Treatment of the CRND8 mouse model for cerebral amyloid angiopathy, exhibited increased levels of neuron specific enolase in brain tissue following long-term treatment with a modified C5a receptor agonist, accompanied by improved cognitive function.

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder characterized by amyloid plaques, neurofibrillary tangles, and cerebral amyloid angiopathy (CAA). CAA is a condition manifesting as amyloid deposits in the cerebral vasculature, eventually leading to microhemorrhage. Here, we have treated the CRND8 mouse model with the C5a agonist (EP67) in order to observe the effects on cerebral amyloidosis, CAA, and hyperphosphorylated tau. EP67 attaches to the C5a receptor on phagocytes and stimulates the engulfment and digestion of fibrillar and prefibrillar amyloid while exhibiting minimal inflammation. Older CRND8 mice and their respective controls were treated with EP67 for a prolonged period of time. Following treatment, the CRND8 mice displayed improved spatial memory, while both amyloid deposition and tau hyperphosphorylation were found to be diminished.

Preliminary In Vitro and In Vivo Insights of In Silico Candidate Repurposed Drugs for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and is the most common type of dementia. Although a considerably large amount of money has been invested in drug development for AD, no disease modifying treatment has been detected so far. In our previous work, we developed a computational method to highlight stage-specific candidate repurposed drugs against AD. In this study, we tested the effect of the top 13 candidate repurposed drugs that we proposed in our previous work in a severity stage-specific manner using an in vitro BACE1 assay and the effect of a top-ranked drug from the list of our previous work, tetrabenazine (TBZ), in the 5XFAD as an AD mouse model. From our in vitro screening, we detected 2 compounds (clomiphene citrate and Pik-90) that showed statistically significant inhibition against the activity of the BACE1 enzyme. The administration of TBZ at the selected dose and therapeutic regimen in 5XFAD in male and female mice showed no significant effect in behavioral tests using the Y-maze and the ELISA immunoassay of Aß40. To our knowledge, this is the first time the drug tetrabenazine has been tested in the 5XFAD mouse model of AD in a sex-stratified manner. Our results highlight 2 drugs (clomiphene citrate and Pik-90) from our previous computational work for further investigation.

Pharmacological activation of the C5a receptor leads to stimulation of the ß-adrenergic receptor and alleviates cognitive impairment in a murine model of familial Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease of the brain causing either familial or sporadic dementia. We have previously administered the modified C5a receptor agonist (EP67) for a short period to a transgenic mouse model of AD (5XFAD) and have observed not only reduction in ß-amyloid deposition and gliosis but also improvement in cognitive impairment. Inquiring, however, on the effects of EP67 in an already heavily burdened animal, thus representing a more realistic scenario, we treated 6-month-old 5XFAD mice for a period of 14 weeks. We recorded a significant decrease in both fibrillar and pre-fibrillar ß-amyloid as well as remarkable amelioration of cognitive impairment. Following proteomic analysis and pathway association, we postulate that these events are triggered through the upregulation of ß-adrenergic and GABAergic signaling. In summary, our results reveal how inflammatory responses can be employed in inducing tangible phenotype improvements even in advanced stages of AD.

Nurses' attitudes and knowledge regarding patient rights: a systematic review.

OBJECTIVE: To synthesize current evidence on nurses' attitudes and/or knowledge on the entire spectrum of patient rights. METHOD: A systematic search of the literature was performed in Web of Science, PubMed, Scopus and CINAHL. Studies were selected according to pre-defined inclusion/exclusion criteria. The Cochrane and PRISMA guidelines, including templates for systematic reviews, were applied. For rigor assessment, the Critical Appraisal Skills Program Qualitative Research Checklist, and the Center for Evidence-Based Management tool were employed. RESULTS: Thirteen studies were included, that exhibited important methodological limitations, such as convenience sampling, mediocre response rates and inadequate instrument validity. Findings indicated: a) low level of awareness regarding patient rights among nurses, b) knowledge discrepancies on specific aspects of patient rights, c) low priority ascribed to a patient's right to access information, and d) insufficient evidence on formal educational sources of knowledge on the topic of patient rights. CONCLUSION: Narrow geographical localization, heterogeneity and methodological limitations render generalizability of the conclusions difficult. Further research based on robust methodology is proposed.

Nurses attitudes and knowledge regarding patient rights: a systematic review / Atitudes e conhecimentos dos enfermeiros em relação aos direitos do paciente: uma revisão sistemática / Actitudes y conocimientos de las enfermeras sobre los derechos de los pacientes: una revisión sistemática

ABSTRACT Objective: To synthesize current evidence on nurses' attitudes and/or knowledge on the entire spectrum of patient rights. Method: A systematic search of the literature was performed in Web of Science, PubMed, Scopus and CINAHL. Studies were selected according to pre-defined inclusion/exclusion criteria. The Cochrane and PRISMA guidelines, including templates for systematic reviews, were applied. For rigor assessment, the Critical Appraisal Skills Program Qualitative Research Checklist, and the Center for Evidence-Based Management tool were employed. Results: Thirteen studies were included, that exhibited important methodological limitations, such as convenience sampling, mediocre response rates and inadequate instrument validity. Findings indicated: a) low level of awareness regarding patient rights among nurses, b) knowledge discrepancies on specific aspects of patient rights, c) low priority ascribed to a patient's right to access information, and d) insufficient evidence on formal educational sources of knowledge on the topic of patient rights. Conclusion: Narrow geographical localization, heterogeneity and methodological limitations render generalizability of the conclusions difficult. Further research based on robust methodology is proposed.

RESUMO Objetivo: Sintetizar as evidências atuais sobre as atitudes e/ou conhecimentos dos enfermeiros sobre todo o espectro dos direitos do paciente. Método: Uma busca sistemática da literatura foi realizada na Web of Science, PubMed, Scopus e CINAHL. Os estudos foram selecionados de acordo com critérios de inclusão/exclusão pré-definidos. As diretrizes Cochrane e PRISMA, incluindo modelos para revisões sistemáticas, foram aplicadas. Para uma avaliação rigorosa, foram utilizados o Critical Appraisal Skills Program Qualitative Research Checklist e a ferramenta do Center for Evidence-Based Management. Resultados: Foram incluídos 13 estudos que exibiram limitações metodológicas importantes, como amostragem por conveniência, taxas de resposta medíocres e validade inadequada do instrumento. Os resultados indicaram: a) baixo nível de consciência sobre os direitos do paciente entre os enfermeiros, b) discrepâncias de conhecimento sobre aspectos específicos dos direitos do paciente, c) baixa prioridade atribuída ao direito do paciente de acessar informações, e d) evidências insuficientes sobre fontes de conhecimento educacionais formais sobre o tema dos direitos do paciente. Conclusão: A localização geográfica estreita, a heterogeneidade e as limitações metodológicas dificultam a generalização das conclusões. Outras pesquisas baseadas em metodologia robusta são propostas.

RESUMEN Objetivo: Sintetizar la evidencia actual sobre las actitudes y/o conocimientos de las enfermeras sobre todo el espectro de los derechos del paciente. Método: Se realizó una búsqueda sistemática de la literatura en Web of Science, PubMed, Scopus y CINAHL. Los estudios se seleccionaron de acuerdo con criterios de inclusión/exclusión predefinidos. Se aplicaron las guías Cochrane y PRISMA, incluidas las plantillas para revisiones sistemáticas. Para una evaluación más rigurosa, se emplearon el Critical Appraisal Skills Program Qualitative Research Checklist y la herramienta del Center for Evidence-Based Management. Resultados: Se incluyeron trece estudios, que exhibieron importantes limitaciones metodológicas, como muestreo por conveniencia, tasas de respuesta mediocres y validez inadecuada del instrumento. Los hallazgos indicaron: a) bajo nivel de conciencia sobre los derechos del paciente entre las enfermeras, b) discrepancias de conocimiento sobre aspectos específicos de los derechos del paciente, c) baja prioridad atribuida al derecho del paciente a acceder a la información, y d) evidencia insuficiente sobre fuentes formales de conocimiento educativo sobre el tema de los derechos del paciente. Conclusión: La estrecha localización geográfica, la heterogeneidad y las limitaciones metodológicas dificultan la generalización de las conclusiones. Se propone más investigación basada en una metodología robusta.

