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INTRODUCTION: Upper gastrointestinal bleeding (UGIB) is an important complication among critically ill adults, especially those having cardiac surgery as management is complicated by the requirement for antiplatelet/anticoagulant therapy. As a result, stress ulcer prophylaxis (SUP) has become routine practice in many centers, utilizing either proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H2RBs). Recent evidence from the PEPTIC trial indicated an increase in mortality risk among cardiac surgery patients receiving PPIs compared to H2RBs. Considering these findings, alongside practical difficulties surrounding the transition to H2RBs as a prophylactic agent in New Zealand, Wellington Hospital intensive care unit elected to discontinue routine PPI use for SUP in cardiac surgery patients. A retrospective study was conducted to assess patient outcomes following the discontinuation of routine SUP. METHOD: A retrospective cohort study was conducted of all adult patients who underwent cardiac surgery at Wellington Hospital between February/2018 and January/2022, and divided patients into cohorts before and after the discontinuation of routine use of SUP on the 31st of January 2020. The primary outcomes were the rate of UGIB, oesophagogastroduodenoscopy (OGD) and 180-day postoperative mortality. Secondary outcomes included rates of postoperative Clostridium difficile enteritis, pneumonia, deep sternal wound infection, and length of stay of the index admission. RESULTS: The rate of UGIB statistically significantly increased since the cessation of routine SUP in January 2020 (2.4% vs 5.4%, P-value = .004). This finding was mirrored with the increased rates of OGD (1.9% vs 4.0%, P-value = .005). There were no significant changes in 180-day mortality, hospital length of stay, or any of the postoperative infective complications analyzed, pneumonia, deep sternal wound infection, or C difficile enteritis. CONCLUSION: This study suggests an association between routine use of SUP and reduced rates of clinically significant UGIB and OGD requirements in cardiac surgery patients without increasing risk of infective complications or postoperative mortality.
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Procedimientos Quirúrgicos Cardíacos , Enteritis , Úlcera Péptica , Neumonía , Úlcera Gástrica , Adulto , Humanos , Estudios Retrospectivos , Úlcera/inducido químicamente , Úlcera/complicaciones , Úlcera/tratamiento farmacológico , Antagonistas de los Receptores H2 de la Histamina/uso terapéutico , Úlcera Péptica/prevención & control , Úlcera Péptica/cirugía , Úlcera Péptica/complicaciones , Úlcera Gástrica/prevención & control , Inhibidores de la Bomba de Protones/uso terapéutico , Hemorragia Gastrointestinal/prevención & control , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Neumonía/tratamiento farmacológico , Enteritis/inducido químicamente , Enteritis/complicaciones , Enteritis/tratamiento farmacológico , Enfermedad Crítica/terapiaRESUMEN
AIM: To determine the effects of RVX-208, a selective bromodomain and extra-terminal domain (BET) inhibitor targeting bromodomain 2 (BD2), on periodontal inflammation and bone loss. MATERIALS AND METHODS: Macrophage-like cells (RAW264.7) and human gingival epithelial cells were challenged by Porphyromonas gingivalis (Pg) with or without RVX-208. Inflammatory gene expression and cytokine production were measured by reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RAW264.7 cells were induced to osteoclast differentiation. After RVX-208 treatment, osteoclast differentiation was evaluated by histology, tartrate-resistant-acid-phosphatase (TRAP) activity and the expression of osteoclast-specific genes. The effect of RVX-208 on osteoclast transcriptome was studied by RNA sequencing. Periodontitis was induced in rats by ligature and local RVX-208 treatment was administered every other day. Alveolar bone loss was measured by micro-computed tomography. RESULTS: RVX-208 inhibited inflammatory gene expression and cytokine production in Pg-infected cells. Osteoclast differentiation was inhibited by RVX-208, as evidenced by reduced osteoclast number, TRAP activity and osteoclast-specific gene expression. RVX-208 displayed a more selective and less profound suppressive impact on transcriptome compared with pan-BET inhibitor, JQ1. RVX-208 administration prevented the alveolar bone loss in vivo. CONCLUSIONS: RVX-208 regulated both upstream (inflammatory cytokine production) and downstream (osteoclast differentiation) events that lead to periodontal tissue destruction, suggesting that it may be a promising 'epi-drug' for the prevention of periodontitis.
