Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 62
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Biometals ; 36(2): 241-253, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-35138503

RESUMO

Obesity enhances the risk of type-2 diabetes, cardiovascular disease and inflammatory conditions and often leads to metal dyshomeostasis, which contributes to the negative health aspects associated with the disease. In severe cases, bariatric surgery can be recommended to achieve sustained weight loss and improvement in health. Here, magnesium, zinc, copper and selenium concentrations were examined in 24 obese patients (7 males; 17 females) before and 9 months after undergoing Roux-en-Y gastric bypass surgery. All patients lost weight over this period, with the mean BMI reducing from 51.2±7.1 kg/m2 to 37.2±5.5 kg/m2. Moreover, whole-blood glycated haemoglobin (HbA1c), as a marker of average glycaemia, was also measured and a correlative analysis of this parameter with metal concentrations performed. Significant alterations in the plasma concentrations of magnesium, zinc (both increased by 13.2% and 25.2% respectively) and copper (decreased by 7.9%) were observed over this period (plasma selenium concentration was unchanged), with BMI values correlating with plasma magnesium (p = 0.004) and zinc (p = 0.022) concentrations. At 9 months post-surgery, an increase in mean zinc/copper ratio was observed (0.86±0.29 compared to 0.63±0.14 pre-surgery). Comparison of whole-blood HbA1c concentrations pre- and post-surgery revealed a reduction from 6.50±1.28% pre-surgery to 5.51±0.49% post-surgery. Differences in plasma HbA1c and magnesium at either pre- and post-surgery correlated significantly, as did HbA1c and magnesium levels when pre- and post-surgery values were analysed together. Collectively, this work reveals that bariatric surgery, in conjunction with lifestyle/dietary changes, lead to improvements in the nutritional status of magnesium, zinc and copper. Furthermore, the observed improvements in magnesium and zinc were associated with weight loss and in the case of magnesium, to better glycaemic control.


Assuntos
Cirurgia Bariátrica , Selênio , Masculino , Feminino , Humanos , Magnésio , Cobre , Zinco , Hemoglobinas Glicadas , Obesidade/cirurgia , Redução de Peso
2.
BMC Infect Dis ; 21(1): 580, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34134647

RESUMO

BACKGROUND: COVID-19 has resulted in significant morbidity and mortality worldwide. Lateral flow assays can detect anti-Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) antibodies to monitor transmission. However, standardized evaluation of their accuracy and tools to aid in interpreting results are needed. METHODS: We evaluated 20 IgG and IgM assays selected from available tests in April 2020. We evaluated the assays' performance using 56 pre-pandemic negative and 56 SARS-CoV-2-positive plasma samples, collected 10-40 days after symptom onset, confirmed by a molecular test and analyzed by an ultra-sensitive immunoassay. Finally, we developed a user-friendly web app to extrapolate the positive predictive values based on their accuracy and local prevalence. RESULTS: Combined IgG + IgM sensitivities ranged from 33.9 to 94.6%, while combined specificities ranged from 92.6 to 100%. The highest sensitivities were detected in Lumiquick for IgG (98.2%), BioHit for both IgM (96.4%), and combined IgG + IgM sensitivity (94.6%). Furthermore, 11 LFAs and 8 LFAs showed perfect specificity for IgG and IgM, respectively, with 15 LFAs showing perfect combined IgG + IgM specificity. Lumiquick had the lowest estimated limit-of-detection (LOD) (0.1 µg/mL), followed by a similar LOD of 1.5 µg/mL for CareHealth, Cellex, KHB, and Vivachek. CONCLUSION: We provide a public resource of the accuracy of select lateral flow assays with potential for home testing. The cost-effectiveness, scalable manufacturing process, and suitability for self-testing makes LFAs an attractive option for monitoring disease prevalence and assessing vaccine responsiveness. Our web tool provides an easy-to-use interface to demonstrate the impact of prevalence and test accuracy on the positive predictive values.


