RESUMEN
BACKGROUND: Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison's disease (AD). METHODS: Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. RESULTS: The prevalence of APS-1 was 2.6 cases/million (range 0.5-17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. CONCLUSIONS: In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.
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Enfermedad de Addison , Candidiasis Mucocutánea Crónica , Hipoparatiroidismo , Interferón Tipo I/inmunología , Poliendocrinopatías Autoinmunes , Factores de Transcripción/genética , Enfermedad de Addison/diagnóstico , Enfermedad de Addison/etiología , Adulto , Autoanticuerpos/sangre , Candidiasis Mucocutánea Crónica/diagnóstico , Candidiasis Mucocutánea Crónica/etiología , Femenino , Humanos , Hipoparatiroidismo/diagnóstico , Hipoparatiroidismo/etiología , Italia/epidemiología , Masculino , Mortalidad , Mutación , Poliendocrinopatías Autoinmunes/diagnóstico , Poliendocrinopatías Autoinmunes/genética , Poliendocrinopatías Autoinmunes/mortalidad , Poliendocrinopatías Autoinmunes/fisiopatología , Prevalencia , Proteína AIRERESUMEN
Many airway diseases in children, notably bronchiolitis, cystic fibrosis (CF), non-CF bronchiectasis including primary ciliary dyskinesia, pneumonia, and severe asthma are associated with retention of airway secretions. Medications to improve secretions clearance, the mucoactive medications, are employed to treat these diseases with varying degrees of success. This manuscript reviews evidence for the use of these medications and future directions of study.
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Asma/tratamiento farmacológico , Bronquiectasia/tratamiento farmacológico , Bronquiolitis Viral/tratamiento farmacológico , Trastornos de la Motilidad Ciliar/tratamiento farmacológico , Fibrosis Quística/tratamiento farmacológico , Expectorantes/uso terapéutico , Fármacos del Sistema Respiratorio/uso terapéutico , Adolescente , Corticoesteroides/uso terapéutico , Niño , Preescolar , Antagonistas Colinérgicos/uso terapéutico , Desoxirribonucleasa I/uso terapéutico , Diuréticos Osmóticos/uso terapéutico , Bloqueadores del Canal de Sodio Epitelial/uso terapéutico , Humanos , Lactante , Macrólidos/uso terapéutico , Manitol , Proteínas Recombinantes/uso terapéutico , Solución Salina Hipertónica , Índice de Severidad de la EnfermedadRESUMEN
Migratory animals encounter multiple parasite communities, raising concerns that migration may aid transport of infectious disease. How migration affects disease spread depends fundamentally on how disease affects migration, specifically whether infection alters individuals' migratory physiology and behavior. We inoculated white-throated sparrows (Zonotrichia albicollis) with avian malaria parasites (Plasmodium sp.), monitored parasite loads for 5 wk as the birds reached spring migratory condition, and compared nocturnal migratory restlessness (Zugunruhe), body composition (fat, lean, and whole-body mass), and hematocrit among experimentally infected birds, sham-inoculated birds, and birds that were exposed to parasites but resisted infection. Migratory restlessness increased over time in the study, but the rate of change varied between sham (control) birds, infected birds, and birds that resisted infection. We were unable to detect any effects of malaria exposure on body condition. Our findings suggest that encountering parasites affects migratory activity, regardless of whether infection occurs or is resisted.
Asunto(s)
Migración Animal/fisiología , Malaria Aviar/fisiopatología , Gorriones/parasitología , Animales , Composición Corporal , Resistencia a la Enfermedad , Femenino , Hematócrito , Malaria Aviar/sangre , Masculino , Plasmodium/patogenicidad , Estaciones del AñoRESUMEN
PURPOSE: Mitotane is the only chemotherapeutic agent available for the treatment of adrenocortical carcinoma (ACC), however, the anti-neoplastic efficacy is limited due to several side-effects in vivo. There is, therefore, a need of exploring for new anti-tumoral agents which can be used either alone or in combination with mitotane. The active vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) acts as an anti-proliferative agent in human cancer by inhibiting the Wnt/beta-catenin pathway through the vitamin D receptor (VDR). The aim of this study was to study the effects of mitotane and 1α,25(OH)2D3, individually or in combination, in an in vitro model with H295R ACC cells, and to elucidate the molecular events behind their effects involving the Wnt/beta-catenin signaling. METHODS AND RESULTS: Multiple concentrations of mitotane and 1α,25(OH)2D3, individually or in combination, were tested on H295R cells for 24-96 h, and the effects analysed by MTT. A reduction in cell growth was observed in a dose/time-dependent manner for both mitotane and 1α,25(OH)2D3. In addition, a combination of clinically sub-therapeutic concentrations of mitotane with 1α,25(OH)2D3, had an additive anti-proliferative effect (Combination Index = 1.02). In a wound healing assay, individual treatments of both mitotane and 1α,25(OH)2D3 reduced the migration ability of H295R cells, with the effect further enhanced on combining both the agents. Western blotting and qRT-PCR analysis showed a modulation of the Wnt/beta-catenin and VDR signaling pathways. CONCLUSION: Our results show an additive effect of mitotane and 1α,25(OH)2D3 on the inhibition of H295R ACC cell growth and viability, and suggest that molecular mechanisms of their effects involve a functional link between VDR and Wnt/beta-catenin pathways.
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Neoplasias de la Corteza Suprarrenal/metabolismo , Corteza Suprarrenal/efectos de los fármacos , Carcinoma Corticosuprarrenal/metabolismo , Calcitriol/farmacología , Mitotano/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Corteza Suprarrenal/metabolismo , Línea Celular Tumoral , Humanos , beta Catenina/metabolismoRESUMEN
BACKGROUND: Wet or productive cough is common in children with chronic cough. We formulated recommendations based on systematic reviews related to the management of chronic wet cough in children (aged ≤ 14 years) based on two key questions: (1) how effective are antibiotics in improving the resolution of cough? If so, what antibiotic should be used and for how long? and (2) when should children be referred for further investigations? METHODS: We used the CHEST expert cough panel's protocol for systematic reviews and the American College of Chest Physicians (CHEST) methodologic guidelines and GRADE framework (the Grading of Recommendations Assessment, Development and Evaluation). Data from the systematic reviews in conjunction with patients' values and preferences and the clinical context were used to form recommendations. Delphi methodology was used to obtain consensus for the recommendations/suggestions made. RESULTS: Combining data from the systematic reviews, we found high-quality evidence in children aged ≤ 14 years with chronic (> 4 weeks' duration) wet/productive cough that using appropriate antibiotics improves cough resolution, and further investigations (eg, flexible bronchoscopy, chest CT scans, immunity tests) should be undertaken when specific cough pointers (eg, digital clubbing) are present. When the wet cough does not improve following 4 weeks of antibiotic treatment, there is moderate-quality evidence that further investigations should be considered to look for an underlying disease. New recommendations include the recognition of the clinical diagnostic entity of protracted bacterial bronchitis. CONCLUSIONS: Compared with the 2006 Cough Guidelines, there is now high-quality evidence for some, but not all, aspects of the management of chronic wet cough in specialist settings. However, further studies particularly in primary health) are required.
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Humanos , Niño , Bronquitis/microbiología , Bronquitis/tratamiento farmacológico , Tos/microbiología , Tos/tratamiento farmacológico , Antibacterianos/uso terapéutico , Enfoque GRADERESUMEN
ARMC5 mutations have recently been identified as a common genetic cause of primary bilateral macronodular adrenal hyperplasia (PBMAH). We aimed to assess the prevalence of ARMC5 germline mutations and correlate genotype with phenotype in a large cohort of PBMAH patients. A multicenter study was performed, collecting patients from different endocrinology units in Italy. Seventy-one PBMAH patients were screened for small mutations and large rearrangements in the ARMC5 gene: 53 were cortisol-secreting (two with a family history of adrenal hyperplasia) and 18 were non-secreting cases of PBMAH. Non-mutated and mutated patients' clinical phenotypes were compared and related to the type of mutation. A likely causative germline ARMC5 mutation was only identified in cortisol-secreting PBMAH patients (one with a family history of adrenal hyperplasia and ten apparently sporadic cases). Screening in eight first-degree relatives of three index cases revealed four carriers of an ARMC5 mutation. Evidence of a second hit at somatic level was identified in five nodules. Mutated patients had higher cortisol levels (p = 0.062), and more severe hypertension and diabetes (p < 0.05). Adrenal glands were significantly larger, with a multinodular phenotype, in the mutant group (p < 0.01). No correlation emerged between type of mutation and clinical parameters. ARMC5 mutations are frequent in cortisol-secreting PBMAH and seem to be associated with a particular pattern of the adrenal masses. Their identification may have implications for the clinical care of PBMAH cases and their relatives.
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Glándulas Suprarrenales/patología , Hiperplasia Suprarrenal Congénita/genética , Mutación de Línea Germinal , Proteínas Supresoras de Tumor/genética , Hiperplasia Suprarrenal Congénita/patología , Adulto , Anciano , Proteínas del Dominio Armadillo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , FenotipoRESUMEN
The WWTR1 (protein is known as TAZ)-CAMTA1 (WC) fusion gene defines epithelioid hemangioendothelioma, a malignant vascular cancer. TAZ (transcriptional coactivator with PDZ binding motif) is a transcriptional coactivator and end effector of the Hippo tumor suppressor pathway. It is inhibited by phosphorylation by the Hippo kinases LATS1 and LATS2. Such phosphorylation causes cytoplasmic localization, 14-3-3 protein binding and the phorphorylation of a terminal phosphodegron promotes ubiquitin-dependent degradation (the phosphorylation of the different motifs has several effects). CAMTA1 is a putative tumor suppressive transcription factor. Here we demonstrate that TAZ-CAMTA1 (TC) fusion results in its nuclear localization and constitutive activation. Consequently, cells expressing TC display a TAZ-like transcriptional program that causes resistance to anoikis and oncogenic transformation. Our findings elucidate the mechanistic basis of TC oncogenic properties, highlight that TC is an important model to understand how the Hippo pathway can be inhibited in cancer, and provide approaches for targeting this chimeric protein.
Asunto(s)
Proteínas de Unión al Calcio/genética , Transformación Celular Neoplásica/genética , Hemangioendotelioma Epitelioide/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de Fusión Oncogénica/genética , Transactivadores/genética , Células 3T3 , Animales , Western Blotting , Técnica del Anticuerpo Fluorescente , Células HEK293 , Humanos , Ratones , Mutagénesis Sitio-Dirigida , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , TransfecciónRESUMEN
Despite immense interest in using antimalarials as autophagy inhibitors to treat cancer, it remains unclear whether these agents act predominantly via autophagy inhibition or whether other pathways direct their anti-cancer properties. By comparing the treatment effects of the antimalarials chloroquine (CQ) and quinacrine (Q) on KRAS mutant lung cancer cells, we demonstrate that inhibition of the oxidative arm of the pentose phosphate pathway (oxPPP) is required for antimalarial induced apoptosis. Despite inhibiting autophagy, neither CQ treatment nor RNAi against autophagy regulators (ATGs) promote cell death. In contrast, Q triggers high levels of apoptosis, both in vitro and in vivo, and this phenotype requires both autophagy inhibition and p53-dependent inhibition of the oxPPP. Simultaneous genetic targeting of the oxPPP and autophagy is sufficient to trigger apoptosis in lung cancer cells, including cells lacking p53. Thus, in addition to reduced autophagy, oxPPP inhibition serves as an important determinant of antimalarial cytotoxicity in cancer cells.
Asunto(s)
Antimaláricos/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Vía de Pentosa Fosfato/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cloroquina/farmacología , Humanos , Neoplasias Pulmonares/patología , Mutación , Oxidación-Reducción/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Felty's syndrome is a triad of rheumatoid arthritis, neutropenia, and splenomegaly. We hereby report an unusual case of non-articular Felty's syndrome and its management along with discussing the importance of appropriately ruling out alternate causes of neutropenia with splenomegaly.
Asunto(s)
Síndrome de Felty/diagnóstico , Anciano , Femenino , Humanos , Neutropenia/etiología , Esplenomegalia/etiologíaRESUMEN
BACKGROUND: Observational studies suggest that orally administered guaifenesin (GGE) may thin lower respiratory tract secretions but none have examined its effects on mucociliary and cough clearance (MCC/CC) during a respiratory tract infection (RTI). The current study was a randomized, parallel-group, double-blind, placebo-controlled study in non-smoking adults who suffered from an acute upper RTI. METHODS: We assessed the effects of a single dose of Mucinex(®) 1200 mg (2 × 600 mg extended release tablets) (ER GGE) on 1) MCC/CC by assessing the rate of removal from the lung of inhaled radioactive tracer particles (Tc99m-sulfur colloid), 2) sputum dynamic rheology by stress/strain creep transformation over the linear part of the curve, 3) sessile drop interfacial tension by the deNouy ring technique, and 4) subjective symptom measures. MCC was measured during the morning (period 1) and compared to that in the afternoon 4 h later (period 2) immediately following either drug (n = 19) or placebo (n = 19). For both period 1 and 2 subjects performed 60 voluntary coughs from 60 to 90 min after inhalation of radio-labeled aerosol for a measure of CC. Sputum properties were measured from subjects who expectorated sputum during the cough period post treatment (n = 8-12 for each cohort). RESULTS: We found no effect of ER GGE on MCC or CC compared to placebo. MCC through 60 min for period 1 vs. 2 = 8.3 vs. 11.8% (placebo) and = 9.7 vs. 11.1% (drug) (NS) and CC for period 1 vs. 2 was 9.9 vs. 9.1% (placebo) and 10.8 vs. 5.6% (drug) (NS). There was no significant difference in sputum biophysical properties after administration of drug or placebo. CONCLUSIONS: There was no significant effect of a single dose of ER GGE on MCC/CC or on sputum biophysical properties compared to placebo in this population of adult patients with an acute RTI. ClinicalTrials.gov Identifier: NCT01114581.
