Concomitant coronary artery bypass graft and aortic and mitral valve replacement for rheumatic heart disease: short- and mid-term outcomes.

PubMed

Davarpasand, Tahereh; Hosseinsabet, Ali; Jalali, Arash

2015-09-01

It has been reported that the short-term mortality of concomitant aortic and mitral valve replacement (AVR and MVR) is considerable and concomitant coronary artery bypass graft (CABG) has adverse effects on the survival of patients with valve replacement surgery. We summarize the short- and mid-term outcome after concomitant CABG, AVR and MVR in our centre. Between 2003 and 2013, 103 patients (68 males, 35 females, age: 60.1 ± 10.1 years) underwent CABG, AVR and MVR for rheumatic heart disease (RHD) and coronary artery disease (CAD). The median follow-up was 47.6 months. Most of the patients were asymptomatic at rest. We analysed demographic, clinical and operative data of patients to define independent predictors of overall survival, cardiac event-free survival as well as cardiac death. The rate of 30-day survival was 93% (n = 96). The corresponding rates of overall survival and cardiac event-free survival and the cumulative incidence rate of cardiac death at 1 year were 80.2, 77.3 and 10.9%; the same at 4 years were 73.7, 64.6 and 15.8%. The corresponding freedom rates from anticoagulation-associated major haemorrhage; a composite of major bleeding events, thromboemboli and valvular thrombosis; cardiac rehospitalization; major adverse valve-associated events; and significant malfunction of the prosthetic valve were 96.2, 95.3, 94.7, 81.6 and 97.7% at 1 year. The corresponding freedom rates from anticoagulation-associated major haemorrhage; a composite of major bleeding events, thromboemboli and valvular thrombosis; cardiac rehospitalization; major adverse valve-associated events; and significant malfunction of the prosthetic valve were 93.5, 91.0, 91.4, 73.5 and 95.5% at 4 years. The independent predictors of overall survival were age, cigarette smoking, chronic kidney diseases and balloon pump insertion. The independent predictors of cardiac event-free survival were age and previous myocardial infarction, while age, cigarette smoking, history of cerebrovascular accident and balloon pump insertion were the independent predictors of cardiac death. Concomitant CABG, AVR and MVR for rheumatic heart disease accompanied by CAD appear to have acceptable short- and mid-term outcomes with symptomatic amelioration. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Unexpected toxicity of combined modality therapy for small cell carcinoma of the lung. A Southwest oncology group study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Livingston, R.B.; Mira, J.; Haas, C.

1979-09-01

Combination chemotherapy with cyclophosphamide, vincristine, methotrexate and Adriamycin was delivered to 35 patients with small-cell carcinoma of the lung (28 with extensive and 7 with limited disease), including elective administration of intrathecal methotrexate. Whole-brain irradiation (3000 rad in 10 fractions) was then administered, with concomitant systemic cyclophosphamide and methotrexate for patients with extensive disease. Those with limited disease received concomitant chest irradiation without chemotherapy. Maintenance therapy then involved cyclophosphamide 750 mg/m/sup 2/ day 1, and methotrexate 30 mg/m/sup 2/ days 1 and 8, every 3 weeks. In only 2 patients reinduction was carried out at 24 weeks with the originalmore » chemotherapy. Myelosuppression was severe; there were at least 2 drug-related deaths from this cause in the induction period, and 15 febrile episodes with leukopenia. Stomatitis was more frequent and more severe in ''maintenance'' than in ''induction'' courses, especially the first maintenance course which was given with concomitant whole-brain irradiation. In addition, 13 episodes of unusual toxicity occurred in close temporal relation to systemic methotrexate administration, usually associated with stomatitis, in patients who were on maintenance therapy. These included 3 episodes of loss of consciousness, 4 of generalized erythroderma, 2 of ''flu''-like syndrome, and 1 each of the following: fatal, bilateral interstitial pneumonia; reversible, eosinophilic pleural effusion; acute myocardial infarction; and renal compromise with hematuria. As a result of this unexpected and protean toxicity, the pilot study was discontinued. However, at this time seven patients (4 with extensive and 3 with limited disease) remain in complete remission.« less

[Endovascular and surgical treatment of a patient with traumatic rupture of the aorta and hepatic artery].

PubMed

Chernaya, N R; Muslimov, R Sh; Selina, I E; Kokov, L S; Vladimirova, E S; Navruzbekov, M S; Gulyaev, V A

2016-01-01

Traumatic rupture of the aorta is the second most common cause of death in closed chest injury. The latest findings of autopsy showed that 80% of lethal outcomes in aortic injury occur in the prehospital period. Taking into consideration the incidence and high rate of death prior to the diagnosis stage, aortic rupture in closed thoracic injury is an important problem. Due to the characteristic mechanism of the development (during sharp deceleration of the body) this type of traumatic lesion of the aorta became known as "deceleration syndrome". The most vulnerable to tension aortic portion is its neck where the mobile part of the thoracic aorta is connected to the fixed arch in the place of the arterial ligament attachment. Open surgical intervention in patients with severe closed chest injury (often concomitant injury) is associated with high mortality and complications. Currently endovascular prosthetic repair of the aorta is a method of choice at the primary stage of treatment of patients with aortic injury. In this article we present a rare case report of concomitant lesion of large vessels (the descending aortic portion and proper hepatic artery) in a patient with severe concomitant injury, as well as peculiarities of diagnosis and combined treatment (endovascular prosthetic repair of the aorta and hepatic artery with an aotovein).

Cerebrovascular Outcomes With Proton Pump Inhibitors and Thienopyridines: A Systematic Review and Meta-Analysis.

PubMed

Malhotra, Konark; Katsanos, Aristeidis H; Bilal, Mohammad; Ishfaq, Muhammad Fawad; Goyal, Nitin; Tsivgoulis, Georgios

2018-02-01

Pharmacokinetic and prior studies on thienopyridine and proton pump inhibitors (PPI) coadministration provide conflicting data for cardiovascular outcomes, whereas there is no established evidence on the association of concomitant use of PPI and thienopyridines with adverse cerebrovascular outcomes. We conducted a systematic review and meta-analysis of randomized controlled trials and cohort studies from inception to July 2017, reporting following outcomes among patients treated with thienopyridine and PPI versus thienopyridine alone (1) ischemic stroke, (2) combined ischemic or hemorrhagic stroke, (3) composite outcome of stroke, myocardial infarction (MI), and cardiovascular death, (4) MI, (5) all-cause mortality, and (6) major or minor bleeding events. After the unadjusted analyses of risk ratios, we performed additional analyses of studies reporting hazard ratios adjusted for potential confounders. We identified 22 studies (12 randomized controlled trials and 10 cohort studies) comprising 131 714 patients. Concomitant use of PPI with thienopyridines was associated with increased risk of ischemic stroke (risk ratio, 1.74; 95% confidence interval [CI], 1.41-2.16; P <0.001), composite stroke/MI/cardiovascular death (risk ratio, 1.14; 95% CI, 1.01-1.29; P =0.04), and MI (risk ratio, 1.19; 95% CI, 1.00-1.40; P =0.05). Likewise, in adjusted analyses concomitant use of PPI with thienopyridines was again associated with increased risk of stroke (hazard ratios adjusted, 1.30; 95% CI, 1.04-1.61; P =0.02), composite stroke/MI/cardiovascular death (hazard ratios adjusted, 1.23; 95% CI, 1.03-1.47; P =0.02), but not with MI (hazard ratios adjusted, 1.19; 95% CI, 0.93-1.52; P =0.16). Co-prescription of PPI and thienopyridines increases the risk of incident ischemic strokes and composite stroke/MI/cardiovascular death. Our findings corroborate the current guidelines for PPI deprescription and pharmacovigilance, especially in patients treated with thienopyridines. © 2018 American Heart Association, Inc.

Mitral valve disease in patients with Marfan syndrome undergoing aortic root replacement.

PubMed

Kunkala, Meghana R; Schaff, Hartzell V; Li, Zhuo; Volguina, Irina; Dietz, Harry C; LeMaire, Scott A; Coselli, Joseph S; Connolly, Heidi

2013-09-10

Cardiac manifestations of Marfan syndrome include aortic root dilation and mitral valve prolapse (MVP). Only scant data exist describing MVP in patients with Marfan syndrome undergoing aortic root replacement. We retrospectively analyzed data from 166 MFS patients with MVP who were enrolled in a prospective multicenter registry of patients who underwent aortic root aneurysm repair. Of these 166 patients, 9% had mitral regurgitation (MR) grade >2, and 10% had MR grade 2. The severity of MVP and MR was evaluated by echocardiography preoperatively and ≤ 3 years postoperatively. Forty-one patients (25%) underwent composite graft aortic valve replacement, and 125 patients (75%) underwent aortic valve-sparing procedures; both groups had similar prevalences of MR grade >2 (P=0.7). Thirty-three patients (20%) underwent concomitant mitral valve (MV) intervention (repair, n=29; replacement, n=4), including all 15 patients with MR grade >2. Only 1 patient required MV reintervention during follow-up (mean clinical follow-up, 31 ± 10 months). Echocardiography performed 21 ± 13 months postoperatively revealed MR >2 in only 3 patients (2%). One early death and 2 late deaths occurred. Although the majority of patients with Marfan syndrome who undergo elective aortic root replacement have MVP, only 20% have concomitant MV procedures. These concomitant procedures do not seem to increase operative risk. In patients with MR grade ≤ 2 who do not undergo a concomitant MV procedure, the short-term incidence of progressive MR is low; however, more follow-up is needed to determine whether patients with MVP and MR grade ≤ 2 would benefit from prophylactic MV intervention.

Metabolic effects of photodynamically induced apoptosis in an erythroleukemic cell line. A (31)P NMR spectroscopic study of Victoria-Blue-BO-sensitized TF-1 cells.

PubMed

Viola, A; Lutz, N W; Maroc, C; Chabannon, C; Julliard, M; Cozzone, P J

2000-03-01

Victoria Blue BO (VB BO) is a new and promising photosensitizer currently being evaluated for photodynamic therapy (PDT). Its photochemical processes are mediated by oxygen radicals, but do not involve singlet oxygen. We used (31)P NMR spectroscopy of VB-BO sensitized TF-1 leukemic cells to gain further insight into the biochemical mechanisms underlying PDT-induced cell death. Sham-treatment experiments were performed to evaluate the effects of this photosensitizer in the absence of light irradiation. Significant metabolic differences were detected for TF-1 cells incubated with VB BO but not exposed to light, as compared with native cells (controls). These changes include reductions in phosphocreatine, UDP-hexose and phosphodiester levels (as percentage of total phosphate) and slightly reduced intracellular pH. Complete phosphocreatine depletion, significant acidification and concomitant inorganic-phosphate accumulation were observed for TF-1 cells irradiated after incubation with VB BO. Moreover, significant changes in phospholipid metabolites, i.e., accumulation of cytidine 5'-diphosphate choline and a decrease in phosphodiester levels, were observed for PDT-treated vs. sham-treated cells. Perturbations of phospholipid metabolism may be involved in programmed cell death, and the detection of a characteristic DNA ladder pattern by gel electrophoresis confirmed the existence of apoptosis in PDT-treated TF-1 cells. Copyright 2000 Wiley-Liss, Inc.

Brucella abortus Induces the Premature Death of Human Neutrophils through the Action of Its Lipopolysaccharide

PubMed Central

Barquero-Calvo, Elías; Mora-Cartín, Ricardo; Arce-Gorvel, Vilma; de Diego, Juana L.; Chacón-Díaz, Carlos; Chaves-Olarte, Esteban; Guzmán-Verri, Caterina; Buret, Andre G.; Gorvel, Jean-Pierre; Moreno, Edgardo

2015-01-01

Most bacterial infections induce the activation of polymorphonuclear neutrophils (PMNs), enhance their microbicidal function, and promote the survival of these leukocytes for protracted periods of time. Brucella abortus is a stealthy pathogen that evades innate immunity, barely activates PMNs, and resists the killing mechanisms of these phagocytes. Intriguing clinical signs observed during brucellosis are the low numbers of Brucella infected PMNs in the target organs and neutropenia in a proportion of the patients; features that deserve further attention. Here we demonstrate that B. abortus prematurely kills human PMNs in a dose-dependent and cell-specific manner. Death of PMNs is concomitant with the intracellular Brucella lipopolysaccharide (Br-LPS) release within vacuoles. This molecule and its lipid A reproduce the premature cell death of PMNs, a phenomenon associated to the low production of proinflammatory cytokines. Blocking of CD14 but not TLR4 prevents the Br-LPS-induced cell death. The PMNs cell death departs from necrosis, NETosis and classical apoptosis. The mechanism of PMN cell death is linked to the activation of NADPH-oxidase and a modest but steadily increase of ROS mediators. These effectors generate DNA damage, recruitments of check point kinase 1, caspases 5 and to minor extent of caspase 4, RIP1 and Ca++ release. The production of IL-1β by PMNs was barely stimulated by B. abortus infection or Br-LPS treatment. Likewise, inhibition of caspase 1 did not hamper the Br-LPS induced PMN cell death, suggesting that the inflammasome pathway was not involved. Although activation of caspases 8 and 9 was observed, they did not seem to participate in the initial triggering mechanisms, since inhibition of these caspases scarcely blocked PMN cell death. These findings suggest a mechanism for neutropenia in chronic brucellosis and reveal a novel Brucella-host cross-talk through which B. abortus is able to hinder the innate function of PMN. PMID:25946018

Cytokinin-induced cell death is associated with elevated expression of alternative oxidase in tobacco BY-2 cells.

PubMed

Mlejnek, Petr

2013-10-01

N(6)-benzyladenine (BA) and N(6)-benzyladenosine ([9R]BA) induce massive production of reactive oxygen species (ROS) that is eventually followed by a loss of cell viability in tobacco BY-2 cells (Mlejnek et al. Plant Cell Environ 26:1723-1735, 2003, Plant Sci 168:389-395, 2005). Results presented in this work suggest that the main sources of ROS are likely mitochondria and that the maintenance of the mitochondrial transmembrane potential is crucial for ROS production in cytokinin-treaded BY-2 cells. Therefore, the possible involvement of alternative oxidase (AOX) in cell death process induced by BA and [9R]BA was studied. About three- to fourfold increase in mRNA levels of AOX1 was observed a few hours after the BA and [9R]BA addition into the growth medium. The elevated expression of AOX1 mRNA could be prevented by adding adenine and adenosine which simultaneously reduced the cytotoxic effects of BA and [9R]BA, respectively. N(6)-benzyladenine 7-β-D-glucoside ([7G]BA) which is a common non-toxic metabolite of BA and [9R]BA did not affect the AOX1 mRNA expression. Although AOX1 seemed to be involved in protection of BY-2 cells against the abiotic stress induced by BA and [9R]BA, the results do not support the idea that it protects cells from death exclusively by scavenging of reactive oxygen species. Indeed, N-propyl gallate, an inhibitor of AOX, decreased cell survival despite it concomitantly decreased the ROS production. This finding is in contrast to the effect of salicylhydroxamic acid, another well-known inhibitor of AOX, which also increased the number of dying cells while it increased the ROS production.

Differences Between Snakebites with Concomitant Use of Alcohol or Drugs and Single Snakebites.

PubMed

Schulte, Joann; Kleinschmidt, Kurt C; Domanski, Kristina; Smith, Eric Anthony; Haynes, Ashley; Roth, Brett

2018-02-01

Published reports have suggested that the concurrent use of alcohol or drugs occurs among some snakebite victims, but no national assessment of such data exists. We used data from US poison control centers collected during telephone calls in calendar years 2000-2013 to compare snake envenomations with concomitant use of drugs, alcohol, or both to snakebites lacking such use. A total of 608 snakebites with 659 instances of concomitant alcohol/drug use were reported, which represent approximately 1% of 92,751 snakebites reported to US poison control centers. An annual mean of 48 snakebites with concomitant use of alcohol/drugs was reported, compared with a mean of 6625 snakebites per year with no concomitant use of alcohol/drugs. Most cases involved men, peaked during the summer months, and involved copperheads or rattlesnakes, which mirrored overall trends. Snakebite victims who also used alcohol/drugs were more likely than victims with only a snakebite reported to be bitten by rattlesnakes, to be admitted to the hospital, and die. Alcohol was the most common reported concomitant substance, but other substances were reported. Snakebites with concomitant use of alcohol/drugs are uncommon, accounting for approximately 1% of the snakebite envenomations reported annually to US poison control centers; however, snakebite victims also reporting alcohol/drug use are more likely to be bitten by rattlesnakes, be admitted to a healthcare facility, and die.

Synergistic cellular effects including mitochondrial destabilization, autophagy and apoptosis following low-level exposure to a mixture of lipophilic persistent organic pollutants.

PubMed

Rainey, Nathan E; Saric, Ana; Leberre, Alexandre; Dewailly, Etienne; Slomianny, Christian; Vial, Guillaume; Zeliger, Harold I; Petit, Patrice X

2017-07-05

Humans are exposed to multiple exogenous environmental pollutants. Many of these compounds are parts of mixtures that can exacerbate harmful effects of the individual mixture components. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is primarily produced via industrial processes including incineration and the manufacture of herbicides. Both endosulfan and TCDD are persistent organic pollutants which elicit cytotoxic effects by inducing reactive oxygen species generation. Sublethal concentrations of mixtures of TCDD and endosulfan increase oxidative stress, as well as mitochondrial homeostasis disruption, which is preceded by a calcium rise and, in fine, induce cell death. TCDD+Endosulfan elicit a complex signaling sequence involving reticulum endoplasmic destalilization which leads to Ca 2+ rise, superoxide anion production, ATP drop and late NADP(H) depletion associated with a mitochondrial induced apoptosis concomitant early autophagic processes. The ROS scavenger, N-acetyl-cysteine, blocks both the mixture-induced autophagy and death. Calcium chelators act similarly and mitochondrially targeted anti-oxidants also abrogate these effects. Inhibition of the autophagic fluxes with 3-methyladenine, increases mixture-induced cell death. These findings show that subchronic doses of pollutants may act synergistically. They also reveal that the onset of autophagy might serve as a protective mechanism against ROS-triggered cytotoxic effects of a cocktail of pollutants in Caco-2 cells and increase their tumorigenicity.

Trends in intentional abuse or misuse of benzodiazepines and opioid analgesics and the associated mortality reported to poison centers across the United States from 2000 to 2014.

PubMed

Calcaterra, S L; Severtson, S G; Bau, G E; Margolin, Z R; Bucher-Bartelson, B; Green, J L; Dart, R C

2018-04-03

Prior works demonstrates an increased risk of death when opioid analgesics and benzodiazepines are used concomitantly to gain a high. Using poison center data, we described trends in abuse or misuse of benzodiazepines and opioid analgesics. We quantified mortality risk associated with abuse or misuse of benzodiazepines, opioid analgesics and the combination of opioid analgesics and benzodiazepines. This was a retrospective chart review of data from the National Poison Data System which collects information from 55 poison centers located across the United States. We identified reported cases of "intentional abuse or misuse" of benzodiazepine and/or opioid analgesic exposures. Poisson regression was used to compare the number of cases from each year between 2001 and 2014 to the year 2000. Logistic regression was used to determine whether cases exposed to both benzodiazepines and opioids had greater odds of death relative to cases exposed to opioid analgesics alone. From 2000 to 2014, there were 125,485 benzodiazepine exposures and 84,627 opioid exposures among "intentional abuse or misuse" cases. Of the benzodiazepine exposures, 17.3% (n = 21,660) also involved an opioid. In 2010, exposures involving both opioids and benzodiazepines were 4.26-fold (95% CI: 3.87-4.70; p < .001) higher than in 2000. The risk of death was 1.55 (95% CI: 1.01-2.37; p = .04) times greater among those who used both an opioid and a benzodiazepine compared to opioids alone. This association held after adjusting for gender and age. Intentional abuse or misuse of benzodiazepines and opioids in combination increased significantly from 2000 to 2014. Benzodiazepine abuse or misuse far exceeded cases of opioid abuse or misuse. Death was greater with co-abuse or misuse of benzodiazepines and opioids. Population-level campaigns to inform the public about the risk of death with co-abuse or misuse of benzodiazepines and opioids are urgently needed to address this overdose epidemic.

An Aspect of the Capability for Suicide-Fearlessness of the Pain Involved in Dying-Amplifies the Association Between Suicide Ideation and Attempts.

PubMed

Smith, Phillip N; Stanley, Ian H; Joiner, Thomas E; Sachs-Ericsson, Natalie J; Van Orden, Kimberly A

2016-01-01

The interpersonal theory of suicide posits that individuals who experience suicide ideation will only develop suicidal intent, and subsequently engage in suicidal behavior when they have concomitant fearlessness about death and tolerance for physical pain (i.e., the capability for suicide). The current studies examined the hypothesis that one aspect of the capability for suicide-fearlessness of the pain involved in dying-would amplify the positive association between current suicide ideation and a previous suicide attempt in two samples at high risk for experiencing suicide ideation and suicide attempts. Study 1 examined this relation using self-report methods in a sample of adults entering treatment in a mental health outpatient clinic. Study 2 utilized similar methods in a sample of adults admitted to inpatient psychiatry. Both studies indicated that those individuals who reported suicide ideation were more likely than non-ideators to report having attempted suicide only if they also reported greater fearlessness of the pain involved in dying. The current findings support the theorized role of the capability for suicide in the transition from ideation to attempt and also support assessing the capability for suicide in risk assessment.

Do Concomitant Cranium and Axis Injuries Predict Worse Outcome? A Trauma Database Quantitative Analysis

PubMed Central

Chittiboina, Prashant; Banerjee, Anirban Deep; Nanda, Anil

2011-01-01

We performed a trauma database analysis to identify the effect of concomitant cranial injuries on outcome in patients with fractures of the axis. We identified patients with axis fractures over a 14-year period. A binary outcome measure was used. Univariate and multiple logistic regression analysis were performed. There were 259 cases with axis fractures. Closed head injury was noted in 57% and skull base trauma in 14%. Death occurred in 17 cases (6%). Seventy-two percent had good outcome. Presence of abnormal computed tomography head findings, skull base fractures, and visceral injury was significantly associated with poor outcome. Skull base injury in association with fractures of the axis is a significant independent predictor of worse outcomes, irrespective of the severity of the head injury. We propose that presence of concomitant cranial and upper vertebral injuries require careful evaluation in view of the associated poor prognosis. PMID:22470268

Activation of the endoplasmic reticulum stress response by the amyloid-beta 1-40 peptide in brain endothelial cells.

PubMed

Fonseca, Ana Catarina R G; Ferreiro, Elisabete; Oliveira, Catarina R; Cardoso, Sandra M; Pereira, Cláudia F

2013-12-01

Neurovascular dysfunction arising from endothelial cell damage is an early pathogenic event that contributes to the neurodegenerative process occurring in Alzheimer's disease (AD). Since the mechanisms underlying endothelial dysfunction are not fully elucidated, this study was aimed to explore the hypothesis that brain endothelial cell death is induced upon the sustained activation of the endoplasmic reticulum (ER) stress response by amyloid-beta (Aβ) peptide, which deposits in the cerebral vessels in many AD patients and transgenic mice. Incubation of rat brain endothelial cells (RBE4 cell line) with Aβ1-40 increased the levels of several markers of ER stress-induced unfolded protein response (UPR), in a time-dependent manner, and affected the Ca(2+) homeostasis due to the release of Ca(2+) from this intracellular store. Finally, Aβ1-40 was shown to activate both mitochondria-dependent and -independent apoptotic cell death pathways. Enhanced release of cytochrome c from mitochondria and activation of the downstream caspase-9 were observed in cells treated with Aβ1-40 concomitantly with caspase-12 activation. Furthermore, Aβ1-40 activated the apoptosis effectors' caspase-3 and promoted the translocation of apoptosis-inducing factor (AIF) to the nucleus demonstrating the involvement of caspase-dependent and -independent mechanisms during Aβ-induced endothelial cell death. In conclusion, our data demonstrate that ER stress plays a significant role in Aβ1-40-induced apoptotic cell death in brain endothelial cells suggesting that ER stress-targeted therapeutic strategies might be useful in AD to counteract vascular defects and ultimately neurodegeneration. © 2013.

Simultaneous cell death in the trigeminal ganglion and in ganglion neurons present in the oculomotor nerve of the bovine fetus.

PubMed Central

Bortolami, R; Lucchi, M L; Callegari, E; Barazzoni, A M; Costerbosa, G L; Scapolo, P A

1990-01-01

A well-developed ganglion and scattered ganglion cells are present in the intracranial portion of the oculomotor nerve during the first half of fetal life in the ox. In the second half of fetal life a dramatic reduction of the ganglion cells associated with the oculomotor nerve occurs because of spontaneous cell death. Concomitantly, the same phenomenon of cell death is found in the trigeminal ganglion, especially in its rostromedial portion. Free degenerating perikarya can be found in the cavernous sinus. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 PMID:2384329

Life and death of neurons in the aging brain

NASA Technical Reports Server (NTRS)

Morrison, J. H.; Hof, P. R.; Bloom, F. E. (Principal Investigator)

1997-01-01

Neurodegenerative disorders are characterized by extensive neuron death that leads to functional decline, but the neurobiological correlates of functional decline in normal aging are less well defined. For decades, it has been a commonly held notion that widespread neuron death in the neocortex and hippocampus is an inevitable concomitant of brain aging, but recent quantitative studies suggest that neuron death is restricted in normal aging and unlikely to account for age-related impairment of neocortical and hippocampal functions. In this article, the qualitative and quantitative differences between aging and Alzheimer's disease with respect to neuron loss are discussed, and age-related changes in functional and biochemical attributes of hippocampal circuits that might mediate functional decline in the absence of neuron death are explored. When these data are viewed comprehensively, it appears that the primary neurobiological substrates for functional impairment in aging differ in important ways from those in neurodegenerative disorders such as Alzheimer's disease.

Role of pelvic and para-aortic lymphadenectomy in abandoned radical hysterectomy in cervical cancer.

PubMed

Barquet-Muñoz, Salim Abraham; Rendón-Pereira, Gabriel Jaime; Acuña-González, Denise; Peñate, Monica Vanessa Heymann; Herrera-Montalvo, Luis Alonso; Gallardo-Alvarado, Lenny Nadia; Cantú-de León, David Francisco; Pareja, René

2017-01-14

Cervical cancer (CC) occupies fourth place in cancer incidence and mortality worldwide in women, with 560,505 new cases and 284,923 deaths per year. Approximately, nine of every ten (87%) take place in developing countries. When a macroscopic nodal involvement is discovered during a radical hysterectomy (RH), there is controversy in the literature between resect macroscopic lymph node compromise or abandonment of the surgery and sending the patient for standard chemo-radiotherapy treatment. The objective of this study is to compare the prognosis of patients with CC whom RH was abandoned and bilateral pelvic lymphadenectomy and para-aortic lymphadenectomy was performed with that of patients who were only biopsied or with removal of a suspicious lymph node, treated with concomitant radiotherapy/chemotherapy in the standard manner. A descriptive and retrospective study was conducted in two institutions from Mexico and Colombia. Clinical records of patients with early-stage CC programmed for RH with an intraoperative finding of pelvic lymph, para-aortic nodes, or any extracervical involvement that contraindicates the continuation of surgery were obtained. Between January 2007 and December 2012, 42 clinical patients complied with study inclusion criteria and were selected for analysis. In patients with CC whom RH was abandoned due to lymph node affectation, there is no difference in overall survival or in disease-free period between systematic lymphadenectomy and tumor removal or lymph node biopsy, in pelvic lymph nodes as well as in para-aortic lymph nodes, when these patients receive adjuvant treatment with concomitant radiotherapy/chemotherapy. This is a hypothesis-generator study; thus, the recommendation is made to conduct randomized prospective studies to procure better knowledge on the impact of bilateral pelvic and para-aortic lymphadenectomy on this group of patients.

A Trichostatin A (TSA)/Sp1-mediated mechanism for the regulation of SALL2 tumor suppressor in Jurkat T cells.

PubMed

Hepp, Matías I; Escobar, David; Farkas, Carlos; Hermosilla, Viviana; Álvarez, Claudia; Amigo, Roberto; Gutiérrez, José L; Castro, Ariel F; Pincheira, Roxana

2018-05-17

SALL2 is a transcription factor involved in development and disease. Deregulation of SALL2 has been associated with cancer, suggesting that it plays a role in the disease. However, how SALL2 is regulated and why is deregulated in cancer remain poorly understood. We previously showed that the p53 tumor suppressor represses SALL2 under acute genotoxic stress. Here, we investigated the effect of Histone Deacetylase Inhibitor (HDACi) Trichostatin A (TSA), and involvement of Sp1 on expression and function of SALL2 in Jurkat T cells. We show that SALL2 mRNA and protein levels were enhanced under TSA treatment. Both, TSA and ectopic expression of Sp1 transactivated the SALL2 P2 promoter. This transactivation effect was blocked by the Sp1-binding inhibitor mithramycin A. Sp1 bound in vitro and in vivo to the proximal region of the P2 promoter. TSA induced Sp1 binding to the P2 promoter, which correlated with dynamic changes on H4 acetylation and concomitant recruitment of p300 or HDAC1 in a mutually exclusive manner. Our results suggest that TSA-induced Sp1-Lys703 acetylation contributes to the transcriptional activation of the P2 promoter. Finally, using a CRISPR/Cas9 SALL2-KO Jurkat-T cell model and gain of function experiments, we demonstrated that SALL2 upregulation is required for TSA-mediated cell death. Thus, our study identified Sp1 as a novel transcriptional regulator of SALL2, and proposes a novel epigenetic mechanism for SALL2 regulation in Jurkat-T cells. Altogether, our data support SALL2 function as a tumor suppressor, and SALL2 involvement in cell death response to HDACi. Copyright © 2018. Published by Elsevier B.V.

Mitochondrial Dysfunction and Its Relationship with mTOR Signaling and Oxidative Damage in Autism Spectrum Disorders.

PubMed

Yui, Kunio; Sato, Atsushi; Imataka, George

2015-01-01

Mitochondria are organelles that play a central role in processes related to cellular viability, such as energy production, cell growth, cell death via apoptosis, and metabolism of reactive oxygen species (ROS). We can observe behavioral abnormalities relevant to autism spectrum disorders (ASDs) and their recovery mediated by the mTOR inhibitor rapamycin in mouse models. In Tsc2(+/-) mice, the transcription of multiple genes involved in mTOR signaling is enhanced, suggesting a crucial role of dysregulated mTOR signaling in the ASD model. This review proposes that the mTOR inhibitor may be useful for the pharmacological treatment of ASD. This review offers novel insights into mitochondrial dysfunction and the related impaired glutathione synthesis and lower detoxification capacity. Firstly, children with ASD and concomitant mitochondrial dysfunction have been reported to manifest clinical symptoms similar to those of mitochondrial disorders, and it therefore shows that the clinical manifestations of ASD with a concomitant diagnosis of mitochondrial dysfunction are likely due to these mitochondrial disorders. Secondly, the adenosine triphosphate (ATP) production/oxygen consumption pathway may be a potential candidate for preventing mitochondrial dysfunction due to oxidative stress, and disruption of ATP synthesis alone may be related to impaired glutathione synthesis. Finally, a decrease in total antioxidant capacity may account for ASD children who show core social and behavioral impairments without neurological and somatic symptoms.

Ultrastructural aspects of autoschizis: a new cancer cell death induced by the synergistic action of ascorbate/menadione on human bladder carcinoma cells.

PubMed

Gilloteaux, J; Jamison, J M; Arnold, D; Taper, H S; Summers, J L

2001-01-01

Scanning and transmission electron microscopy were employed to further characterize the cytotoxic effects of a ascorbic acid/menadione (or vitamin C/vitamin K3) combination on a human bladder carcinoma T24 cell line. Following 1-h treatment T24 cells display membrane and mitochondrial defects as well as excision of cytoplasmic fragments that contain no organelles. These continuous self-excisions reduce the cell size. Concomitant, nuclear changes, chromatin disassembly, nucleolar condensation and fragmentation, and decreased nuclear volume lead to cell death via a process similar to karyorrhexis and karyolysis. Because this cell death is achieved through a progressive loss of cytoplasm due to self-morsellation, the authors named this mode of cell death autoschizis (from the Greek autos, self, and schizein, to split, as defined in Scanning. 1998; 20: 564-575). This morphological characterization of autoschizic cell death confirms and extends the authors previous reports and demonstrates that this cell death is distinct from apoptosis.

Use of the Palmaz stent in the treatment of severe tracheomalacia.

PubMed

Geller, Kenneth A; Wells, Winfield J; Koempel, Jeffrey A; St John, Maie A R

2004-08-01

To present our experience with the use of the Palmaz stent in treating cases of severe, life-threatening tracheomalacia, and to report our experience with the use of tracheal stents in patients who have concomitant tracheotomies, we performed a retrospective study in a tertiary-care children's hospital. Nine patients with multiple congenital anomalies including severe tracheomalacia required placement of a Palmaz stent to prolong life. The congenital anomalies included congenital heart disease, congenital lung disease, meningomyelocele, laryngotracheoesophageal cleft, and tracheoesophageal fistula. Three of the patients had concomitant tracheotomies. Each patient had placement of one or more Palmaz stents in the trachea and/or bronchus. Four patients died, and 5 patients are still alive. Three of the 4 patients who died had concomitant tracheotomies and died of complications associated with significant tracheal hemorrhage. The fourth died of pulmonary complications following repeated episodes of pneumonia. None of the 5 patients who are still alive had a concomitant tracheotomy. The Palmaz stent is a useful tool for treating life-threatening tracheomalacia as a final resort in this difficult patient population; however, the use of these stents may lead to subsequent hemorrhage and death, especially in patients with tracheotomies, so their use must be carefully considered.

Outcomes of pregnancies complicated by liver cirrhosis, portal hypertension, or esophageal varices.

PubMed

Puljic, Anela; Salati, Jennifer; Doss, Amy; Caughey, Aaron B

2016-01-01

To evaluate pregnancy outcomes in women with liver cirrhosis, portal hypertension, or esophageal varices. We analyzed a retrospective cohort of 2,284,218 pregnancies in 2005-2009 recorded in the California Birth Registry database. Utilizing ICD-9 codes we analyzed the following outcomes for liver cirrhosis, portal hypertension, or esophageal varices in pregnancy: preeclampsia (PET), preterm delivery (PTD; <37 weeks), cesarean section, low birth weight (LBW; <2500 g), small for gestational age (SGA; <10th percentile), neonatal death (NND), and postpartum hemorrhage (PPH). Cirrhosis in pregnancy conferred an increased risk of PET, PTD, CS in multiparous women, LBW, and NND. Portal hypertension in pregnancy was associated with PTD, LBW, NND, and PPH. Non-bleeding esophageal varices in pregnancy were not associated with the outcomes assessed in a statistically significant manner. One case of bleeding esophageal varices was observed, resulting in PTD with a LBW infant. There were three cases of concomitant portal hypertension or concomitant esophageal varices with cirrhosis in pregnancy. Pregnancy in women with concomitant liver cirrhosis, portal hypertension, or esophageal varices can be successful. However, pregnancy outcomes are worse and may warrant closer antenatal monitoring and patient counseling. Cirrhosis in pregnancy with concomitant portal hypertension or esophageal varices is rare.

Risk of mortality with concomitant use of tamoxifen and selective serotonin reuptake inhibitors: multi-database cohort study.

PubMed

Donneyong, Macarius M; Bykov, Katsiaryna; Bosco-Levy, Pauline; Dong, Yaa-Hui; Levin, Raisa; Gagne, Joshua J

2016-09-30

 To compare differences in mortality between women concomitantly treated with tamoxifen and selective serotonin reuptake inhibitors (SSRIs) that are potent inhibitors of the cytochrome-P450 2D6 enzyme (CYP2D6) versus tamoxifen and other SSRIs.  Population based cohort study.  Five US databases covering individuals enrolled in private and public health insurance programs from 1995 to 2013.  Two cohorts of women who started taking tamoxifen. In cohort 1, women started taking an SSRI during tamoxifen treatment. In cohort 2, women were already taking an SSRI when they started taking tamoxifen.  All cause mortality in each cohort in women taking SSRIs that are potent inhibitors of CYP2D6 (paroxetine, fluoxetine) versus other SSRIs. Propensity scores were used to match exposure groups in a variable ratio fashion. Results were measured separately for each cohort and combined hazard ratios calculated from Cox regression models across the two cohorts with random effects meta-analysis.  There were 6067 and 8465 new users of tamoxifen in cohorts 1 and 2, respectively. Mean age was 55. A total of 991 and 1014 deaths occurred in cohorts 1 and 2 during a median follow-up of 2.2 (interquartile range 0.9-4.5) and 2.0 (0.8-3.9) years, respectively. The pooled hazard ratio for death for potent inhibitors (rate 58.6/1000 person years) compared with other SSRIs (rate 57.9/1000 person years) across cohorts 1 and 2 was 0.96 (95% confidence interval 0.88 to 1.06). Results were consistent across sensitivity analyses.  Concomitant use of tamoxifen and potent CYP2D6 inhibiting SSRIs versus other SSRIs was not associated with an increased risk of death. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Concomitant injuries are an important determinant of outcome of high-grade blunt hepatic trauma.

PubMed

Schnüriger, B; Inderbitzin, D; Schafer, M; Kickuth, R; Exadaktylos, A; Candinas, D

2009-01-01

Little is known about the clinical importance of concomitant injuries in polytraumatized patients with high-grade blunt liver injury. A retrospective single-centre study was performed to investigate the safety of non-operative management of liver injury and the impact of concomitant intra- and extra-abdominal injuries on clinical outcome. Some 183 patients with blunt liver injury were admitted to Berne University Hospital, Switzerland, between January 2000 and December 2006. Grade 3-5 injuries were considered to be high grade. Immediate laparotomy was required by 35 patients (19.1 per cent), owing to extrahepatic intra-abdominal injury (splenic and vascular injuries, perforations) in 21 cases. The mortality rate was 16.9 per cent; 22 of the 31 deaths were due to concomitant lesions. Of 81 patients with high-grade liver injury, 63 (78 per cent) were managed without surgery; liver-related and extra-abdominal complication rates in these patients were 11 and 17 per cent respectively. Grades 4 and 5 liver injury were associated with hepatic-related and extra-abdominal complications. Concomitant injuries are a major determinant of outcome in patients with blunt hepatic injury and should be given high priority by trauma surgeons. An algorithm for the management of blunt liver injury is proposed. Copyright (c) 2008 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

An Aspect of the Capability for Suicide—Fearlessness of the Pain Involved in Dying—Amplifies the Association between Suicide Ideation and Attempts

PubMed Central

Smith, Phillip N.; Stanley, Ian H.; Joiner, Thomas E.; Sachs-Ericsson, Natalie J.; Van Orden, Kimberly A.

2016-01-01

The interpersonal theory of suicide posits that individuals who experience suicide ideation will only develop suicidal intent, and subsequently engage in suicidal behavior when they have concomitant fearlessness about death and tolerance for physical pain (i.e., the capability for suicide). Objective: The current studies examined the hypothesis that one aspect of the capability for suicide—fearlessness of the pain involved in dying—would amplify the positive association between current suicide ideation and a previous suicide attempt in two samples at high risk for experiencing suicide ideation and suicide attempts. Methods: Study 1 examined this relation using self-report methods in a sample of adults entering treatment in a mental health outpatient clinic. Study 2 utilized similar methods in a sample of adults admitted to inpatient psychiatry. Results: Both studies indicated that those individuals who reported suicide ideation were more likely than non-ideators to report having attempted suicide only if they also reported greater fearlessness of the pain involved in dying. Conclusions: The current findings support the theorized role of the capability for suicide in the transition from ideation to attempt and also support assessing the capability for suicide in risk assessment. PMID:26984289

A fatal outcome after unintentional overdosing of rivastigmine patches.

PubMed

Lövborg, Henrik; Jönsson, Anna K; Hägg, Staffan

2012-02-01

Rivastigmine is an acetylcholine esterase inhibitor used in the treatment of dementia. Patches with rivastigmine for transdermal delivery have been used to increase compliance and to reduce side effects. We describe an 87-year old male with dementia treated with multiple rivastigmine patches (Exelon 9,5 mg/24 h) who developed nausea, vomiting and renal failure with disturbed electrolytes resulting in death. The symptoms occurred after six rivastigmine patches had concomitantly been erroneously applied by health care personnel on two consecutive days. The terminal cause of death was considered to be uremia from an acute tubular necrosis that was assessed as a result of dehydration through vomiting. The rivastigmine intoxication was assessed as having caused or contributed to the dehydrated condition. The medication error occurred at least partly due to ambiguous labeling. The clinical signs were not initially recognized as adverse effects of rivastigmine. The presented case is a description of a rivastigmine overdose due to a medication error involving patches. This case indicates the importance of clear and unambiguous instructions to avoid administration errors with patches and to be vigilant to adverse drug reactions for early detection and correction of drug administration errors. In particular, instructions clearly indicating that only one patch should be applied at a time are important.

Potassium efflux fires the canon: Potassium efflux as a common trigger for canonical and noncanonical NLRP3 pathways.

PubMed

Rivers-Auty, Jack; Brough, David

2015-10-01

Murine caspase-11 and its human orthologues, caspase-4 and caspase-5, activate an inflammatory response following cytoplasmic recognition of cell wall constituents from Gram-negative bacteria, such as LPS. This inflammatory response involves pyroptotic cell death and the concomitant release of IL-1α, as well as the production of IL-1β and IL-18 through the noncanonical NLR family, pyrin domain containing 3 (NLRP3) pathway. This commentary discusses three papers in this issue of the European Journal of Immunology that advance our understanding of the roles of caspase-11, -4, and -5 in the noncanonical pathway. By utilizing the new gene editing technique, clustered regularly interspaced short palindromic repeats (CRISPR), as well as sensitive cell imaging techniques, these papers establish that cytoplasmic LPS-dependent IL-1β production requires the NLRP3 inflammasome and that its activation is dependent on K(+) efflux, whereas IL-1α release and pyroptotic cell death pathways are NLRP3-independent. These findings expand on previous research implicating K(+) efflux as the principal trigger for NLRP3 activation and suggest that canonical and noncanonical NLRP3 pathways are not as dissimilar as first thought. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Histone deacetylase inhibitor belinostat represses survivin expression through reactivation of transforming growth factor beta (TGFbeta) receptor II leading to cancer cell death.

PubMed

Chowdhury, Sanjib; Howell, Gillian M; Teggart, Carol A; Chowdhury, Aparajita; Person, Jonathan J; Bowers, Dawn M; Brattain, Michael G

2011-09-02

Survivin is a cancer-associated gene that functions to promote cell survival, cell division, and angiogenesis and is a marker of poor prognosis. Histone deacetylase inhibitors induce apoptosis and re-expression of epigenetically silenced tumor suppressor genes in cancer cells. In association with increased expression of the tumor suppressor gene transforming growth factor β receptor II (TGFβRII) induced by the histone deacetylase inhibitor belinostat, we observed repressed survivin expression. We investigated the molecular mechanisms involved in survivin down-regulation by belinostat downstream of reactivation of TGFβ signaling. We identified two mechanisms. At early time points, survivin protein half-life was decreased with its proteasomal degradation. We observed that belinostat activated protein kinase A at early time points in a TGFβ signaling-dependent mechanism. After longer times (48 h), survivin mRNA was also decreased by belinostat. We made the novel observation that belinostat mediated cell death through the TGFβ/protein kinase A signaling pathway. Induction of TGFβRII with concomitant survivin repression may represent a significant mechanism in the anticancer effects of this drug. Therefore, patient populations exhibiting high survivin expression with epigenetically silenced TGFβRII might potentially benefit from the use of this histone deacetylase inhibitor.

The Death of Psychology: Integral & Fifth Force Psychologies. Technical Paper No. 36

ERIC Educational Resources Information Center

Fisher, R. Michael

2010-01-01

The purpose here is to translate the Fifth Force Psychologies movement through an integral (Wilberian) lens. One of the most significant impacts of doing this comes from the integral initiative, which has led to Ken Wilber arguing "Psychology is dead." Concomitantly, his view is that the "integral approach" is its replacement. This move…

Drugs Most Frequently Involved in Drug Overdose Deaths: United States, 2010-2014.

PubMed

Warner, Margaret; Trinidad, James P; Bastian, Brigham A; Minino, Arialdi M; Hedegaard, Holly

2016-12-01

Objectives-This report identifies the specific drugs most frequently involved in drug overdose deaths in the United States from 2010 through 2014. Methods-The 2010-2014 National Vital Statistics System mortality files were linked to electronic files containing literal text information from death certificates. Drug overdose was defined using the International Classification of Diseases, Tenth Revision underlying cause-of-death codes X40-X44 (unintentional), X60-X64 (suicide), X85 (homicide), and Y10-Y14 (undetermined intent). Among deaths with an underlying cause of death of drug overdose, the literal text in three fields of the death certificate (i.e., the cause of death from Part I, significant conditions contributing to death from Part II, and a description of how the injury occurred from Box 43) were searched to identify drug mentions. Search term lists were developed using existing drug classification systems as well as from manual review of the literal text. The search term list was then used to identify the specific drugs involved in overdose deaths. Descriptive statistics were reported for drug overdose deaths involving the 10 most frequently mentioned drugs on death certificates. Tables and figures presenting information on the specific drugs involved in deaths are based on deaths with mention of at least one specific drug on the death certificate. Results-From 2010 through 2014, the number of drug overdose deaths per year increased 23%, from 38,329 in 2010 to 47,055 in 2014. During this time period, the percentage of drug overdose deaths involving at least one specific drug increased, from 67% in 2010 to 78% in 2014. Among drug overdose deaths with at least one drug specified on the death certificate, the 10 drugs most frequently involved in overdose deaths included the following opioids: heroin, oxycodone, methadone, morphine, hydrocodone, and fentanyl; the following benzodiazepines: alprazolam and diazepam; and the following stimulants: cocaine and methamphetamine. During this 5-year period, the age-adjusted rate of drug overdose deaths involving heroin more than tripled, and the rate of drug overdose deaths involving methamphetamine more than doubled. The rate of drug overdose deaths involving fentanyl more than doubled in a single year (from 2013 to 2014). In 2014, of the 36,667 drug overdose deaths involving at least one specific drug, 52% of these deaths specified one drug, 38% specified two or three drugs, and 11% specified four or more drugs. Conclusions-Analysis of the literal text from death certificates can be used to identify patterns in the specific drugs most frequently involved in drug overdose deaths. From 2010 through 2014, the top 10 drugs involved were the same, but the relative ranking and age-adjusted rates for deaths involving these drugs changed. Literal text analysis also revealed that many drug overdose deaths involved multiple drugs. Findings should be interpreted in light of the improvement in the quality of the data that resulted from better reporting of specific drugs on death certificates from 2010 through 2014. Relative increases in the death rates involving specific drugs and the rankings of these drugs may be affected by improvements in reporting, real increases in the numbers of death, or both. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.

Life Expectancy Can Explain the Precocity-Longevity Hypothesis Association of Early Career Success and Early Death.

PubMed

McCann, Stewart J H

2015-01-01

The precocity-longevity hypothesis that those who reach career milestones earlier in life have shorter life spans was tested with the 430 men elected to serve in the House of Representatives for the 71st U.S. Congress in 1929-1930 who were alive throughout 1930. There was no tendency for those first serving at an earlier age to die sooner or those serving first at a later age to die later than expected based on individual life expectancy in 1930. Although age at first serving was correlated with death age, the correlation was not significant when expected death age was controlled. The results cast serious doubt on the contention of the precocity-longevity hypothesis that the developmental aspects of the prerequisites, concomitants, and consequences of early career achievement peaks actively enhance the conditions for an earlier death.

Illegal drug-related deaths in East Germany between 1995 and 2004.

PubMed

Zwingenberger, Sabrina; Pietsch, Jörg; Hommola, Annett; Dressler, Jan

2010-06-15

The retrospective analysis determines changes between the deaths caused by illegal drugs in East Germany between 1995 and 2004 with specific regard to the number and manner of deaths, common intoxicants, concomitant drug use, the age and gender of the victims as well as the places of death. The data was collected by the institutes of forensic medicine in the German federal states of Saxony, Thuringia, Brandenburg, Mecklenburg West-Pomerania, Saxony-Anhalt and the State Offices of Criminal Investigation of these federal states. A comparison of these two different sources of data is also made. 510 drug-related deaths occurred in East Germany between 1995 and 2004. This was equivalent to a death rate of 0.4 per 100,000 inhabitants and represented 3% of all drug-related deaths throughout Germany. The average age of the victims was 24 years and male accounted for 85% of all the fatalities. Opiates, especially heroin, caused the majority of deaths (55%). Comparison of the two sources revealed that approximately half of the drug-related deaths were accounted for by national statistics. The analysis reveals an increase of drug-related deaths in East Germany after reunification but no relevant difference between the five East German states. (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Ammonium Accumulation and Cell Death in a Rat 3D Brain Cell Model of Glutaric Aciduria Type I

PubMed Central

Jafari, Paris; Braissant, Olivier; Zavadakova, Petra; Henry, Hugues; Bonafé, Luisa; Ballhausen, Diana

2013-01-01

Glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency) is an inborn error of metabolism that usually manifests in infancy by an acute encephalopathic crisis and often results in permanent motor handicap. Biochemical hallmarks of this disease are elevated levels of glutarate and 3-hydroxyglutarate in blood and urine. The neuropathology of this disease is still poorly understood, as low lysine diet and carnitine supplementation do not always prevent brain damage, even in early-treated patients. We used a 3D in vitro model of rat organotypic brain cell cultures in aggregates to mimic glutaric aciduria type I by repeated administration of 1 mM glutarate or 3-hydroxyglutarate at two time points representing different developmental stages. Both metabolites were deleterious for the developing brain cells, with 3-hydroxyglutarate being the most toxic metabolite in our model. Astrocytes were the cells most strongly affected by metabolite exposure. In culture medium, we observed an up to 11-fold increase of ammonium in the culture medium with a concomitant decrease of glutamine. We further observed an increase in lactate and a concomitant decrease in glucose. Exposure to 3-hydroxyglutarate led to a significantly increased cell death rate. Thus, we propose a three step model for brain damage in glutaric aciduria type I: (i) 3-OHGA causes the death of astrocytes, (ii) deficiency of the astrocytic enzyme glutamine synthetase leads to intracerebral ammonium accumulation, and (iii) high ammonium triggers secondary death of other brain cells. These unexpected findings need to be further investigated and verified in vivo. They suggest that intracerebral ammonium accumulation might be an important target for the development of more effective treatment strategies to prevent brain damage in patients with glutaric aciduria type I. PMID:23326493

Ammonium accumulation and cell death in a rat 3D brain cell model of glutaric aciduria type I.

PubMed

Jafari, Paris; Braissant, Olivier; Zavadakova, Petra; Henry, Hugues; Bonafé, Luisa; Ballhausen, Diana

2013-01-01

Glutaric aciduria type I (glutaryl-CoA dehydrogenase deficiency) is an inborn error of metabolism that usually manifests in infancy by an acute encephalopathic crisis and often results in permanent motor handicap. Biochemical hallmarks of this disease are elevated levels of glutarate and 3-hydroxyglutarate in blood and urine. The neuropathology of this disease is still poorly understood, as low lysine diet and carnitine supplementation do not always prevent brain damage, even in early-treated patients. We used a 3D in vitro model of rat organotypic brain cell cultures in aggregates to mimic glutaric aciduria type I by repeated administration of 1 mM glutarate or 3-hydroxyglutarate at two time points representing different developmental stages. Both metabolites were deleterious for the developing brain cells, with 3-hydroxyglutarate being the most toxic metabolite in our model. Astrocytes were the cells most strongly affected by metabolite exposure. In culture medium, we observed an up to 11-fold increase of ammonium in the culture medium with a concomitant decrease of glutamine. We further observed an increase in lactate and a concomitant decrease in glucose. Exposure to 3-hydroxyglutarate led to a significantly increased cell death rate. Thus, we propose a three step model for brain damage in glutaric aciduria type I: (i) 3-OHGA causes the death of astrocytes, (ii) deficiency of the astrocytic enzyme glutamine synthetase leads to intracerebral ammonium accumulation, and (iii) high ammonium triggers secondary death of other brain cells. These unexpected findings need to be further investigated and verified in vivo. They suggest that intracerebral ammonium accumulation might be an important target for the development of more effective treatment strategies to prevent brain damage in patients with glutaric aciduria type I.

Cytotoxicity and Genotoxicity of Cypermethrin in Hepatocarcinoma Cells: A Dose- and Time-Dependent Study

PubMed Central

AlKahtane, Abdullah A.; Alarifi, Saud; Al-Qahtani, Ahmed A.; Ali, Daoud; Alomar, Suliman Y.; Aleissia, Mohammed S.; Alkahtani, Saad

2018-01-01

Most of the agricultural workers are potentially exposed to pesticides through different routes. Inhalation exposures may result in numerous diseases that can adversely affect an individual’s health and capacity to perform at work. The aim of this study was to determine the cytotoxic potential of cypermethrin pesticide on cultured human hepatocarcinoma (HepG2) cells. The HepG2 cells were exposed to cypermethrin (0, 5, 15, 40 ng/mL) for 24 and 48 hours. We observed that cypermethrin caused cell death of HepG2 cells using 3-(4, 5-dimethylthiozolyl-2)-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase tests. Furthermore, cypermethrin reduced HepG2 cells viability in a time and dose dependent basis, that was probably mediated through the induction of reactive oxygen species (ROS) and apoptosis. An increase in ROS generation with a concomitant increase in expression of the proapoptotic protein Bcl-2 and cytochrome c and decrease in the antiapoptosis protein Bax suggested that a mitochondria-mediated pathway was involved in cypermethrin-induced apoptosis. These findings provide insights into the underlying mechanisms involved in cytotoxicity of cypermethrin in HepG2 cells. PMID:29686591

Cytotoxicity and Genotoxicity of Cypermethrin in Hepatocarcinoma Cells: A Dose- and Time-Dependent Study.

PubMed

AlKahtane, Abdullah A; Alarifi, Saud; Al-Qahtani, Ahmed A; Ali, Daoud; Alomar, Suliman Y; Aleissia, Mohammed S; Alkahtani, Saad

2018-01-01

Most of the agricultural workers are potentially exposed to pesticides through different routes. Inhalation exposures may result in numerous diseases that can adversely affect an individual's health and capacity to perform at work. The aim of this study was to determine the cytotoxic potential of cypermethrin pesticide on cultured human hepatocarcinoma (HepG2) cells. The HepG2 cells were exposed to cypermethrin (0, 5, 15, 40 ng/mL) for 24 and 48 hours. We observed that cypermethrin caused cell death of HepG2 cells using 3-(4, 5-dimethylthiozolyl-2)-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase tests. Furthermore, cypermethrin reduced HepG2 cells viability in a time and dose dependent basis, that was probably mediated through the induction of reactive oxygen species (ROS) and apoptosis. An increase in ROS generation with a concomitant increase in expression of the proapoptotic protein Bcl-2 and cytochrome c and decrease in the antiapoptosis protein Bax suggested that a mitochondria-mediated pathway was involved in cypermethrin-induced apoptosis. These findings provide insights into the underlying mechanisms involved in cytotoxicity of cypermethrin in HepG2 cells.

The fuzzy cube and causal efficacy: representation of concomitant mechanisms in stroke.

PubMed

Jobe, Thomas H.; Helgason, Cathy M.

1998-04-01

Twentieth century medical science has embraced nineteenth century Boolean probability theory based upon two-valued Aristotelian logic. With the later addition of bit-based, von Neumann structured computational architectures, an epistemology based on randomness has led to a bivalent epidemiological methodology that dominates medical decision making. In contrast, fuzzy logic, based on twentieth century multi-valued logic, and computational structures that are content addressed and adaptively modified, has advanced a new scientific paradigm for the twenty-first century. Diseases such as stroke involve multiple concomitant causal factors that are difficult to represent using conventional statistical methods. We tested which paradigm best represented this complex multi-causal clinical phenomenon-stroke. We show that the fuzzy logic paradigm better represented clinical complexity in cerebrovascular disease than current probability theory based methodology. We believe this finding is generalizable to all of clinical science since multiple concomitant causal factors are involved in nearly all known pathological processes.

Differential Effects of Concomitant Use of Vitamins C and E on Trophoblast Apoptosis and Autophagy between Normoxia and Hypoxia-Reoxygenation

PubMed Central

Hung, Tai-Ho; Chen, Szu-Fu; Li, Meng-Jen; Yeh, Yi-Lin; Hsieh, T'sang-T'ang

2010-01-01

Background Concomitant supplementation of vitamins C and E during pregnancy has been reportedly associated with low birth weight, the premature rupture of membranes and fetal loss or perinatal death in women at risk for preeclampsia; however, the cause is unknown. We surmise that hypoxia-reoxygenation (HR) within the intervillous space due to abnormal placentation is the mechanism and hypothesize that concomitant administration of aforementioned vitamin antioxidants detrimentally affects trophoblast cells during HR. Methodology/Principal Findings Using villous explants, concomitant administration of 50 µM of vitamins C and E was observed to reduce apoptotic and autophagic changes in the trophoblast layer at normoxia (8% oxygen) but to cause more prominent apoptosis and autophagy during HR. Furthermore, increased levels of Bcl-2 and Bcl-xL in association with a decrease in the autophagy-related protein LC3-II were noted in cytotrophoblastic cells treated with vitamins C and E under standard culture conditions. In contrast, vitamin treatment decreased Bcl-2 and Bcl-xL as well as increased mitochondrial Bak and cytosolic LC3-II in cytotrophoblasts subjected to HR. Conclusions/Significance Our results indicate that concomitant administration of vitamins C and E has differential effects on the changes of apoptosis, autophagy and the expression of Bcl-2 family of proteins in the trophoblasts between normoxia and HR. These changes may probably lead to the impairment of placental function and suboptimal growth of the fetus. PMID:20808946

Saying Good-by: An Example of Using a Good-by Technique and Concomitant Psychodrama in the Resolving of Family Grief.

ERIC Educational Resources Information Center

Kaminski, Robert C.

A structured technique for saying "good-bye," or terminating a relationship, an important aspect of the therapeutic relationship, is presented. It consists of three distinct phases that are all dynamically interrelated, and can also be structured into separation caused by death. The technique is described in terms of three specific areas…

Familial Brugada syndrome uncovered by hyperkalaemic diabetic ketoacidosis.

PubMed

Postema, Pieter G; Vlaar, Alexander P J; DeVries, J Hans; Tan, Hanno L

2011-10-01

We describe a case of diabetic ketoacidosis with concomitant hyperkalaemia that uncovered a typical Brugada syndrome electrocardiogram (ECG). Further provocation testing in the patient and his son confirmed familial Brugada syndrome. Diabetic ketoacidosis with hyperkalaemia may uncover an inheritable arrhythmia syndrome that may put the patient and his/her next of kin at risk for a sudden death, irrespective of diabetes mellitus.

Apoptosis induced by microtubule disrupting drugs in cultured human lymphoma cells. Inhibitory effects of phorbol ester and zinc sulphate.

PubMed

Takano, Y; Okudaira, M; Harmon, B V

1993-03-01

The effects of the microtubule disrupting drugs (MDD) vinblastine, vincristine and colchicine on a human lymphoma cell line, BM 13674, were investigated. Twelve hours after administration of vinblastine (10(-3) mg/ml), vincristine (10(-2) mg/ml) or colchicine (10(-2) mg/ml), cell death with the characteristic morphology of apoptosis was observed in 71.6%, 82.2% and 76.9% of the cells respectively. The mode of death was confirmed as apoptotic by the occurrence of internucleosomal DNA cleavage, which was demonstrated by agarose gel electrophoresis. For the purpose of casting light on the mechanism involved, inhibition tests were performed on apoptosis induced by one of these drugs, vinblastine, using a phorbol ester (PDBu), zinc sulphate and cycloheximide. PDBu, an activator of protein kinase C, and zinc sulphate, a putative inhibitor of the endonuclease were thought to be responsible for internucleosomal DNA cleavage; both markedly reduced the induction of apoptosis. The protein synthesis inhibitor cycloheximide, on the other hand, had no inhibitory effect. Moreover, cycloheximide treatment per se enhanced apoptosis. This suggests that new protein synthesis is not required for the execution of vinblastine-induced apoptosis. Such a finding is in accord with recent reports suggesting that the "death program" within many cell types may be primed but unable to proceed due to concomitant production of specific "apoptotic inhibitors". It is suggested that phorbol esters prevent vinblastine-induced apoptosis in the BM 13674 cells by activating one or more of these specific "apoptotic inhibitors", possibly by means of PKC-mediated phosphorylation.

Hyperthermia enhances mapatumumab-induced apoptotic death through ubiquitin-mediated degradation of cellular FLIP(long) in human colon cancer cells

PubMed Central

Song, X; Kim, S-Y; Zhou, Z; Lagasse, E; Kwon, Y T; Lee, Y J

2013-01-01

Colorectal cancer is the third leading cause of cancer-related mortality in the world; the main cause of death of colorectal cancer is hepatic metastases, which can be treated with hyperthermia using isolated hepatic perfusion (IHP). In this study, we report that mild hyperthermia potently reduced cellular FLIP(long), (c-FLIPL), a major regulator of the death receptor (DR) pathway of apoptosis, thereby enhancing humanized anti-DR4 antibody mapatumumab (Mapa)-mediated mitochondria-independent apoptosis. We observed that overexpression of c-FLIPL in CX-1 cells abrogated the synergistic effect of Mapa and hyperthermia, whereas silencing of c-FLIP in CX-1 cells enhanced Mapa-induced apoptosis. Hyperthermia altered c-FLIPL protein stability without concomitant reductions in FLIP mRNA. Ubiquitination of c-FLIPL was increased by hyperthermia, and proteasome inhibitor MG132 prevented heat-induced downregulation of c-FLIPL. These results suggest the involvement of the ubiquitin-proteasome system in this process. We also found lysine residue 195 (K195) to be essential for c-FLIPL ubiquitination and proteolysis, as mutant c-FLIPL lysine 195 arginine (arginine replacing lysine) was left virtually un-ubiquitinated and was refractory to hyperthermia-triggered degradation, and thus partially blocked the synergistic effect of Mapa and hyperthermia. Our observations reveal that hyperthermia transiently reduced c-FLIPL by proteolysis linked to K195 ubiquitination, which contributed to the synergistic effect between Mapa and hyperthermia. This study supports the application of hyperthermia combined with other regimens to treat colorectal hepatic metastases. PMID:23559011

Hyperthermia enhances mapatumumab-induced apoptotic death through ubiquitin-mediated degradation of cellular FLIP(long) in human colon cancer cells.

PubMed

Song, X; Kim, S-Y; Zhou, Z; Lagasse, E; Kwon, Y T; Lee, Y J

2013-04-04

Colorectal cancer is the third leading cause of cancer-related mortality in the world; the main cause of death of colorectal cancer is hepatic metastases, which can be treated with hyperthermia using isolated hepatic perfusion (IHP). In this study, we report that mild hyperthermia potently reduced cellular FLIP(long), (c-FLIP(L)), a major regulator of the death receptor (DR) pathway of apoptosis, thereby enhancing humanized anti-DR4 antibody mapatumumab (Mapa)-mediated mitochondria-independent apoptosis. We observed that overexpression of c-FLIP(L) in CX-1 cells abrogated the synergistic effect of Mapa and hyperthermia, whereas silencing of c-FLIP in CX-1 cells enhanced Mapa-induced apoptosis. Hyperthermia altered c-FLIP(L) protein stability without concomitant reductions in FLIP mRNA. Ubiquitination of c-FLIP(L) was increased by hyperthermia, and proteasome inhibitor MG132 prevented heat-induced downregulation of c-FLIP(L). These results suggest the involvement of the ubiquitin-proteasome system in this process. We also found lysine residue 195 (K195) to be essential for c-FLIP(L) ubiquitination and proteolysis, as mutant c-FLIP(L) lysine 195 arginine (arginine replacing lysine) was left virtually un-ubiquitinated and was refractory to hyperthermia-triggered degradation, and thus partially blocked the synergistic effect of Mapa and hyperthermia. Our observations reveal that hyperthermia transiently reduced c-FLIP(L) by proteolysis linked to K195 ubiquitination, which contributed to the synergistic effect between Mapa and hyperthermia. This study supports the application of hyperthermia combined with other regimens to treat colorectal hepatic metastases.

Two Atypical Cases of Kingella kingae Invasive Infection with Concomitant Human Rhinovirus Infection

PubMed Central

Basmaci, Romain; Ilharreborde, Brice; Doit, Catherine; Presedo, Ana; Lorrot, Mathie; Alison, Marianne; Mazda, Keyvan; Bidet, Philippe

2013-01-01

We describe two atypical cases of Kingella kingae infection in children diagnosed by PCR, one case involving a soft tissue abscess and one case a femoral Brodie abscess. Both patients had concomitant human rhinovirus infection. K. kingae strains, isolated from an oropharyngeal swab, were characterized by multilocus sequence typing and rtxA sequencing. PMID:23784119

Epidemiologic trends and geographic patterns of fatal opioid intoxications in Connecticut, USA: 1997-2007.

PubMed

Green, Traci C; Grau, Lauretta E; Carver, H Wayne; Kinzly, Mark; Heimer, Robert

2011-06-01

The leading cause of injury death among adults in Connecticut (CT), USA is drug poisonings. We analyzed the epidemiology and geographic distribution of opioid-involved accidental drug-involved intoxication deaths ("overdoses") in CT over an 11-year period. We reviewed data from 1997 to 2007 on all adult accidental/undetermined drug intoxication deaths in CT that were referred to the Office of the Chief Medical Examiner (OCME). Regression analyses were conducted to uncover risk factors for fatal opioid-involved intoxications and to compare heroin- to prescription opioid- and methadone-involved deaths. Death locations were mapped to visualize differences in the geographic patterns of overdose by opioid type. Of the 2900 qualifying deaths, 2231 (77%) involved opioids. Trends over time revealed increases in total opioid-related deaths although heroin-related deaths remained constant. Methadone, oxycodone and fentanyl, the most frequently cited prescription opioids, exhibited significant increases in opioid deaths. Prescription opioid-only deaths were more likely to involve other medications (e.g., benzodiazepines) and to have occurred among residents of a suburban or small town location, compared to heroin-involved or methadone-involved deaths. Heroin-only deaths tended to occur among non-Whites, were more likely to involve alcohol or cocaine and to occur in public locations and large cities. The epidemiology of fatal opioid overdose in CT exhibits distinct longitudinal, risk factor, and geographic differences by opioid type. Each of these trends has implications for public health and prevention efforts. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Oxidative stress and apoptotic events during thermal stress in the symbiotic sea anemone, Anemonia viridis.

PubMed

Richier, Sophie; Sabourault, Cécile; Courtiade, Juliette; Zucchini, Nathalie; Allemand, Denis; Furla, Paola

2006-09-01

Symbiosis between cnidarian and photosynthetic protists is widely distributed over temperate and tropical seas. These symbioses can periodically breakdown, a phenomenon known as cnidarian bleaching. This event can be irreversible for some associations subjected to acute and/or prolonged environmental disturbances, and leads to the death of the animal host. During bleaching, oxidative stress has been described previously as acting at molecular level and apoptosis is suggested to be one of the mechanisms involved. We focused our study on the role of apoptosis in bleaching via oxidative stress in the association between the sea anemone Anemonia viridis and the dinoflagellates Symbiodinium species. Characterization of caspase-like enzymes were conducted at the biochemical and molecular level to confirm the presence of a caspase-dependent apoptotic phenomenon in the cnidarian host. We provide evidence of oxidative stress followed by induction of caspase-like activity in animal host cells after an elevated temperature stress, suggesting the concomitant action of these components in bleaching.

SUMO regulates proteasome-dependent degradation of FLASH/Casp8AP2

PubMed Central

Vennemann, Astrid; Hofmann, Thomas G.

2013-01-01

FLASH/Casp8AP2 is a huge multifunctional protein involved in multiple cellular processes, reaching from death receptor signaling to regulation of histone gene transcription and histone mRNA processing. Previous work has shown that FLASH localizes to Cajal bodies and promyelocytic leukemia (PML) bodies. However, the function of its nuclear body association remains unclear. Here we demonstrate that murine FLASH is covalently modified by SUMO at Lys residue 1792. Interestingly, ectopic expression of SUMO results in proteasome-dependent degradation of FLASH. A point mutant of FLASH with a mutated SUMO acceptor lysine residue, FLASHK1792R, is resistant to SUMO-induced degradation. Finally, we show that arsenic trioxide, a drug known to potentiate SUMO modification and degradation of PML, triggers recruitment of FLASH to PML bodies and concomitant loss of FLASH protein. Our data suggest that SUMO targets FLASH for proteasome-dependent degradation, which is associated with recruitment of FLASH to PML bodies. PMID:23673342

Sigma receptor 1 modulates ER stress and Bcl2 in murine retina.

PubMed

Ha, Yonju; Shanmugam, Arul K; Markand, Shanu; Zorrilla, Eric; Ganapathy, Vadivel; Smith, Sylvia B

2014-04-01

Sigma receptor 1 (σR1), a non-opiate transmembrane protein located on endoplasmic reticulum (ER) and mitochondrial membranes, is considered to be a molecular chaperone. Marked protection against cell death has been observed when ligands for σR1 have been used in in vitro and in vivo models of retinal cell death. Mice lacking σR1 (σR1(-/-)) manifest late-onset loss of retinal ganglion cells and retinal electrophysiological changes (after many months). The role of σR1 in the retina and the mechanisms by which its ligands afford neuroprotection are unclear. We therefore used σR1(-/-) mice to investigate the expression of ER stress genes (BiP/GRP78, Atf6, Atf4, Ire1α) and proteins involved in apoptosis (BCL2, BAX) and to examine the retinal transcriptome at young ages. Whereas no significant changes occurred in the expression of major ER stress genes (over a period of a year) in neural retina, marked changes were observed in these genes, especially Atf6, in isolated retinal Müller glial cells. BCL2 levels decreased in σR1(-/-) retina concomitantly with decreases in NFkB and pERK1/2. We postulate that σR1 regulates ER stress in retinal Müller cells and that the role of σR1 in retinal neuroprotection probably involves BCL2 and some of the proteins that modify its expression (such as ERK, NFκB). Data from the analysis of the retinal transcriptome of σR1 null mice provide new insights into the role of σR1 in retinal neuroprotection.

Sigma receptor 1 modulates ER stress and Bcl2 in murine retina

PubMed Central

Ha, Yonju; Shanmugam, Arul K.; Markand, Shanu; Zorrilla, Eric; Ganapathy, Vadivel; Smith, Sylvia B.

2014-01-01

Sigma receptor 1 (σR1), a non-opiate transmembrane protein located on endoplasmic reticulum (ER) and mitochondrial membranes, is considered a molecular chaperone. Marked protection against cell death has been observed when ligands for σR1 have been used in in vitro and in vivo models of retinal cell death. Mice lacking σR1 (σR1−/−) manifest late onset loss of retinal ganglion cells and retinal electrophysiological changes (after many months). The role of σR1 in retina and the mechanisms by which its ligands afford neuroprotection are unclear. To explore this we used σR1−/− mice and investigated expression of ER stress genes (BiP/GRP78, Atf6, Atf4, Ire1α) and proteins involved in apoptosis (BCL2, BAX) and examined the retinal transcriptome at young ages. While there were no significant changes in expression of major ER stress genes (over a period of a year) in neural retina, there were marked changes in these genes especially Atf6 in isolated retinal Müller glial cells. BCL2 levels decreased in σR1−/− retina concomitant with decreases in NFkB and pERK1/2. We postulate that σR1 regulates ER stress in retinal Müller cells and that the role of σR1 in retinal neuroprotection likely involves BCL2 and some of the proteins that modify its expression (such as ERK, NFκB). Data from the analysis of the retinal transcriptome of σR1 null mice provides new avenues to understand the role of σR1 in retinal neuroprotection. PMID:24469320

Balancing the risks and benefits of drinking water disinfection: disability adjusted life-years on the scale.

PubMed

Havelaar, A H; De Hollander, A E; Teunis, P F; Evers, E G; Van Kranen, H J; Versteegh, J F; Van Koten, J E; Slob, W

2000-04-01

To evaluate the applicability of disability adjusted life-years (DALYs) as a measure to compare positive and negative health effects of drinking water disinfection, we conducted a case study involving a hypothetical drinking water supply from surface water. This drinking water supply is typical in The Netherlands. We compared the reduction of the risk of infection with Cryptosporidium parvum by ozonation of water to the concomitant increase in risk of renal cell cancer arising from the production of bromate. We applied clinical, epidemiologic, and toxicologic data on morbidity and mortality to calculate the net health benefit in DALYs. We estimated the median risk of infection with C. parvum as 10(-3)/person-year. Ozonation reduces the median risk in the baseline approximately 7-fold, but bromate is produced in a concentration above current guideline levels. However, the health benefits of preventing gastroenteritis in the general population and premature death in patients with acquired immunodeficiency syndrome outweigh health losses by premature death from renal cell cancer by a factor of > 10. The net benefit is approximately 1 DALY/million person-years. The application of DALYs in principle allows us to more explicitly compare the public health risks and benefits of different management options. In practice, the application of DALYs may be hampered by the substantial degree of uncertainty, as is typical for risk assessment.

The cathepsin B inhibitor z-FA-CMK induces cell death in leukemic T cells via oxidative stress.

PubMed

Liow, K Y; Chow, Sek C

2018-01-01

The cathepsin B inhibitor benzyloxycarbonyl-phenylalanine-alanine-chloromethyl ketone (z-FA-CMK) was recently found to induce apoptosis at low concentrations in Jurkat T cells, while at higher concentrations, the cells die of necrosis. In the present study, we showed that z-FA-CMK readily depletes intracellular glutathione (GSH) with a concomitant increase in reactive oxygen species (ROS) generation. The toxicity of z-FA-CMK in Jurkat T cells was completely abrogated by N-acetylcysteine (NAC), suggesting that the toxicity mediated by z-FA-CMK is due to oxidative stress. We found that L-buthionine sulfoximine (BSO) which depletes intracellular GSH through the inhibition of GSH biosynthesis in Jurkat T cells did not promote ROS increase or induce cell death. However, NAC was still able to block z-FA-CMK toxicity in Jurkat T cells in the presence of BSO, indicating that the protective effect of NAC does not involve GSH biosynthesis. This is further corroborated by the protective effect of the non-metabolically active D-cysteine on z-FA-CMK toxicity. Furthermore, in BSO-treated cells, z-FA-CMK-induced ROS increased which remains unchanged, suggesting that the depletion of GSH and increase in ROS generation mediated by z-FA-CMK may be two separate events. Collectively, our results demonstrated that z-FA-CMK toxicity is mediated by oxidative stress through the increase in ROS generation.

Mechanisms underlying 3-bromopyruvate-induced cell death in colon cancer.

PubMed

Sun, Yiming; Liu, Zhe; Zou, Xue; Lan, Yadong; Sun, Xiaojin; Wang, Xiu; Zhao, Surong; Jiang, Chenchen; Liu, Hao

2015-08-01

3-Bromopyruvate (3BP) is an energy-depleting drug that inhibits Hexokinase II activity by alkylation during glycolysis, thereby suppressing the production of ATP and inducing cell death. As such, 3BP can potentially serve as an anti-tumorigenic agent. Our previous research showed that 3BP can induce apoptosis via AKT /protein Kinase B signaling in breast cancer cells. Here we found that 3BP can also induce colon cancer cell death by necroptosis and apoptosis at the same time and concentration in the SW480 and HT29 cell lines; in the latter, autophagy was also found to be a mechanism of cell death. In HT29 cells, combined treatment with 3BP and the autophagy inhibitor 3-methyladenine (3-MA) exacerbated cell death, while viability in 3BP-treated cells was enhanced by concomitant treatment with the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone (z-VAD-fmk) and the necroptosis inhibitor necrostatin (Nec)-1. Moreover, 3BP inhibited tumor growth in a SW480 xenograft mouse model. These results indicate that 3BP can suppress tumor growth and induce cell death by multiple mechanisms at the same time and concentration in different types of colon cancer cell by depleting cellular energy stores.

Use of concomitant variceal embolization and prophylactic antiplatelet/anticoagulative in transjugular intrahepatic portosystemic shunting: A retrospective study of 182 cirrhotic portal hypertension patients.

PubMed

Tang, Yingmei; Zheng, Sheng; Yang, Jinhui; Bao, Weimin; Yang, Lihong; Li, Yingchun; Xu, Ying; Yang, Jing; Tong, Yuyun; Gao, Jinhang; Tang, Chengwei

2017-12-01

Transjugular intrahepatic portosystemic shunting (TIPS) is an effective treatment modality for refractory variceal bleeding and ascites in patients with cirrhotic portal hypertension (CPH). Variceal rebleeding and shunt dysfunction are major post-TIPS morbidities. This study aimed to retrospectively evaluate the effectiveness and safety of use of concomitant variceal embolization and prophylactic antiplatelet/anticoagulative in patients with CPH undergoing TIPS. Between October 2006 and October 2011, 182 patients with CPH were retrospectively and consecutively hospitalized for elective TIPS with Fluency stenting. Concomitant variceal embolization was given after establishing the shunt. Subcutaneous heparin was given after TIPS and replaced by oral clopidogrel, aspirin, or warfarin for at least 6 months. Main outcome measures included shunt patency rate, recurrence of CPH (rebleeding and/or refractory ascites), hepatic encephalopathy (HE) frequency, and post-TIPS survival. The cumulative primary patency rate was 96%, 94%, 90%, 88%, and 88% at 6, 12, 24, 36, and 48 months, respectively. Shunt stenosis occurred in 16 (9%) patients, gastrointestinal (GI) rebleeding in 32 (17.5%) patients, recurrence of refractory ascites 44 (48%) patients, HE in 42 (23%) patients, and death in 36 (20%) patients during the follow-up period. Use of concomitant variceal embolization and prophylactic antiplatelet/anticoagulative was associated with a favorable shunt patency and a low risk of GI rebleeding.

Combination of immunotherapy with chemotherapy and radiotherapy in lung cancer: is this the beginning of the end for cancer?

PubMed Central

Lazzari, Chiara; Karachaliou, Niki; Bulotta, Alessandra; Viganó, Mariagrazia; Mirabile, Aurora; Brioschi, Elena; Santarpia, Mariacarmela; Gianni, Luca; Rosell, Rafael; Gregorc, Vanesa

2018-01-01

Immune checkpoint inhibitors have significantly improved overall survival with an acceptable safety profile in a substantial proportion of non-small cell lung cancer (NSCLC) patients. However, not all patients are sensitive to immune checkpoint blockade and, in some cases, programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors accelerate tumor progression. Several combination strategies are under evaluation, including the concomitant or sequential evaluation of chemotherapy or radiotherapy with immunotherapy. The current review provides an overview on the molecular rationale for the investigation of combinatorial approaches with chemotherapy or radiotherapy. Moreover, the results of completed clinical studies will be reported. PMID:29662546

Combination of immunotherapy with chemotherapy and radiotherapy in lung cancer: is this the beginning of the end for cancer?

PubMed

Lazzari, Chiara; Karachaliou, Niki; Bulotta, Alessandra; Viganó, Mariagrazia; Mirabile, Aurora; Brioschi, Elena; Santarpia, Mariacarmela; Gianni, Luca; Rosell, Rafael; Gregorc, Vanesa

2018-01-01

Immune checkpoint inhibitors have significantly improved overall survival with an acceptable safety profile in a substantial proportion of non-small cell lung cancer (NSCLC) patients. However, not all patients are sensitive to immune checkpoint blockade and, in some cases, programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors accelerate tumor progression. Several combination strategies are under evaluation, including the concomitant or sequential evaluation of chemotherapy or radiotherapy with immunotherapy. The current review provides an overview on the molecular rationale for the investigation of combinatorial approaches with chemotherapy or radiotherapy. Moreover, the results of completed clinical studies will be reported.

Fentanyl Law Enforcement Submissions and Increases in Synthetic Opioid-Involved Overdose Deaths - 27 States, 2013-2014.

PubMed

Gladden, R Matthew; Martinez, Pedro; Seth, Puja

2016-08-26

In March and October 2015, the Drug Enforcement Administration (DEA) and CDC, respectively, issued nationwide alerts identifying illicitly manufactured fentanyl (IMF) as a threat to public health and safety (1,2). IMF is unlawfully produced fentanyl, obtained through illicit drug markets, includes fentanyl analogs, and is commonly mixed with or sold as heroin (1,3,4). Starting in 2013, the production and distribution of IMF increased to unprecedented levels, fueled by increases in the global supply, processing, and distribution of fentanyl and fentanyl-precursor chemicals by criminal organizations (3). Fentanyl is a synthetic opioid 50-100 times more potent than morphine (2).* Multiple states have reported increases in fentanyl-involved overdose (poisoning) deaths (fentanyl deaths) (2). This report examined the number of drug products obtained by law enforcement that tested positive for fentanyl (fentanyl submissions) and synthetic opioid-involved deaths other than methadone (synthetic opioid deaths), which include fentanyl deaths and deaths involving other synthetic opioids (e.g., tramadol). Fentanyl deaths are not reported separately in national data. Analyses also were conducted on data from 27 states(†) with consistent death certificate reporting of the drugs involved in overdoses. Nationally, the number of fentanyl submissions and synthetic opioid deaths increased by 426% and 79%, respectively, during 2013-2014; among the 27 analyzed states, fentanyl submission increases were strongly correlated with increases in synthetic opioid deaths. Changes in fentanyl submissions and synthetic opioid deaths were not correlated with changes in fentanyl prescribing rates, and increases in fentanyl submissions and synthetic opioid deaths were primarily concentrated in eight states (high-burden states). Reports from six of the eight high-burden states indicated that fentanyl-involved overdose deaths were primarily driving increases in synthetic opioid deaths. Increases in synthetic opioid deaths among high-burden states disproportionately involved persons aged 15-44 years and males, a pattern consistent with previously documented IMF-involved deaths (5). These findings, combined with the approximate doubling in fentanyl submissions during 2014-2015 (from 5,343 to 13,882) (6), underscore the urgent need for a collaborative public health and law enforcement response.

Increased reactive oxygen species production during reductive stress: The roles of mitochondrial glutathione and thioredoxin reductases.

PubMed

Korge, Paavo; Calmettes, Guillaume; Weiss, James N

2015-01-01

Both extremes of redox balance are known to cause cardiac injury, with mounting evidence revealing that the injury induced by both oxidative and reductive stress is oxidative in nature. During reductive stress, when electron acceptors are expected to be mostly reduced, some redox proteins can donate electrons to O2 instead, which increases reactive oxygen species (ROS) production. However, the high level of reducing equivalents also concomitantly enhances ROS scavenging systems involving redox couples such as NADPH/NADP+ and GSH/GSSG. Here our objective was to explore how reductive stress paradoxically increases net mitochondrial ROS production despite the concomitant enhancement of ROS scavenging systems. Using recombinant enzymes and isolated permeabilized cardiac mitochondria, we show that two normally antioxidant matrix NADPH reductases, glutathione reductase and thioredoxin reductase, generate H2O2 by leaking electrons from their reduced flavoprotein to O2 when electron flow is impaired by inhibitors or because of limited availability of their natural electron acceptors, GSSG and oxidized thioredoxin. The spillover of H2O2 under these conditions depends on H2O2 reduction by peroxiredoxin activity, which may regulate redox signaling in response to endogenous or exogenous factors. These findings may explain how ROS production during reductive stress overwhelms ROS scavenging capability, generating the net mitochondrial ROS spillover causing oxidative injury. These enzymes could potentially be targeted to increase cancer cell death or modulate H2O2-induced redox signaling to protect the heart against ischemia/reperfusion damage. Copyright © 2015 Elsevier B.V. All rights reserved.

The Triangle of Death in Alzheimer's Disease Brain: The Aberrant Cross-Talk Among Energy Metabolism, Mammalian Target of Rapamycin Signaling, and Protein Homeostasis Revealed by Redox Proteomics.

PubMed

Di Domenico, Fabio; Barone, Eugenio; Perluigi, Marzia; Butterfield, D Allan

2017-03-10

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder and represents one of the most disabling conditions. AD shares many features in common with systemic insulin resistance diseases, suggesting that it can be considered as a metabolic disease, characterized by reduced insulin-stimulated growth and survival signaling, increased oxidative stress (OS), proinflammatory cytokine activation, mitochondrial dysfunction, impaired energy metabolism, and altered protein homeostasis. Recent Advances: Reduced glucose utilization and energy metabolism in AD have been associated with the buildup of amyloid-β peptide and hyperphosphorylated tau, increased OS, and the accumulation of unfolded/misfolded proteins. Mammalian target of rapamycin (mTOR), which is aberrantly activated in AD since early stages, plays a key role during AD neurodegeneration by, on one side, inhibiting insulin signaling as a negative feedback mechanism and, on the other side, regulating protein homeostasis (synthesis/clearance). It is likely that the concomitant and mutual alterations of energy metabolism-mTOR signaling-protein homeostasis might represent a self-sustaining triangle of harmful events that trigger the degeneration and death of neurons and the development and progression of AD. Intriguingly, the altered cross-talk between the components of such a triangle of death, beyond altering the redox homeostasis of the neuron, is further exacerbated by increased levels of OS that target and impair key components of the pathways involved. Redox proteomic studies in human samples and animal models of AD-like dementia led to identification of oxidatively modified components of the pathways composing the triangle of death, therefore revealing the crucial role of OS in fueling this aberrant vicious cycle. The identification of compounds able to restore the function of the pathways targeted by oxidative damage might represent a valuable therapeutic approach to slow or delay AD. Antioxid. Redox Signal. 26, 364-387.

Drug-related celebrity deaths: A cross-sectional study.

PubMed

Just, Johannes M; Bleckwenn, Markus; Schnakenberg, Rieke; Skatulla, Philipp; Weckbecker, Klaus

2016-12-09

Celebrities are at risk for premature mortality as well as drug-related death. Despite being a vulnerable patient group, celebrities influence people's health behaviours through biological, psychological and social processes. Therefore, celebrity endorsement of the topic could be one way to challenge the current "opioid endemic". Our aim was to better understand the factors surrounding drug-related celebrity deaths by investigating the incidence as well as substances used between 1970 and 2015 using a cross-sectional study design. We searched public databases for drug-related celebrity deaths between 1970 and 2015. They were categorized for sex, profession, age at death, year of death and substances involved. The main outcome measures are descriptive values including number of drug deaths per year and substances involved. Secondary outcome measures are analytical questions to examine whether and which factors influence age at death and year of death (e.g. type of substance use disorder). We identified 220 celebrities who died a drug-related death with a clear indication of involved substances between 1970 and 2015. The average age at death was 38.6 years; 75% were male. Most celebrities died between the age of 25 and 40. The number of drug-related deaths increased in the 21st century, with a significant increase in the use of prescription opioids. Deaths involving prescription opioids and heroin were associated with a significantly lower mean age at death compared to deaths where these substances were not involved. Compared to the 20th century, the total number of celebrities who died from a drug-related death in the 21st century increased, possibly due to an increased involvement of prescription opioids. Negative effects on individual health decisions of celebrity's followers could be the result.

Perimortem fractures in Lucy suggest mortality from fall out of tall tree.

PubMed

Kappelman, John; Ketcham, Richard A; Pearce, Stephen; Todd, Lawrence; Akins, Wiley; Colbert, Matthew W; Feseha, Mulugeta; Maisano, Jessica A; Witzel, Adrienne

2016-09-22

The Pliocene fossil 'Lucy' (Australopithecus afarensis) was discovered in the Afar region of Ethiopia in 1974 and is among the oldest and most complete fossil hominin skeletons discovered. Here we propose, on the basis of close study of her skeleton, that her cause of death was a vertical deceleration event or impact following a fall from considerable height that produced compressive and hinge (greenstick) fractures in multiple skeletal elements. Impacts that are so severe as to cause concomitant fractures usually also damage internal organs; together, these injuries are hypothesized to have caused her death. Lucy has been at the centre of a vigorous debate about the role, if any, of arboreal locomotion in early human evolution. It is therefore ironic that her death can be attributed to injuries resulting from a fall, probably out of a tall tree, thus offering unusual evidence for the presence of arborealism in this species.

