RESUMO
A 37-year-old woman was admitted to hospital and over the next 5 days developed a progressive encephalitis. Nuchal skin biopsy, analyzed using a Rabies TaqMan(c) PCR, demonstrated rabies virus RNA. She had a history in keeping with exposure to rabies whilst in South Africa, but had not received pre- or post-exposure prophylaxis. She was treated with a therapeutic coma according to the "Milwaukee protocol," which failed to prevent the death of the patient. Rabies virus was isolated from CSF and saliva, and rabies antibody was demonstrated in serum (from day 11 onwards) and cerebrospinal fluid (day 13 onwards). She died on day-35 of hospitalization. Autopsy specimens demonstrated the presence of rabies antigen, viral RNA, and viable rabies virus in the central nervous system.
Assuntos
Convulsoterapia , Vírus da Raiva/isolamento & purificação , Raiva/diagnóstico , Adulto , Anticorpos Antivirais/sangue , Anticorpos Antivirais/líquido cefalorraquidiano , Antígenos Virais/análise , Evolução Fatal , Feminino , Humanos , Testes de Neutralização , RNA Viral/análise , Raiva/sangue , Raiva/terapia , Raiva/virologia , Vírus da Raiva/genética , Vírus da Raiva/imunologia , Saliva/virologia , África do SulRESUMO
Rabies is a fatal viral encephalitis characterized by a clinically acute and progressive course. With rare exceptions, there is a discrepancy between clinical outcome and frank histological alterations in rabies. Investigators have postulated that rabies virus may modify neurotransmission through occupancy of cellular receptors or alteration of ion channels. We took advantage of these observations to improvise a successful therapy for rabies. The Milwaukee protocol ( www.mcw.edu/rabies ) was further modified to treat two German patients. We measured pterins and monoamine neurotransmitter metabolites in the CSF of patients with rabies by HPLC with electrochemical or fluorescent detection. We report loss of tetrahydrobiopterin (BH(4)) and associated pathological decrease of dopaminergic and serotoninergic neurotransmission in three successive patients with rabies. CSF levels of BH(4) and neurotransmitter metabolites increased in two patients who were supplemented. Our findings support the long-standing speculation of modified neurotransmission in the pathogenesis of rabies, but by another mechanism. Brain turnover of dopamine and serotonin is reduced following rabies-acquired BH(4) deficiency. Neuronal nitric oxide synthase is BH(4)-dependent and may also be involved, possibly causing cerebrovascular insufficiency in one patient. This work must be carefully replicated in animal models and future patients. We are cautiously optimistic at the prospect of readily available, metabolically specific, enteral therapy for rabies.
Assuntos
Biopterinas/análogos & derivados , Fenilcetonúrias/complicações , Raiva/complicações , Adolescente , Adulto , Biopterinas/deficiência , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/etiologia , Raiva/diagnóstico , Raiva/transmissão , Distúrbios da Fala/diagnóstico , Distúrbios da Fala/etiologiaRESUMO
In 2004, a teenager survived bat-associated rabies through the Milwaukee protocol (MP). This survivor and another patient with dog-associated rabies were found to have developed deficiencies of tetrahydrobiopterin (BH4) and associated neurotransmitters. BH4 is also essential for neuronal nitric oxide synthase (nNOS), so rabies is predicted to cause constriction of cerebral arteries. We assume that rabies virus, which almost exclusively targets neurons, would disproportionately affect cerebral over systemic perfusion by disrupting nNOS and lead to generalised cerebral artery spasm. Cranial artery vasospasm, therefore, was actively sought in two rabies patients, with the intention to specifically treat with BH4 and L-arginine when necessary. Flow velocities and resistive (RI) or pulsatility indices (PI) of middle cerebral arteries (MCA) were obtained by transcranial doppler ultrasound (TCD). A survival analysis of 8 attempts at the MP is presented. Of these, two cases are reported here. The first case is one child with bat-associated rabies who developed severe bilateral MCAspasm on hospital day (HD)-10 that responded to very low dose (0.2 mcg/kg/min) nitroprusside. The second case, a child with dog-associated rabies, developed spasm of MCA on HD-6 that responded to 6 mg/kg/day BH4. A second spasm with high RI (without cerebral oedema or increased intracranial pressure) responded to 20 mg/kg/day BH4 and 0.5 g/kg/dose L-arginine. Review of the TCD of the first child showed a similar second spasm seven days after first episode. Cerebral artery vasospasm occurred in the two children with rabies, but was clinically silent by standard monitoring. Spasm responded to drugs directed at the NOS pathway. Animal models for treatment of rabies are sorely needed to evaluate therapy.
Assuntos
Artérias Cerebrais/patologia , Quirópteros/virologia , Óxido Nítrico Sintase/metabolismo , Raiva/patologia , Vasoespasmo Intracraniano/patologia , Animais , Arginina/uso terapêutico , Biopterinas/análogos & derivados , Biopterinas/uso terapêutico , Velocidade do Fluxo Sanguíneo , Artérias Cerebrais/efeitos dos fármacos , Circulação Cerebrovascular , Criança , Doenças do Cão/transmissão , Cães , Humanos , Nitroprussiato/uso terapêutico , Raiva/tratamento farmacológico , Raiva/transmissão , Raiva/veterinária , Resultado do Tratamento , Ultrassonografia Doppler Transcraniana/métodos , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/virologia , ZoonosesRESUMO
OBJECTIVE: Children with HIV infection are particularly susceptible to invasive pneumococcal disease, yet the effect of HIV infection and its medical management on colonization and resistance to antibiotics are poorly described. To provide a basis for medical practice, we determined the prevalence of nasopharyngeal colonization and antibiotic resistance of Streptococcus pneumoniae in children with HIV infection. METHODS: Cross-sectional prevalence sample of children attending the pediatric HIV and pulmonary clinics to examine nasopharyngeal colonization with S. pneumoniae and antibiotic resistance to beta-lactams and trimethoprim-sulfamethoxazole (T/S). Subjects were matched by age and date of clinic visit. RESULTS: The colonization rate with S. pneumoniae of HIV-infected and -indeterminate children was equal to that of controls (20% vs. 19%). HIV infection, CDC staging or receipt of oral antibiotic therapy did not affect colonization. Isolates from HIV-infected and -indeterminate children were less likely to be penicillin-resistant than those from controls (18% vs. 50%). There was no difference in pneumococcal resistance to T/S among isolates from subjects and controls, despite 72% T/S use in the HIV clinic. CONCLUSION: Colonization with S. pneumoniae in HIV disease is no different from that of comparable children. The high incidence of pneumococcal disease and prophylaxis with T/S are not related to nasopharyngeal colonization. Antibiotic prophylaxis of HIV-infected children does not necessarily lead to increased resistance of S. pneumoniae.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/complicações , Infecções por HIV/complicações , Streptococcus pneumoniae/isolamento & purificação , Síndrome da Imunodeficiência Adquirida/complicações , Adolescente , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Portador Sadio/epidemiologia , Portador Sadio/microbiologia , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Resistência Microbiana a Medicamentos , Feminino , Humanos , Lactente , Lactamas/farmacologia , Masculino , Mucosa Nasal/microbiologia , Nasofaringe/microbiologia , Penicilinas/farmacologia , Infecções Pneumocócicas/epidemiologia , Infecções Pneumocócicas/microbiologia , Prevalência , Streptococcus pneumoniae/efeitos dos fármacos , Combinação Trimetoprima e Sulfametoxazol/farmacologiaRESUMO
Infections are considered to play an important role in the pathogenesis of necrotizing enterocolitis (NEC). The evidence for infectious causes of NEC is reexamined, with special attention to the clinical definition and reported outbreaks of NEC. Future areas of study are proposed.
Assuntos
Infecções Bacterianas/complicações , Enterocolite Pseudomembranosa/microbiologia , Enterocolite Pseudomembranosa/prevenção & controle , Humanos , Recém-Nascido , Doenças do Prematuro/microbiologiaAssuntos
Transplante de Medula Óssea , Gastroenterite/complicações , Infecções por Rotavirus/complicações , Criança , Gastroenterite/classificação , Humanos , Tolerância Imunológica , Masculino , RNA Viral/análise , Rotavirus/classificação , Rotavirus/genética , Infecções por Rotavirus/classificaçãoRESUMO
Rotaviruses are the most common cause of severe gastroenteritis in infants and children worldwide. Early events of virus binding and entry are the critical determinants of cellular permissiveness to rotavirus replication. The only known ligands for rotaviruses are sialic acids. We now report that simian rotaviruses bind preferentially to a subset of sialylated glycoconjugates, i.e. glycoproteins containing O-linked sialic acid moieties. Rotaviruses are able to distinguish between sialylated trisaccharide ligands presented as neoglycolipids. Higher avidity binding by rotaviruses is explained by multivalent binding to clustered sialic acid moieties. Our in vitro data are extended to explain the protective effect of mucins in the murine model of rotavirus disease and the specific binding by rotavirus to a high molecular weight sialomucin in the infant mouse intestine. Rotavirus binding to a sialomucin may be analogous to selectin-mediated mechanisms of cellular adhesion, and may be advantageous to the virus in the dynamic environment of the intestine.
Assuntos
Mucinas/metabolismo , Rotavirus/metabolismo , Sialoglicoproteínas/metabolismo , Animais , Sítios de Ligação , Sequência de Carboidratos , Bovinos , Criança , Glicoconjugados/metabolismo , Cobaias , Humanos , Técnicas In Vitro , Lactente , Intestino Delgado/metabolismo , Camundongos , Dados de Sequência Molecular , Peso Molecular , Mucinas/química , Oligossacarídeos/química , Oligossacarídeos/metabolismo , Rotavirus/patogenicidade , Infecções por Rotavirus/etiologia , Ácidos Siálicos/metabolismo , SialomucinasRESUMO
Bovine salivary mucin (BSM) inhibits rotavirus replication in vitro and in vivo. The inhibitory effect of BSM in vitro is abolished by Arthrobacter ureafaciens neuraminidase but not by Clostridia perfringens neuraminidase; it is abolished by mild base deacetylation but not by influenza C acetylesterase. The data suggest that SA11 rotavirus binds to a specific sialic acid structure on BSM different from the sialic acids recognized by other viruses.
Assuntos
Rotavirus/efeitos dos fármacos , Ácidos Siálicos/farmacologia , Acetilação , Animais , Bovinos , Cromatografia Líquida de Alta Pressão , Clostridium perfringens/enzimologia , Mucinas/metabolismo , Ácido N-Acetilneuramínico , Neuraminidase/metabolismo , Testes de Neutralização , Receptores Virais/metabolismo , Rotavirus/metabolismo , Rotavirus/fisiologia , Ácidos Siálicos/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
The balance of current evidence indicates that intrauterine exposure to infection and inflammation contributes to the risk of cerebral palsy. The mechanisms involved are not well understood and may differ in very immature versus term infants. Term infants exposed to maternal infection are predisposed to delivery room depression and neonatal encephalopathy.
Assuntos
Paralisia Cerebral/etiologia , Doenças Fetais , Infecções/complicações , Infecções/embriologia , Inflamação/complicações , Inflamação/embriologia , Paralisia Cerebral/diagnóstico , Paralisia Cerebral/genética , Paralisia Cerebral/microbiologia , Humanos , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Fatores de RiscoRESUMO
Rotaviruses are the major etiologic agents of severe diarrhea in children. Many rotaviruses encode a hemagglutinin which binds to sialic acids. We report that rotaviruses specifically recognize the neutral glycosphingolipid gangliotetraosylceramide (asialo-GM1 or GA1). GA1 resolved by thin-layer chromatography is bound by rotavirus, and binding is blocked by neutralizing rotavirus antiserum. Similar glycosphingolipid structures, such as globoside, gangliotriaosylceramide, and GA1 oxidized with galactose oxidase are ineffective in binding rotavirus. Other enteric viruses also specifically bind GA1. GA1 adsorbed to polystyrene beads inhibits rotavirus replication in vitro (as do anti-GA1 antibodies). The use of orally administered immobilized GA1 or anti-GA1 antibodies may prove useful in preventing or attenuating rotaviral and other enteric viral infections.
Assuntos
Gangliosídeo G(M1) , Glicoesfingolipídeos/metabolismo , Rotavirus/fisiologia , Animais , Bovinos , Linhagem Celular , Glicolipídeos/isolamento & purificação , Glicolipídeos/metabolismo , Glicoesfingolipídeos/isolamento & purificação , Intestinos/análise , Camundongos , Especificidade da Espécie , Ensaio de Placa Viral , Replicação ViralRESUMO
We conducted a retrospective study of neonatal leukocytosis induced by prostaglandin E(1). Among 45 neonates with congenital heart disease, leukocyte counts increased during PGE(1) infusion. We conclude that PGE(1) infusion is a predictable cause of leukocytosis in newborns with congenital heart disease.
Assuntos
Alprostadil/efeitos adversos , Leucocitose/induzido quimicamente , Feminino , Cardiopatias Congênitas/dietoterapia , Humanos , Recém-Nascido , Contagem de Leucócitos , Estudos RetrospectivosRESUMO
Recent observations in children with rotavirus gastroenteritis and in infant mice given rotavirus vaccine by oral administration suggest that this well-known gastrointestinal pathogen may infect the liver. To examine this possibility, the susceptibility of Hep G2 cells to infection with a variety of rotavirus strains was tested. These cells were used because they are considered to be well differentiated and exhibit many liver-specific functions. The Hep G2 cells supported the growth of the simian strain rhesus rotavirus (MMU 18006), a strain currently being used in vaccine trails, but did not support the growth of any human strain (D, DS1, Price or ST3). The rhesus rotavirus infection was cytopathic and resulted in release of lactate dehydrogenase. Rhesus rotavirus growth in Hep G2 cells displayed trypsin-enhanced infectivity and was inhibited by pretreatment of cells with Arthrobacter ureafaciens neuraminidase but not with neuraminidase from Clostridium perfringens. Hep G2 cells were also permissive for another simian strain (SA11), a bovine strain (UK) and single gene substitution reassortants containing VP7 (the major outer capsid neutralization protein) from a human rotavirus strain and the remaining 10 genes from either rhesus rotavirus or UK. In general, UK and its reassortants produced lower levels of antigen than did rhesus rotavirus and its reassortants. Hep G2 cells and other hepatic cell lines may prove to be useful tools to explore the hepatotropic potential of wild-type rotaviruses and candidate vaccine strains.
Assuntos
Antígenos Virais/análise , Carcinoma Hepatocelular/microbiologia , Neoplasias Hepáticas/microbiologia , Rotavirus/crescimento & desenvolvimento , Humanos , Neuraminidase/farmacologia , Rotavirus/imunologia , Tripsina/farmacologia , Células Tumorais CultivadasRESUMO
Rotaviral binding to receptors on epithelial cells in the small intestine is thought to be a key event in the infection process and may be carbohydrate-mediated. Strain SA11 of rotavirus bound in vitro both to glycolipids isolated from mouse small intestine and to authentic glycolipids using thin layer chromatography overlay and microtiter well adsorption assays. Neutral mouse intestinal glycolipids which bound rotavirus were GA1 (Gal beta 1----3GalNAc beta 1---4Glc beta 1----4Glc beta 1----1-ceramide) and pentaosylceramides with terminal N-acetylgalactosamine, while acidic lipids which bound rotavirus included cholesterol 3-sulfate and two compounds termed bands 80 and 81. Digestion with ceramide glycanase suggested that bands 80 and 81 have lactosyl ceramide cores and an unidentified acidic moiety(s). No sialic-acid-containing glycolipids tested were active in viral binding. Band 81, which may have a ganglio core, bound rotavirus with greatest avidity, followed by GA1. Of authentic glycolipids assayed, only GA1 and GA2 (GalNAc beta 1----4Gal beta 1----4Glc beta 1----1-ceramide) displayed rotaviral binding. A phosphatidylethanolamide dipalmitoyl-containing neoglycolipid analog of GA2 bound rotavirus with avidity similar to native GA2. Substitution of beta 1----4-linked GlcNAc or beta 1----3-linked GalNAc for terminal GalNAc of GA2 neoglycolipid supported rotaviral binding, while other substitutions abrogated it. These findings suggest that a carbohydrate epitope similar to that of GA2 is sufficient for in vitro rotaviral binding, although binding may be enhanced by galactose and/or an acidic moiety in a secondary epitope.