Asunto(s)
Tos/tratamiento farmacológico , Expectorantes/uso terapéutico , Guaifenesina/uso terapéutico , Depuración Mucociliar/efectos de los fármacos , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Enfermedad Aguda , Administración Oral , Adulto , Tos/microbiología , Método Doble Ciego , Expectorantes/farmacocinética , Expectorantes/farmacología , Femenino , Guaifenesina/farmacocinética , Guaifenesina/farmacología , Humanos , Masculino , Persona de Mediana Edad , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/fisiopatología , Reología , Esputo/química , Esputo/efectos de los fármacos , Esputo/fisiología , Adulto JovenAsunto(s)
Neoplasias Óseas/diagnóstico por imagen , Lipoma/diagnóstico por imagen , Radiografía Abdominal/métodos , Costillas/diagnóstico por imagen , Pared Torácica/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Diagnóstico Diferencial , Humanos , Hallazgos Incidentales , Masculino , Persona de Mediana Edad , Radiografía Torácica/métodosRESUMEN
Osteopetrosis is a rare and heterogeneous genetic disorder characterized by dense bone mass that is a consequence of defective osteoclast function and/or development. Autosomal recessive osteopetrosis (ARO) is the most severe form and is often fatal within the first years of life; early hematopoietic stem cell transplant (HSCT) remains the only curative treatment for ARO. The majority of the ARO-causing mutations are located in the TCIRG1 gene. We report here the identification and characterization of an A to T transversion in the fourth base of the intron 2 donor splice site (c.117+4AâT) in TCIRG1, a mutation not previously seen in the Ashkenazi Jewish (AJ) population. Analysis of a random sample of individuals of AJ descent revealed a carrier frequency of approximately 1 in 350. Genotyping of five loci adjacent to the c.117+4AâT-containing TCIRG1 allele revealed that the presence of this mutation in the AJ population is due to a single founder. The identification of this mutation will enable population carrier testing and will facilitate the identification and treatment of individuals homozygous for this mutation.
Asunto(s)
Efecto Fundador , Osteopetrosis/genética , Mutación Puntual , Sitios de Empalme de ARN/genética , ATPasas de Translocación de Protón Vacuolares/genética , Análisis Mutacional de ADN , Frecuencia de los Genes , Humanos , Lactante , Intrones , Judíos/genéticaRESUMEN
BACKGROUND: IL-13, a helper T cell type 2 (Th2) cytokine, transforms cultured airway epithelial cells to goblet cells, and this is not inhibited by corticosteroids. IL-33 stimulates Th2 cytokines and is highly expressed in airways of persons with asthma. The effect of IL-33 on goblet cell differentiation and cytokine secretion has not been described. OBJECTIVE: We examined the effect of IL-33 on CXCL8/IL-8 secretion from goblet or normally differentiated human bronchial epithelial (NHBE) cells and signalling pathways associated with IL-33 activation in these cells. METHODS: Normal human bronchial epithelial cells were grown to goblet or normally differentiated ciliated cell phenotype at air-liquid interface in the presence or absence of IL-13. After 14 days, differentiated cells were exposed to IL-33 for 24 h. RESULTS: CXCL8/IL-8 secretion into the apical (air) side of the goblet cells was greater than from normally differentiated cells (P < 0.01), and IL-33 stimulated apical CXCL8/IL-8 release from goblet cells, but not from normally differentiated cells (P < 0.01). IL-33 increased ERK 1/2 phosphorylation in goblet cells (P < 0.05), and PD98059, a MAPK/ERK kinase inhibitor, attenuated IL-33-stimulated CXCL8/IL-8 secretion from goblet cells (P < 0.001). IL-13 induced ST2 mRNA (P < 0.02) and membrane-bound ST2 protein expression on the apical side surface of goblet cells compared with normally differentiated cells, and neutralization with anti-ST2R antibody attenuated IL-33-induced apical CXCL8/IL-8 secretion from goblet cells (P < 0.02). CONCLUSIONS AND CLINICAL RELEVANCE: Goblet cells secrete CXCL8/IL-8, and this is increased by IL-33 through ST2R-ERK pathway, suggesting a mechanism for enhanced airway inflammation in the asthmatic airway with goblet cell metaplasia.
