The number of adult gerontology acute care nurse practitioners is increasing, as well as the number of patients requiring care in the northern Nevada region. The specialty training of adult gerontology nurse practitioners (AGACNPs) enables them to provide care for the increasing number of patients in the acute setting. Unfortunately, there are perceived barriers that inhibit the implementation of AGACNP into practice within this region. There is a need to understand the barriers to use of AGACNPs and provide feedback to organizational leaders throughout the region. Purpose and Objective: While many studies show the benefits of adding AGACNPs or nurse practitioners in general to an organization, there is a need for further literature on the evidence of the barriers to AGACNP use. This study attempts to identify those barriers, specifically looking into the northern Nevada region. Methods: A survey was sent out to 19 hospital and critical care group administrators in the northern Nevada region. There was an attempt made for phone interviews, if the survey was not completed during the allotted timeframe. The survey consisted of both quantitative and qualitative questions that were used to identify potential barriers influencing AGACNP role use. Results: Out of the 19 surveys sent out, six surveys were returned. A total of six surveys from six different organizations were completed for this study. Five of the six respondents do not currently have any AGACNPs within their organizations and the one that did use AGACNPs had less than 10. Four out of six respondents reported confusion on scope of practice as a current barrier to use within their organization. Conclusions: This survey helps AGACNPs understand the barriers to use within the northern Nevada region when looking for an acute care job. For the organizations in the northern Nevada region, there is a need for organizational education regarding the scope of practice of AGACNPs and how to utilize them within their organization, as well as create an effective collaborative practice model for their acute care organization.

The aim was to identify diagnostic difficulties for acute abdominal pain at the emergency department and during hospital stay. A total of 3349 patients admitted to Mora Hospital with acute abdominal pain of up to seven days duration, were registered prospectively for history and clinical signs according to a structured schedule. The preliminary diagnosis from the attending physician at the emergency department, any investigations or surgery and final diagnosis were registered at a follow-up after at least one year. There were no differences in diagnostic performance between physicians with 0.5 to 5 years of medical experience. The information collected and a careful examination of the patient was more important than formal competence. The main differential diagnostic problem was non-specific abdominal pain; this was the same for diagnoses requiring surgery. Patients originally diagnosed as not needing surgery had a median delay before operation of 22 hours (mean 40 hours, with 95% confidence interval of 30-50 hours), compared to 8 hours (mean 15 hours, 95% confidence interval of 12-28 hours) for patients with the same final follow-up diagnosis as the preliminary diagnosis. Constipation was a diagnostic pitfall, as 9% of the patients considered constipated required surgery for potentially life threatening reasons and 8% were later found to have an abdominal malignancy. Both the preliminary diagnosis and the discharge diagnosis were less reliable for elderly patients than for younger patients. Elderly patients often had specific organ disease and arrived at the emergency department after a longer history of abdominal pain. This study confirms that assessment of suspected appendicitis can still be based on clinical judgements combined with laboratory tests. Classical clinical findings indicating localised inflammation, such as isolated pain in the right iliac fossa, rebound tenderness, right-sided rectal tenderness, pain migration to the right iliac fossa, local guarding and aggravation of pain when moving, were reliable for predicting acute appendicitis. A CT scan can be saved for the more equivocal cases of acute abdominal pain. A generous strategy regarding CT scan among elderly patients with acute abdominal pain, even in the absence of pronounced signs of an inflammatory intra-abdominal process, is recommended.