Implantable Cardioverter Defibrillators for Primary Prevention of Mortality in Patients With Nonischemic Cardiomyopathy: A Meta-Analysis of Randomized Controlled Trials.

PubMed

Stavrakis, Stavros; Asad, Zain; Reynolds, Dwight

2017-06-01

Implantable cardioverter defibrillators (ICDs) improve survival in patients with heart failure due to ischemic cardiomyopathy, but their benefit in nonischemic cardiomyopathy (NICM) has been recently questioned. We performed a meta-analysis of randomized clinical trials to examine the effect of ICDs on total mortality and arrhythmic death in patients with NICM. We also examined the impact of age and cardiac resynchronization therapy (CRT) on the relative effect of ICD compared to control. We searched the MEDLINE and EMBASE databases for randomized trials evaluating the effect of ICD versus control in patients with NICM. Hazard ratios (HR) with 95% confidence interval (CI) were calculated using a random effects model. Six trials involving 2,967 patients were included (ICD, n = 1,553; control, n = 1,414). Based on the pooled estimate across the six studies, the use of ICD was associated with a significant reduction in total mortality (HR = 0.78, 95% CI 0.66-0.92; P = 0.003), as well as arrhythmic death (HR = 0.46, 95% CI 0.29-0.71; P = 0.0005) compared to control. ICD decreased total mortality in younger patients compared to control (HR = 0.63, 95% CI 0.46-0.86; P = 0.004), but not in older patients (HR = 0.97, 95% CI 0.56-1.68; P = 0.92). In patients with CRT, ICD reduced total mortality compared to control (HR = 0.78, 95% CI 0.65-0.95; P = 0.02), but not in patients with CRT (HR = 0.71, 95% CI 0.40-1.26). ICDs decrease total mortality and arrhythmic deaths in patients with NICM. The benefit of ICD appears to be dependent on age and concomitant use of CRT. © 2017 Wiley Periodicals, Inc.

A high parasite density environment induces transcriptional changes and cell death in Plasmodium falciparum blood stages.

PubMed

Chou, Evelyn S; Abidi, Sabia Z; Teye, Marian; Leliwa-Sytek, Aleksandra; Rask, Thomas S; Cobbold, Simon A; Tonkin-Hill, Gerry Q; Subramaniam, Krishanthi S; Sexton, Anna E; Creek, Darren J; Daily, Johanna P; Duffy, Michael F; Day, Karen P

2018-03-01

Transient regulation of Plasmodium numbers below the density that induces fever has been observed in chronic malaria infections in humans. This species transcending control cannot be explained by immunity alone. Using an in vitro system we have observed density dependent regulation of malaria population size as a mechanism to possibly explain these in vivo observations. Specifically, Plasmodium falciparum blood stages from a high but not low-density environment exhibited unique phenotypic changes during the late trophozoite (LT) and schizont stages of the intraerythrocytic cycle. These included in order of appearance: failure of schizonts to mature and merozoites to replicate, apoptotic-like morphological changes including shrinking, loss of mitochondrial membrane potential, and blebbing with eventual release of aberrant parasites from infected erythrocytes. This unique death phenotype was triggered in a stage-specific manner by sensing of a high-density culture environment. Conditions of glucose starvation, nutrient depletion, and high lactate could not induce the phenotype. A high-density culture environment induced rapid global changes in the parasite transcriptome including differential expression of genes involved in cell remodeling, clonal antigenic variation, metabolism, and cell death pathways including an apoptosis-associated metacaspase gene. This transcriptional profile was also characterized by concomitant expression of asexual and sexual stage-specific genes. The data show strong evidence to support our hypothesis that density sensing exists in P. falciparum. They indicate that an apoptotic-like mechanism may play a role in P. falciparum density regulation, which, as in yeast, has features quite distinguishable from mammalian apoptosis. Gene expression data are available in the GEO databases under the accession number GSE91188. © 2017 Federation of European Biochemical Societies.

Fatal injuries in the United States construction industry involving cranes 1984-1994.

PubMed

Suruda, A; Liu, D; Egger, M; Lillquist, D

1999-12-01

There is little published information concerning the epidemiology of injuries in the construction industry involving cranes other than for electrical injury from power line contact. For the 11-year period of 1984 through 1994, the US Occupational Safety and Health Administration (OSHA) investigated 502 deaths in 479 incidents involving cranes in the construction industry. Electrocution was the largest category, with 198 deaths (39%) reported. Other major categories were assembly/dismantling (58 deaths, 12%), boom buckling (41 deaths, 8%), crane upset/overturn (37 deaths, 7%), and rigging failure (36 deaths, 7%). The majority of the deaths during assembly/dismantling involved removal of the boom pins from lattice boom cranes. Only 34% of the construction firms employing the fatally injured workers had ever been inspected by OSHA. OSHA cited the employer for safety violations in 436 deaths (83%). Additional worker training, increased OSHA inspections, and crane inspection programs could prevent many crane-related deaths.

Sigma receptor antagonists attenuate acute methamphetamine-induced hyperthermia by a mechanism independent of IL-1β mRNA expression in the hypothalamus

PubMed Central

Seminerio, Michael J.; Robson, Matthew J.; McCurdy, Christopher R.; Matsumoto, Rae R.

2013-01-01

Methamphetamine is currently one of the most widely abused drugs worldwide, with hyperthermia being a leading cause of death in methamphetamine overdose situations. Methamphetamine-induced hyperthermia involves a variety of cellular mechanisms, including increases in hypothalamic interleukin-1 beta (IL-1β) expression. Methamphetamine also interacts with sigma receptors and previous studies have shown that sigma receptor antagonists mitigate many of the behavioral and physiological effects of methamphetamine, including hyperthermia. The purpose of the current study was to determine if the attenuation of methamphetamine-induced hyperthermia by the sigma receptor antagonists, AZ66 and SN79, is associated with a concomitant attenuation of IL-1β mRNA expression, particularly in the hypothalamus. Methamphetamine produced doseand time-dependent increases in core body temperature and IL-1β mRNA expression in the hypothalamus, striatum, and cortex in male, Swiss Webster mice. Pretreatment with the sigma receptor antagonists, AZ66 and SN79, significantly attenuated methamphetamine-induced hyperthermia, but further potentiated IL-1β mRNA in the mouse hypothalamus when compared to animals treated with methamphetamine alone. These findings suggest sigma receptor antagonists attenuate methamphetamine-induced hyperthermia through a different mechanism from that involved in the modulation of hypothalamic IL-1β mRNA expression. PMID:22820108

[Diffuse large B-cell lymphoma with concomitant c-MYC and BCL6 gene rearrangements with primary skin involvement: A case report and a review of literature].

PubMed

Gabeeva, N G; Koroleva, D A; Belyaeva, A V; Chernova, N G; Kuzmina, L A; Sudarikov, A B; Obukhova, T N; Kovrigina, A M; Zvonkov, E E; Savchenko, V G

Double-hit lymphoma (DHL) is a rare aggressive B-cell lymphoma with concomitant c-MYC, BCL2 or BCL6 gene rearrangements, which is characterized by the high frequency of extranodal lesions and by resistance to chemotherapy. The median survival does not exceed 18 months in patients with this disease. The majority of DHL is represented by с-MYC/BCL2 cases. The combination of c-MYC/BCL6 occurs rarely (5-8%). The paper describes a case of DHL with concomitant c-MYC and BCL6 gene rearrangements, which mimics diffuse large B-cell lymphoma, leg-type.

State Variation in Underreporting of Alcohol Involvement on Death Certificates: Motor Vehicle Traffic Crash Fatalities as an Example

PubMed Central

Castle, I-Jen P; Yi, Hsiao-Ye; Hingson, Ralph W; White, Aaron M

2014-01-01

Objective: We used motor vehicle traffic (MVT) crash fatalities as an example to examine the extent of underreporting of alcohol involvement on death certificates and state variations. Method: We compared MVT-related death certificates identified from national mortality data (Multiple Cause of Death [MCoD] data) with deaths in national traffic census data from the Fatality Analysis Reporting System (FARS). Because MCoD data were not individually linked to FARS data, the comparisons were at the aggregate level. Reporting ratio of alcohol involvement on death certificates was thus computed as the prevalence of any mention of alcohol-related conditions among MVT deaths in MCoD, divided by the prevalence of decedents with blood alcohol concentration (BAC) test results (not imputed) of .08% or greater in FARS. Through bivariate analysis and multiple regression, we explored state characteristics correlated with state reporting ratios. Results: Both MCoD and FARS identified about 450,000 MVT deaths in 1999–2009. Reporting ratio was only 0.16 for all traffic deaths and 0.18 for driver deaths nationally, reflecting that death certificates captured only a small percentage of MVT deaths involving BAC of .08% or more. Reporting ratio did not improve over time, even though FARS indicated that the prevalence of BAC of at least .08% in MVT deaths increased from 19.9% in 1999 to 24.2% in 2009. State reporting ratios varied widely, from 0.02 (Nevada and New Jersey) to 0.81 (Delaware). Conclusions: The comparison of MCoD with FARS revealed a large discrepancy in reporting alcohol involvement in MVT deaths and considerable state variation in the magnitude of underreporting. We suspect similar underreporting and state variations in alcohol involvement in other types of injury deaths. PMID:24650824

Neoadjuvant Chemotherapy Followed by Radical Surgery Versus Concomitant Chemotherapy and Radiotherapy in Patients With Stage IB2, IIA, or IIB Squamous Cervical Cancer: A Randomized Controlled Trial.

PubMed

Gupta, Sudeep; Maheshwari, Amita; Parab, Pallavi; Mahantshetty, Umesh; Hawaldar, Rohini; Sastri Chopra, Supriya; Kerkar, Rajendra; Engineer, Reena; Tongaonkar, Hemant; Ghosh, Jaya; Gulia, Seema; Kumar, Neha; Shylasree, T Surappa; Gawade, Renuka; Kembhavi, Yogesh; Gaikar, Madhuri; Menon, Santosh; Thakur, Meenakshi; Shrivastava, Shyam; Badwe, Rajendra

2018-06-01

Purpose We compared the efficacy and toxicity of neoadjuvant chemotherapy followed by radical surgery versus standard cisplatin-based chemoradiation in patients with locally advanced squamous cervical cancer. Patients and Methods This was a single-center, phase III, randomized controlled trial ( ClinicalTrials.gov identifier: NCT00193739). Eligible patients were between 18 and 65 years old and had stage IB2, IIA, or IIB squamous cervical cancer. They were randomly assigned, after stratification by stage, to receive either three cycles of neoadjuvant chemotherapy using paclitaxel and carboplatin once every 3 weeks followed by radical hysterectomy or standard radiotherapy with concomitant cisplatin once every week for 5 weeks. Patients in the neoadjuvant group received postoperative adjuvant radiation or concomitant chemotherapy and radiotherapy, if indicated. The primary end point was disease-free survival (DFS), defined as survival without relapse or death related to cancer, and secondary end points included overall survival and toxicity. Results Between September 2003 and February 2015, 635 patients were randomly assigned, of whom 633 (316 patients in the neoadjuvant chemotherapy plus surgery group and 317 patients in the concomitant chemoradiation group) were included in the final analysis, with a median follow-up time of 58.5 months. The 5-year DFS in the neoadjuvant chemotherapy plus surgery group was 69.3% compared with 76.7% in the concomitant chemoradiation group (hazard ratio, 1.38; 95% CI, 1.02 to 1.87; P = .038), whereas the corresponding 5-year OS rates were 75.4% and 74.7%, respectively (hazard ratio, 1.025; 95% CI, 0.752 to 1.398; P = .87). The delayed toxicities at 24 months or later after treatment completion in the neoadjuvant chemotherapy plus surgery group versus the concomitant chemoradiation group were rectal (2.2% v 3.5%, respectively), bladder (1.6% v 3.5%, respectively), and vaginal (12.0% v 25.6%, respectively). Conclusion Cisplatin-based concomitant chemoradiation resulted in superior DFS compared with neoadjuvant chemotherapy followed by radical surgery in locally advanced cervical cancer.

Comparison of isolated and concomitant liver injuries: is hepatic trauma entirely responsible for the outcome?

PubMed

Yazici, P; Aydin, U; Sozbilen, M

2010-01-01

This study was undertaken to examine both isolated and concomitant liver injuries to clarify the role of liver trauma on outcome. This retrospective study was a review of all abdominal trauma patients who presented with liver injuries, with or without concomitant injury at Ege University School of Medicine over a 3-year period. Presentation, injury grade, management, and outcomes were analyzed. Patients with isolated hepatic injury (Group A) were compared with patients who had concomitant hepatic injury (liver and spleen/small bowel) (Group B). Significance was set at 95% confidence intervals. Of 368 patients, 80 (21%) presented with liver injury. Of these, the aetiology was as follows: 53 (66.2%) blunt injury, 19 (23%) penetrating injury, and 8 (10%) gun shot trauma. There were 38 patients in Group A and 42 in Group B. Of these 42 patients, 19 were diagnosed with serious types of injury ; eight thoracic, three open long bone fracture, one intra-cardiac, one intracranial. Six additional patients were observed with injuries to large abdominal vessels. Eleven patients (28.9%) with isolated hepatic injury were managed non-operatively. Mortality, intensive care unit and hospital length of stay, and transfusion requirements were significantly higher in Group B. Only the number of transfused blood units and the grade of liver injury were found to be effective on outcome whereas stepwise regression analysis revealed that injury type (penetrating) and blood transfusion were predictive for mortality. This study highlighted that although isolated liver injury results in good outcome with non-operative management, concomitant injuries to the liver lead to a higher failure and mortality rate. However, liver injury itself is rarely responsible for death.

Impact of Bone-targeted Therapies in Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer Patients Treated with Abiraterone Acetate: Post Hoc Analysis of Study COU-AA-302

PubMed Central

Saad, Fred; Shore, Neal; Van Poppel, Hendrik; Rathkopf, Dana E.; Smith, Matthew R.; de Bono, Johann S.; Logothetis, Christopher J.; de Souza, Paul; Fizazi, Karim; Mulders, Peter F.A.; Mainwaring, Paul; Hainsworth, John D.; Beer, Tomasz M.; North, Scott; Fradet, Yves; Griffin, Thomas A.; De Porre, Peter; Londhe, Anil; Kheoh, Thian; Small, Eric J.; Scher, Howard I.; Molina, Arturo; Ryan, Charles J.

2016-01-01

Background Metastatic castration-resistant prostate cancer (mCRPC) often involves bone, and bone-targeted therapy (BTT) has become part of the overall treatment strategy. Objective Investigation of outcomes for concomitant BTT in a post hoc analysis of the COU-AA-302 trial, which demonstrated an overall clinical benefit of abiraterone acetate (AA) plus prednisone over placebo plus prednisone in asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients. Design, setting, and participants This report describes the third interim analysis (prespecified at 55% overall survival [OS] events) for the COU-AA-302 trial. Intervention Patients were grouped by concomitant BTT use or no BTT use. Outcome measurements and statistical analysis Radiographic progression-free survival and OS were coprimary end points. This report describes the third interim analysis (prespecified at 55% OS events) and involves patients treated with or without concomitant BTT during the COU-AA-302 study. Median follow-up for OS was 27.1 mo. Median time-to-event variables with 95% confidence intervals (CIs) were estimated using the Kaplan-Meier method. Adjusted hazard ratios (HRs), 95% CIs, and p values for concomitant BTT versus no BTT were obtained via Cox models. Results and limitations While the post hoc nature of the analysis is a limitation, superiority of AA and prednisone versus prednisone alone was demonstrated for clinical outcomes with or without BTT use. Compared with no BTT use, concomitant BTT significantly improved OS (HR 0.75; p = 0.01) and increased the time to ECOG deterioration (HR 0.75; p < 0.001) and time to opiate use for cancer-related pain (HR 0.80; p = 0.036). The safety profile of concomitant BTT with AA was similar to that reported for AA in the overall intent-to-treat population. Osteonecrosis of the jaw (all grade 1/2) with concomitant BTT use was reported in <3% of patients. Conclusions AA with concomitant BTT was safe and well tolerated in men with chemotherapy-naïve mCRPC. The benefits of AA on clinical outcomes were increased with concomitant BTT. Patient summary Treatment of advanced prostate cancer often includes bone-targeted therapy. This post hoc analysis showed that in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone in combination with bone-targeted therapy, there was a continued trend in prolongation of life when compared with patients treated with prednisone alone. Trial registration ClinicalTrials.gov NCT00887198. PMID:25985882

Refractive Errors and Concomitant Strabismus: A Systematic Review and Meta-analysis.

PubMed

Tang, Shu Min; Chan, Rachel Y T; Bin Lin, Shi; Rong, Shi Song; Lau, Henry H W; Lau, Winnie W Y; Yip, Wilson W K; Chen, Li Jia; Ko, Simon T C; Yam, Jason C S

2016-10-12

This systematic review and meta-analysis is to evaluate the risk of development of concomitant strabismus due to refractive errors. Eligible studies published from 1946 to April 1, 2016 were identified from MEDLINE and EMBASE that evaluated any kinds of refractive errors (myopia, hyperopia, astigmatism and anisometropia) as an independent factor for concomitant exotropia and concomitant esotropia. Totally 5065 published records were retrieved for screening, 157 of them eligible for detailed evaluation. Finally 7 population-based studies involving 23,541 study subjects met our criteria for meta-analysis. The combined OR showed that myopia was a risk factor for exotropia (OR: 5.23, P = 0.0001). We found hyperopia had a dose-related effect for esotropia (OR for a spherical equivalent [SE] of 2-3 diopters [D]: 10.16, P = 0.01; OR for an SE of 3-4D: 17.83, P < 0.0001; OR for an SE of 4-5D: 41.01, P < 0.0001; OR for an SE of ≥5D: 162.68, P < 0.0001). Sensitivity analysis indicated our results were robust. Results of this study confirmed myopia as a risk for concomitant exotropia and identified a dose-related effect for hyperopia as a risk of concomitant esotropia.

Refractive Errors and Concomitant Strabismus: A Systematic Review and Meta-analysis

PubMed Central

Tang, Shu Min; Chan, Rachel Y. T.; Bin Lin, Shi; Rong, Shi Song; Lau, Henry H. W.; Lau, Winnie W. Y.; Yip, Wilson W. K.; Chen, Li Jia; Ko, Simon T. C.; Yam, Jason C. S.

2016-01-01

This systematic review and meta-analysis is to evaluate the risk of development of concomitant strabismus due to refractive errors. Eligible studies published from 1946 to April 1, 2016 were identified from MEDLINE and EMBASE that evaluated any kinds of refractive errors (myopia, hyperopia, astigmatism and anisometropia) as an independent factor for concomitant exotropia and concomitant esotropia. Totally 5065 published records were retrieved for screening, 157 of them eligible for detailed evaluation. Finally 7 population-based studies involving 23,541 study subjects met our criteria for meta-analysis. The combined OR showed that myopia was a risk factor for exotropia (OR: 5.23, P = 0.0001). We found hyperopia had a dose-related effect for esotropia (OR for a spherical equivalent [SE] of 2–3 diopters [D]: 10.16, P = 0.01; OR for an SE of 3-4D: 17.83, P < 0.0001; OR for an SE of 4-5D: 41.01, P < 0.0001; OR for an SE of ≥5D: 162.68, P < 0.0001). Sensitivity analysis indicated our results were robust. Results of this study confirmed myopia as a risk for concomitant exotropia and identified a dose-related effect for hyperopia as a risk of concomitant esotropia. PMID:27731389

Poisoning deaths involving opioid analgesics - New York State, 2003-2012.

PubMed

Sharp, Mark J; Melnik, Thomas A

2015-04-17

Deaths involving opioid analgesics have increased dramatically in the United States. Approximately 4,000 such deaths were documented in 1999, increasing to 16,235 in 2013, reflecting a nearly quadrupled death rate from 1.4 to 5.1 deaths per 100,000. To investigate this increase in New York state, trends in poisoning deaths involving opioid analgesics from 2003 to 2012 were examined. Data sources used were New York state vital statistics multiple-cause-of-death data, consisting of data from both the New York City (NYC)* and non-NYC reporting jurisdictions, as well as statewide Medicaid enrollment data. Deaths involving opioid analgesics increased both in number and as a percentage of all drug poisoning deaths, and rates were highest among men, whites, persons aged 45-64 years, persons residing outside of NYC, and Medicaid enrollees. The analysis found that, in 2012, 70.7% of deaths involving opioid analgesics also involved at least one other drug, most frequently a benzodiazepine. These results underscore the potential to mitigate the trend of increasing opioid analgesic-related mortality through initiatives such as New York state's Internet System for Tracking Over-Prescribing (I-STOP) law,† which took effect on August 27, 2013. Provisions under I-STOP include the requirements that providers consult the Prescription Monitoring Program (PMP) Registry when writing prescriptions for controlled substances, and that they use electronic prescribing.

Forensic Toxicology Perspectives of Methadone-associated Deaths in Tehran, Iran, a 7-year Overview.

PubMed

Akhgari, Maryam; Amini-Shirazi, Noushin; Iravani, Fariba Sardari

2018-04-01

Methadone has a long history of pain relief and successful substitute for maintenance treatment in heroin and narcotic addiction. The aim of the study was to assess the trends of methadone-associated deaths in Tehran, Iran, in 2009-2015, from a forensic toxicology point of view. All methadone-associated deaths during this 7-year study period were evaluated according to demographic parameters and forensic toxicology analysis results. Results showed that 1274 cases of methadone-associated deaths were investigated during the study period. The incidence rate of methadone-associated deaths had risen 7.7 times in 2015 in comparison with 2009 (p < 0.05). The majority of cases were men (90.35%), aged from 20 to 40 years. About 80% of cases had shown positive results for other drugs and poisons in combination with methadone. Methamphetamine and tramadol were the most drugs detected in post-mortem samples. Death rates among methadone users in Tehran, Iran, increased year by year during 2009-2015. These findings raise the attention to the concomitant use of drugs with the need for changes in regulation and regulatory policy to restrict access and use of controlled drugs. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Drugs and other chemicals involved in fatal poisoning in England and Wales during 2000 – 2011.

PubMed

Handley, S A; Flanagan, R J

2014-01-01

Fatal poisoning data can reveal trends in the poisons encountered, which can help guide prescribing practices and product safety and other legislation, and more recently has helped to monitor the use of emerging drugs of abuse ( ‘ legal highs ’ ). We searched Mortality Statistics – Injury and poisoning, Series DH4 (2000 – 2005), Mortality Statistics – Deaths registered in England and Wales, Series DR (2006 – 2011), and the Office for National Statistics drug poisoning database for information on fatal poisoning during 2000 – 2011. We also searched the Pubmed database for ‘ fatal ’ and ‘ poisoning ’ and ‘ England ’ and ‘ Wales ’ : this search yielded seven papers that gave relevant information on deaths reported during 2000 – 2011 that were not superseded by later publications. DEATHS FROM POISONING: The annual number of deaths from poisoning fell from 2000 (3092) to 2010 (2749), before increasing to 3341 in 2011. This increase was due in part to a change in the ICD coding relating to alcohol poisoning, suggesting that such deaths had been under-recorded previously. Although fatalities from dextropropoxyphene declined (287 in 2004 and 18 in 2011) following the withdrawal of co-proxamol (paracetamol [acetaminophen] and dextropropoxyphene [propoxyphene] mixture) during 2005 – 2007, deaths involving codeine and most notably tramadol (836 deaths during 2000 – 2011) increased. Deaths from paracetamol poisoning either alone, or with alcohol reached 89 in 2011, the lowest annual figure since 1974. However, in reality there has been no marked downward trend since 1999 despite reductions in pack size, continued publicity as to the dangers of paracetamol overdose, and improved liver failure treatment, including transplantation. The annual number of deaths from antidepressants remained relatively stable (median: 397, range: 335 – 469). Although the number of deaths from dosulepin [dothiepin] decreased (186 in 2000 and 49 in 2011), the number of deaths involving selective serotonin reuptake inhibitors increased (50 in 2000 and 127 in 2011). Although annual numbers of deaths involving diamorphine/morphine (88% unintentional) declined, deaths involving methadone (89% unintentional) increased and the total annual number of deaths from these drugs showed little change (2000: 1061, 2011: 995). Deaths involving amfetamine/metamfetamine remained relatively constant at about 50 annually, and whilst cocaine-related deaths fell by 48% during 2008 – 2011, and deaths involving MDMA and related compounds fell by 69% over this same period, deaths involving ‘ legal highs ’ , notably γ -hydroxybutrate/ γ -butyrolactone and ketamine, increased. Alterations in the availability of paracetamol and of prescription drugs such as dextropropoxyphene and dosulepin have not been accompanied by decreases in the number of deaths from poisoning. Despite intense media and other interest, the annual number of deaths (250 – 300) involving ‘ recreational ’ drugs remains small in relation to the 1000 or so deaths a year from diamorphine and/or methadone.

High glucose-induced Ca2+ overload and oxidative stress contribute to apoptosis of cardiac cells through mitochondrial dependent and independent pathways.

PubMed

Kumar, Sandeep; Kain, Vasundhara; Sitasawad, Sandhya L

2012-07-01

Cardiac cell apoptosis is the initiating factor of cardiac complications especially diabetic cardiomyopathy. Mitochondria are susceptible to the damaging effects of elevated glucose condition. Calcium overload and oxidative insult are the two mutually non-exclusive phenomena suggested to cause cardiac dysfunction. Here, we examined the effect of high-glucose induced calcium overload in calpain-1 mediated cardiac apoptosis in an in vitro setting. H9c2, rat ventricular myoblast cell line was treated with elevated glucose condition and the cellular consequences were studied. Intracellular calcium trafficking, ROS generation, calpain-1 activation and caspase-12 and caspase-9 pathway were studied using flow cytometry, confocal microscopy and Western blot analysis. High-glucose treatment resulted in increased intracellular calcium ([Ca2+]i) which was mobilized to the mitochondria. Concomitant intra-mitochondrial calcium ([Ca2+]m) increase resulted in enhanced reactive oxygen and nitrogen species generation. These events led to mitochondrial dysfunction and apoptosis. Cardiomyocyte death exhibited several classical markers of apoptosis, including activation of caspases, appearance of annexin V on the outer plasma membrane, increased population of cells with sub-G0/G1 DNA content and nuclear condensation. Key findings include elucidation of cell signaling mechanism of high-glucose induced calcium-dependent cysteine protease calpain-1 activation, which triggers non-conventional caspases as alternate mode of cell death. This information increases the understanding of cardiac cell death under hyperglycemic condition and can possibly be extended for designing new therapeutic strategies for diabetic cardiomyopathy. The novel findings of the study reveal that high glucose induces apoptosis by both mitochondria-dependent and independent pathways via concomitant rise in intracellular calcium. Copyright © 2012 Elsevier B.V. All rights reserved.

Analysis of Road Traffic Crashes-Related Maxillofacial Injuries Severity and Concomitant Injuries in 201 Patients Seen at the UCH, Ibadan.

PubMed

Aladelusi, Timothy; Akinmoladun, Victor; Olusanya, Adeola; Akadiri, Oladimeji; Fasola, Abiodun

2014-12-01

The objective of this study was to determine the prevalence of road traffic crashes (RTC)-related maxillofacial injuries, the concomitant injuries occurring with them, and to assess the relationship between the severity of maxillofacial and concomitant injuries. This was a prospective study involving 201 victims of RTC seen at the Accident and Emergency Department of the University College Hospital, Ibadan with maxillofacial injuries during the study period. Demographic data of the patients, the types of maxillofacial injuries, and concomitant injuries sustained were recorded. Severity of maxillofacial injury was determined using the maxillofacial injury severity scale (MFISS), while the severity of concomitant injuries was based on the ISS. Correlations between types and severity of maxillofacial injury and types and severity of concomitant injury were conducted to determine the predictability of concomitant injuries based on maxillofacial injury severity. Data were processed using SPSS Statistical software (SPSS, version 20.0 for windows, IBM SPSS Inc, Chicago, IL). Maxillofacial injuries constituted 25.4% of RTC-related admission by the Accident and Emergency Department. A total of 151 (75.1%) patients who presented with concomitant injuries participated in the study. Eighty-one (53.6%) sustained injuries to more than one body region. Head injury was the commonest (99, 65.6%) concomitant injury, followed by orthopedic injury (69, 45.7%). Increasing severity of maxillofacial injury showed a positive correlation with increasing ISS. Also, positive correlation was noted with increasing severity of maxillofacial injury and presence of polytrauma (p = 0.01), traumatic brain injury (p = 0.034), and eye injuries (p = 0.034). There was a high prevalence of maxillofacial injuries in victims of RTC. There was a high incidence of concomitant injuries noted with these maxillofacial injuries. Significantly, this study showed a direct relationship between the severity of maxillofacial injury and head, ocular and polytrauma. This study further emphasizes the need for thorough examination of patients presenting with RTC-related maxillofacial injuries.

Bisphosphonate therapy and osteonecrosis of the jaw complicated with a temporal abscess in an elderly woman with rheumatoid arthritis: a case report

PubMed Central

Manzon, Licia; Ettorre, Evaristo; Viscogliosi, Giovanni; Ippoliti, Stefano; Filiaci, Fabio; Ungari, Claudio; Fratto, Giovanni; Agrillo, Alessandro

2014-01-01

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an adverse drug reaction described as the progressive destruction and death of bone tissue of the mandible or maxilla, in the course of bisphosphonate therapy. Orally administered bisphosphonates, widely used for the treatment of osteoporosis, are rarely associated with BRONJ. Instead, the risk greatly increases whether the patient is concomitantly taking steroid and/or immunosuppressant agents. The aims of this paper are to briefly discuss the evidence of the associations between bisphosphonate therapy and BRONJ, and the effects of co-occurring factors such as the presence of rheumatoid arthritis, dental surgery, and concomitant corticosteroid therapy. In particular, we present the case of an elderly woman with BRONJ suffering from rheumatoid arthritis, with a recent dental extraction and with a very unusual complication: a temporal abscess, who was successfully treated. PMID:25187700

Overdose Deaths Involving Opioids, Cocaine, and Psychostimulants - United States, 2015-2016.

PubMed

Seth, Puja; Scholl, Lawrence; Rudd, Rose A; Bacon, Sarah

2018-03-30

During 1999‒2015, 568,699 persons died from drug overdoses in the United States.* Drug overdose deaths in the United States increased 11.4% from 2014 to 2015 resulting in 52,404 deaths in 2015, including 33,091 (63.1%) that involved an opioid. The largest rate increases from 2014 to 2015 occurred among deaths involving synthetic opioids other than methadone (synthetic opioids) (72.2%) (1). Because of demographic and geographic variations in overdose deaths involving different drugs (2,3), † CDC examined age-adjusted death rates for overdoses involving all opioids, opioid subcategories (i.e., prescription opioids, heroin, and synthetic opioids), § cocaine, and psychostimulants with abuse potential (psychostimulants) by demographics, urbanization levels, and in 31 states and the District of Columbia (DC). There were 63,632 drug overdose deaths in 2016; 42,249 (66.4%) involved an opioid. ¶ From 2015 to 2016, deaths increased across all drug categories examined. The largest overall rate increases occurred among deaths involving cocaine (52.4%) and synthetic opioids (100%), likely driven by illicitly manufactured fentanyl (IMF) (2,3). Increases were observed across demographics, urbanization levels, and states and DC. The opioid overdose epidemic in the United States continues to worsen. A multifaceted approach, with faster and more comprehensive surveillance, is needed to track emerging threats to prevent and respond to the overdose epidemic through naloxone availability, safe prescribing practices, harm-reduction services, linkage into treatment, and more collaboration between public health and public safety agencies.

Fatal injuries in the United States involving respirators, 1984-1995.

PubMed

Suruda, Anthony; Milliken, William; Stephenson, Dale; Sesek, Richard

2003-04-01

There is little published information concerning the epidemiology of fatal injuries involving respiratory protection. We compiled a case series from U.S. Occupational Safety and Health Administration investigation reports from 1984 through 1995. For the 12-year period there were 41 incidents resulting in 45 deaths due to asphyxiation or chemical poisoning while wearing a respirator. There were 23 deaths related to airline respirators, 17 deaths involving use of negative pressure (air purifying) respirators, and 5 deaths involving self-contained breathing apparatus. Among the 23 deaths involving airline respirators, 15 were associated with compatible connection couplings for breathable air and inert gases. Three workers with beards died who wore tight-fitting respirators in an atmosphere that was immediately dangerous to life and health. Most of the fatalities involved regulatory and procedural violations, and would have been prevented by proper training and compliance with existing regulations. The information concerning the victims was limited but it did not appear that medical screening would have prevented any of the deaths.

Singlet Oxygen-Induced Membrane Disruption and Serpin-Protease Balance in Vacuolar-Driven Cell Death.

PubMed

Koh, Eugene; Carmieli, Raanan; Mor, Avishai; Fluhr, Robert

2016-07-01

Singlet oxygen plays a role in cellular stress either by providing direct toxicity or through signaling to initiate death programs. It was therefore of interest to examine cell death, as occurs in Arabidopsis, due to differentially localized singlet oxygen photosensitizers. The photosensitizers rose bengal (RB) and acridine orange (AO) were localized to the plasmalemma and vacuole, respectively. Their photoactivation led to cell death as measured by ion leakage. Cell death could be inhibited by the singlet oxygen scavenger histidine in treatments with AO but not with RB In the case of AO treatment, the vacuolar membrane was observed to disintegrate. Concomitantly, a complex was formed between a vacuolar cell-death protease, RESPONSIVE TO DESSICATION-21 and its cognate cytoplasmic protease inhibitor ATSERPIN1. In the case of RB treatment, the tonoplast remained intact and no complex was formed. Over-expression of AtSerpin1 repressed cell death, only under AO photodynamic treatment. Interestingly, acute water stress showed accumulation of singlet oxygen as determined by fluorescence of Singlet Oxygen Sensor Green, by electron paramagnetic resonance spectroscopy and the induction of singlet oxygen marker genes. Cell death by acute water stress was inhibited by the singlet oxygen scavenger histidine and was accompanied by vacuolar collapse and the appearance of serpin-protease complex. Over-expression of AtSerpin1 also attenuated cell death under this mode of cell stress. Thus, acute water stress damage shows parallels to vacuole-mediated cell death where the generation of singlet oxygen may play a role. © 2016 American Society of Plant Biologists. All Rights Reserved.

Singlet Oxygen-Induced Membrane Disruption and Serpin-Protease Balance in Vacuolar-Driven Cell Death1[OPEN

PubMed Central

Carmieli, Raanan; Mor, Avishai; Fluhr, Robert

2016-01-01

Singlet oxygen plays a role in cellular stress either by providing direct toxicity or through signaling to initiate death programs. It was therefore of interest to examine cell death, as occurs in Arabidopsis, due to differentially localized singlet oxygen photosensitizers. The photosensitizers rose bengal (RB) and acridine orange (AO) were localized to the plasmalemma and vacuole, respectively. Their photoactivation led to cell death as measured by ion leakage. Cell death could be inhibited by the singlet oxygen scavenger histidine in treatments with AO but not with RB. In the case of AO treatment, the vacuolar membrane was observed to disintegrate. Concomitantly, a complex was formed between a vacuolar cell-death protease, RESPONSIVE TO DESSICATION-21 and its cognate cytoplasmic protease inhibitor ATSERPIN1. In the case of RB treatment, the tonoplast remained intact and no complex was formed. Over-expression of AtSerpin1 repressed cell death, only under AO photodynamic treatment. Interestingly, acute water stress showed accumulation of singlet oxygen as determined by fluorescence of Singlet Oxygen Sensor Green, by electron paramagnetic resonance spectroscopy and the induction of singlet oxygen marker genes. Cell death by acute water stress was inhibited by the singlet oxygen scavenger histidine and was accompanied by vacuolar collapse and the appearance of serpin-protease complex. Over-expression of AtSerpin1 also attenuated cell death under this mode of cell stress. Thus, acute water stress damage shows parallels to vacuole-mediated cell death where the generation of singlet oxygen may play a role. PMID:26884487

Clostridium perfringens Type E Virulence Traits Involved in Gut Colonization

PubMed Central

Redondo, Leandro M.; Carrasco, Juan M. Díaz; Redondo, Enzo A.; Delgado, Fernando; Miyakawa, Mariano E. Fernández

2015-01-01

Clostridium perfringens type E disease in ruminants has been characterized by hemorrhagic enteritis or sudden death. Although type E isolates are defined by the production of alpha and iota toxin, little is known about the pathogenesis of C. perfringens type E infections. Thus far, the role of iota toxin as a virulence factor is unknown. In this report, iota toxin showed positive effects on adherence and colonization of C. perfringens type E while having negative effect on the adherence of type A cells. In-vitro and in-vivo models suggest that toxinotype E would be particularly adapted to exploit the changes induced by iota toxin in the surface of epithelial cells. In addition, type E strains produce metabolites that affected the growth of potential intra-specific competitors. These results suggest that the alteration of the enterocyte morphology induced by iota toxin concomitantly with the specific increase of type E cell adhesion and the strong intra-specific growth inhibition of other strains could be competitive traits inherent to type E isolates that improve its fitness within the bovine gut environment. PMID:25799452

Neurochemical development of brain stem nuclei involved in the control of respiration.

PubMed

Wong-Riley, Margaret T T; Liu, Qiuli

2005-11-15

The first two postnatal weeks are the most dynamic in the development of brain stem respiratory nuclei in the rat, the primary model for this review. Several neurochemicals (glutamate, glycine receptors, choline acetyltransferase, serotonin, norepinephrine, and thyrotropin-releasing hormone) increase expression with age, while others (GABA, serotonin receptor 1A, substance P, neurokinin 1 receptor, and somatostatin) decrease their expression. Surprisingly, a dramatic shift occurs at postnatal day (P) 12 in the rat. Excitatory neurotransmitter glutamate and its NMDA receptors fall precipitously, whereas inhibitory neurotransmitter GABA, GABA(B), and glycine receptors rise sharply. A concomitant drop in cytochrome oxidase activity occurs in respiratory neurons. Several receptor types undergo subunit switches during development. Notably, GABA(A) receptors switch prevalence from alpha3- to an alpha1-dominant form at P12 in the pre-Bötzinger complex of the rat. The transient dominance of inhibitory over excitatory neurotransmission around P12 may render the respiratory system sensitive to failure when stressed. Relating these neurochemical changes to physiological responses in animals and to sudden infant death syndrome in humans will be a challenge for future research.

Balancing the risks and benefits of drinking water disinfection: disability adjusted life-years on the scale.

PubMed Central

Havelaar, A H; De Hollander, A E; Teunis, P F; Evers, E G; Van Kranen, H J; Versteegh, J F; Van Koten, J E; Slob, W

2000-01-01

To evaluate the applicability of disability adjusted life-years (DALYs) as a measure to compare positive and negative health effects of drinking water disinfection, we conducted a case study involving a hypothetical drinking water supply from surface water. This drinking water supply is typical in The Netherlands. We compared the reduction of the risk of infection with Cryptosporidium parvum by ozonation of water to the concomitant increase in risk of renal cell cancer arising from the production of bromate. We applied clinical, epidemiologic, and toxicologic data on morbidity and mortality to calculate the net health benefit in DALYs. We estimated the median risk of infection with C. parvum as 10(-3)/person-year. Ozonation reduces the median risk in the baseline approximately 7-fold, but bromate is produced in a concentration above current guideline levels. However, the health benefits of preventing gastroenteritis in the general population and premature death in patients with acquired immunodeficiency syndrome outweigh health losses by premature death from renal cell cancer by a factor of > 10. The net benefit is approximately 1 DALY/million person-years. The application of DALYs in principle allows us to more explicitly compare the public health risks and benefits of different management options. In practice, the application of DALYs may be hampered by the substantial degree of uncertainty, as is typical for risk assessment. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:10753089

Heart transplantation in patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

PubMed

Groh, Matthieu; Masciocco, Gabriella; Kirchner, Elizabeth; Kristen, Arnt; Pellegrini, Carlo; Varnous, Shaïda; Bortman, Guillermo; Rosenberg, Mark; Brucato, Antonio; Waterworth, Paul; Bonacina, Edgardo; Facchetti, Fabio; Calabrese, Leonard; Gregorini, Gina; Scali, Juan Jose; Starling, Randall; Frigerio, Maria; D'Armini, Andrea Maria; Guillevin, Loïc

2014-08-01

Heart involvement is the leading cause of death of patients with eosinophilic granulomatosis with polyangiitis (EGPA; formerly Churg-Strauss syndrome) and is more frequent in anti-neutrophil cytoplasm antibody (ANCA)-negative patients. Post-transplant outcome has only been reported once. We conducted a retrospective international multicenter study. Patients satisfying the criteria of the American College of Rheumatology and/or revised Chapel Hill Consensus Conference Nomenclature were identified by collaborating vasculitis and transplant specialists, and the help of the Churg-Strauss Syndrome Association. Nine ANCA(-) patients who received transplants between October 1987 and December 2009 were identified. The vasculitis and cardiomyopathy diagnoses were concomitant for 5 patients and separated by 12 to 288 months for the remaining 4 patients. Despite ongoing immunosuppression, histologic examination of 7 (78%) patients' explanted hearts showed histologic patterns suggestive of active vasculitis. The overall 5-year survival rate was low (57%), but rose to 80% when considering only the 6 patients transplanted during the last decade. After survival lasting 3 to 60 months, 4 (44%) patients died sudden deaths. The search for EGPA-related cardiomyopathy is mandatory early in the course of this type of vasculitis. Indeed, prompt treatment with corticosteroids and cyclophosphamide may achieve restore cardiac function. Most patients in this series were undertreated. For patients with refractory EGPA, heart transplantation should be performed, which carries a fair prognosis. No optimal immunosuppressive strategy has yet been identified. Copyright © 2014 International Society for Heart and Lung Transplantation. All rights reserved.

Bromelain inhibits COX-2 expression by blocking the activation of MAPK regulated NF-kappa B against skin tumor-initiation triggering mitochondrial death pathway.

PubMed

Bhui, Kulpreet; Prasad, Sahdeo; George, Jasmine; Shukla, Yogeshwer

2009-09-18

Chemoprevention impels the pursuit for either single targeted or cocktail of multi-targeted agents. Bromelain, potential agent in this regard, is a pharmacologically active compound, present in stems and fruits of pineapple (Ananas cosmosus), endowed with anti-inflammatory, anti-invasive and anti-metastatic properties. Herein, we report the anti tumor-initiating effects of bromelain in 2-stage mouse skin tumorigenesis model. Pre-treatment of bromelain resulted in reduction in cumulative number of tumors (CNT) and average number of tumors per mouse. Preventive effect was also comprehended in terms of reduction in tumor volume up to a tune of approximately 65%. Components of the cell signaling pathways, connecting proteins involved in cell death were targeted. Bromelain treatment resulted in upregulation of p53 and Bax and subsequent activation of caspase 3 and caspase 9 with concomitant decrease in Bcl-2. A marked inhibition in cyclooxygenase-2 (Cox-2) expression and inactivation of nuclear factor-kappa B (NF-kappaB) was recorded, as phosphorylation and consequent degradation of I kappa B alpha was blocked by bromelain. Also, bromelain treatment curtailed extracellular signal regulated protein kinase (ERK1/2), p38 mitogen-activated protein kinase (MAPK) and Akt activity. The basis of anti tumor-initiating activity of bromelain was revealed by its time dependent reduction in DNA nick formation and increase in percentage prevention. Thus, modulation of inappropriate cell signaling cascades driven by bromelain is a coherent approach in achieving chemoprevention.

Increases in Drug and Opioid-Involved Overdose Deaths - United States, 2010-2015.

PubMed

Rudd, Rose A; Seth, Puja; David, Felicita; Scholl, Lawrence

2016-12-30

The U.S. opioid epidemic is continuing, and drug overdose deaths nearly tripled during 1999-2014. Among 47,055 drug overdose deaths that occurred in 2014 in the United States, 28,647 (60.9%) involved an opioid (1). Illicit opioids are contributing to the increase in opioid overdose deaths (2,3). In an effort to target prevention strategies to address the rapidly changing epidemic, CDC examined overall drug overdose death rates during 2010-2015 and opioid overdose death rates during 2014-2015 by subcategories (natural/semisynthetic opioids, methadone, heroin, and synthetic opioids other than methadone).* Rates were stratified by demographics, region, and by 28 states with high quality reporting on death certificates of specific drugs involved in overdose deaths. During 2015, drug overdoses accounted for 52,404 U.S. deaths, including 33,091 (63.1%) that involved an opioid. There has been progress in preventing methadone deaths, and death rates declined by 9.1%. However, rates of deaths involving other opioids, specifically heroin and synthetic opioids other than methadone (likely driven primarily by illicitly manufactured fentanyl) (2,3), increased sharply overall and across many states. A multifaceted, collaborative public health and law enforcement approach is urgently needed. Response efforts include implementing the CDC Guideline for Prescribing Opioids for Chronic Pain (4), improving access to and use of prescription drug monitoring programs, enhancing naloxone distribution and other harm reduction approaches, increasing opioid use disorder treatment capacity, improving linkage into treatment, and supporting law enforcement strategies to reduce the illicit opioid supply.

Six-Year Follow-Up of Impact of Co-proxamol Withdrawal in England and Wales on Prescribing and Deaths: Time-Series Study

PubMed Central

Hawton, Keith; Bergen, Helen; Simkin, Sue; Wells, Claudia; Kapur, Navneet; Gunnell, David

2012-01-01

Background The analgesic co-proxamol (paracetamol/dextropropoxyphene combination) has been widely involved in fatal poisoning. Concerns about its safety/effectiveness profile and widespread use for suicidal poisoning prompted its withdrawal in the UK in 2005, with partial withdrawal between 2005 and 2007, and full withdrawal in 2008. Our objective in this study was to assess the association between co-proxamol withdrawal and prescribing and deaths in England and Wales in 2005–2010 compared with 1998–2004, including estimation of possible substitution effects by other analgesics. Methods and Findings We obtained prescribing data from the NHS Health and Social Care Information Centre (England) and Prescribing Services Partneriaeth Cydwasanaethau GIG Cymru (Wales), and mortality data from the Office for National Statistics. We carried out an interrupted time-series analysis of prescribing and deaths (suicide, open verdicts, accidental poisonings) involving single analgesics. The reduction in prescribing of co-proxamol following its withdrawal in 2005 was accompanied by increases in prescribing of several other analgesics (co-codamol, paracetamol, codeine, co-dydramol, tramadol, oxycodone, and morphine) during 2005–2010 compared with 1998–2004. These changes were associated with major reductions in deaths due to poisoning with co-proxamol receiving verdicts of suicide and undetermined cause of −21 deaths (95% CI −34 to −8) per quarter, equating to approximately 500 fewer suicide deaths (−61%) over the 6 years 2005–2010, and −25 deaths (95% CI −38 to −12) per quarter, equating to 600 fewer deaths (−62%) when accidental poisoning deaths were included. There was little observed change in deaths involving other analgesics, apart from an increase in oxycodone poisonings, but numbers were small. Limitations were that the study was based on deaths involving single drugs alone and changes in deaths involving prescribed morphine could not be assessed. Conclusions During the 6 years following the withdrawal of co-proxamol in the UK, there was a major reduction in poisoning deaths involving this drug, without apparent significant increase in deaths involving other analgesics. Please see later in the article for the Editors' Summary PMID:22589703

Gastrointestinal bleeding and intracranial hemorrhage in concomitant users of warfarin and antihyperlipidemics.

PubMed

Leonard, Charles E; Brensinger, Colleen M; Bilker, Warren B; Kimmel, Stephen E; Han, Xu; Nam, Young Hee; Gagne, Joshua J; Mangaali, Margaret J; Hennessy, Sean

2017-02-01

Drug interactions, particularly those involving warfarin, are a major clinical and public health problem. Minimizing serious bleeding caused by anticoagulants is a recent major focus of the United States (US) Department of Health and Human Services. This study quantified the risk of gastrointestinal bleeding (GIB) and intracranial hemorrhage (ICH) among concomitant users of warfarin and individual antihyperlipidemics. The authors conducted a high-dimensional propensity score-adjusted cohort study of new concomitant users of warfarin and an antihyperlipidemic, among US Medicaid beneficiaries from five states during 1999-2011. Exposure was defined by concomitant use of warfarin plus one of eight antihyperlipidemics. The primary outcome measure was a composite of GIB/ICH within the first 30days of concomitant use. As a secondary outcome measure, GIB/ICH was examined within the first 180days of concomitant use. Among 236,691 persons newly-exposed to warfarin and an antihyperlipidemic, the crude incidence of GIB/ICH was 13.2 (95% confidence interval 12.7 to 13.8) per 100person-years. Users were predominantly older, female, and Caucasian. Adjusted hazard ratios (aHRs) for warfarin and individual statins were consistent with no association. Warfarin+gemfibrozil was associated with an 80% increased risk of GIB/ICH within the first month of concomitant use (aHR=1.8, 1.4 to 2.4). Warfarin+fenofibrate was associated with a similar increased risk (aHR=1.8, 1.2 to 2.7), yet with an onset during the second month of concomitant use. Among warfarin-treated persons, the use of fibrates-but not statins-increases the risk of hospital presentation for GIB/ICH. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Recent Increases in Cocaine-Related Overdose Deaths and the Role of Opioids.

PubMed

McCall Jones, Christopher; Baldwin, Grant T; Compton, Wilson M

2017-03-01

To assess trends in cocaine overdose deaths and examine the role opioids play in these deaths. We used data on drug overdose deaths in the United States from 2000 to 2015 collected in the National Vital Statistics System to calculate annual rates and numbers of cocaine-related overdose deaths overall and deaths both involving and not involving opioids. We assessed statistically significant changes in trends with joinpoint regression. Rates of cocaine-related overdose deaths increased significantly from 1.26 to 2.50 per 100 000 population from 2000 to 2006, declined to 1.35 in 2010, and increased to 2.13 in 2015. Cocaine-related overdose deaths involving opioids increased from 0.37 to 0.91 from 2000 to 2006, declined to 0.57 in 2010, and then increased to 1.36 in 2015. Cocaine-related overdose deaths not involving opioids increased from 0.89 to 1.59 from 2000 to 2006 and then declined to 0.78 in 2015. Opioids, primarily heroin and synthetic opioids, have been driving the recent increase in cocaine-related overdose deaths. This corresponds to the growing supply and use of heroin and illicitly manufactured fentanyl in the United States.

Frequency of signs of excited delirium syndrome in subjects undergoing police use of force: Descriptive evaluation of a prospective, consecutive cohort.

PubMed

Hall, Christine Alison; Kader, Adam Shereef; Danielle McHale, Anne Marie; Stewart, Lauren; Fick, Gordon Hilton; Vilke, Gary Michael

2013-02-01

There has, to date, been no prospective description of the frequency with which police officers encounter individuals who display signs of excited delirium syndrome (ExDS). The ability to document the relationship between signs of excited delirium and subject outcomes and then determine the underlying pathophysiology that results in morbidity and mortality is necessary in order to determine the case definition for ExDS in live individuals. We prospectively evaluated the frequency of signs of ExDS in a cohort of consecutive subjects undergoing use of force by law enforcement officers (LEOs) and determined the frequency with which those features were encountered alone and in combination. Data were collected prospectively for all subjects undergoing use of force (UOF) by LEOs in a single police agency from August 2006 until August 2009. Ten previously published signs of ExDS were prospectively recorded by officers: pain tolerance, constant/near constant physical activity, not responding to police presence, superhuman strength, rapid breathing, not tiring despite heavy physical exertion, naked/inappropriately clothed, sweating profusely, hot to the touch, and attraction to/destruction of glass/reflective surfaces. UOF occurred in 1269 of 1.56 million police-public interactions (0.08%, 95% CI 0.08, 0.086). Of subjects undergoing police use of force, 1101/1269 or 86.8% (95% CI 84.8%, 88.6%) were assessed as having effects of emotional disturbance, drugs, alcohol or a combination of these comorbidities at the scene at the time of the UOF and 837/1269 or 66% (95% CI 63.3, 68.6) were violent at the time of the UOF. Excluding violence, 655/1269 (51.6% 95% CI 48.8, 54.4) had no signs of ExDS at the time of UOF and another 405/1269 (31.9% 95% CI 29.4, 34.6%)) had only one or two signs of ExDS at the time of UOF. The remaining 209/1269 (16.5%, 95% CI 14.5, 18.6) had 3 or more concomitant signs of ExDS at the time of UOF. One person died in our cohort who was experiencing 10 concomitant features of ExDS at the time of the UOF event. With only one death in our 3 year prospective cohort, we cannot comment on causality or correlation between number of Excited Delirium signs and mortality. Further study must be undertaken to determine whether correlation exists between higher numbers of ExDS signs and physiologic measures of acute underlying pathology in live subjects. Law enforcement officers and other prehospital care providers can recognize and describe symptoms of ExDS in the field at the time of interaction. Even though police use of force is rare over 15%, or approximately 1 in 6, of individuals undergoing police UoF have 3 or more concomitant signs of Excited Delirium at the time of the UoF event. The single death in our cohort occurred in an individual with 10 concomitant signs of ExDS. Future work including further clinical outcome data will determine whether higher numbers of concomitant signs of ExDS predicts subject morbidity or mortality and whether any specific symptoms or symptom cluster is associated with death. If so, a case definition will be able to be fully described. Copyright © 2012 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

VX-induced cell death involves activation of caspase-3 in cultured rat cortical neurons.

PubMed

Tenn, Catherine C; Wang, Yushan

2007-05-01

Exposure of cell cultures to organophosphorous compounds such as VX can result in cell death. However, it is not clear whether VX-induced cell death is necrotic or involves programmed cell death mechanisms. Activation of caspases, a family of cysteine proteases, is often involved in cell death, and in particular, caspase-3 activation appears to be a key event in programmed cell death processes including apoptosis. In this study, we investigated VX-induced neuronal cell death, as well as the underlying mechanism in terms of its effect on caspase-3 activity. Primary cortical neuronal cultures were prepared from gestational days 17 to 19 Sprague Dawley rat fetuses. At maturation, the cells were treated with varying concentrations of VX and cell death was evaluated by lactate dehydrogenase (LDH) release. VX induced an increase in LDH release in a concentration-dependent manner. Morphological VX-induced cell death was also characterized by using nuclear staining with propidium iodide and Hoechst 33342. VX induced a concentration- and time-dependent increase in caspase-3 activation. Caspase-3 activation was also confirmed by the proteolytic cleavage of poly(ADP-ribose)polymerase (PARP), an endogenous caspase-3 substrate. These data suggested that in rat cortical neurons, VX-induced cell death via a programmed cell death pathway that involves changes in caspase-3 protease.

Prospective assessment of concomitant lumbar and chronic subdural hematoma: is migration from the intracranial space involved in their manifestation?

PubMed

Kokubo, Rinko; Kim, Kyongsong; Mishina, Masahiro; Isu, Toyohiko; Kobayashi, Shiro; Yoshida, Daizo; Morita, Akio

2014-02-01

Spinal subdural hematomas (SDHs) are rare and some are concomitant with intracranial SDH. Their pathogenesis and etiology remain to be elucidated although their migration from the intracranial space has been suggested. The authors postulated that if migration plays a major role, patients with intracranial SDH may harbor asymptomatic lumbar SDH. The authors performed a prospective study on the incidence of spinal SDH in patients with intracranial SDH to determine whether migration is a key factor in their concomitance. The authors evaluated lumbar MR images obtained in 168 patients (125 males, 43 females, mean age 75.6 years) with intracranial chronic SDH to identify cases of concomitant lumbar SDH. In all cases, the lumbar MRI studies were performed within the 1st week after surgical irrigation of the intracranial SDH. Of the 168 patients, 2 (1.2%) harbored a concomitant lumbar SDH; both had a history of trauma to both the head and the hip and/or lumbar area. One was an 83-year-old man with prostate cancer and myelodysplastic syndrome who suffered trauma to his head and lumbar area in a fall from his bed. The other was a 70-year-old man who had hit his head and lumbar area in a fall. Neither patient manifested neurological deficits and their hematomas disappeared under observation. None of the patients with concomitant lumbar SDH had sustained head trauma only, indicating that trauma to the hip or lumbar region is significantly related to the concomitance of SDH (p < 0.05). As the incidence of concomitant lumbar and intracranial chronic SDH is rare and both patients in this study had sustained a direct impact to the head and hips, the authors suggest that the major mechanism underlying their concomitant SDH was double trauma. Another possible explanation is hemorrhagic diathesis and low CSF syndrome.

Drug-poisoning Deaths Involving Opioid Analgesics: United States, 1999-2011.

PubMed

Chen, Li Hui; Hedegaard, Holly; Warner, Margaret

2014-09-01

Data from the National Vital Statistics System, Mortality File. The age-adjusted rate for opioid-analgesic poisoning deaths nearly quadrupled from 1.4 per 100,000 in 1999 to 5.4 per 100,000 in 2011. Although the opioid-analgesic poisoning death rates increased each year from 1999 through 2011, the rate of increase has slowed since 2006. Natural and semisynthetic opioid analgesics, such as hydrocodone, morphine, and oxycodone, were involved in 11,693 drug-poisoning deaths in 2011, up from 2,749 deaths in 1999. Benzodiazepines were involved in 31% of the opioid-analgesic poisoning deaths in 2011, up from 13% of the opioid-analgesic poisoning deaths in 1999. During the past decade, adults aged 55-64 and non-Hispanic white persons experienced the greatest increase in the rates of opioid-analgesic poisoning deaths. Poisoning is the leading cause of injury death in the United States (1). Drugs-both illicit and pharmaceutical-are the major cause of poisoning deaths, accounting for 90% of poisoning deaths in 2011. Misuse or abuse of prescription drugs, including opioid-analgesic pain relievers, is responsible for much of the recent increase in drug-poisoning deaths (2). This report highlights trends in drug-poisoning deaths involving opioid analgesics (referred to as opioid-analgesic poisoning deaths) and updates previous Data Briefs on this topic. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.

Antipsychotic treatment among youth in foster care.

PubMed

Dosreis, Susan; Yoon, Yesel; Rubin, David M; Riddle, Mark A; Noll, Elizabeth; Rothbard, Aileen

2011-12-01

Despite national concerns over high rates of antipsychotic medication use among youth in foster care, concomitant antipsychotic use has not been examined. In this study, concomitant antipsychotic use among Medicaid-enrolled youth in foster care was compared with disabled or low-income Medicaid-enrolled youth. The sample included 16 969 youths younger than 20 years who were continuously enrolled in a Mid-Atlantic state Medicaid program and had ≥1 claim with a psychiatric diagnosis and ≥1 antipsychotic claim in 2003. Antipsychotic treatment was characterized by days of any use and concomitant use with ≥2 overlapping antipsychotics for >30 days. Medicaid program categories were foster care, disabled (Supplemental Security Income), and Temporary Assistance for Needy Families (TANF). Multicategory involvement for youths in foster care was classified as foster care/Supplemental Security Income, foster care/TANF, and foster care/adoption. We used multivariate analyses, adjusting for demographics, psychiatric comorbidities, and other psychotropic use, to assess associations between Medicaid program category and concomitant antipsychotic use. Average antipsychotic use ranged from 222 ± 110 days in foster care to only 135 ± 101 days in TANF (P < .001). Concomitant use for ≥180 days was 19% in foster care only and 24% in foster care/adoption compared with <15% in the other categories. Conduct disorder and antidepressant or mood-stabilizer use was associated with a higher likelihood of concomitant antipsychotic use (P < .0001). Additional study is needed to assess the clinical rationale, safety, and outcomes of concomitant antipsychotic use and to inform statewide policies for monitoring and oversight of antipsychotic use among youths in the foster care system.

Role of angiotensin II and angiotensin type-1 receptor in scorpion venom-induced cardiac and aortic tissue inflammation.

PubMed

Sifi, Amina; Adi-Bessalem, Sonia; Laraba-Djebari, Fatima

2017-02-01

Scorpion stings are mainly associated with cardiovascular disturbances that may be the cause of death. In this study, the involvement of angiotensin II (Ang II) in cardiac and aortic inflammatory response was studied. Mice were injected with Androctonus australis hector (Aah) scorpion venom (0.5mg/kg, subcutaneously), in the presence or absence of an angiotensin converting enzyme (ACE) inhibitor, captopril (15mg/kg/day/1day intraperitoneally) or an angiotensin type-1 receptor (AT1R) antagonist, valsartan (15mg/kg/day/15days, orally). In the envenomed group, results revealed severe tissue alterations with a concomitant increase of metabolic enzymes (CK and CK-MB) in sera. An important inflammatory cell (neutrophil and eosinophil) infiltration into the heart and aorta were observed, accompanied by imbalanced redox status (NO, MDA, catalase and GSH) and high cytokine levels (IL-6 and TNF-α) in sera with the expression of MMP-2 and MMP-9 metalloproteinases. However, the blockade of the actions of AngII by the ACE inhibitor or by the AT1R antagonist prevented cardiac and aortic tissue alterations, inflammatory cell infiltration, as well as the oxidative stress generation and cytokine and metalloproteinase expression. These results suggest the involvement of AngII, through its AT1R in the inflammation induced by Aah venom, in the heart and the aorta. Copyright © 2016 Elsevier Inc. All rights reserved.

Relationship between tuberculous otomastoiditis and tuberculous meningitis.

PubMed

Sonmez, G; Turhan, V; Senol, M G; Ozturk, E; Sildiroglu, H O; Mutlu, H

2008-09-01

The aim of this study was to determine the correlation between tuberculous meningitis and tuberculous otomastoiditis. Meningeal involvement sites were investigated by magnetic resonance imaging in 32 patients (21 males, 11 females) who had previously been diagnosed with tuberculous meningitis. Clinical and laboratory findings and responses to anti-tuberculous treatment were evaluated, and the presence of concomitant tuberculous otomastoiditis was also investigated. The meningeal involvement site was unilateral (in the sylvian fissure and the perimesencephalic cistern) in 28 patients (87.5 per cent), and bilateral and widespread in four patients (12.5 per cent). Tuberculous otomastoiditis was found in 11 of the patients with tuberculous meningitis (34.3 per cent). Otomastoiditis was on the same side as the meningeal involvement in nine of these 11 patients. Bilateral otomastoiditis with meningeal involvement was observed in two patients. Tuberculous meningitis is frequently accompanied by otomastoiditis, although the exact causal relationship between the two conditions is unclear. Since meningitis is a serious clinical condition, concomitant otomastoiditis generally remains unrecognised. Tuberculosis should be considered in the differential diagnosis of patients with otitis or otomastoiditis who do not respond to antibiotic therapy.

Missing memories of death: Dissociative amnesia in the bereaved the day after a cancer death.

PubMed

Ishida, Mayumi; Onishi, Hideki; Toyama, Hiroaki; Tsutsumi, Chizuko; Endo, Chieko; Tanahashi, Iori; Takahashi, Takao; Uchitomi, Yosuke

2015-12-01

The death of a loved one is one of the most stressful events of life, and such stress affects the physical and psychological well-being of the bereaved. Dissociative amnesia is characterized by an inability to recall important autobiographical information. Dissociative amnesia in the bereaved who have lost a loved one to cancer has not been previously reported. We discuss herein the case of a patient who developed dissociative amnesia the day after the death of here beloved husband. A 38-year-old woman was referred for psychiatric consultation because of restlessness and abnormal behavior. Her 44-year-old husband had died of pancreatic cancer the day before the consultation. On the day of the death, she looked upset and began to hyperventilate. The next day, she behaved as if the deceased were still alive, which embarrassed her family. At her initial psychiatric consultation, she talked and behaved as if her husband was still alive and in the hospital. Her psychiatric features fulfilled the DSM-V criteria for dissociative amnesia. The death of her husband had been very traumatic for her and was considered to have been one of the causes of this dissociation. This report adds to the list of psychiatric symptoms in the bereaved who have lost a loved one to cancer. In an oncology setting, we should consider the impact of death, the concomitant defense mechanisms, and the background of the families.

Combining lymphovascular invasion with reactive stromal grade predicts prostate cancer mortality.

PubMed

Saeter, Thorstein; Vlatkovic, Ljiljana; Waaler, Gudmund; Servoll, Einar; Nesland, Jahn M; Axcrona, Karol; Axcrona, Ulrika

2016-09-01

Previous studies suggest that lymphovascular invasion (LVI) has a weak and variable effect on prognosis. It is uncertain whether LVI, determined by diagnostic prostate biopsy, predicts prostate cancer death. Data from experimental studies have indicated that carcinoma-associated fibroblasts in the reactive stroma could promote LVI and progression to metastasis. Thus, combining LVI with reactive stromal grade may identify prostate cancer patients at high risk of an unfavorable outcome. The purpose of the present study was to examine if LVI, determined by diagnostic biopsy, alone and in combination with reactive stromal grade could predict prostate cancer death. This population-based study included 283 patients with prostate cancer diagnosed by needle biopsy in Aust-Agder County (Norway) from 1991 to 1999. Clinical data were obtained by medical charts review. Two uropathologists evaluated LVI and reactive stromal grade. The endpoint was prostate cancer death. Patients with LVI had marginally higher risk of prostate cancer death compared to patients without LVI (hazard ratio: 1.8, P-value = 0.04). LVI had a stronger effect on prostate cancer death risk when a high reactive stromal grade was present (hazard ratio: 16.0, P-value <0.001). Therefore, patients with concomitant LVI and high reactive stromal grade were at particularly high risk for prostate cancer death. Evaluating LVI together with reactive stromal grade on diagnostic biopsies could be used to identify patients at high risk of death from prostate cancer. Prostate 76:1088-1094, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Hip fracture in the elderly: a re-analysis of the EPIDOS study with causal Bayesian networks.

PubMed

Caillet, Pascal; Klemm, Sarah; Ducher, Michel; Aussem, Alexandre; Schott, Anne-Marie

2015-01-01

Hip fractures commonly result in permanent disability, institutionalization or death in elderly. Existing hip-fracture predicting tools are underused in clinical practice, partly due to their lack of intuitive interpretation. By use of a graphical layer, Bayesian network models could increase the attractiveness of fracture prediction tools. Our aim was to study the potential contribution of a causal Bayesian network in this clinical setting. A logistic regression was performed as a standard control approach to check the robustness of the causal Bayesian network approach. EPIDOS is a multicenter study, conducted in an ambulatory care setting in five French cities between 1992 and 1996 and updated in 2010. The study included 7598 women aged 75 years or older, in which fractures were assessed quarterly during 4 years. A causal Bayesian network and a logistic regression were performed on EPIDOS data to describe major variables involved in hip fractures occurrences. Both models had similar association estimations and predictive performances. They detected gait speed and mineral bone density as variables the most involved in the fracture process. The causal Bayesian network showed that gait speed and bone mineral density were directly connected to fracture and seem to mediate the influence of all the other variables included in our model. The logistic regression approach detected multiple interactions involving psychotropic drug use, age and bone mineral density. Both approaches retrieved similar variables as predictors of hip fractures. However, Bayesian network highlighted the whole web of relation between the variables involved in the analysis, suggesting a possible mechanism leading to hip fracture. According to the latter results, intervention focusing concomitantly on gait speed and bone mineral density may be necessary for an optimal prevention of hip fracture occurrence in elderly people.

Iron overload induced death of osteoblasts in vitro: involvement of the mitochondrial apoptotic pathway

PubMed Central

Dai, Zhipeng; Yang, Jingjing; Zheng, Jin

2016-01-01

Background Iron overload is recognized as a new pathogenfor osteoporosis. Various studies demonstrated that iron overload could induce apoptosis in osteoblasts and osteoporosis in vivo. However, the exact molecular mechanisms involved in the iron overload-mediated induction of apoptosis in osteoblasts has not been explored. Purpose In this study, we attempted to determine whether the mitochondrial apoptotic pathway is involved in iron-induced osteoblastic cell death and to investigate the beneficial effect of N-acetyl-cysteine (NAC) in iron-induced cytotoxicity. Methods The MC3T3-E1 osteoblastic cell line was treated with various concentrations of ferric ion in the absence or presence of NAC, and intracellular iron, cell viability, reactive oxygen species, functionand morphology changes of mitochondria and mitochondrial apoptosis related key indicators were detected by commercial kits. In addition, to further explain potential mechanisms underlying iron overload-related osteoporosis, we also assessed cell viability, apoptosis, and osteogenic differentiation potential in bone marrow-derived mesenchymal stemcells(MSCs) by commercial kits. Results Ferric ion demonstrated concentration-dependent cytotoxic effects on osteoblasts. After incubation with iron, an elevation of intracelluar labile iron levels and a concomitant over-generation of reactive oxygen species (ROS) were detected by flow cytometry in osteoblasts. Nox4 (NADPH oxidase 4), an important ROS producer, was also evaluated by western blot. Apoptosis, which was evaluated by Annexin V/propidium iodide staining, Hoechst 33258 staining, and the activation of caspase-3, was detected after exposure to iron. Iron contributed to the permeabilizatio of mitochondria, leading to the release of cytochrome C (cyto C), which, in turn, induced mitochondrial apoptosis in osteoblasts via activation of Caspase-3, up-regulation of Bax, and down-regulation of Bcl-2. NAC could reverse iron-mediated mitochondrial dysfunction and blocked the apoptotic events through inhibit the generation of ROS. In addition, iron could significantly promote apoptosis and suppress osteogenic differentiation and mineralization in bone marrow-derived MSCs. Conclusions These findings firstly demonstrate that the mitochondrial apoptotic pathway involved in iron-induced osteoblast apoptosis. NAC could relieved the oxidative stress and shielded osteoblasts from apoptosis casused by iron-overload. We also reveal that iron overload in bone marrow-derived MSCs results in increased apoptosis and the impairment of osteogenesis and mineralization. PMID:27843711

Concomitant administration of diphtheria, tetanus, acellular pertussis and inactivated poliovirus vaccine derived from Sabin strains (DTaP-sIPV) with pentavalent rotavirus vaccine in Japanese infants.

PubMed

Tanaka, Yoshiyuki; Yokokawa, Ruriko; Rong, Han Shi; Kishino, Hiroyuki; Stek, Jon E; Nelson, Margaret; Lawrence, Jody

2017-06-03

Rotavirus is the leading cause of severe acute gastroenteritis in infants and young children. Most children are infected with rotavirus, and the health and economic burdens of rotavirus gastroenteritis on healthcare systems and families are considerable. In 2012 pentavalent rotavirus vaccine (RV5) and diphtheria, tetanus, acellular pertussis and inactivated poliovirus vaccine derived from Sabin strains (DTaP-sIPV) were licensed in Japan. We examined the immunogenicity and safety of DTaP-sIPV when administrated concomitantly with RV5 in Japanese infants. A total of 192 infants 6 to 11 weeks of age randomized to Group 1 (N = 96) received DTaP-sIPV and RV5 concomitantly, and Group 2 (N = 96) received DTaP-sIPV and RV5 separately. Antibody titer to diphtheria toxin, pertussis antigens (PT and FHA), tetanus toxin, and poliovirus type 1, 2, and 3 were measured at 4 to 6 weeks following 3-doses of DTaP-sIPV. Seroprotection rates for all components of DTaP-sIPV were 100% in both groups, and the geometric mean titers for DTaP-sIPV in Group 1 were comparable to Group 2. Incidence of systemic AEs (including diarrhea, vomiting, fever, and nasopharyngitis) were lower in Group 1 than in Group 2. All vaccine-related AEs were mild or moderate in intensity. There were no vaccine-related serious AEs, no deaths, and no cases of intussusception during the study. Concomitant administration of DTaP-sIPV and RV5 induced satisfactory immune responses to DTaP-sIPV and acceptable safety profile. The administration of DTaP-sIPV given concomitantly with RV5 is expected to facilitate compliance with the vaccination schedule and improve vaccine coverage in Japanese infants.

The Impact of Improving Suicide Death Classification in South Korea: A Comparison with Japan and Hong Kong

PubMed Central

Chan, Chee Hon; Caine, Eric D.; Chang, Shu Sen; Lee, Won Jin; Cha, Eun Shil; Yip, Paul Siu Fai

2015-01-01

Introduction The suicide rate of South Korea has increased dramatically during the past decades, as opposed to steadily decreasing trends in Japan and Hong Kong. Although the recent increase of suicide in South Korea may be related to changing socioeconomic conditions and other contextual factors, it may also reflect, in part, a reduction of misidentified suicide cases due to improving classification of manner of death. Method We compared the annual proportional change of suicide, undetermined death, and accidental death from South Korea with those of Japan and Hong Kong from 1992 to 2011; a greater proportional change of the manner-of-death categories during the period is indicative of a relatively less stable registration and hence a greater potential for misclassification bias on reported suicide trends. Subgroup analyses stratifying the deaths by methods were also conducted. To estimate the impact, the age-standardized rates of these three death categories in each site were calculated. Results We found that, during the 20-year observation period, the proportional change of suicide, undetermined death, and accidental death in South Korea was significantly greater than Japan and Hong Kong. Similar observations were made in subgroup analyses. While death rates of the three manners in Japan and Hong Kong generally moved in a parallel fashion, the increase of suicide in South Korea occurred concomitantly with a significant reduction of its accidental death rate. 43% of the increase in suicides could be attributed to the decrease in accidental deaths, while 57% of the increase could be due to fundamental causes. Conclusion Our data suggest that, during the mid-1990s and after, the increasing burden of suicide in South Korea initially was masked, in part, by misclassification. Thus, the later apparently rapid increase of suicides reflected steadily improving classification of manner of death, as well as a more fundamental increase in the suicide rate. PMID:25992879

The impact of improving suicide death classification in South Korea: a comparison with Japan and Hong Kong.

PubMed

Chan, Chee Hon; Caine, Eric D; Chang, Shu Sen; Lee, Won Jin; Cha, Eun Shil; Yip, Paul Siu Fai

2015-01-01

The suicide rate of South Korea has increased dramatically during the past decades, as opposed to steadily decreasing trends in Japan and Hong Kong. Although the recent increase of suicide in South Korea may be related to changing socioeconomic conditions and other contextual factors, it may also reflect, in part, a reduction of misidentified suicide cases due to improving classification of manner of death. We compared the annual proportional change of suicide, undetermined death, and accidental death from South Korea with those of Japan and Hong Kong from 1992 to 2011; a greater proportional change of the manner-of-death categories during the period is indicative of a relatively less stable registration and hence a greater potential for misclassification bias on reported suicide trends. Subgroup analyses stratifying the deaths by methods were also conducted. To estimate the impact, the age-standardized rates of these three death categories in each site were calculated. We found that, during the 20-year observation period, the proportional change of suicide, undetermined death, and accidental death in South Korea was significantly greater than Japan and Hong Kong. Similar observations were made in subgroup analyses. While death rates of the three manners in Japan and Hong Kong generally moved in a parallel fashion, the increase of suicide in South Korea occurred concomitantly with a significant reduction of its accidental death rate. 43% of the increase in suicides could be attributed to the decrease in accidental deaths, while 57% of the increase could be due to fundamental causes. Our data suggest that, during the mid-1990s and after, the increasing burden of suicide in South Korea initially was masked, in part, by misclassification. Thus, the later apparently rapid increase of suicides reflected steadily improving classification of manner of death, as well as a more fundamental increase in the suicide rate.

Perceptions of good and bad death among Korean social workers in elderly long-term care facilities.

PubMed

Kim, Eunkyung

2018-06-20

This qualitative study explored the perception of good and bad death among 15 social workers serving in elderly care facilities in Korea. A good death involved dying peacefully without much suffering, dying with family members present, death following a good life, and believing in a better afterlife. A bad death involved burdening children in the dying process, dying after extensive illness, dying isolated from family, and death from suicide. To ensure a good death and avoid a bad death for elders, social workers are encouraged to closely engage with not only elders but also their families.

Mortality related to novel psychoactive substances in Scotland, 2012: an exploratory study.

PubMed

McAuley, Andrew; Hecht, Garry; Barnsdale, Lee; Thomson, Catherine S; Graham, Lesley; Priyadarshi, Saket; Robertson, J Roy

2015-05-01

The growth of novel psychoactive substances (NPS) over the last decade, both in terms of availability and consumption, is of increasing public health concern. Despite recent increases in related mortality, the circumstances surrounding and characteristics of individuals involved in NPS deaths at a population level remain relatively unknown. The Scottish National Drug Related Death Database (NDRDD) collects a wide-range of data relating to the nature and circumstances of individuals who have died a drug-related death (DRD). We conducted exploratory descriptive analysis of DRDs involving NPS recorded by the NDRDD in 2012. Statistical testing of differences between sub-groups was also conducted where appropriate. In 2012, we found 36 DRDs in Scotland to have NPS recorded within post-mortem toxicology. However, in only 23 of these cases were NPS deemed by the reporting pathologist to be implicated in the actual cause of death. The majority of NPS-implicated DRDs involved Benzodiazepine-type drugs (13), mainly Phenazepam (12). The remaining 10 NPS-implicated deaths featured a range of different Stimulant-type drugs. The majority of these NPS-implicated deaths involved males and consumption of more than one drug was recorded by toxicology in all except one case. NPS-implicated deaths involving Benzodiazepine-type NPS drugs appeared to involve older individuals known to be using drugs for a considerable period of time, many of whom had been in prison at some point in their lives. They also typically involved combinations of opioids and benzodiazepines; no stimulant drugs were co-implicated. Deaths where stimulant-type NPS drugs were implicated appeared to be a younger group in comparison, all consuming two or more Stimulant-type drugs in combination. This exploratory study provides an important insight into the circumstances surrounding and characteristics of individuals involved in NPS deaths at a population level. It identifies important issues for policy and practice, not least the prominent role of unlicensed benzodiazepines in drug-related mortality, but also the need for a range of harm reduction strategies to prevent future deaths. Copyright © 2014 Elsevier B.V. All rights reserved.

Use of Rapid Ascertainment Process for Institutional Deaths (RAPID) to identify pregnancy-related deaths in tertiary-care obstetric hospitals in three departments in Haiti.

PubMed

Boyd, Andrew T; Hulland, Erin N; Grand'Pierre, Reynold; Nesi, Floris; Honoré, Patrice; Jean-Louis, Reginald; Handzel, Endang

2017-05-16

Accurate assessment of maternal deaths is difficult in countries lacking standardized data sources for their review. As a first step to investigate suspected maternal deaths, WHO suggests surveillance of "pregnancy-related deaths", defined as deaths of women while pregnant or within 42 days of termination of pregnancy, irrespective of cause. Rapid Ascertainment Process for Institutional Deaths (RAPID), a surveillance tool, retrospectively identifies pregnancy-related deaths occurring in health facilities that may be missed by routine surveillance to assess gaps in reporting these deaths. We used RAPID to review pregnancy-related deaths in six tertiary obstetric care facilities in three departments in Haiti. We reviewed registers and medical dossiers of deaths among women of reproductive age occurring in 2014 and 2015 from all wards, along with any additional available dossiers of deaths not appearing in registers, to capture pregnancy status, suspected cause of death, and timing of death in relation to the pregnancy. We used capture-recapture analyses to estimate the true number of in-hospital pregnancy-related deaths in these facilities. Among 373 deaths of women of reproductive age, we found 111 pregnancy-related deaths, 25.2% more than were reported through routine surveillance, and 22.5% of which were misclassified as non-pregnancy-related. Hemorrhage (27.0%) and hypertensive disorders (18.0%) were the most common categories of suspected causes of death, and deaths after termination of pregnancy were statistically significantly more common than deaths during pregnancy or delivery. Data were missing at multiple levels: 210 deaths had an undetermined pregnancy status, 48.7% of pregnancy-related deaths lacked specific information about timing of death in relation to the pregnancy, and capture-recapture analyses in three hospitals suggested that approximately one-quarter of pregnancy-related deaths were not captured by RAPID or routine surveillance. Across six tertiary obstetric care facilities in Haiti, RAPID identified unreported pregnancy-related deaths, and showed that missing data was a widespread problem. RAPID is a useful tool to more completely identify facility-based pregnancy-related deaths, but its repeated use would require a concomitant effort to systematically improve documentation of clinical findings in medical records. Limitations of RAPID demonstrate the need to use it alongside other tools to more accurately measure and address maternal mortality.

Antipsychotic Treatment Among Youth in Foster Care

PubMed Central

Yoon, Yesel; Rubin, David M.; Riddle, Mark A.; Noll, Elizabeth; Rothbard, Aileen

2011-01-01

OBJECTIVE: Despite national concerns over high rates of antipsychotic medication use among youth in foster care, concomitant antipsychotic use has not been examined. In this study, concomitant antipsychotic use among Medicaid-enrolled youth in foster care was compared with disabled or low-income Medicaid-enrolled youth. PATIENTS AND METHODS: The sample included 16 969 youths younger than 20 years who were continuously enrolled in a Mid-Atlantic state Medicaid program and had ≥1 claim with a psychiatric diagnosis and ≥1 antipsychotic claim in 2003. Antipsychotic treatment was characterized by days of any use and concomitant use with ≥2 overlapping antipsychotics for >30 days. Medicaid program categories were foster care, disabled (Supplemental Security Income), and Temporary Assistance for Needy Families (TANF). Multicategory involvement for youths in foster care was classified as foster care/Supplemental Security Income, foster care/TANF, and foster care/adoption. We used multivariate analyses, adjusting for demographics, psychiatric comorbidities, and other psychotropic use, to assess associations between Medicaid program category and concomitant antipsychotic use. RESULTS: Average antipsychotic use ranged from 222 ± 110 days in foster care to only 135 ± 101 days in TANF (P < .001). Concomitant use for ≥180 days was 19% in foster care only and 24% in foster care/adoption compared with <15% in the other categories. Conduct disorder and antidepressant or mood-stabilizer use was associated with a higher likelihood of concomitant antipsychotic use (P < .0001). CONCLUSIONS: Additional study is needed to assess the clinical rationale, safety, and outcomes of concomitant antipsychotic use and to inform statewide policies for monitoring and oversight of antipsychotic use among youths in the foster care system. PMID:22106072

Increasing deaths involving oxycodone, Victoria, Australia, 2000-09.

PubMed

Rintoul, Angela C; Dobbin, Malcolm D H; Drummer, Olaf H; Ozanne-Smith, Joan

2011-08-01

In light of an emerging epidemic identified in the United States and Canada, to identify trends in fatal drug toxicity involving oxycodone and the demographic characteristics and indicators of socioeconomic disadvantage of the deceased. Population-based observational study in Victoria, Australia. Decedents whose death was reported to the Victorian Coroner between 2000 and 2009 and where oxycodone was detected. Association between supply of oxycodone and deaths. Demographic characteristics of decedents. Rate ratios of the rural or metropolitan location and socioeconomic indicators of disadvantage of the deceased. Supply to Victoria has increased nine-fold from 7.5 mg per capita in 2000 to 67.5 mg per capita in 2009. Detection of oxycodone in deaths reported to the Victorian Coroner has increased from 4 (0.08/100,000 population) in 2000 to 97 (1.78/100,000 population) in 2009-a 21-fold increase in deaths. Of the 320 cases described, 53.8% (172) were the result of drug toxicity. Of these, 52.3% were unintentional and 19.8% intentional self-harm; the remaining 27.9% are either still under investigation by the coroner or intent is unknown. Drug toxicity deaths were overrepresented in both rural areas and areas indexed with high levels of disadvantage. The substantial increase in the number of deaths involving oxycodone is strongly and significantly associated with the increase in supply. Most drug toxicity deaths involving oxycodone were unintentional. This newly identified trend in fatalities in Victoria supports concerns that a pattern of increasing deaths involving oxycodone is emerging globally.

Involvement of Lysosome Membrane Permeabilization and Reactive Oxygen Species Production in the Necrosis Induced by Chlamydia muridarum Infection in L929 Cells.

PubMed

Chen, Lixiang; Wang, Cong; Li, Shun; Yu, Xin; Liu, Xue; Ren, Rongrong; Liu, Wenwen; Zhou, Xiaojing; Zhang, Xiaonan; Zhou, Xiaohui

2016-04-28

Chlamydiae, obligate intracellular bacteria, are associated with a variety of human diseases. The chlamydial life cycle undergoes a biphasic development: replicative reticulate bodies (RBs) phase and infectious elementary bodies (EBs) phase. At the end of the chlamydial intracellular life cycle, EBs have to be released to the surrounded cells. Therefore, the interactions between Chlamydiae and cell death pathways could greatly influence the outcomes of Chlamydia infection. However, the underlying molecular mechanisms remain elusive. Here, we investigated host cell death after Chlamydia infection in vitro, in L929 cells, and showed that Chlamydia infection induces cell necrosis, as detected by the propidium iodide (PI)-Annexin V double-staining flow-cytometric assay and Lactate dehydrogenase (LDH) release assay. The production of reactive oxygen species (ROS), an important factor in induction of necrosis, was increased after Chlamydia infection, and inhibition of ROS with specific pharmacological inhibitors, diphenylene iodonium (DPI) or butylated hydroxyanisole (BHA), led to significant suppression of necrosis. Interestingly, live-cell imaging revealed that Chlamydia infection induced lysosome membrane permeabilization (LMP). When an inhibitor upstream of LMP, CA-074-Me, was added to cells, the production of ROS was reduced with concomitant inhibition of necrosis. Taken together, our results indicate that Chlamydia infection elicits the production of ROS, which is dependent on LMP at least partially, followed by induction of host-cell necrosis. To our best knowledge, this is the first live-cell-imaging observation of LMP post Chlamydia infection and report on the link of LMP to ROS to necrosis during Chlamydia infection.

The expression of selected molecular markers of immune tolerance in psoriatic patients.

PubMed

Bartosińska, Joanna; Purkot, Joanna; Kowal, Małgorzata; Michalak-Stoma, Anna; Krasowska, Dorota; Chodorowska, Grażyna; Giannopoulos, Krzysztof

2018-04-24

Psoriasis is a chronic autoinflammatory disease whose underlying molecular mechanisms remain unclear. The disease is mediated by the cells and molecules of both the innate and adaptive immune systems. Some T cell surface molecules, including neuropilin-1 (NRP1), programmed death 1 (PD-1) and the human leukocyte antigen G (HLA-G), are known to play a role in the maintenance of immune tolerance. The aim of this study was to investigate HLA-G, NRP1 and programmed cell death gene (PDCD1) mRNA expression in psoriatic patients. The study included 72 psoriatic patients and 35 healthy individuals. Twentyone patients (29.17%) suffered from concomitant psoriatic arthritis. The mRNA expression of HLA-G, NRP1, and PDCD1 were determined using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). The severity of skin lesions was assessed by means of the Psoriasis Area and Severity Index (PASI), Body Surface Area (BSA), the Patient Global Assessment (PGA), and the Dermatology Life Quality Index (DLQI). The median value of the PASI was 11.5, and of BSA was 15.8%. The expressions of NRP1 and PDCD1, but not HLA-G, were significantly lower in psoriatic patients in comparison with the control group. The expression of HLA-G, NRP1 and PDCD1 were not significantly different in the psoriatic arthritis and psoriasis vulgaris patients. The results of this study suggest that the molecular markers of immune tolerance, i.e., HLA-G, NRP1, and PD-1, may be involved in the immune response in psoriatic patients.

[Morbimortality in patients with hepatic trauma].

PubMed

Fonseca-Neto, Olival Cirilo Lucena da; Ehrhardt, Rogério; Miranda, Antonio Lopes de

2013-06-01

The liver is the intra-abdominal organ more injured in patient victims of trauma. The injury occurs more frequently in the penetrating trauma. The incidence of mortality for injuries of the liver is 10%. To evaluate the mortality of the patients with hepatic trauma, the treatment applied and its evolution. Were analyzed, retrospectively, the charts of all patients with hepatic trauma and surgical indication. Were analyzed: gender, age, ISS (injury severity score), classification of the abdominal trauma type (open or closed), causing instrument of the open traumas, degree of the injury, hepatic segments involved, presence of associated injuries, type of surgical treatment: not-therapeutic laparotomy and therapeutic laparotomy, reoperations, complications, time of hospitalization in days and mortality. One hundred and thirty-seven patients participated. Of these, 124 were men (90.5%). The majority (56.2%) had 20-29 years old. Closed abdominal trauma was most prevalent (67.9%). Of the penetrating traumas, the originated with firearms were in 24.8%. One hundred and three patients had only one injured hepatic segment (75.2%) and 34 (24.8%) two. Grade II injuries were in 66.4%. Of the 137 patients with laparotomy, 89 had been not-therapeutic, while in 48 it was necessary to repair associated injuries. Spleen and diaphragm had been the more frequently injured structures, 30% and 26%, respectively. The ISS varied of eight to 72, being the ISS > 50 (eight patients) associate with fatal evolution (five patients). Biliary fistula and hepatic abscess had been the main complications. Seven deaths had occurred. Concomitant injuries, hepatic and other organs, associated with ISS > 50 presented higher possibility of complications and death.

Mechanism of Action of Two Flavone Isomers Targeting Cancer Cells with Varying Cell Differentiation Status

PubMed Central

Parsons, Laura B.; Miller, Gerald E.; Whitted, Crystal; Lynch, Kayla E.; Ramsauer, Robert E.; Patel, Jasmine U.; Wyatt, Jarrett E.; Street, Doris S.; Adams, Carolyn B.; McPherson, Brian; Tsui, Hei Man; Evans, Julie A.; Livesay, Christopher; Torrenegra, Ruben D.; Palau, Victoria E.

2015-01-01

Apoptosis can be triggered in two different ways, through the intrinsic or the extrinsic pathway. The intrinsic pathway is mediated by the mitochondria via the release of cytochrome C while the extrinsic pathway is prompted by death receptor signals and bypasses the mitochondria. These two pathways are closely related to cell proliferation and survival signaling cascades, which thereby constitute possible targets for cancer therapy. In previous studies we introduced two plant derived isomeric flavonoids, flavone A and flavone B which induce apoptosis in highly tumorigenic cancer cells of the breast, colon, pancreas, and the prostate. Flavone A displayed potent cytotoxic activity against more differentiated carcinomas of the colon (CaCo-2) and the pancreas (Panc28), whereas flavone B cytotoxic action is observed on poorly differentiated carcinomas of the colon (HCT 116) and pancreas (MIA PaCa). Apoptosis is induced by flavone A in better differentiated colon cancer CaCo-2 and pancreatic cancer Panc 28 cells via the intrinsic pathway by the inhibition of the activated forms of extracellular signal-regulated kinase (ERK) and pS6, and subsequent loss of phosphorylation of Bcl-2 associated death promoter (BAD) protein, while apoptosis is triggered by flavone B in poorly differentiated colon cancer HCT 116 and MIA PaCa pancreatic cancer cells through the extrinsic pathway with the concomitant upregulation of the phosphorylated forms of ERK and c-JUN at serine 73. These changes in protein levels ultimately lead to activation of apoptosis, without the involvement of AKT. PMID:26606169

Infant Deaths and Injuries Associated with Wearable Blankets, Swaddle Wraps, and Swaddling

PubMed Central

McDonnell, Emily; Moon, Rachel Y.

2014-01-01

Objective To assess risks involved in using wearable blankets, swaddle wraps, and swaddling. Study design Retrospective review of incidents reported to the Consumer Product Safety Commission in 2004–2012. Results 36 incidents involving wearable blankets and swaddle wraps were reviewed, including 10 deaths, 2 injuries, and 12 incidents without injury. The median age at death was 3.5 months; 80% of deaths were attributed to positional asphyxia related to prone sleeping. 70% had additional risk factors, usually soft bedding. Two injuries involved tooth extraction from the zipper. The 12 incidents without injury reported concern for strangulation/suffocation when the swaddle wrap became wrapped around the face/neck, and potential choking hazard when the zipper detached. All 12 incidents involving swaddling in ordinary blankets resulted in death. The median age was 2 months; 58% of deaths were attributed to positional asphyxia related to prone sleeping. 92% involved additional risk factors, most commonly soft bedding. Conclusions Reports of sudden unexpected death in swaddled infants are rare. Risks can be reduced by placing infants supine, and discontinuing swaddling as soon as an infant’s earliest attempts to roll are observed. Risks can be further reduced by removing soft bedding and bumper pads from the sleep environment. When using commercial swaddle wraps, fasteners must be securely attached. PMID:24507866

Patient outcomes with endovascular embolectomy therapy for acute ischemic stroke: a study of the national inpatient sample: 2006 to 2008.

PubMed

Brinjikji, Waleed; Rabinstein, Alejandro A; Kallmes, David F; Cloft, Harry J

2011-06-01

Maturing techniques have spurred widespread implementation of endovascular embolectomy therapy for ischemic stroke. We evaluated a large administrative database to determine outcomes in patients treated with endovascular embolectomy in the general population. Using the National Inpatient Sample, we evaluated outcomes of patients treated for acute ischemic stroke in the United States from 2006 to 2008. Patients who had an ischemic stroke and underwent endovascular clot retrieval were identified. Morbidity, defined as "discharge to long-term facility," and mortality were evaluated as a function of patient age and of concomitant thrombolytic agent administration. For 2006 to 2008, a total of 3864 patients received endovascular clot retrieval with 266 (6.9%) patients in 2006, 800 (20.7) patients in 2007, and 2798 (72.4%) patients in 2008. The discharge to a long-term facility rate was 51.3% (1983 of 3864). The in-hospital mortality rate was 24.3% (940 of 3864). For patients <65 years old, the rate of in-hospital death was 17.1% (283 of 1658) as compared with a rate of 29.7% (656 of 2206) for patients ≥65 years old (P<0.0001). The rate of discharge to a long-term facility was 47.6% (789 of 1658) for patients <65 years old and 54.1% (1193 of 2206) for patients ≥65 years old (P<0.0001). The rate of intracranial hemorrhage was 15.5% without concomitant thrombolysis and 20.0% with concomitant thrombolysis (P=0.0009). Rates of morbidity and mortality remain high for patients with acute stroke, even in the setting of endovascular embolectomy. Advanced age portends a worse outcome and patients treated with concomitant use of thrombolytic agent had higher rates of intracranial hemorrhage than those without such therapy.

Geospatial Analysis of Drug Poisoning Deaths Involving Heroin in the USA, 2000-2014.

PubMed

Stewart, Kathleen; Cao, Yanjia; Hsu, Margaret H; Artigiani, Eleanor; Wish, Eric

2017-08-01

We investigate the geographic patterns of drug poisoning deaths involving heroin by county for the USA from 2000 to 2014. The county-level patterns of mortality are examined with respect to age-adjusted rates of death for different classes of urbanization and racial and ethnic groups, while rates based on raw counts of drug poisoning deaths involving heroin are estimated for different age groups and by gender. To account for possible underestimations in these rates due to small areas or small numbers, spatial empirical Baye's estimation techniques have been used to smooth the rates of death and alleviate underestimation when analyzing spatial patterns for these different groups. The geographic pattern of poisoning deaths involving heroin has shifted from the west coast of the USA in the year 2000 to New England, the Mid-Atlantic region, and the Great Lakes and central Ohio Valley by 2014. The evolution over space and time of clusters of drug poisoning deaths involving heroin is confirmed through the SaTScan analysis. For this period, White males were found to be the most impacted population group overall; however, Blacks and Hispanics are highly impacted in counties where significant populations of these two groups reside. Our results show that while 35-54-year-olds were the most highly impacted age group by county from 2000 to 2010, by 2014, the trend had changed with an increasing number of counties experiencing higher death rates for individuals 25-34 years. The percentage of counties across the USA classified as large metro with deaths involving heroin is estimated to have decreased from approximately 73% in 2010 to just fewer than 56% in 2014, with a shift to small metro and non-metro counties. Understanding the geographic variations in impact on different population groups in the USA has become particularly necessary in light of the extreme increase in the use and misuse of street drugs including heroin and the subsequent rise in opioid-related deaths in the USA.

Influence of vigilance state on physiological consequences of seizures and seizure-induced death in mice.

PubMed

Hajek, Michael A; Buchanan, Gordon F

2016-05-01

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. SUDEP occurs more commonly during nighttime sleep. The details of why SUDEP occurs at night are not well understood. Understanding why SUDEP occurs at night during sleep might help to better understand why SUDEP occurs at all and hasten development of preventive strategies. Here we aimed to understand circumstances causing seizures that occur during sleep to result in death. Groups of 12 adult male mice were instrumented for EEG, EMG, and EKG recording and subjected to seizure induction via maximal electroshock (MES) during wakefulness, nonrapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. Seizure inductions were performed with concomitant EEG, EMG, and EKG recording and breathing assessment via whole body plethysmography. Seizures induced via MES during sleep were associated with more profound respiratory suppression and were more likely to result in death. Despite REM sleep being a time when seizures do not typically occur spontaneously, when seizures were forced to occur during REM sleep, they were invariably fatal in this model. An examination of baseline breathing revealed that mice that died following a seizure had increased baseline respiratory rate variability compared with those that did not die. These data demonstrate that sleep, especially REM sleep, can be a dangerous time for a seizure to occur. These data also demonstrate that there may be baseline respiratory abnormalities that can predict which individuals have higher risk for seizure-induced death.

Death Notification: Someone Needs To Call the Family.

PubMed

Ombres, Rachel; Montemorano, Lauren; Becker, Daniel

2017-06-01

The death notification process can affect family grief and bereavement. It can also affect the well-being of involved physicians. There is no standardized process for making death notification phone calls. We assumed that residents are likely to be unprepared before and troubled after. We investigated current death notification practices to develop an evidence-based template for standardizing this process. We used results of a literature review and open-ended interviews with faculty, residents, and widows to develop a survey regarding resident training and experience in death notification by phone. We invited all internal medicine (IM) residents at our institution to complete the survey. Sixty-seven of 93 IM residents (72%) responded to the survey. Eighty-seven percent of responders reported involvement in a death that required notification by phone. Eighty percent of residents felt inadequately trained for this task. Over 25% reported that calls went poorly. Attendings were involved in 17% of cases. Primary care physicians were not involved. Nurses and chaplains were not involved. Respondents never delayed notification of death until family arrived at the hospital. There was no consistent approach to rehearsing or making the call, advising families about safe travel to the hospital, greeting families upon arrival, or following up with expressions of condolence. Poor communication skills during death notification may contribute to complicated grief for surviving relatives and stress among physicians. This study is the first to describe current practices of death notification by IM residents. More training is needed and could be combined with training in disclosure of medical error.

Death Notification: Someone Needs To Call the Family

PubMed Central

Ombres, Rachel; Montemorano, Lauren

2017-01-01

Abstract Background: The death notification process can affect family grief and bereavement. It can also affect the well-being of involved physicians. There is no standardized process for making death notification phone calls. We assumed that residents are likely to be unprepared before and troubled after. Objective: We investigated current death notification practices to develop an evidence-based template for standardizing this process. Design: We used results of a literature review and open-ended interviews with faculty, residents, and widows to develop a survey regarding resident training and experience in death notification by phone. Setting/Subjects: We invited all internal medicine (IM) residents at our institution to complete the survey. Measurements: Sixty-seven of 93 IM residents (72%) responded to the survey. Eighty-seven percent of responders reported involvement in a death that required notification by phone. Results: Eighty percent of residents felt inadequately trained for this task. Over 25% reported that calls went poorly. Attendings were involved in 17% of cases. Primary care physicians were not involved. Nurses and chaplains were not involved. Respondents never delayed notification of death until family arrived at the hospital. There was no consistent approach to rehearsing or making the call, advising families about safe travel to the hospital, greeting families upon arrival, or following up with expressions of condolence. Conclusions: Poor communication skills during death notification may contribute to complicated grief for surviving relatives and stress among physicians. This study is the first to describe current practices of death notification by IM residents. More training is needed and could be combined with training in disclosure of medical error. PMID:28099046

Increases in Drug and Opioid Overdose Deaths--United States, 2000-2014.

PubMed

Rudd, Rose A; Aleshire, Noah; Zibbell, Jon E; Gladden, R Matthew

2016-01-01

The United States is experiencing an epidemic of drug overdose (poisoning) deaths. Since 2000, the rate of deaths from drug overdoses has increased 137%, including a 200% increase in the rate of overdose deaths involving opioids (opioid pain relievers and heroin). CDC analyzed recent multiple cause-of-death mortality data to examine current trends and characteristics of drug overdose deaths, including the types of opioids associated with drug overdose deaths. During 2014, a total of 47,055 drug overdose deaths occurred in the United States, representing a 1-year increase of 6.5%, from 13.8 per 100,000 persons in 2013 to 14.7 per 100,000 persons in 2014. The rate of drug overdose deaths increased significantly for both sexes, persons aged 25-44 years and ≥55 years, non-Hispanic whites and non-Hispanic blacks, and in the Northeastern, Midwestern, and Southern regions of the United States. Rates of opioid overdose deaths also increased significantly, from 7.9 per 100,000 in 2013 to 9.0 per 100,000 in 2014, a 14% increase. Historically, CDC has programmatically characterized all opioid pain reliever deaths (natural and semisynthetic opioids, methadone, and other synthetic opioids) as "prescription" opioid overdoses (1). Between 2013 and 2014, the age-adjusted rate of death involving methadone remained unchanged; however, the age-adjusted rate of death involving natural and semisynthetic opioid pain relievers, heroin, and synthetic opioids, other than methadone (e.g., fentanyl) increased 9%, 26%, and 80%, respectively. The sharp increase in deaths involving synthetic opioids, other than methadone, in 2014 coincided with law enforcement reports of increased availability of illicitly manufactured fentanyl, a synthetic opioid; however, illicitly manufactured fentanyl cannot be distinguished from prescription fentanyl in death certificate data. These findings indicate that the opioid overdose epidemic is worsening. There is a need for continued action to prevent opioid abuse, dependence, and death, improve treatment capacity for opioid use disorders, and reduce the supply of illicit opioids, particularly heroin and illicit fentanyl.

Distinct Effects of Rotenone, 1-methyl-4-phenylpyridinium and 6-hydroxydopamine on Cellular Bioenergetics and Cell Death

PubMed Central

Giordano, Samantha; Lee, Jisun; Darley-Usmar, Victor M.; Zhang, Jianhua

2012-01-01

Parkinson’s disease is characterized by dopaminergic neurodegeneration and is associated with mitochondrial dysfunction. The bioenergetic susceptibility of dopaminergic neurons to toxins which induce Parkinson’s like syndromes in animal models is then of particular interest. For example, rotenone, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP+), and 6-hydroxydopamine (6-OHDA), have been shown to induce dopaminergic cell death in vivo and in vitro. Exposure of animals to these compounds induce a range of responses characteristics of Parkinson’s disease, including dopaminergic cell death, and Reactive Oxygen Species (ROS) production. Here we test the hypothesis that cellular bioenergetic dysfunction caused by these compounds correlates with induction of cell death in differentiated dopaminergic neuroblastoma SH-SY5Y cells. At increasing doses, rotenone induced significant cell death accompanied with caspase 3 activation. At these concentrations, rotenone had an immediate inhibition of mitochondrial basal oxygen consumption rate (OCR) concomitant with a decrease of ATP-linked OCR and reserve capacity, as well as a stimulation of glycolysis. MPP+ exhibited a different behavior with less pronounced cell death at doses that nearly eliminated basal and ATP-linked OCR. Interestingly, MPP+, unlike rotenone, stimulated bioenergetic reserve capacity. The effects of 6-OHDA on bioenergetic function was markedly less than the effects of rotenone or MPP+ at cytotoxic doses, suggesting a mechanism largely independent of bioenergetic dysfunction. These studies suggest that these dopaminergic neurotoxins induce cell death through distinct mechanisms and differential effects on cellular bioenergetics. PMID:22970265

Impact of State Ignition Interlock Laws on Alcohol-Involved Crash Deaths in the United States.

PubMed

Kaufman, Elinore J; Wiebe, Douglas J

2016-05-01

To investigate the impact on alcohol-involved crash deaths of universal ignition interlock requirements, which aim to prevent people convicted of driving under the influence of alcohol from driving while intoxicated. We used data from the National Highway Traffic Safety Administration for 1999 to 2013. From 2004 to 2013, 18 states made interlocks mandatory for all drunk-driving convictions. We compared alcohol-involved crash deaths between 18 states with and 32 states without universal interlock requirements, accounting for state and year effects, and for clustering within states. Policy impact was apparent 3 years after implementation. The adjusted rate of alcohol-involved crash deaths was 4.7 (95% confidence interval [CI] = 4.0, 5.4) per 100,000 in states with the universal interlock requirement, compared with 5.5 (95% CI = 5.48, 5.53) in states without, an absolute reduction of 0.8 (95% CI = 0.1, 1.5) deaths per 100,000 per year. Requiring ignition interlocks for all drunk-driving convictions was associated with 15% fewer alcohol-involved crash deaths, compared with states with less-stringent requirements. Interlocks are a life-saving technology that merit wider use.

Mild-to-moderate functional tricuspid regurgitation in patients undergoing mitral valve surgery.

PubMed

Ro, Sun Kyun; Kim, Joon Bum; Jung, Sung Ho; Choo, Suk Jung; Chung, Cheol Hyun; Lee, Jae Won

2013-11-01

The decision to repair mild-to-moderate functional tricuspid regurgitation (TR) during mitral valve surgery remains controversial. We evaluated the effects of tricuspid valve (TV) repair for functional mild-to-moderate TR during mitral valve surgery. We enrolled 959 patients with mild-to-moderate functional TR who underwent mitral valve surgery with (repair group n = 431) or without (control group n = 528) concomitant TV repair from January 1994 to September 2010. There were no significant differences in early mortality or major morbidity rates. Median follow-up was 64.8 months (range, 0.03-203.6 months). After adjustment for baseline characteristics using a propensity score adjustment model, the repair group had similar risks for TV reoperation (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.10-2.07; P = .31); congestive heart failure (HR, 1.12; 95% CI, 0.37-3.36; P = .84); death (HR, 1.41; 95% CI, 0.82-2.42; P = .22); and the composite of death, TV reoperation, and congestive heart failure (HR, 1.24; 95% CI, 0.76-2.03; P = .39) compared with the control group. On multivariate Cox-regression analysis, old age, atrial fibrillation without a Maze procedure, diabetes mellitus, chronic renal failure, poor left ventricular ejection fraction, and redo surgery emerged as significant independent risk factors for the composite outcome of death, TV reoperation, and congestive heart failure. Early or late clinical benefits of concomitant TV repair for mild-to-moderate TR during mitral valve surgery were uncertain through a long-term follow-up of 959 patients. Several preoperative factors and the performance of Maze procedure for AF seem to be more important than TV repair in overall clinical outcomes. Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Reported fatal and non-fatal incidents involving tourists in Thailand, July 1997-June 1999.

PubMed

Leggat, Peter A; Leggat, Frances W

2003-05-01

Objectives. To examine fatal and non-fatal incidents involving tourists in Thailand. Methods. Press records from a major English language newspaper for the period from July 1997 to June 1999 were examined for reports of fatal and non-fatal incidents involving tourists. Results. From July 1997 to June 1999, up to 233 deaths were reported and up to a further 216 were reported injured in incidents involving tourists. One hundred and one deaths and 45 injured were reported following one major domestic jet aircraft crash in southern Thailand, however, it was not stated what proportion of casualties were tourists. Approximately 90 people perished in a single hotel fire in southeast Thailand. Most of the victims were local travellers attending meetings of two Thai companies. Sixteen deaths and 86 injured resulted from five road accidents. The majority of deaths and injuries involved foreigners. Twelve deaths and at least 33 injured resulted from three ferry and tour boat accidents. Most victims were reported to be foreigners. Three deaths and 35 injured resulted from a single cable car accident in northern Thailand. Most of these were Thai tourists, however, four of the injured were foreigners. Eight deaths and six injured resulted from 11 muggings and other violent incidents. All were foreigners. Six deaths were reportedly connected to a scam at the airport in Bangkok involving unlicensed airport taxis. Three deaths and four injured were due to other reported incidents. Conclusions. Newspaper reports of fatal and non-fatal incidents involving tourists in Thailand were probably uncommon, particularly given the volume of tourists entering the Kingdom, although better reporting mechanisms are needed. With the exception of the unusual major incidents, most reported fatal and non-fatal incidents involving tourists were due to road trauma and other transportation accidents, muggings, and occasional water sports and other accidents, which could occur at any major tourist destination. Travel health advisers should include advice concerning personal safety abroad and tourist authorities should endeavour to promote and advocate for tourism safety.

A review of lapatinib ditosylate in the treatment of refractory or advanced breast cancer

PubMed Central

Nelson, Michael H; Dolder, Christian R

2007-01-01

Breast cancer remains a leading cause of disease and death among women throughout the world. Despite advances in drug therapy, development of novel and improved drugs for breast cancer continues to be of great interest. Lapatinib is a novel dual receptor tyrosine kinase inhibitor that is a selective and potent inhibitor of ErbB-1 and ErbB-2 tyrosine kinases, both of which are growth promoting factors overexpressed in some breast cancers. Cell-based assays have proven lapatinib to be a potent inhibitor of ErbB-1 and ErbB-2 activation and breast cancer cell proliferation. In pharmacokinetic studies, lapatinib has shown mostly linear elimination kinetics over the daily dose range of 10–1600 mg and is metabolized by CYP3A4/5 and CYP2C19. Phase I, II, and III clinical trials involving lapatinib as monotherapy or in combination have shown promise for the treatment of advanced and metastatic breast cancer. Drug-drug interactions may occur secondary to concomitant administration of either CYP450 inhibitors or inducers. While lapatinib appear to be a promising addition to breast cancer therapy, several questions remain to be answered before its optimal role is elucidated. PMID:18472989

A review of lapatinib ditosylate in the treatment of refractory or advanced breast cancer.

PubMed

Nelson, Michael H; Dolder, Christian R

2007-08-01

Breast cancer remains a leading cause of disease and death among women throughout the world. Despite advances in drug therapy, development of novel and improved drugs for breast cancer continues to be of great interest. Lapatinib is a novel dual receptor tyrosine kinase inhibitor that is a selective and potent inhibitor of ErbB-1 and ErbB-2 tyrosine kinases, both of which are growth promoting factors overexpressed in some breast cancers. Cell-based assays have proven lapatinib to be a potent inhibitor of ErbB-1 and ErbB-2 activation and breast cancer cell proliferation. In pharmacokinetic studies, lapatinib has shown mostly linear elimination kinetics over the daily dose range of 10-1600 mg and is metabolized by CYP3A4/5 and CYP2C19. Phase I, II, and III clinical trials involving lapatinib as monotherapy or in combination have shown promise for the treatment of advanced and metastatic breast cancer. Drug-drug interactions may occur secondary to concomitant administration of either CYP450 inhibitors or inducers. While lapatinib appear to be a promising addition to breast cancer therapy, several questions remain to be answered before its optimal role is elucidated.

Proteasome function is not impaired in healthy aging of the lung.

PubMed

Caniard, Anne; Ballweg, Korbinian; Lukas, Christina; Yildirim, Ali Ö; Eickelberg, Oliver; Meiners, Silke

2015-10-01

Aging is the progressive loss of cellular function which inevitably leads to death. Failure of proteostasis including the decrease in proteasome function is one hallmark of aging. In the lung, proteasome activity was shown to be impaired in age-related diseases such as chronic obstructive pulmonary disease. However, little is known on proteasome function during healthy aging. Here, we comprehensively analyzed healthy lung aging and proteasome function in wildtype, proteasome reporter and immunoproteasome knockout mice. Wildtype mice spontaneously developed senile lung emphysema while expression and activity of proteasome complexes and turnover of ubiquitinated substrates was not grossly altered in lungs of aged mice. Immunoproteasome subunits were specifically upregulated in the aged lung and the caspase-like proteasome activity concomitantly decreased. Aged knockout mice for the LMP2 or LMP7 immunoproteasome subunits showed no alteration in proteasome activities but exhibited typical lung aging phenotypes suggesting that immunoproteasome function is dispensable for physiological lung aging in mice. Our results indicate that healthy aging of the lung does not involve impairment of proteasome function. Apparently, the reserve capacity of the proteostasis systems in the lung is sufficient to avoid severe proteostasis imbalance during healthy aging.

How compelling are the data for Epstein-Barr virus being a trigger for systemic lupus and other autoimmune diseases?

PubMed

Draborg, Anette; Izarzugaza, Jose M G; Houen, Gunnar

2016-07-01

Systemic lupus erythematosus (SLE) is caused by a combination of genetic and acquired immunodeficiencies and environmental factors including infections. An association with Epstein-Barr virus (EBV) has been established by numerous studies over the past decades. Here, we review recent experimental studies on EBV, and present our integrated theory of SLE development. SLE patients have dysfunctional control of EBV infection resulting in frequent reactivations and disease progression. These comprise impaired functions of EBV-specific T-cells with an inverse correlation to disease activity and elevated serum levels of antibodies against lytic cycle EBV antigens. The presence of EBV proteins in renal tissue from SLE patients with nephritis suggests direct involvement of EBV in SLE development. As expected for patients with immunodeficiencies, studies reveal that SLE patients show dysfunctional responses to other viruses as well. An association with EBV infection has also been demonstrated for other autoimmune diseases, including Sjögren's syndrome, rheumatoid arthritis, and multiple sclerosis. Collectively, the interplay between an impaired immune system and the cumulative effects of EBV and other viruses results in frequent reactivation of EBV and enhanced cell death, causing development of SLE and concomitant autoreactivities.

Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss.

PubMed

Scekic-Zahirovic, Jelena; Sendscheid, Oliver; El Oussini, Hajer; Jambeau, Mélanie; Sun, Ying; Mersmann, Sina; Wagner, Marina; Dieterlé, Stéphane; Sinniger, Jérome; Dirrig-Grosch, Sylvie; Drenner, Kevin; Birling, Marie-Christine; Qiu, Jinsong; Zhou, Yu; Li, Hairi; Fu, Xiang-Dong; Rouaux, Caroline; Shelkovnikova, Tatyana; Witting, Anke; Ludolph, Albert C; Kiefer, Friedemann; Storkebaum, Erik; Lagier-Tourenne, Clotilde; Dupuis, Luc

2016-05-17

FUS is an RNA-binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS-containing aggregates are often associated with concomitant loss of nuclear FUS Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell-specific CRE-mediated expression of wild-type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons. © 2016 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Causes of Death in Patients with Venous Thromboembolism Anticoagulated with Direct Oral Anticoagulants: A Systematic Review and Meta-Analysis.

PubMed

Gómez-Outes, Antonio; Terleira-Fernández, Ana Isabel; Lecumberri, Ramón; Suárez-Gea, Mª Luisa; Calvo-Rojas, Gonzalo; Vargas-Castrillón, Emilio

2018-06-01

Death is more frequent than nonfatal recurrent venous thromboembolism (VTE) and major bleeding after acute VTE. The analysis of the causes of death is fundamental to explore new strategies to reduce mortality rates in these patients. The authors performed a meta-analysis to analyze mortality and independently adjudicated causes of death in anticoagulated patients due to VTE, and to evaluate potential differences between different anticoagulant schemes. They searched MEDLINE and CENTRAL, from January 1, 2000, to January 31, 2017, and performed additional searches in Web sites of regulatory agencies, clinical trial registers, and conference proceedings. Two investigators independently selected studies and extracted the data. Study quality was assessed with the Cochrane Collaboration's tool for assessing the risk of bias in randomized studies. Seven prospective randomized trials in 29,844 patients (22,025 patient-year follow-up) were included, comparing dabigatran, rivaroxaban, apixaban, and edoxaban with the standard anticoagulant treatment of VTE. A total of 718 patients died during the follow-up (3.4% per year; 95% confidence interval [CI]: 2.3-4.8). The most frequent causes of death were cancer (42%), followed by VTE (20%), infections (13%), hemorrhage (6%), heart disease (4%), and stroke (2%). There were no differences in the overall survival and causes of death according to the anticoagulant type. Concomitant active cancer during the study was significantly associated with death (odds ratio: 15.2; 95% CI: 9.2-25.1). Cancer is the leading cause of death in contemporary VTE trials. Interventions beyond anticoagulation, particularly in patients with active cancer, are needed. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Three cases of communication syringomyelia secondary to midbrain gliomas.

PubMed Central

Williams, B; Timperley, W R

1977-01-01

Three cases of midbrain gliomas are descrbied clinically and pathologically. In each case high pressure symptoms were followed by visual disturbance and the onset of syringomyelia symptoms before death. All the patients had hydrocephalus. In one case with concomitant syringobulbia, the syrinx appeared to due to CSF communicating with the cord cavity through the tissues of the brain stem. In the other cases the communication between the CSF pathways and the syrinx was at the usual site, through the central canal at the obex. Images PMID:845611

Clopidogrel-Proton Pump Inhibitor Drug-Drug Interaction and Risk of Adverse Clinical Outcomes Among PCI-Treated ACS Patients: A Meta-analysis.

PubMed

Serbin, Michael A; Guzauskas, Gregory F; Veenstra, David L

2016-08-01

Uncertainty regarding clopidogrel effectiveness attenuation because of a drug-drug interaction with proton pump inhibitors (PPI) has led to conflicting guidelines on concomitant therapy. In particular, the effect of this interaction in patients who undergo a percutaneous coronary intervention (PCI), a population known to have increased risk of adverse cardiovascular events, has not been systematically evaluated. To synthesize the evidence of the effect of clopidogrel-PPI drug interaction on adverse cardiovascular outcomes in a PCI patient population. We conducted a systematic literature review for studies reporting clinical outcomes in patients who underwent a PCI and were initiated on clopidogrel with or without a PPI. Studies were included in the analysis if they reported at least 1 of the clinical outcomes of interest (major adverse cardiovascular event [MACE], cardiovascular death, all-cause death, myocardial infarction, stroke, stent thrombosis, and bleed events). We excluded studies that were not exclusive to PCI patients or had no PCI subgroup analysis and/or did not report at least a 6-month follow-up. Statistical and clinical heterogeneity were evaluated and HRs and 95% CIs for adverse clinical events were pooled using the DerSimonian and Laird random-effects meta-analysis method. We identified 12 studies comprising 50,277 PCI patients that met our inclusion and exclusion criteria. Our analysis included retrospective analyses of randomized controlled trials (2), health registries (3), claims databases (2), and institutional records (5); no prospective studies of PCI patients were identified. On average, patients were in their mid-60s, male, and had an array of comorbidities, including hyperlipidemia, diabetes, hypertension, and smoking history. Concomitant therapy following PCI resulted in statistically significant increases in composite MACE (HR = 1.28; 95% CI = 1.24-1.32), myocardial infarction (HR = 1.51; 95% CI = 1.40-1.62), and stroke (HR = 1.46; 95% CI = 1.15-1.86). However, concomitant therapy had no statistically significant effect on stent thrombosis, mortality measured by all-cause or cardiovascular death, or major bleeding before or after the grouping of studies that reported a major or minor bleed outcome. Only 1 study reported on gastrointestinal bleed, and pooled analysis could not be conducted. Statistical testing suggested heterogeneity among studies, but subgroup analysis did not reveal a clear source. Based on the results from this meta-analysis of retrospective analyses of randomized controlled trials and observational studies, concomitant clopidogrel-PPI therapy following PCI appears to be significantly associated with adverse cardiovascular events. Further research on the effect of individual PPIs is needed. Serbin, Guzauskas, and Veenstra were supported by the NIH Common Fund and NIA (1U01AG047109-01, Veenstra, PI) via the Personalized Medicine Economics Research (PriMER) project. The authors do not report any conflicting interests. All authors contributed to the study concept and design. Serbin took the lead in data collection; data interpretation was performed primarily by Serbin, with assistance from the other authors. The manuscript was written primarily by Serbin, along with Guzauskas, and revised by Guzauskas and Veenstra, with assistance from Serbin.

Respiratory symptoms are poor predictors of concomitant chronic obstructive pulmonary disease in patients with primary Sjögren's syndrome.

PubMed

Strevens Bolmgren, Victor; Olsson, Peter; Wollmer, Per; Hesselstrand, Roger; Mandl, Thomas

2017-05-01

Involvement of the respiratory system, in particular dry airways and chronic obstructive pulmonary disease (COPD), is common in patients with primary Sjögren's syndrome (pSS). As respiratory symptoms are also common in pSS patients and may have different etiologies, we wanted to evaluate the amount and impact of respiratory symptoms in out-patients with pSS and to assess if such symptoms are related to concomitant COPD. The St George's Respiratory Questionnaire (SGRQ) was used to assess respiratory symptoms. SGRQ scores were compared between 51 consecutive pSS patients, in an out-patient setting, and 80 population-based controls. The patients were also studied by pulmonary function tests and CT scans of the lungs to assess signs of obstructive airway disease, including COPD, as well as to assess signs of interstitial lung disease (ILD). 41 and 18% of pSS patients were found to have COPD and radiographic signs of ILD, respectively. pSS patients had significantly higher SGRQ scores compared to controls, but no significant differences in SGRQ scores were found between patients with and without COPD. Neither did the small group of pSS patients with ILD significantly differ in SGRQ scores in comparison to patients without ILD. Respiratory symptoms were common in pSS, but were not more common in patients with concomitant COPD. Since pulmonary involvement in pSS is associated with an increased mortality and respiratory symptoms is a poor marker for pulmonary involvement, we suggest that pulmonary function tests should be performed liberally in all pSS patients regardless of symptoms.

PD-L1 mAb Treats Ischemic Stroke by Controlling CNS Inflammation

PubMed Central

Bodhankar, Sheetal; Chen, Yingxin; Lapato, Andrew; Dotson, Abby L.; Wang, Jianming; Vandenbark, Arthur A.; Saugstad, Julie A.; Offner, Halina

2015-01-01

Background and Purpose Both pathogenic and regulatory immune processes are involved in the middle cerebral artery occlusion (MCAO) model of experimental stroke, including interactions involving the Programmed Death 1 (PD-1) receptor and its two ligands, PD-L1 and PD-L2. Although PD-1 reduced stroke severity, PD-L1 and PD-L2 appeared to play pathogenic roles, suggesting use of anti-PD-L monoclonal Ab (mAb) therapy for MCAO. Methods Male C57BL/6 mice were treated with a single dose of anti-PD-L1 mAb 4 h after MCAO and evaluated for clinical, histological and immunological changes after 96 h reperfusion. Results Blockade of the PD-L1 checkpoint using a single injection of 200μg anti-PD-L1 mAb given i.v. 4 h after occlusion significantly reduced MCAO infarct volumes and improved neurological outcomes after 96 h reperfusion. Treatment partially reversed splenic atrophy and decreased CNS infiltrating immune cells concomitant with enhanced appearance of CD8+ regulatory T cells in the lesioned CNS hemisphere. Conclusions This study demonstrates for the first time the beneficial therapeutic effects of PD-L1 checkpoint blockade on MCAO, thus validating proposed mechanisms obtained in our previous studies using PD-1 and PD-L deficient mice. These results provide strong support for use of available humanized anti-PD-L1 antibodies for treatment of human stroke subjects. PMID:26306753

Gestational outcomes in patients with neuropsychiatric systemic lupus erythematosus.

PubMed

de Jesus, G R; Rodrigues, B C; Lacerda, M I; Dos Santos, F C; de Jesus, N R; Klumb, E M; Levy, R A

2017-04-01

This study analyzed maternal and fetal outcomes of pregnancies of neuropsychiatric systemic lupus erythematosus patients followed in a reference unit. This retrospective cohort study included 26 pregnancies of patients seen between 2011 and 2015 included with history and/or active neuropsychiatric systemic lupus erythematosus among 135 pregnancies. Three patients had active neuropsychiatric systemic lupus erythematosus at conception, but only one remained with neurological activity during gestation, characteristically related to the inadvertent suspension of medications. Twenty six percent of the newborns were small for gestational age and 40% of live births were premature, with no neonatal death or early complications of prematurity. Preeclampsia was diagnosed in nine pregnancies, with two cases of early severe form that resulted in intrauterine fetal death. Patients with neuropsychiatric systemic lupus erythematosus had more prematurity and preeclampsia compared to patients without neuropsychiatric disease. However, when concomitant lupus nephritis was excluded, the gestational results of neuropsychiatric systemic lupus erythematosus patients were more favorable.

Impact of State Ignition Interlock Laws on Alcohol-Involved Crash Deaths in the United States

PubMed Central

Wiebe, Douglas J.

2016-01-01

Objectives. To investigate the impact on alcohol-involved crash deaths of universal ignition interlock requirements, which aim to prevent people convicted of driving under the influence of alcohol from driving while intoxicated. Methods. We used data from the National Highway Traffic Safety Administration for 1999 to 2013. From 2004 to 2013, 18 states made interlocks mandatory for all drunk-driving convictions. We compared alcohol-involved crash deaths between 18 states with and 32 states without universal interlock requirements, accounting for state and year effects, and for clustering within states. Results. Policy impact was apparent 3 years after implementation. The adjusted rate of alcohol-involved crash deaths was 4.7 (95% confidence interval [CI] = 4.0, 5.4) per 100 000 in states with the universal interlock requirement, compared with 5.5 (95% CI = 5.48, 5.53) in states without, an absolute reduction of 0.8 (95% CI = 0.1, 1.5) deaths per 100 000 per year. Conclusions. Requiring ignition interlocks for all drunk-driving convictions was associated with 15% fewer alcohol-involved crash deaths, compared with states with less-stringent requirements. Interlocks are a life-saving technology that merit wider use. PMID:26985604

Caspase-independent cell death mediated by apoptosis-inducing factor (AIF) nuclear translocation is involved in ionizing radiation induced HepG2 cell death

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Hengwen; Yang, Shana; Li, Jianhua

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. The aim of radiotherapy is to eradicate cancer cells with ionizing radiation. Except for the caspase-dependent mechanism, several lines of evidence demonstrated that caspase-independent mechanism is directly involved in the cell death responding to irradiation. For this reason, defining the contribution of caspase-independent molecular mechanisms represents the main goal in radiotherapy. In this study, we focused on the role of apoptosis-inducing factor (AIF), the caspase-independent molecular, in ionizing radiation induced hepatocellular carcinoma cell line (HepG2) cell death. We found that ionizing radiation has no function on AIF expressionmore » in HepG2 cells, but could induce AIF release from the mitochondria and translocate into nuclei. Inhibition of AIF could reduce ionizing radiation induced HepG2 cell death. These studies strongly support a direct relationship between AIF nuclear translocation and radiation induced cell death. What's more, AIF nuclear translocation is caspase-independent manner, but not caspase-dependent manner, in this process. These new findings add a further attractive point of investigation to better define the complex interplay between caspase-independent cell death and radiation therapy. - Highlights: • AIF nuclear translocation is involved in ionizing radiation induced hepatocellular carcinoma cell line HepG2 cell death. • AIF mediated cell death induced by ionizing radiation is caspase-independent. • Caspase-independent pathway is involved in ionzing radiation induced HepG2 cell death.« less

Trends in Deaths Involving Heroin and Synthetic Opioids Excluding Methadone, and Law Enforcement Drug Product Reports, by Census Region - United States, 2006-2015.

PubMed

O'Donnell, Julie K; Gladden, R Matthew; Seth, Puja

2017-09-01

Opioid overdose deaths quadrupled from 8,050 in 1999 to 33,091 in 2015 and accounted for 63% of drug overdose deaths in the United States in 2015. During 2010-2015, heroin overdose deaths quadrupled from 3,036 to 12,989 (1). Sharp increases in the supply of heroin and illicitly manufactured fentanyl (IMF) are likely contributing to increased deaths (2-6). CDC examined trends in unintentional and undetermined deaths involving heroin or synthetic opioids excluding methadone (i.e., synthetic opioids)* by the four U.S. Census regions during 2006-2015. Drug exhibits (i.e., drug products) obtained by law enforcement and reported to the Drug Enforcement Administration's (DEA's) National Forensic Laboratory Information System (NFLIS) that tested positive for heroin or fentanyl (i.e., drug reports) also were examined. All U.S. Census regions experienced substantial increases in deaths involving heroin from 2006 to 2015. Since 2010, the South and West experienced increases in heroin drug reports, whereas the Northeast and Midwest experienced steady increases during 2006-2015. † In the Northeast, Midwest, and South, deaths involving synthetic opioids and fentanyl drug reports increased considerably after 2013. These broad changes in the U.S. illicit drug market highlight the urgent need to track illicit drugs and enhance public health interventions targeting persons using or at high risk for using heroin or IMF.

26 CFR 20.2014-4 - Application of credit in cases involving a death tax convention.

Code of Federal Regulations, 2010 CFR

2010-04-01

... death tax convention. 20.2014-4 Section 20.2014-4 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT... 16, 1954 Credits Against Tax § 20.2014-4 Application of credit in cases involving a death tax... section 2014, whichever is the more beneficial to the estate. For cases where credit may be taken under...

Total brain death: a reply to Alan Shewmon.

PubMed

Lee, Patrick; GriseZ, Germain

2012-06-01

D. Alan Shewmon has advanced a well-documented challenge to the widely accepted total brain death criterion for death of the human being. We show that Shewmon’s argument against this criterion is unsound, though he does refute the standard argument for that criterion. We advance a distinct argument for the total brain death criterion and answer likely objections. Since human beings are rational animals--sentient organisms of a specific type--the loss of the radical capacity for sentience (the capacity to sense or to develop the capacity to sense) involves a substantial change, the passing away of the human organism. In human beings total brain death involves the complete loss of the radical capacity for sentience, and so in human beings total brain death is death.

Synergistic effect of apoptosis and necroptosis inhibitors in cisplatin-induced nephrotoxicity.

PubMed

Tristão, Vivian Regina; Pessoa, Edson A; Nakamichi, Renata; Reis, Luciana A; Batista, Marcelo Costa; Durão Junior, Marcelino de Souza; Monte, Júlio Cesar Martins

2016-01-01

Necroptosis is a nonapoptotic cell death pathway. We aim to study the effect of necrostatin-1 (a specific necroptosis inhibitor) in cisplatin-induced injury. We analyzed the effect of the combined use of inhibitors of apoptosis (z-vad) and necroptosis (necrostatin-1) in acute kidney injury by cisplatin in human proximal tubule cells. Our results showed moderate effectiveness in cytoprotection after treatment with z-vad. But the concomitant use of inhibitors (z-vad and necrostatin-1) presented synergistic and additive protection. The present study analyzed the caspase-3 activity and we observed a significant decrease in the group treated with z-vad and cisplatin. However we did not observe changes in the group treated with both inhibitors (z-vad and necrostatin-1) and cisplatin. Thus, demonstrating that necroptosis is a caspase-independent mechanism. We also analyzed the effect of necrostatin-1 in vivo model. C57BL/6 mice were treated with cisplatin and/or inhibitors. The concomitant use of inhibitors (z-vad and necrostatin-1) recovered renal function and decreased levels of urinary Ngal. Additionally, we analyzed the expression of RIP-1, a specific marker for necroptosis. In animals treated with cisplatin and z-VAD levels of RIP-1 were higher. This result reinforces that necroptosis occurs only in conditions where apoptosis was blocked. However, the use of both inhibitors (z-vad and necrostatin-1) provided additional protection. In conclusion, our study has a significant potential to show in vitro and in vivo protection obtained by necrostatin-1. Therefore, our results suggest that necroptosis may be an important mechanism of cell death after kidney injury.

The Janus-faced role of ezrin in "linking" cells to either normal or metastatic phenotype.

PubMed

Brambilla, Daria; Fais, Stefano

2009-11-15

In the majority of eukaryotic cells, the ezrin, radixin and moesin (ERM) proteins are involved in many physiologic functions including regulation of actin cytoskeleton, control of cell shape, adhesion, motility and modulation of signal transduction pathways. In a previous study, we used a dominant negative ezrin-mutant to address ezrin involvement in remodeling of actin cytoskeleton and subsequently we depicted ezrin key role in melanoma cell migration and progression. Herein, we highlight recent advances on ezrin involvement in the metastatic phenomenon, including also some more neglected ezrin-related functions. Novel molecular processes driven by ezrin activation include: phagocytosis, acquisition of resistance to chemotherapeutics and triggering of programmed cell death signals. Recent data support an integrated role of ezrin also in development of tumor malignancy. On one hand, ezrin may be responsible of deranged execution of specific known functions such as adhesion and motility and on the other, it may also participate to unique metastatic determinants, through the establishment of aberrant linkages with tumor-related proteins. For instance, ezrin misslocalization, absence or deranged activity has started to be correlated with tumor progression in many tumors of different species, including humans. Concomitantly, ezrin may act simultaneously as a regulatory or deregulatory chaperon in both normal and tumor cells. It is still to be established whether this Janus-faced feature of ezrin is due to some unknown transforming Zelig-like property or to the fact that a tumor-associated molecule preferentially links to ezrin thus distracting it from its normal connections. However, the contribution of ezrin functional deregulation to the acquisition of the metastatic phenotype appears clear and ezrin or ezrin aberrant associations may represent good candidates for future anti-tumor therapies.

Necroptosis-like Neuronal Cell Death Caused by Cellular Cholesterol Accumulation.

PubMed

Funakoshi, Takeshi; Aki, Toshihiko; Tajiri, Masateru; Unuma, Kana; Uemura, Koichi

2016-11-25

Aberrant cellular accumulation of cholesterol is associated with neuronal lysosomal storage disorders such as Niemann-Pick disease Type C (NPC). We have shown previously that l-norephedrine (l-Nor), a sympathomimetic amine, induces necrotic cell death associated with massive cytoplasmic vacuolation in SH-SY5Y human neuroblastoma cells. To reveal the molecular mechanism underling necrotic neuronal cell death caused by l-Nor, we examined alterations in the gene expression profile of cells during l-Nor exposure. DNA microarray analysis revealed that the gene levels for cholesterol transport (LDL receptor and NPC2) as well as cholesterol biosynthesis (mevalonate pathway enzymes) are increased after exposure to 3 mm l-Nor for ∼6 h. Concomitant with this observation, the master transcriptional regulator of cholesterol homeostasis, SREBP-2, is activated by l-Nor. The increase in cholesterol uptake as well as biosynthesis is not accompanied by an increase in cholesterol in the plasma membrane, but rather by aberrant accumulation in cytoplasmic compartments. We also found that cell death by l-Nor can be suppressed by nec-1s, an inhibitor of a regulated form of necrosis, necroptosis. Abrogation of SREBP-2 activation by the small molecule inhibitor betulin or by overexpression of dominant-negative SREBP-2 efficiently reduces cell death by l-Nor. The mobilization of cellular cholesterol in the presence of cyclodextrin also suppresses cell death. These results were also observed in primary culture of striatum neurons. Taken together, our results indicate that the excessive uptake as well as synthesis of cholesterol should underlie neuronal cell death by l-Nor exposure, and suggest a possible link between lysosomal cholesterol storage disorders and the regulated form of necrosis in neuronal cells. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Necroptosis-like Neuronal Cell Death Caused by Cellular Cholesterol Accumulation*

PubMed Central

Funakoshi, Takeshi; Aki, Toshihiko; Tajiri, Masateru; Unuma, Kana; Uemura, Koichi

2016-01-01

Aberrant cellular accumulation of cholesterol is associated with neuronal lysosomal storage disorders such as Niemann-Pick disease Type C (NPC). We have shown previously that l-norephedrine (l-Nor), a sympathomimetic amine, induces necrotic cell death associated with massive cytoplasmic vacuolation in SH-SY5Y human neuroblastoma cells. To reveal the molecular mechanism underling necrotic neuronal cell death caused by l-Nor, we examined alterations in the gene expression profile of cells during l-Nor exposure. DNA microarray analysis revealed that the gene levels for cholesterol transport (LDL receptor and NPC2) as well as cholesterol biosynthesis (mevalonate pathway enzymes) are increased after exposure to 3 mm l-Nor for ∼6 h. Concomitant with this observation, the master transcriptional regulator of cholesterol homeostasis, SREBP-2, is activated by l-Nor. The increase in cholesterol uptake as well as biosynthesis is not accompanied by an increase in cholesterol in the plasma membrane, but rather by aberrant accumulation in cytoplasmic compartments. We also found that cell death by l-Nor can be suppressed by nec-1s, an inhibitor of a regulated form of necrosis, necroptosis. Abrogation of SREBP-2 activation by the small molecule inhibitor betulin or by overexpression of dominant-negative SREBP-2 efficiently reduces cell death by l-Nor. The mobilization of cellular cholesterol in the presence of cyclodextrin also suppresses cell death. These results were also observed in primary culture of striatum neurons. Taken together, our results indicate that the excessive uptake as well as synthesis of cholesterol should underlie neuronal cell death by l-Nor exposure, and suggest a possible link between lysosomal cholesterol storage disorders and the regulated form of necrosis in neuronal cells. PMID:27756839

A case of pediatric B-Lymphoblastic leukemia presenting with a t(9;12)(p24;q11.2) involving JAK2 and concomitant MLL rearrangement with apparent insertion at 6q27

PubMed Central

2013-01-01

Background B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy in pediatric patients and the leading cause of cancer-related death in children and young adults. Translocations of 9p24 involving JAK2 (9p24) and gain-of-function mutations of JAK2 with subsequent activation of the JAK2 kinase have been described in several hematological malignancies including B-ALL. However, rearrangements involving JAK2 are rare in B-ALL as only few cases have been described in the literature. Findings Herein, we present a case of pediatric B-ALL whose conventional cytogenetics revealed an abnormal karyotype with a reciprocal translocation involving 9p24 (JAK2) and 12p11.2. Fluorescence in situ hybridization (FISH) studies using the RP11-927H16 Spectrum Green JAK2 probe on previously G-banded metaphases confirmed the involvement of JAK2 in this rearrangement. Further FISH studies on the same previously G-banded metaphases using the LSI MLL probe helped to characterize an insertion of MLL into 6q27 as an additional abnormality in this karyotype. FISH studies performed on interphase nuclei also revealed an abnormal clone with MLL rearrangements in 23.6% of the nuclei examined as well as an abnormal clonal population with a deletion of the 5'IGH@ region in 88.3% of the nuclei examined. Conclusions Rearrangements of 9p24 can result in constitutive activation of JAK2, and have been observed in B-ALL. Rearrangements of the MLL gene have also been described extensively in B-ALL. However, rearrangements of MLL with a partner at 6q27 and in conjunction with a translocation involving JAK2 have not been previously described. This case pinpoints the importance of FISH and conventional cytogenetics to characterize complex rearrangements in which JAK2 and MLL are involved. The therapeutic targeting of JAK2 and MLL in cases like this may be prognostically beneficial. PMID:24274401

Alcohol involvement in opioid pain reliever and benzodiazepine drug abuse-related emergency department visits and drug-related deaths - United States, 2010.

PubMed

Jones, Christopher M; Paulozzi, Leonard J; Mack, Karin A

2014-10-10

The abuse of prescription drugs has led to a significant increase in emergency department (ED) visits and drug-related deaths over the past decade. Opioid pain relievers (OPRs) and benzodiazepines are the prescription drugs most commonly involved in these events. Excessive alcohol consumption also accounts for a significant health burden and is common among groups that report high rates of prescription drug abuse. When taken with OPRs or benzodiazepines, alcohol increases central nervous system depression and the risk for overdose. Data describing alcohol involvement in OPR or benzodiazepine abuse are limited. To quantify alcohol involvement in OPR and benzodiazepine abuse and drug-related deaths and to inform prevention efforts, the Food and Drug Administration (FDA) and CDC analyzed 2010 data for drug abuse-related ED visits in the United States and drug-related deaths that involved OPRs and alcohol or benzodiazepines and alcohol in 13 states. The analyses showed alcohol was involved in 18.5% of OPR and 27.2% of benzodiazepine drug abuse-related ED visits and 22.1% of OPR and 21.4% of benzodiazepine drug-related deaths. These findings indicate that alcohol plays a significant role in OPR and benzodiazepine abuse. Interventions to reduce the abuse of alcohol and these drugs alone and in combination are needed.

Major Vascular Abutment, Involvement or Encasement is not a Contraindication to Pancreatic Endocrine Tumor Resection

PubMed Central

Norton, Jeffrey A.; Harris, E. John; Chen, Yijun; Visser, Brendan C; Poultsides, George A; Kunz, Pamela C.; Fisher, George A; Jensen, Robert.T.

2010-01-01

Background There is considerable controversy about the treatment of patients with malignant functional or nonfunctional pancreatic endocrine tumors (PETs). Aggressive surgery with dissection and/or reconstruction of major vascular structures is a potentially efficacious antitumor therapy, but is rarely performed, and considered a contraindication to surgery by many. Hypothesis Aggressive resection of locally advanced PETs in which preoperative studies suggest major vascular involvement can be performed with acceptable morbidity and mortality rates and may lead to extended survival. Design The combined databases of the prospective NIH study on PETs (gastrinomas) (from 1982) and Stanford (all PETs)(from 2004) were queried. All patients with possible involvement of major vascular structures were reviewed and preoperative studies, operative findings and surgical results/outcomes correlated. Main Outcome Measures Surgical procedure, pathologic characteristics, complications, mortality rates, and disease-free and overall survival rates. Results Of 273 patients with PETs, 46 (17%) had preoperative CT evidence of major vascular involvement. There were 21 men (45%). Mean age was 42 years (range 24-76). 32 (57%) had functional tumors with 30 gastrinomas and 2 glucagonomas; the remainder (n=14) had nonfunctional PETs. 12 patients (26%) had MEN-1. 44 of 46 underwent surgery. The mean size for the primary PET on preoperative CT was 5.8 cm. The involved major vessel was as follows: portal vein (n=20, 43%), SMV or SMA (n=16, 35%), IVC (n=4, 9%), splenic vein (n=4, 9%) and heart (n=2, 4%). 42 (91%) patients had PET removed: 12 (27%) primary only, 30 (68%) with lymph nodes, and 18 (41%) with liver metastases. PETs were removed by either enucleation (n=5, 12%) or resection (n=36, 86%). Resections included distal or subtotal pancreatectomy in 23 (55%), Whipple in 10 (23%) and total in 2 (5%). 19 (45%) patients had concomitant liver resection: 10 (23%) wedge resection and 9 (21%) anatomic resections (lobectomy or trisegmentectomy). 9 (21%) had vascular reconstruction: each had reconstruction of the SMV and portal vein, while 1 had concomitant reconstruction of the SMA. There were no deaths, but 12 (28%) had complications. 18 (42%) were immediately disease-free and 5 recurred with follow-up leaving 14 (33%) long-term disease-free. The 10-year overall survival was 60%. Functional tumors had a better overall survival (p<0.0001), and liver metastases decreased overall survival (p<0.0001). Conclusions Aggressive surgery including superior mesenteric vein reconstruction, and liver resection can be done with acceptable morbidity and mortality rates for patients with advanced PETs. Although survival rates following surgery are excellent, most patients will develop recurrence. These findings suggest that surgical resection is indicated even in PETs with vascular invasion and nodal or distant metastases. Distant metastases decrease the probability of long-term survival, still 60% are alive at 10 years and one third remain disease-free. PMID:21690450

Structured Discretion, Racial Bias, and the Death Penalty: The First Decade after "Furman" in Texas.

ERIC Educational Resources Information Center

Ekland-Olson, Sheldon

1988-01-01

Analyzes data collected in Texas from the first decade of cases sentenced to death after the Furman v. Georgia decision in order to determine any tendency toward being race-linked or victim-based. Found that cases involving White victims more often precipitate the death penalty than those involving Black or Hispanic victims. (KO)

Coronary artery aneurysm combined with other multiple aneurysms at multiple locations: A case report and systematic review.

PubMed

Jiang, Li-Cheng; Cao, Jia-Yu; Chen, Mao

2017-12-01

Coronary artery aneurysm (CAA) with concomitant aneurysms at multiple sites is quite unusual and rare. The characteristics and the etiology of this phenomenon are unknown. Herein, we present a case with right coronary aneurysm with concomitant abdominal aorta as well as right renal artery aneurysm. A systematic review of the literatures regarding CAA with other coexisting aneurysms at multiple locations was also conducted on Medline and Embase databases. A total of 76 patients (male gender: 58; age: 37.4 ± 26.5) including the present case were included in the final study. The most common etiology of CAA with multiple aneurysms was Kawasaki (43.3%) and atherosclerotic disease (16.4%). CAA was the most frequently found at the right coronary artery (62.7%), following, left anterior descending (51%), left main (43.1%), and left circumflex (35.3%). The most common concomitant aneurysms were abdominal aorta (52.6%) and iliac artery (50%). In addition, 60.5% of the patients had an involved bilateral peripheral artery. CAA with coexisting systemic aneurysms in multiple sites is quite rare. And it usually involves multiple aneurysms at the coronary and bilateral peripheral arteries simultaneously. Currently, there are no general consensus regarding the clinical characteristics, diagnostic method, and treatment of these cases. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Florida's weakened motorcycle helmet law: effects on death rates in motorcycle crashes.

PubMed

Kyrychenko, Sergey Y; McCartt, Anne T

2006-03-01

Effective July 1, 2000, Florida's universal helmet law was amended to exclude riders ages 21 and older with insurance coverage providing at least 10,000 US dollars in medical benefits for injuries sustained in a motorcycle crash. Observed helmet use in Florida was reported to have declined from nearly 100% in 1998, before the law change, to 53% after. This study examined the effects of the law change on the likelihood of death, given involvement in a motorcycle crash. Rates of motorcyclist deaths per crash involvement in Florida for 2001-2002 (after the law change) were compared with those for 1998-1999 (before the law change). Before/after death rate ratios (95% CIs) were examined, and logistic regression models estimated the effect of the helmet law change on the odds of death in a crash, while controlling for rider gender, age, and seating position, and number of vehicles. The motorcyclist death rate increased significantly after the law change, from 30.8 to 38.8 deaths per 1,000 crash involvements. Motorcyclist death rates increased for single- and multiple-vehicle crashes, for male and female operators, and for riders of all ages including those younger than 21. After controlling for gender and age, the likelihood of death given involvement in a motorcycle crash was 25% higher than expected after the law change. It is estimated that 117 motorcyclist deaths could have been avoided during 2001-2002 if Florida's universal helmet law had remained in place. This study provides evidence of the life-saving benefits of universal helmet laws. The results also suggest that age-specific helmet laws are not effective in protecting the youngest drivers. This is not surprising, as these laws are largely unenforceable.

Macrophage Migration Inhibitory Factor Release by Macrophages after Ingestion of Plasmodium chabaudi-Infected Erythrocytes: Possible Role in the Pathogenesis of Malarial Anemia

PubMed Central

Martiney, James A.; Sherry, Barbara; Metz, Christine N.; Espinoza, Marisol; Ferrer, Angel S.; Calandra, Thierry; Broxmeyer, Hal E.; Bucala, Richard

2000-01-01

Human falciparum malaria, caused by Plasmodium falciparum infection, results in 1 to 2 million deaths per year, mostly children under the age of 5 years. The two main causes of death are severe anemia and cerebral malaria. Malarial anemia is characterized by parasite red blood cell (RBC) destruction and suppression of erythropoiesis (the mechanism of which is unknown) in the presence of a robust host erythropoietin response. The production of a host-derived erythropoiesis inhibitor in response to parasite products has been implicated in the pathogenesis of malarial anemia. The identity of this putative host factor is unknown, but antibody neutralization studies have ruled out interleukin-1β, tumor necrosis factor alpha, and gamma interferon while injection of interleukin-12 protects susceptible mice against lethal P. chabaudi infection. In this study, we report that ingestion of P. chabaudi-infected erythrocytes or malarial pigment (hemozoin) induces the release of macrophage migration inhibitory factor (MIF) from macrophages. MIF, a proinflammatory mediator and counter-regulator of glucocorticoid action, inhibits erythroid (BFU-E), multipotential (CFU-GEMM), and granulocyte-macrophage (CFU-GM) progenitor-derived colony formation. MIF was detected in the sera of P. chabaudi-infected BALB/c mice, and circulating levels correlated with disease severity. Liver MIF immunoreactivity increased concomitant with extensive pigment and parasitized RBC deposition. Finally, MIF was elevated three- to fourfold in the spleen and bone marrow of P. chabaudi-infected mice with active disease, as compared to early disease, or of uninfected controls. In summary, the present results suggest that MIF may be a host-derived factor involved in the pathophysiology of malaria anemia. PMID:10722628

The repair of a type Ia endoleak following thoracic endovascular aortic repair using a stented elephant trunk procedure.

PubMed

Qi, Rui-Dong; Zhu, Jun-Ming; Liu, Yong-Min; Chen, Lei; Li, Cheng-Nan; Xing, Xiao-Yan; Sun, Li-Zhong

2018-04-01

Type Ia endoleaks are not uncommon complications that occur after thoracic endovascular aortic repair (TEVAR). Because aortic arch vessels prevent extension of the landing zone, it is very difficult to manipulate a type Ia endoleak using an extension cuff or stent-graft, especially when the aortic arch is involved. Here, we retrospectively review our experience of surgical treatment of type Ia endoleak after TEVAR using a stented elephant trunk procedure. From July 2010 to August 2016, we treated 17 patients diagnosed with a type Ia endoleak following TEVAR using stented elephant trunk procedure. The mean age of our patients was 52 ± 8 years. The mean interval between TEVAR and the open surgical repair was 38 ± 43 months. All cases of type Ia endoleak (100%) were repaired successfully. There were no in-hospital deaths. One case required reintubation and continuous renal replacement therapy due to renal failure; this patient recovered smoothly before discharge. One other patient suffered a stroke and renal failure and did not fully recover following discharge, or follow-up. During follow-up, there were 3 deaths. Acceptable results were obtained using a stented elephant trunk procedure in patients with a type Ia endoleak after TEVAR. This technique allowed us to repair the proximal aortic arch lesions, surgically correct the type Ia endoleak, and promote false lumen thrombosis in the distal aorta. Implantation of a stented elephant trunk, with or without a concomitant aortic arch procedure, is an alternative approach for this type of lesion. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Overcoming 'ageism' bias in the treatment of hypercholesterolaemia : a review of safety issues with statins in the elderly.

PubMed

Jacobson, Terry A

2006-01-01

Atherosclerosis is a progressive, lifelong condition that is the leading cause of death among middle-aged and elderly individuals aged > or =65 years. Up to 80% of elderly patients are found to have evidence of obstructive coronary heart disease at autopsy. Demographic trends, including the advancing median age and life expectancy of Western societies, suggest that a large share of the burden of atherosclerotic plaque is likely to be borne by elderly individuals. These trends are in part due to increases in a number of chronic diseases associated with adverse cardiovascular outcomes, including metabolic syndrome, diabetes mellitus and chronic kidney disease. Because the elderly have a higher attributable risk of coronary heart disease as a result of hypercholesterolaemia, more coronary deaths and overall events can be prevented via treatment in this age group compared with younger persons with hypercholesterolaemia. The efficacy, safety and tolerability of HMG-CoA reductase inhibitors (statins) have been confirmed in randomised, controlled, multicentre trials involving large numbers of patients aged > or =65 years. Although muscle symptoms such as myalgia are relatively common adverse events, more severe signs of myolysis such as myopathy and rhabdomyolysis are rare, but their risk is elevated by conditions (e.g. concomitant medications) that increase the systemic exposure of these agents. Statins differ in their susceptibility to increases in systemic exposure, but most statins have been demonstrated to be well tolerated and safe when administered to elderly patients. These favourable clinical findings should help clinicians counter highly prevalent 'ageism' bias in statin prescribing, whereby elderly patients, particularly those at highest cardiovascular risk, are often denied the benefits of statins without any meaningful foundation.

Inflammatory Effects of the Plant Protection Product Stifenia (FEN560) on Vertebrates.

PubMed

Teyssier, Lény; Colussi, Julie; Delemasure, Stéphanie; Chluba, Johanna; Wendehenne, David; Lamotte, Olivier; Connat, Jean-Louis

2017-01-01

Plant defense stimulators (PDSs) rely on the activation of plant innate immunity in order to protect crops against various pests. These molecules are thought to be a safer alternative to classical plant protection products. Given that innate immune systems share common features in plants and vertebrates, PDS can potentially cross-react with innate immunity of non-target organisms. To test this hypothesis, we studied effects of the commercial PDS Stifenia (FEN560), which is composed of crushed fenugreek seeds. We tested various concentrations of Stifenia (0.03-1 mg mL -1 ) on human peripheral blood mononuclear cells and checked, 20 h later, cell metabolic activity (MA) using XTT assay, cell death by flow cytometry analysis, and IL-1β inflammatory cytokine released in the culture medium using ELISA. Stifenia induced a general decrease of the cell MA, which was concomitant with a dose-dependent release of IL-1β. Our results highlight the activation of human immune cells. The inflammatory effect of Stifenia was partially inhibited by pan-caspase inhibitor. Accordingly, Stifenia induced the release of p20 caspase-1 fragment into the culture medium suggesting the involvement of the NLRP3 inflammasome. Furthermore, we observed that Stifenia can induce cell death. We also tested the effect of Stifenia on Zebrafish larvae. After 24 h of exposure, Stifenia induced a dose-dependent IL-1β and TNFα gene expression. The human-cell-based approach developed in this work revealed a high sensitivity concerning inflammatory properties of a plant protection product. These tests could be routinely used to screen the potential adverse effects of this type of compounds. Finally, our results suggest a potential danger of using extensively certain PDS for crop protection.

Inflammatory Effects of the Plant Protection Product Stifenia (FEN560) on Vertebrates

PubMed Central

Teyssier, Lény; Colussi, Julie; Delemasure, Stéphanie; Chluba, Johanna; Wendehenne, David; Lamotte, Olivier; Connat, Jean-Louis

2017-01-01

Plant defense stimulators (PDSs) rely on the activation of plant innate immunity in order to protect crops against various pests. These molecules are thought to be a safer alternative to classical plant protection products. Given that innate immune systems share common features in plants and vertebrates, PDS can potentially cross-react with innate immunity of non-target organisms. To test this hypothesis, we studied effects of the commercial PDS Stifenia (FEN560), which is composed of crushed fenugreek seeds. We tested various concentrations of Stifenia (0.03–1 mg mL−1) on human peripheral blood mononuclear cells and checked, 20 h later, cell metabolic activity (MA) using XTT assay, cell death by flow cytometry analysis, and IL-1β inflammatory cytokine released in the culture medium using ELISA. Stifenia induced a general decrease of the cell MA, which was concomitant with a dose-dependent release of IL-1β. Our results highlight the activation of human immune cells. The inflammatory effect of Stifenia was partially inhibited by pan-caspase inhibitor. Accordingly, Stifenia induced the release of p20 caspase-1 fragment into the culture medium suggesting the involvement of the NLRP3 inflammasome. Furthermore, we observed that Stifenia can induce cell death. We also tested the effect of Stifenia on Zebrafish larvae. After 24 h of exposure, Stifenia induced a dose-dependent IL-1β and TNFα gene expression. The human-cell-based approach developed in this work revealed a high sensitivity concerning inflammatory properties of a plant protection product. These tests could be routinely used to screen the potential adverse effects of this type of compounds. Finally, our results suggest a potential danger of using extensively certain PDS for crop protection. PMID:28484691

The IKK Inhibitor Bay 11-7082 Induces Cell Death Independent from Inhibition of Activation of NFκB Transcription Factors

PubMed Central

Rauert-Wunderlich, Hilka; Siegmund, Daniela; Maier, Eduard; Giner, Tina; Bargou, Ralf C.; Wajant, Harald; Stühmer, Thorsten

2013-01-01

Multiple myeloma (MM) displays an NFκB activity-related gene expression signature and about 20% of primary MM samples harbor genetic alterations conducive to intrinsic NFκB signaling activation. The relevance of blocking the classical versus the alternative NFκB signaling pathway and the molecular execution mechanisms involved, however, are still poorly understood. Here, we comparatively tested NFκB activity abrogation through TPCA-1 (an IKK2 inhibitor), BAY 11-7082 (an IKK inhibitor poorly selective for IKK1 and IKK2), and MLN4924 (an NEDD8 activating enzyme (NAE)-inhibitor), and analyzed their anti-MM activity. Whereas TPCA-1 interfered selectively with activation of the classical NFκB pathway, the other two compounds inhibited classical and alternative NFκB signaling without significant discrimination. Noteworthy, whereas TPCA-1 and MLN4924 elicited rather mild anti-MM effects with slight to moderate cell death induction after 1 day BAY 11-7082 was uniformly highly toxic to MM cell lines and primary MM cells. Treatment with BAY 11-7082 induced rapid cell swelling and its initial effects were blocked by necrostatin-1 or the ROS scavenger BHA, but a lasting protective effect was not achieved even with additional blockade of caspases. Because MLN4924 inhibits the alternative NFκB pathway downstream of IKK1 at the level of p100 processing, the quite discordant effects between MLN4924 and BAY 11-7082 must thus be due to blockade of IKK1-mediated NFκB-independent necrosis-inhibitory functions or represent an off-target effect of BAY 11-7082. In accordance with the latter, we further observed that concomitant knockdown of IKK1 and IKK2 did not have any major short-term adverse effect on the viability of MM cells. PMID:23527154

Arabidopsis GRI is involved in the regulation of cell death induced by extracellular ROS.

PubMed

Wrzaczek, Michael; Brosché, Mikael; Kollist, Hannes; Kangasjärvi, Jaakko

2009-03-31

Reactive oxygen species (ROS) have important functions in plant stress responses and development. In plants, ozone and pathogen infection induce an extracellular oxidative burst that is involved in the regulation of cell death. However, very little is known about how plants can perceive ROS and regulate the initiation and the containment of cell death. We have identified an Arabidopsis thaliana protein, GRIM REAPER (GRI), that is involved in the regulation of cell death induced by extracellular ROS. Plants with an insertion in GRI display an ozone-sensitive phenotype. GRI is an Arabidopsis ortholog of the tobacco flower-specific Stig1 gene. The GRI protein appears to be processed in leaves with a release of an N-terminal fragment of the protein. Infiltration of the N-terminal fragment of the GRI protein into leaves caused cell death in a superoxide- and salicylic acid-dependent manner. Analysis of the extracellular GRI protein yields information on how plants can initiate ROS-induced cell death during stress response and development.

Arabidopsis GRI is involved in the regulation of cell death induced by extracellular ROS

PubMed Central

Wrzaczek, Michael; Brosché, Mikael; Kollist, Hannes; Kangasjärvi, Jaakko

2009-01-01

Reactive oxygen species (ROS) have important functions in plant stress responses and development. In plants, ozone and pathogen infection induce an extracellular oxidative burst that is involved in the regulation of cell death. However, very little is known about how plants can perceive ROS and regulate the initiation and the containment of cell death. We have identified an Arabidopsis thaliana protein, GRIM REAPER (GRI), that is involved in the regulation of cell death induced by extracellular ROS. Plants with an insertion in GRI display an ozone-sensitive phenotype. GRI is an Arabidopsis ortholog of the tobacco flower-specific Stig1 gene. The GRI protein appears to be processed in leaves with a release of an N-terminal fragment of the protein. Infiltration of the N-terminal fragment of the GRI protein into leaves caused cell death in a superoxide- and salicylic acid-dependent manner. Analysis of the extracellular GRI protein yields information on how plants can initiate ROS-induced cell death during stress response and development. PMID:19279211

p75 Neurotrophin Receptor Signaling Activates Sterol Regulatory Element-binding Protein-2 in Hepatocyte Cells via p38 Mitogen-activated Protein Kinase and Caspase-3.

PubMed

Pham, Dan Duc; Do, Hai Thi; Bruelle, Céline; Kukkonen, Jyrki P; Eriksson, Ove; Mogollón, Isabel; Korhonen, Laura T; Arumäe, Urmas; Lindholm, Dan

2016-05-13

Nerve growth factor (NGF) influences the survival and differentiation of a specific population of neurons during development, but its role in non-neuronal cells has been less studied. We observed here that NGF and its pro-form, pro-NGF, are elevated in fatty livers from leptin-deficient mice compared with controls, concomitant with an increase in low density lipoprotein receptors (LDLRs). Stimulation of mouse primary hepatocytes with NGF or pro-NGF increased LDLR expression through the p75 neurotrophin receptor (p75NTR). Studies using Huh7 human hepatocyte cells showed that the neurotrophins activate the sterol regulatory element-binding protein-2 (SREBP2) that regulates genes involved in lipid metabolism. The mechanisms for this were related to stimulation of p38 mitogen-activated protein kinase (p38 MAPK) and activation of caspase-3 and SREBP2 cleavage following NGF and pro-NGF stimulations. Cell fractionation experiments showed that caspase-3 activity was increased particularly in the membrane fraction that harbors SREBP2 and caspase-2. Experiments showed further that caspase-2 interacts with pro-caspase-3 and that p38 MAPK reduced this interaction and caused caspase-3 activation. Because of the increased caspase-3 activity, the cells did not undergo cell death following p75NTR stimulation, possibly due to concomitant activation of nuclear factor-κB (NF-κB) pathway by the neurotrophins. These results identify a novel signaling pathway triggered by ligand-activated p75NTR that via p38 MAPK and caspase-3 mediate the activation of SREBP2. This pathway may regulate LDLRs and lipid uptake particularly after injury or during tissue inflammation accompanied by an increased production of growth factors, including NGF and pro-NGF. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Rituximab-associated infections.

PubMed

Gea-Banacloche, Juan C

2010-04-01

After more than 10 years of use, rituximab has proven to be remarkably safe. However, accumulated evidence now suggests that under some circumstances it may significantly increase the risk of infections. This risk is difficult to quantify because of confounding factors (namely, concomitant use of immunosuppressive or chemotherapeutic agents and underlying conditions), as well as under-reporting. Increased number of infections has been documented in patients treated with maintenance rituximab for low-grade lymphoma and in patients with concomitant severe immunodeficiency, whether caused by human immunodeficiency virus (HIV) infection or immunosuppressive agents like fludarabine. From the practical standpoint, the most important infection is hepatitis B reactivation, which may be delayed and result in fulminant liver failure and death. Special care should be placed on screening for hepatitis B virus (HBV) and preemptive antiviral treatment. Some investigators have reported an increase in Pneumocystis pneumonia. Finally, there is increasing evidence of a possible association with progressive multifocal leukoencephalopathy (PML), a lethal encephalitis caused by the polyomavirus JC. This review enumerates the described infectious complications, summarizes the possible underlying mechanisms of the increased risk, and makes recommendations regarding prevention, diagnosis and management.

Use of PNA FISH for blood cultures growing Gram-positive cocci in chains without a concomitant antibiotic stewardship intervention does not improve time to appropriate antibiotic therapy.

PubMed

Cosgrove, Sara E; Li, David X; Tamma, Pranita D; Avdic, Edina; Hadhazy, Eric; Wakefield, Teresa; Gherna, Michael; Carroll, Karen C

2016-09-01

Peptide nucleic acid fluorescence in situ hybridization (PNA FISH) is a rapid diagnostic assay that can identify certain organisms growing in blood cultures 30-90 min from the time of positive Gram-stain. Existing studies have demonstrated a clinical utility with this assay when antibiotic stewardship programs assist clinicians with interpreting the results. However, the benefit of these rapid assays in the absence of concomitant antibiotic stewardship involvement is unclear. In this randomized study of 220 patients with enterococcal or streptococcal bacteremia, we found that PNA FISH, in the absence of concomitant input from an antibiotic stewardship program, had no impact on time to effective or optimal therapy, length of hospital stay, or in-hospital mortality. Our results suggest that in the absence of guidance from an antibiotic stewardship program, the clinical benefits of rapid diagnostic microbiological tools may be reduced. Copyright © 2016 Elsevier Inc. All rights reserved.

Onychomycosis of Toenails and Post-hoc Analyses with Efinaconazole 10% Solution Once-daily Treatment: Impact of Disease Severity and Other Concomitant Associated Factors on Selection of Therapy and Therapeutic Outcomes.

PubMed

Del Rosso, James Q

2016-02-01

Topical treatment for toenail onychomycosis has been fraught with a long-standing reputation of poor efficaey, primarily due to physical properties of the nail unit that impede drug penetration. Newer topical agents have been formulated as Solution, which appear to provide better therapeutic response in properly selected patients. It is important to recognize the impact the effects that mitigating and concomitant factors can have on efficaey. These factors include disease severity, gender, presence of tinea pedis, and diabetes. This article reviews results achieved in Phase 3 pivotal studies with topical efinaconazole 10% Solution applied once daily for 48 weeks with a focus on how the aforementioned factors influenced therapeutic outcomes. It is important for clinicians treating patients for onychomycosis to evaluate severity, treat concomitant tinea pedis, address control of diabetes if present by encouraging involvement of the patient's primary care physician, and consider longer treatment courses when clinically relevant.

Tracheomalacia and recurrent exacerbations of chronic obstructive pulmonary disease: a case report and review of the literature

PubMed Central

Kerolus, Ghaly; Ikladios, Ossama

2016-01-01

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of disability and death worldwide. COPD exacerbation is usually treated with antibiotics, systemic corticosteroids, and inhaled bronchodilators. We present a case of recurrent COPD exacerbation that was treated repeatedly with standard therapy. Dynamic expiratory computed tomography of the chest was done, which revealed concomitant tracheomalacia. COPD and tracheomalacia may coexist during recurrent exacerbations of COPD, and delayed diagnosis can be associated with severe comorbidities. Ordering the appropriate imaging may aid in the correct diagnosis and facilitate appropriate management. PMID:27987292

Correlates of a good death and the impact of hospice involvement: findings from the national survey of households affected by cancer.

PubMed

Cagle, John G; Pek, Jolynn; Clifford, Maggie; Guralnik, Jack; Zimmerman, Sheryl

2015-03-01

Knowing how to improve the dying experience for patients with end-stage cancer is essential for cancer professionals. However, there is little evidence on the relationship between clinically relevant factors and quality of death. Also, while hospice has been linked with improved outcomes, our understanding of factors that contribute to a "good death" when hospice is involved remains limited. This study (1) identified correlates of a good death and (2) provided evidence on the impact of hospice on quality of death. Using data from a survey of US households affected by cancer (N = 930, response rate 51 %), we fit regression models with a subsample of 158 respondents who had experienced the death of a family member with cancer. Measures included quality of death (good/bad) and clinically relevant factors including: hospice involvement, symptoms during treatment, whether wishes were followed, provider knowledge/expertise, and compassion. Respondents were 60 % female, 89 % White, and averaged 57 years old. Decedents were most often a respondent's spouse (46 %). While 73 % of respondents reported a good death, Hispanics were less likely to experience good death (p = 0.007). Clinically relevant factors, including hospice, were associated with good death (p < 0.05)--an exception being whether the physician said the cancer was curable/fatal. With adjustments, perceptions of provider knowledge/expertise was the only clinical factor that remained associated with good death. Enhanced provider training/communication, referrals to hospice and greater attention to symptom management may facilitate improved quality of dying. Additionally, the cultural relevance of the concept of a "good death" warrants further research.

Real World Evidence for Regulatory Decisions: Concomitant Administration of Zoster Vaccine Live and Pneumococcal Polysaccharide Vaccine.

PubMed

Bruxvoort, Katia; Sy, Lina S; Luo, Yi; Tseng, Hung Fu

2018-04-11

The US Food and Drug Administration is charged with expanding the use of real world evidence (RWE) for regulatory decisions. As a test case for RWE to support regulatory decisions, we present the scenario of concomitant vaccination with zoster vaccine live (ZVL) and 23-valent pneumococcal polysaccharide vaccine (PPSV23). The prescribing information states that these vaccines should not be given concurrently, based on a small trial using varicella zoster virus antibody levels as a correlate of ZVL efficacy, even though ZVL protects against herpes zoster via cell-mediated immunity. We conducted an observational cohort study involving >30,000 members of Kaiser Permanente Southern California receiving concomitant ZVL and PPSV23 versus PPSV23 prior to ZVL. Occurrence of herpes zoster was assessed through electronic health records from January 1, 2007 to June 30, 2016. The adjusted hazard ratio comparing incidence rates of herpes zoster in the concomitant vaccination cohort and the prior vaccination cohort was 1.04 (95% CI: 0.92, 1.16). This RWE study provides direct evidence for a lack of vaccine interference, relying on herpes zoster occurrence rather than an intermediate marker of immunity. RWE is essential for regulators and policy makers in addressing evidentiary gaps regarding safety, effectiveness, compliance, and vaccine interactions for the new recombinant zoster vaccine.

Early differential cell death and survival mechanisms initiate and contribute to the development of OPIDN: A study of molecular, cellular, and anatomical parameters

DOE Office of Scientific and Technical Information (OSTI.GOV)

Damodaran, T.V., E-mail: tdamodar@nccu.edu; Pharmacology and Cancer biology, Duke University Medical Center, Durham, NC; Dept of Biology, North Carolina Central University, Durham, NC 27707

Organophosphorus-ester induced delayed neurotoxicity (OPIDN) is a neurodegenerative disorder characterized by ataxia progressing to paralysis with a concomitant central and peripheral, distal axonapathy. Diisopropylphosphorofluoridate (DFP) produces OPIDN in the chicken that results in mild ataxia in 7-14 days and severe paralysis as the disease progresses with a single dose. White leghorn layer hens were treated with DFP (1.7 mg/kg, sc) after prophylactic treatment with atropine (1 mg/kg, sc) in normal saline and eserine (1 mg/kg, sc) in dimethyl sulfoxide. Control groups were treated with vehicle propylene glycol (0.1 ml/kg, sc), atropine in normal saline and eserine in dimethyl sulfoxide. Themore » hens were euthanized at different time points such as 1, 2, 5, 10 and 20 days, and the tissues from cerebrum, midbrain, cerebellum, brainstem and spinal cord were quickly dissected and frozen for mRNA (northern) studies. Northern blots were probed with BCL2, GADD45, beta actin, and 28S RNA to investigate their expression pattern. Another set of hens was treated for a series of time points and perfused with phosphate buffered saline and fixative for histological studies. Various staining protocols such as Hematoxylin and Eosin (H and E); Sevier-Munger; Cresyl echt Violet for Nissl substance; and Gallocynin stain for Nissl granules were used to assess various patterns of cell death and degenerative changes. Complex cell death mechanisms may be involved in the neuronal and axonal degeneration. These data indicate altered and differential mRNA expressions of BCL2 (anti apoptotic gene) and GADD45 (DNA damage inducible gene) in various tissues. Increased cell death and other degenerative changes noted in the susceptible regions (spinal cord and cerebellum) than the resistant region (cerebrum), may indicate complex molecular pathways via altered BCL2 and GADD45 gene expression, causing the homeostatic imbalance between cell survival and cell death mechanisms. Semi quantitative analysis revealed that the order of severity of damage declines from the spino-cerebellar, ventral, and dorsal tract respectively, suggesting neuroanatomical specificity. Thus, early activation of cell death and cell survival processes may play significant role in the clinical progression and syndromic clinical feature presentation of OPIDN. -- Highlights: Black-Right-Pointing-Pointer Multiple mechanisms of neurodegeneration were indicated in a study on OPIDN model. Black-Right-Pointing-Pointer Altered expressions of BCL2 and GADD45 were recorded in various tissues of CNS. Black-Right-Pointing-Pointer Multiple anomalous cellular (neuronal and astroglial) features were recorded. Black-Right-Pointing-Pointer Anatomical specificity of the neurodegeneration was described.« less

Patterns of in vitro cell-death, metaloproteinase-9 and pro-inflammatory cytokines in human monocytes induced by the BCG vaccine, Moreau strain.

PubMed

Simas, C J A; Silva, D P H; Ponte, C G G; Castello-Branco, L R R; Antas, P R Z

2011-09-02

Mononuclear cells have been implicated in the primary inflammatory response against mycobacteria. Yet, little is known about the interaction of Mycobacterium bovis bacillus Calmette-Guerin (BCG) with human monocytes. Here, we investigated the potential of BCG Moreau strain to induce in vitro specific cell-death utilizing a flow cytometry approach that revealed an increase in apoptosis events in BCG-stimulated monocytes from healthy adults. We also detected a concomitant release of interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), but not metalloproteinase (MMP)-9. In addition, annexin V-propidium iodide double staining demonstrated an enhancement of monocytes necrosis, but not apoptosis, following BCG Moreau strain stimulation of umbilical vein cells from naïve, neonate. This pattern was paralleled by different pro-inflammatory cytokine levels, as well as MMP-9 induction when compared to the adults. Our findings support the hypothesis that BCG induces distinct cell-death patterns during the maturation of the immune system and that this pattern might set the stage for a subsequent antimycobacterial immune response that might have profound effects during vaccination. Copyright © 2011 Elsevier Ltd. All rights reserved.

Mortality in epilepsy.

PubMed

Hitiris, Nikolas; Mohanraj, Rajiv; Norrie, John; Brodie, Martin J

2007-05-01

All studies report an increased mortality risk for people with epilepsy compared with the general population. Population-based studies have demonstrated that the increased mortality is often related to the cause of the epilepsy. Common etiologies include neoplasia, cerebrovascular disease, and pneumonia. Deaths in selected cohorts, such as sudden unexpected death in epilepsy (SUDEP), status epilepticus (SE), suicides, and accidents are more frequently epilepsy-related. SUDEP is a particular cause for concern in younger people, and whether and when SUDEP should be discussed with patients with epilepsy remain problematic issues. Risk factors for SUDEP include generalized tonic-clonic seizures, increased seizure frequency, concomitant learning disability, and antiepileptic drug polypharmacy. The overall incidence of SE may be increasing, although case fatality rates remain constant. Mortality is frequently secondary to acute symptomatic disorders. Poor compliance with treatment in patients with epilepsy accounts for a small proportion of deaths from SE. The incidence of suicide is increased, particularly for individuals with epilepsy and comorbid psychiatric conditions. Late mortality figures in patients undergoing epilepsy surgery vary and are likely to reflect differences in case selection. Future studies of mortality should be prospective and follow agreed guidelines to better quantify risk and causation in individual populations.

17Beta-estradiol protects against oxidative stress-induced cell death through the glutathione/glutaredoxin-dependent redox regulation of Akt in myocardiac H9c2 cells.

PubMed

Urata, Yoshishige; Ihara, Yoshito; Murata, Hiroaki; Goto, Shinji; Koji, Takehiko; Yodoi, Junji; Inoue, Satoshi; Kondo, Takahito

2006-05-12

The GSH/glutaredoxin (GRX) system is involved in the redox regulation of certain enzyme activities, and this system protects cells from H2O2-induced apoptosis by regulating the redox state of Akt (Murata, H., Ihara, Y., Nakamura, H., Yodoi, J., Sumikawa, K., and Kondo, T. (2003) J. Biol. Chem. 278, 50226-50233). Estrogens, such as 17beta-estradiol (E2), play an important role in development, growth, and differentiation and appear to have protective effects on oxidative stress mediated by estrogen receptor alpha (ERalpha). However, the role of the ERbeta-mediated pathway in this cytoprotection and the involvement of E2 in the redox regulation are not well understood. In the present study, we demonstrated that E2 protected cardiac H9c2 cells, expressing ERbeta from H2O2-induced apoptosis concomitant with an increase in the activity of Akt. E2 induced the expression of glutaredoxin (GRX) as well as gamma-glutamylcysteine synthetase, a rate-limiting enzyme for the synthesis of GSH. Inhibitors for both gamma-glutamylcysteine synthetase and GRX and ICI182,780, a specific inhibitor of ERs, abolished the protective effect of E2 on cell survival as well as the activity of Akt, suggesting that ERbeta is involved in the cytoprotection and redox regulation by E2. Transcription of the GRX gene was enhanced by E2. The promoter activity of GRX was up-regulated by an ERbeta-dependent element. These results suggest that the GRX/GSH system is involved in the cytoprotective and genomic effects of E2 on the redox state of Akt, a pathway that is mediated, at least in part, by ERbeta. This mechanism may also play an antiapoptotic role in cancer cells during carcinogenesis or chemotherapy.