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Pérdida de Hueso Alveolar , Periodontitis , Ratas , Humanos , Animales , Pérdida de Hueso Alveolar/tratamiento farmacológico , Pérdida de Hueso Alveolar/prevención & control , Pérdida de Hueso Alveolar/patología , Microtomografía por Rayos X , Inflamación/tratamiento farmacológico , Periodontitis/tratamiento farmacológico , Periodontitis/prevención & control , Periodontitis/patología , Osteoclastos , CitocinasRESUMEN
Bacillus anthracis and Yersinia pestis, causative pathogens for anthrax and plague, respectively, along with Burkholderia mallei and B. pseudomallei are potential bioterrorism threats. Tebipenem pivoxil hydrobromide (TBP HBr, formerly SPR994), is an orally available prodrug of tebipenem, a carbapenem with activity versus multidrug-resistant (MDR) gram-negative pathogens, including quinolone-resistant and extended-spectrum-ß-lactamase-producing Enterobacterales. We evaluated the in vitro activity and in vivo efficacy of tebipenem against biothreat pathogens. Tebipenem was active in vitro against 30-strain diversity sets of B. anthracis, Y. pestis, B. mallei, and B. pseudomallei with minimum inhibitory concentration (MIC) values of 0.001 - 0.008 µg/ml for B. anthracis, ≤0.0005 - 0.03 µg/ml for Y. pestis, 0.25 - 1 µg/ml for B. mallei, and 1 - 4 µg/ml for B. pseudomallei In a B. anthracis murine model, all control animals died within 52 h post challenge. The survival rates in the groups treated with tebipenem were 75% and 73% when dosed at 12 h and 24 h post challenge, respectively. The survival rates in the positive control groups treated with ciprofloxacin were 75% and when dosed 12 h and 25% when dosed 24 h post challenge, respectively. Survival rates were significantly (p=0.0009) greater in tebipenem groups treated at 12 h and 24 h post challenge and in the ciprofloxacin group 12 h post-challenge vs. the vehicle-control group. For Y. pestis, survival rates for all animals in the tebipenem and ciprofloxacin groups were significantly (p<0.0001) greater than the vehicle-control group. These results support further development of tebipenem for treating biothreat pathogens.
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Marfan syndrome (MFS) is an autosomal dominant genetic disorder caused by mutations in the FBN1 gene. Although many peripheral tissues are affected, aortic complications, such as dilation, dissection and rupture, are the leading causes of MFS-related mortality. Aberrant TGF-beta signalling plays a major role in the pathophysiology of MFS. However, the contributing mechanisms are still poorly understood. Here, we aimed at identifying novel aorta-specific pathways involved in the pathophysiology of MFS. For this purpose, we employed the Fbn1 under-expressing mgR/mgR mouse model of MFS. We performed RNA-sequencing of aortic tissues of 9-week-old mgR/mgR mice compared with wild-type (WT) mice. With a false discovery rate <5%, our analysis revealed 248 genes to be differentially regulated including 20 genes previously unrelated with MFS-related pathology. Among these, we identified Igfbp2, Ccl8, Spp1, Mylk2, Mfap4, Dsp and H19. We confirmed the expression of regulated genes by quantitative real-time PCR. Pathway classification revealed transcript signatures involved in chemokine signalling, cardiac muscle contraction, dilated and hypertrophic cardiomyopathy. Furthermore, our immunoblot analysis of aortic tissues revealed altered regulation of pSmad2 signalling, Perk1/2, Igfbp2, Mfap4, Ccl8 and Mylk2 protein levels in mgR/mgR vs WT mice. Together, our integrative systems approach identified several novel factors associated with MFS-aortic-specific pathophysiology that might offer potential novel therapeutic targets for MFS.