Despite high remission rate in acute myeloid leukaemia (AML) after chemotherapy, relapse of the underlying disease remains a major challenge and one of the most frequent causes of treatment failure. In this study, the presence of leukaemiaassociated phenotypes (LAPs) was first studied retrospectively using our standard diagnostic protocol with 3-colour flow cytometry. LAPs were present in 54 (64%) of 84 AML patients analysed between 2002 to 2004. The presence of LAPs was correlated with failure to respond to induction chemotherapy (p <0.05) in univariate analysis. Presence of LAPs was shown to be an independent predictor for failure to respond to induction chemotherapy with a relative risk ratio of 1.6 (p < 0.05, 95% CI, 1.0-2.6) in multivariate analysis. Subsequently, in a prospective study, we used 5-colour multiparametric flow cytometry (MFC) for detection of LAPs to determine if LAPs could be detected in a greater proportion of leukaemic patients and minimal residual disease (MRD) detection could therefore be applied in more patients. In 54 consecutive, newly diagnosed AML patients from 2005 to 2007, LAPs were identified in 51 (94%). Thus, MRD studies were potentially applicable to virtually all patients. The sensitivity and specificity of MFC technique was improved by analysing 10 normal and 5 regenerating bone marrows (BM) for the presence of these LAPs and by determining maximum log difference (LD). CD7, CD19, CD2, CD11b and CD56 were the most sensitive and reliable markers for MRD studies. LAPs were rarely detected in either normal or regenerating BMs. Through dilutional experiments from 50% LAPs to 0.001%, it was determined that 1 leukaemic in 104 and 105 normal cells could be detected using the improved techniques. Of the 54 patients, 31 received chemotherapy, with 27 achieving complete remission (CR). Two were LAP negative and thus 25 were evaluable for MRD post induction and 22-post consolidation chemotherapy. Detection of MRD >0.15% was able to distinguish between two groups of patients according to relapse status. Although, the number of patients was small, detection of MRD post induction > 0.15% was shown to be an independent predictor of adverse prognosis for both relapse free survival (RFS) and overall survival (OS) in a multivariate analysis [p = 0.037 and 0.026, 95% CI (1.1-20.5 and 1.2-22.2), hazard ratio 4.7 and 5.2 respectively]. Post consolidation, there was a trend for patients with higher MRD values to show shorter RFS (p = 0.06). MFC using 5-colour allows us to detect LAPs in virtually all AML patients and our preliminary results suggest the technique is a suitable approach for MRD analysis. However, 5-colour MFC is technically challenging, resource intensive, and may not be feasible in a routine diagnostic laboratory. This led us to assess whether we could identify other potential markers for LAPs. Interleukin-3 alpha receptor- chain IL-3_ (CD123) has been suggested to be a marker of leukaemic stem cells (LSC). These cells are thought to be responsible for initiating and maintaining leukaemic cell growth post chemotherapy and hence to give rise to relapse of the disease. Therefore, we analysed 34 AML patients for expression of CD123 in the blast population and defined a population containing leukaemic stem cells using the immunophenotypic markers CD123+/CD34+/CD38-. Thirty-two (94%) of AML patients expressed CD123. We then used a molecular marker to determine whether CD123 expression was confined to the LSC. Thirtynine patients were screened for the presence of FMS-like tyrosine kinase 3 - internal tandem duplication (FLT3/ITD) as the most common molecular abnormality in AML patients. Of those, 12 (31%) were FLT3/ITD positive. In seven of them, CD34+/CD38-/CD123+ and CD34+/CD38-/CD123- populations were sorted to homogeneity by Fluorescence Activated Cell Sorting (BD FACSAriaTM Cell Sorter) and tested for FLT3/ITD. In six of seven patients with FLT3/ITD positive AML, we could not detect the mutation in the CD34+/CD38-/CD123- fraction, but the mutation was detected in the CD34+/CD38-/CD123+ fraction in all seven patients. This novel finding demonstrates that, the oncogenic event occurs in CD123 positive cells, thus supporting the concept that CD123 is a marker of the LSC in CD123 positive AML. This observation suggests novel treatment approaches employing surface marker CD123-targeting antibodies may be of use in the treatment of AML. In conclusion, we demonstrate that using five-colour MFC improves LAP detection in AML and enables MRD studies using immunophenotyping to be applied to virtually all AML patients. Additionally, it increases the sensitivity of the technique for detecting LAP populations. Moreover, evaluation of MRD post induction chemotherapy is the most sensitive time point for detection of MRD, with MRD levels >0.15% predicting relapse and worse prognosis. As an alternative to using individualised LAPs specific to each patient, CD34+/CD38-/CD123+ cells may in the future serve as a better marker for MRD studies. This marker identifies the putative LSC, which is responsible for regrowth of leukaemia and relapse of the disease. Thus, instead of looking at whole “blast” population which results in huge data analysis and interpretation for the different LAPs which may have different underlying biology, it may be more informative to look at the frequency of LSC after achieving CR using CD34+/CD38-/CD123+ as the single LAP for MRD studies. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1317088 / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2008

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Thematic Paper (M.C.T.M. (Clinical Tropical Medicine))--Mahidol University, 2008. / LICL has E-Thesis 0038 ; please contact computer services. LIRV has E-Thesis 0038 ; please contact circulation services.

Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2012-07-30T18:14:04Z No. of bitstreams: 1 Maria Brandão Tavares Insufuciencia renal aguda em pacientes....pdf: 663822 bytes, checksum: 274b01e71441d9fca8554368ed006f32 (MD5) / Made available in DSpace on 2012-07-30T18:14:04Z (GMT). No. of bitstreams: 1 Maria Brandão Tavares Insufuciencia renal aguda em pacientes....pdf: 663822 bytes, checksum: 274b01e71441d9fca8554368ed006f32 (MD5) Previous issue date: 2011 / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, Bahia, Brasil / A insuficiência renal aguda é comum em pacientes com síndrome nefrótica, podendo requerer terapia de substituição renal e ser irreversível. A insuficiência renal aguda nesses pacientes pode ser precipitada por processos infecciosos, hipovolemia, drogas nefrotóxicas; entretanto na maioria dos casos a etiologia não é identificada e a insuficiência renal aguda é considerada idiopática. A necrose tubular aguda foi associada à insuficiência renal aguda em adultos com lesão mínima. O objetivo deste estudo é avaliar a correlação entre a necrose tubular aguda definida histologicamente com insuficiência renal aguda em pacientes com doença glomerular. Biópsias renais de pacientes com glomerulopatia foram analisadas quanto à intensidade da necrose tubular aguda e esses dados correlacionados com os dados clínicos e presença de insuficiência renal aguda. A análise foi realizada em duas amostras e a intensidade de necrose tubular aguda graduada de duas formas: na primeira amostra a intensidade de necrose tubular aguda foi graduada em cinco níveis de intensidade; na segunda amostra foi feita uma estimativa em percentual da área da cortical acometida. A acurácia da análise semiquantitativa na primeira amostra foi avaliada por meio da correlação com análise morfométrica relativa ao número de túbulos com características necróticas por área de cortical (Spearman r=0,88, P<0,0001) e ao percentual de área da cortical com necrose tubular aguda (Spearman r=0,93, P<0,0001). A reprodutibilidade da análise intraobservador foi regular (kappa=0,53, P<0,0001). A primeira amostra constou de 149 casos com idade média de 21±16 anos. A síndrome nefrótica esteve presente em 104 (72%) pacientes e os principais diagnósticos foram: doenças do espectro Lesão Mínima – Glomeruesclerose Segmentar e Focal (45%). Necrose tubular aguda foi observada em 114 (77%) pacientes. insuficiência renal aguda foi diagnosticada em 43 (42%) pacientes. Houve correlação positiva entre a intensidade da necrose tubular aguda e a presença de insuficiência renal (gamma=0,70, P<0,0001). A segunda amostra foi composta por 80 pacientes com idade média 32 ± 18 anos. Síndrome nefrótica foi diagnosticada em 72 (90%) casos e os principais diagnósticos foram as doenças do espectro lesão mínima-Glomeruloesclerose segmentar e focal (54, 68%). Necrose tubular aguda foi observada em 60 (75%) pacientes e insuficiência renal aguda foi diagnosticada em 28 (35%) casos. A intensidade de necrose tubular aguda foi maior nos pacientes com (29,1 ± 27,7) que nos pacientes sem insuficiência renal aguda (5.4 ± 5.1, P<0,0001). A presença de necrose tubular aguda apresentou alta especificidade para diagnóstico de insuficiência renal aguda quando estimada em 10% da cortical representada (especificidade 96,1%, curva ROC [AUC=0,832, P<0,0001]). Não houve diferença entre os grupos com e sem insuficiência renal aguda em relação ao sexo, proteinúria, doença renal e albumina sérica, colesterol e triglicérides. A freqüência de hipertensão arterial sistêmica foi maior no grupo com insuficiência renal aguda com idade mais elevada (P=0,015). / Acute renal failure is common in patients with nephrotic syndrome and may require substitutive renal therapy and be irreversible. Acute renal failure in these patients may be precipitated by infection, hypovolemia and nephrotoxic drugs. However, in most cases the etiology of acute renal failure is not identified and the condition is considered idiopathic. Acute tubular necrosis was associated with acute renal failure in adults with minimal change disease. The aim of this study is to estimate the association between the histologically defined acute tubular necrosis with acute renal failure in patients with glomerular disease. Renal biopsies of patients with renal disease were analyzed for the intensity of acute tubular necrosis and these data correlated with the clinical data incouding presence of acute renal failure. The analysis was performed on two samples and the intensity of acute tubular necrosis was estimated in two ways: in the first sample the intensity of acute tubular necrosis was graded into five levels of intensity, in the second sample an estimate was made of the percentage of cortical area affected by acute tubular necrosis. The accuracy of the semiquantitative analysis in the first sample was evaluated by correlation with morphometric estimate of the number of necrotic tubules in a given cortical area (Spearman r = 0.88, P <0.0001) and the percentage of cortical area with acute tubular necrosis (Spearman r = 0.93, P <0.0001). The intraobserver reproducibility of the analysis was fair (kappa = 0.53, P <0.0001). The first sample consisted of 149 cases with mean age of 21 ± 16 years. Nephrotic syndrome was present in 104 (72%) and the main diagnoses were: disease spectrum Minimal Change - Focal and Segmental glomerulosclerosis (45%). Acute tubular necrosis was observed in 114 (77%) patients. Acute renal failure was diagnosed in 43 (42%) patients. There was a positive correlation between the intensity of tubular necrosis and acute renal failure (gamma = 0.70, P <0.0001). The second sample consisted of 80 patients with mean age of 32 ± 18 years. Nephrotic syndrome was diagnosed in 72 (90%) and the main diagnoses were diseases of the spectrum, Minimal Change-Focal and segmental glomerulosclerosis (54, 68%). Acute tubular necrosis was observed in 60 (75%) patients and acute renal failure was diagnosed in 28 (35%). The intensity of acute tubular necrosis was higher in patients with (29 ± 8) than in patients without acute renal failure (5 ± 5, P <0.0001). The presence of acute tubular necrosis showed high specificity for diagnosis of acute renal failure when 10% of represented cortical had necrotic tubules (96.1% specificity, ROC curve [AUC = 0.832, P <0.0001]). No difference between groups with or without acute renal failure was observed in relation to gender, proteinuria, kidney disease and serum albumin, cholesterol and triglycerides. The frequency of hypertension was higher in patients with acute renal failure with higher age (P = 0.015).

nÃo hà / O estudo tem por objetivo revisar o diagnÃstico de enfermagem (DE) Dor aguda em pacientes hospitalizados com infarto agudo do miocÃrdio (IAM). Estudo metodolÃgico de validaÃÃo de diagnÃsticos de enfermagem, desenvolvido em trÃs etapas fundamentadas no modelo de Hoskins (1989): anÃlise de conceito de dor aguda, validaÃÃo por especialistas e validaÃÃo clÃnica. Na primeira etapa utilizaram-se o modelo de Walker e Avant (2005) e a revisÃo integrativa conforme Whittemore; Knafl (2005) a partir da busca em periÃdicos indexados, por meio do acesso nas bases de dados CINHAL, SCOPUS e PUBMED, de estudos publicados sobre dor aguda no infarto agudo do miocÃrdio no perÃodo de 2006 a 2012. Para a busca nas bases de dados utilizou-se o vocabulÃrio MeSH â Medical Subject Headings of U.S National Library of Medicine e o DeCS â Descritores em CiÃncias da SaÃde em lÃngua inglesa e espanhola: acute pain; myocardial infarction e dolor agudo, el infarto miocardio. Para a busca nas trÃs bases de dados e cruzamento dos descritores utilizou-se o operador booliano âANDâ. Para ampliar a busca empregou-se o cruzamento: âacute painâ and âmyocardial infarctionâ. Aplicados os critÃrios de inclusÃo e exclusÃo, restaram 29 estudos. Encontraram-se quatro atributos crÃticos essenciais para a compreensÃo do conceito dor aguda no infarto agudo do miocÃrdio: qualidade (constrictiva, opressiva, pressÃo, aperto e peso, sensaÃÃo de esmagamento, tÃpica isquÃmica, dilacerante e triturante); localizaÃÃo (regiÃo retroesternal, subesternal, torÃcica, do lado esquerdo do peito, centro do esterno emeio do peito, peito direito); tempo e duraÃÃo (inÃcio sÃbito, prolongada com duraÃÃo de 15 a 30 minutos, recorrente e intermitente); irradiaÃÃo (pescoÃo, ombro esquerdo, mandÃbula, regiÃo interescapular, braÃo direito e esquerdo, costas, estÃmago, abdome, epigastro, pulso braquial e radial esquerdo). Foram identificadas 14 caracterÃsticas definidoras(CDs) na anÃlise de conceito, das quais oito encontraram correspondÃncia no DE Dor aguda da NANDA-I. Elaborou-se um instrumento com a definiÃÃo construÃda na anÃlise de conceito, a constante na NANDA-I e as 14 CDs e respectivas definiÃÃes conceituais e referÃncias empÃricas identificadas. Submeteu-se esse instrumento ao crivo de 22 especialistas em terminologias de enfermagem e/ou dor aguda e/ou infarto agudo do miocÃrdio. Dos especialistas (54,54%) optaram pela definiÃÃo resultante da anÃlise de conceito. ApÃs o julgamento, recomenda-se, alÃm das oito CDs identificadas na NANDA-I, o acrÃscimo de mais seis CDs ao DE Dor aguda identificadas na anÃlise de conceito: Dispneia; Fraqueza; Fadiga; NÃusea; VÃmito e Palidez. As 14 CDs analisadas e validadas por especialistas foram testadas na prÃtica clÃnica, por meio de um estudo transversal realizado com 125 pacientes com diagnÃstico de IAM. Os achados mostraram que Relato de dor aguda, Diaforese, Fadiga, Palidez e Fraqueza, sÃo bons indicadores da ocorrÃncia do diagnÃstico de enfermagem Dor aguda no infarto agudo do miocÃrdio. As CDs PressÃo sanguÃnea elevada, DistÃrbio do sono, FrequÃncia cardÃaca elevada, FrequÃncia respiratÃria elevada, DispnÃia, NÃusea, VÃmito, Ansiedade e Medo nÃo foram indicadores satisfatÃrios do diagnÃstico em estudo. Portanto, cinco CDs demonstraram-se conforme a anÃlise de conceito, validaÃÃo por especialistas e validaÃÃo clÃnica, apropriadas para avaliar o DE Dor aguda em pacientes com IAM. / The objective of the study was the nursing diagnosis validation (ND) of Acute Pain of patient with Acute Myocardial Infarction (AMI). Methodological study developed in three stages of nursing diagnosis validation, found by the Hoskins model (1989): concept analysis, validation by specialists and clinical validation. In the first stage were Walker and Avant model (2005) and Whittemore; Knafl (2005) integrative review from the indexed journal search by the CINHAL, SCOPUS and PUBMED database access of studies published in the period between 2006 and 2012. The Pubmed and Cinahl database search used the indicated terminology, the MeSH â Medical Subject Headings of U.S National Library of Medicine English vocabulary. The Scopus database had DeCS â Descriptors Health Science structure vocabulary. To identify the different uses of acute concept, there was a study survey with the controlled descriptors Acute Pain and Myocardial Infarction in English language and Dolor Agudo and Infarto Miocardio in Spanish language. In the three databases search descriptorÂs crossing we used the Boolean operator âANDâ. âAcute painâ and âmyocardial infarctionâ enlarge the crossing search. After applying the exclusion and inclusion criteria, 29 studies remained (from 535). There were four essential critical characteristics to understand acute pain concept. They are quality (constrictive, oppressive, pressure, tightness and weight, crushing feeling, typical ischemic, heartbreaking and grinding); location (retrosternal region, substernal, chest, the left side of the chest, sternum and through the center of the chest, right chest); time length (sudden onset, prolonged lasting 15 to 30 minutes, recurrent and intermittent); irradiation (neck, left shoulder, jaw, interscapular region, right and left arm, back, stomach, abdomen, epigastrium, left radial and brachial pulse). For the Acute Pain ND, NANDA-I presents 18 defined characteristics (DCs) identifying eight in the concept analysis adequate for Acute Pain diagnosis in AMI patients. Besides these ones, we found six more, in 15 DCs. There were elaboration of an instrument with the concept analysis definition, the constant NANDA-I and 14 DCs and their conceptual definitions and identified empiric references. Twenty-two specialists studied this instrument in nursing terminology and/or acute pain and/or acute myocardial infarction. From them (54,54%) they opted concept analysis definition. After appreciation, there were recommendation of the eight DCs identified in the NANDA-I and six new DCs for the ND Acute pain identified in the concept analysis. They were dyspnea; weakness; fatigue; nausea; Vomiting and paleness. The specialist tested in the clinical practice the 14 analyzed and validated DCs, through a transversal study done with 125 patients with AMI diagnosis. The findings showed that the acute pain, Diaphoresis, Fatigue, Paleness and Weakness are good indicators of the Acute Pain nursing diagnosis. The Elevated Blood Pressure, Sleep Disturbance, Elevated Heart Rate, Elevated Respiratory Rate, Dyspnea, Nausea, Vomiting, Anxiety and Fear DCs, were not satisfactory indicators of the study diagnosis. Therefore, five DCs were according to concept analysis, specialist validation and clinical validation, right to evaluate the Acute Pain ND in AMI patients.

Treatment of acute myeloid leukemia, an aggressive hematopoietic malignancy of myeloid progenitors, has remained rather stagnant over the course of several decades. Infusions of cytarabine and anthracycline antibiotics have dominated the landscape of AML therapy, with minor changes to dosing schedule occasionally making slight adjustments to efficacy or tolerability. Improvements in prognosis have been bittersweet, with most progress seen in younger populations less likely to get the disease, and already more likely to achieve remission and to meet survival milestones. Much of this progress is attributed to other factors, such as improved supportive care and availability of hematopoietic stem cell and platelet transfusion. In most patients, occupying the 60-and-above demographic, improvements in survival have not been significant. In turn, the population impact of AML has changed little over time. While accounting for about one-third of total leukemia cases and one percent of total cancer cases, AML accounts for about one half of total leukemia deaths and two percent of total cancer deaths. Most advances straying away from standard treatment have been in important pathways that could be impactful in subsets of the overall AML patient population. Tyrosine kinases are implicated in numerous cancers including AML, with activity-enhancing mutations conferring growth advantages to malignant cells. About one-third of AML patients have mutations in one such kinase, FLT3, and may benefit from inhibitors to tyrosine kinases overall and from FLT3- specific agents. Mutations in isocitrate dehydrogenases highlight another subpopulation, about one-fifth of AML patients, who might benefit from emerging agents that inhibit these pathways from creating a leukemia-favoring environment in the bone marrow. Other pathways similarly implicated in numerous cancers including AML are being targeted with new agents that can benefit some AML patients, such as Hedgehog signaling and apoptotic regulation. Still, breakthroughs are needed that can help most AML patients, particularly in the cases of relapsed leukemia that occurs in most patients within a year or two after remission is achieved. CD33 is among a few molecular targets for AML, though it is just as ubiquitously expressed on healthy myeloid cells. Antibody-drug conjugates like Mylotarg have made progress in this approach, though hematopoietic toxicities have made treatment difficult in older populations. Clever techniques such as ablation of CD33 from healthy myeloid progenitors may be supportive in CD33-based approaches, and immunotherapy involving CD33-targeting is a rapidly growing research focus. This dissertation describes a new type of bispecific antibody that binds CD33 on AML and CD3 on cytotoxic T cells in a proof-of-concept study. Various formats for bifunctional molecules have been created and used clinically, including antibody-drug conjugates and bispecific antibodies that simultaneously engage antigens on two different types of cells. Those like the one described here, bispecific T-cell engagers, have typically taken the form of single-chain fusion proteins containing the variable regions binding to both antigens of interest. Other bispecific antibodies have imitated naturally-occurring immunoglobulin structures, boasting superior pharmacokinetics while facing steep obstacles in large-scale production. The single-chain fusions, easier to produce, can face difficulties in full engagement, with loss of function sometimes seen in fusion partners at the C-terminus. We propose a new format, believed to present two antigen-binding domains in N-terminal positions on a two-chain heterodimeric structure. Capitalizing on an elegantly designed system of hydrophobic cores and hydrogen-bonding networks generating an orthogonal heterodimer, we added an immunoglobulin hinge region to secure a permanently-bound heterodimer, and attached domains binding to CD3 and CD33. We hypothesized that this design, ensured to present its antibody components at N-termini, could bind two antigens at a distance appropriate for facilitating T cell cytotoxicity to AML. After expressing and purifying these proteins in mammalian cells, we demonstrated their ability to persist as a bispecific heterodimer. We showed in vitro that our bispecific heterodimers could bind both CD3+ and CD33+ cells, and that they bolstered T cell cytotoxicity to AML cell lines in a dose-dependent manner. Monomeric components bound only CD3+ or CD33+ cells depending on antibody variable domain present, and had no effect on T cell cytotoxicity. In a mouse model of minimal residual disease, T cells alone did not have a significant effect on the growth of AML, nor did they have an effect on overall survival. T cells with bispecific heterodimer greatly extended survival, and mice of this treatment group were free of leukemia. These findings suggest that this format for bispecific proteins allows for robust simultaneous engagement with both antigens of interest in a manner conducive to T cell cytotoxicity against AML. We believe this presents a compelling modular system for bispecific antibodies, where CD3- and CD33-binding domains can be readily swapped with domains binding to other cancer- or immune cell-specific antigens, and can be further developed into a trispecific system engaging other immune cells or extending half-life with anti-albumin or Fc domains.

In agreement with previous work, adult rats given selective lesions to dopamine (DA)-containing neurons as neonates exhibited a greater behavioral sensitization to repeated phencyclidine (PCP) treatment in comparison to sham-lesioned controls. Acute administration of olanzapine (1-5 mg/kg ip) or clozapine (15 mg/kg ip) decreased sensitized PCP-induced activity in both lesioned and control animals. Acute haloperidol (0.5 mg/kg ip) had no impact on PCP responsiveness in lesioned animals, but significantly antagonized PCP effects in sham-lesioned controls. Ketanserin, a selective 5-HT 2A/5-HT2C-receptor antagonist, significantly reduced PCP activation in both lesioned and control rats, suggesting that the efficacy of atypical antipsychotics against PCP-induced sensitized responses may be mediated by one of the 5-HT2-receptor subtypes. A 6-week chronic regimen of orally administered olanzapine, clozapine, or haloperidol failed to block the sensitization induced by repeated PCP exposure. However, a 10-month oral olanzapine treatment significantly blunted the behavioral sensitization to repeated PCP exposure in lesioned animals, even after withdrawal from chronic olanzapine for more than 3 weeks. A 10-month oral haloperidol treatment had no effect on the sensitization induced by repeated PCP dosing. The persistent effect of chronic olanzapine administration on PCP sensitization may be relevant to the chronic therapeutic efficacy of atypical antipsychotics treating schizophrenia - a clinical syndrome linked to enhanced sensitivity to N-methyl-D-aspartate (NMDA)-receptor antagonists.

What is known and objective: Amiodarone, a commonly used class III antiarrhythmic agent notable for a relatively long half-life of up to 6 months and its pronounced adverse effect profile, is used for both acute and chronic management of cardiac arrhythmias. Chronic use of amiodarone has been associated with asymptomatic hepatotoxicity; however, acute toxicity is thought to be uncommon. There are only six reported cases of acute liver failure (ALF) secondary to amiodarone. In all these cases the outcome of death during the same hospitalization resulted. We aimed to report the only case of acute liver failure secondary to amiodarone infusion in the existing literature where the patient survived. Case summary: A 79-year-old woman admitted with atrial flutter was being treated with intravenous (IV) amiodarone when she abruptly developed coagulopathy, altered mental status and liver enzyme derangement. She was diagnosed with acute liver failure (ALF) secondary to an amiodarone adverse drug reaction, with a calculated score of seven on the Naranjo adverse drug reaction probability scale. Amiodarone was immediately withheld, and N-acetylcysteine (NAC) was initiated. Clinical improvement was seen within 48 hours of holding the drug and within 24 hours of initiating NAC. On post-hospital follow-up visit she was reported to have complete recovery. What is new and conclusion: This report emphasizes the importance of monitoring liver enzymes and mental status while a patient is being administered IV amiodarone. N-acetylcysteine administration may have possibly contributed to the early and successful recovery from ALF in our patient. To date, she is the only patient in the existing literature who has been reported to survive ALF secondary to amiodarone administration.