RESUMEN
The COVID-19 pandemic led ADHD services to modify the clinical practice to reduce in-person contact as much as possible to minimise viral spread. This had far-reaching effects on day-to-day clinical practice as remote assessments were widely adopted. Despite the attenuation of the acute threat from COVID, many clinical services are retaining some remote practices. The lack of clear evidence-based guidance about the most appropriate way to conduct remote assessments meant that these changes were typically implemented in a localised, ad hoc, and un-coordinated way. Here, the European ADHD Guidelines Group (EAGG) discusses the strengths and weaknesses of remote assessment methods of children and adolescents with ADHD in a narrative review based on available data and expert opinions to highlight key recommendations for future studies and clinical practice. We conclude that going forward, despite remote working in clinical services functioning adequately during the pandemic, all required components of ADHD assessment should still be completed following national/international guidelines; however, the process may need adaptation. Social restrictions, including changes in education provision, can either mask or exacerbate features associated with ADHD and therefore assessment should carefully chart symptom profile and impairment prior to, as well as during an ongoing pandemic. While remote assessments are valuable in allowing clinical services to continue despite restrictions and may have benefits for routine care in the post-pandemic world, particular attention must be paid to those who may be at high risk but not be able to use/access remote technologies and prioritize these groups for conventional face-to-face assessments.
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Trastorno por Déficit de Atención con Hiperactividad , COVID-19 , Humanos , Niño , Adolescente , Pandemias , Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/terapia , Atención a la SaludRESUMEN
BACKGROUND: Irritability is common in children and adolescents with Attention Deficit Hyperactivity Disorder (ADHD), Oppositional Defiant Disorder (ODD) and with anxiety/depressive disorders. Although youth irritability is linked with psychiatric morbidity, little is known regarding its non-pharmacological treatments. Developing non-pharmacological treatments for children with severe, chronic irritability is an important target for clinical research. To achieve this goal, we will test the benefits of parent-focused therapies in reducing irritability. The aim of the study is to compare Parent Management Training (PMT) and Non-Violent Resistance Training (NVR) programs with treatment-as-usual (TAU) on the improvement of irritability in children and adolescents with a baseline Parent-rated Affective Reactivity Index of 4 or higher, in the context of ADHD and other emotional and behavioural disorders. Additionally, we will assess (i) improvement of irritability at different times and according to different informants (parents, children, clinicians); (ii) improvement of parental strategies; and (iii) acceptability of the interventions, exploring possible mechanisms of the therapeutic effect. METHODS: Two hundred and seventy participants between 6 and 15 years with ADHD and other emotional and behavioural disorders will be recruited and randomly assigned with their parents to the PMT, NVR, and TAU groups. PMT and NVR programs have 10 online sessions and two booster sessions at 1 and at 3 months. The primary outcome measure is the change from baseline at 3 months after completion of the program of the Clinician-rated Affective Rating Scale (CL-ARI) assessed by a blind evaluator. Secondary outcome measures include the change from baseline from those scales: the CL-ARI, the Clinical Global Impression Improvement scale, the Parenting and Familial Adjustment Scales, the Child-rated Cranky thermometers and the Parent-rated ARI. We will assess the parent's expressed emotions and reflexivity during the online five-minute speech sample, clinical dimensions through the Child Behavior Checklist 6-18 and the Inventory of Callous Unemotional traits. Evaluations will be done remotely at baseline and at 1- and 3-months follow-up visits. DISCUSSION: We expect a benefit in controlling irritability in the treatment groups. This will constitute an important achievement in promoting parental support programs in the treatment of irritability in the context of emotional and behavioural disorders. CLINICALTRIALS: gov. Number: NCT05528926. Registered on the 2nd of September, 2022.
