Mutagenesis Mapping of the Protein-Protein Interaction Underlying FusB-Type Fusidic Acid Resistance

FusB-type proteins represent the predominant mechanism of resistance to fusidic acid in staphylococci and act by binding to and modulating the function of the drug target (elongation factor G [EF-G]). To gain further insight into this antibiotic resistance mechanism, we sought to identify residues important for the interaction of FusB with EF-G and thereby delineate the binding interface within the FusB–EF-G complex. Replacement with alanine of any one of four conserved residues within the C-terminal domain of FusB (F₁₅₆, K₁₈₄, Y₁₈₇, and F₂₀₈) abrogated the ability of the protein to confer resistance to fusidic acid; the purified mutant proteins also lost the ability to bind S. aureus EF-G in vitro. E. coli EF-G, which is not ordinarily able to bind FusB-type proteins, was rendered competent for binding to FusB following deletion of a 3-residue tract (₅₂₉SNP₅₃₁) from domain IV of the protein. This study has identified key regions of both FusB and EF-G that are important for the interaction between the proteins, findings which corroborate our previous in silico prediction for the architecture of the complex formed between the resistance protein and the drug target (G. Cox, G. S. Thompson, H. T. Jenkins, F. Peske, A. Savelsbergh, M. V. Rodnina, W. Wintermeyer, S. W. Homans, T. A. Edwards, and A. J. O''Neill, Proc. Natl. Acad. Sci. U. S. A. 109:2102-2107, 2012).     

Neurodevelopmental Outcomes in Children With Congenital Heart Disease: Evaluation and Management: A Scientific Statement From the American Heart Association

BACKGROUND: The goal of this statement was to review the available literature on surveillance, screening, evaluation, and management strategies and put forward a scientific statement that would comprehensively review the literature and create recommendations to optimize neurodevelopmental outcome in the pediatric congenital heart disease (CHD) population. METHODS AND RESULTS: A writing group appointed by the American Heart Association and American Academy of Pediatrics reviewed the available literature addressing developmental disorder and disability and developmental delay in the CHD population, with specific attention given to surveillance, screening, evaluation, and management strategies. MEDLINE and Google Scholar database searches from 1966 to 2011 were performed for English-language articles cross-referencing CHD with pertinent search terms. The reference lists of identified articles were also searched. The American College of Cardiology/American Heart Association classification of recommendations and levels of evidence for practice guidelines were used. A management algorithm was devised that stratified children with CHD on the basis of established risk factors. For those deemed to be at high risk for developmental disorder or disabilities or for developmental delay, formal, periodic developmental and medical evaluations are recommended. A CHD algorithm for surveillance, screening, evaluation, reevaluation, and management of developmental disorder or disability has been constructed to serve as a supplement to the 2006 American Academy of Pediatrics statement on developmental surveillance and screening. The proposed algorithm is designed to be carried out within the context of the medical home. This scientific statement is meant for medical providers within the medical home who care for patients with CHD. CONCLUSIONS: Children with CHD are at increased risk of developmental disorder or disabilities or developmental delay. Periodic developmental surveillance, screening, evaluation, and reevaluation throughout childhood may enhance identification of significant deficits, allowing for appropriate therapies and education to enhance later academic, behavioral, psychosocial, and adaptive functioning.     

Clinical presentation and outcome prediction of clinical,serological, and histopathological classification schemes in ANCA-associated vasculitis with renal involvement

Several classification schemes have been developed for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), with actual debate focusing on their clinical and prognostic performance. Sixty-two patients with renal biopsy-proven AAV from a single center in Mexico City diagnosed between 2004 and 2013 were analyzed and classified under clinical (granulomatosis with polyangiitis [GPA], microscopic polyangiitis [MPA], renal limited vasculitis [RLV]), serological (proteinase 3 anti-neutrophil cytoplasmic antibodies [PR3-ANCA], myeloperoxidase anti-neutrophil cytoplasmic antibodies [MPO-ANCA], ANCA negative), and histopathological (focal, crescenteric, mixed-type, sclerosing) categories. Clinical presentation parameters were compared at baseline between classification groups, and the predictive value of different classification categories for disease and renal remission, relapse, renal, and patient survival was analyzed. Serological classification predicted relapse rate (PR3-ANCA hazard ratio for relapse 2.93, 1.20–7.17, p?=?0.019). There were no differences in disease or renal remission, renal, or patient survival between clinical and serological categories. Histopathological classification predicted response to therapy, with a poorer renal remission rate for sclerosing group and those with less than 25 % normal glomeruli; in addition, it adequately delimited 24-month glomerular filtration rate (eGFR) evolution, but it did not predict renal nor patient survival. On multivariate models, renal replacement therapy (RRT) requirement (HR 8.07, CI 1.75–37.4, p?=?0.008) and proteinuria (HR 1.49, CI 1.03–2.14, p?=?0.034) at presentation predicted renal survival, while age (HR 1.10, CI 1.01–1.21, p?=?0.041) and infective events during the induction phase (HR 4.72, 1.01–22.1, p?=?0.049) negatively influenced patient survival. At present, ANCA-based serological classification may predict AAV relapses, but neither clinical nor serological categories predict renal or patient survival. Age, renal function and proteinuria at presentation, histopathology, and infectious complications constitute the main outcome predictors and should be considered for individualized management.     

Clinical implications of increased lung uptake of thallium-201 during exercise scintigraphy 2 weeks after myocardial infarction

To determine the prevalence and clinical significance of increased lung thallium-201 uptake during submaximal exercise myocardial scintigraphy performed 2 weeks after acute myocardial infarction, 61 patients underwent submaximal exercise testing (target heart rate, 120 beats/min), multigated blood pool imaging at rest and coronary angiography before hospital discharge. Thallium lung uptake on the initial anterior projection image was graded qualitatively by comparing the intensity of thallium-201 activity in the lungs with that in the mediastinum. In 39 patients (64 percent), it was normal (equal to mediastinal activity) and in 22 (36 percent), it was increased (greater than mediastinal activity). Compared with patients with normal lung uptake, those with increased uptake had a greater prevalence of prior infarction (13 versus 36 percent, probability [p] < 0.05), less global cardiac reserve as assessed by the four level New York Heart Association classification (p < 0.05), more advanced Killip class in the coronary care unit (p < 0.05), a higher Norris coronary prognostic index (2.6 ± 1.9 versus 4.6 ± 2.3 [mean ± standard deviation], p <0.01), failure to achieve the target heart rate because of dyspnea, fatigue or angina (36 versus 86 percent, p < 0.01), a greater prevalence of exercise-induced S-T segment depression (18 versus 45 percent, p < 0.05), a greater number of anterior thallium-201 myocardlal defects (p < 0.05); a lower radionuclide ejection fraction at rest (50.4 ± 6.1 versus 39.6 ± 9.3 percent, p < 0.01) and a greater number of asynergic left ventricular segments (p < 0.05).Thus, the occurrence of increased lung thallium-201 uptake during submaximal exercise scintigraphy in the early postinfarction period is frequent and appears to be a marker of severe and functionally more important coronary artery disease associated with left ventricular dysfunction.     

Cost of care of arterial hypertension and its impact on the budget assigned to health in Mexico

OBJECTIVE: To assess the medical care costs of hypertension and their impact on the health care expenditures and on Mexico's Gross National Product (GNP). MATERIAL AND METHODS: An ecological study was conducted from June to November 1999, at Instituto Mexicano del Seguro Social (Mexican Institute of Social Security, IMSS), in Monterrey, Nuevo Leon, Mexico. A random sample of medical charts of patients with hypertension was selected, to extract data on utilization of health services and unitary costs per care episode. The cost per care episode and per hypertensive patient was calculated by adjusting the unitary cost as a function of standard and extreme utilization of IMSS health services. The resulting figure was then projected to the total population of hypertensive patients and compared to the annual health care expenditures of Mexico. RESULTS: The annual cost per patient with hypertension was $1,067 in the standard scenario and $3,913 in the extreme scenario. The annual expenditures from hypertension corresponded to 13.95% of the budget allocated to health care and to 0.71%, of Mexico's GNP. These figures changed to 51.17% and 2.61% in the extreme scenario, respectively. CONCLUSIONS: The costs of hypertension medical care account for a good portion of healthcare resources. This problem should be analyzed by multidisciplinary health teams in search of more efficient medical care alternatives.