Presence of viremia during febrile neutropenic episodes in patients undergoing chemotherapy for malignant neoplasms.

The importance of viral infections as a leading cause of morbidity and mortality is well documented in severely immunosuppressed patients undergoing allogeneic stem cell transplantation. By contrast, viral infections generally receive less attention in patients with malignant disorders undergoing chemotherapy, where the onset of neutropenic fever is mostly associated with bacterial or fungal infections, and screening for viral infections is not routinely performed. To address the occurrence of invasive viral infections in a clinical setting commonly associated with less pronounced immunosuppression, we have prospectively screened 237 febrile neutropenic episodes in pediatric (n = 77) and adult (n = 69) patients undergoing intensive chemotherapy, primarily for treatment of acute leukemia. Serial peripheral blood specimens were tested by RQ-PCR assays for the presence and quantity of the clinically relevant viruses CMV, EBV, HHV6 and HAdV, commonly reactivated in highly immunocompromised patients. Viremia was documented in 36 (15%) episodes investigated, including the detection of HHV6 (n = 14), EBV (n = 15), CMV (n = 6), or HAdV (n = 1). While low or intermediate levels of viremia (<104 virus copies/mL) were commonly associated with bacterial or fungal co-infection, viremia at higher levels (>104 copies/mL) was documented in patients without evidence for other infections, raising the possibility that at least in some instances the onset of fever may have been attributable to the virus detected. The observations suggest that viral infections, potentially resulting from reactivation, might also play a clinically relevant role in patients receiving chemotherapy for treatment of malignant neoplasms, and routine screening for viremia in this clinical setting might be warranted.

Recém-nascidos com risco de toxoplasmose congênita, revisão de 16 anos / Newborns at risk for congenital toxoplasmosis, review of 16 years

OBJETIVOS: Analisar os dados de gestações com risco de toxoplasmose congênita e investigar a evolução dos recém-nascidos, em um hospital de nível II em Portugal. MÉTODOS: Um estudo transversal retrospetivo incluiu recém-nascidos com risco de toxoplasmose congênita e suas mães, cujo parto ocorreu entre janeiro de 2000 e dezembro de 2015. Os critérios de inclusão foram mãe com soroconversão para toxoplasmose durante a gestação ou primeira amostra sérica com IgM e IgG específicas positivas. O diagnóstico de toxoplasmose congênita foi definido por IgM específica positiva ao nascimento e/ou reação em cadeia da polimerase positiva no líquido amniótico e/ou persistência de IgG específica até os 12 meses de vida. A toxoplasmose congênita foi definida como sintomática quando os achados clínicos foram atribuídos à doença. Os testes Qui-quadrado ou Exato de Fisher foram usados para testar associações entre variáveis, assumindo-se significado estatístico quando p<0,05. RESULTADOS: Ocorreram 39.585 nascimentos vivos no período em estudo e foram identificados 98 casos com risco de toxoplasmose congênita, dos quais 89 completaram o seguimento. A prevalência de IgG para T. gondii nas gestantes foi de 26% (intervalo de confiança [IC] 95% 24-27%). Foram confirmados 22 casos de toxoplasmose congênita (5,6 por 10.000 nascidos vivos, IC95% 3,5-8,5 por 10.000). Dos 22 recém-nascidos, 18 (82%, IC95% 61-93%) eram sintomáticos. Os achados clínicos mais frequentes foram calcificação intracraniana (64%), hepatomegalia e/ou elevação das transaminases (32%) e retinocoroidite (14%). As lesões cerebrais foram mais frequentes quando a infeção materna foi documentada no primeiro e segundo trimestres em comparação com o terceiro (p=0,018). Em 31 casos (35%), as gestantes foram tratadas desde o momento do diagnóstico até o parto com espiramicina, não se tendo encontrado diferenças relativamente à taxa de transmissão vertical ou ao aparecimento de manifestações clínicas entre os recém-nascidos de mães tratadas e não tratadas. CONCLUSÕES: A prevalência de toxoplasmose congênita foi superior à reportada em outros países da Europa. A prevalência de calcificações intracranianas foi maior do que a descrita na literatura, enquanto que a de retinocoroidite e estrabismo foi menor. As alterações cerebrais nos recém-nascidos foram mais frequentes nas infecções de primeiro e segundo trimestre. Não houve diferença na taxa de transmissão vertical e na ocorrência de manifestações clínicas entre os recém-nascidos cujas mães receberam espiramicina na gestação ou não receberam tratamento.

AIMS: To analyze the data on pregnancies with risk of congenital toxoplasmosis and to investigate the newborns' outcome, in a level II hospital in Portugal. METHODS: A cross-sectional retrospective study included newborns at risk for congenital toxoplasmosis and their mothers, whose delivery occurred between January 2000 and December 2015. The inclusion criteria were mother with seroconversion to toxoplasmosis during pregnancy or first serum sample with positive specific IgM and IgG. The diagnosis of congenital toxoplasmosis was defined by positive specific IgM at birth and/or polymerase chain reaction positive in amniotic fluid and/or persistence of specific IgG up to 12 months of life. Congenital toxoplasmosis was defined as symptomatic when clinical findings were attributed to the disease. Chi-square or Fisher's exact tests were used to test associations between variables, assuming statistical significance when p<0.05. RESULTS: There were 39,585 live births in the study period and 98 cases with risk of congenital toxoplasmosis were identified, of which 89 completed the follow-up. The prevalence of anti-T. gondii IgG in the pregnant women was 26% (95% confidence interval [CI] 24-27%). Twenty-two cases of congenital toxoplasmosis (5.6 per 10,000 live births, 95%CI 3.5-8.5 per 10,000) were confirmed. Of the 22 newborns, 18 (82%, 95%CI 61-93%) were symptomatic. The most frequent clinical findings were intracranial calcification (64%), hepatomegaly and / or elevation of transaminases (32%) and retinochoroiditis (14%). Cerebral lesions were more frequent when maternal infection was documented in the first and second trimester compared to the third trimester (p=0.018). In 31 cases (35%), the pregnant women were treated from the time of diagnosis until delivery with spiramycin, and no differences were found regarding the rate of vertical transmission or the appearance of clinical manifestations among the newborns of treated and non-treated mothers treated. CONCLUSIONS: The prevalence of congenital toxoplasmosis was higher than that reported in other European countries. The prevalence of intracranial calcifications was higher than that described in the literature, whereas retinochoroiditis and strabismus occurrence was lower. Brain lesions in newborns were more frequent in first- and second-trimester infections. There was no difference in the rate of vertical transmission and in the occurrence of clinical manifestations among newborns whose mothers received spiramycin during gestation and those whose mothers did not receive treatment.

Cometin is a novel neurotrophic factor that promotes neurite outgrowth and neuroblast migration in vitro and supports survival of spiral ganglion neurons in vivo.

Neurotrophic factors are secreted proteins responsible for migration, growth and survival of neurons during development, and for maintenance and plasticity of adult neurons. Here we present a novel secreted protein named Cometin which together with Meteorin defines a new evolutionary conserved protein family. During early mouse development, Cometin is found exclusively in the floor plate and from E13.5 also in dorsal root ganglions and inner ear but apparently not in the adult nervous system. In vitro, Cometin promotes neurite outgrowth from dorsal root ganglion cells which can be blocked by inhibition of the Janus or MEK kinases. In this assay, additive effects of Cometin and Meteorin are observed indicating separate receptors. Furthermore, Cometin supports migration of neuroblasts from subventricular zone explants to the same extend as stromal cell derived factor 1a. Given the neurotrophic properties in vitro, combined with the restricted inner ear expression during development, we further investigated Cometin in relation to deafness. In neomycin deafened guinea pigs, two weeks intracochlear infusion of recombinant Cometin supports spiral ganglion neuron survival and function. In contrast to the control group receiving artificial perilymph, Cometin treated animals retain normal electrically-evoked brainstem response which is maintained several weeks after treatment cessation. Neuroprotection is also evident from stereological analysis of the spiral ganglion. Altogether, these studies show that Cometin is a potent new neurotrophic factor with therapeutic potential.

Meteorin is a chemokinetic factor in neuroblast migration and promotes stroke-induced striatal neurogenesis.

Ischemic stroke affecting the adult brain causes increased progenitor proliferation in the subventricular zone (SVZ) and generation of neuroblasts, which migrate into the damaged striatum and differentiate to mature neurons. Meteorin (METRN), a newly discovered neurotrophic factor, is highly expressed in neural progenitor cells and immature neurons during development, suggesting that it may be involved in neurogenesis. Here, we show that METRN promotes migration of neuroblasts from SVZ explants of postnatal rats and stroke-subjected adult rats via a chemokinetic mechanism, and reduces N-methyl-D-asparate-induced apoptotic cell death in SVZ cells in vitro. Stroke induced by middle cerebral artery occlusion upregulates the expression of endogenous METRN in cells with neuronal phenotype in striatum. Recombinant METRN infused into the stroke-damaged brain stimulates cell proliferation in SVZ, promotes neuroblast migration, and increases the number of immature and mature neurons in the ischemic striatum. Our findings identify METRN as a new factor promoting neurogenesis both in vitro and in vivo by multiple mechanisms. Further work will be needed to translate METRN's actions on endogenous neurogenesis into improved recovery after stroke.

Thrombospondin-1 binds to ApoER2 and VLDL receptor and functions in postnatal neuronal migration.

Apolipoprotein E receptor 2 (ApoER2), very low-density lipoprotein receptor (VLDLR), and Dab1 are the main components of the Reelin signalling cascade. Reelin is the sole ligand defined so far in signalling through this pathway. Postnatal migration of neuronal precursors from the subventricular zone (SVZ) to the olfactory bulb (OB), however, depends on ApoER2 and Dab1, but functions independently of Reelin. Here, we show that thrombospondin-1 (THBS-1) is a novel physiological ligand for ApoER2 and VLDLR. THBS-1 is present in the SVZ and along the entire rostral migratory stream (RMS). It binds to ApoER2 and VLDLR and induces phosphorylation of Dab1. In contrast to Reelin, it does not induce Dab1 degradation or Akt phosphorylation, but stabilizes neuronal precursor chains derived from subventricular explants. Lack of THBS-1 results in anatomical abnormalities of the RMS and leads to a reduction of postnatal neuronal precursors entering the OB.

ApoER2/VLDL receptor and Dab1 in the rostral migratory stream function in postnatal neuronal migration independently of Reelin.

Postnatal migration of interneuron precursors from the subventricular zone to the olfactory bulb occurs in chains that form the substrate for the rostral migratory stream. Reelin is suggested to induce detachment of neuroblasts from the chains when they arrive at the olfactory bulb. Here we show that ApoER2 and possibly very-low-density lipoprotein receptor (VLDLR) and their intracellular adapter protein Dab1 are involved in chain formation most likely independent of Reelin. F-spondin, which is present in the stream, may act as ligand for ApoER2 and VLDLR. In mice lacking either both receptors or Dab1 chain formation is severely compromised, and as a consequence the rostral migratory stream is virtually absent and neuroblasts accumulate in the subventricular zone. The mutant animals exhibit severe neuroanatomical defects in the subventricular zone and in the olfactory bulb. These data demonstrate a cell-autonomous function of ApoER2, and most likely VLDLR and Dab1, in postnatal migration of neuroblasts in the forebrain, which is suggested to depend on ligands other than Reelin.