Why Death Matters: Understanding Gameworld Experience

This article presents a study of the staging and implementation of death and the death penalty in a number of popular MMOGs and relates it to players general experience of gameworlds. Game mechanics, writings and stories by designers and players, and the results of an online survey are analysed and discussed. The study shows that the death penalty is implemented much in the same way across worlds; that death can be both trivial and non-trivial, part of the grind of everyday life, or essential in the creation of heroes, depending on context. In whatever function death may serves, it is argued that death plays an important part in the shaping and emergence of the social culture of a world, and in the individual players experience of life within it.

Sellar fracture followed by sudden death: an autopsy case

The authors describe a case of sellar fracture followed by sudden death. The victim was involved in a wrangle. The autopsy revealed facial damage and sellar fracture and no evidence of cerebral damage, except for a mild subarachnoid hemorrhage in the left parietotemporal regions and undersurface of both frontal lobes. Sellar fracture is a rare and severe entity, associated with serious complications, which is frequently diagnosed postmortem. In any case, death is rarely a direct consequence of the sellar fracture itself and is usually considered to be the result of associated cerebral trauma. This case prompted us to screen the literature on sellar fracture to gain a better understanding of the mechanism of death.

Cell death in immune thrombocytopenia: novel insights and perspectives

Immune thrombocytopenia (ITP) is a complex disease. The pathogenic and clinical heterogeneity of ITP is reflected by reports on variability in patient history and treatment response, in concert with recent evidence from mechanistic studies. Programmed cell death (PCD) pathways are thought to play a peculiar role in the megakaryocyte lineage in terms of hemostasis and the generation and function of megakaryocytes and platelets; unbalanced genetic or environmental disturbances of these tightly regulated pathways may cause thrombocytopenia. Dysregulated PCD has also been linked to peripheral platelet destruction, intramedullary apoptosis, and inefficient thrombopoiesis in ITP. In this article, we discuss novel and controversial findings on the role of PCD in the megakaryocyte lineage and their potential implications in terms of pathogenesis, diagnosis, and treatment of ITP.

Nitric oxide induces cell death in canine cruciate ligament cells by activation of tyrosine kinase and reactive oxygen species

BACKGROUND: There is increasing evidence suggesting that development of progressive canine cranial cruciate ligament (CCL) rupture involves a gradual degeneration of the CCL itself, initiated by a combination of factors, ranging from mechanical to biochemical. To date, knowledge is lacking to what extent cruciate disease results from abnormal biomechanics on a normal ligament or contrary how far preliminary alterations of the ligament due to biochemical factors provoke abnormal biomechanics. This study is focused on nitric oxide (NO), one of the potential biochemical factors. The NO-donor sodium nitroprusside (SNP) has been used to study NO-dependent cell death in canine cranial and caudal cruciate ligament cells and to characterize signaling mechanisms during NO-stimulation. RESULTS: Sodium nitroprusside increased apoptotic cell death dose- and time-dependently in cruciate ligamentocytes. Cells from the CCL were more susceptible to apoptosis than CaCL cells. Caspase-3 processing in response to SNP was not detected. Testing major upstream and signal transducing pathways, NO-induced cruciate ligament cell death seemed to be mediated on different levels. Specific inhibition of tyrosine kinase significantly decreased SNP-induced cell death. Mitogen activated protein kinase ERK1 and 2 are activated upon NO and provide anti-apoptotic signals whereas p38 kinase and protein kinase C are not involved. Moreover, data showed that the inhibition reactive oxygen species (ROS) significantly reduced the level of cruciate ligament cell death. CONCLUSIONS: Our data support the hypothesis that canine cruciate ligamentocytes, independently from their origin (CCL or CaCL) follow crucial signaling pathways involved in NO-induced cell death. However, the difference on susceptibility upon NO-mediated apoptosis seems to be dependent on other pathways than on these tested in the present study. In both, CCL and CaCL, the activation of the tyrosine kinase and the generation of ROS reveal important signaling pathways. In perspective, new efforts to prevent the development and progression of cruciate disease may include strategies aimed at reducing ROS.