Asunto(s)
Células Caliciformes/efectos de los fármacos , Células Caliciformes/metabolismo , Interleucina-8/biosíntesis , Interleucinas/farmacología , Mucosa Respiratoria/citología , Mucosa Respiratoria/metabolismo , Diferenciación Celular/efectos de los fármacos , Expresión Génica , Células Caliciformes/citología , Humanos , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-13/farmacología , Interleucina-33 , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Compuestos Orgánicos/farmacología , Fosforilación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Mucosa Respiratoria/efectos de los fármacosRESUMEN
Medullary thyroid cancer (MTC) accounts for around 5-10% of all thyroid cancers. Though usually sporadic, 1 in 4 cases are of genetic origin, with germinal mutations in the RET proto-oncogene in familial forms and somatic mutations both in RET and in the RAS family genes in sporadic ones.This study aimed to characterize a rare H-RAS sequence variant -M72I- in a patient with sporadic MTC, focusing on its functional significance.Mutation analysis was performed for the RET, N-RAS, K-RAS and H-RAS genes by direct sequencing. Western blot analysis was done on 4 thyroid tissues from 1 patient carrying the M72I mutation in H-RAS, 1 with the Q61R mutation in H-RAS, 1 with no RET, H-RAS, K-RAS or N-RAS gene mutations, and 1 normal thyroid, using different antibodies against Erk1/2, phospho-Erk1/2 (Thr202/Tyr204), Akt and phospho-Akt (Ser473). Large-scale molecular dynamics simulations were completed for H-RAS wt and H-RAS M72I.Western blot analysis demonstrated that both MAPK and PI3K/Akt pathways were activated in the MTC patient carrying the M72I variant. In silico results showed conformational changes in H-RAS that could influence its activation by Sos and phosphate binding. Results of molecular dynamics were consistent with Western blot experiments.The M72I mutation may contribute effectively to proliferation and survival signaling throughout the MAPK and PI3K/Akt pathways. This work underscores the importance of studying genetic alterations that may lead to carcinogenesis.
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Carcinoma Medular/genética , Genes ras/genética , Mutación/genética , Neoplasias de la Tiroides/genética , Western Blotting , Carcinoma Medular/metabolismo , Codón/genética , ADN/genética , Exones/genética , Femenino , Bocio Nodular/etiología , Humanos , Melanoma/complicaciones , Persona de Mediana Edad , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Conformación Proteica , Proto-Oncogenes Mas , Transducción de Señal/genética , Neoplasias de la Tiroides/metabolismoRESUMEN
We show that electrochemical formation of long probes with nanosharp tips can be controlled by choosing an appropriate thermodynamic pathway of metal to metal oxide and hydroxide transformation. Currently, convection-limited electropolishing (CLE) is extensively used. Nanosharp probes are produced by electrochemically etching a wire until it breaks into two pieces. This process is difficult to control because of the complexity of the associated hydrodynamic flows. We introduce transport-limited electropolishing (TLE), where the electrochemical reaction results in the formation of metal oxides and hydroxides which form a porous surface layer hindering the flow of electrolyte. The developed TLE method enables one to make long tapered needles. The taper can spread over more than 6 mm while the radius of tip curvature can be decreased down to 30 nm. These needles are strong and were successfully applied for piercing single smooth vascular muscle cells.
