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Species within the Aspergillus viridinutans complex are being increasingly recognized as pathogens of animals and humans. An orange-winged Amazon parrot (Amazona amazonica) was referred for a 6 month-history of a slowly developing swelling involving the right nostril. Abnormal physical exam findings included a mild firm swelling at the dorsolateral aspect of the right nostril with no nasal discharge. Computed tomographic examination showed mild deformation of the right naris and nasal conchae without distinct granuloma. A cryptic Aspergillus species in Aspergillus section Fumigati was cultivated and identified by PCR and comparative sequence analysis as Aspergillus pseudoviridinutans. Successful treatment was achieved using topical clotrimazole and systemic antifungals (itraconazole, terbinafine). This is the first report of A. pseudoviridinutans infection in a bird.
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Aerosols interact with radiation and clouds. Substantial progress made over the past 40 years in observing, understanding, and modeling these processes helped quantify the imbalance in the Earth's radiation budget caused by anthropogenic aerosols, called aerosol radiative forcing, but uncertainties remain large. This review provides a new range of aerosol radiative forcing over the industrial era based on multiple, traceable, and arguable lines of evidence, including modeling approaches, theoretical considerations, and observations. Improved understanding of aerosol absorption and the causes of trends in surface radiative fluxes constrain the forcing from aerosol-radiation interactions. A robust theoretical foundation and convincing evidence constrain the forcing caused by aerosol-driven increases in liquid cloud droplet number concentration. However, the influence of anthropogenic aerosols on cloud liquid water content and cloud fraction is less clear, and the influence on mixed-phase and ice clouds remains poorly constrained. Observed changes in surface temperature and radiative fluxes provide additional constraints. These multiple lines of evidence lead to a 68% confidence interval for the total aerosol effective radiative forcing of -1.6 to -0.6 W m-2, or -2.0 to -0.4 W m-2 with a 90% likelihood. Those intervals are of similar width to the last Intergovernmental Panel on Climate Change assessment but shifted toward more negative values. The uncertainty will narrow in the future by continuing to critically combine multiple lines of evidence, especially those addressing industrial-era changes in aerosol sources and aerosol effects on liquid cloud amount and on ice clouds.
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We use a carbon-cycle data assimilation system to estimate the terrestrial biospheric CO(2) flux until 2090. The terrestrial sink increases rapidly and the increase is stronger in the presence of climate change. Using a linearized model, we calculate the uncertainty in the flux owing to uncertainty in model parameters. The uncertainty is large and is dominated by the impact of soil moisture on heterotrophic respiration. We show that this uncertainty can be greatly reduced by constraining the model parameters with two decades of atmospheric measurements.
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Ciclo del Carbono , Cambio Climático , Dióxido de Carbono/metabolismo , Interpretación Estadística de Datos , Ecosistema , Predicción , Historia del Siglo XXI , Modelos Lineales , Modelos BiológicosRESUMEN
OBJECTIVE: To assess if the lithium dosage prescribed according to the Pepin method leads to therapeutic serum concentrations of lithium. METHODS: For 13 healthy volunteers, the initial daily doses of lithium were calculated according to the Pepin formula with a view to obtaining a serum lithium level of 0.8 mmol/L. Lithium was administered twice daily for 21 days, and blood samples were drawn daily, 12 hours after the last dose was taken. Dosage was adjusted if serum concentrations were below 0.6 mmol/L or above 1.0 mmol/L or if major side effects were reported. RESULTS: Daily lithium doses ranged from 1050 mg to 1950 mg (mean 1569 mg, standard deviation [SD] 291 mg), The mean serum lithium concentrations for weeks 1, 2 and 3 were 0.74 mmol/L (SD 0.19 mmol/L), 0.67 mmol/L (SD 0.22 mmol/L) and 0.69 mmol/L (SD 0.13 mmol/L), respectively. Within-subject variance was negligible. Sixty-eight percent of the serum lithium concentration measurements fell between 0.57 mmol/L and 0.83 mmol/L, and 84% fell within the recommended therapeutic range of 0.60 mmol/L and 1.20 mmol/L. CONCLUSIONS: The Pepin method is a safe but conservative method for predicting the appropriate daily dose of lithium.