Assuntos
Anticorpos Antivirais/sangue , Teste Sorológico para COVID-19/métodos , COVID-19/diagnóstico , Imunoglobulina G/sangue , Imunoglobulina M/sangue , SARS-CoV-2/imunologia , Adulto , Idoso , COVID-19/sangue , Feminino , Humanos , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Sensibilidade e Especificidade , Design Centrado no Usuário , Interface Usuário-Computador
3.
Am J Emerg Med ; 40: 32-36, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33340875

RESUMO

OBJECTIVE: Advanced Trauma Life Support guidelines recommend only 1 L of intravenous (IV) crystalloid before transitioning to blood products. We sought to determine if receiving >1 L of IV crystalloid during the initial resuscitation is associated with worse outcomes. We also sought to determine if receiving no crystalloids is associated with better outcomes. METHODS: We performed a single center retrospective study using trauma registry data, which was supplemented by manual chart review. We only included patients who had an initial heart rate ≥ 100 beats/min or a systolic blood pressure ≤ 90 mmHg. For each patient, we determined the total amount of IV crystalloid administered in the first 3 h after arrival to the hospital plus prehospital crystalloid. We performed multivariate regression analyses to determine if there is an association between the administration of >1 L of crystalloids or no crystalloids with in-hospital mortality, hospital length of stay (LOS), or packed red blood cells (PRBCs) transfused. RESULTS: Between January 1, 2018 and September 30, 2019, there were 878 who met criteria for enrollment. Among those, 55.0% received ≤1 L of IV crystalloids, and 45.0% received >1 L. Multivariate analyses showed no significant association between receiving >1 L and mortality (p = 0.61) or PRBCs transfused (p = 0.29), but patients who received >1 L had longer hospital LOS (p = 0.04). We found no association between receiving no crystalloids and mortality, PRBCs transfused, or LOS. CONCLUSION: On a multivariate analysis of trauma patients, we did not find an association between the administration of >1 L of IV crystalloid and in-hospital mortality or the volume of PRBCs transfused. However, receiving >1 L of crystalloids was associated with a longer hospital LOS. We found no benefit to completely withholding crystalloids.


Assuntos
Soluções Cristaloides/administração & dosagem , Ressuscitação/métodos , Centros de Traumatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transfusão de Eritrócitos , Feminino , Mortalidade Hospitalar , Humanos , Infusões Intravenosas , Escala de Gravidade do Ferimento , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Nevada , Sistema de Registros , Estudos Retrospectivos , Resultado do Tratamento
4.
Chemistry ; 24(18): 4710-4717, 2018 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-29377331

RESUMO

Gas-phase activation of CO2 by chloride tagged metal atoms, [ClM]- (M=Mg, Zn), has been investigated by mass spectrometry and high-level quantum chemistry. Both metals activate CO2 with significant bending of the CO2 moiety to form complexes with the general formula [ClM,CO2 ]- . The structure of the metal-CO2 complex depends on the method of formation, and the energy landscapes and reaction dynamics have been probed by collisional induced dissociation and thermal ion molecule reactions with isotopically labeled species. Having established these structural relationships, the gas-phase reactivity of [ClM(κ2 -O2 C)]- with acetaldehyde (here considered a carbohydrate mimic) was then studied. Formation of lactate and enolate-pyruvate complexes are observed, showing that CO2 fixation by C-C bond formation takes place. For M=Zn, even formation of free pyruvate ([C3 H3 O3 ]- ) is observed. Implications of the observed CO2 reactivity for the electrochemical conversion of carbon dioxide, and to biochemical and artificial photosynthesis is briefly discussed. Detailed potential energy diagrams obtained by the quantum chemical calculations offer models consistent with experimental observation.

5.
Org Biomol Chem ; 15(32): 6813-6825, 2017 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-28782776

RESUMO

Three deprotonated 2-oxocarboxylic acids, glyoxylate, pyruvate, and 2-oxobutyrate (RCOCO2-, R = H, CH3, CH3CH2) have been associated with MgCl2 and ZnCl2 to generate [RCOCO2MCl2]- (M = Mg, Zn) complexes. Upon collision-induced dissociation these complexes all undergo efficient eliminations of CO2 and CO, via an intermediate [RCOMCl2]- product, to ultimately give [RMCl2]- products. The pyruvate and 2-oxobutyrate complexes also undergo efficient elimination of HCl to produce the enolate-metal complexes [H2C[double bond, length as m-dash]COCO2MCl]- and [H3CHC[double bond, length as m-dash]COCO2MCl]-. These enolate complexes have binding motifs reminiscent of the active centres in some CO2-fixating enzymes and the CO2 reactivity of these enolate complexes was therefore investigated, but only adduct formation could be observed. Quantum chemical calculations predict the magnesium complexes to decarboxylate without reverse barriers to carboxylation, and the zinc complexes to decarboxylate with considerable reverse barriers. The subsequent CO loss occurs with reverse barriers in all cases. The HCl loss is also predicted to occur overall without reverse barriers for both metals.

