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1.
Am J Drug Alcohol Abuse ; 47(6): 704-710, 2021 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-33780650

RESUMEN

Background: Alcohol use disorder (AUD) is associated with thiamine deficiency and Wernicke-Korsakoff Syndrome (WKS). Thiamine supplementation for the prevention of WKS in patients with suspected AUD in the Emergency Department (ED) is generally recommended. As alcohol-related diagnoses are frequent reasons for visits to EDs, ED thiamine prescribing practices are relevant to the overall management and prevention of WKS in patients with AUD.Objective: To determine the prescription rates of thiamine to patients with alcohol-related diagnoses in the ED.Methods: This was a retrospective chart review conducted at two New York City urban teaching hospitals from January 1 to December 31, 2017. All patients 18 years or older who were given an alcohol-related diagnosis (all F10 ICD-10-CM codes) upon disposition were included. Collected data included details of thiamine prescribing practices, patient demographics and patient disposition.Results: A total of 7,529 patient visits with an alcohol-related diagnosis were identified. The overall median age of included patients was 44; 5747 (76.3%) patient visits were by men; 310 (4.1%) patient visits resulted in admission. Out of all patient visits, thiamine was ordered during 167 (2.2%) visits, with thiamine administered parenterally during 129 (77.2%) visits and orally in 38 (22.8%) visits. Out of patient visits specifically associated with an F10.2 (Alcohol Dependence) diagnosis, thiamine was ordered during 105 (17.8%) visits.Conclusion: We found a very low rate of thiamine prescribing during patient visits associated with alcohol-related diagnoses. This may be a missed opportunity to reduce morbidity and mortality among AUD ED patients.


Asunto(s)
Síndrome de Korsakoff , Deficiencia de Tiamina , Adulto , Servicio de Urgencia en Hospital , Humanos , Síndrome de Korsakoff/diagnóstico , Masculino , Estudios Retrospectivos , Tiamina/uso terapéutico , Deficiencia de Tiamina/tratamiento farmacológico , Deficiencia de Tiamina/epidemiología
2.
mBio ; 11(3)2020 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-32398311

RESUMEN

Candida auris has emerged as a multidrug-resistant pathogen of great clinical concern. Approximately 90% of clinical C. auris isolates are resistant to fluconazole, the most commonly prescribed antifungal agent, and yet it remains unknown what mechanisms underpin this fluconazole resistance. To identify novel mechanisms contributing to fluconazole resistance in C. auris, fluconazole-susceptible C. auris clinical isolate AR0387 was passaged in media supplemented with fluconazole to generate derivative strains which had acquired increased fluconazole resistance in vitro Comparative analyses of comprehensive sterol profiles, [3H]fluconazole uptake, sequencing of C. auris genes homologous to genes known to contribute to fluconazole resistance in other species of Candida, and relative expression levels of C. aurisERG11, CDR1, and MDR1 were performed. All fluconazole-evolved derivative strains were found to have acquired mutations in the zinc-cluster transcription factor-encoding gene TAC1B and to show a corresponding increase in CDR1 expression relative to the parental clinical isolate, AR0387. Mutations in TAC1B were also identified in a set of 304 globally distributed C. auris clinical isolates representing each of the four major clades. Introduction of the most common mutation found among fluconazole-resistant clinical isolates of C. auris into fluconazole-susceptible isolate AR0387 was confirmed to increase fluconazole resistance by 8-fold, and the correction of the same mutation in a fluconazole-resistant isolate, AR0390, decreased fluconazole MIC by 16-fold. Taken together, these data demonstrate that C. auris can rapidly acquire resistance to fluconazole in vitro and that mutations in TAC1B significantly contribute to clinical fluconazole resistance.IMPORTANCECandida auris is an emerging multidrug-resistant pathogen of global concern, known to be responsible for outbreaks on six continents and to be commonly resistant to antifungals. While the vast majority of clinical C. auris isolates are highly resistant to fluconazole, an essential part of the available antifungal arsenal, very little is known about the mechanisms contributing to resistance. In this work, we show that mutations in the transcription factor TAC1B significantly contribute to clinical fluconazole resistance. These studies demonstrated that mutations in TAC1B can arise rapidly in vitro upon exposure to fluconazole and that a multitude of resistance-associated TAC1B mutations are present among the majority of fluconazole-resistant C. auris isolates from a global collection and appear specific to a subset of lineages or clades. Thus, identification of this novel genetic determinant of resistance significantly adds to the understanding of clinical antifungal resistance in C. auris.


Asunto(s)
Antifúngicos/farmacología , Candida/efectos de los fármacos , Candida/genética , Farmacorresistencia Fúngica/genética , Fluconazol/farmacología , Proteínas Fúngicas/genética , Pruebas de Sensibilidad Microbiana , Mutación , Factores de Transcripción/genética
3.
Nat Commun ; 8(1): 676, 2017 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-28939807

RESUMEN

Zika virus infection during pregnancy can cause congenital abnormities or fetal demise. The persistence of Zika virus in the male reproductive system poses a risk of sexual transmission. Here we demonstrate that live-attenuated Zika virus vaccine candidates containing deletions in the 3' untranslated region of the Zika virus genome (ZIKV-3'UTR-LAV) prevent viral transmission during pregnancy and testis damage in mice, as well as infection of nonhuman primates. After a single-dose vaccination, pregnant mice challenged with Zika virus at embryonic day 6 and evaluated at embryonic day 13 show markedly diminished levels of viral RNA in maternal, placental, and fetal tissues. Vaccinated male mice challenged with Zika virus were protected against testis infection, injury, and oligospermia. A single immunization of rhesus macaques elicited a rapid and robust antibody response, conferring complete protection upon challenge. Furthermore, the ZIKV-3'UTR-LAV vaccine candidates have a desirable safety profile. These results suggest that further development of ZIKV-3'UTR-LAV is warranted for humans.Zika virus infection can result in congenital disorders and cause disease in adults, and there is currently no approved vaccine. Here Shan et al. show that a single dose of a live-attenuated Zika vaccine prevents infection, testis damage and transmission to the fetus during pregnancy in different animal models.


Asunto(s)
Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Vacunas Virales/uso terapéutico , Infección por el Virus Zika/prevención & control , Virus Zika/inmunología , Animales , Evaluación Preclínica de Medicamentos , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Embarazo , Testículo/patología , Testículo/virología , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/efectos adversos , Vacunas Atenuadas/uso terapéutico , Vacunas Virales/administración & dosificación , Vacunas Virales/efectos adversos , Virus Zika/genética , Infección por el Virus Zika/transmisión
4.
Ann Agric Environ Med ; 22(4): 685-9, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26706978

RESUMEN

OBJECTIVES: The aim of this study was to describe the aerobiological characteristics of NE Greece, identify the most prevalent taxa, define the duration of the main pollen season and correlate allergen records with meteorological parameters. MATERIALS AND METHOD: A 7-day volumetric trap, running continuously throughout the year, was used to collect circulating pollen. Pollen taxa were characterized by standard protocols and counted as grains/m(3) . The main pollen season was deduced from these data and running means (10-day averages) were plotted against time. Correlations with climatic factors (temperature, rain, humidity, wind velocity) were assessed by single linear regression analysis. RESULTS: In total, 11 pollen families were identified, including 6 arboreal and 5 non-arboreal taxa. The 5 most prevalent taxa were Oleaceae, Fagaceae, Poaceae, Cupressaceae and Pinaceae. Peak pollen concentrations were detected in April and May, with daily averages exceeding 410 grains/m(3) . Compositeae had the longest pollen season of 135 days and Oleaceae the shortest, extending to only 27 days. Correlations with meteorological parameters showed variable associations among different taxa, with mean temperature (p<0.001), relative humidity (p=0.015), and wind speed (p=0.042) emerging as the most significant determinants as regards total pollen counts. CONCLUSIONS: Describing the aerobiological characteristics of NE Greece enabled the identification of allergenic risks that are specific for this region. Records generated in this study can be used to alert sensitized individuals of prevailing seasonal patterns, in order to take necessary precautions against imminent exposures. The monitoring system established here can serve as a reference guide for future epidemiological research focusing on allergic asthma and rhinitis.


Asunto(s)
Alérgenos/inmunología , Polen/inmunología , Tiempo (Meteorología) , Alérgenos/clasificación , Grecia , Humanos , Polen/clasificación , Estaciones del Año
5.
Ann Emerg Med ; 65(4): 410-5, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25441767

RESUMEN

STUDY OBJECTIVE: Calcium channel blocker poisonings account for a substantial number of reported deaths from cardiovascular drugs. Although supportive care is the mainstay of treatment, experimental therapies such as high-dose insulin-euglycemia and lipid emulsion have been studied in animal models and used in humans. In the most severe cases, even aggressive care is inadequate and deaths occur. In both experimental models and clinical cases of vasodilatory shock, methylene blue improves hemodynamic measures. It acts as a nitric oxide scavenger and inhibits guanylate cyclase that is responsible for the production of cyclic guanosine monophosphate (cGMP). Excessive cGMP production is associated with refractory vasodilatory shock in sepsis and anaphylaxis. The aim of this study is to determine the efficacy of methylene blue in an animal model of amlodipine-induced shock. METHODS: Sprague-Dawley rats were anesthetized, ventilated, and instrumented for continuous blood pressure and pulse rate monitoring. The dose of amlodipine that produced death within 60 minutes was 17 mg/kg per hour (LD50). Rats were divided into 2 groups: amlodipine followed by methylene blue or amlodipine followed by normal saline solution, with 15 rats in each group. Rats received methylene blue at 2 mg/kg during 5 minutes or an equivalent amount of normal saline solution in 3 intervals from the start of the protocol: minutes 5, 30, and 60. The animals were observed for a total of 2 hours after the start of the protocol. Mortality risk and survival time were analyzed with Fisher's exact test and Kaplan-Meier survival analysis with the log rank test. RESULTS: Overall, 1 of 15 rats (7%) in the saline solution-treated group survived to 120 minutes compared with 5 of 15 (33%) in the methylene blue-treated group (difference -26%; 95% confidence interval [CI] -54% to 0.3%). The median survival time for the normal saline solution group was 42 minutes (95% CI 28.1 to 55.9 minutes); for the methylene blue group, 109 minutes (95% CI 93.9 to 124.1 minutes). Pulse rate and mean arterial pressure (MAP) differences between groups were analyzed until 60 minutes. Pulse rate was significantly higher in the methylene blue-treated group beginning 25 minutes after the start of the amlodipine infusion (95% CI 30 to 113 minutes) that was analyzed until 60 minutes. MAP was significantly higher in the methylene blue-treated group starting 25 minutes after the amlodipine infusion (95% CI 2 to 30 minutes) that was analyzed until 60 minutes. CONCLUSION: Methylene blue did not result in a significant difference in mortality risk. There was an increased pulse rate, MAP, and median survival time in the methylene blue group.


Asunto(s)
Bloqueadores de los Canales de Calcio/envenenamiento , Depuradores de Radicales Libres/uso terapéutico , Azul de Metileno/uso terapéutico , Choque/inducido químicamente , Amlodipino/envenenamiento , Animales , Modelos Animales de Enfermedad , Guanilato Ciclasa/antagonistas & inhibidores , Ratas Sprague-Dawley
6.
Circ Cardiovasc Qual Outcomes ; 7(4): 508-16, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24987051

RESUMEN

BACKGROUND: The National Institutes of Health.funded Trial to Assess Chelation Therapy (TACT) randomized 1708 stablecoronary disease patients aged .50 years who were .6 months post.myocardial infarction (2003.2010) to 40 infusions ofa multicomponent EDTA chelation solution or placebo. Chelation reduced the primary composite end point of mortality,recurrent myocardial infarction, stroke, coronary revascularization, or hospitalization for angina (hazard ratio, 0.82; 95%confidence interval, 0.69.0.99; P=0.035). METHODS AND RESULTS: In a randomly selected subset of 911 patients, we prospectively collected a battery of quality-of-life(QOL) instruments at baseline and at 6, 12, and 24 months after randomization. The prespecified primary QOL measures were the Duke Activity Status Index (Table I in the Data Supplement) and the Medical Outcomes Study Short-Form 36 Mental Health Inventory-5. All comparisons were by intention to treat. Baseline clinical and QOL variables were well balanced in the 451 patients randomized to chelation and in the 460 patients randomized to placebo. The Duke Activity Status Index improved in both groups during the first 6 months of therapy, but we found no evidence for a treatment-related difference (mean difference [chelation.placebo] during follow-up, 0.9 [95% confidence interval, .0.7 to 2.6; P=0.27]).There was no statistically significant evidence of a treatment-related difference in the Mental Health Inventory-5 during follow-up (mean difference, 1.0; 95% confidence interval, .0.1 to 2.0; P=0.08). None of the secondary QOL measures showed a consistent treatment-related difference. CONCLUSIONS: In stable, predominantly asymptomatic coronary disease patients with a history of myocardial infarction,EDTA chelation therapy did not have a detectable effect on QOL during 2 years of follow-up. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00044213.


Asunto(s)
Terapia por Quelación/métodos , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Ácido Edético/administración & dosificación , Calidad de Vida , Adulto , Anciano , Quelantes del Calcio/administración & dosificación , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento
7.
Magn Reson Med ; 71(5): 1819-25, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-23798343

RESUMEN

PURPOSE: To demonstrate the feasibility of performing 39-potassium MR imaging of a human brain. METHODS: 39-Potassium magnetic resonance imaging of a human brain was performed at 9.4 T using a flexible twisted projection imaging acquisition with a nominal isotropic spatial resolution of 10 mm in 40 min using a single-tuned birdcage radiofrequency coil. Co-registered sodium imaging with a nominal isotropic spatial resolution of 3.5 mm was performed on the same subject in 10 min. RESULTS: The 39-potassium flexible twisted projection imaging imaging had a signal-to-noise ratio of 5.2 in brain paranchyma. This qualitative imaging showed the expected features when compared to co-registered high- and low-resolution sodium imaging of the same subject. CONCLUSION: Potassium MR images may offer complementary information to that of sodium MR images by sampling the intracellular rather that interstitial environment. Quantification will require additional improvement in signal-to-noise ratio to produce clinically useful bioscales as are developing for sodium MR imaging.


Asunto(s)
Química Encefálica , Interpretación de Imagen Asistida por Computador/métodos , Imagen por Resonancia Magnética/métodos , Potasio/química , Medios de Contraste/química , Estudios de Factibilidad , Humanos , Aumento de la Imagen/métodos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Distribución Tisular
8.
Diabetes Care ; 36(2): 260-6, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23033239

RESUMEN

OBJECTIVE: Low vitamin D levels predict the development of diabetes. This double-blind, randomized, control study in subjects with prediabetes and hypovitaminosis D evaluated whether high doses of vitamin D for 1 year affected insulin secretion, insulin sensitivity, and the development of diabetes. RESEARCH DESIGN AND METHODS: A total of 1,551 subjects ≥40 years of age not known to have diabetes were screened with A1C levels. Subjects with A1C levels of 5.8-6.9% underwent an oral glucose tolerance test (OGTT). Subjects with prediabetes and 25-OH vitamin D (25-OHD) levels <30 ng/mL were randomized to receive weekly placebo (n = 53) or vitamin D (n = 56) with doses based on body weight and baseline 25-OHD levels. OGTTs were performed 3, 6, 9, and 12 months later. Insulin secretion and sensitivity were measured, and the proportion of subjects developing diabetes was assessed. RESULTS: 25-OHD levels rapidly rose from 22 to nearly 70 ng/mL after vitamin D supplementation with a mean weekly dose of 88,865 IU. There were no differences between the placebo and vitamin D groups regarding fasting plasma glucose, 2-h glucose, or insulin secretion and sensitivity or in the percent developing diabetes or returning to normal glucose tolerance. No subjects experienced increased serum or urinary calcium levels. At 12 months, A1C levels were significantly slightly less (0.2%) in the vitamin D group. CONCLUSIONS: In individuals with prediabetes and hypovitaminosis D, doses of vitamin D supplementation designed to raise serum 25-OHD levels into the upper-normal range for 1 year had no effect on insulin secretion, insulin sensitivity, or the development of diabetes compared with placebo administration.


Asunto(s)
Estado Prediabético/sangre , Estado Prediabético/tratamiento farmacológico , Vitamina D/sangre , Vitamina D/uso terapéutico , Suplementos Dietéticos , Método Doble Ciego , Femenino , Prueba de Tolerancia a la Glucosa , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Persona de Mediana Edad
10.
J Emerg Med ; 34(4): 435-40, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18242920

RESUMEN

Patients who dislocate their mandible often present to the Emergency Department for care. Dislocation can occur after a variety of activities that hyperextend the mandible or open the mouth widely, such as yawning, laughing, or taking a large bite. Anterior dislocation is the most common type, in which the condylar head of the mandible dislocates out of the glenoid fossa anterior to the articular eminence of the temporal bone. These dislocations are often complicated by muscle spasm and trismus, making reduction more difficult. The emergency physician can often reduce the anterior mandibular dislocation with or without procedural sedation or local anesthesia. A variety of methods are available for closed reduction, including the classic approach and various alternatives such as the recumbent, posterior, and ipsilateral approaches, as well as the wrist pivot method, alternative manual technique, and gag reflex induction. This article will review the pathophysiology and clinical presentation of acute mandibular dislocations, as well as discuss the various closed reduction methods available for the practitioner.


Asunto(s)
Luxaciones Articulares/terapia , Manipulación Quiropráctica/métodos , Articulación Temporomandibular , Servicio de Urgencia en Hospital , Humanos , Mandíbula/anatomía & histología
11.
Am J Physiol Endocrinol Metab ; 288(1): E236-45, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15585599

RESUMEN

The prohormone convertases (PCs) PC1 and PC2 are involved in the tissue-specific endoproteolytic processing of neuropeptide precursors within the secretory pathway. We previously showed that changes in thyroid status altered pituitary PC2 mRNA and that this regulation was due to triiodothyronine-dependent interaction of the thyroid hormone receptor (TR) with negative thyroid hormone response elements (nTREs) contained in a large proximal region of the human PC2 promoter. In the current study, we examined the in vivo regulation of brain PC2 mRNA by thyroid status and found that 6-n-propyl-2-thiouracil-induced hypothyroidism stimulated, whereas thyroxine-induced hyperthyroidism suppressed, PC2 mRNA levels in the rat hypothalamus and cerebral cortex. To address the mechanism of T3 regulation of the PC2 gene, we used human PC2 (hPC2) promoter constructs transiently transfected into GH3 cells and found that triiodothyronine negatively and 9-cis-retinoic acid positively regulated hPC2 promoter activity. EMSAs, using purified TRalpha1 and retinoid X receptor-beta (RXRbeta) proteins demonstrated that TRalpha bound the distal putative nTRE-containing oligonucleotide in the PC2 promoter, and RXR bound to both nTRE-containing oligonucleotides. EMSAs with oligonucleotides containing deletion mutations of the nTREs demonstrated that the binding to TR and RXR separately is reduced, but specific binding to TR and RXR together persists even with deletion of each putative nTRE. We conclude that there are two novel TRE-like sequences in the hPC2 promoter and that these regions act in concert in a unique manner to facilitate the effects of thyroid hormone and 9-cis-retinoic acid on PC2.


Asunto(s)
Encéfalo/fisiología , Regiones Promotoras Genéticas/fisiología , Proproteína Convertasa 2/genética , Triyodotironina/farmacología , Alitretinoína , Animales , Antineoplásicos/farmacología , Corteza Cerebral/fisiología , Ensayo de Cambio de Movilidad Electroforética , Expresión Génica/efectos de los fármacos , Hipocampo/fisiología , Hipotálamo/fisiología , Luciferasas/genética , Masculino , Mutagénesis , Proproteína Convertasa 2/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Elementos de Respuesta , Receptor beta X Retinoide/genética , Receptor beta X Retinoide/metabolismo , Receptores alfa de Hormona Tiroidea/genética , Receptores alfa de Hormona Tiroidea/metabolismo , Tretinoina/farmacología
12.
J Clin Invest ; 114(3): 357-69, 2004 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-15286802

RESUMEN

Regulation of energy balance by leptin involves regulation of several neuropeptides, including thyrotropin-releasing hormone (TRH). Synthesized from a larger inactive precursor, its maturation requires proteolytic cleavage by prohormone convertases 1 and 2 (PC1 and PC2). Since this maturation in response to leptin requires prohormone processing, we hypothesized that leptin might regulate hypothalamic PC1 and PC2 expression, ultimately leading to coordinated processing of prohormones into mature peptides. Using hypothalamic neurons, we found that leptin stimulated PC1 and PC2 mRNA and protein expression and also increased PC1 and PC2 promoter activities in transfected 293T cells. Starvation of rats, leading to low serum leptin levels, decreased PC1 and PC2 gene and protein expression in the paraventricular nucleus (PVN) of the hypothalamus. Exogenous administration of leptin to fasted animals restored PC1 levels in the median eminence (ME) and the PVN to approximately the level found in fed control animals. Consistent with this regulation of PCs in the PVN, concentrations of TRH in the PVN and ME were substantially reduced in the fasted animals relative to the fed animals, and leptin reversed this decrease. Further analysis showed that proteolytic cleavage of pro-thyrotropin-releasing hormone (proTRH) at known PC cleavage sites was reduced by fasting and increased in animals given leptin. Combined, these findings suggest that leptin-dependent stimulation of hypothalamic TRH expression involves both activation of trh transcription and stimulation of PC1 and PC2 expression, which lead to enhanced processing of proTRH into mature TRH.


Asunto(s)
Regulación Enzimológica de la Expresión Génica , Proproteína Convertasa 1/genética , Proproteína Convertasa 2/genética , Procesamiento Proteico-Postraduccional , Hormona Liberadora de Tirotropina/metabolismo , Animales , Células Cultivadas , Ingestión de Energía , Femenino , Hipotálamo/citología , Hipotálamo/embriología , Inmunohistoquímica , Inyecciones Intraperitoneales , Leptina/administración & dosificación , Leptina/farmacología , Masculino , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Embarazo , Proproteína Convertasa 1/biosíntesis , Proproteína Convertasa 1/efectos de los fármacos , Proproteína Convertasa 2/biosíntesis , Proproteína Convertasa 2/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/farmacología , Hormona Liberadora de Tirotropina/genética , Tiroxina/sangre , Triyodotironina/sangre
13.
Kidney Int ; 65(6): 2212-22, 2004 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15149334

RESUMEN

BACKGROUND: Matrilysin, a secreted matrix metalloproteinase and target gene of Wnt signaling, functions in epithelial repair and host defense, but no role in renal injury has been described. METHODS: Matrilysin expression was assessed in human kidney specimens by immunohistochemistry, and in experimental renal injury in mice by immunohistochemistry, Northern blotting, and RNase protection assays (RPA). A relationship to Wnt4, which is also induced in renal injury, was determined by RPA and in situ hybridization. RESULTS: Matrilysin was not detected in the normal human renal tubular epithelium by immunohistochemistry. However, prominent staining was detected in sections from autosomal-dominant polycystic kidney disease in the cyst lining epithelium, atrophic tubules, and cyst micropolyps, and from hydronephrosis in dilated and atrophic tubules. Matrilysin expression was also induced by acute folic acid nephropathy and unilateral ureteral obstruction (UUO) in the mouse, and expression increased as acute injury progressed to tubulointerstitial fibrosis. Matrilysin staining was primarily localized to epithelium of distal tubule/collecting duct origin in both human and murine renal disease. Wnt signaling can induce matrilysin expression, and we found that the pattern of matrilysin expression during progression of renal fibrosis in the mouse after UUO or folic acid nephropathy, and in the jck model of murine polycystic kidney disease, closely paralleled that of Wnt4. CONCLUSION: These observations suggest that matrilysin may have a role in renal tubular injury and progression of tubulointerstitial fibrosis, and that Wnt4 may regulate matrilysin expression in the kidney.


Asunto(s)
Túbulos Renales/lesiones , Túbulos Renales/metabolismo , Metaloproteinasa 7 de la Matriz/genética , Metaloproteinasa 7 de la Matriz/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Animales , Secuencia de Bases , Estudios de Casos y Controles , ADN Complementario/genética , Fibrosis , Expresión Génica , Humanos , Túbulos Renales/patología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Riñón Poliquístico Autosómico Dominante/genética , Riñón Poliquístico Autosómico Dominante/metabolismo , Riñón Poliquístico Autosómico Dominante/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Wnt , Proteína Wnt4
14.
Basic Clin Pharmacol Toxicol ; 94(5): 213-25, 2004 May.
Artículo en Inglés | MEDLINE | ID: mdl-15125691

RESUMEN

Acetaminophen in large doses is well-known as hepatotoxic, and early therapy with N-acetylcysteine is frequently life-saving. However, in later stages of acetaminophen poisoning, treatment with N-acetylcysteine is not always effective. Although some of the pathways of acetaminophen toxicity and the effect of N-acetylcysteine have been elucidated, in depth information on this process is still lacking. Hepatoma-derived HepG2 cultured cells were exposed to acetaminophen (5 and 10 mM), with or without N-acetylcysteine (5 mM), for 24 and 48 hr. For the assessment of oxidative damage, apoptosis and necrosis, we followed redox status, glutathione content, nuclear fragmentation, phosphatidylserine externalization and ultrastructural changes. Variations in Ca2+ level and number of mitochondrial dense granules were also studied. Acetaminophen treatment of HepG2 cells caused oxidative damage and apoptosis. Significant decrease of cellular redox potential and glutathione content were time- and concentration-dependent. The protective effect of N-acetylcysteine was expressed by an increase of intracellular glutathione and of the level of metabolic reduction of the redox indicator Alamar Blue. The apoptogenic effect of acetaminophen was assessed by flow cytometry of annexin V binding, nuclear hypodiploidity, intracellular Ca2+, as well as by ultrastructural examination. Beyond 24 hr of acetaminophen exposure, necrosis was also noticed. We conclude that acetaminophen-induced oxidative damage in HepG2 cultured cells can be prevented by exposure to N-acetylcysteine. However, apoptosis, either early or late, here demonstrated, is not avoided by exposure to N-acetylcysteine. N-Acetylcysteine did not prevent acetaminophen-induced plasma membrane asymmetry, nuclear damage, alterations of Ca2+ homeostasis and ultrastructural changes.


Asunto(s)
Acetilcisteína/farmacología , Antioxidantes/farmacología , Apoptosis , Línea Celular Tumoral/efectos de los fármacos , Acetaminofén/antagonistas & inhibidores , Acetaminofén/toxicidad , Apoptosis/efectos de los fármacos , Calcio/análisis , Cationes Bivalentes , Línea Celular Tumoral/metabolismo , Línea Celular Tumoral/ultraestructura , Núcleo Celular/efectos de los fármacos , Núcleo Celular/ultraestructura , Citometría de Flujo , Glutatión/análisis , Hepatoblastoma , Humanos , Neoplasias Hepáticas , Microscopía Electrónica , Necrosis , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Fosfatidilserinas/análisis
15.
Acad Emerg Med ; 11(4): 335-8, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15064204

RESUMEN

UNLABELLED: Treatment of patients following an organophosphate (OP) exposure can deplete a hospital's entire supply of atropine. Given the possibility of multiple severe exposures after a terrorist attack using OP nerve agents, there exists a need for either greater atropine stores or the development of alternative antidotes. Jimson weed (Datura stramonium) contains atropine and other anticholinergic compounds and is common and readily available. It is used recreationally for its central anticholinergic effects and is made easily into an extract by boiling the crushed seeds. The extract has rapid onset of effects and may be useful for treatment of OP poisoning. OBJECTIVES: To determine whether pretreatment with an easily stored and prepared Datura seed extract (DSE) will increase survival following a severe OP poisoning. METHODS: Datura stramonium seeds were collected, crushed, and then heated in water to make a 2-mg/mL atropine solution (100 seeds contain approximately 6 mg of atropine or 0.007 mg/seed). Male rats were randomized to pretreatment with either saline (n = 10) or 7.5 mg/kg DSE (n = 10) given as a single intraperitoneal injection 5 minutes prior to a subcutaneous injection of 25 mg/kg of dichlorvos. The endpoint was time to death recorded by a blinded observer. RESULTS: The Kaplan-Meier estimates of the 24-hour survival rate was 90% (95% CI = 56% to 100%) for the DSE-pretreated group and 10% (95% CI = 0% to 45%) for the control group. The log-rank test revealed a statistically significant longer survival for the Datura-treated animals (p = 0.0002). Median survival time was 22 minutes 30 seconds for the control group and greater than 24 hours for the DSE-pretreated group. CONCLUSIONS: Pretreatment with DSE significantly increases survival following severe dichlorvos exposure.


Asunto(s)
Datura stramonium , Insecticidas/toxicidad , Fitoterapia/métodos , Extractos Vegetales/uso terapéutico , Sustancias Protectoras/uso terapéutico , Semillas , Animales , Diclorvos/toxicidad , Masculino , Intoxicación/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Análisis de Supervivencia , Resultado del Tratamiento
16.
Acad Emerg Med ; 11(3): 221-7, 2004 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15001400

RESUMEN

UNLABELLED: Calcium chloride (CaCl(2)) alone is an ineffective antidote in severe calcium channel antagonist overdoses. Digoxin has been evaluated as a therapy to increase the effectiveness of calcium in severe calcium channel antagonist overdoses. OBJECTIVE: To determine if there is a dose-dependent hemodynamic effect of digoxin in the setting of severe verapamil toxicity treated with high-dose CaCl(2). METHODS: Eight dogs were instrumented to measure systolic and diastolic blood pressure, cardiac output, pulmonary artery pressures, and left ventricular pressures. Verapamil toxicity (50% decrease in mean arterial pressure) was induced with verapamil 6 mg/kg/hr and maintained for 30 minutes by titrating the verapamil rate. Following verapamil toxicity, each dog received one dose of digoxin equivalent to 0, 1, 1.5, 2, 3, 4, 6, or 8 times the loading dose of digoxin (0.009 mg/kg). The verapamil rate was changed to 4 mg/kg/hr and continued for the next five hours. CaCl(2) boluses were given (0.5 g immediately following verapamil toxicity and 1 g at one, two, and three hours). Measurements were compared with the loading dose of digoxin using linear regression analysis. RESULTS: Digoxin resulted in a dose-dependent increase in systolic blood pressure at 4 hours (10.23 mm Hg/loading dose of digoxin, 95% CI = 2.74 to 17.73), 4 hours, 15 minutes (13.9 mm Hg/loading dose of digoxin, 95% CI = 8.75 to 19.01), and 5 hours (17.04 mm Hg/loading dose of digoxin, 95% CI = 1.76 to 32.32). Digoxin resulted in a dose-dependent increase in maximal ventricular pressure at the end of hour 3 (8.55 mm Hg/loading dose of digoxin, 95% CI = 3.41 to 13.69), 3 hours, 15 minutes (11.81 mm Hg/loading dose of digoxin, 95% CI = 4.89 to 18.73), hour 4 (8.26 mm Hg/loading dose of digoxin, 95% CI = 1.03 to 15.48), and 4 hours, 15 minutes (9.74 mm Hg/loading dose of digoxin, 95% CI = 4.47 to 15.00). The authors were unable to detect a dose-dependent increase in other parameters, including diastolic relaxation (diastolic change in pressure over time) and time to onset of death. No ventricular arrhythmias developed in any dogs. CONCLUSIONS: There is a dose-dependent effect of digoxin on systolic blood pressure and maximal ventricular pressure in the setting of severe verapamil toxicity treated with high-dose CaCl(2).


Asunto(s)
Antídotos/farmacología , Bloqueadores de los Canales de Calcio/toxicidad , Digoxina/farmacología , Hemodinámica/efectos de los fármacos , Verapamilo/toxicidad , Animales , Presión Sanguínea/efectos de los fármacos , Cloruro de Calcio/administración & dosificación , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Masculino , Valores de Referencia , Resultado del Tratamiento
17.
Support Care Cancer ; 11(9): 575-80, 2003 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-12783290

RESUMEN

GOALS: To describe an acute respiratory distress syndrome (ARDS) occurring after chemotherapy for non-seminomatous germ-cell tumors (NSGCT) with diffuse lung metastases, we conducted a retrospective study in a 15-bed intensive care unit (ICU) in a comprehensive cancer center. PATIENTS AND METHODS: During a 10-year period, 16 consecutive patients with diffuse lung metastases from a NSGCT were admitted to the ICU for respiratory distress and high-risk chemotherapy. MAIN RESULTS: Nine patients developed acute respiratory failure requiring mechanical ventilation (MV) within 3 days of the initiation of chemotherapy, while the respiratory status of the seven other patients improved. The evolution was independent of tumor marker levels and the type of chemotherapy regimen. The SAPS II score did not accurately describe the severity of this population. The only predictor of intubation was the initial PaO2/FiO2 ratio upon admission to the ICU. Six out of seven patients who did not require MV were discharged alive from the hospital, whereas all but one patient requiring MV died. Refractory hypoxemia and ventilator-associated pneumonia were the leading causes of death. CONCLUSIONS: Acute respiratory distress in patients with lung metastases from NSGCT is a rare cause of ARDS. Chemotherapy could be responsible for triggering the respiratory worsening. Patients with severe respiratory insufficiency (PaO2 <70 mmHg on room air) on admission to hospital should be promptly transferred to the ICU for the first chemotherapy course.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Germinoma/tratamiento farmacológico , Germinoma/secundario , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Síndrome de Dificultad Respiratoria/inducido químicamente , Adulto , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Respiración Artificial , Síndrome de Dificultad Respiratoria/terapia , Estudios Retrospectivos , Factores de Tiempo
18.
J Am Assoc Gynecol Laparosc ; 10(1): 90-8, 2003 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-12555001

RESUMEN

STUDY OBJECTIVE: To evaluate the effects and feasibility of direct cryothermic and hyperthermic therapy on leiomyomata and adjacent myometrium, and to contribute to evidence-based treatment thresholds based on measurements of direct cell injury. DESIGN: Experimental study (Canadian Task Force classification II-2). SETTING: University hospital. SUBJECTS: Leiomyoma and myometrium tissue from 10 women undergoing total abdominal hysterectomy with or without bilateral salpingo-oophorectomy. INTERVENTION: In vitro cryothermic or hyperthermic therapy was performed with representative leiomyoma and myometrium tissue samples. Using a directional solidification stage to simulate cryothermic therapy, 10 leiomyoma and 6 myometrium specimens were cooled in vitro at a rate of -5 degrees C/minute to end temperatures of -20 degrees, -40 degrees, -60 degrees, and -80 degrees C with a 15-minute hold period and then rapidly thawed to 21 degrees C. Hyperthermic therapy was simulated using a preheated 45 degrees, 55 degrees, 60 degrees, 65 degrees, 70 degrees, 75 degrees, and 80 degrees C constant temperature copper heating block with a 10-minute treatment period. In conjunction with tissue culturing and control tissues, cell death was assessed with routine histology and viability dyes (ethidium homodimer/Hoechst). MEASUREMENTS AND MAIN RESULTS: In cryothermic results, leiomyomata cell death (LCD) increased from 12% to 27% by histology and 26% to 38% by viability dye assay over the thermal range from -20 degrees to -80 degrees C, respectively. Myometrial cell death (MCD) increased from 10% to 12% and 4% to 20% for the same measurements, respectively. Whereas MCD appeared relatively stable from -40 degrees to -80 degrees C, it was significantly less than LCD over this range (p <0.05). For hyperthermic results, LCD increased from 17% to 88% by histology with progressive temperature increase from 45 degrees to 80 degrees C, respectively. The MCD showed a similar increase from 16% to 91% by histology over this temperature range. Hyperthermic histology and dye assay results were similar for LCD and MCD. CONCLUSIONS: In comparison with myometrium, leiomyomata showed greater direct cryothermic and equal hyperthermic cell injury. Whereas cell death increased up to 70 degrees C and down to -80 degrees C, the interval increases in cell injury diminished with more extreme temperatures. In vivo studies of combined direct and ischemic vascular injury thresholds have yet to be performed, but direct LCD matrixes determined in this study will help provide guidelines for minimally invasive surgical techniques for the treatment of leiomyomata.


Asunto(s)
Crioterapia/efectos adversos , Hipertermia Inducida/efectos adversos , Laparoscopía/efectos adversos , Leiomioma/patología , Miometrio/patología , Neoplasias Uterinas/patología , Adulto , Anciano , Supervivencia Celular , Crioterapia/métodos , Técnicas de Cultivo , Femenino , Humanos , Hipertermia Inducida/métodos , Histerectomía/métodos , Inmunohistoquímica , Laparoscopía/métodos , Leiomioma/cirugía , Persona de Mediana Edad , Miometrio/cirugía , Probabilidad , Valores de Referencia , Sensibilidad y Especificidad , Neoplasias Uterinas/cirugía
19.
J Am Geriatr Soc ; 50(6): 1131-40, 2002 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12110078

RESUMEN

Androgen supplementation in women has received enormous attention in the scientific and lay communities. That it enhances some aspects of cognitive function, sexual function, muscle mass, strength, and sense of well-being is not in question. What is not known is whether physiological testosterone replacement can improve health-related outcome in older women without its virilizing side effects. Although it is assumed that the testosterone dose-response relationship is different in women than in men and that clinically relevant outcomes on the above-mentioned effects can be achieved at lower testosterone doses, these assumptions have not been tested rigorously. Androgen deficiency has no clear-cut definition. Clinical features may include impaired sexual function, low energy, depression, and a total testosterone level of less than 15 ng/dL, the lower end of the normal range. Measurement of free testosterone is ideal, because it provides a better estimate of the biologically relevant fraction. It is not widely used in clinical practice, because some methods of measuring free testosterone assay are hampered by methodological difficulties. In marked contrast to the abrupt decline in estrogen and progesterone production at menopause, serum testosterone is lower in older women than in menstruating women, with the decline becoming apparent a decade before menopause. This article reviews testosterone's effects on sexual function, cognitive function, muscle mass, body composition, and immune function in postmenopausal women.


Asunto(s)
Andrógenos/administración & dosificación , Posmenopausia/efectos de los fármacos , Testosterona/farmacología , Anciano , Andrógenos/efectos adversos , Andrógenos/sangre , Andrógenos/metabolismo , Densidad Ósea/efectos de los fármacos , Cognición/efectos de los fármacos , Femenino , Humanos , Sistema Inmunológico/efectos de los fármacos , Persona de Mediana Edad , Fenómenos Fisiológicos Musculoesqueléticos/efectos de los fármacos , Sexualidad/efectos de los fármacos , Testosterona/uso terapéutico
20.
J Forensic Sci ; 47(2): 299-304, 2002 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11908598

RESUMEN

We performed a randomized, cross-over controlled trial to assess the effect of Oleoresin capsicum (OC) spray inhalation on respiratory function by itself and combined with restraint. Thirty-five subjects were exposed to OC or placebo spray, followed by 10 min of sitting or prone maximal restraint position (PMRP). Spirometry, oximetry, and end-tidal CO2 levels were collected at baseline and throughout the 10 min. Data were compared between groups (ANOVA) and with predefined normal values. In the sitting position, OC did not result in any significant changes in mean percent predicted forced vital capacity (%predFVC), percent predicted forced expiratory volume in 1 s (%predFEV1), oxygen, or CO2 levels. In PMRP, mean %predFVC and %predFEV1 fell 14.4 and 16.5% for placebo and 16.2 and 19.1% for OC, but were not significantly different by exposure. There was no evidence of hypoxemia or hypercapnia in either groups. OC exposure did not result in abnormal spirometry, hypoxemia, or hypoventilation when compared to placebo in either sitting or PMRP.


Asunto(s)
Extractos Vegetales/efectos adversos , Fenómenos Fisiológicos Respiratorios/efectos de los fármacos , Adulto , Estudios Cruzados , Femenino , Humanos , Exposición por Inhalación , Masculino , Persona de Mediana Edad , Extractos Vegetales/administración & dosificación , Posición Prona , Pruebas de Función Respiratoria , Restricción Física
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