RESUMEN
BACKGROUND: Studies on the effectiveness of multimodal analgesia, particularly in patients at higher perioperative risk from obstructive sleep apnoea (OSA), are lacking. We aimed to assess the impact of multimodal analgesia on opioid use and complications in this high-risk cohort. METHODS: We conducted a population-based retrospective cohort study of OSA patients undergoing elective lower extremity joint arthroplasty (2006-16, Premier Healthcare database). Multimodal analgesia was defined as opioid use with the addition of one, two, or more non-opioid analgesic modes including, nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 inhibitors, paracetamol/acetaminophen, peripheral nerve blocks, steroids, gabapentin/pregabalin, or ketamine. Multilevel multivariable regression models measured associations between multimodal analgesia and opioid prescription (primary outcome; oral morphine equivalents). Secondary outcomes included opioid- and OSA-related complications, and resource utilisation. Odds ratios (OR) or % change and 95% confidence intervals (CI) are reported. RESULTS: Among 181 182 OSA patients included, 88.5% (n = 160 299) received multimodal analgesia with increasing utilisation trends. Multivariable models showed stepwise beneficial postoperative outcome effects with increasing additional analgesic modes compared with opioid-only analgesia. In patients who received more than two additional analgesia modes (n = 64 174), opioid dose prescription decreased by 14.9% (CI -17.0%; -12.7%), while odds were significantly decreased for gastrointestinal complications (OR 0.65, CI 0.53; 0.78), mechanical ventilation (OR 0.23, CI 0.16; 0.32), and critical care admission (OR 0.60, CI 0.48; 0.75), all P<0.0001. CONCLUSIONS: In a population at high risk for perioperative complications from OSA, multimodal analgesia was associated with a stepwise reduction in opioid use and complications, including critical respiratory failure.
Asunto(s)
Analgésicos no Narcóticos/administración & dosificación , Artroplastia de Reemplazo de Cadera/efectos adversos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Manejo del Dolor/métodos , Dolor Postoperatorio/prevención & control , Apnea Obstructiva del Sueño/complicaciones , Anciano , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Bases de Datos Factuales , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Utilización de Medicamentos/estadística & datos numéricos , Procedimientos Quirúrgicos Electivos/efectos adversos , Femenino , Recursos en Salud/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , North Carolina/epidemiología , Dolor Postoperatorio/epidemiología , Dolor Postoperatorio/etiología , Cuidados Posoperatorios/métodos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , Estudios Retrospectivos , Apnea Obstructiva del Sueño/epidemiologíaRESUMEN
Although the role of metastatic cancer stem cells (mCSCs) in tumor progression has been well documented, our study reveals a hitherto unidentified role of tumorigenic intrinsic CSCs (iCSCs) in breast cancer metastasis. We show that unlike highly migratory mCSCs residing in the breast tumor disseminating/peripheral regions, iCSCs populate the inner mass of the tumor and are non-migratory. However iCSCs, via paracrine signaling, induce conversion of non-stem cancer cells to CSCs that (i) are identical to the previously reported mCSCs, and (ii) in contrast to iCSCs, express chemokine receptor, chemokine (C-X-C motif) receptor 4 (CXCR4), which is crucial for their metastatic potential. These mCSCs also demonstrate high in vivo tumorigenicity. Physical non-participation of iCSCs in metastasis is further validated in vivo, where only mCSCs are found to exist in the metastatic sites, lymph nodes and bone marrow, whereas the primary tumor retains both iCSCs and mCSCs. However, iCSCs ensure metastasis since their presence is crucial for deliverance of highly metastatic CXCR4(+) mCSCs to the migrating fraction of cells. Cumulatively, these results unveil a novel role of iCSCs in breast cancer metastasis as parental regulators of CXCR4(+) mCSCs, and highlight the therapeutic requisite of targeting iCSCs, but not CXCR4(+) mCSCs, to restrain breast cancer metastasis from the root by inhibiting the generation of mCSCs from iCSCs. Considering the pivotal role of iCSCs in tumor metastasis, the possibility of metastasis to be a 'stem cell phenomena' is suggested.