Risk factors for death and unwanted early slaughter in Swiss veal calves kept at a specific animal welfare standard

Calf losses (CL, mortality and unwanted early slaughter) in veal production are of great economic importance and an indicator of welfare. The objective of the present study was to evaluate CL and the causes of death on farms with a specific animal welfare standard (SAW) which exceeds the Swiss statutory regulations. Risk factors for CL were identified based on information about management, housing, feeding, and medication. In total, 74 production cohorts (2783 calves) of 15 farms were investigated. CL was 3.6%, the main causes of death were digestive disorders (52%), followed by respiratory diseases (28%). Factors significantly associated with an increased risk for CL were a higher number of individual daily doses of antibiotics (DDA), insufficient wind deflection in winter, and male gender. For administration of antibiotics to all calves of the cohort, a DDA of 14-21 was associated with a decreased risk for CL compared to a DDA of 7-13 days.

Inhibition of Fas-associated death domain-containing protein (FADD) protects against myocardial ischemia/reperfusion injury in a heart failure mouse model

AIM As technological interventions treating acute myocardial infarction (MI) improve, post-ischemic heart failure increasingly threatens patient health. The aim of the current study was to test whether FADD could be a potential target of gene therapy in the treatment of heart failure. METHODS Cardiomyocyte-specific FADD knockout mice along with non-transgenic littermates (NLC) were subjected to 30 minutes myocardial ischemia followed by 7 days of reperfusion or 6 weeks of permanent myocardial ischemia via the ligation of left main descending coronary artery. Cardiac function were evaluated by echocardiography and left ventricular (LV) catheterization and cardiomyocyte death was measured by Evans blue-TTC staining, TUNEL staining, and caspase-3, -8, and -9 activities. In vitro, H9C2 cells transfected with ether scramble siRNA or FADD siRNA were stressed with chelerythrin for 30 min and cleaved caspase-3 was assessed. RESULTS FADD expression was significantly decreased in FADD knockout mice compared to NLC. Ischemia/reperfusion (I/R) upregulated FADD expression in NLC mice, but not in FADD knockout mice at the early time. FADD deletion significantly attenuated I/R-induced cardiac dysfunction, decreased myocardial necrosis, and inhibited cardiomyocyte apoptosis. Furthermore, in 6 weeks long term permanent ischemia model, FADD deletion significantly reduced the infarct size (from 41.20 ± 3.90% in NLC to 26.83 ± 4.17% in FADD deletion), attenuated myocardial remodeling, improved cardiac function and improved survival. In vitro, FADD knockdown significantly reduced chelerythrin-induced the level of cleaved caspase-3. CONCLUSION Taken together, our results suggest FADD plays a critical role in post-ischemic heart failure. Inhibition of FADD retards heart failure progression. Our data supports the further investigation of FADD as a potential target for genetic manipulation in the treatment of heart failure.

Short- and long-term mortality and causes of death in HIV/tuberculosis patients in Europe

Mortality of HIV/tuberculosis (TB) patients in Eastern Europe is high. Little is known about their causes of death. This study aimed to assess and compare mortality rates and cause of death in HIV/TB patients across Eastern Europe and Western Europe and Argentina (WEA) in an international cohort study. Mortality rates and causes of death were analysed by time from TB diagnosis (<3 months, 3-12 months or >12 months) in 1078 consecutive HIV/TB patients. Factors associated with TB-related death were examined in multivariate Poisson regression analysis. 347 patients died during 2625 person-years of follow-up. Mortality in Eastern Europe was three- to ninefold higher than in WEA. TB was the main cause of death in Eastern Europe in 80%, 66% and 61% of patients who died <3 months, 3-12 months or >12 months after TB diagnosis, compared to 50%, 0% and 15% in the same time periods in WEA (p<0.0001). In multivariate analysis, follow-up in WEA (incidence rate ratio (IRR) 0.12, 95% CI 0.04-0.35), standard TB-treatment (IRR 0.45, 95% CI 0.20-0.99) and antiretroviral therapy (IRR 0.32, 95% CI 0.14-0.77) were associated with reduced risk of TB-related death. Persistently higher mortality rates were observed in HIV/TB patients in Eastern Europe, and TB was the dominant cause of death at any time during follow-up. This has important implications for HIV/TB programmes aiming to optimise the management of HIV/TB patients and limit TB-associated mortality in this region.

