Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations

Background: Heterozygous mutations in OPA1 are a common cause of autosomal dominant optic atrophy, sometimes associated with extra-ocular manifestations. Few cases harboring compound heterozygous OPA1 mutations have been described manifesting complex neurodegenerative disorders in addition to optic atrophy. Results: We report here three patients: one boy showing an early-onset mitochondrial disorder with hypotonia, ataxia and neuropathy that was severely progressive, leading to early death because of multiorgan failure; two unrelated sporadic girls manifesting a spastic ataxic syndrome associated with peripheral neuropathy and, only in one, optic atrophy. Using a targeted resequencing of 132 genes associated with mitochondrial disorders, in two probands we found compound heterozygous mutations in OPA1: in the first a 5 nucleotide deletion, causing a frameshift and insertion of a premature stop codon (p.Ser64Asnfs*7), and a missense change (p.Ile437Met), which has recently been reported to have clinical impact; in the second, a novel missense change (p.Val988Phe) co-occurred with the p.Ile437Met substitution. In the third patient a homozygous mutation, c.1180G > A (p.Ala394Thr) in OPA1 was detected by a trio-based whole exome sequencing approach. One of the patients presented also variants in mitochondrial DNA that may have contributed to the peculiar phenotype. The deleterious effect of the identified missense changes was experimentally validated in yeast model. OPA1 level was reduced in available patients\u2019 biological samples, and a clearly fragmented mitochondrial network was observed in patients\u2019 fibroblasts. Conclusions: This report provides evidence that bi-allelic OPA1 mutations may lead to complex and severe multi-system recessive mitochondrial disorders, where optic atrophy might not represent the main feature

Antamanide, a Derivative of Amanita phalloides, Is a Novel Inhibitor of the Mitochondrial Permeability Transition Pore

Antamanide is a cyclic decapeptide derived from the fungus Amanita phalloides. Here we show that antamanide inhibits the mitochondrial permeability transition pore, a central effector of cell death induction, by targeting the pore regulator cyclophilin D. Indeed, (i) permeability transition pore inhibition by antamanide is not additive with the cyclophilin D-binding drug cyclosporin A, (ii) the inhibitory action of antamanide on the pore requires phosphate, as previously shown for cyclosporin A; (iii) antamanide is ineffective in mitochondria or cells derived from cyclophilin D null animals, and (iv) abolishes CyP-D peptidyl-prolyl cis-trans isomerase activity. Permeability transition pore inhibition by antamanide needs two critical residues in the peptide ring, Phe6 and Phe9, and is additive with ubiquinone 0, which acts on the pore in a cyclophilin D-independent fashion. Antamanide also abrogates mitochondrial depolarization and the ensuing cell death caused by two well-characterized pore inducers, clotrimazole and a hexokinase II N-terminal peptide. Our findings have implications for the comprehension of cyclophilin D activity on the permeability transition pore and for the development of novel pore-targeting drugs exploitable as cell death inhibitors

Global Perspectives on Task Shifting and Task Sharing in Neurosurgery.

BACKGROUND: Neurosurgical task shifting and task sharing (TS/S), delegating clinical care to non-neurosurgeons, is ongoing in many hospital systems in which neurosurgeons are scarce. Although TS/S can increase access to treatment, it remains highly controversial. This survey investigated perceptions of neurosurgical TS/S to elucidate whether it is a permissible temporary solution to the global workforce deficit. METHODS: The survey was distributed to a convenience sample of individuals providing neurosurgical care. A digital survey link was distributed through electronic mailing lists of continental neurosurgical societies and various collectives, conference announcements, and social media platforms (July 2018-January 2019). Data were analyzed by descriptive statistics and univariate regression of Likert Scale scores. RESULTS: Survey respondents represented 105 of 194 World Health Organization member countries (54.1%; 391 respondents, 162 from high-income countries and 229 from low- and middle-income countries [LMICs]). The most agreed on statement was that task sharing is preferred to task shifting. There was broad consensus that both task shifting and task sharing should require competency-based evaluation, standardized training endorsed by governing organizations, and maintenance of certification. When perspectives were stratified by income class, LMICs were significantly more likely to agree that task shifting is professionally disruptive to traditional training, task sharing should be a priority where human resources are scarce, and to call for additional TS/S regulation, such as certification and formal consultation with a neurosurgeon (in person or electronic/telemedicine). CONCLUSIONS: Both LMIC and high-income countries agreed that task sharing should be prioritized over task shifting and that additional recommendations and regulations could enhance care. These data invite future discussions on policy and training programs

