N-Chlorotaurine Exhibits Fungicidal Activity against Therapy-Refractory Scedosporium Species and Lomentospora prolificans

N-Chlorotaurine (NCT), a well-tolerated endogenous long-lived oxidant that can be applied topically as an antiseptic, was tested on its fungicidal activity against Scedosporium and Lomentospora, opportunistic fungi that cause severe infections with limited treatment options, mainly in immunocompromised patients. In quantitative killing assays, both hyphae and conidia of Scedosporium apiospermum, Scedosporium boydii, and Lomentospora prolificans (formerly Scedosporium prolificans) were killed by 55 mM (1.0%) NCT at pH 7.1 and 37°C, with a 1- to 4-log₁₀ reduction in CFU after 4 h and a 4- to >6-log₁₀ reduction after 24 h. The addition of ammonium chloride to NCT markedly increased this activity. LIVE/DEAD staining of conidia treated with 1.0% NCT for 0.5 to 3 h increased the permeability of the cell wall and membrane. Preincubation of the test fungi in 1.0% NCT for 10 to 60 min delayed the time to germination of conidia by 2 h to >12 h and reduced their germination rate by 10.0 to 100.0%. Larvae of Galleria mellonella infected with 1.0 × 10⁷ conidia of S. apiospermum and S. boydii died at a rate of 90.0 to 100% after 8 to 12 days. The mortality rate was reduced to 20 to 50.0% if conidia were preincubated in 1.0% NCT for 0.5 h or if heat-inactivated conidia were used. Our study demonstrates the fungicidal activity of NCT against different Scedosporium and Lomentospora species. A postantifungal effect connected with a loss of virulence occurs after sublethal incubation times. The augmenting effect of ammonium chloride can be explained by the formation of monochloramine.     

Autosomal dominant SCA5 and autosomal recessive infantile SCA are allelic conditions resulting from SPTBN2 mutations

Although many genes have been identified for the autosomal recessive cerebellar ataxias (ARCAs), several patients are unlinked to the respective loci, suggesting further genetic heterogeneity. We combined homozygosity mapping and exome sequencing in a consanguineous Egyptian family with congenital ARCA, mental retardation and pyramidal signs. A homozygous 5-bp deletion in SPTBN2, the gene whose in-frame mutations cause autosomal dominant spinocerebellar ataxia type 5, was shown to segregate with ataxia in the family. Our findings are compatible with the concept of truncating SPTBN2 mutations acting recessively, which is supported by disease expression in homozygous, but not heterozygous, knockout mice, ataxia in Beagle dogs with a homozygous frameshift mutation and, very recently, a homozygous SPTBN2 nonsense mutation underlying infantile ataxia and psychomotor delay in a human family. As there was no evidence for mutations in 23 additional consanguineous families, SPTBN2-related ARCA is probably rare.     

Mutation of POC1B in a Severe Syndromic Retinal Ciliopathy

We describe a consanguineous Iraqi family with Leber congenital amaurosis (LCA), Joubert syndrome (JBTS), and polycystic kidney disease (PKD). Targeted next‐generation sequencing for excluding mutations in known LCA and JBTS genes, homozygosity mapping, and whole‐exome sequencing identified a homozygous missense variant, c.317G>C (p.Arg106Pro), in POC1B, a gene essential for ciliogenesis, basal body, and centrosome integrity. In silico modeling suggested a requirement of p.Arg106 for the formation of the third WD40 repeat and a protein interaction interface. In human and mouse retina, POC1B localized to the basal body and centriole adjacent to the connecting cilium of photoreceptors and in synapses of the outer plexiform layer. Knockdown of Poc1b in zebrafish caused cystic kidneys and retinal degeneration with shortened and reduced photoreceptor connecting cilia, compatible with the human syndromic ciliopathy. A recent study describes homozygosity for p.Arg106Pro_POC1B in a family with nonsyndromic cone‐rod dystrophy. The phenotype associated with homozygous p.Arg106Pro_POC1B may thus be highly variable, analogous to homozygous p.Leu710Ser in WDR19 causing either isolated retinitis pigmentosa or Jeune syndrome. Our study indicates that POC1B is required for retinal integrity, and we propose POC1B mutations as a probable cause for JBTS with severe PKD.     

Patterns of a Sylvatic Yellow Fever Virus Amplification in Southeastern Senegal, 2010

During the wet season of 2010, yellow fever virus (YFV) was detected in field-collected mosquitoes in the Kédougou region in southeastern Senegal. During this outbreak, we studied the association of the abundance of YFV-infected mosquitoes and land cover features to try and understand the dynamics of YFV transmission within the region. In total, 41,234 mosquito females were collected and tested for virus infection in 5,152 pools. YFV was detected in 67 pools; species including Aedes furcifer (52.2% of the infected pools), Ae. luteocephalus (31.3% of the infected pools), Ae. taylori (6.0% of the infected pools) and six other species (10.4% of the infected pools) captured in September (13.4%), October (70.1%), and November (16.4%). Spatially, YFV was detected from mosquitoes collected in all land cover classes but mainly, forest canopies (49.2%). Human infection is likely mediated by Ae. furcifer, the only species found infected with YFV within villages. Villages containing YFV-infected mosquitoes were significantly closer to large forests (> 2 ha) than villages in which no infected mosquitoes were detected.