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Aorta Torácica/metabolismo , Proteínas Portadoras/genética , Proteínas de la Matriz Extracelular/genética , Fibrilina-1/genética , Glicoproteínas/genética , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Síndrome de Marfan/genética , Osteopontina/genética , Animales , Aorta Torácica/fisiopatología , Proteínas Portadoras/metabolismo , Quimiocina CCL8/genética , Quimiocina CCL8/metabolismo , Desmoplaquinas/genética , Desmoplaquinas/metabolismo , Modelos Animales de Enfermedad , Proteínas de la Matriz Extracelular/metabolismo , Fibrilina-1/deficiencia , Regulación de la Expresión Génica , Ontología de Genes , Glicoproteínas/metabolismo , Humanos , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Síndrome de Marfan/metabolismo , Síndrome de Marfan/fisiopatología , Ratones , Ratones Transgénicos , Anotación de Secuencia Molecular , Quinasa de Cadena Ligera de Miosina/genética , Quinasa de Cadena Ligera de Miosina/metabolismo , Osteopontina/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Transducción de Señal , Proteína Smad2/genética , Proteína Smad2/metabolismo , Biología de Sistemas/métodos , eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismoRESUMEN
The latest Zika virus (ZIKV) pandemic caused great international concern from explosively proliferating throughout the Americas. Currently, there is no vaccine to prevent Zika virus infection and available tests rely on antibodies or RNA. Unfortunately, antibody-based detection systems can result in false positive results and RNA-based detection systems are costly, time-consuming, and impractical for testing in remote regions. In this study, a potential point-of-care (POC) diagnostic system was developed using a chip-based potentiometric sensor to detect Zika virus using a 3D molecular imprinting technique. This chip-based potentiometric sensor system was able to detect 10-1 PFU mL-1 ZIKV in a buffered solution under 20 minutes without any sample manipulation. This sensor was tested against Dengue virus at clinical viral loads and showed no sign of cross-reactivity. When tested against human saliva samples containing clinical viral loads, this sensor was able to detect 10 PFU mL-1 ZIKV among the pool of bio-macromolecules. The high sensitivity and high selectivity demonstrated here proved that this lab-on-a-chip diagnostic has the potential to become a POC detection system for rapid and accurate screening of flaviviruses.
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Técnicas Electroquímicas/métodos , Dispositivos Laboratorio en un Chip , Virus Zika/aislamiento & purificación , Adsorción , Técnicas Electroquímicas/instrumentación , Oro/química , Límite de Detección , Impresión Molecular/métodos , Pruebas en el Punto de Atención , Sensibilidad y Especificidad , Virus Zika/química , Infección por el Virus Zika/diagnósticoRESUMEN
A novel series of EP4 agonists and antagonists have been identified, and then used to validate their potential in the treatment of inflammatory pain. This paper describes these novel ligands and their activity within a number of pre-clinical models of pain, ultimately leading to the identification of the EP4 partial agonist GSK726701A.
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Antiinflamatorios/química , Isoindoles/química , Subtipo EP4 de Receptores de Prostaglandina E/agonistas , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/uso terapéutico , Células Sanguíneas/citología , Células Sanguíneas/efectos de los fármacos , Células Sanguíneas/metabolismo , Dinoprostona/química , Dinoprostona/uso terapéutico , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Concentración 50 Inhibidora , Isoindoles/farmacocinética , Isoindoles/uso terapéutico , Lipopolisacáridos/farmacología , Dolor/tratamiento farmacológico , Dolor/patología , Dolor/veterinaria , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Ratas , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Derepression of DUX4 in skeletal muscle has emerged as a likely cause of pathology in facioscapulohumeral muscular dystrophy (FSHD). Here we report on the use of antisense phosphorodiamidate morpholino oligonucleotides to suppress DUX4 expression and function in FSHD myotubes and xenografts. The most effective was phosphorodiamidate morpholino oligonucleotide FM10, which targets the polyadenylation signal of DUX4. FM10 had no significant cell toxicity, and RNA-seq analyses of FSHD and control myotubes revealed that FM10 down-regulated many transcriptional targets of DUX4, without overt off-target effects. Electroporation of FM10 into FSHD patient muscle xenografts in mice also down-regulated DUX4 and DUX4 targets. These findings demonstrate the potential of antisense phosphorodiamidate morpholino oligonucleotides as an FSHD therapeutic option.
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Silenciador del Gen , Terapia Genética , Proteínas de Homeodominio/genética , Morfolinos/genética , Distrofia Muscular Facioescapulohumeral/genética , Animales , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Marcación de Gen , Xenoinjertos , Secuenciación de Nucleótidos de Alto Rendimiento , Proteínas de Homeodominio/metabolismo , Humanos , Ratones , Morfolinos/administración & dosificación , Fibras Musculares Esqueléticas , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Distrofia Muscular Facioescapulohumeral/metabolismo , Distrofia Muscular Facioescapulohumeral/patología , Distrofia Muscular Facioescapulohumeral/terapia , TranscriptomaRESUMEN
OBJECTIVE: Studies of mice with mild Marfan syndrome (MFS) have correlated the development of thoracic aortic aneurysm (TAA) with improper stimulation of noncanonical (Erk-mediated) TGFß signaling by the angiotensin type I receptor (AT1r). This correlation was largely based on comparable TAA modifications by either systemic TGFß neutralization or AT1r antagonism. However, subsequent investigations have called into question some key aspects of this mechanism of arterial disease in MFS. To resolve these controversial points, here we made a head-to-head comparison of the therapeutic benefits of TGFß neutralization and AT1r antagonism in mice with progressively severe MFS (Fbn1(mgR/mgR) mice). APPROACH AND RESULTS: Aneurysm growth, media degeneration, aortic levels of phosphorylated Erk and Smad proteins and the average survival of Fbn1(mgR/mgR) mice were compared after a ≈3-month-long treatment with placebo and either the AT1r antagonist losartan or the TGFß-neutralizing antibody 1D11. In contrast to the beneficial effect of losartan, TGFß neutralization either exacerbated or mitigated TAA formation depending on whether treatment was initiated before (postnatal day 16; P16) or after (P45) aneurysm formation, respectively. Biochemical evidence-related aneurysm growth with Erk-mediated AT1r signaling, and medial degeneration with TGFß hyperactivity that was in part AT1r dependent. Importantly, P16-initiated treatment with losartan combined with P45-initiated administration of 1D11 prevented death of Fbn1(mgR/mgR) mice from ruptured TAA. CONCLUSIONS: By demonstrating that promiscuous AT1r and TGFß drive partially overlapping processes of arterial disease in MFS mice, our study argues for a therapeutic strategy against TAA that targets both signaling pathways although sparing the early protective role of TGFß.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Anticuerpos Neutralizantes/farmacología , Aorta Torácica/efectos de los fármacos , Aneurisma de la Aorta Torácica/prevención & control , Losartán/farmacología , Síndrome de Marfan/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Animales , Aorta Torácica/metabolismo , Aorta Torácica/patología , Aneurisma de la Aorta Torácica/genética , Aneurisma de la Aorta Torácica/metabolismo , Aneurisma de la Aorta Torácica/patología , Rotura de la Aorta/genética , Rotura de la Aorta/metabolismo , Rotura de la Aorta/patología , Rotura de la Aorta/prevención & control , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Fibrilina-1 , Fibrilinas , Humanos , Síndrome de Marfan/genética , Síndrome de Marfan/metabolismo , Síndrome de Marfan/patología , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Mutantes , Proteínas de Microfilamentos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Mutación , Fosforilación , Receptor de Angiotensina Tipo 1/metabolismo , Proteína Smad2/metabolismo , Factores de Tiempo , Factor de Crecimiento Transformador beta/inmunología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
A 35 year old woman with past medical history of hypertension presented to the emergency department with chief complaint of severe abdominal pain for one week. The abdominal pain was located in the epigastrium and described as "cramping" and "intermittent". The pain intensity was quantified initially as 6 out of 10 on the pain scale. As the week progressed the pain became constant and radiated to the back. The intensity of the abdominal pain increased to 10 out of 10. The patient reported some relief from her pain while lying in the prone position. Initially the pain was associated with loose stools for several days. The loose stools resolved spontaneously and then the patient began to experience nausea and vomiting. Her medications included lisinopril-hydrochlorothiazide which she had been taking for the past five months. She had no history of alcohol, tobacco or illicit drug use.
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Dolor Abdominal/etiología , Hidroclorotiazida/uso terapéutico , Lisinopril/uso terapéutico , Pancreatitis Aguda Necrotizante/diagnóstico por imagen , Pancreatitis Aguda Necrotizante/terapia , Adulto , Drenaje , Combinación de Medicamentos , Femenino , Humanos , Hipertensión , Dimensión del Dolor , Tomografía Computarizada por Rayos XRESUMEN
Periodontitis is one of the most common inflammatory diseases in humans. The susceptibility to periodontitis is largely determined by the host response, and the severity of inflammation predicts disease progression. Upon microbial insults, host cells undergo massive changes in their transcription program to trigger an appropriate response (inflammation). It is not surprising that successful keystone pathogens have developed specific mechanisms to manipulate the gene expression network in host cells. Emerging data has indicated that epigenetic regulation plays a significant role in inflammation. Acetylation of lysine residues on histones is a major epigenetic modification of chromatin, highly associated with the accessibility of chromatin and activation of transcription. Specific histone acetylation patterns are observed in inflammatory diseases including periodontitis. Bromo- and extraterminal domain (BET) proteins recognize acetylated histones and then recruit transcription factors and transcription elongation complexes to chromatin. BET proteins are regulated in inflammatory diseases and small molecules blocking the function of BET proteins are promising "epi-drugs" for treating inflammatory diseases.
