Meningitis posquirúrgica por Acinetobacter baumannii multirresistente. Actividad sinérgica in vivo de la asociación sulbactam/avibactam / Post-surgical meningitis due to multiresistant Acinetobacter baumannii. In vivo synergistic activity of the sulbactam/avibactam association

Acinetobacter baumannii (AB) es un bacilo gram negativo, no fermentador,con frecuencia oportunista, ubicuo en el medio ambiente, con capacidad para sobrevivir en condiciones medioambientales adversas promoviendo su persistencia y diseminación en diferentes áreas de un hospital. Ha sido relacionado con múltiples brotes de infecciones asociadas al cuidado de la salud como neumonía, bacteriemias, contaminación de heridas quirúrgicas o infecciones del tracto urinario, especialmente entre pacientes con comorbilidades graves, como aquellos que motivan el ingreso a unidades de cuidados intensivos (UCI). Las cepas más problemáticas son aquellas resistentes a los carbapenémicos, resistencia causada por enzimas de la clase de las oxacilinasas (bla OXA) cromosómicas o plasmídicas y más recientemente bla NDM-1. La aparición de estas cepas deja escasos antimicrobianos activos (colistin, minociclina, tigeciclina; amikacina) que son limitados en su eficacia y su uso se asocia con toxicidad. A esto se agrega, como en la paciente que se describe, que desarrolló una meningitis posquirúrgica, la limitada capacidad de difusión en el sistema nervioso central (SNC) de estas últimas opciones. Una de las alternativas terapéuticas, es buscar asociaciones como sulbactam/avibactam que mostraron una adecuada actividad sinérgica y bactericida en asilamientos resistentes a ampicilina/sulbactam en base a una significativa reducción de la CIM que permite administrar dosis habituales, con mejor tolerancia y lograr concentraciones terapéuticas en SNC. Se presenta una paciente que desarrolló una meningitis posquirúrgica debida a una cepa de AB multirresistente.

Acinetobacter baumannii (AB) is a non-fermenting gram-negative bacillus, largely opportunistic, ubiquitous in the environment, with the ability to survive in adverse environmental conditions, promoting its persistence and dissemination in different areas of the hospital. It has been implicated in many outbreaks of healthcare-associated infections such as pneumonia, bacteremia, surgical wounds contamination, or urinary tract infections, especially among patients with previous severe illnesses such as those requiring admission to intensive care units (ICU). The most problematic strains are those resistant to carbapenems, resistance caused by chromosomal or plasmid oxacillinase class (bla OXA), and more recently bla NDM-1. The appearance of these strains leaves few active antimicrobials (Colistin, Minocycline, Tigecycline; Amikacin) that are limited in their efficacy and toxic. To this we must add, as is the case of our patient who presented post-surgical meningitis, the limited diffusion capacity in the central nervous system (CNS) of these last options. One of the therapeutic alternatives is to search for synergistic associations such as sulbactam/avibactam that showed rapid synergistic and bactericidal activity in isolates resistant to ampicillin/sulbactam due to a significant reduction in its MIC, which allows us to administer usual, better tolerated doses that reach therapeutic concentrations in CNS. Here, we present a patient who developed a post-surgical meningitis due to multiresistant AB

Changes in coexpression of pericytes and endogenous cardiac progenitor cells from heart development to disease state.

Introduction: Focussing on the potential role of cardiovascular cell therapy, we investigated the spatial relationship between pericytes (cells with cardiac repair capabilities that ensheath blood vessels) and endogenous cardiac progenitors within stem cells' niches. We explored possible changes in their co-localisation in developing human hearts from foetal to adult stage and following ischaemia. Methods: Foetal and adult human heart specimens, obtained under ethical consent (University of Edinburgh ethics committee), were used for immunohistochemistry, cell isolation, culture and differentiation. Multi-lineage differentiation in culture, by single and double staining was completed for CD 146+ foetal pericytes and c-kit+ cells. Endothelial markers (CD31) gene expression was quantified by qPCR. Results: c-kit+ cells frequency and coexpression with pericytes decrease with heart development, already evident by gestation week 19th. Pericytes and c-kit+ cells express the early cardiac transcription factors Nkx2.5 and Islet 1. Only c-kit+ cells express the stemness marker SSEA3 (24%), known to progressively decrease with cell differentiation. Endothelial differentiation assessment shows that cardiac pericytes and c-kit+ cells do not form CD31+ networks. This finding correlates with absence of staining for CD31 marker in both cultured cells' types. The cardiac marker α-actin was present in both cell populations. In healthy adult heart, pericyte markers CD146 localise within the vasculature. Following ischaemia this pericyte marker becomes also evident outside the vasculature.In healthy adult atrium, c-kit expression is low and coexpression with other markers inconspicuous. Ischaemia leads to increased c-kit expression, particularly in blood vessels <50um diameter. Furthermore, following ischaemia c-kit, endothelium and pericyte markers co-localise within the same atrial cells. Blood vessels >50µm diameter showed mostly only staining for endothelial (vWF) and pericyte (CD146) markers, with no co-expression of c-kit marker identified. Staining patterns within the ischaemic regions of the right and left atrial appendages revealed low levels of colocalisation between vWF and CD146. Acute ischaemia of the left ventricle affected the detection of cardiac stem cells markers in the area of injury, due to myocardium disruption. Conclusion: Foetal heart pericytes and c-kit+ cells express early cardiac transcription factors and show trans-differentiation potential, which decreases in healthy adult hearts. The preservation and activity of cardiac stem cells niches within the atrium vasculature appears re-activated in post-ischaemic hearts. Better understanding of cardiac c-kit+ and pericyte cells during-human embryonic development and during ischaemia may identify alternative novel therapeutic strategy against coronary artery disease.

Acute treatment costs of intracerebral hemorrhage and ischemic stroke in Argentina.

BACKGROUND AND PURPOSE: Stroke is the third leading cause of death in Argentina, yet little information exists on the acute treatment provided for stroke or its costs. This study estimates the national costs of the acute treatment of first-ever intracerebral hemorrhage (ICH) and ischemic stroke (IS) in Argentina. METHODS: Retrospective hospital-based inception study design using data on resource use and costs from high-volume stroke centers in Argentina, and published population-based incidence data. Treatment provided at two large urban hospitals were evaluated in all patients admitted with a first-ever stroke between 1 January 2004 and 31 August 2006, and costs were assigned using appropriate unit cost data for all resource use. Cost estimates in Argentinian pesos were converted to US dollars ($) using the 2005 purchasing power parity index. National costs of acute treatment for incident strokes were estimated by extrapolation of average costs estimates to national incidence data. Assumptions of the average cost of stroke treatment on a national scale were examined in sensitivity analysis. RESULTS: The acute care of 167 patients with stroke was thoroughly evaluated from hospital admission to hospital discharge. Mean length of hospital stay was 35.4 days for ICH and 13.0 days for IS. Ninety-one percent of the patients with ICH and 68% of the patients with IS were admitted to an ICU for a mean length of stay (LOS) of 12.9 +/- 20.3 and 3.6 +/- 5.9 days respectively. Mean total costs of initial hospitalization were $12,285 (SD +/-14,336) for ICH and $3888 (SD +/-4018) for IS. Costs differed significantly by Glasgow Coma Scale (GCS) score at admission, development of pneumonia and infections during hospitalization, and functional outcome at hospital discharge. Aggregate national healthcare expenditures for acute treatment of incident ICH were $194.2m (range 97.1-388.4) and $239.9m for IS (range 119.9-479.7). CONCLUSION: The direct hospital costs of incident ICH and IS in Argentina are substantial and primarily driven by stroke severity, in-hospital complications and clinical outcomes. With the expected increase in the incidence of stroke over the coming decades, these results emphasize the need for effective preventive and acute medical care.

Estrogen mediates sex differences in stress-induced prefrontal cortex dysfunction.

Many anxiety disorders, as well as major depressive disorder (MDD), are at least twice as prevalent in women as in men, but the neurobiological basis of this discrepancy has not been well studied. MDD is often precipitated by exposure to uncontrollable stress, and is frequently characterized by abnormal or disrupted prefrontal cortex (PFC) function. In animals, exposure to stress has been shown to cause PFC dysfunction, but sex differences in this effect have not been investigated. The present study tested male and female rats on a PFC-dependent working memory task after administration of FG7142, a benzodiazepine inverse agonist that activates stress systems in the brain. Female rats were impaired by lower doses than males during proestrus (high estrogen), but not during estrus (low estrogen). Similarly, ovariectomized females showed increased stress sensitivity only after estrogen replacement. These results suggest that estrogen amplifies the stress response in PFC, which may increase susceptibility to stress-related disorders.

Genetic evidence for adaptation-driven incipient speciation of Drosophila melanogaster along a microclimatic contrast in "Evolution Canyon," Israel.

Substantial genetic differentiation, as great as among species, exists between populations of Drosophila melanogaster inhabiting opposite slopes of a small canyon. Previous work has shown that prezygotic sexual isolation and numerous differences in stress-related phenotypes have evolved between D. melanogaster populations in "Evolution Canyon," Israel, in which slopes 100-400 m apart differ dramatically in aridity, solar radiation, and associated vegetation. Because the canyon's width is well within flies' dispersal capabilities, we examined genetic changes associated with local adaptation and incipient speciation in the absence of geographical isolation. Here we report remarkable genetic differentiation of microsatellites and divergence in the regulatory region of hsp70Ba which encodes the major inducible heat shock protein of Drosophila, in the two populations. Additionally, an analysis of microsatellites suggests a limited exchange of migrants and lack of recent population bottlenecks. We hypothesize that adaptation to the contrasting microclimates overwhelms gene flow and is responsible for the genetic and phenotypic divergence between the populations.

A Drosophila melanogaster strain from sub-equatorial Africa has exceptional thermotolerance but decreased Hsp70 expression.

Drosophila melanogaster collected in sub-equatorial Africa in the 1970s are remarkably tolerant of sustained laboratory culture above 30 degrees C and of acute exposure to much warmer temperatures. Inducible thermotolerance of high temperatures, which in Drosophila melanogaster is due in part to the inducible molecular chaperone Hsp70, is only modest in this strain. Expression of Hsp70 protein and hsp70 mRNA is likewise reduced and has slower kinetics in this strain (T) than in a standard wild-type strain (Oregon R). These strains also differed in constitutive and heat-inducible levels of other molecular chaperones. The lower Hsp70 expression in the T strain apparently has no basis in the activation of the heat-shock transcription factor HSF, which is similar in T and Oregon R flies. Rather, the reduced expression may stem from insertion of two transposable elements, H.M.S. Beagle in the intergenic region of the 87A7 hsp70 gene cluster and Jockey in the hsp70Ba gene promoter. We hypothesize that the reduced Hsp70 expression in a Drosophila melanogaster strain living chronically at intermediate temperatures may represent an evolved suppression of the deleterious phenotypes of Hsp70.

Assessing reinforcers under progressive schedule requirements.

Recent research findings suggest that reinforcing stimuli may be differentially effective as response requirements increase. We extended this line of research by evaluating responding under increasing schedule requirements via progressive-ratio schedules and behavioral economic analyses. The differential effectiveness of preferred stimuli in treating destructive behavior maintained by automatic reinforcement also was examined. Results showed that one of two stimuli was associated with more responding under increasing schedule requirements for the 4 participants. Furthermore, stimuli associated with more responding under increasing schedule requirements generally were more effective in treating destructive behavior than stimuli associated with less responding. These data suggest that progressive-ratio schedules and behavioral economic analyses may be useful for developing a new technology for reinforcer identification. From a clinical perspective, these results suggest that two reinforcers may be similarly effective for low-effort tasks and differentially effective for high-effort tasks.

Laboratory selection at different temperatures modifies heat-shock transcription factor (HSF) activation in Drosophila melanogaster.

The magnitude and time course of activation of the heat-shock transcription factor (HSF) differ among Drosophila melanogaster lines evolving at 18 degrees C, 25 degrees C or 28 degrees C for more than 20 years. At lower heat-shock temperatures (27-35 degrees C), flies from the 18 degrees C population had higher levels of activated HSF (as detected by an electrophoretic mobility shift assay) than those reared at 25 degrees C and 28 degrees C. At higher temperatures (36 and 37 degrees C), however, the 28 degrees C flies had the highest levels of HSF. These differences persisted after one generation of acclimation at 25 degrees C, suggesting that phenotypic plasticity was limited. In addition, larvae from the 28 degrees C lines activated HSF less rapidly after a 35 degrees C heat shock than those from the 18 degrees C and 25 degrees C populations. These results are similar but not identical to previously reported differences in expression of Hsp70 (the major heat-inducible stress protein in Drosophila melanogaster) among the experimental lines. We conclude that HSF activation evolves rapidly during laboratory culture at diverse temperatures and could play an important role in the evolution of the heat-shock response.

A method for analyzing changes in response efficiency.

Although experimental effects typically are evaluated by summarizing levels of responding across time (e.g., calculating the mean levels of problem behavior during 10-min sessions), these data summaries may obscure important mechanisms that may be responsible for changes in responding. A case study is reported to illustrate alternative methods of data analysis when decreasing trends in responding may be due to increases in response efficiency.