6.
Bull Environ Contam Toxicol ; 98(2): 257-261, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27995294

RESUMO

Temperature is a major environmental factor influencing land surface volatilization at the time of agricultural field fumigation. Cooler fumigation soil temperatures relevant to Pacific Northwest (PNW) application practices with metam sodium/potassium should result in appreciably reduced methyl isothiocyanate (MITC) emission rates, thus minimizing off target movement and bystander inhalation exposure. Herein, a series of laboratory controlled flow-through soil column assessments were performed evaluating MITC emissions over the range of cooler temperatures (2-13°C). Assessments were also conducted at the maximum allowed label application temperature of 32°C. All assessments were conducted at registration label-specified field moisture capacity, and no more than 50% cumulative MITC loss was observed over the 2-day post-fumigation timeframe. Three-fold reductions in MITC peak fluxes at cooler PNW application temperatures were observed compared to the label maximum temperature. This study supports current EPA metam sodium/potassium label language that indicates surface fumigations during warmer soil conditions should be discouraged.


Assuntos
Fumigação , Isotiocianatos/análise , Poluentes do Solo/análise , Solo/química , Temperatura , Noroeste dos Estados Unidos
8.
Angew Chem Int Ed Engl ; 53(52): 14407-10, 2014 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-25348666

RESUMO

A magnesium complex incorporating a novel metal-CO2 binding motif is spectroscopically identified. Here we show with the help of infrared photodissociation spectroscopy that the complex exists solely in the [ClMg(η(2) -O2 C)](-) form. This bidentate double oxygen metal-CO2 coordination has previously not been observed in neutral nor in charged unimetallic complexes. The antisymmetric CO2 stretching mode in [ClMg(η(2) -O2 C)](-) is found at 1128 cm(-1) , which is considerably redshifted from the corresponding mode in bare CO2 at 2349 cm(-1) , suggesting that the CO2 moiety has a considerable negative charge (∼1.8 e(-) ). We also employed electronic structure calculations and kinetic analysis to support the interpretation of the experimental results.

9.
J Immunol Methods ; 533: 113742, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39153729

RESUMO

Stability of conjugated critical reagents supporting ligand binding assays to enable biotherapeutic drug development is a universal concern. Formulation buffer employed for long-term cold storage may be key to mitigate protein aggregation issues. We investigated biophysical and functional attributes of murine mAb and human multispecific drug labeled with biotin, ruthenium, and Alexa fluor 647 frozen at -80 °C in PBS or a protein storage buffer for 3-15 months. Aggregation was observed at 4 months in mAb A-Ru (11.2%) and -Alexa (10%) in PBS followed by precipitation and reduced biological binding at 15 months. Increased aggregation in drug Ru (11.7%, 6 months) and Alexa (6.9%, 15 months) were noted but without impact on performance. There were no observations with biotin labeled reagents.


Assuntos
Anticorpos Monoclonais , Soluções Tampão , Humanos , Animais , Anticorpos Monoclonais/química , Camundongos , Biotina/química , Estabilidade de Medicamentos , Agregados Proteicos , Rutênio/química , Estabilidade Proteica
10.
Cureus ; 16(5): e59540, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38826949

RESUMO

Appendiceal mucinous neoplasms (AMNs) are uncommon gastrointestinal tumors characterized by mucus accumulation in the appendix. Patients may complain of acute appendicitis-like symptoms with other alarming features, but approximately half of the cases of AMNs are found incidentally on imaging. Early diagnosis and management of these neoplasms are important to prevent malignant progression and complications such as bowel obstruction and pseudomyxoma peritonei. We report a case of a 28-year-old female who initially presented with vomiting and acute left lower abdominal pain radiating to the left flank. Computed tomography (CT) revealed a 1.5 mm stone in the left ureteral vesicular junction and a 2.3 x 2.4 x 5.2 cm cystic tubular mass at the base of the cecum, suspicious of an appendiceal mucocele. An elective laparoscopic appendectomy was performed on this admission, which was converted to a right hemicolectomy due to the pathologic finding of a focally high-grade AMN on intraoperative frozen specimen pathology. This report aims to provide an example of a case of an incidental AMN and how it was diagnosed and managed surgically. AMNs are rare tumors that originate from the appendix and can pose diagnostic and therapeutic challenges due to their diverse clinical presentations and variable histopathological features. The majority of cases of AMNs are discovered in middle-aged individuals (40-50 years of age) after an appendectomy is performed and examined by pathology. This case report aims to describe a rare presentation of a 28-year-old female patient with an incidental finding of AMN on a CT scan of the abdomen while being worked up for suspected nephrolithiasis. We will provide a comprehensive overview of a unique presentation of AMN, highlighting its clinical manifestations, diagnostic approach, and management strategies. We present the case of a 28-year-old female patient who presented to the emergency department with complaints of acute left lower quadrant abdominal pain radiating to the left flank and vomiting. After an initial assessment and workup, which included lab investigations and imaging, a diagnosis of unilateral hydronephrosis due to a calculus of the ureterovesical junction was made. However, there was also suspicion of an appendiceal mucocele, as evidenced by a CT scan of the abdomen and pelvis. On admission day one, under the care and management of the urology team, she passed the stone with complete resolution of the presenting symptoms. On hospital day two, she underwent an elective laparoscopic appendectomy followed by a right hemicolectomy due to findings of high-grade mucinous neoplasm on the resected frozen specimen near the base of the appendix. AMN was an incidental finding based on CT imaging and macroscopic findings, which was later confirmed by histopathological assessment and report.

11.
Genet Med ; 15(8): 630-8, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23448725

RESUMO

PURPOSE: We examined hospital use of the epidermal growth factor receptor assay in patients with lung cancer in the United States. Our goal was to inform the development of a model to predict phase 3 translation of guideline-directed molecular diagnostic tests. METHODS: This was a retrospective observational study. Using logistic regression, we analyzed the association between hospitals' institutional and regional characteristics and the likelihood that an epidermal growth factor receptor assay would be ordered. RESULTS: Significant institutional predictors included affiliation with an academic medical center (odds ratio, 1.48; 95% confidence interval, 1.20-1.83), participation in a National Cancer Institute clinical research cooperative group (odds ratio, 2.06, 1.66-2.55), and -availability of positron emission tomography scan (odds ratio, 1.44, 1.07-1.94) and cardiothoracic surgery (odds ratio, 1.90, 1.52-2.37) services. Significant regional predictors included metropolitan county (odds ratio, 2.08, 1.48-2.91), population with above-average education (odds ratio, 1.46, 1.09-1.96), and population with above-average income (odds ratio, 1.46, 1.04-2.05). Distance from a National Cancer Institute cancer center was a negative predictor (odds ratio, 0.996, 0.995-0.998), with a 34% decrease in likelihood for every 100 miles. CONCLUSION: In 2010, only 12% of US acute-care hospitals ordered the epidermal growth factor receptor assay, suggesting that most patients with lung cancer did not have access to this test. This case study illustrated the need for: (i) increased dissemination and implementation research, and (ii) interventions to improve adoption of guideline-directed molecular diagnostic tests by community hospitals.


Assuntos
Receptores ErbB/genética , Testes Genéticos/estatística & dados numéricos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Técnicas de Diagnóstico Molecular/estatística & dados numéricos , Estudos Transversais , Atenção à Saúde , Receptores ErbB/análise , Genômica , Guias como Assunto , Humanos , Modelos Logísticos , Mutação , Estudos Retrospectivos , Pesquisa Translacional Biomédica , Estados Unidos
12.
Phys Chem Chem Phys ; 15(39): 16615-25, 2013 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-23959262

RESUMO

On the basis of mass spectrometric experiments and quantum chemical calculations, including detailed kinetic and dynamics calculations, we report the unimolecular dissociation of an isolated glycolate anion. The dominating processes are: loss of formaldehyde; loss of carbon monoxide; loss of carbon dioxide; and loss of a hydrogen molecule, with the latter having the lowest energetic threshold. At higher energies, CO loss is the dominating reaction. The loss of CO may be followed by a second CO loss, leading to the H(-)H2O complex in close mechanistic relationship to the Nibbering reaction. The results provide valuable insights into possible mechanisms for interstellar and prebiotic formation of glycolate via the reverse of the unimolecular dissociation reactions. We propose that the addition of the complex of OH(-) and CO to CH2O is the most feasible route to gas phase synthesis of glycolate, since all species are abundant in interstellar space.


Assuntos
Glicolatos/química , Teoria Quântica , Meio Ambiente Extraterreno , Gases , Transição de Fase
13.
Blood Press ; 22(3): 131-7, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23244451

RESUMO

It is well established that hypertension and obesity appear to be associated. The exact mechanism by which they are linked is unclear and remains a topic of a great deal of research. Current NICE guidelines recommend that patients with a BMI in excess of 35 kg/m(2) should be considered for bariatric surgery if they have a concomitant obesity-associated condition, of which hypertension is one. The commonest bariatric procedure in the UK is the Roux-en-Y gastric bypass, which has been shown to result in long-standing remission of hypertension in up to 93% of patients. This paper summarizes the existing literature on the main theories as to how obesity leads to hypertension as well as the literature concerning the effects of gastric bypass surgery on hypertension.


Assuntos
Derivação Gástrica/métodos , Hipertensão/etiologia , Obesidade/complicações , Obesidade/cirurgia , Índice de Massa Corporal , Derivação Gástrica/efeitos adversos , Humanos
14.
Postgrad Med J ; 89(1053): 411-6; quiz 415, 416, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23472004

RESUMO

Obesity has become an increasingly important health problem over the past 30 years. Presently around a quarter of the UK adult population are obese and this figure is set to increase further in the coming decades. The health consequences of obesity on multiple body systems have been well established as has the financial cost of the condition to both the individuals affected as well as to society as a whole. Bariatric surgery has been shown to be the only long term effective solution in terms of sustained weight loss and comorbidity resolution. The commonest bariatric procedure in the UK is the Roux-en-y gastric bypass which consistently results in the loss of 70%-80% of excess bodyweight. Results however are variable and in order to optimise resource allocation and avoid exposing patients unlikely to benefit from surgery to its inherent risks, much research has been done to try to identify those patients most likely to obtain a good result. The only factor which has been subjected to meta-analysis is that of preoperative weight loss which shows a positive association with postoperative weight loss following bypass surgery. Although the remaining data are not based on level 1 evidence those other preoperatively identifiable factors which are associated with an improved outcome include Caucasian or Hispanic ethnicity, higher educational status, non-shift-work working patterns, female gender and divorced or single marital status. Similarly increased levels of preoperative physical activity and an absence of binge eating behaviour are consistent with a favourable result whereas increased age, smoking and other socioeconomic factors have not been shown to have a significant impact. Conversely diabetes mellitus seems to have a slight negative correlation with postoperative weight loss; however, a history of sexual abuse or psychiatric illness has not been shown to have a lasting influence.


Assuntos
Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Derivação Gástrica/métodos , Obesidade Mórbida/epidemiologia , Obesidade Mórbida/cirurgia , Período Pré-Operatório , Fumar/epidemiologia , Redução de Peso , Adulto , Índice de Massa Corporal , Comorbidade , Transtornos da Alimentação e da Ingestão de Alimentos/complicações , Feminino , Derivação Gástrica/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Atividade Motora , Período Pós-Operatório , Valor Preditivo dos Testes , Valores de Referência , Fumar/efeitos adversos , Fatores Socioeconômicos , Resultado do Tratamento , Reino Unido/epidemiologia
15.
Teach Learn Med ; 25(3): 242-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23848332

RESUMO

BACKGROUND: The subinternship is an integral part of the 4th year of medical school. There is little description of innovations aimed at assessing the preparedness and confidence of graduating students as they move on the next step in their training. DESCRIPTION: An innovation including an Objective Structured Clinical Examination (OSCE) at the conclusion of the subinternship was designed. We focused on key themes of transitions of care, communication within the health care system, and communication with patients and providers. EVALUATION: A pre- and postsurvey addressed student self-perceived skill, confidence, and overall perception of importance. Improvement (p<.05) was seen across all themes from pre- to postsurvey, with more favorable scores on the postsurvey. CONCLUSIONS: A subinternship innovation including an OSCE was feasible and had a positive effect on student assessment, perception and confidence. As the landscape of medical education evolves, assessing students' preparedness for residency will become increasingly imperative.


Assuntos
Competência Clínica , Comunicação , Educação de Graduação em Medicina/normas , Avaliação Educacional/métodos , Adulto , Feminino , Humanos , Internato e Residência , Masculino , Inovação Organizacional
16.
PLoS One ; 18(5): e0284537, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37205680

RESUMO

While most studies on floral hemp (Cannabis sativa L.) concur that additions of nitrogen (N) increase plant growth, the performance of floral hemp is heavily influenced by environmental conditions, management and cultivar selection. In regions with a short growing season, the availability of soil N may determine plant developmental rates, final inflorescence biomass and cannabinoid concentrations, but no studies have addressed this for field-grown hemp under high-desert conditions. This field study evaluated the effect of no supplemental N and N fertilization at 90 kg ha-1 on three hemp cultivars (Berry Blossom, Red Bordeaux, and Tahoe Cinco) in Northern Nevada. N increased plant height, canopy cover, stem diameter and shoot biomass, but other physiological parameters were dependent on cultivar. For instance, inflorescence biomass and inflorescence-to-shoot ratio in Red Bordeaux was not affected by N fertilization. Similarly, cannabinoid concentrations were affected by timing of harvest and cultivar but not by N treatment. We evaluated the use of a SPAD meter for ease of determining leaf N deficiency, and correlations with leaf chlorophyll content showed that the SPAD meter was a reliable tool in two cultivars but not in Tahoe Cinco. N treatment increased overall CBD yield, which was driven by increases in inflorescence biomass. Tahoe Cinco was the best CBD yielding cultivar, as it maintained a high inflorescence-to-shoot ratio regardless of N treatment. Our study suggests that even though hemp may have a positive response to soil N management, adjustments based on genotype by environment interaction should be aimed at maximizing cannabinoid yield either by increasing biomass and/or CBD concentrations as long as THC levels are within the permissible <0.3% for U.S. industrial hemp cultivation.


Assuntos
Canabinoides , Cannabis , Cannabis/genética , Nitrogênio/farmacologia , Solo , Fertilização
17.
Anticancer Drugs ; 23(2): 173-84, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22027537

RESUMO

Palifosfamide, the DNA-alkylating metabolite of ifosfamide (IFOS), has been synthesized as a stabilized tris or lysine salt and found to have preclinical and clinical antitumor activity. Stabilized palifosfamide overcomes limitations of IFOS because of patient-to-patient variability in response resulting from variable prodrug activation, resistance and toxicities of metabolic byproducts, acrolein and chloroacetaldehyde. Palifosfamide represents an effective alternative to IFOS and other DNA-alkylating prodrugs. The antitumor activities of stabilized palifosfamide were investigated in vivo. Dose response, route and schedule of administration, and interaction with docetaxel or doxorubicin were investigated in NCr-nu/nu mice bearing established orthotopic mammary MX-1 tumor xenografts. Oral activity was investigated in P388-1 leukemia in CD2F1 mice. Oral and intraperitoneal bioavailabilities were compared in Sprague-Dawley rats. Stabilized palifosfamide administered by optimized regimens suppressed MX-1 tumor growth (P<0.05) by greater than 80% with 17% complete antitumor responses and up to three-fold increase in time to three tumor doublings over controls. Median survival in the P388-1 (P<0.001) model was increased by 9 days over controls. Oral bioavailability in rats was 48-73% of parenteral administration, and antitumor activity in mice was equivalent by both routes. Treatment with palifosfamide-tris combined with docetaxel or doxorubicin at optimal regimens resulted in complete tumor regression in 62-75% of mice. These studies support investigation of stabilized palifosfamide in human cancers by parenteral or oral administration as a single agent and in combination with other approved drugs. The potential for clinical translation of the cooperative interaction of palifosfamide-tris with doxorubicin by intravenous administration is supported by results from a recent randomized Phase-II study in unresectable or metastatic soft-tissue sarcoma.


Assuntos
Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Ifosfamida/análogos & derivados , Leucemia Experimental/tratamento farmacológico , Lisina/análogos & derivados , Neoplasias Mamárias Experimentais/tratamento farmacológico , Mostardas de Fosforamida/uso terapêutico , Taxoides/uso terapêutico , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Disponibilidade Biológica , Intervalo Livre de Doença , Docetaxel , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Ifosfamida/administração & dosagem , Ifosfamida/farmacocinética , Ifosfamida/uso terapêutico , Injeções Intravenosas , Lisina/administração & dosagem , Lisina/farmacocinética , Lisina/uso terapêutico , Masculino , Camundongos , Camundongos Nus , Mostardas de Fosforamida/administração & dosagem , Mostardas de Fosforamida/farmacocinética , Ratos , Ratos Sprague-Dawley , Taxoides/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Surg Res ; 175(2): 298-304, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21737100

RESUMO

BACKGROUND: The hepatic acute phase response(APR) is an organ-specific response to a diverse array of insults and is largely under transcriptional control. Liver-specific transcription factors, hepatic nuclear factors (HNFs)-1α and 4α play important roles in maintenance of liver phenotype and function and their binding activity changes early after injury. However, their roles in modulation of the liver's response over time are not defined. MATERIALS AND METHODS: C57/BL6 mice were anesthetized and exposed to 95°C water for 10 s to create a 15% body surface area full-thickness burn. At specific time points, the mice were sacrificed. An ELISA for IL-6 was performed on serum and hepatic mRNA levels for fibrinogen-γ and serum amyloid A(SAA)-3 were obtained through polymerase chain reaction (PCR). Transcriptional factor binding activity was assessed with electrophoretic mobility shift assays. RESULTS: Serum IL-6 levels peaked at 3 h and fibrinogen-γ and SAA mRNA levels increased more than 6-fold at 12 h before returning to control levels at 48 h. The binding activity of HNF-4α and HNF-1α rapidly declined after injury (1.5 h) but recovered to near control level at 24 and 6 h, respectively. CONCLUSIONS: Changes in HNF-4α and HNF-1α binding occurred before changes in acute phase protein mRNA levels and were preceded by the peak in IL-6 levels. The rapid suppression and reconstitution of liver-specific transcription factor binding after injury may represent a mechanism that allows the normal liver phenotype to change and an injury-response phenotype to prevail. This mechanism in the liver's adaptive response to injury suggests a central role for both HNF-4α and HNF-1α in transcriptional regulation of the hepatic APR.


Assuntos
Reação de Fase Aguda/etiologia , Reação de Fase Aguda/metabolismo , Queimaduras/complicações , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Fator 4 Nuclear de Hepatócito/metabolismo , Fígado/metabolismo , Animais , Fibrinogênio/metabolismo , Regulação da Expressão Gênica , Interleucina-6/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , RNA Mensageiro/metabolismo , Proteína Amiloide A Sérica/metabolismo
19.
Front Microbiol ; 13: 910156, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35783392

RESUMO

During the first few months of the global Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic, the medical research community had to expeditiously develop, select, and deploy novel diagnostic methods and tools to address the numerous testing challenges presented by the novel virus. Integrating a systematic approach to diagnostic selection with a rapid validation protocol in a clinical setting can shorten the timeline to bring new technologies to practice. In response to the urgent need to provide tools for identifying SARS-CoV-2-positive individuals, we developed a framework for assessing technologies against a set of prioritized performance metrics to guide device selection. We also developed and proposed clinical validation frameworks for the rapid screening of new technologies. The rubric described here represents a versatile approach that can be extended to future technology assessments and can be implemented in preparation for future emerging pathogens.

20.
Am J Trop Med Hyg ; 107(4): 845-849, 2022 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-35970285

RESUMO

Early detection of SARS-CoV-2 infection is crucial to prevent its spread. This study aimed to document test sensitivity/specificity, correlation with cycle threshold value from polymerase chain reaction (PCR), fitness-for-use in different populations and settings, and user perspectives that could inform large-scale implementation. In this study, we evaluated the performance of a rapid antigen detection test, BD Veritor, and compared this (and another rapid test, Standard Q) against reverse transcription PCR (RT-PCR) in terms of sensitivity and specificity in 130 symptomatic and 130 asymptomatic adults. In addition, we evaluated the suitability and ease of use of the BD Veritor test in a subsample of study participants (n = 42) and implementers (n = 5). At 95% confidence interval, the sensitivity of the BD Veritor and Standard Q test were 70% and 63% in symptomatic and 87% and 73% in asymptomatic individuals, respectively, regarding positive SARS-CoV-2 RT-PCR results. Overall, the BD Veritor test was 78% sensitive and 99.5% specific compared with RT-PCR irrespective of the cycle threshold. This warrants large field evaluation as well as use of the rapid antigen test for quick assessment of SARS-CoV-2 for containment of epidemics in the country.


Assuntos
COVID-19 , SARS-CoV-2 , Adulto , Antígenos Virais , Bangladesh/epidemiologia , COVID-19/diagnóstico , Teste para COVID-19 , Humanos , Sensibilidade e Especificidade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA