Pheochromocytoma presenting as an acute coronary syndrome complicated by acute heart failure: The challenge of a great mimic.

PubMed

Sanna, Giuseppe Damiano; Talanas, Giuseppe; Fiore, Giuseppina; Canu, Antonella; Terrosu, Pierfranco

2016-10-01

Pheochromocytoma is a rare neuroendocrine tumor with a highly variable clinical presentation. The serious and potentially lethal cardiovascular complications of these tumors are related to the effects of secreted catecholamines. We describe a case of a 50-year-old woman urgently admitted to our hospital because of symptoms and clinical and instrumental findings consistent with an acute coronary syndrome complicated by acute heart failure. Urgent coronary angiography showed normal coronary arteries. During her hospital stay, the recurrence of episodes characterized by a sudden increase in blood pressure, cold sweating, and nausea allowed us to hypothesize a pheochromocytoma. The diagnosis was confirmed by elevated levels of urinary catecholamines and by the finding of a left adrenal mass on magnetic resonance imaging. The patient underwent left adrenalectomy. Therefore, the initial diagnosis was critically reappraised and reviewed as a cardiac manifestation of a pheochromocytoma during catecholaminergic crisis.

[Prognostic value of the lethal triad among patients with multiple trauma].

PubMed

González Balverde, María; Ramírez Lizardo, Ernesto J; Cardona Muñoz, Ernesto G; Totsuka Sutto, Sylvia E; García Benavides, Leonel

2013-11-01

Patients who have suffered multiple traumatic injuries, have a serious risk for death. Hypothermia, acidosis and coagulopathy are three complications in these patients, whose presence is known as lethal triad and indicates bad prognosis. To determine if the lethal triad in multiple trauma patients is associated with higher mortality and Injury Score Severity (ISS). One hundred multiple trauma patients aged 26 to 56 years (90 males), admitted to an emergency room, were studied. Body temperature, prothrombin time, partial thromboplastin time, platelet count and blood gases were determined on admission. Twenty six patients had the lethal triad and 15% died in the emergency room within the first 6 hours. No death was recorded among the 74 patients without the lethal triad. The mean ISS among patients with and without the lethal triad was 31.7 and 25.6, respectively (p < 0.05). The presence of the lethal triad among patients with multiple trauma is associated with a higher mortality and ISS.

Justified Concern or Exaggerated Fear: The Risk of Anaphylaxis in Percutaneous Treatment of Cystic Echinococcosis—A Systematic Literature Review

PubMed Central

Neumayr, Andreas; Troia, Giuliana; de Bernardis, Chiara; Tamarozzi, Francesca; Goblirsch, Sam; Piccoli, Luca; Hatz, Christoph; Filice, Carlo; Brunetti, Enrico

2011-01-01

Percutaneous treatment (PT) emerged in the mid-1980s as an alternative to surgery for selected cases of abdominal cystic echinococcosis (CE). Despite its efficacy and widespread use, the puncture of echinococcal cysts is still far from being universally accepted. One of the main reasons for this reluctance is the perceived risk of anaphylaxis linked to PTs. To quantify the risk of anaphylactic reactions and lethal anaphylaxis with PT, we systematically searched MEDLINE for publications on PT of CE and reviewed the PT-related complications. After including 124 publications published between 1980 and 2010, we collected a total number of 5943 PT procedures on 5517 hepatic and non-hepatic echinococcal cysts. Overall, two cases of lethal anaphylaxis and 99 reversible anaphylactic reactions were reported. Lethal anaphylaxis occurred in 0.03% of PT procedures, corresponding to 0.04% of treated cysts, while reversible allergic reactions complicated 1.7% of PTs, corresponding to 1.8% of treated echinococcal cysts. Analysis of the literature shows that lethal anaphylaxis related to percutaneous treatment of CE is an extremely rare event and is observed no more frequently than drug-related anaphylactic side effects. PMID:21695106

Disc erosion in Models 103 and 104 of Beall mitral valve prostheses

PubMed Central

Gómez, Ricardo; Verduras, María José; Lopez-Quintana, Alfonso; Riera, Luis; Zerolo, Ignacio; Martinez-Bordiu, Cristóbal

1981-01-01

Three cases of severe disc variance and erosion of the Teflon-disc Beall mitral valve prosthesis (Models 103 and 104) are reported. In two patients, the Beall mitral valves were excised and replaced with two Björk-Shiley mitral valves. The remaining patient did not survive, and at autopsy, the lens was found at the aortic bifurcation level. Because of this potentially lethal complication, careful follow-up of patients with Beall mitral valve prostheses (Models 103 and 104) is recommended. Images PMID:15216211

Hyperbaric oxygen therapy with topical negative pressure: an alternative treatment for the refractory sternal wound infection.

PubMed

Sun, I-Feng; Lee, Su-Shin; Chiu, Chaw-Chi; Lin, Sin-Daw; Lai, Chung-Sheng

2008-01-01

Sternal osteomyelitis is a potentially lethal complication after cardiac surgery. It may be the cause of postoperative morbidity and mortality. We present a case of deep sternal wound infection after sternotomy. The patient received three treatments of surgical debridement, irrigation, topical negative pressure (TNP) dressing, and hyperbaric oxygen (HBO) therapy. Forty-five HBO therapy sessions were administered. After nine weeks, the sternal wound was healed and completely epithelialized. This conservative therapy can be an alternative and inexpensive method for the difficult sternal wound infection patient.

Role of susceptibility-weighted imaging in demonstration of cerebral fat embolism

PubMed Central

Yeap, Pheyming; Kanodia, Avinash Kumar; Main, Gavin; Yong, Aiwain

2015-01-01

Cerebral fat embolism (CFE) is a rare but potentially lethal complication of long bone fractures. Many cases of CFE occur as subclinical events and remain undiagnosed. We report a case of a 22-year-old man, with multiple long bone fractures from a road traffic accident, who subsequently developed hypoxia, neurological abnormality and petechial rash. CT of the head was normal. MRI of the head confirmed the diagnosis with lesions markedly conspicuous and most widespread on susceptibility-weighted imaging as compared to all other sequences including diffusion-weighted imaging. PMID:25572601

[Antibacterial prevention of suppurative complications after operations on the large intestine].

PubMed

Kuzin, M I; Pomelov, V S; Vandiaev, G K; Ialgashev, T Ia; Blatun, L A

1983-05-01

The data on comparative study of complications after operations on the large intestine are presented. During the preoperative period, 62 patients of the control group were treated with phthalylsulfathiazole, nevigramon and nystatin. Thirty-nine patients of the test group were treated with metronidazole and kanamycin monosulfate. Kanamycin monosulfate was used 3 days before the operation in a dose of 0.5 g orally 4 times a day whereas metronidazole in a dose of 0.5 g 3 times a day. The last doses of the drugs were administered 4-5 hours before the operation. After the operations the patients were treated with kanamycin sulfate for 3-5 days in a daily dose of 2 g intramuscularly. The number of the postoperative suppurative complications decreased from 22 to 5 per cent. No lethal outcomes were registered in the test group. The number of lethal outcomes in the control group amounted to 8 per cent.

[The choice of resection volume by the combination of perforative duodenal ulcer with other complications of the ulcer disease].

PubMed

Vachev, A N; Korytsev, V K; Antropov, I V

2013-01-01

Treatment results of 59 patients with the complicated ulcer disease were analyzed. Authors prove, that in cases of perforative duodenal ulcer, the operation should aim the treatment of all the complications. The use of 2/3 gaster resection in combination with Jadd pyloroplasty and trunk vagotomy led to the decrease of the lethality rate on 21%.

The morbidity and survival of 196 consecutive cases undergoing liver transplantation in a single center in Mainland China: ten-year experience.

PubMed

Chen, Peixian; Wang, Wentao; Yan, Lunan

2014-01-13

Right lobar living donor living transplantation (LDLT) has been controversial because of widely differing reports of recipient morbidity. Herein, we present our nearly 10-year experience and identify factors that potentially could be modified to improve recipient outcome. The Clavien 5-tier grading system was applied retrospectively in 196 consecutive adult right lobar recipients. We determined the incidence of potentially life- threatening (Grade III), actually life-threatening (Grade IV), and lethal (Grade V) complications during the first post-transplant year. The most serious and seminal complication was considered if simultaneous or multiple complications appeared. One-year recipient/graft survival was 82%/82%. Within the first year, 68 (34.69%) of the 196 recipients had Grade III (n=31), Grade IV (n=7), or Grade V (n=30) complications. The complications were 19.90% graft-related and 15.82% non-graft-related. Complications during the first half year did not decline with increased team experience over time and adversely affected recipients' long-term survival, albeit not significantly. According to univariate analysis, high Child-Pugh scores before transplantation (P=0.016), prolonged ICU-stay (P=0.003) and hospitalization time (P=0.032) after transplantation were found to be risk factors for the appearance of ≥ Clavien III complications, while duct-to-duct biliary reconstruction (P=0.02) had a beneficial role in reducing serious complications after LDLTs. In conclusion, serious complications during the first post-transplant year shortened recipient survival and prolonged primary hospitalization duration and postoperative ICU-stay, which is more frequent in recipients with higher Child-Pugh scores and in those with hepaticojejunostomy.

[Hypophosphatasia: Clinical manifestations, diagnostic recommendations and therapeutic options].

PubMed

Martos-Moreno, Gabriel A; Calzada, Joan; Couce, María L; Argente, Jesús

2018-06-01

Hypophosphatasia is a very rare bone metabolism disorder caused by a deficiency in alkaline phosphatase activity, due to mutations in the ALPL gene. Its clinical hallmark is the impairment of skeletal and teeth mineralisation, although extra-skeletal manifestations are frequent. Its phenotypic spectrum is widely variable from a subtype with exclusive odontological impairment (odontohypophosphatasia) to five subtypes with systemic involvement, classified according to the age at the onset of the first symptoms (four of them in the paediatric age range: perinatal lethal, perinatal benign, infant and childhood hypophosphatasia). Those subtypes of hypophosphatasia with an earliest onset usually involve a worse prognosis, due to the risk of developing potentially lethal complications, such as seizures or severe respiratory insufficiency, secondary to rib cage malformations. Due to the extremely low prevalence of the severe forms of hypophosphatasia, its clinical variability and overlapping phenotypic features with several more prevalent conditions, the diagnosis of hypophosphatasia in the clinical setting is challenging. However, its potential lethality and impact on the patient's quality of life, along with the recent availability of an enzyme replacement therapy, increases the relevance of the early and accurate identification of patients affected with hypophosphatasia. On the basis of published evidence and clinical experience, this article suggests an algorithm with practical recommendations for the differential diagnosis of childhood hypophosphatasia, as well as an updated review of current therapeutic options. Copyright © 2017 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

[Staged treatment of patients with external small bowel fistulas].

PubMed

Vorob'ev, S A; Levchik, E Iu

2008-01-01

Results of staged treatment of small bowel fistulas in 115 patients were analyzed. Staged treatment of 21.7% of patients resulted in healing the fistulas without operations. Modern methods of nutritional maintenance were shown to allow surgical restorative treatment to be performed in the optimal period in 82.2% of patients. The number of postoperative complications and lethality rate were reduced to 5.6%, general lethality to 7.8%.

Soft tissue gas gangrene: a severe complication of emphysematous cholecystitis.

PubMed

Safioleas, Michael; Stamatakos, Michael; Kanakis, Meletios; Sargedi, Constantina; Safioleas, Constantinos; Smirnis, Anastasios; Vaiopoulos, George

2007-12-01

Soft tissue gas gangrene with myonecrosis is a severe complication of traumatic and non-traumatic conditions with a potentially lethal outcome. Emphysematous cholecystitis is a complication of acute cholecystitis, which is characterized by air accumulation in the gallbladder wall and is reported in the literature as a rare causative factor of soft tissue gas gangrene. Here we report 4 patients who developed soft tissue gas gangrene as a complication of emphysematous cholecystitis. Two patients were female octogenarians (one with a history of diabetes mellitus), and underwent percutaneous trans-gallbladder drainage and fascia incisions of the affected soft tissue with prompt administration of antibiotics. Finally, both of them died. The other two patients were male (32 years old diabetic and 47 years old with a history of chronic alcoholism). They underwent open cholecystectomy. Fascia incisions of the gangrenous areas and antibiotic therapy administration were also performed. Both of them were discharged from the hospital and are currently in excellent clinical status. We also present the ultrasonographic and/or radiologic images of these four patients. Soft tissue gas gangrene may complicate emphysematous cholecystitis, and clinicians should be aware of the coexistence of these two clinical conditions, since immediate management is needed in order to prevent fatal outcome.

The Effect of Oseltamivir on the Disease Progression of Lethal Influenza A Virus Infection: Plasma Cytokine and miRNA Responses in a Mouse Model

PubMed Central

Chockalingam, Ashok K.; Hamed, Salaheldin; Goodwin, David G.; Rosenzweig, Barry A.; Pang, Eric; Boyne II, Michael T.

2016-01-01

Lethal influenza A virus infection leads to acute lung injury and possibly lethal complications. There has been a continuous effort to identify the possible predictors of disease severity. Unlike earlier studies, where biomarkers were analyzed on certain time points or days after infection, in this study biomarkers were evaluated over the entire course of infection. Circulating proinflammatory cytokines and/or miRNAs that track with the onset and progression of lethal A/Puerto Rico/8/34 (PR8) influenza A virus infection and their response to oseltamivir treatment were investigated up to 10 days after infection. Changes in plasma cytokines (IL-1β, IL-10, IL-12p70, IL-6, KC, TNF-α, and IFN-γ) and several candidate miRNAs were profiled. Among the cytokines analyzed, IL-6 and KC/GRO cytokines appeared to correlate with peak viral titer. Over the selected 48 miRNAs profiled, certain miRNAs were up- or downregulated in a manner that was dependent on the oseltamivir treatment and disease severity. Our findings suggest that IL-6 and KC/GRO cytokines can be a potential disease severity biomarker and/or marker for the progression/remission of infection. Further studies to explore other cytokines, miRNAs, and lung injury proteins in serum with different subtypes of influenza A viruses with varying disease severity may provide new insight into other unique biomarkers. PMID:27110056

Gold nanostructure materials in diabetes management

NASA Astrophysics Data System (ADS)

Si, Satyabrata; Pal, Arttatrana; Mohanta, Jagdeep; Sagar Satapathy, Smith

2017-04-01

Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia, and is now one of the most non-communicable diseases globally and can be lethal if not properly controlled. Prolonged exposure to chronic hyperglycemia, without proper management, can lead to various vascular complications and represents the main cause of morbidity and mortality in diabetes patients. Studies have indicated that major long-term complications of diabetes arise from persistent oxidative-nitrosative stress and dysregulation in multiple metabolic pathways. Presently, the main focus for diabetes management is to optimize the available techniques to ensure adequate blood sugar level, blood pressure and lipid profile, thereby minimizing the diabetes complications. In this regard, nanomedicine utilizing gold nanostructures has great potential and seems to be a promising option. The present review highlights the basic concepts and up-to-date literature survey of gold nanostructure materials in management of diabetes in several ways, which include sensing, imaging, drug delivery and therapy. The work can be of interest to various researchers working on basic and applied sciences including nanosciences.

Should we consider IgG hypogammaglobulinemia a risk factor for severe complications of Ludwig angina?

PubMed Central

Baez-Pravia, Orville V.; Díaz-Cámara, Miriam; De La Sen, Oscar; Pey, Carlos; Ontañón Martín, Mercedes; Jimenez Hiscock, Luis; Morató Bellido, Begoña; Córdoba Sánchez, Ángel Luis

2017-01-01

Abstract Rationale: Cervical necrotizing fasciitis (CNF) and descending necrotizing mediastinitis (DNM) are rare forms of complication of Ludwig angina. These potentially lethal infections are difficult to recognize in early stages and are often associated with predisposing factors like diabetes and immunocompromised states. Moreover, IgG hypogammaglobulinemia (hypo-IgG) is considered to be a risk factor of mortality in patients with septic shock; however, it is not routinely quantified in patients with extremely serious infections, particularly in cases with no history or evidence of immunocompromising disorders. Patient concerns: We present a case of a 58-year-old woman who survived Ludwig angina, complicated by CNF and DNM. Despite a rapid diagnosis, aggressive surgical debridement and broad-spectrum antibiotics, the infection and necrosis advanced, requiring multiple surgical interventions and long intensive care unit (ICU) support. Conclusion: We hypothesize that detecting a low level of endogenous IgG and treating with adjuvant passive immunotherapy was key in determining a favorable outcome. PMID:29381958

Traumatic Pancreatitis: A Rare Complication of Cardiopulmonary Resuscitation.

PubMed

Aziz, Muhammad

2017-08-17

An elderly gentleman was successfully revived after undergoing cardiopulmonary resuscitation (CPR) for cardiac arrest. Post CPR, the patient developed acute pancreatitis which was likely complication of inappropriately delivered chest compressions which caused further complications and resulted in the death of the patient. This case underlines the importance of quality chest compressions that includes correct placement of hands by the operator giving chest compressions to avoid lethal injuries to the receiver.

Development of Eczema Vaccinatum in Atopic Mouse Models and Efficacy of MVA Vaccination against Lethal Poxviral Infection

PubMed Central

Knitlova, Jarmila; Hajkova, Vera; Voska, Ludek; Elsterova, Jana; Obrova, Barbora; Melkova, Zora

2014-01-01

Smallpox vaccine based on live, replicating vaccinia virus (VACV) is associated with several potentially serious and deadly complications. Consequently, a new generation of vaccine based on non-replicating Modified vaccinia virus Ankara (MVA) has been under clinical development. MVA seems to induce good immune responses in blood tests, but it is impossible to test its efficacy in vivo in human. One of the serious complications of the replicating vaccine is eczema vaccinatum (EV) occurring in individuals with atopic dermatitis (AD), thus excluding them from all preventive vaccination schemes. In this study, we first characterized and compared development of eczema vaccinatum in different mouse strains. Nc/Nga, Balb/c and C57Bl/6J mice were epicutaneously sensitized with ovalbumin (OVA) or saline control to induce signs of atopic dermatitis and subsequently trans-dermally (t.d.) immunized with VACV strain Western Reserve (WR). Large primary lesions occurred in both mock- and OVA-sensitized Nc/Nga mice, while they remained small in Balb/c and C57Bl/6J mice. Satellite lesions developed in both mock- and OVA-sensitized Nc/Nga and in OVA-sensitized Balb/c mice with the rate 40–50%. Presence of mastocytes and eosinophils was the highest in Nc/Nga mice. Consequently, we have chosen Nc/Nga mice as a model of AD/EV and tested efficacy of MVA and Dryvax vaccinations against a lethal intra-nasal (i.n.) challenge with WR, the surrogate of smallpox. Inoculation of MVA intra-muscularly (i.m.) or t.d. resulted in no lesions, while inoculation of Dryvax t.d. yielded large primary and many satellite lesions similar to WR. Eighty three and 92% of mice vaccinated with a single dose of MVA i.m. or t.d., respectively, survived a lethal i.n. challenge with WR without any serious illness, while all Dryvax-vaccinated animals survived. This is the first formal prove of protective immunity against a lethal poxvirus challenge induced by vaccination with MVA in an atopic organism. PMID:25486419

Liver failure due to antithyroid drugs: report of a case and literature review.

PubMed

Livadas, Sarantis; Xyrafis, Xenofon; Economou, Frangiskos; Boutzios, Georgios; Christou, Maria; Zerva, Aristea; Karachalios, Athanasios; Palioura, Helen; Palimeri, Sotiria; Diamanti-Kandarakis, Evanthia

2010-08-01

Hyperthyroidism is a common endocrine disorder affecting 2% of females and 0.5% of males worldwide and antithyroid drugs constitute the first line of treatment in the majority of cases. These agents may cause severe adverse effects and among them liver failure, although rare, is a potential lethal one. This case illustrates the sudden and abrupt deterioration of hepatic function due to antithyroid drug administration. This case along with a concise literature review is presented aiming to increase the awareness of endocrinologists of possible fatal complications from the everyday use of common agents such as antithyroid drugs.

Role of susceptibility-weighted imaging in demonstration of cerebral fat embolism.

PubMed

Yeap, Pheyming; Kanodia, Avinash Kumar; Main, Gavin; Yong, Aiwain

2015-01-08

Cerebral fat embolism (CFE) is a rare but potentially lethal complication of long bone fractures. Many cases of CFE occur as subclinical events and remain undiagnosed. We report a case of a 22-year-old man, with multiple long bone fractures from a road traffic accident, who subsequently developed hypoxia, neurological abnormality and petechial rash. CT of the head was normal. MRI of the head confirmed the diagnosis with lesions markedly conspicuous and most widespread on susceptibility-weighted imaging as compared to all other sequences including diffusion-weighted imaging. 2015 BMJ Publishing Group Ltd.

Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies Patients With Undiagnosed APS1.

PubMed

Eriksson, Daniel; Dalin, Frida; Eriksson, Gabriel Nordling; Landegren, Nils; Bianchi, Matteo; Hallgren, Åsa; Dahlqvist, Per; Wahlberg, Jeanette; Ekwall, Olov; Winqvist, Ola; Catrina, Sergiu-Bogdan; Rönnelid, Johan; Hulting, Anna-Lena; Lindblad-Toh, Kerstin; Alimohammadi, Mohammad; Husebye, Eystein S; Knappskog, Per Morten; Rosengren Pielberg, Gerli; Bensing, Sophie; Kämpe, Olle

2018-01-01

Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1. To determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease. We systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE. In total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure. We propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications. Copyright © 2017 Endocrine Society

Reversible second degree atrioventricular block after a severe sickle cell crisis.

PubMed

Jaeggi, E; Bolens, M; Friedli, B

1998-01-01

Despite the high prevalence of sickle cell disease and trait in the black population and its serious potential for microinfarction, there are only a few reports on acute myocardial damage during vasoocclusive crisis. We report a unique case of transient second degree atrioventricular (A-V) block of Mobitz I and II type during a severe sickle cell crisis. Localized high ventricular septum hypoperfusion demonstrated by a 99mTc-MIBI radionuclide study and reversible echocardiographic wall motion abnormalities in the same area were strong indicators for a local ischemic event in the A-V node and His bundle area, explaining the observed transient conduction abnormalities. The present report draws attention to a potentially lethal complication of sickle cell crisis.

Abscess of residual lobe after pulmonary resection for lung cancer.

PubMed

Ligabue, Tommaso; Voltolini, Luca; Ghiribelli, Claudia; Luzzi, Luca; Rapicetta, Cristian; Gotti, Giuseppe

2008-04-01

Abscess of the residual lobe after lobectomy is a rare but potentially lethal complication. Between January 1975 and December 2006, 1,460 patients underwent elective pulmonary lobectomy for non-small-cell lung cancer at our institution. Abscess of the residual lung parenchyma occurred in 5 (0.3%) cases (4 bilobectomies and 1 lobectomy). Postoperative chest radiography showed incomplete expansion and consolidation of residual lung parenchyma. Flexible bronchoscopy revealed persistent bronchial occlusion from purulent secretions and/or bronchial collapse. Computed tomography in 3 patients demonstrated lung abscess foci. Surgical treatment included completion right pneumonectomy in 3 patients and a middle lobectomy in one. Complications after repeat thoracotomy comprised contralateral pneumonia and sepsis in 1 patient. Residual lobar abscess after lobectomy should be suspected in patients presenting with fever, leukocytosis, bronchial obstruction and lung consolidation despite antibiotic therapy, physiotherapy and bronchoscopy. Computed tomography is mandatory for early diagnosis. Surgical resection of the affected lobe is recommended.

Nutrition in clinical practice-the refeeding syndrome: illustrative cases and guidelines for prevention and treatment.

PubMed

Stanga, Z; Brunner, A; Leuenberger, M; Grimble, R F; Shenkin, A; Allison, S P; Lobo, D N

2008-06-01

The refeeding syndrome is a potentially lethal complication of refeeding in patients who are severely malnourished from whatever cause. Too rapid refeeding, particularly with carbohydrate may precipitate a number of metabolic and pathophysiological complications, which may adversely affect the cardiac, respiratory, haematological, hepatic and neuromuscular systems leading to clinical complications and even death. We aimed to review the development of the refeeding syndrome in a variety of situations and, from this and the literature, devise guidelines to prevent and treat the condition. We report seven cases illustrating different aspects of the refeeding syndrome and the measures used to treat it. The specific complications encountered, their physiological mechanisms, identification of patients at risk, and prevention and treatment are discussed. Each case developed one or more of the features of the refeeding syndrome including deficiencies and low plasma levels of potassium, phosphate, magnesium and thiamine combined with salt and water retention. These responded to specific interventions. In most cases, these abnormalities could have been anticipated and prevented. The main features of the refeeding syndrome are described with a protocol to anticipate, prevent and treat the condition in adults.

A bacterial cocaine esterase protects against cocaine-induced epileptogenic activity and lethality.

PubMed

Jutkiewicz, Emily M; Baladi, Michelle G; Cooper, Ziva D; Narasimhan, Diwahar; Sunahara, Roger K; Woods, James H

2009-09-01

Cocaine toxicity results in cardiovascular complications, seizures, and death and accounts for approximately 20% of drug-related emergency department visits every year. Presently, there are no treatments to eliminate the toxic effects of cocaine. The present study hypothesizes that a bacterial cocaine esterase with high catalytic efficiency would provide rapid and robust protection from cocaine-induced convulsions, epileptogenic activity, and lethality. Cocaine-induced paroxysmal activity and convulsions were evaluated in rats surgically implanted with radiotelemetry devices (N=6 per treatment group). Cocaine esterase was administered 1 minute after a lethal dose of cocaine or after cocaine-induced convulsions to determine the ability of the enzyme to prevent or reverse, respectively, the effects of cocaine. The cocaine esterase prevented all cocaine-induced electroencephalographic changes and lethality. This effect was specific for cocaine because the esterase did not prevent convulsions and death induced by a cocaine analog, (-)-2beta-carbomethoxy-3beta-phenyltropane. The esterase prevented lethality even after cocaine-induced convulsions occurred. In contrast, the short-acting benzodiazepine, midazolam, prevented cocaine-induced convulsions but not the lethal effects of cocaine. The data showed that cocaine esterase successfully degraded circulating cocaine to prevent lethality and that cocaine-induced convulsions alone are not responsible for the lethal effects of cocaine in this model. Therefore, further investigation into the use of cocaine esterase for treating cocaine overdose and its toxic effects is warranted.

The safety issues and hardware-related complications of deep brain stimulation therapy: a single-center retrospective analysis of 478 patients with Parkinson’s disease

PubMed Central

Zhang, Jing; Wang, Tao; Zhang, Chen-cheng; Zeljic, Kristina; Zhan, Shikun; Sun, Bo-min; Li, Dian-you

2017-01-01

Introduction Deep brain stimulation (DBS) is a well-established therapy for the treatment of advanced Parkinson’s disease (PD) in patients experiencing motor fluctuations and medication-refractory tremor. Despite the relative tolerability and safety of this procedure, associated complications and unnatural deaths are still unavoidable. Methods In this study, hardware-related complications and the causes of unnatural death were retrospectively analyzed in 478 patients with PD who were treated with DBS. Results The results showed a 3-year survival rate of 98.6% and a 5-year survival rate of 96.4% for patients with PD who underwent DBS treatment at the study center. Pneumonia was the cause of death with the highest frequency. Prophylactic antibiotics and steroids or antihistamine drugs were adopted to reduce the risk of infection. Twenty-two patients (4.6%) experienced hardware-related complications. Conclusion Deaths of PD patients who receive DBS are typically unrelated to the disease itself or complications associated with the surgery. Pneumonia, malignant tumors, asphyxia, and multiple-organ failure are the common causes of death. Swallowing-related problems may be the most important clinical symptom in late-stage PD, as they cannot be stabilized or improved by DBS alone, and are potentially lethal. Although prophylactic antibiotics and steroids or antihistamine drugs may reduce the risk of infection, it is imperative to identify high-risk patients for whom a therapeutic approach not requiring an implantable device is more suitable, for example, pallidotomy and potentially transcranial ultrasound. PMID:28652714

Minority mothers' healthcare beliefs, commonly used alternative healthcare practices, and potential complications for infants and children.

PubMed

Hannan, Jean

2015-06-01

Complementary and alternative healthcare practices have increased substantially in the United States especially with low-income ethnic minority mothers. These mothers often have provider mistrust, language barriers, differing health belief systems, and as a result are less likely to seek preventive health screening, access healthcare services, and use alternative remedies for their infants and children that are potentially harmful or lethal. Therefore, the purpose of this article is to examine healthcare beliefs, commonly used alternative healthcare practices, and their potential complications for infants and children. A search of CINAHL and PubMed (1980-2012) was conducted using the following terms: alternative healthcare practice, mothers' health beliefs, cultural health beliefs, folk remedies, and infant health practices. Given the changing U.S. population and an increasing immigrant population, examining alternative healthcare practices mothers use for their infants and children is especially important for providers in addressing healthcare for this group. The use of alternative healthcare practices is rarely discussed by parents with healthcare providers for fear of disapproval. When interviewing ethnic minority mothers and caregivers questions should include the use of alternative healthcare practices for infants and children and information regarding the potential dangers should be provided to them. ©2014 American Association of Nurse Practitioners.

Surgery of a nocardia lung abscess presenting as a tension pyopneumothorax.

PubMed

Fujimoto, Ryo; Omasa, Mitsugu; Ishikawa, Hiroyuki; Aoki, Minoru

2017-05-01

While some cases of nocardial pneumonia develop secondary empyema, tension pyopneumothorax is a very rare and lethal complication. A 74-year-old man who exhibited thrombocytopenia during steroid therapy for autoimmune hepatitis, presented to our department with a nocardial tension pyopneumothorax. He underwent a left lower lobectomy after chest drainage, and was discharged without any complication other than reoperation to remove a postoperative hematoma.

Rat bite fever without fever.

PubMed

Stehle, P; Dubuis, O; So, A; Dudler, J

2003-09-01

Rat bite fever is a rarely reported acute febrile bacterial illness caused by Streptobacillus moniliformis or Spirillum minus following a rat bite. It is classically characterised by abrupt onset of fever with rigors, myalgias, headache, and the appearance of a generalised maculopapular petechial skin rash. Polyarthritis complicates the course of the disease in up to 50% of infected patients, and numerous hurdles can make the diagnosis particularly difficult in the absence of fever or rash, as in the present case. A high degree of awareness is necessary to make the correct diagnosis in such cases. Diagnosis has important prognostic implications as the disease is potentially lethal, but easily treatable.

Soft J-tipped guide wire-induced cardiac perforation in a patient with right ventricular lipomatosis and wall thinning.

PubMed

Hiroshima, Yuki; Tajima, Katsushi; Shiono, Yousuke; Suzuki, Ikuko; Kohno, Kei; Kato, Yuichi; Shunji, Kawamura; Kato, Takeo

2012-01-01

Cardiac tamponade caused by perforation is a rare but potentially lethal complication of central venous catheter (CVC) insertion. We herein report a case of cardiac perforation associated with the use of a soft J-tipped guide wire. Twenty minutes after the insertion of a CVC, the patient developed unexpected cardiac arrest. An autopsy revealed 400 mL of pericardial blood. The right ventricular wall was 1 mm thick with about 10 myocyte layers, which is one-third that of the normal heart. A histological analysis revealed widespread fatty infiltration of the right ventricular wall (right ventricular lipomatosis).

Case report: spontaneous rupture of spleen in patient with Plasmodium ovale malaria.

PubMed

Lemmerer, Raphael; Unger, Manuel; Voßen, Matthias; Forstner, Christina; Jalili, Ahmad; Starzengruber, Peter; Werzowa, Johannes; Ramharter, Michael; Winkler, Stefan; Thalhammer, Florian

2016-01-01

Malaria may lead to spontaneous splenic rupture as a rare but potentially lethal complication. Most frequently, this has been reported in patients infected with Plasmodium falciparum and Plasmodium vivax, while other parasitic agents are less likely to be the cause.We report a 29-year-old British Caucasian, who after returning from a business trip in Democratic Republic Congo was diagnosed with tertian malaria caused by Plasmodium ovale.During his in-patient stay, the patient suffered a splenic rupture requiring immediate surgical intervention and splenectomy. Following this surgical intervention, there was an uneventful recovery, and the patient was discharged in a good general condition.

Intrathecal baclofen withdrawal: A rare cause of reversible cardiomyopathy.

PubMed

Awuor, Stephen O; Kitei, Paul M; Nawaz, Yassir; Ahnert, Amy M

2016-03-01

Baclofen is commonly used to treat spasticity of central etiology. Unfortunately, a potentially lethal withdrawal syndrome can complicate its use. This is especially true when the drug is administered intrathecally. There are very few cases of baclofen withdrawal leading to reversible cardiomyopathy described in the literature. The authors present a patient with a history of chronic intrathecal baclofen use who, in the setting of acute baclofen withdrawal, develops laboratory, electrocardiogram, and echocardiogram abnormalities consistent with cardiomyopathy. Upon reinstitution of intrathecal baclofen, the cardiomyopathy and associated abnormalities quickly resolve. Although rare, it is crucial to be aware of this reversible cardiomyopathy to ensure its prompt diagnosis and treatment.

Brunfelsia australis (Yesterday, Today, and Tomorrow tree) and Solanum poisoning in a dog.

PubMed

Clipsham, Robert

2012-01-01

A 2.5 yr old female beagle presented for acute abdominal pain and vomiting after consuming limited offerings of green potato skins. Progressive complications associated with suspected ingestion of a higher potency toxin followed within 5 hr. Subsequent investigations revealed a significant ingestion of an Australian shrub commonly called a "Yesterday, Today, and Tomorrow" tree (Brunfelsia australis). The toxic principle for this emerging toxicity is referred to as "strychnine-like" and is potentially lethal with gastrointestinal, central nervous system, and cardiac pathology. This plant is currently being aggressively promoted by United States nurserymen for its dramatic tri-colored blooms and drought resistance.

Current Care and Investigational Therapies in Achondroplasia.

PubMed

Unger, Sheila; Bonafé, Luisa; Gouze, Elvire

2017-04-01

The goal of this review is to evaluate the management options for achondroplasia, the most common non-lethal skeletal dysplasia. This disease is characterized by short stature and a variety of complications, some of which can be quite severe. Despite several attempts to standardize care, there is still no widely accepted consensus. This is in part due to absence of concrete data on the incidence of sudden unexplained death in infants with achondroplasia and the best investigation for ascertaining which individuals could benefit from foramen magnum decompression surgery. In this review, we identify the different options of care and management for the various orthopedic, neurologic, and respiratory complications. In parallel, several innovative or drug repositioning therapies are being investigated that would restore bone growth but may also prevent complications. Achondroplasia is the most common non-lethal skeletal dysplasia. It is characterized by short stature and a variety of complications, some of which can be quite severe. Despite several attempts to standardize care, there is still no widely accepted consensus. This is in part due to absence of concrete data on the incidence of sudden unexplained death in infants with achondroplasia and the best investigation for ascertaining which individuals could benefit from foramen magnum decompression surgery. In this review, we identify the different options of care and management for the various orthopedic, neurologic, and respiratory complications. In parallel, several innovative or drug repositioning therapies are being investigated that would restore bone growth but may also prevent complications.

Life-threatening complications of ibogaine: three case reports.

PubMed

Paling, F P; Andrews, L M; Valk, G D; Blom, H J

2012-11-01

Ibogaine is a naturally occurring psychoactive alkaloid extracted from the roots of the Tabernanthe iboga plant, which in alternative medicine is used to treat drug dependency. However, this upcoming, online advocated therapy can be dangerous due to its potentially lethal adverse effects. We present three cases in which toxic side effects were noted. We used the Naranjo scale to estimate the probability of a causal relationship between these effects and ibogaine. Findings in these three cases are suggestive of a causal relationship between the use of ibogaine and serious respiratory and cardiac problems (including lengthening of the QT interval). In our opinion it is of great importance that clinicians are aware of these potentially serious side effects and realise that widespread online marketing practices will give many more people access to ibogaine.

[Injuries of the duodenum].

PubMed

Korolev, M P; Urakcheev, Sh K; Shlosser, K V

2012-01-01

Results of surgical treatment of 69 patients with injuries of the duodenum were analyzed. The most frequent causes of the injury were stab-incised wound of the abdomen (43 patients), gunshot wounds (2 patients), closed injury of the abdomen. Postoperative complications developed in 18 (26%) cases. Lethality was 20.3% (14 patients died). Injuries caused by the closed trauma were considerably more severe than those caused by wounds of the duodenum; lethality was 37.5% and 11.1% respectively. The authors discuss questions of the special diagnostics and surgical strategy for open and closed injuries of the duodenum. Causes of the development of unfavorable outcomes were pyo-septic complications associated with progressing retroperitoneal phlegmons, peritonitis, development of traumatic pancreatitis, incompetent sutures of the duodenum with a formed duodenal fistula. Therefore, the effective prophylactics of incompetent sutures of the duodenum is its decompression with aspiration of the duodenal contents as well as decreased secretion by means of drainage of the bile excreting ducts and medicamental suppression of synthesis of the digestion enzymes of the pancreas and duodenum using Octreatid which allowed considerable decrease of the number of postoperative complications.

A Bacterial Cocaine Esterase Protects Against Cocaine-Induced Epileptogenic Activity and Lethality

PubMed Central

Jutkiewicz, Emily M.; Baladi, Michelle G.; Cooper, Ziva D.; Narasimhan, Diwahar; Sunahara, Roger K.; Woods, James H.

2012-01-01

Study objective Cocaine toxicity results in cardiovascular complications, seizures, and death and accounts for approximately 20% of drug-related emergency department visits every year. Presently, there are no treatments to eliminate the toxic effects of cocaine. The present study hypothesizes that a bacterial cocaine esterase with high catalytic efficiency would provide rapid and robust protection from cocaine-induced convulsions, epileptogenic activity, and lethality. Methods Cocaine-induced paroxysmal activity and convulsions were evaluated in rats surgically implanted with radiotelemetry devices (N=6 per treatment group). Cocaine esterase was administered 1 minute after a lethal dose of cocaine or after cocaine-induced convulsions to determine the ability of the enzyme to prevent or reverse, respectively, the effects of cocaine. Results The cocaine esterase prevented all cocaine-induced electroencephalographic changes and lethality. This effect was specific for cocaine because the esterase did not prevent convulsions and death induced by a cocaine analog, (−)-2β-carbomethoxy-3β-phenyltropane. The esterase prevented lethality even after cocaine-induced convulsions occurred. In contrast, the short-acting benzodiazepine, midazolam, prevented cocaine-induced convulsions but not the lethal effects of cocaine. Conclusion The data showed that cocaine esterase successfully degraded circulating cocaine to prevent lethality and that cocaine-induced convulsions alone are not responsible for the lethal effects of cocaine in this model. Therefore, further investigation into the use of cocaine esterase for treating cocaine overdose and its toxic effects is warranted. PMID:19013687

[The method of duodenal bulb plasty in case of complicated chronic ulcer of back wall of the duodenal bulb].

PubMed

Didigov, M T; Durleshter, V M; Kliuchnikov, O Iu

2014-01-01

It was proposed the method of organ-preserving surgical treatment of chronic ulcers of back wall of duodenal bulb complicated by decompensated stenosis and penetration in intrapancreatic part of common bile duct (RF patent number 2476164 from 27.02.2013). 12 patients were operated by using of this technique. One patient had post-operative pancreatitis. There were not lethal outcomes.

Radiation induced failures of complementary metal oxide semiconductor containing pacemakers: a potentially lethal complication

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

Lewin, A.A.; Serago, C.F.; Schwade, J.G.

1984-10-01

New multi-programmable pacemakers frequently employ complementary metal oxide semiconductors (CMOS). This circuitry appears more sensitive to the effects of ionizing radiation when compared to the semiconductor circuits used in older pacemakers. A case of radiation induced runaway pacemaker in a CMOS device is described. Because of this and other recent reports of radiation therapy-induced CMOS type pacemaker failure, these pacemakers should not be irradiated. If necessary, the pacemaker can be shielded or moved to a site which can be shielded before institution of radiation therapy. This is done to prevent damage to the CMOS circuit and the life threatening arrythmiasmore » which may result from such damage.« less

Infective endocarditis in a hemodialysis patient: a dreaded complication.

PubMed

Schubert, Claudia; Moosa, Mohammed R

2007-10-01

Infection is the most common cause of death in hemodialysis patients, after cardiovascular disease. Dialysis access infections, with secondary septicemia, contribute significantly to patient mortality. The most common source is temporary catheterization. Bacteremia occurs commonly in patients receiving hemodialysis, with infective endocarditis being a relatively uncommon, but potentially lethal complication. Valvular calcification is the most significant risk factor. The diagnosis of infective endocarditis is made clinically and confirmed with the echocardiographic modified Duke's criteria. The most common pathogen is Staphylococcus aureus and the mitral valve is the most common site. Staphylococcus aureus infective endocarditis is commonly associated with embolic phenomenon. A high index of suspicion is critical in the early recognition and management of infective endocarditis. However, prevention of bacteremia is undoubtedly the best strategy with the early placement of arteriovenous fistulae. In the case of temporary catheterization, the use of topical mupirocin or polysporin and gentamicin and/or citrate locking is beneficial. Although catheter salvage has not been studied in randomized trials, catheter removal remains standard therapy during bacteremia.

Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies.

PubMed

Winkelhorst, Dian; Oepkes, Dick; Lopriore, Enrico

2017-08-01

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a relatively rare but potentially lethal disease, leading to severe bleeding complications in 1 in 11.000 newborns. It is the leading cause of thrombocytopenia in healthy term-born neonates. Areas covered: This review summarizes the antenatal as well as postnatal treatment, thus creating a complete overview of all possible management strategies for FNAIT. Expert commentary: The optimal antenatal therapy in order to prevent bleeding complications in pregnancies complicated by FNAIT is non-invasive treatment with weekly intravenous immunoglobulin (IVIG). Based on risk stratification, weekly doses of IVIG of 0.5 or 1.0g/kg should be administered started early in the second in high risk cases or at the end of the second trimester in low risk cases. The optimal postnatal treatment depends on the platelet count and the clinical condition of the newborn. Prompt administration of compatible platelet transfusion is the first treatment of choice in case of severe thrombocytopenia or active bleeding. In case matched platelets are not directly available, random platelets can also be administered initially to gain time until matched platelets are available. In case of persistent thrombocytopenia despite transfusions, IVIG 1.0-2.0g/kg can be administered.

Endoscopic treatment and risk factors of postoperative anastomotic bleeding after gastrectomy for gastric cancer.

PubMed

Kim, Ki-Han; Kim, Min-Chan; Jung, Ghap-Joong; Jang, Jin-Seok; Choi, Seok-Ryeol

2012-01-01

Anastomotic leakage, bleeding, and stricture are major complications after gastrectomy. Of these complications, postoperative anastomotic bleeding is relatively rare, but lethal if not treated immediately. Of 2031 patients with gastric cancer who underwent radical gastrectomy (R0 resection) between January 2002 and December 2010, postoperative anastomotic bleeding was observed in 7 patients. The clinicopathological features, postoperative outcomes such as surgical procedures, bleeding sites and, methods used to achieve hemostasis, and the risk factors of anastomotic bleeding of these 7 patients were analyzed. Of the 2031 patients, 1613 and 418 underwent distal and total gastrectomy, respectively. The bleeding sites were as follows: Billroth-I anastomosis using a circular stapler (n = 1), Billroth-II anastomosis by manual suture (n = 5), and esophagojejunostomy using a circular stapler (n = 1). All patients were treated with endoscopic clipping or epinephrine injection. There was no further endoscopic intervention or reoperation for anastomotic bleeding. Postoperative anastomotic bleeding is an infrequent but potentially life-threatening complication. Scrupulous surgical procedures are essential for the prevention of postoperative bleeding, and endoscopy was useful for both the confirmation of bleeding and therapeutic intervention. Copyright © 2012 Surgical Associates Ltd. All rights reserved.

[Ways to improve efficacy of emergency operative interventions in patients with cancer of the left flank of the colon complicated by obstruction].

PubMed

Beliaev, A M; Bagnenko, S F; Kabanov, M Iu; Vashetko, R V; Surov, D A; Zakharenko, A A; Babkov, O V; Koshevoĭ, A A; Novitskaia, N Iu; Rumiantsev, V N

2011-01-01

In order to improve radicalism of emergency surgical interventions an appropriate method of total mesocolonectomy and D3-lymph node dissection in the medial-lateral direction and the principle of "no-touch technique" were used in 14 patients. This technique is safe, effective, does not prolong the duration of operation and postoperative period, is not followed by increased number of complications and lethality.

CRISPR/Cas9 mediated genome editing in ES cells and its application for chimeric analysis in mice.

PubMed

Oji, Asami; Noda, Taichi; Fujihara, Yoshitaka; Miyata, Haruhiko; Kim, Yeon Joo; Muto, Masanaga; Nozawa, Kaori; Matsumura, Takafumi; Isotani, Ayako; Ikawa, Masahito

2016-08-17

Targeted gene disrupted mice can be efficiently generated by expressing a single guide RNA (sgRNA)/CAS9 complex in the zygote. However, the limited success of complicated genome editing, such as large deletions, point mutations, and knockins, remains to be improved. Further, the mosaicism in founder generations complicates the genotypic and phenotypic analyses in these animals. Here we show that large deletions with two sgRNAs as well as dsDNA-mediated point mutations are efficient in mouse embryonic stem cells (ESCs). The dsDNA-mediated gene knockins are also feasible in ESCs. Finally, we generated chimeric mice with biallelic mutant ESCs for a lethal gene, Dnajb13, and analyzed their phenotypes. Not only was the lethal phenotype of hydrocephalus suppressed, but we also found that Dnajb13 is required for sperm cilia formation. The combination of biallelic genome editing in ESCs and subsequent chimeric analysis provides a useful tool for rapid gene function analysis in the whole organism.

Infectious mononucleosis presenting as spontaneous splenic rupture without other symptoms.

PubMed

Stockinger, Zsolt T

2003-09-01

Splenic rupture is an uncommon complication of infectious mononucleosis (IM), occurring in 0.1% to 0.5% of all patients. It remains the most common lethal complication of IM. Rupture of the spleen with no other symptoms of IM is almost unheard of. This is the report of a case of spontaneous splenic rupture requiring splenectomy in a patient with a positive heterophil antibody test and no other signs or symptoms of IM. The diagnosis and management of splenic rupture in IM are discussed.

Three eyelid localized cutaneous anthrax cases.

PubMed

Esmer, Oktay; Karadag, Remzi; Bilgili, Serap Gunes; Gultepe, Bilge; Bayramlar, Huseyin; Karadag, Ayse Serap

2014-12-01

Anthrax is primarily seen in the developing countries, but it can be a worldwide medical concern due to bioterrorism threats. Palpebral anthrax is a rare form of cutaneous anthrax. Untreated cutaneous anthrax can be lethal. Patients with palpebral anthrax can develop complications including cicatrisation and ectropion. Thus, anthrax should be considered in differential diagnosis for patients presenting with preseptal cellulitis in high-risk regions. Herein, we report three anthrax cases (with different age) involving eyelids that were cured without any complications due to early diagnosis and treatment.

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

Ritter, C. O., E-mail: ritter@roentgen.uni-wuerzburg.de; Wartenberg, M.; Mottok, A.

Spontaneous rupture of hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE) is a rare and life-threatening complication. Pathophysiologic mechanisms are not yet fully known; it is suggested that rupture is preceded by reactive tissue edema and intratumerous bleeding, leading to a rapid expansion of tumour mass with risk of extrahepatic bleeding in the case of subcapsular localisation. This case report discusses a sudden, unexpected lethal complication in a 74 year-old male patient treated with TACE using DC Bead loaded with doxorubicin (DEBDOX) in a progressive multifocal HCC.

MDMA: interactions with other psychoactive drugs.

PubMed

Mohamed, Wael M Y; Ben Hamida, Sami; Cassel, Jean-Christophe; de Vasconcelos, Anne Pereira; Jones, Byron C

2011-10-01

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is one of the most widely abused illegal drugs. Some users self-report euphoria and an increased perception and feeling of closeness to others. When taken in warm environments, MDMA users may develop acute complications with potential fatal consequences. In rodents, MDMA increases locomotor activity and, depending on ambient temperature, may produce a dose-dependent, potentially lethal hyperthermia. Like most other recreational drugs, MDMA is frequently taken in combination with other substances including tobacco, EtOH, marijuana, amphetamines, cocaine and, caffeine. Although polydrug use is very common, the understanding of the effects of this multiple substance use, as well as the analysis of consequences of different drug-drug associations, received rather little attention. The purpose of this review is to summarize our current knowledge about the changes on MDMA-related behavior, pharmacology, and neurotoxicity associated with co-consumption of other drugs of abuse and psychoactive agents. Copyright © 2011 Elsevier B.V. All rights reserved.

Prolonged QT interval in a man with anorexia nervosa

PubMed Central

Macías-Robles, María Dolores; Perez-Clemente, Ana María; Maciá-Bobes, Carmen; Alvarez-Rueda, María Asunción; Pozo-Nuevo, Sergio

2009-01-01

Anorexia nervosa is an eating disorder characterized by the avoidance of food intake, which usually leads to a weight loss. Cardiac co-morbility is common and we can find sometimes a mass loss from the left ventricle, which can be seen by echocardiography. But the commonest complications are rhythm variations, typically bradycardia with a prolonged QT interval in up to a 40% of the cases, which altogether elevates ventricular tachycardia and sudden death risk. We present the case of a male who was diagnosed with anorexia nervosa and developed asthenia, a long QT interval and also a severe both hypokalaemia and hypomagnesaemia. We intend to discuss the pathogenic paths as well as prophylactic and therapeutic measures to this potentially-lethal pathology. PMID:19646241

Potential Linkage Between Cerebrovascular Diseases and Metabolic Syndrome.

PubMed

Jabir, Nasimudeen R; Firoz, Chelapram Kandy; Khan, Mohd Shahnawaz; Zaidi, Syed Kashif; Ashraf, Ghulam Md; Shakil, Shazi; Kamal, Mohammad Amjad; Tabrez, Shams

2017-01-01

Cerebrovascular disease (CD) and metabolic syndrome (MetS) are two devastating health dilemma that continues to be a potential contributor to disability and mortality in human population all across the world. Scientific data clearly shows several mechanistic similarities between these two co-existing and interlinked conditions. The linkage exacerbates ongoing patho-physiological condition towards more lethal events. In view of the presence of modifiable risk factors in both CD and MetS, their management holds potential therapeutic value. Hence, developing common treatment strategies for these diseases could involve common molecular agents. In this communication, we have summarized some of the common pathological conditions viz. abdominal obesity, insulin resistance, dyslipidemia, hypertension, and endothelial dysfunction that further deteriorate existing homeostasis in CD and MetS. Based on our article, it is advocated that substantial improvements in novel multi-targeted drug discovery could provide the effective treatment methods in order to avoid the fatal complications related with CD and MetS. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Lethal effects of Clostridium perfringens epsilon toxin are potentiated by alpha and perfringolysin-O toxins in a mouse model.

PubMed

Fernandez-Miyakawa, Mariano E; Jost, B Helen; Billington, Stephen J; Uzal, Francisco A

2008-03-18

Epsilon toxin (ETX) is the most important virulence factor of Clostridium perfringens type D. Two other important toxins, alpha toxin (CPA) and perfringolysin-O (PFO), are encoded and potentially produced by most C. perfringens type D isolates. The biological effects of these toxins are dissimilar although they are all lethal. Since the possible interaction of these toxins during infection is unknown, the effects of CPA and PFO on the lethal activity of ETX were studied in a mouse model. Mice were injected intravenously or intragastrically with CPA or PFO with or without ETX. Sublethal doses of CPA or PFO did not affect the lethality of ETX when either was injected together with the latter intravenously. However, sublethal or lethal doses of CPA or PFO resulted in reduction of the survival time of mice injected simultaneously with ETX when compared with the intravenous effect of ETX injected alone. When PFO was inoculated intragastrically with ETX, a reduction of the survival time was observed. CPA did not alter the survival time when inoculated intragastrically with ETX. The results of the present study suggest that both CPA and PFO have the potential to enhance the ETX lethal effects during enterotoxemia in natural hosts such as sheep and goats.

Protective or pathogenic effects of vascular endothelial growth factor (VEGF) as potential biomarker in cerebral malaria.

PubMed

Canavese, Miriam; Spaccapelo, Roberta

2014-03-01

Cerebral malaria (CM) is the major lethal complication of Plasmodium falciparum infection. It is characterized by persistent coma along with symmetrical motor signs. Several clinical, histopathological, and laboratory studies have suggested that cytoadherence of parasitized erythrocytes, neural injury by malarial toxin, and excessive inflammatory cytokine production are possible pathogenic mechanisms. Although the detailed pathophysiology of CM remains unsolved, it is thought that the binding of parasitized erythrocytes to the cerebral endothelia of microvessels, leading to their occlusion and the consequent angiogenic dysregulation play a key role in the disease pathogenesis. Recent evidences showed that vascular endothelial growth factor (VEGF) and its receptor-related molecules are over-expressed in the brain tissues of CM patients, as well as increased levels of VEGF are detectable in biologic samples from malaria patients. Whether the modulation of VEGF is causative agent of CM mortality or a specific phenotype of patients with susceptibility to fatal CM needs further evaluation. Currently, there is no biological test available to confirm the diagnosis of CM and its complications. It is hoped that development of biomarkers to identify patients and potential risk for adverse outcomes would greatly enhance better intervention and clinical management to improve the outcomes. We review and discuss here what it is currently known in regard to the role of VEGF in CM as well as VEGF as a potential biomarker.

Mutagenic Potential of Nitroguanidine in the Drosophila melanogaster Sex-Linked Recessive Lethal Test

DTIC Science & Technology

1988-07-01

Security Classification) Mtutagenic potential of nitroguan idine in the Drosophila melano- gaster sex-linked recessive lethal test 12. PERSONAL AUTHOR(S...Frederick, MD 21701-5012 Commander Commandant US Army Environmental Hygine Academy of Health Sciences. US Army Agency ATTN: AHS-CDM ATTN: Librarian, HSDH

[Strut fracture of a convex-concave 60 degree Björk-Shiley mitral valve prosthesis 5 years after implantation--metallurgic analysis of the prosthesis strut].

PubMed

Lemke, B; Rathmann, J; Wiebe, V; Witzel, U

1991-08-01

Acute mechanical failure of prosthetic heart valves is rare, but associated with high mortality when occurring. For convexo-concave Björk-Shiley prostheses only fractures of the outlet strut are reported. We present a case of lethal mechanical complication 5 years after implantation. By additional metallurgic analysis we were able to identify a sequential course of the outlet strut fracture. This could lead to new approaches for early detection of this complication.

Management and outcome of cardiac and endovascular cystic echinococcosis.

PubMed

Díaz-Menéndez, Marta; Pérez-Molina, José Antonio; Norman, Francesca Florence; Pérez-Ayala, Ana; Monge-Maillo, Begoña; Fuertes, Pilar Zamarrón; López-Vélez, Rogelio

2012-01-01

Cystic echinococcosis (CE) can affect the heart and the vena cava but few cases are reported. A retrospective case series of 11 patients with cardiac and/or endovascular CE, followed-up over a period of 15 years (1995-2009) is reported. Main clinical manifestations included thoracic pain or dyspnea, although 2 patients were asymptomatic. Cysts were located mostly in the right atrium and inferior vena cava. Nine patients were previously diagnosed with disseminated CE. Echocardiography was the diagnostic method of choice, although serology, electrocardiogram, chest X-ray, computed tomography/magnetic resonance imaging and histology aided with diagnosis and follow-up. Nine patients underwent cardiac surgery and nine received long-term antiparasitic treatment for a median duration of 25 months (range 4-93 months). One patient died intra-operatively due to cyst rupture and endovascular dissemination. Two patients died 10 and 14 years after diagnosis, due to pulmonary embolism (PE) and cardiac failure, respectively. One patient was lost to follow-up. Patients who had cardiac involvement exclusively did not have complications after surgery and were considered cured. There was only one recurrence requiring a second operation. Patients with vena cava involvement developed PEs and presented multiple complications. Cardiovascular CE is associated with a high risk of potentially lethal complications. Clinical manifestations and complications vary according to cyst location. Isolated cardiac CE may be cured after surgery, while endovascular extracardiac involvement is associated with severe chronic complications. CE should be included in the differential diagnosis of cardiovascular disease in patients from endemic areas. © 2012 Díaz-Menéndez et al.

Management and Outcome of Cardiac and Endovascular Cystic Echinococcosis

PubMed Central

Díaz-Menéndez, Marta; Pérez-Molina, José Antonio; Norman, Francesca Florence; Pérez-Ayala, Ana; Monge-Maillo, Begoña; Fuertes, Pilar Zamarrón; López-Vélez, Rogelio

2012-01-01

Background Cystic echinococcosis (CE) can affect the heart and the vena cava but few cases are reported. Methods A retrospective case series of 11 patients with cardiac and/or endovascular CE, followed-up over a period of 15 years (1995–2009) is reported. Results Main clinical manifestations included thoracic pain or dyspnea, although 2 patients were asymptomatic. Cysts were located mostly in the right atrium and inferior vena cava. Nine patients were previously diagnosed with disseminated CE. Echocardiography was the diagnostic method of choice, although serology, electrocardiogram, chest X-ray, computed tomography/magnetic resonance imaging and histology aided with diagnosis and follow-up. Nine patients underwent cardiac surgery and nine received long-term antiparasitic treatment for a median duration of 25 months (range 4–93 months). One patient died intra-operatively due to cyst rupture and endovascular dissemination. Two patients died 10 and 14 years after diagnosis, due to pulmonary embolism (PE) and cardiac failure, respectively. One patient was lost to follow-up. Patients who had cardiac involvement exclusively did not have complications after surgery and were considered cured. There was only one recurrence requiring a second operation. Patients with vena cava involvement developed PEs and presented multiple complications. Conclusions Cardiovascular CE is associated with a high risk of potentially lethal complications. Clinical manifestations and complications vary according to cyst location. Isolated cardiac CE may be cured after surgery, while endovascular extracardiac involvement is associated with severe chronic complications. CE should be included in the differential diagnosis of cardiovascular disease in patients from endemic areas. PMID:22235354

The effect of lonidamine (LND) on radiation and thermal responses of human and rodent cell lines

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

Raaphorst, G.P.; Feeley, M.M.; Danjoux, C.E.

1991-03-01

Rodent and human cells were tested for response to Lonidamine (LND) (1-(2,4 dichlorobenzyl) 1-indazol-3-carboxylic acid) combined with radiation or hyperthermia. Lonidamine exposure before, during, and after irradiation caused varying degrees of inhibition of potentially lethal damage (PLD) repair which was cell line dependent. In human glioma, melanoma, squamous cell carcinoma, and fibroblasts, LND exposure did not inhibit or only partially inhibited repair of potentially lethal damage. LND up to 100 micrograms/ml produced only a low level of toxicity in these cells and only slightly inhibited glucose consumption at the maximum concentration. In human glioma cells, LND treatment alone did notmore » inhibit PLD repair, but when combined with hyperthermia treatment at moderate levels easily achievable in the clinic, there was complete inhibition of potentially lethal damage repair. These data suggest that LND effectiveness is cell type dependent. Combinations of LND, hyperthermia, and radiation may be effective in cancer therapy especially in tumors such as glioma in which repair of potentially lethal damage may be extensive.« less

Toll-like receptor 4 knockout protects against anthrax lethal toxin-induced cardiac contractile dysfunction: role of autophagy.

PubMed

Kandadi, Machender R; Frankel, Arthur E; Ren, Jun

2012-10-01

Anthrax lethal toxin (LeTx) is known to induce circulatory shock and death, although the underlying mechanisms have not been elucidated. This study was designed to evaluate the role of toll-like receptor 4 (TLR4) in anthrax lethal toxin-induced cardiac contractile dysfunction. Wild-type (WT) and TLR4 knockout (TLR⁻/⁻) mice were challenged with lethal toxin (2 µg·g⁻¹, i.p.), and cardiac function was assessed 18 h later using echocardiography and edge detection. Small interfering RNA (siRNA) was employed to knockdown TLR4 receptor or class III PI3K in H9C2 myoblasts. GFP-LC3 puncta was used to assess autophagosome formation. Western blot analysis was performed to evaluate autophagy (LC3, Becline-1, Agt5 and Agt7) and endoplasmic reticulum (ER) stress (BiP, eIF2α and calreticulin). In WT mice, lethal toxin exposure induced cardiac contractile dysfunction, as evidenced by reduced fractional shortening, peak shortening, maximal velocity of shortening/re-lengthening, prolonged re-lengthening duration and intracellular Ca²⁺ derangement. These effects were significantly attenuated or absent in the TLR4 knockout mice. In addition, lethal toxin elicited autophagy in the absence of change in ER stress. Knockdown of TLR4 or class III PI3 kinase using siRNA but not the autophagy inhibitor 3-methyladenine significantly attenuated or inhibited lethal toxin-induced autophagy in H9C2 cells. Our results suggest that TLR4 may be pivotal in mediating the lethal cardiac toxicity induced by anthrax possibly through induction of autophagy. These findings suggest that compounds that negatively modulate TLR4 signalling and autophagy could be used to treat anthrax infection-induced cardiovascular complications. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Toll-like receptor 4 knockout protects against anthrax lethal toxin-induced cardiac contractile dysfunction: role of autophagy

PubMed Central

Kandadi, Machender R; Frankel, Arthur E; Ren, Jun

2012-01-01

BACKGROUND AND PURPOSE Anthrax lethal toxin (LeTx) is known to induce circulatory shock and death, although the underlying mechanisms have not been elucidated. This study was designed to evaluate the role of toll-like receptor 4 (TLR4) in anthrax lethal toxin-induced cardiac contractile dysfunction. EXPERIMENTAL APPROACH Wild-type (WT) and TLR4 knockout (TLR−/−) mice were challenged with lethal toxin (2 µg·g−1, i.p.), and cardiac function was assessed 18 h later using echocardiography and edge detection. Small interfering RNA (siRNA) was employed to knockdown TLR4 receptor or class III PI3K in H9C2 myoblasts. GFP–LC3 puncta was used to assess autophagosome formation. Western blot analysis was performed to evaluate autophagy (LC3, Becline-1, Agt5 and Agt7) and endoplasmic reticulum (ER) stress (BiP, eIF2α and calreticulin). KEY RESULTS In WT mice, lethal toxin exposure induced cardiac contractile dysfunction, as evidenced by reduced fractional shortening, peak shortening, maximal velocity of shortening/re-lengthening, prolonged re-lengthening duration and intracellular Ca2+ derangement. These effects were significantly attenuated or absent in the TLR4 knockout mice. In addition, lethal toxin elicited autophagy in the absence of change in ER stress. Knockdown of TLR4 or class III PI3 kinase using siRNA but not the autophagy inhibitor 3-methyladenine significantly attenuated or inhibited lethal toxin-induced autophagy in H9C2 cells. CONCLUSION AND IMPLICATIONS Our results suggest that TLR4 may be pivotal in mediating the lethal cardiac toxicity induced by anthrax possibly through induction of autophagy. These findings suggest that compounds that negatively modulate TLR4 signalling and autophagy could be used to treat anthrax infection-induced cardiovascular complications. PMID:22612289

[Caregivers and residents, raising awareness of the influenza vaccine].

PubMed

Plantet, Claire; Sanchez, Stéphane; Cohen, Nadia; Denormandie, Philippe; Dinh, Aurélien

Influenza epidemics in nursing homes can lead to serious complications with a high level of lethality. It has been shown that an active policy of awareness campaigns with obligatory information materials and easy access to influenza immunisation increases the rate of vaccination coverage. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Side-to-side cavocavostomy with an endovascular stapler: Rescue technique for severe hepatic vein and/or inferior vena cava outflow obstruction after liver transplantation using the piggyback technique.

PubMed

Quintini, Cristiano; Miller, Charles M; Hashimoto, Koji; Philip, Ding; Uso, Teresa Diago; Aucejo, Federico; Kelly, Dympna; Winans, Charles; Eghtesad, Bijan; Vogt, David; Fung, John

2009-01-01

Venous outflow obstruction is a rare but potentially lethal complication after orthotopic liver transplantation (OLT) with the "piggyback" technique. Therapeutic options include angioplasty with or without stent placement, surgical reconstruction of the venous anastomosis, and retransplantation. Surgical options are technically very challenging and the outcomes discouraging. We describe here two cases of venous outflow obstruction in recipients of piggyback liver grafts, one involving both the vena cava and hepatic veins and the other affecting only hepatic vein outflow. Both patients were treated successfully with side-to-side cavo-cavostomy using an endovascular (endo-GIA) stapler. This novel technique is fast and effective in resolving the outflow obstruction. Copyright 2008 AASLD.

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

Elliott, T.B.; Madonna, G.S.; Ledney, G.D.

Increased susceptibility to bacterial infection, probably by translocation from the intestinal flora, can be a lethal complication for 2-3 weeks after exposure to ionizing radiation. Antibiotics alone do not provide adequate therapy for induced infections in neutropenic mice. Because some substances that are derived from bacterial cell walls activate macrophages and stimulate nonspecific resistance to infection, such agents might be used to prevent or treat postirradiation infections. In this study, a cell-wall glycolipid, trehalose dimycolate (TDM), was evaluated together with a third-generation cephalosporin, ceftriaxone, for their separate and combined effects on survival of B6D2F1 female mice that were exposed tomore » the sublethal dose of 7.0 Gy Co radiation and challenged s.c. with lethal doses of Klebsiella pneumoniae. A single injection of TDM inoculated i.p. 1 hr postirradiation increased 30-day survival to 80% after a lethal challenge by K. pneumoniae 4 days later. When the challenge dose of K. pneumoniae was increased to 5000 Ld 50/30 on Day 4, all mice died.« less

[Surgical correction of the intraabdominal hypertension in patients with colon cancer].

PubMed

Aliev, S A

2012-01-01

The experience of treatment of 48 patients with colon cancer, complicated with bowe obstruction, colon perforation, abdominal sepsis and intraabdominal hypertension was analyzed. Men were 18, women - 30. Patients' age ranged 24-85 years. 31 patients (64.6%) had the 3rd stage (T4N2M0) of the disease by the time of the diagnosis. Tumor perforation was registered in 35 patients, the rest 13 had suprastenotic perforation. 39 patients developed SIRS and abdominal sepsis. The method of intraoperative "closed" colon decompression and intraluminar colon irrigation with the original modification of vacuum aspiration-irrigation device was introduced, as well as the modified method of end colostomy. Radical treatment was performed in 36 (78.3%) patients, 10 patients received palliative treatment and 2 patients could not be operated on. The postoperative lethality rate was 45.6%, the overall - 47.9%. The suggested method of colon decompression allowed to decrease the postoperative lethality rate from 47.7 to 45.6%, and the overall lethality rate from 50 to 47.9%.

An unusual autopsy case of lethal hypothermia exacerbated by body lice-induced severe anemia.

PubMed

Nara, Akina; Nagai, Hisashi; Yamaguchi, Rutsuko; Makino, Yohsuke; Chiba, Fumiko; Yoshida, Ken-ichi; Yajima, Daisuke; Iwase, Hirotaro

2016-05-01

Pediculus humanus humanus (known as body lice) are commonly found in the folds of clothes, and can cause skin disorders when they feed on human blood, resulting in an itching sensation. Body lice are known as vectors of infectious diseases, including typhus, recurrent fever, and trench fever. An infestation with blood-sucking body lice induces severe cutaneous pruritus, and this skin disorder is known as "vagabond's disease." A body lice infestation is sometimes complicated with iron deficiency anemia. In the present case, a man in his late 70s died of lethal hypothermia in the outdoors during the winter season. The case history and autopsy findings revealed that the cause of the lethal hypothermia was iron deficiency anemia, which was associated with a prolonged infestation of blood-sucking body lice. Also, he had vagabond's disease because the skin on his body was abnormal and highly pigmented. This is an unusual autopsy case since the body lice contributed to the cause of the death.

Cardiovascular Collapse During Transcatheter Aortic Valve Replacement: Diagnosis and Treatment of the “Perilous Pentad”

PubMed Central

El-Gamel, Adam

2013-01-01

Transcatheter aortic valve replacement (TAVR) has, without a doubt, brought an unprecedented excitement to the field of interventional cardiology. The avoidance of a sternotomy by transfemoral or transapical aortic-valve implantation appears to come at the price of some serious complications, including an increased risk of embolic stroke and paravalvular leakage. The technical challenges of the procedure and the complex nature of the high-risk patient cohort make the learning curve for this procedure a steep one, with the potential for unexpected complications always looming. Although most commonly relating to vascular access, these complications can also result from prosthesis-related trauma or malposition, or from unanticipated trauma from the pacing wire or the super stiff wire. Sudden and unexplained hypotension is often the earliest indicator of major complication and must prompt an immediate and detailed exclusion of five major pathologies: retroperitoneal bleeding from access site rupture, aortic dissection or rupture, pericardial tamponade, coronary ostial obstruction, or acute severe aortic regurgitation. In most cases, these can be dealt with quickly, and by percutaneous means, although open surgery may occasionally be necessary. Increased operator and team experience should make prevention and recognition of these catastrophic complications more complete. For this reason, the importance of specific training, such as that provided by the valve manufacturers through workshops and proctorship, cannot be overemphasized. It is essential that all operators, and indeed all members of the implant team, exert extreme vigilance to the development of intraprocedural complications, which could have rapid and potentially lethal consequences. Greater experience with an improved understanding of these risks, along with the development of better devices, deliverable through smaller and less traumatic sheath technology, will undoubtedly improve the safety and, potentially, widen the applicability of TAVR in the future. Forthcoming innovations include a newer generation of the valves with operator-controlled steerability to facilitate negotiation of tortuous aortic anatomy, as well as fully retrievable and resheathable devices to accommodate the events of dislocation or embolization. The fact that Transcatheter aortic valve implantation (TAVI) is new implies learning from experience but also from mistakes. The TAVI team must be vigilant to recognize and diagnose intraprocedure severe hypotension. The “perilous pentad” of catastrophic causes must be constantly borne in mind: retroperitoneal bleeding from access site rupture, aortic dissection or rupture, pericardial tamponade, coronary ostial obstruction, and acute severe aortic insufficiency. PMID:26798706

MIS approach for diverticula of the esophagus

PubMed Central

2010-01-01

Purpose Diverticula of the esophagus represent a rare pathological entity. Distinct classifications of the disease imply different surgical concepts. Surgery should be reserved for symptomatic patients only. Minimally invasive surgery (MIS) for treatment of esophageal diverticula encompasses rigid and flexible intraluminal endoscopy, thoracoscopy and laparoscopy. We here give an overview on the pathogenesis of esophageal diverticula, the minimally invasive surgical techniques for treatment and the recent literature. Additionally, we present our own experience with MIS for midthoracic diverticula. Methods We analyzed the cases of patients who underwent MIS for midthoracic diverticula with regard to preoperative symptoms, perioperative and follow-up data. Results Three patients (two female, one male, age 79, 78 and 59 years) received thoracoscopic surgery for midthoracic diverticula. All patients reported of dysphagia and regurgitation. In two patients pH-investigation showed pathological reflux but manometry was normal in all patients. Operating time was 205, 135 and 141 minutes. We performed intraoperative intraluminal endoscopy in all patients. There were no intraoperative complications and although no surgical complications occured postoperatively one patient developed pneumonia which advanced to sepsis and lethal multi organ failure. Upon follow-up the two patients did not have recurrent diverticula or a recurrence of previous symptoms. Conclusions Surgery for diverticular disease of the esophagus has been associated with high rates of morbidity and mortality. Despite the lethal non-surgical complication we encountered, with regard to recent publications minimally invasive apporaches to treat patients with symptomatic esophageal diverticula entail lower rates of complications with better long term results in comparison to open surgery. PMID:20952348

Sequence editing by Apolipoprotein B RNA-editing catalytic component-B and epidemiological surveillance of transmitted HIV-1 drug resistance

PubMed Central

Gifford, Robert J.; Rhee, Soo-Yon; Eriksson, Nicolas; Liu, Tommy F.; Kiuchi, Mark; Das, Amar K.; Shafer, Robert W.

2008-01-01

Design Promiscuous guanine (G) to adenine (A) substitutions catalysed by apolipoprotein B RNA-editing catalytic component (APOBEC) enzymes are observed in a proportion of HIV-1 sequences in vivo and can introduce artifacts into some genetic analyses. The potential impact of undetected lethal editing on genotypic estimation of transmitted drug resistance was assessed. Methods Classifiers of lethal, APOBEC-mediated editing were developed by analysis of lentiviral pol gene sequence variation and evaluated using control sets of HIV-1 sequences. The potential impact of sequence editing on genotypic estimation of drug resistance was assessed in sets of sequences obtained from 77 studies of 25 or more therapy-naive individuals, using mixture modelling approaches to determine the maximum likelihood classification of sequences as lethally edited as opposed to viable. Results Analysis of 6437 protease and reverse transcriptase sequences from therapy-naive individuals using a novel classifier of lethal, APOBEC3G-mediated sequence editing, the polypeptide-like 3G (APOBEC3G)-mediated defectives (A3GD) index’, detected lethal editing in association with spurious ‘transmitted drug resistance’ in nearly 3% of proviral sequences obtained from whole blood and 0.2% of samples obtained from plasma. Conclusion Screening for lethally edited sequences in datasets containing a proportion of proviral DNA, such as those likely to be obtained for epidemiological surveillance of transmitted drug resistance in the developing world, can eliminate rare but potentially significant errors in genotypic estimation of transmitted drug resistance. PMID:18356601

Regular Aspirin Use and the Risk of Lethal Prostate Cancer in the Physicians' Health Study.

PubMed

Downer, Mary K; Allard, Christopher B; Preston, Mark A; Gaziano, J Michael; Stampfer, Meir J; Mucci, Lorelei A; Batista, Julie L

2017-11-01

Regular aspirin use probably protects against some malignancies including prostate cancer (PC), but its impact on lethal PC is particularly unclear. To investigate the association between regular aspirin and (1) the risk of lethal PC in a large prospective cohort and (2) survival after PC diagnosis. In 1981/82, the Physicians' Health Study randomized 22 071 healthy male physicians to aspirin, β-carotene, both, or placebo. After the trial ended in 1988, annual questionnaires have obtained data on aspirin use, cancer diagnoses, and outcomes up to 2009 for the whole cohort, and to 2015 for PC patients. We evaluated the relationship between regular aspirin (>3 tablets/week) and lethal PC (metastases or PC death). Cox proportional-hazards models estimated hazard ratios (HRs) for the risk of lethal PC in the whole cohort and postdiagnosis survival among men initially diagnosed with nonlethal PC. Risk analysis revealed that 502 men developed lethal PC by 2009. Current and past regular aspirin was associated with a lower risk of lethal PC (current: HR 0.68, 95% confidence interval [CI] 0.52-0.89; past: HR 0.54, 95% CI 0.40-0.74) compared to never users. In the survival analysis, 407/3277 men diagnosed with nonlethal PC developed lethal disease by 2015. Current postdiagnostic aspirin was associated with lower risks of lethal PC (HR 0.68, 95% CI 0.52-0.90) and overall mortality (HR 0.72, 95% CI 0.61-0.9). We could not assess aspirin dose, and inconsistencies were observed in some sensitivity analyses. Current regular aspirin use was associated with a lower risk of lethal PC among all participants. Current postdiagnostic use was associated with improved survival after diagnosis, consistent with a potential inhibitory effect of aspirin on PC progression. A randomized trial is warranted to confirm or refute these findings. We examined the potential effect of regular aspirin use on lethal prostate cancer. We found that taking aspirin was associated with a lower risk of lethal prostate cancer, and taking it after diagnosis may help to prevent prostate cancer from becoming fatal. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Action of caffeine on x-irradiated HeLa cells. V. Identity of the sector of cells that expresses potentially lethal damage in G/sub 1/ and G/sub 2/

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

Beetham, K.L.; Tolmach, L.J.

1982-07-01

When HeLa S3 cells are irradiated in early G/sub 1/ with 4 Gy of 220-kV x rays and are then incubated in growth medium containing up to 5 mM caffeine, survival is reduced (as reported previously), reaching a concentration-dependent plateau. Cell killing presumably occurs as a result of the fixation of a portion of the potentially lethal damage the cells contain. These cells respond to continued treatment with caffeine at concentrations greater than 2 mM during S, but less so than during G/sub 1/. When they reach G/sub 2/ arrest, however, extensive cell killing again occurs (reported previously), presumably alsomore » the result of potentially lethal damage fixation. G/sub 1/-irradiated cultures that are treated with caffeine either continuously at a concentration in the range 1 to 5 mM, or at 10 mM for 8 hr and subsequently with the low concentration, achieve the same survival level in G/sub 2/, provided that the potentially lethal damage is not repaired during G/sub 1/ and S. Repair seems to be completely inhibited in the presence of 3 to 4 mM caffeine. The results indicate that fixation of potentially lethal damage occurs in the same sector of cells in G/sub 1/ and G/sub 2/, suggesting that the same cellular lesion gives rise to cell killing in the two phases.« less

A Case Report of Cannabis Induced Hemoptysis

PubMed Central

Hashmi, Hafiz Rizwan Talib; Duncalf, Richard; Khaja, Misbahuddin

2016-01-01

Abstract As the principal route of marijuana use is by inhalation, potential harmful consequences on pulmonary structure and function can be anticipated. Here, we present a case of hemoptysis attributed to smoking cannabis in a 38-year-old man. The patient experienced an episode of hemoptysis and shortness of breath immediately after smoking marijuana. Chest radiograph and computed tomography (CT) scans of the chest showed bilateral diffuse ground-glass opacities. A fiber optic bronchoscopy confirmed bilateral diffuse bleeding from respiratory tract. Additional evaluation of hemoptysis indicated no infection or immunological responses. Urine toxicology was positive for cannabis. Chronic marijuana smoking causes visible and microscopic injury to the larger airways responsible for symptoms or chronic bronchitis. We review the beneficial and deleterious effects of marijuana and describe a case of significant hemoptysis attributed to smoking marijuana. In addition to other respiratory complications of marijuana use, physicians should educate their patients about this potentially lethal effect of marijuana smoking in the form of hemoptysis. PMID:27043693

Myxedema coma after esophagectomy.

PubMed

Yuan, Yong; Hu, Yang; Xie, Tianpeng; Zhao, Yongfan

2010-07-01

For most patients with esophageal cancer, esophagectomy is an effective therapy. Perioperative management is critical for clinical outcomes after the operation. Great efforts should be made to avoid postoperative complications. We report myxedema coma, an emergency condition caused by severe hypothyroidism, after a patient underwent esophagectomy for esophageal cancer. The patient was successfully treated with intravenous levothyroxine. We strongly recommend that physicians test the thyroid hormone levels in patients with risk factors. If myxedema coma occurs, immediate use of intravenous levothyroxine is effective for this lethal complication. Copyright 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

["Open" surgery of mitral heart diseases complicated by pulmonary hypertension].

PubMed

Abdumazhidov, Kh A; Guliamov, D S; Amanov, A A

2000-01-01

Under analysis were the results of 386 operations on the "open" heart made for mitral diseases complicated by pulmonary hypertension of different degrees. Prosthetics of the mitral valve was performed in 251 patients, in 135 patients the so-called "organ-saving" correction of the defect was fulfilled. The decision on the method of the defect correction depends on the anatomical particularities, morphological alterations of the valvular apparatus. The main place among the causes of postoperative lethality (9-11%) is occupied by cardiac insufficiency and renohepatic failure which are noted mainly in patients of the IVth functional class.

Attacks on German public figures, 1968-2004: warning behaviors, potentially lethal and non-lethal acts, psychiatric status, and motivations.

PubMed

Hoffmann, Jens; Meloy, J Reid; Guldimann, Angela; Ermer, Anneliese

2011-01-01

Fourteen non-terrorist attackers of public figures in Germany between 1968 and 2004 were intensively studied, with a particular focus on warning behaviors, attack behaviors, and the relationship between psychiatric diagnosis, symptoms, and motivations for the assault. A large proportion of the attackers were severely mentally ill, and most likely to be in the potentially lethal rather than the non-lethal group. A new typology of seven warning behaviors was applied to the data, and all were present, most frequently fixation and pathway warning behavior, and least frequently a direct threat. Psychiatric diagnosis could be closely linked to motivation when analyzed at the level of symptom and content of thought, often delusional. Most of the attacks were directed at political figures, and the majority occurred after 1995. Copyright © 2011 John Wiley & Sons, Ltd.

Rancher-reported efficacy of lethal and non-lethal livestock predation mitigation strategies for a suite of carnivores.

PubMed

Scasta, J D; Stam, B; Windh, J L

2017-10-26

Pastoralists have dealt with livestock losses from predators for millennia, yet effective mitigation strategies that balance wildlife conservation and sustainable agriculture are still needed today. In Wyoming, USA, 274 ranchers responded to a retrospective survey, and rated the efficacy of predation mitigation strategies for foxes, dogs, coyotes, wolves, bobcats, mountain lions, bears, and birds (buzzards, eagles, hawks, ravens). Rancher reported efficacy of mitigation varied by predator species, mitigation strategy, and lethality of strategies, but not livestock type. Ranchers perceive they were most effective at mitigating predation by foxes and coyotes, moderately effective at mitigating large carnivores, and the least effective at mitigating birds. Ranchers also reported that avian predators seem to be the most challenging predator type. The general perception was lethal mitigation strategies were more effective than non-lethal strategies, with guard animals showing the most potential among the non-lethal options. In general, ranchers did not perceive non-lethal strategies as a proxy for lethal strategies. However, a few ranchers reported being successful with non-lethal options such as herding, fencing, and stalling at night but more details about such successful applications are needed. Innovation in current or novel non-lethal mitigation strategies, and examples of efficacy, are needed to justify producer adoption.

Risks of non-lethal weapon use: case studies of three French victims of stinger grenades.

PubMed

Scolan, V; Herry, C; Carreta, M; Stahl, C; Barret, L; Romanet, J P; Paysant, F

2012-11-30

The development of non-lethal weapons started in the 1960s. In France, they have been used by the police for about 10 years. We relate the cases of three French women, victims of stinger grenades, non-lethal weapons recently adopted by the French law enforcement to distract and disperse crowds. The three victims presented serious injuries requiring emergency surgical care. One lost her eye. Based on these cases, we discuss the lethal character of these weapons and propose measures to be taken to prevent their dramatic consequences. Although the danger is obviously less than for firearms, stinger grenades are nonetheless potentially lethal and cause serious physical injuries. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Anthrax lethal factor inhibitors as potential countermeasure of the infection.

PubMed

Kumar, B V S Suneel; Malik, Siddharth; Grandhi, Pradeep; Dayam, Raveendra; Sarma, J A R P

2014-01-01

Anthrax Lethal Factor (LF) is a zinc-dependent metalloprotease, one of the virulence factor of anthrax infection. Three forms of the anthrax infection have been identified: cutaneous (through skin), gastrointestinal (through alimentary tract), and pulmonary (by inhalation of spores). Anthrax toxin is composed of protective antigen (PA), lethal factor (LF), and edema factor (EF). Protective antigen mediates the entry of Lethal Factor/Edema Factor into the cytosol of host cells. Lethal factor (LF) inactivates mitogen-activated protein kinase kinase inducing cell death, and EF is an adenylyl cyclase impairing host defenses. In the past few years, extensive studies are undertaken to design inhibitors targeting LF. The current review focuses on the small molecule inhibitors targeting LF activity and its structure activity relationships (SAR).

A NOVEL SCORING SYSTEM: PREDICTING SEPTIC SHOCK AT DIAGNOSIS EASILY IN ACUTE COMPLICATED PYELONEPHRITIS PATIENTS.

PubMed

Kubota, Masashi; Kanno, Toru; Nishiyama, Ryuichi; Okada, Takashi; Higashi, Yoshihito; Yamada, Hitoshi

2016-01-01

(Objectives) Because acute complicated pyelonephritis can easily cause sepsis and concomitant shock status, it is a potentially lethal disease. However, the predictors for the severity of pyelonephritis is not well analyzed. In this study, we aimed at clarifying the clinical characteristic risk factors associated with septic shock in patients with acute complicated pyelonephritis. (Materials and methods) From May 2009 to March 2014, 267 patients with acute complicated pyelonephritis were treated at our institution. We investigated the characteristics of the patients associated with septic shock, and assessed risk factors in these patients. By using these risk factors, we established a novel scoring system to predict septic shock. (Results) 267 patients included 145 patients with ureteral calculi and 75 patients with stent-related pyelonephritis. Septic shock occurred in 35 patients (13%), and the mortality rate was 0.75%. Multivariate analysis revealed that (P): Performance Status ≥3 (p=0.0014), (U): Presence of Ureteral calculi (p=0.043), (S): Sex of female (p=0.023), and (H): the presence of Hydronephrosis (p=0.039) were independent risk factors for septic shock. P.U.S.H. scoring system (range 0-4), which consists of these 4 factors, were positively correlated with the rate of septic shock (score 0: 0%, 1: 5.3%, 2: 3.4%, 3: 25.0%, 4: 42.3%). Importantly, patients with 3-4 P.U.S.H. scores were statistically more likely to become septic shock than those with 0-2 score (p=0.00014). (Conclusions) These results suggest that P.U.S.H. scoring system using 4 clinical factors is useful to predict the status of septic shock in patients with acute complicated pyelonephritis.

Toluene inducing acute respiratory failure in a spray paint sniffer.

PubMed

Peralta, Diego P; Chang, Aymara Y

2012-01-01

Toluene, formerly known as toluol, is an aromatic hydrocarbon that is widely used as an industrial feedstock and as a solvent. Like other solvents, toluene is sometimes also used as an inhalant drug for its intoxicating properties. It has potential to cause multiple effects in the body including death. I report a case of a 27-year-old male, chronic spray paint sniffer, who presented with severe generalized muscle weakness and developed acute respiratory failure requiring ventilatory support. Toluene toxicity was confirmed with measurement of hippuric acid of 8.0 g/L (normal <5.0 g/L). Acute respiratory failure is a rare complication of chronic toluene exposure that may be lethal if it is not recognized immediately. To our knowledge, this is the second case of acute respiratory failure due to toluene exposure.

Toluene inducing acute respiratory failure in a spray paint sniffer

PubMed Central

Peralta, Diego P.; Chang, Aymara Y.

2012-01-01

Summary Background: Toluene, formerly known as toluol, is an aromatic hydrocarbon that is widely used as an industrial feedstock and as a solvent. Like other solvents, toluene is sometimes also used as an inhalant drug for its intoxicating properties. It has potential to cause multiple effects in the body including death. Case Report: I report a case of a 27-year-old male, chronic spray paint sniffer, who presented with severe generalized muscle weakness and developed acute respiratory failure requiring ventilatory support. Toluene toxicity was confirmed with measurement of hippuric acid of 8.0 g/L (normal <5.0 g/L). Conclusions: Acute respiratory failure is a rare complication of chronic toluene exposure that may be lethal if it is not recognized immediately. To our knowledge, this is the second case of acute respiratory failure due to toluene exposure. PMID:23569498

Non-lethal genotyping of Tribolium castaneum adults using genomic DNA extracted from wing tissue.

PubMed

Strobl, Frederic; Ross, J Alexander; Stelzer, Ernst H K

2017-01-01

The red flour beetle Tribolium castaneum has become the second most important insect model organism and is frequently used in developmental biology, genetics and pest-associated research. Consequently, the methodological arsenal increases continuously, but many routinely applied techniques for Drosophila melanogaster and other insect species are still unavailable. For example, a protocol for non-lethal genotyping has not yet been adapted but is particularly useful when individuals with known genotypes are required for downstream experiments. In this study, we present a workflow for non-lethal genotyping of T. castaneum adults based on extracting genomic DNA from wing tissue. In detail, we describe a convenient procedure for wing dissection and a custom method for wing digestion that allows PCR-based genotyping of up to fifty adults in less than an afternoon with a success rate of about 86%. The amount of template is sufficient for up to ten reactions while viability and fertility of the beetles are preserved. We prove the applicability of our protocol by genotyping the white / scarlet gene pair alleles from the black-eyed San Bernadino wild-type and white-eyed Pearl recessive mutant strains spanning four generations. Non-lethal genotyping has the potential to improve and accelerate many workflows: Firstly, during the establishment process of homozygous cultures or during stock keeping of cultures that carry recessively lethal alleles, laborious test crossing is replaced by non-lethal genotyping. Secondly, in genome engineering assays, non-lethal genotyping allows the identification of appropriate founders before they are crossed against wild-types, narrowing the efforts down to only the relevant individuals. Thirdly, non-lethal genotyping simplifies experimental strategies, in which genotype and behavior should be correlated, since the genetic configuration of potential individuals can be determined before the actual behavior assays is performed.

Linear-quadratic dose kinetics or dose-dependent repair/misrepair

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

Braby, L.A.; Nelson, J.M.

1991-09-01

Models for the response of cells exposed to low LET radiation can be grouped into three general types on the basis of assumptions about the nature of the interaction which results in the shoulder of the survival curve. The three forms of interaction are (1) sublethal damage becoming lethal, (2) potentially lethal damage becoming irreparable, and (3) potentially lethal damage saturating'' a repair system. The effects that these three forms of interaction would have on the results of specific types of experiments are investigated. Comparisons with experimental results indicate that only the second type is significant in determining the responsemore » of typical cultured mammalian cells. 5 refs., 2 figs.« less

Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop

PubMed Central

2011-01-01

Background Envenomation by crotaline snakes (rattlesnake, cottonmouth, copperhead) is a complex, potentially lethal condition affecting thousands of people in the United States each year. Treatment of crotaline envenomation is not standardized, and significant variation in practice exists. Methods A geographically diverse panel of experts was convened for the purpose of deriving an evidence-informed unified treatment algorithm. Research staff analyzed the extant medical literature and performed targeted analyses of existing databases to inform specific clinical decisions. A trained external facilitator used modified Delphi and structured consensus methodology to achieve consensus on the final treatment algorithm. Results A unified treatment algorithm was produced and endorsed by all nine expert panel members. This algorithm provides guidance about clinical and laboratory observations, indications for and dosing of antivenom, adjunctive therapies, post-stabilization care, and management of complications from envenomation and therapy. Conclusions Clinical manifestations and ideal treatment of crotaline snakebite differ greatly, and can result in severe complications. Using a modified Delphi method, we provide evidence-informed treatment guidelines in an attempt to reduce variation in care and possibly improve clinical outcomes. PMID:21291549

Therapeutic efficacy of antibodies lacking Fcγ receptor binding against lethal dengue virus infection is due to neutralizing potency and blocking of enhancing antibodies [corrected].

PubMed

Williams, Katherine L; Sukupolvi-Petty, Soila; Beltramello, Martina; Johnson, Syd; Sallusto, Federica; Lanzavecchia, Antonio; Diamond, Michael S; Harris, Eva

2013-02-01

Dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) are life-threatening complications following infection with one of the four serotypes of dengue virus (DENV). At present, no vaccine or antiviral therapies are available against dengue. Here, we characterized a panel of eight human or mouse-human chimeric monoclonal antibodies (MAbs) and their modified variants lacking effector function and dissected the mechanism by which some protect against antibody-enhanced lethal DENV infection. We found that neutralizing modified MAbs that recognize the fusion loop or the A strand epitopes on domains II and III of the envelope protein, respectively, act therapeutically by competing with and/or displacing enhancing antibodies. By analyzing these relationships, we developed a novel in vitro suppression-of-enhancement assay that predicts the ability of modified MAbs to act therapeutically against antibody-enhanced disease in vivo. These studies provide new insight into the biology of DENV pathogenesis and the requirements for antibodies to treat lethal DENV disease.

Microwave and Man—The Direct and Indirect Hazards, and the Precautions

PubMed Central

Merckel, Charles

1972-01-01

Microwave-radar is a form of electromagnetic energy with potential hazards to human health and safety. Its lethal and non-lethal harmful effects have been demonstrated in experimental animals. Lethal effects upon humans from exposure to microwave have not been proved. Alleged non-lethal effects have been limited primarily to cataractogenesis. Increasing use of microwave commercially in communications and domestically, as in micro-ovens, increases the hazard of exposure to microwave. Increasing use of devices which are at risk from microwave, such as implanted cardiac pacemakers and metal surgical appliances and electronic monitoring devices in operating rooms and clinics, present increasing environmental hazards. PMID:5039801

Status and Challenges of Filovirus Vaccines

DTIC Science & Technology

2007-03-01

comprise the family Filoviridae cause ome of the most lethal viral hemorrhagic fevers known. n 1967, an outbreak in Marburg, Germany occurred among...been reported in some but not all cases. ithin 6–8 days of fever , hemorrhagic complications can evelop, and patients develop increasingly severe...with ZEBOV infection cynomolgus acaques and rhesus macaques are more likely to develop petechial rash and coagulation defects while baboons are ore

Clinical Management of Heat-Related Illnesses

DTIC Science & Technology

2012-01-01

rhabdomyolysis and multiorgan dysfunction syndrome, and it may result in death from overwhelming cell necrosis caused by a lethal heat-shock exposure...complications such as rhabdomyolysis and multiorgan dysfunction syndrome, and it may result in death from overwhelming cell necrosis caused by a...acetaminophen lower Tco by normalizing the elevated hypothalamic set point that is caused by pyrogens; in heatstroke, the set point is normal, with

Prediction of lethal/effective concentration/dose in the presence of multiple auxiliary covariates and components of variance

USGS Publications Warehouse

Gutreuter, S.; Boogaard, M.A.

2007-01-01

Predictors of the percentile lethal/effective concentration/dose are commonly used measures of efficacy and toxicity. Typically such quantal-response predictors (e.g., the exposure required to kill 50% of some population) are estimated from simple bioassays wherein organisms are exposed to a gradient of several concentrations of a single agent. The toxicity of an agent may be influenced by auxiliary covariates, however, and more complicated experimental designs may introduce multiple variance components. Prediction methods lag examples of those cases. A conventional two-stage approach consists of multiple bivariate predictions of, say, medial lethal concentration followed by regression of those predictions on the auxiliary covariates. We propose a more effective and parsimonious class of generalized nonlinear mixed-effects models for prediction of lethal/effective dose/concentration from auxiliary covariates. We demonstrate examples using data from a study regarding the effects of pH and additions of variable quantities 2???,5???-dichloro-4???- nitrosalicylanilide (niclosamide) on the toxicity of 3-trifluoromethyl-4- nitrophenol to larval sea lamprey (Petromyzon marinus). The new models yielded unbiased predictions and root-mean-squared errors (RMSEs) of prediction for the exposure required to kill 50 and 99.9% of some population that were 29 to 82% smaller, respectively, than those from the conventional two-stage procedure. The model class is flexible and easily implemented using commonly available software. ?? 2007 SETAC.

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.

Non-Lethal Weapons: Setting Our Phasers on Stun? Potential Stratetgic Blessings and Curses of Non-Lethal Weapons on the Battlefield

DTIC Science & Technology

2003-08-01

improve our ability to verify compliance with the treaty’s global ban on biological weapons and would put national security and confidential business ...he was Assistant Professor of Aeronautics at the U.S. Air Force Academy, Colorado, where he was also instructor pilot in the T - 41 flight-screening...fielded on a greater scale are explored. The ability of non-lethal weapons to positively influence the global war on terrorism is also assessed. It

[Conservative treatment of a spontaneous splenic rupture in a patient with infectious mononucleosis].

PubMed

Toorenvliet, B R; Kortekaas, R Th J; Niggebrugge, A H P

2002-09-07

A 30-year-old man with flu-like symptoms for several weeks presented at the emergency room with pain in the left upper abdomen. There was no history of trauma. The patient had a spontaneous rupture of the spleen due to mononucleosis infectiosa. He was successfully treated with conservative management during a 7-day period of hospitalisation. Spontaneous splenic rupture is a rare but potentially lethal complication of infectious mononucleosis. Alarming symptoms are left upper abdominal pain, worsening during inspiration, and haemodynamic instability. Although splenectomy is the accepted treatment for haemodynamically unstable patients, some patients, may be adequately treated with conservative management. They should be observed during the critical phase and must comply to a period of restricted physical activity after they are discharged from the hospital. There is no consensus about the length or content of this restriction period.

[Rhabdomyolysis in a Bipolar Adolescent. Analysis of Associated Factors].

PubMed

Restrepo, Diana; Montoya, Pablo; Giraldo, Laura; Gaviria, Génesis; Mejía, Catalina

2015-01-01

To describe a case of rhabdomyolysis associated with the use of quetiapine and lamotrigine in an adolescent treated for bipolar disorder. Description of the clinical case, analysis of the associated factors and a non-systematic review of the relevant literature. An 18 year old male, with bipolar disorder and treated pharmacologically with quetiapine and lamotrigine, after two weeks of physical activity presents with rhabdomyolysis. Quetiapine and exercise have been associated with rhabdomyolysis. The mediator mechanism of this association has not been found, although it has been established that there is neuromuscular dysfunction and an increase in sarcomere permeability. This clinical case allowed the complex interaction between antipsychotic agents and increased physical activity to be observed in a psychiatric adolescent patient, as well as the appearance of a potentially lethal medical complication. Copyright © 2014 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Pediatric air gun shot injury.

PubMed

Khan, Ubaid U; Kamal, Naglaa M; Mirza, Shazia J; Sherief, Laila M

2014-12-01

Air guns (AGs) use air or another compressed gas to propel a projectile. Different injuries may occur in children due to their body structure, which is less-resistant with thin soft tissue coverage that can be easily penetrated by an AG shot. We present 3 cases of pediatric AG shot injury. The first-case had right lumber deep tissue penetration of AG pallet without internal damage, the second-case had a complex course of pellet into the perineum, and the third-case was shot in the left shoulder. All cases were accidentally shot. The shooters were all children, and relatives of the victims. All patients were generally stable on arrival. Two cases were operated, and one received conservative management. On follow up, no complications were noted.  At first sight, AGs and air rifles may appear relatively harmless, but they are potentially lethal and children should not be allowed to play with them. 

Inhalation toxicology. XII., Comparison of toxicity rankings of six polymers by lethality and by incapacitation in rats.

DOT National Transportation Integrated Search

1991-12-01

Polymeric aircraft cabin materials have the potential to produce toxic gases in fires. Lethality (LC50) in animal models is a standard index to rank polymers on the basis of their combustion product toxicity. However, the use of times-toincapacitatio...

A Content Analysis of News Reports of Averted School Rampages

ERIC Educational Resources Information Center

Daniels, Jeffrey A.; Buck, Ilene; Croxall, Susan; Gruber, Julia; Kime, Peter; Govert, Heidi

2007-01-01

Although the majority of research into school violence have focused attention on lethal or injury-producing incidents, this focus provides only partial information about school violence prevention. Moore, Petrie, Braga, and McLaughlin (2003) suggested that researchers turn their attention to those incidents in which a potentially lethal situation…

Influence of pre-, post-, and simultaneous perfusion of elevated calcium on the effect of ascending concentrations of lead on digoxin-induced cardiac arrest in isolated frog heart

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

Krishnamoorthy, M.S.; Muthu, P.; Parthiban, N.

1995-10-01

Cardiotoxicity of lead, a ubiquitous environmental pollutant, has already been documented as a potentially lethal, although rarely recognized, complication of lead intoxication. Further, it has already been reported from this laboratory that lead acetate (LA) preperfusion potentiated cardiotoxicity of digoxin (DGN) in isolated frog heart preparation and that exposure to elevated calcium (elev. Ca{sup 2+}) prior to, and simultaneously with LA at 10{sup {minus}7} M concentration, attenuated this potentiation. As an extension of this work, it was considered of interest to study the effect of perfusion of elev. Ca{sup 2+} (6.5 mM) prior to, after and simultaneously with ascending concentrationsmore » of lead (10{sup {minus}9}, 10{sup {minus}7} and 10{sup {minus}5}M) on DGN induced cardiac arrest (CA) in isolated frog heart, since Pb{sup 2+} and Ca{sup 2+} ions are known to compete with each other for the same target sites at the cellular level, an instance of competitive mass action effect. 15 refs., 1 fig., 1 tab.« less

Field and laboratory studies reveal interacting effects of stream oxygenation and warming on aquatic ectotherms.

PubMed

Verberk, Wilco C E P; Durance, Isabelle; Vaughan, Ian P; Ormerod, Steve J

2016-05-01

Aquatic ecological responses to climatic warming are complicated by interactions between thermal effects and other environmental stressors such as organic pollution and hypoxia. Laboratory experiments have demonstrated how oxygen limitation can set heat tolerance for some aquatic ectotherms, but only at unrealistic lethal temperatures and without field data to assess whether oxygen shortages might also underlie sublethal warming effects. Here, we test whether oxygen availability affects both lethal and nonlethal impacts of warming on two widespread Eurasian mayflies, Ephemera danica, Müller 1764 and Serratella ignita (Poda 1761). Mayfly nymphs are often a dominant component of the invertebrate assemblage in streams, and play a vital role in aquatic and riparian food webs. In the laboratory, lethal impacts of warming were assessed under three oxygen conditions. In the field, effects of oxygen availability on nonlethal impacts of warming were assessed from mayfly occurrence in 42 293 UK stream samples where water temperature and biochemical oxygen demand were measured. Oxygen limitation affected both lethal and sublethal impacts of warming in each species. Hypoxia lowered lethal limits by 5.5 °C (±2.13) and 8.2 °C (±0.62) for E. danica and S. ignita respectively. Field data confirmed the importance of oxygen limitation in warmer waters; poor oxygenation drastically reduced site occupancy, and reductions were especially pronounced under warm water conditions. Consequently, poor oxygenation lowered optimal stream temperatures for both species. The broad concordance shown here between laboratory results and extensive field data suggests that oxygen limitation not only impairs survival at thermal extremes but also restricts species abundance in the field at temperatures well below upper lethal limits. Stream oxygenation could thus control the vulnerability of aquatic ectotherms to global warming. Improving water oxygenation and reducing pollution can provide key facets of climate change adaptation for running waters. © 2016 The Authors. Global Change Biology Published by John Wiley & Sons Ltd.

Burden of herpes simplex virus encephalitis in the United States.

PubMed

Modi, S; Mahajan, Abhimanyu; Dharaiya, D; Varelas, P; Mitsias, P

2017-06-01

Herpes simplex virus encephalitis (HSVE) is a disease of public health concern, but its burden on the healthcare of United States has not been adequately assessed recently. We aimed to define the incidence, complications and outcomes of HSVE in the recent decade by analyzing data from a nationally representative database. Healthcare Cost and Utilization Project databases were utilized to identify patients with primary discharge diagnosis of HSVE. Annual hospitalization rate was estimated and several preselected inpatient complications were identified. Regression analyses were used to identify mortality predictors. Key epidemiological factors were compared with those from other countries. Total 4871 patients of HSVE were included in our study. The annual hospitalization rate was 10.3 ± 2.2 cases/million in neonates, 2.4 ± 0.3 cases/million in children and 6.4 ± 0.4 cases/million in adults. Median age was 57 years and male:female incidence ratio was 1:1. Rates of some central nervous system complications were seizures (38.4%), status epilepticus (5.5%), acute respiratory failure (20.1%), ischemic stroke (5.6%) and intracranial hemorrhage (2.7%), all of which were significantly associated with mortality. In-hospital mortality in neonates, children and adults were 6.9, 1.2 and 7.7%, respectively. HSVE still remains a potentially lethal infectious disease with high morbidity and mortality. Most recent epidemiological data in this study may help understanding this public health disease, and the patient outcome data may have prognostic significance.

Lethal Coinfection of Influenza Virus and Streptococcus pneumoniae Lowers Antibody Response to Influenza Virus in Lung and Reduces Numbers of Germinal Center B Cells, T Follicular Helper Cells, and Plasma Cells in Mediastinal Lymph Node

PubMed Central

Wu, Yuet; Lam, Kwok-Tai; Chow, Kin-Hung; Ho, Pak-Leung; Guan, Yi; Peiris, Joseph S. Malik

2014-01-01

ABSTRACT Secondary Streptococcus pneumoniae infection after influenza is a significant clinical complication resulting in morbidity and sometimes mortality. Prior influenza virus infection has been demonstrated to impair the macrophage and neutrophil response to the subsequent pneumococcal infection. In contrast, how a secondary pneumococcal infection after influenza can affect the adaptive immune response to the initial influenza virus infection is less well understood. Therefore, this study focuses on how secondary pneumococcal infection after influenza may impact the humoral immune response to the initial influenza virus infection in a lethal coinfection mouse model. Compared to mice infected with influenza virus alone, mice coinfected with influenza virus followed by pneumococcus had significant body weight loss and 100% mortality. In the lung, lethal coinfection significantly increased virus titers and bacterial cell counts and decreased the level of virus-specific IgG, IgM, and IgA, as well as the number of B cells, CD4 T cells, and plasma cells. Lethal coinfection significantly reduced the size and weight of spleen, as well as the number of B cells along the follicular developmental lineage. In mediastinal lymph nodes, lethal coinfection significantly decreased germinal center B cells, T follicular helper cells, and plasma cells. Adoptive transfer of influenza virus-specific immune serum to coinfected mice improved survival, suggesting the protective functions of anti-influenza virus antibodies. In conclusion, coinfection reduced the B cell response to influenza virus. This study helps us to understand the modulation of the B cell response to influenza virus during a lethal coinfection. IMPORTANCE Secondary pneumococcal infection after influenza virus infection is an important clinical issue that often results in excess mortality. Since antibodies are key mediators of protection, this study aims to examine the antibody response to influenza virus and demonstrates that lethal coinfection reduced the B cell response to influenza virus. This study helps to highlight the complexity of the modulation of the B cell response in the context of coinfection. PMID:25428873

Sub-lethal and lethal toxicities of elevated CO2 on embryonic, juvenile, and adult stages of marine medaka Oryzias melastigma.

PubMed

Lee, Changkeun; Kwon, Bong-Oh; Hong, Seongjin; Noh, Junsung; Lee, Junghyun; Ryu, Jongseong; Kang, Seong-Gil; Khim, Jong Seong

2018-06-06

The potential leakage from marine CO 2 storage sites is of increasing concern, but few studies have evaluated the probable adverse effects on marine organisms. Fish, one of the top predators in marine environments, should be an essential representative species used for water column toxicity testing in response to waterborne CO 2 exposure. In the present study, we conducted fish life cycle toxicity tests to fully elucidate CO 2 toxicity mechanism effects. We tested sub-lethal and lethal toxicities of elevated CO 2 concentrations on marine medaka (Oryzias melastigma) at different developmental stages. At each developmental stage, the test species was exposed to varying concentrations of gaseous CO 2 (control air, 5%, 10%, 20%, and 30%), with 96 h of exposure at 0-4 d (early stage), 4-8 d (middle stage), and 8-12 d (late stage). Sub-lethal and lethal effects, including early developmental delays, cardiac edema, tail abnormalities, abnormal pigmentation, and mortality were monitored daily during the 14 d exposure period. At the embryonic stage, significant sub-lethal and lethal effects were observed at pH < 6.30. Hypercapnia can cause long-term and/or delayed developmental embryonic problems, even after transfer back to clean seawater. At fish juvenile and adult stages, significant mortality was observed at pH < 5.70, indicating elevated CO 2 exposure might cause various adverse effects, even during short-term exposure periods. It should be noted the early embryonic stage was found more sensitive to CO 2 exposure than other developmental stages of the fish life cycle. Overall, the present study provided baseline information for potential adverse effects of high CO 2 concentration exposure on fish developmental processes at different life cycle stages in marine ecosystems. Copyright © 2018 Elsevier Ltd. All rights reserved.

Straightening Beta: Overdispersion of Lethal Chromosome Aberrations following Radiotherapeutic Doses Leads to Terminal Linearity in the Alpha–Beta Model

PubMed Central

Shuryak, Igor; Loucas, Bradford D.; Cornforth, Michael N.

2017-01-01

Recent technological advances allow precise radiation delivery to tumor targets. As opposed to more conventional radiotherapy—where multiple small fractions are given—in some cases, the preferred course of treatment may involve only a few (or even one) large dose(s) per fraction. Under these conditions, the choice of appropriate radiobiological model complicates the tasks of predicting radiotherapy outcomes and designing new treatment regimens. The most commonly used model for this purpose is the venerable linear-quadratic (LQ) formalism as it applies to cell survival. However, predictions based on the LQ model are frequently at odds with data following very high acute doses. In particular, although the LQ predicts a continuously bending dose–response relationship for the logarithm of cell survival, empirical evidence over the high-dose region suggests that the survival response is instead log-linear with dose. Here, we show that the distribution of lethal chromosomal lesions among individual human cells (lymphocytes and fibroblasts) exposed to gamma rays and X rays is somewhat overdispersed, compared with the Poisson distribution. Further, we show that such overdispersion affects the predicted dose response for cell survival (the fraction of cells with zero lethal lesions). This causes the dose response to approximate log-linear behavior at high doses, even when the mean number of lethal lesions per cell is well fitted by the continuously curving LQ model. Accounting for overdispersion of lethal lesions provides a novel, mechanistically based explanation for the observed shapes of cell survival dose responses that, in principle, may offer a tractable and clinically useful approach for modeling the effects of high doses per fraction. PMID:29312888

Significance of Rib Fractures Potentially Caused by Blunt Impact Non Lethal Weapons

DTIC Science & Technology

2017-03-01

Center Drive Alexandria, Virginia 22311-1882 I N S T I T U T E F O R D E F E N S E A N A L Y S E S Significance of Rib Fractures Potentially...F E N S E A N A L Y S E S IDA Document D-8277 Significance of Rib Fractures Potentially Caused by Blunt-Impact Non-Lethal Weapons Shelley M. Cazares...deterrent by inducing pain or muscle spasm at the site of impact of the affected individual. These weapons may induce rib fractures —the focus of this

Pheochromocytoma crisis is not a surgical emergency.

PubMed

Scholten, Anouk; Cisco, Robin M; Vriens, Menno R; Cohen, Jenny K; Mitmaker, Elliot J; Liu, Chienying; Tyrrell, J Blake; Shen, Wen T; Duh, Quan-Yang

2013-02-01

Pheochromocytoma crisis is a feared and potentially lethal complication of pheochromocytoma. We sought to determine the best treatment strategy for pheochromocytoma crisis patients and hypothesized that emergency resection is not indicated. Retrospective cohort study (1993-2011); literature review (1944-2011). Tertiary referral center. There were 137 pheochromocytoma patients from our center and 97 pheochromocytoma crisis patients who underwent adrenalectomy from the literature. Medical management of pheochromocytoma crisis; adrenalectomy. Perioperative complications, conversion, and mortality. In our database, 25 patients (18%) presented with crisis. After medical stabilization and α-blockade, 15 patients were discharged and readmitted for elective surgery and 10 patients were operated on urgently during the same hospitalization. None underwent emergency surgery. Postoperatively, patients who underwent elective surgery had shorter hospital stays (1.7 vs 5.7 d, P = 0.001) and fewer postoperative complications (1 of 15 [7%] vs 5 of 10 [50%], P = 0.045) and were less often admitted to the intensive care unit (1 of 15 [7%] vs 5 of 10 [50%], P = 0.045) in comparison with urgently operated patients. There was no mortality. Review of the literature (n = 97) showed that crisis patients who underwent elective or urgent surgery vs emergency surgery had less intraoperative (13 of 31 [42%] vs 20 of 25 [80%], P < 0.001) and postoperative complications (15 of 45 [33%] vs 15 of 21 [71%], P = 0.047) and a lower mortality (0 of 64 vs 6 of 33 [18%], P = 0.002). Management of patients presenting with pheochromocytoma crisis should include initial stabilization of the acute crisis followed by sufficient α-blockade before surgery. Emergency resection of pheochromocytoma is associated with high surgical morbidity and mortality.

Spontaneous hepatic rupture in pregnancy.

PubMed

Nelson, E W; Archibald, L; Albo, D

1977-12-01

Hepatic rupture as a late complication of toxemic pregnancy is a rare yet lethal condition requiring rapid recognition and surgical management. The clinical triad of toxemia, right upper quadrant pain, and sudden hypotension is the diagnostic hallmark of presentation. Most patients present near the time of delivery and are found to have subcapsular hematomas of the right hepatic lobe with free rupture into the peritoneal cavity and resultant exsanguinating hemorrhage. The association of toxemia and disseminated intravascular coagulation with secondary microembolic damage to the liver and other organs has been discussed. Basic surgical principles in the managment of hepatic subcapsular hematomas, and the prolonged postoperative course and frequent complications in these patients have been stressed.

Interleukin-10 protects neonatal mice from lethal group B streptococcal infection.

PubMed Central

Cusumano, V; Genovese, F; Mancuso, G; Carbone, M; Fera, M T; Teti, G

1996-01-01

We investigated the role of interleukin-10 (IL-10) in a neonatal mouse model of lethal group B streptococci (GBS) sepsis. Plasma IL-10 levels significantly increased at 24 and 48 h after GBS inoculation. Neutralization of IL-10 with specific antibodies had no effect on lethality. Administration of recombinant IL-10 at 20 or 4 h before challenge, but not at later times, resulted in decreased tumor necrosis factor alpha levels and improved survival. IL-10 could be potentially useful for the treatment of GBS sepsis. PMID:8698523

Human cathepsin L rescues the neurodegeneration and lethality incathepsin B/L double deficient mice

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

Sevenich, Lisa; Pennacchio, Len A.; Peters, Christoph

2006-01-09

Cathepsin B (CTSB) and cathepsin L (CTSL) are two widelyexpressed cysteine proteases thought to predominantly reside withinlysosomes. Functional analysis of CTSL in humans is complicated by theexistence of two CTSL-like homologues (CTSL and CTSL2), in contrast tomice which contain only one CTSL enzyme. Thus transgenic expression ofhuman CTSL in CTSL deficient mice provides an opportunity to study the invivo functions of this human protease without interference by its highlyrelated homologue. While mice with single gene deficiencies for murineCTSB or CTSL survive without apparent neuromuscular impairment, murineCTSB/CTSL double deficient mice display degeneration of cerebellarPurkinje cells and neurons of the cerebral cortex,more » resulting in severehypotrophy, motility defects, and lethality during their third to fourthweek of life. Here we show that expression of human CTSL through agenomic transgene results in widespread expression of human CTSL in themouse which is capable of rescuing the lethality found in CTSB/CTSLdouble-deficient animals. Human CTSL is expressed in the brain of thesecompound mutants predominantly in neurons of the cerebral cortex and inPurkinje cells of the cerebellum, where it appears to prevent neuronalcell death.« less

Leaf gas exchange performance and the lethal water potential of five European species during drought.

PubMed

Li, Shan; Feifel, Marion; Karimi, Zohreh; Schuldt, Bernhard; Choat, Brendan; Jansen, Steven

2016-02-01

Establishing physiological thresholds to drought-induced mortality in a range of plant species is crucial in understanding how plants respond to severe drought. Here, five common European tree species were selected (Acer campestre L., Acer pseudoplatanus L., Carpinus betulus L., Corylus avellana L. and Fraxinus excelsior L.) to study their hydraulic thresholds to mortality. Photosynthetic parameters during desiccation and the recovery of leaf gas exchange after rewatering were measured. Stem vulnerability curves and leaf pressure-volume curves were investigated to understand the hydraulic coordination of stem and leaf tissue traits. Stem and root samples from well-watered and severely drought-stressed plants of two species were observed using transmission electron microscopy to visualize mortality of cambial cells. The lethal water potential (ψlethal) correlated with stem P99 (i.e., the xylem water potential at 99% loss of hydraulic conductivity, PLC). However, several plants that were stressed beyond the water potential at 100% PLC showed complete recovery during the next spring, which suggests that the ψlethal values were underestimated. Moreover, we observed a 1 : 1 relationship between the xylem water potential at the onset of embolism and stomatal closure, confirming hydraulic coordination between leaf and stem tissues. Finally, ultrastructural changes in the cytoplasm of cambium tissue and mortality of cambial cells are proposed to provide an alternative approach to investigate the point of no return associated with plant death. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Ethylhexylglycerin Impairs Membrane Integrity and Enhances the Lethal Effect of Phenoxyethanol

PubMed Central

Langsrud, Solveig; Steinhauer, Katrin; Lüthje, Sonja; Weber, Klaus; Goroncy-Bermes, Peter; Holck, Askild L.

2016-01-01

Preservatives are added to cosmetics to protect the consumers from infections and prevent product spoilage. The concentration of preservatives should be kept as low as possible and this can be achieved by adding potentiating agents. The aim of the study was to investigate the mechanisms behind potentiation of the bactericidal effect of a commonly used preservative, 2-phenoxyethanol (PE), by the potentiating agent ethylhexylglycerin (EHG). Sub-lethal concentrations of EHG (0.075%) and PE (0.675%) in combination led to rapid killing of E. coli (> 5 log reduction of cfu after 30 min), leakage of cellular constituents, disruption of the energy metabolism, morphological deformities of cells and condensation of DNA. Used alone, EHG disrupted the membrane integrity even at low concentrations. In conclusion, sub-lethal concentrations of EHG potentiate the effect of PE through damage of the cell membrane integrity. Thus, adding EHG to PE in a 1:9 ratio has a similar effect on membrane damage and bacterial viability as doubling the concentration of PE. This study provides insight about the mechanism of action of a strong potentiating agent, EHG, which is commonly used in cosmetics together with PE. PMID:27783695

Postoperative complications in gastrointestinal cancer patients: the joint role of the nutritional status and the nutritional support.

PubMed

Bozzetti, Federico; Gianotti, Luca; Braga, Mario; Di Carlo, Valerio; Mariani, Luigi

2007-12-01

This study investigated the effects of nutritional support on postoperative complications, in relation with demographic and nutritional factors, intraoperative factors, type and routes of nutritional regimens. A series of 1410 subjects underwent major abdominal surgery for gastrointestinal cancer and received various types of nutritional support: standard intravenous fluids (SIF; n=149), total parenteral nutrition (TPN; n=368), enteral nutrition (EN; n=393), and immune-enhancing enteral nutrition (IEEN; n=500). Postoperative complications, considered as major (if lethal or requiring re-operation, or transfer to intensive care unit), or otherwise minor, were recorded. Major and minor complications occurred in 101 (7.2%) and 446 (31.6%) patients, respectively. Factors correlated with postoperative complications at multivariate analysis were pancreatic surgery, (p<0.001), advanced age (p=0.002), weight loss (p=0.019), low serum albumin (p=0.019) and nutritional support (p=0.001). Nutritional support reduced morbidity versus SIF with an increasing protective effect of TPN, EN, and IEEN. This effect remained valid regardless the severity of risk factors identified at the multivariate analysis and it was more evident by considering infectious complications only. Pancreatic surgery, advanced age, weight loss and low serum albumin are independent risk factors for the onset of postoperative complications. Nutritional support, particularly IEEN, significantly reduced postoperative morbidity.

Abdominal compartment syndrome--the prevention and treatment of possible lethal complications following hip arthroscopy: a case report.

PubMed

Ciemniewska-Gorzela, Kinga; Piontek, Tomasz; Szulc, Andrzej

2014-11-14

Intra-abdominal hypertension and abdominal compartment syndrome have been increasingly recognized as a hip arthroscopy complication over the past decade. In the absence of consensus definitions and treatment guidelines, the diagnosis and management of intra-abdominal hypertension and abdominal compartment syndrome remains variable from institution to institution. We report the occurrence of the extravasation of fluid into the abdomen during arthroscopic treatment of femoroacetabular impingement combined with resection of trochanteric bursa and our management of the condition in a 55-year old Caucasian woman. We present an algorithm of treatment of abdominal compartment syndrome, as a hip arthroscopy complication, according to the consensus definitions and recommendations of the World Society of the Abdominal Compartment Syndrome. In the algorithm options, we have included paracentesis and percutaneous catheter decompression as the main point of treatment. Our algorithm will have a broader clinical impact on orthopedic surgery, anesthesiology and emergency medicine.

Relative Risks for Lethal Prostate Cancer Based on Complete Family History of Prostate Cancer Death.

PubMed

Albright, Frederick S; Stephenson, Robert A; Agarwal, Neeraj; Cannon-Albright, Lisa A

2017-01-01

There are few published familial relative risks (RR) for lethal prostate cancer. This study estimates RRs for lethal prostate cancer based on comprehensive family history data, with the goal of improving identification of those men at highest risk of dying from prostate cancer. We used a population-based genealogical resource linked to a statewide electronic SEER cancer registry and death certificates to estimate relative risks (RR) for death from prostate cancer based upon family history. Over 600,000 male probands were analyzed, representing a variety of family history constellations of lethal prostate cancer. RR estimates were based on the ratio of the observed to the expected number of lethal prostate cancer cases using internal rates. RRs for lethal prostate cancer based on the number of affected first-degree relatives (FDR) ranged from 2.49 (95% CI: 2.27, 2.73) for exactly 1 FDR to 5.30 (2.13, 10.93) for ≥3 affected FDRs. In an absence of affected FDRs, increased risk was also significant for increasing numbers of affected second-degree or third degree relatives. Equivalent risks were observed for similar maternal and paternal family history. This study provides population-based estimates of lethal prostate cancer risk based on lethal prostate cancer family history. Many family history constellations associated with two to greater than five times increased risk for lethal prostate cancer were identified. These lethal prostate cancer risk estimates hold potential for use in identification, screening, early diagnosis, and treatment of men at high risk for death from prostate cancer. Prostate77:41-48, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Recurrent short rib polydactyly syndrome.

PubMed

Eleftheriades, M; Iavazzo, C; Manolakos, E; Hassiakos, D; Botsis, D; Petersen, M; Konstantinidou, A

2013-01-01

We present three consecutive cases of skeletal dysplasias of a non-consanguineous couple with five pregnancies. The diagnosis of short-rib polydactyly syndrome (SRPS) was feasible by ultrasound during the 1st trimester of pregnancy. SRPS represents a heterogeneous group of lethal skeletal dysplasias. It is characterised by short limb dwarfism complicated by thoracic hypoplasia, polydactyly and different anomalies of major organs such as congenital heart defects and renal dysplasia. Four major types of the SRPS have been described: type I (Saldino-Noonan); type II (Majewski); type III (Verma-Naumoff) and type IV (Beemar-Langer). However, there is phenotypic overlapping between four types and with those of non-lethal skeletal dysplasias (i.e. Ellis-van Creveld syndrome and Jeune syndrome). Our cases show the importance of the nuchal translucency (NT) scan that offers the opportunity to examine fetal anatomy in the 1st trimester and diagnose rare skeletal abnormalities early in pregnancy.

Clinical presentations of Ehlers Danlos syndrome type IV.

PubMed Central

Pope, F M; Narcisi, P; Nicholls, A C; Liberman, M; Oorthuys, J W

1988-01-01

Ehlers Danlos syndrome type IV is an often lethal disease caused by various mutations of type III collagen genes. It presents in infancy and childhood in several ways, and the symptoms and signs include low birth weight, prematurity, congenital dislocation of the hips, easy inappropriate bruising (sometimes suspected as child battering), and a diagnostic facial phenotype. These features predict a lethal adult disease often complicated by fatal arterial rupture in early or middle adult life. Most affected patients can be diagnosed from radiolabelled collagen protein profiles by polyacrylamide gel electrophoresis. Prenatal diagnosis by specific type III collagen restriction fragment length polymorphisms is possible in some families, and will become increasingly important. Prenatal diagnosis and prevention of the disease in selected families is already possible and will be widely available in the future. Images Fig 1 Fig 2 Fig 3 Fig 4 Fig 5 Fig 6 Fig 7 Fig 8 Fig 9 Fig 10 Fig 11 PMID:3178263

Variability in mutational fitness effects prevents full lethal transitions in large quasispecies populations

NASA Astrophysics Data System (ADS)

Sardanyés, Josep; Simó, Carles; Martínez, Regina; Solé, Ricard V.; Elena, Santiago F.

2014-04-01

The distribution of mutational fitness effects (DMFE) is crucial to the evolutionary fate of quasispecies. In this article we analyze the effect of the DMFE on the dynamics of a large quasispecies by means of a phenotypic version of the classic Eigen's model that incorporates beneficial, neutral, deleterious, and lethal mutations. By parameterizing the model with available experimental data on the DMFE of Vesicular stomatitis virus (VSV) and Tobacco etch virus (TEV), we found that increasing mutation does not totally push the entire viral quasispecies towards deleterious or lethal regions of the phenotypic sequence space. The probability of finding regions in the parameter space of the general model that results in a quasispecies only composed by lethal phenotypes is extremely small at equilibrium and in transient times. The implications of our findings can be extended to other scenarios, such as lethal mutagenesis or genomically unstable cancer, where increased mutagenesis has been suggested as a potential therapy.

Defects in cholesterol synthesis genes in mouse and in humans: lessons for drug development and safer treatments.

PubMed

Horvat, Simon; McWhir, Jim; Rozman, Damjana

2011-02-01

This review describes the mouse knockout models of cholesterol synthesis, together with human malformations and drugs that target cholesterogenic enzymes. Generally, the sooner a gene acts in cholesterol synthesis, the earlier the phenotype occurs. Humans with loss of function of early cholesterogenic enzymes have not yet been described, and in the mouse, loss of Hmgcr is preimplantation lethal. Together, these results indicate that the widely prescribed cholesterol-lowering statins are potentially teratogenic. The Mvk knockout is early embryonic lethal in the mouse, the absence of Fdft1 is lethal at E9.5-12.5 dpc, while the Cyp51 knockouts die at 15.0 dpc. Fungal CYP51 inhibitor azoles are teratogenic in humans, potentially leading to symptoms of Antley-Bixler syndrome. The X-linked mutations in Nsdhl and Ebp are embryonic lethal in male mice, while heterozygous females are also affected. Consequently, the anticancer drugs, tamoxifen and toremifene, inhibiting human EBP, may be harmful in early pregnancy. The Dhcr7 and Dhcr24 knockout mice die shortly after birth, while humans survive with Smith-Lemli-Opitz syndrome or desmosterolosis. Since cholesterol is essential for hedgehog signaling, disturbance of this pathway by antipsychotics and -depressants explains some drug side effects. In conclusion, defects in cholesterol synthesis are generally lethal in mice, while humans with impaired later steps of the pathway can survive with severe malformations. Evidence shows that drugs targeting or, by coincidence, inhibiting human cholesterol synthesis are better avoided in early pregnancy. Since some drugs with teratogenic potential still stay on the market, this should be avoided in new cholesterol-related drug development.

Pulmonary hypertension and vasculopathy in incontinentia pigmenti: a case report

PubMed Central

Alshenqiti, Abduljabbar; Nashabat, Marwan; AlGhoraibi, Hissah; Tamimi, Omar; Alfadhel, Majid

2017-01-01

Incontinentia pigmenti (IP; Bloch–Sulzberger syndrome) is a rare, genetic syndrome inherited as an X-linked dominant trait. It primarily affects female infants and is lethal in the majority of males during fetal life. The clinical findings include skin lesions, developmental defects, and defects of the eyes, teeth, skeletal system, and central nervous system. Cardiovascular complications of this disease in general, and pulmonary hypertension in particular, are extremely rare. This report describes the case of a 3-year-old girl with IP complicated by pulmonary arterial hypertension. Extensive cardiology workup done to the patient indicates underlying vasculopathy. This report sheds light on the relationship between IP and pulmonary hypertension, reviews the previously reported cases, and compares them with the reported case. PMID:28533687

Pulmonary hypertension and vasculopathy in incontinentia pigmenti: a case report.

PubMed

Alshenqiti, Abduljabbar; Nashabat, Marwan; AlGhoraibi, Hissah; Tamimi, Omar; Alfadhel, Majid

2017-01-01

Incontinentia pigmenti (IP; Bloch-Sulzberger syndrome) is a rare, genetic syndrome inherited as an X-linked dominant trait. It primarily affects female infants and is lethal in the majority of males during fetal life. The clinical findings include skin lesions, developmental defects, and defects of the eyes, teeth, skeletal system, and central nervous system. Cardiovascular complications of this disease in general, and pulmonary hypertension in particular, are extremely rare. This report describes the case of a 3-year-old girl with IP complicated by pulmonary arterial hypertension. Extensive cardiology workup done to the patient indicates underlying vasculopathy. This report sheds light on the relationship between IP and pulmonary hypertension, reviews the previously reported cases, and compares them with the reported case.

Lethality of firearms relative to other suicide methods: a population based study.

PubMed

Shenassa, E D; Catlin, S N; Buka, S L

2003-02-01

(1) To quantify lethality of firearms relative to other suicide methods, (2) to quantify the extent to which suicide mortality may be reduced by limiting access to firearms. Data on suicides and hospitalised para-suicides that occurred in the state of Illinois from 1990 to 1997 were combined. Total number of episodes for each suicide method was estimated as the sum of the number of suicides and the number of para-suicides for that method. Gender and suicide method were used as proxies for intention to die, and estimated lethality of suicide methods within method-gender groups (for example, male firearm users). Logistic regression was used to quantify the lethality of firearms relative to other suicide methods. Excess mortality associated with the use of firearms was estimated by conservatively assuming that in the absence of firearms the next most lethal suicide method would be used. From January 1990 to December 1997, among individuals 10 years or older in the state of Illinois, there were 37,352 hospital admissions for para-suicide and 10,287 completed suicides. Firearms are the most lethal suicide method. Episodes involving firearms are 2.6 times (95% CI 2.1 to 3.1) more lethal than those involving suffocation-the second most lethal suicide method. Preventing access to firearms can reduce the proportion of fatal firearms related suicides by 32% among minors, and 6.5% among adults. Limiting access to firearms is a potentially effective means of reducing suicide mortality.

Non-lethal sampling of walleye for stable isotope analysis: a comparison of three tissues

USGS Publications Warehouse

Chipps, Steven R.; VanDeHey, J.A.; Fincel, M.J.

2012-01-01

Stable isotope analysis of fishes is often performed using muscle or organ tissues that require sacrificing animals. Non-lethal sampling provides an alternative for evaluating isotopic composition for species of concern or individuals of exceptional value. Stable isotope values of white muscle (lethal) were compared with those from fins and scales (non-lethal) in walleye, Sander vitreus (Mitchill), from multiple systems, size classes and across a range of isotopic values. Isotopic variability was also compared among populations to determine the potential of non-lethal tissues for diet-variability analyses. Muscle-derived isotope values were enriched compared with fins and depleted relative to scales. A split-sample validation technique and linear regression found that isotopic composition of walleye fins and scales was significantly related to that in muscle tissue for both δ13C and δ15N (r2 = 0.79–0.93). However, isotopic variability was significantly different between tissue types in two of six populations for δ15N and three of six populations for δ13C. Although species and population specific, these findings indicate that isotopic measures obtained from non-lethal tissues are indicative of those obtained from muscle.

Inhibition of BRCA2 and Thymidylate Synthase Creates Multidrug Sensitive Tumor Cells via the Induction of Combined "Complementary Lethality".

PubMed

Rytelewski, Mateusz; Ferguson, Peter J; Maleki Vareki, Saman; Figueredo, Rene; Vincent, Mark; Koropatnick, James

2013-03-12

A high mutation rate leading to tumor cell heterogeneity is a driver of malignancy in human cancers. Paradoxically, however, genomic instability can also render tumors vulnerable to therapeutic attack. Thus, targeting DNA repair may induce an intolerable level of DNA damage in tumor cells. BRCA2 mediates homologous recombination repair, and BRCA2 polymorphisms increase cancer risk. However, tumors with BRCA2 mutations respond better to chemotherapy and are associated with improved patient prognosis. Thymidylate synthase (TS) is also involved in DNA maintenance and generates cellular thymidylate. We determined that antisense downregulation of BRCA2 synergistically potentiated drugs with mechanisms of action related to BRCA2 function (cisplatin, melphalan), a phenomenon we named "complementary lethality." TS knockdown induced complementary lethality to TS-targeting drugs (5-FUdR and pemetrexed) but not DNA cross-linking agents. Combined targeting of BRCA2 and TS induced complementary lethality to both DNA-damaging and TS-targeting agents, thus creating multidrug sensitive tumors. In addition, we demonstrated for the first time that simultaneous downregulation of both targets induced combined complementary lethality to multiple mechanistically different drugs in the same cell population. In this study, we propose and define the concept of "complementary lethality" and show that actively targeting BRCA2 and TS is of potential therapeutic benefit in multidrug treatment of human tumors. This work has contributed to the development of a BRCA2-targeting antisense oligdeoxynucleotide (ASO) "BR-1" which we will test in vivo in combination with our TS-targeting ASO "SARI 83" and attempt early clinical trials in the future.Molecular Therapy - Nucleic Acids (2013) 2, e78; doi:10.1038/mtna.2013.7 published online 12 March 2013.

Research supporting potential modification of the NASA specification for dry heat microbial reduction of spacecraft hardware

NASA Astrophysics Data System (ADS)

Spry, James A.; Beaudet, Robert; Schubert, Wayne

Dry heat microbial reduction (DHMR) is the primary method currently used to reduce the microbial load of spacecraft and component parts to comply with planetary protection re-quirements. However, manufacturing processes often involve heating flight hardware to high temperatures for purposes other than planetary protection DHMR. At present, the specifica-tion in NASA document NPR8020.12, describing the process lethality on B. atrophaeus (ATCC 9372) bacterial spores, does not allow for additional planetary protection bioburden reduction credit for processing outside a narrow temperature, time and humidity window. Our results from a comprehensive multi-year laboratory research effort have generated en-hanced data sets on four aspects of the current specification: time and temperature effects in combination, the effect that humidity has on spore lethality, and the lethality for spores with exceptionally high thermal resistance (so called "hardies"). This paper describes potential modifications to the specification, based on the data set gener-ated in the referenced studies. The proposed modifications are intended to broaden the scope of the current specification while still maintaining confidence in a conservative interpretation of the lethality of the DHMR process on microorganisms.

Study of the n-methyl-d-aspartate antagonistic properties of anticholinergic drugs

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

McDonough, J.H.; Shih, T.M.

1995-12-31

A study of the N-methyl-D-aspartate antagonistic properties of anticholinergic drugs. PHARMACOL BIOCHEM BEHAV. 51(2/3) 249-253, 1995. Drugs that act at the N-methyl-D-aspartate (NMDA) receptor complex have the ability to terminate nerve agent-induced seizures and modulate the neuropathologic consequences of agent exposure. Drugs with mixed anticholinergic and anti-NMDA properties potentially provide an ideal class of compounds for development as anticonvulsant treatments for nerve agent casualties. The present experiment evaluated the potential NMDA antagonist activity of 11 anticholinergic drugs by determining whether pretreatment with the compound was capable of protecting mice from the lethal effects of NMDA. The following anticholinergic drugs antagonizedmore » NMDA lethality and are ranked according to their potency: mecamylamine > procyclidine = benactyzine > biperiden > tribexyphenidyl. The anticholinergics atropine, aprophen, azaprophen, benztropine, 3-quinudidinyl benzilate (QNB), and scopolamine failed to show NMDA antagonist properties. In addition, and unexpectedly, diazepam, ethanol, and pentobarbital were also shown to be capable of antagonizing NMDA lethality over a certain range of doses. The advantages and limitations of using antagonism of NMDA lethality in mice as a bioassay for determining the NMDA antagonist properties of drugs are also discussed.« less

Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research‐practice gaps, challenges, and insights

PubMed Central

Li, Jin; Kros, Johan M

2017-01-01

Abstract To date, five cancer treatment modalities have been defined. The three traditional modalities of cancer treatment are surgery, radiotherapy, and conventional chemotherapy, and the two modern modalities include molecularly targeted therapy (the fourth modality) and immunotherapy (the fifth modality). The cardiotoxicity associated with conventional chemotherapy and radiotherapy is well known. Similar adverse cardiac events are resurging with the fourth modality. Aside from the conventional and newer targeted agents, even the most newly developed, immune‐based therapeutic modalities of anticancer treatment (the fifth modality), e.g., immune checkpoint inhibitors and chimeric antigen receptor (CAR) T‐cell therapy, have unfortunately led to potentially lethal cardiotoxicity in patients. Cardiac complications represent unresolved and potentially life‐threatening conditions in cancer survivors, while effective clinical management remains quite challenging. As a consequence, morbidity and mortality related to cardiac complications now threaten to offset some favorable benefits of modern cancer treatments in cancer‐related survival, regardless of the oncologic prognosis. This review focuses on identifying critical research‐practice gaps, addressing real‐world challenges and pinpointing real‐time insights in general terms under the context of clinical cardiotoxicity induced by the fourth and fifth modalities of cancer treatment. The information ranges from basic science to clinical management in the field of cardio‐oncology and crosses the interface between oncology and onco‐pharmacology. The complexity of the ongoing clinical problem is addressed at different levels. A better understanding of these research‐practice gaps may advance research initiatives on the development of mechanism‐based diagnoses and treatments for the effective clinical management of cardiotoxicity. PMID:28862319

Transcutaneous yellow fever vaccination of subjects with or without atopic dermatitis

PubMed Central

Slifka, Mark K.; Leung, Donald Y. M.; Hammarlund, Erika; Raué, Hans-Peter; Simpson, Eric L.; Tofte, Susan; Baig-Lewis, Shahana; David, Gloria; Lynn, Henry; Woolson, Rob; Hata, Tissa; Milgrom, Henry; Hanifin, Jon

2013-01-01

Background Atopic dermatitis (AD) is a common inflammatory skin disease with global prevalence ranging from 3% to 20%. AD patients have an increased risk for complications following viral infection (e.g., herpes simplex virus), and vaccination of AD patients with live vaccinia virus is contraindicated due to a heightened risk of eczema vaccinatum, a rare but potentially lethal complication associated with smallpox vaccination. Objective To develop a better understanding of immunity to cutaneous viral infection in AD patients. Methods In a double-blind, randomized study, we investigated the safety and immunogenicity of live attenuated yellow fever virus (YFV) vaccination of non-atopic (NA) subjects and AD patients following standard subcutaneous (SC) inoculation or transcutaneous (TC) vaccination administered with a bifurcated needle. Viremia, neutralizing antibody, and antiviral T cell responses were analyzed for up to 30 days post-vaccination. Results YFV vaccination by either route was well tolerated. SC vaccination resulted in higher seroconversion rates than TC vaccination but elicited similar antiviral antibody levels and T cell responses in both NA and AD groups. Following TC vaccination, both groups mounted similar neutralizing antibody responses, but AD patients demonstrated lower antiviral T cell responses by 30 days after vaccination. Among TC-vaccinated subjects, a significant inverse correlation between baseline IgE levels and the magnitude of antiviral antibody and CD4+ T cell responses was observed. Conclusions YFV vaccination of AD patients by the TC route revealed that high baseline IgE levels provides a potential biomarker for predicting reduced virus-specific immune memory following TC infection with a live virus. PMID:24331381

Usefulness of two- and three-dimensional transesophageal echocardiography in the assessment of proximal left coronary system compression by a paraprosthetic aortic valve abscess.

PubMed

Ahmad, Amier; McElwee, Samuel K; Jiang, Amy Z; Barssoum, Kirolos N; Elkaryoni, Ahmed E; Arisha, Mohammed J; Srialluri, Swetha; Seghatol, Frank; Nanda, Navin C

2017-02-01

Paraprosthetic aortic valve abscess represents a rare, but lethal complication of infective endocarditis. We report a case of proximal left coronary system compression by a paraprosthetic aortic valve abscess whose detection was augmented using live/real time three-dimensional transesophageal echocardiography. Our case illustrates the usefulness of combined two- and three-dimensional transesophageal echocardiography in detecting this finding. © 2017, Wiley Periodicals, Inc.

[Organ-preserving method in the surgical treatment of the spleen injuries].

PubMed

Khripun, A I; Alimov, A N; Salikov, A V; Priamikov, A D; Alimov, V A; Sukiasian, A A; Popov, T V; Urvantseva, O M

2014-01-01

The authors have experience in organ-preserving operations for spleen rupture with the splenic artery ligation in 156 casualties. They consider that such operations let to preserve the spleen, to avoid the postoperative rebleeding and ischemia of pancreas tail and body. Also it is accompanied by the low indications of lethality and postoperative complications. The authors consider that this operation is alternative to splenectomy and other techniques of organ-preserving operations in case of spleen trauma.

Complications of the Middle Cranial Fossa Approach for Acoustic Neuroma Removal.

PubMed

Scheich, Matthias; Ginzkey, Christian; Ehrmann Müller, Desiree; Shehata Dieler, Wafaa; Hagen, Rudolf

2017-08-01

To analyze postoperative complications after microsurgery for acoustic neuroma (AN) via the middle fossa approach (MFA). In total, 203 consecutive patients of a tertiary skull base referral center at a university hospital were included in this retrospective chart and database analysis. All patients had undergone primary microsurgery at the Otorhinolaryngology department via MFA between December 2005 and October 2014. Postoperative complications were documented during the inpatient stay and outpatient follow-up. Overall, 41 complications were registered in 35 patients. The most common was cerebrospinal fluid (CSF) leakage in 13% of the patients. Bleeding complications were documented in seven patients: two cerebellar bleedings, one subdural and one epidural hematoma, two hematomas of the skin, and one bleeding through the closed wound. Two patients experienced meningitis and one patient had a transient ischemic attack. Furthermore, three cases of deep vein thrombosis occurred, which led to a lethal pulmonary embolism in one case. One patient sustained temporary palsy of the vocal fold and another reported antibiotic-associated diarrhea. Acoustic neuroma surgery via the MFA can be conducted with low morbidity and mortality. The most common complication is CSF leakage, which can be treated in most cases in a stepwise conservative manner. Severe adverse events that may require revision surgery are very scarce (1%).

Acute, Sub-lethal Cyanide Poisoning in Mice is Ameliorated by Nitrite Alone: Complications Arising from Concomitant Administration of Nitrite and Thiosulfate as an Antidotal Combination

PubMed Central

Cambal, Leah K.; Swanson, Megan R.; Yuan, Quan; Weitz, Andrew C.; Li, Hui-Hua; Pitt, Bruce R.; Pearce, Linda L.; Peterson, Jim

2011-01-01

Sodium nitrite alone is shown to ameliorate sub-lethal cyanide toxicity in mice when given from ~1 hour before until 20 minutes after the toxic dose as demonstrated by the recovery of righting ability. An optimum dose (12 mg/kg) was determined to significantly relieve cyanide toxicity (5.0 mg/kg) when administered to mice intraperitoneally. Nitrite so administered was shown to rapidly produce NO in the bloodsteam as judged by the dose dependent appearance of EPR signals attributable to nitrosylhemoglobin and methemoglobin. It is argued that antagonism of cyanide inhibition of cytochrome c oxidase by NO is the crucial antidotal activity rather than the methemoglobin-forming action of nitrite. Concomitant addition of sodium thiosulfate to nitrite-treated blood resulted in the detection of sulfidomethemoblobin by EPR spectroscopy. Sulfide is a product of thiosulfate hydrolysis and, like cyanide, is known to be a potent inhibitor of cytochrome c oxidase; the effects of the two inhibitors being essentially additive under standard assay conditions, rather than dominated by either one. The findings afford a plausible explanation for an observed detrimental effect in mice associated with the use of the standard nitrite-thiosulfate combination therapy at sub-lethal levels of cyanide intoxication. PMID:21534623

Use of pellet guns for crowd control in Kashmir: How lethal is "non-lethal"?

PubMed

David, Siddarth

2017-01-01

The use of pellet guns during the recent unrest in Kashmir as a method of crowd control has been questioned because of several deaths and numerous injuries. Across the world, these rubber pellets have been shown to inflict serious injuries, permanent disability, and death. The volatility of mob violence, inaccuracies in aim of the pellets, over-use of the pellet guns, and the perception of their harmlessness enhances the destructive potential of these so-called non-lethal weapons. There is also the larger ethical question whether any form of pain, however minimal, could be inflicted to control violent crowds.

Prevalence of a potentially lethal parasite of wading birds in natural and agricultural wetlands in south Louisiana

USGS Publications Warehouse

Luent, Margaret C.; Collins, Melissa; Jeske, Clinton; Leberg, Paul

2012-01-01

Gambusia affinis (Western Mosquitofish) were sampled from 18 sites representing marsh, forested wetlands, and agricultural wetlands in south Louisiana to determine distribution and infection parameters of Eustrongylides ignotus, a potentially lethal nematode parasite of wading birds, (n = 400 per site). Overall, prevalence of infection was 0.3%, with significantly higher prevalence in agricultural wetlands than in marshes or swamps. Our findings are similar to work in Florida suggesting parasite prevalence is higher in disturbed wetlands, and suggest that birds foraging in crayfish ponds and rice fields may be at increased risk of exposure.

Hypothyroidism After a Cancer Diagnosis: Etiology, Diagnosis, Complications, and Management

PubMed Central

Carter, Yvette; Sippel, Rebecca S.

2014-01-01

Hypothyroidism is a common disease that is easily treated in the majority of cases, when readily diagnosed; however, presentation of an aggregate of its symptoms is often clinically overlooked or attributed to another disease and can potentially be lethal. Already prevalent in older women, its occurrence in younger patients is rising as a result of radiation therapy, radioactive iodine therapy, and newer antineoplastic agents used to manage various malignancies. The presence of nonspecific constitutional symptoms and neuropsychiatric complaints in cancer patients can be attributed to a myriad of other diagnoses and therapies. Thyroid dysfunction can be easily overlooked in cancer patients because of the complexity of cancer’s clinical picture, particularly in the pediatric population. Underdiagnosis can have important consequences for the management of both hypothyroidism and the malignancy. At minimum, quality of life is adversely affected. Untreated hypothyroidism can lead to heart failure, psychosis, and coma and can reduce the effectiveness of potentially life-saving cancer therapies, whereas iatrogenic causes can provoke atrial fibrillation and osteoporosis. Consequently, the diagnosis and treatment of hypothyroidism in cancer patients are pertinent. We summarize the history, epidemiology, pathophysiology, clinical diagnosis, and management of hypothyroidism in cancer patients. PMID:24309982

Hypertensive crisis in pregnancy due to a metamorphosing pheochromocytoma with postdelivery Cushing's syndrome.

PubMed

Langton, Katharina; Gruber, Matthias; Masjkur, Jimmy; Steenblock, Charlotte; Peitzsch, Mirko; Meinel, Jörn; Lenders, Jacques; Bornstein, Stefan; Eisenhofer, Graeme

2018-01-01

Pheochromocytomas in pregnancy are rare but potentially lethal. Even rarer is the combination of pheochromocytoma in pregnancy with subsequent development of ectopic Cushing's syndrome. We report a 36-year-old woman, previously diagnosed with essential hypertension, who developed severe hypertension in pregnancy complicated by insulin-dependent gestational diabetes. A cesarean section was performed at 32 weeks following a hypertensive crisis after routine administration of betamethasone. Postnatal persistence of signs and symptoms of catecholamine excess led to the diagnosis of a left adrenal pheochromocytoma. Between diagnosis and planned tumor removal, the patient developed signs and symptoms of Cushing's syndrome (facial edema and hirsutism, myopathy and fatigue). Biochemical testing confirmed hypercortisolism with extremely elevated levels of plasma adrenocorticotropin, urinary cortisol and multiple steroids of a plasma panel that were all normal at previous testing. The previously noradrenergic tumor also started producing epinephrine. Histopathological examination confirmed the pheochromocytoma, which was also immunohistochemically positive for adrenocorticotropin. Full post-surgical recovery was sustained with normal blood pressure and biochemical findings after one year. This report not only underlines the chameleon behavior of pheochromocytoma but also illustrates its potential for a metamorphosing presentation. Corticosteroid administration in pregnancy requires a cautious approach in patients with hypertension.

Hypothyroidism after a cancer diagnosis: etiology, diagnosis, complications, and management.

PubMed

Carter, Yvette; Sippel, Rebecca S; Chen, Herbert

2014-01-01

Hypothyroidism is a common disease that is easily treated in the majority of cases, when readily diagnosed; however, presentation of an aggregate of its symptoms is often clinically overlooked or attributed to another disease and can potentially be lethal. Already prevalent in older women, its occurrence in younger patients is rising as a result of radiation therapy, radioactive iodine therapy, and newer antineoplastic agents used to manage various malignancies. The presence of nonspecific constitutional symptoms and neuropsychiatric complaints in cancer patients can be attributed to a myriad of other diagnoses and therapies. Thyroid dysfunction can be easily overlooked in cancer patients because of the complexity of cancer's clinical picture, particularly in the pediatric population. Underdiagnosis can have important consequences for the management of both hypothyroidism and the malignancy. At minimum, quality of life is adversely affected. Untreated hypothyroidism can lead to heart failure, psychosis, and coma and can reduce the effectiveness of potentially life-saving cancer therapies, whereas iatrogenic causes can provoke atrial fibrillation and osteoporosis. Consequently, the diagnosis and treatment of hypothyroidism in cancer patients are pertinent. We summarize the history, epidemiology, pathophysiology, clinical diagnosis, and management of hypothyroidism in cancer patients.

Lethal effect of a single dose of rasburicase in a preterm newborn infant.

PubMed

Zaramella, Patrizia; De Salvia, Alessandra; Zaninotto, Martina; Baraldi, Maura; Capovilla, Giovanni; De Leo, Domenico; Chiandetti, Lino

2013-01-01

This case report describes a preterm newborn infant who was treated with a single dose of rasburicase for an increase in uric acid level. He died on the third day as a result of complications of hemolysis, which appeared to be precipitated by rasburicase. The patient's death was preceded by progressive respiratory insufficiency, lactic acidosis, and hyperbilirubinemia, culminating in refractory hypoxia and hypotension. A postmortem assay for glucose-6-phosphate dehydrogenase showed deficiency and the glucose-6-phosphate dehydrogenase Mediterranean genotype.

Association between a Primitive Brain Tumor and Cerebral Aspergillosis

PubMed Central

Hélage, Siegfried; Duyckaerts, Charles; Seilhean, Danielle; Hauw, Jean-Jacques; Chiras, Jacques

2012-01-01

Cerebral aspergillosis is a rare pathology of poor prognosis in spite of the use of adapted antifungal treatments. This infection of the central nervous system is generally the complication of an invasive aspergillosis with hematogenic scattering from pulmonary focal spots. It can arise in immunocompetent patients treated with prolonged corticotherapy or chemoradiotherapy for cancer. A case of lethal cerebral aspergillosis in a patient with an infiltrative glioma treated with corticotherapy and radiotherapy is reported. Clinicopathological aspects and therapeutic approach are described. PMID:22454648

Association between a Primitive Brain Tumor and Cerebral Aspergillosis.

PubMed

Hélage, Siegfried; Duyckaerts, Charles; Seilhean, Danielle; Hauw, Jean-Jacques; Chiras, Jacques

2012-01-01

Cerebral aspergillosis is a rare pathology of poor prognosis in spite of the use of adapted antifungal treatments. This infection of the central nervous system is generally the complication of an invasive aspergillosis with hematogenic scattering from pulmonary focal spots. It can arise in immunocompetent patients treated with prolonged corticotherapy or chemoradiotherapy for cancer. A case of lethal cerebral aspergillosis in a patient with an infiltrative glioma treated with corticotherapy and radiotherapy is reported. Clinicopathological aspects and therapeutic approach are described.

Intrathoracic pressure impulse predicts pulmonary contusion volume in ballistic blunt thoracic trauma.

PubMed

Prat, Nicolas; Rongieras, Frédéric; Voiglio, Eric; Magnan, Pascal; Destombe, Casimir; Debord, Eric; Barbillon, Franck; Fusai, Thierry; Sarron, Jean-Claude

2010-10-01

Blunt thoracic trauma including behind armour blunt trauma or impact from a less lethal kinetic weapon (LLKW) projectile may cause injuries, including pulmonary contusions that can result in potentially lethal secondary complications. These lung injuries may be caused by intrathoracic pressure waves. The aim of this study was to observe dynamic changes in intrathoracic hydrostatic pressure during ballistic blunt thoracic trauma and to find correlations between these hydrostatic pressure parameters (especially the impulse parameter) and physical damages. Thirty anesthetized pigs sustained a blunt thoracic trauma. In group 1 (n = 20), pigs were protected by a National Institute of Justice class III or IV bulletproof vest and shot with 7.62 NATO bullets. In group 2 (n = 10), pigs were shot by an LLKW. Intrathoracic pressure was recorded with an intraesophageal pressure sensor and three parameters were determined: intrathoracic maximum pressure, intrathoracic maximum pressure impulse (PI(max)), and the Pd.P/dt(max), derived from Viano's viscous criterion. Relative right lower lung lobe contusion volume was also measured. Different thoracic loading conditions were obtained. PI(max) best correlated with relative pulmonary contusion volume (R² = 0.64 and p < 0.0001). This result was homogenous for all experiments and was not related to the type of chest impact (LLKW-induced trauma or behind armour blunt trauma). The PI(max) is a good predictor of pulmonary contusion volume after ballistic blunt thoracic trauma. It is a useful criterion when the kinetic energy record or thoracic wall displacement data are unavailable, and the recording and calculation of this physical value are quite simple on animals.

[Treatment of postoperative abdominal hernias with polypropylene endoprosthesis].

PubMed

Chakhvadze, B Iu; Nakashidze, D Kh

2009-06-01

The results of the surgical treatment of 82 patients with postoperative abdominal hernias were analysed. All of the patients underwent surgery with polypropylene endoprosthesis. The choice of a hernioplasty method depended on relative volume of postoperative hernia. Middle-sized hernias were indications for reconstructive surgery (complete adaptation of muscular and aponeurotic layers was maintained). The large and gigantic hernias were indications for correcting surgery (specified diastasis of muscular and aponeurotic layers was maintained). In case of lacking of peritoneum (30 patients) greater omentum was used for isolation of the net from intestinal loops. It is concluded that greater omentum provides good extraperitonisation of transplant from intestinal loop and prevents complications due to contact of net with abdominal organs. Postoperative complications mainly were local and seen in 29% cases. There were no lethal outcomes.

Direct Activation of Adenosine Monophosphate-Activated Protein Kinase (AMPK) by PF-06409577 Inhibits Flavivirus Infection through Modification of Host-Cell Lipid Metabolism.

