A pilot study of rivastigmine in the treatment of delirium after stroke: A safe alternative

<p>Abstract</p> <p>Background</p> <p>Delirium is a common disorder in the early phase of stroke. Given the presumed cholinergic deficiency in delirium, we tested treatment with the acetylcholinesterase inhibitor rivastigmine.</p> <p>Methods</p> <p>This pilot study was performed within an epidemiological study. In 527 consecutive stroke patients presence of delirium was assessed during the first week with the confusion assessment method. Severity was scored with the delirium rating scale (DRS). Sixty-two patients developed a delirium in the acute phase of stroke. Only patients with a severe and persistent delirium (defined as a DRS of 12 or more for more than 24 hours) were enrolled in the present study. In total 26 fulfilled these criteria of whom 17 were treated with orally administered rivastigmine with a total dose between 3 and 12 mg a day. Eight patients could not be treated because of dysphagia and one because of early discharge.</p> <p>Results</p> <p>No major side effects were recorded. In 16 patients there was a considerable decrease in severity of delirium. The mean DRS declined from 14.8 on day one to 8.5 after therapy and 5.6 after tapering. The mean duration of delirium was 6.7 days (range; 2–17).</p> <p>Conclusion</p> <p>Rivastigmine is safe in stroke patients with delirium even after rapid titration. In the majority of patients the delirium improved after treatment. A randomized controlled trial is needed to establish the usefulness of rivastigmine in delirium after stroke.</p> <p>Trial registration</p> <p>Nederlands Trial Register NTR1395</p

Non-native hydrophobic interactions detected in unfolded apoflavodoxin by paramagnetic relaxation enhancement

Transient structures in unfolded proteins are important in elucidating the molecular details of initiation of protein folding. Recently, native and non-native secondary structure have been discovered in unfolded A. vinelandii flavodoxin. These structured elements transiently interact and subsequently form the ordered core of an off-pathway folding intermediate, which is extensively formed during folding of this α–β parallel protein. Here, site-directed spin-labelling and paramagnetic relaxation enhancement are used to investigate long-range interactions in unfolded apoflavodoxin. For this purpose, glutamine-48, which resides in a non-native α-helix of unfolded apoflavodoxin, is replaced by cysteine. This replacement enables covalent attachment of nitroxide spin-labels MTSL and CMTSL. Substitution of Gln-48 by Cys-48 destabilises native apoflavodoxin and reduces flexibility of the ordered regions in unfolded apoflavodoxin in 3.4 M GuHCl, because of increased hydrophobic interactions in the unfolded protein. Here, we report that in the study of the conformational and dynamic properties of unfolded proteins interpretation of spin-label data can be complicated. The covalently attached spin-label to Cys-48 (or Cys-69 of wild-type apoflavodoxin) perturbs the unfolded protein, because hydrophobic interactions occur between the label and hydrophobic patches of unfolded apoflavodoxin. Concomitant hydrophobic free energy changes of the unfolded protein (and possibly of the off-pathway intermediate) reduce the stability of native spin-labelled protein against unfolding. In addition, attachment of MTSL or CMTSL to Cys-48 induces the presence of distinct states in unfolded apoflavodoxin. Despite these difficulties, the spin-label data obtained here show that non-native contacts exist between transiently ordered structured elements in unfolded apoflavodoxin

Identification of alleles of carotenoid pathway genes important for zeaxanthin accumulation in potato tubers

We have investigated the genetics and molecular biology of orange flesh colour in potato (Solanum tuberosum L.). To this end the natural diversity in three genes of the carotenoid pathway was assessed by SNP analyses. Association analysis was performed between SNP haplotypes and flesh colour phenotypes in diploid and tetraploid potato genotypes. We observed that among eleven beta-carotene hydroxylase 2 (Chy2) alleles only one dominant allele has a major effect, changing white into yellow flesh colour. In contrast, none of the lycopene epsilon cyclase (Lcye) alleles seemed to have a large effect on flesh colour. Analysis of zeaxanthin epoxidase (Zep) alleles showed that all (diploid) genotypes with orange tuber flesh were homozygous for one specific Zep allele. This Zep allele showed a reduced level of expression. The complete genomic sequence of the recessive Zep allele, including the promoter, was determined, and compared with the sequence of other Zep alleles. The most striking difference was the presence of a non-LTR retrotransposon sequence in intron 1 of the recessive Zep allele, which was absent in all other Zep alleles investigated. We hypothesise that the presence of this large sequence in intron 1 caused the lower expression level, resulting in reduced Zep activity and accumulation of zeaxanthin. Only genotypes combining presence of the dominant Chy2 allele with homozygosity for the recessive Zep allele produced orange-fleshed tubers that accumulated large amounts of zeaxanthin