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BACKGROUND: The use of crystalloid priming for extracorporeal circuit in adult cardiac surgery causes inevitable haemodilution. The haemodilution can be reduced by using methods such as retrograde autologous priming (RAP) with the patient's blood. This study compares the RAP technique with standard priming with regards to safety and the impact on haemodilution. METHODS: This was a retrospective cohort study between a control group (n = 100) consisting of consecutive patients undergoing first time isolated coronary artery bypass surgery (CABG) with crystalloid priming solution in the circuit, and the RAP group (n = 100) consisting of patients undergoing isolated first time CABG with the RAP method. All demographics, procedure and perfusion data were gathered from the local surgical and perfusion database. RESULTS: Despite starting with comparable mean pre-operative haemoglobin (Hb) levels (control 127 mg/dL versus RAP 129 mg/dL), the RAP group had significantly higher mean post-op Hb level (109 mg/dL versus 92 mg/dL, P < 0.01). Crystalloid use was also significantly lower in RAP group (3.15 L versus 4.17 L P < 0.02). Freedom from red blood cell transfusion (86% versus 76% P = 0.038) and freedom from blood products (78% versus 66%, P = 0.032) was also significantly better in the RAP group. CONCLUSIONS: This study demonstrates that retrograde autologous priming is a safe and effective method for priming the cardiopulmonary bypass circuit in adult cardiac surgery, with significantly beneficial effects on transfusion rates and intra operative fluid requirements. Given these results the RAP method should be considered as a routine step in priming an extracorporeal circuit for adult cardiac operations.
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Procedimientos Quirúrgicos Cardíacos , Puente Cardiopulmonar , Adulto , Humanos , Puente Cardiopulmonar/métodos , Estudios Retrospectivos , Transfusión de Sangre Autóloga/métodos , Procedimientos Quirúrgicos Cardíacos/métodos , Soluciones CristaloidesRESUMEN
Respiratory function is the main cause of mortality in patients with Duchenne muscular dystrophy (DMD). Elevated levels of TGF-ß play a key role in the pathophysiology of DMD. To determine whether therapeutic attenuation of TGF-ß signaling improves respiratory function, mdx mice were treated from 2 weeks of age to 2 months or 9 months of age with either 1D11 (a neutralizing antibody to all three isoforms of TGF-ß), losartan (an angiotensin receptor antagonist), or a combination of the two agents. Respiratory function was measured in nonanesthetized mice by plethysmography. The 9-month-old mdx mice had elevated Penh values and decreased breathing frequency, due primarily to decreased inspiratory flow rate. All treatments normalized Penh values and increased peak inspiratory flow, leading to decreased inspiration times and breathing frequency. Additionally, forelimb grip strength was improved after 1D11 treatment at both 2 and 9 months of age, whereas, losartan improved grip strength only at 2 months. Decreased serum creatine kinase levels (significant improvement for all groups), increased diaphragm muscle fiber density, and decreased hydroxyproline levels (significant improvement for 1D11 only) also suggested improved muscle function after treatment. For all endpoints, 1D11 was equivalent or superior to losartan; coadministration of the two agents was not superior to 1D11 alone. In conclusion, TGF-ß antagonism may be a useful therapeutic approach for treating DMD patients.
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Respiración , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Animales , Biomarcadores/metabolismo , Peso Corporal/efectos de los fármacos , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Creatina Quinasa/sangre , Diafragma/efectos de los fármacos , Diafragma/metabolismo , Diafragma/patología , Diafragma/fisiopatología , Relación Dosis-Respuesta a Droga , Enalapril/administración & dosificación , Enalapril/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Fuerza de la Mano/fisiología , Hidroxiprolina/metabolismo , Inflamación/sangre , Inflamación/metabolismo , Inflamación/patología , Losartán/administración & dosificación , Losartán/farmacología , Ratones , Ratones Endogámicos mdx , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Miogenina/metabolismo , Tamaño de los Órganos/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Respiración/efectos de los fármacos , Pruebas de Función Respiratoria , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
PURPOSE: Quantitative in vivo molecular imaging of fine brain structures requires high-spatial resolution and high-sensitivity. Positron emission tomography (PET) is an attractive candidate to introduce molecular imaging into standard clinical care due to its highly targeted and versatile imaging capabilities based on the radiotracer being used. However, PET suffers from relatively poor spatial resolution compared to other clinical imaging modalities, which limits its ability to accurately quantify radiotracer uptake in brain regions and nuclei smaller than 3 mm in diameter. Here we introduce a new practical and cost-effective high-resolution and high-sensitivity brain-dedicated PET scanner, using our depth-encoding Prism-PET detector modules arranged in a conformal decagon geometry, to substantially reduce the partial volume effect and enable accurate radiotracer uptake quantification in small subcortical nuclei. METHODS: Two Prism-PET brain scanner setups were proposed based on our 4-to-1 and 9-to-1 coupling of scintillators to readout pixels using 1.5 × 1.5 × 20 $1.5 \times 1.5 \times 20$ mm3 and 0.987 × 0.987 × 20 $0.987 \times 0.987 \times 20$ mm3 crystal columns, respectively. Monte Carlo simulations of our Prism-PET scanners, Siemens Biograph Vision, and United Imaging EXPLORER were performed using Geant4 application for tomographic emission (GATE). National Electrical Manufacturers Association (NEMA) standard was followed for the evaluation of spatial resolution, sensitivity, and count-rate performance. An ultra-micro hot spot phantom was simulated for assessing image quality. A modified Zubal brain phantom was utilized for radiotracer imaging simulations of 5-HT1A receptors, which are abundant in the raphe nuclei (RN), and norepinephrine transporters, which are highly concentrated in the bilateral locus coeruleus (LC). RESULTS: The Prism-PET brain scanner with 1.5 mm crystals is superior to that with 1 mm crystals as the former offers better depth-of-interaction (DOI) resolution, which is key to realizing compact and conformal PET scanner geometries. We achieved uniform 1.3 mm full-width-at-half-maximum (FWHM) spatial resolutions across the entire transaxial field-of-view (FOV), a NEMA sensitivity of 52.1 kcps/MBq, and a peak noise equivalent count rate (NECR) of 957.8 kcps at 25.2 kBq/mL using 450-650 keV energy window. Hot spot phantom results demonstrate that our scanner can resolve regions as small as 1.35 mm in diameter at both center and 10 cm away from the center of the transaixal FOV. Both 5-HT1A receptor and norepinephrine transporter brain simulations prove that our Prism-PET scanner enables accurate quantification of radiotracer uptake in small brain regions, with a 1.8-fold and 2.6-fold improvement in the dorsal RN as well as a 3.2-fold and 4.4-fold improvement in the bilateral LC compared to the Biograph Vision and EXPLORER, respectively. CONCLUSIONS: Based on our simulation results, the proposed high-resolution and high-sensitivity Prism-PET brain scanner is a promising cost-effective candidate to achieve quantitative molecular neuroimaging of small but important brain regions with PET clinically viable.
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Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Imagen Molecular , Fantasmas de Imagen , Tomografía de Emisión de Positrones/métodos , Sensibilidad y EspecificidadRESUMEN
Exposure to acute, high-dose, whole-body ionizing radiation results in bone marrow failure (hematopoietic acute radiation syndrome with resultant infection, bleeding, anemia, and increased risk of death). Sargramostim (yeast-derived rhu GM-CSF), a yeast-derived, molecularly cloned, hematopoietic growth factor and pleiotropic cytokine supports proliferation, differentiation, maturation and survival of cells of several myeloid lineages. We evaluated the efficacy of sargramostim in non-human primates (rhesus macaques) exposed to whole-body ionizing radiation at a 50-60% lethal dose. The primary end point was day 60 survival. Non-human primates received daily subcutaneous sargramostim (7 mcg/kg/day) or control. To reflect the anticipated setting of a nuclear or radiologic event, treatment began 48 h postirradiation, and non-human primates received only moderate supportive care (no whole blood transfusions or individualized antibiotics). Sargramostim significantly increased day 60 survival to 78% (95% confidence interval, 61-90%) vs. 42% (26-59%; P = 0.0018) in controls. Neutrophil, platelet and lymphocyte recovery rates were accelerated and infection rates decreased. Improved survival when sargramostim was started 48 h postirradiation, without use of intensive supportive care, suggests sargramostim may be effective in treating humans exposed to acute, high-dose whole-body, ionizing radiation in a scenario such as a mass casualty event.