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Trastorno Bipolar/sangre , Monitoreo de Drogas/métodos , Carbonato de Litio/farmacocinética , Adolescente , Adulto , Trastorno Bipolar/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Carbonato de Litio/administración & dosificación , Carbonato de Litio/efectos adversos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios ProspectivosRESUMEN
Metallothioneins (MTs) are cytosolic proteins involved in cellular stress responses. The objectives of this study were to determine which epididymal cells express MTs, how they are regulated, and whether mRNA levels for 3 MT isoforms (MT I, MT II, and MT III) are modulated by heavy metals. MT expression was noted mainly in basal cells of all epididymal regions but not in all basal cells of any given region. MT I mRNA levels were highest in the testis, followed by levels in the corpus, cauda epididymidis, liver (positive control), caput epididymidis, initial segment, seminal vesicles, and ventral prostate. MT II mRNA levels were also highest in testis, followed by levels in the cauda, corpus, liver, caput, and initial segment, but they were undetectable in the seminal vesicles and ventral prostate. MT III mRNA levels were highest in the caput followed by testis and initial segment. Orchidectomy and orchidectomy with testosterone replacement experiments showed that immunoreactive MT in all epididymal segments was androgen dependent. Epididymal MT I mRNA levels were dependent on androgens in all segments except the corpus. MT II mRNA levels were androgen dependent only in the initial segment and corpus. MT III mRNA levels in the initial segment were not altered by orchidectomy but increased significantly in testosterone-treated rats. In the caput, MT III mRNA levels decreased following orchidectomy, but control levels were maintained by testosterone. In cadmium-injected rats, MT I mRNA levels were significantly increased in the testis and initial segment, but there were no effects in the liver and other epididymal regions. MT II mRNA levels were increased by more than eightfold in the liver and by three- to fourfold in the initial segment and caput. In the corpus, MT II mRNA levels were decreased by cadmium treatment. MT III mRNA levels were unaltered by cadmium treatment. In conclusion, all 3 MT transcripts are present in high abundance in the epididymis. Furthermore, MT is expressed mainly in basal cells with regulation by testosterone. Heavy metal induction appears to affect the proximal regions of the epididymis.
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Epidídimo/enzimología , Metalotioneína/genética , Andrógenos/metabolismo , Animales , Northern Blotting , Cadmio/farmacología , Epidídimo/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/fisiología , Masculino , Metalotioneína/análisis , Metalotioneína 3 , Proteínas del Tejido Nervioso/análisis , Proteínas del Tejido Nervioso/genética , Orquiectomía , ARN Mensajero/análisis , Ratas , Ratas Sprague-DawleyRESUMEN
The blood-epididymal barrier creates a unique microenvironment critical for sperm maturation. There is little information on proteins comprising epididymal tight and adhering junctions or on factors regulating their expression. Claudins are a family of transmembrane proteins reported to be exclusively localized to tight junctions. In the present study the expression of claudin-l (Cl-1) was examined with respect to the different cell types of the epididymis and its various regions as well as its expression during postnatal development and regulation by testicular factors, using both immunocytochemistry and Northern blot analysis. RT-PCR of adult epididymal and testicular RNA (positive control) indicated that Cl-1 messenger RNA (mRNA) transcripts were present in all regions of the epididymis. In the adult, Cl-1 was localized immunocytochemically along the entire length of the lateral plasma membranes between adjacent principal cells, including apical areas containing tight junctions, as well as at the interface between principal and basal cells and along the basal plasma membrane of the epithelium in relation to the basement membrane. Northern blot analysis of adult epididymis with a rat Cl-1 complementary DNA indicated the presence of two hybridizing bands of 4.0 and 1.5 kb. Postnatally, in the caput-corpus and cauda epididymidis, mRNA levels for both transcripts were lowest on day 7. In the caput-corpus epididymidis, mRNA levels for the 1.5-kb transcript increased significantly between 7 and 14 days, whereas the levels of the 4.0-kb transcript were significantly higher by day 21. Postnatal studies revealed that in the initial segment and caput epididymidis, Cl-1 immunostaining was present along the entire length of the lateral plasma membranes of undifferentiated epididymal epithelial cells as early as day 7, including apical areas containing tight junctions. By day 21, staining was identical to that of adult animals, but as this is an age when androgen levels are not at their peak, the data would suggest that they are not a prominent factor regulating Cl-1 expression. Orchidectomy and orchidectomy plus testosterone replacement experiments revealed differences in Cl-1 immunostaining in the initial segment, suggesting that localization of Cl-1 in epididymal tight junctions is androgen dependant. Thus, Cl-1 expression in the initial segment appears to be only partially under the control of androgens. However, in all other epididymal regions, orchidectomy with or without testosterone replacement, revealed no changes to the normal staining pattern, suggesting that androgens do not regulate Cl-1 expression in these regions. Taken together, these studies demonstrate that Cl-1 expression in the epididymis is not localized exclusively to tight junctions, but appears along the entire interfaces of adjacent epithelial cells as well as along the basal plasma membrane, suggesting a role for Cl-1 as an adhesion molecule. The data also suggest that the regulation of Cl-1 in the epididymis is complex and multifactorial.
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Epidídimo/metabolismo , Proteínas de la Membrana/metabolismo , Uniones Estrechas/metabolismo , Envejecimiento/metabolismo , Andrógenos/fisiología , Animales , Claudina-1 , Epidídimo/crecimiento & desarrollo , Epidídimo/ultraestructura , Inmunohistoquímica , Masculino , Microscopía Electrónica , Orquiectomía , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Uniones Estrechas/ultraestructura , Distribución TisularRESUMEN
We have studied the effects of a cardiac sparing thyromimetic, CGS 23425, on postprandial levels of triglycerides, abundance of apolipoprotein B (apo B) protein and hepatic apo B mRNA expression in rats. When compared with control rats, triglyceride clearance was significantly accelerated by treatment with CGS 23425. A full return to baseline values was achieved within 8 h after ingesting a large quantity of fat, as compared to >24 h in control animals. The abundance of apo B-100 protein in CGS 23425-treated hyperlipidemic rats decreased in a dose-dependent manner, but levels of apo B-48 were not significantly affected. Like L-tri-iodothyronine (L-T(3)), treatment with 30 microg/kg CGS 23425 for 6 or 9 days decreased the levels of apo B-100 protein by 80% and 40% respectively. This change was paralleled by a 27% reduction in hepatic apo B-100 mRNA. To investigate a potential mechanism of CGS 23425 action, we measured in vitro apo B mRNA editing activity in hepatocellular extract from control or CGS 23425-treated rats. Treatment with CGS 23425 increased activity of the hepatic apo B-100 editosome, apobec-1. In human hepatoma cells which lack apobec-1 activity, apo B-100 mRNA levels remained the same in cells treated with or without the agent. In summary, these observations show that CGS 23425 decreases the levels of apo B-100 in rats. This action of CGS 23425 involves apo B-100 mRNA editing activity.
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Anticolesterolemiantes/farmacología , Apolipoproteínas B/sangre , Glioxilatos/farmacología , Triyodotironina/farmacología , Desaminasas APOBEC-1 , Animales , Apolipoproteína B-100 , Apolipoproteínas B/genética , Citidina Desaminasa/fisiología , Humanos , Hipercolesterolemia/sangre , Hígado/metabolismo , Masculino , Periodo Posprandial , Edición de ARN/efectos de los fármacos , ARN Mensajero/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Triglicéridos/sangre , Células Tumorales CultivadasRESUMEN
BACKGROUND: Several studies have shown cognitive impairment in short-term memory, long-term memory and psychomotor speed in bipolar patients taking lithium. The aim of the study was to look at the effect of lithium in normal subjects (N=30) taking lithium for 3 weeks. A comprehensive battery was used to assess attention and memory. METHODS: Subjects were randomized to double-blind treatment with either lithium (N=15) or placebo (N=15) for a 3-week period. Thirteen participants in the lithium group and 15 in the placebo group completed the study. The lithium and placebo were administered twice daily in doses varying from 1050 to 1950 mg (mean=1569 mg). The initial daily dose was calculated according to the Pepin formula to achieve a blood serum lithium level of about 0.8 mmol/l. Cognitive performance (attention, memory) was assessed in each subjects during three periods, i.e. at baseline, after 3 weeks of lithium or placebo, and 2 weeks after discontinuation of study medication. RESULTS: In short-term memory tasks, the performance of subjects in the lithium group was worst 3 weeks after lithium treatment compared to 2 weeks after discontinuation. In long-term memory, a significantly higher number of words was recalled by the placebo group but not the lithium group. CONCLUSIONS: Lithium may have an effect on learning when long-term explicit memory test are administered repeatedly. It means that the practice effect when a subject performs the same task several times is less in the lithium-treated group than in the placebo group. This practice effect is related to the learning of a task.
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Antimaníacos/toxicidad , Atención/efectos de los fármacos , Carbonato de Litio/toxicidad , Memoria a Corto Plazo/efectos de los fármacos , Retención en Psicología/efectos de los fármacos , Adolescente , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tiempo de Reacción/efectos de los fármacosRESUMEN
BACKGROUND: Mesangial cell hypertrophy and increased extracellular matrix (ECM) contribute to mesangial expansion in early progressive diabetic nephropathy. Previous studies suggest that the growth factor endothelin-1 (ET-1) is not only up-regulated in diabetes, but may mediate the effects of hyperglycemia on mesangial cell hypertrophy and ECM synthesis. In models of diabetes mellitus, the mechanisms underlying increased ET-1 peptide and mRNA remain unknown. Therefore, our purpose is to determine whether ET-1 gene activity increases in kidneys of streptozotocin (SZT)-treated rats. METHODS: Male Sprague-Dawley rats were injected with either SZT or vehicle. Parameters including glucose, body weight, 24-hour urine volume, urinary protein, and urinary ET-1 excretion were recorded. All rats were sacrificed at 12 weeks postinjection. Prepro-ET-1 mRNA from whole kidneys was determined using both RNase protection and reverse transcription-polymerase chain reaction (RT-PCR). The abundance of ET-1 peptide in primary cultured mesangial cells was detected by indirect immunofluorescence following treatment with 5.6, 11.2, or 22.5 mmol/L D-glucose for 24 hours. Cellular ET-1 mRNA was measured using RT-PCR in control cells at time 0 and also following exposure to increasing concentrations of glucose for 24 hours. Rat mesangial cells were transfected with a luciferase reporter construct containing the rat ET-1 promoter (pET1. Luc), and relative ET-1 promoter activity was measured after a 24-hour exposure to 5.6 and 22.5 mmol/L of D- or L-glucose. RESULTS: After 12 weeks of hyperglycemia, diabetic rats gained less weight (344 +/- 23.9 vs. 548.75 +/- 15.08 g), had increased urinary volume (158.6 +/- 24.32 vs. 8.38 +/- 1.56 mL/day), and had marked proteinuria (101.7 +/- 12.2 vs. 14.1 +/- 2.8 mg/day) compared with controls. Total urinary ET-1 peptide increased 26.4-fold in diabetic versus control rats (17.5083 +/- 5.405 vs. 0.6635 +/- 0.343 ng/day). ET-1 mRNA extracted from whole rat kidneys was increased 2.1-fold in diabetic versus control animals. Primary cultured rat mesangial cells demonstrated a significant increase in immunofluorescence labeling of ET-1 peptide and ET-1 mRNA in response to increasing concentrations of glucose. Furthermore, transfected mesangial cells exposed to 22.5 mmol/L D-glucose showed a 1.6-fold increase in ET-1 promoter activity relative to those treated with 5.6 mmol/L glucose. CONCLUSION: Glucose increases ET-1 gene expression in the kidney of the SZT-treated rat model of diabetes mellitus. Furthermore, high glucose induces ET-1 expression in primary cultured rat mesangial cells and directly enhances ET-1 promoter activity. The greater relative increase in peptide compared with transcription suggests the potential participation of other mechanisms such as increased mRNA stability, protein stability, and/or enhanced translational efficiency.
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Diabetes Mellitus Experimental/fisiopatología , Nefropatías Diabéticas/fisiopatología , Endotelina-1/genética , Mesangio Glomerular/fisiología , Transcripción Genética/fisiología , Animales , Glucemia , Peso Corporal , Células Cultivadas , Diabetes Mellitus Experimental/orina , Nefropatías Diabéticas/orina , Endotelina-1/orina , Endotelinas/genética , Matriz Extracelular/fisiología , Expresión Génica/efectos de los fármacos , Expresión Génica/fisiología , Mesangio Glomerular/citología , Mesangio Glomerular/efectos de los fármacos , Glucosa/farmacología , Hiperglucemia/fisiopatología , Hiperglucemia/orina , Masculino , Regiones Promotoras Genéticas/efectos de los fármacos , Regiones Promotoras Genéticas/fisiología , Precursores de Proteínas/genética , Proteinuria/fisiopatología , Proteinuria/orina , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Transfección , Orina , Vasoconstricción/fisiologíaRESUMEN
Methylmercury (MeHg) is a widespread environmental contaminant that causes reproductive dysfunction in men. Metallothioneins (MTs) are low-molecular-weight proteins that can bind heavy metals and protect the cell from metal toxicity. MT levels are increased by exposure to metals and physiological stressors. Although MTs have been identified in the testis and epididymis, little is known about their distribution and regulation in the epididymis or the effects of MeHg on MT levels in male reproductive tissues. The objective of this study was to determine whether MT I, II, and III mRNA are present in the epididymis, if their relative levels differ between epididymal segments, and if MeHg alters cellular mRNA levels for MT I, II, and III in the testis and epididymal segments of the rat. Northern blot analysis was done on total cellular RNA isolated from each of the four epididymal segments (initial segment [IS], caput [CT], corpus [CS], and cauda [CA] epididymidis) using a cDNA probe for MT I and MT II. MT I transcripts were present in all epididymal segments. The lowest mRNA levels were observed in the IS; these levels were 4-fold less than in the CT and CS and 5.5-fold less than in the CA. MT II mRNA levels were similar in the IS and CT but were eightfold higher in the CS and CA. A cDNA probe for MT III was generated by reverse transcription-polymerase chain reaction using testicular RNA. MT III mRNA was detected only in the IS and CT and not in the CS and CA. To assess whether exposure to MeHg alters MT mRNA levels, rats were exposed for 14 days to one of five MeHg doses (0, 25, 50, 100, and 200 [microg/kg/day] via a subdermal osmotic pump. No changes were observed in either body weight or in the weights of the testis, epididymis, seminal vesicles, or ventral prostate between MeHg-treated and control rats. Serum testosterone levels were significantly decreased only at the highest MeHg dose. In the testis, MeHg treatment resulted in 2.5- to 7-fold increases in MT I mRNA levels. There were no changes in either MT II or MT III mRNA levels. In the initial segment of the epididymis, MT I mRNA levels were significantly increased only at the 50 microg/kg/ day dose, whereas there were no significant differences in MT II mRNA levels. In the caput epididymis, MT I mRNA levels were significantly lower at the 50 and 100 microg/kg/day dose. MT II mRNA levels were also lower, with the exception of the 50 microg/kg/day dose. Although MT III mRNA levels were lower at the two lower doses, levels were not different from controls in the two highest doses tested. In the corpus epididymidis, MeHg did not alter MT I mRNA levels, and MT II was higher only in the 50 microg/kg/day group. In the cauda epididymidis, MT I mRNA levels were decreased in a dose-dependent manner by up to 63%. MT II levels were unaltered. Together these data indicate that exposure of adult rats to MeHg can modulate MT mRNA levels in both the testis and epididymal segments. Furthermore, changes in MT mRNA levels following exposure to MeHg differ between epididymal segments, suggesting either differences in MeHg accumulation or differences in MT modulation.
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Epidídimo/metabolismo , Metalotioneína/genética , Compuestos de Metilmercurio/farmacología , Testículo/metabolismo , Transcripción Genética/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Epidídimo/anatomía & histología , Epidídimo/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Testículo/anatomía & histología , Testículo/efectos de los fármacos , Testosterona/sangreRESUMEN
PURPOSE: Management of advanced-stage Hodgkin's disease with a MOPP/ABV hybrid regimen (mechlorethamine, vincristine, procarbazine, prednisone, Adriamycin, bleomycin and vinblastine) has yielded a high complete response rate (75-85%). However, myelosuppression can limit delivery of treatment. Filgrastim has been shown to reduce chemotherapy-related neutropenia and allow for on-time administration of planned doses of chemotherapeutic agents. The objective of this study was to find the best way to integrate filgrastim with the MOPP/ABV hybrid regimen. METHODS: Enrolled in this study were 24 patients (aged 18-52 years) with newly diagnosed, histologically documented Hodgkin's disease. In schedule I, patients received filgrastim (5 microg/kg s.c. daily) beginning on day 9, 24 h after administration of ABV. In schedule II, patients received filgrastim concomitantly with procarbazine on days 2-7 (starting 24 h after day-1 MOPP administration and stopping 24 h before ABV administration) as well as after ABV beginning on day 9. Filgrastim after ABV administration was administered until two consecutive ANC readings of 10 x 10(9)/l were achieved. RESULTS: All patients were able to complete all six cycles of therapy. There was a trend to fewer dose reductions in schedule II (0.76%) as compared to schedule I (4.2%) with a P-value of 0.077 (chi-squared test). Specifically, 11.6% of MOPP courses and 5.5% of ABV courses were dose-reduced in schedule I versus 1.7% and 1.4%, respectively, in schedule II. CONCLUSION: In conclusion, filgrastim was effective in supporting the delivery of the MOPP/ABV chemotherapy. Concomitant administration of filgrastim with procarbazine (days 2-7) appears to be safe and allows the maximum dose intensity of this therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Enfermedad de Hodgkin/tratamiento farmacológico , Adolescente , Adulto , Femenino , Filgrastim , Humanos , Masculino , Mecloretamina/administración & dosificación , Persona de Mediana Edad , Estadificación de Neoplasias , Prednisona/administración & dosificación , Procarbazina/administración & dosificación , Proteínas Recombinantes , Vincristina/administración & dosificaciónRESUMEN
The entire leader sequence of ten equine arteritis virus (EAV) isolates including the Bucyrus reference strain was determined and analyzed at the primary nucleotide and secondary structure levels. The leader sequence of eight EAV isolates was determined to be 206 nucleotides (nt) in length, whereas those of the 86AB-A1 and 86NY-A1 isolates were found to be 205 and 207 nt in length, respectively. The sequence identity of the leader sequences between the different isolates and the Bucyrus reference strain ranged from 94.2 to 98.5%. An AUG start codon found at position 14 in all EAV isolates could initiate an open reading frame (ORF) that could produce a polypeptide of 37 amino acids, except for the 86NY-A1 isolate where the intraleader polypeptide would contain 54 amino acids. Five patterns of computer-predicted RNA secondary structures were identified in the ten EAV leader regions analyzed. All EAV isolates showed three conserved stem-loops (designated A, B and C). An additional conserved stem-loop (D) was observed in six EAV isolates, including the Bucyrus reference strain. Based on the presence or absence of stem-loop D, all EAV isolates analyzed in this study could be tentatively classified into two genogroups (I and II). The significance of the intraleader ORF and the predicted secondary structures has yet to be determined.
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Regiones no Traducidas 5' , Equartevirus/genética , ARN Viral , Animales , Secuencia de Bases , Equidae , Datos de Secuencia Molecular , Homología de Secuencia de Ácido NucleicoRESUMEN
We have determined the nucleotide sequence of the blaS gene encoding the carbapenem-hydrolyzing L-1 beta-lactamase from Stenotrophomonas maltophilia GN12873. Analysis of the DNA and deduced amino acid sequences identified a product of 290 amino acids. Comparisons of the L-1 amino acid sequence with those of other zinc beta-lactamases showed 88.6% identity with the L-1 enzyme from S. maltophilia IID1275 and less than 20% identity with other class B metalloenzymes.
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Genes Bacterianos/genética , Xanthomonas/genética , Resistencia betalactámica/genética , beta-Lactamasas/genética , Secuencia de Aminoácidos , Secuencia de Bases , Variación Genética , Datos de Secuencia Molecular , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Xanthomonas/enzimologíaRESUMEN
BACKGROUND: The role of intensive chemotherapy with autologous blood and marrow transplantation (ABMT) for patients with relapsed or refractory intermediate grade non-Hodgkin's lymphoma has recently been established. However, conventional dose salvage chemotherapy is frequently used to determine chemotherapy sensitivity and reduce tumor bulk prior to intensive therapy. Different salvage regimens have been proposed but none appears significantly superior. The purpose of this study was to determine the efficacy of mini-BEAM salvage chemotherapy in patients referred for AMBT and to define prognostic factors of response. PATIENTS AND METHODS: One hundred four patients referred for consideration of AMBT after failure of primary anthracycline-based chemotherapy received BCNU 60 mg/m2 day 1, etoposide 75 mg/m2 day 2-5, ara-C 100 mg/m2 q12 h day 2-5, melphalan 30 mg/m2 day 6 (mini-BEAM) until maximum tumor reduction. Median age was 52 (range 18-65), 57% had failed to achieve a complete response (CR) to doxorubicin-based chemotherapy at diagnosis and only 13% had a previous CR lasting > 12 months. Seventy-six received mini-BEAM as first salvage chemotherapy. RESULTS: The overall response rate (RR) was 37% (95% confidence interval (CI) 28-46%) with 12 patients achieving CR and 25 achieving PR. The response rate among patients treated as first salvage was 43% compared to 20% for patients who had failed to respond to a previous salvage regimen. Only 15% of patients who failed to respond to mini-BEAM responded to another conventional dose salvage regimen. Thirty-eight of 104 patients ultimately demonstrated sufficient response to proceed to ABMT. Actuarial survival at four years is 22% for all 104 patients, and 36% for those who went on to AMBT. For those who were not transplanted, four-year survival was 18%. B symptoms and tumor burden at relapse were significant predictors of response to mini-BEAM in multivariate analysis, and identified a poor prognosis group of patients unlikely to be cured by the approach. CONCLUSIONS: Mini-BEAM does not appear to be a superior salvage regimen in this high-risk group of relapsed or refractory NHL patients for whom ABMT was the ultimate treatment intention. Only one-third of patients referred for ABMT ultimately proceed to transplant; alternative treatment strategies should be developed for those with a low likelihood of cure by this approach.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma no Hodgkin/tratamiento farmacológico , Adolescente , Adulto , Anciano , Trasplante de Médula Ósea , Carmustina/administración & dosificación , Carmustina/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Etopósido/administración & dosificación , Etopósido/efectos adversos , Humanos , Melfalán/administración & dosificación , Melfalán/efectos adversos , Persona de Mediana Edad , Recurrencia , Terapia Recuperativa , Resultado del TratamientoRESUMEN
Examining the relationship of stress, dietary disinhibition, and blood glucose control in diabetic young women was the goal of this study. Sixty-five diabetic girls and women, ranging in age from 12 to 26 years, completed eating behaviors and perceived stress scales during regular clinic visits. Blood glucose control was assessed by concurrent glycosylated hemoglobin measurements. Multiple regression analyses indicated that high levels of perceived stress predicted dietary disinhibition and that within the age range studied, young women were more likely than early adolescent girls to perceive their life as stressful. Contrary to previous findings that failed to show that stress can indirectly affect glucose control by interfering with compliance behaviors, the present work indicated a Stress X Dietary Disinhibition interaction in predicting glucose control. Blood glucose control was poorest in those diabetic women who both perceived their lives as stressful and reported medium to high disinhibition. Blood glucose control was unrelated to stress in young women who reported low levels of disinhibition. These results have implications for the development of specific interventions for young diabetic women who perceive their lives as stressful and who may respond to stress by eating.
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Glucemia/metabolismo , Diabetes Mellitus Tipo 1/psicología , Dieta para Diabéticos/psicología , Cooperación del Paciente/psicología , Estrés Psicológico/complicaciones , Adaptación Psicológica , Adolescente , Adulto , Niño , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/dietoterapia , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Factores de Riesgo , Rol del Enfermo , SocializaciónRESUMEN
We have isolated the blaCARB-3 structural gene encoding the CARB-3 carbenicillinase of Pseudomonas aeruginosa strain Cilote, tested the specificity of blaCARB-3 DNA probes and determined the nucleotide sequence of blaCARB-3. Three restriction fragment probes internal or delimiting the blaCARB-3 structural gene were hybridized with purified plasmid DNA coding for 18 other beta-lactamases (Blas). Under high-stringency conditions, only blaPSE-1, blaPSE-4, and blaCARB-4 sequences cross-hybridized with blaCARB-3. Sequencing of blaCARB-3 identified the structural gene which encodes a polypeptide product of 268 amino acids with a calculated estimated Mr of 29,246 for the mature form of the protein. Homology studies and computer analysis of primary structures confirmed that CARB-3 is a class-A Bla. The CARB-3 carbenicillinase differs from PSE-4 at two positions: Phe (PSE-4) instead of Leu188 (CARB-3), and Glu (PSE-4) instead of Ala266 (CARB-3), which changes the isoelectric value from (PSE-4) 5.4 to 5.75 (CARB-3). The possible effects of these two mutations were examined by comparisons on the 2 A crystal structure of the Staphylococcus aureus penicillinase, and they were shown to be silent substitutions causing no changes in the phenotype. The nucleic acid hybridization studies and sequence data confirmed that carbenicillinase-encoding bla genes are closely related and that blaCARB-3 is a variant of blaPSE-4.
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Genes Bacterianos , Penicilinasa/genética , Pseudomonas aeruginosa/genética , Secuencia de Aminoácidos , Resistencia a la Ampicilina/genética , Secuencia de Bases , Clonación Molecular , Elementos Transponibles de ADN/genética , Datos de Secuencia Molecular , Hibridación de Ácido Nucleico , Penicilinasa/química , Pseudomonas aeruginosa/enzimología , Mapeo Restrictivo , Homología de Secuencia de Ácido Nucleico , Staphylococcus aureus/genéticaAsunto(s)
Bromocriptina/uso terapéutico , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Bromocriptina/administración & dosificación , Bromocriptina/efectos adversos , Quimioterapia Combinada , Humanos , Levodopa/administración & dosificación , Levodopa/efectos adversos , Persona de Mediana EdadRESUMEN
The outer membrane of imipenem-resistant mutants of Pseudomonas aeruginosa was shown to have decreased permeability to imipenem but not to cephaloridine. These experiments were performed with intact cells and liposomes containing imipenem-hydrolyzing beta-lactamase derived from Pseudomonas maltophilia, in both cases utilizing an imipenem concentration of 50 microM. In contrast, liposome swelling assays using imipenem at 8 mM detected no significant difference between the imipenem-resistant mutants and their parents. It was found that the outer membrane of P. aeruginosa has a saturable specific channel through which imipenem travels mainly at low concentrations, whereas at high concentrations this pathway is obscured by diffusion through nonspecific porin channels.
Asunto(s)
Permeabilidad de la Membrana Celular/efectos de los fármacos , Imipenem/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Farmacorresistencia Microbiana , Regulación de la Expresión Génica , Genes Bacterianos , Imipenem/metabolismo , Liposomas , Mutación , Plásmidos , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/metabolismo , beta-Lactamasas/aislamiento & purificación , beta-Lactamasas/metabolismoRESUMEN
The incidence of severe hypoglycemia was determined in a 1-yr prospective study of 350 insulin-dependent diabetic (IDDM) children. There were no significant differences in mean glycosylated hemoglobin, age, and duration of disease between the patients who had severe hypoglycemia and those who did not. There were 25 episodes in 24 patients (6.8%). Their insulin doses at the time of the episode (U.kg-1.day-1) were significantly higher than those of the nonhypoglycemic group (mean +/- SD 1.01 +/- 0.30 vs. 0.89 +/- 0.29; P = .04). The hypoglycemic group had a significantly higher mean number of previous episodes of severe hypoglycemia than the nonhypoglycemic group (0.92 +/- 1.18 vs. 0.25 +/- 0.68; P = .01). In only 64% of the episodes, an unusual circumstance such as strenuous physical activity or missed or delayed meals preceded the event. Multivariate analysis of the data by logistic regression showed risks of developing hypoglycemia of 2.5 per 0.5 U/day insulin and of 2.0 per previous episode of severe hypoglycemia. We conclude that severe hypoglycemia may be a recurrent problem in some diabetic children, but it does not appear to be related to age or blood glucose control. The presence of previous episodes may be a guide to identify patients at greater risk of developing severe hypoglycemia. Adherence to regular testing, strict spacing and consistency of meals, and extra food for extra activity may reduce this serious complication.
Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Hipoglucemia/inducido químicamente , Insulina/efectos adversos , Niño , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipoglucemia/etiología , Insulina/uso terapéutico , Masculino , Estudios Prospectivos , Factores de RiesgoRESUMEN
The L-1 penicillinase structural gene, blaS, from Pseudomonas maltophilia was cloned into the vector pACYC184. The pMON01 recombinant plasmid selected by ampicillin resistance carried a 2.6-kilobase (kb) Sau3A fragment of P. maltophilia DNA and was confirmed to express L-1 beta-lactamase by comparative isoelectric focusing. A detailed physical map was constructed, and the blaS structural gene was localized with a 17-mer oligonucleotide mixed probe encoding the L-1 NH2-terminal amino acid sequence. Induction studies confirmed constitutive expression. Isolation of a complete beta-lactamase operon was attempted by construction of a P. maltophilia genomic library into phage lambda 2001. A recombinant phage was selected by DNA hybridization; the 13.4-kb DNA insert was physically mapped and subcloned into the high-copy-number plasmid pACYC184 and into the low-copy-number vector pLG338. The expression of the cloned blaS L-1 structural gene and levels of beta-lactamase synthesis were studied in Escherichia coli. The protein synthesized was found to be similar to the L-1 beta-lactamase of the prototype P. maltophilia, although expression levels were gene dosage dependent for beta-lactamase synthesis.