Cloning and endogenous expression of a Eucalyptus grandis UDP-glucose dehydrogenase cDNA

UDP-glucose dehydrogenase (UGDH) catalyzes the oxidation of UDP-glucose (UDP-Glc) to UDP-glucuronate (UDP-GlcA), a key sugar nucleotide involved in the biosynthesis of plant cell wall polysaccharides. A full-length cDNA fragment coding for UGDH was cloned from the cambial region of 6-month-old E. grandis saplings by RT-PCR. The 1443-bp-ORF encodes a protein of 480 amino acids with a predicted molecular weight of 53 kDa. The recombinant protein expressed in Escherichia coli catalyzed the conversion of UDP-Glc to UDP-GlcA, confirming that the cloned cDNA encodes UGDH. The deduced amino acid sequence of the cDNA showed a high degree of identity with UGDH from several plant species. The Southern blot assay indicated that more than one copy of UGDH is present in Eucalyptus. These results were also confirmed by the proteomic analysis of the cambial region of 3- and 22-year-old E. grandis trees by 2-DE and LC-MS/MS, showing that at least two isoforms are present. The cloned gene is mainly expressed in roots, stem and bark of 6-month-old saplings, with a lower expression in leaves. High expression levels were also observed in the cambial region of 3- and 22-year-old trees. The results described in this paper provide a further view of the hemicellulose biosynthesis during wood formation in E. grandis

Distribution patterns of blue whale (Balaenoptera musculus) and shipping off southern Sri Lanka

Surveys were conducted off the southern coast of Sri Lanka in 2014 and 2015 to investigate the distribution patterns of blue whales (Balaenoptera musculus spp.) in relation to current shipping lanes, and further offshore. There have been several reported ship strikes of blue whales in this area and the IWC Scientific Committee has recognised the potential for ship strikes to have population level impacts on blue whales in the northern Indian Ocean. A total of 3268km of visual survey effort was conducted on 35 survey days along north-south transects between 5°28'N and 5°53'N. These data were used to model patterns of whale density. The highest densities of blue whales were observed in the current shipping lanes, peaking at an average of 0.1 individuals km-2 along the westbound shipping lane. Automatic Identification System transmissions received by satellite were used to estimate shipping density. Between 80°30'E and 81°E, the peak mean shipping density in the westbound lane of the Traffic Separation Scheme was 1090km-1 year-1 and in the eastbound lane 810km-1 year-1. These high densities of whales combined with one of the busiest shipping routes in the world suggest a severe risk of ship strikes. Previous data on blue whale distribution and coastal upwellings indicate consistent and predictable patterns of whale distribution, suggesting there is considerable potential for effective measures to keep ships and whales apart. For example, data from this study would suggest risk could be reduced by 95% if shipping were to transit 15 nm further south than currently

Distribution patterns of blue whale (Balaenoptera musculus) and shipping off southern Sri Lanka

Surveys were conducted off the southern coast of Sri Lanka in 2014 and 2015 to investigate the distribution patterns of blue whales (Balaenoptera musculus spp.) in relation to current shipping lanes, and further offshore. There have been several reported ship strikes of blue whales in this area and the IWC Scientific Committee has recognised the potential for ship strikes to have population level impacts on blue whales in the northern Indian Ocean. A total of 3268km of visual survey effort was conducted on 35 survey days along north-south transects between 5°28'N and 5°53'N. These data were used to model patterns of whale density. The highest densities of blue whales were observed in the current shipping lanes, peaking at an average of 0.1 individuals km-2 along the westbound shipping lane. Automatic Identification System transmissions received by satellite were used to estimate shipping density. Between 80°30'E and 81°E, the peak mean shipping density in the westbound lane of the Traffic Separation Scheme was 1090km-1 year-1 and in the eastbound lane 810km-1 year-1. These high densities of whales combined with one of the busiest shipping routes in the world suggest a severe risk of ship strikes. Previous data on blue whale distribution and coastal upwellings indicate consistent and predictable patterns of whale distribution, suggesting there is considerable potential for effective measures to keep ships and whales apart. For example, data from this study would suggest risk could be reduced by 95% if shipping were to transit 15 nm further south than currently