Safety Monitoring Board in a clinical trial: The CRISIS Study 
Objective
Randomized clinical trials are commonly overseen by a data and safety monitoring board (DSMB) comprised of experts in medicine, ethics, and biostatistics. DSMB responsibilities include protocol approval, interim review of study enrollment, protocol compliance, safety, and efficacy data. DSMB decisions can affect study design and conduct, as well as reported findings. Researchers must incorporate DSMB oversight into the design, monitoring, and reporting of randomized trials.
Design
Case study, narrative review.
Methods
The DSMB’s role during the comparative pediatric Critical Illness Stress-Induced Immune Suppression (CRISIS) Prevention Trial is described.
Findings
The NIH-appointed CRISIS DSMB was charged with monitoring sample size adequacy and feasibility, safety with respect to adverse events and 28-day mortality, and efficacy with respect to the primary nosocomial infection/sepsis outcome. The Federal Drug Administration also requested DSMB interim review before opening CRISIS to children below one year of age. The first interim analysis found higher 28-day mortality in one treatment arm. The DSMB maintained trial closure to younger children, and requested a second interim data review six months later. At this second meeting, mortality was no longer of concern, while a weak efficacy trend of lower infection/sepsis rates in one study arm emerged. As over 40% of total patients had been enrolled, the DSMB elected to examine conditional power, and unmask treatment arm identities. Upon finding somewhat greater efficacy in the placebo arm, the DSMB recommended stopping CRISIS due to futility.
Conclusions
The design and operating procedures of a multicenter randomized trial must consider a pivotal DSMB role. Maximum study design flexibility must be allowed, and investigators must be prepared for protocol modifications due to interim findings. The DSMB must have sufficient clinical and statistical expertise to assess potential importance of interim treatment differences in the setting of multiple looks at accumulating data with numerous outcomes and subgroups.
doi:10.1097/PCC.0b013e318274568c
PMCID: PMC3648617  PMID: 23392377
clinical trials; randomized; interim analysis; safety; nosocomial infection; sepsis
19.  Indications and organisational methods for autologous blood transfusion procedures in Italy: results of a national survey 
Blood Transfusion  2014;12(4):497-508.
Introduction
Pre-operative donation of autologous blood is a practice that is now being abandoned. Alternative methods of transfusing autologous blood, other than predeposited blood, do however play a role in limiting the need for transfusion of allogeneic blood. This survey of autologous blood transfusion practices, promoted by the Italian Society of Transfusion Medicine and Immunohaematology more than 2 years after the publication of national recommendations on the subject, was intended to acquire information on the indications for predeposit in Italy and on some organisational aspects of the alternative techniques of autotransfusion.
Materials and methods
A structured questionnaire consisting of 22 questions on the indications and organisational methods of autologous blood transfusion was made available on a web platform from 15 January to 15 March, 2013. The 232 Transfusion Services in Italy were invited by e-mail to complete the online survey.
Results
Of the 232 transfusion structures contacted, 160 (69%) responded to the survey, with the response rate decreasing from the North towards the South and the Islands. The use of predeposit has decreased considerably in Italy and about 50% of the units collected are discarded because of lack of use. Alternative techniques (acute isovolaemic haemodilution and peri-operative blood salvage) are used at different frequencies across the country.
Discussion
The data collected in this survey can be considered representative of national practice; they show that the already very limited indications for predeposit autologous blood transfusion must be adhered to even more scrupulously, also to avoid the notable waste of resources due to unused units.
Users of alternative autotransfusion techniques must be involved in order to gain a full picture of the degree of use of such techniques; multidisciplinary agreement on the indications for their use is essential in order for these indications to have an effective role in “patient blood management” programmes.
doi:10.2450/2014.0295-13
PMCID: PMC4212030  PMID: 25350961
pre-operative autologous donation; patient blood management; intra-operative blood salvage; post-operative blood salvage; acute normovolaemic haemodilution
20.  The Role of the Toxicologic Pathologist in the Post-Genomic Era# 
Journal of Toxicologic Pathology  2013;26(2):105-110.