PubMed

Jiménez de Oya, Nereida; Blázquez, Ana-Belén; Casas, Josefina; Saiz, Juan-Carlos; Martín Acebes, Miguel A

2018-04-30

Mosquito-borne flaviviruses are a group of RNA viruses that constitute global threats for human and animal health. Replication of these pathogens is strictly dependent on cellular lipid metabolism. We have evaluated the effect of the pharmacological activation of Adenosine Monophosphate-activated Protein Kinase (AMPK), a master regulator of lipid metabolism, on the infection of three medically relevant flaviviruses: West Nile virus (WNV), Zika virus (ZIKV) and dengue virus (DENV). WNV is responsible for recurrent outbreaks of meningitis and encephalitis affecting humans and horses worldwide. ZIKV has caused a recent pandemic associated with birth defects (microcephaly), reproductive disorders, and severe neurological complications (Guillain-Barré syndrome). DENV is the etiological agent of the most prevalent mosquito-borne viral disease that can induce a potentially lethal complication called severe dengue. Our results showed, for the first time, that activation of AMPK using the specific small molecule activator PF-06409577 reduced both WNV, ZIKV, and DENV infection. This antiviral effect was associated to an impairment of viral replication due to the modulation of host cell lipid metabolism exerted by the compound. These results support that the pharmacological activation of AMPK, which currently constitutes an important pharmacological target for human diseases, could also provide a feasible approach for broad-spectrum host-directed antiviral discovery. Copyright © 2018 American Society for Microbiology.

Rifaximin diminishes neutropenia following potentially lethal whole-body radiation.

PubMed

Jahraus, Christopher D; Schemera, Bettina; Rynders, Patricia; Ramos, Melissa; Powell, Charles; Faircloth, John; Brawner, William R

2010-07-01

Terrorist attacks involving radiological or nuclear weapons are a substantial geopolitical concern, given that large populations could be exposed to potentially lethal doses of radiation. Because of this, evaluating potential countermeasures against radiation-induced mortality is critical. Gut microflora are the most common source of systemic infection following exposure to lethal doses of whole-body radiation, suggesting that prophylactic antibiotic therapy may reduce mortality after radiation exposure. The chemical stability, easy administration and favorable tolerability profile of the non-systemic antibiotic, rifaximin, make it an ideal potential candidate for use as a countermeasure. This study evaluated the use of rifaximin as a countermeasure against low-to-intermediate-dose whole-body radiation in rodents. Female Wistar rats (8 weeks old) were irradiated with 550 cGy to the whole body and were evaluated for 30 d. Animals received methylcellulose, neomycin (179 mg/kg/d) or variably dosed rifaximin (150-2000 mg/kg/d) one hour after irradiation and daily throughout the study period. Clinical assessments (e.g. body weight) were made daily. On postirradiation day 30, blood samples were collected and a complete blood cell count was performed. Animals receiving high doses of rifaximin (i.e. 1000 or 2000 mg/kg/d) had a greater increase in weight from the day of irradiation to postirradiation day 30 compared with animals that received placebo or neomycin. For animals with an increase in average body weight from irradiation day within 80-110% of the group average, methylcellulose rendered an absolute neutrophil count (ANC) of 211, neomycin rendered an ANC of 334, rifaximin 300 mg/kg/d rendered an ANC of 582 and rifaximin 1000 mg/kg/d rendered an ANC of 854 (P = 0.05 for group comparison). Exposure to rifaximin after near-lethal whole-body radiation resulted in diminished levels of neutropenia.

Stromal derived factor 1α: A chemokine that delivers a two-pronged defence of the myocardium☆

PubMed Central

Bromage, Daniel I.; Davidson, Sean M.; Yellon, Derek M.

2014-01-01

Alleviating myocardial injury associated with ST elevation myocardial infarction is central to improving the global burden of coronary heart disease. The chemokine stromal cell-derived factor 1α (SDF-1α) has dual potential benefit in this regard. Firstly, SDF-1α is up-regulated in experimental and clinical studies of acute myocardial infarction (AMI) and regulates stem cell migration to sites of injury. SDF-1α delivery to the myocardium after AMI is associated with improved stem cell homing, angiogenesis, and left ventricular function in animal models, and improvements in heart failure and quality of life in humans. Secondly, SDF-1α may have a role in remote ischaemic conditioning (RIC), the phenomenon whereby non-lethal ischaemia–reperfusion applied to an organ or tissue remote from the heart protects the myocardium from lethal ischaemia–reperfusion injury (IRI). SDF-1α is increased in the serum of rats subjected to RIC and protects against myocardial IRI in ex vivo studies. Despite these potential pleiotropic effects, a limitation of SDF-1α is its short plasma half-life due to cleavage by dipeptidyl peptidase-4 (DPP-4). However, DPP-4 inhibitors increase the half-life of SDF-1α by preventing its degradation and are also protective against lethal IRI. In summary, SDF-1 potentially delivers a ‘two-pronged’ defence of the myocardium: acutely protecting it from IRI while simultaneously stimulating repair by recruiting stem cells to the site of injury. In this article we examine the evidence for acute and chronic cardioprotective roles of SDF-1α and discuss potential therapeutic manipulations of this mechanism with DPP-4 inhibitors to protect against lethal tissue injury in the clinical setting. PMID:24704323

ACTIVATION OF COMMON ANTIVIRAL PATHWAYS CAN POTENTIATE INFLAMMATORY RESPONSES TO SEPTIC SHOCK

PubMed Central

Doughty, Lesley A.; Carlton, Stacey; Galen, Benjamin; Cooma-Ramberan, Indranie; Chung, Chung-Shiang; Ayala, Alfred

2006-01-01

Induction of the antiviral cytokine interferon α/β (IFN-α/β) is common in many viral infections. The impact of ongoing antiviral responses on subsequent bacterial infection is not well understood. In human disease, bacterial superinfection complicating a viral infection can result in significant morbidity and mortality. We injected mice with polyinosinic-polycytidylic (PIC) acid, a TLR3 ligand and known IFN-α/β inducer as well as nuclear factor κB (NF-κB) activator to simulate very early antiviral pathways. We then challenged mice with an in vivo septic shock model characterized by slowly evolving bacterial infection to simulate bacterial superinfection early during a viral infection. Our data demonstrated robust induction of IFN-α in serum within 24 h of PIC injection with IFN-α/β–dependent major histocompatibility antigen class II up-regulation on peritoneal macrophages. PIC pretreatment before septic shock resulted in augmented tumor necrosis factor alpha and interleukins 6 and 10 and heightened lethality compared with septic shock alone. Intact IFN-α/β signaling was necessary for augmentation of the inflammatory response to in vivo septic shock and to both TLR2 and TLR4 agonists in vitro. To assess the NF-κB contribution to PIC-modulated inflammatory responses to septic shock, we treated with parthenolide an NF-κB inhibitor before PIC and septic shock. Parthenolide did not inhibit IFN-α induction by PIC. Inhibition of NF-κB by parthenolide did reduce IFN-α–mediated potentiation of the cytokine response and lethality from septic shock. Our data demonstrate that pathways activated early during many viral infections can have a detrimental impact on the outcome of subsequent bacterial infection. These pathways may be critical to understanding the heightened morbidity and mortality from bacterial superinfection after viral infection in human disease. PMID:16878028

Sub-lethal glyphosate exposure alters flowering phenology and causes transient male-sterility in Brassica spp

PubMed Central

2014-01-01

Background Herbicide resistance in weedy plant populations can develop through different mechanisms such as gene flow of herbicide resistance transgenes from crop species into compatible weedy species or by natural evolution of herbicide resistance or tolerance following selection pressure. Results from our previous studies suggest that sub-lethal levels of the herbicide glyphosate can alter the pattern of gene flow between glyphosate resistant Canola®, Brassica napus, and glyphosate sensitive varieties of B. napus and B. rapa. The objectives of this study were to examine the phenological and developmental changes that occur in Brassica crop and weed species following sub-lethal doses of the herbicides glyphosate and glufosinate. We examined several vegetative and reproductive traits of potted plants under greenhouse conditions, treated with sub-lethal herbicide sprays. Results Our results indicate that exposure of Brassica spp. to a sub-lethal dose of glyphosate results in altering flowering phenology and reproductive function. Flowering of all sensitive species was significantly delayed and reproductive function, specifically male fertility, was suppressed. Higher dosage levels typically contributed to an increase in the magnitude of phenotypic changes. Conclusions These results demonstrate that Brassica spp. plants that are exposed to sub-lethal doses of glyphosate could be subject to very different pollination patterns and an altered pattern of gene flow that would result from changes in the overlap of flowering phenology between species. Implications include the potential for increased glyphosate resistance evolution and spread in weedy communities exposed to sub-lethal glyphosate. PMID:24655547

Sub-lethal glyphosate exposure alters flowering phenology and causes transient male-sterility in Brassica spp.

PubMed

Londo, Jason Paul; McKinney, John; Schwartz, Matthew; Bollman, Mike; Sagers, Cynthia; Watrud, Lidia

2014-03-21

Herbicide resistance in weedy plant populations can develop through different mechanisms such as gene flow of herbicide resistance transgenes from crop species into compatible weedy species or by natural evolution of herbicide resistance or tolerance following selection pressure. Results from our previous studies suggest that sub-lethal levels of the herbicide glyphosate can alter the pattern of gene flow between glyphosate resistant Canola®, Brassica napus, and glyphosate sensitive varieties of B. napus and B. rapa. The objectives of this study were to examine the phenological and developmental changes that occur in Brassica crop and weed species following sub-lethal doses of the herbicides glyphosate and glufosinate. We examined several vegetative and reproductive traits of potted plants under greenhouse conditions, treated with sub-lethal herbicide sprays. Our results indicate that exposure of Brassica spp. to a sub-lethal dose of glyphosate results in altering flowering phenology and reproductive function. Flowering of all sensitive species was significantly delayed and reproductive function, specifically male fertility, was suppressed. Higher dosage levels typically contributed to an increase in the magnitude of phenotypic changes. These results demonstrate that Brassica spp. plants that are exposed to sub-lethal doses of glyphosate could be subject to very different pollination patterns and an altered pattern of gene flow that would result from changes in the overlap of flowering phenology between species. Implications include the potential for increased glyphosate resistance evolution and spread in weedy communities exposed to sub-lethal glyphosate.

[Medical aspects of common non-lethal weapons].

PubMed

Kunz, Sebastian Niko; Grove, Christina; Monticelli, Fabio

2014-03-01

The development and provision of non-lethal weapons (NLW) allow military and law enforcement personnel to exploit gradual engagement in countering potentially hazardous threats. Chemical, kinetic and electrical weapons systems are used to curb violence in civilian crowds. With inappropriate usage, these technologies can cause potentially fatal injuries that are not only of clinical, but also of legal relevance. In this context, the practicing physician is faced with treatment as well as assessment issues of new forms of injuries. In order to assure medical care and to be able to draw competent expert's conclusions, a detailed knowledge of the medical effects of these NLW is necessary. The review at hand presents today's most popular NLW and gives an overview of their possible injury potential and required treatments.

Non-lethal effects of an invasive species in the marine environment: the importance of early life-history stages.

PubMed

Rius, Marc; Turon, Xavier; Marshall, Dustin J

2009-04-01

Studies examining the effects of invasive species have focussed traditionally on the direct/lethal effects of the invasive on the native community but there is a growing recognition that invasive species may also have non-lethal effects. In terrestrial systems, non-lethal effects of invasive species can disrupt early life-history phases (such as fertilisation, dispersal and subsequent establishment) of native species, but in the marine environment most studies focus on adult rather than early life-history stages. Here, we examine the potential for an introduced sessile marine invertebrate (Styela plicata) to exert both lethal and non-lethal effects on a native species (Microcosmus squamiger) across multiple early life-history stages. We determined whether sperm from the invasive species interfered with the fertilisation of eggs from the native species and found no effect. However, we did find strong effects of the invasive species on the post-fertilisation performance of the native species. The invasive species inhibited the settlement of native larvae and, in the field, the presence of the invasive species was associated with a ten-fold increase in the post-settlement mortality of the native species, as well as an initial reduction of growth in the native. Our results suggest that larvae of the native species avoid settling near the invasive species due to reduced post-settlement survival in its presence. Overall, we found that invasive species can have complex and pervasive effects (both lethal and non-lethal) across the early life-history stages of the native species, which are likely to result in its displacement and to facilitate further invasion.

Differential antagonism of tetramethylenedisulfotetramine-induced seizures by agents acting at NMDA and GABAA receptors

PubMed Central

Shakarjian, Michael P.; Velíšková, Jana; Stanton, Patric K.; Velíšek, Libor

2012-01-01

Tetramethylenedisulfotetramine (TMDT) is a highly lethal neuroactive rodenticide responsible for many accidental and intentional poisonings in mainland China. Ease of synthesis, water solubility, potency, and difficulty to treat make TMDT a potential weapon for terrorist activity. We characterized TMDT-induced convulsions and mortality in male C57BL/6 mice. TMDT (ip) produced a continuum of twitches, clonic, and tonic-clonic seizures decreasing in onset latency and increasing in severity with increasing dose; 0.4 mg/kg was 100% lethal. The NMDA antagonist, ketamine (35 mg/kg) injected ip immediately after the first TMDT-induced seizure, did not change number of tonic-clonic seizures or lethality, but increased the number of clonic seizures. Doubling the ketamine dose decreased tonic-clonic seizures and eliminated lethality through a 60 min observation period. Treating mice with another NMDA antagonist, MK-801, 0.5 or 1 mg/kg ip, showed similar effects as low and high doses of ketamine, respectively, and prevented lethality, converting status epilepticus EEG activity to isolated interictal discharges. Treatment with these agents 15 min prior to TMDT administration did not increase their effectiveness. Post-treatment with the GABAA receptor allosteric enhancer diazepam (5 mg/kg) greatly reduced seizure manifestations and prevented lethality 60 min post-TMDT, but ictal events were evident in EEG recordings and, hours post-treatment, mice experienced status epilepticus and died. Thus, TMDT is a highly potent and lethal convulsant for which single-dose benzodiazepine treatment is inadequate in managing electrographic seizures or lethality. Repeated benzodiazepine dosing or combined application of benzodiazepines and NMDA receptor antagonists are more likely to be effective in treating TMDT poisoning. PMID:23022509

Superantigens Are Critical for Staphylococcus aureus Infective Endocarditis, Sepsis, and Acute Kidney Injury

PubMed Central

Salgado-Pabón, Wilmara; Breshears, Laura; Spaulding, Adam R.; Merriman, Joseph A.; Stach, Christopher S.; Horswill, Alexander R.; Peterson, Marnie L.; Schlievert, Patrick M.

2013-01-01

ABSTRACT Infective endocarditis and kidney infections are serious complications of Staphylococcus aureus sepsis. We investigated the role of superantigens (SAgs) in the development of lethal sepsis, infective endocarditis, and kidney infections. SAgs cause toxic shock syndrome, but it is unclear if SAgs contribute to infective endocarditis and kidney infections secondary to sepsis. We show in the methicillin-resistant S. aureus strain MW2 that lethal sepsis, infective endocarditis, and kidney infections in rabbits are critically dependent on high-level SAgs. In contrast, the isogenic strain lacking staphylococcal enterotoxin C (SEC), the major SAg in this strain, is attenuated in virulence, while complementation restores disease production. SAgs’ role in infective endocarditis appears to be both superantigenicity and direct endothelial cell stimulation. Maintenance of elevated blood pressure by fluid therapy significantly protects from infective endocarditis, possibly through preventing bacterial accumulation on valves and increased SAg elimination. These data should facilitate better methods to manage these serious illnesses. PMID:23963178

Hydroxyurea therapy of a murine model of sickle cell anemia inhibits the progression of pneumococcal disease by down-modulating E-selectin

PubMed Central

Lebensburger, Jeffrey D.; Howard, Thad; Hu, Yunming; Pestina, Tamara I.; Gao, Geli; Johnson, Melissa; Zakharenko, Stanislav S.; Ware, Russell E.; Tuomanen, Elaine I.; Persons, Derek A.

2012-01-01

Sickle cell anemia is characterized by chronic hemolysis coupled with extensive vascular inflammation. This inflammatory state also mechanistically promotes a high risk of lethal, invasive pneumococcal infection. Current treatments to reduce vaso-occlusive complications include chronic hydroxyurea therapy to induce fetal hemoglobin. Because hydroxyurea also reduces leukocytosis, an understanding of the impact of this treatment on pneumococcal pathogenesis is needed. Using a sickle cell mouse model of pneumococcal pneumonia and sepsis, administration of hydroxyurea was found to significantly improve survival. Hydroxyurea treatment decreased neutrophil extravasation into the infected lung coincident with significantly reduced levels of E-selectin in serum and on pulmonary epithelia. The protective effect of hydroxyurea was abrogated in mice deficient in E-selectin. The decrease in E-selectin levels was also evident in human sickle cell patients receiving hydroxyurea therapy. These data indicate that in addition to induction of fetal hemoglobin, hydroxyurea attenuates leukocyte–endothelial interactions in sickle cell anemia, resulting in protection against lethal pneumococcal sepsis. PMID:22130804

Malaria-Associated Mortality in the Australian Defence Force during the Twentieth Century.

PubMed

Shanks, G Dennis

2017-08-01

Malaria has been a military problem throughout history capable of causing epidemics that stop military operations. Individual mortality was examined from records of the three major wars of the 20th century that involved Australia in which 133 (1914-1919), 92 (1943-1945), and two (1965-1967) soldiers are known to have died with malaria. Those dying were predominately enlisted soldiers with a mean age of 29 years often complicated by other infections such as influenza, pneumonia or scrub typhus. Lethal epidemics of falciparum malaria occurred in Palestine/Syria in October 1918 and New Guinea in September 1943 to March 1944. Although no Australian soldier has died in nearly 50 years from malaria, there were three serious falciparum infections in soldiers in East Timor 1999-2000 who might have died if intensive care had not been provided. Recent military deployments into Africa including United Nations contingents still show falciparum malaria's lethality despite the availability of effective malaria chemoprophylaxis.

Neurologic manifestations of achondroplasia.

PubMed

Hecht, Jacqueline T; Bodensteiner, John B; Butler, Ian J

2014-01-01

Achondroplasia is the best described and most common form of the congenital short-limbed dwarfing conditions. Achondroplasia is apparent at birth and has a birth prevalence of 1 in 20000-30000 live-born infants. Achondroplasia is inherited as an autosomal dominant condition, although 80% of cases occur sporadically as new events in their families. Achondroplasia is caused, in virtually all of the cases, by a G380R mutation in fibroblast growth factor receptor 3 (FGFR3). Patients with achondroplasia should be evaluated by a multidisciplinary team of clinicians including geneticists, neurologists, and orthopedists, since there are numerous bony and neurological complications. The most severe complication results from craniocervical stenosis and medullary and upper spinal cord compression, which can have devastating and even lethal sequelae during early childhood. In subsequent decades, including adolescence, spinal cord and nerve compression are more prominent. The neurological complications of achondroplasia have been recognized in adults for more than a century and are attributed to bony defects, connective tissue structures, or both. Similar neurological complications are now appreciated in infants, young children, and teenagers with achondroplasia. Defective connective tissue elements in achondroplasia frequently lead to ligamentous laxity, which can aggravate the complications associated with bony stenosis. Bony abnormalities are known to cause neurological morbidity and lead to a shortened lifespan. Neurological complications associated with achondroplasia are reviewed, including recommendations for the evaluation and management of these clinical problems. © 2014 Elsevier B.V. All rights reserved.

Lethal and sub-lethal effects of spinosad on bumble bees (Bombus impatiens Cresson).

PubMed

Morandin, Lora A; Winston, Mark L; Franklin, Michelle T; Abbott, Virginia A

2005-07-01

Recent developments of new families of pesticides and growing awareness of the importance of wild pollinators for crop pollination have stimulated interest in potential effects of novel pesticides on wild bees. Yet pesticide toxicity studies on wild bees remain rare, and few studies have included long-term monitoring of bumble bee colonies or testing of foraging ability after pesticide exposure. Larval bees feeding on exogenous pollen and exposed to pesticides during development may result in lethal or sub-lethal effects during the adult stage. We tested the effects of a naturally derived biopesticide, spinosad, on bumble bee (Bombus impatiens Cresson) colony health, including adult mortality, brood development, weights of emerging bees and foraging efficiency of adults that underwent larval development during exposure to spinosad. We monitored colonies from an early stage, over a 10-week period, and fed spinosad to colonies in pollen at four levels: control, 0.2, 0.8 and 8.0 mg kg(-1), during weeks 2 through 5 of the experiment. At concentrations that bees would likely encounter in pollen in the wild (0.2-0.8 mg kg(-1)) we detected minimal negative effects to bumble bee colonies. Brood and adult mortality was high at 8.0 mg kg(-1) spinosad, about twice the level that bees would be exposed to in a 'worst case' field scenario, resulting in colony death two to four weeks after initial pesticide exposure. At more realistic concentrations there were potentially important sub-lethal effects. Adult worker bees exposed to spinosad during larval development at 0.8 mg kg(-1) were slower foragers on artificial complex flower arrays than bees from low or no spinosad treated colonies. Inclusion of similar sub-lethal assays to detect effects of pesticides on pollinators would aid in development of environmentally responsible pest management strategies. Copyright 2005 Society of Chemical Industry

Ureteral Injury After Laparoscopic Versus Open Colectomy

PubMed Central

Ahaghotu, Chiledum A.; Libuit, Laura; Ortega, Gezzer; Coleman, Pamela W.; Cornwell, Edward E.; Tran, Daniel D.; Fullum, Terrence M.

2014-01-01

Background and Objectives: Ureteral injury is an infrequent but potentially lethal complication of colectomy. We aimed to determine the incidence of intraoperative ureteral injury after laparoscopic and open colectomy and to determine the independent morbidity and mortality rates associated with ureteral injury. Methods: We analyzed data from the National Surgical Quality Improvement Program for the years 2005–2010. All patients undergoing colectomy for benign, neoplastic, or inflammatory conditions were selected. Patients undergoing laparoscopic colectomy versus open colectomy were matched on disease severity and clinical and demographic characteristics. Multivariate logistic regression analyses and coarsened exact matching were used to determine the independent difference in the incidence of ureteral injury between the 2 groups. Multivariate models were also used to determine the independent association between postoperative complications associated with ureteral injury. Results: Of a total of 94 526 colectomies, 33 092 (35%) were completed laparoscopically. Ureteral injury occurred in a total of 585 patients (0.6%). The crude incidence in the open group was higher than that in the laparoscopic group (0.66% versus 0.53%, P = .016). CEM produced 14 630 matching pairs. Matched analysis showed the likelihood of ureteral injury after laparoscopic colectomy to be 30% less than after open colectomy (odds ratio, 0.70; 95% confidence interval, 0.51–0.96). Patients with ureteral injury were independently more likely to have septic complications and have longer lengths of hospital stay than those without ureteral injury. Conclusion: Laparoscopic colectomy is associated with a lower incidence of intraoperative ureteral injury when compared with open procedures. Ureteral injury leads to significant postoperative morbidity even if identified and repaired during the colectomy. PMID:25392666

Implantable cardioverter-defibrillator therapy in Brugada syndrome: a 20-year single-center experience.

PubMed

Conte, Giulio; Sieira, Juan; Ciconte, Giuseppe; de Asmundis, Carlo; Chierchia, Gian-Battista; Baltogiannis, Giannis; Di Giovanni, Giacomo; La Meir, Mark; Wellens, Francis; Czapla, Jens; Wauters, Kristel; Levinstein, Moises; Saitoh, Yukio; Irfan, Ghazala; Julià, Justo; Pappaert, Gudrun; Brugada, Pedro

2015-03-10

Patients with Brugada syndrome and aborted sudden cardiac death or syncope have higher risks for ventricular arrhythmias (VAs) and should undergo implantable cardioverter-defibrillator (ICD) placement. Device-based management of asymptomatic patients is controversial. ICD therapy is associated with high rates of inappropriate shocks and device-related complications. The objective of this study was to investigate clinical features, management, and long-term follow-up of ICD therapy in patients with Brugada syndrome. Patients presenting with spontaneous or drug-induced Brugada type 1 electrocardiographic findings, who underwent ICD implantation and continuous follow-up at a single institution, were eligible for this study. A total of 176 consecutive patients were included. During a mean follow-up period of 83.8 ± 57.3 months, spontaneous sustained VAs occurred in 30 patients (17%). Eight patients (4.5%) died. Appropriate ICD shocks occurred in 28 patients (15.9%), and 33 patients (18.7%) had inappropriate shocks. Electrical storm occurred in 4 subjects (2.3%). Twenty-eight patients (15.9%) experienced device-related complications. In multivariate Cox regression analysis, aborted sudden cardiac death and VA inducibility on electrophysiologic studies were independent predictors of appropriate shock occurrence. ICD therapy was an effective strategy in Brugada syndrome, treating potentially lethal arrhythmias in 17% of patients during long-term follow-up. Appropriate shocks were significantly associated with the presence of aborted sudden cardiac death but also occurred in 13% of asymptomatic patients. Risk stratification by electrophysiologic study may identify asymptomatic patients at risk for arrhythmic events and could be helpful in investigating syncope not related to VAs. ICD placement is frequently associated with device-related complications, and rates of inappropriate shocks remain high regardless of careful device programming. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Public acceptance of management methods under different human-wildlife conflict scenarios.

PubMed

Liordos, Vasilios; Kontsiotis, Vasileios J; Georgari, Marina; Baltzi, Kerasia; Baltzi, Ioanna

2017-02-01

Wildlife management seeks to minimise public controversy for successful application of wildlife control methods. Human dimensions research in wildlife seeks a better understanding of public preferences for effective human-wildlife conflict resolution. In face to face interviews, 630 adults in Greece were asked to rate on a 5-point Likert-like scale their acceptance of 3 management methods, i.e., do nothing, non-lethal control, and lethal control, in the context of 5 human-wildlife conflict scenarios: 1) corvids damage crops; 2) starlings damage crops; 3) starlings foul urban structures; 4) coypus damage crops; and 5) coypus transfer disease. Univariate GLMs determined occupation, hunting membership and their interaction as the stronger predictors of public acceptance, generating 4 stakeholder groups: the general public, farmers, hunters, and farmers-hunters. Differences in acceptance and consensus among stakeholder groups were assessed using the Potential for Conflict Index 2 (PCI 2 ). All 4 stakeholder groups agreed that doing nothing was unacceptable and non-lethal control acceptable in all 5 scenarios, with generally high consensus within and between groups. The lethal control method was more controversial and became increasingly more acceptable as the severity of scenarios was increased and between non-native and native species. Lethal control was unacceptable for the general public in all scenarios. Farmers accepted lethal methods in the corvids and starlings scenarios, were neutral in the coypus damage crops scenario, whereas they accepted lethal control when coypus transfer disease. Hunters' opinion was neutral in the corvids, starlings and coypus damage crops and starlings foul urban structures scenarios, but they accepted lethal methods in the coypus transfer disease scenario. Farmers-hunters considered lethal control acceptable in all 5 scenarios. Implications from this study could be used for designing a socio-ecological approach which incorporates wildlife management with public interests. The studied species have a wide distribution, therefore present findings might also prove useful elsewhere. Copyright © 2016 Elsevier B.V. All rights reserved.

Transcutaneous yellow fever vaccination of subjects with or without atopic dermatitis.

PubMed

Slifka, Mark K; Leung, Donald Y M; Hammarlund, Erika; Raué, Hans-Peter; Simpson, Eric L; Tofte, Susan; Baig-Lewis, Shahana; David, Gloria; Lynn, Henry; Woolson, Rob; Hata, Tissa; Milgrom, Henry; Hanifin, Jon

2014-02-01

Atopic dermatitis (AD) is a common inflammatory skin disease with a global prevalence ranging from 3% to 20%. Patients with AD have an increased risk for complications after viral infection (eg, herpes simplex virus), and vaccination of patients with AD with live vaccinia virus is contraindicated because of a heightened risk of eczema vaccinatum, a rare but potentially lethal complication associated with smallpox vaccination. We sought to develop a better understanding of immunity to cutaneous viral infection in patients with AD. In a double-blind randomized study we investigated the safety and immunogenicity of live attenuated yellow fever virus (YFV) vaccination of nonatopic subjects and patients with AD after standard subcutaneous inoculation or transcutaneous vaccination administered with a bifurcated needle. Viremia, neutralizing antibody, and antiviral T-cell responses were analyzed for up to 30 days after vaccination. YFV vaccination administered through either route was well tolerated. Subcutaneous vaccination resulted in higher seroconversion rates than transcutaneous vaccination but elicited similar antiviral antibody levels and T-cell responses in both the nonatopic and AD groups. After transcutaneous vaccination, both groups mounted similar neutralizing antibody responses, but patients with AD demonstrated lower antiviral T-cell responses by 30 days after vaccination. Among transcutaneously vaccinated subjects, a significant inverse correlation between baseline IgE levels and the magnitude of antiviral antibody and CD4(+) T-cell responses was observed. YFV vaccination of patients with AD through the transcutaneous route revealed that high baseline IgE levels provide a potential biomarker for predicting reduced virus-specific immune memory after transcutaneous infection with a live virus. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Safety of tumescent and laser-assisted liposuction: review of the literature.

PubMed

Tierney, Emily P; Kouba, David J; Hanke, C William

2011-12-01

Tumescent liposuction (TL) allows the removal of large volumes of fat with minimal blood loss or postoperative morbidity, excellent cosmesis, and a remarkable safety profile. To review the literature on the safety of tumescent liposuction, liposuction under general anesthesia and laser-assisted liposuction. Aggregate safety data on liposuction under tumescent anesthesia reveals over 100,000 body areas treated with liposuction. There were no serious complications of death, emboli, hypovolemic shock, perforation of thorax or peritoneum, thrombophlebitis, seizures, or toxic reactions to drugs. In contrast, in the plastic surgery literature, liposuction under general anesthesia was associated with complications of deep venous thrombosis or pulmonary embolus, abdominal or other organ perforation, infection, and bleeding. Most recently, survey data in the European literature analyzed data showed 72 cases of severe complications from liposuction, including 23 deaths in a 5-year period from 1998 to 2002. The most frequent complications were bacterial infections such as necrotizing fasciitis, gas gangrene, and different forms of sepsis. Further causes of lethal outcome were hemorrhages, perforation of abdominal viscera, and pulmonary embolism. Tumescent local anesthesia utilizing lidocaine with epinephrine allows the removal of large volumes of fat with minimal associated blood loss and postoperative morbidity.

Characterization of conditionally expressed mutants affecting age-specific survival in inbred lines of Drosophila melanogaster: lethal conditions and temperature-sensitive periods.

PubMed Central

Vermeulen, C J; Bijlsma, R

2004-01-01

The specific genetic basis of inbreeding depression is poorly understood. To address this question, two conditionally expressed lethal effects that were found to cause line-specific life span reductions in two separate inbred lines of Drosophila melanogaster were characterized phenotypically and genetically in terms of whether the accelerated mortality effects are dominant or recessive. The mortality effect in one line (I4) is potentially a temperature-sensitive semilethal that expresses in adult males only and is partially dominant. The other line (I10) responds as one would expect for a recessive lethal. It requires a cold shock for expression and is cold sensitive. Flies exhibiting this lethal condition responded as pupae and freshly eclosed imagoes. The effect is recessive in both males and females. The expression of the lethal effects in both lines is highly dependent upon environmental conditions. These results will serve as a basis for more detailed and mechanistic genetic research on inbreeding depression and are relevant to sex- and environment-specific effects on life span observed in quantitative trait loci studies using inbred lines. PMID:15280238

Chronic Exposure of Corals to Fine Sediments: Lethal and Sub-Lethal Impacts

PubMed Central

Flores, Florita; Hoogenboom, Mia O.; Smith, Luke D.; Cooper, Timothy F.; Abrego, David; Negri, Andrew P.

2012-01-01

Understanding the sedimentation and turbidity thresholds for corals is critical in assessing the potential impacts of dredging projects in tropical marine systems. In this study, we exposed two species of coral sampled from offshore locations to six levels of total suspended solids (TSS) for 16 weeks in the laboratory, including a 4 week recovery period. Dose-response relationships were developed to quantify the lethal and sub-lethal thresholds of sedimentation and turbidity for the corals. The sediment treatments affected the horizontal foliaceous species (Montipora aequituberculata) more than the upright branching species (Acropora millepora). The lowest sediment treatments that caused full colony mortality were 30 mg l−1 TSS (25 mg cm−2 day−1) for M. aequituberculata and 100 mg l−1 TSS (83 mg cm−2 day−1) for A. millepora after 12 weeks. Coral mortality generally took longer than 4 weeks and was closely related to sediment accumulation on the surface of the corals. While measurements of damage to photosystem II in the symbionts and reductions in lipid content and growth indicated sub-lethal responses in surviving corals, the most reliable predictor of coral mortality in this experiment was long-term sediment accumulation on coral tissue. PMID:22662225

[Secondary metabolites, lethality and antimicrobial activity of extracts from three corals and three marine mollusks from Sucre, Venezuela].

PubMed

Ordaz, Gabriel; D'Armas, Haydelba; Yáñez, Dayanis; Hernández, Juan; Camacho, Angel

2010-06-01

The study of biochemical activity of extracts obtained from marine organisms is gaining interest as some have proved to have efficient health or industrial applications. To evaluate lethality and antimicrobial activities, some chemical tests were performed on crude extracts of the octocorals Eunicea sp., Muricea sp. and Pseudopterogorgia acerosa and the mollusks Pteria colymbus, Phyllonotus pomum and Chicoreus brevifrons, collected in Venezuelan waters. The presence of secondary metabolites like alkaloids, unsaturated sterols and pentacyclic triterpenes in all invertebrates, was evidenced. Additionally, sesquiterpenlactones, saponins, tannins, cyanogenic and cardiotonic glycosides were also detected in some octocoral extracts, suggesting that biosynthesis of these metabolites is typical in this group. From the lethality bioassays, all extracts resulted lethal to Artemia salina (LC50<1000 microg/ml) with an increased of lethal activity with exposition time. P. pomum extract showed the highest lethality rate (LC50=46.8 microg/ml). Compared to the octocorals, mollusks extracts displayed more activity and a greater action spectrum against different bacterial strains, whereas octocorals also inhibited some fungi strains growth. Staphylococcus aureus was the most susceptible to the antimicrobial power of the extracts (66.7%), whereas Pseudomonas aeruginosa, Candida albicans and Aspergillus niger were not affected. The antibiosis shown by marine organisms extracts indicates that some of their biosynthesized metabolites are physiologically active, and may have possible cytotoxic potential or as a source of antibiotic components.

The development and validation of a novel model for predicting surgical complications in colorectal cancer of elderly patients: Results from 1008 cases.

PubMed

Shen, Zhanlong; Lin, Yuanpei; Ye, Yingjiang; Jiang, Kewei; Xie, Qiwei; Gao, Zhidong; Wang, Shan

2018-04-01

To establish predicting models of surgical complications in elderly colorectal cancer patients. Surgical complications are usually critical and lethal in the elderly patients. However, none of the current models are specifically designed to predict surgical complications in elderly colorectal cancer patients. Details of 1008 cases of elderly colorectal cancer patients (age ≥ 65) were collected retrospectively from January 1998 to December 2013. Seventy-six clinicopathological variables which might affect postoperative complications in elderly patients were recorded. Multivariate stepwise logistic regression analysis was used to develop the risk model equations. The performance of the developed model was evaluated by measures of calibration (Hosmer-Lemeshow test) and discrimination (the area under the receiver-operator characteristic curve, AUC). The AUC of our established Surgical Complication Score for Elderly Colorectal Cancer patients (SCSECC) model was 0.743 (sensitivity, 82.1%; specificity, 78.3%). There was no significant discrepancy between observed and predicted incidence rates of surgical complications (AUC, 0.820; P = .812). The Surgical Site Infection Score for Elderly Colorectal Cancer patients (SSISECC) model showed significantly better prediction power compared to the National Nosocomial Infections Surveillance index (NNIS) (AUC, 0.732; P ˂ 0.001) and Efficacy of Nosocomial Infection Control index (SENIC) (AUC; 0.686; P˂0.001) models. The SCSECC and SSISECC models show good prediction power for postoperative surgical complication morbidity and surgical site infection in elderly colorectal cancer patients. Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Differential antagonism of tetramethylenedisulfotetramine-induced seizures by agents acting at NMDA and GABA{sub A} receptors

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

Shakarjian, Michael P., E-mail: michael_shakarjian@nymc.edu; Department of Medicine, Division of Pulmonary and Critical Care Medicine, UMDNJ–Robert Wood Johnson Medical School, Piscataway, NJ 08854; Velíšková, Jana, E-mail: jana_veliskova@nymc.edu

Tetramethylenedisulfotetramine (TMDT) is a highly lethal neuroactive rodenticide responsible for many accidental and intentional poisonings in mainland China. Ease of synthesis, water solubility, potency, and difficulty to treat make TMDT a potential weapon for terrorist activity. We characterized TMDT-induced convulsions and mortality in male C57BL/6 mice. TMDT (ip) produced a continuum of twitches, clonic, and tonic–clonic seizures decreasing in onset latency and increasing in severity with increasing dose; 0.4 mg/kg was 100% lethal. The NMDA antagonist, ketamine (35 mg/kg) injected ip immediately after the first TMDT-induced seizure, did not change number of tonic–clonic seizures or lethality, but increased the numbermore » of clonic seizures. Doubling the ketamine dose decreased tonic–clonic seizures and eliminated lethality through a 60 min observation period. Treating mice with another NMDA antagonist, MK-801, 0.5 or 1 mg/kg ip, showed similar effects as low and high doses of ketamine, respectively, and prevented lethality, converting status epilepticus EEG activity to isolated interictal discharges. Treatment with these agents 15 min prior to TMDT administration did not increase their effectiveness. Post-treatment with the GABA{sub A} receptor allosteric enhancer diazepam (5 mg/kg) greatly reduced seizure manifestations and prevented lethality 60 min post-TMDT, but ictal events were evident in EEG recordings and, hours post-treatment, mice experienced status epilepticus and died. Thus, TMDT is a highly potent and lethal convulsant for which single-dose benzodiazepine treatment is inadequate in managing electrographic seizures or lethality. Repeated benzodiazepine dosing or combined application of benzodiazepines and NMDA receptor antagonists is more likely to be effective in treating TMDT poisoning. -- Highlights: ► TMDT produces convulsions and lethality at low doses in mice. ► Diazepam pre- or post-treatments inhibit TMDT-induced convulsions and death. ► Ketamine and MK-801 display biphasic actions on TMDT seizures. ► Diazepam stops convulsions, but ictal EEG events persist to cause lethality hrs later. ► Diazepam repeat dose or paired with ketamine/MK-801 may more effectively block TMDT.« less

[The factors affecting the results of mechanical jaundice management].

PubMed

Malkov, I S; Shaimardanov, R Sh; Korobkov, V N; Filippov, V A; Khisamiev, I G

To improve the results of obstructive jaundice management by rational diagnostic and treatment strategies. Outcomes of 820 patients with obstructive jaundice syndrome were analyzed. Diagnostic and tactical mistakes were made at pre-hospital stage in 143 (17.4%) patients and in 105 (12.8%) at hospital stage. Herewith, in 53 (6.5%) cases the errors were observed at all stages. Retrospective analysis of severe postoperative complications and lethal outcomes in patients with obstructive jaundice showed that in 23.8% of cases they were explained by diagnostic and tactical mistakes at various stages of examination and treatment. We developed an algorithm for obstructive jaundice management to reduce the number of diagnostic and tactical errors, a reduction in the frequency of diagnostic and tactical errors. It reduced the number of postoperative complications up to 16.5% and mortality rate to 3.0%.

Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18

PubMed Central

Wynn, James Lawrence; Wilson, Chris S.; Hawiger, Jacek; Scumpia, Philip O.; Marshall, Andrew F.; Liu, Jin-Hua; Zharkikh, Irina; Wong, Hector R.; Lahni, Patrick; Benjamin, John T.; Plosa, Erin J.; Weitkamp, Jörn-Hendrik; Sherwood, Edward R.; Moldawer, Lyle L.; Ungaro, Ricardo; Baker, Henry V.; Lopez, M. Cecilia; McElroy, Steven J.; Colliou, Natacha; Mohamadzadeh, Mansour; Moore, Daniel Jensen

2016-01-01

Interleukin (IL)-18 is an important effector of innate and adaptive immunity, but its expression must also be tightly regulated because it can potentiate lethal systemic inflammation and death. Healthy and septic human neonates demonstrate elevated serum concentrations of IL-18 compared with adults. Thus, we determined the contribution of IL-18 to lethality and its mechanism in a murine model of neonatal sepsis. We find that IL-18–null neonatal mice are highly protected from polymicrobial sepsis, whereas replenishing IL-18 increased lethality to sepsis or endotoxemia. Increased lethality depended on IL-1 receptor 1 (IL-1R1) signaling but not adaptive immunity. In genome-wide analyses of blood mRNA from septic human neonates, expression of the IL-17 receptor emerged as a critical regulatory node. Indeed, IL-18 administration in sepsis increased IL-17A production by murine intestinal γδT cells as well as Ly6G+ myeloid cells, and blocking IL-17A reduced IL-18–potentiated mortality to both neonatal sepsis and endotoxemia. We conclude that IL-17A is a previously unrecognized effector of IL-18–mediated injury in neonatal sepsis and that disruption of the deleterious and tissue-destructive IL-18/IL-1/IL-17A axis represents a novel therapeutic approach to improve outcomes for human neonates with sepsis. PMID:27114524

Gene expression profiling of prostate tissue identifies chromatin regulation as a potential link between obesity and lethal prostate cancer.

PubMed

Ebot, Ericka M; Gerke, Travis; Labbé, David P; Sinnott, Jennifer A; Zadra, Giorgia; Rider, Jennifer R; Tyekucheva, Svitlana; Wilson, Kathryn M; Kelly, Rachel S; Shui, Irene M; Loda, Massimo; Kantoff, Philip W; Finn, Stephen; Vander Heiden, Matthew G; Brown, Myles; Giovannucci, Edward L; Mucci, Lorelei A

2017-11-01

Obese men are at higher risk of advanced prostate cancer and cancer-specific mortality; however, the biology underlying this association remains unclear. This study examined gene expression profiles of prostate tissue to identify biological processes differentially expressed by obesity status and lethal prostate cancer. Gene expression profiling was performed on tumor (n = 402) and adjacent normal (n = 200) prostate tissue from participants in 2 prospective cohorts who had been diagnosed with prostate cancer from 1982 to 2005. Body mass index (BMI) was calculated from the questionnaire immediately preceding cancer diagnosis. Men were followed for metastases or prostate cancer-specific death (lethal disease) through 2011. Gene Ontology biological processes differentially expressed by BMI were identified using gene set enrichment analysis. Pathway scores were computed by averaging the signal intensities of member genes. Odds ratios (ORs) for lethal prostate cancer were estimated with logistic regression. Among 402 men, 48% were healthy weight, 31% were overweight, and 21% were very overweight/obese. Fifteen gene sets were enriched in tumor tissue, but not normal tissue, of very overweight/obese men versus healthy-weight men; 5 of these were related to chromatin modification and remodeling (false-discovery rate < 0.25). Patients with high tumor expression of chromatin-related genes had worse clinical characteristics (Gleason grade > 7, 41% vs 17%; P = 2 × 10 -4 ) and an increased risk of lethal disease that was independent of grade and stage (OR, 5.26; 95% confidence interval, 2.37-12.25). This study improves our understanding of the biology of aggressive prostate cancer and identifies a potential mechanistic link between obesity and prostate cancer death that warrants further study. Cancer 2017;123:4130-4138. © 2017 American Cancer Society. © 2017 American Cancer Society.

Interventional Radiology in the Management of Visceral Artery Pseudoaneurysms: A Review of Techniques and Embolic Materials

PubMed Central

Venkatesh, Hosur Ananthashayana; Gamanagatti, Shivanand; Garg, Pramod; Srivastava, Deep Narayan

2016-01-01

Visceral artery pseudoaneurysms occur mostly as a result of inflammation and trauma. Owing to high risk of rupture, they require early treatment to prevent lethal complications. Knowledge of the various approaches of embolization of pseudoaneurysms and different embolic materials used in the management of visceral artery pseudoaneurysms is essential for successful and safe embolization. We review and illustrate the endovascular, percutaneous and endoscopic ultrasound techniques used in the treatment of visceral artery pseudoaneurysm and briefly discuss the embolic materials and their benefits and risks. PMID:27134524

Radiosensitizing effects of neem (Azadirachta indica) oil.

PubMed

Kumar, Ashok; Rao, A R; Kimura, H

2002-02-01

Radiosensitization by neem oil was studied using Balbc/3T3 cells and SCID cells. Neem oil enhanced the radiosensitivity of the cells when applied both during and after x-irradiation under aerobic conditions. Neem oil completely inhibited the repair of sublethal damage and potentially lethal damage repair in Balbc/3T3 cells. The cytofluorimeter data show that neem oil treatment before and after x-irradiation reduced the G(2) + M phase, thus inhibiting the expression of the radiation induced arrest of cells in the G(2) phase of the cell cycle. However, SCIK cells (derived from the SCID mouse), deficient in DSB repair, treated with neem oil did not show any enhancement in the radiosensitivity. There was no effect of neem oil on SLD repair or its inhibition in SCIK cells. These results suggest that neem oil enhanced the radiosensitivity of cells by interacting with residual damage after x-irradiation, thereby converting the sublethal damage or potentially lethal damage into lethal damage, inhibiting the double-strand break repair or reducing the G(2) phase of the cell cycle. Copyright 2002 John Wiley & Sons, Ltd.

Body burdens of heavy metals in Lake Michigan wetland turtles.

PubMed

Smith, Dayna L; Cooper, Matthew J; Kosiara, Jessica M; Lamberti, Gary A

2016-02-01

Tissue heavy metal concentrations in painted (Chrysemys picta) and snapping (Chelydra serpentina) turtles from Lake Michigan coastal wetlands were analyzed to determine (1) whether turtles accumulated heavy metals, (2) if tissue metal concentrations were related to environmental metal concentrations, and (3) the potential for non-lethal sampling techniques to be used for monitoring heavy metal body burdens in freshwater turtles. Muscle, liver, shell, and claw samples were collected from painted and snapping turtles and analyzed for cadmium, chromium, copper, iron, lead, magnesium, manganese, and zinc. Turtle tissues had measurable quantities of all eight metals analyzed. Statistically significant correlations between tissue metal concentrations and sediment metal concentrations were found for a subset of metals. Metals were generally found in higher concentrations in the larger snapping turtles than in painted turtles. In addition, non-lethal samples of shell and claw were found to be possible alternatives to lethal liver and muscle samples for some metals. Human consumption of snapping turtles presents potential health risks if turtles are harvested from contaminated areas. Overall, our results suggest that turtles could be a valuable component of contaminant monitoring programs for wetland ecosystems.

Antivenom potential of ethanolic extract of Cordia macleodii bark against Naja venom.

PubMed

Soni, Pranay; Bodakhe, Surendra H

2014-05-01

To evaluate the antivenom potential of ethanolic extract of bark of Cordia macleodii against Naja venom induced pharmacological effects such as lethality, hemorrhagic lesion, necrotizing lesion, edema, cardiotoxicity and neurotoxicity. Wistar strain rats were challenged with Naja venom and treated with the ethanolic extract of Cordia macleodii bark. The effectiveness of the extract to neutralize the lethalities of Naja venom was investigated as recommended by WHO. At the dose of 400 and 800 mg/kg ethanolic extract of Cordia macleodii bark significantly inhibited the Naja venom induced lethality, hemorrhagic lesion, necrotizing lesion and edema in rats. Ethanolic extract of Cordia macleodii bark was effective in neutralizing the coagulant and defibrinogenating activity of Naja venom. The cardiotoxic effects in isolated frog heart and neurotoxic activity studies on frog rectus abdominus muscle were also antagonized by ethanolic extract of Cordia macleodii bark. It is concluded that the protective effect of extract of Cordia macleodii against Naja venom poisoning may be mediated by the cardiotonic, proteolysin neutralization, anti-inflammatory, antiserotonic and antihistaminic activity. It is possible that the protective effect may also be due to precipitation of active venom constituents.

50th Annual Fuze Conference Session 5

DTIC Science & Technology

2006-05-11

level •Underwater Shock NDIA Fuze Conf 2006 5 Warhead Lethality MOFN has two potential warheads EX 183 HE-MOFN •MK 64 PROJECTILE BODY • PBXN - 106 ...EXPLOSIVE FILL EX 184 HE-MOFN •HIFRAG PROJECTILE BODY • PBXN - 106 EXPLOSIVE FILL Warhead lethality effect is fragmentation NDIA Fuze Conf 2006 6 Warhead...NDIA Fuze Conf 2006 19 Min Engagement Hazard • Worst Case Operational Configuration: – Projectile = EX 184 HE-MOFN • MK 64 Projectile w PBXN - 106 fill

Lethal and sub-lethal effects of cyproconazole on freshwater organisms: a case study with Chironomus riparius and Dugesia tigrina.

PubMed

Saraiva, Althiéris S; Sarmento, Renato A; Golovko, Oksana; Randak, Tomas; Pestana, João L T; Soares, Amadeu M V M

2018-04-01

The fungicide cyproconazole (CPZ) inhibits the biosynthesis of ergosterol, an essential sterol component in fungal cell membrane and can also affect non-target organisms by its inhibitory effects on P450 monooxygenases. The predicted environmental concentration of CPZ is up to 49.05 μg/L and 145.89 μg/kg in surface waters and sediments, respectively, and information about CPZ toxicity towards non-target aquatic organisms is still limited. This study aimed to address the lack of ecotoxicological data for CPZ, and thus, an evaluation of the lethal and sub-lethal effects of CPZ was performed using two freshwater invertebrates (the midge Chironomus riparius and the planarian Dugesia tigrina). The estimated CPZ 48 h LC 50 (95% CI) was 17.46 mg/L for C. riparius and 47.38 mg/L for D. tigrina. The emergence time (EmT 50 ) of C. riparius was delayed by CPZ exposure from 0.76 mg/L. On the other hand, planarians showed higher tolerance to CPZ exposure. Sub-lethal effects of CPZ on planarians included reductions in locomotion (1.8 mg/L), delayed photoreceptors regeneration (from 0.45 mg/L), and feeding inhibition (5.6 mg/L). Our results confirm the moderate toxicity of CPZ towards aquatic invertebrates but sub-lethal effects observed also suggest potential chronic effects of CPZ with consequences for population dynamics.

Toxicity of sediments from a mangrove forest patch in an urban area in Pernambuco (Brazil).

PubMed

Oliveira, D D; Souza-Santos, L P; Silva, H K P; Macedo, S J

2014-06-01

Industrial and urban residues are discharged every day to the rivers and may arrive at the mangrove forest and prejudice the quality of the environment and the organisms present there. The mangrove forest patch studied is encircled by an urban area of the city of Recife (Brazil) that has approximate 1.5 million inhabitants and is one of the most industrialized centers in Northeast Brazil. The aim of this study was to assess the quality of the sediments of this mangrove patch in terms of metal contamination and ecotoxicology. Samples of surface sediment were collected in six stations for toxicological tests and trace metal determination (Cr, Zn, Mn, Fe, Cu, Pb, Co and Ni), in July and August, 2006 (rainy season); and in January and February 2007 (dry season). Toxicity tests with solid-phase sediments were carried out with the copepod Tisbe biminiensis in order to observe lethal and sub-lethal endpoints and correlate them with chemical data. In June, there were no observed lethal effect, but two stations presented sub-lethal effects. In January, lethal effect occurred in three stations and sub-lethal in one station. The levels for Zn and Cr were at higher levels than international proposed guidelines (NOAA). There was a negative significant correlation between the copepods׳ fecundity, and Zn and Cr concentrations. Therefore, the studied sediments can be considered to have potential toxic to benthos due to the high content of Zn and Cr. Copyright © 2014 Elsevier Inc. All rights reserved.

Effects of a long-acting mutant bacterial cocaine esterase on acute cocaine toxicity in rats

PubMed Central

Collins, Gregory T.; Zaks, Matthew E.; Cunningham, Alyssa R.; St. Clair, Carley; Nichols, Joseph; Narasimhan, Diwahar; Ko, Mei-Chuan; Sunahara, Roger K.; Woods, James H.

2011-01-01

Background A longer acting, double mutant bacterial cocaine esterase (CocE T172R/G173Q; DM CocE) has been shown to protect mice from cocaine-induced lethality, inhibit the reinforcing effects of cocaine in rats, and reverse cocaine’s cardiovascular effects in rhesus monkeys. The current studies evaluated the effectiveness of DM CocE to protect against, and reverse cocaine’s cardiovascular, convulsant, and lethal effects in male and female rats. Methods Pretreatment studies were used to determine the effectiveness and in vivo duration of action for DM CocE to protect rats against the occurrence of cardiovascular changes, convulsion and lethality associated with acute cocaine toxicity. Posttreatment studies were used to evaluate the capacity of DM CocE to rescue rats from the cardiovascular and lethal effects of large doses of cocaine. In addition, male and female rats were studied to determine if there were any potential effects of sex on the capacity of DM CocE to protect against, or reverse acute cocaine toxicity in rats. Results Pretreatment with DM CocE dose-dependently protected rats against cocaine-induced cardiovascular changes, convulsion and lethality, with higher doses active for up to 4 hrs, and shifting cocaine-induced lethality at least 10-fold to the right. In addition to dose-dependently recovering rats from an otherwise lethal dose of cocaine, post-treatment with DM CocE also reversed the cardiovascular effects of cocaine. There were no sex-related differences in the effectiveness of DM CocE to protect against, or reverse acute cocaine toxicity. Conclusions Together, these results support the development of DM CocE for the treatment of acute cocaine toxicity. PMID:21481548

Inactivation of CDK2 is synthetically lethal to MYCN over-expressing cancer cells

PubMed Central

Molenaar, Jan J.; Ebus, Marli E.; Geerts, Dirk; Koster, Jan; Lamers, Fieke; Valentijn, Linda J.; Westerhout, Ellen M.; Versteeg, Rogier; Caron, Huib N.

2009-01-01

Two genes have a synthetically lethal relationship when the silencing or inhibiting of 1 gene is only lethal in the context of a mutation or activation of the second gene. This situation offers an attractive therapeutic strategy, as inhibition of such a gene will only trigger cell death in tumor cells with an activated second oncogene but spare normal cells without activation of the second oncogene. Here we present evidence that CDK2 is synthetically lethal to neuroblastoma cells with MYCN amplification and over-expression. Neuroblastomas are childhood tumors with an often lethal outcome. Twenty percent of the tumors have MYCN amplification, and these tumors are ultimately refractory to any therapy. Targeted silencing of CDK2 by 3 RNA interference techniques induced apoptosis in MYCN-amplified neuroblastoma cell lines, but not in MYCN single copy cells. Silencing of MYCN abrogated this apoptotic response in MYCN-amplified cells. Inversely, silencing of CDK2 in MYCN single copy cells did not trigger apoptosis, unless a MYCN transgene was activated. The MYCN induced apoptosis after CDK2 silencing was accompanied by nuclear stabilization of P53, and mRNA profiling showed up-regulation of P53 target genes. Silencing of P53 rescued the cells from MYCN-driven apoptosis. The synthetic lethality of CDK2 silencing in MYCN activated neuroblastoma cells can also be triggered by inhibition of CDK2 with a small molecule drug. Treatment of neuroblastoma cells with roscovitine, a CDK inhibitor, at clinically achievable concentrations induced MYCN-dependent apoptosis. The synthetically lethal relationship between CDK2 and MYCN indicates CDK2 inhibitors as potential MYCN-selective cancer therapeutics. PMID:19525400

Asthma and risk of lethal prostate cancer in the Health Professionals Follow-Up Study.

PubMed

Platz, Elizabeth A; Drake, Charles G; Wilson, Kathryn M; Sutcliffe, Siobhan; Kenfield, Stacey A; Mucci, Lorelei A; Stampfer, Meir J; Willett, Walter C; Camargo, Carlos A; Giovannucci, Edward

2015-08-15

Inflammation, and more generally, the immune response are thought to influence the development of prostate cancer. To determine the components of the immune response that are potentially contributory, we prospectively evaluated the association of immune-mediated conditions, asthma and hayfever, with lethal prostate cancer risk in the Health Professionals Follow-up Study. We included 47,880 men aged 40-75 years with no prior cancer diagnosis. On the baseline questionnaire in 1986, the men reported diagnoses of asthma and hayfever and year of onset. On the follow-up questionnaires, they reported new asthma and prostate cancer diagnoses. We used Cox proportional hazards regression to estimate relative risks (RRs). In total, 9.2% reported ever having been diagnosed with asthma. In all, 25.3% reported a hayfever diagnosis at baseline. During 995,176 person-years of follow-up by 2012, we confirmed 798 lethal prostate cancer cases (diagnosed with distant metastases, progressed to distant metastasis or died of prostate cancer [N = 625]). Ever having a diagnosis of asthma was inversely associated with risk of lethal (RR = 0.71, 95% confidence interval [CI] = 0.51-1.00) and fatal (RR = 0.64, 95% CI = 0.42-0.96) disease. Hayfever with onset in the distant past was possibly weakly positively associated with risk of lethal (RR = 1.10, 95% CI = 0.92-1.33) and fatal (RR = 1.12, 95% CI = 0.91-1.37) disease. Men who were ever diagnosed with asthma were less likely to develop lethal and fatal prostate cancer. Our findings may lead to testable hypotheses about specific immune profiles in the etiology of lethal prostate cancer. © 2015 UICC.

Altered cytoskeletal organization characterized lethal but not surviving Brtl+/− mice: insight on phenotypic variability in osteogenesis imperfecta

PubMed Central

Bianchi, Laura; Gagliardi, Assunta; Maruelli, Silvia; Besio, Roberta; Landi, Claudia; Gioia, Roberta; Kozloff, Kenneth M.; Khoury, Basma M.; Coucke, Paul J.; Symoens, Sofie; Marini, Joan C.; Rossi, Antonio; Bini, Luca; Forlino, Antonella

2015-01-01

Osteogenesis imperfecta (OI) is a heritable bone disease with dominant and recessive transmission. It is characterized by a wide spectrum of clinical outcomes ranging from very mild to lethal in the perinatal period. The intra- and inter-familiar OI phenotypic variability in the presence of an identical molecular defect is still puzzling to the research field. We used the OI murine model Brtl+/− to investigate the molecular basis of OI phenotypic variability. Brtl+/− resembles classical dominant OI and shows either a moderately severe or a lethal outcome associated with the same Gly349Cys substitution in the α1 chain of type I collagen. A systems biology approach was used. We took advantage of proteomic pathway analysis to functionally link proteins differentially expressed in bone and skin of Brtl+/− mice with different outcomes to define possible phenotype modulators. The skin/bone and bone/skin hybrid networks highlighted three focal proteins: vimentin, stathmin and cofilin-1, belonging to or involved in cytoskeletal organization. Abnormal cytoskeleton was indeed demonstrated by immunohistochemistry to occur only in tissues from Brtl+/− lethal mice. The aberrant cytoskeleton affected osteoblast proliferation, collagen deposition, integrin and TGF-β signaling with impairment of bone structural properties. Finally, aberrant cytoskeletal assembly was detected in fibroblasts obtained from lethal, but not from non-lethal, OI patients carrying an identical glycine substitution. Our data demonstrated that compromised cytoskeletal assembly impaired both cell signaling and cellular trafficking in mutant lethal mice, altering bone properties. These results point to the cytoskeleton as a phenotypic modulator and potential novel target for OI treatment. PMID:26264579

Lethal Injection for Execution: Chemical Asphyxiation?

PubMed Central

Zimmers, Teresa A; Sheldon, Jonathan; Lubarsky, David A; López-Muñoz, Francisco; Waterman, Linda; Weisman, Richard; Koniaris, Leonidas G

2007-01-01

Background Lethal injection for execution was conceived as a comparatively humane alternative to electrocution or cyanide gas. The current protocols are based on one improvised by a medical examiner and an anesthesiologist in Oklahoma and are practiced on an ad hoc basis at the discretion of prison personnel. Each drug used, the ultrashort-acting barbiturate thiopental, the neuromuscular blocker pancuronium bromide, and the electrolyte potassium chloride, was expected to be lethal alone, while the combination was intended to produce anesthesia then death due to respiratory and cardiac arrest. We sought to determine whether the current drug regimen results in death in the manner intended. Methods and Findings We analyzed data from two US states that release information on executions, North Carolina and California, as well as the published clinical, laboratory, and veterinary animal experience. Execution outcomes from North Carolina and California together with interspecies dosage scaling of thiopental effects suggest that in the current practice of lethal injection, thiopental might not be fatal and might be insufficient to induce surgical anesthesia for the duration of the execution. Furthermore, evidence from North Carolina, California, and Virginia indicates that potassium chloride in lethal injection does not reliably induce cardiac arrest. Conclusions We were able to analyze only a limited number of executions. However, our findings suggest that current lethal injection protocols may not reliably effect death through the mechanisms intended, indicating a failure of design and implementation. If thiopental and potassium chloride fail to cause anesthesia and cardiac arrest, potentially aware inmates could die through pancuronium-induced asphyxiation. Thus the conventional view of lethal injection leading to an invariably peaceful and painless death is questionable. PMID:17455994

Severe angioedema in myxedema coma: a difficult airway in a rare endocrine emergency.

PubMed

Lee, Christopher H; Wira, Charles R

2009-10-01

Myxedema coma is the most lethal manifestation of hypothyroidism. It is a true medical emergency and can result in profound hemodynamic instability and airway compromise. Myxedema coma currently remains a diagnostic challenge due to the rarity of cases seen today, and failure to promptly initiate therapy with replacement thyroid hormone can be fatal. As thyroid hormone therapy can take days or weeks to reverse the manifestations of myxedema coma, interim supportive therapy is critical while awaiting clinical improvement. Some patients will require endotracheal intubation in the emergency department (ED), and physicians should be aware that unanticipated posterior pharyngeal edema in myxedema coma could severely complicate airway management. Although mechanical ventilation is a well-described adjunctive therapy for myxedema coma, reports of the potential difficulty in securing a definitive airway in these patients are rare. We describe a case of an unidentified woman who presented to the ED with myxedema coma requiring urgent endotracheal intubation and was found to have extensive posterior pharyngeal angioedema inconsistent with her relatively benign external examination. This case highlights the typical features of myxedema coma and discusses our necessity for a rescue device in definitive endotracheal tube placement. Emergency physicians should anticipate a potentially difficult airway in all myxedema coma patients regardless of the degree of external facial edema present.

Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association.

PubMed

Baddour, Larry M; Wilson, Walter R; Bayer, Arnold S; Fowler, Vance G; Tleyjeh, Imad M; Rybak, Michael J; Barsic, Bruno; Lockhart, Peter B; Gewitz, Michael H; Levison, Matthew E; Bolger, Ann F; Steckelberg, James M; Baltimore, Robert S; Fink, Anne M; O'Gara, Patrick; Taubert, Kathryn A

2015-10-13

Infective endocarditis is a potentially lethal disease that has undergone major changes in both host and pathogen. The epidemiology of infective endocarditis has become more complex with today's myriad healthcare-associated factors that predispose to infection. Moreover, changes in pathogen prevalence, in particular a more common staphylococcal origin, have affected outcomes, which have not improved despite medical and surgical advances. This statement updates the 2005 iteration, both of which were developed by the American Heart Association under the auspices of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease of the Young. It includes an evidence-based system for diagnostic and treatment recommendations used by the American College of Cardiology and the American Heart Association for treatment recommendations. Infective endocarditis is a complex disease, and patients with this disease generally require management by a team of physicians and allied health providers with a variety of areas of expertise. The recommendations provided in this document are intended to assist in the management of this uncommon but potentially deadly infection. The clinical variability and complexity in infective endocarditis, however, dictate that these recommendations be used to support and not supplant decisions in individual patient management. © 2015 American Heart Association, Inc.

Preparation, pharmacokinetics and tumour-suppressive activity of berberine liposomes.

PubMed

Wang, Xinghui; Wang, Qiong; Liu, Zhihui; Zheng, Xiao

2017-06-01

Berberine (BBR) has shown promising antitumour effects in vitro. However, intravenous administration of BBR solution is complicated by lethal adverse cardiovascular effects. The aim of this study was to prepare common and polyethylene glycol (PEG)-modified long-circulating BBR liposomes and evaluate their efficacy and safety as potential antitumour agents. Physiochemical properties of common and long-circulating BBR liposomes were characterized including particle size, Zeta potential and thermal stability. Pharmacokinetic and tissue distribution study of liposomal BBR was performed in rats and tumour-bearing nude mice, respectively. Antitumour efficacy and safety were observed in SGC-7901 tumour-xenografted mice. Berberine liposomes showed homogenous morphology, storage stability and sustained-releasing behaviour in vitro. BBR liposomes led to significantly increased circulation retention of BBR in comparison with BBR solution. In tumour-bearing mice, BBR liposomes selectively increased BBR concentrations in the liver, spleen, lung and tumour, while conferred lower distribution to the heart and kidney. Importantly, chronic administration of BBR liposomes proved effective and safe in suppressing the tumour growth in nude mice, especially the PEG-modified long-circulating liposomes. Our study suggested that BBR liposomes may provide a safe form of intravenous drug therapy for strengthening the antitumour effects of BBR. © 2017 Royal Pharmaceutical Society.

The New World Health Organization Recommendations on Perioperative Administration of Oxygen to Prevent Surgical Site Infections: A Dangerous Reductionist Approach?

PubMed

Wenk, Manuel; Van Aken, Hugo; Zarbock, Alexander

2017-08-01

In October 2016, the World Health Organization (WHO) published recommendations for preventing surgical site infections (SSIs). Among those measures is a recommendation to administer oxygen at an inspired fraction of 80% intra- and postoperatively for up to 6 hours. SSIs have been identified as a global health problem, and the WHO should be commended for their efforts. However, this recommendation focuses only on the patient's "wound," ignores other organ systems potentially affected by hyperoxia, and may ultimately worsen patient outcomes.The WHO advances a "strong recommendation" for the use of a high inspired oxygen fraction even though the quality of evidence is only moderate. However, achieving this goal by disregarding other potentially lethal complications seems inappropriate, particularly in light of the weak evidence underpinning the use of high fractions of oxygen to prevent SSI. Use of such a strategy thus should be intensely discussed by anesthesiologists and perioperative physicians.Normovolemia, normotension, normoglycemia, normothermia, and normoventilation can clearly be safely applied to most patients in most clinical scenarios. But the liberal application of hyperoxemia intraoperatively and up to 6 hours postoperatively, as suggested by the WHO, is questionable from the viewpoint of anesthesia and perioperative medicine, and its effects will be discussed in this article.

Early experience with activated recombinant factor VII for intractable hemorrhage after cardiovascular surgery.

PubMed

Halkos, Michael E; Levy, Jerrold H; Chen, Edward; Reddy, V Seenu; Lattouf, Omar M; Guyton, Robert A; Song, Howard K

2005-04-01

Intractable hemorrhage after complex cardiovascular operations is a serious and potentially lethal complication. We report our experience with the use of activated recombinant factor VIIa (rFVIIa) as rescue therapy for patients with refractory postoperative hemorrhage. From April 2002 through December 2003, 9 patients received rFVIIa for intractable hemorrhage after cardiovascular surgery. Patients underwent aortic surgery (2), coronary artery bypass graft surgery (4), double valve operations (2), and mitral valve replacement (1). Four of these procedures were reoperations. Intraoperative aprotinin was used in all patients. All patients underwent standard heparinization (300 IU/kg) before cardiopulmonary bypass and reversal with protamine. Five patients underwent reexploration for mediastinal hemorrhage before treatment; 2 were reexplored twice. The average transfusion requirement before rFVIIa administration was 9 U of blood, 7 U of plasma, 22 U of platelets, and 19 U of cryoprecipitate. rFVIIa was administered as an intravenous bolus at 68 to 120 mug/kg. Mean time of administration from the first operation was 10.9 +/- 7.2 hours. At the time of activated rFVIIa administration, chest tube drainage averaged 640 mL/h. In all patients, chest tube drainage was dramatically reduced to less than 100 mL/h within 5 hours after drug delivery. None of the patients required reexploration after treatment. There were no postoperative neurologic or cardiovascular complications. When used as rescue therapy for intractable hemorrhage after cardiovascular surgery, rFVIIa may be effective in promoting hemostasis, preventing reexploration, and reducing transfusion requirements.

A new approach for Roux-en-Y reconstruction after pancreaticoduodenectomy.

PubMed

Xu, Meng; Wang, Min; Zhu, Feng; Tian, Rui; Shi, Cheng-Jian; Wang, Xin; Shen, Ming; Qin, Ren-Yi

2014-12-01

Postoperative pancreatic fistula remains the most common complication of pancreaticoduodenectomy (PD) and is potentially lethal. It contributes significantly to prolonged hospitalization and mortality. In this study, we introduced a new technical approach, a modified Roux-en-Y reconstruction and evaluated its safety and feasibility. We retrospectively reviewed the patients who had undergone PD with the modified Roux-en-Y reconstructive technique for periampullary malignancies from January 2011 to June 2012. The data on complications, hospital stay and outcomes after the modified Roux-en-Y reconstruction were analyzed. The reconstruction was performed in 171 patients, of whom 92 received pancreaticogastrostomy and 79 received pancreaticojejunostomy. The median duration of surgery was 4.0 hours (range 3.1-6.9) in all patients, and the median blood loss was 530 mL (range 200-2000). Sixty-nine patients were subjected to transfusions, with a median transfusion volume of 430 mL (range 200-1400). The median hospital stay of the patients was 14 days (range 11-38). Their operative mortality was zero and overall morbidity was 18.1% (31 patients). Only four patients (2.3%) developed pancreatic fistulas (grade A fistulas in two patients and grade B in two patients); no patients developed grade C fistula. None of the patients developed bile reflux gastritis. The modified Roux-en-Y reconstruction, which isolates biliary anastomosis from pancreatic, gastric or jejunal anastomosis, is a safe, reliable, and favorable technique. But it needs further investigation in randomized controlled trials.

[Gunshot wounds caused by non-lethal ammunition on the porcine model post-mortem].

PubMed

Jabrocký, Peter; Pivko, Juraj; Vondráková, Mária; Tažký, Boris

2013-10-01

In this article we focus on the effects of so called non-lethal ammunition. We studied possible mechanism of firearm injury formation as a consequence of using firearm on the body, to present a more comprehensive material in wound ballistics. We pointed out possible actions of a projectile causes on human, respectively other animal organisms, as well as to a manner in which an injury is caused by rifles or shotguns using non-lethal ammunition with rubber projectiles. In the experiment, we have focused on macroscopic analysis of the tissue penetrated by a rubber projectile fired from a long firearm and pump-action shotgun while focusing on the anatomical-morphological analysis of entry wounds to determine the effectiveness respectively, the wounding potential of the projectile. The results of the experiment based on the macroscopic analysis of entry wounds, cavities and exit wounds, show that when a rubber projectile penetrates the body it causes loss of the tissue (i.e. the minus effect) and mechanical disruption of the tissue similar to lethal projectile. Based on the measures and ballistic computations we concluded that in specific cases, like for example in a close range hit, a penetration of vital organs can cause serious or even lethal injuries.

Genetic loci with parent-of-origin effects cause hybrid seed lethality in crosses between Mimulus species.

PubMed

Garner, Austin G; Kenney, Amanda M; Fishman, Lila; Sweigart, Andrea L

2016-07-01

In flowering plants, F1 hybrid seed lethality is a common outcome of crosses between closely related diploid species, but the genetic basis of this early-acting and potentially widespread form of postzygotic reproductive isolation is largely unknown. We intercrossed two closely related species of monkeyflower, Mimulus guttatus and Mimulus tilingii, to characterize the mechanisms and strength of postzygotic reproductive isolation. Then, using a reciprocal backcross design, we performed high-resolution genetic mapping to determine the genetic architecture of hybrid seed lethality and directly test for loci with parent-of-origin effects. We found that F1 hybrid seed lethality is an exceptionally strong isolating barrier between Mimulus species, with reciprocal crosses producing < 1% viable seeds. This form of postzygotic reproductive isolation appears to be highly polygenic, indicating that multiple incompatibility loci have accumulated rapidly between these closely related Mimulus species. It is also primarily caused by genetic loci with parent-of-origin effects, suggesting a possible role for imprinted genes in the evolution of Mimulus hybrid seed lethality. Our findings suggest that divergence in loci with parent-of-origin effects, which is probably driven by genomic coevolution within lineages, might be an important source of hybrid incompatibilities between flowering plant species. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

Sublethal Effects of Insecticide Exposure on Megacopta cribraria (Fabricius) Nymphs: Key Biological Traits and Acetylcholinesterase Activity.

PubMed

Miao, Jin; Reisig, Dominic D; Li, Guoping; Wu, Yuqing

2016-01-01

Megacopta cribraria F. (Hemiptera: Plataspidae), the kudzu bug, is an invasive insect pest of U.S. soybean. At present, insecticide application is the primary and most effective control option for M. cribraria In this study, the potential effects of sublethal and low-lethal concentrations (LC10 and LC40) of three common insecticides on key biological traits and acetylcholinesterase (AChE) activity of the treated nymphal stage of insect were assessed. The results show that the sublethal concentration of imidacloprid significantly reduced adult emergence rate of M. cribraria A low-lethal concentration of imidacloprid significantly increased nymphal development time, but significantly decreased adult emergence rate and adult longevity. Both sublethal and low-lethal concentrations of acephate caused an increase in nymphal development time and a reduction in adult emergence rate and adult longevity. Fecundity of females was significantly reduced only by exposure to low-lethal concentrations of acephate. Sublethal and low-lethal concentrations of bifenthrin increased nymphal development time, but significantly decreased adult emergence rate. In addition, we found that the AChE activity of M. cribraria was significantly increased only by LC40 imidacloprid, but strongly inhibited by acephate. © The Author 2016. Published by Oxford University Press on behalf of the Entomological Society of America.

Overexpression of Cx43 in cells of the myocardial scar: Correction of post-infarct arrhythmias through heterotypic cell-cell coupling.

PubMed

Roell, Wilhelm; Klein, Alexandra M; Breitbach, Martin; Becker, Torsten S; Parikh, Ashish; Lee, Jane; Zimmermann, Katrin; Reining, Shaun; Gabris, Beth; Ottersbach, Annika; Doran, Robert; Engelbrecht, Britta; Schiffer, Miriam; Kimura, Kenichi; Freitag, Patricia; Carls, Esther; Geisen, Caroline; Duerr, Georg D; Sasse, Philipp; Welz, Armin; Pfeifer, Alexander; Salama, Guy; Kotlikoff, Michael; Fleischmann, Bernd K

2018-05-08

Ventricular tachycardia (VT) is the most common and potentially lethal complication following myocardial infarction (MI). Biological correction of the conduction inhomogeneity that underlies re-entry could be a major advance in infarction therapy. As minimal increases in conduction of infarcted tissue markedly influence VT susceptibility, we reasoned that enhanced propagation of the electrical signal between non-excitable cells within a resolving infarct might comprise a simple means to decrease post-infarction arrhythmia risk. We therefore tested lentivirus-mediated delivery of the gap-junction protein Connexin 43 (Cx43) into acute myocardial lesions. Cx43 was expressed in (myo)fibroblasts and CD45 + cells within the scar and provided prominent and long lasting arrhythmia protection in vivo. Optical mapping of Cx43 injected hearts revealed enhanced conduction velocity within the scar, indicating Cx43-mediated electrical coupling between myocytes and (myo)fibroblasts. Thus, Cx43 gene therapy, by direct in vivo transduction of non-cardiomyocytes, comprises a simple and clinically applicable biological therapy that markedly reduces post-infarction VT.

Electrical injury from subway third rails: serious injury associated with intermediate voltage contact.

PubMed

Rabban, J; Adler, J; Rosen, C; Blair, J; Sheridan, R

1997-09-01

Railway and subway-associated electrical trauma is rare and typically involves high voltage (> 20,000) arc injuries. Not all rail systems utilize such high voltage. We report 16 cases of electrical trauma due to 600 V direct contact with subway 'third' rails. A case series of injured patients presenting to Shriners Burns Institute, Boston or Massachusetts General Hospital between 1970 and 1995 was retrospectively analyzed. A total of 16 cases was identified. Among seven subway workers, the mechanism of rail contact was unintentional by a tool, a hand or by falling; no deaths occurred. Among nine non-occupational victims, injuries involved suicide attempts, unintentional falls, or risk-taking behavior. This group suffered greater burn severity, operative procedures, and complications; three deaths occurred. This is the largest report series of direct electrical trauma from a subway third rail. The high morbidity and mortality from this 600 V contact suggests that the traditional classification of low voltage (< 1000 V) exposure can be subdivided to reflect the serious and lethal potential of intermediate range exposures compared to household range exposures (0-220 V).

Midtrimester preterm prelabour rupture of membranes (PPROM): expectant management or amnioinfusion for improving perinatal outcomes (PPROMEXIL - III trial).