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Síndrome de Radiación Aguda/tratamiento farmacológico , Células de la Médula Ósea/efectos de los fármacos , Trastornos de Fallo de la Médula Ósea/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Síndrome de Radiación Aguda/genética , Síndrome de Radiación Aguda/patología , Animales , Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/efectos de la radiación , Trastornos de Fallo de la Médula Ósea/genética , Trastornos de Fallo de la Médula Ósea/patología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/efectos de la radiación , Movimiento Celular/efectos de los fármacos , Movimiento Celular/efectos de la radiación , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Factor Estimulante de Colonias de Granulocitos , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Macaca mulatta/genética , Masculino , Proteínas Recombinantes/farmacología , Irradiación Corporal Total/efectos adversosRESUMEN
We describe the medicinal chemistry programme that led to the identification of the EP(1) receptor antagonist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with previous EP(1) antagonists such as GW848687X and was found to display excellent activity in preclinical models of inflammatory pain. However, upon cross species pharmacokinetic profiling, GSK269984A was predicted to have suboptimal human pharmacokinetic and was thus progressed to a human microdose study.
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Analgésicos/síntesis química , Química Farmacéutica/métodos , Inflamación/tratamiento farmacológico , Ácidos Nicotínicos/síntesis química , Piridinas/síntesis química , Receptores de Prostaglandina E/antagonistas & inhibidores , Analgésicos/farmacología , Animales , Sistema Nervioso Central/efectos de los fármacos , Diseño de Fármacos , Humanos , Concentración de Iones de Hidrógeno , Concentración 50 Inhibidora , Modelos Químicos , Ácidos Nicotínicos/farmacología , Piridinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Herein we describe the medicinal chemistry programme to identify a potential back-up compound to the EP(1) receptor antagonist GW848687X. This work started with the lipophilic 1,2-biaryl benzene derivative 4 which displayed molecular weight of 414.9g/mol and poor in vivo metabolic stability in the rat and resulted in the identification of compound 7i (GSK345931A) which demonstrated good metabolic stability in the rat and lower molecular weight (381.9g/mol). In addition, 7i (GSK345931A) showed measurable CNS penetration in the mouse and rat and potent analgesic efficacy in acute and sub-chronic models of inflammatory pain.
Asunto(s)
Inflamación/tratamiento farmacológico , Dolor/tratamiento farmacológico , Piridinas/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Evaluación Preclínica de Medicamentos , Piridinas/química , Piridinas/uso terapéutico , Ratas , Subtipo EP1 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
Replacement of the carboxylic acid group in a series of previously described methylene-linked pyrazole EP(1) receptor antagonists led to the discovery of amide, reversed amide and carbamate derivatives. Two compounds, 10a and 10b, were identified as brain penetrant compounds and both demonstrated efficacy in the CFA model of inflammatory pain.
Asunto(s)
Analgésicos/síntesis química , Analgésicos/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Analgésicos/química , Animales , Encéfalo/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Técnicas Químicas Combinatorias , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Estructura Molecular , Dimensión del Dolor , Pirazoles/química , Ratas , Subtipo EP1 de Receptores de Prostaglandina E , Relación Estructura-ActividadRESUMEN
A full understanding of the microenvironmental factors that control the activities of skeletal stem cells (also known as mesenchymal stem cells [MSCs]) in the adult bone marrow holds great promise for developing new therapeutic strategies to mitigate age-related diseases of bone and cartilage degeneration. Bone loss is an understudied manifestation of Marfan syndrome, a multisystem disease associated with mutations in the extracellular matrix protein and TGFß modulator fibrillin-1. Here we demonstrate that progressive loss of cancellous bone in mice with limbs deficient for fibrillin-1 (Fbn1(Prx1-/-) mice) is accounted for by premature depletion of MSCs and osteoprogenitor cells combined with constitutively enhanced bone resorption. Longitudinal analyses of Fbn1(Prx1-/-) mice showed incremental bone loss and trabecular microarchitecture degeneration accompanied by a progressive decrease in the number and clonogenic potential of MSCs. Significant paucity of marrow fat cells in the long bones of Fbn1(Prx1-/-) mice, together with reduced adipogenic potential of marrow stromal cell cultures, indicated an additional defect in MSC differentiation. This postulate was corroborated by showing that an Fbn1-silenced osteoprogenitor cell line cultured in the presence of insulin yielded fewer than normal adipocytes and exhibited relatively lower PPARγ levels. Consonant with fibrillin-1 modulation of TGFß bioavailability, cultures of marrow stromal cells from Fbn1(Prx1-/-) limb bones showed improper overactivation of latent TGFß. In line with this finding, systemic TGFß neutralization improved bone mass and trabecular microarchitecture along with normalizing the number of MSCs, osteoprogenitor cells, and marrow adipocytes. Collectively, our findings show that fibrillin-1 regulates MSC activity by modulating TGFß bioavailability within the microenvironment of marrow niches.
Asunto(s)
Médula Ósea/metabolismo , Diferenciación Celular/fisiología , Células Madre Mesenquimatosas/metabolismo , Proteínas de Microfilamentos/metabolismo , Nicho de Células Madre/fisiología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Fibrilina-1 , Fibrilinas , Ratones , Ratones Noqueados , Proteínas de Microfilamentos/genética , Factor de Crecimiento Transformador beta/genéticaRESUMEN
Polystyrene fibers loaded with an energetic blend of nanoaluminum (n-Al) and perfluoropolyether (PFPE) were successfully fabricated via electrospinning producing nanothermite fabrics. Fibers were generated with loadings up to 17 wt % n-Al/PFPE incorporated into the fiber. Microscopy analysis by SEM and TEM confirm a uniform dispersion of PFPE treated n-Al on the outside and inside of the fibers. Metallized fibers were thermally active upon immediate ignition from a controlled flame source. Thermal analysis by differential scanning calorimetry (DSC) found no change in glass transition temperature when comparing pure polystyrene fibers with fibers loaded up to 17 wt % n-Al/PFPE. Thermal gravimetric analysis (TGA) revealed a shift in decomposition temperatures to lower onsets upon increased loadings of n-Al/PFPE blends, consistent with previous studies. Flame propagation studies confirmed that the metallized fibers are pryolants. These metallized fibers are a recent development in metastable intermolecular composites (MICs) and details of their synthesis, characterization, and thermal properties are presented.
RESUMEN
Pompe disease is an autosomal recessive disorder caused by a deficiency of acid α-glucosidase (GAA; EC 3.2.1.20) and the resultant progressive lysosomal accumulation of glycogen in skeletal and cardiac muscles. Enzyme replacement therapy using recombinant human GAA (rhGAA) has proven beneficial in addressing several aspects of the disease such as cardiomyopathy and aberrant motor function. However, residual muscle weakness, hearing loss, and the risks of arrhythmias and osteopenia persist despite enzyme therapy. Here, we evaluated the relative merits of substrate reduction therapy (by inhibiting glycogen synthesis) as a potential adjuvant strategy. A phosphorodiamidate morpholino oligonucleotide (PMO) designed to invoke exon skipping and premature stop codon usage in the transcript for muscle specific glycogen synthase (Gys1) was identified and conjugated to a cell penetrating peptide (GS-PPMO) to facilitate PMO delivery to muscle. GS-PPMO systemic administration to Pompe mice led to a dose-dependent decrease in glycogen synthase transcripts in the quadriceps, and the diaphragm but not the liver. An mRNA response in the heart was seen only at the higher dose tested. Associated with these decreases in transcript levels were correspondingly lower tissue levels of muscle specific glycogen synthase and activity. Importantly, these reductions resulted in significant decreases in the aberrant accumulation of lysosomal glycogen in the quadriceps, diaphragm, and heart of Pompe mice. Treatment was without any overt toxicity, supporting the notion that substrate reduction by GS-PPMO-mediated inhibition of muscle specific glycogen synthase represents a viable therapeutic strategy for Pompe disease after further development.