The frequency of central nervous system complications in the Cypriot cohort of ATTRV30M neuropathy transplanted patients.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTR) is a hereditary, sensorimotor and autonomic neuropathy caused by deposits of mutated transthyretin (TTR). The commonest TTR mutation is V30M (ATTRV30M) with patients usually living for about 10 years after disease onset. Liver transplantation (LT) until recently was considered the standard treatment. OBJECTIVE AND METHODS: This study aims to assess the frequency of CNS complications in post-LT patients from the Cypriot cohort. Epidemiological data were collected for all genetically confirmed ATTRV30M neuropathy patients diagnosed at CING since 1992, and CNS-associated symptoms were assessed and evaluated by two neurology specialists. RESULTS: Out of the 48 transplanted patients, 10 (20.8%) presented with a CNS complication. All patients had ocular involvement, mainly glaucoma (7/10). Eight presented with transient focal neurological episodes (TFNEs), with expressive dysphasia being reported by four of them. The mean time of TFNE-emergence was 16.6 years after the LT. Three died from cerebral hemorrhage. CONCLUSIONS: CNS complications in post-LT ATTRV30M patients are not rare and usually manifest themselves at a time that surpasses the mean time the patients would have survived without a LT. CNS involvement is associated with increased mortality, due to cerebral hemorrhage.

C5aR agonist enhances phagocytosis of fibrillar and non-fibrillar Aß amyloid and preserves memory in a mouse model of familial Alzheimer's disease.

According to the amyloid hypothesis of Alzheimer's disease (AD) the deposition of prefibrillar and fibrillar Aß peptide sets off the pathogenic cascades of neuroinflammation and neurodegeneration that lead to synaptic and neuronal loss resulting in cognitive decline. Various approaches to reduce amyloid load by reducing production of the Aß peptide or enhancing amyloid clearance by primary or secondary immunization have not proven successful in clinical trials. Interfering with the normal function of secretases and suboptimal timing of Aß peptide removal have been put forward as possible explanations. Complement, an innate component of the immune system, has been found to modulate disease pathology and in particular neuronal loss in the AD mouse model but its mechanism of action is complex. C1Q has been shown to facilitate phagocytosis of Aß peptide but its Ablation attenuates neuroinflammation. Experiments in AD mouse models show that inhibition of complement component C5a reduces amyloid deposition and alleviates neuroinflammation. Phagocytes including microglia, monocytes and neutrophils carry C5a receptors. Here, a widely used mouse model of AD, 5XFAD, was intermittently treated with the oral C5a receptor agonist EP67 and several neuronal and neuroinflammatory markers as well as memory function were assessed. EP67 treatment enhanced phagocytosis, resulting in a significant reduction of both fibrillar and non-fibrillar Aß, reduced astrocytosis and preserved synaptic and neuronal markers as well as memory function. Timely and phasic recruitment of the innate immune system offers a new therapeutic avenue of treating pre-symptomatic Alzheimer disease.

A novel case of inclusion body myositis and myasthenia gravis.

The co-existence of myasthenia gravis and other inflammatory myopathies has been reported in the literature before, but no clinical cases involving inclusion body myositis have been reported. We report a case of a 67-year-old patient who presented with dysphagia, exhibiting the typical electrophysiological features of postsynaptic neuromuscular junction defect with positive muscle acetylcholine receptor antibodies, consistent with the diagnosis of myasthenia gravis. Nevertheless, response to acetylcholinesterase inhibitors and immunomodulatory treatment was unexpectedly poor. As the disease progressed, the patient developed asymmetric muscle weakness, initially affecting mainly the quadriceps and the finger flexors. Muscle MRI imaging supported the presence of an inflammatory myopathy and muscle biopsy confirmed the diagnosis of inclusion body myositis. Thus, our patient represents the first reported overlap case of myasthenia gravis and inclusion body myositis.

Gene variants of adhesion molecules predispose to MS: A case-control study.

OBJECTIVE: To examine the effect of variants in genes encoding molecules that are implicated in leukocyte trafficking into the CNS on the development of MS. METHODS: A total of 389 Greek MS cases and 336 controls were recruited by 3 MS centers in Cyprus and Greece. In total, 147 tagging single nucleotide polymorphisms across 9 genes encoding for P-selectin (SELP), integrins (ITGA4, ITGB1, and ITGB7), adhesion molecules (ICAM1, VCAM1, and MADCAM1), fibronectin 1 (FN1), and osteopontin (SPP1) were genotyped. The clinical end point of the study was diagnosis of MS according to the 2005 revised McDonald criteria. Permutation analysis was used for adjusting for multiple comparisons. RESULTS: Overall, 21 variants across SELP, ITGA4, ITGB1, ICAM1, VCAM1, MADCAM1, FN1, and SSP1 genes were each associated with MS (p perm < 0.05). The most significant were rs3917779 and rs2076074 (SELP), rs6721763 (ITGA4), and rs1250258 (FN1), all with a permutation p value of less than 1e-004. CONCLUSIONS: The current study provides preliminary evidence that variants across genes encoding adhesion molecules, responsible for lymphocyte adhesion and trafficking within the CNS, are implicated in the risk of developing MS.

Epidemiology of ATTRV30M neuropathy in Cyprus and the modifier effect of complement C1q on the age of disease onset.

BACKGROUND: ATTRV30M amyloidosis is a lethal autosomal dominant sensorimotor and autonomic neuropathy caused by amyloid deposition composed of aggregated misfolded TTR monomers with the V30M mutation. The age of onset in patients with ATTRV30M varies in different foci and the mechanism behind it is still unknown. METHODS: The tertiary neurology center following all ATTRV30M patients in Cyprus was used to collect demographic data to estimate; prevalence, incidence, penetrance, anticipation, time from disease onset to diagnosis and transplantation. Ocular, cardiac and leptomeningeal involvement in transplanted patients was explored. Correlation of C1q tagging SNPs with age of disease onset was carried out. RESULTS: Prevalence and incidence for ATTRV30M neuropathy in Cyprus are 5.4/100,000 and 0.3/100,000 respectively. Mean age of onset is 40.6 years and anticipation is 8.3 years. Penetrance reaches 51% and 75% by the ages of 50 and 80 years respectively. In liver transplanted patients rates of ocular, cardiac and leptomeningeal involvement were estimated to be 60%, 20% and 16%, respectively. C1q polymorphisms correlated with age of disease onset. CONCLUSIONS: ATTRV30M neuropathy has a rising prevalence in Cyprus due to improved survival of patients. Late onset complications are becoming a major problem. Complement C1q appears to be a modifier in this disease.

Sequential Role of SOXB2 Factors in GABAergic Neuron Specification of the Dorsal Midbrain.

Studies proposed a model for embryonic neurogenesis where the expression levels of the SOXB2 and SOXB1 factors regulate the differentiation status of the neural stem cells. However, the precise role of the SOXB2 genes remains controversial. Therefore, this study aims to investigate the effects of individual deletions of the SOX21 and SOX14 genes during the development of the dorsal midbrain. We show that SOX21 and SOX14 function distinctly during the commitment of the GABAergic lineage. More explicitly, deletion of SOX21 reduced the expression of the GABAergic precursor marker GATA3 and BHLHB5 while the expression of GAD6, which marks GABAergic terminal differentiation, was not affected. In contrast deletion of SOX14 alone was sufficient to inhibit terminal differentiation of the dorsal midbrain GABAergic neurons. Furthermore, we demonstrate through gain-of-function experiments, that despite the homology of SOX21 and SOX14, they have unique gene targets and cannot compensate for the loss of each other. Taken together, these data do not support a pan-neurogenic function for SOXB2 genes in the dorsal midbrain, but instead they influence, sequentially, the specification of GABAergic neurons.

Gene variants of adhesion molecules act as modifiers of disease severity in MS.

OBJECTIVE: To assess the potential effect of variants in genes encoding molecules that are implicated in leukocyte trafficking into the CNS on the clinical phenotype of multiple sclerosis (MS). METHODS: A total of 389 Greek MS cases and 336 controls were recruited in 3 MS centers from Cyprus and Greece. We genotyped 147 tagging single nucleotide polymorphisms (SNPs) in 9 genes encoding for P-selectin (SELP), integrins (ITGA4, ITGB1, and ITGB7), adhesion molecules (ICAM1, VCAM1, and MADCAM1), fibronectin 1 (FN1), and osteopontin (SPP1) involved in lymphocyte adhesion and trafficking into the CNS. Clinical end points of the study were age at MS onset and MS severity as measured by the Multiple Sclerosis Severity Score. Permutation testing was applied to all analyses. RESULTS: SNPs rs6721763 of the ITGA4 and rs6532040 of the SPP1 were found to significantly influence disease severity (permutation p values: 3.00e-06 and 0.009884, respectively). SNP rs1250249 of the FN1 had a dose-dependent effect on age at disease onset (permutation p value: 0.0002). CONCLUSIONS: This study provides evidence implicating variants encoding adhesion molecules, responsible for lymphocyte adhesion and trafficking within the CNS, as modifiers of MS disease severity. These genetic biomarkers, which can be available at the time of diagnosis, may be used to assess the biological aggressiveness of the disease and thus guide decisions on treatment.

Pharmacological Stimulation of Phagocytosis Enhances Amyloid Plaque Clearance; Evidence from a Transgenic Mouse Model of ATTR Neuropathy.

Hereditary ATTR V30M amyloidosis is a lethal autosomal dominant sensorimotor and autonomic neuropathy caused by deposition of aberrant transthyretin (TTR). Immunohistochemical examination of sural nerve biopsies in patients with amyloidotic neuropathy show co-aggregation of TTR with several proteins; including apolipoprotein E, serum amyloid P and components of the complement cascade. Complement activation and macrophages are increasingly recognized to play a crucial role in amyloidogenesis at the tissue bed level. In the current study we test the effect of two C5a receptor agonists and a C5a receptor antagonist (PMX53) on disease phenotype in ATTR V30M mice. Our results indicate that amyloid deposition was significantly reduced following treatment with the C5a receptor agonists, while treatment with the antagonist resulted in a significant increase of amyloid load. Administration of the C5a receptor agonists triggered increased recruitment of phagocytic cells resulting in clearance of amyloid deposits.

C1q ablation exacerbates amyloid deposition: A study in a transgenic mouse model of ATTRV30M amyloid neuropathy.

ATTRV30M amyloid neuropathy is a lethal autosomal dominant sensorimotor and autonomic neuropathy, caused by deposition of amyloid fibrils composed of aberrant transthyretin (TTR). Ages of onset and penetrance exhibit great variability and genetic factors have been implicated. Complement activation co-localizes with amyloid deposits in amyloidotic neuropathy and is possibly involved in the kinetics of amyloidogenesis. A candidate gene approach has recently identified C1q polymorphisms to correlate with disease onset in a Cypriot cohort of patients with ATTRV30M amyloid neuropathy. In the current study we use a double transgenic mouse model of ATTRV30M amyloid neuropathy in which C1q is ablated to elucidate further a possible modifier role for C1q. Amyloid deposition is found to be increased by 60% in the absence of C1q. Significant up regulation is also recorded in apoptotic and cellular stress markers reflecting extracellular toxicity of pre-fibrillar and fibrillar TTR. Our data further indicate that in the absence of C1q there is marked reduction of macrophages in association with amyloid deposits and thus less effective phagocytosis of TTR.

Vsx1 Transiently Defines an Early Intermediate V2 Interneuron Precursor Compartment in the Mouse Developing Spinal Cord.

Spinal ventral interneurons regulate the activity of motor neurons, thereby controlling motor activities. Interneurons arise during embryonic development from distinct progenitor domains distributed orderly along the dorso-ventral axis of the neural tube. A single ventral progenitor population named p2 generates at least five V2 interneuron subsets. Whether the diversification of V2 precursors into multiple subsets occurs within the p2 progenitor domain or involves a later compartment of early-born V2 interneurons remains unsolved. Here, we provide evidence that the p2 domain produces an intermediate V2 precursor compartment characterized by the transient expression of the transcriptional repressor Vsx1. These cells display an original repertoire of cellular markers distinct from that of any V2 interneuron population. They have exited the cell cycle but have not initiated neuronal differentiation. They coexpress Vsx1 and Foxn4, suggesting that they can generate the known V2 interneuron populations as well as possible additional V2 subsets. Unlike V2 interneurons, the generation of Vsx1-positive precursors does not depend on the Notch signaling pathway but expression of Vsx1 in these cells requires Pax6. Hence, the p2 progenitor domain generates an intermediate V2 precursor compartment, characterized by the presence of the transcriptional repressor Vsx1, that contributes to V2 interneuron development.

Adult spinal cord ependymal layer: a promising pool of quiescent stem cells to treat spinal cord injury.

Spinal cord injury (SCI) is a major health burden and currently there is no effective medical intervention. Research performed over the last decade revealed that cells surrounding the central canal of the adult spinal cord and forming the ependymal layer acquire stem cell properties either in vitro or in response to injury. Following SCI activated ependymal cells generate progeny cells which migrate to the injury site but fail to produce the appropriate type of cells in sufficient number to limit the damage, rendering this physiological response mainly ineffective. Research is now focusing on the manipulation of ependymal cells to produce cells of the oligodendrocyte lineage which are primarily lost in such a situation leading to secondary neuronal degeneration. Thus, there is a need for a more focused approach to understand the molecular properties of adult ependymal cells in greater detail and develop effective strategies for guiding their response during SCI.

Pax6 is expressed in subsets of V0 and V2 interneurons in the ventral spinal cord in mice.

The embryonic spinal cord in mice is organized into eleven progenitor domains. Cells in each domain first produce neurons and then switch to specifying glia. Five of these domains known as p3, pMN, p2, p1 and p0 are located in the ventral spinal cord and each expresses a unique code of transcription factors (TFs) that define the molecular profile of progenitor cells. This code is largely responsible for determining the subtype specification of neurons generated from each domain. Pax6 codes for a homedomain-containing TF that plays a central role in defining the molecular boundaries between the two ventral-most domains, p3 and pMN. Using fate mapping and gene expression studies we show that PAX6, in addition to each patterning function, is expressed in a group of late born interneurons that derive from the p2 and p0 domains. The p2-derived neurons represent a subset of late born V2b interneurons and their specification depends on Notch signaling. The V0 neurons represent V0v ventral neurons expressing Pax2. Our data demonstrate that interneuron diversity in the ventral spinal cord is more complex than originally appreciated and point to the existence of additional mechanisms that determine interneuron diversity, particularly in the p2 domain.

Intraperitoneal melatonin is not neuroprotective in the G93ASOD1 transgenic mouse model of familial ALS and may exacerbate neurodegeneration.

In amyotrophic lateral sclerosis (ALS) reactive oxygen species and apoptosis are implicated in disease pathogenesis. Melatonin with its anti-oxidant and anti-apoptotic properties is expected to ameliorate disease phenotype. The aim of this study was to assess possible neuroprotection of melatonin in the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. Four groups of mice, 14 animals each, were injected intraperitoneally with 0mg/kg, 0.5mg/kg, 2.5mg/kg and 50mg/kg of melatonin from age 40 days. The primary end points were; disease onset, disease duration, survival and rotarod performance. No statistically significant difference in disease onset between the four groups was found. Survival was significantly reduced with the 0.5mg/kg and 50mg/kg doses and tended to be reduced with the 2.5mg/kg dose. Histological analysis of spinal cords revealed increased motoneuron loss in melatonin treated mice. Melatonin treated animals were associated with increased oxidative stress as assessed with 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation. Histochemistry and Western blot data of spinal cord from melatonin treated mice revealed upregulation of human SOD1 compared to untreated mice. In addition, real-time PCR revealed a dose dependent upregulation of human SOD1 in melatonin treated animals. Thus, intraperitoneal melatonin, at the doses used, does not ameliorate and perhaps exacerbates phenotype in the G93ASOD1 mouse ALS model. This is probably due to melatonin's effect on upregulating gene expression of human toxic SOD1. This action presumably overrides any of its direct anti-oxidant and anti-apoptotic properties.

21 Mb deletion in chromosome band 13q22.2q32.1 associated with mild/moderate psychomotor retardation, growth hormone insufficiency, short neck, micrognathia, hypotonia, dysplastic ears and other dysmorphic features.

We report on a 9-month old boy carrying a 21 Mb de novo 13q interstitial deletion. The imbalance was detected by chromosomal analysis and investigated by Fluorescence In Situ Hybridization (FISH) and Comparative Genomic Hybridization (array-CGH) using two different platforms: a BAC microarray with 516 kb resolution (Cytochip) and a 15 kb resolution oligonucleotide microarray (Agilent 244K). The deletion has been estimated to span 21.46 Mb on chromosomal bands 13q22.2-13q32.1. The patient has mild/moderate psychomotor retardation, growth hormone insufficiency, hypertelorism, short neck, micrognathia, hypotonia, dysplastic ears and other dysmorphic features. Further investigation revealed that the abnormality is de novo and causative of the patient's phenotype. The described patient is unique among similar rare cases with different deletion breakpoints. It is the first case of 13q22.2q32.1 deletion where the breakpoints are clearly defined, indicating the importance of detailed clinical description and high-resolution genomic analysis for characterization of rare genetic syndromes.

Sox1 maintains the undifferentiated state of cortical neural progenitor cells via the suppression of Prox1-mediated cell cycle exit and neurogenesis.

Neural stem/progenitor cells maintain their identity via continuous self-renewal and suppression of differentiation. Gain-of-function experiments in the chick revealed an involvement for Sox1-3 transcription factors in the maintenance of the undifferentiated neural progenitor (NP) identity. However, the mechanism(s) employed by each factor has not been resolved. Here, we derived cortical neural/stem progenitor cells from wild-type and Sox1-null mouse embryos and found that Sox1 plays a key role in the suppression of neurogenic cell divisions. Loss of Sox1 leads to progressive depletion of self-renewing cells, elongation of the cell cycle of proliferating cells, and significant increase in the number of cells exiting the cell cycle. In proliferating NP cells, Sox1 acts via a prospero-related homeobox 1 (Prox1)-mediated pathway to block cell cycle exit that leads to neuronal differentiation in vivo and in vitro. Thus, our results demonstrate that Sox1 regulates the size of the cortical NP pool via suppression of Prox1-mediated neurogenic cell divisions.