Paradoxical effects of interleukin-10 on the maturation of murine myeloid dendritic cells

The immunoregulatory cytokine, interleukin-10 (IL-10), has been shown to inhibit the maturation of human myeloid dendritic cells (DC). In the present study, we demonstrate that IL-10 has paradoxical effects on the maturation of murine myeloid bone marrow-derived DC. On the one hand, IL-10 inhibits the maturation of murine myeloid DC. The addition of IL-10 to granulocyte-macrophage colony-stimulating factor (GM-CSF)-supported murine BM-derived DC cultures reduced the frequency of major histocompatibility complex (MHC) class IIbright cells. These IL-10-pretreated DC have a reduced capacity to stimulate T cells in an allogeneic mixed leucocyte reaction. On the other hand, however, and in contrast to the effects of IL-10 on human DC, we found that the addition of IL-10 from the initiation of the culture onwards induced an up-regulation of the expression of the costimulatory molecules CD40, CD80 and CD86 on murine myeloid DC, as compared to DC generated with GM-CSF only. Moreover, a subpopulation of IL-10-pretreated MHC class IIdim DC lacked the capacity to take up dextran-fluorescein isothiocyanate (FITC), a feature of DC maturation. Taken together, our data demonstrate that the generation of murine myeloid DC in the presence of IL-10 results in a population of incompletely matured MHC class IIdim CD80+ CD86+ DC. These DC lack T-cell stimulatory capacity, suggesting a role for IL-10 in conferring tolerogenic properties on murine myeloid DC.     

HRAS-related epidermal nevus syndromes: Expansion of the spectrum with first branchial arch defects

Epidermal nevus syndrome (ENS) comprises a heterogeneous group of neurocutaneous syndromes associated with the presence of epidermal nevi and variable extracutaneous manifestations. Postzygotic activating HRAS pathogenic variants were previously identified in nevus sebaceous (NS), keratinocytic epidermal nevus (KEN), and different ENS, including Schimmelpenning–Feuerstein–Mims and cutaneous-skeletal-hypophosphatasia syndrome (CSHS). Skeletal involvement in HRAS-related ENS ranges from localized bone dysplasia in association with KEN to fractures and limb deformities in CSHS. We describe the first association of HRAS-related ENS and auricular atresia, thereby expanding the disease spectrum with first branchial arch defects if affected by the mosaic variant. In addition, this report illustrates the first concurrent presence of verrucous EN, NS, and nevus comedonicus (NC), indicating the possibility of mosaic HRAS variation as an underlying cause of NC. Overall, this report extends the pleiotropy of conditions associated with mosaic pathogenic variants in HRAS affecting ectodermal and mesodermal progenitor cells.     

Treatment of Newly Diagnosed Acute Promyelocytic Leukemia (APL) by All Transretinoic Acid (ATRA) Combined with Chemotherapy: The European Experience

All transretinoic acid (ATRA) gives complete remission (CR) rates of 80 to 90% in newly diagnosed acute promyelocytic leukemia (APL). However, it has two major drawbracks (1) a rapid rise in WBC in some patients, with potentially fatal ATRA syndrome (2) rapid relapse with maintenance therapy using ATRA alone or low dose chemotherapy. The French APL group therefore designed a treatment approach with ATRA followed by intensive chemotherapy. The latter was administered after CR achievement with ATRA, or was rapidly added to ATRA in case of rapid rise in leukocyte counts. This combined approach, in a pilot study and in a randomized trial, proved superior to intensive chemotherapy alone, by slightly increasing the CR rate but more importantly by reducing the relapse rate. These results were confirmed by the Chinese, Japanese and New York groups. Our group (and other European groups) are now testing in a new randomized trial the better timing of ATRA and chemotherapy administration (ATRA followed by chemotherapy or ATRA plus chemotherapy) and the role (after an intensive consolidation) of maintenance treatment with intermittent ATRA, continuous low dose chemotherapy or both.     