Further analysis of idiosyncratic antecedent influences during the assessment and treatment of problem behavior.

Recent research findings suggest that idiosyncratic variables can influence the outcomes of functional analyses (E. G. Carr, Yarbrough, & Langdon, 1997). In the present study, we examined idiosyncratic environment-behavior relations more precisely after identifying stimuli (i.e., a particular toy and social interaction) associated with increased levels of problem behavior. Two children, an 8-year-old boy with moderate mental retardation and a 5-year-old boy with no developmental delays, participated. Results of functional analyses for both children indicated that idiosyncratic antecedent stimuli set the occasion for occurrences of problem behavior (hand biting or hand flapping) and that problem behavior persisted in the absence of social contingencies. Further analyses were conducted to identify specific components of the stimuli that occasioned problem behavior. Treatments based on results of the analyses successfully reduced self-injury and hand flapping.

Further evaluation of low-ranked items in stimulus-choice preference assessments.

The generality of the findings reported by DeLeon, Iwata, and Roscoe (1997) was examined by conducting two stimulus-choice preference assessments, the second of which evaluated low-ranked items from the initial assessment. Results for the 2 participants suggested that supplementary assessments of low-ranked items may be useful for identifying a wider variety of reinforcing stimuli.

Variable-time reinforcement schedules in the treatment of socially maintained problem behavior.

Noncontingent reinforcement (NCR) consists of delivering a reinforcer on a time-based schedule, independent of responding. Studies evaluating the effectiveness of NCR as treatment for problem behavior have used fixed-time (FT) schedules of reinforcement. In this study, the efficacy of NCR with variable-time (VT) schedules was evaluated by comparing the effects of VT and FT reinforcement schedules with 2 individuals who engaged in problem behavior maintained by positive reinforcement. Both FT and VT schedules were effective in reducing problem behavior. These findings suggest that VT schedules can be used to treat problem behavior maintained by social consequences.

Effects of reinforcement magnitude on spontaneous recovery.

Extinction of operant behavior has been associated with a number of undesirable effects. One such effect is the temporary reappearance of behavior after responding appears to be completely extinguished, known as spontaneous recovery. In this report, the occurrence of spontaneous recovery and its attenuation with large amounts of reinforcement were examined during the treatment of disruption.

A preliminary comparison of guided compliance and high-probability instructional sequences as treatment for noncompliance in children with developmental disabilities.

The efficacy of guided compliance and high-probability instructional sequences was compared with two children referred to an outpatient clinic for treatment of noncompliance. Parents were taught to implement the procedures in their homes, and parent-training outcomes for the two interventions were compared in terms of treatment effectiveness, procedural integrity, and parent satisfaction. Levels of compliance were higher under guided compliance than under high-probability instructional sequences. Nevertheless, parents rapidly learned to implement both treatments with a high degree of accuracy and reported equal satisfaction with the procedures.

Side effects of extinction: prevalence of bursting and aggression during the treatment of self-injurious behavior.

Findings from basic and applied research suggest that treatment with operant extinction may produce adverse side effects; two of these commonly noted are an increase in the frequency of the target response (extinction burst) and an increase in aggression (extinction-induced aggression). Although extinction is often used to treat problem behavior in clinical settings, few applied studies have examined the prevalence of these side effects or their possible attenuation with other operant procedures. An analysis of 41 data sets for individuals who received treatment for self-injurious behavior indicated that extinction bursts or increases in aggression occurred in nearly one half of the cases. The prevalence of bursting and aggression was substantially lower when extinction was implemented as part of a treatment package rather than as the sole intervention.

Within-session patterns of responding during functional analyses: the role of establishing operations in clarifying behavioral function.

Functional analysis procedures have been demonstrated to be effective for identifying the operant mechanisms underlying problem behavior. However, functional analyses sometimes yield results that are undifferentiated (i.e., show similar levels of responding across test conditions). Within-session (i.e., minute-by-minute) analyses of response patterns during undifferentiated functional analyses have proven useful in clarifying behavioral function. This study extends previous research by examining within-session changes in responding associated with variations in relevant establishing operations. Levels of problem behavior during the presentation and removal of reinforcement were compared when responding occurred in test conditions associated with sources of social reinforcement (i.e., access to attention, materials, escape). Results showed that changes in responding associated with changes in relevant establishing operations could be examined to clarify behavioral function.

Effects of reinforcement choice on task responding in individuals with developmental disabilities.

The effects of reinforcement choice on task performance were examined with 6 individuals who had been diagnosed with severe to profound mental retardation. Five highly preferred items were identified for each participant via stimulus preference assessments. Participants then were exposed to choice and no-choice conditions that were alternated within reversal and multielement designs. During choice sessions, participants were permitted to select between two preferred stimuli contingent on responding. During no-choice sessions, the therapist delivered a single item contingent on responding. Preference for the stimuli was held constant across conditions by yoking the items delivered during no-choice sessions to those selected during the immediately preceding choice sessions. All participants exhibited similar rates of responding across choice and no-choice conditions. These findings indicate that for individuals with severe disabilities, access to choice may not improve task performance when highly preferred items are already incorporated into instructional programs.

Effects of intermittent punishment on self-injurious behavior: an evaluation of schedule thinning.

Although the use of punishment often raises ethical issues, such procedures may be needed when the reinforcers that maintain behavior cannot be identified or controlled, or when competing reinforcers cannot be found. Results of several studies on the effects of intermittent schedules of punishment suggest that therapists must use fairly rich schedules of punishment to suppress problem behavior. However, residential caretakers, teachers, and parents often have difficulty implementing programs that require constant monitoring of the client's behavior. In this study, we examined the feasibility of gradually thinning the delivery of punishment from a continuous schedule to an intermittent schedule during the course of treatment for self-injurious behavior (SIB). Results of functional analyses for 5 individuals who had been diagnosed with profound mental retardation indicated that their SIB was not maintained by social consequences. Treatment with continuous schedules of time-out (for 1 participant) or contingent restraint (for the other 4 participants) produced substantial reductions in SIB. When they were exposed to intermittent schedules of punishment (fixed-interval [FI] 120 s or FI 300 s), SIB for all but 1 of the participants increased to levels similar to those observed during baseline. For these 4 participants, the schedule of punishment was gradually thinned from continuous to FI 120 s or FI 300 s. For 2 participants, SIB remained low across the schedule changes, demonstrating the utility of thinning from continuous to intermittent schedules of punishment. Results for the other 2 participants showed that intermittent punishment was ineffective, despite repeated attempts to thin the schedule.

Does functional communication training compete with ongoing contingencies of reinforcement? An analysis during response acquisition and maintenance.

We examined the effectiveness of functional communication training (FCT) in reducing self-injurious behavior (SIB) and in shaping an alternative (communicative) response while SIB continued to be reinforced. Following a functional analysis of 3 individuals' SIB, we attempted to teach an alternative response consisting of a manual sign to each individual, using the reinforcer that maintained SIB. When FCT was implemented without extinction. SIB remained at baseline rates for all participants, and none of the participants acquired the alternative response. When extinction was added to the training procedure, SIB decreased and manual signing increased for all participants. To determine if signing, when established, would compete with SIB when both were reinforced, extinction was then withdrawn. Signing was maintained and SIB occurred at low rates for 2 individuals, but SIB returned to baseline rates for the 3rd individual, necessitating the reimplementation of extinction. These results suggest that it may be difficult to establish alternative behaviors if inappropriate behavior continues to be reinforced, but that, when established, alternative behavior might compete successfully with ongoing contingencies of reinforcement for inappropriate behavior.

Responding maintained by intermittent reinforcement: implications for the use of extinction with problem behavior in clinical settings.

Results of basic research have demonstrated that behavior maintained on an intermittent schedule of reinforcement (INT) will be extinguished more slowly than behavior maintained on a continuous schedule (CRF). Although these findings suggest that problem behaviors may be difficult to treat with extinction if they have been maintained on INT rather than on CRF schedules, few applied studies have examined this phenomenon with human behavior in clinical settings. The purpose of this study was to determine whether problem behavior maintained on CRF schedules would be extinguished more rapidly than behavior maintained on INT schedules. Three individuals diagnosed with profound mental retardation participated after results of pretreatment functional analyses had identified the sources of reinforcement that were maintaining their self-injury, aggression, or disruption. Subjects were exposed to extinction following baseline conditions with CRF or INT schedules alternated within reversal or multielement designs. Results suggested that problem behavior may not be more difficult to treat with extinction if they have been maintained on INT rather than CRF schedules. However, switching from an INT to a CRF schedule prior to extinction may lower the baseline response rate as well as the total number of responses exhibited during extinction.