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Trastorno por Déficit de Atención con Hiperactividad , Genio Irritable , Adolescente , Humanos , Déficit de la Atención y Trastornos de Conducta Disruptiva/terapia , Déficit de la Atención y Trastornos de Conducta Disruptiva/complicaciones , Trastorno por Déficit de Atención con Hiperactividad/terapia , Responsabilidad Parental , Padres/educaciónRESUMEN
This article provides a quantitative and conceptual review of emotion regulation difficulties in trauma-exposed young people, and informs future directions in the field. Despite long-standing interest in the influence of emotion regulation difficulties on different internalizing and externalizing psychiatric disorders in childhood, several questions remain unresolved with respect to children and adolescents with PTSD (post-traumatic stress disorder). Meta-analytic data from adult victims suggest that emotion regulation problems are associated with PTSD, but this has never been studied in children and young people. We therefore provide a conceptual review of features related to the phenomenology, assessment, severity and treatment of emotion regulation difficulties in trauma-exposed children and young people. We combine this with a meta-analysis of published literature. We searched studies in Medline, PsychINFO, and Embase databases based on pre-selected criteria. Eight hundred and eighty-six papers were identified and 41 were included. We found that children and adolescents with a diagnosis of PTSD reported more emotion regulation difficulties than those who did not develop PTSD, and that the overall association between the two symptom dimensions was moderately strong. We identify a number of research priorities: the development of instruments to assess emotion regulation difficulties in children, the design of studies that describe its prevalence in young epidemiological traumatized samples, its predictive role in the onset, severity and persistence of post-traumatic symptoms, and its relevance as a moderator, outcome or treatment target for young survivors.
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Emociones/fisiología , Trastornos por Estrés Postraumático/psicología , Adolescente , Adulto , Niño , Femenino , Humanos , SobrevivientesRESUMEN
Severe irritability is one of the commonest reasons prompting referral to mental health services. It is frequently seen in neurodevelopmental disorders that manifest early in development, especially attention-deficit/hyperactivity disorder (ADHD). However, irritability can also be conceptualized as a mood problem because of its links with anxiety/depressive disorders; notably DSM-5 currently classifies severe, childhood-onset irritability as a mood disorder. Investigations into the genetic nature of irritability are lacking although twin studies suggest it shares genetic risks with both ADHD and depression. We investigated the genetic underpinnings of irritability using a molecular genetic approach, testing the hypothesis that early irritability (in childhood/adolescence) is associated with genetic risk for ADHD, as indexed by polygenic risk scores (PRS). As a secondary aim we investigated associations between irritability and PRS for major depressive disorder (MDD). Three UK samples were utilized: two longitudinal population-based cohorts with irritability data from childhood (7 years) to adolescence (15-16 years), and one ADHD patient sample (6-18 years). Irritability was defined using parent reports. PRS were derived from large genome-wide association meta-analyses. We observed associations between ADHD PRS and early irritability in our clinical ADHD sample and one of the population samples. This suggests that early irritability traits share genetic risk with ADHD in the general population and are a marker of higher genetic loading in individuals with an ADHD diagnosis. Associations with MDD PRS were not observed. This suggests that early-onset irritability could be conceptualized as a neurodevelopmental difficulty, behaving more like disorders such as ADHD than mood disorders.
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Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno Depresivo Mayor/genética , Genio Irritable , Adolescente , Niño , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Estudios Longitudinales , Masculino , Herencia MultifactorialRESUMEN
Up to 40% of youth with autism spectrum disorder (ASD) also suffer from anxiety, and this comorbidity is linked with significant functional impairment. However, the mechanisms of this overlap are poorly understood. We investigated the interplay between ASD traits and anxiety during reward processing, known to be affected in ASD, in a community sample of 1472 adolescents (mean age=14.4 years) who performed a modified monetary incentive delay task as part of the Imagen project. Blood-oxygen-level dependent (BOLD) responses to reward anticipation and feedback were compared using a 2x2 analysis of variance test (ASD traits: low/high; anxiety symptoms: low/high), controlling for plausible covariates. In addition, we used a longitudinal design to assess whether neural responses during reward processing predicted anxiety at 2-year follow-up. High ASD traits were associated with reduced BOLD responses in dorsal prefrontal regions during reward anticipation and negative feedback. Participants with high anxiety symptoms showed increased lateral prefrontal responses during anticipation, but decreased responses following feedback. Interaction effects revealed that youth with combined ASD traits and anxiety, relative to other youth, showed high right insula activation when anticipating reward, and low right-sided caudate, putamen, medial and lateral prefrontal activations during negative feedback (all clusters PFWE<0.05). BOLD activation patterns in the right dorsal cingulate and right medial frontal gyrus predicted new-onset anxiety in participants with high but not low ASD traits. Our results reveal both quantitatively enhanced and qualitatively distinct neural correlates underlying the comorbidity between ASD traits and anxiety. Specific neural responses during reward processing may represent a risk factor for developing anxiety in ASD youth.
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Trastornos de Ansiedad/diagnóstico por imagen , Trastorno del Espectro Autista/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Imagen por Resonancia Magnética , Recompensa , Adolescente , Anticipación Psicológica/fisiología , Trastornos de Ansiedad/fisiopatología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/fisiopatología , Comorbilidad , Dominancia Cerebral/fisiología , Retroalimentación , Femenino , Estudios de Seguimiento , Lóbulo Frontal/diagnóstico por imagen , Lóbulo Frontal/fisiopatología , Giro del Cíngulo/diagnóstico por imagen , Giro del Cíngulo/fisiopatología , Humanos , Estudios Longitudinales , Masculino , Oxígeno/sangre , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiopatologíaRESUMEN
Traumatic or stressful life events have long been hypothesized to play a role in causing or precipitating obsessive-compulsive symptoms but the impact of these environmental factors has rarely been investigated using genetically informative designs. We tested whether a wide range of retrospectively-reported stressful life events (SLEs) influence the lifetime presence and severity of obsessive-compulsive symptoms (OCS) in a large Swedish population-based cohort of 22,084 twins. Multiple regression models examined whether differences in SLEs within twin pairs were significantly associated with differences in OCS. In the entire sample (i.e., both monozygotic [MZ] and dizygotic twin pairs), two SLEs factors, "abuse and family disruption" and "sexual abuse", were significantly associated with the severity of OCS even after controlling for depressive symptoms. Other SLEs factors were either not associated with OCS ("loss", "non-sexual assault") or were no longer associated with OCS after controlling for depression ("illness/injury"). Within MZ pair analyses, which effectively control for genetic and shared environmental effects, showed that only the "abuse and family disruption" factor remained independently related to within-pair differences in OCS severity, even after controlling for depressive symptoms. Despite being statistically significant, the magnitude of the associations was small; "abuse and family disruption" explained approximately 3% of the variance in OCS severity. We conclude that OCS are selectively associated with certain types of stressful life events. In particular, a history of interpersonal abuse, neglect and family disruption may make a modest but significant contribution to the severity of OCS. Further replication in longitudinal cohorts is essential before causality can be firmly established.
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Maltrato a los Niños/psicología , Enfermedades en Gemelos/etiología , Conflicto Familiar , Acontecimientos que Cambian la Vida , Trastorno Obsesivo Compulsivo/diagnóstico , Trastorno Obsesivo Compulsivo/etiología , Gemelos Monocigóticos/psicología , Adolescente , Adulto , Niño , Abuso Sexual Infantil/psicología , Estudios de Cohortes , Depresión/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastorno Obsesivo Compulsivo/genética , Autoinforme , Índice de Severidad de la Enfermedad , Suecia , Gemelos Dicigóticos/psicologíaRESUMEN
BACKGROUND: Despite the inclusion of disruptive mood dysregulation disorder (DMDD) in DSM-5, little empirical data exist on the disorder. We estimated rates, co-morbidity, correlates and early childhood predictors of DMDD in a community sample of 6-year-olds. METHOD: DMDD was assessed in 6-year-old children (n = 462) using a parent-reported structured clinical interview. Age 6 years correlates and age 3 years predictors were drawn from six domains: demographics; child psychopathology, functioning, and temperament; parental psychopathology; and the psychosocial environment. RESULTS: The 3-month prevalence rate for DMDD was 8.2% (n = 38). DMDD occurred with an emotional or behavioral disorder in 60.5% of these children. At age 6 years, concurrent bivariate analyses revealed associations between DMDD and depression, oppositional defiant disorder, the Child Behavior Checklist - Dysregulation Profile, functional impairment, poorer peer functioning, child temperament (higher surgency and negative emotional intensity and lower effortful control), and lower parental support and marital satisfaction. The age 3 years predictors of DMDD at age 6 years included child attention deficit hyperactivity disorder, oppositional defiant disorder, the Child Behavior Checklist - Dysregulation Profile, poorer peer functioning, child temperament (higher child surgency and negative emotional intensity and lower effortful control), parental lifetime substance use disorder and higher parental hostility. CONCLUSIONS: A number of children met DSM-5 criteria for DMDD, and the diagnosis was associated with numerous concurrent and predictive indicators of emotional and behavioral dysregulation and poor functioning.
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Manual Diagnóstico y Estadístico de los Trastornos Mentales , Genio Irritable , Trastornos del Humor/diagnóstico , Trastornos del Humor/epidemiología , Problema de Conducta , Déficit de la Atención y Trastornos de Conducta Disruptiva/epidemiología , Niño , Preescolar , Comorbilidad , Depresión/epidemiología , Femenino , Humanos , Masculino , Prevalencia , TemperamentoRESUMEN
BACKGROUND: Depression is commonly co-morbid with obsessive-compulsive disorder (OCD). However, it is unknown whether depression is a functional consequence of OCD or whether these disorders share a common genetic aetiology. This longitudinal twin study compared these two hypotheses. METHOD: Data were drawn from a longitudinal sample of adolescent twins and siblings (n = 2651; Genesis 12-19 study) and from a cross-sectional sample of adult twins (n = 4920). The longitudinal phenotypic associations between OCD symptoms (OCS) and depressive symptoms were examined using a cross-lag model. Multivariate twin analyses were performed to explore the genetic and environmental contributions to the cross-sectional and longitudinal relationship between OCS and depressive symptoms. RESULTS: In the longitudinal phenotypic analyses, OCS at time 1 (wave 2 of the Genesis 12-19 study) predicted depressive symptoms at time 2 (wave 3 of the Genesis 12-19 study) to a similar extent to which depressive symptoms at time 1 predicted OCS at time 2. Cross-sectional twin analyses in both samples indicated that common genetic factors explained 52-65% of the phenotypic correlation between OCS and depressive symptoms. The proportion of the phenotypic correlation due to common non-shared environmental factors was considerably smaller (35%). In the adolescent sample, the longitudinal association between OCS at time 1 and subsequent depressive symptoms was accounted for by the genetic association between OCS and depressive symptoms at time 1. There was no significant environmental association between OCS and later depressive symptoms. CONCLUSIONS: The present findings show that OCS and depressive symptoms co-occur primarily due to shared genetic factors and suggest that genetic, rather than environmental, effects account for the longitudinal relationship between OCS and depressive symptoms.
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Depresión/genética , Enfermedades en Gemelos/genética , Trastorno Obsesivo Compulsivo/genética , Sistema de Registros , Adolescente , Adulto , Depresión/etiología , Enfermedades en Gemelos/etiología , Femenino , Pleiotropía Genética/genética , Humanos , Estudios Longitudinales , Masculino , Trastorno Obsesivo Compulsivo/etiología , Hermanos , Adulto JovenRESUMEN
BACKGROUND: Mood lability is a concept widely used. However, data on its prevalence and morbid associations are scarce. We sought to establish the occurrence and importance of mood lability in a large community sample of children and adolescents by testing a priori hypotheses. METHOD: Cross-sectional data were taken from a national mental health survey including 5326 subjects aged 8-19 years in the UK. The outcomes were prevalence and characteristics of mood lability and its associations with psychopathology and overall impairment. RESULTS: Mood lability occurred in more than 5% of the population of children and adolescents, both by parent and self-report. Mood lability was strongly associated with a wide range of psychopathology and was linked to significant impairment even in the absence of psychiatric disorders. Mood lability was particularly strongly associated with co-morbidity between internalizing and externalizing disorders, even when adjusting for the association with individual disorders. The pattern of results did not change after excluding youth with bipolar disorder or with episodes of elated mood. CONCLUSIONS: Clinically significant mood lability is relatively common in the community. Our findings indicate that mood lability is not a mere consequence of other psychopathology in that it is associated with significant impairment even in the absence of psychiatric diagnoses. Moreover, the pattern of association of mood lability with co-morbidity suggests that it could be a risk factor shared by both internalizing and externalizing disorders. Our data point to the need for greater awareness of mood lability and its implications for treatment.
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Afecto , Trastorno Bipolar/diagnóstico , Adolescente , Ira , Trastorno Bipolar/psicología , Niño , Trastornos de la Conducta Infantil/diagnóstico , Trastornos de la Conducta Infantil/psicología , Comorbilidad , Femenino , Felicidad , Encuestas Epidemiológicas , Humanos , Control Interno-Externo , Masculino , Determinación de la Personalidad/estadística & datos numéricos , Inventario de Personalidad/estadística & datos numéricos , PsicometríaRESUMEN
OBJECTIVE: Follistatin (FS) is the specific binding protein of activin and expression of both factors is regulated by inflammatory agents. Therefore, FS concentrations were determined in cerebrospinal fluid (CSF) of patients with bacterial and viral meningitis or multiple sclerosis (MS), as well as in the CSF of patients without meningial inflammation or autoimmune diseases. Furthermore, a mouse pneumococcal meningitis model was used to localise the cellular sources of FS in brains of normal and meningitic mice. METHODS: FS concentrations in CSF were determined by ELISA; FS in mice was localised by in situ hybridisation and immunohistochemistry. RESULTS: FS concentrations were > or =0.4 microg/l in 22 of 66 CSF samples of meningitis patients versus 2 of 27 CSF samples from patients with multiple sclerosis (P<0.05) and 2 of 41 CSF specimen from patients without neuroinflammatory diseases (P<0.01). In the CSF of patients with meningitis, the concentration of FS was correlated with total protein (P<0.005) and lactate concentrations (P<0.05), but not with leukocyte counts, interval between onset of disease and CSF analysis, or clinical outcome. The CSF-to-serum ratios of FS and albumin also correlated significantly (P<0.0005). In some patients with meningitis the CSF-to-serum ratios suggested that the elevated FS in CSF did not originate from serum alone. FS was localised in mice brains to neurones of the hippocampus, dentate gyrus, neocortex, and to the choroid plexus. Analyses of brains and other organs from uninfected and infected animals sacrificed 6-36 h after infection did not reveal any obvious differences in the distribution and intensity of FS mRNA and protein expression. CONCLUSIONS: The concentration of FS in humans is elevated during meningitis. In some patients the increase is caused by a release of FS from brain into CSF. Data from the mouse meningitis model suggest that increased CSF concentrations of FS in meningitis appear not to be accompanied by an elevated number of cells containing FS mRNA or protein in the brain.
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Glicoproteínas/líquido cefalorraquídeo , Glicoproteínas/genética , Meningitis Bacterianas/líquido cefalorraquídeo , Meningitis Viral/líquido cefalorraquídeo , Animales , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Folistatina , Regulación de la Expresión Génica , Glicoproteínas/sangre , Sustancias de Crecimiento/sangre , Sustancias de Crecimiento/líquido cefalorraquídeo , Sustancias de Crecimiento/genética , Humanos , Masculino , Meningitis Bacterianas/sangre , Meningitis Neumocócica/sangre , Meningitis Neumocócica/líquido cefalorraquídeo , Meningitis Viral/sangre , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/sangre , Esclerosis Múltiple/líquido cefalorraquídeo , Valores de Referencia , Streptococcus pneumoniaeRESUMEN
The mammalian mitochondrial genome is a double-stranded circular DNA molecule, which is transcribed from both strands as polycistronic RNAs, which are further processed to yield the mature polyadenylated mRNAs, rRNAs and tRNAs. We compared the gene expression patterns of foetal and adult porcine brains and identified a sequence tag from the ATPase 6 region of the mitochondrial genome which, in adult brain, was more abundant in the sense (H-strand) form, but, in foetal brain, more abundant in the antisense form (L-strand). By means of solution hybridisation/S1 nuclease protection assay, Northern blotting, and PCR based techniques, we demonstrated that the ATPase 6 region of the porcine mitochondrial genome is transcribed as co-existing, stable sense and antisense RNAs. Furthermore, we identified sense and antisense transcripts from this region consisting of inversely assembled fragments joined together at a direct repeat of 7 nucleotides. Our results suggest that transcription and post-transcriptional processing of mitochondrial RNAs are much more complex than presently thought.