Transient Receptor Potential Vanilloid 1 Expression Mediates Capsaicin-Induced Cell Death.

PubMed

Ramírez-Barrantes, Ricardo; Córdova, Claudio; Gatica, Sebastian; Rodriguez, Belén; Lozano, Carlo; Marchant, Ivanny; Echeverria, Cesar; Simon, Felipe; Olivero, Pablo

2018-01-01

The transient receptor potential (TRP) ion channel family consists of a broad variety of non-selective cation channels that integrate environmental physicochemical signals for dynamic homeostatic control. Involved in a variety of cellular physiological processes, TRP channels are fundamental to the control of the cell life cycle. TRP channels from the vanilloid (TRPV) family have been directly implicated in cell death. TRPV1 is activated by pain-inducing stimuli, including inflammatory endovanilloids and pungent exovanilloids, such as capsaicin (CAP). TRPV1 activation by high doses of CAP (>10 μM) leads to necrosis, but also exhibits apoptotic characteristics. However, CAP dose-response studies are lacking in order to determine whether CAP-induced cell death occurs preferentially via necrosis or apoptosis. In addition, it is not known whether cytosolic Ca 2+ and mitochondrial dysfunction participates in CAP-induced TRPV1-mediated cell death. By using TRPV1-transfected HeLa cells, we investigated the underlying mechanisms involved in CAP-induced TRPV1-mediated cell death, the dependence of CAP dose, and the participation of mitochondrial dysfunction and cytosolic Ca 2+ increase. Together, our results contribute to elucidate the pathophysiological steps that follow after TRPV1 stimulation with CAP. Low concentrations of CAP (1 μM) induce cell death by a mechanism involving a TRPV1-mediated rapid and transient intracellular Ca 2+ increase that stimulates plasma membrane depolarization, thereby compromising plasma membrane integrity and ultimately leading to cell death. Meanwhile, higher doses of CAP induce cell death via a TRPV1-independent mechanism, involving a slow and persistent intracellular Ca 2+ increase that induces mitochondrial dysfunction, plasma membrane depolarization, plasma membrane loss of integrity, and ultimately, cell death.

A change of heart and a change of mind? Technology and the redefinition of death in 1968.

PubMed

Giacomini, M

1997-05-01

In 1968, an ad hoc committee of Harvard faculty publicly redefined death as "brain death". What interests and issues compelled the redefinition of death, and formed the "spirit" of this precedent-setting policy? This paper reports on an historical study of the files of the Harvard ad hoc committee, the proceedings of an international conference on ethical issues in organ transplantation, and a review of the medical literature and media in the decades preceding the redefinition of death. This analysis of the technological and professional forces involved in the redefinition of death in 1968 questions two common theses: that technological "progress", primarily in the areas of life support and electroencephalography, literally created brain-dead bodies and dictated their defining features (respectively), and that Harvard's definition of brain death by committee constituted a net loss of autonomy for medicine. In fact, medical researchers through the 1960s disputed and negotiated many features of the brain death syndrome, and transplantation interests-perhaps more kidney than heart-played a particularly influential role in tailoring the final criteria put forth by Harvard in 1968. It is also doubtful whether Harvard's definition of brain death by multidisciplinary committee undermined medical privilege and autonomy. The Harvard Ad Hoc Committee may not have succeeded in establishing definitive, indisputable brain death criteria and ensuring their consistent application to all clinical cases of brain death. However, it did gain significant ground for transplant and other medical interests by (1) establishing brain death as a technical "fact" and the definition of brain death as an exercise for medical theorists, (2) involving non-medical ethics and humanities experts in supporting the technical redefinition of death, and, (3) successfully involving transplant surgeons in the redefinition of death and attempting (albeit unsuccessfully) not to exclude them from the actual diagnosis of death in individual cases.

Forensic molecular pathology: its impacts on routine work, education and training.

PubMed

Maeda, Hitoshi; Ishikawa, Takaki; Michiue, Tomomi

2014-03-01

The major role of forensic pathology is the investigation of human death in relevance to social risk management to determine the cause and process of death, especially in violent and unexpected sudden deaths, which involve social and medicolegal issues of ultimate, personal and public concerns. In addition to the identification of victims and biological materials, forensic molecular pathology contributes to general explanation of the human death process and assessment of individual death on the basis of biological molecular evidence, visualizing dynamic functional changes involved in the dying process that cannot be detected by morphology (pathophysiological or molecular biological vital reactions); the genetic background (genomics), dynamics of gene expression (up-/down-regulation: transcriptomics) and vital phenomena, involving activated biological mediators and degenerative products (proteomics) as well as metabolic deterioration (metabolomics), are detected by DNA analysis, relative quantification of mRNA transcripts using real-time reverse transcription-PCR (RT-PCR), and immunohisto-/immunocytochemistry combined with biochemistry, respectively. Thus, forensic molecular pathology involves the application of omic medical sciences to investigate the genetic basis, and cause and process of death at the biological molecular level in the context of forensic pathology, that is, 'advanced molecular autopsy'. These procedures can be incorporated into routine death investigations as well as guidance, education and training programs in forensic pathology for 'dynamic assessment of the cause and process of death' on the basis of autopsy and laboratory data. Postmortem human data can also contribute to understanding patients' critical conditions in clinical management. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Sustained 35-GHz radiofrequency irradiation induces circulatory failure.

PubMed

Frei, M R; Ryan, K L; Berger, R E; Jauchem, J R

1995-10-01

The objective of this study was to determine the thermal distribution and concomitant cardiovascular changes produced by whole-body exposure of ketamine-anesthetized rats to radiofrequency radiation of millimeter wave (MMW) length. Rats (n = 13) were implanted with a flow probe on the superior mesenteric artery and with a catheter in the carotid artery for the measurement of arterial blood pressure. Temperature was measured at five sites: left (Tsl) and right subcutaneous (sides toward and away From the MMW source, respectively), colonic (Tc), tympanic, and tail. The animals were exposed until death to MMW (35 GHz) at a power density that resulted in a whole-body specific absorption rate of 13 W/kg. During irradiation, the Tsl increase was significantly greater than the Tc increase. Heart rate increased throughout irradiation. Mean arterial pressure (MAP) as well maintained until Tsl reached 42 degrees C, at which point MAP declined until death. Mesenteric vascular resistance tended to increase during the early stages of irradiation but began to decrease at Tsl > or = 41 degrees C. The declines in both mesenteric vascular resistance and MAP began at Tc < 37.5 degrees C; death occurred at Tc = 40.3 +/- .3 degrees C and Tsl = 48.0 +/- .4 degrees C. These data indicate that circulatory failure and subsequent death may occur when skin temperature is rapidly elevated, even in the presence of relatively normal Tc.

Elevated extracellular [K+] inhibits death-receptor- and chemical-mediated apoptosis prior to caspase activation and cytochrome c release.

PubMed Central

Thompson, G J; Langlais, C; Cain, K; Conley, E C; Cohen, G M

2001-01-01

Efflux of intracellular K(+) and cell shrinkage are features of apoptosis in many experimental systems, and a regulatory role has been proposed for cytoplasmic [K(+)] in initiating apoptosis. We have investigated this in both death-receptor-mediated and chemical-induced apoptosis. Using Jurkat T cells pre-loaded with the K(+) ion surrogate (86)Rb(+), we have demonstrated an efflux of intracellular K(+) during apoptosis that was concomitant with, but did not precede, other apoptotic changes, including phosphatidylserine externalization, mitochondrial depolarization and cell shrinkage. To further clarify the role of K(+) ions in apoptosis, cytoprotection by elevated extracellular [K(+)] was studied. Induction of apoptosis by diverse death-receptor and chemical stimuli in two cell lines was inhibited prior to phosphatidylserine externalization, mitochondrial depolarization, cytochrome c release and caspase activation. Using a cell-free system, we have demonstrated a novel mechanism by which increasing [K(+)] inhibited caspase activation. In control dATP-activated lysates, Apaf-1 oligomerized to a biologically active caspase processing approximately 700 kDa complex and an inactive approximately 1.4 MDa complex. Increasing [K(+)] inhibited caspase activation by preventing formation of the approximately 700 kDa complex, but not of the inactive complex. Thus intracellular and extracellular [K(+)] markedly affect caspase activation and the initiation of apoptosis induced by both death-receptor ligation and chemical stress. PMID:11415444

Biliary complications after orthotopic liver transplantation from donors after cardiac death: broad spectrum of disease.

PubMed

Abou Abbass, A; Abouljoud, M; Yoshida, A; Kim, D Y; Slater, R; Hundley, J; Kazimi, M; Moonka, D

2010-11-01

Donation-after-death liver transplantation (DCD-LT) carries higher complication rates compared with donation-after-brain death liver transplantation (DBD-LT). In this report we describe our experience with biliary complications in DCD-LT with emphasis on anatomical patterns and outcomes. We performed retrospective review of patients' medical records from August 2004 to December 2008, during which time total of 26 DCD-LTs were performed. Mean follow-up was 29 months (range 3 to 51 months). Biliary complications occurred in 12 patients (46%), of whom 9 were related to DCD (35%). Four patients had more than 1 biliary complication, and 4 had concomitant arterial problems (stricture/thrombosis). Treatment of complications included: ERCP (n = 5, 3 resolved), conversion to roux (n = 5, 2 resolved), revision of roux (n = 1), percutaneous transhepatic cholangiography (n = 1), artery revision (n = 3). Three patients with casts had operative extraction of casts depicting a mummified biliary tree; histology showed casts and fibrosis and anastomotic suture material. Six patients underwent retransplantation (23%). Among retransplanted patients, 2 deaths occurred (7.7%). Our experience with DCD-LT reveals a high prevalence of biliary complications with a new and wide spectrum of clinicopathologic findings. Better strategies for prevention of these unique biliary complications are needed to better justify the added risks and costs for performance of DCD-LT. Copyright © 2010 Elsevier Inc. All rights reserved.

Iron overload causes endolysosomal deficits modulated by NAADP-regulated 2-pore channels and RAB7A

PubMed Central

Fernández, Belén; Fdez, Elena; Gómez-Suaga, Patricia; Gil, Fernando; Molina-Villalba, Isabel; Ferrer, Isidro; Patel, Sandip; Churchill, Grant C.; Hilfiker, Sabine

2016-01-01

ABSTRACT Various neurodegenerative disorders are associated with increased brain iron content. Iron is known to cause oxidative stress, which concomitantly promotes cell death. Whereas endolysosomes are known to serve as intracellular iron storage organelles, the consequences of increased iron on endolysosomal functioning, and effects on cell viability upon modulation of endolysosomal iron release remain largely unknown. Here, we show that increasing intracellular iron causes endolysosomal alterations associated with impaired autophagic clearance of intracellular protein aggregates, increased cytosolic oxidative stress and increased cell death. These effects are subject to regulation by NAADP, a potent second messenger reported to target endolysosomal TPCNs (2-pore channels). Consistent with endolysosomal iron storage, cytosolic iron levels are modulated by NAADP, and increased cytosolic iron is detected when overexpressing active, but not inactive TPCNs, indicating that these channels can modulate endolysosomal iron release. Cell death triggered by altered intralysosomal iron handling is abrogated in the presence of an NAADP antagonist or when inhibiting RAB7A activity. Taken together, our results suggest that increased endolysosomal iron causes cell death associated with increased cytosolic oxidative stress as well as autophagic impairments, and these effects are subject to modulation by endolysosomal ion channel activity in a RAB7A-dependent manner. These data highlight alternative therapeutic strategies for neurodegenerative disorders associated with increased intracellular iron load. PMID:27383256

Ten-year results of accelerated hypofractionated adjuvant whole-breast radiation with concomitant boost to the lumpectomy cavity after conserving surgery for early breast cancer.

PubMed

Cante, Domenico; Petrucci, Edoardo; Sciacero, Piera; Piva, Cristina; Ferrario, Silvia; Bagnera, Silvia; Patania, Sebastiano; Mondini, Guido; Pasquino, Massimo; Casanova Borca, Valeria; Vellani, Giorgio; La Porta, Maria Rosa; Franco, Pierfrancesco

2017-09-01

Accelerated hypofractionated whole-breast radiotherapy (WBRT) is considered a standard therapeutic option for early breast cancer (EBC) in the postoperative setting after breast conservation (BCS). A boost to the lumpectomy cavity may further increase local control. We herein report on the 10-year results of a series of EBC patients treated after BCS with hypofractionated WBRT with a concomitant photon boost to the surgical bed over 4 weeks. Between 2005 and 2007, 178 EBC patients were treated with a basic course of radiotherapy consisting of 45 Gy to the whole breast in 20 fractions (2.25 Gy daily) with an additional boost dose of 0.25 Gy delivered concomitantly to the lumpectomy cavity, for an additional dose of 5 Gy. Median follow-up period was 117 months. At 10-year, overall, cancer-specific, disease-free survival and local control were 92.2% (95% CI 88.7-93.4%), 99.2% (95% CI 96.7-99.7%), 95.5% (95% CI 91.2-97.2%) and 97.3% (95% CI 94.5-98.9%), respectively. Only eight patients recurred. Four in-breast recurrences, two axillary node relapses and two metastatic localizations were observed. Fourteen patients died during the observation period due to other causes while breast cancer-related deaths were eight. At last follow-up, ≥G2 fibrosis and telangiectasia were seen in 7% and 5% of patients. No major lung and heart toxicities were observed. Cosmetic results were excellent/good in 87.8% of patients and fair/poor in 12.2%. Hypofractionated WBRT with concomitant boost to the lumpectomy cavity after BCS in EBC led to consistent clinical results at 10 years. Hence, it can be considered a valid treatment option in this setting.

Scorched earth strategy

PubMed Central

Wrzaczek, Michael; Brosché, Mikael

2009-01-01

Programmed cell death is a common feature of developmental processes and responses to environmental cues in many multicellular organisms. Examples of programmed cell death in plants are leaf abscission in autumn and the hypersensitive response during pathogen attack. Reactive oxygen species (ROS) have been implicated in the regulation of various types of cell death.1,2 However, the precise mechanics of the involvement of ROS in the processes leading to initiation of cell death and subsequent containment are currently unknown. We recently showed the involvement of an Arabidopsis protein GRIM REAPER in the regulation of ROS-induced cell death under stress conditions.3 Our results indicated that the presence of a truncated protein primes plants for cell death in the presence of ROS leading to ozone sensitivity and increased resistance to hemibiotrophic pathogens. PMID:19820355

Drug Overdose Deaths Among Adolescents Aged 15-19 in the United States: 1999-2015.

PubMed

Curtin, Sally C; Tejada-Vera, Betzaida; Warmer, Margaret

2017-08-01

Drug overdose deaths in the United States are a pressing public health challenge (1–3). In particular, drug overdoses involving opioids have increased since 1999 (1). This report focuses specifically on drug overdose deaths for older adolescents aged 15–19. In 2015, 772 drug overdose deaths occurred in this age group. Rates for 1999–2015 are presented and trends compared for both females and males. Percent distributions of drug overdose deaths for 2015 by intent (e.g., unintentional, suicide, homicide) are presented. Trends in drug overdose death rates by type of drug involved are also presented. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.

Volatile substance misuse deaths in Washington State, 2003-2012.

PubMed

Ossiander, Eric M

2015-01-01

Volatile substance misuse (VSM - also known as huffing or sniffing) causes some deaths, but because there are no specific cause-of-death codes for VSM, these deaths are rarely tabulated. Count and describe VSM deaths occurring in Washington State during 2003-2012. We used the textual cause-of-death information on death certificates to count VSM-associated deaths that occurred in Washington State during 2003-2012. We extracted records that contained words suggesting either a method of inhalation or a substance commonly used for VSM, and reviewed those records to identify deaths on which the inhalation of a volatile substance was mentioned. We conducted a descriptive analysis of those deaths. Fifty-six deaths involving VSM occurred in Washington State during 2003-2012. VSM deaths occurred primarily among adults age 20 and over (91%), males (88%), and whites (93%). Twelve different chemicals were associated with deaths, but 1 of them, difluoroethane, was named on 30 death certificates (54%), and its involvement increased during the study period. Gas duster products were named as the source of difluoroethane for 12 deaths; no source was named for the other 18 difluoroethane deaths. Most VSM deaths occurred among white male adults, and gas duster products containing difluoroethane were the primary source of inhalants. Approaches to deter VSM, such as the addition of bitterants to gas dusters, should be explored.

Deaths from pesticide poisoning in England and Wales: 1945-1989.

PubMed

Casey, P; Vale, J A

1994-02-01

1. Data on deaths from pesticide poisoning occurring in England and Wales between 1945 and 1989 (no data are available for 1954) have been collated; pesticides were responsible for only 1012 (1.1%) of the 87,385 deaths from poisoning (excluding those due to carbon monoxide) occurring over this 44 year period. At least 73% of all pesticide fatalities were due to suicide and overall there was a predominance of males (male:female ratio 2.4:1). No deaths from pesticide poisoning in children under 10 years have been reported since 1974 although almost 50% of suspected pesticide poisoning incidents involve this age group. 2. Herbicides were responsible for 787 (78%) fatal poisonings, 110 (11%) were caused by insecticides, 69 (6.8%) by rodenticides, 30 (3.0%) by wood preservatives and 16 (1.6%) by other pesticides. 3. The herbicide, paraquat, was responsible for 570 of 1012 (56%) deaths and, although there has been a progressive decline in the annual number of deaths from paraquat poisoning since 1982, paraquat remains the most common cause of fatal pesticide poisoning in England and Wales. 4. Sodium chlorate caused 113 (11.2%) deaths, most of these fatalities occurring between 1965 and 1983; only one death has been recorded since 1984. The phenoxyacetate herbicides resulted in 50 deaths; 2,4-D was implicated most commonly. Sixty-eight deaths were due to organophosphorus insecticides; demeton-S-methyl, malathion and mevinphos were involved most frequently. Only eight deaths resulted from organochlorine insecticides and two of these also involved an organophosphorus insecticide.(ABSTRACT TRUNCATED AT 250 WORDS)

Fatal occupational injuries.

PubMed

Baker, S P; Samkoff, J S; Fisher, R S; Van Buren, C B

1982-08-13

Deaths resulting from work-related injuries during a one-year period in Maryland were identified and reviewed. Of 148 workers killed, all but two were male. Transportation vehicles were involved in 41% of the deaths, with road vehicles accounting for 25% of the total. Other major groups involved nonroad land vehicles (16%) and firearms, primarily handguns (11%). Two thirds of the workers died at the scene or were dead on arrival at the hospital. Head injuries were the most common cause of death. Eleven percent of the workers tested had blood alcohol concentrations of 0.08% by weight or greater. The majority of the deaths involved either hazards that are not addressed by the Occupational Safety and Health Act of 1970 or workers in categories that are excluded by law from regulation under this act.

38 CFR 3.312 - Cause of death.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Cause of death. 3.312... Cause of death. (a) General. The death of a veteran will be considered as having been due to a service... contributory cause of death. The issue involved will be determined by exercise of sound judgment, without...

38 CFR 3.312 - Cause of death.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2013-07-01 2013-07-01 false Cause of death. 3.312... Cause of death. (a) General. The death of a veteran will be considered as having been due to a service... contributory cause of death. The issue involved will be determined by exercise of sound judgment, without...

38 CFR 3.312 - Cause of death.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2014-07-01 2014-07-01 false Cause of death. 3.312... Cause of death. (a) General. The death of a veteran will be considered as having been due to a service... contributory cause of death. The issue involved will be determined by exercise of sound judgment, without...

38 CFR 3.312 - Cause of death.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2011-07-01 2011-07-01 false Cause of death. 3.312... Cause of death. (a) General. The death of a veteran will be considered as having been due to a service... contributory cause of death. The issue involved will be determined by exercise of sound judgment, without...

38 CFR 3.312 - Cause of death.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2012-07-01 2012-07-01 false Cause of death. 3.312... Cause of death. (a) General. The death of a veteran will be considered as having been due to a service... contributory cause of death. The issue involved will be determined by exercise of sound judgment, without...

Synchronous isolated splenic metastasis from colon carcinoma and concomitant splenic abscess: A case report and review of the literature

PubMed Central

Pisanu, Adolfo; Ravarino, Alberto; Nieddu, Riccardo; Uccheddu, Alessandro

2007-01-01

This study aimed to describe a case in which an isolated splenic metastasis was synchronous with the colonic primary and a concomitant splenic abscess was associated. A wide review of the literature was also performed. A 54-year-old woman with abdominal pain and fever was admitted to our department. Abdominal CT revealed two low-density areas in the spleen and wall-thickening of the left colonic flexure, which was indistinguishable from the spleen parenchyma. The patient underwent emergency celiotomy, with the presumptive diagnosis of obstructing colon carcinoma of the splenic flexure, and concomitant splenic abscess. Subtotal colectomy and splenectomy were performed. Pathological findings were consistent with mucinous colonic carcinoma, synchronous isolated splenic metastasis and concomitant splenic abscess. This paper is also a review of the existing literature on the association between colorectal cancer and splenic metastasis. Only 41 cases of isolated splenic metastasis from colon carcinoma have been reported in the literature. This report is the third described case of synchronous isolated splenic metastasis from colon carcinoma. Only one case with concomitant splenic abscess has been previously reported. When obstructing left-sided colorectal cancer is suspected, careful CT examination can allow early diagnosis of splenic involvement by the tumor. The literature review suggests that there might be a significant improvement in survival following splenectomy for a metachronous isolated splenic metastasis from colon carcinoma. Prognosis for synchronous splenic metastasis seems to be related to the advanced stage of the disease. Nevertheless, no definitive conclusions can be drawn because of the small number of cases. PMID:17907299

PD-1 blocks lytic granule polarization with concomitant impairment of integrin outside-in signaling in the natural killer cell immunological synapse.

PubMed

Huang, Yu; Chen, Zhiying; Jang, Joon Hee; Baig, Mirza S; Bertolet, Grant; Schroeder, Casey; Huang, Shengjian; Hu, Qian; Zhao, Yong; Lewis, Dorothy E; Qin, Lidong; Zhu, Michael Xi; Liu, Dongfang

2018-04-18

The inhibitory receptor programmed cell death protein 1 (PD-1) is upregulated on a variety of immune cells, including natural killer (NK) cells, during chronic viral infection and tumorigenesis. Blockade of PD-1 or its ligands produces durable clinical responses with tolerable side effects in patients with a broad spectrum of cancers. However, the underlying molecular mechanisms of how PD-1 regulates NK cell function remain poorly characterized. We sought to determine the effect of PD-1 signaling on NK cells. PD-1 was overexpressed in CD16-KHYG-1 (a human NK cell line with both antibody-dependent cellular cytotoxicity through CD16 and natural cytotoxicity through NKG2D) cells and stimulated by exposing the cells to NK-sensitive target cells expressing programmed death ligand 1 (PD-L1). PD-1 engagement by PD-L1 specifically blocked NK cell-mediated cytotoxicity without interfering with the conjugation between NK cells and target cells. Further examination showed that PD-1 signaling blocked lytic granule polarization in NK cells, which was accompanied by failure of integrin-linked kinase, a key molecule in the integrin outside-in signaling pathway, to accumulate in the immunological synapse after NK-target cell conjugation. Our results suggest that NK cell cytotoxicity is inhibited by PD-1 engagement, which blocks lytic granule polarization to the NK cell immunological synapse with concomitant impairment of integrin outside-in signaling. This study provides novel mechanistic insights into how PD-1 inhibition disrupts NK cell function. Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Pioglitazone and the risk of cardiovascular events in patients with Type 2 diabetes receiving concomitant treatment with nitrates, renin-angiotensin system blockers, or insulin: results from the PROactive study (PROactive 20).

PubMed

Erdmann, Erland; Spanheimer, Robert; Charbonnel, Bernard

2010-09-01

Patients with Type 2 diabetes mellitus (T2DM) are often treated with multiple glucose-lowering and cardiovascular agents. The concomitant use of nitrates, renin-angiotensin system (RAS) blockers, or insulin has been linked to a potential increase in myocardial ischemic risk with rosiglitazone. The PROactive database provides an opportunity to investigate the effects of these medications on the potential macrovascular benefits reported with pioglitazone. The PROactive study was a randomized double-blind prospective trial that evaluated mortality and cardiovascular morbidity in 5238 patients with T2DM and macrovascular disease. Patients received pioglitazone or placebo in addition to their baseline glucose-lowering and cardiovascular medications. The effect of pioglitazone on composite endpoints was evaluated, including all-cause death, myocardial infarction (MI), and stroke, as well as safety events of edema and serious heart failure, in subgroups using nitrates, RAS blockers, or insulin at baseline. The risk of all-cause death, MI, and stroke for pioglitazone versus placebo was similar regardless of the baseline use of nitrates, RAS blockers, or insulin, with hazard ratios ranging from 0.81 to 0.87. Similar results were obtained for the other composite endpoints analyzed. There were no significant interactions between baseline medication subgroups and treatment. The increased risk of edema and serious heart failure was consistent across the baseline medication subgroups. This post hoc analysis did not reveal an increased risk of macrovascular events with pioglitazone in patients receiving nitrates, RAS blockers, or insulin. Rather, all patients realized the same trend towards benefit with pioglitazone, and adverse events of edema and heart failure were predictable. © 2010 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

[Tracheobronchomalacia].

PubMed

Majid, Adnan; Fernández, Liliana; Fernández-Bussy, Sebastián; Herth, Felix; Ernst, Armin

2010-04-01

Tracheobronchomalacia is a central airway disease characterised by weakness of the wall and dynamic decrease in the tracheal lumen and the large bronchi, particularly while exhaling. It is more common in middle age and the elderly with previous exposure to cigarettes. It causes chronic symptoms such as cough, dyspnea, increase in recurrent infections, and poor secretion management, but it can also progress to chronic respiratory failure and death. It is usually confused with other common diseases like chronic obstructive pulmonary disease (COPD) or asthma. Its causes can be congenital or acquired and its diagnosis involves the dynamic assessment of the airway with tomography and fibrobronchoscopy. It is classified as mild, moderate or severe depending on the degree of collapse of the airway when exhaling. Management consists of a primary phase, in which concomitant diseases must be controlled, such as COPD, asthma or gastro-oesophageal reflux. In diffuse moderate to severe symptomatic tracheobronchomalacia tracheobronchoplasty must be considered with strengthening of the posterior wall. Silicone and "Y" stents can be used to identify patients who could potentially benefit from surgical treatment as well as being used for the definitive symptomatic treatment with high surgical risk. More prospective studies need to be done in order to standardise certain common criteria for the management of this usually under-diagnosed disease. Copyright (c) 2009 SEPAR. Published by Elsevier Espana. All rights reserved.

Monoamine oxidase inhibition prevents mitochondrial dysfunction and apoptosis in myoblasts from patients with collagen VI myopathies.

PubMed

Sorato, E; Menazza, S; Zulian, A; Sabatelli, P; Gualandi, F; Merlini, L; Bonaldo, P; Canton, M; Bernardi, P; Di Lisa, F

2014-10-01

Although mitochondrial dysfunction and oxidative stress have been proposed to play a crucial role in several types of muscular dystrophy (MD), whether a causal link between these two alterations exists remains an open question. We have documented that mitochondrial dysfunction through opening of the permeability transition pore plays a key role in myoblasts from patients as well as in mouse models of MD, and that oxidative stress caused by monoamine oxidases (MAO) is involved in myofiber damage. In the present study we have tested whether MAO-dependent oxidative stress is a causal determinant of mitochondrial dysfunction and apoptosis in myoblasts from patients affected by collagen VI myopathies. We find that upon incubation with hydrogen peroxide or the MAO substrate tyramine myoblasts from patients upregulate MAO-B expression and display a significant rise in reactive oxygen species (ROS) levels, with concomitant mitochondrial depolarization. MAO inhibition by pargyline significantly reduced both ROS accumulation and mitochondrial dysfunction, and normalized the increased incidence of apoptosis in myoblasts from patients. Thus, MAO-dependent oxidative stress is causally related to mitochondrial dysfunction and cell death in myoblasts from patients affected by collagen VI myopathies, and inhibition of MAO should be explored as a potential treatment for these diseases. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Fatal overdoses involving hydromorphone and morphine among inpatients: a case series

PubMed Central

Lowe, Amanda; Hamilton, Michael; Greenall BScPhm MHSc, Julie; Ma, Jessica; Dhalla, Irfan; Persaud, Nav

2017-01-01

Background: Opioids have narrow therapeutic windows, and errors in ordering or administration can be fatal. The purpose of this study was to describe deaths involving hydromorphone and morphine, which have similar-sounding names, but different potencies. Methods: In this case series, we describe deaths of patients admitted to hospital or residents of long-term care facilities that involved hydromorphone and morphine. We searched for deaths referred to the Patient Safety Review Committee of the Office of the Chief Coroner for Ontario between 2007 and 2012, and subsequently reviewed by 2014. We reviewed each case to identify intervention points where errors could have been prevented. Results: We identified 8 cases involving decedents aged 19 to 91 years. The cases involved errors in prescribing, order processing and transcription, dispensing, administration and monitoring. For 7 of the 8 cases, there were multiple (2 or more) possible intervention points. Six cases may have been prevented by additional patient monitoring, and 5 cases involved dispensing errors. Interpretation: Opioid toxicity deaths in patients living in institutions can be prevented at multiple points in the prescribing and dispensing processes. Interventions aimed at preventing errors in hydromorphone and morphine prescribing, administration and patient monitoring should be implemented and rigorously evaluated. PMID:28401133

Fatal overdoses involving hydromorphone and morphine among inpatients: a case series.

PubMed

Lowe, Amanda; Hamilton, Michael; Greenall BScPhm MHSc, Julie; Ma, Jessica; Dhalla, Irfan; Persaud, Nav

2017-01-01

Opioids have narrow therapeutic windows, and errors in ordering or administration can be fatal. The purpose of this study was to describe deaths involving hydromorphone and morphine, which have similar-sounding names, but different potencies. In this case series, we describe deaths of patients admitted to hospital or residents of long-term care facilities that involved hydromorphone and morphine. We searched for deaths referred to the Patient Safety Review Committee of the Office of the Chief Coroner for Ontario between 2007 and 2012, and subsequently reviewed by 2014. We reviewed each case to identify intervention points where errors could have been prevented. We identified 8 cases involving decedents aged 19 to 91 years. The cases involved errors in prescribing, order processing and transcription, dispensing, administration and monitoring. For 7 of the 8 cases, there were multiple (2 or more) possible intervention points. Six cases may have been prevented by additional patient monitoring, and 5 cases involved dispensing errors. Opioid toxicity deaths in patients living in institutions can be prevented at multiple points in the prescribing and dispensing processes. Interventions aimed at preventing errors in hydromorphone and morphine prescribing, administration and patient monitoring should be implemented and rigorously evaluated.

The impact of age on complications, survival, and cause of death following colon cancer surgery

PubMed Central

Aquina, Christopher T; Mohile, Supriya G; Tejani, Mohamedtaki A; Becerra, Adan Z; Xu, Zhaomin; Hensley, Bradley J; Arsalani-Zadeh, Reza; Boscoe, Francis P; Schymura, Maria J; Noyes, Katia; Monson, John RT; Fleming, Fergal J

2017-01-01

Background: Given scarce data regarding the relationship among age, complications, and survival beyond the 30-day postoperative period for oncology patients in the United States, this study identified age-related differences in complications and the rate and cause of 1-year mortality following colon cancer surgery. Methods: The NY State Cancer Registry and Statewide Planning and Research Cooperative System identified stage I–III colon cancer resections (2004–2011). Multivariable logistic regression and survival analyses assessed the relationship among age (<65, 65–74, ⩾75), complications, 1-year survival, and cause of death. Results: Among 24 426 patients surviving >30 days, 1-year mortality was 8.5%. Older age groups had higher complication rates, and older age and complications were independently associated with 1-year mortality (P<0.0001). Increasing age was associated with a decrease in the proportion of deaths from colon cancer with a concomitant increase in the proportion of deaths from cardiovascular disease. Older age and sepsis were independently associated with higher risk of colon cancer-specific death (65–74: HR=1.59, 95% CI=1.26–2.00; ⩾75: HR=2.57, 95% CI=2.09–3.16; sepsis: HR=2.58, 95% CI=2.13–3.11) and cardiovascular disease-specific death (65–74: HR=3.72, 95% CI=2.29–6.05; ⩾75: HR=7.02, 95% CI=4.44–11.10; sepsis: HR=2.33, 95% CI=1.81–2.99). Conclusions: Older age and sepsis are associated with higher 1-year overall, cancer-specific, and cardiovascular-specific mortality, highlighting the importance of geriatric assessment, multidisciplinary care, and cardiovascular optimisation for older patients and those with infectious complications. PMID:28056465

Is survival improved by the use of NIV and PEG in amyotrophic lateral sclerosis (ALS)? A post-mortem study of 80 ALS patients.

PubMed

Burkhardt, Christian; Neuwirth, Christoph; Sommacal, Andreas; Andersen, Peter M; Weber, Markus

2017-01-01

Non-invasive ventilation (NIV) and percutaneous gastrostomy (PEG) are guideline-recommended interventions for symptom management in amyotrophic lateral sclerosis (ALS). Their effect on survival is controversial and the impact on causes of death is unknown. To investigate the effect of NIV and PEG on survival and causes of death in ALS patients. Eighty deceased ALS patients underwent a complete post mortem analysis for causes of death between 2003 and 2015. Forty-two of these patients consented for genetic testing. Effects of NIV and PEG on survival and causes of death were analyzed in a multivariable Cox proportional hazard regression. Six patients, who requested assisted suicide causing drug-induced hypoxia, were excluded from final analysis. Respiratory failure was the main cause of death in 72 out of 74 patients. Fifteen out of 74 died of aspiration pneumonia 23/74 of bronchopneumonia and 8/74 of a combination of aspiration pneumonia and bronchopneumonia. Twenty died of hypoxia without concomitant infection, and six patients had pulmonary embolism alone or in combination with pneumonia. NIV (p = 0.01) and PEG (p<0.01) had a significant impact on survival. In patients using NIV bronchopneumonia was significantly more frequent (p <0.04) compared to non-NIV patients. This effect was even more pronounced in limb onset patients (p<0.002). Patients with C9orf72 hexanucleotide repeat expansions showed faster disease progression and shorter survival (p = 0.01). The use of NIV and PEG prolongs survival in ALS. This study supports current AAN and EFNS guidelines which recommend NIV and PEG as a treatment option in ALS. The risk of bronchopneumonia as cause of death may be increased by NIV.

Antecedents and Sequelae of Sudden Parental Death in Offspring and Surviving Caregivers

PubMed Central

Melhem, Nadine M.; Walker, Monica; Moritz, Grace; Brent, David A.

2008-01-01

Objectives To examine the psychiatric antecedents that put parents at risk for early death, and the psychological sequelae of bereavement in offspring and caregivers. Design A population-based study. Setting Bereaved families were recruited through the coroner’s records and by advertisement. Control families were recruited by random-digit dialing and advertisement. Participants Families with biological offspring from 7 to 25 years of age in which 1 parent died of suicide, accident, or sudden natural death were included (n=140). Controls (n=99) had 2 living parents and their biological offspring and had no death of a first-degree relative within the past 2 years. Main Outcome Measures Lifetime psychiatric history for deceased parents (probands) and new-onset psychiatric disorders, self-reported symptoms, and functional status in offspring and surviving caregivers. Results Bipolar disorder, substance abuse, and personality disorders are more common in probands who died of suicide or accident than in control parents. Bereaved offspring and their caregivers were at increased risk for depression and posttraumatic stress disorder. Bereaved offspring had a 3-fold (95% confidence interval, 1.3–7.0) increased risk of depression, even after controlling for antecedent and concomitant risk factors. Offspring bereaved by suicide showed similar outcomes compared with those bereaved by other types of death. Conclusions Bereavement conveys an increased risk of depression and posttraumatic stress disorder above and beyond other vulnerability factors. Better integration of medical and psychiatric care may prevent premature parental death, but once it occurs, physicians should be alert to the increased risk for depression and posttraumatic stress disorder in bereaved offspring and their caregivers. PMID:18458185

Early neonatal death: A challenge worldwide.

PubMed

Lehtonen, Liisa; Gimeno, Ana; Parra-Llorca, Anna; Vento, Máximo

2017-06-01

Early neonatal death (ENND), defined as the death of a newborn between zero and seven days after birth, represents 73% of all postnatal deaths worldwide. Despite a 50% reduction in childhood mortality, reduction of ENND has significantly lagged behind other Millennium Developmental Goal achievements and is a growing contributor to overall mortality in children aged <5 years. The etiology of ENND is closely related to the level of a country's industrialization. Hence, prematurity and congenital anomalies are the leading causes in high-income countries. Furthermore, sudden unexpected early neonatal deaths (SUEND) and collapse have only recently been identified as relevant and often preventable causes of death. Concomitantly, perinatal-related events such as asphyxia and infections are extremely relevant in Africa, South East Asia, and Latin America and, together with prematurity, are the principal contributors to ENND. In high-income countries, according to current research evidence, survival may be improved by applying antenatal and perinatal therapies and immediate newborn resuscitation, as well as by centralizing at-risk deliveries to centers with appropriate expertise available around the clock. In addition, resources should be allocated to the close surveillance of newborn infants, especially during the first hours of life. Many of the conditions leading to ENND in low-income countries are preventable with relatively easy and cost-effective interventions such as contraception, vaccination of pregnant women, hygienic delivery at a hospital, training health care workers in resuscitation practices, simplified algorithms that allow for early detection of perinatal infections, and early initiation of breastfeeding and skin-to-skin care. The future is promising. As initiatives undertaken in previous decades have led to substantial reduction in childhood mortality, it is expected that new initiatives targeting the perinatal/neonatal periods are bound to reduce ENND and provide these babies with a better future. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cryptosporidium parvum Induces an Endoplasmic Stress Response in the Intestinal Adenocarcinoma HCT-8 Cell Line*

PubMed Central

Morada, Mary; Pendyala, Lakhsmi; Wu, Gang; Merali, Salim; Yarlett, Nigel

2013-01-01

Invasion of human intestinal epithelial cells (HCT-8) by Cryptosporidium parvum resulted in a rapid induction of host cell spermidine/spermine N1-acetyltransferase 1 (hSSAT-1) mRNA, causing a 4-fold increase in SSAT-1 enzyme activity after 24 h of infection. In contrast, host cell SSAT-2, spermine oxidase, and acetylpolyamine oxidase (hAPAO) remained unchanged during this period. Intracellular polyamine levels of C. parvum-infected human epithelial cells were determined, and it was found that spermidine remained unchanged and putrescine increased by 2.5-fold after 15 h and then decreased after 24 h, whereas spermine decreased by 3.9-fold after 15 h. Concomitant with these changes, N1-acetylspermine and N1-acetylspermidine both increased by 115- and 24-fold, respectively. Increased SSAT-1 has previously been shown to be involved in the endoplasmic reticulum (ER) stress response leading to apoptosis. Several stress response proteins were increased in HCT-8 cells infected with C. parvum, including calreticulin, a major calcium-binding chaperone in the ER; GRP78/BiP, a prosurvival ER chaperone; and Nrf2, a transcription factor that binds to antioxidant response elements, thus activating them. However, poly(ADP-ribose) polymerase, a protein involved in DNA repair and programmed cell death, was decreased. Cumulatively, these results suggest that the invasion of HCT-8 cells by C. parvum results in an ER stress response by the host cell that culminates in overexpression of host cell SSAT-1 and elevated N1-acetylpolyamines, which can be used by a parasite that lacks ornithine decarboxylase. PMID:23986438

Endoscopic bilio-duodenal bypass: outcomes of primary and revision efficacy of combined metallic stents in malignant duodenal and biliary obstructions.

PubMed

Canena, Jorge; Coimbra, João; Carvalho, Diana; Rodrigues, Catarina; Silva, Mário; Costa, Mariana; Horta, David; Mateus Dias, António; Seves, Isabel; Ramos, Gonçalo; Ricardo, Leonel; Coutinho, António Pereira; Romão, Carlos; Veiga, Pedro Mota

2014-11-01

Self-expandable metal stents (SEMSs) can be used for palliation of combined malignant biliary and duodenal obstructions. However, the results of the concomitant stent placement for the duration of the patients' lives, as well as the need for and efficacy of endoscopic revision, are unclear. This study evaluated the clinical effectiveness of SEMS placement for combined biliary and duodenal obstructions throughout the patients' lives and the need for endoscopic revision. This study is a retrospective multicenter study of 50 consecutive patients who underwent simultaneous or sequential SEMS placement for malignant biliary and duodenal obstructions. The data were collected to analyze the sustained relief of obstructive symptoms until the patients' death and the efficacy of endoscopic revision, as well as stent patency, adverse events, survival and prognostic factors for stent patency. Technical and immediate clinical success was achieved in all of the patients. Duodenal stricture occurred before the papilla in 35 patients (70 %), involved the papilla in 11 patients (22 %) and was observed distal to the papilla in four patients (8 %). Initial biliary stenting was performed endoscopically in 42 patients (84 %) and percutaneously in eight patients. After combined stenting, 30 patients (60 %) required no additional intervention until the time of their death. The remaining 20 patients were successfully treated using endoscopic stent reinsertion: nine patients needed biliary revision, three patients needed duodenal restenting and eight patients needed both biliary and duodenal reinsertion. The median duodenal stent patency and median biliary stent patency were 34 and 27 weeks, respectively. The median survival after combined stent placement was 18 weeks. A Cox multivariate analysis showed that duodenal stent obstruction after combined stenting was a risk factor for biliary stent obstruction (hazard ratio 6.85; 95 % confidence interval 1.43-198.98; P = 0.025). Endoscopic bilio-duodenal bypass is clinically effective, and the majority of the patients need no additional intervention until their death. Endoscopic revision is feasible and has a high success rate.

Outcomes of 847 childhood-onset systemic lupus erythematosus patients in three age groups.

PubMed

Lopes, S R M; Gormezano, N W S; Gomes, R C; Aikawa, N E; Pereira, R M R; Terreri, M T; Magalhães, C S; Ferreira, J C; Okuda, E M; Sakamoto, A P; Sallum, A M E; Appenzeller, S; Ferriani, V P L; Barbosa, C M; Lotufo, S; Jesus, A A; Andrade, L E C; Campos, L M A; Bonfá, E; Silva, C A

2017-08-01

Objective The objective of this study was to assess outcomes of childhood systemic lupus erythematosus (cSLE) in three different age groups evaluated at last visit: group A early-onset disease (<6 years), group B school age (≥6 and <12 years) and group C adolescent (≥12 and <18 years). Methods An observational cohort study was performed in ten pediatric rheumatology centers, including 847 cSLE patients. Results Group A had 39 (4%), B 395 (47%) and C 413 (49%). Median disease duration was significantly higher in group A compared to groups B and C (8.3 (0.1-23.4) vs 6.2 (0-17) vs 3.3 (0-14.6) years, p < 0.0001). The median Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI) (0 (0-9) vs 0 (0-6) vs 0 (0-7), p = 0.065) was comparable in the three groups. Further analysis of organ/system damage revealed that frequencies of neuropsychiatric (21% vs 10% vs 7%, p = 0.007), skin (10% vs 1% vs 3%, p = 0.002) and peripheral vascular involvements (5% vs 3% vs 0.3%, p = 0.008) were more often observed in group A compared to groups B and C. Frequencies of severe cumulative lupus manifestations such as nephritis, thrombocytopenia, and autoimmune hemolytic anemia were similar in all groups ( p > 0.05). Mortality rate was significantly higher in group A compared to groups B and C (15% vs 10% vs 6%, p = 0.028). Out of 69 deaths, 33/69 (48%) occurred within the first two years after diagnosis. Infections accounted for 54/69 (78%) of the deaths and 38/54 (70%) had concomitant disease activity. Conclusions This large multicenter study provided evidence that early-onset cSLE group had distinct outcomes. This group was characterized by higher mortality rate and neuropsychiatric/vascular/skin organ damage in spite of comparable frequencies of severe cumulative lupus manifestations. We also identified that overall death in cSLE patients was an early event mainly attributed to infection associated with disease activity.

Dreams of Death.

ERIC Educational Resources Information Center

Barrett, Deirdre

1989-01-01

Examined frequency and characteristics of overt dreams of dying among healthy young adults. Dreams of dying were found to be rare but distinctive content category, representing overwhelmingly pleasant dreams. Over one-half of death dreams involved lengthy afterlife sequence, remainder focused on process of death. Death dreams of these healthy…

Stroke/Death Rates Following Carotid Artery Stenting and Carotid Endarterectomy in Contemporary Administrative Dataset Registries: A Systematic Review.

PubMed

Paraskevas, K I; Kalmykov, E L; Naylor, A R

2016-01-01

Randomised trials have reported higher stroke/death rates after carotid artery stenting (CAS) versus carotid endarterectomy (CEA). Despite this, the 2011 American Heart Association (AHA) guidelines expanded CAS indications, partly because of the Carotid Revascularization Endarterectomy versus Stenting Trial, but also because of improving outcomes in industry sponsored CAS Registries. The aim of this systematic review was: (i) to compare stroke/death rates after CAS/CEA in contemporary dataset registries, (ii) to examine whether published stroke/death rates after CAS fall within AHA thresholds, and, (iii) to see if there had been a decline (over time) in procedural risk after CAS/CEA. PubMed/Medline, Embase, and Cochrane databases were systematically searched according to the recommendations of the PRISMA statement from January 1, 2008 until February 23, 2015 for administrative dataset registries reporting outcomes after both CEA and CAS. Twenty-one registries reported outcomes involving more than 1,500,000 procedures. Stroke/death after CAS was significantly higher than after CEA in 11/21 registries (52%) involving "average risk for CEA" asymptomatic patients and in 11/18 registries (61%) involving "average risk for CEA" symptomatic patients. In another five registries, CAS was associated with higher stroke/death rates than CEA for both symptomatic and asymptomatic patients, but formal statistical comparison was not reported. CAS was associated with stroke/death rates that exceeded risk thresholds recommended by the AHA in 9/21 registries (43%) involving "average risk for CEA" asymptomatic patients and in 13/18 registries (72%) involving "average risk for CEA" symptomatic patients. In 5/18 registries (28%), the procedural risk after CAS in "average risk" symptomatic patients exceeded 10%. Data from contemporary administrative dataset registries suggest that stroke/death rates following CAS remain significantly higher than after CEA and often exceed accepted AHA thresholds. There was no evidence of a sustained decline in procedural risk after CAS. Copyright © 2015 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Anthranilate Fluorescence Marks a Calcium-Propagated Necrotic Wave That Promotes Organismal Death in C. elegans

PubMed Central

Coburn, Cassandra; Allman, Erik; Mahanti, Parag; Benedetto, Alexandre; Cabreiro, Filipe; Pincus, Zachary; Matthijssens, Filip; Araiz, Caroline; Mandel, Abraham; Vlachos, Manolis; Edwards, Sally-Anne; Fischer, Grahame; Davidson, Alexander; Pryor, Rosina E.; Stevens, Ailsa; Slack, Frank J.; Tavernarakis, Nektarios; Braeckman, Bart P.; Schroeder, Frank C.; Nehrke, Keith; Gems, David

2013-01-01

For cells the passage from life to death can involve a regulated, programmed transition. In contrast to cell death, the mechanisms of systemic collapse underlying organismal death remain poorly understood. Here we present evidence of a cascade of cell death involving the calpain-cathepsin necrosis pathway that can drive organismal death in Caenorhabditis elegans. We report that organismal death is accompanied by a burst of intense blue fluorescence, generated within intestinal cells by the necrotic cell death pathway. Such death fluorescence marks an anterior to posterior wave of intestinal cell death that is accompanied by cytosolic acidosis. This wave is propagated via the innexin INX-16, likely by calcium influx. Notably, inhibition of systemic necrosis can delay stress-induced death. We also identify the source of the blue fluorescence, initially present in intestinal lysosome-related organelles (gut granules), as anthranilic acid glucosyl esters—not, as previously surmised, the damage product lipofuscin. Anthranilic acid is derived from tryptophan by action of the kynurenine pathway. These findings reveal a central mechanism of organismal death in C. elegans that is related to necrotic propagation in mammals—e.g., in excitotoxicity and ischemia-induced neurodegeneration. Endogenous anthranilate fluorescence renders visible the spatio-temporal dynamics of C. elegans organismal death. PMID:23935448

Fatal dog attacks, 1989-1994.

PubMed

Sacks, J J; Lockwood, R; Hornreich, J; Sattin, R W

1996-06-01

To update data on fatal dog bites and see if past trends have continued. To merge data from vital records, the Humane Society of the United States, and searches of electronic news files. United States. U.S. residents dying in the U.S. from 1989 through 1994 from dog bites. We identified 109 dog bite-related fatalities, of which 57% were less than 10 years of age. The death rate for neonates was two orders of magnitude higher than for adults and the rate for children one order of magnitude higher. Of classifiable deaths, 22% involved an unrestrained dog off the owner's property, 18% involved a restrained dog on the owner's property, and 59% involved an unrestrained dog on the owner's property. Eleven attacks involved a sleeping infant; 19 dogs involved in fatal attacks had a prior history of aggression; and 19 of 20 classifiable deaths involved an unneutered dog. Pit bulls, the most commonly reported breed, were involved in 24 deaths; the next most commonly reported breeds were rottweilers (16) and German shepherds (10). The dog bite problem should be reconceptualized as a largely preventable epidemic. Breed-specific approaches to the control of dog bites do not address the issue that many breeds are involved in the problem and that most of the factors contributing to dog bites are related to the level of responsibility exercised by dog owners. To prevent dog bite-related deaths and injuries, we recommend public education about responsible dog ownership and dog bite prevention, stronger animal control laws, better resources for enforcement of these laws, and better reporting of bites. Anticipatory guidance by pediatric health care providers should address dog bite prevention.

AML cells have low spare reserve capacity in their respiratory chain that renders them susceptible to oxidative metabolic stress

PubMed Central

Sriskanthadevan, Shrivani; Jeyaraju, Danny V.; Chung, Timothy E.; Prabha, Swayam; Xu, Wei; Skrtic, Marko; Jhas, Bozhena; Hurren, Rose; Gronda, Marcela; Wang, Xiaoming; Jitkova, Yulia; Sukhai, Mahadeo A.; Lin, Feng-Hsu; Maclean, Neil; Laister, Rob; Goard, Carolyn A.; Mullen, Peter J.; Xie, Stephanie; Penn, Linda Z.; Rogers, Ian M.; Dick, John E.; Minden, Mark D.

2015-01-01

Mitochondrial respiration is a crucial component of cellular metabolism that can become dysregulated in cancer. Compared with normal hematopoietic cells, acute myeloid leukemia (AML) cells and patient samples have higher mitochondrial mass, without a concomitant increase in respiratory chain complex activity. Hence these cells have a lower spare reserve capacity in the respiratory chain and are more susceptible to oxidative stress. We therefore tested the effects of increasing the electron flux through the respiratory chain as a strategy to induce oxidative stress and cell death preferentially in AML cells. Treatment with the fatty acid palmitate induced oxidative stress and cell death in AML cells, and it suppressed tumor burden in leukemic cell lines and primary patient sample xenografts in the absence of overt toxicity to normal cells and organs. These data highlight a unique metabolic vulnerability in AML, and identify a new therapeutic strategy that targets abnormal oxidative metabolism in this malignancy. PMID:25631767

Death related to consumption of Rauvolfia sp. powder mislabeled as Tabernanthe iboga.

PubMed

Gicquel, Thomas; Hugbart, Chloé; Le Devehat, Françoise; Lepage, Sylvie; Baert, Alain; Bouvet, Renaud; Morel, Isabelle

2016-09-01

Powdered roots of iboga (Tabernanthe iboga) contain ibogaine, an alkaloid that has been used to treat addictions. We report the case of a 30-year-old woman who died after ingesting a powder labeled as Tabernanthe iboga she had bought online. Analysis of the powder revealed the absence of ibogaine but the presence of toxic alkaloids (ajmaline, yohimbine and reserpine) found in Rauvolfia sp. plant species. An original and specific LC-MS/MS method developed to quantify ajmaline, yohimbine and reserpine showed respective concentrations of 109.1ng/mL, 98.2ng/mL and 30.8ng/mL in blood, and 1528.2ng/mL, 914.2ng/mL and 561.2ng/mL in bile. Moreover, systematic toxicological analyses of biological samples showed the presence of oxazepam at therapeutic concentration and cannabinoids. Death could be attributed to ingestion of a substantial quantity of crushed roots of Rauvolfia in association with concomitant drug withdrawal. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Metabolic reprogramming during TGFβ1-induced epithelial-to-mesenchymal transition

PubMed Central

Jiang, Lei; Xiao, Ling; Sugiura, Hidekazu; Huang, Xiumei; Ali, Aktar; Kuro-o, Makoto; Deberardinis, Ralph J.; Boothman, David A.

2014-01-01

Metastatic progression, including extravasation and micro-metastatic outgrowth, is the main cause of cancer patient death. Recent studies suggest that cancer cells reprogram their metabolism to support increased proliferation through increased glycolysis and biosynthetic activities, including lipogenesis pathways. However, metabolic changes during metastatic progression, including alterations in regulatory gene expression, remain undefined. We show that transforming growth factor beta 1 (TGFβ1) induced Epithelial-to-Mesenchymal Transition (EMT) is accompanied by coordinately reduced enzyme expression required to convert glucose into fatty acids, and concomitant enhanced respiration. Over-expressed Snail1, a transcription factor mediating TGFβ1-induced EMT, was sufficient to suppress carbohydrate-responsive-element-binding protein (ChREBP, a master lipogenic regulator), and fatty acid synthase (FASN), its effector lipogenic gene. Stable FASN knock-down was sufficient to induce EMT, stimulate migration and extravasation in vitro. FASN silencing enhanced lung metastasis and death in vivo. These data suggest that a metabolic transition that suppresses lipogenesis and favors energy production is an essential component of TGFβ1-induced EMT and metastasis. PMID:25284588

Are the children of fathers whose jobs involve contact with many people at an increased risk of leukaemia?

PubMed Central

Fear, N. T.; Roman, E.; Reeves, G.; Pannett, B.

1999-01-01

OBJECTIVES: To investigate the hypothesis that children of men whose jobs involve contact with many people (particularly children) are at an increased risk of leukaemia. METHODS: A population based dataset obtained from routinely collected death certificates involving 14,168 cancer deaths occurring before the age of 15 years registered in England and Wales between 1959-63 and 1970-90. Associations were assessed with the proportional cancer mortality ratio (PCMR), with all childhood cancer deaths forming the standard for comparison. The PCMRs were adjusted, by stratification, for age and year of death (in 1-year bands) and paternal social class (nine categories). Analyses were performed by estimated level of paternal occupational social contact (high, medium, and low) for all leukaemias, leukaemia subtype, age at death, year of death, and individual occupation. RESULTS: Out of 223 occupations, 36 (16%) were identified as having potentially high levels of social contact, and 27 (12%) as having potentially medium levels of social contact. No associations were found between paternal occupational social contact and death during childhood from leukaemia (high social contact: PCMR 94, 95% confidence interval (95% CI) 87 to 102; medium social contact: 101, 95 to 106). No associations were found when the data were analysed by leukaemia subtype, age at death, year of death, or individual occupation. CONCLUSION: The findings presented here do not support the suggestion that childhood leukaemia is related to the amount of social contact that fathers experience at work.   PMID:10472313

State of the art in forensic investigation of sudden cardiac death.

PubMed

Oliva, Antonio; Brugada, Ramon; D'Aloja, Ernesto; Boschi, Ilaria; Partemi, Sara; Brugada, Josep; Pascali, Vincenzo L

2011-03-01

The sudden death of a young person is a devastating event for both the family and community. Over the last decade, significant advances have been made in understanding both the clinical and genetic basis of sudden cardiac death. Many of the causes of sudden death are due to genetic heart disorders, which can lead to both structural (eg, hypertrophic cardiomyopathy) and arrhythmogenic abnormalities (eg, familial long QT syndrome, Brugada syndrome). Most commonly, sudden cardiac death can be the first presentation of an underlying heart problem, leaving the family at a loss as to why an otherwise healthy young person has died. Not only is this a tragic event for those involved, but it also presents a great challenge to the forensic pathologist involved in the management of the surviving family members. Evaluation of families requires a multidisciplinary approach, which should include cardiologists, a clinical geneticist, a genetic counselor, and the forensic pathologist directly involved in the sudden death case. This multifaceted cardiac genetic service is crucial in the evaluation and management of the clinical, genetic, psychological, and social complexities observed in families in which there has been a young sudden cardiac death. The present study will address the spectrum of structural substrates of cardiac sudden death with particular emphasis given to the possible role of forensic molecular biology techniques in identifying subtle or even merely functional disorders accounting for electrical instability.

Mechanism of cell death resulting from DNA interstrand cross-linking in mammalian cells

PubMed Central

Osawa, T; Davies, D; Hartley, J A

2011-01-01

DNA interstrand cross-links (ICLs) are critical cytotoxic lesions produced by cancer chemotherapeutic agents such as the nitrogen mustards and platinum drugs; however, the exact mechanism of ICL-induced cell death is unclear. Here, we show a novel mechanism of p53-independent apoptotic cell death involving prolonged cell-cycle (G2) arrest, ICL repair involving HR, transient mitosis, incomplete cytokinesis, and gross chromosomal abnormalities resulting from ICLs in mammalian cells. This characteristic ‘giant' cell death, observed by using time-lapse video microscopy, was reduced in ICL repair ERCC1- and XRCC3-deficient cells. Collectively, the results illustrate the coordination of ICL-induced cellular responses, including cell-cycle arrest, DNA damage repair, and cell death. PMID:21814285

From gunstore to smoking gun: tracking guns that kill children in North Carolina.

PubMed

Campbell, Brendan T; Radisch, Deborah L; Phillips, J Duncan; von Allmen, Daniel

2004-12-01

This study reviews the epidemiology of pediatric firearm deaths in North Carolina and estimates the time from the retail sale of guns to their involvement in pediatric firearm deaths. The authors reviewed autopsy reports for all children 0 to 14 years of age that died of firearm-related injuries in North Carolina from January 1999 through December 2002. Data obtained included demographic information, firearm type, and manner of death. Data from the Bureau of Alcohol, Tobacco and Firearms, which traced guns involved in crimes and determined the time elapsed from purchase to their involvement in a crime (ie, time-to-crime were also reviewed). During the study period, 40 children died of firearm injuries. Mean age was 7.6 years. Handguns were responsible for the majority of deaths (59%) followed by shotguns (27%), rifles (10%), and undetermined cause (10%). Most deaths were homicides (67%) followed by unintentional death (18%), suicide (13%), and undetermined cause (2%). Most crime guns (76%) were purchased legally, and many (40%) had a time-to-crime of less than 3 years. Legally purchased firearms pose a significant threat to children in North Carolina. A more restrictive approach to the sale of handguns is a logical approach to reducing pediatric firearm-related deaths in the United States.

The Molecular Autopsy: Should the Evaluation Continue After the Funeral?

PubMed Central

Tester, David J.; Ackerman, Michael J.

2012-01-01

Sudden cardiac death (SCD) is one of the most common causes of death in developed countries, with most SCDs involving the elderly, and structural heart disease evident at autopsy. Each year, however, thousands of sudden deaths involving individuals younger than 35 years of age remain unexplained after a comprehensive medicolegal investigation that includes an autopsy. In fact, several epidemiologic studies have estimated that at least 3% and up to 53% of sudden deaths involving previously healthy children, adolescents, and young adults show no morphologic abnormalities identifiable at autopsy. Cardiac channelopathies associated with structurally normal hearts such as long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS) yield no evidence to be found at autopsy, leaving coroners, medical examiners, and forensic pathologists only to speculate that a lethal arrhythmia might lie at the heart of a sudden unexplained death (SUD). In cases of autopsy-negative SUD, continued investigation through either a cardiologic and genetic evaluation of first- or second-degree relatives or a molecular autopsy may elucidate the underlying mechanism contributing to the sudden death and allow for identification of living family members with the pathogenic substrate that renders them vulnerable, with an increased risk for cardiac events including syncope, cardiac arrest, and sudden death. PMID:22307399

Teaching about Death to Undergraduates.

ERIC Educational Resources Information Center

Pine, Vanderlyn R.; And Others

Development, implementation, and teaching of a college-level course on dying and death are described. The authors review their own experiences in becoming involved with death education and describe teaching methods, problems, and content of their current course in dying and death at the State University of New York, College at New Paltz. Because…

Survival, causes of death, and prognostic factors in systemic sclerosis: analysis of 947 Brazilian patients.

PubMed

Sampaio-Barros, Percival D; Bortoluzzo, Adriana B; Marangoni, Roberta G; Rocha, Luiza F; Del Rio, Ana Paula T; Samara, Adil M; Yoshinari, Natalino H; Marques-Neto, João Francisco

2012-10-01

To analyze survival, prognostic factors, and causes of death in a large cohort of patients with systemic sclerosis (SSc). From 1991 to 2010, 947 patients with SSc were treated at 2 referral university centers in Brazil. Causes of death were considered SSc-related and non-SSc-related. Multiple logistic regression analysis was used to identify prognostic factors. Survival at 5 and 10 years was estimated using the Kaplan-Meier method. One hundred sixty-eight patients died during the followup. Among the 110 deaths considered related to SSc, there was predominance of lung (48.1%) and heart (24.5%) involvement. Most of the 58 deaths not related to SSc were caused by infection, cardiovascular or cerebrovascular disease, and cancer. Male sex, modified Rodnan skin score (mRSS) > 20, osteoarticular involvement, lung involvement, and renal crisis were the main prognostic factors associated to death. Overall survival rate was 90% for 5 years and 84% for 10 years. Patients presented worse prognosis if they had diffuse SSc (85% vs 92% at 5 yrs, respectively, and 77% vs 87% at 10 yrs, compared to limited SSc), male sex (77% vs 90% at 5 yrs and 64% vs 86% at 10 yrs, compared to female sex), and mRSS > 20 (83% vs 90% at 5 yrs and 66% vs 86% at 10 yrs, compared to mRSS < 20). Survival was worse in male patients with diffuse SSc, and lung and heart involvement represented the main causes of death in this South American series of patients with SSc.

Motor vehicle fatal crash profiles of 13-15-year-olds.

PubMed

Williams, Allan F; Tison, Julie

2012-04-01

The goal was to provide a description of fatal crashes involving 13-15-year-old drivers and passengers. Information was obtained from the Fatality Analysis Reporting System for 2005-2009. The 1,994 passenger deaths during the 2005-2009 period far exceeded the number of driver deaths (299) or the number of drivers in fatal crashes (744). Passenger deaths occurring with teenage drivers, particularly 16-17-year-olds, increased with passenger age. Most 13-15-year-old drivers in crashes were driving either with no license or permit (63%), or with a permit but without required adult presence (10 percent). Fatal crashes involving illegal driving were most likely to involve high-risk actions such as speeding and nonuse of belts. Supervised learners were few in number (about 12 per year) and had the lowest rates of high-risk actions. The main issues for 13-15-year-olds' motor vehicle deaths are passenger deaths and driving without a license or adult supervision. Parents, pediatricians, and others need to recognize the increase in motor vehicle occupant deaths that occurs in the early teen years. Copyright © 2012 National Safety Council and Elsevier Ltd. All rights reserved.

Surgical Resection and Inferior Vena Cava Reconstruction for Treatment of the Malignant Tumor: Technical Success and Outcomes

PubMed Central

2014-01-01

Objective: The purpose of this study was to review patients who underwent inferior vena cava (IVC) resection with concomitant malignant tumor resection and to consider the operative procedures and the outcomes. Materials and Methods: Between 2000 and 2012, 41 patients underwent resection of malignant tumors concomitant with surgical resection of the IVC at our institute. The records of these patients were retrospectively reviewed. Results: Primary tumor resections included nephrectomy, hepatectomy, retroperitoneal tumor extirpation, lymph node dissection, and pancreaticoduodenectomy. The IVC interventions were partial resection in 23 patients and total resection in 18 patients. Four patients underwent IVC replacement. Operation-related complications included pulmonary embolism, acute myocardial infarction, deep vein thrombosis, leg edema and temporary hemodialysis. There were no operative deaths. The mean follow-up period was 24.9 months (range: 2–98 months). The prognosis depended on the type and stage of the tumor. Conclusion: Resection and reconstruction of the IVC can be performed safely if the preoperative evaluations and surgical procedures are performed properly. The IVC resection without reconstruction was permissive if the IVC was completely obstructed preoperatively, but it may also be considered in cases where the IVC is not completely obstructed. PMID:24995055

Coupling of lipid membrane elasticity and in-plane dynamics

NASA Astrophysics Data System (ADS)

Tsang, Kuan-Yu; Lai, Yei-Chen; Chiang, Yun-Wei; Chen, Yi-Fan

2017-07-01

Biomembranes exhibit liquid and solid features concomitantly with their in-plane fluidity and elasticity tightly regulated by cells. Here, we present experimental evidence supporting the existence of the dynamics-elasticity correlations for lipid membranes and propose a mechanism involving molecular packing densities to explain them. This paper thereby unifies, at the molecular level, the aspects of the continuum mechanics long used to model the two membrane features. This ultimately may elucidate the universal physical principles governing the cellular phenomena involving biomembranes.

Leishmania tropica-induced cutaneous and presumptive concomitant viscerotropic leishmaniasis with prolonged incubation.

PubMed

Weiss, Francesca; Vogenthaler, Nicholas; Franco-Paredes, Carlos; Parker, Sareeta R S

2009-09-01

Leishmaniasis includes a spectrum of diseases caused by protozoan parasites belonging to the genus Leishmania. The disease is traditionally classified into visceral, cutaneous, or mucocutaneous leishmaniasis, depending on clinical characteristics as well as the species involved. Leishmania tropica is one of the causative agents of cutaneous leishmaniasis, with a typical incubation period of weeks to months. Observation We describe a 17-year-old Afghani girl who had lived in the United States for 4 years and who presented with a 6-month history of pretibial ulcerations, 9.1-kg weight loss, abdominal pain, splenomegaly, and extreme fatigue. Histopathologic examination and culture with isoenzyme electrophoresis speciation of her skin lesions confirmed the presence of L tropica. In addition, results of serum laboratory and serological studies were highly suggestive of concomitant visceral involvement. The patient was treated with a 28-day course of intravenous pentavalent antimonial compound sodium stibogluconate with complete resolution of her systemic signs and symptoms and improvement of her pretibial ulcerations. This is an exceptional case in that our patient presented with disease after an incubation period of years rather than the more typical weeks to months. In addition, this patient had confirmed cutaneous involvement, as well as strong evidence of viscerotropic disease caused by L tropica, a species that characteristically displays dermotropism, not viscerotropism.

78 FR 68074 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-13

...). Background and Brief Description In 2009, drug overdose deaths became the leading cause of injury death in the United States (U.S.), exceeding motor vehicle traffic crash deaths for the first time, a trend... the main driver of this increase. The number of overdose deaths per year involving opioid pain...

Correlates of a Good Death and the Impact of Hospice Involvement: Findings from the National Survey of Households Affected by Cancer

PubMed Central

Cagle, John G.; Pek, Jolynn; Clifford, Maggie; Guralnik, Jack; Zimmerman, Sheryl

2017-01-01

Purpose Knowing how to improve the dying experience for patients with end-stage cancer is essential for cancer professionals. However, there is little evidence on the relationship between clinically relevant factors and quality of death. Also, while hospice has been linked with improved outcomes, our understanding of factors that contribute to a “good death” when hospice is involved remains limited. This study (1) identified correlates of a good death; and, (2) provided evidence on the impact of hospice on quality of death. Methods Using data from a survey of US households affected by cancer (N=930, response rate 51%), we fit regression models with a subsample of 158 respondents who had experienced the death of a family member with cancer. Measures included quality of death (good/bad) and clinically relevant factors including: hospice involvement, symptoms during treatment, whether wishes were followed, provider knowledge/expertise and compassion. Results Respondents were 60% female, 89% White, and averaged 57 years old. Decedents were most often a respondent's spouse (46%). While 73% of respondents reported a good death, Hispanics were less likely to experience good death (p=.007). Clinically relevant factors, including hospice, were associated with good death (p<.05) -- an exception being whether the physician said the cancer was curable/fatal. With adjustments, perceptions of provider knowledge/expertise was the only clinical factor that remained associated with good death. Conclusions Enhanced provider training/communication, referrals to hospice and greater attention to symptom management may facilitate improved quality of dying. Additionally, the cultural relevance of the concept of a “good death” warrants further research. PMID:25194877

Persuasive Style: Some Verbal Concomitants of Conversational Persuasion.

ERIC Educational Resources Information Center

Sherblom, John; Reinsch, N. L., Jr.

To test whether verbal choices in a persuasive setting would show less diversity and more qualification than those in a nonpersuasive setting, a study involving 24 college students was undertaken. The subjects were divided into five groups and each group was asked to role play two situations: one calling for the subjects merely to be…

Online Help Systems

DTIC Science & Technology

1989-09-07

online materials (and the concomitant increase in the cost for hardcopy materials) will make online delivery the marketing choice. In sum, medium of...involved in programming, marketing , human factors research, training, and business management. Job Titles of Online Help Designers Job Title...of Company Senior Research Librarian Advisory Information Developer Research Staff Assistant Marketing Manager Manager of Online Documentation Table

From Serendipity to Resolve: Graduate Student Motivations to Teach Using Service-Learning

ERIC Educational Resources Information Center

Garrison, Jonathan D.; Jaeger, Audrey J.

2014-01-01

With the expansion of service-learning has come a concomitant growth in research related to all the stakeholders involved with this pedagogy--students, faculty, community, and higher education institutions. However, no studies have examined the use of service-learning by a strong segment of college instructors--graduate students. To address the…

Substance P/Neurokinin 1 and Trigeminal System: A Possible Link to the Pathogenesis in Sudden Perinatal Deaths

PubMed Central

Mehboob, Riffat

2017-01-01

Sudden demise of a healthy fetus or a neonate is a very tragic episode in the life of parents. These deaths have been a mystery since ages but still remain unexplained. This review proposes the involvement of trigeminal nerve, neurotransmitter substance P (SP), and its receptor neurokinin 1 (NK-1R) in regulation of cardiorespiratory control in fetuses and newborns. Anomalies and immaturity of neuroregulatory systems such as trigeminal system in medulla oblongata of brainstem may provide a possible mechanism of sudden perinatal deaths. Vulnerable infants are born with respiratory center immaturity which in combination with any stressor such as cold, hypoxia, and smoking may lead to cessation of breathing and ventilatory response. SP/NK-1R may be involved in regulating the ventilatory control in neonates while it is decreased in fetal and adult life in humans, and any alterations from these may lead to irreversible sleep apnea and fatal breathing, ultimately sudden death. This review summarizes the studies performed to highlight the expression of SP or NK-1R in sudden perinatal deaths and proposes the involvement of trigeminal ganglion along with its nerve and SP/NK-1R expression alteration as one of the possible pathophysiological underlying mechanism. However, further studies are required to explore the role of SP, NK-1R, and trigeminal system in the pathogenesis of sudden infant deaths, sudden intrauterine deaths, stillbirths, and sudden deaths later in human life. PMID:28348544

Substance P/Neurokinin 1 and Trigeminal System: A Possible Link to the Pathogenesis in Sudden Perinatal Deaths.

PubMed

Mehboob, Riffat

2017-01-01

Sudden demise of a healthy fetus or a neonate is a very tragic episode in the life of parents. These deaths have been a mystery since ages but still remain unexplained. This review proposes the involvement of trigeminal nerve, neurotransmitter substance P (SP), and its receptor neurokinin 1 (NK-1R) in regulation of cardiorespiratory control in fetuses and newborns. Anomalies and immaturity of neuroregulatory systems such as trigeminal system in medulla oblongata of brainstem may provide a possible mechanism of sudden perinatal deaths. Vulnerable infants are born with respiratory center immaturity which in combination with any stressor such as cold, hypoxia, and smoking may lead to cessation of breathing and ventilatory response. SP/NK-1R may be involved in regulating the ventilatory control in neonates while it is decreased in fetal and adult life in humans, and any alterations from these may lead to irreversible sleep apnea and fatal breathing, ultimately sudden death. This review summarizes the studies performed to highlight the expression of SP or NK-1R in sudden perinatal deaths and proposes the involvement of trigeminal ganglion along with its nerve and SP/NK-1R expression alteration as one of the possible pathophysiological underlying mechanism. However, further studies are required to explore the role of SP, NK-1R, and trigeminal system in the pathogenesis of sudden infant deaths, sudden intrauterine deaths, stillbirths, and sudden deaths later in human life.

Toddler run-overs--a persistent problem.

PubMed

Byard, Roger W; Jensen, Lisbeth L

2009-05-01

Trauma accounts for a high percentage of unexpected deaths in toddlers and young children, mostly due to vehicle accidents, drowning and fires. Given recent efforts to publicise the dangers of toddler run-overs a study was undertaken to determine how significant this problem remains in South Australia. Review of coronial files over 7 years from 2000 to 2006 revealed 50 cases of sudden and unexpected death in children aged between 1 and 3 years of which 12 of 28 accidents involved motor vehicles (6 run-overs and 6 passengers). The 6 children who were killed by vehicle run-overs were aged from 12 months to 22 months (ave=16.8 months) with a male to female ratio of 1:1. Four deaths occurred with reversing vehicles in home driveways and one at a community centre. The remaining death involved a child being run over at the beach by a forward moving vehicle. Vehicles included sedans in four cases and a four-wheel drive in one case (one vehicle was not described), and were driven by the victim's parent in four cases, a friend of the family in one, and an unrelated person in the final case. Deaths were all due to blunt cranial trauma. Despite initiatives to prevent these deaths, toddler run-overs in South Australia approximate the number of sudden deaths due to homicides, drownings and natural diseases, respectively, for the same age group; deaths are also occurring in places other than home driveways, and sedans were more often involved than four-wheel drive vehicles.

Oxidative stress induces protein and DNA radical formation in follicular dendritic cells (FDCs) of the germinal center and modulates its cell death patterns in late sepsis

PubMed Central

Chatterjee, Saurabh; Lardinois, Olivier; Bhattacharjee, Suchandra; Tucker, Jeff; Corbett, Jean; Deterding, Leesa; Ehrenshaft, Marilyn; Bonini, Marcelo; Mason, Ronald P.

2011-01-01

Profound depletion of follicular dendritic cells (FDCs) is a hallmark of sepsis-like syndrome, but the exact causes for the ensuing cell death are unknown. The cell death-driven depletion contributes to immunoparalysis and is responsible for most of the morbidity and mortality in sepsis. Here we have utilized immuno-spin trapping, a method for detection of free radical formation, to detect oxidative stress-induced protein and DNA radical adducts in FDCs isolated from the spleen of septic mice and human tonsil-derived HK cells, a subtype of germinal center FDCs, to study their role in FDC depletion. At 24 h post-LPS administration, protein radical formation and oxidation was significantly elevated in vivo and in HK cells as shown by ELISA and confocal microscopy. The xanthine oxidase inhibitor allopurinol and the iron chelator desferrioxamine significantly decreased the formation of protein radicals, suggesting the role of xanthine oxidase and Fenton-like chemistry in radical formation. Protein and DNA radical formation correlated mostly with apoptotic features at 24 h and necrotic morphology of all the cell types studied at 48 h with concomitant inhibition of caspase-3. The cytotoxity of FDCs resulted in decreased CD45R/CD138+ve plasma cell numbers, indicating a possible defect in B cell differentiation. In one such mechanism, radical formation initiated by xanthine oxidase formed protein and DNA radicals which may lead to cell death of germinal center FDCs. PMID:21215311

Impact of Chronic Obstructive Pulmonary Disease on Long-Term Outcome in Patients with Coronary Artery Disease Undergoing Percutaneous Coronary Intervention.

PubMed

Zhang, Ming; Cheng, Yun-Jiu; Zheng, Wei-Ping; Liu, Guang-Hui; Chen, Huai-Sheng; Ning, Yu; Zhao, Xin; Su, Li-Xiao; Liu, Li-Juan

2016-01-01

Objective . The aim of this study was to investigate the association between COPD and major adverse cardiovascular and cerebral events (MACCE) in patients undergoing percutaneous coronary intervention (PCI). Methods . 2,362 patients who underwent PCI were included in this study. Subjects were divided into 2 groups: with COPD ( n = 233) and without COPD ( n = 2,129). Cox proportional hazards models were analyzed to determine the effect of COPD on the incidence of MACCE. Results . The patients with COPD were older ( P < 0.0001) and were more likely to be current smokers ( P = 0.02) and have had hypertension ( P = 0.02) and diabetes mellitus ( P = 0.01). Prevalence of serious cardiovascular comorbidity was higher in the patients with COPD, including a history of MI ( P = 0.02) and HF ( P < 0.0001). Compared with non-COPD group, the COPD group showed a higher risk of all-cause death (hazard ratio (HR): 2.45, P < 0.0001), cardiac death (HR: 2.53, P = 0.0002), MI (HR: 1.387, P = 0.027), and HF (HR: 2.25, P < 0.0001). Conclusions . Patients with CAD and concomitant COPD are associated with a higher incidence of MACCE (all-cause death, cardiac death, MI, and HF) compared to patients without COPD. The patients with a history of COPD have higher in-hospital and long-term mortality rates than those without COPD after PCI.

Acute administration of ucf-101 ameliorates the locomotor impairments induced by a traumatic spinal cord injury.

PubMed

Reigada, D; Nieto-Díaz, M; Navarro-Ruiz, R; Caballero-López, M J; Del Águila, A; Muñoz-Galdeano, T; Maza, R M

2015-08-06

Secondary death of neural cells plays a key role in the physiopathology and the functional consequences of traumatic spinal cord injury (SCI). Pharmacological manipulation of cell death pathways leading to the preservation of neural cells is acknowledged as a main therapeutic goal in SCI. In the present work, we hypothesize that administration of the neuroprotective cell-permeable compound ucf-101 will reduce neural cell death during the secondary damage of SCI, increasing tissue preservation and reducing the functional deficits. To test this hypothesis, we treated mice with ucf-101 during the first week after a moderate contusive SCI. Our results reveal that ucf-101 administration protects neural cells from the deleterious secondary mechanisms triggered by the trauma, reducing the extension of tissue damage and improving motor function recovery. Our studies also suggest that the effects of ucf-101 may be mediated through the inhibition of HtrA2/OMI and the concomitant increase of inhibitor of apoptosis protein XIAP, as well as the induction of ERK1/2 activation and/or expression. In vitro assays confirm the effects of ucf-101 on both pathways as well as on the reduction of caspase cascade activation and apoptotic cell death in a neuroblastoma cell line. These results suggest that ucf-101 can be a promising therapeutic tool for SCI that deserves more detailed analyses. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Hyperosmolar sodium chloride is toxic to cultured neurons and causes reduction of glucose metabolism and ATP levels, an increase in glutamate uptake, and a reduction in cytosolic calcium.

PubMed

Morland, Cecilie; Pettersen, Mi Nguyen; Hassel, Bjørnar

2016-05-01

Elevation of serum sodium, hypernatremia, which may occur during dehydration or treatment with sodium chloride, may cause brain dysfunction and damage, but toxic mechanisms are poorly understood. We found that exposure to excess NaCl, 10-100mmol/L, for 20h caused cell death in cultured cerebellar granule cells (neurons). Toxicity was due to Na(+), since substituting excess Na(+) with choline reduced cell death to control levels, whereas gluconate instead of excess Cl(-) did not. Prior to cell death from hyperosmolar NaCl, glucose consumption and lactate formation were reduced, and intracellular aspartate levels were elevated, consistent with reduced glycolysis or glucose uptake. Concomitantly, the level of ATP became reduced. Pyruvate, 10mmol/L, reduced NaCl-induced cell death. The extracellular levels of glutamate, taurine, and GABA were concentration-dependently reduced by excess NaCl; high-affinity glutamate uptake increased. High extracellular [Na(+)] caused reduction in intracellular free [Ca(2+)], but a similar effect was seen with mannitol, which was not neurotoxic. We suggest that inhibition of glucose metabolism with ensuing loss of ATP is a neurotoxic mechanism of hyperosmolar sodium, whereas increased uptake of extracellular neuroactive amino acids and reduced intracellular [Ca(2+)] may, if they occur in vivo, contribute to the cerebral dysfunction and delirium described in hypernatremia. Copyright © 2016. Published by Elsevier B.V.

Drug treatment at the end of life: an epidemiologic study in nursing homes.

PubMed

Jansen, Kristian; Schaufel, Margrethe Aase; Ruths, Sabine

2014-12-01

To examine drug treatment in nursing home patients at the end of life, and identify predictors of palliative drug therapy. A historical cohort study. Three urban nursing homes in Norway. All patients admitted from January 2008 and deceased before February 2013. Drug prescriptions, diagnoses, and demographic data were collected from electronic patient records. Palliative end-of-life drug treatment was defined on the basis of indication, drug, and formulation. 524 patients were included, median (range) age at death 86 (19-104) years, 59% women. On the day of death, 99.4% of the study population had active prescriptions; 74.2% had palliative drugs either alone (26.9%) or concomitantly with curative/preventive drugs (47.3%). Palliative drugs were associated with nursing home, length of stay > 16 months (AOR 2.10, 95% CI 1.12-3.94), age (1.03, 1.005-1.05), and a diagnosis of cancer (2.12, 1.19-3.76). Most initiations of palliative drugs and withdrawals of curative/preventive drugs took place on the day of death. Palliative drug therapy and drug therapy changes are common for nursing home patients on the last day of life. Improvements in end-of-life care in nursing homes imply addressing prognostication and earlier response to palliative needs.

Mammalian cells loaded with platinum-containing molecules are sensitized to fast atomic ions.

PubMed

Usami, N; Furusawa, Y; Kobayashi, K; Lacombe, S; Reynaud-Angelin, A; Sage, E; Wu, Ting-Di; Croisy, A; Guerquin-Kern, J-L; Le Sech, C

2008-07-01

This work investigates whether a synergy in cell death induction exists in combining atomic ions irradiation and addition of platinum salts. Such a synergy could be of interest in view of new cancer therapy protocol based on atomic ions--hadrontherapy--with the addition of radiosensitizing agents containing high-Z atoms. The experiment consists in irradiating by fast ions cultured cells previously exposed to dichloroterpyridine Platinum (PtTC) and analyzing cell survival by a colony-forming assay. Chinese Hamster Ovary (CHO) cells were incubated for six hours in medium containing 350 microM PtTC, and then irradiated by fast ions C(6+) and He(2+), with Linear Energy Transfer (LET) within range 2-70 keV/microm. In some experiments, dimethyl sulfoxide (DMSO) was added to investigate the role of free radicals. The intracellular localization of platinum was determined by Nano Secondary Ion Mass Spectroscopy (Nano-SIMS). For all LET examined, cell death rate is largely enhanced when irradiating in presence of PtTC. At fixed irradiation dose, cell death rate increases with increasing LET, while the platinum relative effect is larger at low LET. This finding suggests that hadrontherapy or protontherapy therapeutic index could be improved by combining irradiation procedure with concomitant chemotherapy protocols using platinum salts.

The outcome of tuberculosis treatment in subjects with chronic kidney disease in Brazil: a multinomial analysis*

PubMed Central

Reis-Santos, Barbara; Gomes, Teresa; Horta, Bernardo Lessa; Maciel, Ethel Leonor Noia

2013-01-01

OBJECTIVE: To analyze the association between clinical/epidemiological characteristics and outcomes of tuberculosis treatment in patients with concomitant tuberculosis and chronic kidney disease (CKD) in Brazil. METHODS: We used the Brazilian Ministry of Health National Case Registry Database to identify patients with tuberculosis and CKD, treated between 2007 and 2011. The tuberculosis treatment outcomes were compared with epidemiological and clinical characteristics of the subjects using a hierarchical multinomial logistic regression model, in which cure was the reference outcome. RESULTS: The prevalence of CKD among patients with tuberculosis was 0.4% (95% CI: 0.37-0.42%). The sample comprised 1,077 subjects. The outcomes were cure, in 58%; treatment abandonment, in 7%; death from tuberculosis, in 13%; and death from other causes, in 22%. The characteristics that differentiated the ORs for treatment abandonment or death were age; alcoholism; AIDS; previous noncompliance with treatment; transfer to another facility; suspected tuberculosis on chest X-ray; positive results in the first smear microscopy; and indications for/use of directly observed treatment, short-course strategy. CONCLUSIONS: Our data indicate the importance of sociodemographic characteristics for the diagnosis of tuberculosis in patients with CKD and underscore the need for tuberculosis control strategies targeting patients with chronic noncommunicable diseases, such as CKD. PMID:24310632

In Situ Gelation-Induced Death of Cancer Cells Based on Proteinosomes.

PubMed

Zhou, Yuting; Song, Jianmin; Wang, Lei; Xue, Xuting; Liu, Xiaoman; Xie, Hui; Huang, Xin

2017-08-14

Hydrogels are an excellent type of material that can be utilized as a platform for cell culture. However, when a bulky hydrogel forms on the inside of cancer cells, the result would be different. In this study, we demonstrate a method for in situ gelation inside cancer cells that can efficiently induce cell death. Glutathione-responsive proteinosomes with good biocompatibility were prepared as carriers for sodium alginate to be endocytosed by cancer cells, where the chelation between sodium alginate and free calcium ions in the culture medium occurs during the diffusion process. The uptake of the hydrogel-loaded proteinosomes into the cancer cells, and then the triggered release of hydrogel with concomitant aggregation, was well-confirmed by monitoring the change of the Young's modulus of the cells based on AFM force measurements. Accordingly, when a large amount of hydrogel formed in cells, the cell viability would be inhibited by ∼90% by MTT assay at a concentration of 5.0 μM of hydrogel-loaded proteinosomes after 48 h incubation, which clearly proves the feasibility of the demonstrated method for killing cancer cells. Although more details regarding the mechanism of cell death should be conducted in the near future, such a demonstrated method of in situ gelation inside cells provides another choice for killing cancer cells.

Prevalence of prescription and illicit drugs in pregnancy-associated non-natural deaths of Florida mothers, 1999-2005.

PubMed

Hardt, Nancy; Wong, Tit D; Burt, Martha J; Harrison, Ross; Winter, Will; Roth, Jeffrey

2013-11-01

Abuse of prescription and illicit drugs has been rapidly increasing. This study examines the prevalence of drug use in the non-natural deaths of pregnant or recently pregnant women. Records from Florida's Pregnancy Associated Mortality Review conducted between 1999 and 2005 (n = 415) were linked to 385 toxicology reports obtained from Florida medical examiners' offices. The final study sample consisted of 169 drug-positive, pregnancy-associated non-natural deaths. Of these, 86 were positive for both blood and urine, 64 were positive for blood only and five for urine only, and the remainder were positive for some other specimen. Among these deaths, 91 cases (54%) involved prescription drugs, 78 cases (46%) involved illicit drugs, and 69 cases (41%) involved alcohol. Opioids constituted the majority of deaths associated with prescription drugs. Substantial co-use of opioids and benzodiazepines was seen. Pregnant or recently pregnant women may have more interactions with healthcare providers, which may present more opportunities for intervention and prevention. © 2013 American Academy of Forensic Sciences.

When domestic goes capital: Juror decision making in capital murder trials involving domestic homicide.

PubMed

Richards, Tara N; Smith, M Dwayne; Fogel, Sondra J; Bjerregaard, Beth

2015-08-01

Prior research suggests that homicide cases involving familial offenders and victims are subject to a "domestic discount" that reduces sentencing severity. However, the operation of a domestic discount in regard to death penalty sentencing has been rarely examined. The current research uses a near-population of jury decisions in capital murder trials conducted in North Carolina from 1991 to 2009 (n = 800), and a series of logistic regression analyses to determine whether there is (a) a direct effect between offender-victim relationship (e.g., domestic, friend/acquaintance, and stranger) and jury decision making, and/or (b) whether domestic offender-victim relationship (as well as other offender-victim relationships) moderates the effect of legal and extralegal case characteristics on jury assessment of the death penalty. Our findings revealed no empirical support for a "domestic discount" whereby juries are less likely to impose death sentences in cases involving domestic homicides. However, substantial differences in predictors of death sentencing were found across offender-victim dyads; most notably, domestic homicide cases demonstrated the most legalistic model of jury decisions to impose death sentences. (c) 2015 APA, all rights reserved).

Increase in Drug Overdose Deaths Involving Fentanyl-Rhode Island, January 2012-March 2014.

PubMed

Mercado, Melissa C; Sumner, Steven A; Spelke, M Bridget; Bohm, Michele K; Sugerman, David E; Stanley, Christina

2018-03-01

This study identified sociodemographic, substance use, and multiple opioid prescriber and dispenser risk factors among drug overdose decedents in Rhode Island, in response to an increase in overdose deaths (ODs) involving fentanyl. This cross-sectional investigation comprised all ODs reviewed by Rhode Island's Office of the State Medical Examiners (OSME) during January 2012 to March 2014. Data for 536 decedents were abstracted from OSME's charts, death certificates, toxicology reports, and Prescription Monitoring Program (PMP) databases. Decedents whose cause of death involved illicit fentanyl (N = 69) were compared with decedents whose causes of death did not involve fentanyl (other drug decedents; N = 467). Illicit-fentanyl decedents were younger than other drug decedents (P = 0.005). While more other-drug decedents than illicit fentanyl decedents had postmortem toxicological evidence of consuming heroin (31.9% vs 19.8%, P < 0.001) and various pharmaceutical substances (P = 0.002-0.027), third party reports indicated more recent heroin use among illicit fentanyl decedents (62.3% vs 45.6%, P = 0.002). Approximately 35% of decedents filled an opioid prescription within 90 days of death; of these, one-third had a mean daily dosage greater than 100 morphine milligram equivalents (MME/day). Most decedents' opioid prescriptions were filled at one to two dispensers (83.9%) and written by one to two prescribers (75.8%). Notably, 29.2% of illicit fentanyl and 10.5% of other drug decedents filled prescriptions for buprenorphine, which is used to treat opioid use disorders. Illicit-fentanyl deaths frequently involved other illicit drugs (e.g., cocaine, heroin). The proportion of all decedents acquiring greater than 100 MME/day prescription dosages written and/or filled by few prescribers and dispensers is concerning. To protect patients, prescribers and dispensers should review PMP records and substance abuse history prior to providing opioids.

Work-related deaths among youth: Understanding the contribution of US child labor violations.

PubMed

Rauscher, Kimberly J; Myers, Douglas J; Miller, Mary E

2016-11-01

Evidence shows that violations of the United States (US) child labor regulations are common. The main purpose of this study was to investigate the magnitude and nature of work-related deaths among youth involving violations of US child labor regulations. We analyzed Census of Fatal Occupational Injury data from 2001 to 2012 using descriptive statistics and Chi-square tests. Between 2001 and 2012, 406 workers under age 18 were recorded in the CFOI as having suffered a fatal work-related injury. Among these cases, 233 were covered by the US child labor regulations. Forty-three percent of these cases involved at least one violation. The majority of cases that were not covered by the regulations involved decedents working on their family's farms (N = 139). Violations of federal child labor regulations are a significant contributor to work-related deaths among youth in the United States. Increased investment in enforcement is needed to prevent further young worker deaths involving child labor violations. Am. J. Ind. Med. 59:959-968, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Photoreceptor cell death and rescue in retinal detachment and degenerations

PubMed Central

Murakami, Yusuke; Notomi, Shoji; Hisatomi, Toshio; Nakazawa, Toru; Ishibashi, Tatsuro; Miller, Joan W.; Vavvas, Demetrios G.

2013-01-01

Photoreceptor cell death is the ultimate cause of vision loss in various retinal disorders, including retinal detachment (RD). Photoreceptor cell death has been thought to occur mainly through apoptosis, which is the most characterized form of programmed cell death. The caspase family of cysteine proteases plays a central role for inducing apoptosis, and in experimental models of RD, dying photoreceptor cells exhibit caspase activation; however, there is a paradox that caspase inhibition alone does not provide a sufficient protection against photoreceptor cell loss, suggesting that other mechanisms of cell death are involved. Recent accumulating evidence demonstrates that non-apoptotic forms of cell death, such as autophagy and necrosis, are also regulated by specific molecular machinery, such as those mediated by autophagy-related proteins and receptor-interacting protein kinases, respectively. Here we summarize the current knowledge of cell death signaling and its roles in photoreceptor cell death after RD and other retinal degenerative diseases. A body of studies indicate that not only apoptotic but also autophagic and necrotic signaling are involved in photoreceptor cell death, and that combined targeting of these pathways may be an effective neuroprotective strategy for retinal diseases associated with photoreceptor cell loss. PMID:23994436

Causes of death in patients with chronic sarcoidosis.

PubMed

Hu, Xiaowen; Carmona, Eva M; Yi, Eunhee S; Pellikka, Patricia A; Ryu, Jay

2016-10-07

Sarcoidosis is a multi-system, granulomatous disorder of unknown etiology that is associated with a variable prognosis and sometimes results in death. There are conflicting reports regarding the causes of death in patients with sarcoidosis. Forty-four consecutive patients with sarcoidosis who underwent an autopsy (35 patients) or died at Mayo Clinic (Rochester, MN, USA) over a 20-yr period, from January 1, 1994 to December 31, 2013 were analyzed. The median age at death was 63 years (range, 33-94 years) and there were 22 (50%) women. Sarcoidosis had not been clinically diagnosed in 16 (36%) patients before death. Fifteen deaths (34%) were related to sarcoidosis and included seven deaths (16%) from cardiac sarcoidosis and four deaths (9%) from progressive pulmonary sarcoidosis. Other sarcoidosis-related causes of death included advanced hepatic sarcoidosis (5%) and opportunistic infections (5%) related to immunosuppressive therapy for treating sarcoidosis. Among seven patients dying from cardiac sarcoidosis, three had been diagnosed with sarcoidosis during life and cardiac involvement was known in two of them. Six of seven deaths from cardiac sarcoidosis occurred in the autopsied cohort while all four deaths from pulmonary sarcoidosis occurred in those not autopsied. In the majority of patients dying with sarcoidosis the cause of death is unrelated to sarcoidosis. Cardiac involvement is the most common cause of sarcoidosis-related deaths in patients subjected to postmortem examination and was usually undiagnosed during life. The cause distribution of death in patients with sarcoidosis differed depending on whether autopsy was performed.

Cocaine-related deaths.

PubMed

Lora-Tamayo, C; Tena, T; Rodriguez, A

1994-07-15

Cocaine availability has been increasing in Spain in the past few years. A review of all the toxicological analyses carried out at the Madrid Department of the Instituto Nacional de Toxicología, with subjects who had died of drugs from 1990 to 1992, found 533 persons who had cocaine in their blood and/or tissues; 450 (84%) deaths involved cocaine and heroin together whereas 83 (16%) deaths involved cocaine with an absence of heroin. This paper reports the circumstances, cocaine and benzoylecgonine concentrations in the blood and other toxicological findings for the two major groups of deaths where cocaine was found with an absence of heroin, i.e., possible overdose cases (35 cases) and traffic accidents (23 cases).

Hypertrophic Cardiomyopathy: Practical Steps for Preventing Sudden Death.

ERIC Educational Resources Information Center

Maron, Barry J.

2002-01-01

Hypertrophic cardiomyopathy (HCM) is a rare cause of death among athletes, with deaths occurring in young, apparently healthy people. Differentiating HCM from conditioning hypertrophy is challenging. Routine detection involves family history, physical examination, electrocardiography, and echocardiography. Keys to differential diagnosis include…

Nonnatural deaths of adolescents and teenagers: Fulton County, Georgia, 1985-2004.

PubMed

Heninger, Michael; Hanzlick, Randy

2008-09-01

Childhood deaths are carefully scrutinized by many different government agencies, fatality review panels, researchers, and other groups. Many such deaths, especially those that involve external causes such as injury and poisoning, are amenable to prevention. Characterizing the causes and circumstances of nonnatural childhood deaths may provide information that is useful for development of prevention strategies and programs. This is a retrospective review of all nonnatural deaths investigated and certified by the Fulton County Medical Examiner involving persons 10 to 19 years of age during the years 1985-2004, inclusive. Cases were identified by searching electronic death investigation files maintained during the study period. Demographic and circumstantial information were tabulated for homicides, suicides, motor-vehicle fatalities, and other accidental deaths, and crude death rates were calculated for each 5-year period during the study. During the 20 year period there were 961 nonnatural deaths among persons 10 to 19 years of age. Most deaths were due to homicide (48%) followed by motor-vehicle fatalities (30%), suicide (12%), and nontraffic accidental fatalities (10%). Black males had the highest death rates among the homicide, suicide, and nontraffic accidental deaths, although the rates for each of these were lower in the most recent 5 year period than the first 5-year period. The number of deaths increased in each category as age increased, and this observation was most marked for homicides and least marked for nontraffic accidental deaths. Firearms were involved in 88% of homicides and 61% of suicides. Most nontraffic accidental deaths were due to water-related accidents, followed by drug and/or alcohol toxicity, fire-related injuries, and accidental firearms injuries. Homicide accounts for almost half of all deaths among persons 10 to 19 years of age. Black males are at particularly high risk for nonnatural death in comparison with other race/sex groups, especially for homicide. If effective firearm fatality prevention strategies and programs could be implemented, data in this study suggests that such a measure alone could cut in half the nonnatural mortality rate in the 10 to 19 year age group in Fulton County. Although homicide and suicide rates have declined, there remains room for improvement in these areas, as is the case for traffic-related and other accidental fatalities.

Contending With Preplanned Death: Questions for Clinicians.

PubMed

Yager, Joel

2017-09-01

The goal of this column is to assist readers in reflecting on their attitudes and responses toward clinical and nonclinical situations involving preplanned deaths by decisionally capable individuals. Such circumstances range from encountering individuals in one's personal and professional lives who desire and intend to end their lives under their own terms, to having such individuals request assistance with predeath and postdeath arrangements. Attending to pertinent literature, this essay uses Socratic inquiry to question conventional assumptions and attitudes, push readers' thoughts beyond typical comfort zones, and consider alternative modes of responding to challenges posed by preplanned death. Studies indicate that, for their own end-of-life circumstances, physicians would prefer a briefer, higher quality life to prolonged low-quality life, dignity in infirmity and death, and avoidance of terminal suffering. Lay people generally endorse similar preferences. Although contemporary society generally shuns contemplating preplanned death, cultural attitudes regarding preplanned death are rapidly evolving, and variations of "Death with Dignity" legislation have gained traction in increasing numbers of US states as well as internationally. As yet, no broad consensus exists as to how clinicians should manage circumstances involving preplanned death. Considerations regarding preplanned deaths merit greater professional and public discussion. Many options exist for improving how professionals address the quality of human experiences surrounding death.

Single stab injuries.

PubMed

Burke, Michael P; Baber, Yeliena; Cheung, Zoe; Fitzgerald, Mark

2018-05-01

Determining the manner of death in cases involving multiple stab injuries from a knife is generally straightforward. The medico-legal investigation of a stabbing death caused by a single stab injury from a knife comprises a smaller but potentially more problematic subset of forensic cases. We reviewed our institute's experience with single stab injuries and endeavored to identify features identified at the post-mortem examination which may aid in the differentiation between cases of homicide, suicide and accidental death. The single stab injury was to the left chest in the majority of deaths from homicide and from suicide. Clothing was nearly always involved in cases of homicide, but was also seen in cases of suicide. The knife was found in situ in 9 of the 11 cases of suicide involving a chest injury, but was not seen in any of the cases of homicide. There were no cases of an accidental single stab death from a knife in our records. Clinical data on accidental stab injuries was sought via a search of the medical records of a major tertiary referral hospital. A single non-fatal case of an accidental single stab injury from a knife was identified after the conclusion of our study period. Accidental stab injuries from a knife causing injury or death are rare.

Quality of Care: A Review of Maternal Deaths in a Regional Hospital in Ghana.

PubMed

Adusi-Poku, Yaw; Antwil, Edward; Osei-Kwakye, Kingsley; Tetteh, Chris; Detoh, Eric Kwame; Antwi, Phyllis

2015-09-01

The government of Ghana and key stakeholders have put into place several interventions aimed at reducing maternal deaths. At the institutional level, the conduct of maternal deaths audit has been instituted. This also contributes to reducing maternal deaths as shortcomings that may have contributed to such deaths could be identified to inform best practice and forestall such occurrences in the future. The objective of this study was to review the quality of maternal care in a regional hospital. A review of maternal deaths using Quality of Care Evaluation Form adapted from the Komfo Anokye Teaching Hospital (KATH) Maternal Death Audit Evaluation Committee was used. About fifty-five percent, 18 (55%) of cases were deemed to have received adequate documentation, senior clinicians were involved in 26(85%) of cases. Poor documentation, non-involvement of senior clinicians in the management of cases, laboratory related issues particularly in relation to blood and blood products as well as promptness of care and adequacy of intensive care facilities and specialists in the hospital were contributory factors to maternal deaths . These are common themes contributing to maternal deaths in developing countries which need to be urgently tackled. Maternal death review with emphasis on quality of care, coupled with facility gap assessment, is a useful tool to address the adequacy of emergency obstetric care services to prevent further maternal deaths.

Deaths Involving Fentanyl, Fentanyl Analogs, and U-47700 - 10 States, July-December 2016.

PubMed

O'Donnell, Julie K; Halpin, John; Mattson, Christine L; Goldberger, Bruce A; Gladden, R Matthew

2017-11-03

Preliminary estimates of U.S. drug overdose deaths exceeded 60,000 in 2016 and were partially driven by a fivefold increase in overdose deaths involving synthetic opioids (excluding methadone), from 3,105 in 2013 to approximately 20,000 in 2016 (1,2). Illicitly manufactured fentanyl, a synthetic opioid 50-100 times more potent than morphine, is primarily responsible for this rapid increase (3,4). In addition, fentanyl analogs such as acetylfentanyl, furanylfentanyl, and carfentanil are being detected increasingly in overdose deaths (5,6) and the illicit opioid drug supply (7). Carfentanil is estimated to be 10,000 times more potent than morphine (8). Estimates of the potency of acetylfentanyl and furanylfentanyl vary but suggest that they are less potent than fentanyl (9). Estimates of relative potency have some uncertainty because illicit fentanyl analog potency has not been evaluated in humans. This report describes opioid overdose deaths during July-December 2016 that tested positive for fentanyl, fentanyl analogs, or U-47700, an illicit synthetic opioid, in 10 states participating in CDC's Enhanced State Opioid Overdose Surveillance (ESOOS) program.* Fentanyl analogs are similar in chemical structure to fentanyl but not routinely detected because specialized toxicology testing is required. Fentanyl was detected in at least half of opioid overdose deaths in seven of 10 states, and 57% of fentanyl-involved deaths also tested positive for other illicit drugs, such as heroin. Fentanyl analogs were present in >10% of opioid overdose deaths in four states, with carfentanil, furanylfentanyl, and acetylfentanyl identified most frequently. Expanded surveillance for opioid overdoses, including testing for fentanyl and fentanyl analogs, assists in tracking the rapidly changing illicit opioid market and informing innovative interventions designed to reduce opioid overdose deaths.

Calcium-dependent nitric oxide production is involved in the cytoprotective properties of n-acetylcysteine in glycochenodeoxycholic acid-induced cell death in hepatocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gonzalez-Rubio, Sandra; Linares, Clara I.; Bello, Rosario I.

The intracellular oxidative stress has been involved in bile acid-induced cell death in hepatocytes. Nitric oxide (NO) exerts cytoprotective properties in glycochenodeoxycholic acid (GCDCA)-treated hepatocytes. The study evaluated the involvement of Ca{sup 2+} on the regulation of NO synthase (NOS)-3 expression during N-acetylcysteine (NAC) cytoprotection against GCDCA-induced cell death in hepatocytes. The regulation of Ca{sup 2+} pools (EGTA or BAPTA-AM) and NO (L-NAME or NO donor) production was assessed during NAC cytoprotection in GCDCA-treated HepG2 cells. The stimulation of Ca{sup 2+} entrance was induced by A23187 in HepG2. Cell death, Ca{sup 2+} mobilization, NOS-1, -2 and -3 expression, AP-1 activation,more » and NO production were evaluated. GCDCA reduced intracellular Ca{sup 2+} concentration and NOS-3 expression, and enhanced cell death in HepG2. NO donor prevented, and L-NAME enhanced, GCDCA-induced cell death. The reduction of Ca{sup 2+} entry by EGTA, but not its release from intracellular stores by BAPTA-AM, enhanced cell death in GCDCA-treated cells. The stimulation of Ca{sup 2+} entrance by A23187 reduced cell death and enhanced NOS-3 expression in GCDCA-treated HepG2 cells. The cytoprotective properties of NAC were related to the recovery of intracellular Ca{sup 2+} concentration, NOS-3 expression and NO production induced by GCDCA-treated HepG2 cells. The increase of NO production by Ca{sup 2+}-dependent NOS-3 expression during NAC administration reduces cell death in GCDCA-treated hepatocytes.« less

Accidental drug deaths in Fulton County, Georgia, 2002: characteristics, case management and certification issues.

PubMed

Graham, Jason K; Hanzlick, Randy

2008-09-01

Historically, the duty of the medical examiner in assigning cause and manner of death in drug-related death cases has been fraught with controversial challenges. The lack of standardization in certifying drug-related deaths may involve differences among practicing forensic pathologists in their approach to such cases. The central objectives of the present study include characterization of current drug death patterns and the variability among medical examiners with respect to autopsy performance and death certification practices in one county medical examiner's office. Death certificates, scene information/investigative reports, autopsy reports, and toxicological laboratory results for each of the 100 cases of drug-related death occurring in 2002 in Fulton County, Georgia were reviewed. Comparison of overall autopsy rates and autopsy rates in drug-related death cases for each medical examiner individually and for the group collectively was performed. In examining cocaine-related deaths (most common), statistical analysis was performed for comparison of drug concentrations (cocaine and benzoylecgonine) between deaths certified as cocaine toxicity (poisoning) versus cocaine-complicating disease or causing an adverse event such as cerebral hemorrhage. Causes of accidental drug deaths included cocaine 40%, mixed drug intoxication 37%, opioids 10%, ethanol 7%, and prescription medication (nonopioid) 5%. Overall total autopsy rates in 2002 for each of the 6 independent medical examiners ranged from 51% to 69% (mean 64%), whereas autopsy rates in drug-related death ranged from 55% to 91% (mean 81%). In review of the subset of 40 cocaine-related deaths, 25% were certified as cocaine toxicity (poisoning), with the remaining 75% certified as cocaine-complicating disease or causing and adverse event. Autopsy rates in cocaine-related deaths were as follows: cocaine toxicity 80%, cocaine-complicating disease 77.3%, and cocaine causing adverse event 62.5%. Thirty-eight percent of cocaine-related deaths were considered to be of "low suspicion" for drug involvement at the time the death was reported to the medical examiner with the remaining 62% being of "high suspicion". Autopsy rates were somewhat lower in the low suspicion group (67%) versus the high suspicion group (72%). Comparison of drug levels between cocaine-related death certification groups was performed. No statistically significant difference was shown in drug levels (cocaine, P > 0.3; benzoylecgonine, P > 0.2) between deaths certified as cocaine toxicity versus those certified as cocaine-complicating disease or causing adverse event. In Fulton County, accidental drug deaths in 2002 most often involved cocaine either alone or in combination with opiates and/or alcohol. Cocaine, opiates, or both were involved in greater than three-fourths (77%) of all drug-related deaths. The majority of all decedents were black (57%) and male (76%) with an average age of 42.2 years. Cocaine and ethanol were more frequently detected in black decedents, whereas opiates and polydrug abuse were more common in white decedents throughout the period studied. Preliminary investigation showed a high index of suspicion for the specific drug involved in virtually all opiate and alcohol cases, and in 62% of cocaine-related cases. Overall, the 100 accidental drug deaths in 2002 accounted for 7.5% of all deaths investigated and certified by the Fulton County Medical Examiner's Office. Our study provides further evidence to support the lack of correlation between serum drug levels and the mechanism of drug toxicity in cocaine-related deaths. No statistically significant differences were shown in parent cocaine or benzoylecgonine concentrations between those cases certified as toxicities or poisonings versus those cases certified as aggravating underlying disease or causing an adverse event. In addition, 62% of the cocaine-related death cases were considered initially to be of high suspicion for drug-related death, thus emphasizing the strong importance of scene information/investigative reports in evaluating drug-death cases and in formulating plans of action to handle each individual case. Among the drug-death cases handled by 6 staff medical examiners at the Fulton County Medical Examiner's Office, variation existed in autopsy performance and death certification practices. These issues are discussed in the context of the National Association of Medical Examiners' (NAME) Position Paper on Cocaine, NAME Forensic Autopsy Performance Standards, and other relevant literature. Most variations relate to completeness of the cause-of-death statement (whether or not comorbid conditions are included) rather than classification of manner of death within the office. However, specific wording in the cause of death may have significant ramifications regarding drug-related mortality statistics processed by the vital statistics system, with possible under-representation of drug-related deaths in single-cause mortality data.

Is target oriented surgery sufficient with borderline ovarian tumors? - Role of accompanying pathologies.

PubMed

Gungor, Tayfun; Cetinkaya, Nilufer; Yalcin, Hakan; Ozdal, Bulent; Ozgu, Emre; Baser, Eralp; Yilmaz, Nafiye; Caglar, Mete; Zergeroglu, Sema; Erkaya, Salim

2014-01-01

There are limited data in the literature related to concomitant genital or extra-genital organ pathologies in patients with borderline ovarian tumors (BOTs). The aim of this study was to evaluate our experience with 183 patients to draw attention to the accompanying organ pathologies with BOTs. One hundred eighty-three patients with BOTs, diagnosed and/or treated in our center between January of 2000 and March of 2013 were evaluated retrospectively. Data related to age, tumor histology, lesion side, disease stage, accompanying incidental ipsilateral and/or contralateral ovarian pathologies, treatment approaches, and follow-up periods were investigated. Incidental gynecologic and non-gynecologic concomitant organ pathologies were also recorded. The mean age at diagnosis was 40.6 years (range: 17-78). Ninety- five patients (51%) were ≤40 years. A hundred and forty-seven patients (80%) were at stage IA of the disease. The most common type of BOT was serous in histology. Non-invasive tumor implants were diagnosed in 4% and uterine involvement was found 2% among patients who underwent hysterectomies. There were 12 patients with positive peritoneal washings. Only 17 and 84 patients respectively had concomitant ipsilateral and concomitant contralateral incidental ovarian pathologies. The most common type of uterine, appendicular and omental pathologies were chronic cervicitis, lymphoid hyperplasia and chronic inflammatory reaction. According to our findings most of accompanying pathologies for BOT are benign in nature. Nevertheless, there were additional malignant diseases necessitating further therapy. We emphasize the importance of the evaluation of all abdominal organs during surgery.

[A retrospective clinicopathological study of aspiration pneumonia in the elderly].

PubMed

Pu, Chun; Zhong, Xuefeng; Fang, Fang; Yang, Yimeng; Xu, Xiaomao; Sun, Tieying

2014-08-01

To explore the clinicopathological characteristics of aspiration pneumonia in the elderly. The clinical data of 30 cases of autopsy-proven aspiration pneumonia in Beijing Hospital from 1973 to 2002 were reviewed. The patients consisted of 28 males and 2 females, aged from 63 to 103 [mean (83 ± 9)] years. Only 15 cases were clinically diagnosed as aspiration pneumonia before death. Concomitant diseases were severe and complex, mostly coronary disease, cerebrovascular disease, hypertension, COPD, and diabetes mellitus. All the patients suffered from at least 3 concomitant diseases. Long-term bedridden and nasogastric feeding was seen in 11 and 17 patients respectively. The clinical presentation and chest X-ray of aspiration pneumonia in the elderly were nonspecific and variable. Mixed infections were common . The main bacteria isolated were Gram-negative bacilli, in particular Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Escherichia coli and Candida albicans. By pathology, macrophages with foreign bodies were found in all the 30 cases and multiple small abscesses were found in 14 cases. The lesions were adjacent to the bronchioles and in the lung tissue around the bronchioles, mostly multi-lobar and bilateral. Unilateral or bilateral pleural effusion developed in 20 patients. The accordance between radiological and pathological diagnosis of aspiration pneumonia was very poor. The foci of infection detected by X-ray were proven by autopsy in 13 patients, while pleural effusions in X-ray were proven by autopsy in 15 patients. Multi-concomitant diseases, mixed infection and extra-pulmonary presentations were common in elderly patients with aspiration pneumonia. Multiple small abscesses were the pathological characteristics of aspiration pneumonia in the aged. A definite clinical diagnosis of aspiration pneumonia was difficult. Recurrent silent microaspiration was a feature of aspiration in the elderly. The assessment of risk factor of aspiration played an important role in the clinical diagnosis of aspiration pneumonia.

Survival benefit of glioblastoma patients after FDA approval of temozolomide concomitant with radiation and bevacizumab: A population-based study.

PubMed

Zhu, Ping; Du, Xianglin L; Lu, Guangrong; Zhu, Jay-Jiguang

2017-07-04

Few population-based analyses have investigated survival change in glioblastoma multiforme (GBM) patients treated with concomitant radiotherapy-temozolomide (RT-TMZ) and adjuvant temozolomide (TMZ) and then bevacizumab (BEV) after Food and Drug Administration (FDA) approval, respectively. We aimed to explore the effects on survival with RT-TMZ, adjuvant TMZ and BEV in general GBM population based on the Surveillance, Epidemiology, and End Results (SEER) and Texas Cancer Registry (TCR) databases. A total of 28933 GBM patients from SEER (N = 24578) and TCR (N = 4355) between January 2000 and December 2013 were included. Patients were grouped into three calendar periods based on date of diagnosis: pre-RT-TMZ and pre-BEV (1/2000-2/2005, P1), post-RT-TMZ and pre-BEV (3/2005-4/2009, P2), and post-RT-TMZ and post-BEV (5/2009-12/2013, P3). The association between calendar period of diagnosis and survival was analyzed in SEER and TCR, separately, by the Kaplan-Meier method and Cox proportional hazards model. We found a significant increase in median overall survival (OS) across the three periods in both populations. In multivariate models, the risk of death was significantly reduced during P2 and further decreased in P3, which remained unchanged after stratification. Comparison and validation analysis were performed in the combined dataset, and consistent results were observed. We conclude that the OS of GBM patients in a "real-world" setting has been steadily improved from January 2000 to December 2013, which likely resulted from the administrations of TMZ concomitant with RT and adjuvant TMZ for newly diagnosed GBM and then BEV for recurrent GBM after respective FDA approval.

Influence of Bleeding Pattern on Ischemic Lesions After Spontaneous Hypertensive Intracerebral Hemorrhage with Intraventricular Hemorrhage.

PubMed

Rivera-Lara, Lucia; Murthy, Santosh B; Nekoovaght-Tak, Saman; Ali, Hasan; McBee, Nichol; Dlugash, Rachel; Ram, Malathi; Thompson, Richard; Awad, Issam A; Hanley, Daniel F; Ziai, Wendy C

2018-03-27

Concomitant acute ischemic lesions are detected in up to a quarter of patients with spontaneous intracerebral hemorrhage (ICH). Influence of bleeding pattern and intraventricular hemorrhage (IVH) on risk of ischemic lesions has not been investigated. Retrospective study of all 500 patients enrolled in the CLEAR III randomized controlled trial of thrombolytic removal of obstructive IVH using external ventricular drainage. The primary outcome measure was radiologically confirmed ischemic lesions, as reported by the Safety Event Committee and confirmed by two neurologists. We assessed predictors of ischemic lesions including analysis of bleeding patterns (ICH, IVH and subarachnoid hemorrhage) on computed tomography scans (CT). Secondary outcomes were blinded assessment of mortality and modified Rankin scale (mRS) at 30 and 180 days. Ischemic lesions occurred in 23 (4.6%) during first 30 days after ICH. Independent risk factors associated with ischemic lesions in logistic regression models adjusted for confounders were higher IVH volume (p = 0.004) and persistent subarachnoid hemorrhage on CT scan (p = 0.03). Patients with initial IVH volume ≥ 15 ml had five times the odds of concomitant ischemic lesions compared to IVH volume < 15 ml. Patients with ischemic lesions had significantly higher odds of death at 1 and 6 months (but not poor outcome; mRS 4-6) compared to patients without concurrent ischemic lesions. Occurrence of ischemic lesions in the acute phase of IVH is not uncommon and is significantly associated with increased early and late mortality. Extra-parenchymal blood (larger IVH and visible subarachnoid hemorrhage) is a strong predictor for development of concomitant ischemic lesions after ICH.

Concomitant canine distemper, infectious canine hepatitis, canine parvoviral enteritis, canine infectious tracheobronchitis, and toxoplasmosis in a puppy.

PubMed

Headley, Selwyn Arlington; Alfieri, Amauri Alcindo; Fritzen, Juliana Torres Tomazi; Garcia, João Luis; Weissenböck, Herbert; da Silva, Ana Paula; Bodnar, Livia; Okano, Werner; Alfieri, Alice Fernandes

2013-01-01

The concomitant infections of Canine distemper virus (CDV), Canine adenovirus A types 1 (CAdV-1) and 2 (CAdV-2), Canine parvovirus type 2 (CPV-2), and Toxoplasma gondii are described in a 43-day-old mixed-breed puppy. Clinically, there were convulsions and blindness with spontaneous death; 14 siblings of this puppy, born to a 10-month-old dam, which was seropositive (titer: 1,024) for T. gondii, also died. Necropsy revealed unilateral corneal edema (blue eye), depletion of intestinal lymphoid tissue, non-collapsible lungs, congestion of meningeal vessels, and a pale area in the myocardium. Histopathology demonstrated necrotizing myocarditis associated with intralesional apicomplexan protozoa; necrotizing and chronic hepatitis associated with rare intranuclear inclusion bodies within hepatocytes; necrotizing bronchitis and bronchiolitis; interstitial pneumonia associated with eosinophilic intracytoplasmic inclusion bodies within epithelial cells; atrophy and fusion of intestinal villi with cryptal necrosis; and white matter demyelination of the cerebrum and cerebellum associated with intranuclear inclusion bodies within astrocytes. Polymerase chain reaction (PCR) amplified the partial fragments (bp) of the CDV N gene (290 bp), CPV-2c VP2 capsid protein gene (583 bp), and CAdV-1 (508 bp) and CAdV-2 (1,030 bp) E gene from urine and tissue samples. The PCR assays demonstrated that the apicomplexan protozoa observed within several organs contained DNA specific for T. gondii; genotyping revealed T. gondii type III. The findings support the characterization of concomitant infections of CDV, CAdV-1, CAdV-2, CPV-2, and T. gondii in this puppy. Further, seroreactivity to T. gondii of the dam in association with the systemic disease observed in the puppy described herein is suggestive of congenital toxoplasmosis.

Sex, timing, and depression among suicide victims with schizophrenia.

PubMed

Karvonen, Kaisa; Sammela, Hanna-Lena; Rahikkala, Heidi; Hakko, Helinä; Särkioja, Terttu; Meyer-Rochow, V Benno; Räsänen, Pirkko; Timonen, Markku

2007-01-01

Schizophrenia and depression by themselves and especially in combination with each other are known to be important risk factors of suicide. An increased risk of suicide has also been reported for the period immediately after a psychiatric patient's discharge from the hospital. However, to the best of our knowledge, it remains unknown whether survival times differ between suicide victims with schizophrenia concomitantly with and those without depression. This study aimed to examine survival times from the discharge of last hospital treatment (irrespective of the kind of illness) to the day of death in suicide victims with schizophrenia with or without concomitant depression. A 16-year database of all suicides (1535 males, 342 females) committed during the years 1988-2003 in the province of Oulu in northern Finland, and information available from the national hospital discharge registers formed the basis of this study. In male suicide victims with schizophrenia, the median survival time after final hospitalization was approximately 1 day in those with a history of depression and 90 days in those without depression (P = .005). The corresponding times for females were 50 and 24 days, respectively (P = .396). Using Cox regression analysis after adjusting for confounders, we noticed a statistically significant difference in survival times from last hospitalization to suicide between depressive and nondepressive male patients with schizophrenia (hazard ratio, 1.80; 95% confidence interval, 1.04-3.11), but not females (hazard ratio, 0.72; 95% confidence interval, 0.34-1.53). Concomitant depression was markedly linked with shorter survival time in male suicide victims with schizophrenia after last hospitalization. Psychiatric inpatient facilities appear to be in a key position to establish suicide prevention programs for patients with schizophrenia, especially those with depression.

Outcomes of aortopulmonary window repair in children: 33 years of experience.

PubMed

Naimo, Phillip S; Yong, Matthew S; d'Udekem, Yves; Brizard, Christian P; Kelly, Andrew; Weintraub, Robert; Konstantinov, Igor E

2014-11-01

The purpose of this study was to assess the outcomes of children undergoing repair of aortopulmonary window (APW). We conducted a retrospective review of all children (n=43) who underwent surgical repair of APW between 1980 and 2013. Median age at surgery was 40 days (range, 13 to 125). Simple APW was present in 15 of 43 patients (35%), and 28 of 43 patients (65%) patients had concomitant cardiovascular anomalies. The aorta was repaired by direct suturing in 36 patients (84%) patients and patching in 7 patients (16%). The main pulmonary artery was repaired by direct suturing in 22 patients (51%) patients and by patching in 21 (49%). Cardiopulmonary bypass was used in 42 of the 43 patients (97.7%). Single-staged repair of concomitant cardiovascular anomalies was undertaken in 26 of 28 patients (93%). Only 2 of the 28 patients (7%) underwent repair of interrupted aortic arch before APW repair. Operative mortality was 6.7% (1 of 15 patients) among patients with simple APW and 18% (5 of 28 patients) among patients with concomitant anomalies. Operative weight less than 2.5 kg was associated with mortality on univariable analysis (p=0.02). Median follow-up was 10.1 years (range, 0.17 to 24.2). There were no late deaths. Overall survival was 86% (95% confidence interval: 71.3 to 94.2) at 10 years. Freedom from reoperation was 95.3% (95% confidence interval: 86.2 to 99.9) at 10 years. At last follow-up, all patients were in New York Heart Association functional class I/II. Survival beyond discharge from the hospital is associated with excellent outcomes. Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Prescription histories and dose strengths associated with overdose deaths.

PubMed

Hirsch, Anne; Proescholdbell, Scott K; Bronson, William; Dasgupta, Nabarun

2014-07-01

Misuse, abuse, and diversion of prescription drugs are large and growing public health problems that have resulted in an overdose epidemic. We investigated whether short-acting or extended-release opioids were more frequently prescribed to those who died of an overdose and whether there was a linear relationship between dose strength and associated overdose deaths. The study population was North Carolina residents in 2010. We conducted a retrospective, population-based, descriptive study of medication histories of overdose decedents using data from vital statistics, medical examiner records, and a prescription drug monitoring program. Unintentional or undetermined drug overdoses were responsible for 892 deaths. Out of 191 deaths involving methadone, only two were patients in opioid treatment programs. Immediate-release oxycodone was involved in the greatest number of opioid-related deaths. Out of 221 oxycodone deaths, 134 (61%) of the decedents filled a prescription for oxycodone in the 60 days prior to death. The most common strength dispensed within 60 days to a decedent who died of an oxycodone overdose was 10 mg for immediate-release (72 prescriptions). Immediate-release oxycodone products (rho = 1.00, P < 0.01) and extended-release fentanyl products (rho = 1.00, P < 0.01) showed strong increasing linear trends between dose strength and proportion of prescriptions dispensed to decedents. A significant proportion of overdose decedents had been prescribed the same type of drugs that contributed to their death, especially for decedents who died from overdoses involving oxycodone, hydrocodone, and alprazolam. Higher dose strengths for certain opioids had higher associated mortality, and certain immediate-release opioids may be considered for public health prevention efforts.

Sudden death involving inhalation of 1,1-difluoroethane (HFC-152a) with spray cleaner: three case reports.

PubMed

Sakai, Kentaro; Maruyama-Maebashi, Kyoko; Takatsu, Akihiro; Fukui, Kenji; Nagai, Tomonori; Aoyagi, Miwako; Ochiai, Eriko; Iwadate, Kimiharu

2011-03-20

Spray cleaner is a cleaning product containing compressed 1,1-difluoroethane (HFC-152a) to blow dust off electric devices and other sensitive equipment; however, it is also inhaled to induce euphoria. This report describes three cases of death involving HFC-152a inhalation with spray cleaner under different circumstances. In case 1, death was during inhalation for euphoria with which led to having frostbite. In case 2, death may have been associated with suicidal intention. Case 3 was also considered an accidental autoerotic death. In all three cases, HFC-152a was detected at 99.2-136.2mg/l in blood samples, 94.5-191.9 mg/l in urine samples and 3.6-18.4 mg in the gastric contents according to gas chromatography with flame ionization detection. To prevent death associated with HFC-152a inhalation from spray cleaner, the danger of the sudden death should be announced to people, given the ready availability of commercial products containing HFC-152a. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma

PubMed Central

Chamcheu, Jean Christopher; Haidar, Omar; Mukhtar, Hasan

2014-01-01

The prognosis of malignant melanoma remains poor in spite of recent advances in therapeutic strategies for the deadly disease. Fisetin, a dietary flavonoid is currently being investigated for its growth inhibitory properties in various cancer models. We previously showed that fisetin inhibited melanoma growth in vitro and in vivo. Here, we evaluated the molecular basis of fisetin induced cytoxicity in metastatic human melanoma cells. Fisetin treatment induced endoplasmic reticulum (ER) stress in highly aggressive A375 and 451Lu human melanoma cells, as revealed by up- regulation of ER stress markers including IRE1α, XBP1s, ATF4 and GRP78. Time course analysis indicated that the ER stress was associated with activation of the extrinsic and intrinsic apoptotic pathways. Fisetin treated 2-D melanoma cultures displayed autophagic response concomitant with induction of apoptosis. Prolonged treatment (16 days) with fisetin in a 3-D reconstituted melanoma model resulted in inhibition of melanoma progression with significant apoptosis, as evidenced by increased staining of cleaved Caspase-3 in the treated constructs. However, no difference in the expression of autophagic marker LC-3 was noted between treated and control groups. Fisetin treatment to 2-D melanoma cultures resulted in phosphorylation and activation of the multifunctional AMPK-activated protein kinase (AMPK) involved in the regulation of diverse cellular processes, including autophagy and apoptosis. Silencing of AMPK failed to prevent cell death indicating that fisetin induced cytotoxicity is mediated through both AMPK-dependent and -independent mechanisms. Taken together, our studies confirm apoptosis as the primary mechanism through which fisetin inhibits melanoma cell growth and that activation of both extrinsic and intrinsic pathways contributes to fisetin induced cytotoxicity. PMID:25016296

Statin-induced inhibition of breast cancer proliferation and invasion involves attenuation of iron transport: intermediacy of nitric oxide and antioxidant defence mechanisms.

PubMed

Kanugula, Anantha Koteswararao; Gollavilli, Paradesi Naidu; Vasamsetti, Sathish Babu; Karnewar, Santosh; Gopoju, Raja; Ummanni, Ramesh; Kotamraju, Srigiridhar

2014-08-01

Accumulating evidence from in vitro, in vivo, clinical and epidemiological studies shows promising results for the use of statins against many cancers including breast carcinoma. However, the molecular mechanisms responsible for the anti-proliferative and anti-invasive properties of statins still remain elusive. In this study, we investigated the involvement of nitric oxide, iron homeostasis and antioxidant defence mechanisms in mediating the anti-proliferative and anti-invasive properties of hydrophobic statins in MDA-MB-231, MDA-MB-453 and BT-549 metastatic triple negative breast cancer cells. Fluvastatin and simvastatin significantly increased cytotoxicity which was reversed with mevalonate. Interestingly, fluvastatin downregulated transferrin receptor (TfR1), with a concomitant depletion of intracellular iron levels in these cells. Statin-induced effects were mimicked by geranylgeranyl transferase inhibitor (GGTI-298) but not farnesyl transferase inhibitor (FTI-277). Further, it was observed that TfR1 downregulation is mediated by increased nitric oxide levels via inducible nitric oxide synthase (iNOS) expression. NOS inhibitors (asymmetric dimethylarginine and 1400W) counteracted and sepiapterin, a precursor of tetrahydrobiopterin, exacerbated statin-induced depletion of intracellular iron levels. Notably, fluvastatin increased manganese superoxide dismutase (by repressing the transcription factor DNA damage-binding protein 2), catalase and glutathione which, in turn, diminished H2 O2 levels. Fluvastatin-induced downregulation of TfR1, matrix metalloproteinase-2, -9 and inhibition of invasion were reversed in the presence of aminotriazole, a specific inhibitor of catalase. Finally, we conclude that fluvastatin, by altering iron homeostasis, nitric oxide generation and antioxidant defence mechanisms, induces triple negative breast cancer cell death. © 2014 FEBS.

Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma.

PubMed

Syed, Deeba N; Lall, Rahul K; Chamcheu, Jean Christopher; Haidar, Omar; Mukhtar, Hasan

2014-12-01

The prognosis of malignant melanoma remains poor in spite of recent advances in therapeutic strategies for the deadly disease. Fisetin, a dietary flavonoid is currently being investigated for its growth inhibitory properties in various cancer models. We previously showed that fisetin inhibited melanoma growth in vitro and in vivo. Here, we evaluated the molecular basis of fisetin induced cytotoxicity in metastatic human melanoma cells. Fisetin treatment induced endoplasmic reticulum (ER) stress in highly aggressive A375 and 451Lu human melanoma cells, as revealed by up-regulation of ER stress markers including IRE1α, XBP1s, ATF4 and GRP78. Time course analysis indicated that the ER stress was associated with activation of the extrinsic and intrinsic apoptotic pathways. Fisetin treated 2-D melanoma cultures displayed autophagic response concomitant with induction of apoptosis. Prolonged treatment (16days) with fisetin in a 3-D reconstituted melanoma model resulted in inhibition of melanoma progression with significant apoptosis, as evidenced by increased staining of cleaved Caspase-3 in the treated constructs. However, no difference in the expression of autophagic marker LC-3 was noted between treated and control groups. Fisetin treatment to 2-D melanoma cultures resulted in phosphorylation and activation of the multifunctional AMP-activated protein kinase (AMPK) involved in the regulation of diverse cellular processes, including autophagy and apoptosis. Silencing of AMPK failed to prevent cell death indicating that fisetin induced cytotoxicity is mediated through both AMPK-dependent and -independent mechanisms. Taken together, our studies confirm apoptosis as the primary mechanism through which fisetin inhibits melanoma cell growth and that activation of both extrinsic and intrinsic pathways contributes to fisetin induced cytotoxicity.

When Students Rebel: The American Collegiate Experience.

ERIC Educational Resources Information Center

McCarthy, Joseph M.

Student unrest has always been a concomitant of student life, going as far back as 1200 and 1229 when students were killed in Paris during town-gown battles. Much of the student unrest in early America was simply a matter of youthful high spirits, though there were some serious cases often involving mass rebellion. The greatest single cause for…

The molecular autopsy: an indispensable step following sudden cardiac death in the young?

PubMed Central

Boczek, Nicole J.; Tester, David J.; Ackerman, Michael J.

2013-01-01

Annually thousands of sudden deaths involving young individuals (< 35 years of age) remain unexplained following a complete medicolegal investigation that includes an autopsy. In fact, epidemiological studies have estimated that over half of sudden deaths involving previously healthy young individuals have no morphological abnormalities identifiable at autopsy. Cardiac channelopathies associated with structurally normal hearts such as long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS), leave no evidence to be found at autopsy, leaving investigators to only speculate that a lethal arrhythmia might lie at the heart of a sudden unexplained death (SUD). In cases of autopsy-negative SUD, continued investigation, through the use of a cardiological and genetic evaluation of first- or second-degree relatives and/or a molecular autopsy, may pinpoint the underlying mechanism attributing to the sudden death and allow for the identification of living family members with the pathogenic substrate that renders them vulnerable to an increased risk for cardiac events, including sudden death. PMID:22993115

Death and Dying Course Offerings in Psychology: A Survey of Nine Midwestern States

ERIC Educational Resources Information Center

Eckerd, Lizabeth M.

2009-01-01

The certainty of facing death and bereavement and the complex personal and societal issues involved argue for the importance of death education. The current study addresses a gap in knowledge by beginning to assess the extent of dying, death, and bereavement (DD&B) course offerings by U.S. psychology departments. This article reports on data…

38 CFR 20.1106 - Rule 1106. Claim for death benefits by survivor-prior unfavorable decisions during veteran's...

Code of Federal Regulations, 2010 CFR

2010-07-01

... of 38 U.S.C. 6104 and 6105, issues involved in a survivor's claim for death benefits will be decided... death benefits by survivor-prior unfavorable decisions during veteran's lifetime. 20.1106 Section 20... VETERANS' APPEALS: RULES OF PRACTICE Finality § 20.1106 Rule 1106. Claim for death benefits by survivor...

Death Anxiety as a Predictor of Posttraumatic Stress Levels among Individuals with Spinal Cord Injuries

ERIC Educational Resources Information Center

Martz, Erin

2004-01-01

Because the onset of a spinal cord injury may involve a brush with death and because serious injury and disability can act as a reminder of death, death anxiety was examined as a predictor of posttraumatic stress levels among individuals with disabilities. This cross-sectional study used multiple regression and multivariate multiple regression to…

Beyond Newton's Law of Cooling--Estimation of Time since Death

ERIC Educational Resources Information Center

Leinbach, Carl

2011-01-01

The estimate of the time since death and, thus, the time of death is strictly that, an estimate. However, the time of death can be an important piece of information in some coroner's cases, especially those that involve criminal or insurance investigations. It has been known almost from the beginning of time that bodies cool after the internal…

[Сhanges in heart rate variability in presymptomatic and symptomatic stages of Parkinson's disease under pharmacological influences: an experimental study].

PubMed

Mamalyga, M L

2013-01-01

The disbalance of autonomic heart regulation (AHR) develops already in the presymptomatic stage of Parkinson's disease. The early symptomatic stage is accompanied by the aggravation of heart dysfunction due to the shift of the autonomic balance towards the increase of sympathetic and decrease of parasympathic effect on the heart. Coronary disorders concomitant to Parkinson's disease increase a risk of life threatening arrhythmia and sudden death syndrome not only in the early symptomatic stage but also in the presymptomatic stage. L-DOPA effectively restores the structure of AHR and prevents the risk of life threatening arrhythmia only in the presymptomatic stage of Parkinson's disease.

Air gun wounding and current UK laws controlling air weapons.

PubMed

Bruce-Chwatt, Robert Michael

2010-04-01

Air weapons whether rifles or pistols are, potentially, lethal weapons. The UK legislation is complex and yet little known to the public. Hunting with air weapons and the laws controlling those animals that are permitted to be shot with air weapons is even more labyrinthine due to the legal power limitations on the possession of air weapons. Still relatively freely available by mail order or on the Internet, an increasing number of deaths have been reported from the misuse of air weapons or accidental discharges. Ammunition for air weapons has become increasingly sophisticated, effective and therefore increasingly dangerous if misused, though freely available being a mere projectile without a concomitant cartridge containing a propellant and an initiator.

[Relationship between multi-slice spiral CT angiography imaging features and in-hospital death of patients with aortic dissection].

PubMed

Xiao, Z Y; Wang, H J; Yao, C L; Gu, G R; Xue, Y; Yin, J; Chen, J; Zhang, C; Tong, C Y; Song, Z J

2017-03-24

Objective: To explore the imaging manifestations of multi-slice spiral CT angiography (CTA) and relationship with in-hospital death in patients with aortic dissection (AD). Methods: The clinical data of 429 patients with AD who underwent CTA in Zhongshan Hospital of Fudan University between January 2009 and January 2016 were retrospectively analyzed. AD patients were divided into 2 groups, including operation group who underwent surgery or interventional therapy (370 cases) and non-operation group who underwent medical conservative treatment(59 cases). The multi-slice spiral CTA imaging features of AD were analyzed, and multivariate logistic regression analysis was used to investigate the relationship between imaging manifestations and in-hospital death in AD patients. Results: There were 12 cases (3.24%) of in-hospital death in operation group, and 28 cases (47.46%) of in-hospital death in non-operation group( P <0.001). AD involved different vascular branches. Multi-slice spiral CTA can clearly show the dissection of true and false lumen, and intimal tear was detected in 363 (84.62%) cases, outer wall calcification was revealed in 63 (14.69%) cases, and thrombus formation was present in 227 (52.91%) cases. The multivariate logistic regression analysis showed that the number of branch vessels involved ( OR =1.374, 95% CI 1.081-1.745, P =0.009) and tearing false lumen range( OR =2.059, 95% CI 1.252-3.385, P =0.004) were independent risk factors of in-hospital death in AD patients, and the number of branch vessels involved ( OR =1.600, 95% CI 1.062-2.411, P =0.025) was independent risk factor of in-hospital death in the operation group, while the tearing false lumen range ( OR =2.315, 95% CI 1.019-5.262, P =0.045) was independent risk factor of in-hospital death of non-operation group. Conclusions: Multi-slice spiral CTA can clearly show the entire AD, true and false lumen, intimal tear, wall calcification and thrombosis of AD patients. The number of branch vessels involved and tearing false lumen range are the independent risk factors of in-hospital death in AD patients.

Ferroptosis is Involved in Acetaminophen Induced Cell Death.

PubMed

Lőrincz, Tamás; Jemnitz, Katalin; Kardon, Tamás; Mandl, József; Szarka, András

2015-09-01

The recently described form of programmed cell death, ferroptosis can be induced by agents causing GSH depletion or the inhibition of GPX4. Ferroptosis clearly shows distinct morphologic, biochemical and genetic features from apoptosis, necrosis and autophagy. Since NAPQI the highly reactive metabolite of the widely applied analgesic and antipyretic, acetaminophen induces a cell death which can be characterized by GSH depletion, GPX inhibition and caspase independency the involvement of ferroptosis in acetaminophen induced cell death has been investigated. The specific ferroptosis inhibitor ferrostatin-1 failed to elevate the viability of acetaminophen treated HepG2 cells. It should be noticed that these cells do not form NAPQI due to the lack of phase I enzyme expression therefore GSH depletion cannot be observed. However in the case of acetaminophen treated primary mouse hepatocytes the significant elevation of cell viability could be observed upon ferrostatin-1 treatment. Similar to ferrostatin-1 treatment, the addition of the RIP1 kinase inhibitor necrostatin-1 could also elevate the viability of acetaminophen treated primary hepatocytes. Ferrostatin-1 has no influence on the expression of CYP2E1 or on the cellular GSH level which suggest that the protective effect of ferrostatin-1 in APAP induced cell death is not based on the reduced metabolism of APAP to NAPQI or on altered NAPQI conjugation by cellular GSH. Our results suggest that beyond necroptosis and apoptosis a third programmed cell death, ferroptosis is also involved in acetaminophen induced cell death in primary hepatocytes.

Psychic trauma as cause of death.

PubMed

Terranova, C; Snenghi, R; Thiene, G; Ferrara, S D

2011-01-01

of study Psychic trauma is described as the action of 'an emotionally overwhelming factor' capable of causing neurovegetative alterations leading to transitory or persisting bodily changes. The medico-legal concept of psychic trauma and its definition as a cause in penal cases is debated. The authors present three cases of death after psychic trauma, and discuss the definition of cause within the penal ambit of identified 'emotionally overwhelming factors'. The methodological approach to ascertainment and criterion-based assessment in each case involved the following phases: (1) examination of circumstantial evidence, clinical records and documentation; (2) autopsy; (3) ascertainment of cause of death; and (4) ascertainment of psychic trauma, and its coexisting relationship with the cause of death. The results and assessment of each of the three cases are discussed from the viewpoint of the causal connotation of psychic trauma. In the cases presented, psychic trauma caused death, as deduced from assessment of the type of externally caused emotional insult, the subjects' personal characteristics and the circumstances of the event causing death. In cases of death due to psychic trauma, careful methodological ascertainment is essential, with the double aim of defining 'emotionally overwhelming factors' as a significant cause of death from the penal point of view, and of identifying the responsibility of third parties involved in the death event and associated dynamics of homicide.

Induction of a massive endoplasmic reticulum and perinuclear space expansion by expression of lamin B receptor mutants and the related sterol reductases TM7SF2 and DHCR7.

PubMed

Zwerger, Monika; Kolb, Thorsten; Richter, Karsten; Karakesisoglou, Iakowos; Herrmann, Harald

2010-01-15

Lamin B receptor (LBR) is an inner nuclear membrane protein involved in tethering the nuclear lamina and the underlying chromatin to the nuclear envelope. In addition, LBR exhibits sterol reductase activity. Mutations in the LBR gene cause two different human diseases: Pelger-Huët anomaly and Greenberg skeletal dysplasia, a severe chrondrodystrophy causing embryonic death. Our study aimed at investigating the effect of five LBR disease mutants on human cultured cells. Three of the tested LBR mutants caused a massive compaction of chromatin coincidental with the formation of a large nucleus-associated vacuole (NAV) in several human cultured cell lines. Live cell imaging and electron microscopy revealed that this structure was generated by the separation of the inner and outer nuclear membrane. During NAV formation, nuclear pore complexes and components of the linker of nucleoskeleton and cytoskeleton complex were lost in areas of membrane separation. Concomitantly, a large number of smaller vacuoles formed throughout the cytoplasm. Notably, forced expression of the two structurally related sterol reductases transmembrane 7 superfamily member 2 and 7-dehydrocholesterol reductase caused, even in their wild-type form, a comparable phenotype in susceptible cell lines. Hence, LBR mutant variants and sterol reductases can severely interfere with the regular organization of the nuclear envelope and the endoplasmic reticulum.

Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model

PubMed Central

Bargiela, Ariadna; Cerro-Herreros, Estefanía; Fernandez-Costa, Juan M.; Vilchez, Juan J.; Llamusi, Beatriz; Artero, Ruben

2015-01-01

ABSTRACT Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1) disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. Heat-shock induced expression of 480 CUG repeats in adult flies resulted in a reduction in the area of the indirect flight muscles. In these model flies, reduction of muscle area was concomitant with increased apoptosis and autophagy. Inhibition of apoptosis or autophagy mediated by the overexpression of DIAP1, mTOR (also known as Tor) or muscleblind, or by RNA interference (RNAi)-mediated silencing of autophagy regulatory genes, achieved a rescue of the muscle-loss phenotype. In fact, mTOR overexpression rescued muscle size to a size comparable to that in control flies. These results were validated in skeletal muscle biopsies from DM1 patients in which we found downregulated autophagy and apoptosis repressor genes, and also in DM1 myoblasts where we found increased autophagy. These findings provide new insights into the signaling pathways involved in DM1 disease pathogenesis. PMID:26092529

Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model.

PubMed

Bargiela, Ariadna; Cerro-Herreros, Estefanía; Fernandez-Costa, Juan M; Vilchez, Juan J; Llamusi, Beatriz; Artero, Ruben

2015-07-01

Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1) disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. Heat-shock induced expression of 480 CUG repeats in adult flies resulted in a reduction in the area of the indirect flight muscles. In these model flies, reduction of muscle area was concomitant with increased apoptosis and autophagy. Inhibition of apoptosis or autophagy mediated by the overexpression of DIAP1, mTOR (also known as Tor) or muscleblind, or by RNA interference (RNAi)-mediated silencing of autophagy regulatory genes, achieved a rescue of the muscle-loss phenotype. In fact, mTOR overexpression rescued muscle size to a size comparable to that in control flies. These results were validated in skeletal muscle biopsies from DM1 patients in which we found downregulated autophagy and apoptosis repressor genes, and also in DM1 myoblasts where we found increased autophagy. These findings provide new insights into the signaling pathways involved in DM1 disease pathogenesis. © 2015. Published by The Company of Biologists Ltd.

Porcine circovirus type 2 induces the activation of nuclear factor kappa B by I{kappa}B{alpha} degradation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wei Li; Kwang, Jimmy; Wang Jin

The transcription factor NF-{kappa}B is commonly activated upon virus infection and a key player in the induction and regulation of the host immune response. The present study demonstrated for the first time that porcine circovirus type 2 (PCV2), which is the primary causative agent of an emerging swine disease, postweaning multisystemic wasting syndrome, can activate NF-{kappa}B in PCV2-infected PK15 cells. In PCV2-infected cells, NF-{kappa}B was activated concomitantly with viral replication, which was characterized by increased DNA binding activity, translocation of NF-{kappa}B p65 from the cytoplasm to the nucleus, as well as degradation and phosphorylation of I{kappa}B{alpha} protein. We further demonstratedmore » PCV2-induced activation of NF-{kappa}B and colocalization of p65 nuclear translocation with virus replication in cultured cells. Treatment of cells with CAPE, a selective inhibitor of NF-{kappa}B activation, reduced virus protein expression and progeny production followed by decreasing PCV2-induced apoptotic caspase activity, indicating the involvement of this transcription factor in induction of cell death. Taken together, these data suggest that NF-{kappa}B activation is important for PCV2 replication and contributes to virus-mediated changes in host cells. The results presented here provide a basis for understanding molecular mechanism of PCV2 infection.« less

Prognostic impact of RITA expression in patients with anal squamous cell carcinoma treated with chemoradiotherapy.

PubMed

Rödel, Franz; Steinhäuser, Kerstin; Kreis, Nina-Naomi; Friemel, Alexandra; Martin, Daniel; Wieland, Ulrike; Rave-Fränk, Margret; Balermpas, Panagiotis; Fokas, Emmanouil; Louwen, Frank; Rödel, Claus; Yuan, Juping

2018-02-01

RBP-J interacting and tubulin-associated protein (RITA) has been identified as a negative regulator of the Notch signalling pathway and its deregulation is involved in the pathogenesis of several tumour entities. RITA's impact on the response of anal squamous cell carcinoma (SCC) to anticancer treatment, however, remains elusive. In our retrospective study immunohistochemical evaluation of RITA was performed on 140 pre-treatment specimens and was correlated with clinical and histopathologic characteristics and clinical endpoints cumulative incidence of local control (LC), distant recurrence (DC), disease-free survival (DFS) and overall survival (OS). We observed significant inverse correlations between RITA expression and tumour grading, the levels of HPV-16 virus DNA load, CD8 (+) tumour infiltrating lymphocytes and programmed death protein (PD-1) immunostaining. In univariate analyses, elevated levels of RITA expression were predictive for decreased local control (p = 0.001), decreased distant control (p = 0.040), decreased disease free survival (p = 0.001) and overall survival (p < 0.0001), whereas in multivariate analyses RITA expression remained significant for decreased local control (p = 0.009), disease free survival (p = 0.032) and overall survival (p = 0.012). These data indicate that elevated levels of pretreatment RITA expression are correlated with unfavourable clinical outcome in anal carcinoma treated with concomitant chemoradiotherapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Multiple programmed cell death pathways are involved in N-methyl-N-nitrosourea-induced photoreceptor degeneration.

PubMed

Reisenhofer, Miriam; Balmer, Jasmin; Zulliger, Rahel; Enzmann, Volker

2015-05-01

To identify programmed cell death (PCD) pathways involved in N-methyl-N-nitrosourea (MNU)-induced photoreceptor (PR) degeneration. Adult C57BL/6 mice received a single MNU i.p. injection (60 mg/kg bodyweight), and were observed over a period of 7 days. Degeneration was visualized by H&E overview staining and electron microscopy. PR cell death was measured by quantifying TUNEL-positive cells in the outer nuclear layer (ONL). Activity measurements of key PCD enzymes (calpain, caspases) were used to identify the involved cell death pathways. Furthermore, the expression level of C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78), key players in endoplasmic reticulum (ER) stress-induced apoptosis, was analyzed using quantitative real-time PCR. A decrease in ONL thickness and the appearance of apoptotic PR nuclei could be detected beginning 3 days post-injection (PI). This was accompanied by an increase of TUNEL-positive cells. Significant upregulation of activated caspases (3, 9, 12) was found at different time periods after MNU injection. Additionally, several other players of nonconventional PCD pathways were also upregulated. Consequently, calpain activity increased in the ONL, with a maximum on day 7 PI and an upregulation of CHOP and GRP78 expression beginning on day 1 PI was found. The data indicate that regular apoptosis is the major cause of MNU-induced PR cell death. However, alternative PCD pathways, including ER stress and calpain activation, are also involved. Knowledge about the mechanisms involved in this mouse model of PR degeneration could facilitate the design of putative combinatory therapeutic approaches.

Clinical, laboratory and radiologic characteristics of 2009 pandemic influenza A/H1N1 pneumonia: primary influenza pneumonia versus concomitant/secondary bacterial pneumonia

PubMed Central

Song, Joon Y.; Cheong, Hee J.; Heo, Jung Y.; Noh, Ji Y.; Yong, Hwan S.; Kim, Yoon K.; Kang, Eun Y.; Choi, Won S.; Jo, Yu M.; Kim, Woo J.

2011-01-01

Please cite this paper as: Song et al. (2011). Clinical, laboratory and radiologic characteristics of 2009 pandemic influenza A/H1N1 pneumonia: primary influenza pneumonia versus concomitant/secondary bacterial pneumonia. Influenza and Other Respiratory Viruses 5(6), e535–e543. Background  Although influenza virus usually involves the upper respiratory tract, pneumonia was seen more frequently with the 2009 pandemic influenza A/H1N1 than with seasonal influenza. Methods  From September 1, 2009, to January 31, 2010, a specialized clinic for patients (aged ≥15 years) with ILI was operated in Korea University Guro Hospital. RT‐PCR assay was performed to diagnose 2009 pandemic influenza A/H1N1. A retrospective case–case–control study was performed to determine the predictive factors for influenza pneumonia and to discriminate concomitant/secondary bacterial pneumonia from primary influenza pneumonia during the 2009–2010 pandemic. Results  During the study period, the proportions of fatal cases and pneumonia development were 0·12% and 1·59%, respectively. Patients with pneumonic influenza were less likely to have nasal symptoms and extra‐pulmonary symptoms (myalgia, headache, and diarrhea) compared to patients with non‐pneumonic influenza. Crackle was audible in just about half of the patients with pneumonic influenza (38·5% of patients with primary influenza pneumonia and 53·3% of patients with concomitant/secondary bacterial pneumonia). Procalcitonin, C‐reactive protein (CRP), and lactate dehydrogenase were markedly increased in patients with influenza pneumonia. Furthermore, procalcitonin (cutoff value 0·35 ng/ml, sensitivity 81·8%, and specificity 66·7%) and CRP (cutoff value 86·5 mg/IU, sensitivity 81·8%, and specificity 59·3%) were discriminative between patients with concomitant/secondary bacterial pneumonia and patients with primary influenza pneumonia. Conclusions  Considering the subtle manifestations of 2009 pandemic influenza A/H1N1 pneumonia in the early stage, high clinical suspicion is required to detect this condition. Both procalcitonin and CRP would be helpful to differentiate primary influenza pneumonia from concomitant/secondary bacterial pneumonia. PMID:21682848

Benefit and outcome of using temozolomide-based chemoradiotherapy followed by temozolomide alone for glioblastoma in clinical practice.

PubMed

Salma, Svetlana; Djan, Igor; Bjelan, Mladen; Vulekovic, Petar; Novakovic, Mico; Vidovic, Vladimir; Lucic, Milos

2017-01-01

Temozolomide (TEM), an oral alkylating agent, has shown promising activity in the last 10 years in the treatment of glioblastoma multiforme (GBM). Our goal was to show the benefit of concomitant therapy involving 3D conformal radiotherapy and temozolomide in clinical practice. This was a retrospective/prospective study and included a total of 113 patients with GBM diagnosis. Forty- seven patients received postoperative radiotherapy and 66 received concomitant temozolomide plus 3D conformal radiotherapy. The mean overall survival of patients who received postoperative radiotherapy alone was 9.93±6.475 months, compared to statistically longer overall survival in the group of patients who received radiotherapy plus temozolomide (13.89±8.049 months) (p=0.006). The latter group was divided into two subgroups, one consisting of patients who received 6 complete cycles of temozolomide, and a second with patients who received incomplete treatment. Statistically significant longer overall survival was registered in the first subgroup compared to the second (p=0.006). The concomitant usage of temozolomide and radiotherapy was beneficial, and statistically significant difference among groups and subgroups was observed regarding overall survival.

SK channel blocker apamin attenuates the effect of SSRI fluoxetine upon cell firing in dorsal raphe nucleus: a concomitant electrophysiological and electrochemical in vivo study reveals implications for modulating extracellular 5-HT.

PubMed

Crespi, Francesco

2010-06-02

A dual probing methodology was implemented so that combined in vivo voltammetric (electrochemical) and in vivo electrophysiological analysis could be carried out concomitantly in two distinct brain regions of the same anaesthetized animal, i.e., cell body such as the dorsal raphe nucleus (DRN) and related terminal region such as the hippocampus, the frontal cortex, and the amygdala. In particular, this methodology allowed: In addition, the dual probing methodology has been applied to verify the original proposal that a combined treatment with a potassium (SK) channel blocker such as apamin and an SSRI (i.e., fluoxetine) could overcome the slow onset of the SSRI upon central 5-HT activity that could be related to the slow onset of its therapeutic action. Briefly, the effect of apamin either alone or followed by fluoxetine upon cell firing in the DRN (in vivo electrophysiology) and concomitantly upon 5-HT levels (in vivo voltammetry) in the amygdala (forebrain structure involved in mood regulation and innervated by ascending 5-HT projections from the DRN) was studied. Copyright 2010 Elsevier B.V. All rights reserved.

Cardiac abnormalities in Parkinson's disease and Parkinsonism.

PubMed

Scorza, Fulvio A; Fiorini, Ana C; Scorza, Carla A; Finsterer, Josef

2018-07-01

Though there is increasing evidence for primary cardiac disease in Parkinson's disease (PD) and Parkinsonism (PS), this evidence is hardly included in the general management of these patients. Literature review. PD is one of the most common age-related neurodegenerative disorders. Epidemiological studies have shown that PD is accompanied by high rates of premature death compared with the general population. In general, death in PD/PS is usually caused by determinant factors such as pneumonia, cerebrovascular, and cardiovascular disease. There is a significant body of literature demonstrating involvement of the heart in PD/PS. Cardiac involvement in PD/PS includes cardiac autonomic dysfunction, cardiomyopathy, coronary heart disease, arrhythmias, conduction defects, and sudden cardiac death (SCD), and sudden unexpected death in Parkinson's disease (SUDPAR). Cardiac abnormalities found in PD/PS are manifold but the most prominent is cardiac autonomic dysfunction. The frequency of coronary heart disease in PD is a matter of debate. Only rarely reported in PD/PS are cardiomyopathies, arrhythmias, and sudden cardiac death, and SUDPAR. It is particularly recommended that PD/PS patients are more intensively investigated cardiologically as soon as the diagnosis is established. Early recognition of cardiac involvement is important for preventing SCD and SUDPAR. Copyright © 2018 Elsevier Ltd. All rights reserved.

Silicone stent placement for primary tracheal amyloidosis accompanied by cartilage destruction.

PubMed

Ryu, Duck Hyun; Eom, Jung Seop; Jeong, Ho Jung; Kim, Jung Hoon; Lee, Ji Eun; Jun, Ji Eun; Song, Dae Hyun; Han, Joungho; Kim, Hojoong

2014-06-01

Primary tracheal amyloidosis (PTA) can lead to airway obstructions, and patients with severe PTA should undergo bronchoscopic interventions in order to maintain airway patency. Focal airway involvements with amyloidosis can only be treated with mechanical dilatation. However, the PTA with diffused airway involvements and concomitant cartilage destructions requires stent placement. Limited information regarding the usefulness of silicone stents in patients with PTA has been released. Therefore, we report a case of diffused PTA with tracheomalacia causing severe cartilage destruction, which is being successfully managed with bronchoscopic interventions and silicone stent placements.

Anti-cancer effect of bee venom toxin and melittin in ovarian cancer cells through induction of death receptors and inhibition of JAK2/STAT3 pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jo, Miran; Park, Mi Hee; Kollipara, Pushpa Saranya

We investigated whether bee venom and melittin, a major component of bee venom, inhibit cell growth through enhancement of death receptor expressions in the human ovarian cancer cells, SKOV3 and PA-1. Bee venom (1–5 μg/ml) and melittin (0.5–2 μg/ml) inhibited the growth of SKOV3 and PA-1 ovarian cancer cells by the induction of apoptotic cell death in a dose dependent manner. Consistent with apoptotic cell death, expression of death receptor (DR) 3 and DR6 was increased in both cancer cells, but expression of DR4 was increased only in PA-1 cells. Expression of DR downstream pro-apoptotic proteins including caspase-3, 8, andmore » Bax was concomitantly increased, but the phosphorylation of JAK2 and STAT3 and the expression of Bcl-2 were inhibited by treatment with bee venom and melittin in SKOV3 and PA-1 cells. Expression of cleaved caspase-3 was increased in SKOV3, but cleaved caspase-8 was increased in PA-1 cells. Moreover, deletion of DR3, DR4, and DR6 by small interfering RNA significantly reversed bee venom and melittin-induced cell growth inhibitory effect as well as down regulation of STAT3 by bee venom and melittin in SKOV3 and PA-1 ovarian cancer cell. These results suggest that bee venom and melittin induce apoptotic cell death in ovarian cancer cells through enhancement of DR3, DR4, and DR6 expression and inhibition of STAT3 pathway. -- Highlights: ► Some studies have showed that bee venom and/or melittin have anti-cancer effects. ► We found that bee venom and melittin inhibited cell growth in ovarian cancer cells. ► Bee venom and melittin induce apoptosis in SKOV3 and PA-1.« less

Ozone-Induced Cell Death in Tobacco Cultivar Bel W3 Plants. The Role of Programmed Cell Death in Lesion Formation

PubMed Central

Pasqualini, Stefania; Piccioni, Claudia; Reale, Lara; Ederli, Luisa; Della Torre, Guido; Ferranti, Francesco

2003-01-01

Treatment of the ozone-sensitive tobacco (Nicotiana tabacum L. cv Bel W3) with an ozone pulse (150 nL L–1 for 5 h) induced visible injury, which manifested 48 to 72 h from onset of ozone fumigation. The “classical” ozone symptoms in tobacco cv Bel W3 plants occur as sharply defined, dot-like lesions on the adaxial side of the leaf and result from the death of groups of palisade cells. We investigated whether this reaction had the features of a hypersensitive response like that which results from the incompatible plant-pathogen interaction. We detected an oxidative burst, the result of H2O2 accumulation at 12 h from the starting of fumigation. Ozone treatment induced deposition of autofluorescent compounds and callose 24 h from the start of treatment. Total phenolic content was also strongly stimulated at the 10th and 72nd h from starting fumigation, concomitant with an enhancement in phenylalanine ammonia-lyase a and phenylalanine ammonia-lyase b expression, as evaluated by reverse transcriptase-polymerase chain reaction. There was also a marked, but transient, increase in the mRNA level of pathogenesis-related-1a, a typical hypersensitive response marker. Overall, these results are evidence that ozone triggers a hypersensitive response in tobacco cv Bel W3 plants. We adopted four criteria for detecting programmed cell death in ozonated tobacco cv Bel W3 leaves: (a) early release of cytochrome c from mitochondria; (b) activation of protease; (c) DNA fragmentation by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling of DNA 3′-OH groups; and (d) ultrastructural changes characteristic of programmed cell death, including chromatin condensation and blebbing of plasma membrane. We, therefore, provide evidence that ozone-induced oxidative stress triggers a cell death program in tobacco cv Bel W3. PMID:14612586

Porcine circovirus-2 capsid protein induces cell death in PK15 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walia, Rupali; Dardari, Rkia, E-mail: rdardari@ucalgary.ca; Chaiyakul, Mark

Studies have shown that Porcine circovirus (PCV)-2 induces apoptosis in PK15 cells. Here we report that cell death is induced in PCV2b-infected PK15 cells that express Capsid (Cap) protein and this effect is enhanced in interferon gamma (IFN-γ)-treated cells. We further show that transient PCV2a and 2b-Cap protein expression induces cell death in PK15 cells at rate similar to PCV2 infection, regardless of Cap protein localization. These data suggest that Cap protein may have the capacity to trigger different signaling pathways involved in cell death. Although further investigation is needed to gain deeper insights into the nature of the pathwaysmore » involved in Cap-induced cell death, this study provides evidence that PCV2-induced cell death in kidney epithelial PK15 cells can be mapped to the Cap protein and establishes the need for future research regarding the role of Cap-induced cell death in PCV2 pathogenesis. - Highlights: • IFN-γ enhances PCV2 replication that leads to cell death in PK15 cells. • IFN-γ enhances nuclear localization of the PCV2 Capsid protein. • Transient PCV2a and 2b-Capsid protein expression induces cell death. • Cell death is not dictated by specific Capsid protein sub-localization.« less

The art and science of low-energy applications in medicine: pathology perspectives

NASA Astrophysics Data System (ADS)

Thomsen, Sharon L.

2011-03-01

Applications of low energy non-ionizing irradiation result in non-lethal and lethal effects in cells, tissues and intact individuals. The effects of these applications depend on the physical parameters of the applied energies, the mechanisms of interaction of these energies on the target and the biologic status of the target. Recently, cell death has been found not to be a random accident of situation or age but a range of complicated physiological responses to various extrinsic and intrinsic events some of which are genetically programmed and/ or physiologically regulated. Therefore, cell death has been classified into three general groups: 1) Programmed cell death including apoptosis and necroptosis, cornefication and autophagy; 2) Accidental (traumatic) cell death due to the direct, immediate effects of the lethal event and 3) Necrotic cell death which is, by default, all cell death not associated with programmed or accidental cell death. Lethal low energy non-ionizing application biologic effects involve mechanisms of all three groups as compared to high energy applications that predominantly involve the mechanisms of accidental cell death. Currently, the mechanisms of all these modes of cell death are being vigorously investigated. As research and development of new low energy applications continues, the need to understand the mechanisms of cell death that they produce will be critical to the rational creation of safe, yet effective instruments.

Tributyltin induces oxidative damage, inflammation and apoptosis via disturbance in blood-brain barrier and metal homeostasis in cerebral cortex of rat brain: an in vivo and in vitro study.

PubMed

Mitra, Sumonto; Gera, Ruchi; Siddiqui, Waseem A; Khandelwal, Shashi

2013-08-09

Tributyltin (TBT), a member of the organotin family, is primarily used for its biocidal activity. Persistent environmental levels of TBT pose threat to the ecosystem. Since neurotoxic influence of TBT remains elusive, we therefore, studied its effect on cerebral cortex of male Wistar rats. A single oral dose of Tributyltin-Chloride (TBTC) (10, 20, 30mg/kg) was administered and the animals were sacrificed on day 3 and day 7. Blood-brain barrier permeability remained disrupted significantly till day 7 with all the doses of TBTC. Pro-oxidant metal levels (Fe, Cu) were increased with a concomitant decrease in Zn. ROS generation was substantially raised resulting in oxidative damage (increased protein carbonylation and lipid peroxidation) with marked decline in tissue antioxidant status (GSH/GSSG levels). Protein expression studies indicated astrocyte activation, upregulation of inflammatory molecules (IL-6, Cox-2 and NF-κB) and simultaneous elevation in the apoptotic index (Bax/Bcl2). Neurodegeneration was evident by reduced neurofilament expression and increased calpain cleaved Tau levels. The in-vitro study demonstrated involvement of calcium and signaling molecules (p38), with downstream activation of caspase-3 and -8, and apoptotic cell death was evident by nuclear fragmentation, DNA laddering and Annexin V binding experiments. Ca(2+) inhibitors (BAPTA-AM, EGTA, and RR) and free radical scavengers (NAC and biliprotein [C-PC]) increased cell viability (MTT assay), signifying specific roles of Ca(2+) and ROS. Significance of p38 signaling was evaluated on pro-apoptotic proteins by using SB203580, a selective p38 inhibitor. Our data collectively illustrates that TBTC can disrupt BBB, induce oxidative stress, cause cell death and initiate neurodegeneration in rat brain. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma.

PubMed

Stempel, David A; Szefler, Stanley J; Pedersen, Søren; Zeiger, Robert S; Yeakey, Anne M; Lee, Laurie A; Liu, Andrew H; Mitchell, Herman; Kral, Kenneth M; Raphiou, Ibrahim H; Prillaman, Barbara A; Buaron, Kathleen S; Yun Kirby, Suyong; Pascoe, Steven J

2016-09-01

Long-acting beta-agonists (LABAs) have been shown to increase the risk of asthma-related death among adults and the risk of asthma-related hospitalization among children. It is unknown whether the concomitant use of inhaled glucocorticoids with LABAs mitigates those risks. This trial prospectively evaluated the safety of the LABA salmeterol, added to fluticasone propionate, in a fixed-dose combination in children. We randomly assigned, in a 1:1 ratio, children 4 to 11 years of age who required daily asthma medications and had a history of asthma exacerbations in the previous year to receive fluticasone propionate plus salmeterol or fluticasone alone for 26 weeks. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization), as assessed in a time-to-event analysis. The statistical design specified that noninferiority would be shown if the upper boundary of the 95% confidence interval of the hazard ratio for the primary safety end point was less than 2.675. The main efficacy end point was the first severe asthma exacerbation that led to treatment with systemic glucocorticoids, as assessed in a time-to-event analysis. Among the 6208 patients, 27 patients in the fluticasone-salmeterol group and 21 in the fluticasone-alone group had a serious asthma-related event (all were hospitalizations); the hazard ratio with fluticasone-salmeterol versus fluticasone alone was 1.28 (95% confidence interval [CI], 0.73 to 2.27), which showed the noninferiority of fluticasone-salmeterol (P=0.006). A total of 265 patients (8.5%) in the fluticasone-salmeterol group and 309 (10.0%) in the fluticasone-alone group had a severe asthma exacerbation (hazard ratio, 0.86; 95% CI, 0.73 to 1.01). In this trial involving children with asthma, salmeterol in a fixed-dose combination with fluticasone was associated with the risk of a serious asthma-related event that was similar to the risk with fluticasone alone. (Funded by GlaxoSmithKline; VESTRI ClinicalTrials.gov number, NCT01462344 .).

[Maternal deaths due to infectious cause, results from the French confidential enquiry into maternal deaths, 2010-2012].

PubMed

Rigouzzo, A; Tessier, V; Zieleskiewicz, L

2017-12-01

Over the period 2010-2012, maternal mortality from infectious causes accounted for 5% of maternal deaths by direct causes and 16% of maternal deaths by indirect causes. Among the 22 deaths caused by infection occurred during this period, 6 deaths were attributed to direct causes from genital tract origin, confirming thus the decrease in direct maternal deaths by infection during the last ten years. On the contrary, indirect maternal deaths by infection, from extragenital origin, doubled during the same period, with 16 deaths in the last triennium, dominated by winter respiratory infections, particularly influenza: the 2009-2010 influenza A (H1N1) virus pandemic was the leading cause of indirect maternal mortality by infection during the studied period. The main infectious agents involved in maternal deaths from direct causes were Streptococcus A, Escherichia Coli and Clostridium perfringens: these bacterias were responsible for toxic shock syndrome, severe sepsis, secondary in some cases to cellulitis or necrotizing fasciitis. Of the 6 deaths due to direct infection, 4 were considered avoidable because of inadequate management: delayed or missed diagnosis, delayed or inadequate initiation of a specific medical and/or surgical treatment. Of the 16 indirect maternal deaths due to infection causes, the most often involved infectious agents were influenza A (H1N1) virus and Streptococcus pneumonia with induced purpura fulminans: the absence of influenza vaccination during pregnancy, delayed diagnosis and emergency initiation of a specific treatment, were the main contributory factors to these deaths and their avoidability in 70% of the cases analyzed. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Electrocardiographic features of sudden unexpected death in epilepsy.

PubMed

Chyou, Janice Y; Friedman, Daniel; Cerrone, Marina; Slater, William; Guo, Yu; Taupin, Daniel; O'Rourke, Sean; Priori, Silvia G; Devinsky, Orrin

2016-07-01

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of epilepsy-related mortality. We hypothesized that electrocardiography (ECG) features may distinguish SUDEP cases from living subjects with epilepsy. Using a matched case-control design, we compared ECG studies of 12 consecutive cases of SUDEP over 10 years and 22 epilepsy controls matched for age, sex, epilepsy type (focal, generalized, or unknown/mixed type), concomitant antiepileptic, and psychotropic drug classes. Conduction intervals and prevalence of abnormal ventricular conduction diagnosis (QRS ≥110 msec), abnormal ventricular conduction pattern (QRS <110 msec, morphology of incomplete right or left bundle branch block or intraventricular conduction delay), early repolarization, and features of inherited cardiac channelopathies were assessed. Abnormal ventricular conduction diagnosis and pattern distinguished SUDEP cases from matched controls. Abnormal ventricular conduction diagnosis was present in two cases and no controls. Abnormal ventricular conduction pattern was more common in cases than controls (58% vs. 18%, p = 0.04). Early repolarization was similarly prevalent in cases and controls, but the overall prevalence exceeded that of published community-based cohorts. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

[Refeeding syndrome: a review of the literature].

PubMed

Rohrer, S; Dietrich, J W

2014-06-01

The refeeding syndrome is a dangerous condition, which may even lead to death. The syndrome occurs after re-establishment of adequate nutrition in malnourished and cachectic patients. More specifically its occurrence has been reported during oral, enteral and parenteral feeding. Early diagnosis is crucial for adequate and timely therapy. However, due to a lack of knowledge in the community this is not always achieved. The leading symptom is hypophosphatemia, often accompanied by electrolyte disturbances and vitamin and trace element deficiencies. Due to a concomitant administration of carbohydrates and intravenous fluid volume it may also lead to hypervolemia with cardiac failure. Compromise of other organ functions with a varying degree of severity, even leading to death, have been reported. The most efficient prevention of the refeeding syndrom is recommended by an early identification of patients at risk and the administration of an initially lower caloric nutrition accompanied by a tight and regularly scheduled observation of relevant laboratory parameters. This literature research included the following terms: "refeeding syndrome" and "hypophosphataemia" including the 2006 guidelines from the National Institute for Health and Clinical Excellence (UK). © Georg Thieme Verlag KG Stuttgart · New York.

Metabolic modulation of Ewing sarcoma cells inhibits tumor growth and stem cell properties

PubMed Central

Dasgupta, Atreyi; Trucco, Matteo; Rainusso, Nino; Bernardi, Ronald J.; Shuck, Ryan; Kurenbekova, Lyazat; Loeb, David M.; Yustein, Jason T.

2017-01-01

Ewing sarcoma (EWS) is a highly aggressive and metabolically active malignant tumor. Metabolic activity can broadly be characterized by features of glycolytic activity and oxidative phosphorylation. We have further characterized metabolic features of EWS cells to identify potential therapeutic targets. EWS cells had significantly more glycolytic activity compared to their non-malignant counterparts. Thus, metabolic inhibitors of glycolysis such as 2-deoxy-D-glucose (2DG) and of the mitochondrial respiratory pathway, such as metformin, were evaluated as potential therapeutic agents against a panel of EWS cell lines in vitro. Results indicate that 2DG alone or in combination with metformin was effective at inducing cell death in EWS cell lines. The predominant mechanism of cell death appears to be through stimulating apoptosis leading into necrosis with concomitant activation of AMPK-α. Furthermore, we demonstrate that the use of metabolic modulators can target putative EWS stem cells, both in vitro and in vivo, and potentially overcome chemotherapeutic resistance in EWS. Based on these data, clinical strategies using drugs targeting tumor cell metabolism present a viable therapeutic modality against EWS. PMID:29100387

Analysis of wounds incurred by U.S. Army Seventh Corps personnel treated in Corps hospitals during Operation Desert Storm, February 20 to March 10, 1991.

PubMed

Carey, M E

1996-03-01

One hundred and forty-three soldiers who received ballistic injury were actively treated at U.S. Army Seventh Corps hospitals during Operation Desert Storm. Ninety-five percent were wounded by fragments, 5% by bullets. Many had wounds of several body parts, including 17.3% who received a head wound; 4.3% a neck wound; 5.8% a chest wound; 9.3% an abdominal wound; and 90% who had extremity wounds. Three hospital deaths occurred--a 2.1% mortality rate. Only two soldiers sustained a brain wound; in both, the missile entered below the skull area protected by the Kevlar helmet. One brainwounded individual was treated and lived; the other died from hemorrhage and shock from concomitant traumatic lower-extremity amputations. The current U.S. helmet appears to provide significant protection from fragmenting ordnance as does the armored vest. Hemorrhage from proximal extremity wounds caused hospital deaths. Treatment of such wounds will have to be improved to reduce future combat mortality.

Drug Overdose Deaths among Adolescents Aged 15-19 in the United States: 1999-2015. NCHS Data Brief. Number 282

ERIC Educational Resources Information Center

Curtin, Sally C.; Tejada-Vera, Betzaida; Warner, Margaret

2017-01-01

Drug overdose deaths in the United States are a pressing public health challenge. In particular, drug overdoses involving opioids have increased since 1999. This report focuses specifically on drug overdose deaths for older adolescents aged 15-19. In 2015, 772 drug overdose deaths occurred in this age group. Rates for 1999-2015 are presented and…

The phenoptosis problem: what is causing the death of an organism? Lessons from acute kidney injury.

PubMed

Zorov, D B; Plotnikov, E Y; Jankauskas, S S; Isaev, N K; Silachev, D N; Zorova, L D; Pevzner, I B; Pulkova, N V; Zorov, S D; Morosanova, M A

2012-07-01

Programmed execution of various cells and intracellular structures is hypothesized to be not the only example of elimination of biological systems - the general mechanism can also involve programmed execution of organs and organisms. Modern rating of programmed cell death mechanisms includes 13 mechanistic types. As for some types, the mechanism of actuation and manifestation of cell execution has been basically elucidated, while the causes and intermediate steps of the process of fatal failure of organs and organisms remain unknown. The analysis of deaths resulting from a sudden heart arrest or multiple organ failure and other acute and chronic pathologies leads to the conclusion of a special role of mitochondria and oxidative stress activating the immune system. Possible mechanisms of mitochondria-mediated induction of the signaling cascades involved in organ failure and death of the organism are discussed. These mechanisms include generation of reactive oxygen species and damage-associated molecular patterns in mitochondria. Some examples of renal failure-induced deaths are presented with mechanisms and settings determined by some hypothetical super system rather than by the kidneys themselves. This system plays the key role in the process of physiological senescence and termination of an organism. The facts presented suggest that it is the immune system involved in mitochondrial signaling that can act as the system responsible for the organism's death.