An era can be defined as a period in time identified by distinctive character, events, or practices. We are now in the genomic era. The pre-genomic era: There was a pre-genomic era. It started many years ago with novel and seminal animal experiments, primarily directed at studying cancer. It is marked by the development of the two-year rodent cancer bioassay and the ultimate realization that alternative approaches and short-term animal models were needed to replace this resource-intensive and time-consuming method for predicting human health risk. Many alternatives approaches and short-term animal models were proposed and tried but, to date, none have completely replaced our dependence upon the two-year rodent bioassay. However, the alternative approaches and models themselves have made tangible contributions to basic research, clinical medicine and to our understanding of cancer and they remain useful tools to address hypothesis-driven research questions. The pre-genomic era was a time when toxicologic pathologists played a major role in drug development, evaluating the cancer bioassay and the associated dose-setting toxicity studies, and exploring the utility of proposed alternative animal models. It was a time when there was shortage of qualified toxicologic pathologists. The genomic era: We are in the genomic era. It is a time when the genetic underpinnings of normal biological and pathologic processes are being discovered and documented. It is a time for sequencing entire genomes and deliberately silencing relevant segments of the mouse genome to see what each segment controls and if that silencing leads to increased susceptibility to disease. What remains to be charted in this genomic era is the complex interaction of genes, gene segments, post-translational modifications of encoded proteins, and environmental factors that affect genomic expression. In this current genomic era, the toxicologic pathologist has had to make room for a growing population of molecular biologists. In this present era newly emerging DVM and MD scientists enter the work arena with a PhD in pathology often based on some aspect of molecular biology or molecular pathology research. In molecular biology, the almost daily technological advances require one’s complete dedication to remain at the cutting edge of the science. Similarly, the practice of toxicologic pathology, like other morphological disciplines, is based largely on experience and requires dedicated daily examination of pathology material to maintain a well-trained eye capable of distilling specific information from stained tissue slides - a dedicated effort that cannot be well done as an intermezzo between other tasks. It is a rare individual that has true expertise in both molecular biology and pathology. In this genomic era, the newly emerging DVM-PhD or MD-PhD pathologist enters a marketplace without many job opportunities in contrast to the pre-genomic era. Many face an identity crisis needing to decide to become a competent pathologist or, alternatively, to become a competent molecular biologist. At the same time, more PhD molecular biologists without training in pathology are members of the research teams working in drug development and toxicology. How best can the toxicologic pathologist interact in the contemporary team approach in drug development, toxicology research and safety testing? Based on their biomedical training, toxicologic pathologists are in an ideal position to link data from the emerging technologies with their knowledge of pathobiology and toxicology. To enable this linkage and obtain the synergy it provides, the bench-level, slide-reading expert pathologist will need to have some basic understanding and appreciation of molecular biology methods and tools. On the other hand, it is not likely that the typical molecular biologist could competently evaluate and diagnose stained tissue slides from a toxicology study or a cancer bioassay. The post-genomic era: The post-genomic era will likely arrive approximately around 2050 at which time entire genomes from multiple species will exist in massive databases, data from thousands of robotic high throughput chemical screenings will exist in other databases, genetic toxicity and chemical structure-activity-relationships will reside in yet other databases. All databases will be linked and relevant information will be extracted and analyzed by appropriate algorithms following input of the latest molecular, submolecular, genetic, experimental, pathology and clinical data. Knowledge gained will permit the genetic components of many diseases to be amenable to therapeutic prevention and/or intervention. Much like computerized algorithms are currently used to forecast weather or to predict political elections, computerized sophisticated algorithms based largely on scientific data mining will categorize new drugs and chemicals relative to their health benefits versus their health risks for defined human populations and subpopulations. However, this form of a virtual toxicity study or cancer bioassay will only identify probabilities of adverse consequences from interaction of particular environmental and/or chemical/drug exposure(s) with specific genomic variables. Proof in many situations will require confirmation in intact in vivo mammalian animal models. The toxicologic pathologist in the post-genomic era will be the best suited scientist to confirm the data mining and its probability predictions for safety or adverse consequences with the actual tissue morphological features in test species that define specific test agent pathobiology and human health risk.
doi:10.1293/tox.26.105
PMCID: PMC3695332  PMID: 23914052
genomic era; history of toxicologic pathology; molecular biology
21.  Clinical effects of blood donor characteristics in transfusion recipients: protocol of a framework to study the blood donor–recipient continuum 
BMJ Open  2015;5(1):e007412.