PubMed

van Teeffelen, Augustinus S P; van der Ham, David P; Willekes, Christine; Al Nasiry, Salwan; Nijhuis, Jan G; van Kuijk, Sander; Schuyt, Ewoud; Mulder, Twan L M; Franssen, Maureen T M; Oepkes, Dick; Jansen, Fenna A R; Woiski, Mallory D; Bekker, Mireille N; Bax, Caroline J; Porath, Martina M; de Laat, Monique W M; Mol, Ben W; Pajkrt, Eva

2014-04-04

Babies born after midtrimester preterm prelabour rupture of membranes (PPROM) are at risk to develop neonatal pulmonary hypoplasia. Perinatal mortality and morbidity after this complication is high. Oligohydramnios in the midtrimester following PPROM is considered to cause a delay in lung development. Repeated transabdominal amnioinfusion with the objective to alleviate oligohydramnios might prevent this complication and might improve neonatal outcome. Women with PPROM and persisting oligohydramnios between 16 and 24 weeks gestational age will be asked to participate in a multi-centre randomised controlled trial. random allocation to (repeated) abdominal amnioinfusion (intervention) or expectant management (control). The primary outcome is perinatal mortality. Secondary outcomes are lethal pulmonary hypoplasia, non-lethal pulmonary hypoplasia, survival till discharge from NICU, neonatal mortality, chronic lung disease (CLD), number of days ventilatory support, necrotizing enterocolitis (NEC), periventricular leucomalacia (PVL) more than grade I, severe intraventricular hemorrhage (IVH) more than grade II, proven neonatal sepsis, gestational age at delivery, time to delivery, indication for delivery, successful amnioinfusion, placental abruption, cord prolapse, chorioamnionitis, fetal trauma due to puncture. The study will be evaluated according to intention to treat. To show a decrease in perinatal mortality from 70% to 35%, we need to randomise two groups of 28 women (two sided test, β-error 0.2 and α-error 0.05). This study will answer the question if (repeated) abdominal amnioinfusion after midtrimester PPROM with associated oligohydramnios improves perinatal survival and prevents pulmonary hypoplasia and other neonatal morbidities. Moreover, it will assess the risks associated with this procedure. NTR3492 Dutch Trial Register (http://www.trialregister.nl).

[Bacterial toxic shock as a complication of calculous pyelonephritis].

PubMed

Lopatkin, N A; Rumiantsev, V B; Ianenko, E K

1994-01-01

The causes of bacteriotoxic shock were examined in 33 patients (11 lethal outcomes). It has arisen as a complication of treatment given to 7830 patients for urolithiasis. Aggravation of chronic pyelonephritis, occlusion of the urinary tracts, urogenital mucosal and parenchymal injuries, low resistance to infection contribute to microbacteria and their toxins entering blood with resultant bacteriotoxic shock. Transcutaneous operative interventions, therapeutic and diagnostic procedures also produce high risk of blood infection with gram-negative microflora, especially in violation of asepsis and antisepsis rules. As shown by microflora tests, the dominating bacteria consisted of opportunistic agents which had acquired the resistance to antibacterial drugs. In view of rapid progression of bacteriotoxic shock therapeutic efforts should be concentrated on fast normalization of hemodynamics, recovery of urine passage, introduction of sorption detoxication, prevention of DIC syndrome. The schemes of combined antibiotic treatment adjusted to the kind of infectious agent are suggested.

Clinical features and management of primary sclerosing cholangitis

PubMed Central

Silveira, Marina G; Lindor, Keith D

2008-01-01

Primary sclerosing cholangitis is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts, resulting in cirrhosis and need for liver transplantation and reduced life expectancy. The majority of cases occur in young and middle-aged men, often in association with inflammatory bowel disease. The etiology of primary sclerosing cholangitis includes immune-mediated components and elements of undefined nature. No effective medical therapy has been identified. The multiple complications of primary sclerosing cholangitis include metabolic bone disease, dominant strictures, bacterial cholangitis, and malignancy, particularly cholangiocarcinoma, which is the most lethal complication of primary sclerosing cholangitis. Liver transplantation is currently the only life-extending therapeutic alternative for patients with end-stage disease, although recurrence in the allografted liver has been described. A PSC-like variant attracting attention is cholangitis marked by raised levels of the immunoglobulin G4 subclass, prominence of plasma cells within the lesions, and steroid responsiveness. PMID:18528931

[Rupture of splenic artery pseudoaneurysm: an unusual cause of upper gastrointetinal bleeding].

PubMed

Herrera-Fernández, Francisco Antonio; Palomeque-Jiménez, Antonio; Serrano-Puche, Félix; Calzado-Baeza, Salvador Francisco; Reyes-Moreno, Montserrat

2014-01-01

Bleeding from a pancreatic pseudocyst is a severe complication after pancreatitis that can lead to a massive gastrointestinal blood loss. Pseudocyst rupture into the stomach is an unusual complication. We report the case of a 34-year-old woman with a history of alcoholism and a pancreatic pseudocyst. One year after follow-up of her pseudocyst, she arrived at the emergency room with an episode of upper gastrointestinal bleeding. An upper digestive endoscopy showed active bleeding in the subcardial fundus, which could not be endoscopically controlled. Abdominal angio-CT confirmed the diagnosis of a splenic artery pseudoaneurysm in close contact with the back wall of the stomach, as well as a likely fistulization of it. The patient was urgently operated and a distal splenopancreatectomy and fistulorrhaphy was performed. The rupture of a splenic artery pseudoaneurysm may rarely present as upper gastrointestinal bleeding. This may be lethal if not urgently treated.

Weapons used in serious violence against a parent: retrospective comparative register study.

PubMed

Liettu, Anu; Säävälä, Hannu; Hakko, Helinä; Joukamaa, Matti; Räsänen, Pirkko

2012-08-01

Our aim was to compare the weapons used in lethal or potentially lethal violence against parents according to the age (adolescent vs. adult) of the offender and victim (mother vs. father) of the offence. All forensic psychiatric examination statements of male offenders who had offended violently against one of their parents during 1973-2004 in Finland (n=192) were reviewed retrospectively. Data on the weapons used by adolescent and adult offenders in relation to the sex of the victim, mental disorder, criminal responsibility and intelligence were gathered. In the whole sample, sharp-edged weapons were the most commonly used weapons. Firearms were more commonly used in offences against fathers (i.e. patricidal offences) than against mothers (i.e. matricidal offences). Adolescent offenders were more likely to use firearms than adult offenders in violent acts against a parent. Among personality-disordered subjects, patricidal offenders used firearms more commonly than did matricidal offenders. Homicidal matricidal offenders had higher full-scale and verbal IQ scores as compared to homicidal patricidal offenders. The matricidal offenders using firearms were shown to be more intelligent as measured by full-scale and verbal scale IQs than the patricidal offenders using firearms. Consistent with the physical strength hypothesis, firearms are used more often in lethal or potentially lethal violence against parents by adolescents than by adults in Finland. As firearms legislation in Finland is currently under reform the study findings suggest that restriction of gun availability may have an influence on intrafamilial homicides, particularly those committed by adolescents.

Point of no return: experimental determination of the lethal hydraulic threshold during drought for loblolly pine (Pinus taeda)

NASA Astrophysics Data System (ADS)

Hammond, W.; Yu, K.; Wilson, L. A.; Will, R.; Anderegg, W.; Adams, H. D.

2017-12-01

The strength of the terrestrial carbon sink—dominated by forests—remains one of the greatest uncertainties in climate change modelling. How forests will respond to increased variability in temperature and precipitation is poorly understood, and experimental study to better inform global vegetation models in this area is needed. Necessary for achieving­­­­ this goal is an understanding of how increased temperatures and drought will affect landscape level distributions of plant species. Quantifying physiological thresholds representing a point of no return from drought stress, including thresholds in hydraulic function, is critical to this end. Recent theoretical, observational, and modelling research has converged upon a threshold of 60 percent loss of hydraulic conductivity at mortality (PLClethal). However, direct experimental determination of lethal points in conductivity and cavitation during drought is lacking. We quantified thresholds in hydraulic function in Loblolly pine, Pinus taeda, a commercially important timber species. In a greenhouse experiment, we exposed saplings (n = 96 total) to drought and rewatered treatment groups at variable levels of increasing water stress determined by pre-selected targets in pre-dawn water potential. Treatments also included a watered control with no drought, and drought with no rewatering. We measured physiological responses to water stress, including hydraulic conductivity, native PLC, water potential, foliar color, canopy die-back, and dark-adapted chlorophyll fluorescence. Following the rewatering treatment, we observed saplings for at least two months to determine which survived and which died. Using these data we calculated lethal physiological thresholds in water potential, directly measured PLC, and PLC inferred from water potential using a hydraulic vulnerability curve. We found that PLClethal inferred from water potential agreed with the 60% threshold suggested by previous research. However, directly measured PLC supported a much higher threshold. Beyond PLClethal, some trees survived by basal and epicormic re-sprouting, despite complete top-kill of existing foliage. Additional empirical study of multiple species to represent functional groups is needed to provide lethal thresholds for models presently in development.

Lethal mutagenesis: targeting the mutator phenotype in cancer.

PubMed

Fox, Edward J; Loeb, Lawrence A

2010-10-01

The evolution of cancer and RNA viruses share many similarities. Both exploit high levels of genotypic diversity to enable extensive phenotypic plasticity and thereby facilitate rapid adaptation. In order to accumulate large numbers of mutations, we have proposed that cancers express a mutator phenotype. Similar to cancer cells, many viral populations, by replicating their genomes with low fidelity, carry a substantial mutational load. As high levels of mutation are potentially deleterious, the viral mutation frequency is thresholded at a level below which viral populations equilibrate in a traditional mutation-selection balance, and above which the population is no longer viable, i.e., the population undergoes an error catastrophe. Because their mutation frequencies are fine-tuned just below this error threshold, viral populations are susceptible to further increases in mutational load and, recently this phenomenon has been exploited therapeutically by a concept that has been termed lethal mutagenesis. Here we review the application of lethal mutagenesis to the treatment of HIV and discuss how lethal mutagenesis may represent a novel therapeutic approach for the treatment of solid cancers. Copyright © 2010 Elsevier Ltd. All rights reserved.

Successful control of Epstein-Barr virus (EBV)-infected cells by allogeneic nonmyeloablative stem cell transplantation in a patient with the lethal form of chronic active EBV infection.

PubMed

Uehara, Taeko; Nakaseko, Chiaki; Hara, Satoru; Harima, Akane; Ejiri, Megumi; Yokota, Akira; Saito, Yasushi; Nishimura, Miki

2004-08-01

Chronic active Epstein-Barr virus infection (CAEBV) is a heterogeneous EBV-related disorder, ranging from mild/moderate forms to rapidly lethal disorders. The lethal form of CAEBV is characterized by multiple organ failure, hemophagocytic syndrome, and development of lymphomas. Allogeneic stem cell transplantation is considered as the only potentially curative treatment for the lethal form of CAEBV, but it is not always desirable because of the high incidence of regimen-related toxicities. A 17-year-old female with CAEBV, who was refractory to conventional therapies and considered to be unable to receive a myeloablative regimen because of multiple organ dysfunction, underwent allogeneic nonmyeloablative stem cell transplantation (allo-NST) before developing a hematological malignancy. She has been well without any signs of CAEBV for 27 months after allo-NST, and we confirmed that specific cytotoxic T lymphocyte activity against EBV was reconstituted. This outcome suggests that allo-NST can control CAEBV by reconstituting the host immunity against EBV. Copyright 2004 Wiley-Liss, Inc.

[Wounds and injuries to the colon].

PubMed

Sheianov, S D; Tsybuliak, G N

1997-01-01

On the basis of a retrospective analysis of results of treatment of 1097 patients with wounds and injuries of the colon of the peace and war time as well as of experiments in 160 dogs it has been established that the level of lethal outcomes and amount of complications are dependent on the size, number and localization of the colon wounds, severity of peritonitis by the moment of primary operation, degree of traumatic shock, blood loss volume, severity of the coexisting injuries and the chosen method of surgical treatment. A classification of the wounds according to the volume of injuries of the colon is proposed. Different variants of surgical treatment and outcomes are considered. Experiments in dogs have shown the indisputable effectiveness of precise one-row sero-musculo-submucous sutures with the present-day sutural material as compared with other methods of treatment of wounds of the colon. The peritoneal sorption with liquid colloid sorbents at the early postoperative period facilitate the prophylaxis and treatment of peritonitis, reduce lethality. A surgical classification of injuries of the colon is developed and types of operative interventions are recommended.

Baseline blood Pb levels of black-necked stilts on the upper Texas coast

USGS Publications Warehouse

Riecke, Thomas V.; Conway, Warren C.; Haukos, David A.; Moon, Jena A.; Comer, Christopher E.

2015-01-01

There are no known biological requirements for lead (Pb), and elevated Pb levels in birds can cause a variety of sub-lethal effects and mortality. Historic and current levels of Pb in mottled ducks (Anas fulvigula) suggest that environmental sources of Pb remain available on the upper Texas coast. Because of potential risks of Pb exposure among coexisting marsh birds, black-necked stilt (Himantopus mexicanus) blood Pb concentrations were measured during the breeding season. Almost 80 % (n = 120) of 152 sampled stilts exceeded the background threshold (>20 μg/dL) for Pb exposure. However, blood Pb concentrations did not vary by age or gender, and toxic or potentially lethal concentrations were rare (<5 %). Consistent, low-level blood Pb concentrations of black-necked stilts in this study suggest the presence of readily bioavailable sources of Pb, although potential impacts on local stilt populations remain unclear.

The staphylococcal enterotoxin (SE) family: SEB and siblings.

PubMed

Krakauer, Teresa; Stiles, Bradley G

2013-11-15

Staphylococcus aureus plays an important role in numerous human cases of food poisoning, soft tissue, and bone infections, as well as potentially lethal toxic shock. This common bacterium synthesizes various virulence factors that include staphylococcal enterotoxins (SEs). These protein toxins bind directly to major histocompatibility complex class II on antigen-presenting cells and specific Vβ regions of T-cell receptors, resulting in potentially life-threatening stimulation of the immune system. Picomolar concentrations of SEs ultimately elicit proinflammatory cytokines that can induce fever, hypotension, multi-organ failure, and lethal shock. Various in vitro and in vivo models have provided important tools for studying the biological effects of, as well as potential vaccines/therapeutics against, the SEs. This review succinctly presents known physical and biological properties of the SEs, including various intervention strategies. In particular, SEB will often be portrayed as per biodefense concerns dating back to the 1960s.

The staphylococcal enterotoxin (SE) family

PubMed Central

Krakauer, Teresa; Stiles, Bradley G

2013-01-01

Staphylococcus aureus plays an important role in numerous human cases of food poisoning, soft tissue, and bone infections, as well as potentially lethal toxic shock. This common bacterium synthesizes various virulence factors that include staphylococcal enterotoxins (SEs). These protein toxins bind directly to major histocompatibility complex class II on antigen-presenting cells and specific Vβ regions of T-cell receptors, resulting in potentially life-threatening stimulation of the immune system. Picomolar concentrations of SEs ultimately elicit proinflammatory cytokines that can induce fever, hypotension, multi-organ failure, and lethal shock. Various in vitro and in vivo models have provided important tools for studying the biological effects of, as well as potential vaccines/therapeutics against, the SEs. This review succinctly presents known physical and biological properties of the SEs, including various intervention strategies. In particular, SEB will often be portrayed as per biodefense concerns dating back to the 1960s. PMID:23959032

Daboia russellii and Naja kaouthia venom neutralization by lupeol acetate isolated from the root extract of Indian sarsaparilla Hemidesmus indicus R.Br.

PubMed

Chatterjee, Ipshita; Chakravarty, A K; Gomes, A

2006-06-15

The present study reports the isolation and purification of lupeol acetate from the methanolic root extract of Indian medicinal plant Hemidesmus indicus (L.) R.Br. (family: Asclepiadaceae) which could neutralize venom induced action of Daboia russellii and Naja kaouthia on experimental animals. Lupeol acetate could significantly neutralize lethality, haemorrhage, defibrinogenation, edema, PLA(2) activity induced by Daboia russellii venom. It also neutralized Naja kaouthia venom induced lethality, cardiotoxicity, neurotoxicity and respiratory changes in experimental animals. Lupeol acetate potentiated the protection by snake venom antiserum action against Daboia russellii venom induced lethality in male albino mice. Venom induced changes in lipid peroxidation and super oxide dismutase activity was antagonized by lupeol acetate. Snake venom neutralization by lupeol acetate and its possible mechanism of action has been discussed.

Perioperative Management of Severe Hypertension during Laparoscopic Surgery for Pheochromocytoma

PubMed Central

Erdoğan, Mehmet Ali; Uçar, Muharrem; Özkan, Ahmet Selim; Özgül, Ülkü; Durmuş, Mahmut

2016-01-01

Phaeochromocytoma is a catecholamine-secreting vascular tumour that is derived from chromaffin cell. Lethal cardiovascular complications, such as serious hypertension, myocardial infarction and aortic dissection, may occur because of uncontrolled catecholamine release. Each stage of anaesthesia management has vital importance because of this destructive catecholamine secretion that may occur during induction, perioperative stage and surgical manipulation. In this study, we report regarding the preoperative preparation and severe, persistent hypertension attack management with a combination of α-adrenergic blockade, β-adrenergic blockade, sodium nitroprusside and remifentanil in a patient who underwent laparoscopic surgery for phaeochromocytoma. PMID:27366556

[Sudden and fatal malfunction of a Björk-Shiley prosthesis in mitral position due to rupture of the ventricular bracket and disk embolization].

PubMed

Casarotto, D; Motta, A; Fabbri, A; Pugliese, P; Muneretto, C; Zanini, M; Sheiban, I

1985-04-01

Mechanical complications of prosthetic valves are increasing. The following report describes a case of fracture of a Björk-Shiley mitral prosthetic strut with dislogment of the valve occluder into the thoracic aorta. At the reoperation a new prosthesis was implanted but the patient died of acute heart failure. The diagnosis of valve disfunction must be made non invasively, because the time required for cardiac catherization usually constitutes a lethal delay. The only hope for survival is prompt surgical treatment.

A retrospective report (2003-2013) of the complications associated with the use of a one-man (head and tail) rope recovery system in horses following general anaesthesia.

PubMed

Niimura Del Barrio, Maria Chie; David, Florent; Hughes, J M Lynne; Clifford, David; Wilderjans, Hans; Bennett, Rachel

2018-01-01

The mortality rate of horses undergoing general anaesthesia is high when compared to humans or small animal patients. One of the most critical periods during equine anaesthesia is recovery, as the horse attempts to regain a standing position. This study was performed in a private equine practice in Belgium that uses a purpose-designed one-man (head and tail) rope recovery system to assist the horse during the standing process.The main purpose of the retrospective study was to report and analyse complications and the mortality rate in horses during recovery from anaesthesia using the described recovery system. Information retrieved from the medical records included patient signalment, anaesthetic protocol, duration of anaesthesia, ASA grade, type of surgery, recovery time and complications during recovery. Sedation was administered to all horses prior to recovery with the rope system. Complications were divided into major complications in which the horse was euthanized and minor complications where the horse survived. Major complications were further subdivided into those where the rope system did not contribute to the recovery complication (Group 1) and those where it was not possible to determine if the rope system was of any benefit (Group 2). Five thousand eight hundred fifty two horses recovered from general anaesthesia with rope assistance. Complications were identified in 30 (0.51%). Major complications occurred in 12 horses (0.20%) of which three (0.05%) were assigned to Group 1 and nine (0.15%) to Group 2. Three horses in Group 2 suffered musculoskeletal injuries (0.05%). Eighteen horses (0.31%) suffered minor complications, of which five (0.08%) were categorised as failures of the recovery system. This study reports the major and minor complication and mortality rate during recovery from anaesthesia using a specific type of rope recovery system. Mortality associated with the rope recovery system was low. During recovery from anaesthesia this rope system may reduce the risk of lethal complications, particularly major orthopaedic injuries.

Lethal effect of electric fields on isolated ventricular myocytes.

PubMed

de Oliveira, Pedro Xavier; Bassani, Rosana Almada; Bassani, José Wilson Magalhães

2008-11-01

Defibrillator-type shocks may cause electric and contractile dysfunction. In this study, we determined the relationship between probability of lethal injury and electric field intensity (E in isolated rat ventricular myocytes, with emphasis on field orientation and stimulus waveform. This relationship was sigmoidal with irreversible injury for E > 50 V/cm . During both threshold and lethal stimulation, cells were twofold more sensitive to the field when it was applied longitudinally (versus transversally) to the cell major axis. For a given E, the estimated maximum variation of transmembrane potential (Delta V(max)) was greater for longitudinal stimuli, which might account for the greater sensitivity to the field. Cell death, however, occurred at lower maximum Delta V(max) values for transversal shocks. This might be explained by a less steep spatial decay of transmembrane potential predicted for transversal stimulation, which would possibly result in occurrence of electroporation in a larger membrane area. For the same stimulus duration, cells were less sensitive to field-induced injury when shocks were biphasic (versus monophasic). Ours results indicate that, although significant myocyte death may occur in the E range expected during clinical defibrillation, biphasic shocks are less likely to produce irreversible cell injury.

Antivenom potential of ethanolic extract of Cordia macleodii bark against Naja venom

PubMed Central

Soni, Pranay; Bodakhe, Surendra H.

2014-01-01

Objective To evaluate the antivenom potential of ethanolic extract of bark of Cordia macleodii against Naja venom induced pharmacological effects such as lethality, hemorrhagic lesion, necrotizing lesion, edema, cardiotoxicity and neurotoxicity. Methods Wistar strain rats were challenged with Naja venom and treated with the ethanolic extract of Cordia macleodii bark. The effectiveness of the extract to neutralize the lethalities of Naja venom was investigated as recommended by WHO. Results At the dose of 400 and 800 mg/kg ethanolic extract of Cordia macleodii bark significantly inhibited the Naja venom induced lethality, hemorrhagic lesion, necrotizing lesion and edema in rats. Ethanolic extract of Cordia macleodii bark was effective in neutralizing the coagulant and defibrinogenating activity of Naja venom. The cardiotoxic effects in isolated frog heart and neurotoxic activity studies on frog rectus abdominus muscle were also antagonized by ethanolic extract of Cordia macleodii bark. Conclusions It is concluded that the protective effect of extract of Cordia macleodii against Naja venom poisoning may be mediated by the cardiotonic, proteolysin neutralization, anti-inflammatory, antiserotonic and antihistaminic activity. It is possible that the protective effect may also be due to precipitation of active venom constituents. PMID:25183127

Acute toxicity of 353-nonylphenol and its metabolites for zebrafish embryos.

PubMed

Kammann, Ulrike; Vobach, Michael; Wosniok, Werner; Schäffer, Andreas; Telscher, Andreas

2009-03-01

Nonylphenol (NP) can be detected in the aquatic environment all over the world. It is applied as a technical mixture of isomers of which 353-NP is the most relevant both in terms of abundance (about 20% of total mass) and endocrine potential. 353-NP is metabolised in sewage sludge. The aims of the present study were to determine and to compare the acute toxicity of t-NP, 353-NP and its metabolites as well as to discuss if the toxicity of 353-NP changes during degradation. 353-NP and two of its metabolites were synthesised. The zebrafish embryo test was performed according to standard protocols. Several lethal and non-lethal endpoints during embryonal development were reported. NOEL, LOEL and EC50 were calculated. All tested compounds caused lethal as well as non-lethal malformations during embryo development. 353-NP showed a higher toxicity (EC50 for lethal endpoints 6.7 mg/L) compared to its metabolites 4-(3.5-dimethyl-3-heptyl)-2-nitrophenol (EC50 13.3 mg/L) and 4-(3,5-dimethyl-3-heptyl)-2-bromophenol (EC50 27.1 mg/L). In surface water, concentrations of NP are far below the NOEC identified by the zebrafish embryo test. However, in soils and sewage sludge, concentrations may reach or even exceed these concentrations. Therefore, sludge-treated sites close to surface waters should be analysed for NP and its metabolites in order to detect an unduly high contamination due to runoff events. The results of the present study point out that the toxicity of 353-NP probably declines during metabolisation in water, sediment and soil, but does not vanish since the major metabolites exhibit a clear toxic potential for zebrafish embryos. Metabolites of environmental pollutants should be included in the ecotoxicological test strategy for a proper risk assessment.

Comparison of complication outcomes in acute pancreatitis following ERCP and conservative management at UKM medical centre: a six years retrospective study.

PubMed

Zamri, Z; Razman, J

2012-11-01

Acute pancreatitis is one of the common reasons for surgical admission. It is a potentially lethal disease that is increasing in its incidence. The most common causes of acute pancreatitis is from gallstones and alcohol. Other causes of acute pancreatitis include hypertriglyceridaemia, hyperparathyroidism, pancreatic malignancy, Endoscopic retrograde cholangiopancreatography (ERCP), trauma, infectious agents, drugs, autoimmunity, and hereditary. The treatment of acute pancreatitis is mainly supportive. The complication of ERCP in acute pancreatitis can be divided into local complication (pancreatic abscess, pseudocyst), systemic complications (renal failure, respiratory failure, cardiogenic shock) and biliary sepsis (acute cholangitis and acute cholecystitis). However, early ERCP and possible sphincterotomy should be kept in mind for patients with severe disease and biliary obstruction who are not improving with medical therapy. This study is done to compare the complication rate of ERCP and conservative management in acute pancreatitis for past 6 years in Pusat Perubatan UKM. The study is conducted retrospectively and the study population was from January 2003 until December 2008. About 100 patients involving 51 males and 49 females were included in this study. All of them were diagnosed acute pancreatitis based on the serum amylase level of 4 times than normal value detected from Chemistry Pathology record, Pathology Department, PPUKM. Then, data were collected from the patient's file which include the demographic data and patient clinical presentation, ultrasound finding, either patient went for ERCP within 72 hours or not. If ERCP not done within 72 hours of admission then it will considered that the patient is under conservative management. From 100 patients that involved in this study about 44% was Malay, 36 % was Chinese, 18 % was Indian and the other 2 % was from other origin. There were 28 cases (28%) where ERCP was done within 72 hours, and the other 72 cases (72%) the treatment was conservative. Among 28 cases that ERCP was done within 72 hours after admission, 20 cases are mild where as only 8 cases are severe. However, in conservative group about 56 cases are mild and the other 16 are severe. Among the conservative group there are 12 cases which have complications. The complications are respiratory failure, renal failure, sepsis, shock and pancreatic necrosis. There are 7 cases whose have respiratory failure alone, 1 case developed renal failure and 1 case has a shock. 1 case developed both pancreatic necrosis with sepsis. 1 case each developed respiratory failure with sepsis and respiratory failure with renal failure. However no complications were noted in early ERCP group. As a conclusion in this study we found out that early ERCP have a significant role in acute pancreatitis compare to conservative management.

Embryonic lethality is not sufficient to explain hourglass-like conservation of vertebrate embryos.

PubMed

Uchida, Yui; Uesaka, Masahiro; Yamamoto, Takayoshi; Takeda, Hiroyuki; Irie, Naoki

2018-01-01

Understanding the general trends in developmental changes during animal evolution, which are often associated with morphological diversification, has long been a central issue in evolutionary developmental biology. Recent comparative transcriptomic studies revealed that gene expression profiles of mid-embryonic period tend to be more evolutionarily conserved than those in earlier or later periods. While the hourglass-like divergence of developmental processes has been demonstrated in a variety of animal groups such as vertebrates, arthropods, and nematodes, the exact mechanism leading to this mid-embryonic conservation remains to be clarified. One possibility is that the mid-embryonic period (pharyngula period in vertebrates) is highly prone to embryonic lethality, and the resulting negative selections lead to evolutionary conservation of this phase. Here, we tested this "mid-embryonic lethality hypothesis" by measuring the rate of lethal phenotypes of three different species of vertebrate embryos subjected to two kinds of perturbations: transient perturbations and genetic mutations. By subjecting zebrafish ( Danio rerio ), African clawed frog ( Xenopus laevis ), and chicken ( Gallus gallus ) embryos to transient perturbations, namely heat shock and inhibitor treatments during three developmental periods [early (represented by blastula and gastrula), pharyngula, and late], we found that the early stages showed the highest rate of lethal phenotypes in all three species. This result was corroborated by perturbation with genetic mutations. By tracking the survival rate of wild-type embryos and embryos with genetic mutations induced by UV irradiation in zebrafish and African clawed frogs, we found that the highest decrease in survival rate was at the early stages particularly around gastrulation in both these species. In opposition to the "mid-embryonic lethality hypothesis," our results consistently showed that the stage with the highest lethality was not around the conserved pharyngula period, but rather around the early period in all the vertebrate species tested. These results suggest that negative selection by embryonic lethality could not explain hourglass-like conservation of animal embryos. This highlights the potential contribution of alternative mechanisms such as the diversifying effect of positive selections against earlier and later stages, and developmental constraints which lead to conservation of mid-embryonic stages.

The Toll-Like Receptor 5 Agonist Entolimod Mitigates Lethal Acute Radiation Syndrome in Non-Human Primates.

PubMed

Krivokrysenko, Vadim I; Toshkov, Ilia A; Gleiberman, Anatoli S; Krasnov, Peter; Shyshynova, Inna; Bespalov, Ivan; Maitra, Ratan K; Narizhneva, Natalya V; Singh, Vijay K; Whitnall, Mark H; Purmal, Andrei A; Shakhov, Alexander N; Gudkov, Andrei V; Feinstein, Elena

2015-01-01

There are currently no approved medical radiation countermeasures (MRC) to reduce the lethality of high-dose total body ionizing irradiation expected in nuclear emergencies. An ideal MRC would be effective even when administered well after radiation exposure and would counteract the effects of irradiation on the hematopoietic system and gastrointestinal tract that contribute to its lethality. Entolimod is a Toll-like receptor 5 agonist with demonstrated radioprotective/mitigative activity in rodents and radioprotective activity in non-human primates. Here, we report data from several exploratory studies conducted in lethally irradiated non-human primates (rhesus macaques) treated with a single intramuscular injection of entolimod (in the absence of intensive individualized supportive care) administered in a mitigative regimen, 1-48 hours after irradiation. Following exposure to LD50-70/40 of radiation, injection of efficacious doses of entolimod administered as late as 25 hours thereafter reduced the risk of mortality 2-3-fold, providing a statistically significant (P<0.01) absolute survival advantage of 40-60% compared to vehicle treatment. Similar magnitude of survival improvement was also achieved with drug delivered 48 hours after irradiation. Improved survival was accompanied by predominantly significant (P<0.05) effects of entolimod administration on accelerated morphological recovery of hematopoietic and immune system organs, decreased severity and duration of thrombocytopenia, anemia and neutropenia, and increased clonogenic potential of the bone marrow compared to control irradiated animals. Entolimod treatment also led to reduced apoptosis and accelerated crypt regeneration in the gastrointestinal tract. Together, these data indicate that entolimod is a highly promising potential life-saving treatment for victims of radiation disasters.

Severe craniocerebral trauma with sequelae caused by Flash-Ball® shot, a less-lethal weapon: Report of one case and review of the literature.

PubMed

Hiquet, Jean; Gromb-Monnoyeur, Sophie

2016-07-01

The use of Flash-Ball® as a non-lethal weapon by several special units within the police and police forces started in France in 1995. Little literature is available concerning injuries caused by Flash-Ball® shooting. However, we report the case of a healthy 34-year-old male victim of a Flash-Ball® shooting during a riot following a sports event. This young man presented serious craniocerebral injuries with a left temporal fracture, moderate cerebral oedema, fronto-temporal haemorrhagic contusion along with an extra-dural hematoma and subarachnoid hemorrhage requiring neurological and rehabilitation care for two months leaving important sequelae. Although the risk is obviously lower than with firearms, Flash-Ball® is nonetheless potentially lethal and may cause serious physical injuries, particularly after a shot to the head. © The Author(s) 2015.

A 3-D QSAR-BASED IDENTIFICATION ALGORITHM FOR POTENTIAL ESTROGEN RECEPTOR LIGANDS

EPA Science Inventory

Recent reports concerning the lethal effects of solar ultraviolet-B (UV-B) radiation on amphibians suggest that this stressor has the potential to impact some amphibian populations. In this study embryos and larvae of three anuran species, Rana pipiens, R. clamitans, and R. septe...

Midtrimester preterm prelabour rupture of membranes (PPROM): expectant management or amnioinfusion for improving perinatal outcomes (PPROMEXIL – III trial)

PubMed Central

2014-01-01

Background Babies born after midtrimester preterm prelabour rupture of membranes (PPROM) are at risk to develop neonatal pulmonary hypoplasia. Perinatal mortality and morbidity after this complication is high. Oligohydramnios in the midtrimester following PPROM is considered to cause a delay in lung development. Repeated transabdominal amnioinfusion with the objective to alleviate oligohydramnios might prevent this complication and might improve neonatal outcome. Methods/Design Women with PPROM and persisting oligohydramnios between 16 and 24 weeks gestational age will be asked to participate in a multi-centre randomised controlled trial. Intervention: random allocation to (repeated) abdominal amnioinfusion (intervention) or expectant management (control). The primary outcome is perinatal mortality. Secondary outcomes are lethal pulmonary hypoplasia, non-lethal pulmonary hypoplasia, survival till discharge from NICU, neonatal mortality, chronic lung disease (CLD), number of days ventilatory support, necrotizing enterocolitis (NEC), periventricular leucomalacia (PVL) more than grade I, severe intraventricular hemorrhage (IVH) more than grade II, proven neonatal sepsis, gestational age at delivery, time to delivery, indication for delivery, successful amnioinfusion, placental abruption, cord prolapse, chorioamnionitis, fetal trauma due to puncture. The study will be evaluated according to intention to treat. To show a decrease in perinatal mortality from 70% to 35%, we need to randomise two groups of 28 women (two sided test, β-error 0.2 and α-error 0.05). Discussion This study will answer the question if (repeated) abdominal amnioinfusion after midtrimester PPROM with associated oligohydramnios improves perinatal survival and prevents pulmonary hypoplasia and other neonatal morbidities. Moreover, it will assess the risks associated with this procedure. Trial registration NTR3492 Dutch Trial Register (http://www.trialregister.nl). PMID:24708702

Are High-Lethality Suicide Attempters With Bipolar Disorder a Distinct Phenotype?

PubMed Central

Oquendo, Maria A.; Carballo, Juan Jose; Rajouria, Namita; Currier, Dianne; Tin, Adrienne; Merville, Jessica; Galfalvy, Hanga C.; Sher, Leo; Grunebaum, Michael F.; Burke, Ainsley K.; Mann, J. John

2013-01-01

Because Bipolar Disorder (BD) individuals making highly lethal suicide attempts have greater injury burden and risk for suicide, early identification is critical. BD patients were classified as high- or low-lethality attempters. High-lethality attempts required inpatient medical treatment. Mixed effects logistic regression models and permutation analyses examined correlations between lethality, number, and order of attempts. High-lethality attempters reported greater suicidal intent and more previous attempts. Multiple attempters showed no pattern of incremental lethality increase with subsequent attempts, but individuals with early high-lethality attempts more often made high-lethality attempts later. A subset of high-lethality attempters make only high-lethality attempts. However, presence of previous low-lethality attempts does not indicate that risk for more lethal, possibly successful, attempts is reduced. PMID:19590998

PARP1 inhibitor olaparib (Lynparza) exerts synthetic lethal effect against ligase 4-deficient melanomas

PubMed Central

Czyż, Małgorzata; Toma, Monika; Gajos-Michniewicz, Anna; Majchrzak, Kinga; Hoser, Grazyna; Szemraj, Janusz; Nieborowska-Skorska, Margaret; Cheng, Phil; Gritsyuk, Daniel; Levesque, Mitchell; Dummer, Reinhard; Sliwinski, Tomasz; Skorski, Tomasz

2016-01-01

Cancer including melanoma may be “addicted” to double strand break (DSB) repair and targeting this process could sensitize them to the lethal effect of DNA damage. PARP1 exerts an important impact on DSB repair as it binds to both single- and double- strand breaks. PARP1 inhibitors might be highly effective drugs triggering synthetic lethality in patients whose tumors have germline or somatic defects in DNA repair genes. We hypothesized that PARP1-dependent synthetic lethality could be induced in melanoma cells displaying downregulation of DSB repair genes. We observed that PARP1 inhibitor olaparib sensitized melanomas with reduced expression of DNA ligase 4 (LIG4) to an alkylatimg agent dacarbazine (DTIC) treatment in vitro, while normal melanocytes remained intact. PARP1 inhibition caused accumulation of DSBs, which was associated with apoptosis in LIG4 deficient melanoma cells. Our hypothesis that olaparib is synthetic lethal with LIG4 deficiency in melanoma cells was supported by selective anti-tumor effects of olaparib used either alone or in combination with dacarbazine (DTIC) in LIG4 deficient, but not LIG4 proficient cells. In addition, olaparib combined with DTIC inhibited the growth of LIG4 deficient human melanoma xenografts. This work for the first time demonstrates the effectiveness of a combination of PARP1 inhibitor olaparib and alkylating agent DTIC for treating LIG4 deficient melanomas. In addition, analysis of the TCGA and transcriptome microarray databases revealed numerous individual melanoma samples potentially displaying specific defects in DSB repair pathways, which may predispose them to synthetic lethality triggered by PARP1 inhibitor combined with a cytotoxic drug. PMID:27705909

Prevalence of pulmonary edema among the deceased cases with acute Methadone poisoning: A report from Iran.

PubMed

Eizadi-Mood, Nastaran; Naeini, Seyed Amir Hossein Madani; Hedaiaty, Mahrang; Sabzghabaee, Ali Mohammad; Moudi, Maryam

2016-01-01

Methadone poisoning is common in our society, mainly in drug addicts. One of its lethal complications is pulmonary edema. Therefore, we evaluated the prevalence of pulmonary edema in the deceased cases with methadone poisoning and its possible relationship with some medical variables. In this cross-sectional study which was done in 2014, we have investigated the deceased patients with methadone toxicity who underwent autopsy at Isfahan Forensic Medicine Department (Iran). All variables including age, gender, and autopsy findings were recorded and analyzed. Demographic characteristics and medical complications of the patients were compared between the patients with or without pulmonary edema in the autopsy findings. There were 64 cases who died with methadone poisoning during the 1-year study period. The average age of cases (±standard deviation) was 32.1 ± 10.29 years, among which 92.2% were male. Based on the autopsy findings, 64.1% were diagnosed with pulmonary edema. There was no statistically significant relationship between pulmonary edema and age, gender, history of addiction, and hepatic or cardiovascular complications. Pulmonary edema is a common finding in deceased methadone poisoning cases and must be considered and ruled out in patients with acute methadone toxicity.

Teratogenic and toxic effects of Lingzhi or Reishi medicinal mushroom, Ganoderma lucidum (W.Curt.:Fr.) P. Karst. (higher Basidiomycetes), on zebrafish embryo as model.

PubMed

Dulay, Rich Milton R; Kalaw, Sofronio P; Reyes, Renato G; Alfonso, Noel F; Eguchi, Fumio

2012-01-01

This paper highlights the teratogenic and toxic effects of Ganoderma lucidum (Lingzhi or Reishi mushroom) extract on zebrafish embryos. Hatchability, malformations, and lethality rate of zebrafish embryos were assessed to provide valuable information regarding the potential teratogenic activity of G. lucidum. Hatching was completed 48 h post treatment application (hpta) at 1% or lower concentrations of extract and embryo water. The hatching rate of embryos treated with 5% or higher concentrations was significantly lower (p> 0.05) than the control. Tail malformation was the most marked morphological abnormality in embryos at 72 hpta, which was obviously caused by 1% extract (55.56% tail malformation) and was observed in all embryos exposed to 5% of extract. Growth retardation was evident in embryos exposed to 5%, 10%, and 20%. However, lethal effect of extract of G. lucidum was dependent on dose and time of exposure. Mortality rates of embryos treated with 5% (44.44%) or higher concentrations of the extract was significantly higher (p > 0.05) than that of the control embryos at 72 hpta. These results suggest that G. lucidum extract has lethal and sub-lethal effects on zebrafish embryos.

Executive functions and social cognition in highly lethal self-injuring patients with borderline personality disorder.

PubMed

Williams, Gregory E; Daros, Alexander R; Graves, Bryanna; McMain, Shelley F; Links, Paul S; Ruocco, Anthony C

2015-04-01

Risk for potentially lethal self-injurious behavior in borderline personality disorder (BPD) may be associated with deficits in neuropsychological functions and social cognition. In particular, individuals with BPD engaging in more medically damaging self-injurious behaviors may have more severe executive function deficits and altered emotion perception as compared to patients engaging in less lethal acts. In the current study, 58 patients with BPD reporting a lifetime history of self-injurious behavior were administered neuropsychological measures of response inhibition, planning and problem-solving,and tests of facial emotion recognition and discrimination. Patients who engaged in more medically lethal self-injurious behaviors reported engaging in impulsive behaviors more frequently and displayed neuropsychological deficits in problem-solving and response inhibition. They were also less accurate in recognizing happy facial expressions and in discerning subtle differences in emotional intensity in sad facial expressions. These findings suggest that patients with BPD that engage in more physically damaging self-injurious behaviors may have greater difficulties with behavioral control and employ less efficient problem-solving strategies. Problems in facial emotion recognition and discrimination may contribute to interpersonal difficulties in patients with BPD who self-injure. (c) 2015 APA, all rights reserved).

Detection of COPB2 as a KRAS synthetic lethal partner through integration of functional genomics screens

PubMed Central

Christodoulou, Eleni G.; Yang, Hai; Lademann, Franziska; Pilarsky, Christian; Beyer, Andreas; Schroeder, Michael

2017-01-01

Mutated KRAS plays an important role in many cancers. Although targeting KRAS directly is difficult, indirect inactivation via synthetic lethal partners (SLPs) is promising. Yet to date, there are no SLPs from high-throughput RNAi screening, which are supported by multiple screens. Here, we address this problem by aggregating and ranking data over three independent high-throughput screens. We integrate rankings by minimizing the displacement and by considering established methods such as RIGER and RSA. Our meta analysis reveals COPB2 as a potential SLP of KRAS with good support from all three screens. COPB2 is a coatomer subunit and its knock down has already been linked to disabled autophagy and reduced tumor growth. We confirm COPB2 as SLP in knock down experiments on pancreas and colorectal cancer cell lines. Overall, consistent integration of high throughput data can generate candidate synthetic lethal partners, which individual screens do not uncover. Concretely, we reveal and confirm that COPB2 is a synthetic lethal partner of KRAS and hence a promising cancer target. Ligands inhibiting COPB2 may, therefore, be promising new cancer drugs. PMID:28415695

A Translational Murine Model of Sub-Lethal Intoxication with Shiga Toxin 2 Reveals Novel Ultrastructural Findings in the Brain Striatum

PubMed Central

Tironi-Farinati, Carla; Geoghegan, Patricia A.; Cangelosi, Adriana; Pinto, Alipio; Loidl, C. Fabian; Goldstein, Jorge

2013-01-01

Infection by Shiga toxin-producing Escherichia coli causes hemorrhagic colitis, hemolytic uremic syndrome (HUS), acute renal failure, and also central nervous system complications in around 30% of the children affected. Besides, neurological deficits are one of the most unrepairable and untreatable outcomes of HUS. Study of the striatum is relevant because basal ganglia are one of the brain areas most commonly affected in patients that have suffered from HUS and since the deleterious effects of a sub-lethal dose of Shiga toxin have never been studied in the striatum, the purpose of this study was to attempt to simulate an infection by Shiga toxin-producing E. coli in a murine model. To this end, intravenous administration of a sub-lethal dose of Shiga toxin 2 (0.5 ηg per mouse) was used and the correlation between neurological manifestations and ultrastructural changes in striatal brain cells was studied in detail. Neurological manifestations included significant motor behavior abnormalities in spontaneous motor activity, gait, pelvic elevation and hind limb activity eight days after administration of the toxin. Transmission electron microscopy revealed that the toxin caused early perivascular edema two days after administration, as well as significant damage in astrocytes four days after administration and significant damage in neurons and oligodendrocytes eight days after administration. Interrupted synapses and mast cell extravasation were also found eight days after administration of the toxin. We thus conclude that the chronological order of events observed in the striatum could explain the neurological disorders found eight days after administration of the toxin. PMID:23383285

Aerodigestive Foreign Bodies in Adult Ethiopian Patients: A Prospective Study at Tikur Anbessa Hospital, Ethiopia

PubMed Central

Bekele, Abebe

2014-01-01

Introduction. Foreign bodies (FBs) in the aerodigestive tract are important causes of morbidity and mortality and pose diagnostic and therapeutic challenges. The best method of removal of an esophageal and tracheobronchial FB is endoscopic guided extraction. Objective. To present our experience of the removal of aerodigestive FBs in adult Ethiopian patients using rigid endoscopes. Methods. A hospital-based prospective study, at Tikur Anbessa Referral and Teaching Hospital, from January 2011 to December 2012 (over two years). Results. A total of 32 patients (18 males and 14 females) with a mean age of 28.0 ± 12.74 years were treated for FB ingestion and aspiration at Tikur Anbessa Hospital. The FBs were impacted at the esophagus in 18 (56.2%) patients, at the pharynx in 7 (21.8%), and at the air way in 7 (21.8%) patients. Pieces of bones were the commonest objects found in the esophagus (17/18 of the cases) and the pharynx (4/7), while fractured tracheostomy tubes and needles were frequently seen in the air way (3/7 cases each). The foreign bodies were visible in plain radiographs of 26 (81.2%) patients. Successful extraction of FBs was achieved by using Mc gill forceps in 11 cases, rigid esophagoscopes in 9 patients, and bronchoscopes in 4 cases. Four cases required open surgery to remove the foreign bodies. Two complications (one pneumothorax and one esophageal perforation) occurred. All patients were discharged cured. Discussion and Recommendations. Aerodigestive FBs are not so rare in the hospital and timely diagnosis and removal of accidentally ingested and aspirated foreign body should be performed so as to avoid the potentially lethal complications associated. Rigid esophagoscopy requires general anesthesia and is associated with its own complications, but our experience and outcome of its use are encouraging. PMID:24834074

The long-term results of resection and multiple resections in Crohn's disease.

PubMed

Krupnick, A S; Morris, J B

2000-01-01

Crohn's disease is a panenteric, transmural inflammatory disease of unknown origin. Although primarily managed medically, 70% to 90% of patients will require surgical intervention. Surgery for small bowel Crohn's is usually necessary for unrelenting stenotic complications of the disease. Fistula, abscess, and perforation can also necessitate surgical intervention. Most patients benefit from resection or strictureplasty with an improved quality of life and remission of disease, but recurrence is common and 33% to 82% of patients will need a second operation, and 22% to 33% will require more than two resections. Short-bowel syndrome is unavoidable in a small percentage of Crohn's patients because of recurrent resection of affected small bowel and inflammatory destruction of the remaining mucosa. Although previously a lethal and unrelenting disease with death caused by malnutrition, patients with short-bowel syndrome today can lead productive lives with maintenance on total parenteral nutrition (TPN). This lifestyle, however, does not come without a price. Severe TPN-related complications, such as sepsis of indwelling central venous catheters and liver failure, do occur. Future developments will focus on more powerful and effective anti-inflammatory medication specifically targeting the immune mechanisms responsible for Crohn's disease. Successful medical management of the disease will alleviate the need for surgical resection and reduce the frequency of short-bowel syndrome. Improving the efficacy of immunosuppression and the understanding of tolerance induction should increase the safety and applicability of small-bowel transplant for those with short gut. Tissue engineering offers the potential to avoid immunosuppression altogether and supplement intestinal length using the patient's own tissues.

Hereditary hemochromatosis.

PubMed

Walker, E M; Wolfe, M D; Norton, M L; Walker, S M; Jones, M M

1998-01-01

Genetic (hereditary) hemochromatosis is probably the most common autosomal recessive disorder found in white Americans, of whom about 5/1,000 (0.5 percent) are homozygous for the associated gene. The hemochromatosis gene is probably located close to the HLA-A locus on the short arm of chromosome 6. Homozygous individuals may develop severe and potentially lethal hemochromatosis, especially after age 39. Hereditary hemochromatosis involves an increased rate of iron absorption from the gut with subsequent progressive storage of iron in soft organs of the body. Excess iron storage eventually produces pituitary, pancreatic, cardiac, and liver dysfunction and death may result from cardiac arrhythmias, congestive heart failure, and/or hepatic failure or cancer. Early diagnosis can prevent these excess iron-induced problems. Iron overload owing to HLA-linked hereditary hemochromatosis can be distinguished from other causes of hemochromatosis by liver biopsies and interpretations. Patients at risk for genetic hemochromatosis should be screened, identified, and treated as early as age 20 to prevent or minimize the deadly complications of hemochromatosis. Population screening should include measurements of serum iron concentration, total iron binding capacity (TIBC), percent saturation of transferrin, and serum ferritin concentrations. Family members of hereditary hemochromatosis patients are at increased risk and should be tested. Screening, identification and early treatment (phlebotomies, sometimes in combination with the use of Desferal or other iron-chelating agents) may help prevent or reduce iron-related organ damage and premature deaths. Early diagnosis and treatment will reduce the population of aging individuals with severe, complicated hemochromatosis and dramatically reduce medical costs (billions of U.S. dollars per annum) associated with the management of this disease.

Intraoperative colonic pulse oximetry in left-sided colorectal surgery: can it predict anastomotic leak?

PubMed

Salusjärvi, Johannes M; Carpelan-Holmström, Monika A; Louhimo, Johanna M; Kruuna, Olli; Scheinin, Tom M

2018-03-01

An anastomotic leak is a fairly common and a potentially lethal complication in colorectal surgery. Objective methods to assess the viability and blood circulation of the anastomosis could help in preventing leaks. Intraoperative pulse oximetry is a cheap, easy to use, fast, and readily available method to assess tissue viability. Our aim was to study whether intraoperative pulse oximetry can predict the development of an anastomotic leak. The study was a prospective single-arm study conducted between the years 2005 and 2011 in Helsinki University Hospital. Patient material consisted of 422 patients undergoing elective left-sided colorectal surgery. The patients were operated by one of the three surgeons. All of the operations were partial or total resections of the left side of the colon with a colorectal anastomosis. The intraoperative colonic oxygen saturation was measured with pulse oximetry from the colonic wall, and the values were analyzed with respect to post-operative complications. 2.3 times more operated anastomotic leaks occurred when the colonic StO 2 was ≤ 90% (11/129 vs 11/293). The mean colonic StO 2 was 91.1 in patients who developed an operated anastomotic leak and 93.0 in patients who did not. With logistic regression analysis, the risk of operated anastomotic leak was 4.2 times higher with StO 2 values ≤ 90%. Low intraoperative colonic StO 2 values are associated with the occurrence of anastomotic leak. Despite its handicaps, the method seems to be useful in assessing anastomotic viability.

Averting Opioid-induced Respiratory Depression without Affecting Analgesia.

PubMed

Dahan, Albert; van der Schrier, Rutger; Smith, Terry; Aarts, Leon; van Velzen, Monique; Niesters, Marieke

2018-05-01

The ventilatory control system is highly vulnerable to exogenous administered opioid analgesics. Particularly respiratory depression is a potentially lethal complication that may occur when opioids are overdosed or consumed in combination with other depressants such as sleep medication or alcohol. Fatalities occur in acute and chronic pain patients on opioid therapy and individuals that abuse prescription or illicit opioids for their hedonistic pleasure. One important strategy to mitigate opioid-induced respiratory depression is cotreatment with nonopioid respiratory stimulants. Effective stimulants prevent respiratory depression without affecting the analgesic opioid response. Several pharmaceutical classes of nonopioid respiratory stimulants are currently under investigation. The majority acts at sites within the brainstem respiratory network including drugs that act at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (ampakines), 5-hydroxytryptamine receptor agonists, phospodiesterase-4 inhibitors, D1-dopamine receptor agonists, the endogenous peptide glycyl-glutamine, and thyrotropin-releasing hormone. Others act peripherally at potassium channels expressed on oxygen-sensing cells of the carotid bodies, such as doxapram and GAL021 (Galleon Pharmaceuticals Corp., USA). In this review we critically appraise the efficacy of these agents. We conclude that none of the experimental drugs are adequate for therapeutic use in opioid-induced respiratory depression and all need further study of efficacy and toxicity. All discussed drugs, however, do highlight potential mechanisms of action and possible templates for further study and development.

Non-thermal plasma jet without electrical shock for biomedical applications

NASA Astrophysics Data System (ADS)

Baik, Ku Youn; Kang, Han Lim; Kim, Junseong; Park, Shin Young; Bang, Ji Yun; Uhm, Han S.; Choi, Eun Ha; Cho, Guangsup

2013-10-01

A plasma jet without an electrical shock was generated through a Y-shaped tube in which voltages with opposite phases were applied to a pair of tubes. The plasma plume generated at the intersection had a plasma potential of a 60-90 V and high concentrations of reactive species sufficient to induce a high level of lethality on gram-negative bacteria on a tissue mimic. The selective lethality of bacteria on an epithelial-cell-containing tissue mimic could be modulated using oxidant and antioxidant chemicals, thereby leading to the possibility of a shock-reduced plasma jet for biomedical applications.

A chimeric measles virus with canine distemper envelope protects ferrets from lethal distemper challenge.

PubMed

Rouxel, Ronan Nicolas; Svitek, Nicholas; von Messling, Veronika

2009-08-06

CDV infects a broad range of carnivores, and over the past decades it has caused outbreaks in a variety of wild carnivore populations. Since the currently available live-attenuated vaccine is not sufficiently safe in these highly susceptible species, we produced a chimeric virus combining the replication complex of the measles Moraten vaccine strain with the envelope of a recent CDV wild type isolate. The resulting virus did not cause disease or immunosuppression in ferrets and conferred protection from challenge with a lethal wild type strain, demonstrating its potential value for wildlife conservation efforts.

Ligand-induced expansion of the S1' site in the anthrax toxin lethal factor

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

Maize, Kimberly M.; Kurbanov, Elbek K.; Johnson, Rodney L.

2016-07-05

The Bacillus anthracis lethal factor (LF) is one component of a tripartite exotoxin partly responsible for persistent anthrax cytotoxicity after initial bacterial infection. Inhibitors of the zinc metalloproteinase have been investigated as potential therapeutic agents, but LF is a challenging target because inhibitors lack sufficient selectivity or possess poor pharmaceutical properties. These structural studies reveal an alternate conformation of the enzyme, induced upon binding of specific inhibitors, that opens a previously unobserved deep pocket termed S1'* which might afford new opportunities to design selective inhibitors that target this subsite.

Pigeon chest: comparative analysis of surgical techniques in minimal access repair of pectus carinatum (MARPC).

PubMed

Muntean, Ancuta; Stoica, Ionica; Saxena, Amulya K

2018-02-01

After minimally invasive repair for pectus excavatum (MIRPE), similar procedures for pectus carinatum were developed. This study aimed to analyse the various published techniques of minimal access repair for pectus carinatum (MARPC) and compare the outcomes. Literature was reviewed on PubMed with the terms "pectus carinatum", "minimal access repair", "thoracoscopy" and "children". Twelve MARPC techniques that included 13 articles and 140 patients with mean age 15.46 years met the inclusion criteria. Success rate of corrections was n = 125, about 89% in cumulative reports, with seven articles reporting 100%. The complication rate was 39.28%. Since the pectus bar is placed over the sternum and has a large contact area, skin irritation was the most frequent morbidity (n = 20, 14.28%). However, within the complication group (n = 55), wire breakage (n = 21, 38.18%) and bar displacement (n = 10, 18.18%) were the most frequent complications. Twenty-two (15.71%) patients required a second procedure. Recurrences have been reported in four of twelve techniques. There were no lethal outcomes. MARPC techniques are not standardized, as MIRPE are, so comparative analysis is difficult as the only common denominator is minimal access. Surgical morbidity is high in MARPC and affects > 2/3rd patients with about 15% requiring surgery for complication management.

Targeted Silencing of Anthrax Toxin Receptors Protects against Anthrax Toxins*

PubMed Central

Arévalo, Maria T.; Navarro, Ashley; Arico, Chenoa D.; Li, Junwei; Alkhatib, Omar; Chen, Shan; Diaz-Arévalo, Diana; Zeng, Mingtao

2014-01-01

Anthrax spores can be aerosolized and dispersed as a bioweapon. Current postexposure treatments are inadequate at later stages of infection, when high levels of anthrax toxins are present. Anthrax toxins enter cells via two identified anthrax toxin receptors: tumor endothelial marker 8 (TEM8) and capillary morphogenesis protein 2 (CMG2). We hypothesized that host cells would be protected from anthrax toxins if anthrax toxin receptor expression was effectively silenced using RNA interference (RNAi) technology. Thus, anthrax toxin receptors in mouse and human macrophages were silenced using targeted siRNAs or blocked with specific antibody prior to challenge with anthrax lethal toxin. Viability assays were used to assess protection in macrophages treated with specific siRNA or antibody as compared with untreated cells. Silencing CMG2 using targeted siRNAs provided almost complete protection against anthrax lethal toxin-induced cytotoxicity and death in murine and human macrophages. The same results were obtained by prebinding cells with specific antibody prior to treatment with anthrax lethal toxin. In addition, TEM8-targeted siRNAs also offered significant protection against lethal toxin in human macrophage-like cells. Furthermore, silencing CMG2, TEM8, or both receptors in combination was also protective against MEK2 cleavage by lethal toxin or adenylyl cyclase activity by edema toxin in human kidney cells. Thus, anthrax toxin receptor-targeted RNAi has the potential to be developed as a life-saving, postexposure therapy against anthrax. PMID:24742682

Drugging the Cancers Addicted to DNA Repair.

PubMed

Nickoloff, Jac A; Jones, Dennie; Lee, Suk-Hee; Williamson, Elizabeth A; Hromas, Robert

2017-11-01

Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations (such as BRCA1 or 2). It now appears that a clinically significant fraction of cancers have acquired DNA repair defects. DNA repair pathways operate in related networks, and cancers arising from loss of one DNA repair component typically become addicted to other repair pathways to survive and proliferate. Drug inhibition of the rescue repair pathway prevents the repair-deficient cancer cell from replicating, causing apoptosis (termed synthetic lethality). However, the selective pressure of inhibiting the rescue repair pathway can generate further mutations that confer resistance to the synthetic lethal drugs. Many such drugs currently in clinical use inhibit PARP1, a repair component to which cancers arising from inherited BRCA1 or 2 mutations become addicted. It is now clear that drugs inducing synthetic lethality may also be therapeutic in cancers with acquired DNA repair defects, which would markedly broaden their applicability beyond treatment of cancers with inherited DNA repair defects. Here we review how each DNA repair pathway can be attacked therapeutically and evaluate DNA repair components as potential drug targets to induce synthetic lethality. Clinical use of drugs targeting DNA repair will markedly increase when functional and genetic loss of repair components are consistently identified. In addition, future therapies will exploit artificial synthetic lethality, where complementary DNA repair pathways are targeted simultaneously in cancers without DNA repair defects. © The Author 2017. Published by Oxford University Press.

Country made scare gun vs. air gun--a comparative study of terminal ballistics using gelatine blocks.

PubMed

Hallikeri, Vinay R; Gouda, Hareesh S; Kadagoudar, Shivanand A

2012-01-10

Country made scare gun also called as bandook in the vernacular language designed with an intention of scaring away the menacing animals is not only unique and effective but also potentially lethal and has found wide spread usage in the rural parts of India. Here an attempt has been made to study the characteristic features such as physical dimensions, mechanism of action of this weapon and to compare its penetrating ability with that of air gun, whose potential lethality is a well-documented fact, using the ballistic gelatine blocks at various ranges. It is hoped that keeping the existence of such firearms in mind by the forensic experts might help to solve the unexplained and bizarre firearm injuries encountered in day to day practice. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Analysis of Lethality and Malformations During Zebrafish (Danio rerio) Development.

PubMed

Raghunath, Azhwar; Perumal, Ekambaram

2018-01-01

The versatility offered by zebrafish (Danio rerio) makes it a powerful and an attractive vertebrate model in developmental toxicity and teratogenicity assays. Apart from the newly introduced chemicals as drugs, xenobiotics also induce abnormal developmental abnormalities and congenital malformations in living organisms. Over the recent decades, zebrafish embryo/larva has emerged as a potential tool to test teratogenicity potential of these chemicals. Zebrafish responds to compounds as mammals do as they share similarities in their development, metabolism, physiology, and signaling pathways with that of mammals. The methodology used by the different scientists varies enormously in the zebrafish embryotoxicity test. In this chapter, we present methods to assess lethality and malformations during zebrafish development. We propose two major malformations scoring systems: binomial and relative morphological scoring systems to assess the malformations in zebrafish embryos/larvae. Based on the scoring of the malformations, the test compound can be classified as a teratogen or a nonteratogen and its teratogenic potential is evaluated.

Adjuvant effects and antiserum action potentiation by a (herbal) compound 2-hydroxy-4-methoxy benzoic acid isolated from the root extract of the Indian medicinal plant 'sarsaparilla' (Hemidesmus indicus R. Br.).

PubMed

Alam, M I; Gomes, A

1998-10-01

The adjuvant effect and antiserum potentiation of a compound 2-hydroxy-4-methoxy benzoic acid were explored in the present investigation. This compound, isolated and purified from the Indian medicinal plant Hemidesmus indicus R. Br, possessed antisnake venom activity. Rabbits immunized with Vipera russellii venom in the presence and absence of the compound along with Freund's complete adjuvant, produced a precipitating band in immunogel diffusion and immunogel electrophoresis. The venom neutralizing capacity of this antiserum showed positive adjuvant effects as evident by the higher neutralization capacity (lethal and hemorrhage) when compared with the antiserum raised with venom alone. The pure compound potentiated the lethal action neutralization of venom by commercial equine polyvalent snake venom antiserum in experimental models. These observations raised the possibility of the use of chemical antagonists (from herbs) against snake bite, which may provide a better protection in presence of antiserum, especially in the rural parts of India.

Clinical Effects and Lethal and Forensic Aspects of Propofol*

PubMed Central

Levy, Richard J.

2010-01-01

Propofol is a potent intravenous anesthetic agent that rapidly induces sedation and unconsciousness. The potential for propofol dependency, recreational use and abuse has only recently been recognized and several cases of accidental overdose and suicide have emerged. In addition, the first documented case of murder using propofol was reported a few months ago and a high profile case of suspected homicide with propofol is currently under investigation. A number of analytical methods have been employed to detect and quantify propofol concentrations in biological specimens. The reported propofol related deaths and post-mortem blood and tissue levels are reviewed. Importantly, limitations of propofol detection are discussed and future considerations are presented. Because propofol has the potential for diversion with lethal consequences, the forensic scientist must have a basic understanding of its clinical indications and uses, pharmacologic properties, and detection methods. In addition, medical institutions should develop systems to prevent and detect diversion of this potential drug of abuse. PMID:20950316

[25 year experience with using surgical correction of dislipidemia in treatment of patients with atherosclerosis].

PubMed

Sedov, V M; Mirchuk, K K; Sedletskiĭ, Iu I

2011-01-01

An analysis of results of using partial ileoshunting for the treatment of dislipidemia in 159 patients with atherosclerosis has shown that operation of partial ileoshunting has an obligatory, pronounced and lifelong lipidcorrecting effect. An antiatherogenic effect of the operation of partial ileoshunting is manifested as the improvement of the clinical course of the disease caused by atherosclerosis, by less number of thrombotic complications of atherosclerosis and less lethality from cardio-vascular diseases. At a longer follow-up period, the efficiency of partial ileoshunting as a means of secondary prophylactics of atherosclerosis is confirmed but in case of liquidation after operation of dislipoproteidemia.

Rare incidence of tumor lysis syndrome in metastatic prostate cancer following treatment with docetaxel.

PubMed

Bhardwaj, Sharonlin; Varma, Seema

2018-03-01

Tumor lysis syndrome is a serious and sometimes lethal complication of cancer treatment that is comprised of a set of metabolic disturbances along with clinical manifestations. Initiating chemotherapy in bulky, rapidly proliferating tumors causes rapid cell turnover that in turn releases metabolites into circulation that give rise to metabolic derangements that can be dangerous. This syndrome is usually seen in high-grade hematological malignancies. Less commonly, tumor lysis syndrome can present in solid tumors and even rarely in genitourinary tumors. In this report, the authors describe a specific case of tumor lysis syndrome in a patient with metastatic prostate cancer following treatment with docetaxel.

ECMO and cytokine removal for bridging to surgery in a patient with ischemic ventricular septal defect - a case report.

PubMed

Marek, Stefanie; Gamper, Gunnar; Reining, Georg; Bergmann, Peter; Mayr, Harald; Kliegel, Andreas

2017-09-15

Even in the modern era of percutaneous coronary intervention, postinfarction ventricular septal defect (VSD) remains a serious and often lethal complication. Whether or not immediate surgical repair or delaying surgery a few days aided by intra-aortic counterpulsation provides the optimal strategy remains a matter of debate. An interdisciplinary approach of intensivists and cardiac surgeons in this setting is mandatory. We report the use of veno-arterial extracorporeal membrane oxygenation and extracorporeal blood purification therapy (CytoSorb®) as bridging to surgical closure in a patient with an ischemic VSD leading to protracted cardiogenic shock after posterior myocardial infarction.

[IMPROVEMENT AND CHOICE OF COLOSTOMY METHOD IN THE TREATMENT OF PATIENTS, SUFFERING AN ACUTE OBTURATIVE IMPASSABILITY OF LARGE BOWEL].

PubMed

Kustryo, V I; Langazo, O V

2015-11-01

Colostomy was done in 49 patients, suffering an acute obturative impassability of large bowel (AOILB). In 28 patients (1st group) colostomy was conducted in accordance to standard method; in 21 (2nd group)--in accordance to the method, proposed by us. Application of the method proposed for surgical treatment of AOILB have guaranteed a reduction of postoperative paracolostomal complications rate in 6.8 times, of postoperative lethality--in 2.2 times, duration of the patient stationary treatment--in 1.4 times, the rate of dressings and the dressing material expanses--in 10 times.

Lethal acute demyelinization with encephalo-myelitis as a complication of cured Cushing's disease.

PubMed

Chevalier, N; Hieronimus, S; Vandenbos, F; Delmont, E; Cua, E; Cherick, F; Paquis, P; Michiels, J-F; Fenichel, P; Brucker-Davis, F

2010-12-01

Cushing's disease is usually associated with higher mortality rate, especially from cardiovascular causes. Development or exacerbation of autoimmune or inflammatory diseases is known to occur in patients with hypercortisolism after cure. We report for the first time a 34-year old woman with a psychiatric background, who developed four months after the surgical cure of Cushing's disease an acute disseminated encephalomyelitis (ADEM) presenting initially as a psychiatric illness. We hypothesize that the recent correction of hypercortisolism triggered ADEM and that the atypical presentation, responsible for diagnosis delay, led to the death of this patient. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Delineating the requirements for spontaneous DNA damage resistance pathways in genome maintenance and viability in Saccharomyces cerevisiae.

PubMed

Morey, Natalie J; Doetsch, Paul W; Jinks-Robertson, Sue

2003-06-01

Cellular metabolic processes constantly generate reactive species that damage DNA. To counteract this relentless assault, cells have developed multiple pathways to resist damage. The base excision repair (BER) and nucleotide excision repair (NER) pathways remove damage whereas the recombination (REC) and postreplication repair (PRR) pathways bypass the damage, allowing deferred removal. Genetic studies in yeast indicate that these pathways can process a common spontaneous lesion(s), with mutational inactivation of any pathway increasing the burden on the remaining pathways. In this study, we examine the consequences of simultaneously compromising three or more of these pathways. Although the presence of a functional BER pathway alone is able to support haploid growth, retention of the NER, REC, or PRR pathway alone is not, indicating that BER is the key damage resistance pathway in yeast and may be responsible for the removal of the majority of either spontaneous DNA damage or specifically those lesions that are potentially lethal. In the diploid state, functional BER, NER, or REC alone can support growth, while PRR alone is insufficient for growth. In diploids, the presence of PRR alone may confer a lethal mutation load or, alternatively, PRR alone may be insufficient to deal with potentially lethal, replication-blocking lesions.

Detection of the source of hemorrhage using postmortem computerized tomographic angiography in a case of a giant juvenile nasopharyngeal angiofibroma after surgical treatment.

PubMed

do Nascimento, Felipe Barjud Pereira; dos Santos, Glaucia Aparecida Bento; Melo, Nelson Almeida d'Ávila; Damasceno, Eduarda Bittencourt; Mauad, Thais

2015-09-01

Postmortem computerized tomographic angiography (PMCTA) has been increasingly used in forensic medicine to detect and locate the source of bleeding in cases of fatal acute hemorrhage. In this paper, we report a case of postoperative complication in a patient with a giant juvenile nasopharyngeal angiofibroma in which the source of bleeding was detected by PMCTA. A case description and evaluations of the pre- and postoperative exams, postmortem CT angiogram, and conventional autopsy results are provided. The source of bleeding was identified by postmortem CT angiography but not by conventional autopsy. The established protocol, injecting contrast medium into the femoral artery, was effective in identifying the source of bleeding. Postoperative bleeding is a rare and frequently fatal complication of juvenile nasopharyngeal angiofibroma. As a complement to conventional autopsy, postmortem angiography is a valuable tool for the detection of lethal acute hemorrhagic foci, and establishing a routine procedure for PMCTA may improve its efficiency.

[Listeriosis in pregnancy--case report].

PubMed

Barlik, Magdalena; Seremak-Mrozikiewicz, Agnieszka; Drews, Krzysztof

2014-04-01

Listeriosis is a rather rare infectious disease but its incidence in pregnancy is over 20 times higher than in the general population. Pregnant women with listeriosis comprise one-third of all listeriosis cases. Listeriosis is a foodborne disease. Sporadic as well as epidemic cases of listeriosis are usually related to contaminated processed food, especially meat dishes served in fast-food restaurants and dairy products. Pregnant women are at an increased risk for listeriosis infection. Unfortunately the symptoms are not specific and the diagnosis presents a considerable challenge. Although the literature offers some case reports on a complicated course of listeriosis during pregnancy the infection usually runs a mild course in pregnant women. Regardless, fetal or neonatal infection is related to very high risk of lethal complications in the newborn, among others: sepsis, meningitis or pneumonia. In this paper we present a case of a 28-year-old gravida with listeriosis. We described the course of the infection, diagnostic process and treatment in both, the mother and the newborn.

[Multidisciplinary approach to the treatment of colorectal cancer, complicated by urinary tract invasion].

PubMed

Likhter, M S; Shelygin, Iu A; Achkasov, S I

2012-01-01

Results of treatment of 277 patients with colorectal cancer stage IV complicated by the urinary tract invasion, were analyzed. Men were 168 (60.7%); women - 109 (39.3%). Patients aged 31-79 years (59.6±5.7) years. All patients were operated on radically with the resection of the invaded parts of the urinary tract en bloc. Both abdominal surgeons and urologists took part in the operation. The study proved that the invasion of the urinary tract by colorectal cancer should not become a reason for the surgery refusal. The subtotal resection of the urinary bladder by its cancer invasion demonstrated the appropriate radicalism and functional postoperative results. The efficacy of such combined operations was proved by the high level of social adaptation of the operated patients - 18 (51.4%) of 35 followed up patients came back to the previous level of social activity. Urinary tracts' resection did not influenced the level of postoperative lethality.

A Prevention of Pre-eclampsia with the Use of Acetylsalicylic Acid and Low-molecular Weight Heparin - Molecular Mechanisms.

PubMed

Darmochwal-Kolarz, Dorota; Kolarz, Bogdan; Korzeniewski, Michal; Kimber-Trojnar, Zaneta; Patro-Malysza, Jolanta; Mierzynski, Radzisław; Przegalinska-Kałamucka, Monika; Oleszczuk, Jan

Pre-eclampsia appears to be the main cause for the maternal and fetal morbidity and mortality. Pregnant women with pre-eclampsia are more likely to be threatened with conditions which potentially may be lethal, such as: disseminated intravascular coagulation, cerebral hemorrhage, liver and renal failure. Pregnancy complicated with pre-eclampsia is also associated with a greater risk for iatrogenic prematurity, intrauterine growth retardation, premature abruption of placenta, and even intrauterine fetal death. In the majority of cases the reasons for arterial hypertension among pregnant women remain obscure. For the past decades, there were many abortive attempts in the use of some microelements, vitamins or specific diets, such as polyunsaturated fatty acids, for the prophylaxis of pre-eclampsia. Recently, it has been shown that a prevention of pre-eclampsia with the use of a lowmolecular- weight heparins (LMWHs) and acetylsalicylic acid (ASA) could considerably reduce the frequency of preeclampsia. In this review, we present the studies concerning the applications of LMWHs and aspirin in the prophylaxis of pre-eclampsia and some important data about the mechanisms of anti-inflammatory actions of LMWHs and ASA.

Silencing of BAG3 promotes the sensitivity of ovarian cancer cells to cisplatin via inhibition of autophagy.

PubMed

Qiu, Shuang; Sun, Liang; Jin, Ye; An, Qi; Weng, Changjiang; Zheng, Jianhua

2017-07-01

Ovarian cancer is the most lethal disease among all gynecological malignancies. Interval cytoreductive surgery and cisplatin‑based chemotherapy are the recommended therapeutic strategies. However, acquired resistance to cisplatin remains a big challenge for the overall survival and prognosis in ovarian cancer. Complicated molecular mechanisms are involved in the process. At present, increasing evidence indicates that autophagy plays an important role in the prosurvival and resistance against chemotherapy. In the present study, as a novel autophagy regulator, BCL2‑associated athanogene 3 (BAG3) was investigated to study its role in cisplatin sensitivity in epithelial ovarian cancer. However, whether BAG3 participates in cisplatin sensitivity by inducing autophagy and the underlying mechanism in ovarian cancer cells remain to be clarified. Through the use of quantitative real-time PCR, western blot analysis, CCK-8 and immunofluorescence assays our data revealed that cisplatin-induced autophagy protected ovarian cancer cells from the toxicity of the drug and that this process was regulated by BAG3. Silencing of BAG3 increased cisplatin-induced apoptosis. The results also revealed BAG3 as a potential therapeutic target which enhanced the efficacy of cisplatin in ovarian cancer.

In vivo retroviral gene transfer into human bronchial epithelia of xenografts.

PubMed

Engelhardt, J F; Yankaskas, J R; Wilson, J M

1992-12-01

Cystic fibrosis (CF) is the most common lethal inherited disease in the Caucasian population with an incidence of approximately 1 in 2,500 live births. Pulmonary complications of CF, which are the most morbid aspects of the disease, are caused by primary abnormalities in epithelial cells that lead to impaired mucociliary clearance. One potential therapeutic strategy is to reconstitute expression of the CF gene in airway epithelia by somatic gene transfer. To this end, we have developed an animal model of the human airway using bronchial xenografts and have tested the efficiency of in vivo retroviral gene transfer. Using the LacZ reporter gene, we find the efficiency of in vivo retroviral gene transfer to be dramatically dependent on the regenerative and mitotic state of the epithelium. Within an undifferentiated regenerating epithelium in which 40% of nuclei labeled with BrdU, 5-10% retroviral gene transfer was obtained. In contrast, no gene transfer was noted in a fully differentiated epithelium in which 1% of nuclei labeled with BrdU. These findings suggest that retroviral mediated gene transfer to the airway in vivo may be feasible if the proper regenerative state can be induced.

Mechanism of Bacterial Inactivation by (+)-Limonene and Its Potential Use in Food Preservation Combined Processes

PubMed Central

Espina, Laura; Gelaw, Tilahun K.; de Lamo-Castellví, Sílvia; Pagán, Rafael; García-Gonzalo, Diego

2013-01-01

This work explores the bactericidal effect of (+)-limonene, the major constituent of citrus fruits' essential oils, against E. coli. The degree of E. coli BJ4 inactivation achieved by (+)-limonene was influenced by the pH of the treatment medium, being more bactericidal at pH 4.0 than at pH 7.0. Deletion of rpoS and exposure to a sub-lethal heat or an acid shock did not modify E. coli BJ4 resistance to (+)-limonene. However, exposure to a sub-lethal cold shock decreased its resistance to (+)-limonene. Although no sub-lethal injury was detected in the cell envelopes after exposure to (+)-limonene by the selective-plating technique, the uptake of propidium iodide by inactivated E. coli BJ4 cells pointed out these structures as important targets in the mechanism of action. Attenuated Total Reflectance Infrared Microspectroscopy (ATR-IRMS) allowed identification of altered E. coli BJ4 structures after (+)-limonene treatments as a function of the treatment pH: β-sheet proteins at pH 4.0 and phosphodiester bonds at pH 7.0. The increased sensitivity to (+)-limonene observed at pH 4.0 in an E. coli MC4100 lptD4213 mutant with an increased outer membrane permeability along with the identification of altered β-sheet proteins by ATR-IRMS indicated the importance of this structure in the mechanism of action of (+)-limonene. The study of mechanism of inactivation by (+)-limonene led to the design of a synergistic combined process with heat for the inactivation of the pathogen E. coli O157:H7 in fruit juices. These results show the potential of (+)-limonene in food preservation, either acting alone or in combination with lethal heat treatments. PMID:23424676

Mechanism of bacterial inactivation by (+)-limonene and its potential use in food preservation combined processes.

PubMed

Espina, Laura; Gelaw, Tilahun K; de Lamo-Castellví, Sílvia; Pagán, Rafael; García-Gonzalo, Diego

2013-01-01

This work explores the bactericidal effect of (+)-limonene, the major constituent of citrus fruits' essential oils, against E. coli. The degree of E. coli BJ4 inactivation achieved by (+)-limonene was influenced by the pH of the treatment medium, being more bactericidal at pH 4.0 than at pH 7.0. Deletion of rpoS and exposure to a sub-lethal heat or an acid shock did not modify E. coli BJ4 resistance to (+)-limonene. However, exposure to a sub-lethal cold shock decreased its resistance to (+)-limonene. Although no sub-lethal injury was detected in the cell envelopes after exposure to (+)-limonene by the selective-plating technique, the uptake of propidium iodide by inactivated E. coli BJ4 cells pointed out these structures as important targets in the mechanism of action. Attenuated Total Reflectance Infrared Microspectroscopy (ATR-IRMS) allowed identification of altered E. coli BJ4 structures after (+)-limonene treatments as a function of the treatment pH: β-sheet proteins at pH 4.0 and phosphodiester bonds at pH 7.0. The increased sensitivity to (+)-limonene observed at pH 4.0 in an E. coli MC4100 lptD4213 mutant with an increased outer membrane permeability along with the identification of altered β-sheet proteins by ATR-IRMS indicated the importance of this structure in the mechanism of action of (+)-limonene. The study of mechanism of inactivation by (+)-limonene led to the design of a synergistic combined process with heat for the inactivation of the pathogen E. coli O157:H7 in fruit juices. These results show the potential of (+)-limonene in food preservation, either acting alone or in combination with lethal heat treatments.

Phytochemistry, Brine shrimp lethality and mice acute oral toxicity studies on seed extracts of Vernonia anthelmintica.

PubMed

Jamil, Subia; Khan, Rafeeq Alam; Afroz, Syeda; Ahmed, Shadab

2016-11-01

Despite the widespread use of Vernonia anthelmintica seeds in traditional medicine, the need to establish the safety of the Vernonia anthelmintica is required to ascertain the safe use of this herbal medicine. The aim of the present study is to establish the acute toxicity profile of different extracts of Vernonia anthelmintica. Hexane and ethanol extract of Vernonia Anthelmintica has been studied for its brine shrimp lethality potential. Water decoction (WDVA), Hexane (HEVA) and Ethanol (EEVA) extracts of Vernonia anthelmintica has also been evaluated for their in-vivo acute oral toxicity in mice by Lorke's method. Phytochemistry of all three extracts was also evaluated for the presence of their secondary metabolites. All three extracts showed the presence of flavonoids and terpenoids, while alkaloids, tannins and fixed oils were present in HEVA and EEVA. Furthermore EEVA also showed presence of carbohydrates and HEVA also showed the presence of cardiac glycosides. Ethanol and hexane extracts of Vernonia anthelmintica showed a positive cytotoxicity in brine shrimp lethality test at 24 hours with LC50 104.16 (224.0-48.05)μg/ml and 216.11μg/ml (378.2-128.7) respectively as compared to standard drug etoposide LC50 7.46μg/ml. The oral LD50 for EEVA, HEVA and WDVA in mice by Lorke's method was greater than 5000mg/kg. The result of brine shrimp lethality test clearly exhibited the presence of bioactive compounds with cytotoxic potential; however seems to be safe for oral use since LD50 was higher than 5000mg/kg and thus safety of acute dosing in vivo practices is justified.

Enhancement of P2X(7)-induced pore formation and apoptosis: an early effect of diabetes on the retinal microvasculature.

PubMed

Sugiyama, Tetsuya; Kobayashi, Masato; Kawamura, Hajime; Li, Qing; Puro, Donald G; Kobayshi, Masato

2004-03-01

A sight-threatening complication of diabetes is cell death in retinal capillaries. Currently, the mechanisms responsible for this classic manifestation of diabetic retinopathy remain uncertain. The hypothesis for the current study is that diabetes increases the vulnerability of retinal microvessels to the potentially lethal consequences of having their P2X(7) purinoceptors activated. A pathophysiological role is suspected for these receptor-operated channels because, in addition to transducing retinovascular responses to extracellular adenosine triphosphate (ATP), the sustained opening of these channels can induce the formation of large transmembrane pores. In pericyte-containing retinal microvessels that were freshly isolated from nondiabetic and streptozotocin-injected rats, cells with pores were identified by the uptake of YO-PRO-1. Cell viability was assayed by trypan blue dye exclusion, and cleaved caspase-3 immunoreactivity, TUNEL positivity, and nuclear morphology were used to detect apoptotic cells. Patch-clamp recordings assessed electrophysiological parameters. Activation of P2X(7) receptors caused large pores to form and apoptosis to occur in retinal capillaries of nondiabetic and diabetic rats. Of importance to diabetes, the agonist concentration needed to open pores and trigger apoptosis decreased markedly soon after the onset of streptozotocin-induced hyperglycemia. However, despite this increased sensitivity, diabetes minimally affected the P2X(7)-induced ionic currents. Thus, rather than upregulate the number of functional P2X(7) receptor/channels, diabetes appears to facilitate the channel-to-pore transition that occurs during activation of these purinoceptors. In this way, normally nonlethal concentrations of P2X(7) ligands may trigger apoptosis in microvessels of the diabetic retina. A diabetes-induced increase in the vulnerability of retinal microvessels to the lethal effect of P2X(7) receptor activation may be a previously unrecognized mechanism by which diabetic retinopathy progresses.

An H5N1-based matrix protein 2 ectodomain tetrameric peptide vaccine provides cross-protection against lethal infection with H7N9 influenza virus.

PubMed

Leung, Ho-Chuen; Chan, Chris Chung-Sing; Poon, Vincent Kwok-Man; Zhao, Han-Jun; Cheung, Chung-Yan; Ng, Fai; Huang, Jian-Dong; Zheng, Bo-Jian

2015-04-01

In March 2013, a patient infected with a novel avian influenza A H7N9 virus was reported in China. Since then, there have been 458 confirmed infection cases and 177 deaths. The virus contains several human-adapted markers, indicating that H7N9 has pandemic potential. The outbreak of this new influenza virus highlighted the need for the development of universal influenza vaccines. Previously, we demonstrated that a tetrameric peptide vaccine based on the matrix protein 2 ectodomain (M2e) of the H5N1 virus (H5N1-M2e) could protect mice from lethal infection with different clades of H5N1 and 2009 pandemic H1N1 influenza viruses. In this study, we investigated the cross-protection of H5N1-M2e against lethal infection with the new H7N9 virus. Although five amino acid differences existed at positions 13, 14, 18, 20, and 21 between M2e of H5N1 and H7N9, H5N1-M2e vaccination with either Freund's adjuvant or the Sigma adjuvant system (SAS) induced a high level of anti-M2e antibody, which cross-reacted with H7N9-M2e peptide. A mouse-adapted H7N9 strain, A/Anhui/01/2013m, was used for lethal challenge in animal experiments. H5N1-M2e vaccination provided potent cross-protection against lethal challenge of the H7N9 virus. Reduced viral replication and histopathological damage of mouse lungs were also observed in the vaccinated mice. Our results suggest that the tetrameric H5N1-M2e peptide vaccine could protect against different subtypes of influenza virus infections. Therefore, this vaccine may be an ideal candidate for developing a universal vaccine to prevent the reemergence of avian influenza A H7N9 virus and the emergence of potential novel reassortants of influenza virus.

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

Schmidt, Tobias; Bertermann, Rüdiger; Rusch, George M.

2,3,3,3-Tetrafluoropropene (HFO-1234yf) is a novel refrigerant intended for use in mobile air conditioning. It showed a low potential for toxicity in rodents studies with most NOAELs well above 10,000 ppm in guideline compliant toxicity studies. However, a developmental toxicity study in rabbits showed mortality at exposure levels of 5,500 ppm and above. No lethality was observed at exposure levels of 2,500 and 4,000 ppm. Nevertheless, increased subacute inflammatory heart lesions were observed in rabbits at all exposure levels. Since the lethality in pregnant animals may be due to altered biotransformation of HFO-1234yf and to evaluate the potential risk to pregnantmore » women facing a car crash, this study compared the acute toxicity and biotransformation of HFO-1234yf in male, female and pregnant female rabbits. Animals were exposed to 50,000 ppm and 100,000 ppm for 1 h. For metabolite identification by {sup 19}F NMR and LC/MS-MS, urine was collected for 48 h after inhalation exposure. In all samples, the predominant metabolites were S-(3,3,3-trifluoro-2-hydroxypropanyl)-mercaptolactic acid and N-acetyl-S-(3,3,3-trifluoro-2-hydroxypropanyl)-L-cysteine. Since no major differences in urinary metabolite pattern were observed between the groups, only N-acetyl-S-(3,3,3-trifluoro-2-hydroxypropanyl)-L-cysteine excretion was quantified. No significant differences in recovery between non-pregnant (43.10 ± 22.35 μmol) and pregnant female (50.47 ± 19.72 μmol) rabbits were observed, male rabbits exposed to 100,000 ppm for one hour excreted 86.40 ± 38.87 μmol. Lethality and clinical signs of toxicity were not observed in any group. The results suggest that the lethality of HFO-1234yf in pregnant rabbits unlikely is due to changes in biotransformation patterns or capacity in pregnant rabbits. -- Highlights: ► No lethality and clinical signs were observed. ► No differences in metabolic pattern between pregnant and non-pregnant rabbits. ► Rapid and similar metabolite excretion in all groups. ► Very low amount of biotransformation in all groups (< 0.1%).« less

Induction of Immune Mediators in Glioma and Prostate Cancer Cells by Non-Lethal Photodynamic Therapy

PubMed Central

Kammerer, Robert; Buchner, Alexander; Palluch, Patrick; Pongratz, Thomas; Oboukhovskij, Konstantin; Beyer, Wolfgang; Johansson, Ann; Stepp, Herbert; Baumgartner, Reinhold; Zimmermann, Wolfgang

2011-01-01

Background Photodynamic therapy (PDT) uses the combination of photosensitizing drugs and harmless light to cause selective damage to tumor cells. PDT is therefore an option for focal therapy of localized disease or for otherwise unresectable tumors. In addition, there is increasing evidence that PDT can induce systemic anti-tumor immunity, supporting control of tumor cells, which were not eliminated by the primary treatment. However, the effect of non-lethal PDT on the behavior and malignant potential of tumor cells surviving PDT is molecularly not well defined. Methodology/Principal Findings Here we have evaluated changes in the transcriptome of human glioblastoma (U87, U373) and human (PC-3, DU145) and murine prostate cancer cells (TRAMP-C1, TRAMP-C2) after non-lethal PDT in vitro and in vivo using oligonucleotide microarray analyses. We found that the overall response was similar between the different cell lines and photosensitizers both in vitro and in vivo. The most prominently upregulated genes encoded proteins that belong to pathways activated by cellular stress or are involved in cell cycle arrest. This response was similar to the rescue response of tumor cells following high-dose PDT. In contrast, tumor cells dealing with non-lethal PDT were found to significantly upregulate a number of immune genes, which included the chemokine genes CXCL2, CXCL3 and IL8/CXCL8 as well as the genes for IL6 and its receptor IL6R, which can stimulate proinflammatory reactions, while IL6 and IL6R can also enhance tumor growth. Conclusions Our results indicate that PDT can support anti-tumor immune responses and is, therefore, a rational therapy even if tumor cells cannot be completely eliminated by primary phototoxic mechanisms alone. However, non-lethal PDT can also stimulate tumor growth-promoting autocrine loops, as seen by the upregulation of IL6 and its receptor. Thus the efficacy of PDT to treat tumors may be improved by controlling unwanted and potentially deleterious growth-stimulatory pathways. PMID:21738796

Evaluating the lethal and pre-lethal effects of a range of fungi against adult Anopheles stephensi mosquitoes.

PubMed

Blanford, Simon; Jenkins, Nina E; Read, Andrew F; Thomas, Matthew B

2012-11-05

Insecticide resistance is seriously undermining efforts to eliminate malaria. In response, research on alternatives to the use of chemical insecticides against adult mosquito vectors has been increasing. Fungal entomopathogens formulated as biopesticides have received much attention and have shown considerable potential. This research has necessarily focused on relatively few fungal isolates in order to 'prove concept'. Further, most attention has been paid to examining fungal virulence (lethality) and not the other properties of fungal infection that might also contribute to reducing transmission potential. Here, a range of fungal isolates were screened to examine variation in virulence and how this relates to additional pre-lethal reductions in feeding propensity. The Asian malaria vector, Anopheles stephensi was exposed to 17 different isolates of entomopathogenic fungi belonging to species of Beauveria bassiana, Metarhizium anisopliae, Metarhizium acridum and Isaria farinosus. Each isolate was applied to a test substrate at a standard dose rate of 1×109 spores ml-1 and the mosquitoes exposed for six hours. Subsequently the insects were removed to mesh cages where survival was monitored over the next 14 days. During this incubation period the mosquitoes' propensity to feed was assayed for each isolate by offering a feeding stimulant at the side of the cage and recording the number probing. Fungal isolates showed a range of virulence to A. stephensi with some causing >80% mortality within 7 days, while others caused little increase in mortality relative to controls over the study period. Similarly, some isolates had a large impact on feeding propensity, causing >50% pre-lethal reductions in feeding rate, whereas other isolates had very little impact. There was clear correlation between fungal virulence and feeding reduction with virulence explaining nearly 70% of the variation in feeding reduction. However, there were some isolates where either feeding decline was not associated with high virulence, or virulence did not automatically prompt large declines in feeding. These results are discussed in the context of choosing optimum fungal isolates for biopesticide development.

Proposed modification to the specification for dry heat microbial reduction of spacecraft hardware for future US missions

NASA Astrophysics Data System (ADS)

James; Spry, A.; Beaudet, Robert; Schubert, Wayne

Dry heat microbial reduction (DHMR) is the primary technique used to reduce the microbial load of spacecraft and component parts to comply with planetary protection requirements. Often, manufacturing processes involve heating flight hardware to high temperatures for purposes other than planetary protection DHMR. At present, the existing specification in NASA document NPR8020.12C, describing the process lethality on B. atrophaeus (ATCC 9372) bacterial spores, does not allow for additional planetary protection bioburden reduction credit for processing outside a narrow temperature, time and humidity window. However, recent studies (Schubert et al., COSPAR 2008) from a comprehensive multi-year laboratory research effort have generated enhanced data sets on four aspects of the current specification: time and temperature combination effects, the effect that humidity has on spore lethality, the lethality for spores with exceptionally high thermal resistance (so called "hardies"), and the extended exposure requirement for encapsulated microorganisms. This paper describes proposed modifications to the specification, based on the data set generated in the referenced study. The proposed modifications are intended to broaden the scope of the current specification while still maintaining a confident conservative interpretation of the lethality of the DHMR process on microorganisms. Potential cost and schedule benefits to future missions utilizing the revised specification will be highlighted.

Ebola GP-specific monoclonal antibodies protect mice and guinea pigs from lethal Ebola virus infection.

PubMed

Qiu, Xiangguo; Fernando, Lisa; Melito, P Leno; Audet, Jonathan; Feldmann, Heinz; Kobinger, Gary; Alimonti, Judie B; Jones, Steven M

2012-01-01

Ebola virus (EBOV) causes acute hemorrhagic fever in humans and non-human primates with mortality rates up to 90%. So far there are no effective treatments available. This study evaluates the protective efficacy of 8 monoclonal antibodies (MAbs) against Ebola glycoprotein in mice and guinea pigs. Immunocompetent mice or guinea pigs were given MAbs i.p. in various doses individually or as pools of 3-4 MAbs to test their protection against a lethal challenge with mouse- or guinea pig-adapted EBOV. Each of the 8 MAbs (100 µg) protected mice from a lethal EBOV challenge when administered 1 day before or after challenge. Seven MAbs were effective 2 days post-infection (dpi), with 1 MAb demonstrating partial protection 3 dpi. In the guinea pigs each MAb showed partial protection at 1 dpi, however the mean time to death was significantly prolonged compared to the control group. Moreover, treatment with pools of 3-4 MAbs completely protected the majority of animals, while administration at 2-3 dpi achieved 50-100% protection. This data suggests that the MAbs generated are capable of protecting both animal species against lethal Ebola virus challenge. These results indicate that MAbs particularly when used as an oligoclonal set are a potential therapeutic for post-exposure treatment of EBOV infection.

Prevention of Suicidal Behavior in Prisons

PubMed Central

2016-01-01

Abstract. Background: Worldwide, prisoners are at high risk of suicide. Research on near-lethal suicide attempts can provide important insights into risk and protective factors, and inform suicide prevention initiatives in prison. Aims: To synthesize findings of research on near-lethal attempts in prisons, and consider their implications for suicide prevention policies and practice, in the context of other research in custody and other settings. Method: We searched two bibliographic indexes for studies in any language on near-lethal and severe self-harm in prisoners, supplemented by targeted searches over the period 2000–2014. We extracted information on risk factors descriptively. Data were not meta-analyzed owing to heterogeneity of samples and methods. Results: We identified eight studies reporting associations between prisoner near-lethal attempts and specific factors. The latter included historical, prison-related, and clinical factors, including psychiatric morbidity and comorbidity, trauma, social isolation, and bullying. These factors were also identified as important in prisoners' own accounts of what may have contributed to their attempts (presented in four studies). Conclusion: Factors associated with prisoners' severe suicide attempts include a range of potentially modifiable clinical, psychosocial, and environmental factors. We make recommendations to address these factors in order to improve detection, management, and prevention of suicide risk in prisoners. PMID:27278569

Knockdown of genes in the Toll pathway reveals new lethal RNA interference targets for insect pest control.

PubMed

Bingsohn, L; Knorr, E; Billion, A; Narva, K E; Vilcinskas, A

2017-02-01

RNA interference (RNAi) is a promising alternative strategy for ecologically friendly pest management. However, the identification of RNAi candidate genes is challenging owing to the absence of laboratory strains and the seasonality of most pest species. Tribolium castaneum is a well-established model, with a strong and robust RNAi response, which can be used as a high-throughput screening platform to identify potential RNAi target genes. Recently, the cactus gene was identified as a sensitive RNAi target for pest control. To explore whether the spectrum of promising RNAi targets can be expanded beyond those found by random large-scale screening, to encompass others identified using targeted knowledge-based approaches, we constructed a Cactus interaction network. We tested nine genes in this network and found that the delivery of double-stranded RNA corresponding to fusilli and cactin showed lethal effects. The silencing of cactin resulted in 100% lethality at every developmental stage from the larva to the adult. The knockdown of pelle, Dorsal-related immunity factor and short gastrulation reduced or even prevented egg hatching in the next generation. The combination of such targets with lethal and parental RNAi effects can now be tested against different pest species in field studies. © 2016 The Royal Entomological Society.

Multidisciplinary Intervention of Early, Lethal Metastatic Prostate Cancer: Report From the 2015 Coffey-Holden Prostate Cancer Academy Meeting

PubMed Central

Miyahira, Andrea K.; Lang, Joshua M.; Den, Robert B.; Garraway, Isla P.; Lotan, Tamara L.; Ross, Ashley E.; Stoyanova, Tanya; Cho, Steve Y.; Simons, Jonathan W.; Pienta, Kenneth J.; Soule, Howard R.

2018-01-01

BACKGROUND The 2015 Coffey-Holden Prostate Cancer Academy Meeting, themed: “Multidisciplinary Intervention of Early, Lethal Metastatic Prostate Cancer,” was held in La Jolla, California from June 25 to 28, 2015. METHODS The Prostate Cancer Foundation (PCF) sponsors an annual, invitation-only, action-tank-structured meeting on a critical topic concerning lethal prostate cancer. The 2015 meeting was attended by 71 basic, translational, and clinical investigators who discussed the current state of the field, major unmet needs, and ideas for addressing earlier diagnosis and treatment of men with lethal prostate cancer for the purpose of extending lives and making progress toward a cure. RESULTS The questions addressed at the meeting included: cellular and molecular mechanisms of tumorigenesis, evaluating, and targeting the microenvironment in the primary tumor, advancing biomarkers for clinical integration, new molecular imaging technologies, clinical trials, and clinical trial design in localized high-risk and oligometastatic settings, targeting the primary tumor in advanced disease, and instituting multi-modal care of high risk and oligometastatic patients. DISCUSSION This article highlights the current status, greatest unmet needs, and anticipated field changes that were discussed at the meeting toward the goal of optimizing earlier interventions to potentiate cures in high-risk and oligometastatic prostate cancer patients. PMID:26477609

The Novel Application of Non-Lethal Citizen Science Tissue Sampling in Recreational Fisheries.

PubMed

Williams, Samuel M; Holmes, Bonnie J; Pepperell, Julian G

2015-01-01

Increasing fishing pressure and uncertainty surrounding recreational fishing catch and effort data promoted the development of alternative methods for conducting fisheries research. A pilot investigation was undertaken to engage the Australian game fishing community and promote the non-lethal collection of tissue samples from the black marlin Istiompax indica, a valuable recreational-only species in Australian waters, for the purpose of future genetic research. Recruitment of recreational anglers was achieved by publicizing the project in magazines, local newspapers, social media, blogs, websites and direct communication workshops at game fishing tournaments. The Game Fishing Association of Australia and the Queensland Game Fishing Association were also engaged to advertise the project and recruit participants with a focus on those anglers already involved in the tag-and-release of marlin. Participants of the program took small tissue samples using non-lethal methods which were stored for future genetic analysis. The program resulted in 165 samples from 49 participants across the known distribution of I. indica within Australian waters which was a sufficient number to facilitate a downstream population genetic analysis. The project demonstrated the potential for the development of citizen science sampling programs to collect tissue samples using non-lethal methods in order to achieve targeted research objects in recreationally caught species.

Multidisciplinary intervention of early, lethal metastatic prostate cancer: Report from the 2015 Coffey-Holden Prostate Cancer Academy Meeting.

PubMed

Miyahira, Andrea K; Lang, Joshua M; Den, Robert B; Garraway, Isla P; Lotan, Tamara L; Ross, Ashley E; Stoyanova, Tanya; Cho, Steve Y; Simons, Jonathan W; Pienta, Kenneth J; Soule, Howard R

2016-02-01

The 2015 Coffey-Holden Prostate Cancer Academy Meeting, themed: "Multidisciplinary Intervention of Early, Lethal Metastatic Prostate Cancer," was held in La Jolla, California from June 25 to 28, 2015. The Prostate Cancer Foundation (PCF) sponsors an annual, invitation-only, action-tank-structured meeting on a critical topic concerning lethal prostate cancer. The 2015 meeting was attended by 71 basic, translational, and clinical investigators who discussed the current state of the field, major unmet needs, and ideas for addressing earlier diagnosis and treatment of men with lethal prostate cancer for the purpose of extending lives and making progress toward a cure. The questions addressed at the meeting included: cellular and molecular mechanisms of tumorigenesis, evaluating, and targeting the microenvironment in the primary tumor, advancing biomarkers for clinical integration, new molecular imaging technologies, clinical trials, and clinical trial design in localized high-risk and oligometastatic settings, targeting the primary tumor in advanced disease, and instituting multi-modal care of high risk and oligometastatic patients. This article highlights the current status, greatest unmet needs, and anticipated field changes that were discussed at the meeting toward the goal of optimizing earlier interventions to potentiate cures in high-risk and oligometastatic prostate cancer patients. © 2015 Wiley Periodicals, Inc.

Sub-lethal effects of essential oil of Lippia sidoides on drywood termite Cryptotermes brevis (Blattodea: Termitoidea).

PubMed

Santos, Abraão Almeida; de Oliveira, Bruna Maria Santos; Melo, Carlisson Ramos; Lima, Ana Paula Santana; Santana, Emile Dayara Rabelo; Blank, Arie Fitzgerald; Picanço, Marcelo Coutinho; Araújo, Ana Paula Albano; Cristaldo, Paulo Fellipe; Bacci, Leandro

2017-11-01

The drywood termite Cryptotermes brevis (Walker, 1853) (Kalotermitidae) is one of the most important wood structural pest in the world. Substances from the secondary metabolism of plants (e.g., essential oils) have been considered an environmentally safer form of control for urban pests, such as termites. In the present study, we analyzed the lethal and sub-lethal effects of essential oil of Lippia sidoides and its major components on C. brevis pseudergates in two routes of exposure (contact and fumigation). The essential oil of L. sidoides and thymol were more toxic to C. brevis pseudergates when applied by contact (LD 50 = 9.33 and 8.20µgmg -1 , respectively) and by fumigation (LC 50 = 9.10 and 23.6µLL -1 , respectively). In general, treatments changed the individual and collective behaviors of C. brevis pseudergates, as well as the displacement and walking speed. The essential oil of L. sidoides and its major components showed a high potential to control C. brevis pseudergates, due to the bioactivity in the two routes of exposure and the sub-lethal effects on the behavior and walking, important activities for the cohesion of C. brevis colonies. Copyright © 2017 Elsevier Inc. All rights reserved.

LSD1 activates a lethal prostate cancer gene network independently of its demethylase function.

PubMed

Sehrawat, Archana; Gao, Lina; Wang, Yuliang; Bankhead, Armand; McWeeney, Shannon K; King, Carly J; Schwartzman, Jacob; Urrutia, Joshua; Bisson, William H; Coleman, Daniel J; Joshi, Sunil K; Kim, Dae-Hwan; Sampson, David A; Weinmann, Sheila; Kallakury, Bhaskar V S; Berry, Deborah L; Haque, Reina; Van Den Eeden, Stephen K; Sharma, Sunil; Bearss, Jared; Beer, Tomasz M; Thomas, George V; Heiser, Laura M; Alumkal, Joshi J

2018-05-01

Medical castration that interferes with androgen receptor (AR) function is the principal treatment for advanced prostate cancer. However, clinical progression is universal, and tumors with AR-independent resistance mechanisms appear to be increasing in frequency. Consequently, there is an urgent need to develop new treatments targeting molecular pathways enriched in lethal prostate cancer. Lysine-specific demethylase 1 (LSD1) is a histone demethylase and an important regulator of gene expression. Here, we show that LSD1 promotes the survival of prostate cancer cells, including those that are castration-resistant, independently of its demethylase function and of the AR. Importantly, this effect is explained in part by activation of a lethal prostate cancer gene network in collaboration with LSD1's binding protein, ZNF217. Finally, that a small-molecule LSD1 inhibitor-SP-2509-blocks important demethylase-independent functions and suppresses castration-resistant prostate cancer cell viability demonstrates the potential of LSD1 inhibition in this disease.

Survival of Escherichia coli under lethal heat stress by L-form conversion.

PubMed

Markova, Nadya; Slavchev, Georgi; Michailova, Lilia; Jourdanova, Mimi

2010-06-09

Transition of bacteria to cell wall deficient L-forms in response to stress factors has been assumed as a potential mechanism for survival of microbes under unfavorable conditions. In this article, we provide evidence of paradoxal survival through L-form conversion of E. coli high cell density population after lethal treatments (boiling or autoclaving). Light and transmission electron microscopy demonstrated conversion from classical rod to polymorphic L-form shape morphology and atypical growths of E. coli. Microcrystal formations observed at this stage were interpreted as being closely linked to the processes of L-form conversion and probably involved in the general phenomenon of protection against lethal environment. Identity of the morphologically modified L-forms as E. coli was verified by species specific DNA-based test. Our study might contribute to a better understanding of the L-form phenomenon and its importance for bacterial survival, as well as provoke reexamination of the traditional view of killing strategies against bacteria.

Survival of Escherichia coli under lethal heat stress by L-form conversion

PubMed Central

Markova, Nadya; Slavchev, Georgi; Michailova, Lilia; Jourdanova, Mimi

2010-01-01

Transition of bacteria to cell wall deficient L-forms in response to stress factors has been assumed as a potential mechanism for survival of microbes under unfavorable conditions. In this article, we provide evidence of paradoxal survival through L-form conversion of E. coli high cell density population after lethal treatments (boiling or autoclaving). Light and transmission electron microscopy demonstrated conversion from classical rod to polymorphic L-form shape morphology and atypical growths of E. coli. Microcrystal formations observed at this stage were interpreted as being closely linked to the processes of L-form conversion and probably involved in the general phenomenon of protection against lethal environment. Identity of the morphologically modified L-forms as E. coli was verified by species specific DNA-based test. Our study might contribute to a better understanding of the L-form phenomenon and its importance for bacterial survival, as well as provoke reexamination of the traditional view of killing strategies against bacteria. PMID:20582223

Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis

PubMed Central

Wang, Zeneng; Roberts, Adam B.; Buffa, Jennifer A.; Levison, Bruce S.; Zhu, Weifei; Org, Elin; Gu, Xiaodong; Huang, Ying; Zamanian-Daryoush, Maryam; Culley, Miranda K.; DiDonato, Anthony J.; Fu, Xiaoming; Hazen, Jennie E.; Krajcik, Daniel; DiDonato, Joseph A.; Lusis, Aldons J.; Hazen, Stanley L.

2016-01-01

SUMMARY Trimethylamine N-oxide (TMAO), a gut microbiota dependent metabolite, both enhances atherosclerosis in animal models and is associated with cardiovascular risks in clinical studies. Here we investigate the impact of targeted inhibition of the first step in TMAO generation, commensal microbial trimethylamine (TMA) production, on diet-induced atherosclerosis. A structural analogue of choline, 3,3-dimethyl-1-butanol (DMB), is shown to non-lethally inhibit TMA formation from cultured microbes, to inhibit distinct microbial TMA lyases, and to both inhibit TMA production from physiologic polymicrobial cultures (eg intestinal contents, human feces) and reduce TMAO levels in mice fed a high choline or carnitine diet. DMB inhibited choline diet-enhanced endogenous macrophage foam cell formation and atherosclerotic lesion development in apolipoprotein e−/− mice without alterations in circulating cholesterol levels. The present studies suggest gut microbial production of TMA specifically, and non-lethal microbial inhibitors in general, may serve as a potential therapeutic approach for the treatment of cardiometabolic diseases. PMID:26687352

CHARACTERIZATION OF VIRULENCE OF Leptospira ISOLATES IN A HAMSTER MODEL

PubMed Central

Silva, Éverton F.; Santos, Cleiton S.; Athanazio, Daniel A.; Seyffert, Núbia; Seixas, Fabiana K.; Cerqueira, Gustavo M.; Fagundes, Michel Q.; Brod, Claudiomar S.; Reis, Mitermayer G.; Dellagostin, Odir A.; Ko, Albert I.

2008-01-01

Effort has been made to identify protective antigens in order to develop a recombinant vaccine against leptospirosis. Several attempts failed to conclusively demonstrate efficacy of vaccine candidates due to the lack of an appropriate model of lethal leptospirosis. The purposes of our study were: (i) to test the virulence of leptospiral isolates from Brazil, which are representative of important serogroups that cause disease in humans and animals; and (ii) to standardize the lethal dose 50% (LD50) for each of the virulent strains using a hamster (Mesocricetus auratus) model. Five of seven Brazilian isolates induced lethality in a hamster model, with inocula lower than 200 leptospires. Histopathological examination of infected animals showed typical lesions found in both natural and experimental leptospirosis. Results described here demonstrated the potential use of Brazilian isolates as highly virulent strains in challenge experiments using hamster as an appropriate animal model for leptospirosis. Furthermore these strains may be useful in heterologous challenge studies which aim to evaluate cross-protective responses induced by subunit vaccine candidates. PMID:18547690

Kunjin Virus Replicon-Based Vaccines Expressing Ebola Virus Glycoprotein GP Protect the Guinea Pig Against Lethal Ebola Virus Infection

PubMed Central

Reynard, O.; Mokhonov, V.; Mokhonova, E.; Leung, J.; Page, A.; Mateo, M.; Pyankova, O.; Georges-Courbot, M. C.; Raoul, H.; Khromykh, A. A.

2011-01-01

Pre- or postexposure treatments against the filoviral hemorrhagic fevers are currently not available for human use. We evaluated, in a guinea pig model, the immunogenic potential of Kunjin virus (KUN)–derived replicons as a vaccine candidate against Ebola virus (EBOV). Virus like particles (VLPs) containing KUN replicons expressing EBOV wild-type glycoprotein GP, membrane anchor-truncated GP (GP/Ctr), and mutated GP (D637L) with enhanced shedding capacity were generated and assayed for their protective efficacy. Immunization with KUN VLPs expressing full-length wild-type and D637L-mutated GPs but not membrane anchor–truncated GP induced dose-dependent protection against a challenge of a lethal dose of recombinant guinea pig-adapted EBOV. The surviving animals showed complete clearance of the virus. Our results demonstrate the potential for KUN replicon vectors as vaccine candidates against EBOV infection. PMID:21987742

Kratom: a dangerous player in the opioid crisis.

PubMed

Tayabali, Khadija; Bolzon, Colin; Foster, Paul; Patel, Janki; Kalim, Mohammad Omar

2018-01-01

Kratom use as a herbal supplement is on the rise in the United States, with reported medical outcomes and lethal effects suggesting a public health threat. Even though the Drug Enforcement Administration has included kratom on its drugs of concern list and the FDA has published a press release to identify it as an opioid with a potential for abuse, its therapeutic and side effects are still not well defined in the literature. Here, we present a case of a 32-year-old man with a history of kratom use who became acutely ill with a brief prodromal illness, followed by jaundice and elevated liver enzymes showing a cholestatic picture, and his successful treatment. In this case, we emphasize the need for awareness of kratom exposure as a key contributor in the expansion of the opioid crisis, with therapeutic benefits earned at the expense of potentially lethal side effects.

Fentanyl novel derivative-related deaths.

PubMed

Giorgetti, Arianna; Centola, Carmela; Giorgetti, Raffaele

2017-05-01

Fentanyl (FEN) is a potent, synthetic narcotic used as an anaesthetic and a pain reliever, but also illegally manufactured. For diversion purpose, it is being steadily modified to produce new analogous compounds and derivatives (FENS), categorised as novel psychoactive substances. While potential FEN abuse is already known, even in the absence of a clear lethal dosage, there is still a shortage of data on its derivatives. A literature review of FENS-related deaths was performed, to better understand potential damage and future perspectives of FEN congeners. Epidemiological data, pathological findings, administration routes, average concentrations and lethal doses, toxicological issues, trends in misuses, comparison among FENS, and possible explanation for FENS abuse are reviewed and discussed in depth. This study provides a medical-legal and toxicological assessment of this phenomenon in order to understand the role of illegal fentanyl and its congeners in deaths from FENS overdose. Copyright © 2017 John Wiley & Sons, Ltd.

Synthetic Lethal Screens Identify Vulnerabilities in GPCR Signaling and Cytoskeletal Organization in E-Cadherin-Deficient Cells.

PubMed

Telford, Bryony J; Chen, Augustine; Beetham, Henry; Frick, James; Brew, Tom P; Gould, Cathryn M; Single, Andrew; Godwin, Tanis; Simpson, Kaylene J; Guilford, Parry

2015-05-01

The CDH1 gene, which encodes the cell-to-cell adhesion protein E-cadherin, is frequently mutated in lobular breast cancer (LBC) and diffuse gastric cancer (DGC). However, because E-cadherin is a tumor suppressor protein and lost from the cancer cell, it is not a conventional drug target. To overcome this, we have taken a synthetic lethal approach to determine whether the loss of E-cadherin creates druggable vulnerabilities. We first conducted a genome-wide siRNA screen of isogenic MCF10A cells with and without CDH1 expression. Gene ontology analysis demonstrated that G-protein-coupled receptor (GPCR) signaling proteins were highly enriched among the synthetic lethal candidates. Diverse families of cytoskeletal proteins were also frequently represented. These broad classes of E-cadherin synthetic lethal hits were validated using both lentiviral-mediated shRNA knockdown and specific antagonists, including the JAK inhibitor LY2784544, Pertussis toxin, and the aurora kinase inhibitors alisertib and danusertib. Next, we conducted a 4,057 known drug screen and time course studies on the CDH1 isogenic MCF10A cell lines and identified additional drug classes with linkages to GPCR signaling and cytoskeletal function that showed evidence of E-cadherin synthetic lethality. These included multiple histone deacetylase inhibitors, including vorinostat and entinostat, PI3K inhibitors, and the tyrosine kinase inhibitors crizotinib and saracatinib. Together, these results demonstrate that E-cadherin loss creates druggable vulnerabilities that have the potential to improve the management of both sporadic and familial LBC and DGC. ©2015 American Association for Cancer Research.

Immunization with a Novel Human type 5 Adenovirus-Vectored Vaccine Expressing the Premembrane and Envelope Proteins of Zika Virus Provides Consistent and Sterilizing Protection in Multiple Immunocompetent and Immunocompromised Animal Models.

PubMed

Guo, Qiang; Chan, Jasper Fuk-Woo; Poon, Vincent Kwok-Man; Wu, Shipo; Chan, Chris Chung-Sing; Hou, Lihua; Yip, Cyril Chik-Yan; Ren, Changpeng; Cai, Jian-Piao; Zhao, Mengsu; Zhang, Anna Jinxia; Song, Xiaohong; Chan, Kwok-Hung; Wang, Busen; Kok, Kin-Hang; Wen, Yanbo; Yuen, Kwok-Yung; Chen, Wei

2018-03-29

Zika virus (ZIKV) infection may be associated with severe complications and disseminated via both vector-borne and non-vector-borne routes. Adenovirus-vectored vaccines represent a favorable controlling measure for the ZIKV epidemic as they have been shown to be safe, immunogenic, and rapidly generable for other emerging viral infections. Evaluations of two previously reported adenovirus-vectored ZIKV vaccines were performed using non-lethal animal models and/or non-epidemic ZIKV strain. We constructed and evaluated two human adenovirus-5-vectored vaccines containing the ZIKV premembrane-envelope(Ad5-Sig-prM-Env) and envelope(Ad5-Env) proteins, respectively, in multiple non-lethal and lethal animal models using epidemic ZIKV strains. Both vaccines elicited robust humoral and cellular immune responses in immunocompetent BALB/c mice. Dexamethasone-immunosuppressed mice vaccinated with either vaccine demonstrated robust and durable antibody responses and significantly lower blood/tissue viral loads than controls(P<0.05). Similar findings were also observed in interferon-α/β-receptor-deficient A129 mice. In both these immunocompromised animal models, Ad5-Sig-prM-Env-vaccinated mice had significantly(P<0.05) higher titers of anti-ZIKV-specific neutralizing antibody titers and lower(undetectable) viral loads than Ad5-Env-vaccinated mice. The close correlation between the neutralizing antibody titer and viral load helped to explain the better protective effect of Ad5-Sig-prM-Env than Ad5-Env. Anamnestic response was absent in Ad5-Sig-prM-Env-vaccinated A129 mice. Ad5-Sig-prM-Env provided sterilizing protection against ZIKV infection in mice.

Non-Lethal Weapons Program

Science.gov Websites

), 26th Marine Expeditionary Unit (MEU), practice non-lethal control techniques during a non-lethal Skip to main content (Press Enter). Toggle navigation Non-Lethal Weapons Program Search Search JNLWP: Search Search JNLWP: Search Non-Lethal Weapons Program U.S. Department of Defense Non-Lethal

[Bladder tumor lethality. Results in the autonomous community of Rioja between 1975-1991].

PubMed

Fernández Fernández, A; Gil Fabra, J; Fernández Ruíz, M; Angulo Castellanos, M G; Blanco Martín, E; Otero Mauricio, G

1998-01-01

Between 1975-1991, a total of 557 cases of bladder carcinoma were identified in the Autonomous Community of La Rioja (CAR) which were followed up to December 1994. The overall lethality was 21.9%. 492 cases with 22.35% lethality were identified in males. In females, however, there was 65 cases with 18.46% lethality. The comparison of males and females lethality resulted in p = 0.525. Lethality between cases diagnosed within each 5-year period analyzed is: 1975-1981: 177 cases, lethality 23.72%. 1982-1986: 168 cases, lethality 30.95%. 1987-1991: 212 cases, lethality 13.20%. Between the first and the second 5-year periods, p = 0.132; between the first and third 5-year periods p = 0.007 and between the second and third 5-year periods p < 0.000. Bladder tumours accounts in CAR for a 22.35% lethality. Lethality is higher in males that in females but the difference is not statistically significant. In the last 5-year period assessed, 1987-1991, a reduction of lethality from bladder neoplasms has been documented.

Insights into the CuO nanoparticle ecotoxicity with suitable marine model species.

PubMed

Rotini, A; Gallo, A; Parlapiano, I; Berducci, M T; Boni, R; Tosti, E; Prato, E; Maggi, C; Cicero, A M; Migliore, L; Manfra, L

2018-01-01

Metal oxide nanoparticles, among them copper oxide nanoparticles (CuO NPs), are widely used in different applications (e.g. batteries, gas sensors, superconductors, plastics and metallic coatings), increasing their potential release in the environment. In aquatic matrix, the behavior of CuO NPs may strongly change, depending on their surface charge and some physical-chemical characteristics of the medium (e.g. ionic strength, salinity, pH and natural organic matter content). Ecotoxicity of CuO NPs to aquatic organisms was mainly studied on freshwater species, few tests being performed on marine biota. The aim of this study was to assess the toxicity of CuO NPs on suitable indicator species, belonging to the ecologically relevant level of consumers. The selected bioassays use reference protocols to identify Effect/Lethal Concentrations (E(L)C), by assessing lethal and sub-lethal endpoints. Mortality tests were performed on rotifer (Brachionus plicatilis), shrimp (Artemia franciscana) and copepod (Tigriopus fulvus). While moult release failure and fertilization rate were studied, as sub-lethal endpoints, on T. fulvus and sea urchin (Paracentrotus lividus), respectively. The size distribution and sedimentation rates of CuO NPs, together with the copper dissolution, were also analyzed in the exposure media. The CuO NP ecotoxicity assessment showed a concentration-dependent response for all species, indicating similar mortality for B. plicatilis (48hLC 50 = 16.94 ± 2.68mg/l) and T. fulvus (96hLC 50 = 12.35 ± 0.48mg/l), followed by A. franciscana (48hLC 50 = 64.55 ± 3.54mg/l). Comparable EC 50 values were also obtained for the sub-lethal endpoints in P. lividus (EC 50 = 2.28 ± 0.06mg/l) and T. fulvus (EC 50 = 2.38 ± 0.20mg/l). Copper salts showed higher toxicity than CuO NPs for all species, with common sensitivity trend as follows: P. lividus ≥ T. fulvus (sublethal endpoint) ≥ B. plicatilis >T. fulvus (lethal endpoint) >A. franciscana. CuO NP micrometric aggregates and high sedimentation rates were observed in the exposure media, with different particle size distributions depending on the medium. The copper dissolution was about 0.16% of the initial concentration, comparable to literature values. The integrated ecotoxicological-physicochemical approach was used to better describe CuO NP toxicity and behavior. In particular, the successful application of ecotoxicological reference protocols allowed to produce reliable L(E)C data useful to identify thresholds and assess potential environmental hazard due to NPs. Copyright © 2017 Elsevier Inc. All rights reserved.

The Combination of Cobinamide and Sulfanegen Is Highly Effective in Mouse Models of Cyanide Poisoning

PubMed Central

Chan, Adriano; Crankshaw, Daune L.; Monteil, Alexandre; Patterson, Steven E.; Nagasawa, Herbert T.; Briggs, Jackie E.; Kozocas, Joseph A.; Mahon, Sari B.; Brenner, Matthew; Pilz, Renate B.; Bigby, Timothy D.; Boss, Gerry R.

2013-01-01

SUMMARY Context Cyanide poisoning is a major contributor to death in smoke inhalation victims and accidental exposure to cyanide occurs in a variety of industries. Moreover, cyanide has the potential to be used by terrorists, particularly in a closed space such as an airport or train station. Current therapies for cyanide poisoning must be given by intravenous administration, limiting their use in treating mass casualties. Objective We are developing two new cyanide antidotes—cobinamide, a vitamin B12 analog, and sulfanegen, a 3-mercaptopyruvate prodrug. Both drugs can be given by intramuscular administration, and therefore could be used to treat a large number of people quickly. We now asked if the two drugs would have an augmented effect when combined. Materials and Methods We used a non-lethal and two different lethal models of cyanide poisoning in mice. The non-lethal model assesses neurologic recovery by quantitatively evaluating the innate righting reflex time of a mouse. The two lethal models are a cyanide injection and a cyanide inhalation model. Results We found that the two drugs are at least additive when used together in both the non-lethal and lethal models: at doses where all animals died with either drug alone, the combination yielded 80 and 40% survival in the injection and inhalation models, respectively. Similarly, drug doses that yielded 40% survival with either drug alone yielded 80 and 100% survival in the injection and inhalatiion models, respectively. As part of the inhalation model, we developed a new paradigm in which animals are exposed to cyanide gas, injected intramuscularly with antidote, and then re-exposed to cyanide gas. This simulates cyanide exposure of a large number of people in a closed space, because people would remain exposed to cyanide, even after receiving an antidote. Conclusion The combination of cobinamide and sulfanegen shows great promise as a new approach to treating cyanide poisoning. PMID:21740135

Infectious Complications in Children With Acute Myeloid Leukemia and Down Syndrome: Analysis of the Prospective Multicenter Trial AML-BFM 2004.

PubMed

Hassler, Angela; Bochennek, Konrad; Gilfert, Julia; Perner, Corinna; Schöning, Stefan; Creutzig, Ursula; Reinhardt, Dirk; Lehrnbecher, Thomas

2016-06-01

Children with acute myeloid leukemia (AML) and Down syndrome have high survival rates with intensity-reduced chemotherapeutic regimens, although the optimal balance between dose intensity and treatment toxicity has not been determined. We, therefore, characterized infectious complications in children with AML and Down syndrome treated according to AML-BFM 2004 study (ClinicalTrials.gov NCT00111345; amended 2006 for Down syndrome with reduced intensity). Data on infectious complications were gathered from the medical records in the hospital where the patient was treated. Infectious complications were categorized as fever without identifiable source (FUO), or as microbiologically or clinically documented infections. A total of 157 infections occurred in 61 patients (60.5% FUO, 9.6% and 29.9% clinically and microbiologically documented infections, respectively). Almost 90% of the pathogens isolated from the bloodstream were Gram-positive bacteria, and approximately half of them were viridans group streptococci. All seven microbiologically documented episodes of pneumonia were caused by viruses. Infection-related mortality was 4.9%, and all three patients died due to viral infection. Our data demonstrate that a reduced-intensity chemotherapeutic regimen in children with AML and Down syndrome is still associated with high morbidity. Although no patient died due to bacteria or fungi, viruses were responsible for all lethal events. Future studies, therefore, have to focus on the impact of viruses on morbidity and mortality of patients with AML and Down syndrome. © 2016 Wiley Periodicals, Inc.

Positron emission tomography quantification of serotonin(1A) receptor binding in suicide attempters with major depressive disorder.

PubMed

Sullivan, Gregory M; Oquendo, Maria A; Milak, Matthew; Miller, Jeffrey M; Burke, Ainsley; Ogden, R Todd; Parsey, Ramin V; Mann, J John

2015-02-01

Serotonergic system dysfunction has been associated with increased lethal suicide attempts and suicide. Dysfunction includes higher binding of serotonin(1A) autoreceptor in the brainstem raphe of individuals who die by suicide. To determine the relationships between brain serotonin(1A) binding and suicidal behavior in vivo in major depressive disorder (MDD) using positron emission tomography and the serotonin(1A) antagonist radiotracer carbon C 11 [11C]-labeled WAY-100635. Cross-sectional positron emission tomography study at an academic medical center from 1999 through 2009. We compared serotonin(1A) binding between individuals with MDD who did not attempt suicide (nonattempters) (n = 62) and those who attempted suicide (attempters) (n = 29). We subdivided the attempters into those with lower (n = 16) and higher (n = 13) levels of lethality. The binding potential (BPF) of [11C]WAY-100635 (calculated as the number of receptors available divided by affinity) in the prefrontal cortex (PFC) and brainstem, estimated by kinetic modeling with an arterial input function; the severity of suicidal behaviors, including lethality and intent of suicide attempts; and suicidal ideation. Using a linear mixed-effects model, we found no difference between attempters and nonattempters with MDD in serotonin(1A) BPF in the PFC regions (F1,88 = 0.03; P = .87) or in the raphe nuclei (F1,88 = 0.29; P = .59). Raphe nuclei serotonin(1A) BPF was 45.1% greater in higher-lethality attempters compared with lower-lethality attempters (F1,25 = 7.33; P = .01), whereas no difference was observed in the PFC regions (F1,25 = 0.12; P = .73). Serotonin(1A )BPF in the raphe nuclei of suicide attempters was positively correlated with the lethality rating (F1,25 = 10.56; P = .003) and the subjective lethal intent factor (F1,25 = 10.63; P = .003; R2 = 0.32) based on the most recent suicide attempt. Suicide ideation in participants with MDD was positively correlated with serotonin(1A) BPF in the PFC regions (F1,88 = 5.19; P = .03) and in the raphe nuclei (F1,87 = 7.38; P = .008; R2 = 0.12). Higher brainstem raphe serotonin(1A)BPF observed in higher-lethality suicide attempters with MDD is in agreement with findings in suicide studies and also with the finding of low cerebrospinal fluid levels of 5-hydroxyindoleacetic acid in higher-lethality suicide attempters. Higher brainstem raphe serotonin(1A) BPF would be consistent with lower levels of serotonin neuron firing and release and supports a model of impaired serotonin signaling in suicide and higher-lethality suicidal behavior. Severity of suicidal ideation in MDD is related to brainstem and prefrontal serotonin(1A) BPF, suggesting a role for both regions in suicidal ideation. Lower levels of serotonin release at key brain projection sites, such as the prefrontal regions, may favor more severe suicidal ideation and higher-lethality suicide attempts.

Positron Emission Tomography Quantification of Serotonin1A Receptor Binding in Suicide Attempters With Major Depressive Disorder

PubMed Central

Sullivan, Gregory M.; Oquendo, Maria A.; Milak, Matthew; Miller, Jeffrey M.; Burke, Ainsley; Ogden, R. Todd; Parsey, Ramin V.; Mann, J. John

2015-01-01

IMPORTANCE Serotonergic system dysfunction has been associated with increased lethal suicide attempts and suicide. Dysfunction includes higher binding of serotonin1A autoreceptor in the brainstem raphe of individuals who die by suicide. OBJECTIVES To determine the relationships between brain serotonin1A binding and suicidal behavior in vivo in major depressive disorder (MDD) using positron emission tomography and the serotonin1A antagonist radiotracer carbon C 11 [11C]–labeled WAY-100635. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional positron emission tomography study at an academic medical center from 1999 through 2009. We compared serotonin1A binding between individuals with MDD who did not attempt suicide (nonattempters) (n = 62) and those who attempted suicide (attempters) (n = 29). We subdivided the attempters into those with lower (n = 16) and higher (n = 13) levels of lethality. MAIN OUTCOMES AND MEASURES The binding potential (BPF) of [11C]WAY-100635 (calculated as the number of receptors available divided by affinity) in the prefrontal cortex (PFC) and brainstem, estimated by kinetic modeling with an arterial input function; the severity of suicidal behaviors, including lethality and intent of suicide attempts; and suicidal ideation. RESULTS Using a linear mixed-effects model, we found no difference between attempters and nonattempters with MDD in serotonin1A BPF in the PFC regions (F1,88 = 0.03; P = .87) or in the raphe nuclei (F1,88 = 0.29; P = .59). Raphe nuclei serotonin1A BPF was 45.1% greater in higher-lethality attempters compared with lower-lethality attempters (F1,25 = 7.33; P = .01), whereas no difference was observed in the PFC regions (F1,25 = 0.12; P = .73). Serotonin1A BPF in the raphe nuclei of suicide attempters was positively correlated with the lethality rating (F1,25 = 10.56; P = .003) and the subjective lethal intent factor (F1,25 = 10.63; P = .003; R2 = 0.32) based on the most recent suicide attempt. Suicide ideation in participants with MDD was positively correlated with serotonin1A BPF in the PFC regions (F1,88 = 5.19; P = .03) and in the raphe nuclei (F1,87 = 7.38; P = .008; R2 = 0.12). CONCLUSIONS AND RELEVANCE Higher brainstem raphe serotonin1A BPF observed in higher-lethality suicide attempters with MDD is in agreement with findings in suicide studies and also with the finding of low cerebrospinal fluid levels of 5-hydroxyindoleacetic acid in higher-lethality suicide attempters. Higher brainstem raphe serotonin1A BPF would be consistent with lower levels of serotonin neuron firing and release and supports a model of impaired serotonin signaling in suicide and higher-lethality suicidal behavior. Severity of suicidal ideation in MDD is related to brainstem and prefrontal serotonin1A BPF, suggesting a role for both regions in suicidal ideation. Lower levels of serotonin release at key brain projection sites, such as the prefrontal regions, may favor more severe suicidal ideation and higher-lethality suicide attempts. PMID:25549105

Transcatheter arterial embolisation in upper gastrointestinal bleeding in a sample of 29 patients in a gastrointestinal referral center in Germany.

PubMed

Heining-Kruz, S; Finkenzeller, T; Schreyer, A; Dietl, K H; Kullmann, F; Paetzel, C; Schedel, J

2015-09-01

This is a retrospective analysis of interventional embolisation performed with catheter angiography in 29 patients with upper gastrointestinal bleeding in the setting of a secondary care hospital. From April 2007 to February 2013, 29 patients with upper gastrointestinal bleeding underwent endovascular diagnostics and treatment. The diagnosis was established by endoscopy, computed tomography or clinically based on a significant decrease in hemoglobin. Transcatheter arterial embolisation was performed with coils, liquid embolic agents, and particles. The technical and clinical outcomes were assessed by postinterventional endoscopy, hemoglobin concentrations, number of necessary transfusions, or surgical interventions, as well as by post-interventional mortality within 28 days after the procedure. Selective angiographic embolisation in upper gastrointestinal bleeding was primarily successful technically and clinically in 22 of 29 patients. In 4/29 cases an angiographic reintervention was performed, which was successful in 3 cases. In 3 cases of primarily technically unsuccessful procedures reintervention was not attempted. No catheterisation-related complications were recorded. Peri-interventional mortality was 31%, but only 2 of these patients died due to uncontrolled massive bleeding, whereas the lethal outcome in the other 7 patients was due to their underlying diseases. Transcatheter arterial embolisation is an effective and rapid method in the management of upper gastrointestinal bleeding. Radiological endovascular interventions may considerably contribute to reduced mortality in GI bleeding by avoiding a potential surgical procedure following unsuccessful endoscopic treatment. The study underlines the importance of the combination of interventional endoscopy with interventional radiology in secondary care hospitals for patient outcome in complex and complicated upper gastrointestinal bleeding situations. © Georg Thieme Verlag KG Stuttgart · New York.

Dysfunction of mechanical heart valve prosthesis: experience with surgical management in 48 patients

PubMed Central

Ma, Wei-Guo; Hou, Bin; Abdurusul, Adiljan; Gong, Ding-Xu; Tang, Yue; Chang, Qian; Xu, Jian-Ping

2015-01-01

Background Dysfunction of mechanical heart valve prostheses is an unusual but potentially lethal complication after mechanical prosthetic valve replacement. We seek to report our experience with mechanical valve dysfunction regarding etiology, surgical techniques and early outcomes. Methods Clinical data of 48 patients with mechanical valve dysfunction surgically treated between October 1996 and June 2011 were analyzed. Results Mean age was 43.7±10.9 years and 34 were female (70.8%). The median interval from primary valve implantation to dysfunction was 44.5 months (range, 1 hour to 20 years). There were 21 emergent and 27 elective reoperations. The etiology was thrombosis in 19 cases (39.6%), pannus in 12 (25%), thrombosis and pannus in 11 (22.9%), improper disc orientation in 2 (4.1%), missing leaflet in 1 (2.1%), excessively long knot end in 1 (2.1%), endogenous factor in 1 (2.1%) and unidentified in 1 (2.1%). Surgical procedure was mechanical valve replacement in 37 cases (77.1%), bioprosthetic valve replacement in 7 (14.9%), disc rotation in 2 (4.2%) and excision of excessive knot end in 1 (2.1%). Early deaths occurred in 7 patients (14.6%), due to low cardiac output in 3 (6.3%), multi-organ failure in 2 (4.2%) and refractory ventricular fibrillation in 2 (4.2%). Complications occurred in 10 patients (20.8%). Conclusions Surgical management of mechanical valve dysfunction is associated with significant mortality and morbidity. Earlier identification and prompt reoperation are vital to achieving better clinical outcomes. The high incidence of thrombosis in this series highlights the need for adequate anticoagulation and regular follow-up after mechanical valve replacement. PMID:26793354

Management of inferior vena cava aneurysm.

PubMed

Montero-Baker, M F; Branco, B C; Leon, L L; Labropoulos, N; Echeverria, A; Mills, J L

2015-10-01

Inferior vena cava (IVC) aneurysm is an infrequent but potentially lethal abnormality. We have seen one such case in our group practice. We have added this case to a review of 53 previously reported cases in order to develop a management algorithm for this entity. We conducted a MedLine search of all English-language articles from the first reported case in 1950 through August 2013. Patient demographics, clinical data, management and outcomes were extracted. IVC aneurysms were categorized in 4 types as per Gradman and Steinberg classification. The mean patient age was 27.1 years (range 5-89) and 57.4% were male. A total of 11 (20.3%) had associated vascular anomalies and iliocaval thrombosis was found in 10 (18.5%). There were 23 type I aneurysms, 8 type IIs, 21 type IIIs and 2 type IVs. All but 1 type I was successfully managed conservatively without complications. For type IIs, only 3 patients were managed conservatively with 1 death related to stroke from paradoxical embolus. For type IIIs, resection was the most common management option (14 patients). One patient was treated endovascularly with aneurysm embolization. A total of 6 asymptomatic patients were treated conservatively with 1 death due to thromboembolism. For type IVs, all cases underwent expectant management with 1 death due to aneurysm rupture. IVC aneurysms are rare with only 54 cases reported in the literature. Associated vascular anomalies and iliocaval thrombosis should be expected in approximately 20% of cases. Type I aneurysms can be managed expectantly with close surveillance unless symptomatic. For type II-IV, surgical consideration should be given based on high rates of thromboembolic complications and non-negligible risk of rupture.

Metal-Polycyclic Aromatic Hydrocarbon Mixture Toxicity in Hyalella azteca. 1. Response Surfaces and Isoboles To Measure Non-additive Mixture Toxicity and Ecological Risk.

PubMed

Gauthier, Patrick T; Norwood, Warren P; Prepas, Ellie E; Pyle, Greg G

2015-10-06

Mixtures of metals and polycyclic aromatic hydrocarbons (PAHs) occur ubiquitously in aquatic environments, yet relatively little is known regarding their potential to produce non-additive toxicity (i.e., antagonism or potentiation). A review of the lethality of metal-PAH mixtures in aquatic biota revealed that more-than-additive lethality is as common as strictly additive effects. Approaches to ecological risk assessment do not consider non-additive toxicity of metal-PAH mixtures. Forty-eight-hour water-only binary mixture toxicity experiments were conducted to determine the additive toxic nature of mixtures of Cu, Cd, V, or Ni with phenanthrene (PHE) or phenanthrenequinone (PHQ) using the aquatic amphipod Hyalella azteca. In cases where more-than-additive toxicity was observed, we calculated the possible mortality rates at Canada's environmental water quality guideline concentrations. We used a three-dimensional response surface isobole model-based approach to compare the observed co-toxicity in juvenile amphipods to predicted outcomes based on concentration addition or effects addition mixtures models. More-than-additive lethality was observed for all Cu-PHE, Cu-PHQ, and several Cd-PHE, Cd-PHQ, and Ni-PHE mixtures. Our analysis predicts Cu-PHE, Cu-PHQ, Cd-PHE, and Cd-PHQ mixtures at the Canadian Water Quality Guideline concentrations would produce 7.5%, 3.7%, 4.4% and 1.4% mortality, respectively.

The initial tolerance to sub-lethal Cd exposure is the same among ten naïve pond populations of Daphnia magna, but their micro-evolutionary potential to develop resistance is very different.

PubMed

Messiaen, Marlies; Janssen, Colin Roger; De Meester, Luc; De Schamphelaere, Karel André Clara

2013-11-15

Genetic variation complicates predictions of both the initial tolerance and the long-term (micro-evolutionary) response of natural Daphnia populations to chemical stressors from results of standard single-clone laboratory ecotoxicity tests. In order to investigate possible solutions to this problem, we aimed to compare the initial sub-lethal tolerance to Cd of 10 naïve natural pond populations of Daphnia magna as well as their evolutionary potential to develop increased resistance. We did so by measuring reproductive performance of 120 clones, i.e. 12 clones hatched from the recent dormant egg bank of each of 10 populations, both in absence (Cd-free control) and presence of 4.4 μg Cd/L. We show that the initial tolerance, defined as the reproductive performance of individuals of the first generation exposed to Cd relative to that in a Cd-free control was not significantly different among the 10 studied pond populations and averaged 0.82 ± 0.04 over these populations. Moreover, these populations' initial tolerances were also not significantly different from the mean initial tolerance of 0.87 ± 0.08 at 4.0 μg Cd/L measured for a group of 7 often-used laboratory clones, collected from a range of European ecotoxicity testing laboratories. This indicates that the initial response of naïve natural pond populations to sub-lethal Cd can be relatively accurately predicted from ecotoxicity test data from only a handful of laboratory clones. We then used estimates of broad-sense heritability of Cd tolerance (H(2)) - based on the same dataset - as a proxy of these populations' capacities to evolutionarily respond to Cd in terms of the development of increased resistance, which is here defined as the increase with time of the frequency of clones with a higher Cd tolerance in the population (accompanied with an increase of mean Cd-tolerance of the population above the initial tolerance). We show that the populations' estimated H(2) values of Cd-tolerance cover almost the entire theoretically possible range, ranging from not significantly different from zero (for five populations) to between 0.48 and 0.81 (for the five other populations). This indicates that, unlike the initial tolerance to Cd, the (long-term) micro-evolutionary response to Cd may be very different among natural pond populations. Therefore, we conclude that it may be very difficult to predict the long-term response of an unstudied population to chemical stress from tolerance data on a sample of other populations. It is therefore suggested that new methods for forecasting long-term responses should be explored, such as the development of predictive models based on the combination of population-genomic and tolerance time-series data. Copyright © 2013 Elsevier B.V. All rights reserved.

Infectious and lethal doses of H5N1 highly pathogenic avian influenza virus for house sparrows (Passer domesticus) and rock pigeons (Columbia livia)

USDA-ARS?s Scientific Manuscript database

Terrestrial wild birds commonly associated with poultry farms have the potential to contribute to the spread of H5N1 highly pathogenic avian influenza virus within or between poultry facilities or between domesticated and wild bird populations. This potential, however, varies between species and is...

Alternative transmission routes in the malaria elimination era: an overview of transfusion-transmitted malaria in the Americas.

PubMed

Alho, Regina M; Machado, Kim Vinícius Amaral; Val, Fernando F A; Fraiji, Nelson A; Alexandre, Marcia A A; Melo, Gisely C; Recht, Judith; Siqueira, André M; Monteiro, Wuelton M; Lacerda, Marcus V G

2017-02-15

Transfusion-transmitted (TT) malaria is an alternative infection route that has gained little attention from authorities, despite representing a life-threatening condition. There has been no systematic review of this health problem in American countries. The aim of this study was to describe the clinical and epidemiological characteristics of TT malaria in the Americas and identify factors associated with lethality based on the studies published in the literature. Potentially relevant papers in all languages were retrieved from MEDLINE and LILACS. Additional articles were obtained from reviews and original papers. Publications on screening of candidate blood donors and on surveillance of TT malaria cases were included. Odds ratios with respective 95% confidence intervals (95% CI) were calculated. Epidemiological characteristics of blood donors of TT malaria cases, including a pooled positivity of different tests for malaria diagnosis, were retrieved. A total of 63 publications regarding TT malaria from seven countries were included, from 1971 to 2016. A total of 422 cases of TT malaria were recorded. Most TT malaria cases were in females (62.0%) and 39.5% were in the ≥61 years-old age group. About half of all cases were from Mexico (50.7%), 40.3% from the United States of America (USA) and 6.6% from Brazil. Gyneco-obstetrical conditions (67.3%), surgical procedures (20.6%) and complications from neoplasias (6.1%) were the most common indications of transfusion. Packed red blood cells (RBCs) (50.7%) and whole blood (43.3%) were the blood products mostly associated with TT malaria. Cases were mostly caused by Plasmodium malariae (58.4%), followed by Plasmodium vivax (20.7%) and Plasmodium falciparum (17.9%). A total of 66.6% of cases were diagnosed by microscopy. Incubation period of 2-3 weeks was the most commonly observed (28.6%). Lethality was seen in 5.3% of cases and was associated with living in non-endemic countries, P. falciparum infection and concomitant neoplastic diseases. There is an important research and knowledge gap regarding the TT malaria burden in Latin American countries where malaria remains endemic. No screening method that is practical, affordable and suitably sensitive is available at blood banks in Latin American countries, where infections with low parasitaemia contribute greatly to transmission. Lethality from TT malaria was not negligible. TT malaria needs to be acknowledged and addressed in areas moving toward elimination.

Allogeneic Hematopoietic Cell Transplantation for Dyskeratosis Congenita: A Report of 3 Cases.

PubMed

Tamura, Shinichi; Imamura, Toshihiko; Urata, Takayo; Kobayashi, Miki; Gen, Mari; Tomii, Toshihiro; Do, Junko; Osone, Shinya; Ishida, Hiroyuki; Hosoi, Hajime; Kuroda, Hiroshi

2017-10-01

Although bone marrow failure in patients with dyskeratosis congenita (DKC) can be successfully treated with allogeneic hematopoietic cell transplantation (allo-HCT) using a reduced intensity conditioning (RIC) regimen, the outcome of nonhematological disorders in patients with DKC treated with allo-HCT using RIC has not been fully elucidated. Here, we describe the clinical course of nonhematological disorders after allo-HCT with RIC in 3 consecutive patients with DKC. Allo-HCT with RIC was feasible in all cases; however, patient 1 developed lethal pulmonary disease and patient 2 experienced progression of hepatic fibrosis. Careful follow-up of patient-specific complications is required after allo-HCT in patients with DKC.

Technical Guidance for Hazardous Analysis, Emergency Planning for Extremely Hazardous Substances

EPA Pesticide Factsheets

This current guide supplements NRT-1 by providing technical assistance to LEPCs to assess the lethal hazards related to potential airborne releases of extremely hazardous substances (EHSs) as designated under Section 302 of Title Ill of SARA.

Contemporary Strategies in the Management of Civilian Abdominal Vascular Trauma

PubMed Central

Karaolanis, Georgios; Moris, Dimitrios; McCoy, C. Cameron; Tsilimigras, Diamantis I.; Georgopoulos, Sotirios; Bakoyiannis, Chris

2018-01-01

The evaluation and management of patients with abdominal vascular trauma or injury requires immediate and effective decision-making in these unfavorable circumstances. The majority of these patients arrive at trauma centers in profound shock, secondary to massive blood loss, which is often unrelenting. Moreover, ischemia, compartment syndrome, thrombosis, and embolization may also be life threatening and require immediate intervention. To minimize the risk of these potentially lethal complications, early understanding of the disease process and emergent therapeutic intervention are necessary. In the literature, the management of acute traumatic vascular injuries is restricted to traditional open surgical techniques. However, in penetrating injuries surgeons often face a potentially contaminated field, which renders the placement of prosthetic grafts inappropriate. Currently, however, there are sparse data on the management of vascular trauma with endovascular techniques. The role of endovascular technique in penetrating abdominal vascular trauma, which is almost always associated with severe active bleeding, is limited. It is worth mentioning that hybrid operating rooms with angiographic radiology capabilities offer more opportunities for the management of this kind of injuries by either temporary control of the devastating bleeding using endovascular balloon tamponade or with embolization and stenting. On the other hand, blunt abdominal injuries are less dangerous and they could be treated at most times by endovascular means. Since surgeons continue to encounter abdominal vascular trauma, open and endovascular techniques will evolve constantly giving us encouraging messages for the near future. PMID:29516005

Zika antiviral chemotherapy: identification of drugs and promising starting points for drug discovery from an FDA-approved library.

PubMed

Pascoalino, Bruno S; Courtemanche, Gilles; Cordeiro, Marli T; Gil, Laura H V G; Freitas-Junior, Lucio

2016-01-01

Background The recent epidemics of Zika virus (ZIKV) implicated it as the cause of serious and potentially lethal congenital conditions such microcephaly and other central nervous system defects, as well as the development of the Guillain-Barré syndrome in otherwise healthy patients. Recent findings showed that anti-Dengue antibodies are capable of amplifying ZIKV infection by a mechanism similar to antibody-dependent enhancement, increasing the severity of the disease. This scenario becomes potentially catastrophic when the global burden of Dengue and the advent of the newly approved anti-Dengue vaccines in the near future are taken into account. Thus, antiviral chemotherapy should be pursued as a priority strategy to control the spread of the virus and prevent the complications associated with Zika. Methods Here we describe a fast and reliable cell-based, high-content screening assay for discovery of anti-ZIKV compounds. This methodology has been used to screen the National Institute of Health Clinical Collection compound library, a small collection of FDA-approved drugs. Results and conclusion From 725 FDA-approved compounds triaged, 29 (4%) were found to have anti-Zika virus activity, of which 22 had confirmed (76% of confirmation) by dose-response curves. Five candidates presented selective activity against ZIKV infection and replication in a human cell line. These hits have abroad spectrum of chemotypes and therapeutic uses, offering valuable opportunities for selection of leads for antiviral drug discovery.

Deep neck infections: A single-center analysis of 63 cases

PubMed Central

Cordesmeyer, Robert; Tröltzsch, Markus; Sömmer, Christian; Laskawi, Rainer

2017-01-01

Background and Purpose With the use of antibiotic therapy, the incidence of deep neck infections has decreased in recent decades. The aim of this investigation was to review the clinical course and the management of deep neck infections in our department, compare them to the experiences of the common literature and identify predisposing factors for lethal complications. Material and Methods In this single-center analysis, 63 patients with deep neck infections were treated surgically. The following clinical data were analyzed and compared: age, gender, laboratory data, spatial manifestation, therapeutic modalities, comorbidities, length of hospitalization and complications. Results There was a predominance of male patients (58.7%) and a mean age of 57.9 years. The most common symptoms at diagnosis were sore throat (96.8%) and neck swelling (92.0%). Cardio/pulmonary diseases and diabetes mellitus were the most common comorbidities. There was a significantly longer hospital stay for patients with diabetes mellitus. The most common manifestation was a parapharyngeal abscess in 24 patients (38.1%), followed by peri-/retrotonsillar infections in 19 patients (30.2%). In 29 patients, a multiple space infection was observed, with a significantly longer duration of hospitalization and a higher rate of complications. The main life-threatening complication was the development of airway obstruction in 20 patients (31.7%), who all received a tracheostomy. The duration of hospitalization for patients with complications was significantly longer. Conclusions Close attention must be paid to the management of patients with deep neck infections, especially patients with diabetes mellitus and cardio/pulmonary diseases or patients with multiple space infections. Key words:Deep neck infections, comorbidities, surgical treatment, tracheostomy, diabetes mellitus. PMID:28809368

Comparing biomarker responses during thermal acclimation: A lethal vs non-lethal approach in a tropical reef clownfish.

PubMed

Madeira, Carolina; Madeira, Diana; Diniz, Mário S; Cabral, Henrique N; Vinagre, Catarina

2017-02-01

Knowledge of thermal stress biology for most tropical fish species in reef ecosystems under climate change is still quite limited. Thus, the objective of this study was to measure the time-course changes of thermal stress biomarkers in the commercially exploited coral reef fish Amphiprion ocellaris, during a laboratory simulated event of increased temperature. Heat shock protein 70kDa (Hsp70) and total ubiquitin (Ub) were determined in the muscle (lethal method) and in the fin (non-lethal alternative method) under two temperature treatments (control - 26°C and elevated temperature - 30°C) throughout one month with weekly samplings. Results suggest that biomarker basal levels are tissue-specific and influence the degree of response under temperature exposure. Responses were highly inducible in the muscle but not in fin tissue, indicating that the latter is not reliable for monitoring purposes. Thermal stress was observed in the muscle after one week of exposure (both biomarkers increased significantly) and Ub levels then decreased, suggesting the animals were able to acclimate by maintaining high levels of Hsp70 and through an effective protein turnover. In addition, the results show that mortality rates did not differ between treatments. This indicates that A. ocellaris is capable of displaying a plastic response to elevated temperature by adjusting the protein quality control system to protect cell functions, without decreasing survival. Thus, this coral reef fish species presents a significant acclimation potential under ocean warming scenarios of +4°C. Monitoring of thermal stress through a non-lethal method, fin-clipping, although desirable proved to be inadequate for this species. Copyright © 2016 Elsevier Inc. All rights reserved.

Alveolar Macrophages Prevent Lethal Influenza Pneumonia By Inhibiting Infection Of Type-1 Alveolar Epithelial Cells

PubMed Central

Cardani, Amber; Boulton, Adam; Kim, Taeg S.; Braciale, Thomas J.

2017-01-01

The Influenza A virus (IAV) is a major human pathogen that produces significant morbidity and mortality. To explore the contribution of alveolar macrophages (AlvMΦs) in regulating the severity of IAV infection we employed a murine model in which the Core Binding Factor Beta gene is conditionally disrupted in myeloid cells. These mice exhibit a selective deficiency in AlvMΦs. Following IAV infection these AlvMΦ deficient mice developed severe diffuse alveolar damage, lethal respiratory compromise, and consequent lethality. Lethal injury in these mice resulted from increased infection of their Type-1 Alveolar Epithelial Cells (T1AECs) and the subsequent elimination of the infected T1AECs by the adaptive immune T cell response. Further analysis indicated AlvMΦ-mediated suppression of the cysteinyl leukotriene (cysLT) pathway genes in T1AECs in vivo and in vitro. Inhibition of the cysLT pathway enzymes in a T1AECs cell line reduced the susceptibility of T1AECs to IAV infection, suggesting that AlvMΦ-mediated suppression of this pathway contributes to the resistance of T1AECs to IAV infection. Furthermore, inhibition of the cysLT pathway enzymes, as well as blockade of the cysteinyl leukotriene receptors in the AlvMΦ deficient mice reduced the susceptibility of their T1AECs to IAV infection and protected these mice from lethal infection. These results suggest that AlvMΦs may utilize a previously unappreciated mechanism to protect T1AECs against IAV infection, and thereby reduce the severity of infection. The findings further suggest that the cysLT pathway and the receptors for cysLT metabolites represent potential therapeutic targets in severe IAV infection. PMID:28085958

A cardiovascular drug rescues mice from lethal sepsis by selectively attenuating a late-acting proinflammatory mediator, high mobility group box 1.

PubMed

Li, Wei; Li, Jianhua; Ashok, Mala; Wu, Rongqian; Chen, Dazhi; Yang, Lihong; Yang, Huan; Tracey, Kevin J; Wang, Ping; Sama, Andrew E; Wang, Haichao

2007-03-15

The pathogenesis of sepsis is mediated in part by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF, IL-1, and IFN-gamma) and late (e.g., high mobility group box 1 (HMGB1) protein) proinflammatory cytokines. The recent discovery of HMGB1 as a late mediator of lethal sepsis has prompted investigation for development of new experimental therapeutics. We found that many steroidal drugs (such as dexamethasone and cortisone) and nonsteroidal anti-inflammatory drugs (such as aspirin, ibuprofen, and indomethacin) failed to influence endotoxin-induced HMGB1 release even at superpharmacological concentrations (up to 10-25 microM). However, several steroid-like pigments (tanshinone I, tanshinone IIA, and cryptotanshinone) of a popular Chinese herb, Danshen (Salvia miltiorrhiza), dose dependently attenuated endotoxin-induced HMGB1 release in macrophage/monocyte cultures. A water-soluble tanshinone IIA sodium sulfonate derivative (TSNIIA-SS), which has been widely used as a Chinese medicine for patients with cardiovascular disorders, selectively abrogated endotoxin-induced HMGB1 cytoplasmic translocation and release in a glucocorticoid receptor-independent manner. Administration of TSNIIA-SS significantly protected mice against lethal endotoxemia and rescued mice from lethal sepsis even when the first dose was given 24 h after the onset of sepsis. The therapeutic effects were partly attributable to attenuation of systemic accumulation of HMGB1 (but not TNF and NO) and improvement of cardiovascular physiologic parameters (e.g., decrease in total peripheral vascular resistance and increase in cardiac stroke volume) in septic animals. Taken together, these data re-enforce the pathogenic role of HMGB1 in lethal sepsis, and support a therapeutic potential for TSNIIA-SS in the treatment of human sepsis.

A Cardiovascular Drug Rescues Mice from Lethal Sepsis by Selectively Attenuating a Late-Acting Proinflammatory Mediator, High Mobility Group Box 11

PubMed Central

Li, Wei; Li, Jianhua; Ashok, Mala; Wu, Rongqian; Chen, Dazhi; Yang, Lihong; Yang, Huan; Tracey, Kevin J.; Wang, Ping; Sama, Andrew E.; Wang, Haichao

2007-01-01

The pathogenesis of sepsis is mediated in part by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF, IL-1, and IFN-γ) and late (e.g., high mobility group box 1 (HMGB1) protein) proinflammatory cytokines. The recent discovery of HMGB1 as a late mediator of lethal sepsis has prompted investigation for development of new experimental therapeutics. We found that many steroidal drugs (such as dexamethasone and cortisone) and nonsteroidal anti-inflammatory drugs (such as aspirin, ibuprofen, and indomethacin) failed to influence endotoxin-induced HMGB1 release even at superpharmacological concentrations (up to 10–25 μM). However, several steroid-like pigments (tanshinone I, tanshinone IIA, and cryptotanshinone) of a popular Chinese herb, Danshen (Salvia miltiorrhiza), dose dependently attenuated endotoxin-induced HMGB1 release in macrophage/monocyte cultures. A water-soluble tanshinone IIA sodium sulfonate derivative (TSNIIA-SS), which has been widely used as a Chinese medicine for patients with cardiovascular disorders, selectively abrogated endotoxin-induced HMGB1 cytoplasmic translocation and release in a glucocorticoid receptor-independent manner. Administration of TSNIIA-SS significantly protected mice against lethal endotoxemia and rescued mice from lethal sepsis even when the first dose was given 24 h after the onset of sepsis. The therapeutic effects were partly attributable to attenuation of systemic accumulation of HMGB1 (but not TNF and NO) and improvement of cardiovascular physiologic parameters (e.g., decrease in total peripheral vascular resistance and increase in cardiac stroke volume) in septic animals. Taken together, these data re-enforce the pathogenic role of HMGB1 in lethal sepsis, and support a therapeutic potential for TSNIIA-SS in the treatment of human sepsis. PMID:17339485

Role of T Cells and Gamma Interferon during Induction of Hypersensitivity to Lipopolysaccharide by Toxic Shock Syndrome Toxin 1 in Mice

PubMed Central

Dinges, Martin M.; Schlievert, Patrick M.

2001-01-01

The superantigenic function of toxic shock syndrome toxin 1 (TSST-1) is generally regarded as an important determinant of its lethal effects in humans or experimental animals. This study examined the role of superantigenicity in a BALB/c mouse model of lethal TSST-1-induced hypersensitivity to lipopolysaccharide (LPS). In this model, TSST-1 greatly potentiated both LPS-induced lethality, as well as LPS-induced serum tumor necrosis factor alpha (TNF-α) activity. Although BALB/c-SCID mice were resistant to these LPS enhancement effects of TSST-1, BALB/c-SCID mice reconstituted with T cells were completely susceptible to the enhancement effect of TSST-1 on LPS-induced serum TNF-α. Mice pretreated with cyclosporine (Cs) or neutralizing antibodies against gamma interferon (IFN-γ) did not develop lethal LPS hypersensitivity when injected with TSST-1, and these agents reduced the enhancement effect of TSST-1 on LPS-induced serum TNF-α by 99 and 85%, respectively. Cs pretreatment also completely inhibited the known capacity of TSST-1 to amplify LPS-induced levels of IFN-γ in serum. In contrast, mice given Cs after a priming injection of TSST-1, but before LPS, still exhibited lethal hypersensitivity to LPS. Cs given after TSST-1 also did not inhibit enhancement of LPS-induced serum TNF-α by TSST-1 but inhibited the enhancement effect of TSST-1 on LPS-induced serum IFN-γ by 50%. These experiments support the theory that TSST-1-induced hypersensitivity to LPS is mediated primarily by IFN-γ derived from superantigen-activated T cells. PMID:11179286

Dietary Lycopene, Angiogenesis, and Prostate Cancer: A Prospective Study in the Prostate-Specific Antigen Era

PubMed Central

2014-01-01

Background The role of lycopene in prostate cancer prevention remains controversial. We examined the associations between dietary lycopene intake and prostate cancer, paying particular attention to the influence of prostate-specific antigen screening, and evaluated tissue biomarkers in prostate cancers in relation to lycopene intake. Methods Among 49898 male health professionals, we obtained dietary information through questionnaires and ascertained total and lethal prostate cancer cases from 1986 through January 31, 2010. Cox regression was used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). Tissue microarrays and immunohistochemistry were used to assess tumor biomarker expression in a subset of men. Two-sided χ2 tests were used to calculate the P values. Results Higher lycopene intake was inversely associated with total prostate cancer and more strongly with lethal prostate cancer (top vs bottom quintile: HR = 0.72; 95% CI = 0.56 to 0.94; P trend = .04). In a restricted population of screened participants, the inverse associations became markedly stronger (for lethal prostate cancer: HR = 0.47; 95% CI = 0.29 to 0.75; P trend = .009). Comparing different measures of dietary lycopene, early intake, but not recent intake, was inversely associated with prostate cancer. Higher lycopene intake was associated with biomarkers in the cancer indicative of less angiogenic potential. Conclusions Dietary intake of lycopene was associated with reduced risk of lethal prostate cancer and with a lesser degree of angiogenesis in the tumor. Because angiogenesis is a strong progression factor, an endpoint of lethal prostate cancer may be more relevant than an endpoint of indolent prostate cancer for lycopene in the era of highly prevalent prostate-specific antigen screening. PMID:24463248

Ribavirin protects Syrian hamsters against lethal hantavirus pulmonary syndrome--after intranasal exposure to Andes virus.

PubMed

Ogg, Monica; Jonsson, Colleen B; Camp, Jeremy V; Hooper, Jay W

2013-11-08

Andes virus, ANDV, harbored by wild rodents, causes the highly lethal hantavirus pulmonary syndrome (HPS) upon transmission to humans resulting in death in 30% to 50% of the cases. As there is no treatment for this disease, we systematically tested the efficacy of ribavirin in vitro and in an animal model. In vitro assays confirmed antiviral activity and determined that the most effective doses were 40 µg/mL and above. We tested three different concentrations of ribavirin for their capability to prevent HPS in the ANDV hamster model following an intranasal challenge. While the highest level of ribavirin (200 mg/kg) was toxic to the hamster, both the middle (100 mg/kg) and the lowest concentration (50 mg/kg) prevented HPS in hamsters without toxicity. Specifically, 8 of 8 hamsters survived intranasal challenge for both of those groups whereas 7 of 8 PBS control-treated animals developed lethal HPS. Further, we report that administration of ribavirin at 50 mg/kg/day starting on days 6, 8, 10, or 12 post-infection resulted in significant protection against HPS in all groups. Administration of ribavirin at 14 days post-infection also provided a significant level of protection against lethal HPS. These data provide in vivo evidence supporting the potential use of ribavirin as a post-exposure treatment to prevent HPS after exposure by the respiratory route.

Cytotoxicity assays with fish cells as an alternative to the acute lethality test with fish.

PubMed

Segner, Helmut

2004-10-01

In ecotoxicology, in vitro assays with fish cells are currently applied for mechanistic studies, bioanalytical purposes and toxicity screening. This paper discusses the potential of cytotoxicity assays with fish cells to reduce, refine or replace acute lethality tests using fish. Basal cytotoxicity data obtained with fish cell lines or fish primary cell cultures show a reasonable to good correlation with lethality data from acute toxicity tests, with the exception of compounds that exert a specific mode of toxic action. Basal cytotoxicity data from fish cell lines also correlate well with cytotoxicity data from mammalian cell lines. However, both the piscine and mammalian in vitro assays are clearly less sensitive than the fish test. Therefore, in vivo LC50 values (concentrations of the test compounds that are lethal to 50% of the fish in the experiment within 96 hours) currently cannot be predicted from in vitro values. This in vitro-in vivo difference in sensitivity appears to be true for both fish cell lines and mammalian cell lines. Given the good in vitro-in vivo correlation in toxicity ranking, together with the clear-cut difference in sensitivity, the role of cytotoxicity assays in a tiered alternative testing strategy could be in priority setting in relation to toxic hazard and in the toxicity classification of chemicals and environmental samples.

Lethal and sub-lethal effects of five pesticides used in rice farming on the earthworm Eisenia fetida.

PubMed

Rico, Andreu; Sabater, Consuelo; Castillo, María-Ángeles

2016-05-01

The toxicity of five pesticides typically used in rice farming (trichlorfon, dimethoate, carbendazim, tebuconazole and prochloraz) was evaluated on different lethal and sub-lethal endpoints of the earthworm Eisenia fetida. The evaluated endpoints included: avoidance behaviour after an exposure period of 2 days; and mortality, weight loss, enzymatic activities (cholinesterase, lactate dehydrogenase and alkaline phosphatase) and histopathological effects after an exposure period of 14 days. Carbendazim was found to be highly toxic to E. fetida (LC50=2mg/kg d.w.), significantly reducing earthworm weight and showing an avoidance response at soil concentrations that are close to those predicted in rice-fields and in surrounding ecosystems. The insecticide dimethoate showed a moderate acute toxicity (LC50=28mg/kg d.w.), whereas the rest of tested pesticides showed low toxicity potential (LC50 values above 100mg/kg d.w.). For these pesticides, however, weight loss was identified as a sensitive endpoint, with NOEC values approximately 2 times or lower than the calculated LC10 values. The investigated effects on the enzymatic activities of E. fetida and the observed histopathological alterations (longitudinal and circular muscle lesions, edematous tissues, endothelial degeneration and necrosis) proved to be sensitive biomarkers to monitor pesticide contamination and are proposed as alternative measures to evaluate pesticide risks on agro-ecosystems. Copyright © 2016 Elsevier Inc. All rights reserved.

Effect of salinity on the upper lethal temperature tolerance of early-juvenile red drum.

PubMed

McDonald, Dusty; Bumguardner, Britt; Cason, Paul

2015-10-01

Previous work investigating the temperature tolerance of juvenile red drum ranging 18-50mm TL found evidence for positive size dependence (smaller fish less tolerant to higher temperatures) suggesting smaller size classes (<18mm TL) potentially may succumb to extreme summer water temperatures. Here, we explored the upper lethal temperature tolerance (ULT) in smaller-sized red drum which ranged from 10 to 20mm TL across multiple salinities to further understand the thermal limitations of this propagated game fish. In order to investigate the combined effect of temperature and salinity on ULT, temperature trials were conducted under three levels of salinity which commonly occur along the coast of Texas (25, 35, and 45ppt). The rate of temperature increase (+0.25°C/h) was designed to mimic a natural temperature increase of a summer day in Texas. We determined that the lethal temperature at 50% (LT50) did not differ between the three salinities examined statistically; median lethal temperature for individuals exposed to 25ppt ranged from 36.4 to 37.7°C, 35ppt ranged from 36.4 to 37.7°C, and 45ppt ranged from 36.1 to 37.4°C. Further, LT50 data obtained here for early-juvenile red drum did not differ from data of a similar experiment examining 25mm TL sized fish. Published by Elsevier Ltd.

Prevention and treatment of Clostridium perfringens epsilon toxin intoxication in mice with a neutralizing monoclonal antibody (c4D7) produced in Nicotiana benthamiana.

PubMed

Garcia, J P; Beingesser, J; Bohorov, O; Bohorova, N; Goodman, C; Kim, D; Pauly, M; Velasco, J; Whaley, K; Zeitlin, L; Roy, C J; Uzal, F A

2014-09-01

Epsilon toxin (ETX), produced by Clostridium perfringens types B and D, is among the most lethal toxins known. ETX is a potential bioterrorism threat that was listed as a Category B agent by the U.S. Centers for Disease Control until 2012 and it still remains a toxin of interest for several government agencies. We produced a monoclonal antibody (MAb) against ETX (ETX MAb c4D7) in Nicotiana benthamiana and characterized its preventive and therapeutic efficacy in mice. The ETX preparation used was highly lethal for mice (LD50 = 1.6 μg/kg) and resulted in a mean time from inoculation to death of 18 and 180 min when administered intravenously or intraperitoneally, respectively. High lethal challenge resulted in dramatic increases of a variety of pro-inflammatory cytokines in serum, while lower, but still lethal doses, did not elicit such responses. ETX MAb c4D7 was highly effective prophylactically (ED50 = 0.3 mg/kg; ED100 = 0.8 mg/kg) and also provided protection when delivered 15-30 min post-ETX intoxication. These data suggest that ETX MAb c4D7 may have use as a pre- and post-exposure treatment for ETX intoxication. Copyright © 2014 Elsevier Ltd. All rights reserved.

Inflammatory Biomarkers Associated with Lethal Rift Valley Fever Encephalitis in the Lewis Rat Model

PubMed Central

Caroline, Amy L.; Kujawa, Michael R.; Oury, Tim D.; Reed, Douglas S.; Hartman, Amy L.

2016-01-01

Rift Valley fever (RVF) is an emerging viral disease that causes significant human and veterinary illness in Africa and the Arabian Peninsula. Encephalitis is one of the severe complications arising from RVF virus (RVFV) infection of people, and the pathogenesis of this form of RVF is completely unknown. We use a novel reproducible encephalitic disease model in rats to identify biomarkers of lethal infection. Lewis rats were infected with RVFV strain ZH501 by aerosol exposure, then sacrificed daily to determine the course of infection and evaluation of clinical, virological, and immunological parameters. Weight loss, fever, and clinical signs occurred during the last 1–2 days prior to death. Prior to onset of clinical indications of disease, rats displayed marked granulocytosis and thrombocytopenia. In addition, high levels of inflammatory chemokines (MCP-1, MCS-F, Gro/KC, RANTES, and IL-1β) were detected first in serum (3–5 dpi) followed by brain (5–7 dpi). The results of this study are consistent with clinical data from human RVF patients and validate Lewis rats as an appropriate small animal model for RVF encephalitis. The biomarkers we identified here will be useful in future studies evaluating the efficacy of novel vaccines and therapeutics. PMID:26779164

Allopurinol Reduces the Lethality Associated with Acute Renal Failure Induced by Crotalus durissus terrificus Snake Venom: Comparison with Probenecid

PubMed Central

Frezzatti, Rodrigo; Silveira, Paulo Flavio

2011-01-01

Background Acute renal failure is one of the most serious complications of envenoming resulting from Crotalus durissus terrificus bites. This study evaluated the relevance of hyperuricemia and oxidative stress and the effects of allopurinol and probenecid in renal dysfunction caused by direct nephrotoxicity of C. d. terrificus venom. Methodology/Principal Findings Hematocrit, protein, renal function and redox status were assessed in mice. High ratio of oxidized/reduced glutathione and hyperuricemia induced by C. d. terrificus venom were ameliorated by both, allopurinol or probenecid, but only allopurinol significantly reduced the lethality caused by C. d. terrificus venom. The effectiveness of probenecid is compromised probably because it promoted hypercreatinemia and hypocreatinuria and worsed the urinary hypo-osmolality in envenomed mice. In turn, the highest effectiveness of allopurinol might be due to its ability to diminish the intracellular formation of uric acid. Conclusions/Significance Data provide consistent evidences linking uric acid with the acute renal failure induced by C. d. terrificus venom, as well as that this envenoming in mice constitutes an attractive animal model suitable for studying the hyperuricemia and that the allopurinol deserves to be clinically evaluated as an approach complementary to anti-snake venom serotherapy. PMID:21909449

Immune Protection against Lethal Fungal-Bacterial Intra-Abdominal Infections.

PubMed

Lilly, Elizabeth A; Ikeh, Melanie; Nash, Evelyn E; Fidel, Paul L; Noverr, Mairi C

2018-01-16

Polymicrobial intra-abdominal infections (IAIs) are clinically prevalent and cause significant morbidity and mortality, especially those involving fungi. Our laboratory developed a mouse model of IAI and demonstrated that intraperitoneal inoculation with Candida albicans or other virulent non- albicans Candida (NAC) species plus Staphylococcus aureus resulted in 70 to 80% mortality in 48 to 72 h due to robust local and systemic inflammation (sepsis). Surprisingly, inoculation with Candida dubliniensis or Candida glabrata with S. aureus resulted in minimal mortality, and rechallenge of these mice with lethal C. albicans / S. aureus (i.e., coninfection) resulted in >90% protection. The purpose of this study was to define requirements for C. dubliniensis / S. aureus -mediated protection and interrogate the mechanism of the protective response. Protection was conferred by C. dubliniensis alone or by killed C. dubliniensis plus live S. aureus S. aureus alone was not protective, and killed S. aureus compromised C. dubliniensis -induced protection. C. dubliniensis / S. aureus also protected against lethal challenge by NAC plus S. aureus and could protect for a long-term duration (60 days between primary challenge and C. albicans/S. aureus rechallenge). Unexpectedly, mice deficient in T and B cells (Rag-1 knockouts [KO]) survived both the initial C. dubliniensis/S. aureus challenge and the C. albicans/S. aureus rechallenge, indicating that adaptive immunity did not play a role. Similarly, mice depleted of macrophages prior to rechallenge were also protected. In contrast, protection was associated with high numbers of Gr-1 hi polymorphonuclear leukocytes (PMNLs) in peritoneal lavage fluid within 4 h of rechallenge, and in vivo depletion of Gr-1 + cells prior to rechallenge abrogated protection. These results suggest that Candida species can induce protection against a lethal C. albicans / S. aureus IAI that is mediated by PMNLs and postulated to be a unique form of trained innate immunity. IMPORTANCE Polymicrobial intra-abdominal infections are clinically devastating infections with high mortality rates, particularly those involving fungal pathogens, including Candida species. Even in patients receiving aggressive antimicrobial therapy, mortality rates remain unacceptably high. There are no available vaccines against IAI, which is complicated by the polymicrobial nature of the infection. IAI leads to lethal systemic inflammation (sepsis), which is difficult to target pharmacologically, as components of the inflammatory response are also needed to control the infection. Our studies demonstrate that prior inoculation with low-virulence Candida species provides strong protection against subsequent lethal infection with C. albicans and S. aureus Surprisingly, protection is long-lived but not mediated by adaptive (specific) immunity. Instead, protection is dependent on cells of the innate immune system (nonspecific immunity) and provides protection against other virulent Candida species. This discovery implies that a form of trained innate immunity may be clinically effective against polymicrobial IAI. Copyright © 2018 Lilly et al.

CSF Analysis

MedlinePlus

... one or more hours to avoid a potential post-test headache. The lumbar puncture procedure usually takes less ... in CSF with laboratory tests such as molecular tests or culture. Parasitic meningitis or encephalitis are rare and can be lethal. One example is an infection caused by the free-living ...

The role of monamine oxidase inhibition in the acute toxicity of chlordimeform.

DOT National Transportation Integrated Search

1977-08-01

This paper presents data from experiments on male rats performed to determine whether drugs which interfere with central amine mechanisms would decrease the lethality of the acaricide chlordimeform (and thus be of potential value as antidotes for acc...

Incidence and treatment of procedural cardiovascular complications associated with trans-arterial and trans-apical interventional aortic valve implantation in 412 consecutive patients.

PubMed

Lange, Rüdiger; Bleiziffer, Sabine; Piazza, Nicolo; Mazzitelli, Domenico; Hutter, Andrea; Tassani-Prell, Peter; Laborde, Jean-Claude; Bauernschmitt, Robert

2011-11-01

Trans-catheter aortic valve implantation (TAVI) technology is rapidly evolving, with 412 procedures having been performed at our institution. Herein, we report a complete, prospective analysis of complications occurring during transvascular and trans-apical implantations with two different prostheses. Between June 2007 and June 2010, 412 patients (258 female, mean age 80.3±7.2 years, logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) 20.2%±13.0%) underwent TAVI through either a retrograde (n=252 transfemoral, n=28 transaxillary, and n=5 transaortic) or antegrade (n=127 trans-apical) approach at our institution. The trans-apical access was chosen only in cases where transvascular implantation was not possible. As many as 283 CoreValve and 129 Edwards Sapien prostheses were implanted. Thirty-day survival was 90.9%. Vascular complications occurred in 42 patients (10.2%). In four patients, lethal aortic root (n=3) or abdominal (n=1) aortic rupture occurred. Pericardial effusion developed in 53 patients (12.8%), which resulted in cardiac tamponade in 12 patients (2.9%). Twenty-three patients (5.6%) with valve malplacement were treated interventionally. In five patients (1.2%), emergency institution of cardiopulmonary bypass was required during the procedure for temporary support; all patients survived. Seventeen patients underwent re-intervention on the catheter valve (4.1%). With growing experience, complications with TAVI may be avoided by proper patient selection and skillful management. Other complications, when they occur, require a specific treatment algorithm to avoid delay in decision making. A considerable number of complications after TAVI require surgical treatment. Therefore, the ideal environment for TAVI procedures is a hybrid operating room, where a multidisciplinary team of surgeons, cardiologists, and anesthesiologists is best fitted to meet the current needs associated with TAVI technology. A reduction in complications was seen after 300 cases. This finding attests to the complexity of the procedure in addition to the experience required to reduce the incidence of complications. Copyright © 2011 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Knockdown of RNA interference pathway genes in western corn rootworm, Diabrotica virgifera virgifera, identifies no fitness costs associated with Argonaute 2 or Dicer-2.

PubMed

Camargo, Carolina; Wu, Ke; Fishilevich, Elane; Narva, Kenneth E; Siegfried, Blair D

2018-06-01

The use of transgenic crops that induce silencing of essential genes using double-stranded RNA (dsRNA) through RNA interference (RNAi) in western corn rootworm, Diabrotica virgifera virgifera, is likely to be an important component of new technologies for the control of this important corn pest. Previous studies have demonstrated that the dsRNA response in D. v. virgifera depends on the presence of RNAi pathway genes including Dicer-2 and Argonaute 2, and that downregulation of these genes limits the lethality of environmental dsRNA. A potential resistance mechanism to lethal dsRNA may involve loss of function of RNAi pathway genes. Howver, the potential for resistance to evolve may depend on whether these pathway genes have essential functions such that the loss of function of core proteins in the RNAi pathway will have fitness costs in D. v. virgifera. Fitness costs associated with potential resistance mechanisms have a central role in determining how resistance can evolve to RNAi technologies in western corn rootworm. We evaluated the effect of dsRNA and microRNA pathway gene knockdown on the development of D. v. virgifera larvae through short-term and long-term exposures to dsRNA for Dicer and Argonaute genes. Downregulation of Argonaute 2, Dicer-2, Dicer-1 did not significantly affect larval survivorship or development through short and long-term exposure to dsRNA. However, downregulation of Argonaute 1 reduced larval survivorship and delayed development. The implications of these results as they relate to D. v. virgifera resistance to lethal dsRNA are discussed. Copyright © 2018 Elsevier Inc. All rights reserved.

Increased H+ efflux is sufficient to induce dysplasia and necessary for viability with oncogene expression

PubMed Central

Grillo-Hill, Bree K; Choi, Changhoon; Jimenez-Vidal, Maite; Barber, Diane L

2015-01-01

Intracellular pH (pHi) dynamics is increasingly recognized as an important regulator of a range of normal and pathological cell behaviors. Notably, increased pHi is now acknowledged as a conserved characteristic of cancers and in cell models is confirmed to increase proliferation and migration as well as limit apoptosis. However, the significance of increased pHi for cancer in vivo remains unresolved. Using Drosophila melanogaster, we show that increased pHi is sufficient to induce dysplasia in the absence of other transforming cues and potentiates growth and invasion with oncogenic Ras. Using a genetically encoded biosensor we also confirm increased pHi in situ. Moreover, in Drosophila models and clonal human mammary cells we show that limiting H+ efflux with oncogenic Raf or Ras induces acidosis and synthetic lethality. Further, we show lethality in invasive primary tumor cell lines with inhibiting H+ efflux. Synthetic lethality with reduced H+ efflux and activated oncogene expression could be exploited therapeutically to restrain cancer progression while limiting off-target effects. DOI: http://dx.doi.org/10.7554/eLife.03270.001 PMID:25793441

Nutritional supplement chromium picolinate causes sterility and lethal mutations in Drosophila melanogaster

PubMed Central

Hepburn, Dion D. D.; Xiao, Jiarong; Bindom, Sharell; Vincent, John B.; O'Donnell, Janis

2003-01-01

The nutritional dietary supplement chromium picolinate, [Cr(pic)3], has gained much notoriety as a safe supplement that supposedly promotes fat loss and muscle enhancement in humans. Thus, a significant industry has materialized around the incorporation of [Cr(pic)3] in many sports foods and drinks and a variety of weight loss products. However, in vitro studies have suggested that low levels of [Cr(pic)3] in the presence of biological reducing agents can catalytically generate reactive oxygen species, and recent in vivo studies have detected oxidative damage in rats receiving the supplement. The potential deleterious in vivo effects of this activity were examined by using Drosophila melanogaster. [Cr(pic)3], but not CrCl3, at levels of 260 μg Cr/kg food or less were found to lower the success rate of pupation and eclosion and to arrest development of pupae in a concentration dependent fashion. X-linked lethal analysis indicates that the supplement greatly enhances the rate of appearance of lethal mutations and dominant female sterility. PMID:12649323

Effects of polystyrene microbeads in marine planktonic crustaceans.

PubMed

Gambardella, Chiara; Morgana, Silvia; Ferrando, Sara; Bramini, Mattia; Piazza, Veronica; Costa, Elisa; Garaventa, Francesca; Faimali, Marco

2017-11-01

Plastic debris accumulates in the marine environment, fragmenting into microplastics (MP), causing concern about their potential toxic effects when ingested by marine organisms. The aim of this study was to verify whether 0.1µm polystyrene beads are likely to trigger lethal and sub-lethal responses in marine planktonic crustaceans. MP build-up, mortality, swimming speed alteration and enzyme activity (cholinesterases, catalase) were investigated in the larval stages of Amphibalanus amphitrite barnacle and of Artemia franciscana brine shrimp exposed to a wide range of MP concentrations (from 0.001 to 10mgL -1 ) for 24 and 48h. The results show that MP were accumulated in crustaceans, without affecting mortality. Swimming activity was significantly altered in crustaceans exposed to high MP concentrations (> 1mgL -1 ) after 48h. Enzyme activities were significantly affected in all organisms exposed to all the above MP concentrations, indicating that neurotoxic effects and oxidative stress were induced after MP treatment. These findings provide new insight into sub-lethal MP effects on marine crustaceans. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of reduced risk pesticides for use in greenhouse vegetable production on Bombus impatiens (Hymenoptera: Apidae).

PubMed

Gradish, Angela E; Scott-Dupree, Cynthia D; Shipp, Les; Harris, C Ron; Ferguson, Gillian

2010-02-01

Bumble bees [Bombus impatiens (Cresson)] are widely used for supplemental pollination of greenhouse vegetables and are at risk of pesticide exposure while foraging. The objective of this study was to determine the lethal and sub-lethal effects of four insecticides (imidacloprid, abamectin, metaflumizone and chlorantraniliprole) and three fungicides (myclobutanil, potassium bicarbonate and cyprodinil + fludioxonil) used or with potential for use in Ontario greenhouse vegetable production to B. impatiens. Imidacloprid, abamectin, and metaflumizone were harmful to worker bees following direct contact, while chlorantraniliprole and all fungicides tested were harmless. Worker bees fed imidacloprid-contaminated pollen had shortened life spans and were unable to produce brood. Worker bees consumed less pollen contaminated with abamectin. Metaflumizone, chlorantraniliprole and all fungicides tested caused no sub-lethal effects in bumble bee micro-colonies. We conclude that the new reduced risk insecticides metaflumizone and chlorantraniliprole and the fungicides myclobutanil, potassium bicarbonate and cyprodinil + fludioxonil are safe for greenhouse use in the presence of bumble bees. This information can be used preserve greenhouse pollination programs while maintaining acceptable pest management.

Purification and biophysical characterization of the core protease domain of anthrax lethal factor

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

Gkazonis, Petros V.; Dalkas, Georgios A.; Chasapis, Christos T.

2010-06-04

Anthrax lethal toxin (LeTx) stands for the major virulence factor of the anthrax disease. It comprises a 90 kDa highly specific metalloprotease, the anthrax lethal factor (LF). LF possesses a catalytic Zn{sup 2+} binding site and is highly specific against MAPK kinases, thus representing the most potent native biomolecule to alter and inactivate MKK [MAPK (mitogen-activated protein kinase) kinases] signalling pathways. Given the importance of the interaction between LF and substrate for the development of anti-anthrax agents as well as the potential treatment of nascent tumours, the analysis of the structure and dynamic properties of the LF catalytic site aremore » essential to elucidate its enzymatic properties. Here we report the recombinant expression and purification of a C-terminal part of LF (LF{sub 672-776}) that harbours the enzyme's core protease domain. The biophysical characterization and backbone assignments ({sup 1}H, {sup 13}C, {sup 15}N) of the polypeptide revealed a stable, well folded structure even in the absence of Zn{sup 2+}, suitable for high resolution structural analysis by NMR.« less

Immobilized Hydrolytic Enzymes Exhibit Antibiofilm Activity Against Escherichia coli at Sub-Lethal Concentrations.

PubMed

Villa, Federica; Secundo, Francesco; Polo, Andrea; Cappitelli, Francesca

2015-07-01

The effects of two commercially available immobilized enzymes (namely the glycosidase pectinase and the protease subtilisin A) at sub-lethal concentrations were investigated in terms of their influence on biofilm genesis, on the composition of the biofilm matrix, and their antibiotic synergy against Escherichia coli biofilm, used as a model system of bacterial biofilms. The best antibiofilm performance of solid-supported hydrolases was obtained at the surface concentration of 0.022 and 0.095 U/cm(2) with a reduction of 1.2 and 2.3 log CFU/biofilm for pectinase and subtilisin, respectively. At these enzyme surface concentrations, the biocatalysts affected the structural composition of the biofilm matrix, impacting biofilm thickness. Finally, the immobilized hydrolases enhanced biofilm sensitivity to a clinically relevant concentration of the antibiotic ampicillin. At the final antibiotic concentration of 0.1 mg/ml, a reduction of 2 and 3.5 log10 units in presence of 0.022 Upectinase/cm(2) and 0.095 Usubtilisin/cm(2) was obtained, respectively, in comparison the antibiotic alone. Immobilized pectinase and subtilisin at sub-lethal concentrations demonstrated a great potential for antibiofilm applications.

Linking ciguatera poisoning to spatial ecology of fish: a novel approach to examining the distribution of biotoxin levels in the great barracuda by combining non-lethal blood sampling and biotelemetry.

PubMed

O'Toole, Amanda C; Dechraoui Bottein, Marie-Yasmine; Danylchuk, Andy J; Ramsdell, John S; Cooke, Steven J

2012-06-15

Ciguatera in humans is typically caused by the consumption of reef fish that have accumulated Ciguatoxins (CTXs) in their flesh. Over a six month period, we captured 38 wild adult great barracuda (Sphyraena barracuda), a species commonly associated with ciguatera in The Bahamas. We sampled three tissues (i.e., muscle, liver, and blood) and analysed them for the presence of ciguatoxins using a functional in vitro N2A bioassay. Detectable concentrations of ciguatoxins found in the three tissue types ranged from 2.51 to 211.74pg C-CTX-1 equivalents/g. Blood and liver toxin concentrations were positively correlated (ρ=0.86, P=0.003), indicating that, for the first time, blood sampling provides a non-lethal method of detecting ciguatoxin in wild fish. Non-lethal blood sampling also presents opportunities to couple this approach with biotelemetry and biologging techniques that enable the study of fish distribution and movement. To demonstrate the potential for linking ciguatoxin occurrence with barracuda spatial ecology, we also present a proof-of-concept case study where blood samples were obtained from 20 fish before releasing them with acoustic transmitters and tracking them in the coastal waters using a fixed acoustic telemetry array covering 44km(2). Fish that tested positive for CTX may have smaller home ranges than non-toxic fish (median distance travelled, U=2.21, P=0.03). Results presented from this study may help identify high risk areas and source-sink dynamics of toxins, potentially reducing the incidence and human health risk of ciguatera fish poisoning. Moreover, development of the non-lethal sampling approach and measurement of ciguatera from blood provide future opportunities to understand the mechanistic relationship between toxins and the spatial ecology of a broad range of marine fish species. Copyright © 2012 Elsevier B.V. All rights reserved.

Complex physiological traits as biomarkers of the sub-lethal toxicological effects of pollutant exposure in fishes.

PubMed

McKenzie, D J; Garofalo, E; Winter, M J; Ceradini, S; Verweij, F; Day, N; Hayes, R; van der Oost, R; Butler, P J; Chipman, J K; Taylor, E W

2007-11-29

Complex physiological traits, such as routine aerobic metabolic rate or exercise performance, are indicators of the functional integrity of fish that can reveal sub-lethal toxicological effects of aquatic pollutants. These traits have proved valuable in laboratory investigations of the sub-lethal effects of heavy metals, ammonia and various xenobiotics. It is not known, however, whether they can also function as biomarkers of the complex potential range of effects upon overall functional integrity caused by exposure to mixtures of chemicals in polluted natural environments. The current study used portable swimming respirometers to compare exercise performance and respiratory metabolism of fish exposed in cages for three weeks to either clean or polluted sites on three urban European river systems: the river Lambro, Milan, Italy; the rivers Blythe, Cole and Tame, Birmingham, UK; and the river Amstel, Amsterdam, The Netherlands. The UK and Italian rivers were variously polluted with high levels of both bioavailable heavy metals and organics, and the Amstel by mixtures of bioavailable organics at high concentrations. In both the UK and Italy, indigenous chub (Leuciscus cephalus) exposed to clean or polluted sites swam equally well in an initial performance test, but the chub from polluted sites could not repeat this performance after a brief recovery interval. These animals were unable to raise the metabolic rate and allocate oxygen towards exercise in the second trial, an effect confirmed in successive campaigns in Italy. Swimming performance was therefore a biomarker indicator of pollutant exposure in chub exposed at these sites. Exposure to polluted sites on the river Amstel did not affect the repeat swimming performance of cultured cloned carp (Cyprinus carpio), indicating either a species-specific tolerance or relative absence of heavy metals. However, measurements of oxygen uptake during swimming revealed increased rates of routine aerobic metabolism in both chub and carp at polluted sites in all of the rivers studied, indicating a sub-lethal metabolic loading effect. Therefore, the physiological traits of exercise performance and metabolic rate have potential as biomarkers of the overall sub-lethal toxic effects of exposure to complex mixtures of pollutants in rivers, and may also provide insight into why fish do not colonize some polluted environments.

Close Call: Magic.

ERIC Educational Resources Information Center

Journal of Adventure Education and Outdoor Leadership, 1993

1993-01-01

Staff at a residential camp for high-risk youth dealt with campers eating potentially lethal hallucinogenic mushrooms by eliminating the mushrooms instead of confronting the group and thereby jeopardizing the relationship between staff and campers. Analyzes the situation and provides suggestions for handling similar incidents in the future. (LP)

Necrotizing fasciitis after internal fixation of fracture of femoral trochanteric☆☆☆

PubMed Central

Santos, Leandro Emílio Nascimento; Pires, Robinson Esteves Santos; Figueiredo, Leonardo Brandão; Soares, Eduardo Augusto Marques

2014-01-01

Necrotizing fasciitis is a rare and potentially lethal soft tissue infection. We report a case of trochanteric femur fracture in a patient who underwent fracture fixation and developed necrotizing fasciitis. A literature review on the topic will be addressed. PMID:26229777

Ecotoxicological effects of buprofezin on fecundity, growth, development, and predation of the wolf spider Pirata piratoides (Schenkel).

PubMed

Deng, Lingling; Xu, Muqi; Cao, Hong; Dai, Jiayin

2008-11-01

The toxicological effects of buprofezin, an insect growth regulator, on the fecundity, development, and pest control potential of the wolf spider Pirata piratoides (Schenkel) (Araneae: Lycosidae) were investigated in the laboratory. It was shown that buprofezin had low toxicity to P. piratoides and that the median lethal dosage (LD(50)) 48 h and 10% lethal dosage (LD(10)) after topical application for female spiders were 653 and 316 mg buprofezin/mg fresh weight of spider, respectively. Buprofezin significantly reduced the percent hatching of spiders' eggs but had only a slight effect on egg production. No negative effects on the development and growth were observed. However, spider predation rates were strongly affected: Insecticide-treated females predated on fewer prey than the controls, and their predation rate did not recover even 5 days after insecticide application. This indicated that their pest control potential might be influenced by buprofezin, and the use of buprofezin in biological control of insects is discussed.

Three-step management of pneumothorax: time for a re-think on initial management†

PubMed Central

Kaneda, Hiroyuki; Nakano, Takahito; Taniguchi, Yohei; Saito, Tomohito; Konobu, Toshifumi; Saito, Yukihito

2013-01-01

Pneumothorax is a common disease worldwide, but surprisingly, its initial management remains controversial. There are some published guidelines for the management of spontaneous pneumothorax. However, they differ in some respects, particularly in initial management. In published trials, the objective of treatment has not been clarified and it is not possible to compare the treatment strategies between different trials because of inappropriate evaluations of the air leak. Therefore, there is a need to outline the optimal management strategy for pneumothorax. In this report, we systematically review published randomized controlled trials of the different treatments of primary spontaneous pneumothorax, point out controversial issues and finally propose a three-step strategy for the management of pneumothorax. There are three important characteristics of pneumothorax: potentially lethal respiratory dysfunction; air leak, which is the obvious cause of the disease; frequent recurrence. These three characteristics correspond to the three steps. The central idea of the strategy is that the lung should not be expanded rapidly, unless absolutely necessary. The primary objective of both simple aspiration and chest drainage should be the recovery of acute respiratory dysfunction or the avoidance of respiratory dysfunction and subsequent complications. We believe that this management strategy is simple and clinically relevant and not dependent on the classification of pneumothorax. PMID:23117233

Etanercept therapy for toxic epidermal necrolysis.

PubMed

Paradisi, Andrea; Abeni, Damiano; Bergamo, Fabio; Ricci, Francesco; Didona, Dario; Didona, Biagio

2014-08-01

Toxic epidermal necrolysis (TEN) is a severe and potentially lethal drug reaction for which no standard treatment is available. To describe a case series of patients with TEN treated with a single dose of etanercept. We observed 10 consecutive patients with TEN. For each patient, we recorded the presence of comorbidities and all the drugs recently started (ie, in the last month). In all cases, 50 mg of etanercept was administered in a single subcutaneous injection. The clinical severity of disease was computed using the SCORe of Toxic Epidermal Necrosis (SCORTEN) scale. Using the probabilities of death linked to each level of SCORTEN score, we calculated the expected probability of death in our patients. Healing was defined as complete reepithelialization, and a time to healing curve was then obtained using the Kaplan-Meier method. All patients promptly responded to treatment, reaching complete reepithelialization without complications or side effects. The median time to healing was 8.5 days. This is a small, uncontrolled case series. These preliminary results suggest the possibility that tumor necrosis factor-alfa may be an effective target for control of TEN, a dangerous skin condition for which no effective cure has yet been found. Copyright © 2014 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

Methamphetamine Use With Subsequent Thyrotoxicosis/Thyroid Storm, Agranulocytosis, and Modified Total Thyroidectomy: A Case Report.

PubMed

Viswanath, Omar; Menapace, Deanna C; Headley, Don B

2017-01-01

Thyroid storm is a rare, potentially lethal condition involving collapse of the hypothalamic-pituitary-thyroid feedback loop. Thyroid storm carries a significant mortality rate, thus requiring prompt identification and treatment. A 47-year-old woman presented to the emergency department complaining of palpitations, shortness of breath, and emesis for 24 hours after using methamphetamine. Past medical history was significant for untreated hyperthyroidism. Physical examination revealed a prominent, palpable thyroid. The Burch-Wartofsky-Score was 35. Management for thyroid storm included propylthiouracil (PTU), super saturated potassium iodide, intravenous hydrocortisone, and propranolol. However, a rare drug reaction to PTU on day 3 resulted in agranulocytosis. Propylthiouracil was withheld and a modified total thyroidectomy performed on day 8 without complications and the patient discharged on day 10 with levothyroxine. Undertreated hyperthyroidism may predispose patients to catecholamine-induced thyrotoxicosis due to catecholamine hypersensitivity. With known methamphetamine use, methamphetamine toxicity and a methamphetamine-exacerbated thyroid storm need to be included in the differential diagnosis in a patient presenting with signs of thyrotoxicosis. In addition, treating patients with agranulocytosis from PTU with a modified total thyroidectomy using ligation of the vascular supply as the initial surgical step limits release of thyroid hormone into the blood stream during thyroidectomy and decreases the possibility of intra operative thyroid storm.

eFAST for the diagnosis of a perioperative complication during percutaneous nephrolithotomy.

PubMed

Sharma, Achyut; Bhattarai, Prajjwal; Sharma, Apurb

2018-04-03

A 29-year-old patient with normal preanesthetic evaluation was planned for percutaneous nephrolithotomy (PCNL) for right nephrolithiasis with right pyelolithiasis. Surgery was performed under general anesthesia with endotracheal intubation with muscle relaxation. At the conclusion of surgery, when the patient was turned over to supine position, tense abdomen was noted. Immediately extended focused assessment with sonography in trauma (eFAST) was done in which both right and left quadrants of abdomen including pericardial and suprapubic region, right and left thoracic, and both lung basis were examined. Fluid collection was seen in Morison's pouch which was drained by the urologist under real-time ultrasonography guidance by anesthesiologist. Distension of abdomen subsequently subsided and patient had normal vitals. Trachea was extubated and patient shifted to post-operative ward. eFAST and FAST scans are routine procedures in the rapid assessment of trauma victims in emergency settings. The fluid extravasation during a routine PCNL procedure may lead to abdominal compartment syndrome. This case demonstrated that use of eFAST rapidly detected abdominal collection and ruled out life-threatening conditions such as hemothorax and pneumothorax and prevented abdominal compartment syndrome. Our case is only an example that potentially lethal conditions like these may be encountered in the perioperative setting and the knowledge of eFAST scan may be of great help.

Prophylactic Hypogastric Artery Ballooning in a Patient with Complete Placenta Previa and Increta

PubMed Central

Yi, Kyong Wook; Seo, Tae-Seok; So, Kyeong A; Paek, Yu Chin; Kim, Hai-Joong

2010-01-01

Abnormal attachment of the placenta (Placenta accreta, increta, and percreta) is an uncommon but potentially lethal cause of maternal mortality from massive postpartum hemorrhage. A 33-yr-old woman, who had been diagnosed with a placenta previa, was referred at 30 weeks gestation. On ultrasound, a complete type of placenta previa and multiple intraplacental lacunae, suggestive of placenta accreta, were noted. For further evaluation of the placenta, pelvis MRI was performed and revealed findings suspicious of a placenta increta. An elective cesarean delivery and subsequent hysterectomy were planned for the patient at 38 weeks gestation. On the day of delivery, endovascular catheters for balloon occlusion were placed within the hypogastric arteries, prior to the cesarean section. In the operating room, immediately after the delivery of the baby, bilateral hypogastric arteries were occluded by inflation of the balloons in the catheters previously placed within. With the placenta retained within the uterus, a total hysterectomy was performed in the usual fashion. The occluding balloons were deflated after closure of the vaginal cuff with hemostasis. The patient had stable vital signs and normal laboratory findings during the recovery period; she was discharged six days after delivery without complications. The final pathology confirmed a placenta increta. PMID:20358016

Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases.

PubMed

Al-Bari, Md Abdul Alim

2017-02-01

Emerging viruses such as HIV, dengue, influenza A, SARS coronavirus, Ebola, and other viruses pose a significant threat to human health. Majority of these viruses are responsible for the outbreaks of pathogenic lethal infections. To date, there are no effective therapeutic strategies available for the prophylaxis and treatment of these infections. Chloroquine analogs have been used for decades as the primary and most successful drugs against malaria. Concomitant with the emergence of chloroquine-resistant Plasmodium strains and a subsequent decrease in the use as antimalarial drugs, other applications of the analogs have been investigated. Since the analogs have interesting biochemical properties, these drugs are found to be effective against a wide variety of viral infections. As antiviral action, the analogs have been shown to inhibit acidification of endosome during the events of replication and infection. Moreover, immunomodulatory effects of analogs have been beneficial to patients with severe inflammatory complications of several viral diseases. Interestingly, one of the successful targeting strategies is the inhibition of HIV replication by the analogs in vitro which are being tested in several clinical trials. This review focuses on the potentialities of chloroquine analogs for the treatment of endosomal low pH dependent emerging viral diseases.

Portal vein thrombosis as a rare cause of abdominal pain: When to consider?

PubMed Central

Tavusbay, Cengiz; Kamer, Erdinç; Acar, Turan; Kokulu, İbrahim; Kar, Haldun; Gür, Özlem

2017-01-01

Extrahepatic portal vein thrombosis (PVT) is a rare condition that is characterized by the presence of thrombus within any segment of the portal vein, including the right and left intrahepatic branches. It may also extend to the splenic or superior mesenteric veins. Portal vein thrombosis may be related to cirrhosis or liver malignancy as well as to local inflammatory conditions in the abdomen and genetic or acquired thrombophilic diseases. Currently, PVT is being increasingly diagnosed due to advances in modern imaging techniques. The clinical presentation has a wide range, from an asymptomatic lesion to a potentially life-threatening situation. In this study, we present three patients with PVT. The diagnosis was made by radiologic and clinical findings. In the first patient, genetic testing revealed factor V Leiden mutation as the cause of PVT. The second patient was diagnosed with lupus anticoagulant syndrome as the cause of PVT. Portal vein thrombosis was associated with intra abdominal infection due to anastomotic leakage in the third patient. Two patients were successfully treated with anticoagulant therapy. This report emphasizes that even though PVT is a rare cause of abdominal pain, timely diagnosis and appropriate management is vital due to its lethal complications such as mesenteric ischemia and mesenteric infarct. PMID:28740966

Postexposure protection of guinea pigs against a lethal ebola virus challenge is conferred by RNA interference.

PubMed

Geisbert, Thomas W; Hensley, Lisa E; Kagan, Elliott; Yu, Erik Zhaoying; Geisbert, Joan B; Daddario-DiCaprio, Kathleen; Fritz, Elizabeth A; Jahrling, Peter B; McClintock, Kevin; Phelps, Janet R; Lee, Amy C H; Judge, Adam; Jeffs, Lloyd B; MacLachlan, Ian

2006-06-15

Ebola virus (EBOV) infection causes a frequently fatal hemorrhagic fever (HF) that is refractory to treatment with currently available antiviral therapeutics. RNA interference represents a powerful, naturally occurring biological strategy for the inhibition of gene expression and has demonstrated utility in the inhibition of viral replication. Here, we describe the development of a potential therapy for EBOV infection that is based on small interfering RNAs (siRNAs). Four siRNAs targeting the polymerase (L) gene of the Zaire species of EBOV (ZEBOV) were either complexed with polyethylenimine (PEI) or formulated in stable nucleic acid-lipid particles (SNALPs). Guinea pigs were treated with these siRNAs either before or after lethal ZEBOV challenge. Treatment of guinea pigs with a pool of the L gene-specific siRNAs delivered by PEI polyplexes reduced plasma viremia levels and partially protected the animals from death when administered shortly before the ZEBOV challenge. Evaluation of the same pool of siRNAs delivered using SNALPs proved that this system was more efficacious, as it completely protected guinea pigs against viremia and death when administered shortly after the ZEBOV challenge. Additional experiments showed that 1 of the 4 siRNAs alone could completely protect guinea pigs from a lethal ZEBOV challenge. Further development of this technology has the potential to yield effective treatments for EBOV HF as well as for diseases caused by other agents that are considered to be biological threats.

Clinical and Pathological Findings Associated with Aerosol Exposure of Macaques to Ricin Toxin.

PubMed

Pincus, Seth H; Bhaskaran, Manoj; Brey, Robert N; Didier, Peter J; Doyle-Meyers, Lara A; Roy, Chad J

2015-06-09

Ricin is a potential bioweapon that could be used against civilian and military personnel. Aerosol exposure is the most likely route of contact to ricin toxin that will result in the most severe toxicity. Early recognition of ricin exposure is essential if specific antidotes are to be applied. Initial diagnosis will most likely be syndromic, i.e., fitting clinical and laboratory signs into a pattern which then will guide the choice of more specific diagnostic assays and therapeutic interventions. We have studied the pathology of ricin toxin in rhesus macaques exposed to lethal and sublethal ricin aerosols. Animals exposed to lethal ricin aerosols were followed clinically using telemetry, by clinical laboratory analyses and by post-mortem examination. Animals exposed to lethal aerosolized ricin developed fever associated with thermal instability, tachycardia, and dyspnea. In the peripheral blood a marked neutrophilia (without immature bands) developed at 24 h. This was accompanied by an increase in monocytes, but depletion of lymphocytes. Red cell indices indicated hemoconcentration, as did serum chemistries, with modest increases in sodium and blood urea nitrogen (BUN). Serum albumin was strikingly decreased. These observations are consistent with the pathological observations of fluid shifts to the lungs, in the form of hemorrhages, inflammatory exudates, and tissue edema. In macaques exposed to sublethal aerosols of ricin, late pathologic consequences included chronic pulmonary fibrosis, likely mediated by M2 macrophages. Early administration of supportive therapy, specific antidotes after exposure or vaccines prior to exposure have the potential to favorably alter this outcome.

The ability of filgrastim to mitigate mortality following LD50/60 total-body irradiation is administration time-dependent.

PubMed

Farese, Ann M; Brown, Cassandra R; Smith, Cassandra P; Gibbs, Allison M; Katz, Barry P; Johnson, Cynthia S; Prado, Karl L; MacVittie, Thomas J

2014-01-01

The identification of the optimal administration schedule for an effective medical countermeasure is critical for the effective treatment of individuals exposed to potentially lethal doses of radiation. The efficacy of filgrastim (Neupogen®), a potential medical countermeasure, to improve survival when initiated at 48 h following total body irradiation in a non-human primate model of the hematopoietic syndrome of the acute radiation syndrome was investigated. Animals were exposed to total body irradiation, antero-posterior exposure, total midline tissue dose of 7.5 Gy, (target lethal dose 50/60) delivered at 0.80 Gy min, using linear accelerator-derived 6 MV photons. All animals were administered medical management. Following irradiation on day 0, filgrastim (10 μg kg d) or the control (5% dextrose in water) was administered subcutaneously daily through effect (absolute neutrophil count ≥ 1,000 cells μL for three consecutive days). The study (n = 80) was powered to demonstrate a 25% improvement in survival following the administration of filgrastim or control beginning at 48 ± 4 h post-irradiation. Survival analysis was conducted on the intention-to-treat population using a two-tailed null hypothesis at a 5% significance level. Filgrastim, initiated 48 h after irradiation, did not improve survival (2.5% increase, p = 0.8230). These data demonstrate that efficacy of a countermeasure to mitigate lethality in the hematopoietic syndrome of the acute radiation syndrome can be dependent on the interval between irradiation and administration of the medical countermeasure.

Coagulopathy as a complication of kidney biopsies in paediatric systemic lupus erythematosus patients with antiphospholipid syndrome.

PubMed

Nagata, Hiroko; Sato, Mai; Ogura, Masao; Yoshikawa, Takahisa; Yamamoto, Kazuna; Matsumura, Sohshi; Kano, Yuji; Saida, Ken; Sako, Mayumi; Kamei, Koichi; Yoshioka, Takako; Ogata, Kentaro; Ito, Shuichi; Ishikura, Kenji

2018-06-01

Children with systemic lupus erythematosus (SLE) generally undergo a pretreatment kidney biopsy. However, some of these patients, especially those with antiphospholipid syndrome (APS), may experience serious coagulopathic complications. We report herein two cases of paediatric SLE with APS in which, despite normal blood test results, the disparate coagulopathic complications of haemorrhage and embolism developed following a kidney biopsy. Case 1 was, an 8-year-old male in whom, primary APS was initially diagnosed. Fourteen months later SLE was diagnosed. Based on a percutaneous kidney biopsy, International Society of Nephrology and the Renal Pathology Society (ISN/RPS) class III-A lupus nephritis was histologically diagnosed. On post-biopsy Day 9, a giant haematoma in the fascia of the left kidney developed and was accompanied by changes in the vital signs. Case 2, a 13-year-old male, initially received the diagnosis of SLE with APS and underwent two courses of pulse methylprednisolone therapy. His coagulation abnormalities improved, and a percutaneous needle kidney biopsy was performed, leading to the histological diagnosis of ISN/RPS class III-A lupus nephritis. Furthermore, thrombotic microangiopathy was also detected in the renal histopathology. On post biopsy Day 6, the patient experienced right leg pain. A contrast CT and lower extremity ultrasonography detected a massive deep vein thrombosis and partial left pulmonary artery thrombosis. A kidney biopsy in children with SLE and APS can cause lethal coagulopathic complications, and the risks to such patients should be weighed carefully before the procedure is performed. © 2017 Asian Pacific Society of Nephrology.

Mortality risks in new-onset childhood epilepsy.

PubMed

Berg, Anne T; Nickels, Katherine; Wirrell, Elaine C; Geerts, Ada T; Callenbach, Petra M C; Arts, Willem F; Rios, Christina; Camfield, Peter R; Camfield, Carol S

2013-07-01

Estimate the causes and risk of death, specifically seizure related, in children followed from onset of epilepsy and to contrast the risk of seizure-related death with other common causes of death in the population. Mortality experiences from 4 pediatric cohorts of newly diagnosed patients were combined. Causes of death were classified as seizure related (including sudden unexpected death [SUDEP]), natural causes, nonnatural causes, and unknown. Of 2239 subjects followed up for >30 000 person-years, 79 died. Ten subjects with lethal neurometabolic conditions were ultimately excluded. The overall death rate (per 100 000 person-years) was 228; 743 in complicated epilepsy (with associated neurodisability or underlying brain condition) and 36 in uncomplicated epilepsy. Thirteen deaths were seizure-related (10 SUDEP, 3 other), accounting for 19% of all deaths. Seizure-related death rates were 43 overall, 122 for complicated epilepsy, and 14 for uncomplicated epilepsy. Death rates from other natural causes were 159, 561, and 9, respectively. Of 48 deaths from other natural causes, 37 were due to pneumonia or other respiratory complications. Most excess death in young people with epilepsy is not seizure-related. Mortality is significantly higher compared with the general population in children with complicated epilepsy but not uncomplicated epilepsy. The SUDEP rate was similar to or higher than sudden infant death syndrome rates. In uncomplicated epilepsy, sudden and seizure-related death rates were similar to or higher than rates for other common causes of death in young people (eg, accidents, suicides, homicides). Relating the risk of death in epilepsy to familiar risks may facilitate discussions of seizure-related mortality with patients and families.

Synthetic Lethal Networks for Precision Oncology: Promises and Pitfalls.

PubMed

Shen, John Paul; Ideker, Trey

2018-06-19

Synthetic lethal interactions, in which the simultaneous loss-of-function of two genes produces a lethal phenotype, are being explored as a means to therapeutically exploit cancer-specific vulnerabilities and expand the scope of precision oncology. Currently, three FDA approved drugs work by targeting the synthetic lethal interaction between BRCA1/2 and PARP. This review examines additional efforts to discover networks of synthetic lethal interactions and discusses both challenges and opportunities regarding the translation of new synthetic lethal interactions into the clinic. Copyright © 2018. Published by Elsevier Ltd.

The effect of hyperthermia on the radiation response of crypt cells in mouse jejunum

NASA Technical Reports Server (NTRS)

Wilson, J. D.

1978-01-01

The effect of hyperthermia and/or gamma-radiation on the survival of intestinal crypt cells was studied in BDF sub 1 mice using a microcolony assay. Hyperthermia treatments, which in themselves caused no detectable cell lethality, inhibited the capacity of crypt cells to repair sublethal radiation damage. In addition, heat applied either before or after single radiation exposures potentiated lethal damage to crypt cells; the degree of enhancement was dependent on the time interval between treatments. At the levels of heating employed, DNA synthesis in the intestinal epithelium was significantly reduced immediately following exposure, but returned rapidly to normal levels. No further disturbances in cellular kinetics were observed for up to 10 days after heating.

Fatal combination of moclobemide overdose and whisky.

PubMed

Bleumink, G S; van Vliet, A C M; van der Tholen, A; Stricker, B H Ch

2003-03-01

The antidepressant moclobemide (Aurorix) is a reversible inhibitor of monoamine oxidase-A. Pure moclobemide overdose is considered to be relatively safe. Mixed drug overdoses including moclobemide are potentially lethal, especially when serotonergical drugs are involved. So far, only one fatality due to moclobemide mono-overdose has been reported. We report here on a fatality following the ingestion of a moclobemide overdose in combination with half a bottle of whisky. Although dietary restrictions during moclobemide therapy are not considered necessary, the combination of large quantities of moclobemide and tyramine-containing products seems to be lethal, probably because monoamine oxidase-A selectivity is overwhelmed after massive overdoses. Since there is no specific antidote and treatment is only symptomatic, the severity of an overdose with moclobemide must not be underestimated.

Relative toxicity testing of spacecraft materials. 2: Aircraft materials

NASA Technical Reports Server (NTRS)

Lawrence, W. H.

1980-01-01

The relative toxicity of thermodegradation (pyrolysis/combustion) products of aircraft materials was studied. Two approaches were taken to assess the biological activity of the pyrolysis/combustion products of these materials: (1) determine the acute lethality to rats from inhalation of these pyrolysates and (2) examine the tendency for sublethal exposure to the pyrolysates to disrupt behavioral (shock avoidance) performance of exposed rats. The ralative importance of lethality vs. behavioral effects in selection of a material may be dictated by whether or not individuals potentially exposed to such products, would have an opportunity to escape if they were behaviorally capable of doing so. If so, the second parameter would assume greater importance, but if not the first parameter may be of much greater importance in selecting materials.

Fat embolism after fractures in Duchenne muscular dystrophy: an underdiagnosed complication? A systematic review.

PubMed

Feder, David; Koch, Miriam Eva; Palmieri, Beniamino; Fonseca, Fernando Luiz Affonso; Carvalho, Alzira Alves de Siqueira

2017-01-01

Duchenne muscular dystrophy is the most frequent lethal genetic disease. Several clinical trials have established both the beneficial effect of steroids in Duchenne muscular dystrophy and the well-known risk of side effects associated with their daily use. For many years it has been known that steroids associated with ambulation loss lead to obesity and also damage the bone structure resulting in the bone density reduction and increased incidence of bone fractures and fat embolism syndrome, an underdiagnosed complication after fractures. Fat embolism syndrome is characterized by consciousness disturbance, respiratory failure and skin rashes. The use of steroids in Duchenne muscular dystrophy may result in vertebral fractures, even without previous trauma. Approximately 25% of patients with Duchenne muscular dystrophy have a long bone fracture, and 1% to 22% of fractures have a chance to develop fat embolism syndrome. As the patients with Duchenne muscular dystrophy have progressive cardiac and respiratory muscle dysfunction, the fat embolism may be unnoticed clinically and may result in increased risk of death and major complications. Different treatments and prevention measures of fat embolism have been proposed; however, so far, there is no efficient therapy. The prevention, early diagnosis and adequate symptomatic treatment are of paramount importance. The fat embolism syndrome should always be considered in patients with Duchenne muscular dystrophy presenting with fractures, or an unexplained and sudden worsening of respiratory and cardiac symptoms.

Fat embolism after fractures in Duchenne muscular dystrophy: an underdiagnosed complication? A systematic review

PubMed Central

Feder, David; Koch, Miriam Eva; Palmieri, Beniamino; Fonseca, Fernando Luiz Affonso; Carvalho, Alzira Alves de Siqueira

2017-01-01

Duchenne muscular dystrophy is the most frequent lethal genetic disease. Several clinical trials have established both the beneficial effect of steroids in Duchenne muscular dystrophy and the well-known risk of side effects associated with their daily use. For many years it has been known that steroids associated with ambulation loss lead to obesity and also damage the bone structure resulting in the bone density reduction and increased incidence of bone fractures and fat embolism syndrome, an underdiagnosed complication after fractures. Fat embolism syndrome is characterized by consciousness disturbance, respiratory failure and skin rashes. The use of steroids in Duchenne muscular dystrophy may result in vertebral fractures, even without previous trauma. Approximately 25% of patients with Duchenne muscular dystrophy have a long bone fracture, and 1% to 22% of fractures have a chance to develop fat embolism syndrome. As the patients with Duchenne muscular dystrophy have progressive cardiac and respiratory muscle dysfunction, the fat embolism may be unnoticed clinically and may result in increased risk of death and major complications. Different treatments and prevention measures of fat embolism have been proposed; however, so far, there is no efficient therapy. The prevention, early diagnosis and adequate symptomatic treatment are of paramount importance. The fat embolism syndrome should always be considered in patients with Duchenne muscular dystrophy presenting with fractures, or an unexplained and sudden worsening of respiratory and cardiac symptoms. PMID:29066903

Lethality of home-style dehydrator processes against Escherichia coli O157:H7 and salmonella serovars in the manufacture of ground-and-formed beef jerky and the potential for using a pathogen surrogate in process validation.

PubMed

Borowski, A G; Ingham, S C; Ingham, B H

2009-10-01

Ground-and-formed beef jerky can be made easily at home with ground beef and kits that include spice, cure, and jerky-forming equipment. Ground beef poses inherent risks of illness due to Escherichia coli O157:H7 and Salmonella contamination, making adequate pathogen lethality important in jerky manufacturing. We evaluated the effectiveness of drying regimes at eliminating E. coli O157:H7 and Salmonella in seasoned ground-and-formed beef jerky manufactured with three home-style dehydrators and one small commercial unit. Inoculated jerky strips were dried for up to 12 or 24 h in a home-style or the commercial unit, respectively, with target drying temperatures ranging from 51.7 degrees C (125 degrees F) to 71.1 degrees C (160 degrees F). Pathogen lethality varied with seasoning, temperature, and drying time (n = 288 samples). Lethality against E. coli O157:H7 ranged from 1.5 log CFU (Jerky Xpress, 57.2 degrees C [135 degrees F], 4 h) to 6.4 log CFU (Gardenmaster, 68.3 degrees C [155 degrees F], 12 h), and varied with seasoning. Lethality against Salmonella ranged from 1.7 log CFU (Jerky Xpress, 57.2 degrees C [135 degrees F], 4 h) to 6.0 log CFU (Gardenmaster, 68.3 degrees C [155 degrees F], 12 h), and also varied with seasoning. There was a > or =5-log CFU reduction in both pathogens in 0, 10, and 27 % of samples at 4, 8, and 12 h, respectively. Heating jerky for 10 min at 135 degrees C (275 degrees F) 4 or 6 h postdrying increased lethality, on average, 2.99 log CFU for Salmonella and 3.02 log CFU for E. coli O157:H7. The use of a lactic acid bacterium culture (Pediococcus spp.) as a pathogen surrogate accurately predicted safety in 28 % of samples containing E. coli O157:H7 and 78% of Salmonella-inoculated samples.

Ecdysone receptor agonism leading to lethal molting disruption in arthropods: Review and adverse outcome pathway development

EPA Science Inventory

Molting is a key biological process in growth, development, reproduction and survival in arthropods. Complex neuroendocrine pathways are involved in the regulation of molting and may potentially become targets of environmental endocrine disrupting compounds (EDCs). For example, s...

Suicide Risk Response: Enhancing Patient Safety Through Development of Effective Institutional Policies

DTIC Science & Technology

2004-01-01

potentially lethal self harm ). The CWG recognized the importance of having well-defined policies for response to suicidal TIDES and WAVES patients, and...calculates responses and automatically triggers the suicidality protocol 3.1 3 Spontaneous mention of suicide, self - harm , or persistent thoughts

Cold hardiness of Helicoverpa zea (Lepidoptera: Noctuidae) pupae

Treesearch

A.C. Morey; W.D. Hutchison; R.C. Venette; E.C. Burkness

2012-01-01

An insect's cold hardiness affects its potential to overwinter and outbreak in different geographic regions. In this study, we characterized the response of Helicoverpa zea (Boddie) pupae to low temperatures by using controlled laboratory measurements of supercooling point (SCP), lower lethal temperature (LT50), and lower...

Effects of Culling on Leptospira interrogans Carriage by Rats

PubMed Central

Byers, Kaylee A.; Donovan, Christina M.; Bidulka, Julie J.; Stephen, Craig; Patrick, David M.; Himsworth, Chelsea G.

2018-01-01

We found that lethal, urban rat control is associated with a significant increase in the odds that surviving rats carry Leptospira interrogans. Our results suggest that human interventions have the potential to affect and even increase the prevalence of zoonotic pathogens within rat populations. PMID:29350160

JUVENILE AMPHIBIANS DO NOT AVOID POTENTIALLY LETHAL LEVELS OF UREA ON SOIL SUBSTRATE. (U915529)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

[The diseases of Bossuet].

PubMed

Charon, Pierre

2015-01-01

Jacques Bénigne Bossuet--nicknamed 'the Bright Eagle from Meaux' by Voltaire--died at 77, in his Parisian place of residence, on April 12th 1704. Which disease so took this robust prelate of Burgundian origin, bishop since he was 53 and whose active life had been filled with important duties and honours. If bibliography about his life is copious we owe before any trusting the testimony of his private secretary, priest François Le Dieu, whose diary describes everyday life in detail. Thus we know his fevers, skin rashes in 1699, and his bronchial and digestive problems and we can follow the evolution of his vesical lithiasis complicated with purulent, necrosing cystisis which led to the lethal evolution in spite of the efforts of renowned praticians.

Cerebral fat embolism syndrome after long bone fracture due to gunshot injury.

PubMed

Duran, Latif; Kayhan, Servet; Kati, Celal; Akdemir, Hizir Ufuk; Balci, Kemal; Yavuz, Yucel

2014-03-01

Cerebral fat embolism syndrome is a lethal complication of long-bone fractures and clinically manifasted with respiratory distress, altered mental status, and petechial rash. We presented a 20-year-old male admitted with gun-shot wounds to his left leg. Twenty-four hours after the event, he had generalized tonic clonic seizures, decorticate posture and a Glascow Coma Scale of seven with localization of painful stimuli. Subsequent magnetic resonance imaging of the brain showed a star-field pattern defining multiple lesions of restricted diffusion. On a 4-week follow-up, he had returned to normal neurological function. Despite the severity of the neurological condition upon initial presentation, the case cerebral fat embolism illustrates that, cerebral dysfunction associated with cerebral fat embolism illustrates reversible.

The ethics of withholding/withdrawing nutrition in the newborn.

PubMed

Carter, Brian S; Leuthner, Steven R

2003-12-01

The provision of nutrition and hydration to newborn infants is considered fundamental care. For premature and critically ill newborns, similar considerations generally hold true. Nutrition may be provided for these infants using assisted measures such as parenteral nutrition or tube feedings. However, for some newborn infants the provision of medically assisted nutrition may be a more complicated issue. In particular, the goals of nutrition need to be clearly elaborated for newborns with lethal conditions or for whom appropriately administered intensive care is unsuccessful in sustaining life. These infants may benefit from palliative measures of care and a limitation or withdrawal of burdensome or nonbeneficial interventions. This article explores issues pertinent to deciding and communicating the appropriate withdrawal of medically assisted nutrition and implementing palliative comfort measures.

Effectiveness of opioids in the treatment of chronic non-cancer pain.

PubMed

Trescot, Andrea M; Glaser, Scott E; Hansen, Hans; Benyamin, Ramsin; Patel, Samir; Manchikanti, Laxmaiah

2008-03-01

For thousands of years, opioids have been used to treat pain, and they continue to be one of the most commonly prescribed medications for pain. It is estimated that 90% of patients presenting to pain centers and receiving treatment in such facilities are on opioids. Opioids can be considered broad-spectrum analgesics that act at multiple points along the pain pathway. Unfortunately, opioids also have the potential for great harm, with multiple side effects and potential complications, some of which are lethal. They are also uniquely addictive, which can lead to misuse and diversion. We reviewed the relevant English literature and did thorough manual searches of the bibliographies of known primary and review articles. We utilized pain relief as the primary outcome measure. Other outcome measures were functional improvement, improvement of psychological status, improvement in work status, and evidence of addiction. Short-term use and improvement was defined as less than 6 months and long-term relief was defined as 6 months or longer. The 3 systematic reviews evaluating long-term effectiveness of opioids for chronic non-cancer pain provided unclear and weak evidence. The results of this review showed that many patients in the included studies were dissatisfied with adverse events or insufficient pain relief from opioids and withdrew from the studies. For patients able to continue on opioids, evidence was weak suggesting that their pain scores were lower than before therapy and that this relief could be maintained long-term (> 6 months). There was also weak evidence that long-term opioid therapy with morphine and transdermal fentanyl not only decreases pain but also improves functioning. Limited evidence was available for the most commonly used opioids, oxycodone and hydrocodone. Evidence for the ability to drive on chronic opioid therapy was moderate without major side effects or complications. It is concluded that, for long-term opioid therapy of 6 months or longer in managing chronic non-cancer pain, with improvement in function and reduction in pain, there is weak evidence for morphine and transdermal fentanyl. However, there is limited or lack of evidence for all other controlled substances, including the most commonly used drugs, oxycodone and hydrocodone.

MASM, a Matrine Derivative, Offers Radioprotection by Modulating Lethal Total-Body Irradiation-Induced Multiple Signaling Pathways in Wistar Rats.

PubMed

Li, Jianzhong; Xu, Jing; Lu, Yiming; Qiu, Lei; Xu, Weiheng; Lu, Bin; Hu, Zhenlin; Chu, Zhiyong; Chai, Yifeng; Zhang, Junping

2016-05-17

Matrine is an alkaloid extracted from Sophora flavescens Ait and has many biological activities, such as anti-inflammatory, antitumor, anti-fibrosis, and immunosuppressive properties. In our previous studies, the matrine derivative MASM was synthesized and exhibited potent inhibitory activity against liver fibrosis. In this study, we mainly investigated its protection against lethal total-body irradiation (TBI) in rats. Administration of MASM reduced the radiation sickness characteristics and increased the 30-day survival of rats before or after lethal TBI. Ultrastructural observation illustrated that pretreatment of rats with MASM significantly attenuated the TBI-induced morphological changes in the different organs of irradiated rats. Gene expression profiles revealed that pretreatment with MASM had a dramatic effect on gene expression changes caused by TBI. Pretreatment with MASM prevented differential expression of 53% (765 genes) of 1445 differentially expressed genes induced by TBI. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 21 pathways, such as metabolic pathways, pathways in cancer, and mitogen-activated protein kinase (MAPK) pathways. Our data indicated that pretreatment of rats with MASM modulated these pathways induced by TBI, suggesting that the pretreatment with MASM might provide the protective effects on lethal TBI mainly or partially through the modulation of these pathways, such as multiple MAPK pathways. Therefore, MASM has the potential to be used as an effective therapeutic or radioprotective agent to minimize irradiation damages and in combination with radiotherapy to improve the efficacy of cancer therapy.

Filgrastim Improves Survival in Lethally Irradiated Nonhuman Primates

PubMed Central

Farese, Ann M.; Cohen, Melanie V.; Katz, Barry P.; Smith, Cassandra P.; Gibbs, Allison; Cohen, Daniel M.; MacVittie, Thomas J.

2015-01-01

Treatment of individuals exposed to potentially lethal doses of radiation is of paramount concern to health professionals and government agencies. We evaluated the efficacy of filgrastim to increase survival of nonhuman primates (NHP) exposed to an approximate mid-lethal dose (LD50/60) (7.50 Gy) of LINAC-derived photon radiation. Prior to total-body irradiation (TBI), nonhuman primates were randomized to either a control (n =22) or filgrastim-treated (n =24) cohorts. Filgrastim (10 μg/kg/d) was administered beginning 1 day after TBI and continued daily until the absolute neutrophil count (ANC) was >1,000/μL for 3 consecutive days. All nonhuman primates received medical management as per protocol. The primary end point was all cause overall mortality over the 60 day in-life study. Secondary end points included mean survival time of decedents and all hematologic-related parameters. Filgrastim significantly (P < 0.004) reduced 60 day overall mortality [20.8% (5/24)] compared to the controls [59.1% (13/22)]. Filgrastim significantly decreased the duration of neutropenia, but did not affect the absolute neutrophil count nadir. Febrile neutropenia (ANC <500/μL and body temperature ≥103°F) was experienced by 90.9% (20/22) of controls compared to 79.2% (19/24) of filgrastim-treated animals (P = 0.418). Survival was significantly increased by 38.3% over controls. Filgrastim, administered at this dose and schedule, effectively mitigated the lethality of the hematopoietic subsyndrome of the acute radiation syndrome. PMID:23210705

Green tea extract-induced lethal toxicity in fasted but not in nonfasted dogs.

PubMed

Wu, Kuei-Meng; Yao, Jiaqin; Boring, Daniel

2011-02-01

Recent chronic toxicity studies performed on green tea extracts in fasted dogs have revealed some unique dose-limiting lethal liver, gastrointestinal, and renal toxicities. Key findings included necrosis of hepatic cells, gastrointestinal epithelia and renal tubules, atrophy of reproductive organs, atrophy and necrosis of hematopoietic tissues, and associated hematological changes. The polyphenol cachetins (a mixture of primarily epigallocatechin gallate [≥55%]; plus up to 10% each of epigallocatechin, epicatechin, and epigallocatechin gallate) appeared to be the causative agents for the observed toxicities because they are the active ingredients of green tea extract studied. Conduct of the study in nonfasted dogs under the same testing conditions and dose levels showed unremarkable results. Assuming both studies were valid, at the identified no observed adverse effect levels (NOAEL) of each study, systemic exposures (based on area under the curve [AUC]) were actually lower in fasted than nonfasted dogs, suggesting that fasting may have rendered the target organ systems potentially more vulnerable to the effects of green tea extract. The toxicity mechanisms that produced lethality are not known, but the results are scientifically intriguing. Because tea drinking has become more popular in the United States and abroad, the mode of action and site of action of green tea extract-induced lethal toxicities during fasting and the role of other phytochemical components of Folia Camellia sinensis (including nonpolyphenol fractions, which are often consumed when whole-leaf products are presented) warrant further investigation.

Differential sensitivity of developmental stages of the South American toad to a fungicide based on fludioxonil and metalaxyl-M.

PubMed

Svartz, Gabriela; Acquaroni, Mercedes; Pérez Coll, Cristina

2018-06-07

Agricultural fungicide application in Argentina has increased twice since 2008, with Maxim® XL (2.5% fludioxonil +1% metalaxyl-M) as one of the most used fungicide formulation. The toxicity of this pesticide on Rhinella arenarum was assessed by means of continuous (from embryo and larval development) and 24-h pulse exposure standardized bioassays. Lethality was concentration- and exposure time-dependent. Maxim® XL caused a progressive lethal effect along the bioassays with higher toxicity on embryos than larvae, obtaining 50% lethal concentrations at 96, 336, and 504 h of 10.85, 2.89, and 1.71 mg/L for embryos, and 43.94, 11.79, and 5.76 mg/L for larvae respectively. Lethal 504-h no observed effect concentration values for embryos and larvae were 1 and 2.5 mg/L respectively. A stage-dependent toxicity of Maxim® XL was also demonstrated within the embryo development, with early stages more sensitive than the later ones, and blastula as the most sensitive developmental stage. The risk quotients obtained for chronic risk assessment determined a potential threat for the survival and continuity of R. arenarum populations under these conditions. The results indicate that the levels of the fungicide reaching amphibian habitats could be risky for the early development of this amphibian species. This study also emphasizes the necessity to evaluate the chronic effects of fungicides in pesticide risk assessment.

Risk assessment of ritual use of oral dimethyltryptamine (DMT) and harmala alkaloids.

PubMed

Gable, Robert S

2007-01-01

To extend previous reviews by assessing the acute systemic toxicity and psychological hazards of a dimethyltryptamine and beta-carboline brew (ayahuasca/hoasca) used in religious ceremonies. A systematic literature search, supplemented by interviews with ceremony participants. No laboratory animal models were located that tested the acute toxicity or the abuse potential of ayahuasca. Separate animal studies of the median lethal dose of dimethyltryptamine (DMT) and of several harmala alkaloids indicated that a lethal dose of these substances in humans is probably greater than 20 times the typical ceremonial dose. Adverse health effects may occur from casual use of ayahuasca, particularly when serotonergic substances are used in conjunction. DMT is capable of inducing aversive psychological reactions or transient psychotic episodes that resolve spontaneously in a few hours. There was no evidence that ayahuasca has substantial or persistent abuse potential. Long-term psychological benefits have been documented when ayahuasca is used in a well-established social context. A decoction of DMT and harmala alkaloids used in religious ceremonies has a safety margin comparable to codeine, mescaline or methadone. The dependence potential of oral DMT and the risk of sustained psychological disturbance are minimal.

Identification of the epigenetic reader CBX2 as a potential drug target in advanced prostate cancer.

PubMed

Clermont, Pier-Luc; Crea, Francesco; Chiang, Yan Ting; Lin, Dong; Zhang, Amy; Wang, James Z L; Parolia, Abhijit; Wu, Rebecca; Xue, Hui; Wang, Yuwei; Ding, Jiarui; Thu, Kelsie L; Lam, Wan L; Shah, Sohrab P; Collins, Colin C; Wang, Yuzhuo; Helgason, Cheryl D

2016-01-01

While localized prostate cancer (PCa) can be effectively cured, metastatic disease inevitably progresses to a lethal state called castration-resistant prostate cancer (CRPC). Emerging evidence suggests that aberrant epigenetic repression by the polycomb group (PcG) complexes fuels PCa progression, providing novel therapeutic opportunities. In the search for potential epigenetic drivers of CRPC, we analyzed the molecular profile of PcG members in patient-derived xenografts and clinical samples. Overall, our results identify the PcG protein and methyl-lysine reader CBX2 as a potential therapeutic target in advanced PCa. We report that CBX2 was recurrently up-regulated in metastatic CRPC and that elevated CBX2 expression was correlated with poor clinical outcome in PCa cohorts. Furthermore, CBX2 depletion abrogated cell viability and induced caspase 3-mediated apoptosis in metastatic PCa cell lines. Mechanistically explaining this phenotype, microarray analysis in CBX2-depleted cells revealed that CBX2 controls the expression of many key regulators of cell proliferation and metastasis. Taken together, this study provides the first evidence that CBX2 inhibition induces cancer cell death, positioning CBX2 as an attractive drug target in lethal CRPC.

Complications of Recanalization of Chronic Total Occlusion

PubMed Central

Kalyanasundaram, Arun; Lombardi, William L.

2015-01-01

Percutaneous Coronary Intervention (PCI) of Chronic Total Occlusions (CTO) is an accepted revascularization procedure. These complex procedures carry with them certain risks and potential complications. Complications of PCI such as contrast induced renal dysfunction, radiation, etc, assume more relevance given the length and complexity of these procedures. Further, certain complications such as donor vessel injury, foreign body entrapment are unique to CTO PCI. A thorough understanding of the potential complications is important in mitigating risk during these complex procedures.

Issues surrounding lethal injection as a means of capital punishment.

PubMed

Romanelli, Frank; Whisman, Tyler; Fink, Joseph L

2008-12-01

Lethal injection as a method of state-sanctioned capital punishment was initially proposed in the United States in 1977 and used for the first time in 1982. Most lethal injection protocols use a sequential drug combination of sodium thiopental, pancuronium bromide, and potassium chloride. Lethal injection was originally introduced as a more humane form of execution compared with existing mechanical methods such as electrocution, toxic gassing, hanging, or firing squad. Lethal injection has not, however, been without controversy. Several states are considering whether lethal injection meets constitutional scrutiny forbidding cruel and unusual punishment. Recently in the case of Ralph Baze and Thomas C. Bowling, Petitioners, v John D. Rees, Commissioner, Kentucky Department of Corrections et al, the United States Supreme Court upheld the constitutionality of the lethal injection protocol as carried out in the Commonwealth of Kentucky. Most of the debate has surrounded the dosing and procedures used in lethal injection and whether the drug combinations and measures for administering the drugs truly produce a timely, pain-free, and fail-safe death. Many have also raised issues regarding the "medicalization" of execution and the ethics of health care professionals' participation in any part of the lethal injection process. As a result of all these issues, the future of lethal injection as a means of execution in the United States is under significant scrutiny. Outcomes of ongoing legislative and judicial reviews might result in cessation of lethal injection in totality or in alterations involving specific drug combinations or administration procedures.

EVALUATING THE PREDICTIVE VALIDITY OF SUICIDAL INTENT AND MEDICAL LETHALITY IN YOUTH

PubMed Central

Sapyta, Jeffrey; Goldston, David B.; Erkanli, Alaattin; Daniel, Stephanie S.; Heilbron, Nicole; Mayfield, Andrew; Treadway, S. Lyn

2012-01-01

Objectives To examine whether suicidal intent and medical lethality of past suicide attempts are predictive of future attempts, the association between intent and lethality, and the consistency of these characteristics across repeated attempts among youth. Method Suicide attempts in a 15-year prospective study of 180 formerly psychiatrically hospitalized adolescents (Mage at hospitalization = 14.83; 51% female; 80% Caucasian) were characterized using the Subjective Intent Rating Scale and Lethality of Attempt Rating Scale. Anderson-Gill recurrent events survival models and generalized estimating equations were used to assess predictive validity. Generalized linear models were used to examine stability of characteristics across attempts. Results Neither intent nor lethality from the most recent attempt predicted future attempts. The highest level of intent and most severe lethality of attempts during the follow-up predicted subsequent attempts, but the degree to which highest intent and most severe lethality contributed to prediction after considering methods of suicide attempts, past number of attempts, or psychiatric diagnoses was mixed. Across successive attempts, there was little consistency in reported characteristics. Intent and lethality were related to each other only for attempts occurring in early adulthood. Conclusions Highest intent and lethality were better predictors of future attempts than intent and lethality of the most recent attempt. However, these characteristics should only be considered as predictors within the context of other factors. For youth, clinicians should not infer true intent from the lethality of attempts, nor assume that characteristics of future suicide attempts will be similar to previous attempts. PMID:22250854

AMBIENT SOLAR UV RADIATION CAUSES MORTALITY IN LARVAE OF THREE SPECIES OF RANA

EPA Science Inventory

Recent reports concerning the lethal effects of solar ultraviolet-B (UV-B) radiation on amphibians suggest that this stressor has the potential to impact some amphibian populations. In this study embryos and larvae of three anuran species, Rana pipiens, R. clamitans, and R. septe...

Lethal trap trees: a potential option for emerald ash borer (Agrilus planipennis Fairmaire) management

Treesearch

Deborah G McCullough; Therese M. Poland; Phillip A. Lewis

2015-01-01

BACKGROUND: Economic and ecological impacts of ash (Fraxinus spp.) mortality resulting from emerald ash borer (EAB) (Agrilus planipennis Fairmaire) invasion are severe in forested, residential and urban areas. Management options include girdling ash trees to attract ovipositing adult beetles and then destroying infested trees...

Adolescents' Misperceptions of the Dangerousness of Acetaminophen in Overdose.

ERIC Educational Resources Information Center

Harris, Hope Elaine; Myers, Wade C.

1997-01-01

Assesses the generality and strength of nonclinical youths' (N=569) perceptions of the harmfulness and lethality of acetaminophen in overdose. Findings indicate that adolescents have ready access to acetaminophen and use it in suicide attempts but underestimate its potential for toxicity, lacking knowledge regarding side effects of overdose. (RJM)

Reconsidering the Relationship between Alcohol and Lethal Violence

ERIC Educational Resources Information Center

Phillips, Scott; Matusko, Jacqueline; Tomasovic, Elizabeth

2007-01-01

Prior event-based research regarding the relationship between alcohol and violence suffers from important limitations, including the absence of a comparison group, an inappropriate comparison group, or a comparison group that could be considered appropriate but does not control for potential confounders. To overcome such limitations, we use a…

Lethality of Rendang packaged in multilayer retortable pouch with sterilization process

NASA Astrophysics Data System (ADS)

Praharasti, A. S.; Kusumaningrum, A.; Frediansyah, A.; Nurhikmat, A.; Khasanah, Y.; Suprapedi

2017-01-01

Retort Pouch had become a choice to preserve foods nowadays, besides the used of the can. Both had their own advantages, and Retort Pouch became more popular for the reason of cheaper and easier to recycle. General Method usually used to estimate the lethality of commercial heat sterilization process. Lethality value wa s used for evaluating the efficacy of the thermal process. This study aimed to find whether different layers of pouch materials affect the lethality value and to find differences lethality in two types of multilayer retort pouch, PET/Aluminum Foil/Nylon/RCPP and PET/Nylon/Modified Aluminum/CPP. The result showed that the different layer arrangement was resulted different Sterilization Value (SV). PET/Nylon/Modified Aluminum/CPP had better heat penetration, implied by the higher value of lethality. PET/Nylon/Modified Aluminum/CPP had the lethality value of 6,24 minutes, whereas the lethality value of PET/Aluminum Foil/Nylon/RCPP was 3,54 minutes.

Impulsivity, aggression and brain structure in high and low lethality suicide attempters with borderline personality disorder.

PubMed

Soloff, Paul; White, Richard; Diwadkar, Vaibhav A

2014-06-30

Impulsivity and aggressiveness are trait dispositions associated with the vulnerability to suicidal behavior across diagnoses. They are associated with structural and functional abnormalities in brain networks involved in regulation of mood, impulse and behavior. They are also core characteristics of borderline personality disorder (BPD), a disorder defined, in part, by recurrent suicidal behavior. We assessed the relationships between personality traits, brain structure and lethality of suicide attempts in 51 BPD attempters using multiple regression analyses on structural MRI data. BPD was diagnosed by the Diagnostic Interview for Borderline Patients-revised, impulsivity by the Barratt Impulsiveness Scale (BIS), aggression by the Brown-Goodwin Lifetime History of Aggression (LHA), and high lethality by a score of 4 or more on the Lethality Rating Scale (LRS). Sixteen High Lethality attempters were compared to 35 Low Lethality attempters, with no significant differences noted in gender, co-morbidity, childhood abuse, BIS or LHA scores. Degree of medical lethality (LRS) was negatively related to gray matter volumes across multiple fronto-temporal-limbic regions. Effects of impulsivity and aggression on gray matter volumes discriminated High from Low Lethality attempters and differed markedly within lethality groups. Lethality of suicide attempts in BPD may be related to the mediation of these personality traits by specific neural networks. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Fos metamorphoses: Lessons from mutants in model organisms (Drosophila).

PubMed

Alfonso-Gonzalez, Carlos; Riesgo-Escovar, Juan Rafael

2018-05-10

The Fos oncogene gene family is evolutionarily conserved throughout Eukarya. Fos proteins characteristically have a leucine zipper and a basic region with a helix-turn-helix motif that binds DNA. In vertebrates, there are several Fos homologs. They can homo- or hetero-dimerize via the leucine zipper domain. Fos homologs coupled with other transcription factors, like Jun oncoproteins, constitute the Activator Protein 1 (AP-1) complex. From its original inception as an oncogene, the subsequent finding that they act as transcription factors binding DNA sequences known as TRE, to the realization that they are activated in many different scenarios, and to loss-of-function analysis, the Fos proteins have traversed a multifarious path in development and physiology. They are instrumental in 'immediate early genes' responses, and activated by a seemingly myriad assemblage of different stimuli. Yet, the majority of these studies were basically gain-of-function studies, since it was thought that Fos genes would be cell lethal. Loss-of-function mutations in vertebrates were recovered later, and were not cell lethal. In fact, c-fos null mutations are viable with developmental defects (osteopetrosis and myeloid lineage abnormalities). It was then hypothesized that vertebrate genomes exhibit partial redundancy, explaining the 'mild' phenotypes, and complicating assessment of complete loss-of-function phenotypes. Due to its promiscuous activation, fos genes (especially c-fos) are now commonly used as markers for cellular responses to stimuli. fos homologs high sequence conservation (including Drosophila) is advantageous as it allows critical assessment of fos genes functions in this genetic model. Drosophila melanogaster contains only one fos homolog, the gene kayak. kayak mutations are lethal, and allow study of all the processes where fos is required. The kayak locus encodes several different isoforms, and is a pleiotropic gene variously required for development involving cell shape changes. In general, fos genes seem to primarily activate programs involved in cellular architectural rearrangements and cell shape changes. Copyright © 2018. Published by Elsevier B.V.

Tissue residues of dieldrin in relation to mortality in birds and mammals

USGS Publications Warehouse

Stickel, W.H.; Stickel, L.F.; Spann, J.W.; Miller, M.W.; Berg, G.G.

1969-01-01

An experiment was performed with Coturnix to learn what residue levels were indicative of death from dieldrin poisoning. Birds were fed diets containing 250, 50, 10, and 2 ppm dieldrin for periods up to 158 days. The dieldrin was 95% pure HEOD, which is 1,2,3,4,10,10-hexachloro-6, 7.epoxy. l,4,4a,5,6,7,8,8a-octahydro-l,4-endo,exo-5,8- dimethanonaphthalene. When half of a group was dead, the other half was sacrificed for comparison of residues in dead and survivors. Dosage levels controlled time to death, but did not control residue levels in the dead. Residues in liver and carcass proved to be misleading and complicated by changes in lipid content. Brain residues correlated well with death although residues in dead and survivors overlapped. Brain residues of animals killed by dieldrin in the field and in other experiments are listed. Data agree in general for several species of birds and mammals. There is evidence, however, for species differences in average lethal brain residues. It is concluded that brain residues of 4 or 5 ppm (wet weight) or higher indicate that the animal was in the known danger zone and may have died from dieldrin. Brain residues averaged lower in wild than in experimental animals. Possible explanations include species differences, more stress and exertion in the wild, and overrepresentation in the field series of individuals that will die with low but lethal brain residues. The latter is supported by the fact that the first Coturnix to die in each sex and treatment group had the lowest brain residue of its group. Birds receiving 2 ppm dieldrin, and some receiving 10 ppm, were able to maintain low brain residues throughout the experiment. However, birds of the 10 ppm group could withstand little stress and mobilization of toxicant, for a few micrograms in the brain were lethal and bodies contained hundreds or thousands of micrograms.

Developmental toxicity and risk assessment of nonylphenol to the South American toad, Rhinella arenarum.

PubMed

Mariel, Aronzon Carolina; Alejandra, Babay Paola; Silvia, Pérez Coll Cristina

2014-09-01

The toxicity of Nonylphenol, an emerging pollutant, on the common South American toad Rhinella arenarum was stage and time dependent, thus Median Lethal Concentrations (LC50) for acute (96h), short-term chronic (168h) and chronic exposure (336h) were 1.06; 0.96 and 0.17mgNP/L from embryonic period (S.4), whereas for exposure from larvae (S.25), LC50 remained constant at 0.37mgNP/L from 96h to 168h, decreasing to 0.11mgNP/L at 336h. NOEC-168h for exposure from embryos was 0.025mgNP/L. The Teratogenic Potential (NOEC-lethality/NOEC-sublethal effects) was 23 times higher than the threshold value, indicating a high risk for embryos to be malformed in absence of significant lethality and representing a threat for the species conservation. By comparing with other amphibians, the early development of R. arenarum was very sensitive to NP. The results highlight the relevance of extending the exposure time and look for the most sensitive stage in order to perform the bioassays for conservation purposes. Copyright © 2014 Elsevier B.V. All rights reserved.

Gene expression and mutation-guided synthetic lethality eradicates proliferating and quiescent leukemia cells

PubMed Central

Nieborowska-Skorska, Margaret; Sullivan, Katherine; Dasgupta, Yashodhara; Podszywalow-Bartnicka, Paulina; Maifrede, Silvia; Di Marcantonio, Daniela; Bolton-Gillespie, Elisabeth; Cramer-Morales, Kimberly; Lee, Jaewong; Li, Min; Slupianek, Artur; Gritsyuk, Daniel; Cerny-Reiterer, Sabine; Seferynska, Ilona; Bullinger, Lars; Gorbunova, Vera; Piwocka, Katarzyna; Valent, Peter; Civin, Curt I.; Muschen, Markus; Dick, John E.; Wang, Jean C.Y.; Bhatia, Smita; Bhatia, Ravi; Eppert, Kolja; Minden, Mark D.; Sykes, Stephen M.

2017-01-01

Quiescent and proliferating leukemia cells accumulate highly lethal DNA double-strand breaks that are repaired by 2 major mechanisms: BRCA-dependent homologous recombination and DNA-dependent protein kinase–mediated (DNA-PK–mediated) nonhomologous end-joining, whereas DNA repair pathways mediated by poly(ADP)ribose polymerase 1 (PARP1) serve as backups. Here we have designed a personalized medicine approach called gene expression and mutation analysis (GEMA) to identify BRCA- and DNA-PK–deficient leukemias either directly, using reverse transcription-quantitative PCR, microarrays, and flow cytometry, or indirectly, by the presence of oncogenes such as BCR-ABL1. DNA-PK–deficient quiescent leukemia cells and BRCA/DNA-PK–deficient proliferating leukemia cells were sensitive to PARP1 inhibitors that were administered alone or in combination with current antileukemic drugs. In conclusion, GEMA-guided targeting of PARP1 resulted in dual cellular synthetic lethality in quiescent and proliferating immature leukemia cells, and is thus a potential approach to eradicate leukemia stem and progenitor cells that are responsible for initiation and manifestation of the disease. Further, an analysis of The Cancer Genome Atlas database indicated that this personalized medicine approach could also be applied to treat numerous solid tumors from individual patients. PMID:28481221

Inhibition of anthrax lethal factor by ssDNA aptamers.

PubMed

Lahousse, Mieke; Park, Hae-Chul; Lee, Sang-Choon; Ha, Na-Reum; Jung, In-Pil; Schlesinger, Sara R; Shackelford, Kaylin; Yoon, Moon-Young; Kim, Sung-Kun

2018-05-15

Anthrax is caused by Bacillus anthracis, a bacterium that is able to secrete the toxins protective antigen, edema factor and lethal factor. Due to the high level of secretion from the bacteria and its severe virulence, lethal factor (LF) has been sought as a biomarker for detecting bacterial infection and as an effective target to neutralize toxicity. In this study, we found three aptamers, and binding affinity was determined by fluorescently labeled aptamers. One of the aptamers exhibited high affinity, with a K d value of 11.0 ± 2.7 nM, along with low cross reactivity relative to bovine serum albumin and protective antigen. The therapeutic functionality of the aptamer was examined by assessing the inhibition of LF protease activity against a mitogen-activated protein kinase kinase. The aptamer appears to be an effective inhibitor of LF with an IC 50 value of 15 ± 1.5 μM and approximately 85% cell viability, suggesting that this aptamer provides a potential clue for not only development of a sensitive diagnostic device of B. anthracis infection but also the design of novel inhibitors of LF. Copyright © 2018 Elsevier Inc. All rights reserved.

hERG trafficking inhibition in drug-induced lethal cardiac arrhythmia.

PubMed

Nogawa, Hisashi; Kawai, Tomoyuki

2014-10-15

Acquired long QT syndrome induced by non-cardiovascular drugs can cause lethal cardiac arrhythmia called torsades de points and is a significant problem in drug development. The prolongation of QT interval and cardiac action potential duration are mainly due to reduced physiological function of the rapidly activating voltage-dependent potassium channels encoded by human ether-a-go-go-related gene (hERG). Structurally diverse groups of drugs are known to directly inhibit hERG channel conductance. Therefore, the ability of acute hERG inhibition is routinely assessed at the preclinical stages in pharmaceutical testing. Recent findings indicated that chronic treatment with various drugs not only inhibits hERG channels but also decreases hERG channel expression in the plasma membrane of cardiomyocytes, which has become another concern in safety pharmacology. The mechanisms involve the disruption of hERG trafficking to the surface membrane or the acceleration of hERG protein degradation. From this perspective, we present a brief overview of mechanisms of drug-induced trafficking inhibition and pathological regulation. Understanding of drug-induced hERG trafficking inhibition may provide new strategies for predicting drug-induced QT prolongation and lethal cardiac arrhythmia in pharmaceutical drug development. Copyright © 2014 Elsevier B.V. All rights reserved.

Synergistic Antibacterial and Anti-Inflammatory Activity of Temporin A and Modified Temporin B In Vivo

PubMed Central

Capparelli, Rosanna; Romanelli, Alessandra; Iannaccone, Marco; Nocerino, Nunzia; Ripa, Raffaella; Pensato, Soccorsa; Pedone, Carlo; Iannelli, Domenico

2009-01-01

Temporins are antimicrobial peptides secreted by the granular glands of the European red frog (Rana temporaria). They are 10–14 amino acid long polypeptides active prevalently against gram positive bacteria. This study shows that a synthetic temporin B analogue (TB-YK), acquires the capacity to act in synergism with temporin A and to exert antimicrobial and anti-inflammatory activity in vivo against gram positive and gram negative bacteria. Administration of 3.4 mg/Kg of temporin A (TA)+1.6 mg/Kg TB-YK, given to individual mice concurrently with a lethal dose of bacteria (gram positive or negative), rescued 100% of the animals. More importantly, the same doses of temporins, administered one week after experimental infection with a sub lethal dose of bacteria, sterilized 100% of the animals within 3–6 days. Also, it is described an animal model based on the use of sub lethal doses of bacteria, which closely mimics bacterial infection in humans. The model offers the possibility to test in a preclinical setting the true potential of TA and TB-YK in combination as antimicrobial and anti-inflammatory agents. PMID:19784377

DNA vaccines targeting heavy chain C-terminal fragments of Clostridium botulinum neurotoxin serotypes A, B, and E induce potent humoral and cellular immunity and provide protection from lethal toxin challenge.

PubMed

Scott, Veronica L; Villarreal, Daniel O; Hutnick, Natalie A; Walters, Jewell N; Ragwan, Edwin; Bdeir, Khalil; Yan, Jian; Sardesai, Niranjan Y; Finnefrock, Adam C; Casimiro, Danilo R; Weiner, David B

2015-01-01

Botulinum neurotoxins (BoNTs) are deadly, toxic proteins produced by the bacterium Clostridium botulinum that can cause significant diseases in humans. The use of the toxic substances as potential bioweapons has raised concerns by the Centers for Disease Control and Prevention and the United States Military. Currently, there is no licensed vaccine to prevent botulinum intoxication. Here we present an immunogenicity study to evaluate the efficacy of novel monovalent vaccines and a trivalent cocktail DNA vaccine targeting the heavy chain C-terminal fragments of Clostridium botulinum neurotoxin serotypes A, B, and E. These synthetic DNA vaccines induced robust humoral and polyfunctional CD4(+) T-cell responses which fully protected animals against lethal challenge after just 2 immunizations. In addition, naïve animals administered immunized sera mixed with the lethal neurotoxin were 100% protected against intoxication. The data demonstrate the protective efficacy induced by a combinative synthetic DNA vaccine approach. This study has importance for the development of vaccines that provide protective immunity against C. botulinum neurotoxins and other toxins.

Three homicides with darts tainted with succinylcholine: autopsy and toxicology.

PubMed

Xing, Jingjun; Li, Wenhe; Tong, Fang; Liang, Yue; He, Guanglong; Zhou, Yiwu

2016-11-01

In emergency departments, intoxication with the muscle relaxant succinylcholine (SUX) often leads to a potentially lethal respiratory paralysis or other deleterious side effects. However, homicide cases with SUX poisoning are very rare because the toxic or lethal concentration ranges of SUX have not yet been determined. We described three uncommon homicide cases due to acute poisoning by darts contaminated with SUX. All the victims died quickly (less than 30 min) after being shot by an especially designed dart gun. Succinylmonocholine (SMC), a metabolite of SUX, was used as a marker to detect the latter. HPLC-MS/MS analysis demonstrated the presence of SUX in the droplet residues of the darts and SMC in the blood and urine in all cases. SMC concentrations of 0.45, 14.0, and 17.9 ng/ml were detected in the victims' blood and 259.0 ng/ml in the urine from the third case. The main pathological changes consisted of hemorrhage of the injured soft tissues, visceral congestion, severe pulmonary edema, and multifocal petechial hemorrhage of the heart and lungs. Taken together, the findings supported a diagnosis of fatal SUX poisoning. Futhermore, our study provided a reference for the lethal concentrations of SUX poisoning.

Experimental Respiratory Infection of Marmosets (Callithrix jacchus) With Ebola Virus Kikwit.

PubMed

Smither, Sophie J; Nelson, Michelle; Eastaugh, Lin; Nunez, Alejandro; Salguero, Francisco J; Lever, Mark S

2015-10-01

Ebola virus (EBOV) causes a highly infectious and lethal hemorrhagic fever in primates with high fatality rates during outbreaks and EBOV may be exploited as a potential biothreat pathogen. There is therefore a need to develop and license appropriate medical countermeasures against this virus. To determine whether the common marmoset (Callithrix jacchus) would be an appropriate model to assess vaccines or therapies against EBOV disease (EVD), initial susceptibility, lethality and pathogenesis studies were performed. Low doses of EBOV-Kikwit, between 4 and 27 times the 50% tissue culture infectious dose, were sufficient to cause a lethal, reproducible infection. Animals became febrile between days 5 and 6, maintaining a high fever before succumbing to EVD between 6 and 8 days after challenge. Typical signs of EVD were observed. Pathogenesis studies revealed that virus was isolated from the lungs of animals beginning on day 3 after challenge and from the liver, spleen and blood beginning on day 5. The most striking features were observed in animals that succumbed to infection, including high viral titers in all organs, increased levels of liver function enzymes and blood clotting times, decreased levels of platelets, multifocal moderate to severe hepatitis, and perivascular edema. © Crown copyright 2015.

Post-exposure treatment of non-human primates lethally infected with Ebola virus with EBOTAb, a purified ovine IgG product.

PubMed

Dowall, Stuart D; Jacquot, Frédéric; Landon, John; Rayner, Emma; Hall, Graham; Carbonnelle, Caroline; Raoul, Hervé; Pannetier, Delphine; Cameron, Ian; Coxon, Ruth; Al Abdulla, Ibrahim; Hewson, Roger; Carroll, Miles W

2017-06-22

Despite sporadic outbreaks of Ebola virus (EBOV) over the last 4 decades and the recent public health emergency in West Africa, there are still no approved vaccines or therapeutics for the treatment of acute EBOV disease (EVD). In response to the 2014 outbreak, an ovine immunoglobulin therapy was developed, termed EBOTAb. After promising results in the guinea pig model of EBOV infection, EBOTAb was tested in the cynomolgus macaque non-human primate model of lethal EBOV infection. To ensure stringent therapeutic testing conditions to replicate likely clinical usage, EBOTAb was first delivered 1, 2 or 3 days post-challenge with a lethal dose of EBOV. Results showed a protective effect of EBOTAb given post-exposurally, with survival rates decreasing with increasing time after challenge. Viremia results demonstrated that EBOTAb resulted in a decreased circulation of EBOV in the bloodstream. Additionally, assay of liver enzymes and histology analysis of local tissues identified differences between EBOTAb-treated and untreated groups. The results presented demonstrate that EBOTAb conferred protection against EBOV when given post-exposure and should be explored and developed further as a potential intervention strategy for future outbreaks, which are likely to occur.

Toxicity and bioconcentration evaluation of RDX and HMX using sheepshead minnows in water exposures.

PubMed

Lotufo, Guilherme R; Gibson, Alfreda B; Yoo, J Leslie

2010-10-01

Lethal effects of the explosives RDX and HMX were assessed using ten-day water exposures to juvenile sheepshead minnows (Cyprinodon variegatus). For RDX, maximum mortality occurred during the first two days of exposure with a 10-d median lethal concentration (LC50) of 9.9 mg L(-1). The RDX 10-d median lethal residue (LR50) was 9.6 mg kg(-1) (34.9 μmol kg(-1)) wet weight (ww), the first RDX critical body residue reported for fish. Previous investigations reported that RDX body residues in marine amphipods up to 96 μmol kg(-1) ww and in marine mussels up to 86 μmol kg(-1) ww failed to result in significant mortality. The highest HMX concentration tested, corresponding to its apparent solubility limit in seawater (2.0 mg L(-1)), and the associated mean body residue (3 mg kg(-1) or 14 μmol kg(-1) ww) resulted in no significant mortality for exposed minnows. The mean 10-d bioconcentration factors for RDX (0.6-0.9 L kg(-1)) and HMX (0.3-1.6 L kg(-1)) were typically lower than 1, reflecting the low bioaccumulative potential for these compounds. Published by Elsevier Inc.

ZTI-01 Treatment Improves Survival of Animals Infected with Multidrug Resistant Pseudomonas aeruginosa

PubMed Central

Lawrenz, Matthew B; denDekker, Ashley Eb; Cramer, Daniel E; Gabbard, Jon D; Lafoe, Kathryn M; Pfeffer, Tia L; Sotsky, Julie B; Vanover, Carol D; Ellis-Grosse, Evelyn J; Warawa, Jonathan M

2017-01-01

Abstract Background ZTI-01 (fosfomycin, FOS, for injection) is currently under US development to treat complicated urinary tract infections. ZTI-01 is unique compared with other antimicrobials in that it inhibits an early step in cell wall synthesis via covalent binding to MurA. ZTI-01 demonstrates broad in vitro activity against Gram-negative (GN) and -positive (GP) bacteria, including multidrug-resistant (MDR) organisms. Our study goals were to determine the efficacy of ZTI-01 as a monotherapy or in combination with meropenem against MDR Pseudomonas aeruginosa in a preclinical model of pulmonary infection. Methods 8 week old neutropenic mice were infected with a MDR strain of P. aeruginosa via intubation-mediated intratracheal (IMIT) instillation. 3 hours after instillation, mice received treatment with ZTI-01, meropenem, or ZTI-01 plus meropenem (combination therapy) q8h for 5 days. Mice were monitored every 8 hours for 7 days for development of disease and moribund animals were humanely euthanized. Lungs and spleens were harvested at euthanasia, or at 7 days for survivors, and processed for bacterial enumeration and development of pathology. Results Mice were challenged with a lethal dose of P. aeruginosa UNC-D. Mock treated animals succumbed to infection within 36 hours post-infection. Animals that received 6 g/kg/day ZTI-01 showed an increase in the MTD (52 hours) and 25% of the cohort were protected from lethal disease. Combining ZTI-01 with meropenem resulted in a significant increase in survival (≥75% of cohorts survived infection). Combination therapy also significantly decreased bacterial numbers in the lungs and inhibited dissemination to the spleens. Furthermore, animals receiving combination therapy were protected from significant inflammation in the lungs and the development of pneumonia. Conclusion Here we report that combination therapy with ZTI-01 and meropenem provides significant improvements in all disease manifestations over treatment with each drug individually in a preclinical model for pulmonary infection with MDR P. aeruginosa. These data strongly support further evaluation of ZTI-01 in combination with other antibiotics as potential therapies against pulmonary infections with MDR bacteria. Disclosures E. J. Ellis-Grosse, Zavante Therapeutics, Inc.: Employee and Shareholder, Salary

Possible role of gamma ray bursts on life extinction in the universe.

PubMed

Piran, Tsvi; Jimenez, Raul

2014-12-05

As a copious source of gamma rays, a nearby galactic gamma ray burst (GRB) can be a threat to life. Using recent determinations of the rate of GRBs, their luminosity function, and properties of their host galaxies, we estimate the probability that a life-threatening (lethal) GRB would take place. Amongst the different kinds of GRBs, long ones are most dangerous. There is a very good chance (but no certainty) that at least one lethal GRB took place during the past 5 gigayears close enough to Earth as to significantly damage life. There is a 50% chance that such a lethal GRB took place during the last 500×10^{6}  years, causing one of the major mass extinction events. Assuming that a similar level of radiation would be lethal to life on other exoplanets hosting life, we explore the potential effects of GRBs to life elsewhere in the Galaxy and the Universe. We find that the probability of a lethal GRB is much larger in the inner Milky Way (95% within a radius of 4 kpc from the galactic center), making it inhospitable to life. Only at the outskirts of the Milky Way, at more than 10 kpc from the galactic center, does this probability drop below 50%. When considering the Universe as a whole, the safest environments for life (similar to the one on Earth) are the lowest density regions in the outskirts of large galaxies, and life can exist in only ≈10% of galaxies. Remarkably, a cosmological constant is essential for such systems to exist. Furthermore, because of both the higher GRB rate and galaxies being smaller, life as it exists on Earth could not take place at z>0.5. Early life forms must have been much more resilient to radiation.

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

Park, Hyejin; Yoon, Min-Sik; Ryu, Kwon-Yul, E-mail: kyryu@uos.ac.kr

Highlights: •Proliferation capacity of Ubc{sup −/−} FLCs was reduced during culture in vitro. •Ubc is required for proliferation of both hepatocytes and bipotent FLEPCs. •Bipotent FLEPCs exhibit highest Ubc transcription and proliferation capacity. •Cell types responsible for Ubc{sup −/−} fetal liver developmental defect were identified. -- Abstract: We have previously demonstrated that disruption of polyubiquitin gene Ubc leads to mid-gestation embryonic lethality most likely due to a defect in fetal liver development, which can be partially rescued by ectopic expression of Ub. In a previous study, we assessed the cause of embryonic lethality with respect to the fetal liver hematopoieticmore » system. We confirmed that Ubc{sup −/−} embryonic lethality could not be attributed to impaired function of hematopoietic stem cells, which raises the question of whether or not FLECs such as hepatocytes and bile duct cells, the most abundant cell types in the liver, are affected by disruption of Ubc and contribute to embryonic lethality. To answer this, we isolated FLCs from E13.5 embryos and cultured them in vitro. We found that proliferation capacity of Ubc{sup −/−} cells was significantly reduced compared to that of control cells, especially during the early culture period, however we did not observe the increased number of apoptotic cells. Furthermore, levels of Ub conjugate, but not free Ub, decreased upon disruption of Ubc expression in FLCs, and this could not be compensated for by upregulation of other poly- or mono-ubiquitin genes. Intriguingly, the highest Ubc expression levels throughout the entire culture period were observed in bipotent FLEPCs. Hepatocytes and bipotent FLEPCs were most affected by disruption of Ubc, resulting in defective proliferation as well as reduced cell numbers in vitro. These results suggest that defective proliferation of these cell types may contribute to severe reduction of fetal liver size and potentially mid-gestation lethality of Ubc{sup −/−} embryos.« less

Production of high titre antibody response against Russell's viper venom in mice immunized with ethanolic extract of fruits of Piper longum L. (Piperaceae) and piperine.

PubMed

Shenoy, P A; Nipate, S S; Sonpetkar, J M; Salvi, N C; Waghmare, A B; Chaudhari, P D

2014-01-15

Piper longum L. fruits have been traditionally used against snakebites in north-eastern and southern region of India. The aim of the study was to assess the production of antibody response against Russell's viper venom in mice after prophylactic immunization with ethanolic extract of fruits of Piper longum L. and piperine. The mice sera were tested for the presence of antibodies against Russell's viper venom by in vitro lethality neutralization assay and in vivo lethality neutralization assay. Polyvalent anti-snake venom serum (antivenom) manufactured by Haffkine Bio-Pharmaceutical Corporation Ltd. was used as standard. Further confirmation of presence of antibodies against the venom in sera of mice immunized with PLE and piperine was done using indirect enzyme-linked immunosorbent assay (ELISA) and double immunodiffusion test. Treatment with PLE-treated mice serum and piperine-treated mice serum was found to inhibit the lethal action of venom both in the in vitro lethality neutralization assay and in vivo lethality neutralization assay. ELISA testing indicated that there were significantly high (p<0.01) levels of cross reactions between the PLE and piperine treated mice serum and the venom antigens. In double immunodiffusion test, a white band was observed between the two wells of antigen and antibodies for both the PLE-treated and piperine-treated mice serum. Thus it can be concluded that immunization with ethanolic extract of fruits of Piper longum and piperine produced a high titre antibody response against Russell's viper venom in mice. The antibodies against PLE and piperine could be useful in antivenom therapy of Russell's viper bites. PLE and piperine may also have a potential interest in view of the development of antivenom formulations used as antidote against snake bites. Copyright © 2013 Elsevier GmbH. All rights reserved.

Both epsilon-toxin and beta-toxin are important for the lethal properties of Clostridium perfringens type B isolates in the mouse intravenous injection model.

PubMed

Fernandez-Miyakawa, Mariano E; Fisher, Derek J; Poon, Rachael; Sayeed, Sameera; Adams, Vicki; Rood, Julian I; McClane, Bruce A; Uzal, Francisco A

2007-03-01

Clostridium perfringens is capable of producing up to 15 toxins, including alpha-toxin (CPA), beta-toxin (CPB), epsilon-toxin (ETX), enterotoxin, beta2-toxin (CPB2), and perfringolysin O. Type B isolates, which must produce CPA, CPB, and ETX, are associated with animal illnesses characterized by sudden death or acute neurological signs, with or without intestinal damage. Type B pathogenesis in ruminants is poorly understood, with some animals showing lesions and clinical signs similar to those caused by either type C or type D infections. It is unknown whether host or environmental conditions are dominant for determining the outcome of type B disease or if disease outcomes are determined by variable characteristics of type B isolates. To help clarify this issue, 19 type B isolates were evaluated for toxin production during late-log-phase growth via quantitative Western blotting and by biological activity assays. Most type B isolates produced CPB levels similar to those produced by type C isolates in vitro and have the potential to produce genotype C-like disease. The lethality of type B isolate supernatants administered intravenously to mice was evaluated with or without prior trypsin treatment, and monoclonal antibody neutralization studies also were performed. Correlation analyses comparing toxin levels in type B supernatants versus lethality and neutralization studies both found that the main contributor to lethality without pretreatment with trypsin was CPB, whereas neutralization studies indicated that CPB and ETX were both important after trypsin pretreatment. At least part of the CPB produced by type B isolates remained active after trypsin treatment. However, the overall lethalities of most supernatants were lower after trypsin pretreatment. Also, there was a significant association between ETX, CPB2, and CPA production in vitro among type B isolates. However, our results suggest that both CPB and ETX are likely the most important contributors to the pathogenesis of C. perfringens type B infections in domestic animals.

Pathology of carbon monoxide poisoning in two cats.

PubMed

Sobhakumari, Arya; Poppenga, Robert H; Pesavento, J Brad; Uzal, Francisco A

2018-03-05

Carbon monoxide (CO), a common cause of poisoning in human beings has also been implicated in the death of animals. Though there are multiple studies on CO poisoning and relevant lethal blood COHb concentrations in humans, there are no reliable reports of diagnostic lethal carboxyhemoglobin percentage of saturation (COHb%) in cats. Additionally, due to shared housing environments, exposures to companion animals can be a surrogate for lethal exposures in human beings and provide valuable information in concurrent forensic investigations. Two adult Singapura brown ticked cats were submitted to the California Animal Health and Food Safety Laboratory (CAHFS) for necropsy and diagnostic work-up. These animals were found dead along with their two deceased owners. Similar lesions were observed in both cats. At necropsy, gross lesions consisted of multifocal, large, irregular, bright red spots on the skin of the abdomen and the inner surface of ear pinnae, bright red muscles and blood. The carcasses, and tissues fixed in formalin retained the bright red discoloration for up to two weeks. Microscopic lesions included diffuse pulmonary congestion and edema, and multifocal intense basophilia of cardiomyocytes mostly affecting whole fibers or occasionally a portion of the fiber. Based on the clinical history,gross and microscopic changes, cyanide or carbon monoxide poisoning was suspected. Blood samples analyzed for carbon monoxide showed 57 and 41% carboxyhemoglobin COHb%. Muscle samples were negative for cyanide. There are no established reference values for lethal COHb concentration in cats. The COHb % values detected in this case which fell within the lethal range reported for other species, along with the gross lesions and unique histological findings in the heart suggest a helpful criteria for diagnosis of CO intoxication associated death in cats. This case demonstrates that since pets share the same environment as human beings and often are a part of their activities, they can be useful adjuncts in potential forensic investigations to help solve human cases.

Epigenome-Wide Tumor DNA Methylation Profiling Identifies Novel Prognostic Biomarkers of Metastatic-Lethal Progression in Men Diagnosed with Clinically Localized Prostate Cancer.

PubMed

Zhao, Shanshan; Geybels, Milan S; Leonardson, Amy; Rubicz, Rohina; Kolb, Suzanne; Yan, Qingxiang; Klotzle, Brandy; Bibikova, Marina; Hurtado-Coll, Antonio; Troyer, Dean; Lance, Raymond; Lin, Daniel W; Wright, Jonathan L; Ostrander, Elaine A; Fan, Jian-Bing; Feng, Ziding; Stanford, Janet L

2017-01-01

Aside from Gleason sum, few factors accurately identify the subset of prostate cancer patients at high risk for metastatic progression. We hypothesized that epigenetic alterations could distinguish prostate tumors with life-threatening potential. Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from a population-based (n = 430) and a replication (n = 80) cohort of prostate cancer patients followed prospectively for at least 5 years. Metastasis was confirmed by positive bone scan, MRI, CT, or biopsy, and death certificates confirmed cause of death. AUC, partial AUC (pAUC, 95% specificity), and P value criteria were used to select differentially methylated CpG sites that robustly stratify patients with metastatic-lethal from nonrecurrent tumors, and which were complementary to Gleason sum. Forty-two CpG biomarkers stratified patients with metastatic-lethal versus nonrecurrent prostate cancer in the discovery cohort, and eight of these CpGs replicated in the validation cohort based on a significant (P < 0.05) AUC (range, 0.66-0.75) or pAUC (range, 0.007-0.009). The biomarkers that improved discrimination of patients with metastatic-lethal prostate cancer include CpGs in five genes (ALKBH5, ATP11A, FHAD1, KLHL8, and PI15) and three intergenic regions. In the validation dataset, the AUC for Gleason sum alone (0.82) significantly increased with the addition of four individual CpGs (range, 0.86-0.89; all P <0.05). Eight differentially methylated CpGs that distinguish patients with metastatic-lethal from nonrecurrent tumors were validated. These novel epigenetic biomarkers warrant further investigation as they may improve prognostic classification of patients with clinically localized prostate cancer and provide new insights on tumor aggressiveness. Clin Cancer Res; 23(1); 311-9. ©2016 AACR. ©2016 American Association for Cancer Research.

Myc requires RhoA/SRF to reprogram glutamine metabolism.

PubMed

Haikala, Heidi M; Marques, Elsa; Turunen, Mikko; Klefström, Juha

2018-05-04

RhoA regulates actin cytoskeleton but recent evidence suggest a role for this conserved Rho GTPase also in other cellular processes, including transcriptional control of cell proliferation and survival. Interestingy, loss of RhoA is synthetic lethal with oncogenic Myc, a master transcription factor that turns on anabolic metabolism to promote cell growth in many cancers. We show evidence indicating that the synthetic lethal interaction between RhoA loss and Myc arises from deficiency in glutamine utilization, resulting from impaired co-regulation of glutaminase expression and anaplerosis by Myc and RhoA - serum response factor (SRF) pathway. The results suggest metabolic coordination between Myc and RhoA/SRF in sustaining cancer cell viability and indicate RhoA/SRF as a potential vulnerability in cancer cells for therapeutic targeting.

Establishment of conditional vectors for hairpin siRNA knockdowns

PubMed Central

Matsukura, Shiro; Jones, Peter A.; Takai, Daiya

2003-01-01

Small interference RNA (siRNA) is an emerging methodology in reverse genetics. Here we report the development of a new tetracycline-inducible vector-based siRNA system, which uses a tetracycline-responsive derivative of the U6 promoter and the tetracycline repressor for conditional in vivo transcription of short hairpin RNA. This method prevents potential lethality immediately after transfection of a vector when the targeted gene is indispensable, or the phenotype of the knockdown is lethal or results in a growth abnormality. We show that the controlled knockdown of DNA methyltransferase 1 (DNMT1) in human cancer resulted in growth arrest. Removal of the inducer, doxycycline, from treated cells led to re-expression of the targeted gene. Thus the method allows for a highly controlled approach to gene knockdown. PMID:12888529

Airpower’s Emasculation? -- Non-lethal Weapons in Joint Urban Operations

DTIC Science & Technology

2005-02-14

Lethal, Subdue the Enemy Without Killing,” 14, US Military Non-Lethal Weapons, 10 November 1997, <http://www.geocities.com/ Area51 /Shadowlands/6583...37 “Non-Lethal, Subdue the Enemy Without Killing,” 10-11, US Military Non-Lethal Weapons, 10 November 1997, <http://www.geocities.com/ Area51 ... Area51 /Shadowlands/6583/project035.html> [15 December 2004]. 42 “US Plans for Use of Gas in Iraq,” The Sunshine Project, 7 February 2003, <http

Heterochromatin position effects on circularized sex chromosomes cause filicidal embryonic lethality in Drosophila melanogaster.

PubMed

Ferree, Patrick M; Gomez, Karina; Rominger, Peter; Howard, Dagnie; Kornfeld, Hannah; Barbash, Daniel A

2014-04-01

Some circularized X-Y chromosomes in Drosophila melanogaster are mitotically unstable and induce early embryonic lethality, but the genetic basis is unknown. Our experiments suggest that a large region of X-linked satellite DNA causes anaphase bridges and lethality when placed into a new heterochromatic environment within certain circularized X-Y chromosomes. These results reveal that repetitive sequences can be incompatible with one another in cis. The lethal phenotype also bears a remarkable resemblance to a case of interspecific hybrid lethality.

Organophosphorus insecticides in honey, pollen and bees (Apis mellifera L.) and their potential hazard to bee colonies in Egypt.

PubMed

Al Naggar, Yahya; Codling, Garry; Vogt, Anja; Naiem, Elsaied; Mona, Mohamed; Seif, Amal; Giesy, John P

2015-04-01

There is no clear single factor to date that explains colony loss in bees, but one factor proposed is the wide-spread application of agrochemicals. Concentrations of 14 organophosphorous insecticides (OPs) in honey bees (Apis mellifera) and hive matrices (honey and pollen) were measured to assess their hazard to honey bees. Samples were collected during spring and summer of 2013, from 5 provinces in the middle delta of Egypt. LC/MS-MS was used to identify and quantify individual OPs by use of a modified Quick Easy Cheap Effective Rugged Safe (QuEChERS) method. Pesticides were detected more frequently in samples collected during summer. Pollen contained the greatest concentrations of OPs. Profenofos, chlorpyrifos, malation and diazinon were the most frequently detected OPs. In contrast, ethoprop, phorate, coumaphos and chlorpyrifos-oxon were not detected. A toxic units approach, with lethality as the endpoint was used in an additive model to assess the cumulative potential for adverse effects posed by OPs. Hazard quotients (HQs) in honey and pollen ranged from 0.01-0.05 during spring and from 0.02-0.08 during summer, respectively. HQs based on lethality due to direct exposure of adult worker bees to OPs during spring and summer ranged from 0.04 to 0.1 for best and worst case respectively. It is concluded that direct exposure and/or dietary exposure to OPs in honey and pollen pose little threat due to lethality of bees in Egypt. Copyright © 2014 Elsevier Inc. All rights reserved.

Uptake of hexanitrohexaazaisowurtzitane (CL-20) by the earthworm Eisenia fetida through dermal contact.

PubMed

Gong, Ping; Escalon, B Lynn; Hayes, Charolett A; Perkins, Edward J

2008-02-01

The explosive compound hexanitrohexaazaisowurtzitane (CL-20) has been shown to cause both lethal and sublethal (reproductive and neurotoxic) effects in exposed oligochaetes. However, whether worms take up CL-20 and how much CL-20 enters worm bodies leading to toxicity (e.g., lethality) remain to be determined. In the present study, we used high performance liquid chromatography (HPLC) and radiolabeled tracer methods to investigate the CL-20 uptake in the whole worm body after contact exposures. Worms (Eisenia fetida) were exposed to filter paper spiked with non-radioactive or [U-(14)C]-labeled CL-20 for 1-3 d. The radiolabeled tracer method allowed us to detect the parent compound and transformation products in worms exposed to as low as 0.04 microg CL-20 cm(-2) of filter paper. The HPLC method without radiolabeled tracer was far less sensitive with a detection limit of 2.17 microg CL-20 cm(-2). Using the radiolabeled tracer, we were able to demonstrate that the worm body concentration linearly correlated to the filter paper concentration < or =0.34 microg cm(-2) (r=0.94) if no breakdown products are assumed. At higher concentrations, the body concentration increased slowly and saturated at around 11 microg g(-1) dry mass resulting in an estimated lethal critical body burden of 10-15 microg CL-20 g(-1) dry mass. These findings demonstrate that CL-20 or potential transformation products are taken into the earthworm body through dermal contact. This information should prove valuable in assessing the bioaccumulation potential and ecological risks of CL-20.

Targeting synthetic lethality between the SRC kinase and the EPHB6 receptor may benefit cancer treatment.

PubMed

Paul, James M; Toosi, Behzad; Vizeacoumar, Frederick S; Bhanumathy, Kalpana Kalyanasundaram; Li, Yue; Gerger, Courtney; El Zawily, Amr; Freywald, Tanya; Anderson, Deborah H; Mousseau, Darrell; Kanthan, Rani; Zhang, Zhaolei; Vizeacoumar, Franco J; Freywald, Andrew

2016-08-02

Application of tumor genome sequencing has identified numerous loss-of-function alterations in cancer cells. While these alterations are difficult to target using direct interventions, they may be attacked with the help of the synthetic lethality (SL) approach. In this approach, inhibition of one gene causes lethality only when another gene is also completely or partially inactivated. The EPHB6 receptor tyrosine kinase has been shown to have anti-malignant properties and to be downregulated in multiple cancers, which makes it a very attractive target for SL applications. In our work, we used a genome-wide SL screen combined with expression and interaction network analyses, and identified the SRC kinase as a SL partner of EPHB6 in triple-negative breast cancer (TNBC) cells. Our experiments also reveal that this SL interaction can be targeted by small molecule SRC inhibitors, SU6656 and KX2-391, and can be used to improve elimination of human TNBC tumors in a xenograft model. Our observations are of potential practical importance, since TNBC is an aggressive heterogeneous malignancy with a very high rate of patient mortality due to the lack of targeted therapies, and our work indicates that FDA-approved SRC inhibitors may potentially be used in a personalized manner for treating patients with EPHB6-deficient TNBC. Our findings are also of a general interest, as EPHB6 is downregulated in multiple malignancies and our data serve as a proof of principle that EPHB6 deficiency may be targeted by small molecule inhibitors in the SL approach.

Mapping evaporative water loss in desert passerines reveals an expanding threat of lethal dehydration.

PubMed

Albright, Thomas P; Mutiibwa, Denis; Gerson, Alexander R; Smith, Eric Krabbe; Talbot, William A; O'Neill, Jacqueline J; McKechnie, Andrew E; Wolf, Blair O

2017-02-28

Extreme high environmental temperatures produce a variety of consequences for wildlife, including mass die-offs. Heat waves are increasing in frequency, intensity, and extent, and are projected to increase further under climate change. However, the spatial and temporal dynamics of die-off risk are poorly understood. Here, we examine the effects of heat waves on evaporative water loss (EWL) and survival in five desert passerine birds across the southwestern United States using a combination of physiological data, mechanistically informed models, and hourly geospatial temperature data. We ask how rates of EWL vary with temperature across species; how frequently, over what areas, and how rapidly lethal dehydration occurs; how EWL and die-off risk vary with body mass; and how die-off risk is affected by climate warming. We find that smaller-bodied passerines are subject to higher rates of mass-specific EWL than larger-bodied counterparts and thus encounter potentially lethal conditions much more frequently, over shorter daily intervals, and over larger geographic areas. Warming by 4 °C greatly expands the extent, frequency, and intensity of dehydration risk, and introduces new threats for larger passerine birds, particularly those with limited geographic ranges. Our models reveal that increasing air temperatures and heat wave occurrence will potentially have important impacts on the water balance, daily activity, and geographic distribution of arid-zone birds. Impacts may be exacerbated by chronic effects and interactions with other environmental changes. This work underscores the importance of acute risks of high temperatures, particularly for small-bodied species, and suggests conservation of thermal refugia and water sources.

Mapping evaporative water loss in desert passerines reveals an expanding threat of lethal dehydration

PubMed Central

Mutiibwa, Denis; Gerson, Alexander. R.; Smith, Eric Krabbe; Talbot, William A.; O’Neill, Jacqueline J.; McKechnie, Andrew E.; Wolf, Blair O.

2017-01-01

Extreme high environmental temperatures produce a variety of consequences for wildlife, including mass die-offs. Heat waves are increasing in frequency, intensity, and extent, and are projected to increase further under climate change. However, the spatial and temporal dynamics of die-off risk are poorly understood. Here, we examine the effects of heat waves on evaporative water loss (EWL) and survival in five desert passerine birds across the southwestern United States using a combination of physiological data, mechanistically informed models, and hourly geospatial temperature data. We ask how rates of EWL vary with temperature across species; how frequently, over what areas, and how rapidly lethal dehydration occurs; how EWL and die-off risk vary with body mass; and how die-off risk is affected by climate warming. We find that smaller-bodied passerines are subject to higher rates of mass-specific EWL than larger-bodied counterparts and thus encounter potentially lethal conditions much more frequently, over shorter daily intervals, and over larger geographic areas. Warming by 4 °C greatly expands the extent, frequency, and intensity of dehydration risk, and introduces new threats for larger passerine birds, particularly those with limited geographic ranges. Our models reveal that increasing air temperatures and heat wave occurrence will potentially have important impacts on the water balance, daily activity, and geographic distribution of arid-zone birds. Impacts may be exacerbated by chronic effects and interactions with other environmental changes. This work underscores the importance of acute risks of high temperatures, particularly for small-bodied species, and suggests conservation of thermal refugia and water sources. PMID:28193891

The ability of filgrastim to mitigate mortality following LD50/60 total-body irradiation is administration time-dependent

PubMed Central

Farese, AM; Brown, CR; Smith, CP; Gibbs, AM; Katz, B P; Johnson, CS; Prado, K; MacVittie, TJ

2013-01-01

The identification of the optimal administration schedule for an effective medical countermeasure is critical for the effective treatment of individuals exposed to potentially lethal doses of radiation. The efficacy of filgrastim (Neupogen®), a potential medical countermeasure, to improve survival when initiated at 48 hours following total body irradiation in a nonhuman primate model of the hematopoietic syndrome of the acute radiation syndrome was investigated. Animals were exposed to total body irradiation, antero-posterior exposure, total midline tissue dose of 7.5 Gray, (target lethal dose 50/60) delivered at 0.80 Gray minute-1, using linear accelerator-derived 6 Megavolt photons. All animals were administered medical management. Following irradiation on day 0, filgrastim (10 μg kg day-1) or the control (5% dextrose in water) was administered subcutaneously, daily through effect (absolute neutrophil count ≥ 1,000 cells μL-1 for 3 consecutive days). The study (n = 80) was powered to demonstrate a 25% improvement in survival following the administration of filgrastim or control beginning at 48 ± 4 hours post-irradiation. Survival analysis was conducted on the intention-to-treat population using a two-tailed null hypothesis at a 5% significance level. Filgrastim, initiated 48 hours after irradiation, did not improve survival (2.5% increase, P = 0.8230). These data demonstrate that efficacy of a countermeasure to mitigate lethality in the hematopoietic syndrome of the acute radiation syndrome can be dependent on the interval between irradiation and administration of the medical countermeasure. PMID:24276548

Clinical and Pathological Findings Associated with Aerosol Exposure of Macaques to Ricin Toxin

PubMed Central

Pincus, Seth H.; Bhaskaran, Manoj; Brey, Robert N.; Didier, Peter J.; Doyle-Meyers, Lara A.; Roy, Chad J.

2015-01-01

Ricin is a potential bioweapon that could be used against civilian and military personnel. Aerosol exposure is the most likely route of contact to ricin toxin that will result in the most severe toxicity. Early recognition of ricin exposure is essential if specific antidotes are to be applied. Initial diagnosis will most likely be syndromic, i.e., fitting clinical and laboratory signs into a pattern which then will guide the choice of more specific diagnostic assays and therapeutic interventions. We have studied the pathology of ricin toxin in rhesus macaques exposed to lethal and sublethal ricin aerosols. Animals exposed to lethal ricin aerosols were followed clinically using telemetry, by clinical laboratory analyses and by post-mortem examination. Animals exposed to lethal aerosolized ricin developed fever associated with thermal instability, tachycardia, and dyspnea. In the peripheral blood a marked neutrophilia (without immature bands) developed at 24 h. This was accompanied by an increase in monocytes, but depletion of lymphocytes. Red cell indices indicated hemoconcentration, as did serum chemistries, with modest increases in sodium and blood urea nitrogen (BUN). Serum albumin was strikingly decreased. These observations are consistent with the pathological observations of fluid shifts to the lungs, in the form of hemorrhages, inflammatory exudates, and tissue edema. In macaques exposed to sublethal aerosols of ricin, late pathologic consequences included chronic pulmonary fibrosis, likely mediated by M2 macrophages. Early administration of supportive therapy, specific antidotes after exposure or vaccines prior to exposure have the potential to favorably alter this outcome. PMID:26067369

Ebola Virus Altered Innate and Adaptive Immune Response Signalling Pathways: Implications for Novel Therapeutic Approaches.

PubMed

Kumar, Anoop

2016-01-01

Ebola virus (EBOV) arise attention for their impressive lethality by the poor immune response and high inflammatory reaction in the patients. It causes a severe hemorrhagic fever with case fatality rates of up to 90%. The mechanism underlying this lethal outcome is poorly understood. In 2014, a major outbreak of Ebola virus spread amongst several African countries, including Leone, Sierra, and Guinea. Although infections only occur frequently in Central Africa, but the virus has the potential to spread globally. Presently, there is no vaccine or treatment is available to counteract Ebola virus infections due to poor understanding of its interaction with the immune system. Accumulating evidence indicates that the virus actively alters both innate and adaptive immune responses and triggers harmful inflammatory responses. In the literature, some reports have shown that alteration of immune signaling pathways could be due to the ability of EBOV to interfere with dendritic cells (DCs), which link innate and adaptive immune responses. On the other hand, some reports have demonstrated that EBOV, VP35 proteins act as interferon antagonists. So, how the Ebola virus altered the innate and adaptive immune response signaling pathways is still an open question for the researcher to be explored. Thus, in this review, I try to summarize the mechanisms of the alteration of innate and adaptive immune response signaling pathways by Ebola virus which will be helpful for designing effective drugs or vaccines against this lethal infection. Further, potential targets, current treatment and novel therapeutic approaches have also been discussed.

Lethal Zika Virus Disease Models in Young and Older Interferon α/β Receptor Knock Out Mice.

PubMed

Marzi, Andrea; Emanuel, Jackson; Callison, Julie; McNally, Kristin L; Arndt, Nicolette; Chadinha, Spencer; Martellaro, Cynthia; Rosenke, Rebecca; Scott, Dana P; Safronetz, David; Whitehead, Stephen S; Best, Sonja M; Feldmann, Heinz

2018-01-01

The common small animal disease models for Zika virus (ZIKV) are mice lacking the interferon responses, but infection of interferon receptor α/β knock out (IFNAR -/- ) mice is not uniformly lethal particularly in older animals. Here we sought to advance this model in regard to lethality for future countermeasure efficacy testing against more recent ZIKV strains from the Asian lineage, preferably the American sublineage. We first infected IFNAR -/- mice subcutaneously with the contemporary ZIKV-Paraiba strain resulting in predominantly neurological disease with ~50% lethality. Infection with ZIKV-Paraiba by different routes established a uniformly lethal model only in young mice (4-week old) upon intraperitoneal infection. However, intraperitoneal inoculation of ZIKV-French Polynesia resulted in uniform lethality in older IFNAR -/- mice (10-12-weeks old). In conclusion, we have established uniformly lethal mouse disease models for efficacy testing of antivirals and vaccines against recent ZIKV strains representing the Asian lineage.

28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Use of less-than-lethal weapons... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is such...

28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Use of less-than-lethal weapons... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is such...

28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Use of less-than-lethal weapons... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is such...

Calculating Hematopoietic-Mode-Lethality Risk Avoidance Associated with Radionuclide Decorporation Countermeasures Related to a Radiological Terrorism Incident

PubMed Central

Scott, Bobby R.

2009-01-01

This paper provides theoretical health-risk-assessment tools that are designed to facilitate planning for and managing radiological terrorism incidents that involve ingestion exposure to bone-seeking radionuclides (e.g., radiostrontium nuclides). The focus is on evaluating lethality risk avoidance (RAV; i.e., the decrease in risk) that is associated with radionuclide decorporation countermeasures employed to remove ingested bone-seeking beta and/or gamma-emitting radionuclides from the body. To illustrate the application of tools presented, hypothetical radiostrontium decorporation scenarios were considered that involved evaluating the hematopoietic-mode-lethality RAV. For evaluating the efficacy of specific decorporation countermeasures, the lethality risk avoidance proportion (RAP; which is the RAV divided by the total lethality risk in the absence of protective countermeasures) is introduced. The lethality RAP is expected to be a useful tool for designing optimal radionuclide decorporation schemes and for identifying green, yellow and red dose-rate zones. For the green zone, essentially all of the lethality risk is expected to be avoided (RAP = 1) as a consequence of the radionuclide decorporation scheme used. For the yellow zone, some but not all of the lethality risk is expected to be avoided. For the red zone, none of the lethality risk (which equals 1) is expected to be avoided. PMID:20011652

A most dangerous game: death and injury to birds from porcupine quills

Treesearch

Todd Katzner; Tricia A. Miller; Jane Rodrigue; Steven Shaffer

2015-01-01

Predation is dangerous, not only for the prey but sometimes also for the predator. Because these dangers to predators are not well understood, we document evidence of predation or scavenging by a Golden Eagle (Aquila chrysaetos) on a North American porcupine (Erethizon dorsatum) in Pennsylvania, USA, with potentially lethal...

ASSESSING THE INFLUENCE OF PLANT GROWTH REGULATOR HERBICIDE VAPOR DRIFT ON ARTHROPOD COMMUNITIES IN FIELD CROP AGRO-ECOSYSTEMS

EPA Science Inventory

Sub-lethal herbicide damage is likely to have negative consequences for plant health. This in turn could lead to positive or negative effects on insects. Plants that are not healthy may not provide the best floral resources for pollinators, potentially further stressing hon...

Enhancing the stability and ecological safety of mass-reared transgenic strains for field release by redundant conditional lethality systems

USDA-ARS?s Scientific Manuscript database

Advances in the genetic manipulation of agriculturally important insects now allows the development of genetic sexing and male sterility systems for more highly efficient biologically-based population control programs, most notably SIT, in fruit pests throughout the world. Potentially, these condit...

Effects of high pressure processing on the composition, functional and rheological properties of fresh Queso Fresco

USDA-ARS?s Scientific Manuscript database

Although Queso Fresco (QF), a popular high moisture Hispanic-style cheese sold in the U.S., is made from pasteurized milk it is subject to post pasteurization bacterial contamination. High pressure processing (HPP) of cheese is being considered because of its lethality to bacteria and potential to ...

Dietary silver nanoparticles reduce fitness in a beneficial, but not, pest insect species

USDA-ARS?s Scientific Manuscript database

Silver nanoparticles (AgNPs) have antimicrobial and insecticidal properties and they have been considered for their potential use as insecticides. While they do, indeed, kill some insects, two broader issues have not been considered in a critical way. First, reports of insect-lethal AgNPs are often ...

Radioprotection by polysaccharides alone and in combination with aminothiols

NASA Astrophysics Data System (ADS)

Patchen, Myra L.; Macvittie, Thomas J.; Solberg, Brian D.; D'Alesandro, Michele M.; Brook, Itzhak

We demonstrated that glucan, a beta-1,3 polysaccharide immunomodulator, enhances survival of mice when administered before radiation exposure. Glucan's prophylactic survival-enhancing effects are mediated by several mechanisms including (1) increasing macrophage-mediated resistance to potentially lethal postirradiation opportunistic infections, (2) increasing the Do of hematopoietic progenitor cells, and (3) accelerating hematopoietic reconstitution. In addition, even when administered shortly after some otherwise lethal doses of radiation, glucan increases survival. Glucan's therapeutic survival-enhancing effects are also mediated through its ability to enhance macrophage function and to accelerate hematopoietic reconstitution; glucan's therapeutic potential, however, is ultimately dependent on the survival of a critical number of hematopoietic stem cells capable of responding to glucan's stimulatory effects. Preirradiation administration of the traditional aminothiol radioprotectants WR-2721 and WR-3689 has been previously demonstrated to be an extremely effective means to increase hematopoietic stem cell survival. Therapeutic glucan treatment administered in combination with preirradiation WR-2721 or WR-3689 treatment synergistically increases both hematopoietic reconstitution and survival. Such combined modality treatments offer new promise in treating acute radiation injury.

An Ultrasensitive Gold Nanoparticle-based Lateral Flow Test for the Detection of Active Botulinum Neurotoxin Type A

NASA Astrophysics Data System (ADS)

Liu, Jing; Gao, Shan; Kang, Lin; Ji, Bin; Xin, Wenwen; Kang, Jingjing; Li, Ping; Gao, Jie; Wang, Hanbin; Wang, Jinglin; Yang, Hao

2017-03-01

Botulism is a severe and potentially lethal paralytic disease caused by several botulinum neurotoxin-producing Clostridia spp. In China, the majority of the cases caused by botulism were from less-developed rural areas. Here, we designed specific substrate peptides and reconfigured gold nanoparticle-based lateral flow test strip (LFTS) to develop an endopeptidase-based lateral flow assay for the diagnosis of botulism. We performed this lateral flow assay on botulinum neurotoxin-spiked human serum samples. The as-prepared LFTS had excellent performance in the detection of botulinum neurotoxin using only 1 μL of simulated serum, and its sensitivity and specificity were comparable to that of mouse lethality assay. Moreover, the assay takes only half a day and does not require highly trained laboratory staff, specialized facility, or equipment. Finally, our LFTS can be potentially extended to other serotypes of BoNTs by designing specific substrate peptides against the different types of BoNTs. Overall, we demonstrate a strategy by which LFTS and endopeptidase activity assays can be integrated to achieve facile and economic diagnosis of botulism in resource-limited settings.

Weapon Involvement in the Victimization of Children.

PubMed

Mitchell, Kimberly J; Hamby, Sherry L; Turner, Heather A; Shattuck, Anne; Jones, Lisa M

2015-07-01

To report the prevalence of weapons involved in the victimization of youth with particular emphasis on weapons with a "high lethality risk" and how such exposure fits into the broader victimization and life experiences of children and adolescents. Data were collected as part of the Second National Survey of Children's Exposure to Violence, a nationally representative telephone survey of youth ages 2 to 17 years and caregivers (N = 4114) conducted in 2011. Estimates from the Second National Survey of Children's Exposure to Violence indicate that almost 14 million youth, ages 2–17, in the United States have been exposed to violence involving a weapon in their lifetimes as witnesses or victims,or .1 in 5 children in this age group [corrected]. More than 2 million youth in the United States (1 in 33) have been directly assaulted in incidents where the high lethality risk weapons of guns and knives were used. Differences were noted between victimizations involving higher and lower lethality risk weapons as well as between any weapon involvement versus none. Poly-victims, youth with 7 or more victimization types, were particularly likely to experience victimization with any weapon, as well as victimization with a highly lethal weapon compared with nonpoly-victims. Findings add to the field's broadening conceptualization of youth victimization highlighting the potentially highly consequential risk factor of weapon exposure as a component of victimization experiences on the mental health of youth. Further work on improving gun safety practices and taking steps to reduce children's exposure to weapon-involved violence is warranted to reduce this problem. Copyright © 2015 by the American Academy of Pediatrics.

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

Herkovits, J.; Herkovits, F.D.; Perez-Coll

As a result of their aquatic embryonic and larval development, many species of amphibians are potentially affected by adverse environmental conditions. In this study the possibility of reducing the lethal effect of aluminum (ALC13, Mallinckrodt) in Bufo arenarum embryos by means of simultaneous zinc (ZnSO4) treatment is reported. The aluminum hazard was evaluated in a 7 day renewal toxicity testing study conducted with batches of 10 individuals (by quadruplicate) in six concentrations of aluminum plus the control at 20 C. The pH of the experimental solutions were measured. The LC100 expressed as Al(3 +) mg/L at 24 and up tillmore » 168 hours of treatment were 0.9 (the pH of the solution was 6.2 while in control Holtfreter solution the pH was 6.8). Therefore, aluminum exert a lethal effect on amphibian embryos in concentrations which reduce only slightly the pH of the maintaining solution. The lethal effect of aluminum could be reduced 100% by means of simultaneous treatment with 2 mg Zn(2 +)/L. The results point out the high sensibility of the amphibian embryos to aluminum (LC100/24hs:0.9mg Al(3 +)/L) and therefore, episodic increases in dissolved aluminum, usually concomitant with surface water pH decreases, could produce very harmful effects during embryonic stages of amphibians. The noteworthy beneficial effect of zinc against the lethal effect of aluminum could be of practical value in reducing the harmful effects exerted by aluminum. The conspicuous Al-Zn antagonism points out the need of biological test systems for recording the integrated effects of substances released to the environment.« less

Reanalysis of parabiosis of obesity mutants in the age of leptin.

PubMed

Zeng, Wenwen; Lu, Yi-Hsueh; Lee, Jonah; Friedman, Jeffrey M

2015-07-21

In this study we set out to explain the differing effects of parabiosis with genetically diabetic (db) mice versus administration of recombinant leptin. Parabiosis of db mutant, which overexpress leptin, to wildtype (WT) or genetically obese (ob) mice has been reported to cause death by starvation, whereas leptin infusions do not produce lethality at any dose or mode of delivery tested. Leptin is not posttranslationally modified other than a single disulphide bond, raising the possibility that it might require additional factor(s) to exert the maximal appetite-suppressing effect. We reconfirmed the lethal effect of parabiosis of db mutant on WT mice and further showed that this lethality could not be rescued by administration of ghrelin or growth hormone. We then initiated a biochemical fractionation of a high-molecular-weight leptin complex from human plasma and identified clusterin as a major component of this leptin-containing complex. However, in contrast to previous reports, we failed to observe a leptin-potentiating effect of either exogenous or endogenous clusterin, and parabiosis of db clusterin(-/-) double-mutant to WT mice still caused lethality. Intriguingly, in parabiotic pairs of two WT mice, leptin infusion into one of the mice led to an enhanced starvation response during calorie restriction as evidenced by increased plasma ghrelin and growth-hormone levels. Moreover, leptin treatment resulted in death of the parabiotic pairs. These data suggest that the appetite suppression in WT mice after parabiosis to db mutants is the result of induced hyperleptinemia combined with the stress or other aspect(s) of the parabiosis procedure.

A hepatic metabolomics-based diagnostic approach to assess lethal toxicity of dithiocarbamate fungicide polycarbamate in three marine fish species.

PubMed

Hano, Takeshi; Ohkubo, Nobuyuki; Mochida, Kazuhiko

2017-04-01

The present study was performed to evaluate the toxic effect of the dithiocarbamate fungicide polycarbamate (PC) on the hepatic metabolic profiles of three marine fish species, red sea bream (Pagrus major), spotted halibut (Verasper variegatus), and marbled flounder (Pleuronectes yokohamae). First, juvenile fish were exposed to graded concentrations of PC for 96h; the 96-h LC 50 values obtained were 22-29, 239-553, and 301-364µgL -1 for red sea bream, spotted halibut, and marbled flounder, respectively, indicating that red sea bream possessed higher sensitivity to PC than the two benthic species. Second, the fish were exposed to lethal-equivalent concentration (H group) or sub-lethal (one-tenth of the H group concentrations; L group) for 24 and 96h and gas-chromatography based metabolomics approach was employed to explore the crucial biomarker metabolite associated with lethal toxicity. Of the 53 metabolites identified, only reduced glutathione (GSH) was consistently elevated in the H group for the three fish species at 96h. The calculated cut-off value of GSH (mM) based on receiver operating curve analysis between H group and the other treatment groups (control, solvent control, and L group) was obtained at 0.56mM, which allowed to distinguish between the groups with high confidence for the three fish species. These results are the first to demonstrate the potential of using GSH as a possible biomarker metabolite and its usefulness of threshold cut-off value for diagnosing life-threatening health conditions of fish. Copyright © 2016 Elsevier Inc. All rights reserved.

Immunobiotic Lactobacillus administered post-exposure averts the lethal sequelae of respiratory virus infection.

PubMed

Percopo, Caroline M; Rice, Tyler A; Brenner, Todd A; Dyer, Kimberly D; Luo, Janice L; Kanakabandi, Kishore; Sturdevant, Daniel E; Porcella, Stephen F; Domachowske, Joseph B; Keicher, Jesse D; Rosenberg, Helene F

2015-09-01

We reported previously that priming of the respiratory tract with immunobiotic Lactobacillus prior to virus challenge protects mice against subsequent lethal infection with pneumonia virus of mice (PVM). We present here the results of gene microarray which document differential expression of proinflammatory mediators in response to PVM infection alone and those suppressed in response to Lactobacillus plantarum. We also demonstrate for the first time that intranasal inoculation with live or heat-inactivated L. plantarum or Lactobacillus reuteri promotes full survival from PVM infection when administered within 24h after virus challenge. Survival in response to L. plantarum administered after virus challenge is associated with suppression of proinflammatory cytokines, limited virus recovery, and diminished neutrophil recruitment to lung tissue and airways. Utilizing this post-virus challenge protocol, we found that protective responses elicited by L. plantarum at the respiratory tract were distinct from those at the gastrointestinal mucosa, as mice devoid of the anti-inflammatory cytokine, interleukin (IL)-10, exhibit survival and inflammatory responses that are indistinguishable from those of their wild-type counterparts. Finally, although L. plantarum interacts specifically with pattern recognition receptors TLR2 and NOD2, the respective gene-deleted mice were fully protected against lethal PVM infection by L. plantarum, as are mice devoid of type I interferon receptors. Taken together, L. plantarum is a versatile and flexible agent that is capable of averting the lethal sequelae of severe respiratory infection both prior to and post-virus challenge via complex and potentially redundant mechanisms. Published by Elsevier B.V.

Sudden cardiac death: the pro-arrhythmic interaction of an acute loading with an underlying substrate.

PubMed

Sutherland, George R

2017-10-21

Sudden cardiac death (SCD) is a complex phenomenon, occurring either in apparently normal individuals or in those where there is a recognized underlying cardiac abnormality. In both groups, the lethal arrhythmia has frequently been related to the physiologic trigger of either exercise or stress. Prior research into SCD has focused mainly on a combination of identifying either vulnerable myocardial substrates; pharmacological approaches to altering electrical activation/repolarisation in substrates; or the suppression of induced lethal arrhythmias with implantable defibrillators. However, it has been suggested that in a significant number of cases, the interaction of a transient induced trigger with a pre-existing electrical or mechanical substrate is the basis for the induction of the sustained lethal arrhythmia. In this manuscript we will discuss the precise mechanisms whereby one of such potential physiologic trigger: an acute change in systolic blood pressure, can induce a sequence of alterations in global and local cardiac mechanics which in turn result in regional left ventricular post-systolic deformation which, mediated (through stretch-induced changes in local mechano-electrical coupling) provokes local electrical after-depolarisations which can spill over into complex runs of premature ventricular beats. These local acute pressure/stretch induced runs of ventricular ectopy originate in either basal or apical normal myocardium and, in combination with a co-existing distal pro-arrhymic substrate, can interact to induce a lethal arrhythmia. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For Permissions, please email: journals.permissions@oup.com.

Thermal tolerance of the invasive Belonesox belizanus, pike killifish, throughout ontogeny.

PubMed

Kerfoot, James Roy

2012-06-01

The goal of this study was to characterize the variability of thermal tolerances between life-history stages of the invasive Belonesox belizanus and attempt to describe the most likely stage of dispersal across south Florida. In the laboratory, individuals were acclimated to three temperatures (20, 25, or 30°C). Upper and lower lethal thermal limits and temperatures at which feeding ceased were measured for neonates, juveniles, and adults. Thermal tolerance polygons were developed to represent the thermal tolerance range of each life-history stage. Results indicated that across acclimation temperatures upper lethal thermal limits were similar for all three stages (38°C). However, minimum lethal thermal limits were significantly different at the 30°C acclimation temperature, where juveniles (9°C) had an approximately 2.0°C and 4.0°C lower minimum lethal thermal limit compared with adults and neonates, respectively. According to thermal tolerance polygons, juveniles had an average tolerance polygonal area almost 20°C(2) larger than adults, indicating the greatest thermal tolerance of the three life-history stages. Variation in cessation of feeding temperatures indicated no significant difference between juveniles and adults. Overall, results of this study imply that juvenile B. belizanus may be equipped with the physiological flexibility to exercise habitat choice and reduce potential intraspecific competition with adults for limited food resources. Given its continued dispersal, the minimum thermal limit of juveniles may aid in continued dispersal of this species, especially during average winter temperatures throughout Florida where juveniles could act to preserve remnant populations until seasonal temperatures increase. © 2012 WILEY PERIODICALS, INC.

Reanalysis of parabiosis of obesity mutants in the age of leptin

PubMed Central

Zeng, Wenwen; Lu, Yi-Hsueh; Lee, Jonah; Friedman, Jeffrey M.

2015-01-01

In this study we set out to explain the differing effects of parabiosis with genetically diabetic (db) mice versus administration of recombinant leptin. Parabiosis of db mutant, which overexpress leptin, to wildtype (WT) or genetically obese (ob) mice has been reported to cause death by starvation, whereas leptin infusions do not produce lethality at any dose or mode of delivery tested. Leptin is not posttranslationally modified other than a single disulphide bond, raising the possibility that it might require additional factor(s) to exert the maximal appetite-suppressing effect. We reconfirmed the lethal effect of parabiosis of db mutant on WT mice and further showed that this lethality could not be rescued by administration of ghrelin or growth hormone. We then initiated a biochemical fractionation of a high-molecular-weight leptin complex from human plasma and identified clusterin as a major component of this leptin-containing complex. However, in contrast to previous reports, we failed to observe a leptin-potentiating effect of either exogenous or endogenous clusterin, and parabiosis of db clusterin−/− double-mutant to WT mice still caused lethality. Intriguingly, in parabiotic pairs of two WT mice, leptin infusion into one of the mice led to an enhanced starvation response during calorie restriction as evidenced by increased plasma ghrelin and growth-hormone levels. Moreover, leptin treatment resulted in death of the parabiotic pairs. These data suggest that the appetite suppression in WT mice after parabiosis to db mutants is the result of induced hyperleptinemia combined with the stress or other aspect(s) of the parabiosis procedure. PMID:26150485

Smyd1 Facilitates Heart Development by Antagonizing Oxidative and ER Stress Responses

PubMed Central

Park, Chong Yon; Harriss, June; Pierce, Stephanie A.; Dekker, Joseph D.; Valenzuela, Nicolas; Srivastava, Deepak; Schwartz, Robert J.; Stewart, M. David; Tucker, Haley O.

2015-01-01

Smyd1/Bop is an evolutionary conserved histone methyltransferase previously shown by conventional knockout to be critical for embryonic heart development. To further explore the mechanism(s) in a cell autonomous context, we conditionally ablated Smyd1 in the first and second heart fields of mice using a knock-in (KI) Nkx2.5-cre driver. Robust deletion of floxed-Smyd1 in cardiomyocytes and the outflow tract (OFT) resulted in embryonic lethality at E9.5, truncation of the OFT and right ventricle, and additional defects consistent with impaired expansion and proliferation of the second heart field (SHF). Using a transgenic (Tg) Nkx2.5-cre driver previously shown to not delete in the SHF and OFT, early embryonic lethality was bypassed and both ventricular chambers were formed; however, reduced cardiomyocyte proliferation and other heart defects resulted in later embryonic death at E11.5-12.5. Proliferative impairment prior to both early and mid-gestational lethality was accompanied by dysregulation of transcripts critical for endoplasmic reticulum (ER) stress. Mid-gestational death was also associated with impairment of oxidative stress defense—a phenotype highly similar to the previously characterized knockout of the Smyd1-interacting transcription factor, skNAC. We describe a potential feedback mechanism in which the stress response factor Tribbles3/TRB3, when directly methylated by Smyd1, acts as a co-repressor of Smyd1-mediated transcription. Our findings suggest that Smyd1 is required for maintaining cardiomyocyte proliferation at minimally two different embryonic heart developmental stages, and its loss leads to linked stress responses that signal ensuing lethality. PMID:25803368

Resistance to genetic insect control: Modelling the effects of space.

PubMed

Watkinson-Powell, Benjamin; Alphey, Nina

2017-01-21

Genetic insect control, such as self-limiting RIDL 2 (Release of Insects Carrying a Dominant Lethal) technology, is a development of the sterile insect technique which is proposed to suppress wild populations of a number of major agricultural and public health insect pests. This is achieved by mass rearing and releasing male insects that are homozygous for a repressible dominant lethal genetic construct, which causes death in progeny when inherited. The released genetically engineered ('GE') insects compete for mates with wild individuals, resulting in population suppression. A previous study modelled the evolution of a hypothetical resistance to the lethal construct using a frequency-dependent population genetic and population dynamic approach. This found that proliferation of resistance is possible but can be diluted by the introgression of susceptible alleles from the released homozygous-susceptible GE males. We develop this approach within a spatial context by modelling the spread of a lethal construct and resistance trait, and the effect on population control, in a two deme metapopulation, with GE release in one deme. Results show that spatial effects can drive an increased or decreased evolution of resistance in both the target and non-target demes, depending on the effectiveness and associated costs of the resistant trait, and on the rate of dispersal. A recurrent theme is the potential for the non-target deme to act as a source of resistant or susceptible alleles for the target deme through dispersal. This can in turn have a major impact on the effectiveness of insect population control. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

From tails to toes: developing nonlethal tissue indicators of mercury exposure in five amphibian species.

PubMed

Pfleeger, Adam Z; Eagles-Smith, Collin A; Kowalski, Brandon M; Herring, Garth; Willacker, James J; Jackson, Allyson K; Pierce, John R

2016-04-01

Exposure to environmental contaminants has been implicated as a factor in global amphibian decline. Mercury (Hg) is a particularly widespread contaminant that biomagnifies in amphibians and can cause a suite of deleterious effects. However, monitoring contaminant exposure in amphibian tissues may conflict with conservation goals if lethal take is required. Thus, there is a need to develop non-lethal tissue sampling techniques to quantify contaminant exposure in amphibians. Some minimally invasive sampling techniques, such as toe-clipping, are common in population-genetic research, but it is unclear if these methods can adequately characterize contaminant exposure. We examined the relationships between mercury (Hg) concentrations in non-lethally sampled tissues and paired whole-bodies in five amphibian species. Specifically, we examined the utility of three different tail-clip sections from four salamander species and toe-clips from one anuran species. Both tail and toe-clips accurately predicted whole-body THg concentrations, but the relationships differed among species and the specific tail-clip section or toe that was used. Tail-clips comprised of the distal 0-2 cm segment performed the best across all salamander species, explaining between 82 and 92% of the variation in paired whole-body THg concentrations. Toe-clips were less effective predictors of frog THg concentrations, but THg concentrations in outer rear toes accounted for up to 79% of the variability in frog whole-body THg concentrations. These findings suggest non-lethal sampling of tails and toes has potential applications for monitoring contaminant exposure and risk in amphibians, but care must be taken to ensure consistent collection and interpretation of samples.

[Thrombotic microangiopathy in pregnancy complicated by acute hemorrhagic-necrotic pancreatitis during early puerperium].

PubMed

Redechová, S; Féderová, L; Hammerová, L; Filkászová, A; Horváthová, D; Redecha, M

2014-06-01

Authors in the article describe a case of a patient with thrombotic thrombocytopenic purpurain 37 weeks gestation complicated by acute severe hemorrhagic-necrotic pancreatitis during the early puerperium. Case report. Ist Department of gynaecology and obstetrics of the Comenius University Bratislava. 33-years-old patient in the 37 weeks gestation was admitted to our department with the signs of HELLP syndrome (hemolysis, elevated liver enzymes, low platelets). Due to the worsening clinical status, we have performed caesarean section. After the transient stabilization of the patient's clinical status, the hemolysis with severe thrombocytopenia reappeared. Based on the clinical signs of abdominal pain and computer tomography, the diagnosis of acute hemorrhagic-necrotic pancreatitis was set. The primary diagnosis was thrombotic thrombocytopenic purpura. Therefore, therapeutic plasma exchange was performed with consequent improvement of the patients clinical state. Normalization of the platelet count was achieved after 4.plasma exchanges. Consequently 5 plasma exchanges were performed. However, one month later, the disease relapsed. Therapeutic plasma exchanges were needed again (4x), with anti CD 20 administration. This therapy had good clinical outcome, without the need for further plasma exchanges. Thrombotic thrombocytopenic purpura is highly lethal disease. Early diagnosis, treatment, and multidisciplinary approach are essential.

Primary sclerosing cholangitis

PubMed Central

Silveira, Marina G; Lindor, Keith D

2008-01-01

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts, resulting in end-stage liver disease and reduced life expectancy. PSC primarily affects young and middle-aged men, often in association with underlying inflammatory bowel disease. The etiology of PSC includes immune-mediated components and elements of undefined nature. A cholestatic picture of liver biochemistries with elevations in serum alkaline phosphatase, nonspecific autoantibodies such as perinuclear antineutrophilic antibody, antinuclear antibodies and smooth muscle antibodies, and diffuse multifocal biliary strictures, resulting in a ‘beaded’ appearance on radiographic studies, are the hallmarks of the disease. No effective medical therapy is currently available, although clinical studies are in progress. Ursodeoxycholic acid at high doses (28 mg/kg/day to 30 mg/kg/day) is the most promising agent but is unproven so far. Liver transplantation is currently the only life-extending therapy for patients with end-stage disease, although recurrent disease can be observed in the transplanted liver. The multiple complications of PSC include pruritus, fatigue, vitamin deficiencies, metabolic bone disease, peristomal varices, bacterial cholangitis, dominant biliary strictures, gallbladder stones and polyps, and malignancy, particularly cholangiocarcinoma, which is the most lethal complication of PSC. PMID:18701947

Esophagorespiratory fistulas of tumorous origin. Non-operative management of 264 cases in a 20-year period.

PubMed

Balazs, Akos; Kupcsulik, Peter K; Galambos, Zoltan

2008-11-01

Esophagorespiratory fistulas developing from malignant tumors have serious complications by maintaining continuous airway contamination. The objective was to reveal the incidence, causes and characteristics of fistula formation and to examine the possibilities and efficiency of the treatment. In a single-center study between 1984 and 2004, the data of 2113 patients with tumorous esophageal stenosis were analyzed. Esophagorespiratory fistulas were detected in 264 cases (12.5%). Successful esophageal intubation, stent correction or replacement was performed in 188 cases, while there was one lethal complication. Twenty-seven patients had an intervention for nutritional support: 25 gastrostomies, 1 jejunostomy and 1 percutaneous endoscopic gastrostomy. The mean survival period of all patients was 2.8 months; patients with implanted endoprosthesis 3.4 months; with nutritional support 1.1 months and with only supportive therapy 1.3 months, respectively. The differences between the endoprosthesis implanted group and the other two groups were significant (p<0.001). By sealing the fistula, a successful endoscopic esophageal intubation ends the severe respiratory contamination and the inability to swallow, improving the quality of life and survival period. After the procedure, it is the malignant tumor and not the fistula that determines the future of the patient.

[Surgical tactics in duodenal trauma].

PubMed

Ivanov, P A; Grishin, A V

2004-01-01

Results of surgical treatment of 61 patients with injuries of the duodenum are analyzed. The causes of injuries were stab-incised wounds in 24 patients, missile wound -- in 7, closed abdominal trauma -- in 26, trauma of the duodenum during endoscopic papillosphincterotomy -- in 4. All the patients underwent surgery. Complications were seen in 32 (52.5%) patients, 21 patients died, lethality was 34.4%. Within the first 24 hours since the trauma 7 patients died due to severe combined trauma, blood loss, 54 patients survived acute period of trauma, including 28 patients after open trauma, 26 -- after closed and 4 -- after trauma of the duodenum during endoscopic papillosphincterotomy. Diagnostic and surgical policies are discussed. Results of treatment depending on kind and time of surgery are regarded. It is demonstrated that purulent complications due to retroperitoneal phlegmona, traumatic pancreatitis, pneumonia are the causes of significant number of unfavorable outcomes. Therefore, it is important to adequately incise and drainage infected parts of retroperitoneal fat tissue with two-lumen drainages. Decompression through duodenal tube is the effective procedure for prophylaxis of suture insufficiency and traumatic pancreatitis. Suppression of pancreatic and duodenal secretion with octreotid improves significantly surgical treatment results.

[The multiple organ failure syndrome after cardiac surgery with artificial blood circulation].

PubMed

Babaev, M A; Eremenko, A A; Minbolatova, N M; Dzemeshkevich, S L

2013-01-01

The 10-year study of etiology, pathogenesis, diagnostic, treatment and prevention of the multiple organ failure syndrome (MOFS) after cardiovascular operations with artificial blood circulation was conducted in the SCS. 4383 patients, aged 16-75 years, were observed. Of them, MOFS was diagnosed in 206 (4.7%) patients. Extracorporal detoxication was used in 385 patients. When used in patients with complicated postoperative period, the extracorporal detoxication prevents MOFS and decreases lethality in 3 times (from 59.3 to 19.2%). The method is indicated to patients with MOFS severity estimated of 13.5 points and damage of 5-6 organ systems. Herewith the duration of veno-venous ultrahemodiafiltration should not exceed 80 hours and the number of sessions should not be more then 3.

Cerebral fat embolism syndrome after long bone fracture due to gunshot injury

PubMed Central

Duran, Latif; Kayhan, Servet; Kati, Celal; Akdemir, Hizir Ufuk; Balci, Kemal; Yavuz, Yucel

2014-01-01

Cerebral fat embolism syndrome is a lethal complication of long-bone fractures and clinically manifasted with respiratory distress, altered mental status, and petechial rash. We presented a 20-year-old male admitted with gun-shot wounds to his left leg. Twenty-four hours after the event, he had generalized tonic clonic seizures, decorticate posture and a Glascow Coma Scale of seven with localization of painful stimuli. Subsequent magnetic resonance imaging of the brain showed a star-field pattern defining multiple lesions of restricted diffusion. On a 4-week follow-up, he had returned to normal neurological function. Despite the severity of the neurological condition upon initial presentation, the case cerebral fat embolism illustrates that, cerebral dysfunction associated with cerebral fat embolism illustrates reversible. PMID:24701067

Fatal Cerebral Edema, Seizures, and Hyponatremia After Trazodone Overdose.

PubMed

Avila, Jose David

Trazodone is a serotonin antagonist and reuptake inhibitor that is widely used for the treatment of depression and insomnia. Fatal overdose is rare and usually occurs when combined with other drugs or alcohol. Only a few lethal cases of pure trazodone overdose have been reported, all attributed to cardiotoxicity. We reported a 37-year-old woman who presented after ingesting 6.45 g of trazodone in a suicidal attempt. She was hyponatremic because of the syndrome of inappropriate antidiuretic hormone secretion and, shortly after, had a seizure and developed fatal cerebral edema. Others have described seizures and hyponatremia after pure trazodone overdose, but this is the first report of cerebral edema and death from a neurological complication. Careful monitoring and correction of sodium levels may be necessary in these patients.

Presentations and treatment of childhood scleroderma: localized scleroderma, eosinophilic fasciitis, systemic sclerosis, and graft-versus-host disease.

PubMed

Hedrich, Christian Michael; Fiebig, Barbara; Hahn, Gabriele; Suttorp, Meinolf; Gahr, Manfred

2011-07-01

Juvenile scleroderma is a rare connective tissue disease that involves the skin and subcutaneous tissue. Among all presentations of juvenile scleroderma, localized scleroderma (JLSc) is the most frequent, followed by systemic disease (JSSc) and eosinophilic fasciitis (EF). In posttransplantation chronic graft-versus-host disease (GvHD), scleroderma-like skin involvement can occur. Systemic forms of juvenile scleroderma and GvHD can affect the internal organs, such as the lungs, the gastrointestinal tract, the heart, and kidneys and cause disability and severe, sometimes lethal, complications. Here, the authors give an overview of different presentations of juvenile scleroderma. They report their experience with the different forms and presentations of scleroderma, diagnostic workups, treatment, and outcome of all forms of childhood scleroderma in the context of the existing literature.

Refractory Cardiogenic Shock During Tramadol Poisoning: A Case Report.

PubMed

Belin, Nicolas; Clairet, Anne-Laure; Chocron, Sidney; Capellier, Gilles; Piton, Gaël

2017-04-01

Tramadol is a weak opioid analgesic indicated for the treatment of moderate to severe pain. Tramadol intoxication can be lethal, and this drug is frequently involved in voluntary overdose. Classically, tramadol intoxication is associated with neurological and respiratory side effects. In contrast, cardiac effects are poorly documented in the literature. We report a case of severe tramadol intoxication, with plasma concentration 20 times the toxic threshold, complicated by refractory cardiogenic shock, successfully treated by extra corporeal life support (ECLS) with a favorable cardiac outcome and ECLS weaning at day 10. Seizure, clonus, and nonreactive mydriasis were present during 4 days, and complete awakening was delayed to day 15. Poisoning caused by high doses of tramadol can lead to refractory cardiogenic shock, and ECLS can be considered as effective rescue therapy in this context.

[Chronic Pancreatitis and Pancreatic Cancer - Tumor Risk and Screening].

PubMed

Beyer, Georg; D'Haese, Jan G; Ormanns, Steffen; Mayerle, Julia

2018-06-01

Chronic pancreatitis is a fibroinflammatory syndrome of the exocrine pancreas, which is characterized by an increasing incidence, high morbidity and lethality. Common etiologies besides alcohol and nicotine consumption include genetic causes and risk factors. The life time risk for the development of pancreatic cancer is elevated 13- to 45-fold depending on the underlying etiology. In patients with chronic pancreatitis clinical, laboratory and imaging surveillance for early detection of complications, including pancreatic cancer, is recommended, although the available methods lack the desired sensitivity and specificity. In this article we review the epidemiology, etiologies and risk factors for chronic pancreatitis and pancreatic cancer and discuss current recommendations for screening and management of patients at risk for tumor development. © Georg Thieme Verlag KG Stuttgart · New York.

Full recovery from a potentially lethal dose of mercuric chloride.

PubMed

Beasley, D Michael G; Schep, Leo J; Slaughter, Robin J; Temple, Wayne A; Michel, Jonathan M

2014-03-01

Mercuric chloride poisoning is rare yet potentially life-threatening. We report a case of poisoning with a potentially significant amount of mercuric chloride which responded to aggressive management. A 19-year-old female presented to the Emergency Department with nausea, abdominal discomfort, vomiting of blood-stained fluid, and diarrhea following suicidal ingestion of 2-4 g of mercuric chloride powder. An abdominal radiograph showed radio-opaque material within the gastric antrum and the patient's initial blood mercury concentration was 17.9 μmol/L (or 3.58 mg/L) at 3 h post-ingestion. Given the potential toxicity of inorganic mercury, the patient was admitted to the intensive care unit and chelation with dimercaprol was undertaken. Further clinical effects included mild hemodynamic instability, acidosis, hypokalemia, leukocytosis, and fever. The patient's symptoms began to improve 48 h after admission and resolved fully within a week. Mercuric chloride has an estimated human fatal dose of between 1 and 4 g. Despite a reported ingestion of a potentially lethal dose and a high blood concentration, this patient experienced mild to moderate poisoning only and she responded to early and appropriate intervention. Mercuric chloride can produce a range of toxic effects including corrosive injury, severe gastrointestinal disturbances, acute renal failure, circulatory collapse, and eventual death. Treatment includes close observation and aggressive supportive care along with chelation, preferably with 2,3-dimercapto-1-propane sulfonate or 2,3-meso-dimercaptosuccinic acid.

Lethal acrodysgenital dwarfism: a severe lethal condition resembling Smith-Lemli-Opitz syndrome.

PubMed Central

Merrer, M L; Briard, M L; Girard, S; Mulliez, N; Moraine, C; Imbert, M C

1988-01-01

We report eight cases of a lethal association of failure to thrive, facial dysmorphism, ambiguous genitalia, syndactyly, postaxial polydactyly, and internal developmental anomalies (Hirschsprung's disease, cardiac and renal malformation). This syndrome is likely to be autosomal recessive and resembles Smith-Lemli-Opitz (SLO) syndrome. However, the lethality, the common occurrence of polydactyly, and the sexual ambiguity distinguishes this condition from SLO syndrome. A review of published reports supports the separate classification of this syndrome for which we propose the name lethal acrodysgenital dwarfism. Images PMID:2831368

Thyroidectomy: post-operative care and common complications.

PubMed

Furtado, L

Any surgical procedure involves risks. Thyroid surgery can cause potentially fatal complications during the early post-operative phase. It is essential that nurses have the knowledge and skills to detect early signs and symptoms of potential complications and take appropriate action. Early detection and rapid response are key to maintaining patient safety and minimising harm.

Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer

PubMed Central

Bilen, Mehmet Asim; Hess, Kenneth R.; Broaddus, Russell R.; Kopetz, Scott; Wei, Chongjuan; Pagliaro, Lance C.; Karam, Jose A.; Ward, John F.; Wood, Christopher G.; Rao, Priya; Tu, Zachary H.; General, Rosale; Chen, Adrienne H.; Nieto, Yago L.; Yeung, Sai‐ching J.; Lin, Sue‐Hwa; Logothetis, Christopher J.; Pisters, Louis L.

2016-01-01

BACKGROUND Intratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype. METHODS In this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next‐generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations. RESULTS Six hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac‐seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected. CONCLUSIONS The current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016;122:1836–43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMID:27018785

Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer.

PubMed

Tu, Shi-Ming; Bilen, Mehmet Asim; Hess, Kenneth R; Broaddus, Russell R; Kopetz, Scott; Wei, Chongjuan; Pagliaro, Lance C; Karam, Jose A; Ward, John F; Wood, Christopher G; Rao, Priya; Tu, Zachary H; General, Rosale; Chen, Adrienne H; Nieto, Yago L; Yeung, Sai-Ching J; Lin, Sue-Hwa; Logothetis, Christopher J; Pisters, Louis L

2016-06-15

Intratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype. In this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next-generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations. Six hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac-seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected. The current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016;122:1836-43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2016 American Cancer Society.

Young coconut water ameliorates depression via modulation of neurotransmitters: possible mechanism of action.

PubMed

Rao, Sadia Saleem; Najam, Rahila

2016-10-01

In the current era, plants are frequently tested for its antidepressant potential. Therefore young coconut water, a commonly used plant based beverage, was selected to explore its antidepressant potential. Rodents were selected for this study and forced swim test was conducted to explore antidepressant activity. Analysis of brain biogenic amines using high performance liquid chromatography coupled with electrochemical detection and potentiation of noradrenaline toxicity model were also incorporated in this study to demonstrate probable antidepressant mechanism of action. Coconut water was administered orally at the dose of 4 ml/100 g. Young coconut water showed highly significant increase in struggling time (p < 0.001) in forced swim test. This suggests antidepressant effect of young coconut water. In noradrenaline toxicity model, it was observed that young coconut water is not a good adrenergic component as its lethality percentage in this test was observed 0 % unlike imipramine which showed lethality of 100 %. High performance liquid chromatography-electrochemical detection of rodent's brain revealed decline in 5-hydroxytryptamine, noradrenaline and dopamine, with concomitant decline in metabolites 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, homovanillic acid and increase in 5-hydroxyindoleacetic acid/5-hydroxytryptamine ratio. Findings from the exploration of monoamines suggest antidepressant effect of young coconut water via homeostasis of monoamines synthesis.

Suicide Lethality: A Concept Analysis.

PubMed

DeBastiani, Summer; De Santis, Joseph P

2018-02-01

Suicide is a significant health problem internationally. Those who complete suicide may have different behaviors and risk factors than those who attempt a non-fatal suicide. The purpose of this article is to analyze the concept of suicide lethality and propose a clear definition of the concept through the identification of antecedents, attributes, and consequences. A literature search for articles published in the English language between 1970 and 2016 was conducted using MEDLINE, the Cochrane Library, Pubmed, Psychlit, Ovid, PsycINFO, and Proquest. The bibliographies of all included studies were also reviewed to identify additional relevant citations. A concept analysis was conducted on the literature findings using six stages of Walker and Avant's method. The concept analysis differentiated between suicide, lethality, suicidal behavior, and suicide lethality. Presence of a suicide plan or a written suicide note was not found to be associated with the majority of completed suicides included in the definition of suicide lethality. There are a few scales that measure the lethality of a suicide attempt, but none that attempt to measure the concept of suicide lethality as described in this analysis. Clarifying the concept of suicide lethality encourages awareness of the possibility of different suicidal behaviors associated with different suicide outcomes and will inform the development of future nursing interventions. A clearer definition of the concept of suicide lethality will guide clinical practice, research, and policy development aimed at suicide prevention.

Potential of Dietary Non-Provitamin A Carotenoids in the Prevention and Treatment of Diabetic Microvascular Complications12

PubMed Central

Murillo, Ana Gabriela

2016-01-01

Diabetes is a chronic metabolic disease that affects a substantial part of the population around the world. Whether type I or type II, this disease has serious macro- and microvascular complications that constitute the primary cause of death in diabetic patients. Microvascular complications include diabetic retinopathy, nephropathy, and neuropathy. Although these complications are clinically and etiologically diverse, they share a common factor: glucose-induced damage. In the progression of diabetic complications, oxidative stress, inflammation, and the formation of glycation end products play an important role. Previous studies have shown that a healthy diet is vital in preventing these complications; in particular, the intake of antioxidants has been studied for their potential effect in ameliorating hyperglycemic injuries. Carotenoids are lipid-soluble pigments synthesized by plants, bacteria, and some kinds of algae that are responsible for the yellow, red, and orange colors in food. These compounds are part of the antioxidant machinery in plants and have also shown their efficacy in quenching free radicals, scavenging reactive oxygen species, modulating gene expression, and reducing inflammation in vitro and in vivo, showing that they can potentially be used as part of a preventive strategy for metabolic disorders, including diabetes and its related complications. This review highlights the potential protective effects of 4 non-provitamin A carotenoids—lutein, zeaxanthin, lycopene, and astaxanthin—in the development and progression of diabetic microvascular complications. PMID:26773012

Lethal trap trees and semiochemical repellents as area host protection strategies for spruce beetle (Coleoptera: Curculionidae, Scolytinae) in Utah

Treesearch

Matt Hansen; A. Steven Munson; Darren C. Blackford; David Wakarchuk; Scott Baggett

2016-01-01

We tested lethal trap trees and repellent semiochemicals as area treatments to protect host trees from spruce beetle (Dendroctonus rufipennis Kirby) attacks. Lethal trap tree treatments ("spray treatment") combined a spruce beetle bait with carbaryl treatment of the baited spruce. Repellent treatments ("spray-repellent”) combined a baited lethal...

Review: the use of sodium hypochlorite in endodontics--potential complications and their management.

PubMed

Spencer, H R; Ike, V; Brennan, P A

2007-05-12

Aqueous sodium hypochlorite (bleach) solution is widely used in dental practice during root canal treatment. Although it is generally regarded as being very safe, potentially severe complications can occur when it comes into contact with soft tissue. This paper discusses the use of sodium hypochlorite in dental treatment, reviews the current literature regarding hypochlorite complications, and considers the appropriate management for a dental practitioner when faced with a potentially adverse incident with this agent.

Effect of lethality on the extinction and on the error threshold of quasispecies.

PubMed

Tejero, Hector; Marín, Arturo; Montero, Francisco

2010-02-21

In this paper the effect of lethality on error threshold and extinction has been studied in a population of error-prone self-replicating molecules. For given lethality and a simple fitness landscape, three dynamic regimes can be obtained: quasispecies, error catastrophe, and extinction. Using a simple model in which molecules are classified as master, lethal and non-lethal mutants, it is possible to obtain the mutation rates of the transitions between the three regimes analytically. The numerical resolution of the extended model, in which molecules are classified depending on their Hamming distance to the master sequence, confirms the results obtained in the simple model and shows how an error catastrophe regime changes when lethality is taken in account. (c) 2009 Elsevier Ltd. All rights reserved.

mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice

PubMed Central

Inoki, Ken; Mori, Hiroyuki; Wang, Junying; Suzuki, Tsukasa; Hong, SungKi; Yoshida, Sei; Blattner, Simone M.; Ikenoue, Tsuneo; Rüegg, Markus A.; Hall, Michael N.; Kwiatkowski, David J.; Rastaldi, Maria P.; Huber, Tobias B.; Kretzler, Matthias; Holzman, Lawrence B.; Wiggins, Roger C.; Guan, Kun-Liang

2011-01-01

Diabetic nephropathy (DN) is among the most lethal complications that occur in type 1 and type 2 diabetics. Podocyte dysfunction is postulated to be a critical event associated with proteinuria and glomerulosclerosis in glomerular diseases including DN. However, molecular mechanisms of podocyte dysfunction in the development of DN are not well understood. Here we have shown that activity of mTOR complex 1 (mTORC1), a kinase that senses nutrient availability, was enhanced in the podocytes of diabetic animals. Further, podocyte-specific mTORC1 activation induced by ablation of an upstream negative regulator (PcKOTsc1) recapitulated many DN features, including podocyte loss, glomerular basement membrane thickening, mesangial expansion, and proteinuria in nondiabetic young and adult mice. Abnormal mTORC1 activation caused mislocalization of slit diaphragm proteins and induced an epithelial-mesenchymal transition–like phenotypic switch with enhanced ER stress in podocytes. Conversely, reduction of ER stress with a chemical chaperone significantly protected against both the podocyte phenotypic switch and podocyte loss in PcKOTsc1 mice. Finally, genetic reduction of podocyte-specific mTORC1 in diabetic animals suppressed the development of DN. These results indicate that mTORC1 activation in podocytes is a critical event in inducing DN and suggest that reduction of podocyte mTORC1 activity is a potential therapeutic strategy to prevent DN. PMID:21606597

Molecular Pathways: Disrupting polyamine homeostasis as a therapeutic strategy for neuroblastoma

PubMed Central

Evageliou, Nicholas F.; Hogarty, Michael D.

2009-01-01

MYC genes are deregulated in a plurality of human cancers. Through direct and indirect mechanisms the MYC network regulates the expression of >15% of the human genome, including both protein-coding and non-coding RNAs. This complexity has complicated efforts to define the principal pathways mediating MYC’s oncogenic activity. MYC plays a central role providing for the bioenergetic and biomass needs of proliferating cells, and polyamines are essential cell constituents supporting many of these functions. The rate-limiting enzyme in polyamine biosynthesis, ODC, is a bona fide MYC target, as are other regulatory enzymes in this pathway. A wealth of data link enhanced polyamine biosynthesis to cancer progression, and polyamine-depletion may limit malignant transformation of pre-neoplastic lesions. Studies using transgenic cancer models also supports that the effect of MYC on tumor initiation and progression can be attenuated through repression of polyamine production. High-risk neuroblastomas (an often lethal embryonal tumor in which MYC activation is paramount) deregulate numerous polyamine enzymes to promote expansion of intracellular polyamine pools. Selective inhibition of key enzymes in this pathway, e.g., using DFMO and/or SAM486, reduces tumorigenesis and synergizes with chemotherapy to regress tumors in pre-clinical models. Here we review the potential clinical application of these and additional polyamine-depletion agents to neuroblastoma and other advanced cancers in which MYC is operative. PMID:19789308

Cellular immunotherapy for patients with reactivation of JC and BK polyomaviruses after transplantation.

PubMed

Mani, Jiju; Jin, Nan; Schmitt, Michael

2014-10-01

Immunosuppression of patients after hematopoietic stem cell or kidney transplantation potentially leads to reactivation of JC and BK polyomaviruses. In hematopoietic stem cell transplantation, the reactivation rate of BKV can be up to 60%, resulting in severe complications of the urogenital tract, particularly hemorrhagic cystitis and renal dysfunction. After kidney transplantation, BKV reactivation can cause a loss of the graft. JCV can cause progressive multifocal leukoencephalopathy, a lethal disease. Adoptive transfer of donor-derived polyomavirus-specific T cells is an attractive and promising treatment that restores virus-specific cellular immunity. Pioneering work in the early 1990s on the reconstitution of cellular immunity against cytomegalovirus and recent development in the field of monitoring and isolation of antigen-specific T cells paved the way toward a personalized T-cell therapy. Multimer technology and magnetic beads are available to produce untouched T cells in a single-step, good manufacturing practice-compliant procedure. Another exciting aspect of T-cell therapy against polyomaviruses is the fact that both JCV and BKV can be targeted simultaneously because of their high sequence homology. Finally, "designer T cells" can be redirected to recognize polyomavirus antigens with high-affinity T-cell receptors. This review summarizes the state-of-the art technologies and gives an outlook of future developments in the field. Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Constipation: an overlooked, unmanaged symptom of patients with pheochromocytoma and sympathetic paraganglioma.

PubMed

Thosani, Sonali; Ayala-Ramirez, Montserrat; Román-González, Alejandro; Zhou, Shouhao; Thosani, Nirav; Bisanz, Annette; Jimenez, Camilo

2015-09-01

Pheochromocytomas (PHs) and sympathetic paragangliomas (PGs) are tumors that produce catecholamines, predisposing patients to cardiovascular disease and gastrointestinal effects such as constipation. i) determine the prevalence of constipation, its risk factors, and its impact on survival; ii) identify whether a systematic combination of fiber, water, and laxatives was effective for treatment of constipation. We retrospectively studied 396 patients with PH/PG diagnosed in 2005-2014. The study population was patients with constipation as a presenting symptom; the control group was patients without constipation as a presenting symptom. The MD Anderson Symptom Inventory was used to assess constipation and quality of life. Twenty-three patients (6%) had constipation. Constipation was associated with headaches, palpitations, diaphoresis, weight loss, and excessive noradrenaline production (P<0.0001). Eighteen of these patients had non-metastatic primary tumors larger than 5 cm and/or extensive metastases. No statistically significant differences in age, sex, and genotype were noted between the study and control groups. In patients without metastases, resection of the primary tumor led to symptom disappearance. A systematic combination of fiber, water, and laxatives was associated with symptom improvement. Two patients who presented unmanaged constipation died because of sepsis from toxic megacolon. Constipation is a rare and potentially lethal complication in patients with PH/PGs. Severe constipation can be prevented by recognizing and treating mild symptoms. © 2015 European Society of Endocrinology.

An agent-based model of cattle grazing toxic Geyer's larkspur.

PubMed

Jablonski, Kevin E; Boone, Randall B; Meiman, Paul J

2018-01-01

By killing cattle and otherwise complicating management, the many species of larkspur (Delphinium spp.) present a serious, intractable, and complex challenge to livestock grazing management in the western United States. Among the many obstacles to improving our understanding of cattle-larkspur dynamics has been the difficulty of testing different grazing management strategies in the field, as the risk of dead animals is too great. Agent-based models (ABMs) provide an effective method of testing alternate management strategies without risk to livestock. ABMs are especially useful for modeling complex systems such as livestock grazing management, and allow for realistic bottom-up encoding of cattle behavior. Here, we introduce a spatially-explicit, behavior-based ABM of cattle grazing in a pasture with a dangerous amount of Geyer's larkspur (D. geyeri). This model tests the role of herd cohesion and stocking density in larkspur intake, finds that both are key drivers of larkspur-induced toxicosis, and indicates that alteration of these factors within realistic bounds can mitigate risk. Crucially, the model points to herd cohesion, which has received little attention in the discipline, as playing an important role in lethal acute toxicosis. As the first ABM to model grazing behavior at realistic scales, this study also demonstrates the tremendous potential of ABMs to illuminate grazing management dynamics, including fundamental aspects of livestock behavior amidst ecological heterogeneity.

The Blue Coma: The Role of Methylene Blue in Unexplained Coma After Cardiac Surgery.

PubMed

Martino, Enrico Antonio; Winterton, Dario; Nardelli, Pasquale; Pasin, Laura; Calabrò, Maria Grazia; Bove, Tiziana; Fanelli, Giovanna; Zangrillo, Alberto; Landoni, Giovanni

2016-04-01

Methylene blue commonly is used as a dye or an antidote, but also can be used off label as a vasopressor. Serotonin toxicity is a potentially lethal and often misdiagnosed condition that can result from drug interaction. Mild serotonin toxicity previously was reported in settings in which methylene blue was used as a dye. The authors report 3 cases of life-threatening serotonin toxicity in patients undergoing chronic selective serotonin reuptake inhibitor (SSRI) therapy who also underwent cardiac surgery and received methylene blue to treat vasoplegic syndrome. An observational study. A cardiothoracic intensive care unit (ICU) in a teaching hospital. Three patients who received methylene blue after cardiac surgery, later discovered to be undergoing chronic SSRI therapy. None. All 3 patients received high doses of fentanyl during general anesthesia. They all developed vasoplegic syndrome and consequently were given methylene blue in the ICU. All 3 patients developed serotonin toxicity, including coma, after this administration and diagnostic tests were negative for acute intracranial pathology. Coma lasted between 1 and 5 days. Two patients were discharged from the ICU shortly after awakening, whereas the third patient experienced a complicated postoperative course for concomitant refractory low-cardiac-output syndrome. Patients undergoing chronic SSRI therapy should not be administered methylene blue to treat vasoplegic syndrome. Copyright © 2016 Elsevier Inc. All rights reserved.

Artificial Intelligence for Diabetes Management and Decision Support: Literature Review

PubMed Central

Contreras, Ivan

2018-01-01

Background Artificial intelligence methods in combination with the latest technologies, including medical devices, mobile computing, and sensor technologies, have the potential to enable the creation and delivery of better management services to deal with chronic diseases. One of the most lethal and prevalent chronic diseases is diabetes mellitus, which is characterized by dysfunction of glucose homeostasis. Objective The objective of this paper is to review recent efforts to use artificial intelligence techniques to assist in the management of diabetes, along with the associated challenges. Methods A review of the literature was conducted using PubMed and related bibliographic resources. Analyses of the literature from 2010 to 2018 yielded 1849 pertinent articles, of which we selected 141 for detailed review. Results We propose a functional taxonomy for diabetes management and artificial intelligence. Additionally, a detailed analysis of each subject category was performed using related key outcomes. This approach revealed that the experiments and studies reviewed yielded encouraging results. Conclusions We obtained evidence of an acceleration of research activity aimed at developing artificial intelligence-powered tools for prediction and prevention of complications associated with diabetes. Our results indicate that artificial intelligence methods are being progressively established as suitable for use in clinical daily practice, as well as for the self-management of diabetes. Consequently, these methods provide powerful tools for improving patients’ quality of life. PMID:29848472

Efficacy of Favipiravir Alone and in Combination With Ribavirin in a Lethal, Immunocompetent Mouse Model of Lassa Fever.

PubMed

Oestereich, Lisa; Rieger, Toni; Lüdtke, Anja; Ruibal, Paula; Wurr, Stephanie; Pallasch, Elisa; Bockholt, Sabrina; Krasemann, Susanne; Muñoz-Fontela, César; Günther, Stephan

2016-03-15

We studied the therapeutic potential of favipiravir (T-705) for Lassa fever, both alone and in combination with ribavirin. Favipiravir suppressed Lassa virus replication in cell culture by 5 log10 units. In a novel lethal mouse model, it lowered the viremia level and the virus load in organs and normalized levels of cell-damage markers. Treatment with 300 mg/kg per day, commenced 4 days after infection, when the viremia level had reached 4 log10 virus particles/mL, rescued 100% of Lassa virus-infected mice. We found a synergistic interaction between favipiravir and ribavirin in vitro and an increased survival rate and extended survival time when combining suboptimal doses in vivo. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.

Myxoma Virus Expressing Interleukin-15 Fails To Cause Lethal Myxomatosis in European Rabbits▿

PubMed Central

Liu, Jia; Wennier, Sonia; Reinhard, Mary; Roy, Edward; MacNeill, Amy; McFadden, Grant

2009-01-01

Myxoma virus (MYXV) is a poxvirus pathogenic only for European rabbits, but its permissiveness in human cancer cells gives it potential as an oncolytic virus. A recombinant MYXV expressing both the tdTomato red fluorescent protein and interleukin-15 (IL-15) (vMyx-IL-15-tdTr) was constructed. Cells infected with vMyx-IL-15-tdTr secreted bioactive IL-15 and had in vitro replication kinetics similar to that of wild-type MYXV. To determine the safety of this virus for future oncolytic studies, we tested its pathogenesis in European rabbits. In vivo, vMyx-IL-15-tdTr no longer causes lethal myxomatosis. Thus, ectopic IL-15 functions as an antiviral cytokine in vivo, and vMyx-IL-15-tdTr is a safe candidate for animal studies of oncolytic virotherapy. PMID:19279088

Myxoma virus expressing interleukin-15 fails to cause lethal myxomatosis in European rabbits.

PubMed

Liu, Jia; Wennier, Sonia; Reinhard, Mary; Roy, Edward; MacNeill, Amy; McFadden, Grant

2009-06-01

Myxoma virus (MYXV) is a poxvirus pathogenic only for European rabbits, but its permissiveness in human cancer cells gives it potential as an oncolytic virus. A recombinant MYXV expressing both the tdTomato red fluorescent protein and interleukin-15 (IL-15) (vMyx-IL-15-tdTr) was constructed. Cells infected with vMyx-IL-15-tdTr secreted bioactive IL-15 and had in vitro replication kinetics similar to that of wild-type MYXV. To determine the safety of this virus for future oncolytic studies, we tested its pathogenesis in European rabbits. In vivo, vMyx-IL-15-tdTr no longer causes lethal myxomatosis. Thus, ectopic IL-15 functions as an antiviral cytokine in vivo, and vMyx-IL-15-tdTr is a safe candidate for animal studies of oncolytic virotherapy.

The type IV pilin of Burkholderia mallei is highly immunogenic but fails to protect against lethal aerosol challenge in a murine model.

PubMed

Fernandes, Paula J; Guo, Qin; Waag, David M; Donnenberg, Michael S

2007-06-01

Burkholderia mallei is the cause of glanders and a proven biological weapon. We identified and purified the type IV pilin protein of this organism to study its potential as a subunit vaccine. We found that purified pilin was highly immunogenic. Furthermore, mice infected via sublethal aerosol challenge developed significant increases in titers of antibody against the pilin, suggesting that it is expressed in vivo. Nevertheless, we found no evidence that high-titer antipilin antisera provided passive protection against a sublethal or lethal aerosol challenge and no evidence of protection afforded by active immunization with purified pilin. These results contrast with the utility of type IV pilin subunit vaccines against other infectious diseases and highlight the need for further efforts to identify protective responses against this pathogen.

Aspiration pneumonia after concurrent chemoradiotherapy for head and neck cancer.

PubMed

Xu, Beibei; Boero, Isabel J; Hwang, Lindsay; Le, Quynh-Thu; Moiseenko, Vitali; Sanghvi, Parag R; Cohen, Ezra E W; Mell, Loren K; Murphy, James D

2015-04-15

Aspiration pneumonia represents an under-reported complication of chemoradiotherapy in patient with head and neck cancer. The objective of the current study was to evaluate the incidence, risk factors, and mortality of aspiration pneumonia in a large cohort of patients with head and neck cancer who received concurrent chemoradiotherapy. Patients who had head and neck cancer diagnosed between 2000 and 2009 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Aspiration pneumonia was identified from Medicare billing claims. The cumulative incidence, risk factors, and survival after aspiration pneumonia were estimated and compared with a noncancer population. Of 3513 patients with head and neck cancer, 801 developed aspiration pneumonia at a median of 5 months after initiating treatment. The 1-year and 5-year cumulative incidence of aspiration pneumonia was 15.8% and 23.8%, respectively, for patients with head and neck cancer and 3.6% and 8.7%, respectively, for noncancer controls. Among the patients with cancer, multivariate analysis identified independent risk factors (P < .05) for aspiration pneumonia, including hypopharyngeal and nasopharyngeal tumors, male gender, older age, increased comorbidity, no surgery before radiation, and care received at a teaching hospital. Among the patients with cancer who experienced aspiration pneumonia, 674 (84%) were hospitalized; and, of these, 301 (45%) were admitted to an intensive care unit. The 30-day mortality rate after hospitalization for aspiration pneumonia was 32.5%. Aspiration pneumonia was associated with a 42% increased risk of death (hazard ratio, 1.42; P < .001) after controlling for confounders. The current results indicated that nearly 25% of elderly patients will develop aspiration pneumonia within 5 years after receiving chemoradiotherapy for head and neck cancer. A better understanding of mitigating factors will help identify patients who are at risk for this potentially lethal complication. © 2014 American Cancer Society.

A Nationwide Random Sampling Survey of Potential Complicated Grief in Japan

ERIC Educational Resources Information Center

Mizuno, Yasunao; Kishimoto, Junji; Asukai, Nozomu

2012-01-01

To investigate the prevalence of significant loss, potential complicated grief (CG), and its contributing factors, we conducted a nationwide random sampling survey of Japanese adults aged 18 or older (N = 1,343) using a self-rating Japanese-language version of the Complicated Grief Brief Screen. Among them, 37.0% experienced their most significant…

DefenseLink.mil - Special Report - Soldiers Train with Non-lethal Weapons

Science.gov Websites

Training 10th Mountain Division soldiers feel the effects of a Taser during non-lethal weapons training Nov soldiers feel the effects of a Taser during non-lethal weapons training Nov. 19, 2008, at Fort Drum, N.Y situation can be resolved without lethal measures, Army Staff Sgt. Eric Johnson said during training and

Stimulating Central Carbon Metabolism to Re-sensitize Pseudomonas aeruginosa to Aminoglycosides.

PubMed

Martins, Dorival; Nguyen, Dao

2017-02-16

In this issue of Cell Chemical Biology, Meylan et al. (2017) examine how stimulation of central carbon metabolism of Pseudomonas aeruginosa modulates aminoglycoside lethality in tolerant bacteria. They identify fumarate as a tobramycin potentiator that stimulates proton motive force-dependent drug uptake and increases respiration-dependent killing. Copyright © 2017. Published by Elsevier Ltd.

Overstory removal and residue treatments affect soil surface, air, and soil temperature: implications for seedling survival

Treesearch

Roger D. Hungerford; Ronald E. Babbitt

1987-01-01

Potentially lethal ground surface temperatures were measured at three locations in the Northern Rocky Mountains but occurred more frequently under treatments with greater overstory removal. Observed maximum and minimum temperatures of exposed surfaces are directly related to the thermal properties of the surface materials. Survival of planted seedlings was consistent...

Sickle cell hepatopathy.

PubMed

Bandyopadhyay, Ranjana; Bandyopadhyay, Sanjay K; Dutta, Anita

2008-01-01

Sickle cell hepatopathy is a well-documented entity that ranges from the self-limiting hepatic right upper quadrant syndrome to the potentially lethal intrahepatic cholestasis and acute hepatic sequestration syndromes. We describe a 26-year-male with homozygous sickle cell disease who had this unique hepatic presentation and was documented to have characteristic findings of cholestasis, portal inflammation and sinusoidal dilatation on histopathology.

High pressure processing of Queso Fresco: effects on textural and rheological properties over 12 weeks of storage

USDA-ARS?s Scientific Manuscript database

High pressure processing (HPP) is a non-thermal post-packaging process with the potential to improve cheese safety and shelf life because of its lethality to bacteria (spoilage and pathogens) and ability to inactivate many enzymes. Queso Fresco (QF), a high moisture Hispanic-style cheese popular in ...

The Decade Dance

PubMed Central

Neher, Jon O.

2005-01-01

This essay portrays the moment an adult survivor of childhood sexual abuse tells his physician about his traumatic past. Because of denial by both parties, the diagnosis had remained buried for years, and opportunities for appropriate intervention were repeatedly missed. When the patient is finally able to face his past, it unleashes a torrent of potentially lethal anger that challenges everyone involved. PMID:16189064

Effects of invertebrate iridescent virus 6 in Phyllophaga vandinei and its potential as a biocontrol delivery system

USDA-ARS?s Scientific Manuscript database

Invertebrate iridescent virus 6 (IIV6) was determined to cause infection in Phyllophaga vandinei Smyth, through a range of modes of transmissions. This is the first evidence of IIV6 infection in P. vandinei, which caused both patent and sub-lethal covert infections in larvae and adults. Mortality r...

White pine blister rust resistance in limber pine: Evidence for a major gene

Treesearch

A. W. Schoettle; R. A. Sniezko; A. Kegley; K. S. Burns

2014-01-01

Limber pine (Pinus flexilis) is being threatened by the lethal disease white pine blister rust caused by the non-native pathogen Cronartium ribicola. The types and frequencies of genetic resistance to the rust will likely determine the potential success of restoration or proactive measures. These first extensive inoculation trials using individual tree seed collections...

Evolution of a zoonotic pathogen: investigating prophage diversity in enterohaemorrhagic E. coli O157 by long-read sequencing

USDA-ARS?s Scientific Manuscript database

Enterohaemorrhagic Escherichia Coli (EHEC) is a zoonotic pathogen known to be potentially lethal in humans. Its main animal reservoir is ruminants, specifically cattle, and yearly outbreaks occur worldwide with the most prevalent serotype being EHEC O157:H7. Most virulence factors of EHEC O157, incl...

Time-response characteristic and potential biomarker identification of heavy metal induced toxicity in zebrafish.

PubMed

Yin, Jian; Wang, Ai-Ping; Li, Wan-Fang; Shi, Rui; Jin, Hong-Tao; Wei, Jin-Feng

2018-01-01

The present work aims to explore the time-response (from 24 h to 96 h) characteristic and identify early potential sensitive biomarkers of copper (Cu) (as copper chloride dihydrate), cadmium (Cd) (as cadmium acetate), lead (Pb) (as lead nitrate) and chromium (Cr) (as potassium dichromate) exposure in adult zebrafish, focusing on reactive oxygen species (ROS), SOD activity, lipid peroxidation and gene expression related to oxidative stress and inflammatory response. Furthermore, the survival rate decreased apparently by a concentration-dependent manner after Cu, Cr, Cd and Pb exposure, and we selected non-lethal concentrations 0.05 mg/L for Cu, 15 mg/L for Cr, 3 mg/L for Cd and 93.75μg/L for Pb to test the effect on the following biological indicators. Under non-lethal concentration, the four heavy metals have no apparent histological change in adult zebrafish gills. Similar trends in ROS production, MDA level and SOD activity were up-regulated by the four heavy metals, while MDA level responded more sensitive to Pb by time-dependent manner than the other three heavy metals. In addition, mRNA levels related to antioxidant system (SOD1, SOD2 and Nrf2) were up-regulated by non-lethal concentration Cu, Cr, Cd and Pb exposure. MDA level and SOD1 gene have a more delayed response to heavy metals. Genes related to immunotoxicity were increased significantly after heavy metals exposure at non-lethal concentrations. TNF-α and IL-1β gene have similar sensibility to the four heavy metals, while IL-8 gene was more responsive to Cr, Cd and Pb exposure at 48 h groups and IFN-γ gene showed more sensitivity to Cu at 48 h groups than the other heavy metals. In conclusion, the present works have suggested that the IFN-γ gene may applied as early sensitive biomarker to identify Cu-induced toxicity, while MDA content and IL-8 gene may use as early sensitive biomarkers for evaluating the risk of Pb exposure. Moreover, IL-8 and IFN-γ gene were more responsive to heavy metals, which may become early sensitive and potential biomarkers for evaluating inflammatory response induced by heavy metals. This work reinforces the concept of the usefulness of gene expression assays in the evaluation of chemicals effects and helps to establish a background data as well as contributes to evaluate early environmental risk for chemicals, even predicting toxicity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Choline intake and risk of lethal prostate cancer: incidence and survival123

PubMed Central

Richman, Erin L; Kenfield, Stacey A; Stampfer, Meir J; Giovannucci, Edward L; Zeisel, Steven H; Willett, Walter C; Chan, June M

2012-01-01

Background: Meat, milk, and eggs have been inconsistently associated with the risk of advanced prostate cancer. These foods are sources of choline—a nutrient that may affect prostate cancer progression through cell membrane function and one-carbon metabolism. No study has examined dietary choline and the risk of lethal prostate cancer. Objective: Our objective was to examine whether dietary choline, choline-containing compounds, and betaine (a choline metabolite) increase the risk of lethal prostate cancer. Design: We prospectively examined the intake of these nutrients and the risk of lethal prostate cancer among 47,896 men in the Health Professionals Follow-Up Study. In a case-only survival analysis, we examined the postdiagnostic intake of these nutrients and the risk of lethal prostate cancer among 4282 men with an initial diagnosis of nonmetastatic disease during follow-up. Diet was assessed with a validated questionnaire 6 times during 22 y of follow-up. Results: In the incidence analysis, we observed 695 lethal prostate cancers during 879,627 person-years. Men in the highest quintile of choline intake had a 70% increased risk of lethal prostate cancer (HR: 1.70; 95% CI: 1.18, 2.45; P-trend = 0.005). In the case-only survival analysis, we observed 271 lethal cases during 33,679 person-years. Postdiagnostic choline intake was not statistically significantly associated with the risk of lethal prostate cancer (HR for quintile 5 compared with quintile 1: 1.69; 95% CI: 0.93, 3.09; P-trend = 0.20). Conclusion: Of the 47,896 men in our study population, choline intake was associated with an increased risk of lethal prostate cancer. PMID:22952174

Examining the impact of psychiatric diagnosis and comorbidity on the medical lethality of adolescent suicide attempts.

PubMed

McManama O'Brien, Kimberly H; Berzin, Stephanie C

2012-08-01

Specific psychiatric diagnoses and comorbidity patterns were examined to determine if they were related to the medical lethality of suicide attempts among adolescents presenting to an urban general hospital (N=375). Bivariate analysis showed that attempters with substance abuse disorders had higher levels of lethality than attempters without substance abuse. Regression results indicated having depression comorbid with any other diagnosis was not associated with medical lethality. However, having a substance abuse disorder was associated with higher suicide attempt lethality, highlighting the importance of substance abuse as a risk factor for lethal suicide attempts in adolescents. This finding stimulates critical thinking around the understanding of suicidal behavior in youth and the development and implementation of treatment strategies for suicidal adolescents with substance abuse disorders. © 2012 The American Association of Suicidology.

Lethal and sub-lethal responses of native freshwater mussels exposed to granular Bayluscide®, a sea lamprey larvicide

USGS Publications Warehouse

Newton, Teresa; Boogaard, Michael A.; Gray, Brian R.; Hubert, Terrance D.; Schloesser, Nicholas

2017-01-01

The invasive sea lamprey (Petromyzon marinus) poses a substantial threat to fish communities in the Great Lakes. Efforts to control sea lamprey populations typically involve treating tributary streams with lampricides on a recurring cycle. The presence of a substantial population of larval sea lampreys in the aquatic corridor between Lakes Huron and Erie prompted managers to propose a treatment using the granular formulation of Bayluscide® that targets larval sea lampreys that reside in sediments. However, these treatments could cause adverse effects on native freshwater mussels—imperiled animals that also reside in sediments. We estimated the risk of mortality and sub-lethal effects among eight species of adult and sub-adult mussels exposed to Bayluscide® for durations up to 8 h to mimic field applications. Mortality was appreciable in some species, especially in sub-adults (range, 23–51%). The lethal and sub-lethal effects were positively associated with the duration of exposure in most species and life stage combinations. Estimates of the median time of exposure that resulted in lethal and sub-lethal effects suggest that sub-adults were often affected by Bayluscide® earlier than adults. Siphoning activity and burrowing position of mussels during exposure may have moderated the uptake of Bayluscide® and may have influenced lethal and sub-lethal responses. Given that the various species and life stages were differentially affected, it will be difficult to predict the effects of Bayluscide® treatments on mussels.

Candida albicans and Escherichia coli are synergistic pathogens during experimental microbial peritonitis.

PubMed

Klaerner, H G; Uknis, M E; Acton, R D; Dahlberg, P S; Carlone-Jambor, C; Dunn, D L

1997-07-01

Candida albicans has been isolated with increasing frequency during intraabdominal infection; yet its role as a pathogen or copathogen remains controversial. A recent experimental study of its effect during polymicrobial peritonitis indicated that it did not enhance mortality when added to an Escherichia coli challenge, but that study used fecal or mucin-based adjuvants which are known to markedly potentiate the lethality of intraperitoneal bacteria. Therefore, we sought to examine the hypothesis that C. albicans and E. coli are synergistic copathogens that act in concert to increase mortality rates in experimental models of polymicrobial peritonitis, irrespective of the presence of growth adjuvant. To test this hypothesis, we assessed the mortality rates of previously healthy Swiss-Webster mice (20 g) that were challenged intraperitoneally (i.p.) with E. coli, C. albicans, or both, in either the presence or the absence of hemoglobin-mucin. In the absence of hemoglobin-mucin, E. coli plus C. albicans resulted in 83.3% mortality (P < 0.02) compared to either E. coli (0%) or C. albicans (0%) alone. In the presence of hemoglobin-mucin, the synergistic effect was not observed, lower numbers of E. coli alone (62.5%), C. albicans alone (75%), or both organisms together (100%, P > 0.05) provoked high lethality. These data demonstrate that in the absence of adjuvant, E. coli plus C. albicans provoked synergistic lethality. However, in the presence of hemoglobin-mucin the synergistic effect was no longer observed. Therefore, this study provides support for the contention that C. albicans is capable of acting as a copathogen during experimental peritonitis, but that this effect may be obscured by the presence of an adjuvant substance that itself markedly potentiates microbial growth.

Evaluation of the Natural Zeolite Lethal Effects on Adults of the Bean Weevil Under Different Temperatures and Relative Humidity Regimes.

PubMed

Floros, George D; Kokkari, Anastasia I; Kouloussis, Nikolaos A; Kantiranis, Nikolaos A; Damos, Petros; Filippidis, Anestis A; Koveos, Dimitris S

2018-02-09

We studied the insecticidal activity of different concentrations of very high quality natural zeolites (zeolitic rock containing 92 wt% clinoptilolite) applied on dry beans. The test species was adult bean weevils Acanthoscelides obtectus (Say; Coleoptera: Bruchidae), and the variables included different temperatures and humidity regimes. At certain natural zeolite concentrations the adult mortality approached 100% within the first day of exposure. The lethal natural zeolite concentration for 50% adult mortality (LD50) was 1.1 g/kg dry beans 1 d after exposure. The temperature had no significant effects on the insecticidal potential of the tested natural zeolite formulations. The lethal time (LT) for 50% adult mortality (LT50), at a concentration of 0.5 g/kg dry beans was 106.429, 101.951, and 90.084 min at 15, 20, and 25°C, respectively. It did not differ significantly. In contrast, relative humidity (RH) and exposure time as well as their interactions had a significant effect on natural zeolite formulation and insecticidal potential. At a constant concentration of 0.5 g/kg dry beans and 25°C at 23%, 34%, 53%, and 88% RH the LT50 ranged from 61.6 to 75.9 min; at 72% RH the LT50 was 110.6 min. The results indicate that natural zeolite at low concentrations is promising for the control of the bean weevil under different temperatures and RH regimes. © The Author(s) 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Lethal and sublethal toxicity of the industrial chemical epichlorohydrin on Rhinella arenarum (Anura, Bufonidae) embryos and larvae.

PubMed

Hutler Wolkowicz, Ianina R; Aronzon, Carolina M; Pérez Coll, Cristina S

2013-12-15

Lethal and sublethal toxicity of the major chemical used in epoxide compounds, epichlorohydrin (ECH) was evaluated on the early life cycle of the common South American toad, Rhinella arenarum (Anura, Bufonidae). The stages evaluated were (according to Del Conte and Sirlin): early blastula (S.3-S.4), gastrula (S.10-S.12), rotation (S.15), tail bud (S.17), muscular response (S.18), gill circulation (S.20), open mouth (S.21), opercular folds (S.23) and complete operculum (S.25). The LC50 and EC50 values for lethal and sublethal effects were calculated. The early blastula was the most sensitive stage to ECH both for continuously and pulse-exposures (LC50-24h=50.9 mg L(-1)), while S.20 was the most resistant (LC50-24h=104.9 mg L(-1)). Among sublethal effects, early blastula was also the most sensitive stage (LOEC-48 h=20 mg L(-1)) and it has a Teratogenic Index of 2.5, which indicates the teratogenic potential of the substance. The main abnormalities were persistent yolk plugs, cell dissociation, tumors, hydropsy, oral malformations, axial/tail flexures, delayed development and reduced body size. ECH also caused neurotoxicity including scarce response to stimuli, reduction in the food intake, general weakness, spasms and shortening, erratic or circular swimming. Industrial contamination is considered an important factor on the decline of amphibian populations. Considering the available information about ECH's toxicity and its potential hazard to the environment, this work shows the first results of its developmental toxicity on a native amphibian species, Rhinella arenarum. Copyright © 2013 Elsevier B.V. All rights reserved.

Acute oral toxicity of colchicine in rats: effects of gender, vehicle matrix and pre-exposure to lipopolysaccharide.

PubMed

Wiesenfeld, Paddy L; Garthoff, Larry H; Sobotka, Thomas J; Suagee, Jessica K; Barton, Curtis N

2007-01-01

The oral toxicity of a single administration by gavage (10, 20 or 30 mg kg(-1) body weight) of colchicine (COL) was determined in young, mature male and female Sprague-Dawley rats. The effect of COL was evaluated in the presence or absence of additional treatment variables that included vehicle and lipopolysaccharide (LPS) pre-exposure. The vehicle for COL was either Half and Half cream (H & H) or saline, and each group included pretreatment with either saline or a low, minimally toxic dose (83 microg kg(-1) body weight) of LPS. Colchicine toxicity in both male and female age-matched rats was characterized by progressively more severe dose-related clinical signs of toxicity. These included mortality, decreased body weight and feed intake during the first several days after dosing, with recovery thereafter in surviving animals. There were differences in the severity of the toxic response to COL between male and female rats. The most notable sex-related difference was in COL lethality. Female rats were two times more susceptible to the lethal effects of COL than male rats. Saline or H & H delivery vehicles did not result in any apparent qualitative or quantitative differences in COL toxicity. LPS pretreatment significantly potentiated COL lethality in both males and females, although the potentiation in males was greater than in females. LPS pretreatment modestly increased the COL induced anorexic effect in surviving males, but not in surviving female animals. LPS did not appear to modulate either the body weights or clinical signs of COL induced toxicity in surviving males or females. (c) 2007 John Wiley & Sons, Ltd.

Modeling Conventional Land Combat in a Multi-Agent System Using Generalization of the Different Combat Entities and Combat Operations

DTIC Science & Technology

2001-09-01

Blue and Red Death Rates for Red Lethality = 1 ..........................66 xi Figure 23 Blue and Red Death Rates for Red Lethality = 2...67 Figure 24 Blue and Red Death Rates for Red Lethality = 3 ..........................67 Figure 25 Blue and Red Casualties...vs. Red Lethality....................................68 Figure 26 Blue and Red Death Rates for Blue Training = 100%...................69 Figure

Identification of lethal cluster of genes in the yeast transcription network

NASA Astrophysics Data System (ADS)

Rho, K.; Jeong, H.; Kahng, B.

2006-05-01

Identification of essential or lethal genes would be one of the ultimate goals in drug designs. Here we introduce an in silico method to select the cluster with a high population of lethal genes, called lethal cluster, through microarray assay. We construct a gene transcription network based on the microarray expression level. Links are added one by one in the descending order of the Pearson correlation coefficients between two genes. As the link density p increases, two meaningful link densities pm and ps are observed. At pm, which is smaller than the percolation threshold, the number of disconnected clusters is maximum, and the lethal genes are highly concentrated in a certain cluster that needs to be identified. Thus the deletion of all genes in that cluster could efficiently lead to a lethal inviable mutant. This lethal cluster can be identified by an in silico method. As p increases further beyond the percolation threshold, the power law behavior in the degree distribution of a giant cluster appears at ps. We measure the degree of each gene at ps. With the information pertaining to the degrees of each gene at ps, we return to the point pm and calculate the mean degree of genes of each cluster. We find that the lethal cluster has the largest mean degree.

Risk-taking behaviors and subgrouping of suicide in Iran: A latent class analysis of national registries data.

PubMed

Hajebi, Ahmad; Abbasi-Ghahramanloo, Abbas; Hashemian, Seyed Sepehr; Khatibi, Seyed Reza; Ghasemzade, Masomeh; Khodadost, Mahmoud

2017-09-01

Suicide is one the most important public health problem which is rapidly growing concerns. The aim of this study was to subgroup suicide using LCA method. This cross-sectional study was conducted in Iran based on 66990 records registered in Ministry of Health in 2014. A case report questionnaire in the form of software was used for case registries. Latent class analysis was used to achieve the research objectives. Four latent classes were identified; (a) Non-lethal attempters without a history of psychiatric disorders, (b) Non-lethal attempters with a history of psychiatric disorders, (c) Lethal attempters without a history of psychiatric disorders, (d) Lethal attempters with a history of psychiatric disorders. The probability of completed/an achieved suicide is high in lethal attempter classes. Being male increases the risk of inclusion in lethal attempters' classes (OR = 4.93). Also, being single (OR = 1.16), having an age lower than 25 years (OR = 1.14) and being a rural citizen (OR = 2.36) associate with lethal attempters classes. The males tend to use more violent methods and have more completed suicide. Majority of the individuals are non-lethal attempters who need to be addressed by implementing preventive interventions and mental support provision. Copyright © 2017. Published by Elsevier B.V.

Clostridium sordellii lethal toxin kills mice by inducing a major increase in lung vascular permeability.

PubMed

Geny, Blandine; Khun, Huot; Fitting, Catherine; Zarantonelli, Leticia; Mazuet, Christelle; Cayet, Nadège; Szatanik, Marek; Prevost, Marie-Christine; Cavaillon, Jean-Marc; Huerre, Michel; Popoff, Michel R

2007-03-01

When intraperitoneally injected into Swiss mice, Clostridium sordellii lethal toxin reproduces the fatal toxic shock syndrome observed in humans and animals after natural infection. This animal model was used to study the mechanism of lethal toxin-induced death. Histopathological and biochemical analyses identified lung and heart as preferential organs targeted by lethal toxin. Massive extravasation of blood fluid in the thoracic cage, resulting from an increase in lung vascular permeability, generated profound modifications such as animal dehydration, increase in hematocrit, hypoxia, and finally, cardiorespiratory failure. Vascular permeability increase induced by lethal toxin resulted from modifications of lung endothelial cells as evidenced by electron microscopy. Immunohistochemical analysis demonstrated that VE-cadherin, a protein participating in intercellular adherens junctions, was redistributed from membrane to cytosol in lung endothelial cells. No major sign of lethal toxin-induced inflammation was observed that could participate in the toxic shock syndrome. The main effect of the lethal toxin is the glucosylation-dependent inactivation of small GTPases, in particular Rac, which is involved in actin polymerization occurring in vivo in lungs leading to E-cadherin junction destabilization. We conclude that the cells most susceptible to lethal toxin are lung vascular endothelial cells, the adherens junctions of which were altered after intoxication.

Clostridium sordellii Lethal Toxin Kills Mice by Inducing a Major Increase in Lung Vascular Permeability

PubMed Central

Geny, Blandine; Khun, Huot; Fitting, Catherine; Zarantonelli, Leticia; Mazuet, Christelle; Cayet, Nadège; Szatanik, Marek; Prevost, Marie-Christine; Cavaillon, Jean-Marc; Huerre, Michel; Popoff, Michel R.

2007-01-01

When intraperitoneally injected into Swiss mice, Clostridium sordellii lethal toxin reproduces the fatal toxic shock syndrome observed in humans and animals after natural infection. This animal model was used to study the mechanism of lethal toxin-induced death. Histopathological and biochemical analyses identified lung and heart as preferential organs targeted by lethal toxin. Massive extravasation of blood fluid in the thoracic cage, resulting from an increase in lung vascular permeability, generated profound modifications such as animal dehydration, increase in hematocrit, hypoxia, and finally, cardiorespiratory failure. Vascular permeability increase induced by lethal toxin resulted from modifications of lung endothelial cells as evidenced by electron microscopy. Immunohistochemical analysis demonstrated that VE-cadherin, a protein participating in intercellular adherens junctions, was redistributed from membrane to cytosol in lung endothelial cells. No major sign of lethal toxin-induced inflammation was observed that could participate in the toxic shock syndrome. The main effect of the lethal toxin is the glucosylation-dependent inactivation of small GTPases, in particular Rac, which is involved in actin polymerization occurring in vivo in lungs leading to E-cadherin junction destabilization. We conclude that the cells most susceptible to lethal toxin are lung vascular endothelial cells, the adherens junctions of which were altered after intoxication. PMID:17322384

In vitro lethal photosensitization of S. mutans using methylene blue and toluidine blue O as photosensitizers.

PubMed

Araújo, Patrícia V; Teixeira, Karina I R; Lanza, Lincoln D; Cortes, Maria E; Poletto, Luiz T A

2009-01-01

The purpose of this in vitro study was to evaluate the antimicrobial effect of photodynamic therapy on Streptococcus mutans (A TCC 25175) suspensions, using a red laser for one minute in combination with toluidine blue O (TBO) or methylene blue (MB). Both photosensitizers were used in three concentrations (25, 10 and 5 mg/L). The activity ofphotosensitizers and laser irradiation were tested separately on the bacteria, as well as the irradiation of this light source in the presence of the TBO or MB. These groups were compared to a control group, in which the microorganism did not receive any treatment. The activity of both TBO and MB or laser irradiation, alone, were not able to reduce the number of S. mutans. In the groups of lethal photosensitization, a bacterial reduction of 70% for TBO and 73% for MB was observed when these photosensitizers were used at 25 mg/L and a reduction of 48% was observed for MB at 5mg/L. In other concentrations there were no significant differences in comparison to the control group. Both the TBO and the MB at 25 mg/L associated with a red laser had an excellent potential for use in PDT in lethal sensitization of S. mutans.

Experimental respiratory Marburg virus haemorrhagic fever infection in the common marmoset (Callithrix jacchus)

PubMed Central

Smither, Sophie J; Nelson, Michelle; Eastaugh, Lin; Laws, Thomas R; Taylor, Christopher; Smith, Simon A; Salguero, Francisco J; Lever, Mark S

2013-01-01

Marburg virus causes a highly infectious and lethal haemorrhagic fever in primates and may be exploited as a potential biothreat pathogen. To combat the infection and threat of Marburg haemorrhagic fever, there is a need to develop and license appropriate medical countermeasures. To determine whether the common marmoset (Callithrix jacchus) would be an appropriate model to assess therapies against Marburg haemorrhagic fever, initial susceptibility, lethality and pathogenesis studies were performed. Low doses of virus, between 4 and 28 TCID50, were sufficient to cause a lethal, reproducible infection. Animals became febrile between days 5 and 6, maintaining a high fever before succumbing to disease between 8 and 11 days postchallenge. Typical signs of Marburg virus infection were observed including haemorrhaging and a transient rash. In pathogenesis studies, virus was isolated from the animals’ lungs from day 3 postchallenge and from the liver, spleen and blood from day 5 postchallenge. Early signs of histopathology were apparent in the kidney and liver from day 3. The most striking features were observed in animals exhibiting severe clinical signs, which included high viral titres in all organs, with the highest levels in the blood, increased levels in liver function enzymes and blood clotting times, decreased levels in platelets, multifocal moderate-to-severe hepatitis and perivascular oedema. PMID:23441639

Delayed Time-to-Treatment of an Antisense Morpholino Oligomer Is Effective against Lethal Marburg Virus Infection in Cynomolgus Macaques.

PubMed

Warren, Travis K; Whitehouse, Chris A; Wells, Jay; Welch, Lisa; Charleston, Jay S; Heald, Alison; Nichols, Donald K; Mattix, Marc E; Palacios, Gustavo; Kugleman, Jeffrey R; Iversen, Patrick L; Bavari, Sina

2016-02-01

Marburg virus (MARV) is an Ebola-like virus in the family Filovirdae that causes sporadic outbreaks of severe hemorrhagic fever with a case fatality rate as high as 90%. AVI-7288, a positively charged antisense phosphorodiamidate morpholino oligomer (PMOplus) targeting the viral nucleoprotein gene, was evaluated as a potential therapeutic intervention for MARV infection following delayed treatment of 1, 24, 48, and 96 h post-infection (PI) in a nonhuman primate lethal challenge model. A total of 30 cynomolgus macaques were divided into 5 groups of 6 and infected with 1,830 plaque forming units of MARV subcutaneously. AVI-7288 was administered by bolus infusion daily for 14 days at 15 mg/kg body weight. Survival was the primary endpoint of the study. While none (0 of 6) of the saline group survived, 83-100% of infected monkeys survived when treatment was initiated 1, 24, 48, or 96 h post-infection (PI). The antisense treatment also reduced serum viremia and inflammatory cytokines in all treatment groups compared to vehicle controls. The antibody immune response to virus was preserved and tissue viral antigen was cleared in AVI-7288 treated animals. These data show that AVI-7288 protects NHPs against an otherwise lethal MARV infection when treatment is initiated up to 96 h PI.

Severe Hypoglycemia–Induced Lethal Cardiac Arrhythmias Are Mediated by Sympathoadrenal Activation

PubMed Central

Reno, Candace M.; Daphna-Iken, Dorit; Chen, Y. Stefanie; VanderWeele, Jennifer; Jethi, Krishan; Fisher, Simon J.

2013-01-01

For people with insulin-treated diabetes, severe hypoglycemia can be lethal, though potential mechanisms involved are poorly understood. To investigate how severe hypoglycemia can be fatal, hyperinsulinemic, severe hypoglycemic (10–15 mg/dL) clamps were performed in Sprague-Dawley rats with simultaneous electrocardiogram monitoring. With goals of reducing hypoglycemia-induced mortality, the hypotheses tested were that: 1) antecedent glycemic control impacts mortality associated with severe hypoglycemia; 2) with limitation of hypokalemia, potassium supplementation could limit hypoglycemia-associated deaths; 3) with prevention of central neuroglycopenia, brain glucose infusion could prevent hypoglycemia-associated arrhythmias and deaths; and 4) with limitation of sympathoadrenal activation, adrenergic blockers could prevent hypoglycemia-induced arrhythmic deaths. Severe hypoglycemia–induced mortality was noted to be worsened by diabetes, but recurrent antecedent hypoglycemia markedly improved the ability to survive an episode of severe hypoglycemia. Potassium supplementation tended to reduce mortality. Severe hypoglycemia caused numerous cardiac arrhythmias including premature ventricular contractions, tachycardia, and high-degree heart block. Intracerebroventricular glucose infusion reduced severe hypoglycemia–induced arrhythmias and overall mortality. β-Adrenergic blockade markedly reduced cardiac arrhythmias and completely abrogated deaths due to severe hypoglycemia. Under conditions studied, sudden deaths caused by insulin-induced severe hypoglycemia were mediated by lethal cardiac arrhythmias triggered by brain neuroglycopenia and the marked sympathoadrenal response. PMID:23835337

Photo-activated disinfection based on indocyanine green against cell viability and biofilm formation of Porphyromonas gingivalis.

PubMed

Pourhajibagher, Maryam; Chiniforush, Nasim; Ghorbanzadeh, Roghayeh; Bahador, Abbas

2017-03-01

Photo-activated disinfection (PAD) is a novel treatment approach, in which bacteria in the root canal system may be exposed to sub-lethal doses of PAD. Such exposure can affect bacterial survival and virulence features, such as biofilm formation ability. The aim of this study was to evaluate the effects of sub-lethal doses of PAD (sPAD) using indocyanine green (ICG) on load and biofilm formation ability of Porphyromonas gingivalis as an anaerobic bacterium associated with endodontic infection. The anti-bacterial and anti-biofilm potential of sPAD against P. gingivalis at sub-lethal doses of ICG as a photosensitizer and using 810nm wavelength of diode laser light via colony forming unit and crystal violet assays, respectively, was determined. High concentrations of ICG and light irradiation time significantly reduced bacteria. High doses of sPAD markedly reduced the number of bacteria and the formation of biofilm, up to 30.4% and 25.1%, respectively. High doses of sPAD affected cell viability and the biofilm formation ability of P. gingivalis; lower doses did not. Thus, selection of appropriate PAD dosage should be considered for the successful treatment of endodontic in vivo. Copyright © 2016 Elsevier B.V. All rights reserved.

Insecticidal activity of garlic essential oil and their constituents against the mealworm beetle, Tenebrio molitor Linnaeus (Coleoptera: Tenebrionidae).

PubMed

Plata-Rueda, Angelica; Martínez, Luis Carlos; Santos, Marcelo Henrique Dos; Fernandes, Flávio Lemes; Wilcken, Carlos Frederico; Soares, Marcus Alvarenga; Serrão, José Eduardo; Zanuncio, José Cola

2017-04-20

This study evaluated the insecticidal activity of garlic, Allium sativum Linnaeus (Amaryllidaceae) essential oil and their principal constituents on Tenebrio molitor. Garlic essential oil, diallyl disulfide, and diallyl sulfide oil were used to compare the lethal and repellent effects on larvae, pupae and adults of T. molitor. Six concentrations of garlic essential oil and their principal constituents were topically applied onto larvae, pupae and adults of this insect. Repellent effect and respiration rate of each constituent was evaluated. The chemical composition of garlic essential oil was also determined and primary compounds were dimethyl trisulfide (19.86%), diallyl disulfide (18.62%), diallyl sulfide (12.67%), diallyl tetrasulfide (11.34%), and 3-vinyl-[4H]-1,2-dithiin (10.11%). Garlic essential oil was toxic to T. molitor larva, followed by pupa and adult. In toxic compounds, diallyl disulfide was the most toxic than diallyl sulfide for pupa > larva > adult respectively and showing lethal effects at different time points. Garlic essential oil, diallyl disulfide and diallyl sulfide induced symptoms of intoxication and necrosis in larva, pupa, and adult of T. molitor between 20-40 h after exposure. Garlic essential oil and their compounds caused lethal and sublethal effects on T. molitor and, therefore, have the potential for pest control.

Insecticidal activity of garlic essential oil and their constituents against the mealworm beetle, Tenebrio molitor Linnaeus (Coleoptera: Tenebrionidae)

PubMed Central

Plata-Rueda, Angelica; Martínez, Luis Carlos; Santos, Marcelo Henrique Dos; Fernandes, Flávio Lemes; Wilcken, Carlos Frederico; Soares, Marcus Alvarenga; Serrão, José Eduardo; Zanuncio, José Cola

2017-01-01

This study evaluated the insecticidal activity of garlic, Allium sativum Linnaeus (Amaryllidaceae) essential oil and their principal constituents on Tenebrio molitor. Garlic essential oil, diallyl disulfide, and diallyl sulfide oil were used to compare the lethal and repellent effects on larvae, pupae and adults of T. molitor. Six concentrations of garlic essential oil and their principal constituents were topically applied onto larvae, pupae and adults of this insect. Repellent effect and respiration rate of each constituent was evaluated. The chemical composition of garlic essential oil was also determined and primary compounds were dimethyl trisulfide (19.86%), diallyl disulfide (18.62%), diallyl sulfide (12.67%), diallyl tetrasulfide (11.34%), and 3-vinyl-[4H]-1,2-dithiin (10.11%). Garlic essential oil was toxic to T. molitor larva, followed by pupa and adult. In toxic compounds, diallyl disulfide was the most toxic than diallyl sulfide for pupa > larva > adult respectively and showing lethal effects at different time points. Garlic essential oil, diallyl disulfide and diallyl sulfide induced symptoms of intoxication and necrosis in larva, pupa, and adult of T. molitor between 20–40 h after exposure. Garlic essential oil and their compounds caused lethal and sublethal effects on T. molitor and, therefore, have the potential for pest control. PMID:28425475

Population-level effects of fitness costs associated with repressible female-lethal transgene insertions in two pest insects

PubMed Central

Harvey-Samuel, Tim; Ant, Thomas; Gong, Hongfei; Morrison, Neil I; Alphey, Luke

2014-01-01

Genetic control strategies offer great potential for the sustainable and effective control of insect pests. These strategies involve the field release of transgenic insects with the aim of introducing engineered alleles into wild populations, either permanently or transiently. Their efficacy can therefore be reduced if transgene-associated fitness costs reduce the relative performance of released insects. We describe a method of measuring the fitness costs associated with transgenes by analyzing their evolutionary trajectories when placed in competition with wild-type alleles in replicated cage populations. Using this method, we estimated lifetime fitness costs associated with two repressible female-lethal transgenes in the diamondback moth and olive fly as being acceptable for field suppression programs. Furthermore, using these estimates of genotype-level fitness costs, we were able to project longer-term evolutionary trajectories for the transgenes investigated. Results from these projections demonstrate that although transgene-associated fitness costs will ultimately cause these transgenes to become extinct, even when engineered lethality is repressed, they may persist for varying periods of time before doing so. This implies that tetracycline-mediated transgene field persistence in these strains is unlikely and suggests that realistic estimates of transgene-associated fitness costs may be useful in trialing ‘uncoupled’ gene drive system components in the field. PMID:24944572