Comparative Transcriptome and iTRAQ Proteome Analyses of Citrus Root Responses to Candidatus Liberibacter asiaticus Infection

PubMed Central

Jiang, Nong-hui; Jiang, Bo; Zhang, Yong-yan; Wu, Bo; Hu, Min-lun; Zeng, Ji-wu; Yan, Hua-xue; Yi, Gan-jun; Zhong, Guang-yan

2015-01-01

Root samples of ‘Sanhu’ red tangerine trees infected with and without Candidatus Liberibacter asiaticus (CLas) were collected at 50 days post inoculation and subjected to RNA-sequencing and isobaric tags for relative and absolute quantification (iTRAQ) to profile the differentially expressed genes (DEGs) and proteins (DEPs), respectively. Quantitative real-time PCR was subsequently used to confirm the expression of 16 selected DEGs. Results showed that a total of 3956 genes and 78 proteins were differentially regulated by HLB-infection. Among the most highly up-regulated DEPs were sperm specific protein 411, copper ion binding protein, germin-like proteins, subtilisin-like proteins and serine carboxypeptidase-like 40 proteins whose transcript levels were concomitantly up-regulated as shown by RNA-seq data. Comparison between our results and those of the previously reported showed that known HLB-modulated biological pathways including cell-wall modification, protease-involved protein degradation, carbohydrate metabolism, hormone synthesis and signaling, transcription activities, and stress responses were similarly regulated by HLB infection but different or root-specific changes did exist. The root unique changes included the down-regulation in genes of ubiquitin-dependent protein degradation pathway, secondary metabolism, cytochrome P450s, UDP-glucosyl transferases and pentatricopeptide repeat containing proteins. Notably, nutrient absorption was impaired by HLB-infection as the expression of the genes involved in Fe, Zn, N and P adsorption and transportation were significantly changed. HLB-infection induced some cellular defense responses but simultaneously reduced the biosynthesis of the three major classes of secondary metabolites, many of which are known to have anti-pathogen activities. Genes involved in callose deposition were up-regulated whereas those involved in callose degradation were also up-regulated, indicating that the sieve tube elements in roots were hanging on the balance of life and death at this stage. In addition, signs of carbohydrate starvation were already eminent in roots at this stage. Other interesting genes and pathways that were changed by HLB-infection were also discussed based on our findings. PMID:26046530

Nitric Oxide and Protein S-Nitrosylation Are Integral to Hydrogen Peroxide-Induced Leaf Cell Death in Rice1[W][OA

PubMed Central

Lin, Aihong; Wang, Yiqin; Tang, Jiuyou; Xue, Peng; Li, Chunlai; Liu, Linchuan; Hu, Bin; Yang, Fuquan; Loake, Gary J.; Chu, Chengcai

2012-01-01

Nitric oxide (NO) is a key redox-active, small molecule involved in various aspects of plant growth and development. Here, we report the identification of an NO accumulation mutant, nitric oxide excess1 (noe1), in rice (Oryza sativa), the isolation of the corresponding gene, and the analysis of its role in NO-mediated leaf cell death. Map-based cloning revealed that NOE1 encoded a rice catalase, OsCATC. Furthermore, noe1 resulted in an increase of hydrogen peroxide (H2O2) in the leaves, which consequently promoted NO production via the activation of nitrate reductase. The removal of excess NO reduced cell death in both leaves and suspension cultures derived from noe1 plants, implicating NO as an important endogenous mediator of H2O2-induced leaf cell death. Reduction of intracellular S-nitrosothiol (SNO) levels, generated by overexpression of rice S-nitrosoglutathione reductase gene (GSNOR1), which regulates global levels of protein S-nitrosylation, alleviated leaf cell death in noe1 plants. Thus, S-nitrosylation was also involved in light-dependent leaf cell death in noe1. Utilizing the biotin-switch assay, nanoliquid chromatography, and tandem mass spectrometry, S-nitrosylated proteins were identified in both wild-type and noe1 plants. NO targets identified only in noe1 plants included glyceraldehyde 3-phosphate dehydrogenase and thioredoxin, which have been reported to be involved in S-nitrosylation-regulated cell death in animals. Collectively, our data suggest that both NO and SNOs are important mediators in the process of H2O2-induced leaf cell death in rice. PMID:22106097

Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway.

PubMed

Allen, Joshua E; Krigsfeld, Gabriel; Patel, Luv; Mayes, Patrick A; Dicker, David T; Wu, Gen Sheng; El-Deiry, Wafik S

2015-05-01

We previously reported the identification of ONC201/TIC10, a novel small molecule inducer of the human TRAIL gene that improves efficacy-limiting properties of recombinant TRAIL and is in clinical trials in advanced cancers based on its promising safety and antitumor efficacy in several preclinical models. We performed a high throughput luciferase reporter screen using the NCI Diversity Set II to identify TRAIL-inducing compounds. Small molecule-mediated induction of TRAIL reporter activity was relatively modest and the majority of the hit compounds induced low levels of TRAIL upregulation. Among the candidate TRAIL-inducing compounds, TIC9 and ONC201/TIC10 induced sustained TRAIL upregulation and apoptosis in tumor cells in vitro and in vivo. However, ONC201/TIC10 potentiated tumor cell death while sparing normal cells, unlike TIC9, and lacked genotoxicity in normal fibroblasts. Investigating the effects of TRAIL-inducing compounds on cell signaling pathways revealed that TIC9 and ONC201/TIC10, which are the most potent inducers of cell death, exclusively activate Foxo3a through inactivation of Akt/ERK to upregulate TRAIL and its pro-apoptotic death receptor DR5. These studies reveal the selective activity of ONC201/TIC10 that led to its selection as a lead compound for this novel class of antitumor agents and suggest that ONC201/TIC10 is a unique inducer of the TRAIL pathway through its concomitant regulation of the TRAIL ligand and its death receptor DR5.

The role of illicit drug use in sudden death in the young.

PubMed

Fischbach, Peter

2017-01-01

The recreational use of illicit drugs remains an enormous and growing problem throughout the United States of America and around the world. Cocaine is most frequently thought of when considering the cardiovascular toxicity of illicit drugs. The association of cocaine use with sudden death due to myocardial ischaemia and infarction is well recognised, and this risk appears to be amplified by concomitant cigarette smoking and alcohol consumption. Like cocaine, amphetamine and its derivatives lead to indirect stimulation of the autonomic nervous system through the release of norepinephrine, dopamine, and serotonin in nerve terminals of the central and autonomic nervous systems. However, amphetamine lacks the ion channel-blocking properties of cocaine. Also similar to cocaine, coronary artery spasm may be induced in individuals with or without atherosclerotic disease and may lead to myocardial infarction. With the movement across the United States of America to legalise marijuana, or cannabis, for medicinal and recreational purposes, it is important to consider its potential deleterious effects. Marijuana has long been thought to have very few adverse effects with the exception of long-term dependence. There are, however, scattered reports of acute adverse events up to and including sudden death. These appear to be due to myocardial infarction. In conclusion, the incidence of sudden death associated with the use of these drugs varies from rare in the case of marijuana use to not infrequent with some drugs such as cocaine. It is important for care providers to recognise the potential for drug abuse when caring for a sudden cardiac arrest survivor.

Extensive Loss of Islet Mass Beyond the First Day After Intraportal Human Islet Transplantation in a Mouse Model.

PubMed

Liljebäck, Hanna; Grapensparr, Liza; Olerud, Johan; Carlsson, Per-Ola

2016-01-01

Clinical islet transplantation is characterized by a progressive deterioration of islet graft function, which renders many patients once again dependent on exogenous insulin administration within a couple of years. In this study, we aimed to investigate possible engraftment factors limiting the survival and viability of experimentally transplanted human islets beyond the first day after their transplantation to the liver. Human islets were transplanted into the liver of nude mice and characterized 1 or 30 days after transplantation by immunohistochemistry. The factors assessed were endocrine mass, cellular death, hypoxia, vascular density and amyloid formation in the transplanted islets. One day posttransplantation, necrotic cells, as well as apoptotic cells, were commonly observed. In contrast to necrotic death, apoptosis rates remained high 1 month posttransplantation, and the total islet mass was reduced by more than 50% between 1 and 30 days posttransplantation. Islet mass at 30 days posttransplantation correlated negatively to apoptotic death. Vascular density within the transplanted islets remained less than 30% of that in native human islets up to 30 days posttransplantation and was associated with prevailing hypoxia. Amyloid formation was rarely observed in the 1-day-old transplants, but was commonly observed in the 30-day-old islet transplants. We conclude that substantial islet cell death occurs beyond the immediate posttransplantation phase, particularly through apoptotic events. Concomitant low vascularization with prevailing hypoxia and progressive amyloid development was observed in the human islet grafts. Strategies to improve engraftment at the intraportal site or change of implantation site in the clinical setting are needed.

CD4 decline is associated with increased risk of cardiovascular disease, cancer, and death in virally suppressed patients with HIV.

PubMed

Helleberg, Marie; Kronborg, Gitte; Larsen, Carsten S; Pedersen, Gitte; Pedersen, Court; Obel, Niels; Gerstoft, Jan

2013-07-01

The clinical implications of a considerable CD4 decline despite antiretroviral treatment and viral suppression are unknown. We aimed to test the hypothesis that a major CD4 decline could be a marker of cardiovascular disease or undiagnosed cancer. Patients with human immunodeficiency virus (HIV) were followed in the Danish nationwide, population-based cohort study in the period 1995-2010 with quarterly CD4 measurements. Associations between a CD4 decline of ≥30% and cardiovascular disease, cancer, and death were analyzed using Poisson regression with date of CD4 decline as a time-updated variable. We followed 2584 virally suppressed HIV patients for 13 369 person-years (PY; median observation time, 4.7 years). Fifty-six patients developed CD4 decline (incidence rate, 4.2/1000 PY [95% confidence interval {CI}, 3.2-5.4]). CD4 counts dropped from a median of 492 cells/µL to 240 cells/µL. CD8, CD3, and total lymphocyte counts dropped concomitantly. No HIV-related factors, apart from treatment with didanosine, were associated with CD4 decline. The risk of cardiovascular disease, cancer, and death increased markedly ≤6 months after CD4 decline (incidence rate ratio, 11.7 [95% CI, 3.6-37.4] and 13.7 [95% CI, 4.3-43.6], respectively, and mortality rate ratio 4.3 [95% CI, 1.1-17.6]). A major decline in CD4 count is associated with a marked increased risk of cardiovascular disease, cancer, and death among virally suppressed HIV patients.

Can proton pump inhibitors reduce rebleeding following Histoacryl sclerotherapy for gastric variceal hemorrhage?

PubMed

Kim, Ka Rham; Jun, Chung Hwan; Cho, Kyu Man; Wi, Jin Woo; Park, Seon Young; Cho, Sung Bum; Lee, Wan Sik; Park, Chang Hwan; Joo, Young Eun; Kim, Hyun Soo; Choi, Sung Kyu; Rew, Jong Sun

2015-09-01

To evaluate the efficacy of proton pump inhibitors (PPIs) in reducing rebleeding and bleeding-related death rates after endoscopic gastric variceal obliteration (GVO) using N-butyl-2-cyanoacrylate (NBC). This study enrolled 341 patients who were consecutively diagnosed with and treated for bleeding gastric varices. The patients were divided into PPI and non-PPI groups, and their endoscopic findings, initial hemostasis outcomes, rebleeding and bleeding-related death rates, and treatment-related complications were analyzed. The rate of initial hemostasis was 97.1%. rebleeding occurred in 2.2% of patients within 2 weeks, 3.9% of patients within 4 weeks, 18.9% of patients within 6 months, and 27.6% of patients within 12 months of the GVO procedure. A previous history of variceal bleeding (relative risk [RR], 1.955; 95% confidence interval [CI], 1.263 to 3.028; p = 0.003) and use of PPIs (RR, 0.554; 95% CI, 0.352 to 0.873; p = 0.011) were associated with rebleeding. Child-Pugh class C (RR, 10.914; 95% CI, 4.032 to 29.541; p < 0.001), failure of initial hemostasis (RR, 13.329; 95% CI, 2.795 to 63.556; p = 0.001), and the presence of red-colored concomitant esophageal varices (RR, 4.096; 95% CI, 1.320 to 12.713; p = 0.015) were associated with bleeding-related death. The prophylactic use of PPIs reduces rebleeding after GVO using NBC in patients with gastric variceal hemorrhage. However, prophylactic use of PPIs does not reduce bleeding-related death.

Study of the evolution and variability of nontraumatic orthopedic surgeries in Brazil-9 years of follow-up: A database study.

PubMed

Luciano, Alexandre de Paiva; Almeida, Tábata Cristina do Carmo; Dos Santos Figueiredo, Francisco Winter; Schoueri, Jean Henri Maselli; Abreu, Luiz Carlos de; Adami, Fernando

2018-05-01

In Brazil, there are no epidemiological statistics that map nontraumatic orthopedic injuries, their rate of variability, distribution by specialty, fatality rate, and the economic impact that these lesions and their consequences can bring to the country. The objective of this study was to evaluate the rates of variability for skills, deaths, mortality, and the economic impact of nontraumatic orthopedic surgeries in Brazil from 2008 to 2016.This is a descriptive study conducted through the analysis of data relating to the indicators of hospital production regarding orthopedic procedures of the Department of Informatics of the Unified Health System (Departamento de Informática do Sistema Único de saúde-DATASUS) between 2008 and 2016. The level of significance was 5%.There was a predominance of hospitalizations for surgery of the lower limbs, which also resulted in the largest number of deaths. The surgical mortality rate recorded for the hip also needs to be considered. In general, there is a national increase in the number of orthopedic surgeries performed, accompanied by a concomitant increase in the number of deaths and mortality of the population exposed.We observed a growing demand for hospitalization with a consequent increase in lethality and deaths. We can conclude that between 2008 and 2016, the number of hospitalizations for elective nontraumatic orthopedic surgical procedures increased significantly, driven mainly by lower limb surgeries, along with the cost of the Unified Health System (Sistema Único de Saúde-SUS) for these surgeries.

Physician-assisted deaths under the euthanasia law in Belgium: a population-based survey.

PubMed

Chambaere, Kenneth; Bilsen, Johan; Cohen, Joachim; Onwuteaka-Philipsen, Bregje D; Mortier, Freddy; Deliens, Luc

2010-06-15

Legalization of euthanasia and physician-assisted suicide has been heavily debated in many countries. To help inform this debate, we describe the practices of euthanasia and assisted suicide, and the use of life-ending drugs without an explicit request from the patient, in Flanders, Belgium, where euthanasia is legal. We mailed a questionnaire regarding the use of life-ending drugs with or without explicit patient request to physicians who certified a representative sample (n = 6927) of death certificates of patients who died in Flanders between June and November 2007. The response rate was 58.4%. Overall, 208 deaths involving the use of life-ending drugs were reported: 142 (weighted prevalence 2.0%) were with an explicit patient request (euthanasia or assisted suicide) and 66 (weighted prevalence 1.8%) were without an explicit request. Euthanasia and assisted suicide mostly involved patients less than 80 years of age, those with cancer and those dying at home. Use of life-ending drugs without an explicit request mostly involved patients 80 years of older, those with a disease other than cancer and those in hospital. Of the deaths without an explicit request, the decision was not discussed with the patient in 77.9% of cases. Compared with assisted deaths with the patient's explicit request, those without an explicit request were more likely to have a shorter length of treatment of the terminal illness, to have cure as a goal of treatment in the last week, to have a shorter estimated time by which life was shortened and to involve the administration of opioids. Physician-assisted deaths with an explicit patient request (euthanasia and assisted suicide) and without an explicit request occurred in different patient groups and under different circumstances. Cases without an explicit request often involved patients whose diseases had unpredictable end-of-life trajectories. Although opioids were used in most of these cases, misconceptions seem to persist about their actual life-shortening effects.

Tobacco TTG2 and ARF8 function concomitantly to control flower colouring by regulating anthocyanin synthesis genes.

PubMed

Li, P; Chen, X; Sun, F; Dong, H

2017-07-01

Recently we elucidated that tobacco TTG2 cooperates with ARF8 to regulate the vegetative growth and seed production. Here we show that TTG2 and ARF8 control flower colouring by regulating expression of ANS and DFR genes, which function in anthocyanin biosynthesis. Genetic modifications that substantially altered expression levels of the TTG2 gene and production quantities of TTG2 protein were correlated with flower development and colouring. Degrees of flower colour were increased by TTG2 overexpression but decreased through TTG2 silencing, in coincidence with high and low concentrations of anthocyanins in flowers. Of five genes involved in the anthocyanin biosynthesis pathway, only ANS and DFR were TTG2-regulated and displayed enhancement and diminution of expression with TTG2 overexpression and silencing, respectively. The floral expression of ANS and DFR also needed a functional ARF8 gene, as ANS and DFR expression were attenuated by ARF8 silencing, which concomitantly diminished the role of TTG2 in anthocyanin production. While ARF8 required TTG2 to be expressed by itself and to regulate ANS and DFR expression, the concurrent presence of normally functional TTG2 and ARF8 was critical for floral production of anthocyanins and also for flower colouration. Our data suggest that TTG2 functions concomitantly with ARF8 to control degrees of flower colour by regulating expression of ANS and DFR, which are involved in the anthocyanin biosynthesis pathway. ARF8 depends on TTG2 to regulate floral expression of ANS and DFR with positive effects on anthocyanin production and flower colour. © 2017 German Botanical Society and The Royal Botanical Society of the Netherlands.

Analysis of Pediatric Maxillofacial Fractures Requiring Operative Treatment: Characteristics, Management, and Outcomes.

PubMed

Allred, Lindsay J; Crantford, John C; Reynolds, Michael F; David, Lisa R

2015-11-01

Maxillofacial fractures in pediatric trauma patients require significant force and frequently are associated with concomitant injuries. The anatomic and developmental differences between the adult and child that impact patterns of injury also affect management and outcomes. The aim of this study was to analyze fracture location, mechanism, concomitant injuries as well as methods of surgical treatment and outcomes, to improve management of this patient population. A retrospective review was conducted of pediatric patients with maxillofacial fractures presenting to a level-1 trauma center during an 8-year span. Only patients requiring surgical intervention, 204, were included in this study. Data pertaining to the location of injury, mechanism, associated injuries, surgical treatment, outcomes, and complications were analyzed. The most common fracture location was the mandible (36.3%), then the nasal bone (35.3%), followed by the tripod fracture (10.8%). A total of 30.7% of patients were involved in motor vehicle accidents, with the next most common mechanisms being sports (24.4%), and assault (13.7%). A total of 46% of the patients sustained concomitant injuries, with the majority involving cerebral trauma (14.7%) or the extremities (9.3%). Total 75.4% of all fractures, excluding the nose, were treated with open reduction and internal fixation (ORIF). Our complication rate was 11.2%. Pediatric craniofacial trauma remains a frequent presentation to the emergency department of trauma centers. Facial fracture patterns and mechanism of trauma observed in the pediatric population presenting to this facility are consistent with incidences reported in the literature. Knowledge of treatment options and potential complications is an important tool in the management of the pediatric trauma patient.

Orthopaedic injuries in children with nonaccidental trauma: demographics and incidence from the 2000 kids' inpatient database.

PubMed

Loder, Randall T; Feinberg, Judy R

2007-06-01

The purpose of this study was to examine the demographic and injury characteristics of children hospitalized with nonaccidental trauma as a causative factor using a large national database. Of the nearly 2.5 million cases in the database, 1794 (0.1%) were identified through diagnostic coding of abuse. Both sexes were equally represented, and two thirds had Medicaid as their primary payer. About one half of the children were younger than 1 year, but all ages were represented. The most common orthopaedic injuries were fractures of the femur or humerus, and most of those fractures occurred in children younger than 2 years. The most common nonorthopaedic injuries were contusions and brain injuries, with or without skull fracture, and 62 (3.5%) of the abused children died; almost all deaths were associated with brain trauma. Nearly one half of the abused hospitalized children between the ages of 3 and 20 years had a concomitant psychiatric or neurological condition. These data provide the orthopaedic surgeon with additional information to assist in identification of potential cases of nonaccidental trauma. In addition to presence of long bone fractures in infants and toddlers, older children with concomitant psychiatric or neurological conditions presenting with nonaccidental injuries should be assessed for possible abuse.

Antithrombotic therapy in peripheral artery disease: A review of the EUCLID trial results and current ongoing trials.

PubMed

Ward, Rachael; Long, Chandler; Patel, Manesh R; Jones, William S

2018-01-01

In addition to risk-factor modification, antithrombotic therapy is the hallmark of management to reduce cardiovascular ischemic events in patients with peripheral artery disease (PAD). Currently, the guidelines recommend long-term antiplatelet therapy with aspirin or clopidogrel in this patient population to reduce myocardial infarction, stroke, and vascular death. Past outcomes studies have shown some benefit of ticagrelor, another antiplatelet agent, as compared with clopidogrel in patients with coronary disease and concomitant PAD. However, most recently, the Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial has shown no additional benefit of ticagrelor over clopidogrel. In this trial, a minority of patients had concomitant coronary artery disease, making it unique to previous studies. The EUCLID trial's evidence of neutrality between clopidogrel and ticagrelor sheds light into the complexity of studying the PAD population and the continued need to meticulously design trials to investigate the optimal therapies. The topics that will be discussed in this review include the role of antiplatelet therapy in the management of patients with PAD, a review of the EUCLID trial results and the important factors to be considered in interpreting the surprising results, and promising recent ongoing clinical trials assessing therapies in the treatment of patients with PAD. © 2018 Wiley Periodicals, Inc.

Severe radiotherapy-induced extracutaneous toxicity under vemurafenib.

PubMed

Peuvrel, Lucie; Ruellan, Anne-Lise; Thillays, François; Quereux, Gaëlle; Brocard, Anabelle; Saint-Jean, Mélanie; Aumont, Maud; Drouet, Franck; Dreno, Brigitte

2013-01-01

Vemurafenib is a BRAF inhibitor indicated for the treatment of metastatic melanoma. We report the two first cases of severe and prolonged radiotherapy-induced visceral toxicity in patients treated concomitantly with vemurafenib: a brain radionecrosis and an anorectitis. It raises the question of both the risks of this association and its benefit in melanoma. The first patient, a female aged 32, treated with vemurafenib for three months, presented a steroid-dependent radionecrosis after brain stereotactic radiosurgery. Symptoms persisted until her death six months later. The second patient, a male aged 64 and treated with vemurafenib for nineteen days, presented a radiation-induced anorectitis complicated by diarrhoea, anorexia and weight loss following the concomitant radiation of a primary rectal tumour. A colostomy was needed after ten months in order to improve local status and general health. In our patients, the radiotherapy-induced toxicity under vemurafenib was unusual in its intensity and duration, suggesting a radiosensitization phenomenon. This hypothesis is reinforced by the publication of six cases of severe radiodermatitis under vemurafenib and by in vitro data. The combination of vemurafenib and radiotherapy should thus lead to discussion of a transient cessation of vemurafenib, given the severity of the adverse events experienced. Meanwhile, further studies are needed to determine the potential benefit of this combined treatment in metastatic melanoma.

Trauma-induced systemic inflammatory response versus exercise-induced immunomodulatory effects.

PubMed

Fehrenbach, Elvira; Schneider, Marion E

2006-01-01

Accidental trauma and heavy endurance exercise, both induce a kind of systemic inflammatory response, also called systemic inflammatory response syndrome (SIRS). Exercise-related SIRS is conditioned by hyperthermia and concomitant heat shock responses, whereas trauma-induced SIRS manifests concomitantly with tissue necrosis and immune activation, secondarily followed by fever. Inflammatory cytokines are common denominators in both trauma and exercise, although there are marked quantitative differences. Different anti-inflammatory cytokines may be involved in the control of inflammation in trauma- and exercise-induced stress. Exercise leads to a balanced equilibrium between inflammatory and anti-inflammatory responses. Intermittent states of rest, as well as anti-oxidant capacity, are lacking or minor in trauma but are high in exercising individuals. Regular training may enhance immune competence, whereas trauma-induced SIRS often paves the way for infectious complications, such as sepsis.

Can oesophagectomy be performed for patients with oesophageal carcinoma and concomitant liver cirrhosis? A retrospective study based on a propensity-matched cohort.

PubMed

Wang, Zhi-Qiang; Deng, Han-Yu; Yang, Yu-Shang; Wang, Yun; Hu, Yang; Yuan, Yong; Wang, Wen-Ping; Chen, Long-Qi

2017-09-01

For patients with oesophageal carcinoma and concomitant liver cirrhosis, the safety profile and postoperative prognosis of oesophagectomy are not clearly established due to the lack of relevant studies with large sample sizes. Our objective was to explore the surgical indications and postoperative prognosis in patients with oesophageal carcinoma and liver cirrhosis. A total of 2226 patients with oesophageal carcinoma underwent curative oesophagectomy (37 with liver cirrhosis and 2189 without) in our department from April 2008 to September 2013. Overall, 37 patients with liver cirrhosis (30 Child-Pugh Grade A and 7 Child-Pugh Grade B) and a propensity-matched cohort of 74 patients without cirrhosis were analysed. We compared the rates of postoperative complications and 5-year survival in these 2 groups. In addition, we performed an analysis of any potential risk factors for death, including patient demographic information and of operation performed. A higher operative mortality rate was observed in patients with oesophageal carcinoma and liver cirrhosis compared to patients with oesophageal carcinoma but without cirrhosis (11 vs 1%, P = 0.042). Patients with cirrhosis included those with Child-Pugh Grade B (43%), preoperative moderate ascites (100%), a prothrombin time of ≥ 4 s (75%) and greater weight loss. Although the rates of surgical death and postoperative hydrothorax were significantly higher in patients with liver cirrhosis, the rates of other major complications and 5-year overall survival were not significantly different compared to patients without cirrhosis. Curative oesophagectomy is a feasible, beneficial treatment option for patients with oesophageal carcinoma and liver cirrhosis, with a higher perioperative risk but reasonable longer term survival compared to patients without cirrhosis. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Postoperative tricuspid regurgitation after adult congenital heart surgery is associated with adverse clinical outcomes.

PubMed

Lewis, Matthew J; Ginns, Jonathan N; Ye, Siqin; Chai, Paul; Quaegebeur, Jan M; Bacha, Emile; Rosenbaum, Marlon S

2016-02-01

Many patients with adult congenital heart disease will require cardiac surgery during their lifetime, and some will have concomitant tricuspid regurgitation. However, the optimal management of significant tricuspid regurgitation at the time of cardiac surgery remains unclear. We assessed the determinants of adverse outcomes in patients with adult congenital heart disease and moderate or greater tricuspid regurgitation undergoing cardiac surgery for non-tricuspid regurgitation-related indications. All adult patients with congenital heart disease and greater than moderate tricuspid regurgitation who underwent cardiac surgery for non-tricuspid regurgitation-related indications were included in a retrospective study at the Schneeweiss Adult Congenital Heart Center. Cohorts were defined by the type of tricuspid valve intervention at the time of surgery. The primary end point of interest was a composite of death, heart transplantation, and reoperation on the tricuspid valve. A total of 107 patients met inclusion criteria, and 17 patients (17%) reached the primary end point. A total of 68 patients (64%) underwent tricuspid valve repair, 8 patients (7%) underwent tricuspid valve replacement, and 31 patients (29%) did not have a tricuspid valve intervention. By multivariate analysis, moderate or greater postoperative tricuspid regurgitation was associated with a hazard ratio of 6.12 (1.84-20.3) for the primary end point (P = .003). In addition, failure to perform a tricuspid valve intervention at the time of surgery was associated with an odds ratio of 4.17 (1.26-14.3) for moderate or greater postoperative tricuspid regurgitation (P = .02). Moderate or greater postoperative tricuspid regurgitation was associated with an increased risk of death, transplant, or reoperation in adult patients with congenital heart disease undergoing cardiac surgery for non-tricuspid regurgitation-related indications. Concomitant tricuspid valve intervention at the time of cardiac surgery should be considered in patients with adult congenital heart disease with moderate or greater preoperative tricuspid regurgitation. Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Atypical autoerotic deaths

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gowitt, G.T.; Hanzlick, R.L.

1992-06-01

So-called typical' autoerotic fatalities are the result of asphyxia due to mechanical compression of the neck, chest, or abdomen, whereas atypical' autoeroticism involves sexual self-stimulation by other means. The authors present five atypical autoerotic fatalities that involved the use of dichlorodifluoromethane, nitrous oxide, isobutyl nitrite, cocaine, or compounds containing 1-1-1-trichloroethane. Mechanisms of death are discussed in each case and the pertinent literature is reviewed.

Choosing the right graduate school and getting the job you've always wanted

Treesearch

Gary D. Grossman

1998-01-01

The recent sustained growth of the U.S. economy has directly affected the field of fisheries as more and more individuals have become interested in both revenue-producing and recreational activities involving fish. Concomitant with this growth is an apparent proliferation of education opportunities in our field. Although probably more jobs are available in fisheries...

Visual Sexual Stimulation and Erection, a Brief Review with New fMRI Data.

PubMed

Wu, Sharon L; Chow, Maggie S M; L, Jiang Y; Yang, Jingjin; Zhou, Hao; Yew, David T

2017-05-31

This review examines brain sites involved in sexual stimulation. New data on brain activation sites in individuals having erections concomitant with visual erotic stimulation were documented. The activation was chiefly at the midbrain around the cerebral peduncle, and in the pons centering on the tegmentum, they are indicated by blood oxygenation level dependent (BOLD) images captured by functional magnetic resonance imaging (fMRI). The cerebellum and inferior temporal lobe were activated more extensively in individuals viewing pornographic movie with a concomitant erection than those without. Similarly, individuals with erection had activations in the midbrain and pons, while drug addicts had neither erections nor any of these brainstem active sites. From our observation in the new data, we deduced three possible transmitters might be involved in erection: i) cholinergic neurons forming descending pathways and associated with motor activity ii) gamma-aminobutyric acid (GABA), directly or indirectly via decreasing pathways, modulating autonomic vascular responses in the penile vasculature causing the filling of blood iii) GABA decreases to stimulate dopamine increase in ventral tegmentum of the brain, leading to euphoric responses. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Location of fatal prescription opioid-related deaths in 12 states, 2008–2010: Implications for prevention programs☆,☆☆

PubMed Central

Easterling, Keith W.; Mack, Karin A.; Jones, Christopher M.

2016-01-01

Introduction Prescription opioid pain reliever overdose is a major public health issue in the United States. To characterize the location of drug-related deaths, we examined fatal prescription opioid and illicit drug-related deaths reported in 12 states. Methods Data are from the Substance Abuse and Mental Health Services Administration's Drug Abuse Warning Network (DAWN). Medical examiners or coroners in 12 states (MA, MD, ME, NH, NM, OK, OR, RI, UT, VA, VT, WV) reported details of state-wide drug-related mortality during 2008–2010. DAWN data included location and manner of death, age, race, and drugs involved. Deaths were coded into three categories: prescription opioid-related, illicit drug-related, and cases that involved both a prescription opioid and an illicit drug. Results During a 3-year period, there were 14,091 opioid or illicit drug-related deaths in 12 states. More than half of the prescription opioid-related deaths in all states, except Maryland, occurred at home, rather than in public or in a health care facility. Although it was still the predominant category, lower percentages of illicit drug-related deaths occurred at home. Conclusion Prescription opioid overdoses have increased substantially, and the location of the person at the time of death can have important public health implications for interventions. Practical applications This paper highlights that bystander support can be a critical lifesaving factor in drug related deaths but may be more likely for illicit drug-related deaths than for prescription opioid-related deaths. PMID:27620940

Language used by health care professionals to describe dying at an acute care hospital.

PubMed

Wentlandt, Kirsten; Toupin, Philippe; Novosedlik, Natalia; Le, Lisa W; Zimmermann, Camilla; Kaya, Ebru

2018-05-21

To understand the language used to describe the deterioration and death of patients in an acute academic tertiary care centre, and to identify whether patient diagnoses or palliative care(PC) involvement was associated with clearer descriptions of this process. We conducted a retrospective chart review of the final admission of 150 patients who died on an inpatient internal medicine unit. Conventional and summative content analysis was performed of the language used to describe, either directly or indirectly, that the patient's death was imminent. Of the 150 deaths, the median age was 79.5(range22-101), 58% were male, and 69% spoke English. A total of 45% of deaths were from cancer, and 66% occurred with prior PC team involvement. There was no documentation of the dying process in 18(12%) of charts. In the remainder, clinicians' documentation of imminent death fell into three categories: 1 identification of the current state using specific labels, e.g. 'dying'(24.7%), or 'end of life'(15.3%), or less specific language, 'unwell' or 'doing poorly'(6.0%); 2 predicting the future state using specific or more vague predictions: e.g.'hours to days'(7.3%) or 'poor or guarded prognosis'(26.0%); 3 using care provided to the patient to imply patient status: e.g. palliative care(49.3%) or comfort care(28.7%). PC involvement, but not a malignant diagnosis, was associated with more frequent use of specific language to describe the current(p=0.004) or future state(p=0.02). Death and dying in hospital is inadequately documented and is often described using unclear and vague language. PC involvement is associated with clearer language to describe this process. Copyright © 2018. Published by Elsevier Inc.

Intracerebral hemorrhage location and outcome among INTERACT2 participants.

PubMed

Delcourt, Candice; Sato, Shoichiro; Zhang, Shihong; Sandset, Else Charlotte; Zheng, Danni; Chen, Xiaoying; Hackett, Maree L; Arima, Hisatomi; Hata, Jun; Heeley, Emma; Al-Shahi Salman, Rustam; Robinson, Thompson; Davies, Leo; Lavados, Pablo M; Lindley, Richard I; Stapf, Christian; Chalmers, John; Anderson, Craig S

2017-04-11

To clarify associations between intracerebral hemorrhage (ICH) location and clinical outcomes among participants of the main phase Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). Associations between ICH sites and poor outcomes (death [6] or major disability [3-5] of modified Rankin Scale) and European Quality of Life Scale (EQ-5D) utility scores at 90 days were assessed in logistic regression models. Of 2,066 patients included in the analyses, associations were identified between ICH sites and poor outcomes: involvement of posterior limb of internal capsule increased risks of death or major disability (odds ratio [OR] 2.10) and disability (OR 1.81); thalamic involvement increased risks of death or major disability (OR 2.24) and death (OR 1.97). Involvement of the posterior limb of the internal capsule, thalamus, and infratentorial sites were each associated with poor EQ-5D utility score (≤0.7 [median]; OR 1.87, 2.14, and 2.81, respectively). Posterior limb of internal capsule involvement was strongly associated with low scores across all health-related quality of life domains. ICH encompassing the thalamus and posterior limb of internal capsule were associated with death or major disability, major disability, and poor EQ-5D utility score (OR 1.72, 2.26, and 1.71, respectively). Poor clinical outcomes are related to ICH affecting the posterior limb of internal capsule, thalamus, and infratentorial sites. The highest association with death or major disability and poor EQ-5D utility score was seen in ICH encompassing the thalamus and posterior limb of internal capsule. NCT00716079. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

MCP-1 causes cardiomyoblast death via autophagy resulting from ER stress caused by oxidative stress generated by inducing a novel zinc-finger protein, MCPIP.

PubMed

Younce, Craig W; Kolattukudy, Pappachan E

2010-01-27

MCP-1 (monocyte chemotactic protein-1) plays a critical role in the development of heart failure that is known to involve apoptosis. How MCP-1 contributes to cell death involved in the development of heart disease is not understood. In the present study we show that MCP-1 causes death in cardiac myoblasts, H9c2 cells, by inducing oxidative stress which causes ER stress leading to autophagy via a novel zinc-finger protein, MCPIP (MCP-1-induced protein). MCPIP expression caused cell death, and knockdown of MCPIP attenuated MCP-1-induced cell death. It caused induction of iNOS (inducible NO synthase), translocation of the NADPH oxidase subunit phox47 from the cytoplasm to the membrane, production of ROS (reactive oxygen species), and induction of ER (endoplasmic reticulum) stress markers HSP40 (heat-shock protein 40), PDI (protein disulfide-isomerase), GRP78 (guanine-nucleotide-releasing protein 78) and IRE1alpha (inositol-requiring enzyme 1alpha). It also caused autophagy, as indicated by beclin-1 induction, cleavage of LC3 (microtubule-associated protein 1 light chain 3) and autophagolysosome formation, and apoptosis, as indicated by caspase 3 activation and TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling) assay. Inhibitors of oxidative stress, including CeO2 nanoparticles, inhibited ROS formation, ER stress, autophagy and cell death. Specific inhibitors of ER stress inhibited autophagy and cell death as did knockdown of the ER stress signalling protein IRE1. Knockdown of beclin-1 and autophagy inhibitors prevented cell death. This cell death involved caspase 2 and caspase 12, as specific inhibitors of these caspases prevented MCPIP-induced cell death. Microarray analysis showed that MCPIP expression caused induction of a variety of genes known to be involved in cell death. MCPIP caused activation of JNK (c-Jun N-terminal kinase) and p38 and induction of p53 and PUMA (p53 up-regulated modulator of apoptosis). Taken together, these results suggest that MCPIP induces ROS/RNS (reactive nitrogen species) production that causes ER stress which leads to autophagy and apoptosis through caspase 2/12 and IRE1alpha-JNK/p38-p53-PUMA pathway. These results provide the first molecular insights into the mechanism by which elevated MCP-1 levels associated with chronic inflammation may contribute to the development of heart failure.

The association of antidepressant and statin use with death and incident cardiovascular disease varies by depression severity.

PubMed

May, Heidi T; Bair, Tami L; Reiss-Brennan, Brenda; Knight, Stacey; Anderson, Jeffrey L; Horne, Benjamin D; Brunisholz, Kimberly D; Muhlestein, Joseph B

2017-09-01

Depression has been reported to be associated with a greater risk of death and cardiovascular disease (CVD); however, the impact of antidepressants (ADM) on CVD risk remains controversial. Statin use is known to decrease CVD risk. Whether the use of these medications together affects CVD risk has not been studied. Patients (N = 26,828) completing the patient health questionnaire (PHQ-9), ≥40 years of age, without prior CVD, and no prior ADM use were studied. Depressive severity was categorized as none-mild (PHQ-9 score ≤14, n = 21,517) and moderate-severe (PHQ-9 score ≥15, n = 5311). Cox hazard regression was used to evaluate the association of no ADM/no statin use (n = 23,104 [86.1%]), ADM/no statin use (n = 877 [3.3%]), no ADM/statin use (n = 2627 [9.8%]), and ADM/statin use (n = 220 [.8%]) with major adverse cardiovascular events (MACE: death, CAD, stroke). Patients averaged 56 ± 12 years; 61% female. There were 1182 (4.4%) 3 year MACE events. The association of ADM and statin use with MACE varied by depressive symptom severity, with statin therapy associated with a decreased risk in the none-mild group (HR = .78, p = .007) and ADM in the moderate-high group (HR = 0.58, p = 0.02). Concomitant use of ADMs and statins did not appear to provide additive benefit.

PARENTS 2 study protocol: pilot of Parents' Active Role and ENgagement in the review of Their Stillbirth/perinatal death.

PubMed

Bakhbakhi, Danya; Siassakos, Dimitrios; Storey, Claire; Heazell, Alexander; Lynch, Mary; Timlin, Laura; Burden, Christy

2018-01-10

The perinatal mortality review meeting that takes place within the hospital following a stillbirth or neonatal death enables clinicians to learn vital lessons to improve care for women and their families for the future. Recent evidence suggests that parents are unaware that a formal review following the death of their baby takes place. Many would welcome the opportunity to feedback into the meeting itself. Parental involvement in the perinatal mortality review meeting has the potential to improve patient satisfaction, drive improvements in patient safety and promote an open culture within healthcare. Yet evidence on the feasibility of involving bereaved parents in the review process is lacking. This paper describes the protocol for the Parents' Active Role and Engangement iN the review of their Stillbirth/perinatal death study (PARENTS 2) , whereby healthcare professionals' and stakeholders' perceptions of parental involvement will be investigated, and parental involvement in the perinatal mortality review will be piloted and evaluated at two hospitals. We will investigate perceptions of parental involvement in the perinatal mortality review process by conducting four focus groups. A three-round modified Delphi technique will be employed to gain a consensus on principles of parental involvement in the perinatal mortality review process. We will use three sequential rounds, including a national consensus meeting workshop with experts in stillbirth, neonatal death and bereavement care, and a two-stage anonymous online questionnaire. We will pilot a new perinatal mortality review process with parental involvement over a 6-month study period. The impact of the new process will be evaluated by assessing parents' experiences of their care and parents' and staff perceptions of their involvement in the process by conducting further focus groups and using a Parent Generated Index questionnaire. This study has ethical approval from the UK Health Research Authority. We will disseminate the findings through national and international conferences and international peer-reviewed journals. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Overexpression of BAX INHIBITOR-1 Links Plasma Membrane Microdomain Proteins to Stress.

PubMed

Ishikawa, Toshiki; Aki, Toshihiko; Yanagisawa, Shuichi; Uchimiya, Hirofumi; Kawai-Yamada, Maki

2015-10-01

BAX INHIBITOR-1 (BI-1) is a cell death suppressor widely conserved in plants and animals. Overexpression of BI-1 enhances tolerance to stress-induced cell death in plant cells, although the molecular mechanism behind this enhancement is unclear. We recently found that Arabidopsis (Arabidopsis thaliana) BI-1 is involved in the metabolism of sphingolipids, such as the synthesis of 2-hydroxy fatty acids, suggesting the involvement of sphingolipids in the cell death regulatory mechanism downstream of BI-1. Here, we show that BI-1 affects cell death-associated components localized in sphingolipid-enriched microdomains of the plasma membrane in rice (Oryza sativa) cells. The amount of 2-hydroxy fatty acid-containing glucosylceramide increased in the detergent-resistant membrane (DRM; a biochemical counterpart of plasma membrane microdomains) fraction obtained from BI-1-overexpressing rice cells. Comparative proteomics analysis showed quantitative changes of DRM proteins in BI-1-overexpressing cells. In particular, the protein abundance of FLOTILLIN HOMOLOG (FLOT) and HYPERSENSITIVE-INDUCED REACTION PROTEIN3 (HIR3) markedly decreased in DRM of BI-1-overexpressing cells. Loss-of-function analysis demonstrated that FLOT and HIR3 are required for cell death by oxidative stress and salicylic acid, suggesting that the decreased levels of these proteins directly contribute to the stress-tolerant phenotypes in BI-1-overexpressing rice cells. These findings provide a novel biological implication of plant membrane microdomains in stress-induced cell death, which is negatively modulated by BI-1 overexpression via decreasing the abundance of a set of key proteins involved in cell death. © 2015 American Society of Plant Biologists. All Rights Reserved.

Autophagy regulates death of retinal pigment epithelium cells in age-related macular degeneration.

PubMed

Kaarniranta, Kai; Tokarz, Paulina; Koskela, Ali; Paterno, Jussi; Blasiak, Janusz

2017-04-01

Age-related macular degeneration (AMD) is an eye disease underlined by the degradation of retinal pigment epithelium (RPE) cells, photoreceptors, and choriocapillares, but the exact mechanism of cell death in AMD is not completely clear. This mechanism is important for prevention of and therapeutic intervention in AMD, which is a hardly curable disease. Present reports suggest that both apoptosis and pyroptosis (cell death dependent on caspase-1) as well as necroptosis (regulated necrosis dependent on the proteins RIPK3 and MLKL, caspase-independent) can be involved in the AMD-related death of RPE cells. Autophagy, a cellular clearing system, plays an important role in AMD pathogenesis, and this role is closely associated with the activation of the NLRP3 inflammasome, a central event for advanced AMD. Autophagy can play a role in apoptosis, pyroptosis, and necroptosis, but its contribution to AMD-specific cell death is not completely clear. Autophagy can be involved in the regulation of proteins important for cellular antioxidative defense, including Nrf2, which can interact with p62/SQSTM, a protein essential for autophagy. As oxidative stress is implicated in AMD pathogenesis, autophagy can contribute to this disease by deregulation of cellular defense against the stress. However, these and other interactions do not explain the mechanisms of RPE cell death in AMD. In this review, we present basic mechanisms of autophagy and its involvement in AMD pathogenesis and try to show a regulatory role of autophagy in RPE cell death. This can result in considering the genes and proteins of autophagy as molecular targets in AMD prevention and therapy.

Programmed Cell Death During Caenorhabditis elegans Development

PubMed Central

Conradt, Barbara; Wu, Yi-Chun; Xue, Ding

2016-01-01

Programmed cell death is an integral component of Caenorhabditis elegans development. Genetic and reverse genetic studies in C. elegans have led to the identification of many genes and conserved cell death pathways that are important for the specification of which cells should live or die, the activation of the suicide program, and the dismantling and removal of dying cells. Molecular, cell biological, and biochemical studies have revealed the underlying mechanisms that control these three phases of programmed cell death. In particular, the interplay of transcriptional regulatory cascades and networks involving multiple transcriptional regulators is crucial in activating the expression of the key death-inducing gene egl-1 and, in some cases, the ced-3 gene in cells destined to die. A protein interaction cascade involving EGL-1, CED-9, CED-4, and CED-3 results in the activation of the key cell death protease CED-3, which is tightly controlled by multiple positive and negative regulators. The activation of the CED-3 caspase then initiates the cell disassembly process by cleaving and activating or inactivating crucial CED-3 substrates; leading to activation of multiple cell death execution events, including nuclear DNA fragmentation, mitochondrial elimination, phosphatidylserine externalization, inactivation of survival signals, and clearance of apoptotic cells. Further studies of programmed cell death in C. elegans will continue to advance our understanding of how programmed cell death is regulated, activated, and executed in general. PMID:27516615

Procedures in child deaths in The Netherlands: a comparison with child death review.

PubMed

Gijzen, Sandra; Petter, Jessica; L'Hoir, Monique P; Boere-Boonekamp, Magda M; Need, Ariana

2017-01-01

Child Death Review (CDR) is a method in which every child death is systematically and multidisciplinary examined to (1) improve death statistics, (2) identify factors that give direction for prevention, (3) translate the results into possible interventions, and (4) support families. The aim of this study was to determine to what extent procedures of organizations involved in the (health) care for children in The Netherlands cover these four objectives of CDR. Organizations in the Eastern part of The Netherlands and Dutch umbrella organizations involved in child (health) care were asked to provide their protocols, guidelines or other working agreements that describe their activities and responsibilities in case of a child's death. Eighteen documents and nine interview reports were made available. For the analyses we used scorecards for each CDR objective. The procedures of Perined, the National Cot Death Study Group, Dutch Cot Death Foundation and Child Protection Service cover the largest part of the objectives of CDR. Organizations pay most attention to the translation of results into possible interventions. Family support gets the least attention in protocols, guidelines and other working agreements. Dutch organizations separately cover parts of CDR. When the procedures of organizations are combined, all CDR objectives are covered in the response to only specific groups of child deaths, i.e., perinatal deaths, Sudden Unexpected Deaths in Infants and fatal child abuse cases. Further research into the conditions that are needed for an optimal implementation of CDR in The Netherlands is necessary. This research should also evaluate the recently implemented NODOK procedure (Further Examination of the Causes of death in Children), directed to investigate unexplained deaths in minors 0-18 years old.

MPP+ induces necrostatin-1- and ferrostatin-1-sensitive necrotic death of neuronal SH-SY5Y cells.

PubMed

Ito, Keisuke; Eguchi, Yutaka; Imagawa, Yusuke; Akai, Shuji; Mochizuki, Hideki; Tsujimoto, Yoshihide

2017-01-01

Regulation of cell death is potentially a powerful treatment modality for intractable diseases such as neurodegenerative diseases. Although there have been many reports about the possible involvement of various types of cell death in neurodegenerative diseases, it is still unclear exactly how neurons die in patients with these diseases, thus treatment strategies based on cell death regulation have not been established yet. To obtain some insight into the mechanisms of cell death involved in neurodegenerative diseases, we studied the effect of 1-methyl-4-phenylpyridinium (MPP+) on the human neuroblastoma cell line SH-SY5Y (a widely used model of Parkinson's disease). We found that MPP+ predominantly induced non-apoptotic death of neuronally differentiated SH-SY5Y cells. This cell death was strongly inhibited by necrostatin-1 (Nec-1), a necroptosis inhibitor, and by an indole-containing compound (3,3'-diindolylmethane: DIM). However, it occurred independently of receptor-interacting serine/threonine-protein kinase 1/3 (RIP1/RIP3), indicating that this form of cell death was not necroptosis. MPP+-induced cell death was also inhibited by several inhibitors of ferroptosis, including ferrostatin-1 (Fer-1). Although MPP+-induced death and ferroptosis shared some features, such as occurrence of lipid peroxidation and inhibition by Fer-1, MPP+-induced death seemed to be distinct from ferroptosis because MPP+-induced death (but not ferroptosis) was inhibited by Nec-1, was independent of p53, and was accompanied by ATP depletion and mitochondrial swelling. Further investigation of MPP+-induced non-apoptotic cell death may be useful for understanding the mechanisms of neuronal loss and for treatment of neurodegenerative diseases such as Parkinson's disease.

MPP+ induces necrostatin-1- and ferrostatin-1-sensitive necrotic death of neuronal SH-SY5Y cells

PubMed Central

Ito, Keisuke; Eguchi, Yutaka; Imagawa, Yusuke; Akai, Shuji; Mochizuki, Hideki; Tsujimoto, Yoshihide

2017-01-01

Regulation of cell death is potentially a powerful treatment modality for intractable diseases such as neurodegenerative diseases. Although there have been many reports about the possible involvement of various types of cell death in neurodegenerative diseases, it is still unclear exactly how neurons die in patients with these diseases, thus treatment strategies based on cell death regulation have not been established yet. To obtain some insight into the mechanisms of cell death involved in neurodegenerative diseases, we studied the effect of 1-methyl-4-phenylpyridinium (MPP+) on the human neuroblastoma cell line SH-SY5Y (a widely used model of Parkinson’s disease). We found that MPP+ predominantly induced non-apoptotic death of neuronally differentiated SH-SY5Y cells. This cell death was strongly inhibited by necrostatin-1 (Nec-1), a necroptosis inhibitor, and by an indole-containing compound (3,3′-diindolylmethane: DIM). However, it occurred independently of receptor-interacting serine/threonine-protein kinase 1/3 (RIP1/RIP3), indicating that this form of cell death was not necroptosis. MPP+-induced cell death was also inhibited by several inhibitors of ferroptosis, including ferrostatin-1 (Fer-1). Although MPP+-induced death and ferroptosis shared some features, such as occurrence of lipid peroxidation and inhibition by Fer-1, MPP+-induced death seemed to be distinct from ferroptosis because MPP+-induced death (but not ferroptosis) was inhibited by Nec-1, was independent of p53, and was accompanied by ATP depletion and mitochondrial swelling. Further investigation of MPP+-induced non-apoptotic cell death may be useful for understanding the mechanisms of neuronal loss and for treatment of neurodegenerative diseases such as Parkinson’s disease. PMID:28250973

Toxicology and characteristics of deaths involving zolpidem in New South Wales, Australia 2001-2010.

PubMed

Darke, Shane; Deady, Mark; Duflou, Johan

2012-09-01

All cases presenting to the New South Wales Department of Forensic Medicine between January 1, 2001 and September 31, 2010 in which zolpidem was detected, were retrieved. A total of 91 cases were identified. The mean age was 49.4 years, 65.9% were male, and 61.5% were suicides. Zolpidem was a factor contributing to death in 35 (37.3%) cases, of which 31 (34.1%) involved zolpidem toxicity. The median blood zolpidem concentration was 0.20 mg/L (range 0.05-3.50 mg/L), with no significant gender difference. Drug toxicity cases involving zolpidem had significantly higher median blood zolpidem concentrations than other cases (0.50 vs. 0.10 mg/L). In 83.5% of cases, psychoactive substances other than zolpidem were detected, most commonly antidepressants (46.2%), benzodiazepines (35.2%), opioids (26.4%), and alcohol (39.6%). In summary, zolpidem was a factor contributing to death in a large proportion of cases, predominately involving drug toxicity and suicide. © 2012 American Academy of Forensic Sciences.

Missed opportunities?: an evaluation of potentially preventable poisoning deaths.

PubMed

Srisuma, Sahaphume; Cao, Dazhe; Kleinschmidt, Kurt; Heffner, Alan C; Lavonas, Eric J

2016-06-01

Although most poisoning deaths are not preventable with current medical technology, in some cases different management decisions may have prevented fatal outcomes. This study aims to review reported poisoning-related deaths for preventability to provide insight to improve future care. Fatality abstracts published in the US National Poison Data System (NPDS) Annual Reports (2008-2012) were analyzed. Preventability was graded using a Likert scale of 1 (definitely non-preventable) to 6 (definitely preventable). Two medical toxicologists screened all cases. Cases deemed definitely not preventable (score 1) by both reviewers were excluded from further review and considered to be "non-preventable". All cases considered at least possibly preventable by either screener were reviewed by a multidisciplinary panel of 5 physicians for preventability scoring. Differences were resolved by consensus. Cases determined to be "preventable" (scores 4-6) were characterized by type of improvement issue involved (diagnosis, treatment, monitoring, other) and recurring scenarios. Of 390 published abstracts, 78 (20.0%) deaths were considered at least possibly preventable by at least one screener. Of these, 34 (8.7%) deaths were determined to be "preventable" by the panel. Inter-observer agreement by weighted kappa analysis was 0.58 for screening, 0.24 for preventability, and 0.44 for specific aspects of care. The most common toxicants were salicylates (n = 9), opioids (n = 4), toxic alcohols (n = 3), fluoride containing product (n = 3), and bupropion (n = 3). The most common improvement opportunities involved treatment and monitoring. Most of the ingested substances in preventable deaths have delayed GI absorption or require metabolic activation to produce a delayed effect (such as salicylates, opioids, and toxic alcohols), and therefore provide an opportunity for early recognition and successful interventions. Most improvement opportunities are clearly described in the literature but may be not recognized. Based on an analysis of published NPDS data, a considerable number of poisoning-related deaths reaching medical attention may be preventable. The most common scenarios involved in potentially preventable poisoning fatalities related to monitoring and treatment. Salicylates and opioids were the most common agents involved in preventable deaths.

Advancing efforts to address youth violence involvement.

PubMed

Weist, M D; Cooley-Quille, M

2001-06-01

Discusses the increased public attention on violence-related problems among youth and the concomitant increased diversity in research. Youth violence involvement is a complex construct that includes violence experienced in multiple settings (home, school, neighborhood) and in multiple forms (as victims, witnesses, perpetrators, and through family members, friends, and the media). Potential impacts of such violence involvement are considerable, including increased internalizing and externalizing behaviors among youth and future problems in school adjustment and life-course development. This introductory article reviews key dimensions of youth-related violence, describes an American Psychological Association Task Force (Division 12) developed to advance relevant research, and presents examples of national resources and efforts that attempt to address this critical public health issue.

Multifocal Epithelial Hyperplasia of Oral Cavity Expressing HPV 16 Gene: A Rare Entity

PubMed Central

Prabhat, M. P. V.; Raja Lakshmi, Chintamaneni; Sai Madhavi, N.; Bhavana, Sujana Mulk; Sarat, Gummadapu; Ramamohan, Kodali

2013-01-01

Focal epithelial hyperplasia is a rare contagious disease caused by human papilloma virus. Usually HPV involves either cutaneous or mucosal surfaces, whereas concomitant mucocutaneous involvement is extremely rare. We report such a unique case of multifocal epithelial hyperplasia involving multiple sites of oral cavity along with skin lesions in a 65-year-old female. We also discuss the probable multifactorial etiology and variable clinical presentations of the lesions, including evidence of HPV 16 expression, as detected by polymerase chain reaction. The present report illustrates the need for careful examination and prompt diagnosis of the disease, as it might be associated with high risk genotypes such as HPV 16 and 18. PMID:24455323

A multicenter study of outcome in systemic lupus erythematosus. II. Causes of death.

PubMed

Rosner, S; Ginzler, E M; Diamond, H S; Weiner, M; Schlesinger, M; Fries, J F; Wasner, C; Medsger, T A; Ziegler, G; Klippel, J H; Hadler, N M; Albert, D A; Hess, E V; Spencer-Green, G; Grayzel, A; Worth, D; Hahn, B H; Barnett, E V

1982-06-01

Causes of death were examined for 1,103 systemic lupus erythematosus patients who were followed from 1965 to 1978 at 9 centers that participated in the Lupus Survival Study Group. A total of 222 patients (20%) died. Lupus-related organ system involvement (mainly active nephritis) and infection were the most frequent primary causes of death. Causes of death were similar throughout the followup period. Hemodialysis had little impact on the length of survival for patients with nephritis. Active central nervous system disease and myocardial infarction were infrequent causes of death. There were no deaths from malignancy.

Takayasu Arteritis of the Coronary Arteries Presenting as Sudden Death in a White Teenager.

PubMed

Hlavaty, Leigh; Diaz, Francisco; Sung, LokMan

2015-09-01

Takayasu arteritis is a rare disease that expresses chronic, large vessel inflammation. The etiology remains unclear and its presentation depends on the affected arteries. With coronary artery involvement, manifestations range from chest pain and shortness of breath to sudden death. We report a case of a 15-year-old white girl who presented with syncope immediately before passing. On autopsy, all 3 major coronary arteries grossly contained multiple proximal lesions that were consistent with Takayasu arteritis, microscopically. Takayasu arteritis solely affecting multiple coronary arteries is exceedingly rare. This report discusses the significance of coronary involvement in Takayasu arteritis at autopsy and sudden death.

A Two-Year Review on Epidemiology and Clinical Characteristics of Dengue Deaths in Malaysia, 2013-2014

PubMed Central

Woon, Yuan Liang; Hor, Chee Peng; Hussin, Narwani; Zakaria, Ariza; Goh, Pik Pin; Cheah, Wee Kooi

2016-01-01

Background Dengue infection is the fastest spreading mosquito-borne viral disease, which affects people living in the tropical and subtropical countries. Malaysia had large dengue outbreaks in recent years. We aimed to study the demographics and clinical characteristics associated with dengue deaths in Malaysia. Methods We conducted a retrospective review on all dengue deaths that occurred nationwide between 1st January 2013 and 31st December 2014. Relevant data were extracted from mortality review reports and investigational forms. These cases were categorized into children (<15 years), adults (15–59 years) and elderly (≥60 years) to compare their clinical characteristics. Results A total of 322 dengue deaths were reviewed. Their mean age was 40.7±19.30 years, half were females and 72.5% were adults. The median durations of first medical contact, and hospitalization were 1 and 3 days, respectively. Diabetes and hypertension were common co-morbidities among adults and elderly. The most common warning signs reported were lethargy and vomiting, with lethargy (p = 0.038) being more common in children, while abdominal pain was observed more often in the adults (p = 0.040). But 22.4% did not have any warning signs. Only 34% were suspected of dengue illness at their initial presentation. More adults developed severe plasma leakage (p = 0.018). More than half (54%) suffered from multi-organ involvement, and 20.2% were free from any organ involvement. Dengue deaths occurred at the median of 3 days post-admission. Dengue shock syndrome (DSS) contributed to more than 70% of dengue deaths, followed by severe organ involvement (69%) and severe bleeding (29.7%). Conclusion In Malaysia, dengue deaths occurred primarily in adult patients. DSS was the leading cause of death, regardless of age groups. The atypical presentation and dynamic progression of severe dengue in this cohort prompts early recognition and aggressive intervention to prevent deaths. Trial Registration National Medical Research Registry (NMRR, NMRR-14-1374-23352) PMID:27203726

A Two-Year Review on Epidemiology and Clinical Characteristics of Dengue Deaths in Malaysia, 2013-2014.

PubMed

Woon, Yuan Liang; Hor, Chee Peng; Hussin, Narwani; Zakaria, Ariza; Goh, Pik Pin; Cheah, Wee Kooi

2016-05-01

Dengue infection is the fastest spreading mosquito-borne viral disease, which affects people living in the tropical and subtropical countries. Malaysia had large dengue outbreaks in recent years. We aimed to study the demographics and clinical characteristics associated with dengue deaths in Malaysia. We conducted a retrospective review on all dengue deaths that occurred nationwide between 1st January 2013 and 31st December 2014. Relevant data were extracted from mortality review reports and investigational forms. These cases were categorized into children (<15 years), adults (15-59 years) and elderly (≥60 years) to compare their clinical characteristics. A total of 322 dengue deaths were reviewed. Their mean age was 40.7±19.30 years, half were females and 72.5% were adults. The median durations of first medical contact, and hospitalization were 1 and 3 days, respectively. Diabetes and hypertension were common co-morbidities among adults and elderly. The most common warning signs reported were lethargy and vomiting, with lethargy (p = 0.038) being more common in children, while abdominal pain was observed more often in the adults (p = 0.040). But 22.4% did not have any warning signs. Only 34% were suspected of dengue illness at their initial presentation. More adults developed severe plasma leakage (p = 0.018). More than half (54%) suffered from multi-organ involvement, and 20.2% were free from any organ involvement. Dengue deaths occurred at the median of 3 days post-admission. Dengue shock syndrome (DSS) contributed to more than 70% of dengue deaths, followed by severe organ involvement (69%) and severe bleeding (29.7%). In Malaysia, dengue deaths occurred primarily in adult patients. DSS was the leading cause of death, regardless of age groups. The atypical presentation and dynamic progression of severe dengue in this cohort prompts early recognition and aggressive intervention to prevent deaths. National Medical Research Registry (NMRR, NMRR-14-1374-23352).

MLKL-PITPα signaling-mediated necroptosis contributes to cisplatin-triggered cell death in lung cancer A549 cells.

PubMed

Jing, Lin; Song, Fei; Liu, Zhenyu; Li, Jianghua; Wu, Bo; Fu, Zhiguang; Jiang, Jianli; Chen, Zhinan

2018-02-01

Necroptosis has been reported to be involved in cisplatin-induced cell death, but the mechanisms underlying the occurrence of necroptosis are not fully elucidated. In this study, we show that apart from apoptosis, cisplatin induces necroptosis in A549 cells. The alleviation of cell death by two necroptosis inhibitors-necrostatin-1 (Nec-1) and necrosulfonamide (NSA), and the phosphorylation of mixed lineage kinase domain-like protein (MLKL) at serine 358, suggest the involvement of receptor-interacting protein kinase 1 (RIPK1)-RIPK3-MLKL signaling in cisplatin-treated A549 cells. Additionally, the initiation of cisplatin-induced necroptosis relies on autocrine tumor necrosis factor alpha (TNF-α). Furthermore, we present the first evidence that phosphatidylinositol transfer protein alpha (PITPα) is involved in MLKL-mediated necroptosis by interacting with the N terminal MLKL on its sixth helix and the preceding loop, which facilitates MLKL oligomerization and plasma membrane translocation in necroptosis. Silencing of PITPα expression interferes with MLKL function and reduces cell death. Our data elucidate that cisplatin-treated lung cancer cells undergo a new type of programmed cell death called necroptosis and shed new light on how MLKL translocates to the plasma membrane. Copyright © 2017 Elsevier B.V. All rights reserved.

Deaths among railroad trespassers. The role of alcohol in fatal injuries.

PubMed

Pelletier, A

1997-04-02

To describe the characteristics of persons killed by trains while trespassing (ie, using railroad property for activities unrelated to railroad operations). Case series obtained from records of the state medical examiner. North Carolina, 1990 through 1994. One hundred twenty-eight persons ranging in age from 7 to 84 years who were killed in 125 separate incidents. Of 224 railroad-related deaths during the study period, 128 cases (57%) involved trespassers. Trespasser fatalities typically involved unmarried male pedestrians 20 to 49 years of age with less than a high school education. Eighty-two percent of incidents occurred in the trespassers' county of residence, indicating that few deaths involved transients. Fatalities among railroad trespassers exhibited both geographic and temporal clustering. Seventy-eight percent of trespassers were killed while intoxicated (median alcohol level, 56 mmol/L [260 mg/dL]). Deaths among trespassers are the leading cause of railroad-related mortality in North Carolina. Greater efforts are needed to reduce this type of preventable injury. Prevention of trespasser fatalities is dependent on control of alcohol abuse, enforcement of existing laws, and education of the public regarding the dangers of railroad trespassing.

Mortality of Youth Offenders Along a Continuum of Justice System Involvement.

PubMed

Aalsma, Matthew C; Lau, Katherine S L; Perkins, Anthony J; Schwartz, Katherine; Tu, Wanzhu; Wiehe, Sarah E; Monahan, Patrick; Rosenman, Marc B

2016-03-01

Black male youth are at high risk of homicide and criminal justice involvement. This study aimed to determine how early mortality among youth offenders varies based on race; gender; and the continuum of justice system involvement: arrest, detention, incarceration, and transfer to adult courts. Criminal and death records of 49,479 youth offenders (ages 10-18 years at first arrest) in Marion County, Indiana, from January 1, 1999, to December 31, 2011, were examined. Statistical analyses were completed in November 2014. From 1999 to 2011 (aggregate exposure, 386,709 person-years), 518 youth offender deaths occurred. The most common cause of death was homicide (48.2%). The mortality rate of youth offenders was nearly 1.5 times greater than that among community youth (standardized mortality ratio, 1.48). The youth offender mortality rate varied depending on the severity of justice system involvement. Arrested youth had the lowest rate of mortality (90/100,000), followed by detained youth (165/100,000); incarcerated youth (216/100,000); and youth transferred to adult court (313/100,000). A proportional hazards model demonstrated that older age, male gender, and more severe justice system involvement 5 years post-arrest predicted shorter time to mortality. Youth offenders face greater risk for early death than community youth. Among these, black male youth face higher risk of early mortality than their white male counterparts. However, regardless of race/ethnicity, mortality rates for youth offenders increase as youth involvement in the justice system becomes more protracted and severe. Thus, justice system involvement is a significant factor to target for intervention. Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

A novel initiation mechanism of death in Streptococcus pneumoniae induced by the human milk protein-lipid complex HAMLET and activated during physiological death.

PubMed

Clementi, Emily A; Marks, Laura R; Duffey, Michael E; Hakansson, Anders P

2012-08-03

To cause colonization or infection, most bacteria grow in biofilms where differentiation and death of subpopulations is critical for optimal survival of the whole population. However, little is known about initiation of bacterial death under physiological conditions. Membrane depolarization has been suggested, but never shown to be involved, due to the difficulty of performing such studies in bacteria and the paucity of information that exists regarding ion transport mechanisms in prokaryotes. In this study, we performed the first extensive investigation of ion transport and membrane depolarization in a bacterial system. We found that HAMLET, a human milk protein-lipid complex, kills Streptococcus pneumoniae (the pneumococcus) in a manner that shares features with activation of physiological death from starvation. Addition of HAMLET to pneumococci dissipated membrane polarity, but depolarization per se was not enough to trigger death. Rather, both HAMLET- and starvation-induced death of pneumococci specifically required a sodium-dependent calcium influx, as shown using calcium and sodium transport inhibitors. This mechanism was verified under low sodium conditions, and in the presence of ionomycin or monensin, which enhanced pneumococcal sensitivity to HAMLET- and starvation-induced death. Pneumococcal death was also inhibited by kinase inhibitors, and indicated the involvement of Ser/Thr kinases in these processes. The importance of this activation mechanism was made evident, as dysregulation and manipulation of physiological death was detrimental to biofilm formation, a hallmark of bacterial colonization. Overall, our findings provide novel information on the role of ion transport during bacterial death, with the potential to uncover future antimicrobial targets.

A Novel Initiation Mechanism of Death in Streptococcus pneumoniae Induced by the Human Milk Protein-Lipid Complex HAMLET and Activated during Physiological Death*

PubMed Central

Clementi, Emily A.; Marks, Laura R.; Duffey, Michael E.; Hakansson, Anders P.

2012-01-01

To cause colonization or infection, most bacteria grow in biofilms where differentiation and death of subpopulations is critical for optimal survival of the whole population. However, little is known about initiation of bacterial death under physiological conditions. Membrane depolarization has been suggested, but never shown to be involved, due to the difficulty of performing such studies in bacteria and the paucity of information that exists regarding ion transport mechanisms in prokaryotes. In this study, we performed the first extensive investigation of ion transport and membrane depolarization in a bacterial system. We found that HAMLET, a human milk protein-lipid complex, kills Streptococcus pneumoniae (the pneumococcus) in a manner that shares features with activation of physiological death from starvation. Addition of HAMLET to pneumococci dissipated membrane polarity, but depolarization per se was not enough to trigger death. Rather, both HAMLET- and starvation-induced death of pneumococci specifically required a sodium-dependent calcium influx, as shown using calcium and sodium transport inhibitors. This mechanism was verified under low sodium conditions, and in the presence of ionomycin or monensin, which enhanced pneumococcal sensitivity to HAMLET- and starvation-induced death. Pneumococcal death was also inhibited by kinase inhibitors, and indicated the involvement of Ser/Thr kinases in these processes. The importance of this activation mechanism was made evident, as dysregulation and manipulation of physiological death was detrimental to biofilm formation, a hallmark of bacterial colonization. Overall, our findings provide novel information on the role of ion transport during bacterial death, with the potential to uncover future antimicrobial targets. PMID:22700972

Work, love, and death-thought accessibility: A terror management investigation.

PubMed

McCabe, Simon; Daly, Michael

2018-05-07

Terror management theory suggests that following culturally derived scripts for valued behaviour protects people from death concerns, and conversely, not meeting standards for cultural value can weaken this protection, heightening mortality concerns. Using this conceptual framework, we examine (1) how considerations of loss of employment, a source of cultural value for many, relates to the accessibility of death-related cognition, and (2) the moderating role of job market health, and (3) involvement in close relationships. Study 1 found that writing about being unemployed (vs. a control topic) led to greater mortality-related cognition. Study 2 found that considering unemployment heightened death cognition, but only when participants were led to perceive the job market as unhealthy. Finally, Study 3 found that considering unemployment led to greater death cognition, but not for those involved in a close relationship. Findings offer insight into a previously overlooked consequence of unemployment, and factors that may serve a protective function. © 2018 The British Psychological Society.

Near-death experiences and the temporal lobe.

PubMed

Britton, Willoughby B; Bootzin, Richard R

2004-04-01

Many studies in humans suggest that altered temporal lobe functioning, especially functioning in the right temporal lobe, is involved in mystical and religious experiences. We investigated temporal lobe functioning in individuals who reported having transcendental "near-death experiences" during life-threatening events. These individuals were found to have more temporal lobe epileptiform electroencephalographic activity than control subjects and also reported significantly more temporal lobe epileptic symptoms. Contrary to predictions, epileptiform activity was nearly completely lateralized to the left hemisphere. The near-death experience was not associated with dysfunctional stress reactions such as dissociation, posttraumatic stress disorder, and substance abuse, but rather was associated with positive coping styles. Additional analyses revealed that near-death experiencers had altered sleep patterns, specifically, a shorter duration of sleep and delayed REM sleep relative to the control group. These results suggest that altered temporal lobe functioning may be involved in the near-death experience and that individuals who have had such experiences are physiologically distinct from the general population.

Historical Y. pestis Genomes Reveal the European Black Death as the Source of Ancient and Modern Plague Pandemics.

PubMed

Spyrou, Maria A; Tukhbatova, Rezeda I; Feldman, Michal; Drath, Joanna; Kacki, Sacha; Beltrán de Heredia, Julia; Arnold, Susanne; Sitdikov, Airat G; Castex, Dominique; Wahl, Joachim; Gazimzyanov, Ilgizar R; Nurgaliev, Danis K; Herbig, Alexander; Bos, Kirsten I; Krause, Johannes

2016-06-08

Ancient DNA analysis has revealed an involvement of the bacterial pathogen Yersinia pestis in several historical pandemics, including the second plague pandemic (Europe, mid-14(th) century Black Death until the mid-18(th) century AD). Here we present reconstructed Y. pestis genomes from plague victims of the Black Death and two subsequent historical outbreaks spanning Europe and its vicinity, namely Barcelona, Spain (1300-1420 cal AD), Bolgar City, Russia (1362-1400 AD), and Ellwangen, Germany (1485-1627 cal AD). Our results provide support for (1) a single entry of Y. pestis in Europe during the Black Death, (2) a wave of plague that traveled toward Asia to later become the source population for contemporary worldwide epidemics, and (3) the presence of an historical European plague focus involved in post-Black Death outbreaks that is now likely extinct. Copyright © 2016 Elsevier Inc. All rights reserved.

What about the Children? Dealing with Death. Project Enlightenment.

ERIC Educational Resources Information Center

Helms, Rose; Blazer, Doris

This pamphlet offers practical guidance to parents of young children who have experienced the death of a close relative or other loved one. It is intended to explain the child's emotional needs and assist the parent in planning for the child's involvement in the various stages of the death-funeral-mourning process. The text is presented as answers…

At Death's Door: What Are the Choices? An Issue Book for National Issues Forums.

ERIC Educational Resources Information Center

Hinds, Michael deCourcy

This paper questions how society should care for people who are suffering and near death? Underlying this issue are very difficult questions about the evolving rights of patients, medical standards, and societal norms--questions about the American way of death, which often involves needless pain and unwanted treatment. Three choices are presented…

30 CFR 50.10 - Immediate notification.

Code of Federal Regulations, 2010 CFR

2010-07-01

... that an accident has occurred involving: (a) A death of an individual at the mine; (b) An injury of an individual at the mine which has a reasonable potential to cause death; (c) An entrapment of an individual at the mine which has a reasonable potential to cause death; or (d) Any other accident. [74 FR 68919, Dec...

Silicone Stent Placement for Primary Tracheal Amyloidosis Accompanied by Cartilage Destruction

PubMed Central

Ryu, Duck Hyun; Eom, Jung Seop; Jeong, Ho Jung; Kim, Jung Hoon; Lee, Ji Eun; Jun, Ji Eun; Song, Dae Hyun; Han, Joungho

2014-01-01

Primary tracheal amyloidosis (PTA) can lead to airway obstructions, and patients with severe PTA should undergo bronchoscopic interventions in order to maintain airway patency. Focal airway involvements with amyloidosis can only be treated with mechanical dilatation. However, the PTA with diffused airway involvements and concomitant cartilage destructions requires stent placement. Limited information regarding the usefulness of silicone stents in patients with PTA has been released. Therefore, we report a case of diffused PTA with tracheomalacia causing severe cartilage destruction, which is being successfully managed with bronchoscopic interventions and silicone stent placements. PMID:25024724

Surveillance for violent deaths--National Violent Death Reporting System, 16 states, 2009.

PubMed

Karch, Debra L; Logan, Joseph; McDaniel, Dawn; Parks, Sharyn; Patel, Nimesh

2012-09-14

An estimated 50,000 persons die annually in the United States as a result of violence-related injuries. This report summarizes data from CDC's National Violent Death Reporting System (NVDRS) regarding violent deaths from 16 U.S. states for 2009. Results are reported by sex, age group, race/ethnicity, marital status, location of injury, method of injury, circumstances of injury, and other selected characteristics. 2009. NVDRS collects data regarding violent deaths obtained from death certificates, coroner/medical examiner reports, and law enforcement reports. NVDRS data collection began in 2003 with seven states (Alaska, Maryland, Massachusetts, New Jersey, Oregon, South Carolina, and Virginia) participating; six states (Colorado, Georgia, North Carolina, Oklahoma, Rhode Island, and Wisconsin) joined in 2004, four (California, Kentucky, New Mexico, and Utah) in 2005, and two (Ohio and Michigan) in 2010, for a total of 19 states. This report includes data from 16 states that collected statewide data in 2009. California is excluded because data were collected in only four counties. Ohio and Michigan are excluded because data collection did not begin until 2010. For 2009, a total of 15,981 fatal incidents involving 16,418 deaths were captured by NVDRS in the 16 states included in this report. The majority (60.6%) of deaths were suicides, followed by homicides and deaths involving legal intervention (i.e., deaths caused by police and other persons with legal authority to use deadly force, excluding legal executions) (24.7%), deaths of undetermined intent (14.2%), and unintentional firearm deaths (0.5%). Suicides occurred at higher rates among males, non-Hispanic whites, American Indians/Alaska Natives, and persons aged 45-54 years. Suicides occurred most often in a house or apartment and involved the use of firearms. Suicides were preceded primarily by mental health, intimate partner, or physical health problems or by a crisis during the previous 2 weeks. Homicides occurred at higher rates among males and persons aged 20-24 years; rates were highest among non-Hispanic black males. The majority of homicides involved the use of a firearm and occurred in a house or apartment or on a street/highway. Homicides were preceded primarily by arguments and interpersonal conflicts or in conjunction with another crime. Characteristics associated with other manners of death, circumstances preceding death, and special populations also are highlighted in this report. This report provides a detailed summary of data from NVDRS for 2009. The results indicate that violent deaths resulting from self-inflicted or interpersonal violence disproportionately affected adults aged <55 years, males, and certain racial/ethnic minority populations. For homicides and suicides, relationship problems, interpersonal conflicts, mental health problems, and recent crises were among the primary factors that might have precipitated the fatal injuries. Because additional information might be reported subsequently as participating states update their findings, the data provided in this report are preliminary. For the occurrence of violent deaths in the United States to be better understood and ultimately prevented, accurate, timely, and comprehensive surveillance data are necessary. NVDRS data can be used to monitor the occurrence of violence-related fatal injuries and assist public health authorities in the development, implementation, and evaluation of programs and policies to reduce and prevent violent deaths at the national, state, and local levels. The continued development and expansion of NVDRS is essential to CDC's efforts to reduce the personal, familial, and societal costs of violence. Additional efforts are needed to increase the number of states participating in NVDRS, with an ultimate goal of full national representation.

Surveillance for violent deaths--national violent death reporting system, 16 States, 2006.

PubMed

Karch, Debra L; Dahlberg, Linda L; Patel, Nimesh; Davis, Terry W; Logan, Joseph E; Hill, Holly A; Ortega, Lavonne

2009-03-20

An estimated 50,000 persons die annually in the United States as a result of violence-related injuries. This report summarizes data from CDC's National Violent Death Reporting System (NVDRS) regarding violent deaths from 16 U.S. states for 2006. Results are reported by sex, age group, race/ethnicity, marital status, location of injury, method of injury, circumstances of injury, and other selected characteristics. 2006. NVDRS collects data regarding violent deaths obtained from death certificates, coroner/medical examiner reports, and law enforcement reports. NVDRS began operation in 2003 with seven states (Alaska, Maryland, Massachusetts, New Jersey, Oregon, South Carolina, and Virginia) participating; six states (Colorado, Georgia, North Carolina, Oklahoma, Rhode Island, and Wisconsin) joined in 2004 and four (California, Kentucky, New Mexico, and Utah) in 2005, for a total of 17 states. This report includes data from 16 states that collected statewide data; data from California are not included in this report because NVDRS has been implemented only in a limited number of California cities and counties rather than statewide. For 2006, a total of 15,007 fatal incidents involving 15,395 violent deaths occurred in the 16 NVDRS states included in this report. The majority (55.9%) of deaths were suicides, followed by homicides and deaths involving legal intervention (e.g. a suspect is killed by a law enforcement officer in the line of duty)(28.2%), violent deaths of undetermined intent (15.1%), and unintentional firearm deaths (0.7%). Suicides occurred at higher rates among males, American Indians/Alaska Natives (AI/ANs), non-Hispanic whites, and persons aged 45--54 years and occurred most often in a house or apartment and involved the use of firearms. Suicides were precipitated primarily by mental-health, intimate-partner, or physical-health problems or by a crisis during the preceding 2 weeks. Homicides occurred at higher rates among males and persons aged 20--24 years; rates were highest among non-Hispanic black males. The majority of homicides involved the use of a firearm and occurred in a house or apartment or on a street/highway. Homicides were precipitated primarily by arguments and interpersonal conflicts or in conjunction with another crime. Other manners of death and special situations or populations also are highlighted in this report. This report provides a detailed summary of data concerning violent deaths collected by NVDRS for 2006. The results indicate that violent deaths resulting from self-inflicted or interpersonal violence affected adults aged 20--54 years, males, and certain minority populations disproportionately. For many types of violent death, relationship problems, interpersonal conflicts, mental-health problems, and recent crises were among the primary precipitating factors. Because additional information might be reported subsequently as participating states update their findings, the data provided in this report are preliminary. For the occurrence of violent deaths in the United States to be better understood and ultimately prevented, accurate, timely, and comprehensive surveillance data are necessary. NVDRS data can be used to track the occurrence of violence-related fatal injuries and assist public health authorities in the development, implementation, and evaluation of programs and policies to reduce and prevent violent deaths at the national, state, and local levels. The continued development and expansion of NVDRS is essential to CDC's efforts to reduce the personal, familial, and societal costs of violence. Further efforts are needed to increase the number of states participating in NVDRS, with an ultimate goal of full national representation.

Docosahexaenoic acid prevents trans-10, cis-12 conjugated linoleic acid-induced non-alcoholic fatty liver disease in mice by altering expression of hepatic genes regulating fatty acid synthesis and oxidation

USDA-ARS?s Scientific Manuscript database

Background: Concomitant supplementation with docosahexaenoic acid (22:6 n-3; DHA) prevented t10, c12- conjugated linoleic acid (CLA)-induced non-alcoholic fatty liver disease (NAFLD) and insulin resistance. Effective dose of DHA and mechanisms involved are poorly understood. Methods: We examined abi...

Concomitant Mycobacterium tuberculosis infection promotes lung tumor growth through enhancing Treg development.

PubMed

Zhou, Yan; Hu, Zhangguo; Cao, Shuhui; Yan, Bo; Qian, Jialin; Zhong, Hua

2017-08-01

Lung cancer is the most common malignancy in humans. An increased population of CD4+Foxp3+ regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. The exact role and the involved mechanisms of concomitant H37Rv infection in non-small cell lung cancer (NSCLC) development are still not clear. Here, we showed that H37Rv infection promoted NSCLC cell growth with a higher percentage of Tregs found in draining lymph nodes. We also determined in vitro that H37Rv infection induced macrophage maturation and PD-L1 expression, which promoted Treg proportion, with enhanced proliferation suppression function. Mechanism analysis revealed that AKT-mTORC1 signal was important for PD-L1 expression induced by H37Rv infection. Suppressing of AKT-mTORC1 signal by rapamycin or raptor deficiency showed decreased PD-L1 levels which further reduced Treg proportion in a co-culture system. Finally, tumor-bearing mice injected with H37Rv plus rapamycin enhance the immune response of lung cancer compared with injected with H37Rv alone. This study demonstrated that concomitant H37Rv infection promote NSCLC tumor immune eacape through enhancing Treg proportion.

The Crosstalk between Hypoxia and Innate Immunity in the Development of Obesity-Related Nonalcoholic Fatty Liver Disease

PubMed Central

Arias-Loste, María Teresa; Fábrega, Emilio; López-Hoyos, Marcos; Crespo, Javier

2015-01-01

Nonalcoholic fatty liver disease (NAFLD) has become a major health issue in western countries in parallel with the dramatic increase in the prevalence of obesity and all obesity related conditions, including respiratory diseases as obstructive sleep apnea-hypopnea syndrome (OSAHS). Interestingly, the severity of the liver damage in obesity-related NAFLD has been associated with the concomitant presence of OSAHS. In the presence of obesity, the proinflammatory state in these patients together with intermittent episodes of hypoxia, characteristic of OSAHS pathogenesis, may lead to an enhanced inflammatory response mediated by a positive feedback loop mechanism that implicates HIF-1 and NFκB. Thus, the severity of liver involvement in obese NAFLD patients with a concomitant diagnosis of OSAHS could be explained. In this review, we focus on the molecular mechanisms underlying the hepatic response to chronic intermittent hypoxia and its interaction with innate immunity in obesity-related NAFLD. PMID:26491664

Significant anti-tumor effect of bevacizumab in treatment of pineal gland glioblastoma multiforme.

PubMed

Mansour, Joshua; Fields, Braxton; Macomson, Samuel; Rixe, Olivier

2014-12-01

Glioblastoma multiforme (GBM) is the most aggressive subtype of malignant gliomas. Current standard treatment for GBM involves a combination of cytoreduction through surgical resection, followed by radiation with concomitant and adjuvant chemotherapy (temozolomide). The role of bevacizumab in the treatment of GBM continues to be a topic of ongoing research and debate. Despite aggressive treatment, these tumors remain undoubtedly fatal, especially in the elderly. Furthermore, tumors present in the pineal gland are extremely rare, accounting for only 0.1-0.4 % of all adult brain tumors, with this location adding to the complexity of treatment. We present a case of GBM, at the rare location of pineal gland, in an elderly patient who was refractory to initial standard of care treatment with radiation and concomitant and adjuvant temozolomide, but who developed a significant response to anti-angiogenic therapy using bevacizumab.

Onychomycosis of Toenails and Post-hoc Analyses with Efinaconazole 10% Solution Once-daily Treatment

PubMed Central

2016-01-01

Topical treatment for toenail onychomycosis has been fraught with a long-standing reputation of poor efficaey, primarily due to physical properties of the nail unit that impede drug penetration. Newer topical agents have been formulated as Solution, which appear to provide better therapeutic response in properly selected patients. It is important to recognize the impact the effects that mitigating and concomitant factors can have on efficaey. These factors include disease severity, gender, presence of tinea pedis, and diabetes. This article reviews results achieved in Phase 3 pivotal studies with topical efinaconazole 10% Solution applied once daily for 48 weeks with a focus on how the aforementioned factors influenced therapeutic outcomes. It is important for clinicians treating patients for onychomycosis to evaluate severity, treat concomitant tinea pedis, address control of diabetes if present by encouraging involvement of the patient’s primary care physician, and consider longer treatment courses when clinically relevant. PMID:27047631

[Causes and management of severe acute liver damage during pregnancy].

PubMed

Sepulveda-Martinez, Alvaro; Romero, Carlos; Juarez, Guido; Hasbun, Jorge; Parra-Cordero, Mauro

2015-05-01

Abnormalities in liver function tests appear in 3% of pregnancies. Severe acute liver damage can be an exclusive condition of pregnancy (dependent or independent of pre-eclampsia) or a concomitant disease. HELLP syndrome and acute fatty liver of pregnancy are the most severe liver diseases associated with pregnancy. Both appear during the third trimester and have a similar clinical presentation. Acute fatty liver may be associated with hypoglycemia and HELLP syndrome is closely linked with pre-eclampsia. Among concomitant conditions, fulminant acute hepatitis caused by medications or virus is the most severe disease. Its clinical presentation may be hyper-acute with neurological involvement and severe coagulation disorders. It has a high mortality and patients should be transplanted. Fulminant hepatic failure caused by acetaminophen overdose can be managed with n-acetyl cysteine. Because of the high fetal mortality rate, the gestational age at diagnosis is crucial.

Fatal poisonings involving propoxyphene before and after voluntary withdrawal from the United States' market: An analysis from the state of Florida.

PubMed

Delcher, Chris; Chen, Guanming; Wang, Yanning; Slavova, Svetla; Goldberger, Bruce A

2017-11-01

The synthetic opioid propoxyphene was a schedule IV controlled substance with multiple reported health risks before the US Food and Drug Administration issued a request for voluntary market withdrawal in November 2010. The purpose of this study is to investigate the characteristics and occurrences of propoxyphene-related deaths in Florida before and after voluntary market removal. Decedent-level toxicology data from Florida's Medical Examiners Commission was used to compare the temporal, polysubstance use, sociodemographic, and geographic profiles associated with propoxyphene-involved deaths for a pre-withdrawal (November 2008-November 2010) and post-withdrawal (December 2010-December 2012) period. Sensitivity analyses using multiple data sources, including Florida's Prescription Drug Monitoring Program and other states' data, were conducted to examine potential reporting bias. Results showed that the number of propoxyphene-involved deaths declined by 84% from 580 deaths to 92 deaths after market withdrawal. The co-occurrence of other prevalent drugs, such as oxycodone (17.2% to 26.1%, p=0.0422) increased significantly in the post-withdrawal study period. A larger proportion of the propoxyphene-related deaths were reported from South Florida after the withdrawal (28.4% to 56.5%, p<0.0001). No significant changes in age and race/ethnicity were observed. Sensitivity analyses revealed that several deaths occurred in other states after market withdrawal, as recently as 2016. Our findings are consistent with previous studies that propoxyphene was still available after removal from the US market. Continued surveillance is recommended after highly abused opioids are withdrawn from the market due to on-going safety risks. Copyright © 2017 Elsevier B.V. All rights reserved.