Introduction
When used appropriately, transfusion of red blood cells (RBCs) is a necessary life-saving therapy. However, RBC transfusions have been associated with negative outcomes such as infection and organ damage. Seeking explanations for the beneficial and deleterious effects of RBC transfusions is necessary to ensure the safe and optimal use of this precious resource. This study will create a framework to analyse the influence of blood donor characteristics on recipient outcomes.
Methods and analysis
We will conduct a multisite, longitudinal cohort study using blood donor data routinely collected by Canadian Blood Services, and recipient data from health administrative databases. Our project will include a thorough validation of primary data, the linkage of various databases into one large longitudinal database, an in-depth epidemiological analysis and a careful interpretation and dissemination of the results to assist the decision-making process of clinicians, researchers and policymakers in transfusion medicine. Our primary donor characteristic will be age of blood donors and our secondary donor characteristics will be donor–recipient blood group compatibility and blood donor sex. Our primary recipient outcome will be a statistically appropriate survival analysis post-RBC transfusion up to a maximum of 8 years. Our secondary recipient outcomes will include 1-year, 2-year and 5-year mortality; hospital and intensive care unit length of stay; rehospitalisation; new cancer and cancer recurrence rate; infection rate; new occurrence of myocardial infarctions and need for haemodialysis.
Ethics and dissemination
Our results will help determine whether we need to tailor transfusion based on donor characteristics, and perhaps this will improve patient outcome. Our results will be customised to target the different stakeholders involved with blood transfusions and will include presentations, peer-reviewed publications and the use of the dissemination network of blood supply organisations. We obtained approval from the Research Ethics boards and privacy offices of all involved institutions.
doi:10.1136/bmjopen-2014-007412
PMCID: PMC4305074  PMID: 25600255
EPIDEMIOLOGY; HAEMATOLOGY
22.  Nuclear depletion of apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) is an indicator of energy disruption in neurons 
Free radical biology & medicine  2012;53(9):1782-1790.
Apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) is a multifunctional protein critical for cellular survival. Its involvement in adaptive survival responses includes key roles in redox sensing, transcriptional regulation and repair of DNA damage via the base excision repair (BER) pathway. Ape1 is abundant in most cell types and central in integrating the first BER step catalyzed by different DNA glycosylases. BER is the main process for removal of oxidative DNA lesions in post mitotic brain cells, and after ischemic brain injury preservation of Ape1 coincides with neuronal survival, while its loss has been associated with neuronal death. Here, we report that in cultured primary neurons, diminution of cellular ATP by either oligomycin or H2O2, is accompanied by depletion of nuclear Ape1, while other BER proteins are unaffected and retain their nuclear localization under these conditions. Importantly, while H2O2 induces γH2AX phosphorylation, indicative of chromatin rearrangements in response to DNA damage, oligomycin does not. Furthermore, despite comparable diminution of ATP content, H2O2 and oligomycin differentially affect critical parameters of mitochondrial respiration that ultimately determine cellular ATP content. Taken together, our findings demonstrate that in neurons, nuclear compartmentalization of Ape1 depends on ATP and loss of nuclear Ape1 reflects disruption of neuronal energy homeostasis. Energy crisis is a hallmark of stroke and other ischemic/hypoxic brain injuries. In vivo studies have shown that Ape1 deficit precedes neuronal loss in injured brain regions. Thus, our findings bring to light the possibility that energy failure-induced Ape1 depletion triggers neuronal death in ischemic brain injuries.
doi:10.1016/j.freeradbiomed.2012.07.025
PMCID: PMC3487712  PMID: 22841870
Ape1; ATP; neuron; base excision repair; DNA damage; mitochondrial respiration; ischemia
23.  Preventing surgical disputes through early detection and intervention: a case control study in China 
Background
Medical disputes have become a serious issue in China. A crisis cannot usually be predicted and managed through a cost–benefit strategy; therefore, researchers believe that prevention is better than containment and post-crisis resolution. This study aimed to identify solutions to prevent medical disputes in surgical cases through early warning and intervention of potential cases.
Methods
A case–control study was conducted to identify early detection indicators of medical disputes in the surgical treatment of liver cancer through Delphi consultation and logistic regression on the basis of which interventions were undertaken to prevent potential cases.
Results
The dispute detection model was composed of patient age (P = 0.08), frequency of hospitalization (P = 0.003), length of hospital stay (P < 0.001), terminal condition (P = 0.004), unplanned reoperation (P = 0.048), blood transfusion volume (P = 0.006), and arrearage (P < 0.001). Risk management interventions through quality improvement and enhanced communication in cases with an abnormal performance indicator proved effective in practice.
Conclusions
This study explored the use of an evidence-based medical risk management strategy for medical disputes that involved early detection and intervention and could potentially be adopted by hospitals to prevent medical disputes.
Electronic supplementary material
The online version of this article (doi:10.1186/s12913-014-0671-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12913-014-0671-5
PMCID: PMC4312442  PMID: 25608604
Medical disputes; Prevention; Early detection; Intervention; Surgical treatment
24.  Socio economic crisis and mortality. Epidemiological testimony of the financial collapse of Argentina 
Thrombosis Journal  2005;3:22.
Background
Natural disasters, war, and terrorist attacks, have been linked to cardiac mortality. We sought to investigate whether a major financial crisis may impact on the medical management and outcomes of acute coronary syndromes.
Methods
We analyzed the Argentine cohort of the international multicenter Global Registry of Acute Coronary Events (GRACE). The primary objective was to estimate if there was an association between the financial crisis period (April 1999 to December 2002) and in- hospital cardiovascular mortality, with the post-crisis period (January 2003 to September 2004) as the referent. Each period was defined according to the evolution of the Gross Domestic Product. We investigated the demographic characteristics, diagnostic and therapeutic procedures, morbidity and mortality.
Results
We analyzed data from 3220 patients, 2246 (69.8%) patients in the crisis period and 974 (30.2%) in the post-crisis frame. The distribution of demographic and clinical baseline characteristics were not significantly different between both periods. During the crisis period the incidence of in-hospital myocardial infarction was higher (6.9% Vs 2.9%; p value < 0.0001), as well as congestive heart failure (16% Vs 11%; p value < 0.0001). Time to intervention with angioplasty was longer during the crisis, especially among public sites (median 190 min Vs 27 min). The incidence proportion of mortality during hospitalization was 6.2% Vs 5.1% after crisis. The crude OR for mortality was 1.2 (95% C.I. 0.87, 1.7). The odds for mortality were higher among private institutions {1.9 (95% C.I. 0.9, 3.8)} than for public centers {1.2 (95% C.I. 0.83, 1.79)}. We did not observe a significant interaction between type of hospital and crisis.
Conclusion
Our findings suggest that the financial crisis may have had a negative impact on cardiovascular mortality during hospitalization, and higher incidence of medical complications.
doi:10.1186/1477-9560-3-22
PMCID: PMC1325268  PMID: 16351728
25.  Trends in Blood Transfusion Among Hospitalized Children With Sickle Cell Disease 
Pediatric blood & cancer  2013;60(11):1753-1758.
Background
Blood transfusions represent a major therapeutic option in acute management of sickle cell disease (SCD). Few data exist documenting trends in transfusion among children with SCD, particularly during hospitalization.
Procedure
This was an analysis of cross-sectional data of hospital discharges within the Kid’s Inpatient Database (years 1997, 2000, 2003, 2006, 2009). Hospitalizations for children (0–18 years) with a primary or secondary SCD-related diagnosis were examined. The primary outcome was blood transfusion. Trends in transfusion were assessed using weighted multivariate logistic regression in a merged dataset with year as the primary independent variable. Co-variables consisted of child and hospital characteristics. Multivariate logistic regression was conducted for 2009 data to assess child and hospital-level factors associated with transfusion.
Results
From 1997 to 2009, the percentage of SCD-related hospitalizations with transfusion increased from 14.2% to 28.8% (P <0.0001). Among all SCD-related hospitalizations, the odds of transfusion increased over 20% for each successive study interval. Hospitalizations with vaso-occlusive pain crisis (OR 1.35, 95% CI 1.27–1.43) or acute chest syndrome/pneumonia (OR 1.24, 95% CI 1.13–1.35) as the primary diagnoses had the highest odds of transfusion for each consecutive study interval. Older age and male gender were associated with higher odds of transfusion.
Conclusions
Blood transfusion is increasing over time among hospitalized children with SCD. Further study is warranted to identify indications contributing to the rise in transfusions and if transfusions in the inpatient setting have been used appropriately. Future studies should also assess the impact of rising trends on morbidity, mortality, and other health-related outcomes.
doi:10.1002/pbc.24630
PMCID: PMC4091906  PMID: 23775719
epidemiology; health care utilization; outcomes research; sickle cell disease

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