Cardiac channel molecular autopsy: insights from 173 consecutive cases of autopsy-negative sudden unexplained death referred for postmortem genetic testing

OBJECTIVE To perform long QT syndrome and catecholaminergic polymorphic ventricular tachycardia cardiac channel postmortem genetic testing (molecular autopsy) for a large cohort of cases of autopsy-negative sudden unexplained death (SUD). METHODS From September 1, 1998, through October 31, 2010, 173 cases of SUD (106 males; mean ± SD age, 18.4 ± 12.9 years; age range, 1-69 years; 89% white) were referred by medical examiners or coroners for a cardiac channel molecular autopsy. Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, a comprehensive mutational analysis of the long QT syndrome susceptibility genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) and a targeted analysis of the catecholaminergic polymorphic ventricular tachycardia type 1-associated gene (RYR2) were conducted. RESULTS Overall, 45 putative pathogenic mutations absent in 400 to 700 controls were identified in 45 autopsy-negative SUD cases (26.0%). Females had a higher yield (26/67 [38.8%]) than males (19/106 [17.9%]; P<.005). Among SUD cases with exercise-induced death, the yield trended higher among the 1- to 10-year-olds (8/12 [66.7%]) compared with the 11- to 20-year-olds (4/27 [14.8%]; P=.002). In contrast, for those who died during a period of sleep, the 11- to 20-year-olds had a higher yield (9/25 [36.0%]) than the 1- to 10-year-olds (1/24 [4.2%]; P=.01). CONCLUSION Cardiac channel molecular autopsy should be considered in the evaluation of autopsy-negative SUD. Several interesting genotype-phenotype observations may provide insight into the expected yields of postmortem genetic testing for SUD and assist in selecting cases with the greatest potential for mutation discovery and directing genetic testing efforts.

Loss-of-function mutations in the KCNJ8-encoded Kir6.1 K(ATP) channel and sudden infant death syndrome.

BACKGROUND Approximately 10% of sudden infant death syndrome (SIDS) may stem from cardiac channelopathies. The KCNJ8-encoded Kir6.1 (K(ATP)) channel critically regulates vascular tone and cardiac adaptive response to systemic metabolic stressors, including sepsis. KCNJ8-deficient mice are prone to premature sudden death, particularly with infection. We determined the spectrum, prevalence, and function of KCNJ8 mutations in a large SIDS cohort. METHODS AND RESULTS Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, comprehensive open reading frame/splice-site mutational analysis of KCNJ8 was performed on genomic DNA isolated from necropsy tissue on 292 unrelated SIDS cases (178 males, 204 white; age, 2.9±1.9 months). KCNJ8 mutations were coexpressed heterologously with SUR2A in COS-1 cells and characterized using whole-cell patch-clamp. Two novel KCNJ8 mutations were identified. A 5-month-old white male had an in-frame deletion (E332del) and a 2-month-old black female had a missense mutation (V346I). Both mutations localized to Kir6.1's C-terminus, involved conserved residues and were absent in 400 and 200 ethnic-matched reference alleles respectively. Both cases were negative for mutations in established channelopathic genes. Compared with WT, the pinacidil-activated K(ATP) current was decreased 45% to 68% for Kir6.1-E332del and 40% to 57% for V346I between -20 mV and 40 mV. CONCLUSIONS Molecular and functional evidence implicated loss-of-function KCNJ8 mutations as a novel pathogenic mechanism in SIDS, possibly by predisposition of a maladaptive cardiac response to systemic metabolic stressors akin to the mouse models of KCNJ8 deficiency.

Sudden infant death syndrome-associated mutations in the sodium channel beta subunits.

BACKGROUND Approximately 10% of sudden infant death syndrome (SIDS) cases may stem from potentially lethal cardiac channelopathies, with approximately half of channelopathic SIDS involving the Na(V)1.5 cardiac sodium channel. Recently, Na(V) beta subunits have been implicated in various cardiac arrhythmias. Thus, the 4 genes encoding Na(V) beta subunits represent plausible candidate genes for SIDS. OBJECTIVE This study sought to determine the spectrum, prevalence, and functional consequences of sodium channel beta-subunit mutations in a SIDS cohort. METHODS In this institutional review board-approved study, mutational analysis of the 4 beta-subunit genes, SCN1B to 4B, was performed using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing of DNA derived from 292 SIDS cases. Engineered mutations were coexpressed with SCN5A in HEK 293 cells and were whole-cell patch clamped. One of the putative SIDS-associated mutations was similarly studied in adenovirally transduced adult rat ventricular myocytes. RESULTS Three rare (absent in 200 to 800 reference alleles) missense mutations (beta3-V36M, beta3-V54G, and beta4-S206L) were identified in 3 of 292 SIDS cases. Compared with SCN5A+beta3-WT, beta3-V36M significantly decreased peak I(Na) and increased late I(Na), whereas beta3-V54G resulted in a marked loss of function. beta4-S206L accentuated late I(Na) and positively shifted the midpoint of inactivation compared with SCN5A+beta4-WT. In native cardiomyocytes, beta4-S206L accentuated late I(Na) and increased the ventricular action potential duration compared with beta4-WT. CONCLUSION This study provides the first molecular and functional evidence to implicate the Na(V) beta subunits in SIDS pathogenesis. Altered Na(V)1.5 sodium channel function due to beta-subunit mutations may account for the molecular pathogenic mechanism underlying approximately 1% of SIDS cases.

Alpha1-syntrophin mutations identified in sudden infant death syndrome cause an increase in late cardiac sodium current.

BACKGROUND Sudden infant death syndrome (SIDS) is a leading cause of death during the first 6 months after birth. About 5% to 10% of SIDS may stem from cardiac channelopathies such as long-QT syndrome. We recently implicated mutations in alpha1-syntrophin (SNTA1) as a novel cause of long-QT syndrome, whereby mutant SNTA1 released inhibition of associated neuronal nitric oxide synthase by the plasma membrane Ca-ATPase PMCA4b, causing increased peak and late sodium current (I(Na)) via S-nitrosylation of the cardiac sodium channel. This study determined the prevalence and functional properties of SIDS-associated SNTA1 mutations. METHODS AND RESULTS Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing of SNTA1's open reading frame, 6 rare (absent in 800 reference alleles) missense mutations (G54R, P56S, T262P, S287R, T372M, and G460S) were identified in 8 (approximately 3%) of 292 SIDS cases. These mutations were engineered using polymerase chain reaction-based overlap extension and were coexpressed heterologously with SCN5A, neuronal nitric oxide synthase, and PMCA4b in HEK293 cells. I(Na) was recorded using the whole-cell method. A significant 1.4- to 1.5-fold increase in peak I(Na) and 2.3- to 2.7-fold increase in late I(Na) compared with controls was evident for S287R-, T372M-, and G460S-SNTA1 and was reversed by a neuronal nitric oxide synthase inhibitor. These 3 mutations also caused a significant depolarizing shift in channel inactivation, thereby increasing the overlap of the activation and inactivation curves to increase window current. CONCLUSIONS Abnormal biophysical phenotypes implicate mutations in SNTA1 as a novel pathogenic mechanism for the subset of channelopathic SIDS. Functional studies are essential to distinguish pathogenic perturbations in channel interacting proteins such as alpha1-syntrophin from similarly rare but innocuous ones.