Child Passenger Deaths Involving Alcohol-Impaired Drivers

PubMed Central

Quinlan, Kyran; Shults, Ruth A.; Rudd, Rose A.

2017-01-01

BACKGROUND AND OBJECTIVE Approximately 1 in 5 child passenger deaths in the United States involves an alcohol-impaired driver, most commonly the child’s own driver. The objective of this study was to document recent trends and state-specific rates of these deaths. METHODS A descriptive analysis of 2001–2010 Fatality Analysis Reporting System data for child passengers aged <15 years killed in alcohol-impaired driving crashes. Driver impairment was defined as a blood alcohol concentration of ≥0.08 g/dL. RESULTS During 2001–2010, 2344 children <15 years were killed in crashes involving at least 1 alcohol-impaired driver. Of these children, 1515 (65%) were riding with an impaired driver. Annual deaths among children riding with an alcohol-impaired driver decreased by 41% over the decade. Among the 37 states included in the state-level analysis, Texas (272) and California (135) had the most children killed while riding with an impaired driver and South Dakota (0.98) and New Mexico (0.86) had the highest annualized child passenger death rates (per 100 000 children). Most (61%) child passengers of impaired drivers were unrestrained at the time of the crash. One-third of the impaired drivers did not have a valid driver’s license. CONCLUSIONS Alcohol-impaired driving remains a substantial threat to the safety of child passengers in the United States, and typically involves children being driven by impaired drivers. This risk varies meaningfully among states. To make further progress, states and communities could consider increased use of effective interventions and efforts aimed specifically at protecting child passengers from impaired drivers. PMID:24799550

The involvement of cancer patients in the four stages of decision-making preceding continuous sedation until death: A qualitative study.

PubMed

Robijn, Lenzo; Seymour, Jane; Deliens, Luc; Korfage, Ida; Brown, Jayne; Pype, Peter; Van Der Heide, Agnes; Chambaere, Kenneth; Rietjens, Judith

2018-04-01

Involving patients in decision-making is considered to be particularly appropriate towards the end of life. Professional guidelines emphasize that the decision to initiate continuous sedation should be made in accordance with the wishes of the dying person and be preceded by their consent. To describe the decision-making process preceding continuous sedation until death with particular attention to the involvement of the person who is dying. Qualitative case studies using interviews. Interviews with 26 physicians, 30 nurses and 24 relatives caring for 24 patients with cancer who received continuous sedation until death in Belgium, the United Kingdom and the Netherlands. We distinguished four stages of decision-making: initiation, information exchange, deliberation and the decision to start continuous sedation until death. There was wide variation in the role the patient had in the decision-making process. At one end of the spectrum (mostly in the United Kingdom), the physician discussed the possible use of sedation with the patient, but took the decision themselves. At the other end (mostly in Belgium and the Netherlands), the patient initiated the conversation and the physician's role was largely limited to evaluating if and when the medical criteria were met. Decision-making about continuous sedation until death goes through four stages and the involvement of the patient in the decision-making varies. Acknowledging the potential sensitivity of raising the issue of end-of-life sedation, we recommend building into clinical practice regular opportunities to discuss the goals and preferences of the person who is dying for their future medical treatment and care.

Patient-centred care of patients with ventricular arrhythmias and risk of sudden cardiac death: What do the 2015 European Society of Cardiology guidelines add?

PubMed

Norekvål, Tone M; Kirchhof, Paulus; Fitzsimons, Donna

2017-10-01

Nurses and allied professionals are at the forefront of care delivery in patients with arrythmogenic risk and have a responsibility to deliver care that is focused on their individual needs. The 2015 European Society of Cardiology guideline on prevention of ventricular arrhythmia and sudden cardiac death heralds a step-change in patient and family focus and interdisciplinary involvement. This development reflects a recognition within the European Society of Cardiology that chronic care of patients with cardiovascular conditions can be improved by involving all stakeholders, making use of multidisciplinary interventions, and placing the patient at the centre of the care process. In this article, taskforce contributors discuss the latest evidence and highlight some of the most pertinent issues for nurses involved in patient-centred care of patients and families with ventricular arrhythmias and/or risk of sudden death.

Assessing the Awareness of Agents Involved in Issuance of Death Certificates About Death Registration Rules in Iran

PubMed Central

Mahdavi, Abdollah; Sedghi, Shahram; Sadoghi, Farahnaz; Azar, Farbod Ebadi Fard

2015-01-01

Introduction: In the death registration system, issuance of death certificate, as a binding rule, is considered among the major necessities of preparation of death statistics. In order to prepare death statistics that are adequately valid for subsequent applications, it is necessary to properly encode death certificates and fully follow rules on causes underlying death. This study aimed to assess the awareness and performance of agents involved in issuance of death certificate in the national death records system. Methods: It was a descriptive cross-sectional research, which was performed from September 2013 to March 2014 on 96 agents involved in issuance of death certificate Imam Khomeini, Alavi, Fatemi and BuAli education and treatment centers of Ardebil University of Medical Sciences. The population included faculty staff physicians, residents and health information management staffs. The research scale was also a researcher-made questionnaire that questioned the demographic information as well as awareness and performance of participants regarding death certificate coding rules. Research data was analyzed based on descriptive statistics and the chi-square test method in the SPSS software at a confidence level of 95%. Findings: A total of 34.42% of participants were aware of the general rules on issuance of death certificates while faculty staff higher specialists (41.67%) and clinical coders (38.34%) with five years of experience demonstrated the highest awareness levels. Only 23 participants (24.6%) were trained to issue death certificates. A total of 76 participants (79.3%) announced their need for learning how to complete death certificate forms on a constant basis. The awareness of participants about the general principle was assessed to be low (30.25%). Moreover, their awareness of selection rules and modification rules was low (27.75%) and moderate (45.25%), respectively. The chi-square test revealed a significant relationship between work experience and awareness of participants about coding rules (P=0.001), but no significant relationship was observed between education and awareness of coding rules (P=0.497). Conclusion: The awareness of participants about rules on coding death causes and their performance in this field was so satisfactory. That is to say, the awareness of faculty staff and health information management staffs was unexpectedly low. Seemingly, lack of adequate training is an international issue that causes mistakes in the recording of information on mortality. Hence, a short-term solution is to train faculty staff and residents and also revise the training provided to health information management staffs. As a long-term solution it is possible to provide related courses to general practitioner students. PMID:26156914

Unintentional and undetermined firearm related deaths: a preventable death analysis for three safety devices.

PubMed

Vernick, J S; O'Brien, M; Hepburn, L M; Johnson, S B; Webster, D W; Hargarten, S W

2003-12-01

To determine the proportion of unintentional and undetermined firearm related deaths preventable by three safety devices: personalization devices, loaded chamber indicators (LCIs), and magazine safeties. A personalized gun will operate only for an authorized user, a LCI indicates when the gun contains ammunition, and a magazine safety prevents the gun from firing when the ammunition magazine is removed. Information about all unintentional and undetermined firearm deaths from 1991-98 was obtained from the Office of the Chief Medical Examiner for Maryland, and from the Wisconsin Firearm Injury Reporting System for Milwaukee. Data regarding the victim, shooter, weapon, and circumstances were abstracted. Coding rules to classify each death as preventable, possibly preventable, or not preventable by each of the three safety devices were also applied. There were a total of 117 firearm related deaths in our sample, 95 (81%) involving handguns. Forty three deaths (37%) were classified as preventable by a personalized gun, 23 (20%) by a LCI, and five (4%) by a magazine safety. Overall, 52 deaths (44%) were preventable by at least one safety device. Deaths involving children 0-17 (relative risk (RR) 3.3, 95% confidence interval (CI) 2.1 to 5.1) and handguns (RR 8.1, 95% CI 1.2 to 53.5) were more likely to be preventable. Projecting the findings to the entire United States, an estimated 442 deaths might have been prevented in 2000 had all guns been equipped with these safety devices. Incorporating safety devices into firearms is an important injury intervention, with the potential to save hundreds of lives each year.

Photodynamic therapy: the role of paraptosis

NASA Astrophysics Data System (ADS)

Kessel, David; Cho, Won-Jin; Kim, Hyeong-Reh

2018-02-01

Apoptosis is a pathway to cell death frequently observed after photodynamic therapy (PDT). Sub-cellular photodamage to mitochondria, lysosomes, the ER, or combinations of these targets, can lead to apoptotic death. We have recently investigated another pathway to cell death after PDT termed `paraptosis'. This is characterized by extensive cytoplasmic vacuolization, does not involve caspase activation or nuclear fragmentation, requires a brief interval of continued protein synthesis and appears to derive from ER stress. Determinants and further characteristics of PDT-derived paraptosis are explored in the A549 non small-cell lung cancer cell line and in cells derived from head and neck cancer tissues. We provide evidence that ER photodamage and JNK pathway activation are involved in PDT-mediated paraptosis.

Surveillance for violent deaths--National Violent Death Reporting System, 16 States, 2007.

PubMed

Karch, Debra L; Dahlberg, Linda L; Patel, Nimesh

2010-05-14

An estimated 50,000 persons die annually in the United States as a result of violence-related injuries. This report summarizes data from CDC's National Violent Death Reporting System (NVDRS) regarding violent deaths from 16 states for 2007. Results are reported by sex, age group, race/ethnicity, marital status, location of injury, method of injury, circumstances of injury, and other selected characteristics. 2007. NVDRS collects data regarding violent deaths obtained from death certificates, coroner/medical examiner reports, and law enforcement reports. NVDRS began operation in 2003 with seven states (Alaska, Maryland, Massachusetts, New Jersey, Oregon, South Carolina, and Virginia) participating; six states (Colorado, Georgia, North Carolina, Oklahoma, Rhode Island, and Wisconsin) joined in 2004, four (California, Kentucky, New Mexico, and Utah) in 2005, and two states (Ohio and Michigan) were funded to begin data collection in 2010, totaling 19 states. This report includes data from 16 states that collected statewide data in 2007. California data are not included in this report because NVDRS data are collected only in a limited number of California cities and counties rather than statewide. Ohio and Michigan are excluded because they did not begin data collection until 2010. For 2007, a total of 15,882 fatal incidents involving 16,319 deaths occurred in the 16 NVDRS states included in this report. The majority (56.6%) of deaths was suicides, followed by homicides and deaths involving legal intervention (i.e., deaths caused by police and other persons with legal authority to use deadly force, excluding legal executions) (28.0%), deaths of undetermined intent (14.7%), and unintentional firearm deaths (0.7%). Suicides occurred at higher rates among males, American Indians/Alaska Natives, non-Hispanic whites, and persons aged 45--54 years. Suicides occurred most often in a house or apartment and involved the use of firearms. Suicides were precipitated primarily by mental-health, intimate-partner, or physical-health problems, or by a crisis during the preceding 2 weeks. Homicides occurred at higher rates among males and persons aged 20--24 years; rates were highest among non-Hispanic black males. The majority of homicides involved the use of a firearm and occurred in a house or apartment or on a street/highway. Homicides were precipitated primarily by arguments and interpersonal conflicts or in conjunction with another crime. Other manners of death and special situations or populations also are highlighted in this report. This report provides a detailed summary of data from NVDRS for 2007. The results indicate that violent deaths resulting from self-inflicted or interpersonal violence disproportionately affected adults aged <55 years, males, and certain minority populations. For homicides and suicides, relationship problems, interpersonal conflicts, mental-health problems, and recent crises were among the primary precipitating factors. Because additional information might be reported subsequently as participating states update their findings, the data provided in this report are preliminary. For the occurrence of violent deaths in the United States to be better understood and ultimately prevented, accurate, timely, and comprehensive surveillance data are necessary. NVDRS data can be used to monitor the occurrence of violence-related fatal injuries and assist public health authorities in the development, implementation, and evaluation of programs and policies to reduce and prevent violent deaths at the national, state, and local levels. The continued development and expansion of NVDRS is essential to CDC's efforts to reduce the personal, familial, and societal costs of violence. Further efforts are needed to increase the number of states participating in NVDRS, with an ultimate goal of full national representation.

Retrospective Reports of the Lived School Experience of Adolescents after the Death of a Parent

ERIC Educational Resources Information Center

Masterson, Ann

2013-01-01

This qualitative phenomenological study was done to better understand the school experience of adolescents after the death of a parent. The participants were adults over the age of 19 and between 3 and 43 years past the death of a parent during adolescence. The study involved personal, reflective interviews with each of the participants. The…

[Sport's related sudden death].

PubMed

Carré, François

2014-01-01

Non-traumatic sudden death related to sport is a rare but always dramatic event. Its causes are mainly cardiovascular. Prevention of sudden death depends on effective medical examination involving history, physical examination and resting ECG, as education of athletes who must follow the rules for safe sport practice and lastly training for emergency actions of the population. Copyright © 2014. Published by Elsevier Masson SAS.

3 CFR 8940 - Proclamation 8940 of March 15, 2013. National Poison Prevention Week, 2013

Code of Federal Regulations, 2014 CFR

2014-01-01

... have dramatically reduced childhood death rates from accidental poisoning—but work remains. To keep our...-800-222-1222. Today, the majority of unintentional poisoning deaths are caused by overdoses involving...

Dying at Home: Can Families Cope?

ERIC Educational Resources Information Center

Hine, Virginia H.

1979-01-01

Examines five considerations involved in decision for home death: (1) sources of moral support necessary for family; (2) kinds of professional aid available; (3) special equipment necessary; (4) necessary nursing skills; and (5) basic information about death. (Author)

3-Bromopyruvate induces rapid human prostate cancer cell death by affecting cell energy metabolism, GSH pool and the glyoxalase system.

PubMed

Valenti, Daniela; Vacca, Rosa A; de Bari, Lidia

2015-12-01

3-bromopyruvate (3-BP) is an anti-tumour drug effective on hepatocellular carcinoma and other tumour cell types, which affects both glycolytic and mitochondrial targets, depleting cellular ATP pool. Here we tested 3-BP on human prostate cancer cells showing, differently from other tumour types, efficient ATP production and functional mitochondrial metabolism. We found that 3-BP rapidly induced cultured androgen-insensitive (PC-3) and androgen-responsive (LNCaP) prostate cancer cell death at low concentrations (IC(50) values of 50 and 70 μM, respectively) with a multimodal mechanism of action. In particular, 3-BP-treated PC-3 cells showed a selective, strong reduction of glyceraldeide 3-phosphate dehydrogenase activity, due to the direct interaction of the drug with the enzyme. Moreover, 3-BP strongly impaired both glutamate/malate- and succinate-dependent mitochondrial respiration, membrane potential generation and ATP synthesis, concomitant with the inhibition of respiratory chain complex I, II and ATP synthase activities. The drastic reduction of cellular ATP levels and depletion of GSH pool, associated with significant increase in cell oxidative stress, were found after 3-BP treatment of PC-3 cells. Interestingly, the activity of both glyoxalase I and II, devoted to the elimination of the cytotoxic methylglyoxal, was strongly inhibited by 3-BP. Both N-acetylcysteine and aminoguanidine, GSH precursor and methylglyoxal scavenger, respectively, prevented 3-BP-induced PC-3 cell death, showing that impaired cell antioxidant and detoxifying capacities are crucial events leading to cell death. The provided information on the multi-target cytotoxic action of 3-BP, finally leading to PC-3 cell necrosis, might be useful for future development of 3-BP as a therapeutic option for prostate cancer treatment.

Evidence for Two Modes of Synergistic Induction of Apoptosis by Mapatumumab and Oxaliplatin in Combination with Hyperthermia in Human Colon Cancer Cells

PubMed Central

Song, Xinxin; Kim, Seog-Young; Lee, Yong J.

2013-01-01

Colorectal cancer is the third leading cause of cancer-related mortality in the world-- the main cause of death from colorectal cancer is hepatic metastases, which can be treated with isolated hepatic perfusion (IHP). Searching for the most clinically relevant approaches for treating colorectal metastatic disease by isolated hepatic perfusion (IHP), we developed the application of oxaliplatin concomitantly with hyperthermia and humanized death receptor 4 (DR4) antibody mapatumumab (Mapa), and investigated the molecular mechanisms of this multimodality treatment in human colon cancer cell lines CX-1 and HCT116 as well as human colon cancer stem cells Tu-12, Tu-21 and Tu-22. We showed here, in this study, that the synergistic effect of the multimodality treatment-induced apoptosis was caspase dependent and activated death signaling via both the extrinsic apoptotic pathway and the intrinsic pathway. Death signaling was activated by c-Jun N-terminal kinase (JNK) signaling which led to Bcl-xL phosphorylation at serine 62, decreasing the anti-apoptotic activity of Bcl-xL, which contributed to the intrinsic pathway. The downregulation of cellular FLICE inhibitory protein long isoform (c-FLIPL) in the extrinsic pathway was accomplished through ubiquitination at lysine residue (K) 195 and protein synthesis inhibition. Overexpression of c-FLIPL mutant (K195R) and Bcl-xL mutant (S62A) completely abrogated the synergistic effect. The successful outcome of this study supports the application of multimodality strategy to patients with colorectal hepatic metastases who fail to respond to standard chemoradiotherapy that predominantly targets the mitochondrial apoptotic pathway. PMID:24013390

Cardiorenal Syndrome Type 5 in Sepsis: Role of Endotoxin in Cell Death Pathways and Inflammation.

PubMed

Virzì, Grazia Maria; Clementi, Anna; Brocca, Alessandra; de Cal, Massimo; Marcante, Stefano; Ronco, Claudio

2016-01-01

Cardiorenal Syndrome Type 5 (CRS Type 5) is characterized by concomitant cardiac and renal dysfunction in the setting of different systemic disorders, such as sepsis. In this study, we investigated the possible relationship between endotoxin levels, renal cell death and inflammation in septic patients with CRS Type 5. We enrolled 11 patients with CRS Type 5. CRS Type 5 was defined according to the current classification system. AKI was defined by Acute Kidney Injury Network (AKIN) criteria. Acute cardiac dysfunction was documented by echocardiography as acute left and/or right ventricular dysfunction leading to decreased ejection fraction. Endotoxin activity was measured by the Endotoxin Activity Assay (EAA). Plasma from CRS Type 5 patients was incubated with renal tubular cells (RTCs) and cell death levels were evaluated. Plasma cytokines levels were measured as well. Accordingly to EAA levels, patients were divided into two groups: 45.4% of patients had low endotoxin activity level (negative EAA), while 54.5% of patients showed high endotoxin activity (positive EAA). RTCs incubated with plasma from EAA positive patients showed significantly higher apoptosis levels and higher caspase-3 activation compared to cells incubated with plasma from EAA negative patients, and a significant positive correlation was observed between EAA levels and RTC apoptosis levels. Furthermore, IL-6 and IFN-γ levels were significantly higher in CRS Type 5 patients with positive EAA. Our data suggest a possible relationship between endotoxin levels and renal cell death in septic patients with CRS Type 5. Furthermore, this study highlights the presence of renal apoptosis, the immune deregulation and the strong inflammation in CRS Type 5 patients, especially in those with high endotoxin activity. © 2017 S. Karger AG, Basel.

Methamphetamine-induced neurotoxicity linked to UPS dysfunction and autophagy related changes that can be modulated by PKCδ in dopaminergic neuronal cells

PubMed Central

Lin, Mengshien; Shivalingappa, Prashanth Chandramani; Jin, Huajun; Ghosh, Anamitra; Anantharam, Vellareddy; Ali, Syed; Kanthasamy, Anumantha G.; Kanthasamy, Arthi

2012-01-01

A compromised protein degradation machinery has been implicated in methamphetamine (MA)-induced neurodegeneration. However, the signaling mechanisms that induce autophagy and UPS dysfunction are not well understood. The present study investigates the contributions of PKC delta (PKCδ) mediated signaling events in MA-induced autophagy, UPS dysfunction and cell death. Using an in vitro mesencephalic dopaminergic cell culture model, we demonstrate that MA-induced early induction of autophagy is associated with reduction in proteasomal function and concomitant dissipation of mitochondrial membrane potential (MMP), followed by significantly increased of PKCδ activation, caspase-3 activation, accumulation of ubiquitin positive aggregates and microtubule associated light chain-3 (LC3-II) levels. Interestingly, siRNA mediated knockdown of PKCδ or overexpression of cleavage resistant mutant of PKCδ dramatically reduced MA-induced autophagy, proteasomal function, and associated accumulation of ubiquitinated protein aggregates, which closely paralleled cell survival. Importantly, when autophagy was inhibited either pharmacologically (3-MA) or genetically (siRNA mediated silencing of LC3), the dopaminergic cells became sensitized to MA-induced apoptosis through caspase-3 activation. Conversely, overexpression of LC3 partially protected against MA-induced apoptotic cell death, suggesting a neuroprotective role for autophagy in MA-induced neurotoxicity. Notably, rat striatal tissue isolated from MA treated rats also exhibited elevated LC3-II, ubiquitinated protein levels, and PKCδ cleavage. Taken together, our data demonstrate that MA-induced autophagy serves as an adaptive strategy for inhibiting mitochondria mediated apoptotic cell death and degradation of aggregated proteins. Our results also suggest that the sustained activation of PKCδ leads to UPS dysfunction, resulting in the activation of caspase-3 mediated apoptotic cell death in the nigrostriatal dopaminergic system. PMID:22445524

Opioid Deaths in Milwaukee County, Wisconsin 2013-2017: The Primacy of Heroin and Fentanyl.

PubMed

Peterson, Brian L; Schreiber, Sara; Fumo, Nicole; Brooke Lerner, E

2018-04-23

Heroin and fentanyl are the overwhelming and increasing cause of opioid deaths in Milwaukee County, Wisconsin. We reviewed all drug and opioid deaths from 2013 to 2017 to delineate the specific opioid drugs involved and changes in their incidence. From 2013 to 2017, 980 deaths were due to opioids, rising from 184 in 2013 to 337 in 2017. In 2017, opioid deaths exceeded combined non-natural deaths from homicide and suicide. Illicit heroin and fentanyl/analogs caused 84% of opioid deaths and 80% of drug deaths, with no increase in deaths due to oral prescription drugs such as oxycodone and hydrocodone. Any approach to decreasing this dramatic increase in opioid deaths should first focus on interdicting the supply and cheap availability of these illicit opioids. Fentanyl and its analogs represent the most deadly opioids and the greatest threat to human life in our population. © 2018 American Academy of Forensic Sciences.

Intracellular cholesterol level regulates sensitivity of glioblastoma cells against temozolomide-induced cell death by modulation of caspase-8 activation via death receptor 5-accumulation and activation in the plasma membrane lipid raft.

PubMed

Yamamoto, Yutaro; Tomiyama, Arata; Sasaki, Nobuyoshi; Yamaguchi, Hideki; Shirakihara, Takuya; Nakashima, Katsuhiko; Kumagai, Kosuke; Takeuchi, Satoru; Toyooka, Terushige; Otani, Naoki; Wada, Kojiro; Narita, Yoshitaka; Ichimura, Koichi; Sakai, Ryuichi; Namba, Hiroki; Mori, Kentaro

2018-01-01

Development of resistance against temozolomide (TMZ) in glioblastoma (GBM) after continuous treatment with TMZ is one of the critical problems in clinical GBM therapy. Intracellular cholesterol regulates cancer cell biology, but whether intracellular cholesterol is involved in TMZ resistance of GBM cells remains unclear. The involvement of intracellular cholesterol in acquired resistance against TMZ in GBM cells was investigated. Intracellular cholesterol levels were measured in human U251 MG cells with acquired TMZ resistance (U251-R cells) and TMZ-sensitive control U251 MG cells (U251-Con cells), and found that the intracellular cholesterol level was significantly lower in U251-R cells than in U251-Con cells. In addition, treatment by intracellular cholesterol remover, methyl-beta cyclodextrin (MβCD), or intracellular cholesterol inducer, soluble cholesterol (Chol), regulated TMZ-induced U251-Con cell death in line with changes in intracellular cholesterol level. Involvement of death receptor 5 (DR5), a death receptor localized in the plasma membrane, was evaluated. TMZ without or with MβCD and/or Chol caused accumulation of DR5 into the plasma membrane lipid raft and formed a complex with caspase-8, an extrinsic caspase cascade inducer, reflected in the induction of cell death. In addition, treatment with caspase-8 inhibitor or knockdown of DR5 dramatically suppressed U251-Con cell death induced by combination treatment with TMZ, MβCD, and Chol. Combined treatment of Chol with TMZ reversed the TMZ resistance of U251-R cells and another GBM cell model with acquired TMZ resistance, whereas clinical antihypercholesterolemia agents at physiological concentrations suppressed TMZ-induced cell death of U251-Con cells. These findings suggest that intracellular cholesterol level affects TMZ treatment of GBM mediated via a DR5-caspase-8 mechanism. Copyright © 2017 Elsevier Inc. All rights reserved.

[Hypothermia as the cause of death in forensic pathology: autopsy study].

PubMed

Nikolić, Slobodan; Zivković, Magdalena; Zivković, Vladimir; Juković, Fehim

2010-01-01

The body cooling process goes through few clinical phases. These are followed by some morphological thanatological changes such as frost erythema and Wischnewsky's spots, which are used in diagnosis of death due to hypothermia. In such cases there is no any specific autopsy finding. To establish the frequency of hypothermia as the cause of death for a ten-year-period, and to analyze the sample according to gender and age, risk factors and autopsy findings of subjects. A retrospective autopsy study was performed for a ten-year-period (total of 12,765 forensic autopsies). The relevant data were collected from autopsy records, police reports and heteroanamnestic interviews. The sample was analyzed according to gender, age, scene of death, blood alcohol concentration, risk factors, and autopsy findings of all observed subjects. The sample included 67 subjects, 42 males and 25 females (chi2 = 4.31; p < 0.05), of average age 63.9 +/- 14.7 years (min=27, max=92; med=65, mod=55). Nineteen of subjects were found at in-door places. In 13 subjects blood alcohol concentration ranged from 0.50 to 3.32 promille (average 1.81 +/- 0.93). The younger the observed subject was, the higher the blood alcohol concentration (p = -0.251; p = 0.04). One third of the observed subjects were chronic alcohol abusers. Thirteen persons had psychiatric diseases. In 43 observed subjects the concomitant appearance of frost erythema and Wischniewsky's spots were established (chi2 = 49.59; df = 3; p < 0.001). In the analyzed ten-year period hypothermia was not often the cause of death; it was disclosed only in 0.5% of the total number of the studied autopsies. The most of the deceased were older males with cardiovascular problems found in unprotected open-air places. The most frequent thanatological findings in the analyzed subjects were frost erythema and Wischnewsky's spots.

Prognostic effects of rosuvastatin in patients with co-existing chronic obstructive pulmonary disease and chronic heart failure: A sub-analysis of GISSI-HF trial.

PubMed

Rossi, Andrea; Inciardi, Riccardo M; Rossi, Andrea; Temporelli, Pier Luigi; Lucci, Donata; Gonzini, Lucio; Marchioli, Roberto; Nicolosi, Gian Luigi; Tavazzi, Luigi

2017-06-01

Rising evidences showed a possible protective role of statins in chronic obstructive pulmonary disease (COPD). We aimed to evaluate in a post-hoc analysis of the GISSI-HF trial the prognostic effect of the use of rosuvastatin in patients with co-existing COPD and HF, assuming that the anti-inflammatory properties of these drugs may imply a potential beneficial effect in these associated chronic inflammatory conditions. We analyzed patients with chronic HF and history of COPD deriving from the GISSI-HF study. Of all 4574 patients eligible to statin, 1060 ambulatory patients with HF and concomitant COPD were enrolled and randomly assigned to rosuvastatin 10 mg daily (538 patients) or placebo (522 patients). The primary end-point was to compare all cause death rate in patients randomized to rosuvastatin or placebo. Further, we assessed the effects of rosuvastatin (10 mg daily) on cardiovascular (CV) death, non-CV death and hospital admissions. Median follow-up was 3.9 years with an interquartile range (IQR) of 3.0-4.4. During the follow-up 438 (41.3%) patients died, 304 (28.6%) for CV death and 687 (64.8%) had at least one hospitalization. The two patient groups had similar outcome, irrespective of randomization, in terms of all-cause mortality (log-rank test p = 0.30) CV, non CV-death (p = 0.88 and 0.09 respectively) and all-cause hospitalization (p = 0.82). Cox regression analysis did not show a favorable association between the use of statin and the examined end-points both on unadjusted and adjusted models. Statin use is not associated with a beneficial effects on all cause, CV, non CV mortality and hospitalization in patients with coexistent chronic HF and history of COPD. ClinicalTrials.gov Identifier: NCT00336336. Copyright © 2017. Published by Elsevier Ltd.

A review of the use of clozapine levels to guide treatment and determine cause of death.

PubMed

Stark, Anne; Scott, James

2012-09-01

To review the literature to examine the use of clozapine levels to (i) guide therapy and prevent toxicity in clinical care and (ii) determine cause of death in post-mortem examination of patients who were treated with clozapine. MEDLINE was searched in December 2010 using the following keywords: 'clozapine levels', 'clozapine and toxicity', 'clozapine and death', 'clozapine and mortality' and 'post-mortem redistribution'. Data was also collected from the 2010 MIMS Annual. The literature reported significant variation in clozapine levels attained with any given dose, and considerable variability in the clinical response achieved at any given clozapine level. The lowest effective clozapine levels ranged from 250 to 550 µg/L, while the recommended upper limit to prevent toxicity varied from 600 to 2000 µg/L. There was minimal correlation between clozapine levels and side effects, with the exception of sedation, hypotension and seizure activity. The risk of seizures increased with plasma clozapine levels greater than 600 µg/L or rapid upward titration. In addition to prescribed dose, there are many factors that influence plasma clozapine levels. After death, the process of post-mortem drug redistribution resulted in 3.00 to 4.89 times increases in clozapine levels in central blood vessels and 1.5 fold increases in peripheral vessels compared to ante-mortem levels. The exact range of clozapine levels that corresponds to toxicity remains unclear. However, levels between 350 µg/L and 1000 µg/L achieved with gradual upward titration are more likely to be effective and less likely to cause toxicity. Ongoing clozapine level monitoring is indicated, especially when (i) prescribing higher doses (> 600 mg/day) of clozapine, (ii) there has been a change in a patient's concomitant pharmacotherapy or cigarette use and (iii) there has been a suboptimal response to treatment. The use of post-mortem clozapine levels to determine clozapine toxicity as a cause of death is unreliable.

Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study.

PubMed

Imai, E; Chan, J C N; Ito, S; Yamasaki, T; Kobayashi, F; Haneda, M; Makino, H

2011-12-01

The renal and cardiovascular protective effects of angiotensin receptor blocker (ARB) remain controversial in type 2 diabetic patients treated with a contemporary regimen including an angiotensin converting enzyme inhibitor (ACEI). We examined the effects of olmesartan, an ARB, on primary composite outcome of doubling of serum creatinine, endstage renal disease and death in type 2 diabetic patients with overt nephropathy. Secondary outcome included composite cardiovascular outcomes, changes in renal function and proteinuria. Randomisation and allocation to trial group were carried out by a central computer system. Participants, caregivers, the people carrying out examinations and people assessing the outcomes were blinded to group assignment. Five hundred and seventy-seven (377 Japanese, 200 Chinese) patients treated with antihypertensive therapy (73.5% [n = 424] received concomitant ACEI), were given either once-daily olmesartan (10-40 mg) (n = 288) or placebo (n = 289) over 3.2 ± 0.6 years (mean±SD). In the olmesartan group, 116 developed the primary outcome (41.1%) compared with 129 (45.4%) in the placebo group (HR 0.97, 95% CI 0.75, 1.24; p = 0.791). Olmesartan significantly decreased blood pressure, proteinuria and rate of change of reciprocal serum creatinine. Cardiovascular death was higher in the olmesartan group than the placebo group (ten vs three cases), whereas major adverse cardiovascular events (cardiovascular death plus non-fatal stroke and myocardial infarction) and all-cause death were similar between the two groups (major adverse cardiovascular events 18 vs 21 cases, all-cause deaths; 19 vs 20 cases). Hyperkalaemia was more frequent in the olmesartan group than the placebo group (9.2% vs 5.3%). Olmesartan was well tolerated but did not improve renal outcome on top of ACEI. ClinicalTrials.gov NCT00141453.

Long-term projections of temperature-related mortality risks for ischemic stroke, hemorrhagic stroke, and acute ischemic heart disease under changing climate in Beijing, China.

PubMed

Li, Tiantian; Horton, Radley M; Bader, Daniel A; Liu, Fangchao; Sun, Qinghua; Kinney, Patrick L

2018-03-01

Changing climates have been causing variations in the number of global ischemic heart disease and stroke incidences, and will continue to affect disease occurrence in the future. To project temperature-related mortality for acute ischemic heart disease, and ischemic and hemorrhagic stroke with concomitant climate warming. We estimated the exposure-response relationship between daily cause-specific mortality and daily mean temperature in Beijing. We utilized outputs from 31 downscaled climate models and two representative concentration pathways (RCPs) for the 2020s, 2050s, and 2080s. This strategy was used to estimate future net temperature along with heat- and cold-related deaths. The results for predicted temperature-related deaths were subsequently contrasted with the baseline period. In the 2080s, using the RCP8.5 and no population variation scenarios, the net total number of annual temperature-related deaths exhibited a median value of 637 (with a range across models of 434-874) for ischemic stroke; this is an increase of approximately 100% compared with the 1980s. The median number of projected annual temperature-related deaths was 660 (with a range across models of 580-745) for hemorrhagic stroke (virtually no change compared with the 1980s), and 1683 (with a range across models of 1351-2002) for acute ischemic heart disease (a slight increase of approximately 20% compared with the 1980s). In the 2080s, the monthly death projection for hemorrhagic stroke and acute ischemic heart disease showed that the largest absolute changes occurred in summer and winter while the largest absolute changes for ischemic stroke occurred in summer. We projected that the temperature-related mortality associated with ischemic stroke will increase dramatically due to climate warming. However, projected temperature-related mortality pertaining to acute ischemic heart disease and hemorrhagic stroke should remain relatively stable over time. Copyright © 2017 Elsevier Ltd. All rights reserved.

Serum total cholesterol levels and all-cause mortality in a home-dwelling elderly population: a six-year follow-up

PubMed Central

Tuikkala, Päivi; Hartikainen, Sirpa; Korhonen, Maarit J.; Lavikainen, Piia; Kettunen, Raimo; Sulkava, Raimo; Enlund, Hannes

2010-01-01

Objective To investigate the association between serum total cholesterol and all-cause mortality in elderly individuals aged ≥ 75 years. Design A prospective cohort study with a six-year follow-up. Setting and subjects A random sample (n = 700) of all persons aged ≥ 75 years living in Kuopio, Finland. After exclusion of participants living in institutional care and participants using lipid-modifying agents or missing data on blood pressure and cholesterol levels, the final study population consisted of 490 home-dwelling elderly persons with clinical examination. We used the Cox proportional hazard model and the propensity score (PS) method. Main outcome measure All-cause mortality. Results In an age- and sex-adjusted analysis, participants with S-TC ≥ 6mmol/l had the lowest risk of death (hazard ratio, HR = 0.48, 95% CI 0.33–0.70) compared with those with S-TC < 5 mmol/l. HR of death for a 1 mmol increase in S-TC was 0.78. In multivariate analyses, the HR of death for a 1 mmol increase in S-TC was 0.82 and using S-TC < 5 mmol/l as a reference, the HR of death for S-TC ≥ 6 mmol/l was 0.59 (95% CI 0.39–0.89) and for S-TC 5.0–5.9 mmol/l, the HR was 0.62 (95% CI 0.42–0.93). In a PS-adjusted model using S-TC < 5 mmol/l as a reference, the HR of death for S-TC ≥ 6 mmol/l was 0.42 (95% CI 0.28–0.62) and for S-TC 5.0–5.9 mmol/l, the HR was 0.57 (95% CI 0.38–0.84). Conclusions. Participants with low serum total cholesterol seem to have a lower survival rate than participants with an elevated cholesterol level, irrespective of concomitant diseases or health status. PMID:20470020

On the role of phosphatidylinositol 3-kinase, protein kinase b/Akt, and glycogen synthase kinase-3β in photodynamic injury of crayfish neurons and glial cells.

PubMed

Komandirov, Maxim A; Knyazeva, Evgeniya A; Fedorenko, Yulia P; Rudkovskii, Mikhail V; Stetsurin, Denis A; Uzdensky, Anatoly B

2011-10-01

Photodynamic treatment that causes intense oxidative stress and cell death is currently used in neurooncology. However, along with tumor cells, it may damage healthy neurons and glia. To study the involvement of signaling processes in photodynamic injury or protection of neurons and glia, we used crayfish mechanoreceptor consisting of a single neuron surrounded by glial cells. It was photosensitized with alumophthalocyanine Photosens. Application of specific inhibitors showed that phosphatidylinositol 3-kinase did not participate in photoinduced death of neurons and glia. Akt was involved in photoinduced necrosis but not in apoptosis of neurons and glia. Glycogen synthase kinase-3β participated in photoinduced apoptosis of glial cells and in necrosis of neurons. Therefore, phosphatidylinositol 3-kinase/protein kinase Akt/glycogen synthase kinase-3β pathway was not involved as a whole in photodynamic injury of crayfish neurons and glia but its components, Akt and glycogen synthase kinase-3β, independently and cell specifically regulated death of neurons and glial cells. According to these data, necrosis in this system was a controlled but not a non-regulated cell death mode. The obtained results may be used for the search of pharmacological agents selectively modulating death and survival of normal neurons and glial cells during photodynamic therapy of brain tumors.

Accommodating Grief on Twitter: An Analysis of Expressions of Grief Among Gang Involved Youth on Twitter Using Qualitative Analysis and Natural Language Processing.

PubMed

Patton, Desmond Upton; MacBeth, Jamie; Schoenebeck, Sarita; Shear, Katherine; McKeown, Kathleen

2018-01-01

There is a dearth of research investigating youths' experience of grief and mourning after the death of close friends or family. Even less research has explored the question of how youth use social media sites to engage in the grieving process. This study employs qualitative analysis and natural language processing to examine tweets that follow 2 deaths. First, we conducted a close textual read on a sample of tweets by Gakirah Barnes, a gang-involved teenaged girl in Chicago, and members of her Twitter network, over a 19-day period in 2014 during which 2 significant deaths occurred: that of Raason "Lil B" Shaw and Gakirah's own death. We leverage the grief literature to understand the way Gakirah and her peers express thoughts, feelings, and behaviors at the time of these deaths. We also present and explain the rich and complex style of online communication among gang-involved youth, one that has been overlooked in prior research. Next, we overview the natural language processing output for expressions of loss and grief in our data set based on qualitative findings and present an error analysis on its output for grief. We conclude with a call for interdisciplinary research that analyzes online and offline behaviors to help understand physical and emotional violence and other problematic behaviors prevalent among marginalized communities.

Accommodating Grief on Twitter: An Analysis of Expressions of Grief Among Gang Involved Youth on Twitter Using Qualitative Analysis and Natural Language Processing

PubMed Central

Patton, Desmond Upton; MacBeth, Jamie; Schoenebeck, Sarita; Shear, Katherine; McKeown, Kathleen

2018-01-01

There is a dearth of research investigating youths’ experience of grief and mourning after the death of close friends or family. Even less research has explored the question of how youth use social media sites to engage in the grieving process. This study employs qualitative analysis and natural language processing to examine tweets that follow 2 deaths. First, we conducted a close textual read on a sample of tweets by Gakirah Barnes, a gang-involved teenaged girl in Chicago, and members of her Twitter network, over a 19-day period in 2014 during which 2 significant deaths occurred: that of Raason “Lil B” Shaw and Gakirah’s own death. We leverage the grief literature to understand the way Gakirah and her peers express thoughts, feelings, and behaviors at the time of these deaths. We also present and explain the rich and complex style of online communication among gang-involved youth, one that has been overlooked in prior research. Next, we overview the natural language processing output for expressions of loss and grief in our data set based on qualitative findings and present an error analysis on its output for grief. We conclude with a call for interdisciplinary research that analyzes online and offline behaviors to help understand physical and emotional violence and other problematic behaviors prevalent among marginalized communities. PMID:29636619

Relationship between KCNQ1 (LQT1) and KCNH2 (LQT2) gene mutations and sudden death during illegal drug use.

PubMed

Nagasawa, Sayaka; Saitoh, Hisako; Kasahara, Shiori; Chiba, Fumiko; Torimitsu, Suguru; Abe, Hiroko; Yajima, Daisuke; Iwase, Hirotaro

2018-05-31

Long QT syndrome (LQTS), a congenital genetic disorder, can cause torsades de pointes (TdP), and lethal cardiac arrhythmia may result from ingestion of cardiotoxic drugs. Methamphetamine (MP) and new psychoactive substances (NPSs) can trigger TdP due to QT prolongation, leading to sudden death. We therefore analysed variations in the LQTS-associated genes KCNQ1 (LQT1) and KCNH2 (LQT2) using cardiac blood and myocardial tissue from subjects having died suddenly during MP or NPS use to investigate the relationship between congenital genetic abnormalities and sudden death during illegal drug use. We amplified and sequenced all exons of these genes using samples from 20 subjects, half of whom had died taking MP and half after using NPSs. G643S, a KCNQ1 missense polymorphism, was significantly more common among sudden deaths involving NPSs (6 subjects) than those involving MP (1 subject) and healthy Japanese subjects (P = 0.001). Notably, synthetic cathinones were detected in 2 of 3 cases involving G643S carriers. Previous functional analyses have indicated that the G643S polymorphism in the KCNQ1 potassium channel gene causes mild I Ks channel dysfunction. Our data suggest that use of NPSs, particularly synthetic cathinones, is associated with elevated risk of serious cardiac arrhythmia and sudden death for subjects carrying KCNQ1 G643S.

Floating elbow injuries in adults: prognostic factors affecting clinical outcomes.

PubMed

Ditsios, Konstantinos; Boutsiadis, Achilleas; Papadopoulos, Pericles; Karataglis, Dimitrios; Givissis, Panagiotis; Hatzokos, Ippokratis; Christodoulou, Anastasios

2013-01-01

Floating elbow fractures in adults are rare and complex injuries with unpredictable outcomes. The present study was designed to assess our experience, analyze possible compilations and illustrate prognostic factors of the final outcome. Between 2002 and 2009, 19 patients with floating elbow fractures were treated in our department (mean follow-up, 26 months). The fractures were open in 10 patients (52.6%), and concomitant nerve palsy was present in 10 patients. Although the term "floating elbow" refers only to concomitant ipsilateral humeral and forearm shaft fractures, we also included injuries with intra-articular involvement. We categorized the patients into 4 groups: group I (10 patients) included shaft fractures of humerus and forearm, group IIa (5 patients) and IIb (1 patient) included partial intra-articular injuries, and group III (3 patients) involved only intra-articular comminuted fractures of the elbow region. Fracture healing was observed 14 weeks postoperatively, except in 2 patients, in which elbow arthroplasty was applied, and in 1 with brachial artery injury. Nine patients with nerve neuropraxia recovered 4 months postoperatively, and tendon transfers were necessary in 1 patient. Recovery in patients with nerve palsy was worse than in those without nerve injury (Mayo Elbow Performance Score, 73 vs 88.34; Khalfayan score, 72 vs 88.3). In addition, intra-articular involvement (groups II and III) negatively influenced the final clinical outcome compared with isolated shaft fractures (group I; Mayo Elbow Performance Score, 71.1 vs 88.5; Khalfayan score, 72.67 vs 86.1). Although the nature of floating elbow injuries is complex, the presence of nerve injury and intra-articular involvement predispose to worse clinical outcomes. Copyright © 2013 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Mosby, Inc. All rights reserved.

Effect of Right Insular Involvement on Death and Functional Outcome After Acute Ischemic Stroke in the IST-3 Trial (Third International Stroke Trial).

PubMed

Sposato, Luciano A; Cohen, Geoffrey; Wardlaw, Joanna M; Sandercock, Peter; Lindley, Richard I; Hachinski, Vladimir

2016-12-01

In patients with acute ischemic stroke, whether involvement of the insular cortex influences outcome is controversial. Much of the apparent adverse outcome may relate to such strokes usually being severe. We examined the influence of right and left insular involvement on stroke outcomes among patients from the IST-3 study (Third International Stroke Trial) who had visible ischemic stroke on neuroimaging. We used multiple logistic regression to compare outcomes of left versus right insular and noninsular strokes across strata of stroke severity, on death, proportion dead or dependent, and level of disability (ordinalized Oxford Handicap Score) at 6 months, with adjustment for the effects of age, lesion size, and presence of atrial fibrillation. Of 3035 patients recruited, 2099 had visible ischemic strokes limited to a single hemisphere on computed tomography/magnetic resonance scans. Of these, 566 and 714 had infarction of right and left insula. Six months after randomization, right insular involvement was associated with increased odds of death when compared with noninsular strokes on the left side (adjusted odds ratio, 1.83; 95% confidence interval, 1.33-2.52), whereas the adjusted odds ratio comparing mortality after insular versus noninsular strokes on the left side was not significant. Among mild/moderate strokes, outcomes for right insular involvement were worse than for left insular, but among more severe strokes, the difference in outcomes was less substantial. We found an association between right insular involvement and higher odds of death and worse functional outcome. The difference between right- and left-sided insular lesions on outcomes seemed to be most evident for mild/moderate strokes. URL: http://www.isrctn.com. Unique identifier: ISRCTN25765518. © 2016 American Heart Association, Inc.

Increasing number of fractured ribs is not predictive of the severity of splenic injury following blunt trauma: an analysis of a National Trauma Registry database.

PubMed

Boris, Kessel; Forat, Swaid; Itamar, Ashkenazi; Oded, Olsha; Kobi, Peleg; Adi, Givon; Igor, Jeroukhimov; Ricardo, Alfici

2014-05-01

Association between rib fractures and incidence of abdominal solid organs injury is well described. However, the correlation between the number of fractured ribs and severity of splenic injury is not clear. The purpose of this study was to assess whether an increasing number of rib fractures predicts the severity of splenic injury in blunt trauma patients. A retrospective cohort study involving blunt trauma patients with concomitant splenic injuries and rib fractures, between the years 1998 and 2012, registered in the Israeli National Trauma Registry. Of 321,618 patients with blunt mechanism of trauma, 57,130 had torso injuries, and of these 14,651 patients sustained rib fractures, and 3691 patients suffered from splenic injury. Concomitant splenic injury occurred in 1326 of the patients with rib fractures (9.1%), as compared to 2365 patients sustaining splenic injury without rib fractures (5.6%). The incidence of splenic injury among patients sustaining 5 or more rib fractures was significantly higher compared to patients suffering from 1 to 4 rib fractures. Among patients with splenic injury, the tendency to sustain associated rib fractures increased steadily with age. Patients with concomitant rib fractures had higher Injury Severity Score (ISS), but similar mortality rates, compared to patients with splenic injury without rib fractures. Among patients with concomitant rib fractures and splenic injury, there was no relation between the number of fractured ribs and the severity of splenic injury, neither as a whole group, nor after stratification according to the mechanism of injury. Although the presence of rib fractures increases the probability of splenic injury in blunt torso trauma, there is no relation between the number of fractured ribs and splenic injury severity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Analysis of drug-drug interactions among patients receiving antiretroviral regimens using data from a large open-source prescription database.

PubMed

Patel, Nimish; Borg, Peter; Haubrich, Richard; McNicholl, Ian

2018-06-14

Results of a study of contraindicated concomitant medication use among recipients of preferred antiretroviral therapy (ART) regimens are reported. A retrospective study was conducted to evaluate concomitant medication use in a cohort of previously treatment-naive, human immunodeficiency virus (HIV)-infected U.S. patients prescribed preferred ART regimens during the period April 2014-March 2015. Data were obtained from a proprietary longitudinal prescription database; elements retrieved included age, sex, and prescription data. The outcome of interest was the frequency of drug-drug interactions (DDIs) associated with concomitant use of contraindicated medications. Data on 25,919 unique treatment-naive patients who used a preferred ART regimen were collected. Overall, there were 384 instances in which a contraindicated medication was dispensed for concurrent use with a recommended ART regimen. Rates of contraindicated concomitant medication use differed significantly by ART regimen; the highest rate (3.2%) was for darunavir plus ritonavir plus emtricitabine-tenofovir disoproxil fumarate (DRV plus RTV plus FTC/TDF), followed by elvitegravir-cobicistat-emtricitabine-tenofovir disoproxil fumarate (EVG/c/FTC/TDF)(2.8%). The highest frequencies of DDIs were associated with ART regimens that included a pharmacoenhancing agent: DRV plus RTV plus FTC/TDF (3.2%) and EVG/c/FTC/TDF (2.8%). In a large population of treatment-naive HIV-infected patients, ART regimens that contained a pharmacoenhancing agent were involved most frequently in contraindicated medication-related DDIs. All of the DDIs could have been avoided by using therapeutic alternatives within the same class not associated with a DDI. Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

The aqueous extract of Hibiscus sabdariffa calices modulates the production of monocyte chemoattractant protein-1 in humans.

PubMed

Beltrán-Debón, R; Alonso-Villaverde, C; Aragonès, G; Rodríguez-Medina, I; Rull, A; Micol, V; Segura-Carretero, A; Fernández-Gutiérrez, A; Camps, J; Joven, J

2010-03-01

Diet supplementation and/or modulation is an important strategy to significantly improve human health. The search of plants as additional sources of bioactive phenolic compounds is relevant in this context. The aqueous extract of Hibiscus sabdariffa is rich in anthocyanins and other phenolic compounds including hydroxycitric and chlorogenic acids. Using this extract we have shown an effective protection of cultured peripheral blood mononuclear cells from the cellular death induced by H(2)O(2) and a significant role in the production of inflammatory cytokines. In vitro, the extract promotes the production of IL-6 and IL-8 and decreases the concentration of MCP-1 in supernatants in a dose-dependent manner. In humans, the ingestion of an acute dose of the extract (10g) was well tolerated and decreased plasma MCP-1 concentrations significantly without further effects on other cytokines. This effect was not due to a concomitant increase in the antioxidant capacity of plasma. Instead, its mechanisms probably involve a direct inhibition of inflammatory and/or metabolic pathways responsible for MCP-1 production, and may be relevant in inflammatory and chronic conditions in which the role of MCP-1 is well established. If beneficial effects are confirmed in patients, Hibiscus sabdariffa could be considered a valuable traditional herbal medicine for the treatment of chronic inflammatory diseases with the advantage of being devoid of caloric value or potential alcohol toxicity. Copyright 2009 Elsevier GmbH. All rights reserved.

Bacopa monnieri Extract (CDRI-08) Modulates the NMDA Receptor Subunits and nNOS-Apoptosis Axis in Cerebellum of Hepatic Encephalopathy Rats

PubMed Central

Mondal, Papia; Trigun, Surendra Kumar

2015-01-01

Hepatic encephalopathy (HE), characterized by impaired cerebellar functions during chronic liver failure (CLF), involves N-methyl-D-aspartate receptor (NMDAR) overactivation in the brain cells. Bacopa monnieri (BM) extract is a known neuroprotectant. The present paper evaluates whether BM extract is able to modulate the two NMDAR subunits (NR2A and NR2B) and its downstream mediators in cerebellum of rats with chronic liver failure (CLF), induced by administration of 50 mg/kg bw thioacetamide (TAA) i.p. for 14 days, and in the TAA group rats orally treated with 200 mg/kg bw BM extract from days 8 to 14. NR2A is known to impart neuroprotection and that of NR2B induces neuronal death during NMDAR activation. Neuronal nitric oxide synthase- (nNOS-) apoptosis pathway is known to mediate NMDAR led excitotoxicity. The level of NR2A was found to be significantly reduced with a concomitant increase of NR2B in cerebellum of the CLF rats. This was consistent with significantly enhanced nNOS expression, nitric oxide level, and reduced Bcl2/Bax ratio. Moreover, treatment with BM extract reversed the NR2A/NR2B ratio and also normalized the levels of nNOS-apoptotic factors in cerebellum of those rats. The findings suggest modulation of NR2A and NR2B expression by BM extract to prevent neurochemical alterations associated with HE. PMID:26413124

Major role of the PI3K/Akt pathway in ischemic tolerance induced by sublethal oxygen-glucose deprivation in cortical neurons in vitro.

PubMed

Bhuiyan, Mohammad Iqbal Hossain; Jung, Seo Yun; Kim, Hyoung Ja; Lee, Yong Sup; Jin, Changbae

2011-06-01

Ischemic preconditioning can provide protection to neurons from subsequent lethal ischemia. The molecular mechanisms of neuronal ischemic tolerance, however, are still not well-known. The present study, therefore, examined the role of MAPK and PI3K/Akt pathways in ischemic tolerance induced by preconditioning with sublethal oxygen-glucose deprivation (OGD) in cultured rat cortical neurons. Ischemic tolerance was simulated by preconditioning of the neurons with sublethal 1-h OGD imposed 12 h before lethal 3-h OGD. The time-course studies of relative phosphorylation and expression levels of ERK1/2, JNK and p38 MAPK showed lack of their involvement in ischemic tolerance. However, there were significant increases in Akt phosphorylation levels during the reperfusion period following preconditioned lethal OGD. In addition, Bcl-2 associated death promoter (Bad) and GSK-3β were also found to be inactivated during that reperfusion period. Finally, treatment with an inhibitor of PI3K, wortmannin, applied from 15 min before and during lethal OGD abolished not only the preconditioning-induced neuroprotection but also the Akt activation. Concomitant with blockade of the Akt activation, PI3K inhibition also resulted in activation of Bad and GSK-3β. The results suggest that ischemic tolerance induced by sublethal OGD preconditioning is primarily mediated through activation of the PI3K/Akt pathway, but not the MAPK pathway, in rat cortical neurons.

Thyroid hormone suppresses hepatocarcinogenesis via DAPK2 and SQSTM1-dependent selective autophagy.

PubMed

Chi, Hsiang-Cheng; Chen, Shen-Liang; Tsai, Chung-Ying; Chuang, Wen-Yu; Huang, Ya-Hui; Tsai, Ming-Ming; Wu, Sheng-Ming; Sun, Cheng-Pu; Yeh, Chau-Ting; Lin, Kwang-Huei

2016-12-01

Recent studies have demonstrated a critical association between disruption of cellular thyroid hormone (TH) signaling and the incidence of hepatocellular carcinoma (HCC), but the underlying mechanisms remain largely elusive. Here, we showed that disruption of TH production results in a marked increase in progression of diethylnitrosamine (DEN)-induced HCC in a murine model, and conversely, TH administration suppresses the carcinogenic process via activation of autophagy. Inhibition of autophagy via treatment with chloroquine (CQ) or knockdown of ATG7 (autophagy-related 7) via adeno-associated virus (AAV) vectors, suppressed the protective effects of TH against DEN-induced hepatic damage and development of HCC. The involvement of autophagy in TH-mediated protection was further supported by data showing transcriptional activation of DAPK2 (death-associated protein kinase 2; a serine/threonine protein kinase), which enhanced the phosphorylation of SQSTM1/p62 (sequestosome 1) to promote selective autophagic clearance of protein aggregates. Ectopic expression of DAPK2 further attenuated DEN-induced hepatoxicity and DNA damage though enhanced autophagy, whereas, knockdown of DAPK2 displayed the opposite effect. The pathological significance of the TH-mediated hepatoprotective effect by DAPK2 was confirmed by the concomitant decrease in the expression of THRs and DAPK2 in matched HCC tumor tissues. Taken together, these findings indicate that TH promotes selective autophagy via induction of DAPK2-SQSTM1 cascade, which in turn protects hepatocytes from DEN-induced hepatotoxicity or carcinogenesis.

Structure and Mode-of-Action of the Two-Peptide (Class-IIb) Bacteriocins.

PubMed

Nissen-Meyer, Jon; Oppegård, Camilla; Rogne, Per; Haugen, Helen Sophie; Kristiansen, Per Eugen

2010-03-01

This review focuses on the structure and mode-of-action of the two-peptide (class-IIb) bacteriocins that consist of two different peptides whose genes are next to each other in the same operon. Optimal antibacterial activity requires the presence of both peptides in about equal amounts. The two peptides are synthesized as preforms that contain a 15-30 residue double-glycine-type N-terminal leader sequence that is cleaved off at the C-terminal side of two glycine residues by a dedicated ABC-transporter that concomitantly transfers the bacteriocin peptides across cell membranes. Two-peptide bacteriocins render the membrane of sensitive bacteria permeable to a selected group of ions, indicating that the bacteriocins form or induce the formation of pores that display specificity with respect to the transport of molecules. Based on structure-function studies, it has been proposed that the two peptides of two-peptide bacteriocins form a membrane-penetrating helix-helix structure involving helix-helix-interacting GxxxG-motifs that are present in all characterized two-peptide bacteriocins. It has also been suggested that the membrane-penetrating helix-helix structure interacts with an integrated membrane protein, thereby triggering a conformational alteration in the protein, which in turn causes membrane-leakage. This proposed mode-of-action is similar to the mode-of-action of the pediocin-like (class-IIa) bacteriocins and lactococcin A (a class-IId bacteriocin), which bind to a membrane-embedded part of the mannose phosphotransferase permease in a manner that causes membrane-leakage and cell death.

Fifty hertz extremely low-frequency magnetic field exposure elicits redox and trophic response in rat-cortical neurons.

PubMed

Di Loreto, Silvia; Falone, Stefano; Caracciolo, Valentina; Sebastiani, Pierluigi; D'Alessandro, Antonella; Mirabilio, Alessandro; Zimmitti, Vincenzo; Amicarelli, Fernanda

2009-05-01

Large research activity has raised around the mechanisms of interaction between extremely low-frequency magnetic fields (ELF-MFs) and biological systems. ELF-MFs may interfere with chemical reactions involving reactive oxygen species (ROS), thus facilitating oxidative damages in living cells. Cortical neurons are particularly susceptible to oxidative stressors and are also highly dependent on the specific factors and proteins governing neuronal development, activity and survival. The aim of the present work was to investigate the effects of exposures to two different 50 Hz sinusoidal ELF-MFs intensities (0.1 and 1 mT) in maturing rat cortical neurons' major anti-oxidative enzymatic and non-enzymatic cellular protection systems, membrane peroxidative damage, as well as growth factor, and cytokine expression pattern. Briefly, our results showed that ELF-MFs affected positively the cell viability and concomitantly reduced the levels of apoptotic death in rat neuronal primary cultures, with no significant effects on the main anti-oxidative defences. Interestingly, linear regression analysis suggested a positive correlation between reduced glutathione (GSH) and ROS levels in 1 mT MF-exposed cells. On this basis, our hypothesis is that GSH could play an important role in the antioxidant defence towards the ELF-MF-induced redox challenge. Moreover, the GSH-based cellular response was achieved together with a brain-derived neurotrophic factor over-expression as well as with the interleukin 1beta-dependent regulation of pro-survival signaling pathways after ELF-MF exposure.

Robotic vascular resections during Whipple procedure.

PubMed

Allan, Bassan J; Novak, Stephanie M; Hogg, Melissa E; Zeh, Herbert J

2018-01-01

Indications for resection of pancreatic cancers have evolved to include selected patients with involvement of peri-pancreatic vascular structures. Open Whipple procedures have been the standard approach for patients requiring reconstruction of the portal vein (PV) or superior mesenteric vein (SMV). Recently, high-volume centers are performing minimally invasive Whipple procedures with portovenous resections. Our institution has performed seventy robotic Whipple procedures with concomitant vascular resections. This report outlines our technique.

Aberrant Upregulation of Astroglial Ceramide Potentiates Oligodendrocyte Injury

PubMed Central

Kim, SunJa; Steelman, Andrew J.; Zhang, Yumin; Kinney, Hannah C.; Li, Jianrong

2015-01-01

Oligodendroglial injury is a pathological hallmark of many human white matter diseases, including multiple sclerosis and periventricular leukomalacia. Critical regulatory mechanisms of oligodendroglia destruction, however, remain incompletely understood. Ceramide, a bioactive sphingolipid pivotal to sphingolipid metabolism pathways, regulates cell death in response to diverse stimuli and has been implicated in neurodegenerative disorders. We report here that ceramide accumulates in reactive astrocytes in active lesions of multiple sclerosis and periventricular leukomalacia, as well as in animal models of demyelination. Serine palmitoyltransferase, the rate-limiting enzyme for ceramide de novo biosynthesis, was consistently upregulated in reactive astrocytes in the cuprizone mouse model of demyelination. Mass spectrometry confirmed the upregulation of specific ceramides during demyelination and revealed a concomitant increase of sphingosine as well as a suppression of sphingosine-1-phosphate, a potent signaling molecule with key roles in cell survival and mitogenesis. Importantly, this altered sphingolipid metabolism during demyelination was restored upon active remyelination. In culture, ceramide acted synergistically with tumor necrosis factor leading to apoptotic death of oligodendroglia in an astrocyte-dependent manner. Taken together, our findings implicate that disturbed sphingolipid pathways in reactive astrocytes may indirectly contribute to oligodendroglial injury in cerebral white matter disorders. PMID:21615590

Fipronil is a powerful uncoupler of oxidative phosphorylation that triggers apoptosis in human neuronal cell line SHSY5Y.

PubMed

Vidau, Cyril; González-Polo, Rosa A; Niso-Santano, Mireia; Gómez-Sánchez, Rubén; Bravo-San Pedro, José M; Pizarro-Estrella, Elisa; Blasco, Rafael; Brunet, Jean-Luc; Belzunces, Luc P; Fuentes, José M

2011-12-01

Fipronil is a phenylpyrazole insecticide known to elicit neurotoxicity via an interaction with ionotropic receptors, namely GABA and glutamate receptors. Recently, we showed that fipronil and other phenylpyrazole compounds trigger cell death in Caco-2 cells. In this study, we investigated the mode of action and the type of cell death induced by fipronil in SH-SY5Y human neuroblastoma cells. Flow cytometric and western blot analyses demonstrated that fipronil induces cellular events belonging to the apoptosis process, such as mitochondrial potential collapse, cytochrome c release, caspase-3 activation, nuclear condensation and phosphatidylserine externalization. In addition, fipronil induces a rapid ATP depletion with concomitant activation of anaerobic glycolysis. This cellular response is characteristic of mitochondrial injury associated with a defect of the respiration process. Therefore, we also investigated the effect of fipronil on the oxygen consumption in isolated mitochondria. Interestingly, we show for the first time that fipronil is a strong uncoupler of oxidative phosphorylation at relative low concentrations. Thus in this study, we report a new mode of action by which the insecticide fipronil could triggers apoptosis. Copyright © 2011 Elsevier Inc. All rights reserved.

Curcumin inhibits cellular condensation and alters microfilament organization during chondrogenic differentiation of limb bud mesenchymal cells.

PubMed

Kim, Dong Kyun; Kim, Song Ja; Kang, Shin Sung; Jin, Eun Jung

2009-09-30

Curcumin is a well known natural polyphenol product isolated from the rhizome of the plant Curcuma longa, anti-inflammatory agent for arthritis by inhibiting synthesis of inflammatory prostaglandins. However, the mechanisms by which curcumin regulates the functions of chondroprogenitor, such as proliferation, precartilage condensation, cytoskeletal organization or overall chondrogenic behavior, are largely unknown. In the present report, we investigated the effects and signaling mechanism of curcumin on the regulation of chondrogenesis. Treating chick limb bud mesenchymal cells with curcumin suppressed chondrogenesis by stimulating apoptotic cell death. It also inhibited reorganization of the actin cytoskeleton into a cortical pattern concomitant with rounding of chondrogenic competent cells and down-regulation of integrin beta1 and focal adhesion kinase (FAK) phosphorylation. Curcumin suppressed the phosphorylation of Akt leading to Akt inactivation. Activation of Akt by introducing a myristoylated, constitutively active form of Akt reversed the inhibitory actions of curcumin during chondrogenesis. In summary, for the first time, we describe biological properties of curcumin during chondrogenic differentiation of chick limb bud mesenchymal cells. Curcumin suppressed chondrogenesis by stimulating apoptotic cell death and down-regulating integrin-mediated reorganization of actin cytoskeleton via modulation of Akt signaling.

Characterization of human dopamine responsive protein DRG-1 that binds to p75NTR-associated cell death executor NADE.

PubMed

Yu, Yao; Wang, Jiadong; Yuan, Hanying; Qin, Feng; Wang, Jing; Zhang, Nailing; Li, Yu-Yang; Liu, Jianping; Lu, Hong

2006-07-19

Expression of human dopamine responsive gene-1 (DRG-1) is up-regulated in response to treatment of dopamine in the rat astrocytes. However, its functions are not clear up to now. In the presented studies, DRG-1 was identified to be a conserved gene in the vertebrate and expressed abundantly in human testis, brain and skeletal muscle. DRG-1 was shown to interact with human p75NTR-associated cell death executor (NADE) in vivo and in vitro, and the interaction occurred in cytoplasm. The regions required for the interaction were subsequently mapped to the N-terminal of DRG-1 and the C-terminal of NADE. Furthermore, MTT assay showed that stable expression of DRG-1 in 293 cells could promote cell proliferation, and this promotion was suppressed by overexpression of NADE. In flow cytometry cell cycle analysis, overexpression of DRG-1 in 293 or PC12 cells increased the population of cells in the S phase with a concomitant decrease in G0/G1 population. These findings suggest that DRG-1 may contribute to the dopamine-induced cell growth, which is negatively regulated by NADE.

Cleavage and shedding of E-cadherin after induction of apoptosis.

PubMed

Steinhusen, U; Weiske, J; Badock, V; Tauber, R; Bommert, K; Huber, O

2001-02-16

Apoptotic cell death induces dramatic molecular changes in cells, becoming apparent on the structural level as membrane blebbing, condensation of the cytoplasm and nucleus, and loss of cell-cell contacts. The activation of caspases is one of the fundamental steps during programmed cell death. Here we report a detailed analysis of the fate of the Ca(2+)-dependent cell adhesion molecule E-cadherin in apoptotic epithelial cells and show that during apoptosis fragments of E-cadherin with apparent molecular masses of 24, 29, and 84 kDa are generated by two distinct proteolytic activities. In addition to a caspase-3-mediated cleavage releasing the cytoplasmic domain of E-cadherin, a metalloproteinase sheds the extracellular domain from the cell surface during apoptosis. Immunofluorescence analysis confirmed that concomitant with the disappearance of E-cadherin staining at the cell surface, the E-cadherin cytoplasmic domain accumulates in the cytosol. In the presence of inhibitors of caspase-3 and/or metalloproteinases, cleavage of E-cadherin was almost completely blocked. The simultaneous cleavage of the intracellular and extracellular domains of E-cadherin may provide a highly efficient mechanism to disrupt cadherin-mediated cell-cell contacts in apoptotic cells, a prerequisite for cell rounding and exit from the epithelium.

Mutant PFN1 causes ALS phenotypes and progressive motor neuron degeneration in mice by a gain of toxicity

PubMed Central

Yang, Chunxing; Danielson, Eric W.; Qiao, Tao; Metterville, Jake; Brown, Robert H.; Landers, John E.; Xu, Zuoshang

2016-01-01

Mutations in the profilin 1 (PFN1) gene cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease caused by the loss of motor neurons leading to paralysis and eventually death. PFN1 is a small actin-binding protein that promotes formin-based actin polymerization and regulates numerous cellular functions, but how the mutations in PFN1 cause ALS is unclear. To investigate this problem, we have generated transgenic mice expressing either the ALS-associated mutant (C71G) or wild-type protein. Here, we report that mice expressing the mutant, but not the wild-type, protein had relentless progression of motor neuron loss with concomitant progressive muscle weakness ending in paralysis and death. Furthermore, mutant, but not wild-type, PFN1 forms insoluble aggregates, disrupts cytoskeletal structure, and elevates ubiquitin and p62/SQSTM levels in motor neurons. Unexpectedly, the acceleration of motor neuron degeneration precedes the accumulation of mutant PFN1 aggregates. These results suggest that although mutant PFN1 aggregation may contribute to neurodegeneration, it does not trigger its onset. Importantly, these experiments establish a progressive disease model that can contribute toward identifying the mechanisms of ALS pathogenesis and the development of therapeutic treatments. PMID:27681617

Polyphenols of virgin coconut oil prevent pro-oxidant mediated cell death.

PubMed

Illam, Soorya Parathodi; Narayanankutty, Arunaksharan; Raghavamenon, Achuthan C

2017-07-01

Virgin coconut oil (VCO), extracted from the fresh coconut kernel, is a food supplement enriched with medium chain saturated fatty acids and polyphenolic antioxidants. It is reported to have several health benefits including lipid lowering, antioxidant and anti-inflammatory activities. The pharmacological benefits of VCO have been attributed to its polyphenol content (VCOP), the mechanistic basis of which is less explored. Liquid chromatography/mass spectroscopy (LC/MS) analysis of VCOP documented the presence of gallic acid, ferulic acid (FA), quercetin, methyl catechin, dihydrokaempferol and myricetin glycoside. Pre-treatment of VCOP at different concentrations (25-100 μg/mL) significantly reduced the H 2 O 2 and 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) induced cell death in HCT-15 cells. Giving further insight to its mechanistic basis, oxidative stress induced alterations in glutathione (GSH) levels and activities of GR (Glutathione-Reductase), GPx (Glutathione-Peroxidase), GST (Glutathione-S-Transferase) and catalase (CAT) were restored to near-normal by VCOP, concomitantly reducing lipid peroxidation. The efficacy of VCOP was similar to that of Trolox and FA added in culture. The study thus suggests that VCOP protects cells from pro-oxidant insults by modulating cellular antioxidant status.

Aerobic function in mitochondria persists beyond death by heat stress in insects.

PubMed

Heinrich, Erica C; Gray, Emilie M; Ossher, Ashley; Meigher, Stephen; Grun, Felix; Bradley, Timothy J

2017-10-01

The critical thermal maximum (CT max ) of insects can be determined using flow-through thermolimit respirometry. It has been demonstrated that respiratory patterns cease and insects do not recover once the CT max temperature has been reached. However, if high temperatures are maintained following the CT max , researchers have observed a curious phenomenon whereby the insect body releases a large burst of carbon dioxide at a rate and magnitude that often exceed that of the live insect. This carbon dioxide release has been termed the post-mortal peak (PMP). We demonstrate here that the PMP is observed only at high temperatures, is oxygen-dependent, is prevented by cyanide exposure, and is associated with concomitant consumption of oxygen. We conclude that the PMP derives from highly active, aerobic metabolism in the mitochondria. The insect tracheal system contains air-filled tubes that reach deep into the tissues and allow mitochondria access to oxygen even upon organismal death. This unique condition permits the investigation of mitochondrial function during thermal failure in a manner that cannot be achieved using vertebrate organisms or in vitro preparations. Copyright © 2017 Elsevier Ltd. All rights reserved.

TCDD decreases ATP levels and increases reactive oxygen production through changes in mitochondrial F F{sub 1}-ATP synthase and ubiquinone

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shertzer, Howard G.; Genter, Mary Beth; Shen, Dongxiao

2006-12-15

Mitochondria generate ATP and participate in signal transduction and cellular pathology and/or cell death. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) decreases hepatic ATP levels and generates mitochondrial oxidative DNA damage, which is exacerbated by increasing mitochondrial glutathione redox state and by inner membrane hyperpolarization. This study identifies mitochondrial targets of TCDD that initiate and sustain reactive oxygen production and decreased ATP levels. One week after treating mice with TCDD, liver ubiquinone (Q) levels were significantly decreased, while rates of succinoxidase and Q-cytochrome c oxidoreductase activities were increased. However, the expected increase in Q reduction state following TCDD treatment did not occur; instead, Q wasmore » more oxidized. These results could be explained by an ATP synthase defect, a premise supported by the unusual finding that TCDD lowers ATP/O ratios without concomitant changes in respiratory control ratios. Such results suggest either a futile cycle in ATP synthesis, or hydrolysis of newly synthesized ATP prior to release. The TCDD-mediated decrease in Q, concomitant with an increase in respiration, increases complex 3 redox cycling. This acts in concert with glutathione to increase membrane potential and reactive oxygen production. The proposed defect in ATP synthase explains both the greater respiratory rates and the lower tissue ATP levels.« less

Impact of Concomitant Chemotherapy on Outcomes of Radiation Therapy for Head-and-Neck Cancer: A Population-Based Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gupta, Shlok; Kong, Weidong; Booth, Christopher M.

2014-01-01

Purpose: Clinical trials have shown that the addition of chemotherapy to radiation therapy (RT) improves survival in advanced head-and-neck cancer. The objective of this study was to describe the effectiveness of concomitant chemoradiation therapy (C-CRT) in routine practice. Methods and Materials: This was a population-based cohort study. Electronic records of treatment from all provincial cancer centers were linked to a population--based cancer registry to describe the adoption of C-CRT for head-and-neck cancer patients in Ontario, Canada. The study population was then divided into pre- and postadoption cohorts, and their outcomes were compared. Results: Between 1992 and 2008, 18,867 patients hadmore » diagnoses of head-and-neck cancer in Ontario, of whom 7866 (41.7%) were treated with primary RT. The proportion of primary RT cases that received C-CRT increased from 2.2% in the preadoption cohort (1992-1998) to 39.3% in the postadoption cohort (2003-2008). Five-year survival among all primary RT cases increased from 43.6% in the preadoption cohort to 51.8% in the postadoption cohort (P<.001). Over the same period, treatment-related hospital admissions increased significantly, but there was no significant increase in treatment-related deaths. Conclusions: C-CRT was widely adopted in Ontario after 2003, and its adoption was temporally associated with an improvement in survival.« less

Video-assisted thoracoscopic lobectomy after percutaneous coronary intervention in lung cancer patients with concomitant coronary heart disease.

PubMed

Li, Xin; Fu, YiLi; Miao, JinBai; Li, Hui; Hu, Bin

2017-09-01

In recent years, based on clinical observations, the number of lung cancer patients with concomitant coronary heart disease (CHD) has gradually increased. However, because of the requirement of long-term anticoagulant therapy after percutaneous coronary intervention (PCI), some of these patients lose the opportunity for surgical treatment, resulting in tumor progression. The objective of this study was to determine the appropriate timing of video-assisted thoracic surgery (VATS) lobectomy after PCI without increasing perioperative cardiovascular risk. This study retrospectively analyzed clinical data of patients with a combination of NSCLC and CHD who underwent selective pulmonary lobectomy by VATS in the early postoperative PCI period between 2010 and 2015 at Beijing Chaoyang Hospital, China. Fourteen patients received VATS lobectomy after PCI. The disease had progressed to T stage in two patients after PCI. No perioperative death occurred. Two patients suffered postoperative atrial fibrillation: one had a pulmonary infection, and the other had acute coronary syndrome. All patients recovered and were discharged. For NSCLC patients with severe CHD, the use of VATS lobectomy in the early postoperative PCI period could not only advance the timing of surgery, but may also control perioperative hemorrhage and CHD event risks within acceptable ranges, which could provide more patients with an opportunity to undergo surgical treatment. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

Aortic valve replacement using continuous suture technique in patients with aortic valve disease.

PubMed

Choi, Jong Bum; Kim, Jong Hun; Park, Hyun Kyu; Kim, Kyung Hwa; Kim, Min Ho; Kuh, Ja Hong; Jo, Jung Ku

2013-08-01

The continuous suture (CS) technique has several advantages as a method for simple, fast, and secure aortic valve replacement (AVR). We used a simple CS technique without the use of a pledget for AVR and evaluated the surgical outcomes. Between October 2007 and 2012, 123 patients with aortic valve disease underwent AVR alone (n=28) or with other concomitant cardiac procedures (n=95), such as mitral, tricuspid, or aortic surgery. The patients were divided into two groups: the interrupted suture (IS) group (n=47), in which the conventional IS technique was used, and the CS group (n=76), in which the simple CS technique was used. There were two hospital deaths (1.6%), which were not related to the suture technique. There were no significant differences in cardiopulmonary bypass time or aortic cross-clamp time between the two groups for AVR alone or AVR with concomitant cardiac procedures. In the IS group, two patients had prosthetic endocarditis and one patient experienced significant perivalvular leak. These patients underwent reoperations. In the CS group, there were no complications related to the surgery. Postoperatively, the two groups had similar aortic valve gradients. The simple CS method is useful and secure for AVR in patients with aortic valve disease, and it may minimize surgical complications, as neither pledgets nor braided sutures are used.

B-type natriuretic peptides. A diagnostic breakthrough in heart failure.

PubMed

McCullough, P A

2003-04-01

B-type natriuretic peptide (BNP) is a neurohormone synthesized in the cardiac ventricles, which is released as N-terminal pro-brain natriuretic peptide (NT-proBNP) and then enzymatically cleaved in to the NT fragment and the immunoreactive BNP. Both tests have been used to identify patients with congestive heart failure (CHF). Important considerations for these tests include their half-lives in plasma, dependence on renal function for clearance, and the interpretation of their units of measure. In general, a BNP level below 100 pg/mL has strong negative predictive value in the assessment of patients with dyspnea caused by a disorder other than CHF. In addition, BNP levels can be used to gauge the effect of short-term treatment of acutely decompensated heart failure, and the peptide has been shown to be a reliable independent predictor of sudden cardiac death. In the absence of renal dysfunction NT-proBNP has also been shown to be an independent predictor of sudden death in CHF patients. Because both a large area of myonecrosis or concomitant left ventricular failure are related to prognosis in acute coronary syndromes, B-type natriuretic peptides have also been linked to outcomes in this condition. This article describes the physiology and timing of release of B-type natriuretic peptides and the rationale for their use in the following settings: 1) evaluation of decompensated CHF, 2) screening for chronic CHF, 3) prognosis of CHF and sudden death, and 4) prognosis in acute coronary syndromes with inferred left ventricular dysfunction.

Sepsis in acute myeloid leukaemia patients receiving high-dose chemotherapy: no impact of chitotriosidase and mannose-binding lectin polymorphisms.

PubMed

Klostergaard, Anja; Steffensen, Rudi; Møller, Jens K; Peterslund, Niels; Juhl-Christensen, Caroline; Mølle, Ingolf

2010-07-01

Infections after chemotherapy often cause significant morbidity in patients with acute myeloid leukaemia (AML). Chitotriosidase (CHIT) and mannose-binding lectin (MBL) are part of the innate immune system. Polymorphism in the CHIT-coding gene (CHIT1) may be associated with Gram-negative sepsis in children with AML, and polymorphism in the MBL-coding gene (MBL2) seems to modify the risk of infections in several patient groups. The purpose of this study was to investigate the possible associations between polymorphisms in CHIT1, MBL2 and sepsis in adult patients treated with high-dose chemotherapy for AML. We included 190 patients treated with 526 cycles of chemotherapy. The follow-up period was 6 months from the diagnosis of AML. Prophylactic antibiotics were not used. We identified 604 febrile episodes with 246 episodes of sepsis. Thirty-two patients (17%) either died from infection or infection was a major concomitant factor for death. No significant associations between CHIT1 polymorphism and sepsis (P = 0.85) or death caused by sepsis (P = 0.14) were found. Furthermore, no significant associations between MBL2 polymorphism and sepsis (P = 0.76) or death caused by sepsis (P = 0.24) were observed. The severe and long-lasting neutropenia and mucositis after chemotherapy may explain why the MBL system does not protect against sepsis in patients with AML. Replacement therapy with recombinant MBL is not likely to decrease the risk of sepsis in patients with AML.

Spatiotemporal modeling of laser tissue soldering using photothermal nanocomposites.

PubMed

Mushaben, Madaline; Urie, Russell; Flake, Tanner; Jaffe, Michael; Rege, Kaushal; Heys, Jeffrey

2018-02-01

Laser tissue soldering using photothermal solders is a technology that facilitates rapid sealing using heat-induced changes in the tissue and the solder material. The solder material is made of gold nanorods embedded in a protein matrix patch that can be placed over the tissue rupture site and heated with a laser. Although laser tissue soldering is an attractive approach for surgical repair, potential photothermal damage can limit the success of this approach. Development of predictive mathematical models of photothermal effects including cell death, can lead to more efficient approaches in laser-based tissue repair. We describe an experimental and modeling investigation into photothermal solder patches for sealing porcine and mouse cadaver intestine sections using near-infrared laser irradiation. Spatiotemporal changes in temperature were determined at the surface as well as various depths below the patch. A mathematical model, based on the finite element method, predicts the spatiotemporal temperature distribution in the patch and surrounding tissue, as well as concomitant cell death in the tissue is described. For both the porcine and mouse intestine systems, the model predicts temperatures that are quantitatively similar to the experimental measurements with the model predictions of temperature increase often being within a just a few degrees of experimental measurements. This mathematical model can be employed to identify optimal conditions for minimizing healthy cell death while still achieving a strong seal of the ruptured tissue using laser soldering. Lasers Surg. Med. 50:143-152, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Nature of Medical Malpractice Claims Against Radiation Oncologists.

PubMed

Marshall, Deborah; Tringale, Kathryn; Connor, Michael; Punglia, Rinaa; Recht, Abram; Hattangadi-Gluth, Jona

2017-05-01

To examine characteristics of medical malpractice claims involving radiation oncologists closed during a 10-year period. Malpractice claims filed against radiation oncologists from 2003 to 2012 collected by a nationwide liability insurance trade association were analyzed. Outcomes included the nature of claims and indemnity payments, including associated presenting diagnoses, procedures, alleged medical errors, and injury severity. We compared the likelihood of a claim resulting in payment in relation to injury severity categories (death as referent) using binomial logistic regression. There were 362 closed claims involving radiation oncology, 102 (28%) of which were paid, resulting in $38 million in indemnity payments. The most common alleged errors included "improper performance" (38% of closed claims, 18% were paid; 29% [$11 million] of total indemnity), "errors in diagnosis" (25% of closed claims, 46% were paid; 44% [$17 million] of total indemnity), and "no medical misadventure" (14% of closed claims, 8% were paid; less than 1% [$148,000] of total indemnity). Another physician was named in 32% of claims, and consent issues/breach of contract were cited in 18%. Claims for injury resulting in death represented 39% of closed claims and 25% of total indemnity. "Improper performance" was the primary alleged error associated with injury resulting in death. Compared with claims involving death, major temporary injury (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.29-5.85, P=.009), significant permanent injury (OR 3.1, 95% CI 1.48-6.46, P=.003), and major permanent injury (OR 5.5, 95% CI 1.89-16.15, P=.002) had a higher likelihood of a claim resulting in indemnity payment. Improper performance was the most common alleged malpractice error. Claims involving significant or major injury were more likely to be paid than those involving death. Insights into the nature of liability claims against radiation oncologists may help direct efforts to improve quality of care and minimize the risk of being sued. Copyright © 2017 Elsevier Inc. All rights reserved.

Nature of Medical Malpractice Claims Against Radiation Oncologists

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marshall, Deborah; Tringale, Kathryn; Connor, Michael

Purpose: To examine characteristics of medical malpractice claims involving radiation oncologists closed during a 10-year period. Methods and Materials: Malpractice claims filed against radiation oncologists from 2003 to 2012 collected by a nationwide liability insurance trade association were analyzed. Outcomes included the nature of claims and indemnity payments, including associated presenting diagnoses, procedures, alleged medical errors, and injury severity. We compared the likelihood of a claim resulting in payment in relation to injury severity categories (death as referent) using binomial logistic regression. Results: There were 362 closed claims involving radiation oncology, 102 (28%) of which were paid, resulting in $38more » million in indemnity payments. The most common alleged errors included “improper performance” (38% of closed claims, 18% were paid; 29% [$11 million] of total indemnity), “errors in diagnosis” (25% of closed claims, 46% were paid; 44% [$17 million] of total indemnity), and “no medical misadventure” (14% of closed claims, 8% were paid; less than 1% [$148,000] of total indemnity). Another physician was named in 32% of claims, and consent issues/breach of contract were cited in 18%. Claims for injury resulting in death represented 39% of closed claims and 25% of total indemnity. “Improper performance” was the primary alleged error associated with injury resulting in death. Compared with claims involving death, major temporary injury (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.29-5.85, P=.009), significant permanent injury (OR 3.1, 95% CI 1.48-6.46, P=.003), and major permanent injury (OR 5.5, 95% CI 1.89-16.15, P=.002) had a higher likelihood of a claim resulting in indemnity payment. Conclusions: Improper performance was the most common alleged malpractice error. Claims involving significant or major injury were more likely to be paid than those involving death. Insights into the nature of liability claims against radiation oncologists may help direct efforts to improve quality of care and minimize the risk of being sued.« less

Catalytically active Yersinia outer protein P induces cleavage of RIP and caspase-8 at the level of the DISC independently of death receptors in dendritic cells.

PubMed

Gröbner, Sabine; Adkins, Irena; Schulz, Sebastian; Richter, Kathleen; Borgmann, Stefan; Wesselborg, Sebastian; Ruckdeschel, Klaus; Micheau, Olivier; Autenrieth, Ingo B

2007-10-01

Yersinia outer protein P (YopP) is injected by Y. enterocolitica into host cells thereby inducing apoptotic and necrosis-like cell death in dendritic cells (DC). Here we show the pathways involved in DC death caused by the catalytic activity of YopP. Infection with Yersinia enterocolitica, translocating catalytically active YopP into DC, triggered procaspase-8 cleavage and c-FLIPL degradation. YopP-dependent caspase-8 activation was, however, not mediated by tumor necrosis factor (TNF) receptor family members since the expression of both CD95/Fas/APO-1 and TRAIL-R2 on DC was low, and DC were resistant to apoptosis induced by agonistic anti-CD95 antibodies or TNF-related apoptosis-inducing ligand (TRAIL). Moreover, DC from TNF-Rp55-/- mice were not protected against YopP-induced cell death demonstrating that TNF-R1 is also not involved in this process. Activation of caspase-8 was further investigated by coimmunoprecitation of FADD from Yersinia-infected DC. We found that both cleaved caspase-8 and receptor interacting protein 1 (RIP1) were associated with the Fas-associated death domain (FADD) indicating the formation of an atypical death-inducing signaling complex (DISC). Furthermore, degradation of RIP mediated by the Hsp90 inhibitor geldanamycin significantly impaired YopP-induced cell death. Altogether our findings indicate that Yersinia-induced DC death is independent of death domain containing receptors, but mediated by RIP and caspase-8 at the level of DISC.

Reliability of postmortem fentanyl concentrations in determining the cause of death.

PubMed

Gill, James R; Lin, Peter T; Nelson, Lewis

2013-03-01

Transdermal fentanyl, an opioid used for management of marked pain, also is abused and may cause death. We reviewed medical examiner reports of 92 decedents who had one or more fentanyl transdermal patches on their body and had fentanyl detected in their postmortem toxicology analysis. The manners of death included 40 accidents, 36 natural, 8 suicides, 5 therapeutic complications, and 3 undetermined deaths. Among the accidental fentanyl intoxication deaths, 32 of 37 involved substance abuse. The majority (95 %) of the 37 accidental deaths involving fentanyl were multi-drug intoxications. The substance abuse deaths had a mean fentanyl blood concentration (26.4 ng/ml or μg/L) that was over twice that of the natural group (11.8 ng/ml). Our analysis suggests a relationship between total patch dosage and mean postmortem fentanyl concentration up to the 100-μg/h dose. The very wide and overlapping ranges of postmortem fentanyl concentrations effectively nullify the utility of correlating the dose and expected postmortem concentration for any particular death. Based on the variable relationship between dose and blood concentration, the antemortem dose cannot be reliably predicted based on the postmortem concentration. This does not, however, render the medical examiner/coroner unable to determine the cause and manner of death because the toxicology results are only one datum point among several that are considered. Although there was a weakly positive relationship between body mass index and fentanyl concentration, further research is needed to determine whether adipose tissue represents a significant depot for postmortem release of fentanyl.

Patterns of failure in patients with locally advanced head and neck cancer treated postoperatively with irradiation or concomitant irradiation with Mitomycin C and Bleomycin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zakotnik, Branko; Budihna, Marjan; Smid, Lojze

2007-03-01

Purpose: The long term results and patterns of failure in patients with squamous cell head and neck carcinoma (SCHNC) treated in a prospective randomized trial in which concomitant postoperative radiochemotherapy with Mitomycin C and Bleomycin (CRT) was compared with radiotherapy only (RT), were analyzed. Patients and Methods: Between March 1997 and December 2001, 114 eligible patients with Stage III or IV SCHNC were randomized. Primary surgical treatment was performed with curative intent in all patients. Patients in both groups were postoperatively irradiated to the total dose of 56-70 Gy. Chemotherapy included Mitomycin C 15 mg/m{sup 2} after 10 Gy andmore » 5 mg of Bleomycin twice weekly during irradiation. Median follow-up was 76 months (48-103 months). Results: At 5 years in the RT and CRT arms, the locoregional control was 65% and 88% (p = 0.026), disease-free survival 33% and 53% (p = 0.035), and overall survival 37% and 55% (p = 0.091) respectively. Patients who benefited from chemotherapy were those with high-risk factors. The probability of distant metastases was 22% in RT and 20% in CRT arm (p = 0.913), of grade III or higher late toxicity 19% in RT and 26% in CRT arm (p = 0.52) and of thyroid dysfunction 36% in RT and 56% in CRT arm (p = 0.24). The probability to develop a second primary malignancy (SPM) was 34% in the RT and 8% in the CRT arm (p = 0.023). One third of deaths were due to infection, but there was no difference between the 2 groups. Conclusion: With concomitant radiochemotherapy, locoregional control and disease free survival were significantly improved. Second primary malignancies in the CRT arm compared to RT arm were significantly less frequent. The high probability of post treatment hypothyroidism in both arms warrants regular laboratory evaluation.« less

Unintentional and undetermined firearm related deaths: a preventable death analysis for three safety devices

PubMed Central

Vernick, J; O'Brien, M; Hepburn, L; Johnson, S; Webster, D; Hargarten, S

2003-01-01

Objective: To determine the proportion of unintentional and undetermined firearm related deaths preventable by three safety devices: personalization devices, loaded chamber indicators (LCIs), and magazine safeties. A personalized gun will operate only for an authorized user, a LCI indicates when the gun contains ammunition, and a magazine safety prevents the gun from firing when the ammunition magazine is removed. Design: Information about all unintentional and undetermined firearm deaths from 1991–98 was obtained from the Office of the Chief Medical Examiner for Maryland, and from the Wisconsin Firearm Injury Reporting System for Milwaukee. Data regarding the victim, shooter, weapon, and circumstances were abstracted. Coding rules to classify each death as preventable, possibly preventable, or not preventable by each of the three safety devices were also applied. Results: There were a total of 117 firearm related deaths in our sample, 95 (81%) involving handguns. Forty three deaths (37%) were classified as preventable by a personalized gun, 23 (20%) by a LCI, and five (4%) by a magazine safety. Overall, 52 deaths (44%) were preventable by at least one safety device. Deaths involving children 0–17 (relative risk (RR) 3.3, 95% confidence interval (CI) 2.1 to 5.1) and handguns (RR 8.1, 95% CI 1.2 to 53.5) were more likely to be preventable. Projecting the findings to the entire United States, an estimated 442 deaths might have been prevented in 2000 had all guns been equipped with these safety devices. Conclusion: Incorporating safety devices into firearms is an important injury intervention, with the potential to save hundreds of lives each year. PMID:14693889

[Distribution of and changes in Danish traffic deaths].

PubMed

Bjerre, Johannes; Kirkebjerg, Peer Gregersen; Larsen, Lars Binderup

2006-05-01

Traffic accidents were the primary cause of death for Danes aged 15 to 24 years in 1999; per million inhabitants, that figure was 62% higher than in Great Britain. Reduction to the level in Great Britain would have reduced the number killed in traffic accidents in Denmark in 2002 from 465 to 289. The data used are from StatBank Denmark, the Danish Road Directorate and the Danish Transport Research Institute. The number of traffic deaths per billion kilometers driven was 57% higher in 1994 than in 2001. Those aged 65 and over had the largest decrease, with 67% fewer traffic deaths. Per billion kilometers driven, rural roads had around twice the number of traffic deaths as city streets and motorways. The geographic distribution showed few traffic deaths in the capital, Copenhagen, while the rest of the country had up to twice the number per 100,000 inhabitants from 1997 to 2002. Car drivers were well protected by seat belts, while people who were walking or on a motorcycle had high casualty rates per billion kilometers driven. 29% of the traffic deaths in Denmark in 2002 were registered as alcohol-related, while only 1% of drivers overall were influenced by alcohol. Men had twice the risk of traffic death compared with women per kilometer driven. Men were convicted in 93% of cases involving illegal blood alcohol level and 84% of cases involving other traffic offences. The greatest potential for reduction of traffic deaths seems to be traffic behaviour; females' behaviour, with rare drunk driving and few convictions for traffic offences, seems rational. If all drivers adhered to women's traffic behaviour, the number of road deaths in 1999 could have been reduced by 169, equivalent to 30%.

Conducted energy devices: pilot analysis of (non-)attributability of death using a modified Naranjo algorithm.

PubMed

Fox, Anthony W; Payne-James, J Jason

2012-11-30

Alleged fatalities associated with conductive-energy devices (CEDs) are similar to alleged serious adverse events (SAEs) after the use of pharmaceutical products: both types of case arise rarely, in complex (if not unique) combinations of circumstances, frequently when there are multiple concomitant putative aetiologies for the injury, and after the suspected product has been previously well-designed and tested. Attribution (or otherwise) of SAEs to pharmaceutical products is often assessed by use of the Naranjo algorithm. The purpose of this study was to investigate whether an adapted Naranjo algorithm could be used to assess alleged CED-associated fatalities. Unique cases had four independent identifiers. Prospectively, 7 (of the 10) Naranjo algorithm questions were chosen as being potentially applicable to CED use. These had maximum score 9, and the associated ordinal probability scale (doubtful, possible, probable, and definite) was retained by linear proportion to the integral scores. An arbitrary requirement was for database sufficiency≥50%=([n unique cases×7 questions answerable]×0.5); a pilot sample (n=29 unique cases) suggested feasibility (see below). One hundred and seventy-five unique cases were found, with a data sufficiency of 56.8%. Modified Naranjo algorithm scores had an unequally bimodal distribution. CED-attributability was suggested in 21 (12% of 175) cases. Substantial numbers of concomitant conditions existed among cases with low algorithm scores, all being potentially lethal under field conditions without CED exposure. The number of CED-administered shocks sustained was unrelated to CED-attributability of fatality. Two of the Naranjo questions (regarding dechallenge and the effects of challenge with a non-identical but similar agent) proved to be non-contributory. An algorithmic approach to assessment of CED-associated fatality seems feasible. By these pharmacovigilance standards, some published case fatality rates attributable to CED exposure seem exaggerated. CED-attributable deaths have close similarity to Type-B SAEs. The latter are rare, unpredictable, and usually due to a patient idiosyncrasy. In the person being restrained, such idiosyncratic factors may be unavoidable by law enforcement officers (LEO) in the field. These are unlike predictable (Type-A) SAEs, which have their corollary amongst secondary CED-associated deaths, e.g., head injury among cyclists or ignition of an inflammable atmosphere by the CED, and are identifiable risk factors for which LEO can train. Regardless, absolute CED tolerability is obviously greater than that for firearms. A prospective registry of CED deployments would measure this more precisely. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Plant a Potato--Learn about Life (and Death).

ERIC Educational Resources Information Center

Furman, Erna

1990-01-01

Discusses a method by which young children learn about life and death by studying plants. Plants are used because their life cycle has minimal emotional significance to the children. Parent involvement, teacher attitudes, and experiences with the method are discussed. (DG)

29 CFR 18.902 - Self-authentication.

Code of Federal Regulations, 2014 CFR

2014-07-01

..., estimates, and reports. In actions involving injury, illness, disease, death, disability, or physical or... injury, illness, disease, death, disability or physical or mental impairment, doctor, hospital... including a summary of experience as an expert witness in litigation, when including the basic facts, data...

29 CFR 18.902 - Self-authentication.

Code of Federal Regulations, 2013 CFR

2013-07-01

..., estimates, and reports. In actions involving injury, illness, disease, death, disability, or physical or... injury, illness, disease, death, disability or physical or mental impairment, doctor, hospital... including a summary of experience as an expert witness in litigation, when including the basic facts, data...

29 CFR 18.902 - Self-authentication.

Code of Federal Regulations, 2012 CFR

2012-07-01

..., estimates, and reports. In actions involving injury, illness, disease, death, disability, or physical or... injury, illness, disease, death, disability or physical or mental impairment, doctor, hospital... including a summary of experience as an expert witness in litigation, when including the basic facts, data...

29 CFR 18.902 - Self-authentication.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., estimates, and reports. In actions involving injury, illness, disease, death, disability, or physical or... injury, illness, disease, death, disability or physical or mental impairment, doctor, hospital... including a summary of experience as an expert witness in litigation, when including the basic facts, data...

29 CFR 18.902 - Self-authentication.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., estimates, and reports. In actions involving injury, illness, disease, death, disability, or physical or... injury, illness, disease, death, disability or physical or mental impairment, doctor, hospital... including a summary of experience as an expert witness in litigation, when including the basic facts, data...

Investigating the Mechanisms Underlying Neuronal Death in Ischemia Using In Vitro Oxygen-Glucose Deprivation: Potential Involvement of Protein SUMOylation

PubMed Central

CIMAROSTI, HELENA; HENLEY, JEREMY M.

2012-01-01

It is well established that brain ischemia can cause neuronal death via different signaling cascades. The relative importance and interrelationships between these pathways, however, remain poorly understood. Here is presented an overview of studies using oxygen-glucose deprivation of organotypic hippocampal slice cultures to investigate the molecular mechanisms involved in ischemia. The culturing techniques, setup of the oxygen-glucose deprivation model, and analytical tools are reviewed. The authors focus on SUMOylation, a posttranslational protein modification that has recently been implicated in ischemia from whole animal studies as an example of how these powerful tools can be applied and could be of interest to investigate the molecular pathways underlying ischemic cell death. PMID:19029060

Violacein Induces Death of Resistant Leukaemia Cells via Kinome Reprogramming, Endoplasmic Reticulum Stress and Golgi Apparatus Collapse

PubMed Central

Queiroz, Karla C. S.; Milani, Renato; Ruela-de-Sousa, Roberta R.; Fuhler, Gwenny M.; Justo, Giselle Z.; Zambuzzi, Willian F.; Duran, Nelson; Diks, Sander H.; Spek, C. Arnold; Ferreira, Carmen V.; Peppelenbosch, Maikel P.

2012-01-01

It is now generally recognised that different modes of programmed cell death (PCD) are intimately linked to the cancerous process. However, the mechanism of PCD involved in cancer chemoprevention is much less clear and may be different between types of chemopreventive agents and tumour cell types involved. Therefore, from a pharmacological view, it is crucial during the earlier steps of drug development to define the cellular specificity of the candidate as well as its capacity to bypass dysfunctional tumoral signalling pathways providing insensitivity to death stimuli. Studying the cytotoxic effects of violacein, an antibiotic dihydro-indolone synthesised by an Amazon river Chromobacterium, we observed that death induced in CD34+/c-Kit+/P-glycoprotein+/MRP1+ TF1 leukaemia progenitor cells is not mediated by apoptosis and/or autophagy, since biomarkers of both types of cell death were not significantly affected by this compound. To clarify the working mechanism of violacein, we performed kinome profiling using peptide arrays to yield comprehensive descriptions of cellular kinase activities. Pro-death activity of violacein is actually carried out by inhibition of calpain and DAPK1 and activation of PKA, AKT and PDK, followed by structural changes caused by endoplasmic reticulum stress and Golgi apparatus collapse, leading to cellular demise. Our results demonstrate that violacein induces kinome reprogramming, overcoming death signaling dysfunctions of intrinsically resistant human leukaemia cells. PMID:23071514

Vancomycin-associated acute kidney injury: A cross-sectional study from a single center in China

PubMed Central

Ma, Lingyun; Xiang, Qian; Li, Xueying; Li, Haixia; Zhou, Ying; Yang, Li; Cui, Yimin

2017-01-01

Objective The objective of this study was to investigate the current situation of vancomycin (VAN)-associated acute kidney injury (VA-AKI) in China and identify the risk factors for VA-AKI, as well as to comprehensively examine the risk related to concurrent drug use. Further, we assessed the outcomes of patients who developed VA-AKI and the risk factors for these outcomes. Finally, we aimed to provide suggestions for improving the prevention and treatment of VA-AKI in China. Methods We conducted a retrospective observational study of inpatients who had been treated with VAN between January 2013 and December 2013 at Peking University First Hospital. AKI was defined as an increase in SCr of ≥0.3 mg/dl (≥26.5 μmol/l) within 48 hours or an increase to ≥1.5 times the baseline certainly or presumably within the past 7 days. VA-AKI was defined as the development of AKI during VAN therapy or within 7 days following the termination of VAN therapy. In addition, we compared patients with NO-AKI, who did not develop AKI during their hospitalization, with those with VA-AKI. Results Of the 934 patients treated with VAN during their hospital stay, 740 were included in this study. Among those excluded, 38.1% (74/194) were excluded because of a lack of data on serum creatinine (SCr). Among the included patients, 120 had confirmed VA-AKI, with an incidence of 16.2% (120/740). Multiple logistic regression analysis revealed that an elevated baseline estimated glomerular filtration rate (eGFR) (odds ratio [OR] = 1.009; p = 0.017) and concomitant vasopressor therapy (OR = 2.942; p = 0.009), nitrate use (OR = 2.869; p = 0.007), imipenem-cilastatin treatment (OR = 4.708; p = 0.000), and contrast medium administration (OR = 6.609 p = 0.005) were independent risk factors for VA-AKI; in addition, the receipt of orthopedic/trauma/burn surgery (OR = 0.3575; p = 0.011) and concomitant compound glycyrrhizin use (OR = 0.290; p = 0.017) were independent protective factors for VA-AKI. Multiple logistic regression analysis also demonstrated that among the patients who developed VA-AKI, coronary heart disease (CHD) (OR = 12.6; p = 0.006) and concomitant vasopressor therapy (OR = 15.4; p = 0.001) were independent risk factors for death. We also evaluated the factors influencing improvement of renal function. Multiple logistic regression analysis demonstrated that CHD (OR = 8.858, p = 0.019) and concomitant contrast medium administration (OR = 9.779, p = 0.005) were independent risk factors and that simultaneous β-blocker treatment (OR = 0.124, p = 0.001) was an independent protective factor for improvement of renal function. Conclusion Patients treated with VAN received insufficient monitoring of SCr and inadequate therapeutic drug monitoring. We recommend that hospitals increase their investment in clinical pharmacists. An elevated baseline eGFR and concomitant vasopressor therapy, nitrate use, imipenem-cilastatin treatment, and contrast medium administration were independent risk factors for VA-AKI; in addition, orthopedic/trauma/burn surgery and concomitant compound glycyrrhizin use were independent protective factors for VA-AKI. PMID:28426688

Vancomycin-associated acute kidney injury: A cross-sectional study from a single center in China.

PubMed

Pan, Kunming; Ma, Lingyun; Xiang, Qian; Li, Xueying; Li, Haixia; Zhou, Ying; Yang, Li; Cui, Yimin

2017-01-01

The objective of this study was to investigate the current situation of vancomycin (VAN)-associated acute kidney injury (VA-AKI) in China and identify the risk factors for VA-AKI, as well as to comprehensively examine the risk related to concurrent drug use. Further, we assessed the outcomes of patients who developed VA-AKI and the risk factors for these outcomes. Finally, we aimed to provide suggestions for improving the prevention and treatment of VA-AKI in China. We conducted a retrospective observational study of inpatients who had been treated with VAN between January 2013 and December 2013 at Peking University First Hospital. AKI was defined as an increase in SCr of ≥0.3 mg/dl (≥26.5 μmol/l) within 48 hours or an increase to ≥1.5 times the baseline certainly or presumably within the past 7 days. VA-AKI was defined as the development of AKI during VAN therapy or within 7 days following the termination of VAN therapy. In addition, we compared patients with NO-AKI, who did not develop AKI during their hospitalization, with those with VA-AKI. Of the 934 patients treated with VAN during their hospital stay, 740 were included in this study. Among those excluded, 38.1% (74/194) were excluded because of a lack of data on serum creatinine (SCr). Among the included patients, 120 had confirmed VA-AKI, with an incidence of 16.2% (120/740). Multiple logistic regression analysis revealed that an elevated baseline estimated glomerular filtration rate (eGFR) (odds ratio [OR] = 1.009; p = 0.017) and concomitant vasopressor therapy (OR = 2.942; p = 0.009), nitrate use (OR = 2.869; p = 0.007), imipenem-cilastatin treatment (OR = 4.708; p = 0.000), and contrast medium administration (OR = 6.609 p = 0.005) were independent risk factors for VA-AKI; in addition, the receipt of orthopedic/trauma/burn surgery (OR = 0.3575; p = 0.011) and concomitant compound glycyrrhizin use (OR = 0.290; p = 0.017) were independent protective factors for VA-AKI. Multiple logistic regression analysis also demonstrated that among the patients who developed VA-AKI, coronary heart disease (CHD) (OR = 12.6; p = 0.006) and concomitant vasopressor therapy (OR = 15.4; p = 0.001) were independent risk factors for death. We also evaluated the factors influencing improvement of renal function. Multiple logistic regression analysis demonstrated that CHD (OR = 8.858, p = 0.019) and concomitant contrast medium administration (OR = 9.779, p = 0.005) were independent risk factors and that simultaneous β-blocker treatment (OR = 0.124, p = 0.001) was an independent protective factor for improvement of renal function. Patients treated with VAN received insufficient monitoring of SCr and inadequate therapeutic drug monitoring. We recommend that hospitals increase their investment in clinical pharmacists. An elevated baseline eGFR and concomitant vasopressor therapy, nitrate use, imipenem-cilastatin treatment, and contrast medium administration were independent risk factors for VA-AKI; in addition, orthopedic/trauma/burn surgery and concomitant compound glycyrrhizin use were independent protective factors for VA-AKI.

Tafenoquine, an Antiplasmodial 8-Aminoquinoline, Targets Leishmania Respiratory Complex III and Induces Apoptosis ▿

PubMed Central

Carvalho, Luis; Luque-Ortega, Juan Román; Manzano, José Ignacio; Castanys, Santiago; Rivas, Luis; Gamarro, Francisco

2010-01-01

Tafenoquine (TFQ), an 8-aminoquinoline analogue of primaquine, which is currently under clinical trial (phase IIb/III) for the treatment and prevention of malaria, may represent an alternative treatment for leishmaniasis. In this work, we have studied the mechanism of action of TFQ against Leishmania parasites. TFQ impaired the overall bioenergetic metabolism of Leishmania promastigotes, causing a rapid drop in intracellular ATP levels without affecting plasma membrane permeability. TFQ induced mitochondrial dysfunction through the inhibition of cytochrome c reductase (respiratory complex III) with a decrease in the oxygen consumption rate and depolarization of mitochondrial membrane potential. This was accompanied by ROS production, elevation of intracellular Ca2+ levels and concomitant nuclear DNA fragmentation. We conclude that TFQ targets Leishmania mitochondria, leading to an apoptosis-like death process. PMID:20837758

Tafenoquine, an antiplasmodial 8-aminoquinoline, targets leishmania respiratory complex III and induces apoptosis.

PubMed

Carvalho, Luis; Luque-Ortega, Juan Román; Manzano, José Ignacio; Castanys, Santiago; Rivas, Luis; Gamarro, Francisco

2010-12-01

Tafenoquine (TFQ), an 8-aminoquinoline analogue of primaquine, which is currently under clinical trial (phase IIb/III) for the treatment and prevention of malaria, may represent an alternative treatment for leishmaniasis. In this work, we have studied the mechanism of action of TFQ against Leishmania parasites. TFQ impaired the overall bioenergetic metabolism of Leishmania promastigotes, causing a rapid drop in intracellular ATP levels without affecting plasma membrane permeability. TFQ induced mitochondrial dysfunction through the inhibition of cytochrome c reductase (respiratory complex III) with a decrease in the oxygen consumption rate and depolarization of mitochondrial membrane potential. This was accompanied by ROS production, elevation of intracellular Ca(2+) levels and concomitant nuclear DNA fragmentation. We conclude that TFQ targets Leishmania mitochondria, leading to an apoptosis-like death process.

Outbreak of avian cholera on the wintering grounds of the Mississippi Valley Canada goose flock

USGS Publications Warehouse

Windingstad, R.M.; Duncan, R.M.; Thornburg, D.

1983-01-01

Avian cholera is reported for the first time in Canada geese, Branta canadensis, of the Mississippi Valley population. The disease was detected in weekly surveillance transects and was responsible for the loss of about 850 geese during the winter of 1978-1979 at localized areas in southern Illinois. Necropsies performed on 480 geese that died at Union County Conservation Area and on 133 birds at Horseshoe Lake Conservation Area during January and February 1979 revealed that the majority of losses (64%) were caused by avian cholera. Lead poisoning was responsible for the death of 14% of the geese analyzed and the remaining 22%, most of which were decomposed, were undiagnosed. Lethal lead levels and Pasteurella multocida occurred concomitantly in a few instances.

Corticosteroids in Myositis and Scleroderma.

PubMed

Postolova, Anna; Chen, Jennifer K; Chung, Lorinda

2016-02-01

Idiopathic inflammatory myopathies (IIMs) involve inflammation of the muscles and are classified by the patterns of presentation and immunohistopathologic features on skin and muscle biopsy into 4 categories: dermatomyositis, polymyositis, inclusion body myositis, and immune-mediated necrotizing myopathy. Systemic corticosteroid (CS) treatment is the standard of care for IIM with muscle and organ involvement. The extracutaneous features of systemic sclerosis are frequently treated with CS; however, high doses have been associated with scleroderma renal crisis in high-risk patients. Although CS can be effective first-line agents, their significant side effect profile encourages concomitant treatment with other immunosuppressive medications to enable timely tapering. Published by Elsevier Inc.

Earth materials research: Report of a Workshop on Physics and Chemistry of Earth Materials

NASA Technical Reports Server (NTRS)

1987-01-01

The report concludes that an enhanced effort of earth materials research is necessary to advance the understanding of the processes that shape the planet. In support of such an effort, there are new classes of experiments, new levels of analytical sensitivity and precision, and new levels of theory that are now applicable in understanding the physical and chemical properties of geological materials. The application of these capabilities involves the need to upgrade and make greater use of existing facilities as well as the development of new techniques. A concomitant need is for a sample program involving their collection, synthesis, distribution, and analysis.

Factors related to the involvement of nurses in medical end-of-life decisions in Belgium: a death certificate study.

PubMed

Inghelbrecht, Els; Bilsen, Johan; Mortier, Freddy; Deliens, Luc

2008-07-01

Although nurses play an important role in end-of-life care for patients, they are not systematically involved in end-of-life decisions with a possible or certain life-shortening effect (ELDs). Until now we know little about factors relating to the involvement of nurses in these decisions. To explore which patient- and decision-characteristics are related to the consultation of nurses and to the administering of life-ending drugs by nurses in actual ELDs in institutions and home care, as reported by physicians. We sampled at random 5005 of all registered deaths in the second half of 2001--before euthanasia was legalized--in Flanders, Belgium. We mailed anonymous questionnaires to physicians who signed the death certificates and asked them to report on ELDs, including nurses' involvement. Response rate was 59% (n=2950). Physicians reported nurses involved in decision making more often in institutions than at home, and more often in care homes for the elderly than in hospitals (OR 1.70, 95% CI 1.15, 2.52). This involvement was more frequently when physicians intended to hasten the patient's death than when they had no such intention (institutions: OR 2.05, 95% CI 1.41, 2.99; home: OR 2.04, 95% CI 1.19, 3.49). In institutions, this involvement was also more likely where patients were of lower rather than higher education (OR 2.95, 95% CI 1.49, 5.84). The administering of life-ending drugs by nurses, as reported by physicians was also found more frequently in institutions than at home, and in institutions more frequently with lower rather than higher educated patients (p=.037). These findings raise questions about physicians' perception of the nurse's role in ELDs, but also about physicians' skills in interacting with all patients. Education and guidelines for physicians and nurses are needed to optimize good communication and to promote a clearer assignment of responsibilities concerning the execution of those decisions.

Violent deaths of media workers associated with conflict in Iraq, 2003-2012.

PubMed

Collinson, Lucie; Wilson, Nick; Thomson, George

2014-01-01

Background. The violent deaths of media workers is a critical issue worldwide, especially in areas of political and social instability. Such deaths can be a particular concern as they may undermine the development and functioning of an open and democratic society. Method. Data on the violent deaths of media workers in Iraq for ten years (2003-2012) were systematically collated from five international databases. Analyses included time trends, weapons involved, nationality of the deceased, outcome for perpetrators and location of death. Results. During this ten-year period, there were 199 violent deaths of media workers in Iraq. The annual number increased substantially after the invasion in 2003 (peaking at n = 47 in 2007) and then declined (n = 5 in 2012). The peak years (2006-2007) for these deaths matched the peak years for estimated violent deaths among civilians. Most of the media worker deaths (85%) were Iraqi nationals. Some were killed whilst on assignment in the field (39%) and 28% involved a preceding threat. Common perpetrators of the violence were: political groups (45%), and coalition forces (9%), but the source of the violence was often unknown (29%). None of the perpetrators have subsequently been prosecuted (as of April 2014). For each violent death of a media worker, an average of 3.1 other people were also killed in the same attack (range 0-100 other deaths). Discussion. This analysis highlights the high number of homicides of media workers in Iraq in this conflict period, in addition to the apparently total level of impunity. One of the potential solutions may be establishing a functioning legal system that apprehends offenders and puts them on trial. The relatively high quality of data on violent deaths in this occupational group, suggests that it could act as one sentinel population within a broader surveillance system of societal violence in conflict zones.

Violent deaths of media workers associated with conflict in Iraq, 2003–2012

PubMed Central

Wilson, Nick; Thomson, George

2014-01-01

Background. The violent deaths of media workers is a critical issue worldwide, especially in areas of political and social instability. Such deaths can be a particular concern as they may undermine the development and functioning of an open and democratic society. Method. Data on the violent deaths of media workers in Iraq for ten years (2003–2012) were systematically collated from five international databases. Analyses included time trends, weapons involved, nationality of the deceased, outcome for perpetrators and location of death. Results. During this ten-year period, there were 199 violent deaths of media workers in Iraq. The annual number increased substantially after the invasion in 2003 (peaking at n = 47 in 2007) and then declined (n = 5 in 2012). The peak years (2006–2007) for these deaths matched the peak years for estimated violent deaths among civilians. Most of the media worker deaths (85%) were Iraqi nationals. Some were killed whilst on assignment in the field (39%) and 28% involved a preceding threat. Common perpetrators of the violence were: political groups (45%), and coalition forces (9%), but the source of the violence was often unknown (29%). None of the perpetrators have subsequently been prosecuted (as of April 2014). For each violent death of a media worker, an average of 3.1 other people were also killed in the same attack (range 0–100 other deaths). Discussion. This analysis highlights the high number of homicides of media workers in Iraq in this conflict period, in addition to the apparently total level of impunity. One of the potential solutions may be establishing a functioning legal system that apprehends offenders and puts them on trial. The relatively high quality of data on violent deaths in this occupational group, suggests that it could act as one sentinel population within a broader surveillance system of societal violence in conflict zones. PMID:24883251

Language and motor abilities of preschool children who stutter: Evidence from behavioral and kinematic indices of nonword repetition performance

PubMed Central

Smith, Anne; Goffman, Lisa; Sasisekaran, Jayanthi; Weber-Fox, Christine

2012-01-01

Stuttering is a disorder of speech production that typically arises in the preschool years, and many accounts of its onset and development implicate language and motor processes as critical underlying factors. There have, however, been very few studies of speech motor control processes in preschool children who stutter. Hearing novel nonwords and reproducing them engages multiple neural networks, including those involved in phonological analysis and storage and speech motor programming and execution. We used this task to explore speech motor and language abilities of 31 children aged 4–5 years who were diagnosed as stuttering. We also used sensitive and specific standardized tests of speech and language abilities to determine which of the children who stutter had concomitant language and/or phonological disorders. Approximately half of our sample of stuttering children had language and/or phonological disorders. As previous investigations would suggest, the stuttering children with concomitant language or speech sound disorders produced significantly more errors on the nonword repetition task compared to typically developing children. In contrast, the children who were diagnosed as stuttering, but who had normal speech sound and language abilities, performed the nonword repetition task with equal accuracy compared to their normally fluent peers. Analyses of interarticulator motions during accurate and fluent productions of the nonwords revealed that the children who stutter (without concomitant disorders) showed higher variability in oral motor coordination indices. These results provide new evidence that preschool children diagnosed as stuttering lag their typically developing peers in maturation of speech motor control processes. Educational objectives The reader will be able to: (a) discuss why performance on nonword repetition tasks has been investigated in children who stutter; (b) discuss why children who stutter in the current study had a higher incidence of concomitant language deficits compared to several other studies; (c) describe how performance differed on a nonword repetition test between children who stutter who do and do not have concomitant speech or language deficits; (d) make a general statement about speech motor control for nonword production in children who stutter compared to controls. PMID:23218217

Sudden death: bereavement sequelae and interventions.

PubMed

Davidson, G P

1981-10-14

Just the phrase "sudden death' carries its sense of trepidation and even horror. So fear-inducing is its reality and prospect, that we have attempted to sanitise it by the colloquialisms such as a "sudden death play off' in sport, and even (recalling my days in military service) as the name of a particularly ferocious mix of alcoholic beverage. One of the reasons why the phrase is so evocative is the force of the unexpected bereavement that follows sudden death. This paper purports to examine, using a systems approach, the psychological sequelae of the emotionally involved survivors of sudden death, and to relate this to possible intervention strategies.

Death Penalty in America.

ERIC Educational Resources Information Center

Clifford, Amie L.

1997-01-01

Examines the legal and moral issues, controversies, and unique trial procedures involved with the death penalty. Discusses the 1972 landmark Supreme Court decision that resulted in many states abolishing this punishment, only to reintroduce it later with different provisions. Reviews the controversial case of Sam Sheppard. (MJP)

An analysis of possible mechanisms of unexpected death occurring in hydatid disease (echinococcosis).

PubMed

Byard, Roger W

2009-07-01

Most cases of hydatid disease in human populations are due to Echinococcus granulosus. The hydatid life cycle involves passage between definitive hosts such as dogs and intermediate hosts such as sheep. Humans become accidental intermediate hosts following ingestion of food or water contaminated with eggs or by contact with infected dogs. Although hydatid disease may remain asymptomatic, occasional cases of sudden and unexpected death present to autopsy. Causes of rapid clinical decline involve a wide range of mechanisms including anaphylaxis (with or without cyst rupture), cardiac outflow obstruction or conduction tract disturbance, pulmonary and cerebral embolism, pericarditis, cardiac tamponade, myocardial ischemia, pulmonary hypertension, peritonitis, hollow organ perforation, intracerebral mass effect, obstructive hydrocephalus, seizures, cerebral ischemia/infarction, and pregnancy complications. The autopsy assessment of cases therefore requires careful examination of all organ systems for characteristic cystic lesions, as multiorgan involvement is common, with integration of findings so that possible mechanisms of death can be determined. Measurement of serum tryptase and specific IgE levels should be undertaken for possible anaphylaxis.

ARTD1 (PARP1) activation and NAD+ in DNA repair and cell death

PubMed Central

Fouquerel, Elise; Sobol, Robert W.

2014-01-01

Nicotinamide adenine dinucleotide, NAD+, is a small metabolite coenzyme that is essential for the progress of crucial cellular pathways including glycolysis, the tricarboxylic acid cycle (TCA) and mitochondrial respiration. These processes consume and produce both oxidative and reduced forms of NAD (NAD+ and NADH). NAD+ is also important for ADP(ribosyl)ation reactions mediated by the ADP-ribosyltransferase enzymes (ARTDs) or deacetylation reactions catalysed by the sirtuins (SIRTs) which use NAD+ as a substrate. In this review, we highlight the significance of NAD+ catabolism in DNA repair and cell death through its utilization by ARTDs and SIRTs. We summarize the current findings on the involvement of ARTD1 activity in DNA repair and most specifically its involvement in the trigger of cell death mediated by energy depletion. By sharing the same substrate, the activities of ARTDs and SIRTs are tightly linked and dependent on each other and are thereby involved in the same cellular processes that play an important role in cancer biology, inflammatory diseases and ischemia/reperfusion. PMID:25283336

Survival and recurrent venous thromboembolism in patients with first proximal or isolated distal deep vein thrombosis and no pulmonary embolism.

PubMed

Barco, S; Corti, M; Trinchero, A; Picchi, C; Ambaglio, C; Konstantinides, S V; Dentali, F; Barone, M

2017-07-01

Essentials The long-term risk of recurrence and death after distal deep vein thrombosis (DVT) is uncertain. We included subjects with first proximal or isolated distal DVT (IDDVT) and no pulmonary embolism. The risk of symptomatic and asymptomatic recurrence is lower after IDDVT (vs. proximal). IDDVT may be associated with a lower long-term risk of death, especially after unprovoked DVT. Background A few studies have focused on the risk of recurrence after first acute isolated distal deep vein thrombosis (IDDVT) compared with proximal DVT (PDVT), whereas the incremental risk of death has never been explored beyond the first 3 years after acute event. Methods Our single-center cohort study included patients with first symptomatic acute PDVT or IDDVT. Patients were excluded if they had concomitant pulmonary embolism (PE) or prior venous thromboembolism. The primary outcomes were symptomatic objectively diagnosed recurrent PDVT or PE and all-cause death. Results In total, 4759 records were screened and 831 subjects included: 202 had symptomatic IDDVT and 629 had PDVT. The median age was 66 years and 50.5% were women. A total of 125 patients had recurrent PDVT or PE during 3175 patient-years of follow-up: 109 events occurred after PDVT (17.3%) and 16 after IDDVT (7.9%). Annual recurrence rates were 4.5% (95% confidence interval [CI], 3.7-5.4%) and 2.0% (95% CI, 1.1-3.2%), respectively, for an adjusted hazard ratio (aHR) for IDDVT patients of 0.32 (95% CI, 0.19-0.55). Death occurred in 263 patients (31.6% [95% CI, 28.6-34.9%]) during 5469 patient-years of follow-up for an overall annual incidence rate of 4.8% (95% CI, 4.2-5.4%). The mortality rate was 33.5% (n = 211) in PDVT patients and 25.7% (n = 52) in IDDVT patients. The long-term hazard of death appeared lower for IDDVT patients (aHR, 0.75 [95% CI, 0.55-1.02]), especially after unprovoked events (aHR, 0.58 [95% CI, 0.26-1.31]). Conclusions Compared with PDVT, IDDVT patients were at a lower risk of recurrent VTE. The risk of death appeared lower after IDDVT during a median follow-up of 7.6 years. © 2017 International Society on Thrombosis and Haemostasis.

Randomized phase II--study evaluating EGFR targeting therapy with cetuximab in combination with radiotherapy and chemotherapy for patients with locally advanced pancreatic cancer--PARC: study protocol [ISRCTN56652283].

PubMed

Krempien, R; Muenter, M W; Huber, P E; Nill, S; Friess, H; Timke, C; Didinger, B; Buechler, P; Heeger, S; Herfarth, K K; Abdollahi, A; Buchler, M W; Debus, J

2005-10-11

Pancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR. The PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patient's enrollment. The primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with chemoradiation therapy with gemcitabine and intensity modulated radiation therapy (IMRT) and EGFR-targeted therapy using cetuximab and to compare between two different methods of cetuximab treatment schedules (concomitant versus concomitant and sequential cetuximab treatment). Secondary objectives are to determine the role and the mechanism of cetuximab in patient's chemoradiation regimen, the response rate, the potential of this combined modality treatment to concert locally advanced lesions to potentially resectable lesions, the time to progression interval and the quality of life.

Magnetic resonance cholangiogram patterns and clinical profiles of ketamine-related cholangiopathy in drug users.

PubMed

Seto, Wai-Kay; Mak, Siu-King; Chiu, Keith; Vardhanabhuti, Varut; Wong, Ho-Fai; Leong, Heng-Tat; Lee, Paul S F; Ho, Y C; Lee, Chi-Kei; Cheung, Ka-Shing; Yuen, Man-Fung; Leung, Wai K

2018-07-01

Recreational ketamine use has emerged as an important health and social issue worldwide. Although ketamine is associated with biliary tract damage, the clinical and radiological profiles of ketamine-related cholangiopathy have not been well described. Chinese individuals who had used ketamine recreationally at least twice per month for six months in the previous two years via a territory-wide community network of charitable organizations tackling substance abuse were recruited. Magnetic resonance cholangiography (MRC) was performed, and the findings were interpreted independently by two radiologists, with the findings analysed in association with clinical characteristics. Among the 343 ketamine users referred, 257 (74.9%) were recruited. The mean age and ketamine exposure duration were 28.7 (±5.8) and 10.5 (±3.7) years, respectively. A total of 159 (61.9%) had biliary tract anomalies on MRC, categorized as diffuse extrahepatic dilatation (n = 73), fusiform extrahepatic dilatation (n = 64), and intrahepatic ductal changes (n = 22) with no extrahepatic involvement. Serum alkaline phosphatase (ALP) level (odds ratio [OR] 1.007; 95% CI 1.002-1.102), lack of concomitant recreational drug use (OR 1.99; 95% CI 1.11-3.58), and prior emergency attendance for urinary symptoms (OR 1.95; 95% CI 1.03-3.70) had high predictive values for biliary anomalies on MRC. Among sole ketamine users, ALP level had an AUC of 0.800 in predicting biliary anomalies, with an optimal level of ≥113 U/L having a positive predictive value of 85.4%. Cholangiographic anomalies were reversible after ketamine abstinence, whereas decompensated cirrhosis and death were possible after prolonged exposure. We have identified distinctive MRC patterns in a large cohort of ketamine users. ALP level and lack of concomitant drug use predicted biliary anomalies, which were reversible after abstinence. The study findings may aid public health efforts in combating the growing epidemic of ketamine abuse. Recreational inhalation of ketamine is currently an important substance abuse issue worldwide, and can result in anomalies of the biliary system as demonstrated by magnetic resonance imaging. Although prolonged exposure may lead to further clinical deterioration, such biliary system anomalies might be reversible after ketamine abstinence. Clinical trial number: NCT02165488. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Hyperthyroidism, hyperfunctioning thyroid nodule, and thyroid cancer in a young female: a rare and unusual coexistence.

PubMed

Hernán-Martínez, José; Uzcategui, María; Corder, Eric; Castillo, Manuel; Sostre, Samuel; Alicea, Luz

2010-03-01

The prevalence of concomitant thyroid carcinoma with Grave's disease has been reported to range from 0 to 10%. Many controversies exist in the literature regarding the diagnostic workup and management in these types of patients. We are reporting a case of a 31 year old woman who had Graves' disease, a palpable thyroid nodule, and results from a thyroid scan revealed a "hot" nodule. Interestingly, an ultrasound guided FNA of the "hot" nodule showed papillary thyroid microcarcinoma. Finally, a total thyroidectomy showed multilobar tumor involvement. The diagnostic tools employed to establish the proper management strategy for this patient were based on data in the literature that is full of discrepancies. The fact that Grave's disease occurs concomitantly with thyroid cancer, specifically the papillary type, is an indisputably rare combination. One rare feature on our clinical case was the reported malignancy of a papillary carcinoma within a "hot" nodule which usually is much less that 1%. Many studies describe an increasing incidence of Grave's disease patients with concomitant papillary thyroid carcinoma. One possible explanation for these findings could be improvements in medical technology of screening tools. We propose that, thyroid ultrasonography should be integrated in the diagnostic workup in patients presenting with Graves' disease, especially in those presenting with palpable nodules. Fine needle biopsy should not be restricted to cold nodules.

Clinical impact of concomitant immunomodulators on biologic therapy: Pharmacokinetics, immunogenicity, efficacy and safety.

PubMed

Xu, Zhenhua; Davis, Hugh M; Zhou, Honghui

2015-03-01

Immune-mediated inflammatory diseases encompass a variety of different clinical syndromes, manifesting as either common diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and psoriasis, or rare diseases such as cryopyrin-associated periodic syndromes. The therapy for these diseases often involves the use of a wide range of drugs including nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, immunomodulators, and biologic therapies. Due to the abundance of relevant clinical data, this article provides a general overview on the clinical impact of the concomitant use of immunomodulators and biologic therapies, with a focus on anti-tumor necrosis factor-α agents (anti-TNFα), for the treatment of RA and Crohn's disease (CD). Compared to biologic monotherapy, concomitant use of immunomodulators (methotrexate, azathioprine, and 6-mercaptopurine) often increases the systemic exposure of the anti-TNFα agent and decreases the formation of antibodies to the anti-TNFα agent, consequently enhancing clinical efficacy. Nevertheless, long-term combination therapy with immunomodulators and anti-TNFα agents may be associated with increased risks of serious infections and malignancies. Therefore, the determination whether combination therapy is suitable for a patient should always be based on an individualized benefit-risk evaluation. More research should be undertaken to identify and validate prognostic markers for predicting patients who would benefit the most and those who are at greater risk from combination therapy with immunomodulators and anti-TNFα agents. © 2015, The American College of Clinical Pharmacology.

UV-Induced cell death in plants.

PubMed

Nawkar, Ganesh M; Maibam, Punyakishore; Park, Jung Hoon; Sahi, Vaidurya Pratap; Lee, Sang Yeol; Kang, Chang Ho

2013-01-14

Plants are photosynthetic organisms that depend on sunlight for energy. Plants respond to light through different photoreceptors and show photomorphogenic development. Apart from Photosynthetically Active Radiation (PAR; 400-700 nm), plants are exposed to UV light, which is comprised of UV-C (below 280 nm), UV-B (280-320 nm) and UV-A (320-390 nm). The atmospheric ozone layer protects UV-C radiation from reaching earth while the UVR8 protein acts as a receptor for UV-B radiation. Low levels of UV-B exposure initiate signaling through UVR8 and induce secondary metabolite genes involved in protection against UV while higher dosages are very detrimental to plants. It has also been reported that genes involved in MAPK cascade help the plant in providing tolerance against UV radiation. The important targets of UV radiation in plant cells are DNA, lipids and proteins and also vital processes such as photosynthesis. Recent studies showed that, in response to UV radiation, mitochondria and chloroplasts produce a reactive oxygen species (ROS). Arabidopsis metacaspase-8 (AtMC8) is induced in response to oxidative stress caused by ROS, which acts downstream of the radical induced cell death (AtRCD1) gene making plants vulnerable to cell death. The studies on salicylic and jasmonic acid signaling mutants revealed that SA and JA regulate the ROS level and antagonize ROS mediated cell death. Recently, molecular studies have revealed genes involved in response to UV exposure, with respect to programmed cell death (PCD).

UV-Induced Cell Death in Plants

PubMed Central

Nawkar, Ganesh M.; Maibam, Punyakishore; Park, Jung Hoon; Sahi, Vaidurya Pratap; Lee, Sang Yeol; Kang, Chang Ho

2013-01-01

Plants are photosynthetic organisms that depend on sunlight for energy. Plants respond to light through different photoreceptors and show photomorphogenic development. Apart from Photosynthetically Active Radiation (PAR; 400–700 nm), plants are exposed to UV light, which is comprised of UV-C (below 280 nm), UV-B (280–320 nm) and UV-A (320–390 nm). The atmospheric ozone layer protects UV-C radiation from reaching earth while the UVR8 protein acts as a receptor for UV-B radiation. Low levels of UV-B exposure initiate signaling through UVR8 and induce secondary metabolite genes involved in protection against UV while higher dosages are very detrimental to plants. It has also been reported that genes involved in MAPK cascade help the plant in providing tolerance against UV radiation. The important targets of UV radiation in plant cells are DNA, lipids and proteins and also vital processes such as photosynthesis. Recent studies showed that, in response to UV radiation, mitochondria and chloroplasts produce a reactive oxygen species (ROS). Arabidopsis metacaspase-8 (AtMC8) is induced in response to oxidative stress caused by ROS, which acts downstream of the radical induced cell death (AtRCD1) gene making plants vulnerable to cell death. The studies on salicylic and jasmonic acid signaling mutants revealed that SA and JA regulate the ROS level and antagonize ROS mediated cell death. Recently, molecular studies have revealed genes involved in response to UV exposure, with respect to programmed cell death (PCD). PMID:23344059

Sevoflurane post-conditioning protects primary rat cortical neurons against oxygen-glucose deprivation/resuscitation via down-regulation in mitochondrial apoptosis axis of Bid, Bim, Puma-Bax and Bak mediated by Erk1/2.

PubMed

Zhang, Li-Min; Zhao, Xiao-Chun; Sun, Wen-Bo; Li, Rui; Jiang, Xiao-Jing

2015-10-15

Temporal post-conditioning helps provide neuroprotection against brain injury secondary to ischemia-reperfusion and is considered an effective intervention, but the exact mechanism of sevoflurane post-conditioning is unclear. The essential axis involves activator Bid, Bim, Puma (BH3s), Bax, and Bak; activates the mitochondrial death program; and might be involved in a cell death signal. Extracellular signal-related kinases 1/2 (Erk1/2) play a pivotal role in cell growth and proliferation. We hypothesized that sevoflurane post-conditioning might inhibit Bid, Bim, Puma, Bax, and Bak expression and is activated by phosphor-Erk1/2 to decrease neuronal death. To test this hypothesis, we exposed primary cortical neuron cultures to oxygen-glucose deprivation for 1h, along with resuscitation for 24h (OGD/R). MTT assays, propidium iodide uptake (PI), JC-1 fluorescence, and Western blot indicated the following: decreased cell viability (P<0.05); increased cell death (P<0.05); decreased mitochondrial membrane potential (P<0.05); and decreased Bid, Bim, Puma, Bax, and Bak expression with OGD/R exposure. Inhibition of Erk1/2 phosphorylation could attenuate sevoflurane post-conditioning that mediated an increase in neuronal viability and mitochondrial membrane potential, as well as a decrease in cell death and Bid, Bim, Puma, Bax, and Bak expression after OGD/R treatment. The results demonstrated that sevoflurane post-conditioning caused a marked decrease in cortical neuronal death secondary to OGD/R exposure through the downregulation of the mitochondrial apoptosis axis involving Bid, Bim, Puma, Bax, and Bak that was mediated by the phosphorylation/activation of Erk1/2. Copyright © 2015 Elsevier B.V. All rights reserved.

Repatriation of human remains following death in international travellers.

PubMed

Connolly, Ruairi; Prendiville, Richard; Cusack, Denis; Flaherty, Gerard

2017-03-01

Death during international travel and the repatriation of human remains to one's home country is a distressing and expensive process. Much organization is required involving close liaison between various agencies. A review of the literature was conducted using the PubMed database. Search terms included: 'repatriation of remains', 'death', 'abroad', 'tourism', 'travel', 'travellers', 'travelling' and 'repatriation'. Additional articles were obtained from grey literature sources and reference lists. The local national embassy, travel insurance broker and tour operator are important sources of information to facilitate the repatriation of the deceased traveller. Formal identification of the deceased's remains is required and a funeral director must be appointed. Following this, the coroner in the country or jurisdiction receiving the repatriated remains will require a number of documents prior to providing clearance for burial. Costs involved in repatriating remains must be borne by the family of the deceased although travel insurance may help defray some of the costs. If the death is secondary to an infectious disease, cremation at the site of death is preferred. No standardized procedure is in place to deal with the remains of a migrant's body at present and these remains are often not repatriated to their country of origin. Repatriation of human remains is a difficult task which is emotionally challenging for the bereaving family and friends. As a travel medicine practitioner, it is prudent to discuss all eventualities, including the risk of death, during the pre-travel consultation. Awareness of the procedures involved in this process may ease the burden on the grieving family at a difficult time. © International Society of Travel Medicine, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Bistability in Doped Organic Thin Film Transistors (Preprint)

DTIC Science & Technology

2007-03-01

small molecules (e.g. pentacene ). As such, they do not necessarily compete with these more typical organic transistors, but rather have pertinence...involves dipping a substrate between two dilute polyelectrolyte solutions of opposite charge to build up a thin film via the electrostatic interactions...recovery is due to trapped O2(g) remaining in the film, which causes the reverse of reaction (1) to occur and the concomitant increase in the level of

Opioid Deaths in Rural Virginia: A Description of the High Prevalence of Accidental Fatalities Involving Prescribed Medications

PubMed Central

Wunsch, Martha J.; Nakamoto, Kent; Behonick, George; Massello, William

2009-01-01

In rural Virginia, drug overdose deaths increased 300% from 1997 to 2003. Polydrug deaths predominate (57.9%) in this review of 893 medical examiner cases. Prescription opioids (74.0%), antidepressants (49.0%), and benzodiazepines (39.3%) were more prevalent than illicit drugs. Two-thirds of decedents were 35–54 years old; 37% were female. When compared to western Virginia metropolitan cases, polydrug abuse was more common, specific medication combinations were found, the death rate per population was higher, and fewer illicit drugs were detected. These rural prescription overdose deaths differ from urban illicit drug deaths, suggesting the need for different strategies in prevention, treatment, and intervention by clinicians and policymakers. PMID:19219660

Prosperity as a cause of death.

PubMed

Eyer, J

1977-01-01

The general death rate rises during business booms and falls during depressions. The causes of death involved in this variation range from infectious diseases through accidents to heart disease, cancer, and cirrhosis of the liver, and include the great majority of all causes of death. Less than 2 percent of the death rate-that for suicide and homicide-varies directly with unemployment. In the older historical data, deterioration of housing and rise of alcohol consumption on the boom may account for part of this variation. In twentieth-century cycles, the role of social stress is probably predominant. Overwork and fragmentation of community through migration are two important sources of stress which rise with the boom, and they are demonstrably related to the causes of death which show this variation.

[Amyotrophic neuralgia associated with bilateral phrenic paralysis treated with non-invasive mechanical ventilation].

PubMed

García García, María Del Carmen; Hernández Borge, Jacinto; Antona Rodríguez, María José; Pires Gonçalves, Pedro; García García, Gema

2015-09-07

Amyotrophic neuralgia is an uncommon neuropathy characterized by severe unilateral shoulder pain. Isolated or concomitant involvement of other peripheral motor nerves depending on the brachial plexus such as phrenic or laryngeal nerves is unusual(1). Its etiology is unknown, yet several explanatory factors have been proposed. Phrenic nerve involvement, either unilateral or bilateral, is exceedingly rare. Diagnosis relies on anamnesis, functional and imaging investigations and electromyogram. We report the case of a 48-year-old woman with a past history of renal transplantation due to proliferative glomerulonephritis with subsequent transplant rejection, who was eventually diagnosed with amyotrophic neuralgia with bilateral phrenic involvement, and who required sustained non-invasive mechanical ventilation. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Cell Death Pathways and Phthalocyanine as an Efficient Agent for Photodynamic Cancer Therapy

PubMed Central

Mfouo-Tynga, Ivan; Abrahamse, Heidi

2015-01-01

The mechanisms of cell death can be predetermined (programmed) or not and categorized into apoptotic, autophagic and necrotic pathways. The process of Hayflick limits completes the execution of death-related mechanisms. Reactive oxygen species (ROS) are associated with oxidative stress and subsequent cytodamage by oxidizing and degrading cell components. ROS are also involved in immune responses, where they stabilize and activate both hypoxia-inducible factors and phagocytic effectors. ROS production and presence enhance cytodamage and photodynamic-induced cell death. Photodynamic cancer therapy (PDT) uses non-toxic chemotherapeutic agents, photosensitizer (PS), to initiate a light-dependent and ROS-related cell death. Phthalocyanines (PCs) are third generation and stable PSs with improved photochemical abilities. They are effective inducers of cell death in various neoplastic models. The metallated PCs localize in critical cellular organelles and are better inducers of cell death than other previous generation PSs as they favor mainly apoptotic cell death events. PMID:25955645

Electronic Certification of Death in Slovenia - System Considerations and Development Opportunities.

PubMed

Stanimirovic, Dalibor

2016-01-01

Accurate and consistent death certification facilitates morbidity and mortality surveillance, and consequently supports evidence-informed health policies. The paper initially explores the current death certification practice in Slovenia, and identifies related deficiencies and system inconsistencies. Finally, the paper outlines a conceptualization of ICT-based model of death certification including renovation of business processes and organizational changes. The research is based on focus group methodology. Structured discussions were conducted with 29 experts from cross-sectional areas related to death certification. Research results imply that effective ICT-based transformation of the existing death certification model should involve a redefinition of functions and relationships between the main actors, as well as a reconfiguration of the technological, organizational, and regulatory elements in the field. The paper provides an insight into the complexities of the death certification and may provide the groundwork for ICT-based transformation of the death certification model in Slovenia.

Non-conventional apoptotic response to ionising radiation mediated by N-methyl D-aspartate receptors in immature neuronal cells

PubMed Central

SAMARI, NADA; DE SAINT-GEORGES, LOUIS; PANI, GIUSEPPE; BAATOUT, SARAH; LEYNS, LUC; BENOTMANE, MOHAMMED ABDERRAFI

2013-01-01

During cortical development, N-methyl D-aspartate (NMDA) receptors are highly involved in neuronal maturation and synapse establishment. Their implication in the phenomenon of excitotoxicity has been extensively described in several neurodegenerative diseases due to the permissive entry of Ca2+ ions and massive accumulation in the intracellular compartment, which is highly toxic to cells. Ionising radiation is also a source of stress to the cells, particularly immature neurons. Their capacity to induce cell death has been described for various cell types either by directly damaging the DNA or indirectly through the generation of reactive oxygen species responsible for the activation of a battery of stress response effectors leading in certain cases, to cell death. In this study, in order to determine whether a link exists between NMDA receptors-mediated excitotoxicity and radiation-induced cell death, we evaluated radiation-induced cell death in vitro and in vivo in maturing neurons during the fetal period. Cell death induction was assessed by TUNEL, caspase-3 activity and DNA ladder assays, with or without the administration of dizocilpine (MK-801), a non-competitive NMDA receptor antagonist which blocks neuronal Ca2+ influx. To further investigate the possible involvement of Ca2+-dependent enzyme activation, known to occur at high Ca2+ concentrations, we examined the protective effect of a calpain inhibitor on cell death induced by radiation. Doses ranging from 0.2 to 0.6 Gy of X-rays elicited a clear apoptotic response that was prevented by the injection of dizocilpine (MK-801) or calpain inhibitor. These data demonstrate the involvement of NMDA receptors in radiation-induced neuronal death by the activation of downstream effectors, including calpain-related pathways. An increased apoptotic process elicited by radiation, occurring independently of the normal developmental scheme, may eliminate post-mitotic but immature neuronal cells and deeply impair the establishment of the neuronal network, which in the case of cortical development is critical for cognitive capacities. PMID:23338045

Characteristics of Homeless Adults Who Died of Drug Overdose: A Retrospective Record Review

PubMed Central

Brody, Jennifer K.; León, Casey; Baggett, Travis P.

2016-01-01

Drug overdose is a major cause of death among homeless people, but little is known about the characteristics of homeless overdose decedents. We conducted a retrospective record review of 219 adult patients of Boston Health Care for the Homeless Program (BHCHP) who died of drug overdose in 2003–2008. We assessed the substances implicated in overdose and the health and service use characteristics of decedents prior to death. Eighty-one percent of overdose deaths involved opioids and 40% involved multiple drugs. Problem substance use (85%), psychiatric illness (61%), and chronic pain (45%) were common, and 32% had documentation of all three. Half were well-connected to BHCHP, and 35% had a clinic visit within 90 days of death. The complex health histories and frequent health care contacts of homeless drug overdose decedents suggest that clinical facilities may be an important frontline venue for overdose education, naloxone distribution, and integrated substance use treatment programming. PMID:27180712

[Cardiac involvement in Acute Chagas' Disease cases in the Amazon region].

PubMed

Barbosa-Ferreira, João Marcos; Guerra, Jorge Augusto de Oliveira; Santana Filho, Franklin Simões de; Magalhães, Belisa Maria Lopes; Coelho, Leíla I A R C; Barbosa, Maria das Graças Vale

2010-06-01

The cardiac involvement of five patients from the Amazon region with Acute Chagas' Disease (ACD) is described. Four of these patients presented probable oral transmission. All of them presented some degree of cardiac involvement, but there were no deaths.

Survival and causes of death in systemic sclerosis patients: a single center registry report from Iran.

PubMed

Poormoghim, Hadi; Andalib, Elham; Jalali, Arash; Ghaderi, Afshin; Ghorbannia, Ali; Mojtabavi, Nazanin

2016-07-01

The aims of the study were to determine prognostic factors for survival and causes of death in a cohort of patients with systemic sclerosis (SSc). This was a cohort study of SSc patients in single rheumatologic center from January 1998 to August 2012. They fulfilled the American College of Rheumatology classification criteria for SSc or had calcinosis Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia or sine sclerosis. Causes of death were classified as SSc related and non-SSc related. Kaplan-Meier and Cox proportional hazard regression models were used in univariate and multivariate analysis to analyse survival in subgroups and determine prognostic factors of survival. The study includes 220 patients (192 female, 28 male). Out of thirty-two (14.5 %) who died, seventeen (53.1 %) deaths were SSc related and in nine (28.1 %) non-SSc-related causes, and in six (18.8 %) of patients causes of death were not defined. Overall survival rate was 92.6 % (95 % CI 87.5-95.7 %) after 5 years and 82.3 % (95 % CI 73.4-88.4 %) after 10 years. Pulmonary involvement was a major SSc-related cause of death, occurred in seven (41.1 %) patients. Cardiovascular events were leading cause of in overall death (11) 34.3 % and 6 in non-SSc-related death. Independent risk factors for mortality were age >50 at diagnosis (HR 5.10) advance pulmonary fibrosis (HR 11.5), tendon friction rub at entry (HR 6.39), arthritis (HR 3.56). In this first Middle Eastern series of SSc registry, pulmonary and cardiac involvements were the leading cause of SSc-related death.

Mechanisms of Action and Cell Death Associated with Clostridium perfringens Toxins.

PubMed

Navarro, Mauricio A; McClane, Bruce A; Uzal, Francisco A

2018-05-22

Clostridium perfringens uses its large arsenal of protein toxins to produce histotoxic, neurologic and intestinal infections in humans and animals. The major toxins involved in diseases are alpha (CPA), beta (CPB), epsilon (ETX), iota (ITX), enterotoxin (CPE), and necrotic B-like (NetB) toxins. CPA is the main virulence factor involved in gas gangrene in humans, whereas its role in animal diseases is limited and controversial. CPB is responsible for necrotizing enteritis and enterotoxemia, mostly in neonatal individuals of many animal species, including humans. ETX is the main toxin involved in enterotoxemia of sheep and goats. ITX has been implicated in cases of enteritis in rabbits and other animal species; however, its specific role in causing disease has not been proved. CPE is responsible for human food-poisoning and non-foodborne C. perfringens -mediated diarrhea. NetB is the cause of necrotic enteritis in chickens. In most cases, host⁻toxin interaction starts on the plasma membrane of target cells via specific receptors, resulting in the activation of intracellular pathways with a variety of effects, commonly including cell death. In general, the molecular mechanisms of cell death associated with C. perfringens toxins involve features of apoptosis, necrosis and/or necroptosis.

Mechanisms of Action and Cell Death Associated with Clostridium perfringens Toxins

PubMed Central

Navarro, Mauricio A.; Uzal, Francisco A.

2018-01-01

Clostridium perfringens uses its large arsenal of protein toxins to produce histotoxic, neurologic and intestinal infections in humans and animals. The major toxins involved in diseases are alpha (CPA), beta (CPB), epsilon (ETX), iota (ITX), enterotoxin (CPE), and necrotic B-like (NetB) toxins. CPA is the main virulence factor involved in gas gangrene in humans, whereas its role in animal diseases is limited and controversial. CPB is responsible for necrotizing enteritis and enterotoxemia, mostly in neonatal individuals of many animal species, including humans. ETX is the main toxin involved in enterotoxemia of sheep and goats. ITX has been implicated in cases of enteritis in rabbits and other animal species; however, its specific role in causing disease has not been proved. CPE is responsible for human food-poisoning and non-foodborne C. perfringens-mediated diarrhea. NetB is the cause of necrotic enteritis in chickens. In most cases, host–toxin interaction starts on the plasma membrane of target cells via specific receptors, resulting in the activation of intracellular pathways with a variety of effects, commonly including cell death. In general, the molecular mechanisms of cell death associated with C. perfringens toxins involve features of apoptosis, necrosis and/or necroptosis. PMID:29786671

[The knowledge, involvement and feelings of students graduating in medicine, nursing and psychology about orthothanasia].

PubMed

dos Santos, Luís Roberto Gonçalves; Menezes, Mariana Pires; Gradvohl, Silvia Mayumi Obana

2013-09-01

Orthothanasia involves the suspension of medical procedures for terminal phase patients, which leads to a natural death, relieving the symptoms that cause suffering. In this process, professionals such as physicians, nurses and psychologists, interact with patients and their families. Therefore, it is desirable that during undergraduate studies these professionals should take subjects geared to handle this aspect. The scope of this qualitative study was to evaluate the awareness with respect to orthothanasia of undergraduates in medicine, nursing and psychology courses in a university. Trigger questions in semi-structured interviews were conducted with 22 students. The interviews were recorded and transcribed for content analysis and core identification themes. Three categories were identified: knowledge about orthothanasia; who should be involved in this process; and feelings experienced when facing death. The data revealed that students have scant knowledge about the subject, consider the family involvement in the orthothanasia decision to be important and they do not feel prepared to deal with death situations. The conclusion points to the need to change the focus on the end-of-life issue in the undergraduate courses in the area of health care in order to prepare the future professional adequately.

Involvement of the CD200 receptor complex in microglia activation in experimental glaucoma

PubMed Central

Taylor, Sarah; Calder, Claudia J.; Albon, Julie; Erichsen, Jonathan T.; Boulton, Micheal E.; Morgan, James E.

2013-01-01

The interaction of the myeloid restricted molecule CD200R with its widely expressed ligand CD200 is involved in the down-regulation of microglia activation. In the present study, we examined the involvement of CD200R in microglia activation in experimental ocular hypertension to determine the role of microglia activation in retinal ganglion cell (RGC) death, the key pathological event in glaucoma. Experimental glaucoma was induced in adult Brown Norway rats by sclerosis of the episcleral veins with the injection of hypertonic saline. Immunohistochemical methods were used to determine the involvement of microglia using GFAP, CD45, OX42 and OX41 and the involvement of CD200 and CD200R in the optic nerve head. Our data demonstrate the increased presence of microglia within the optic nerve head during ocular hypertension, identified by positive staining with OX42 and OX41. The peak of microglia correlates with peak in RGC death at days 20–27 (T3) post OHT induction. In addition, CD200 and CD200R positive cells were increased in ocular hypertensive eyes. Increased expression of CD200 was detected in the early phase (days 1–7; T1) of OHT and decreased over time, whilst the expression of CD200R was detected in the middle phase (days 20–27; T3) of OHT, correlating with the increase in microglia markers. Changes in the expression of CD200R/CD200 occur early in experimental glaucoma and precede the peak in microglia infiltration and RGC death, suggesting that CD200R-positive microglia play an important role in the initiation of RGC death during OHT, indicating a potential area for therapeutic intervention in treating glaucoma. PMID:21296076

Mastoparan-induced programmed cell death in the unicellular alga Chlamydomonas reinhardtii

PubMed Central

Yordanova, Zhenya P.; Woltering, Ernst J.; Kapchina-Toteva, Veneta M.; Iakimova, Elena T.

2013-01-01

Background and Aims Under stress-promoting conditions unicellular algae can undergo programmed cell death (PCD) but the mechanisms of algal cellular suicide are still poorly understood. In this work, the involvement of caspase-like proteases, DNA cleavage and the morphological occurrence of cell death in wasp venom mastoparan (MP)-treated Chlamydomonas reinhardtii were studied. Methods Algal cells were exposed to MP and cell death was analysed over time. Specific caspase inhibitors were employed to elucidate the possible role of caspase-like proteases. YVADase activity (presumably a vacuolar processing enzyme) was assayed by using a fluorogenic caspase-1 substrate. DNA breakdown was evaluated by DNA laddering and Comet analysis. Cellular morphology was examined by confocal laser scanning microscopy. Key Results MP-treated C. reinhardtii cells expressed several features of necrosis (protoplast shrinkage) and vacuolar cell death (lytic vesicles, vacuolization, empty cell-walled corpse-containing remains of digested protoplast) sometimes within one single cell and in different individual cells. Nucleus compaction and DNA fragmentation were detected. YVADase activity was rapidly stimulated in response to MP but the early cell death was not inhibited by caspase inhibitors. At later time points, however, the caspase inhibitors were effective in cell-death suppression. Conditioned medium from MP-treated cells offered protection against MP-induced cell death. Conclusions In C. reinhardtii MP triggered PCD of atypical phenotype comprising features of vacuolar and necrotic cell deaths, reminiscent of the modality of hypersensitive response. It was assumed that depending on the physiological state and sensitivity of the cells to MP, the early cell-death phase might be not mediated by caspase-like enzymes, whereas later cell death may involve caspase-like-dependent proteolysis. The findings substantiate the hypothesis that, depending on the mode of induction and sensitivity of the cells, algal PCD may take different forms and proceed through different pathways. PMID:23250917

All-Cause Mortality for Life Insurance Applicants with a History of Breast Cancer.

PubMed

Freitas, Stephen A; MacKenzie, Ross; Wylde, David N; Roudebush, Bradley T; Bergstrom, Richard L; Holowaty, J Carl; Hart, Anna; Rigatti, Steven J; Gill, Stacy

2017-01-01

Breast cancer is the most commonly diagnosed cancer worldwide. Breast cancer is also the second leading cause of cancer death among women in the United States after lung cancer with over 40,000 breast cancer deaths occurring each year. The purpose of this research was to determine the all-cause mortality of applicants diagnosed with breast cancer currently or at some time in the past. Life insurance applicants with reported breast cancer were extracted from data covering United States residents between November 2007 and November 2014. Information about these applicants was matched to the Social Security Death Master (SSDMF) file for deaths occurring from 2007 to 2011 and to another commercially available death source file (Other Death Source, ODS) for deaths occurring from 2007 to 2014 to determine vital status. If there was a death from the other death source, then the SSDMF was searched to verify the death. The study had approximately 561,000 person-years of exposure. Actual-to-expected (A/E) mortality ratios were calculated using the Society of Actuaries 2008 Valuation Basic Table (2008VBT), select and ultimate table (age last birthday) and the 2010 US population as expected mortality ratios. Since the A/Es presented in this paper were known to be an underestimate due to the exclusion of the recent SSDMF deaths, comparative analysis of the mortality ratios was done. Since there was no smoking status information in this study, all expected bases were not smoker distinct. Overall, the 35-44 age group had 6.3 times the relative mortality ratio than those in the 65-75 age group. The relative mortality ratio for the 35-44 age group applicants, when cancer severity was accounted for in combination with 3 or more nodes of cancer involvement, was 29.3 times that when compared to those in the 65-75 age group having localized cancer, where no nodes are involved. The 35-44 age group applicants who were diagnosed with cancer within the last year had over 10-fold increase in relative mortality ratios compared to the 65-75 age group, who were over 10 years from diagnosis. Taking the severity of cancer along with time from diagnosis showed over a 12 times relative mortality ratio between the low rate of over 10 years from diagnosis and localized involvement to those diagnosed within the last year having 3 or more nodes with cancer. Applicant age, time since diagnosis and cancer severity were the most significant variables to predict the relative mortality ratios.

Commercial fishing industry deaths - forensic issues.

PubMed

Byard, Roger W

2013-04-01

The commercial fishing industry has one of the highest injury and mortality rates of all occupational areas. This results from the nature of the work involving vessels often manned by only a few individuals who are working with heavy-duty equipment in dangerous environments at all hours. Economic pressures may force inappropriately geared vessels to operate further out to sea than is safe. Deaths result from a wide variety of situations involving vessel loss, falls overboard, fire and explosions, cable entanglements and gas exposure. Autopsies are often difficult as there are no diagnostic features of either drowning or hypothermia and features may be obscured by putrefaction and postmortem animal predation. The forensic implications of deaths in the fishing industry are reviewed. Copyright © 2012 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Dignity, death, and dilemmas: a study of Washington hospices and physician-assisted death.

PubMed

Campbell, Courtney S; Black, Margaret A

2014-01-01

The legalization of physician-assisted death in states such as Washington and Oregon has presented defining ethical issues for hospice programs because up to 90% of terminally ill patients who use the state-regulated procedure to end their lives are enrolled in hospice care. The authors recently partnered with the Washington State Hospice and Palliative Care Organization to examine the policies developed by individual hospice programs on program and staff participation in the Washington Death with Dignity Act. This article sets a national and local context for the discussion of hospice involvement in physician-assisted death, summarizes the content of hospice policies in Washington State, and presents an analysis of these findings. The study reveals meaningful differences among hospice programs about the integrity and identity of hospice and hospice care, leading to different policies, values, understandings of the medical procedure, and caregiving practices. In particular, the authors found differences 1) in the language used by hospices to refer to the Washington statute that reflect differences among national organizations, 2) the values that hospice programs draw on to support their policies, 3) dilemmas created by requests by patients for hospice staff to be present at a patient's death, and 4) five primary levels of noninvolvement and participation by hospice programs in requests from patients for physician-assisted death. This analysis concludes with a framework of questions for developing a comprehensive hospice policy on involvement in physician-assisted death and to assist national, state, local, and personal reflection. Copyright © 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Prolactin-induced neuroprotection against glutamate excitotoxicity is mediated by the reduction of [Ca2+]i overload and NF-κB activation

PubMed Central

Rivero-Segura, Nadia A.; Flores-Soto, Edgar; García de la Cadena, Selene; Coronado-Mares, Isabel; Gomez-Verjan, Juan C.; Ferreira, Diana G.; Cabrera-Reyes, Erika Alejandra; Lopes, Luísa V.; Massieu, Lourdes

2017-01-01

Prolactin (PRL) is a peptidic hormone that displays pleiotropic functions in the organism including different actions in the brain. PRL exerts a neuroprotective effect against excitotoxicity produced by glutamate (Glu) or kainic acid in both in vitro and in vivo models. It is well known that Glu excitotoxicity causes cell death through apoptotic or necrotic pathways due to intracellular calcium ([Ca2+] i) overload. Therefore, the aim of the present study was to assess the molecular mechanisms by which PRL maintains cellular viability of primary cultures of rat hippocampal neurons exposed to Glu excitotoxicity. We determined cell viability by monitoring mitochondrial activity and using fluorescent markers for viable and dead cells. The intracellular calcium level was determined by a fluorometric assay and proteins involved in the apoptotic pathway were determined by immunoblot. Our results demonstrated that PRL afforded neuroprotection against Glu excitotoxicity, as evidenced by a decrease in propidium iodide staining and by the decrease of the LDH activity. In addition, the MTT assay shows that PRL maintains normal mitochondrial activity even in neurons exposed to Glu. Furthermore, the Glu-induced intracellular [Ca2+]i overload was attenuated by PRL. These data correlate with the reduction found in the level of active caspase-3 and the pro-apoptotic ratio (Bax/Bcl-2). Concomitantly, PRL elicited the nuclear translocation of the transcriptional factor NF-κB, which was detected by immunofluorescence and confocal microscopy. To our knowledge, this is the first report demonstrating that PRL prevents Glu excitotoxicity by a mechanism involving the restoration of the intracellular calcium homeostasis and mitochondrial activity, as well as an anti-apoptotic action possibly mediated by the activity of NF-κB. Overall, the current results suggest that PRL could be of potential therapeutic advantage in the treatment of neurodegenerative diseases. PMID:28475602

Regulatory mechanism of the flavoprotein Tah18-dependent nitric oxide synthesis and cell death in yeast.

PubMed

Yoshikawa, Yuki; Nasuno, Ryo; Kawahara, Nobuhiro; Nishimura, Akira; Watanabe, Daisuke; Takagi, Hiroshi

2016-07-01

Nitric oxide (NO) is a ubiquitous signaling molecule involved in the regulation of a large number of cellular functions. The regulatory mechanism of NO generation in unicellular eukaryotic yeast cells is poorly understood due to the lack of mammalian and bacterial NO synthase (NOS) orthologues, even though yeast produces NO under oxidative stress conditions. Recently, we reported that the flavoprotein Tah18, which was previously shown to transfer electrons to the iron-sulfur cluster protein Dre2, is involved in NOS-like activity in the yeast Saccharomyces cerevisiae. On the other hand, Tah18 was reported to promote apoptotic cell death after exposure to hydrogen peroxide (H2O2). Here, we showed that NOS-like activity requiring Tah18 induced cell death upon treatment with H2O2. Our experimental results also indicate that Tah18-dependent NO production and cell death are suppressed by enhancement of the interaction between Tah18 and its molecular partner Dre2. Our findings indicate that the Tah18-Dre2 complex regulates cell death as a molecular switch via Tah18-dependent NOS-like activity in response to environmental changes. Copyright © 2016 Elsevier Inc. All rights reserved.

Reducing death on the road: the effects of minimum safety standards, publicized crash tests, seat belts, and alcohol.

PubMed Central

Robertson, L S

1996-01-01

OBJECTIVES. Two phases of attempts to improve passenger car crash worthiness have occurred: minimum safety standards and publicized crash tests. This study evaluated these attempts, as well as changes in seat belt and alcohol use, in terms of their effect on occupant death and fatal crash rates. METHODS. Data on passenger car occupant fatalities and total involvement in fatal crashes, for 1975 through 1991, were obtained from the Fatal Accident Reporting System. Rates per mile were calculated through published sources on vehicle use by vehicle age. Regression estimates of effects of regulation, publicized crash tests, seat belt use and alcohol involvement were obtained. RESULTS. Substantial reductions in fatalities occurred in the vehicle model years from the late 1960s through most of the 1970s, when federal standards were applied. Some additional increments in reduced death rates, attributable to additional improved vehicle crashworthiness, occurred during the period of publicized crash tests. Increased seat belt use and reduced alcohol use also contributed significantly to reduced deaths. CONCLUSIONS. Minimum safety standards, crashworthiness improvements, seat belt use laws, and reduced alcohol use each contributed to a large reduction in passenger car occupant deaths. PMID:8561238

The role of alcohol use on recent trends in distracted driving.

PubMed

Wilson, Fernando A; Stimpson, Jim P; Tibbits, Melissa K

2013-11-01

Distracted driving is now an increasingly deadly threat to road safety. We provide evidence that intoxicated driving is increasingly responsible for recent increases in fatalities from distracted driving crashes. This study describes trends in deaths on U.S. public roads caused by alcohol-involved and distracted drivers using the Fatality Analysis Reporting System (FARS)-a census of fatal crashes on U.S. public roads. Fatality rates per vehicle-miles traveled are calculated using data from the Federal Highway Administration. Alcohol-involved drivers who are simultaneously distracted were responsible for 1750 deaths in 2009, an increase of more than 63% from 2005 when there were 1072 deaths. Alcohol use while driving is increasingly responsible for a growing number of fatalities from distracted driving, accounting for 32% of deaths from distracted driving in 2009 versus 24% in 2005. The fatality rate from these crashes increased from 35.9 to 59.2 deaths per 100 billion vehicle-miles traveled after 2005. Alcohol use is quickly increasing as an important factor behind distracted driving fatalities. This has implications for policies combating distracted driving that do not address the role of alcohol use in distracted driving. Copyright © 2013 Elsevier Ltd. All rights reserved.

Outcome of Lateral Transfer of the FHL or FDL for Concomitant Peroneal Tendon Tears.

PubMed

Seybold, Jeffrey D; Campbell, John T; Jeng, Clifford L; Short, Kelly W; Myerson, Mark S

2016-06-01

Concomitant tears of the peroneus longus and brevis tendons are rare injuries, with literature limited to case reports and small patient series. Only 1 recent study directly compared the results of single-stage lateral deep flexor transfer, and no previous series objectively evaluated power and balance following transfer. The purpose of this study was to evaluate clinical outcomes, patient satisfaction, and objective power and balance data following single-stage flexor hallucis longus (FHL) and flexor digitorum longus (FDL) tendon transfers for treatment of concomitant peroneus longus and brevis tears. Over an 8-year period (2005-2012), 9 patients underwent lateral transfer of the FHL or FDL tendon for treatment of concomitant peroneus longus and brevis tears. All but 1 patient underwent additional procedures to address hindfoot malalignment or other contributing deformity at the time of surgery. Mean age was 56.9 years, and average body mass index was 27.9. Lateral transfer of the FHL was performed in 5 patients, and FDL transfer performed in 4 with mean follow-up 35.7 months (range: 11-94). Eight of 9 patients completed SF-12 and Foot Function Index (FFI) scores, and 7 returned for range of motion (ROM) and manual strength testing of the involved and normal extremities. These 7 patients also completed force plate balance tests, in addition to peak force and power testing on a PrimusRS machine with a certified physical therapist. All patients were satisfied with the results of the procedure. Mean SF-12 physical and mental scores were 32 and 55, respectively; mean FFI total score was 56.7. No postoperative infections were noted. Two patients continued to utilize orthotics or braces, and 2 patients reported occasional pain with weightbearing activity. Three patients noted mild paresthesias in the distribution of the sural nerve and 2 demonstrated tibial neuritis. All patients demonstrated 4/5 eversion strength in the involved extremity. Average loss of inversion and eversion ROM were 24.7% and 27.2% of normal, respectively. Mean postoperative eversion peak force and power were decreased greater than 55% relative to the normal extremity. Patients demonstrated nearly 50% increases in both center-of-pressure tracing length and velocity during balance testing. There were no statistically significant differences between the FHL and FDL transfer groups with regards to clinical examination or objective power and balance tests. The FHL and FDL tendons were both successful options for lateral transfer in cases of concomitant peroneus longus and brevis tears. Objective measurements of strength and balance demonstrated significant deficits in the operative extremity, even years following the procedure. These differences, however, did not appear to alter or inhibit patient activity levels or high satisfaction rates with the procedure. Although anatomic studies have demonstrated benefits of FHL transfer over the FDL tendon, further studies with increased patient numbers are needed to determine if these differences are clinically significant. Level IV, retrospective case series. © The Author(s) 2016.

Primary prevention of sudden cardiac death of the young athlete: the controversy about the screening electrocardiogram and its innovative artificial intelligence solution.

PubMed

Chang, Anthony C

2012-03-01

The preparticipation screening for athlete participation in sports typically entails a comprehensive medical and family history and a complete physical examination. A 12-lead electrocardiogram (ECG) can increase the likelihood of detecting cardiac diagnoses such as hypertrophic cardiomyopathy, but this diagnostic test as part of the screening process has engendered considerable controversy. The pro position is supported by argument that international screening protocols support its use, positive diagnosis has multiple benefits, history and physical examination are inadequate, primary prevention is essential, and the cost effectiveness is justified. Although the aforementioned myriad of justifications for routine ECG screening of young athletes can be persuasive, several valid contentions oppose supporting such a policy, namely, that the sudden death incidence is very (too) low, the ECG screening will be too costly, the false-positive rate is too high, resources will be allocated away from other diseases, and manpower is insufficient for its execution. Clinicians, including pediatric cardiologists, have an understandable proclivity for avoiding this prodigious national endeavor. The controversy, however, should not be focused on whether an inexpensive, noninvasive test such as an ECG should be mandated but should instead be directed at just how these tests for young athletes can be performed in the clinical imbroglio of these disease states (with variable genetic penetrance and phenotypic expression) with concomitant fiscal accountability and logistical expediency in this era of economic restraint. This monumental endeavor in any city or region requires two crucial elements well known to business scholars: implementation and execution. The eventual solution for the screening ECG dilemma requires a truly innovative and systematic approach that will liberate us from inadequate conventional solutions. Artificial intelligence, specifically the process termed "machine learning" and "neural networking," involves complex algorithms that allow computers to improve the decision-making process based on repeated input of empirical data (e.g., databases and ECGs). These elements all can be improved with a national database, evidence-based medicine, and in the near future, innovation that entails a Kurzweilian artificial intelligence infrastructure with machine learning and neural networking that will construct the ultimate clinical decision-making algorithm.

Causes of unintentional deaths from carbon monoxide poisonings in California.

PubMed Central

Girman, J R; Chang, Y L; Hayward, S B; Liu, K S

1998-01-01

The purpose of this study was to determine the annual number and incidence of unintentional deaths from carbon monoxide (CO) poisonings in California and to identify specific factors that caused or contributed to the deaths. Unintentional CO deaths in California over a ten-year period (1979 to 1988) were identified from the database of the California Master Mortality File and coroners' investigation reports. Factors associated with unintentional CO deaths were determined based on the information from the investigation reports. The annual number of unintentional CO deaths varied from 27 to 58 over the ten years examined, with an average annual death incidence of 1.7 x 10(-6). Death rates were high among males and African-Americans. Alcohol appeared to be a factor in 31% of the cases. The types of combustion sources associated with unintentional CO deaths were: heating or cooking appliances; motor vehicles; charcoal grills and hibachis; small engines; and camping equipment. Factors associated with unintentional CO deaths interact in a complex way. To reduce the rate of unintentional CO deaths effectively, joint efforts involving several prevention methods are suggested. PMID:9549414

Audit of sharp weapon deaths in metropolis of Karachi--an autopsy based study.

PubMed

Mirza, Farhat Hussain; Hasan, Qudsia; Memon, Akhtar Amin; Adil, Syeda Ezz-e-Rukhshan

2010-01-01

Sharp weapons are one of the most violent and abhorrent means of deaths. This study assesses the frequency of sharp weapon deaths in Karachi. This was a cross sectional study, and involves the deaths by sharp weapons autopsied in Karachi during Mar 2008-Feb 2009. This study reports that the frequency of sharp weapon deaths in Karachi is similar to some other studies conducted in different regions of Pakistan, yet it is very high as the population of Karachi is way more than any other metropolis of Pakistan. Our study reported that out of 2090 medico-legal deaths in Karachi during the study period, 91 deaths were due to sharp weapons, including 73 (80.2%) males and 18 (19.8%) females. 100% of the deaths were homicides, so none were suicides. Deaths were more frequent in age group ranging from 20-39 years (59.3%). Sharp weapon deaths continue to be a means of quite a number of deaths in Karachi. Such violence depicts intolerant and frustrated nature of the citizens.

A case of late-onset, thymoma-associated myasthenia gravis with ryanodine receptor and titin antibodies and concomitant granulomatous myositis.

PubMed

Stefanou, M I; Komorowski, L; Kade, S; Bornemann, A; Ziemann, U; Synofzik, M

2016-09-13

Myasthenia gravis is an autoimmune neuromuscular disorder, which has only rarely been reported to co-manifest with myositis. The diagnosis of concomitant myositis in patients with myasthenia gravis is clinically challenging, and requires targeted investigations for the differential diagnosis, including EMG, autoantibody assays, muscle biopsy and, importantly, imaging of the mediastinum for thymoma screening. This report presents a case-vignette of a 72-year-old woman with progressive proximal muscle weakness and myalgias, diagnosed with thymoma-associated myasthenia and bioptically verified granulomatous myositis, with positive autoantibody status for ryanodine receptor and titin antibodies. The diagnosis of concurrent myositis and myasthenia gravis, especially in the presence of ryanodine receptor and titin antibodies, should lead neurologists to adopt different treatment strategies compared to those applied in myasthenia or myositis alone. Moreover, further evidence is warranted that titin and, particularly, ryanodine receptor antibodies may co-occur or be pathophysiologically involved in myasthenia-myositis cases.

Concomitant Ordering and Symmetry Lowering

ERIC Educational Resources Information Center

Boo, William O. J.; Mattern, Daniell L.

2008-01-01

Examples of concomitant ordering include magnetic ordering, Jahn-Teller cooperative ordering, electronic ordering, ionic ordering, and ordering of partially-filled sites. Concomitant ordering sets in when a crystal is cooled and always lowers the degree of symmetry of the crystal. Concomitant ordering concepts can also be productively applied to…

Surveillance for violent deaths--National Violent Death Reporting System, 16 states, 2005.

PubMed

Karch, Debra L; Lubell, Keri M; Friday, Jennifer; Patel, Nimesh; Williams, Dionne D

2008-04-11

An estimated 50,000 persons die annually in the United States as a result of violence-related injuries. This report summarizes data from CDC's National Violent Death Reporting System (NVDRS) regarding violent deaths from 16 U.S. states for 2005. Results are reported by sex, age group, race/ethnicity, marital status, location of injury, method of injury, circumstances of injury, and other selected characteristics. 2005. NVDRS collects data regarding violent deaths obtained from death certificates, coroner/medical examiner reports, and law enforcement reports. NVDRS began operation in 2003 with seven states (Alaska, Maryland, Massachusetts, New Jersey, Oregon, South Carolina, and Virginia) participating; six states (Colorado, Georgia, North Carolina, Oklahoma, Rhode Island, and Wisconsin) joined in 2004 and four (California, Kentucky, New Mexico, and Utah) in 2005, for a total of 17 states. This report includes data from 16 states; data from California are not included in this report because NVDRS has been implemented only in a limited number of California cities and counties rather than statewide as in other states. For 2005, a total of 15,495 fatal incidents involving 15,962 violent deaths occurred in the 16 NVDRS states included in this report. The majority (56.1%) of deaths were suicides, followed by homicides and deaths involving legal interventions (29.6%), violent deaths of undetermined intent (13.3%), and unintentional firearm deaths (0.7%). Fatal injury rates varied by sex, race/ethnicity, age group, and method of injury. Rates were substantially higher for males than for females and for American Indians/Alaska Natives (AI/ANs) and blacks than for whites and Hispanics. Rates were highest for persons aged 20-24 years. For method of injury, the three highest rates were reported for firearms, poisonings, and hanging/strangulation/suffocation. Suicides occurred at higher rates among males, AI/ANs, whites, and older persons and most often involved the use of firearms in the home. Suicides were precipitated primarily by mental illness, intimate partner or physical health problems, or a crisis during the previous 2 weeks. Homicides occurred at higher rates among males and young adult blacks and most often involved the use of firearms in the home or on a street/highway. Homicides were precipitated primarily by an argument over something other than money or property or in conjunction with another crime. Similar variation was reported among the other manners of death and special situations or populations highlighted in this report. This report provides the first detailed summary of data concerning violent deaths collected by NVDRS. The results indicate that deaths resulting from self-inflicted or interpersonal violence occur to a varying extent among males and females of every age group and racial/ethnic population. Key factors affecting rates of violent fatal injuries include sex, age group, method of injury, location of injury, and precipitating circumstances (e.g., mental health and substance abuse). Because additional information might be reported subsequently as participating states update their findings, the data provided in this report are preliminary. Accurate, timely, and comprehensive surveillance data are necessary for the occurrence of violent deaths in the United States to be understood better and ultimately prevented. NVDRS data can be used to track the occurrence of violence-related fatal injuries and assist public health authorities in the development, implementation, and evaluation of programs and policies to reduce and prevent violent deaths and injuries at the national, state, and local levels. The continued development and expansion of NVDRS is essential to CDC's efforts to reduce the personal, familial, and societal costs of violence. Further efforts are needed to increase the number of states using NVDRS, with an ultimate goal of full national representation.