Antenatal treatment in two Dutch families with pyridoxine-dependent seizures

Contains fulltext : 88199.pdf (publisher's version ) (Closed access)Incidental reports suggest that antenatal treatment of pyridoxine dependent seizures (PDS) may improve neurodevelopmental outcome of affected patients. Two families with PDS are reported, both with two affected siblings. Antenatal treatment with pyridoxine was instituted during the second pregnancy in each family (50 and 60 mg daily from 3 and 10 weeks of gestation, respectively). Perinatal characteristics and neurodevelopmental outcome at 4 (Family A) and 12 (Family B) years of age were compared between the untreated and treated child within each family. Meconium-stained amniotic fluid was present in both first pregnancies and abnormal foetal movements were noticed in one. In the treated infants, pregnancy and birth were uncomplicated. In family A, postnatal pyridoxine supplementation prevented neonatal seizures. Both children in family A were hypotonic and started walking after 2 years of age; both had white matter changes on MRI, and the first child was treated for squint. IQ was 73 and 98 in the antenatally untreated and treated child, respectively. The second child in family B developed seizures on the seventh day, because pyridoxine maintenance therapy had not been instituted after birth. Seizures responded rapidly to pyridoxine supplementation. MRI showed large ventricles and a mega cisterna magna. IQ was 80 and 106 in the antenatally untreated and treated child respectively. Both children had normal motor development. These results suggest that antenatal pyridoxine supplementation may be effective in preventing intrauterine seizures, decreasing the risk of complicated birth and improving neurodevelopmental outcome in PDS.1 maart 201

Brain size regulations by cbp haploinsufficiency evaluated by in-vivo MRI based volumetry

