ABSTRACT
Intestinal inflammation challenges both function and structure of the enteric nervous system (ENS). In the animal model of TNBS-induced colitis, an influx of immune cells causes early neuron death in the neuromuscular layers, followed by axonal outgrowth from surviving neurons associated with upregulation of the neurotrophin GDNF (glial cell line-derived neurotrophic factor). Inflammation could involve ischemia and metabolic inhibition leading to neuronal damage, which might be countered by a protective action of GDNF. This was examined in a primary co-culture model of rat myenteric neurons and smooth muscle, where metabolic challenge was caused by dinitrophenol (DNP), O-methyl glucose (OMG) or hypoxia. These caused the specific loss of 50% of neurons by 24 h that was blocked by GDNF both in vitro and in whole mounts. Neuroprotection was lost with RET inhibition by vandetanib or GSK3179106, which also caused neuron loss in untreated controls. Thus, both basal and upregulated GDNF levels signal via RET for neuronal survival. This includes a key role for upregulation of HIF-1α, which was detected in neurons in colitis, since the inhibitor chetomin blocked rescue by GDNF or ischemic pre-conditioning in vitro. In DNP-treated co-cultures, neuron death was not inhibited by zVAD, necrosulfonamide or GSK872, and cleaved caspase-3 or - 8 were undetectable. However, combinations of inhibitors or the RIP1kinase inhibitor Nec-1 prevented neuronal death, evidence for RIPK1-dependent necroptosis. Therefore, inflammation challenges enteric neurons via ischemia, while GDNF is neuroprotective, activating RET and HIF-1α to limit programmed cell death. This may support novel strategies to address recurrent inflammation in IBD.
Subject(s)
Enteric Nervous System , Glial Cell Line-Derived Neurotrophic Factor/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Animals , Apoptosis , Cell Survival , Glial Cell Line-Derived Neurotrophic Factor Receptors , Neurons , Proto-Oncogene Proteins c-ret , RatsABSTRACT
We prospectively examined the epidemiology of invasive Haemophilus influenzae type b (Hib) infections among children under 5 y of age in the Greater Athens area before the introduction of immunization. The annual incidence of systemic Hib infections was 12/100000. Meningitis was the most common clinical entity and accounted for 69% of the cases. In the prevaccine era, the incidence of systemic Hib disease, particularly that of meningitis, was much lower in Greece compared to rates reported from Northern and Central Europe.
Subject(s)
Bacteremia/epidemiology , Haemophilus Infections/epidemiology , Haemophilus influenzae type b/isolation & purification , Bacteremia/diagnosis , Child, Preschool , Cohort Studies , Female , Greece/epidemiology , Haemophilus Infections/diagnosis , Humans , Immunization/trends , Incidence , Infant , Male , Meningitis, Haemophilus/diagnosis , Meningitis, Haemophilus/epidemiology , Prospective Studies , Risk Factors , Sex Distribution , Time FactorsABSTRACT
Four-day dexamethasone therapy has been used to treat bacterial meningitis. This prospective, randomized study compared the effect of a 2-day versus a 4-day regimen. Children (n = 118, ages 2.5 months to 15 years) were evaluated; 50% of the cases were due to Neisseria meningitidis and 40% to Haemophilus influenzae type b. Patients were treated intravenously (iv) mainly with conventional antimicrobial therapy and were randomly assigned to receive dexamethasone, 0.15 mg/kg iv every 6 h for 2 or 4 days. The clinical response was similar for both dexamethasone regimens. The meningococcal meningitis patients survived without neurologic or audiologic sequelae. On long-term follow-up, neurologic sequelae or moderate or more severe unilateral or bilateral hearing impairment (or both) were found in 1.8% and 3.8% of patients treated with dexamethasone for 2 and 4 days, respectively. The 2-day regimen appears appropriate for the treatment of H. influenzae and meningococcal meningitis.
Subject(s)
Dexamethasone/therapeutic use , Meningitis, Haemophilus/drug therapy , Meningitis, Meningococcal/drug therapy , Meningitis, Pneumococcal/drug therapy , Adolescent , Anti-Bacterial Agents/therapeutic use , Cerebrospinal Fluid/chemistry , Cerebrospinal Fluid/cytology , Cerebrospinal Fluid Proteins/analysis , Child , Child, Preschool , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Drug Administration Schedule , Drug Therapy, Combination , Female , Follow-Up Studies , Gastrointestinal Hemorrhage/chemically induced , Glucose/cerebrospinal fluid , Hearing Loss/etiology , Humans , Infant , Leukocyte Count , Male , Meningitis, Haemophilus/complications , Meningitis, Meningococcal/complications , Meningitis, Pneumococcal/complications , Nervous System Diseases/etiology , Prospective Studies , Treatment OutcomeABSTRACT
Cerebrospinal fluid (CSF) and serum lysozyme concentrations were determined in infants and children with and without acute infectious disease of the central nervous system. Serum lysozyme values from patients with bacterial and viral meningitis were found within the normal range. Lysozyme activity was absent or very low (below 0.5 microgram/ml) in normal CSF. High levels (4-12 microgram/ml) in patients with viral meningitis. A decrease of the lysozyme activity coincided with the clinical improvement of the bacterial meningitis. The lysozyme activity in CSF should be of significant value in detecting an inflammatory disease of the central nervous system.