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Neoplasias de la Mama/genética , Movimiento Celular/genética , Células Madre Neoplásicas/patología , Receptores CXCR4/genética , Neoplasias de la Mama/patología , Carcinogénesis/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ganglios Linfáticos/patología , Células MCF-7 , Metástasis de la Neoplasia , Receptores CXCR4/biosíntesis , Transducción de SeñalRESUMEN
Despite the increasing prevalence of sleep apnoea, little information is available regarding its impact on the peri-operative outcome of patients undergoing posterior lumbar fusion. Using a national database, patients who underwent lumbar fusion between 2006 and 2010 were identified, sub-grouped by diagnosis of sleep apnoea and compared. The impact of sleep apnoea on various outcome measures was assessed by regression analysis. The records of 84,655 patients undergoing posterior lumbar fusion were identified and 7.28% (n = 6163) also had a diagnostic code for sleep apnoea. Compared with patients without sleep apnoea, these patients were older, more frequently female, had a higher comorbidity burden and higher rates of peri-operative complications, post-operative mechanical ventilation, blood product transfusion and intensive care. Patients with sleep apnoea also had longer and more costly periods of hospitalisation. In the regression analysis, sleep apnoea emerged as an independent risk factor for the development of peri-operative complications (odds ratio (OR) 1.50, confidence interval (CI) 1.38;1.62), blood product transfusions (OR 1.12, CI 1.03;1.23), mechanical ventilation (OR 6.97, CI 5.90;8.23), critical care services (OR 1.86, CI 1.71;2.03), prolonged hospitalisation and increased cost (OR 1.28, CI 1.19;1.37; OR 1.10, CI 1.03;1.18). Patients with sleep apnoea who undergo posterior lumbar fusion pose significant challenges to clinicians.
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Vértebras Lumbares/cirugía , Vigilancia de la Población , Complicaciones Posoperatorias/etiología , Medición de Riesgo/métodos , Síndromes de la Apnea del Sueño/epidemiología , Enfermedades de la Columna Vertebral/cirugía , Fusión Vertebral/métodos , Adulto , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Prevalencia , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Síndromes de la Apnea del Sueño/complicaciones , Síndromes de la Apnea del Sueño/diagnóstico , Enfermedades de la Columna Vertebral/complicaciones , Estados Unidos/epidemiologíaRESUMEN
With the existing knowledge of ATM's role in therapeutic resistance, the present study aimed at identifying the molecular mechanisms that influence ATM to oscillate between chemoresistance and chemosensitivity. We observed that the redox status of tumors functions as a major determinant of ATM-dependent 'resistance-to-apoptosis' molecular switch. At a low reactive oxygen species (ROS) condition during genotoxic insult, the ATM/sumoylated-IKKγ interaction induced NFκB activation that resisted JNK-mediated apoptosis, whereas increasing cellular ROS restored ATM/JNK apoptotic signaling. A search for the upstream missing link revealed that high ROS induces oxidation and ubiquitin-mediated degradation of PIASγ, thereby disrupting PIASγ-IKKγ cross talk, a pre-requisite for IKKγ sumoylation and subsequent NFκB activation. Interruption in the PIASγ-mediated resistance pathway channels ATM signaling toward ATM/JNK pro-death circuitry. These in vitro results also translated to sensitive and resistant tumor allograft mouse models in which low ROS-induced resistance was over-ruled in PIASγ knockout tumors, while its overexpression inhibited high ROS-dependent apoptotic cues. Cumulatively, our findings identified an unappreciated yet critical combinatorial function of cellular ROS and PIASγ in regulating ATM-mediated chemosensitization of resistant tumors. Thus, therapeutic strategies employing ROS upregulation to inhibit PIASγ during genotoxic therapy may, in future, help to eliminate the problems of NFκB-mediated tumor drug resistance.
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Apoptosis , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Resistencia a Antineoplásicos , Neoplasias/metabolismo , Proteínas Inhibidoras de STAT Activados/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Animales , Antineoplásicos/administración & dosificación , Proteínas de la Ataxia Telangiectasia Mutada/genética , Femenino , Humanos , Quinasa I-kappa B/genética , Quinasa I-kappa B/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , FN-kappa B/genética , FN-kappa B/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/fisiopatología , Proteínas de Unión a Poli-ADP-Ribosa , Proteínas Inhibidoras de STAT Activados/genética , Receptor Cross-Talk , SumoilaciónRESUMEN
Increasing numbers of posterior lumbar fusions are being performed. The purpose of this study was to identify trends in demographics, mortality and major complications in patients undergoing primary posterior lumbar fusion. We accessed data collected for the Nationwide Inpatient Sample for each year between 1998 and 2008 and analysed trends in the number of lumbar fusions, mean patient age, comorbidity burden, length of hospital stay, discharge status, major peri-operative complications and mortality. An estimated 1 288 496 primary posterior lumbar fusion operations were performed between 1998 and 2008 in the United States. The total number of procedures, mean patient age and comorbidity burden increased over time. Hospital length of stay decreased, although the in-hospital mortality (adjusted and unadjusted for changes in length of hospital stay) remained stable. However, a significant increase was observed in peri-operative septic, pulmonary and cardiac complications. Although in-hospital mortality rates did not change over time in the setting of increases in mean patient age and comorbidity burden, some major peri-operative complications increased. These trends highlight the need for appropriate peri-operative services to optimise outcomes in an increasingly morbid and older population of patients undergoing lumbar fusion.
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Vértebras Lumbares/cirugía , Fusión Vertebral/tendencias , Factores de Edad , Comorbilidad/tendencias , Femenino , Mortalidad Hospitalaria/tendencias , Humanos , Tiempo de Internación/estadística & datos numéricos , Tiempo de Internación/tendencias , Masculino , Persona de Mediana Edad , Distribución por Sexo , Fusión Vertebral/efectos adversos , Fusión Vertebral/mortalidad , Fusión Vertebral/estadística & datos numéricos , Estados Unidos/epidemiologíaRESUMEN
Abrogation of functional p53 is responsible for malignant cell transformation and maintenance of human papilloma virus (HPV)-infected cancer cells. Restoration of p53 has, therefore, been regarded as an important strategy for molecular intervention of HPV-associated malignancies. Here we report that differential regulation of pro- and anti-p53 setups not only upregulates p53 transcription but also stabilizes and activates p53 protein to ensure p53-induced apoptosis in HPV-18-infected cervical cancer. Functional restoration of p53 can be achieved by non-steroidal anti-inflammatory drug celecoxib via multiple molecular mechanisms: (i) inhibition of p53 degradation by suppressing viral oncoprotein E6 expression, (ii) promoting p53 transcription by downmodulating cycloxygenase-2 (Cox-2) and simultaneously retrieving p53 from Cox-2 association and (iii) activation of p53 via ataxia telangiectasia mutated-/p38 mitogen-activated protein kinase-mediated phosphorylations at serine-15/-46 residues. That restored p53 is functional has been confirmed by its ability of transactivating Bax and p53-upregulated modulator of apoptosis, which in turn switch on the apoptotic machinery in these cells. Studies undertaken in biopsy samples of cervical carcinoma further validated celecoxib effect. Our approaches involving gene manipulation and pharmacological interference finally highlight that celecoxib alters pro- and anti-p53 networks, not in isolation but in concert, to rejuvenate p53-dependent apoptotic program in HPV-infected cervical cancer cells.
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Genes p53 , Papillomavirus Humano 18/fisiología , Neoplasias del Cuello Uterino/virología , Apoptosis/efectos de los fármacos , Proteínas de la Ataxia Telangiectasia Mutada , Secuencia de Bases , Celecoxib , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Cartilla de ADN , Proteínas de Unión al ADN/metabolismo , Femenino , Papillomavirus Humano 18/aislamiento & purificación , Humanos , Fosforilación , Reacción en Cadena de la Polimerasa , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazoles/farmacología , Sulfonamidas/farmacología , Transcripción Genética/efectos de los fármacos , Proteínas Supresoras de Tumor/metabolismo , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
PURPOSE: Both patellofemoral arthroplasty (PFA) and total knee arthroplasty (TKA) are successful in treating isolated patellofemoral osteoarthritis, but the complication rates after PFA are concerning. We performed a meta-analysis to compare the incidence of complications, re-operations, and revision following PFA and TKA for patellofemoral osteoarthritis. METHODS: We systematically identified publications with patients who underwent PFA or TKA for patellofemoral osteoarthritis with minimum 1.5 year follow-up. Demographics, implant (TKA, first [1G] or second-generation [2G] PFA), complications, and cause of re-operations were extracted. Random-effects meta-analysis was used to pool incidence data, which was compared between groups using logistic regression to adjust for length of follow-up. RESULTS: Twenty-eight observational studies and no randomized trials were included in this meta-analysis, which limits its generalizability. There was a higher likelihood of any re-operation (odds ratio 8.06) and revision (OR 8.11) in PFA compared to TKA. Re-operation (OR 4.33) and revision (OR 4.93) were more likely in 1G-PFA than 2G-PFA. When comparing 2G-PFA to TKA, there was no significant difference in re-operation, revision, pain, or mechanical complications. CONCLUSIONS: Patients who undergo PFA rather than TKA are more likely to experience complications and require re-operation or revision, but subgroup analysis suggests a relation to implant design. There is no significant difference in re-operation, revision, pain, or mechanical complications between 2G-PFA and TKA. LEVEL OF EVIDENCE: Systematic review of Level III therapeutic studies, Level III.
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Artroplastia de Reemplazo de Rodilla/efectos adversos , Osteoartritis de la Rodilla/cirugía , Articulación Patelofemoral/cirugía , Artralgia/etiología , Artroplastia de Reemplazo de Rodilla/métodos , Progresión de la Enfermedad , Humanos , Prótesis de la Rodilla , ReoperaciónRESUMEN
Employment status is related to treatment recovery and quality of life in breast cancer survivors, yet little is known about return to work in immigrant and minority survivors. We conducted an exploratory qualitative study using ethnically cohesive focus groups of urban breast cancer survivors who were African-American, African-Caribbean, Chinese, Filipina, Latina, or non-Latina white. We audio- and video-recorded, transcribed, and thematically coded the focus group discussions and we analyzed the coded transcripts within and across ethnic groups. Seven major themes emerged related to the participants' work experiences after diagnosis: normalcy, acceptance, identity, appearance, privacy, lack of flexibility at work, and employer support. Maintaining a sense of normalcy was cited as a benefit of working by survivors in each group. Acceptance of the cancer diagnosis was most common in the Chinese group and in participants who had a family history of breast cancer; those who described this attitude were likely to continue working throughout the treatment period. Appearance was important among all but the Chinese group and was related to privacy, which many thought was necessary to derive the benefit of normalcy at work. Employer support included schedule flexibility, medical confidentiality, and help maintaining a normal work environment, which was particularly important to our study sample. Overall, we found few differences between the different ethnic groups in our study. These results have important implications for the provision of support services to and clinical management of employed women with breast cancer, as well as for further large-scale research in disparities and employment outcomes.
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Neoplasias de la Mama/etnología , Emigrantes e Inmigrantes/psicología , Empleo/psicología , Grupos Minoritarios/psicología , Sobrevivientes/psicología , Población Urbana , Adaptación Psicológica , Adulto , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/psicología , Emigrantes e Inmigrantes/estadística & datos numéricos , Empleo/estadística & datos numéricos , Etnicidad/psicología , Etnicidad/estadística & datos numéricos , Femenino , Grupos Focales , Humanos , Relaciones Interprofesionales , Persona de Mediana Edad , Grupos Minoritarios/estadística & datos numéricos , Investigación Cualitativa , Sobrevivientes/estadística & datos numéricos , Población Urbana/estadística & datos numéricosRESUMEN
BACKGROUND AND PURPOSE: Hypotension and bradycardia are common in carotid artery stenting (CAS) and are particularly worrisome in the high risk patient who is typically referred for CAS. The purpose of this work was to assess the incidence and predictors of hypotension and bradycardia and the risk of their delayed occurrence after CAS. MATERIALS AND METHODS: A total of 53 men and 40 women (median age, 71 years) with symptomatic (57%) or asymptomatic (42%) carotid artery stenosis had CAS performed in our institution between December 2002 and January 2007. Patient vital sign records for the 12 hours post-CAS were analyzed. The relative decrease of blood pressure and pulse rate were used as primary end points, and the requirement of pressor or anticholinergic drugs was used as a surrogate end point. Significant predictors of hypotension and bradycardia were analyzed with a logistic regression model. Cumulative freedom from hypotension and bradycardia was calculated by using the Kaplan-Meier method. Negative predictive value (NPV) of screening for early hypotension and bradycardia was determined. RESULTS: The incidence of hypotension, bradycardia, and both was 14%, 23%, and 15%, respectively. Drug intervention was required in 45 patients (48%). Asymptomatic stenosis was an independent predictor of hypotension and bradycardia. Stenosis proximity to the bifurcation and dilation percentage were independent predictors of the drug intervention requirement. Seven patients (8%) had new onset of hypotension or bradycardia later than 6 hours post-CAS. The NPV of early hypotension and bradycardia was 97% and 93%, respectively. CONCLUSION: In this retrospective study, the risk of hypotension or bradycardia after CAS is significantly influenced by the degree of dilation performed, and the risk of their delayed occurrence may justify a minimum of 12 hours postprocedural vital sign monitoring.
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Prótesis Vascular/estadística & datos numéricos , Bradicardia/epidemiología , Arterias Carótidas/cirugía , Enfermedades de las Arterias Carótidas/epidemiología , Enfermedades de las Arterias Carótidas/cirugía , Hipotensión/epidemiología , Medición de Riesgo/métodos , Stents/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Comorbilidad , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , New York , Evaluación de Resultado en la Atención de Salud , Factores de Riesgo , Resultado del TratamientoRESUMEN
Type 1 17beta-hydroxysteroid dehydrogenase (17beta-HSD1) is a key steroidogenic enzyme that catalyses the reduction of steroid estrone into the most potent endogenous estrogen estradiol using the cofactor NAD(P)H. Bisubstrate inhibition is a good way to enhance the potency of inhibitors of cofactor-assisted enzymes. The design of a bisubstrate inhibitor of 17beta-HSD1, the estradiol/adenosine hybrid EM-1745, is reviewed and strategies for future designs of inhibitors are proposed.
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17-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , 17-Hidroxiesteroide Deshidrogenasas/química , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Cristalización , Humanos , Especificidad por SustratoRESUMEN
OBJECTIVE: This prospective blinded comparison of helical CT and helical CT arterial portography aimed to detect liver metastasis from colorectal carcinoma. METHODS AND MATERIALS: 50 patients with colorectal carcinoma were evaluated comparing helical CT with helical CT arterial portography. Each imaging study was evaluated on a 5-point ROC scale by radiologists blinded to the other imaging findings, and the results were compared, with the surgical and pathologic findings as the gold standard. RESULTS: Of the 127 lesions found at pathology identified as metastatic colorectal cancer, helical CT correctly identified 85 (69%) and CT portography 96 (76%). When subgroups with lesions <3 cm (48 patients) and patients with maximum tumor size <3 cm (18 patients) were considered, CT portography was always better than helical CT in terms of sensitivity, specificity, positive predictive value, and negative predictive value. ROC analysis adjusting for multiple lesions per patient revealed significantly greater area under the curve (AUC) for the subgroup of lesions <3 cm (CT-AUC of 77% and CT portography AUC of 81%; P = 0.002). CONCLUSIONS: For identification of large metastases, helical CT and CT portography have similar yield. However, for detection of small liver metastases, CT portography remains superior for lesion detectability.
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Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/secundario , Portografía/métodos , Tomografía Computarizada Espiral , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Hepatectomía , Humanos , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Estudios Prospectivos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Protein crystal growth (PCG) remains the bottleneck of crystallography despite many decades of study. The nucleation zone in the two-dimensional-phase diagram has been used to evaluate the relative crystallizability of proteins, which is expressed as a percentage over the phase area delineated by experimental protein and precipitating agent concentration ranges. For protein-salts which are subject to a direct temperature effect on solubility, as represented by Egg Lysozyme, a decrease in temperature augments the nucleation zone percentage whereas for those with retrograde solubility as a function of temperature, for example fructose-1,6-bisphosphatase in the presence and absence of AMP, an increase in temperature can significantly enhance the relative crystallizability. These results have been confirmed by the number of "hits" using PEGs as precipitating agents in Sparse Matrix Screen experiments for different proteins and are in excellent agreement with the relative crystallizability. The relationship between solubility dependence, relative crystallizability and crystallization success, has been evidenced. Such crystallizability can become a guide to identify efficient crystallization regions, providing a rational approach to PCG and structural biology.
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Cristalización , Cristalografía por Rayos X/métodos , Músculos/metabolismo , Proteínas/química , Adenosina Monofosfato/química , Animales , Pollos , Fructosa-Bifosfatasa/química , Concentración de Iones de Hidrógeno , Muramidasa/química , Polietilenglicoles/química , Conformación Proteica , Serpientes , Solubilidad , TemperaturaRESUMEN
We report two unrelated boys with the X-linked creatine transporter defect (CRTR) and clinical features more severe than those previously described with this disorder. These two boys presented at ages 12 and 30 months with severe mental retardation, absent speech development, hypotonia, myopathy and extra-pyramidal movement disorder. One boy has seizures and some dysmorphic features; he also has evidence of an oxidative phosphorylation defect. They both had classical absence of creatine peak on brain magnetic resonance spectroscopy (MRS). In one, however, this critical finding was overlooked in the initial interpretation and was discovered upon subsequent review of the MRS. Molecular studies showed large genomic deletions of a large part of the 3' end of the complete open reading frame of the SLC6A8 gene. This report emphasizes the importance of MRS in evaluating neurological symptoms, broadens the phenotypic spectrum of CRTR and adds knowledge about the pathogenesis of creatine depletion in the brain and retina.
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Cromosomas Humanos X , Proteínas de Transporte de Membrana/deficiencia , Proteínas de Transporte de Membrana/genética , Errores Innatos del Metabolismo/genética , Preescolar , Ojo/patología , Eliminación de Gen , Humanos , Lactante , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Espectroscopía de Resonancia Magnética , Masculino , Errores Innatos del Metabolismo/diagnóstico , Proteínas del Tejido Nervioso/genética , Oxígeno/metabolismo , Fenotipo , Fosforilación , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/genéticaRESUMEN
The present study aimed to determine whether beta-endorphin immunoreactivity (bEP-ir) in the neurones of the nucleus lateralis tuberis (NLT) is linked to the seasonal cycle and shows correlation with the number of luteinising hormone (LH) cells in the pituitary gland and ovaries in the teleost, Cirrhinus mrigala. Although LH cells were moderately immunostained during the resting phase (December to January), the morphological profile suggested increased synthetic and secretory activity during the preparatory (February to April) and prespawning (May to June) phases. However, LH immunoreactivity was greatly reduced (P < 0.001) in the spawning (July to August) phase, suggesting massive discharge of the hormone; this pool was partly replenished in the postspawning (September to November) phase. The ovaries grew rapidly in the preparatory and prespawning phases; maximal size was attained during spawning, when ovulation occurred. Thereafter, the ovaries regressed. The NLT of C. mrigala is divisible into the pars lateralis (NLTl) and medialis (NLTm). During the postspawning and resting phases, bEP-ir was readily detectable in the NLTm as well as NLTl neurones. However, a steady reduction in the immunoreactivity was observed in the NLTm neurones during the preparatory through spawning phases (P < 0.001), suggesting a negative correlation with the LH cells-ovary axis. Thus, the inhibitory influence of beta-endorphin on the gonadotrophin-releasing hormone (GnRH)-LH axis appears to be attenuated during the preparatory through spawning phases. This may be necessary for the rapid stimulation of the axis culminating in spawning. Neurones of the NLTl also showed a gradual reduction in bEP-ir during the preparatory and prespawning phases (P < 0.01) and may therefore play a similar role. However, significant augmentation of the immunoreactivity was noticed in these neurones during the spawning phase (P < 0.001), the physiological significance of which is unknown. Although the present study demonstrated a temporal correlation between the beta-endorphin in the NLT, LH cells and the ovary, we suggest that the peptide in the NLTl and NLTm may show functional duality during the spawning phase.
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Carpas/metabolismo , Hipotálamo/metabolismo , Reproducción/fisiología , Estaciones del Año , betaendorfina/metabolismo , Animales , Femenino , Sistema Hipotálamo-Hipofisario/metabolismo , Hipotálamo/citología , Hormona Luteinizante/metabolismo , Neuronas/metabolismo , Ovario/metabolismo , Hipófisis/citología , Hipófisis/metabolismoRESUMEN
BACKGROUND: Accurate response assessment is essential for evaluating new cancer treatments. We evaluated the impact of Response Evaluation Criteria in Solid Tumors (RECIST), World Health Organization (WHO) criteria and tumor shape on response assessment in patients with metastatic esophageal cancer. PATIENTS AND METHODS: In 19 patients with metastatic esophageal cancer in a phase II trial of bryostatin-1 and paclitaxel, response was retrospectively assessed for 89 lesions with RECIST and WHO criteria on baseline and serial follow-up CT scans. The eccentricity factor (EF) was introduced for measuring the degree to which tumor shape diverges from a perfect sphere [EF = radical1-(LPD/MD)(2), where LPD is the largest perpendicular diameter and MD is the maximal diameter]. RESULTS: The disagreement rate in best overall response categorization between RECIST (unidimensional) and WHO (bidimensional) criteria was 26.3%. Change in eccentricity was significantly greater (P < 0.01) for patients with disagreement (mean 0.31, range 0-0.91). When the short axis was used for unidimensional lymph node measurement, disagreement between WHO and RECIST lessened. CONCLUSIONS: Response assessment by WHO and RECIST differs substantially. Greater change in eccentricity is associated with greater discordance between WHO and RECIST. The discordance between WHO and RECIST may impact on how effective a therapy is judged to be.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/terapia , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Brioestatinas , Neoplasias Esofágicas/patología , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Macrólidos/administración & dosificación , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/patología , Paclitaxel/administración & dosificación , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: The purpose of this study was to retrospectively analyze the relationship between neo-adjuvant chemotherapy (NAC) and outcome in patients with high-grade extremity sarcomas. PATIENTS AND METHODS: Inclusion criteria were high-grade, deep, >5 cm extremity soft tissue sarcomas. Patients diagnosed between 1990 and 2001 were treated with surgery only (n=282) or NAC containing doxorubicin/ifosfamide/mesna (AIM) (n=74). The stratified Cox proportional hazards model was used to test the effect of NAC on disease-specific survival and recurrence while adjusting for known prognostic factors. RESULTS: NAC was associated with improved disease-specific survival for this cohort of patients (P=0.02). This overall improvement appears to be driven by the benefit of NAC on disease-specific survival for patient with tumors >10 cm. The 3-year disease-specific survival for tumors >10 cm was 0.62 (95% CI: 0.53-0.71) for patients not receiving NAC and 0.83 (95% CI: 0.72-0.95) for patients receiving NAC. CONCLUSION: NAC with AIM was associated with a significant improvement in disease-specific survival in patients with high-grade extremity soft tissue sarcomas >10 cm. These data emphasize the need for further prospective clinical studies of neo-adjuvant or adjuvant chemotherapy for patients with large high-grade extremity sarcomas.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Extremidades , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Estudios de Cohortes , Humanos , Ifosfamida/administración & dosificación , Mesna/administración & dosificación , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Estudios Retrospectivos , Sarcoma/patología , Neoplasias de los Tejidos Blandos/patología , Análisis de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
STATEMENT OF THE PROBLEM: The sheep erythrocyte membrane glycoprotein T11TS/SLFA-3 can form a ligand-receptor complex with CD2 present on immunocyte and exert stimuli for activation and proliferation. Regression of brain tumor with the application of T11TS indicates the probable role of microglia, the chief immunomodulatory cell within the brain compartment. In the present study microglial activation and immunophenotypic modulation were assessed in T11TS treated brain tumor-bearing animal models. Rat glioma models induced by chemical carcinogen ENU were treated with three consecutive doses of T11TS. Microglial cells from brain were isolated and assessed through E-rosette formation, SEM and FACS for CD2, MHC class II, CD25, and CD4. The preliminary indication of presence of CD2 on microglia through E-rosette formation was confirmed by SEM and FACS. MHC class II and CD2 single and double positive subpopulations exist, and their expression is also modulated in different doses of T11TS. A general trend of highest receptor saturation and microglial activation, measured through the activation marker CD25 and CD4 expression, was observed in 2nd dose of T11TS administration, which was then dampened via a complex immune feedback mechanism in the 3rd dose.
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Neoplasias Encefálicas/inmunología , Membrana Celular/metabolismo , Glioma/patología , Microglía/metabolismo , Alquilantes , Animales , Biomarcadores/química , Encéfalo/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Antígenos CD2/biosíntesis , Antígenos CD4/biosíntesis , Proliferación Celular , Separación Celular , Eritrocitos/citología , Etilnitrosourea , Citometría de Flujo , Glioma/metabolismo , Glicopéptidos/química , Inmunofenotipificación , Ligandos , Microscopía Electrónica de Rastreo , Unión Proteica , Ratas , Receptores de Interleucina-2/biosíntesis , Formación de Roseta , OvinosRESUMEN
The relationship between pretreatment clinical features and survival was studied from patients treated on clinical trials for metastatic renal cell carcinoma (RCC) at the Memorial Sloan-Kettering Cancer Center. The primary analysis was performed on 670 patients treated with cytokines or chemotherapy, from which a multivariate model was derived to predict survival. Studies which followed addressed: (1) the survival of patients given interferon-alpha as first-line therapy; (2) a comparison of survival for patients treated with chemotherapy versus cytokine therapy; and (3) survival of patients with non-clear cell histology. Prospective identification of patients more likely to benefit from cytokine therapy is important as a stratification factor in phase III trials, and in risk-directed therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/secundario , Factores Inmunológicos/uso terapéutico , Interferón-alfa/uso terapéutico , Interleucina-2/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/mortalidad , Ensayos Clínicos como Asunto , Supervivencia sin Enfermedad , Humanos , Neoplasias Renales/inmunología , Neoplasias Renales/mortalidad , Análisis Multivariante , Metástasis de la Neoplasia , PronósticoRESUMEN
PURPOSE: This paper reports on the development and validation of two biologic response modifier (BRM) subscales for use with the Functional Assessment of Cancer Therapy-General (FACT-G) quality of life (QOL) questionnaire. METHODS: Using the FACT-G as a base, 17 additional questions related to symptoms common to interferon and retinoid therapy were developed. Data collected at baseline (n = 191) and week 2 (n = 168) in a randomized trial of interferon +/- 13-cis-retinoic acid in advanced renal cell carcinoma patients were used to validate this measure. RESULTS: Using a combined empirical and conceptual approach, the 17 questions were reduced to 13 questions consisting of two subscales: 'BRM-physical' (7 items; baseline coefficient alpha(alpha) = 0.70; week-2 alpha = 0.75) and 'BRM-mental' (6 items; baseline alpha = 0.79; week-2 alpha = 0.78). Internal consistency of the trial outcome index (TOI) combining physical well-being, functional well-being and the BRM subscales, was 0.91 for baseline assessments and 0.92 for week 2. Discriminant validity was demonstrated for the TOI by its ability to differentiate among prognostic risk groups, and for the total FACT-G, TOI and total FACT-BRM scores by their ability to distinguish between groups differing in performance, response and toxicity status. CONCLUSIONS: The 'BRM-physical' and 'BRM-mental' subscales can be combined with the FACT-G to form the 'FACT BRM' scale, useful for measuring QOL in cancer patients who are receiving treatment with biologic response modifiers.