RESUMEN
Brucella spp. and Sinorhizobium meliloti are alphaproteobacteria that share not only an intracellular lifestyle in their respective hosts, but also a crucial requirement for cell envelope components and their timely regulation for a successful infectious cycle. Here, we report the characterization of Brucella melitensis mucR, which encodes a zinc finger transcriptional regulator that has previously been shown to be involved in cellular and mouse infections at early time points. MucR modulates the surface properties of the bacteria and their resistance to environmental stresses (i.e., oxidative stress, cationic peptide, and detergents). We show that B. melitensis mucR is a functional orthologue of S. meliloti mucR, because it was able to restore the production of succinoglycan in an S. meliloti mucR mutant, as detected by calcofluor staining. Similar to S. meliloti MucR, B. melitensis MucR also represses its own transcription and flagellar gene expression via the flagellar master regulator ftcR. More surprisingly, we demonstrate that MucR regulates a lipid A core modification in B. melitensis. These changes could account for the attenuated virulence of a mucR mutant. These data reinforce the idea that there is a common conserved circuitry between plant symbionts and animal pathogens that regulates the relationship they have with their hosts.
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Proteínas Bacterianas/metabolismo , Brucella melitensis/metabolismo , Detergentes/farmacología , Estrés Oxidativo , Sinorhizobium meliloti/metabolismo , Cloruro de Sodio/farmacología , Animales , Proteínas Bacterianas/genética , Brucella melitensis/genética , Brucelosis/microbiología , Membrana Celular , Regulación Bacteriana de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Glucosiltransferasas/genética , Glucosiltransferasas/metabolismo , Peróxido de Hidrógeno/farmacología , Ratones , Ratones Endogámicos BALB C , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Factores de TiempoRESUMEN
AIM: Laparoscopic adhesiolysis has been demonstrated to be technically feasible in small bowel obstruction and carries advantages in terms of post-surgical course. The increasing dissemination of laparoscopic surgery in the emergency setting and the lack of concrete evidence in the literature have called for a consensus conference to draw recommendations for clinical practice. METHODS: A literature search was used to outline the evidence, and a consensus conference was held between experts in the field. A survey of international experts added expertise to the debate. A public jury of surgeons discussed and validated the statements, and the entire process was reviewed by three external experts. RESULTS: Recommendations concern the diagnostic evaluation, the timing of the operation, the selection of patients, the induction of the pneumoperitoneum, the removal of the cause of obstructions, the criteria for conversion, the use of adhesion-preventing agents, the need for high-technology dissection instruments and behaviour in the case of misdiagnosed hernia or the need for bowel resection. CONCLUSION: Evidence of this kind of surgery is scanty because of the absence of randomized controlled trials. Nevertheless laparoscopic skills in emergency are widespread. The recommendations given with the consensus process might be a useful tool in the hands of surgeons.
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Obstrucción Intestinal/cirugía , Laparoscopía , Humanos , Obstrucción Intestinal/etiología , Intestino Delgado , Adherencias Tisulares/complicaciones , Adherencias Tisulares/cirugíaRESUMEN
The aim of the study was to test the hypothesis that the gene defect causing congenital absence of maxillary lateral incisors also causes narrowing of the dentition. A total of 81 patients with one or two congenitally missing lateral incisors were retrieved; 52 (64.2 per cent) patients presented bilateral agenesis, whereas 29 (35.8 per cent) had unilateral agenesis. The control group consisted of 90 consecutively treated patients. The largest mesiodistal crown dimension for all teeth, except for the maxillary second and third molars, was measured on plaster casts using a digital caliper to the nearest 10th of a millimetre. Statistical testing was performed using the analysis of variance model (P < 0.05) to test for differences in the mesiodistal dimension between the sample and the control group. Significance has been assessed using a P-value threshold level of 5 per cent. Agenesis of maxillary lateral incisors was found to be a significant predictor of tooth size. Patients who were missing maxillary lateral incisors had smaller teeth compared to control subjects, except for the maxillary right and left first molars. This finding was true for both unilateral and bilateral lateral incisor agenesis. Interaction between maxillary lateral incisor agenesis and gender was not significant. Patients with congenitally missing lateral incisors have narrower teeth than patients without any dental anomalies, except for maxillary first molars. A higher prevalence of microdontic contralateral incisors was found in patients with unilateral agenesis with respect to the control group.
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Anodoncia/genética , Incisivo/anomalías , Corona del Diente/patología , Adolescente , Análisis de Varianza , Anodoncia/epidemiología , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Maxilar , Diente Molar/anatomía & histología , Tercer Molar/anatomía & histología , Adulto JovenRESUMEN
INTRODUCTION AND IMPORTANCE: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. It may be asymptomatic; nevertheless, gastrointestinal bleeding is the most frequent symptom, due to mucosal erosion. Its poor lymph node metastatic spread makes GIST often suitable of minimally invasive surgical approach. The importance of this study is to increase the awareness among physicians about this condition in particular scenarios as in our case and to stress the role of laparoscopic surgery. CASE PRESENTATION: A 74-year-old female patient presented to the emergency department with hematemesis, followed by haematochezia and melena. The patient had a medical history of type 1 Neurofibromatosis (NF1). She underwent, after CT scan, esophagogastroduodenoscopy, and endoscopic haemostasis. Finally, we performed a laparoscopic resection of a mass of the first jejunal loop. The postoperative period was predominantly uneventful. Pathological examination confirmed a low-risk GIST. CLINICAL DISCUSSION: Proximal jejunal GIST may cause an upper and lower gastrointestinal bleeding. A multidisciplinary team approach is mandatory for the correct management of this disease and its complications (bleeding). GISTs are indicated as the most commonly gastrointestinal NF1 associated tumours. In case of localised and resectable GIST surgical treatment is the mainstay and laparoscopic surgery is a valid alternative. CONCLUSION: In case of abdominal bleeding mass in a NF1 patient, it is important to keep in mind the well-known association between NF1 and GIST to facilitate the diagnosis and to quickly perform the appropriate treatment. Laparoscopic approach is safe and effective if the oncological radicality is respected.
RESUMEN
BACKGROUND: Acute mesenteric ischemia is a rare affection with high related mortality. NOMI presents the most important diagnostic problems and is related with the higher risk of white laparotomy. This study wants to give a contribution for the validation of laparoscopic approach in case of NOMI. METHODS: Thirty-two consecutive patients were admitted in last 10 years in ICU of Paolo Giaccone University Hospital of Palermo for AMI. Diagnosis was obtained by multislice CT and selective angiography was done if clinical conditions were permissive. If necrosis was already present or suspected, surgical approach was done. Endovascular or surgical embolectomy was performed when necessary. Twenty NOMI patients underwent medical treatment performing laparoscopy 24 h later to verify the evolution of AMI. A three-port technique was used. In all patients we performed a bed side procedure 48-72 h later in both non-resected and resected group. RESULTS: In 14 up 20 case of NOMI the disease was extended throughout the splanchnic district, in 6 patients it involved the ileum and the colon; after a first look, only 6 patients underwent resection. One patient died 35 h after diagnosis of NOMI. The second look, 48 h later, demonstrated 4 infarction recurrences in the group of resected patients and onset signs of necrosis in 5 patients of non-resected group. A total of 15 resections were performed on 11 patients. Mortality rate was 6/20-30% but it was much higher in resected group (5/11-45,5%). Non-therapeutic laparotomy was avoided in 9/20 patients and in this group mortality rate was 1/9-11%. No morbidity was recorded related to laparoscopic procedure. CONCLUSIONS: Laparoscopy could be a feasible and safety surgical approach for management of patient with NOMI. Our retrospective study demonstrates that laparoscopy don't increase morbidity, reduce mortality avoiding non-therapeutic laparotomy.
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Laparoscopía/métodos , Isquemia Mesentérica/cirugía , Anciano , Anciano de 80 o más Años , Colon/cirugía , Femenino , Humanos , Unidades de Cuidados Intensivos/organización & administración , Unidades de Cuidados Intensivos/estadística & datos numéricos , Masculino , Isquemia Mesentérica/diagnóstico por imagen , Isquemia Mesentérica/mortalidad , Persona de Mediana Edad , Estudios Retrospectivos , Segunda Cirugía , EspañaRESUMEN
To evaluate the release of catecholamines and their relationship with systemic blood pressure (BP) in normotensive patients with obstructive sleep apnea syndrome (OSAS), diurnal and nocturnal urinary norepinephrine (NE) and epinephrine (E) excretion in 12 normal subjects and in 10 OSAS patients were compared; in addition, nocturnal NE and E excretion were measured in the patients while receiving short-term CPAP. Blood pressure was continuously monitored in the patients during both nights of urine collection. In normal subjects, both NE and E excretion decreased from day to night. In the patients without CPAP, only NE excretion decreased at night, and BP increased from wakefulness to sleep; both NE and E excretion were higher in patients than in normal subjects. With CPAP, which prevented apneas, only E excretion decreased with respect to the previous night, while BP no longer increased during sleep. The extent of nocturnal E decrease with CPAP was not correlated to BP variations. These results suggest that in normotensive OSAS subjects, sympathetic nervous system activity, based on NE excretion, is continuously increased and is not affected by short-term CPAP treatment. Conversely, adrenal activity, based on E excretion, is also increased, but it tends to be normalized by short-term CPAP. No clear relationship could be found between sympatho-adrenal behavior and BP during sleep.
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Presión Sanguínea , Catecolaminas/orina , Síndromes de la Apnea del Sueño/orina , Adulto , Análisis de Varianza , Ritmo Circadiano , Diástole , Epinefrina/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Norepinefrina/orina , Respiración con Presión Positiva , Síndromes de la Apnea del Sueño/epidemiología , Síndromes de la Apnea del Sueño/fisiopatología , Síndromes de la Apnea del Sueño/terapia , SístoleRESUMEN
Circumstances under which the use of oxygen-therapy in lung disease can be effective and harmless, depend upon a careful evaluation of its indications: they are suggested by the clinical need of correction of hypoxaemia as well as by the awareness of factors determining respiratory failure and of problems concerning O(2) transport and supply to tissues in health and disease. Blood gases monitoring enables to control the effects of treatment on arterial O2 and CO2 tensions thus giving all the useful data for oxygen administering particularly as far as components of hyperoxygenated mixtures, flow rate, duration, use of very effective low-risk devices (Venturi masks) are concerned. Correction of hypoxaemia involves the reduction of hypertension of the pulmonary circulation and hyperglobulia, improvement of tolerance of exertion, and attention to the metabolic compensation of respiratory acidosis. These results are influenced by the nature of the pathogenetic factors behind broncho-obstructive disease, which may lead to either a primarily "bronchitis" or a primarily "emphysematous" syndrome. An interesting feature relates to prognosis in the case of patients making home use of hyperoxygenated mixtures as part of a rehabilitation program, or to improve their quality of life. The cost and benifits of such treatment should be carefully weighed. Lastly, in the event of protracted treatment, attention must be paid to the possibility of toxicity and the means to be adopted for its prevention.
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Enfermedades Pulmonares Obstructivas/terapia , Terapia por Inhalación de Oxígeno , Insuficiencia Respiratoria/terapia , Acidosis Respiratoria/prevención & control , Análisis de los Gases de la Sangre , Humanos , Hipertensión/prevención & control , Hipoxia/prevención & control , Consumo de Oxígeno , Insuficiencia Respiratoria/metabolismoRESUMEN
This article presents a clinical case of bilateral partial edentulism in the posterior mandible with severe horizontal and moderate vertical bone atrophy. A new technique using rapid orthodontics after ridge splitting is presented. The split-crest technique was carried out using piezosurgical instruments in the first molar and second premolar areas to widen the bone crest and open a channel for tooth movement. Immediately after, orthodontic appliances were used to move the first premolars distally and the second molars mesially into the surgical site. The rationale was to facilitate and accelerate orthodontic movement of the teeth, which is otherwise difficult in a cortical knife-edged ridge. The bone defect was filled with the alveolar bone of the adjacent teeth that were moved into the surgically opened path. Adequate bone volume for implant placement was generated in the first premolar area. Implants were then inserted, and the patient was rehabilitated.
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Implantes Dentales , Mandíbula/cirugía , Osteotomía/métodos , Técnicas de Movimiento Dental/métodos , Adulto , Alveoloplastia/métodos , Atrofia , Diente Premolar/patología , Densidad Ósea/fisiología , Arco Dental/cirugía , Femenino , Esponja de Gelatina Absorbible/uso terapéutico , Humanos , Arcada Parcialmente Edéntula/rehabilitación , Arcada Parcialmente Edéntula/cirugía , Mandíbula/patología , Diente Molar/patología , Métodos de Anclaje en Ortodoncia/instrumentación , Alambres para Ortodoncia , Osteogénesis/fisiología , Piezocirugía/instrumentación , Técnicas de Movimiento Dental/instrumentaciónRESUMEN
PURPOSE: To evaluate the soft and hard tissue response to orthodontic implant site development (OISD) (ie, forced extraction), to measure the amount of tissue that was regenerated and its relationship to the amount of orthodontic vertical tooth movement, to evaluate the tissue response in teeth with different degrees of periodontal attachment loss, to understand the limits of OISD, and to evaluate the implant survival rate. MATERIALS AND METHODS: A total of 32 hopeless teeth were treated with OISD, and 27 implants were placed in 13 patients consecutively. The level of periodontal attachment on the teeth to be extracted, amount of augmented alveolar bone, changes in soft tissue volume, and the rate of orthodontic tooth movement were recorded. RESULTS: Mean values after OISD were as follows: orthodontic extrusive movement, 6.2 ± 1.4 mm; bone augmentation, 4 ± 1.4 mm; coronal movement of the gingival margin, 3.9 ± 1.5 mm; coronal movement of the mucogingival junction, 2.1 ± 1.3 mm; keratinized gingival augmentation, 1.8 ± 1.1 mm; gingival thickness (buccolingual dimension) augmentation, 0.7 ± 0.4 mm; recession, 1.8 ± 1.2 mm; bone augmentation/orthodontic movement ratio (efficacy), 68.9% ± 17.3%; gingival augmentation/orthodontic movement ratio (efficacy), 65.2% ± 19.9%; and pocket depth reduction, 1.8 ± 0.9 mm. The implant survival rate was 96.3%. CONCLUSIONS: OISD was a viable treatment for these hopeless teeth to regenerate hard and soft tissues. Its efficacy was about 70% for bone regeneration and 60% for gingival augmentation. The residual attachment level on the tooth was not a limitation. OISD might be a valuable treatment option to regenerate tissues for implant site development in patients in need of conventional orthodontic therapy.
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Implantes Dentales de Diente Único , Extrusión Ortodóncica/métodos , Enfermedades Periodontales/terapia , Pérdida de Hueso Alveolar/terapia , Proceso Alveolar/patología , Aumento de la Cresta Alveolar/métodos , Diseño de Implante Dental-Pilar , Restauración Dental Provisional/métodos , Femenino , Estudios de Seguimiento , Encía/patología , Recesión Gingival/terapia , Humanos , Carga Inmediata del Implante Dental/métodos , Masculino , Pérdida de la Inserción Periodontal/terapia , Ligamento Periodontal/patología , Bolsa Periodontal/terapia , Regeneración/fisiología , Extracción Dental , Alveolo Dental/patología , Resultado del TratamientoAsunto(s)
Aptitud , Percepción Auditiva , Cognición , Humanos , Masculino , Memoria , Discriminación de la Altura Tonal , Factores de TiempoAsunto(s)
Adaptación Fisiológica , Ergonomía , Audición , Pruebas Auditivas , Humanos , Masculino , SonidoRESUMEN
The volume of distribution (Vd) of theophylline and the relevant aminophylline loading dose (LD) are usually calculated on the basis of total body weight (TBW). In obese subjects it has been suggested that lean or ideal body weight (IBW) is the best predictor. In a sample of 40 acutely ill asthmatic patients (aged 22 to 78 yr, weighing 45 to 176 kg) we measured Vd and found that (1) it increases with TBW, (2) it cannot be accurately predicted from either TBW or IBW alone by a simple regression analysis. Power functions have been usefully applied in comparing the pharmacokinetics of animal species, including humans, with different body mass. In our sample, data were best fitted by the equation Vd = 1.29 TBW 0.74, which seems to take care of lean as well as obese patients. Results were confirmed (r = 0.89 between predicted and measured values) in a second independent sample of patients (aged 26 to 77 yr, weighing 38 to 167 kg). This helps to minimize the error in obtaining the target serum concentration of theophylline when giving a LD calculated from a predicted Vd value.
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Peso Corporal , Obesidad/metabolismo , Teofilina/farmacocinética , Adulto , Anciano , Asma/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión , Teofilina/administración & dosificaciónRESUMEN
This study was aimed at assessing the pharmacokinetics of a single dose of theophylline solution (aminophylline 480 mg) administered by intramuscular (i.m.) route to 16 subjects (age 28-61 years, body weight 52-75 kg). The same dose was given a week apart by oral route in fasting conditions. The intraindividual comparison shows that by i.m. route the rate, but not the extent, of absorption may be somewhat lower. From the first hour on, until hour 3-4 after i.m. dosing, all subjects achieved a safe and effective serum theophylline concentration (9-17 mg/liter). This suggests that, although usually not recommended, self-administration of a single dose of aminophylline by i.m. route may temporarily help theophylline-responsive patients in distress, when other routes of administration are not available and facilities for intensive conventional treatment are lacking.
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Teofilina/farmacocinética , Enfermedad Aguda , Administración Oral , Adulto , Asma/tratamiento farmacológico , Disponibilidad Biológica , Bronquitis/tratamiento farmacológico , Femenino , Humanos , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , Autoadministración , Teofilina/administración & dosificaciónRESUMEN
Site-specific recombination in Saccharomyces cerevisiae was used to generate non-replicative DNA rings containing yeast telomeric sequences. In topoisomerase mutants expressing Escherichia coli topoisomerase I, the rings adopted a novel DNA topology consistent with the ability of yeast telomeric DNA to block or retard the axial rotation of DNA. DNA fragments bearing portions of the terminal repeat sequence C1-3 A/TG1-3 were both necessary and sufficient to create a barrier to DNA rotation. Synthetic oligonucleotide sequences containing Rap1p binding sites, a well represented motif in naturally occurring C1-3A arrays, also conferred immobilization; mutant Rap1p binding sites and telomeric sequences from other organisms were not sufficient. DNA anchoring was diminished by addition of competing telomeric sequences, implicating a role for an as yet unidentified limiting trans-acting factor. Though Rap1p is a likely protein constituent of the DNA anchor, deletion of the non-essential C-terminal domain did not affect the topology of telomeric DNA rings. Similarly, disruption of SIR2, SIR3 and SIR4, genes which influence a variety of telomere functions in yeast, also had no effect. We propose that telomeric DNA supports the formation of a SIR-independent macromolecular protein-DNA assembly that hinders the motion of DNA because of its linkage to an insoluble nuclear structure. Potential roles for DNA anchoring in telomere biology are discussed.
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Cromosomas/metabolismo , ADN-Topoisomerasas de Tipo I/metabolismo , ADN/metabolismo , Saccharomyces cerevisiae/metabolismo , Telómero/metabolismo , Sitios de Unión/genética , ADN Superhelicoidal/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/farmacología , Electroforesis en Gel de Agar , Escherichia coli/enzimología , Conformación de Ácido Nucleico , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
The purpose of this study was to identify risk factors for apical root resorption in adult orthodontic patients. Standardized periapical radiographs of maxillary anterior teeth and cephalograms made before and after treatment and treatment charts of 343 adults, representing groups of consecutively treated patients from four orthodontic practices, were examined. Apical root resorption was calculated by subtracting posttreatment tooth length measurements from the corresponding pretreatment measurements. Root width was measured from the mesial to the distal outline of the roots 4 mm from the apex. Root form was scored subjectively as normal, pointed, eroded, blunt, bent, and bottle shaped. Root movement was calculated from measurements of superimposed tracings of pretreatment and posttreatment cephalograms. Proximity of the central incisor roots to the palatal cortical bone was scored subjectively as present or absent. Severity of initial malocclusion and treatment variables were collected from the charts. Multiple linear regression analyses revealed that amount of root movement, long roots, narrow roots, abnormal root shape, and use of Class II elastics were significant risk factors. However, the statistical model had a low explained variance, strongly suggesting a weak prediction power. No association was found between type of initial malocclusion, treatment time, use of rectangular arch wires, proximity of the root to the palate or treatment with maxillary osteotomy, and root resorption. Endodontic treatment was a preventive factor.
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Ortodoncia Correctiva/efectos adversos , Resorción Radicular/etiología , Adulto , Anciano , Cefalometría , Distribución de Chi-Cuadrado , Diente Canino/fisiopatología , Humanos , Incisivo/fisiopatología , Modelos Lineales , Maxilar , Persona de Mediana Edad , Radiografía , Reproducibilidad de los Resultados , Factores de Riesgo , Resorción Radicular/diagnóstico por imagen , Raíz del Diente/patologíaRESUMEN
The purpose of this study was to evaluate prevalence and severity of apical root resorption of maxillary anterior teeth in a large sample of adult orthodontic patients, to analyse any difference between subgroups of patients with and without a history of earlier orthodontic treatment, and to test the hypothesis that endodontically treated teeth are less likely to experience apical root resorption. Differences in tooth length measurements of standardized periapical radiographs made before and after treatment of 343 adults, representing groups of consecutively treated patients from four orthodontic practices, were calculated. Sample means of averaged root resorption of all six anterior teeth and of the most severely resorbed tooth per patient were 0.94 mm (SD 0.88) and 2.39 mm (SD 1.43), respectively. Forty per cent of the adults had one or more teeth with 2.5 mm resorption or greater. The subsample of 31 patients with a history of earlier orthodontic treatment had less root resorption than the remaining patients (P < 0.001). Evaluation of the 39 contralateral pairs of teeth with and without endodontic treatment in 36 of the patients revealed less resorption of the endodontically treated teeth (P < 0.05).
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Ortodoncia Correctiva/efectos adversos , Resorción Radicular/etiología , Adulto , Factores de Edad , Humanos , Odontometría , Prevalencia , Radiografía , Tratamiento del Conducto Radicular , Resorción Radicular/diagnóstico por imagenRESUMEN
Maximum expiratory flows at 50% of vital capacity while breathing air and a He-O2 mixture and delta Vmax50 observed during three sittings (morning, noon and morning the day after) in reference subjects and in patients with bronchial hyperreactivity were submitted to statistical analysis by between sittings comparison, looking for correlation coefficients, paired "t" test and variation coefficient. Results of paired "t" test ruled out the influence of fatigue and of training in performing forced expiratory manoeuvres. Correlation coefficients relevant to absolute flows are highly significant in both groups, whereas coefficients of variation are satisfactory in reference subjects and slightly higher although still acceptable in patients with bronchial hyperreactivity. As far as delta Vmax50 is concerned, the results of statistical analysis are positively unacceptable, thus demonstrating that this arithmetic manipulation of absolute flows is the ground for a poor reproducibility of results.
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Asma/diagnóstico , Flujo Espiratorio Forzado , Flujo Espiratorio Máximo , Curvas de Flujo-Volumen Espiratorio Máximo , Adulto , Anciano , Aire , Obstrucción de las Vías Aéreas/fisiopatología , Femenino , Helio , Humanos , Masculino , Persona de Mediana Edad , OxígenoRESUMEN
We examined two rapid methods of measuring theophylline clearance using pairs of serum concentration measurements, and compared them with the steady-state values in 31 patients with acute asthma. A constant intravenous aminophylline infusion was started at a rate given by current guidelines. Theophylline clearance was estimated from two serum measurements made with an interval of at least 4 h, providing clearance estimates 5 h from commencement. Duplicate estimates were made, using either a 3rd serum measurement at 12 h or a 3rd and 4th at 7 and 14 h. A steady-state estimate was finally made after 48 h constant infusion. The two rapid estimates agreed well both between themselves and with the steady-state determination despite wide variations in the clinical status of the patients. These methods provide a rapid means of monitoring dosage in the individual patient. This is particularly important when the predicted dose is inappropriate.