The course and outcome of SD is highly variable; male gender and prevalent tonic phenotype predict a poor outcome.
Both active and passive immunization strategies against Staphylococcus aureus have thus far failed to show efficacy in humans. With the attempt to develop an effective S. aureus vaccine, we selected five conserved antigens known to have different roles in S. aureus pathogenesis. They include the secreted factors α-hemolysin (Hla), ess extracellular A (EsxA), and ess extracellular B (EsxB) and the two surface proteins ferric hydroxamate uptake D2 and conserved staphylococcal antigen 1A. The combined vaccine antigens formulated with aluminum hydroxide induced antibodies with opsonophagocytic and functional activities and provided consistent protection in four mouse models when challenged with a panel of epidemiologically relevant S. aureus strains. The importance of antibodies in protection was demonstrated by passive transfer experiments. Furthermore, when formulated with a toll-like receptor 7-dependent (TLR7) agonist recently designed and developed in our laboratories (SMIP.7-10) adsorbed to alum, the five antigens provided close to 100% protection against four different staphylococcal strains. The new formulation induced not only high antibody titers but also a Th1 skewed immune response as judged by antibody isotype and cytokine profiles. In addition, low frequencies of IL-17-secreting T cells were also observed. Altogether, our data demonstrate that the rational selection of mixtures of conserved antigens combined with Th1/Th17 adjuvants can lead to promising vaccine formulations against S. aureus.Staphylococcus aureus | vaccine | TLR7 | adjuvant | Hla C urrent antibiotics are not efficacious against emerging multidrug-resistant strains of Staphylococcus aureus, a major human pathogen. Therefore, there is an urgent need to develop vaccines to target this pathogen. Two prophylactic vaccines have been tested recently for efficacy in humans: StaphVAX, which contained capsular polysaccharides type 5 and 8 (CP5 and CP8), and V710, based on a single protein antigen (IsdB) (1, 2). Both vaccines failed in phase III efficacy trials (3, 4). On the basis of these disappointing results and taking into account that S. aureus produces a plethora of virulence and immune evasion factors, different vaccine candidates, constituted by multiple components, are currently in phase I/II trials, but efficacy data are not available yet (5). In line with the multicomponent strategy, our laboratory has undertaken a vaccine discovery project aiming at the identification of conserved antigens, which play important roles in S. aureus virulence and pathogenicity. The main objective of the study was to combine the selected antigens in the presence of appropriate adjuvants and to demonstrate protective efficacy against a panel of genetically different S. aureus clinical isolates in different mouse models. ResultsAntigen Selection. The antigens included in our candidate combination vaccine were selected among surface and secreted factors previously shown to be protective and involved in S. aureus virulence. Two of them, the ferric hydroxamat...
Mutations in genes coding for transducers participating in the RAS/MAPK pathway have been identified as the molecular cause underlying a group of clinically related developmental disorders with cognitive deficits of variable severity. To determine the spectrum of cognitive defects associated with dysregulation of this signal cascade, we studied the profile of cognitive abilities in patients with mutations affecting the PTPN11, SOS1, HRAS, KRAS, BRAF, RAF1, and MEK1 genes and phenotype-genotype correlations. Our findings support the observation that heterogeneity in cognitive abilities can be at least partially ascribed to the individual affected genes and type of mutation involved. While mutations affecting transducers upstream of RAS were less frequently associated with mental retardation, mutations in downstream components of the pathway were generally associated with a more severe cognitive impairment. Among patients with a heterozygous PTPN11 mutation, the T468M substitution was associated with a mean IQ significantly higher compared to that of individuals carrying the N308D change. Our study provides insights on the range of cognitive abilities in patients with gene mutations causing dysregulation of RAS signaling suggesting that the presence and severity of cognitive involvement can be predicted in part by the gene involved.
Status dystonicus (SD) is a life threatening disorder that develops in patients with both primary and secondary dystonia, characterized by acute worsening of symptoms with generalized and severe muscle contractions. To date, no information is available on the best way to treat this disorder. We review the previously described cases of SD and two new cases are reported, one of which occurring in a child with static encephalopathy, and the other one in a patient with pantothenate kinase-associated neurodegeneration. Both patients were admitted to an intensive care unit and treated with midazolam and propofol. This approach proved to be useful in the former while the progressive nature of the dystonia of the second patient required the combination of intrathecal baclofen infusion and bilateral pallidal deep brain stimulation. We believe that a rapid and aggressive approach is justified to avoid the great morbidity and mortality which characterize SD. Our experience, combined with the data available in the literature, might permit to establish the best strategies in managing this rare and severe condition.
Erwarte das Unerwartete: Die Reaktion von Imidazoliumpyridinium‐Salzen mit [{IrCp*Cl2}2] und [{RhCp*Cl2}2] lieferte eine Serie von Komplexen. Neben den erwarteten Bis(NHC)‐Komplexen wurden auch Spezies beobachtet, die aus der C‐C‐Kupplung zwischen den Pyridyliden‐ und den Cp*‐Liganden hervorgehen (siehe Schema; Cp*=Pentamethylcyclopentadienyl).
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