RESUMEN
Management of vascular surgical emergencies requires rapid access to a vascular surgeon and hospital with the infrastructure necessary to manage vascular emergencies. The purpose of this study was to assess the impact of regionalization of vascular surgery services in Toronto to University Health Network (UHN) and St Michael's Hospital (SMH) on the ability of CritiCall Ontario to transfer patients with life- and limb-threatening vascular emergencies for definitive care. A retrospective review of the CritiCall Ontario database was used to assess the outcome of all calls to CritiCall regarding patients with vascular disease from April 2003 to March 2010. The number of patients with vascular emergencies referred via CritiCall and accepted in transfer by the vascular centers at UHN or SMH increased 500% between 1 April 2003-31 December 2005 and 1 January 2006-31 March 2010. Together, the vascular centers at UHN and SMH accepted 94.8% of the 1002 vascular surgery patients referred via CritiCall from other hospitals between 1 January 2006 and 31 March 2010, and 72% of these patients originated in hospitals outside of the Toronto Central Local Health Integration Network. Across Ontario, the number of physicians contacted before a patient was accepted in transfer fell from 2.9 ± 0.4 before to 1.7 ± 0.3 after the vascular centers opened. In conclusion, the vascular surgery centers at UHN and SMH have become provincial resources that enable the efficient transfer of patients with vascular surgical emergencies from across Ontario. Regionalization of services is a viable model to increase access to emergent care.
Asunto(s)
Servicios Médicos de Urgencia/organización & administración , Accesibilidad a los Servicios de Salud/organización & administración , Hospitales Universitarios/organización & administración , Mejoramiento de la Calidad/organización & administración , Regionalización/organización & administración , Procedimientos Quirúrgicos Vasculares/organización & administración , Análisis de Varianza , Humanos , Modelos Organizacionales , Ontario , Admisión del Paciente , Transferencia de Pacientes/organización & administración , Evaluación de Programas y Proyectos de Salud , Derivación y Consulta/organización & administración , Estudios Retrospectivos , Factores de Tiempo , Tiempo de Tratamiento/organización & administraciónRESUMEN
Alveolar rhabdomyosarcoma is an aggressive pediatric cancer exhibiting skeletal-muscle differentiation. New therapeutic targets are required to improve the dismal prognosis for invasive or metastatic alveolar rhabdomyosarcoma. Protein kinase C iota (PKCι) has been shown to have an important role in tumorigenesis of many cancers, but little is known about its role in rhabdomyosarcoma. Our gene-expression studies in human tumor samples revealed overexpression of PRKCI. We confirmed overexpression of PKCι at the mRNA and protein levels using our conditional mouse model that authentically recapitulates the progression of rhabdomyosarcoma in humans. Inhibition of Prkci by RNA interference resulted in a dramatic decrease in anchorage-independent colony formation. Interestingly, treatment of primary cell cultures using aurothiomalate (ATM), which is a gold-containing classical anti-rheumatic agent and a PKCι-specific inhibitor, resulted in decreased interaction between PKCι and Par6, decreased Rac1 activity and reduced cell viability at clinically relevant concentrations. Moreover, co-treatment with ATM and vincristine (VCR), a microtubule inhibitor currently used in rhabdomyosarcoma treatment regimens, resulted in a combination index of 0.470-0.793 through cooperative accumulation of non-proliferative multinuclear cells in the G2/M phase, indicating that these two drugs synergize. For in vivo tumor growth inhibition studies, ATM demonstrated a trend toward enhanced VCR sensitivity. Overall, these results suggest that PKCι is functionally important in alveolar rhabdomyosarcoma anchorage-independent growth and tumor-cell proliferation and that combination therapy with ATM and microtubule inhibitors holds promise for the treatment of alveolar rhabdomyosarcoma.
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Isoenzimas/metabolismo , Terapia Molecular Dirigida/métodos , Proteína Quinasa C/metabolismo , Rabdomiosarcoma Alveolar/tratamiento farmacológico , Rabdomiosarcoma Alveolar/enzimología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quimioterapia Adyuvante , Sinergismo Farmacológico , Fase G2/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Tiomalato Sódico de Oro/farmacología , Tiomalato Sódico de Oro/uso terapéutico , Humanos , Isoenzimas/deficiencia , Isoenzimas/genética , Ratones , Proteína Quinasa C/deficiencia , Proteína Quinasa C/genética , Interferencia de ARN , ARN Interferente Pequeño/genética , Rabdomiosarcoma Alveolar/metabolismo , Rabdomiosarcoma Alveolar/patología , Vincristina/farmacología , Vincristina/uso terapéuticoRESUMEN
Bordetella bronchiseptica is a zoonotic respiratory pathogen commonly found in domesticated farm and companion animals, including dogs and cats. Here, we report isolation of B. bronchiseptica from a sputum sample of a cystic fibrosis patient recently exposed to a kitten with an acute respiratory illness. Genetic characterization of the isolate and comparison with other isolates of human or feline origin strongly suggest that the kitten was the source of infection.