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Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismo , Encéfalo/metabolismo , ADN sin Sentido/metabolismo , ADN Mitocondrial/metabolismo , ARN/metabolismo , Adenosina Trifosfatasas/química , Animales , Secuencia de Bases , Northern Blotting , Encéfalo/embriología , Expresión Génica , ATPasas de Translocación de Protón Mitocondriales , Datos de Secuencia Molecular , ARN Complementario/metabolismo , ARN Mitocondrial , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Endonucleasas Específicas del ADN y ARN con un Solo Filamento/metabolismo , Porcinos/embriología , Distribución TisularRESUMEN
BACKGROUND AND PURPOSE: The mechanisms behind the demyelination that is characteristic of multiple sclerosis (MS) are still poorly understood. The purpose of this study was to compare immunopathologic findings in demyelinating lesions of three patients with in vivo assessments obtained by quantitative proton MR spectroscopy (MRS). METHODS: Between four and seven stereotactic needle brain biopsies were performed in three young adults with diagnostically equivocal findings for MS. Axonal density, gliosis, blood brain-barrier breakdown, and demyelinating activity of lesions were determined. Combined MR/MRS studies were performed (T1-weighted fast low-angle shot and single-voxel stimulated-echo acquisition mode), and absolute metabolite levels were obtained with a user-independent fitting routine. Metabolite control values were obtained from a group of age-matched healthy volunteers (n = 40, age range, 20-25 years old). Alterations of metabolite levels of control subjects were considered significant when exceeding two standard deviations. RESULTS: There were parallel decreases of N-acetylaspartate (21%-82%) and reductions of axonal density (44%-74%) in demyelinating plaques. Concomitant increases of choline (75%-152%) and myo-inositol (84%-160%) corresponded to glial proliferation. Elevated lactate was associated with inflammation. CONCLUSION: The present data suggest that in vivo MRS indicates key pathologic features of demyelinating lesions.
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Enfermedades Desmielinizantes/diagnóstico , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Esclerosis Múltiple/diagnóstico , Adulto , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Axones/patología , Biopsia con Aguja , Barrera Hematoencefálica/fisiología , Encéfalo/patología , División Celular/fisiología , Colina/metabolismo , Enfermedades Desmielinizantes/patología , Diagnóstico Diferencial , Dominancia Cerebral/fisiología , Femenino , Gliosis/patología , Humanos , Inositol/metabolismo , Masculino , Esclerosis Múltiple/patología , Neuroglía/patologíaRESUMEN
Granulocyte colony-stimulating factor (G-CSF) possesses an antimicrobial effect in several animal models of infection. To evaluate a possible effect of G-CSF on the course of pneumococcal meningitis, rabbits infected intracisternally (i.c.) with Streptococcus pneumoniae type 3 (n = 7) received 50 microgram/kg of rhG-CSF intravenously (i.v.) 1 h prior to infection. Seven infected animals served as controls. Uninfected rabbits received 10 microgram of G-CSF (n = 3), 2 microgram G-CSF (n = 3) or saline (n = 3) i.c. G-CSF injected i.c. did not produce cerebrospinal fluid (CSF) leucocytosis. Compared with the control group, i.v. G-CSF given prior to i.c. infection increased the percentage of granulocytes in blood 6 h and 12 h after infection. Twelve hours after infection, CSF tumour necrosis factor (TNF) activity and CSF interleukin (IL)-1beta concentrations were significantly higher in G-CSF-treated animals. G-CSF did not decrease bacterial growth in the subarachnoid space and the CSF leucocyte densities were not influenced. At 24 h after infection, G-CSF did not reduce the CSF concentrations of neurone-specific enolase and the density of apoptotic neurones in the dentate gyrus of the hippocampus. In conclusion, i.v. G-CSF increased the concentration of pro-inflammatory cytokines in the CSF but did not decrease the growth of Streptococcus pneumoniae in the subarachnoid space.
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Factor Estimulante de Colonias de Granulocitos/inmunología , Interleucina-1/inmunología , Meningitis Neumocócica/inmunología , Meningitis Neumocócica/microbiología , Factor de Necrosis Tumoral alfa/inmunología , Animales , Modelos Animales de Enfermedad , Factor Estimulante de Colonias de Granulocitos/farmacología , Humanos , Inyecciones Intravenosas , Interleucina-1/líquido cefalorraquídeo , Recuento de Leucocitos , Meningitis Neumocócica/líquido cefalorraquídeo , Conejos , Proteínas Recombinantes , Streptococcus pneumoniae/crecimiento & desarrollo , Streptococcus pneumoniae/inmunología , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeoRESUMEN
To study the effect of high-dose glycerol therapy on inflammation and neuronal destruction in a model of experimental pneumococcal meningitis, 14 New Zealand White rabbits were infected intracisternally with Streptococcus pneumoniae type 3. Sixteen hours after infection, 7 animals received intravenous glycerol therapy (1 g kg(-1) bolus and 0.5 g kg (1)h(-1) maintenance dose) and 7 animals served as untreated controls.After 8 h of therapy, the glycerol CSF:serum ratio exceeded the previously observed values in rabbits with an intact blood-CSF barrier (0.72+/-0.25 vs. 0.35), i.e. glycerol crossed the blood-CSF barrier more readily in animals altered by meningitis than in healthy animals. In contrast, the brain tissue:serum ratio of glycerol (grey matter 0.33+/-0.29, white matter 0.30+/-0.31) was substantially lower than the CSF:serum ratio (p=0.03 and p=0.047). There was no significant effect of glycerol on intracranial pressure, brain water content and neuron-specific enolase release into the CSF. Glycerol significantly increased the density of neuronal apoptosis in the dentate gyrus of the hippocampal formation. Therefore, glycerol does not appear to be beneficial in experimental pneumococcal meningitis.
RESUMEN
Rifabutin is a lipophilic antibacterial with high in vitro activity against many pathogens involved in bacterial meningitis including pneumococci. Resistance to beta-lactam antibiotics in pneumococci is not associated with a decreased sensitivity to rifabutin (30 strains from Germany with intermediate penicillin resistance; MIC range of penicillin: 0.125-1 mg/l, MIC of rifabutin: < 0.008-0.015 mg/l). Rifabutin at doses of 0.625, 1.25, 2.5, 5 and 10 mg/kg/h i.v. was investigated in a rabbit model of meningitis using a Streptococcus pneumoniae type 3 (MIC/MBC of rifabutin: 0.015/0.06 mg/l). The bacterial density in CSF at the onset of treatment was 7.3 +/- 0.6 log CFU/ml (mean +/- SD). Rifabutin decreased bacterial CSF titers in a dose-dependent manner [delta log CFU/ml/h (slope of the regression line log CFU/ml vs. time) at a dose of 0.625 mg/kg/h: -0.16 +/- 0.06 (n = 3), at 1.25 mg/kg/h: -0.20 +/- 0.12 (n = 4), at 2.5 mg/kg/h: -0.24 +/- 0.04 (n = 4), at 5 mg/kg/h: -0.31 +/- 0.10 (n = 8), and at 10 mg/kg/h: -0.29 +/- 0.10 (n = 5)]. At high doses rifabutin was as active as ceftriaxone at 10 mg/kg/h (delta log CFU/ml/h: -0.29 +/- 0.10, n = 10). Two and 5 h after initiation of therapy, CSF TNF-alpha activities were lower with rifabutin 5 mg/kg/h than with ceftriaxone (medians 2 vs. 141 U/ml, p = 0.005 at 2 h; median 51 vs. 120 U/ml 5 h after initiation of therapy, p = 0.04). This did not result, however, in a decrease of indicators of neuronal damage. In conclusion, intravenous rifabutin was bactericidal in experimental pneumococcal meningitis. Provided that a well-tolerated i.v. formulation will be available it may qualify as a reserve antibiotic for pneumococcal meningitis, in particular when strains with a reduced sensitivity to beta-lactam antibiotics are the causative pathogens.
Asunto(s)
Antibacterianos/uso terapéutico , Meningitis Neumocócica/tratamiento farmacológico , Rifabutina/uso terapéutico , Animales , Ceftriaxona/uso terapéutico , Modelos Animales de Enfermedad , Meningitis Neumocócica/líquido cefalorraquídeo , Pruebas de Sensibilidad Microbiana , Conejos , Streptococcus pneumoniae/efectos de los fármacosRESUMEN
This study evaluates the ability of the new fluoroquinolone trovafloxacin to attenuate the inflammatory burst known to occur after initiation of antibiotic treatment in pneumococcal meningitis. After exposure to trovafloxacin or ceftriaxone for 3 h in vitro, Streptococcus pneumoniae was injected intracisternally (i.c.) into rabbits every 3 h over 9 h (n = 6 for each antibiotic). Ceftriaxone-treated S. pneumoniae induced consistently higher CSF leucocyte counts (median 2568/microL versus 543/microL at 6 h; P = 0.03; 4560/microL versus 2207/microL at 18 h; P = 0.03) than trovafloxacin-treated bacteria. Meningitis induced in rabbits by i.c. injection of live S. pneumoniae was treated with equal doses of trovafloxacin or ceftriaxone i.v. (ten per group). The bactericidal rates of both antibacterial agents in CSF were almost identical. In comparison with ceftriaxone, trovafloxacin resulted in lower tumour necrosis factor (TNF) and interleukin 1beta (IL-1beta) CSF levels 2 h after the initiation of treatment (TNF levels, median 26 U/mL versus 141 U/mL; P = 0.02; IL-1beta levels 455 pg/mL versus 1399 pg/mL; P = 0.02). Twelve hours after initiation of therapy, however, TNF and IL-1beta were higher in trovafloxacin-treated animals (TNF, 61 U/mL versus 7 U/mL; P = 0.001; IL-1beta, 4320 pg/mL versus 427 pg/mL; P = 0.006). The increase in CSF lactate was less during trovafloxacin therapy than with ceftriaxone (median: 2.0 mmol/L versus 4.0 mmol/L; P = 0.03). In conclusion, S. pneumoniae treated in vitro with trovafloxacin induced less CSF leucocytosis than ceftriaxone-treated S. pneumoniae. After i.c. inoculation of live S. pneumoniae, trovafloxacin therapy delayed, but did not inhibit, the release of the proinflammatory cytokines TNF and IL-1beta, probably by slowing the liberation of bacterial cell wall components into the subarachnoid space.
Asunto(s)
Antiinfecciosos/farmacología , Fluoroquinolonas , Interleucina-1/líquido cefalorraquídeo , Meningitis Neumocócica/prevención & control , Naftiridinas/farmacología , Streptococcus pneumoniae/efectos de los fármacos , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeo , Adulto , Animales , Ceftriaxona/farmacología , Cefalosporinas/farmacología , Modelos Animales de Enfermedad , Humanos , Inyecciones Intravenosas , Ácido Láctico/metabolismo , Meningitis Neumocócica/líquido cefalorraquídeo , ConejosRESUMEN
Glutamine synthetase (GS), glial fibrillary acidic protein (GFAP) immunohistochemistry and neuronal apoptotic cell death were evaluated in a rabbit model of pneumococcal meningitis. Meningitis caused an increase of GS immunoreactivity in the cerebral cortex, but not in the hippocampal formation. GFAP immunoreactivity remained unchanged. This may represent a protective mechanism for cortical neurons. The inability of hippocampal GS to counteract the detrimental effects of glutamate may be the cause of neural apoptosis observed in the dentate gyrus during meningitis.