The Rubinstein-Taybi Syndrome (RSTS) is a congenital disease that affects brain development causing severe cognitive deficits. In most cases the disease is associated with dominant mutations in the gene encoding the CREB binding protein (CBP). In this work, we present the first quantitative analysis of brain abnormalities in a mouse model of RSTS using magnetic resonance imaging (MRI) and two novel self-developed automated algorithms for image volumetric analysis. Our results quantitatively confirm key syndromic features observed in RSTS patients, such as reductions in brain size (-16.31%, p < 0.05), white matter volume (-16.00%, p < 0.05), and corpus callosum (-12.40%, p < 0.05). Furthermore, they provide new insight into the developmental origin of the disease. By comparing brain tissues in a region by region basis between cbp(+/-) and cbp(+/+) littermates, we found that cbp haploinsufficiency is specifically associated with significant reductions in prosencephalic tissue, such us in the olfactory bulb and neocortex, whereas regions evolved from the embryonic rhombencephalon were spared. Despite the large volume reductions, the proportion between gray-, white-matter and cerebrospinal fluid were conserved, suggesting a role of CBP in brain size regulation. The commonalities with holoprosencephaly and arhinencephaly conditions suggest the inclusion of RSTS in the family of neuronal migration disorders.We are grateful to Begona Fernandez for her excellent technical assistance. We would like to thank S. Sawiak (Wolfson Imaging Centre, University of Cambridge, Cambridge, United Kingdom) for the mouse brain tissue probability maps and the SPMmouse plug-in, and to N. Kovacevic (Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada) for the atlas of the mouse brain. Supported by grants from the Spanish MINECO to S.C. (BFU 2012-39958) and MINECO and FEDER to D.M. (TEC 2012-33778) and from MINECO (SAF2011-22855) and Generalitat Valenciana (Prometeo/2012/005) to A.B. The Instituto de Neurociencias is "Centre of Excellence Severo Ochoa".Ateca Cabarga, JC.; Cosa, A.; Pallares, V.; Lopez-Atalaya, JP.; Barco, A.; Canals, S.; Moratal Pérez, D. (2015). Brain size regulations by cbp haploinsufficiency evaluated by in-vivo MRI based volumetry. Scientific Reports. 5. https://doi.org/10.1038/srep16256S5Rubinstein, J. H. & Taybi, H. Broad thumbs and toes and facial abnormalities. A possible mental retardation syndrome. Am J Dis Child 105, 588–608 (1963).Van Belzen, M., Bartsch, O., Lacombe, D., Peters, D. J. & Hennekam, R. C. Rubinstein-Taybi syndrome (CREBBP, EP300). Eur J Hum Genet. 19, preceeding 118–120 (2011).Hennekam, R. C. Rubinstein-Taybi syndrome. Eur J Hum Genet. 14, 981–985 (2006).Wiley, S., Swayne, S., Rubinstein, J. H., Lanphear, N. E. & Stevens, C. A. Rubinstein-Taybi syndrome medical guidelines. Am J Med Genet A. 119A, 101–110 (2003).Michail, J., Matsoukas, J. & Theodorou, S. Pouce bot arqué en forte abduction-extension et autres symptomes concomitants. Rev Chir Orthop 43, 142–146 (1957).Barco A. The Rubinstein-Taybi syndrome: modeling mental impairment in the mouse. Genes Brain Behav 6, 32–39 (2007).Lopez-Atalaya, J. P., Valor, L. M. & Barco, A. Epigenetic factors in intellectual disability: the Rubinstein-Taybi syndrome as a paradigm of neurodevelopmental disorder with epigenetic origin. Prog Mol Biol Transl Sci. 128, 139–176 (2014).Petrij, F., Giles, R. H., Dauwerse, H. G., Saris, J. J., Hennekam, R. C. M., Masuno, M., Tommerup, N., Van Ommen, G. J. B., Goodman, R. H., Peters, D. J. M. & Breuning, M. H. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. 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Phenotypic expansion of the interstitial 16p13.3 duplication: a case report and review of the literature. Gene. 531, 502–505 (2013).Demeer, B. et al. Duplication 16p13.3 and the CREBBP gene: confirmation of the phenotype. Eur J Med Genet. 56, 26–31 (2013).Kumar, S., Suthar, R., Panigrahi, I. & Marwaha, R. K. Rubinstein-Taybi syndrome: Clinical profile of 11 patients and review of literature. Indian J Hum Genet. 18, 161–166 (2012).Giussani, C. et al. The association of neural axis and craniovertebral junction anomalies with scoliosis in Rubinstein-Taybi syndrome. Childs Nerv Syst. 28, 2163–2168 (2012).Parsley, L., Bellus, G., Handler, M. & Tsai, A. C. Identical twin sisters with Rubinstein-Taybi syndrome associated with Chiari malformations and syrinx. Am J Med Genet A. 155A, 2766–2770 (2011).Thienpont, B. et al. Duplications of the critical Rubinstein-Taybi deletion region on chromosome 16p13.3 cause a novel recognisable syndrome. J Med Genet. 47, 155–161 (2010).Kim, S. H., Lim, B. C., Chae, J. H., Kim, K. J. & Hwang, Y. S. A case of Rubinstein-Taybi Syndrome with a CREB-binding protein gene mutation. Korean J Pediatr. 53, 718–721 (2010).Wójcik, C. et al. Rubinstein-Taybi syndrome associated with Chiari type I malformation caused by a large 16p13.3 microdeletion: a contiguous gene syndrome? Am J Med Genet A. 152A, 479–483 (2010).Wachter-Giner, T., Bieber, I., Warmuth-Metz, M., Bröcker, E. B. & Hamm, H. Multiple pilomatricomas and gliomatosis cerebri--a new association? Pediatr Dermatol. 26, 75–78 (2009).Verstegen, M. J., van den Munckhof, P., Troost, D. & Bouma, G. J. Multiple meningiomas in a patient with Rubinstein-Taybi syndrome. Case report. J Neurosurg. 102, 167–168 (2005).Agarwal, R., Aggarwal, R., Kabra, M. & Deorari, A. K. Dandy-Walker malformation in Rubinstein-Taybi syndrome: a rare association. Clin Dysmorphol. 11, 223–224 (2002).Ihara, K., Kuromaru, R., Takemoto, M. & Hara, T. Rubinstein-Taybi syndrome: a girl with a history of neuroblastoma and premature thelarche. Am J Med Genet. 83, 365–366 (1999).Sener, R. N. Rubinstein-Taybi syndrome: cranial MR imaging findings. Comput Med Imaging Graph 19, 417–418 (1995).Robinson, T. W., Stewart, D. L. & Hersh, J. H. Monozygotic twins concordant for Rubinstein-Taybi syndrome and implications for genetic counseling. Am J Med Genet. 45, 671–673 (1993).Guion-Almeida, M. L. & Richieri-Costa, A. Callosal agenesis, iris coloboma and megacolon in a Brazilian boy with Rubinstein-Taybi syndrome. Am J Med Genet. 43, 929–931 (1992).Albanese, A. et al. [Role of diagnostic imaging in Rubinstein-Taybi syndrome. personal experience with 8 cases]. Radiol Med. 81, 253–261 (1991).Rubinstein, J. H. Broad thumb-hallux (Rubinstein-Taybi) syndrome 1957-1988. Am J Med Genet Suppl. 6, 3–16 (1990).Hennekam, R. C., Stevens, C. A. & Van de Kamp, J. J. Etiology and recurrence risk in Rubinstein-Taybi syndrome. Am J Med Genet Suppl. 6, 56–64 (1990).Bonioli, E., Bellini, C. & Di Stefano, A. Unusual association: Dandy-Walker-like malformation in the Rubinstein-Taybi syndrome. Am J Med Genet. 33, 420–421 (1989).Beluffi, G., Pazzaglia, U. E., Fiori, P., Pricca, P. & Poznanski, A. K. [Oto-palato-digital syndrome. Clinico-radiological study]. Radiol Med. 74, 176–184 (1987).Cantani, A. & Gagliesi, D. Rubinstein-Taybi syndrome. Review of 732 cases and analysis of the typical traits. Eur Rev Med Pharmacol Sci. 2, 81–87 (1998).Viosca, J., Lopez-Atalaya, J. P., Olivares, R., Eckner, R. & Barco, A. Syndromic features and mild cognitive impairment in mice with genetic reduction on p300 activity: Differential contribution of p300 and CBP to Rubinstein-Taybi syndrome etiology. Neurobiol Dis. 37, 186–194 (2010).Martínez-Martínez, M. A., Pacheco-Torres, J., Borrell, V. & Canals, S. Phenotyping the central nervous system of the embryonic mouse by magnetic resonance microscopy. Neuroimage. 97, 95–106 (2014).Heikkinen, T. et al. Characterization of neurophysiological and behavioral changes, MRI brain volumetry and 1H MRS in zQ175 knock-in mouse model of Huntington’s disease. PLoS One. 7, e50717 (2012), 10.1371/journal.pone.0050717.Alarcón, J. M. et al. Chromatin acetylation, memory and LTP are impaired in CBP+/− mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron. 42, 947–959 (2004).Smith, S. M. et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23 Supp 1, S208–19 (2004).Smith, S. M. Fast robust automated brain extraction. Hum Brain Mapp 17, 143–155 (2002).Ashburner, J. & Friston, K. J. Unified segmentation. Neuroimage 26, 839–851 (2005).Sawiak, S. J., Wood, N. I., Williams, G. B., Morton, A. J. & Carpenter, T. A. Voxel-based morphometry in the R6/2 transgenic mouse reveals differences between genotypes not seen with manual 2D morphometry. 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The importance of the altricial – precocial spectrum for social complexity in mammals and birds:A review

