Sustainable Development Goals' health-related indicators for Brazil and Ecuador: an analysis for the period of 1990-2019.

OBJECTIVE: This article aims to analyse the evolution of 40 Sustainable Development Goals' (SDGs) health-related indicators in Brazil and Ecuador from 1990 to 2019. STUDY DESIGN: Epidemiological study of long-term trends in 40 SDGs' health-related indicators for Brazil and Ecuador from 1990 to 2019, using estimates from the Global Burden of Disease Study. METHODS: Forty SDGs' health-related indicators and an index from 1990 to 2017 for Brazil and Ecuador, and their projections up to 2030 were extracted from the Institute for Health Metrics and Evaluation's Global Burden of Disease website and analysed. The percent annual change (PC) between 1990 and 2019 was calculated for both countries. RESULTS: Both countries have made progress on child stunting (Brazil: PC = -38%; Ecuador: PC = -43%) and child wasting prevalences (Brazil: PC = -42%; Ecuador: PC = -41%), percent of vaccine coverage (Brazil: PC = +215%; Ecuador: PC = +175%), under-5 (Brazil: PC = -75%; Ecuador: PC = -60%) and neonatal mortality rates (Brazil: PC = -69%; Ecuador: PC = -51%), health worker density per 1000 population (Brazil: PC = +153%; Ecuador: PC = +175%), reduction of neglected diseases prevalences (Brazil: PC = -40%; Ecuador: PC = -58%), tuberculosis (Brazil: PC = -27%; Ecuador: PC = -55%) and malaria incidences (Brazil: PC = -97%; Ecuador: PC = -100%), water, sanitation and hygiene mortality rates (Brazil and Ecuador: PC = -89%). However, both countries did not show sufficient improvement in maternal mortality ratio to meet SDGs targets (Brazil: PC = -37%; Ecuador: PC = -40%). Worsening of indicators were found for violence, such as non-intimate partner violence for both countries (Brazil: PC = +26%; Ecuador: PC = +18%) and suicide mortality rate for Ecuador (PC = +66%), child overweight indicator for Brazil (PC = -67%), disaster mortality rates (Brazil: PC = +100%; Ecuador: PC = +325%) and alcohol consumption (Brazil: PC = +46%; Ecuador: PC = +35%). CONCLUSIONS: Significant improvements are necessary in both countries requiring the strengthening of health and other policies, particularly concerning the prevention and management of violence and alcohol consumption, and preparedness for dealing with environmental disasters.

Development of FPGA-based multi-sensor excitation low voltage (MSELV) chassis at Jefferson Lab.

The design and development of the sensor excitation and read back chassis was driven by the requirements for the monitoring and control of two conduction-cooled superconducting magnets in Hall B for the 12 GeV accelerator upgrade. The torus and solenoid superconducting magnets require extensive instrumentation. Sensor selection was accomplished by applying Jefferson Lab's (JLab) risk mitigation process, which employed a failure modes and effects analysis approach. The goal was to accommodate all sensor types for monitoring and control and to develop a generic multisensor excitation low voltage chassis that would be used across both magnet systems with a reduced set of functions. The chassis has been deployed in experimental Hall B at JLab and has been performing successfully since July 2016.

Parallel mapping of genotypes to phenotypes contributing to overall biological fitness.

Laboratory selection is a powerful approach for engineering new traits in metabolic engineering applications. This approach is limited because determining the genetic basis of improved strains can be difficult using conventional methods. We have recently reported a new method that enables the measurement of fitness for all clones contained within comprehensive genomic libraries, thus enabling the genome-scale mapping of fitness altering genes. Here, we demonstrate a strategy for relating these measurements to the individual phenotypes selected for in a particular environment. We first provide a mathematical framework for decomposing fitness into selectable phenotypes. We then employed this framework to predict that single-batch selections would enrich primarily for library clones with increased growth rate, serial-batch would enrich for a broad collection of clones enhanced via a combination of increased growth rate and/or reduced lag times, and that overlap among selected clones would be minimal. We used the SCalar Analysis of Library Enrichments (SCALEs) method to test these predictions. We mapped all genomic regions for which increased copy number conferred a selective advantage to Escherichia coli when cultured via single- or serial-batch in the presence of 1-naphthol. We identified a surprisingly large collection (163 total) of tolerance regions, including all previously identified solvent tolerance genes in E. coli. We show that the majority of the identified regions were unique to the different selection strategies examined and that such differences were indeed due to differences among enriched clones in growth rate and lag times over the solvent concentrations examined. The combination of a framework for decomposing overall fitness into selectable phenotypes along with a genome-scale method for mapping genes to such phenotypes lays the groundwork for improving the rational design of laboratory selections.

A genomics approach to improve the analysis and design of strain selections.

Strain engineering has been traditionally centered on the use of mutation, selection, and screening to develop improved strains. Although mutational and screening methods are well-characterized, selection remains poorly understood. We hypothesized that we could use a genome-wide method for assessing laboratory selections to design selections with enhanced sensitivity (true positives) and specificity (true negatives) towards a single desired phenotype. To test this hypothesis, we first applied multi-SCale Analysis of Library Enrichments (SCALEs) to identify genes conferring increased fitness in continuous flow selections with increasing levels of 3-hydroxypropionic acid (3-HP). We found that this selection not only enriched for 3-HP tolerance phenotypes but also for wall adherence phenotypes (41% false positives). Using this genome-wide data, we designed a serial-batch selection with a decreasing 3-HP gradient. Further examination by ROC analysis confirmed that the serial-batch approach resulted in significantly increased sensitivity (46%) and specificity (10%) for our desired phenotype (3-HP tolerance).

Amaranth addition to enzymatically modified wheat flour improves dough functionality, bread immunoreactivity and quality.

Consumers with gluten-related disorders require gluten-free (GF) foods to avoid an immune response. Alternative to the use of non-gluten containing grains to prepare GF bread, the gluten reactivity has been greatly reduced using a proline specific cleavage enzyme, however, the gluten functionality was lost. The aim of this study was to evaluate the effect of adding an amaranth flour blend (AFB) to enzymatically modified wheat-flour proteins on dough functionality and to evaluate the immunoreactivity and acceptability of the prepared bread. First, wheat flour (20% w/v, substrate) was hydrolyzed using 8.4 U mg-1 protein Aspergillus niger prolyl-endopeptidase (AnPEP) for 8 h at 40 °C under constant agitation. Four types of breads were prepared with the same formulation except for the type of flour (14% w.b.): wheat flour (WF), WF-AFB unmodified not incubated, WF-AFB unmodified incubated and WF-AFB modified. The protein composition and free thiols were analyzed before and after amaranth addition, and the flour and bread proteins were run using SDS-PAGE and immune-detected in blots with IgA from celiac disease patients. The immunoreactive gluten content, specific volume and bread acceptability were evaluated. The polymeric proteins and free thiol groups of WF decreased after AnPEP treatment. The electrophoretic patterns of the modified flour and bread proteins were different and the IgA-immunodetection in blots was highly reduced, particularly for the higher molecular weight subunits. The addition of AFB to the modified wheat flour prepared using AnPEP improved the dough functionality by increasing the thiol groups and allowed the preparation of a sensorially acceptable bread with only 60 mg kg-1 immunoreactive gluten.

Manejo de extrusión forzada ortodóntica: Reporte de un caso / Management and Follow-up of Orthodontic Forced Extrusion: A Case Report

El presente caso clínico se enfoca en el diagnóstico y el tratamiento de erupción forzada en un paciente con trauma dental. Objetivo: Proponer una alternativa de tratamiento multidisciplinario el cual permita incrementar estructura dentaria a través de la extrusión forzada y posteriormente rehabilitarlo en función y estética. Métodos: Se describe el caso de un paciente adulto de 78 años de sexo masculino, sano y sin antecedentes patológicos, acude a la clínica de la Especialidad de Ortodoncia y Ortopedia Dentomaxilo facial, referido por un especialista en Endodoncia, debido a fractura corono-radicular de canino superior derecho, pilar de puente fijo de tres unidades En la exploración intraoral presenta fractura cervical de la corona del canino superior derecho. Como primer paso, se realizó tratamiento endodóntico en la pieza dentaria y colocación de un aditamento intraconducto de soporte (endoposte vaciado), con el objeto de mejorar la tracción ortodóntica. Este aditamento consistió en un poste colado con perforaciones. Se procede a colocar aparatología fija en la arcada superior con técnica MBT (slot 0.022), del molar derecho hasta el canino izquierdo de cementado indirecto y pasivo (con los slots de los brackets alineados). Inmediatamente después, se colocó un arco rectangular 0.019 x 0.025 de acero inoxidable con un doblez de extrusión a nivel del canino superior derecho. En el mismo doblez, se adaptó un loop tipo helix que funcionó como apoyo para colocar la ligadura pasiva (lace back). Resultados : El tratamiento realizado en este paciente es satisfactorio, coadyuvando en su estado de salud general mejorando su autoestima. Conclusión: Aquí se aprovecharon todas las ventajas que ofrece la extrusión ortodóntica forzada, incluso en un paciente adulto mayor, logrando una tracción de cuatro milímetros, que se consiguió gracias al empleo de fuerzas extrusivas ligeras y controladas sobre el órgano dentario afectado. Con la modalidad de tratamiento descrita se puede lograr un alargamiento de corona sin la necesidad de realizar una resección ósea, lo que permite una correcta rehabilitación protésica, devolviendo la función y estética al diente lesionado y brindando un beneficio integral al paciente.

The case of an adult patient with a complicated Crown fracture of the right upper canine due to trauma is reported, diagnosing a class VII Ellis coronal fracture. There are several treatment alternatives that range from the extraction, placement of a bone graft and placement of an implant, to a forced root extrusión with bone removal to allow the biological space and subsequently be restored. In the present case, a multidisciplinary orthodontic forced extrusion treatment is performed, which allows to increase the amount of clinical remnant, preserving the periodontal support and maintaining the biologic thickness, thus achieving to maintain the root remnant with good length so that prosthetic rehabilitation is facilitated. The clinical and radiographic follow-up was 12 months. The multidisciplinary treatment involved: Root canal treatment, forced extrusion with orthodontics, fibrotomy with root planing and fixed prosthesis.

Pulmonary tuberculosis in an indigenous community in the mountains of Ecuador.

SETTING: An aboriginal community of 653 persons. OBJECTIVE: To determine the prevalence of pulmonary tuberculosis (PTB) and to analyse related factors. DESIGN: The total population was surveyed; those with chronic productive cough were asked to provide sputum specimens. PTB was diagnosed by bacilloscopy (acid-fast bacilli [AFB]). An analysis of socio-economic factors and clinical history associated with chronic cough or positive smear for PTB was carried out using multiple correspondence analysis and logistic regression models. RESULTS: Two hundred and two patients were identified with chronic cough and 173 with chronic productive cough. Chronic cough was associated with having a history of PTB (adjusted OR=4.89, 95%CI 2.6-9.4) and with work-related migratory movements (adjusted OR=2.05, 95%CI 1.3-3.3). Of 92 coughers with sputum samples analysed, 44 (47.8%) were PTB-positive, giving a prevalence of 6.7% in the whole population. In the groups aged 15-34 and >or=45 years, women had higher positivity rates than men, whereas in the group aged 35-44 years rates were higher in men. Twenty-seven per cent of families had one to four smear-positive members. CONCLUSION: The Tuberculosis Control Programme in the area studied needs to be strengthened, taking into account the ethnic context, work-related migration and the socio-economic and geographic context.

Concomitant mitral valve or atrial septal defect surgery and the modified Cox-maze procedure.

Atrial fibrillation (AF) is generally associated with rheumatic valve disease and atrial septal defects (ASD) in young adults. Surgical correction of both disorders fails to convert to sinus rhythm or prevent further episodes of paroxysmal or chronic AF in most patients. The role and efficacy of combining mitral valve surgery or ASD correction with AF surgery in this setting has not been widely addressed and remains to be established. The present study prospectively assessed the recovery of sinus rhythm, functional status, and atrial function in 21 patients (mean age 42 +/- 9.2 years) who underwent a modified Cox-maze procedure concomitant with mitral valve or ASD surgery at our institution between March 1993 and February 1995. Seventeen (81%) had chronic AF, and 4 (19%) had paroxysmal AF, with a mean AF duration of 3.5 +/- 3.6 years (range 0.6 to 15.3). Concomitant surgery was performed in 9 patients (42.9%) with mitral stenosis, 5 (23.8%) with mitral regurgitation, 1 (4.8%) with mitral and aortic regurgitation, and 3 (14.3%) with ASD. Eighteen patients (86%) were in New York Heart Association class II to IV before operation. Doppler echocardiography was performed in all patients before surgery, and 1 week, and 3 and 6 months after surgery in patients maintaining sinus rhythm. One patient with severe mitral stenosis and depressed ventricular function died in the immediate postoperative period. Sinus rhythm was restored in the immediate postoperative period in 7 patients (35%), and in another 10 patients (50%) before discharge (mean 5.8 +/- 2 days). Overall, sinus rhythm was restored before discharge in 17 patients (85%); 3 (15%) patients required antiarrhythmic therapy. Doppler echocardiography performed 3 months after surgery documented atrial contractility (A and E waves) in 12 patients (71%). After a mean follow-up period of 8 months (range 3 to 23), 18 (90%) remained in sinus rhythm. Sinus rhythm was successfully restored and maintained in most patients with drug refractory AF undergoing a concomitant Cox-maze procedure with mitral valve or ASD surgery improving atrial function and New York Heart Association class.

Catheter ablation of ventricular tachycardia in Chagasic Cardiomyopathy.

There is a limited experience with catheter ablation for treatment of ventricular tachycardia (VT) in Chagasic cardiomyopathy. A 30-year-old woman experienced episodes of palpitations and syncope due to attacks of VT. A diagnosis of Chagas disease was established on a biological basis. Two-dimensional echo and contrast ventriculography showed an apical aneurysm with thrombus. Surgery was indicated to resect the aneurysm and ablate the VT. Ventricular tachycardia recurred 1 month later despite therapy, including amiodarone. Two clinical frequent and well-tolerated tachycardias were identified. The site of origin was located in the right ventricular apex and in the apical-lateral wall of the left ventricle, respectively. Catheter ablation was performed at two sites with DC shocks (total energy 600 J) after unsuccessful radiofrequency ablation. Holter recordings performed during the post-operative period showed only infrequent extrasystoles. After follow-up of 24 months the patient remains asymptomatic. Drug-refractory VT in Chagasic cardiomyopathy can be ablated by medium-energy DC shocks after failure of radiofrequency ablation.

Experimental vertical transmission of Piscirickettsia salmonis and in vitro study of attachment and mode of entrance into the fish ovum.

Piscirickettsia salmonis is a pathogenic bacterial agent causing septicaemic disease in salmon. Since its isolation in Chile in 1989, P. salmonis has continually produced high mortality rates in salmon farms. Little information exists regarding the mechanisms of vertical transmission of this pathogen. Experimental vertical transmission was established in the present study by inoculation of male and female rainbow trout broodstock with P. salmonis. The bacterium was subsequently detected using indirect immunofluorescence in milt and coelomic fluid of the majority of inoculated broodstock (14/15). Bacteria were detected in the fry when 1 or both parents were inoculated, although none of the infected fry presented signs of the disease. P. salmonis was also detected in progeny obtained through fertilisation ova from non-inoculated females incubated in a medium containing a bacterial suspension, demonstrating transmission during the process of fertilisation. Ova infected in vitro were examined at sample periods from 30 s to 60 min using scanning electron microscopy. This demonstrated that the bacterium attaches to the ova by means of membrane extensions, structures which we have called 'piscirickettsial attachment complex' (PAC) and which would allow later penetration into the ovum.

The epithelial mesenchymal transition process may contribute to the pathogenesis of amniotic band syndrome.

The etiology of the amniotic band syndrome is unknown, and has been subject of debate since the time of Hippocrates. The most accepted theories fail to cover all the abnomalities found in affected children. During organogenesis the epithelial-mesenchymal transition process (EMTP) participates in adequate formation of different organs from three embryo layers. Altered activation of EMTP occurs when the epithelial homeostasis is disturbed, the resulting myofibroblasts are able to secrete extracellular matrix proteins and deposit them on the tissues contributing to a fibrotic phenotype. If injury occurs during organogenesis, wound healing could be exaggerated and fibrotic response could be triggered. The molecule that regulates both of these processes (EMTP and fibrosis) is the transforming growth factor ß (TGFß); indeed null animals for TGFß isoforms show similar defects than those seen in the amniotic band syndrome. Based on documented evidence this review intends to explain how the epithelial mesenchymal transition process may contribute to the pathogenesis of amniotic band syndrome.

Haematophagous bat bites in Ecuadorian Amazon: characterisation and implications for sylvatic rabies prevention.

OBJECTIVE: To characterise the risk factors of haematophagous bat bites and to provide information to contribute to the prevention of rabies in Ecuador. DESIGN: Cross-sectional study based on interviews with 3518 individuals, from which two sets of variables were generated: characteristics of haematophagous bat attacks in the previous year among humans and risk factors for being bitten. METHODS: Data were analysed using multivariate logistic regression models, taking history of bat bites in the previous year as the response variable. RESULTS: In the previous year 723 (20.6%, 95%CI 19.3-21.9) of the participants declared having received haematophagous bat bites and 50.4% in the previous month, giving an incidence rate of 10.4% (95%CI 9.6-11.6) per month. Sleeping on the floor or in a hammock (adjusted odds ratio [aOR] 1.58, 95%CI 1.21-2.06), not using a protective bed net (aOR 1.25, 95%CI 1.03-1.50) and living in a dwelling with permanent openings in the structure (aOR 1.49, 95%CI 1.12-1.95) were associated with a higher probability of bat bites. Those most affected were the group aged ≤12 years (age 13-19 years, aOR 0.39, 95%CI 0.32-0.48; age ≥20 years, aOR 0.67, 95%CI 0.50-0.90). CONCLUSION: Primary prevention based on pre-exposure vaccination would be justifiable given the high dispersion of the population and the high incidence of bat bites. As a secondary protective measure, communities should work towards increasing the use of protective measures and putting barriers in permanent openings in their dwellings.

Risk of tuberculosis in public transport sector workers, Lima, Peru.

SETTING: Delays from symptom onset to the diagnosis and treatment of smear-positive pulmonary tuberculosis (TB) produces possible new cases in persons in close contact with TB cases, especially in confined spaces such as overcrowded public transport, which puts other users and transport workers at risk. OBJECTIVE: To estimate TB incidence rates in patients of a health micro-network, and the percentage of transport sector workers among TB and multidrug-resistant TB (MDR-TB) patients. DESIGN: Crude and indirect standardised incidence rates of TB were calculated from an exhaustive analysis of all clinical histories of incident patients in a health micro-network between 1 January 2007 and 30 June 2008. The percentage of transport sector workers and the association between MDR-TB and working in the transport sector were analysed. RESULTS: Standardised incidence rates for transport sector workers are 2.7-4.5 times higher than those in the total working-age male and global population of the micro-network studied. The association between TB and transport occupation and MDR-TB and transport occupation is high (respectively OR 3.06, 95%CI 2.2-4.2 and OR 3.14, 95%CI 1.1-9.1). CONCLUSION: These results indicate that the use of informal public transport is a risk factor for TB infection and an occupational risk in countries with characteristics similar to those in Peru.

DOTS strategy and community participation: an experience in the Ecuadorian Andes.

SETTING: The Chine community in Angamarca parish, Cotopaxi Province, in the Ecuadorian Andes. OBJECTIVE: To relate the DOTS strategy to the world view of the indigenous community in the diagnosis and treatment of smear-positive pulmonary tuberculosis (TB) patients. DESIGN: Cross-sectional study involving all inhabitants of Chine. RESULTS: Aspects of the community's world view were considered in the community-based application of DOTS. A cure rate of 100% was attained, with 0% defaulting from treatment. CONCLUSION: The results obtained indicate that involving the world view of the community in the management of tuberculosis has several advantages.

Estudio de caso de una preescolar con déficit en los requisitos universales de autocuidado secundario a osteogénesis imperfecta / Study on a pre-scholar patient with universal requisites self-care deficit due to osteogenesis imperfecta

La elaboración del presente trabajo tiene la finalidad de aplicar el modelo teórico de Dorothea Orem como fundamento teórico para la aplicación del proceso enfermero a una paciente con diagnóstico clínico de osteogénesis imperfecta (OI), mismo que afecta sus requisitos de autocuidado universal. Para la elaboración de los diagnósticos de Enfermería se utilizó el formato PES (Problema, Etiología, Signos y síntomas), se realizó una jerarquización de los mismos con base en prioridades, y posteriormente, para la elaboración del plan de cuidados, recurrimos a la Enfermería Basada en Evidencia, para lo cual se consultaron diferentes bibliotecas virtuales. La evaluación de las intervenciones de Enfermería fue favorable, colaborando a la resolución de los requisitos alterados y a la adquisición de competencias necesarias en la familia para compensar las deficiencias.

The preparation of this paper aims to apply the theoretical model of Dorothea Orem as theoretical foundation for the application of the nursing process in a patient with clinical diagnosis of osteogenesis imperfect (OI), it affects their universal self-care requirements. For the development of nursing diagnoses used the PES format (Problem, Etiology, Signs and Symptoms), there was a hierarchy of them on a priority basis, and subsequently, to the development of the care plan based nursing resort to in evidence, to which were consulted different virtual libraries. Evaluating nursing interventions was favorable, contributing to the resolution of the changed requirements and the acquisition of skills needed in the family to compensate for deficiencies.

A new PCR-based approach for the specific amplification of DNA from different Schistosoma species applicable to human urine samples.

Currently available methods for the diagnosis of human schistosomiasis often lack enough sensitivity and specificity. Recently, several authors have developed more specific and sensitive diagnostic methods, mainly based on the polymerase chain reaction (PCR) technique. Nevertheless, these have been only applied for the diagnosis of 1 out of 4 Schistosoma species affecting man (S. mansoni). Additionally, application of specific PCR has been exclusively used for blood or faecal patients' samples. Here, we develop a new, high sensitive PCR approach that allows the genus- and species-specific amplification of the main 4 Schistosoma species causing disease in man plus S. bovis. We further successfully apply this technique for the detection of parasite DNA in easy-to-handle urine samples from patients with schistosomiasis. With these samples, we have found 94.4% sensitivity and 99.9% specificity when applying a genus-specific (Schistosoma spp.) primer pair, and 100% sensitivity and 98.9% specificity in a species-specific (S. mansoni) PCR.

[Tumors caused by methylcholanthrene and lapachol. Follow-up of development with cytology]. / Tumores provocados por metilcolantreno y lapachol. Seguimiento del desarrollo mediante citología.

This present work was carried out in order to study the effect of Lapachol (LAP) administrated to rats simultaneously with a chemical carcinogen 20-Methylcholanthrene (MCA). Animals were divided in 4 groups: A-Group treated with 80 mg of MCA I(n = 11 rats), B-Group treated with 80 mg of MCA+LAP 100 mg/kg weight/day, (n = 15 rats), C-Group treated with LAP 100 mg/kg weight/day (n = 12 rats), D-Group control-no treatment (n = 13 rats). Cytological studies as well as cytochemical techniques allowed the recognition of benign and malignant conditions at the time of the tumor appearance. Histopathological evaluation posteriorly confirmed the development of tumors in 53% of the animals in group B. Morphologically consistent with poorly differentiated adenocarcinomas of the salivary glands and fibroadenomas of the breast in 18.2% (2/11) of the rats in group A. Besides the presence of one or several supra-hepatic nodules in vecinity of the suspensory ligament corresponding to nodular hyperplasia were observed in 33% (4/12) of group C and in 13.3% (12/15) of group B. No nodules were observed in groups A and D. Tubular dilatation of kidneys were noted in 60% (9/15) and 83.3/ (10/12) of the rats in group E and C respectively. From the original salivary gland tumor a series of transplantables tumors were developed and followed by cytological evaluations. The importance of the cytological and histopathological diagnosis for the pharmacological effects studies of certain drugs like Lapachol that are widely used as antitumoral agents without exact knowledge of the adverse effects is emphasized.

Propofol dosing regimens for ICU sedation based upon an integrated pharmacokinetic-pharmacodynamic model.

BACKGROUND: The pharmacology of propofol infusions administered for long-term sedation of intensive care unit (ICU) patients has not been fully characterized. The aim of the study was to develop propofol dosing guidelines for ICU sedation based on an integrated pharmacokinetic-pharmacodynamic model of propofol infusions in ICU patients. METHODS: With Institutional Review Board approval, 30 adult male medical and surgical ICU patients were given target-controlled infusions of propofol for sedation, adjusted to maintain a Ramsay sedation scale score of 2-5. Propofol administration in the first 20 subjects was based on a previously derived pharmacokinetic model for propofol. The last 10 subjects were given propofol based on a pharmacokinetic model derived from the first 20 subjects. Plasma propofol concentrations were measured, together with sedation score. Population pharmacokinetic and pharmacodynamic parameters were estimated by means of nonlinear regression analysis in the first 20 subjects, then prospectively tested in the last 10 subjects. An integrated pharmacokinetic-pharmacodynamic model was used to construct dosing regimens for light and deep sedation with propofol in ICU patients. RESULTS: The pharmacokinetics of propofol were described by a three-compartment model with lean body mass and fat body mass as covariates. The pharmacodynamics of propofol were described by a sigmoid model, relating the probability of sedation to plasma propofol concentration. The pharmacodynamic model for propofol predicted light and deep levels of sedation with 73% accuracy. Plasma propofol concentrations corresponding to the probability modes for sedation scores of 2, 3, 4, and 5 were 0.25, 0.6, 1.0, and 2.0 microg/ml. Predicted emergence times in a typical subject after 24 h, 72 h, 7 days, and 14 days of light sedation (sedation score = 3 --> 2) with propofol were 13, 34, 198, and 203 min, respectively. Corresponding emergence times from deep sedation (sedation score = 5 --> 2) with propofol were 25, 59, 71, and 74 h. CONCLUSIONS: Emergence time from sedation with propofol in ICU patients varies with the depth of sedation, the duration of sedation, and the patient's body habitus. Maintaining a light level of sedation ensures a rapid emergence from sedation with long-term propofol administration.

The genomic organization of a human creatine transporter (CRTR) gene located in Xq28.

During the course of a large-scale sequencing project in Xq28, a human creatine transporter (CRTR) gene was discovered. The gene is located approximately 36 kb centromeric to ALD. The gene contains 13 exons and spans about 8.5 kb of genomic DNA. Since the creatine transporter has a prominent function in muscular physiology, it is a candidate gene for Barth syndrome and infantile cardiomyopathy mapped to Xq28.

Characterization of ATM gene mutations in 66 ataxia telangiectasia families.

Ataxia telangiectasia (AT) is an autosomal recessive disease characterized by neurological and immunological symptoms, radiosensitivity and cancer predisposition. The gene mutated in AT, designated the ATM gene, encodes a large protein kinase with a PI-3 kinase-related domain. In this study, we investigated the mutational spectrum of the ATM gene in a cohort of AT patients living in Germany. We amplified and sequenced all 66 exons and the flanking untranslated regions from genomic DNA of 66 unrelated AT patients. We identified 46 different ATM mutations and 26 sequence polymorphisms and variants scattered throughout the gene. A total of 34 mutations have not been described in other populations. Seven mutations occurred in more than one family, but none of these accounted for more than five alleles in our patient group. The majority of the mutations were truncating, confirming that the absence of full-length ATM protein is the most common molecular basis of AT. Transcript analyses demonstrated single exon skipping as the consequence of most splice site substitutions, but a more complex pattern was observed for two mutations. Immunoblot studies of cell lines carrying ATM missense substitutions or in-frame deletions detected residual ATM protein in four cases. One of these mutations, a valine deletion proximal to the kinase domain, resulted in ATM protein levels >20% of normal in an AT lymphoblastoid cell line. In summary, our results survey and characterize a plethora of variations in the ATM gene identified by exon scanning sequencing and indicate a high diversity of mutations giving rise to AT in a non-isolated population.