Results of multimodality treatment for 141 patients with brain arteriovenous malformations and seizures: factors associated with seizure incidence and seizure outcomes

OBJECTIVE: Previous reports of seizure outcomes after arteriovenous malformation (AVM) treatment have involved single-treatment modality (surgery, radiosurgery, or embolization) series. Such series reflect only selected lesions, of certain sizes, locations, and other clinical and anatomic characteristics, that are amenable to the single therapy, limiting the analysis of those factors. We report the results of AVM treatment using a multimodality approach that we think encompasses a broader spectrum of treatable brain AVMs. We tested for factors associated with seizure presentation and seizure outcomes. METHODS: Between 1991 and 1999, the multidisciplinary neurovascular unit at Massachusetts General Hospital treated 424 patients with brain AVMs. Treatment consisted of surgical resection, radiosurgery, or embolization, either alone or in combination. One hundred forty-one patients (33%) experienced seizures before treatment. We studied the following factors: sex, age, AVM size, AVM location, occurrence of intracranial hemorrhage, seizure type, duration of seizure history, treatment modality, and AVM obliteration. We tested for statistical associations between these factors and seizure presentation and outcomes. Clinical follow-up monitoring was via mailed questionnaires. RESULTS: When we compared the 141 patients with seizures with the 283 patients who did not experience seizures (total of 424 patients), male sex, age of less than 65 years, AVM size of more than 3 cm, and temporal lobe AVM location were statistically associated with seizures (P < 0.01, P < 0.05, P < 0.0001, and P < 0.01, respectively). Posterior fossa and deep locations were statistically associated with no seizures (P < 0.0001). One hundred ten (78%) of the 141 patients who experienced seizures before treatment responded to the mailed questionnaires, with a mean follow-up period of 2.9 years. A detailed comparison of responders and nonresponders demonstrated no statistically significant differences in pertinent characteristics. As determined with the Engel Seizure Outcome Scale, there were 73 (66%) Class I (free of disabling seizures), 11 (10%) Class II (rare disabling seizures), 1 (0.9%) Class III (worthwhile improvement), and 22 (20%) Class IV (no worthwhile improvement) outcomes. Three patients died during the follow-up period. We tested for factors associated with Engel Class I outcomes. Sex, age, and AVM size were not associated with Class I outcomes. Short seizure history, association of seizures with intracranial hemorrhage, generalized tonicoclonic seizure type, deep and posterior fossa AVM locations, surgical resection, and complete AVM obliteration were statistically associated with Class I outcomes (P < 0.0001, P < 0.05, P < 0.05, P < 0.05, P < 0.001, and P < 0.001, respectively). When only completely obliterated AVMs were considered, there were no statistically significant differences between surgery, radiosurgery, and embolization. CONCLUSION: Certain factors, as identified in an analysis of a wide spectrum of treatable brain AVMs, can facilitate predictions of the incidence of seizure presentation with AVMs, as well as seizure outcomes after multimodality treatment.     

Broad-spectrum antiviral activity of PNU-183792, a 4-oxo-dihydroquinoline, against human and animal herpesviruses

We identified a novel class of 4-oxo-dihydroquinolines represented by PNU-183792 which specifically inhibit herpesvirus polymerases. PNU-183792 was highly active against human cytomegalovirus (HCMV, IC(50) value 0.69 microM), varicella zoster virus (VZV, IC(50) value 0.37 microM) and herpes simplex virus (HSV, IC(50) value 0.58 microM) polymerases but was inactive (IC(50) value >40 microM) against human alpha (alpha), gamma (gamma), or delta (delta) polymerases. In vitro antiviral activity against HCMV was determined using cytopathic effect, plaque reduction and virus yield reduction assays (IC(50) ranging from 0.3 to 2.4 microM). PNU-183792 antiviral activity against both VZV (IC(50) value 0.1 microM) and HSV (IC(50) ranging from 3 to 5 microM) was analyzed using plaque reduction assays. PNU-183792 was also active (IC(50) ranging 0.1-0.7 microM) in cell culture assays against simian varicella virus (SVV), murine cytomegalovirus (MCMV) and rat cytomegalovirus (RCMV). Cell culture activity was compared with the appropriate licensed drugs ganciclovir (GCV), cidofovir (CDV) and acyclovir (ACV). PNU-183792 was also active against both GCV-resistant and CDV-resistant HCMV and against ACV-resistant HSV. Toxicity assays using four different species of proliferating mammalian cells indicated PNU-183792 was not cytotoxic at relevant drug concentrations (CC(50) value >100 microM). PNU-183792 was inactive against unrelated DNA and RNA viruses indicating specificity for herpesviruses. In animals, PNU-183792 was orally bioavailable and was efficacious in a model of lethal MCMV infection.