Various types of long-term stable relationships that individuals uphold, including cooperation and competition between group members, define social complexity in vertebrates. Numerous life history, physiological and cognitive traits have been shown to affect, or to be affected by, such social relationships. As such, differences in developmental modes, i.e. the ‘altricial-precocial’ spectrum, may play an important role in understanding the interspecific variation in occurrence of social interactions, but to what extent this is the case is unclear because the role of the developmental mode has not been studied directly in across-species studies of sociality. In other words, although there are studies on the effects of developmental mode on brain size, on the effects of brain size on cognition, and on the effects of cognition on social complexity, there are no studies directly investigating the link between developmental mode and social complexity. This is surprising because developmental differences play a significant role in the evolution of, for example, brain size, which is in turn considered an essential building block with respect to social complexity. Here, we compiled an overview of studies on various aspects of the complexity of social systems in altricial and precocial mammals and birds. Although systematic studies are scarce and do not allow for a quantitative comparison, we show that several forms of social relationships and cognitive abilities occur in species along the entire developmental spectrum. Based on the existing evidence it seems that differences in developmental modes play a minor role in whether or not individuals or species are able to meet the cognitive capabilities and requirements for maintaining complex social relationships. Given the scarcity of comparative studies and potential subtle differences, however, we suggest that future studies should consider developmental differences to determine whether our finding is general or whether some of the vast variation in social complexity across species can be explained by developmental mode. This would allow a more detailed assessment of the relative importance of developmental mode in the evolution of vertebrate social systems

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries