RESUMO
Sorsby's fundus dystrophy (SFD) is an autosomal dominant macular degeneration developing in the third or fourth decade. Patients lose central vision from subretinal neovascularization and atrophy of the choriocapillaris, pigment epithelium and retina. SFD shares some striking clinical features with age-related macular degeneration (AMD), the most common cause of blindness in western countries thereby providing a valuable genetic model for AMD. To map the SFD locus, we performed linkage analysis in a single large SFD family. After exclusion of approximately 65% of the autosomal genome, we found significant linkage to several markers from chromosome 22. Recombinant chromosomes sublocalize the SFD gene to 22q13-qter between D22S275 and D22S274.
Assuntos
Cromossomos Humanos Par 22 , Ligação Genética , Degeneração Macular/genética , Feminino , Genes Dominantes , Marcadores Genéticos , Humanos , Escore Lod , Masculino , LinhagemRESUMO
Huntington disease is associated with an unstable and expanded (CAG) trinucleotide repeat. We have analysed the CAG expansion in different tissues from 12 affected individuals. All tissues examined were found to display some repeat mosaicism, with the greatest levels detected in brain and sperm. Regions within the brain showing most obvious neuropathology, such as the basal ganglia and the cerebral cortex, displayed the greatest mosaicism, whereas the cerebellar cortex, which is seldom involved, displayed the lowest degree of CAG instability. In two cases of childhood onset disease we detected differences of 8 and 13 trinucleotides between the cerebellum and other regions of the brain. Our results provide evidence for tissue specific instability of the CAG repeat, with the largest CAG repeat lengths in affected regions of the brain.
Assuntos
Células Sanguíneas/química , Química Encefálica , DNA/genética , Doença de Huntington/genética , Mosaicismo , Músculos/química , Sequências Repetitivas de Ácido Nucleico , Espermatozoides/química , Vísceras/química , Adulto , Idade de Início , Gânglios da Base/química , Criança , Pré-Escolar , DNA/isolamento & purificação , Feminino , Humanos , Doença de Huntington/epidemiologia , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/genética , Proteínas do Tecido Nervoso/genética , Especificidade de Órgãos , Reação em Cadeia da PolimeraseRESUMO
The purpose of this paper was to determine whether recommendations made by King & Murphy (Journal of Autism and Developmental Disorders 44:2717-2733, 2014) in their review of the evidence on autistic people in contact with the criminal justice system (CJS) have been addressed. Research published since 2013 was systematically examined and synthesised. The quality of 47 papers was assessed using the Mixed Methods Appraisal Tool. Findings suggest a limited amount of good quality research has been conducted that has focused on improving our understanding of autistic people in contact with the CJS since 2013. Methodological limitations make direct comparisons between autistic and non-autistic offenders difficult. Autistic people commit a range of crimes and appear to have unique characteristics that warrant further exploration (i.e., vulnerabilities, motivations for offending).
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Criminosos , Humanos , Direito Penal , CrimeRESUMO
OBJECTIVES: A previous single-country pilot study indicated serum anti-GM2 and anti-GA1 anti-glycolipid antibodies as potential biomarkers for acute canine polyradiculoneuritis. This study aims to validate these findings in a large geographically heterogenous cohort. MATERIALS AND METHODS: Sera from 175 dogs clinically diagnosed with acute canine polyradiculoneuritis, 112 dogs with other peripheral nerve, cranial nerve or neuromuscular disorders and 226 neurologically normal dogs were screened for anti-glycolipid antibodies against 11 common glycolipid targets to determine the immunoglobulin G anti-glycolipid antibodies with the highest combined sensitivity and specificity for acute canine polyradiculoneuritis. RESULTS: Anti-GM2 anti-glycolipid antibodies reached the highest combined sensitivity and specificity (sensitivity: 65.1%, 95% confidence interval 57.6 to 72.2%; specificity: 90.2%, 95% confidence interval 83.1 to 95.0%), followed by anti-GalNAc-GD1a anti-glycolipid antibodies (sensitivity: 61.7%, 95% confidence interval 54.1 to 68.9%; specificity: 89.3%, 95% confidence interval 82.0 to 94.3%) and these anti-glycolipid antibodies were frequently present concomitantly. Anti-GA1 anti-glycolipid antibodies were detected in both acute canine polyradiculoneuritis and control animals. Both for anti-GM2 and anti-GalNAc-GD1a anti-glycolipid antibodies, sex was found a significantly associated factor with a female to male odds ratio of 2.55 (1.27 to 5.31) and 3.00 (1.22 to 7.89), respectively. Anti-GalNAc-GD1a anti-glycolipid antibodies were more commonly observed in dogs unable to walk (OR 4.56, 1.56 to 14.87). CLINICAL SIGNIFICANCE: Anti-GM2 and anti-GalNAc-GD1a immunoglobulin G anti-glycolipid antibodies represent serum biomarkers for acute canine polyradiculoneuritis.
Assuntos
Doenças do Cão , Polirradiculoneuropatia , Animais , Biomarcadores , Doenças do Cão/diagnóstico , Cães , Feminino , Gangliosídeo G(M2) , Humanos , Imunoglobulina G , Masculino , Projetos Piloto , Polirradiculoneuropatia/diagnóstico , Polirradiculoneuropatia/veterináriaRESUMO
OBJECTIVES: To assess the utility of the Idexx ProCyte Dx® haematology analyser for assessing total nucleated cell count and differential cell counts in canine cerebrospinal fluid. MATERIALS AND METHODS: Seventy-three client-owned dogs undergoing investigations for pyrexia and/or neurological signs were prospectively included. Cerebrospinal fluid samples were assessed using an Idexx ProCyte Dx® analyser and the results were compared to those obtained with the external laboratory reference standard. RESULTS: The Idexx ProCyte Dx® performed with good sensitivity (92.6%) and moderate specificity (67.4%) for total nucleated cell count when compared to the reference standard. Qualitative assessment of the Idexx ProCyte Dx® scatter plots, and quantitative assessment of differential cell counts where available, appeared to correlate well with the external laboratory manual differential cell counts, with a good-to-high agreement in 25 of 26 samples (96.2%). CLINICAL SIGNIFICANCE: The Idexx ProCyte Dx® analyser performed well in determining the total nucleated cell count and differential cell counts in canine cerebrospinal fluid when compared to a reference standard of external laboratory analysis, except for cell counts higher than ~1000/µL. As the Idexx ProCyte Dx® currently only provides a cell count in 10 cells/µL increments, software modification may improve agreement between the two methods. As in human medicine, automated methods may prove useful in the future for cerebrospinal fluid analysis in addition to manual assessment, particularly in an emergency setting.
Assuntos
Software , Animais , Contagem de Células/veterinária , Cães , Sensibilidade e EspecificidadeRESUMO
In order to identify additional factors required for nuclear export of messenger RNA, a genetic screen was conducted with a yeast mutant deficient in a factor Gle1p, which associates with the nuclear pore complex (NPC). The three genes identified encode phospholipase C and two potential inositol polyphosphate kinases. Together, these constitute a signaling pathway from phosphatidylinositol 4, 5-bisphosphate to inositol hexakisphosphate (IP6). The common downstream effects of mutations in each component were deficiencies in IP6 synthesis and messenger RNA export, indicating a role for IP6 in GLE1 function and messenger RNA export.
Assuntos
Proteínas de Transporte/metabolismo , Membrana Nuclear/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , Fosfolipases Tipo C/metabolismo , Transporte Biológico , Proteínas de Transporte/genética , Genes Fúngicos , Teste de Complementação Genética , Fosfatos de Inositol/metabolismo , Mutação , Complexo de Proteínas Formadoras de Poros Nucleares , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Ácido Fítico/metabolismo , RNA Fúngico/metabolismo , Saccharomyces cerevisiae/genética , Transdução de SinaisAssuntos
Doenças do Cão , Doenças da Medula Espinal , Neoplasias da Medula Espinal , Cães , Animais , Imageamento por Ressonância Magnética/veterinária , Doenças da Medula Espinal/veterinária , Neoplasias da Medula Espinal/patologia , Neoplasias da Medula Espinal/cirurgia , Neoplasias da Medula Espinal/veterinária , Doenças do Cão/diagnóstico por imagem , Doenças do Cão/cirurgia , Doenças do Cão/patologiaRESUMO
The neuronal ceroid lipofuscinoses (NCLs) are the commonest neurodegenerative disorders of children. The aims of this study were to determine the incidence of NCL in Newfoundland, identify the causative genes, and analyze the relationship between phenotype and genotype. Patients with NCL diagnosed between 1960 and 2005 were ascertained through the provincial genetics and pediatric neurology clinics. Fifty-two patients from 34 families were identified. DNA was obtained from 28/34 (82%) families; 18 families had mutations in the CLN2 gene, comprising five different mutations of which two were novel. One family had a CLN3 mutation, another had a novel mutation in CLN5, and five families shared the same mutation in CLN6. One family was misdiagnosed, and in two, molecular testing was inconclusive. Disease from CLN2 mutations had an earlier presentation (p = 0.003) and seizure onset (p < 0.001) compared with CLN6 mutation. There was a slower clinical course for those with CLN5 mutation compared with CLN2 mutation. NCL in Newfoundland has a high incidence, 1 in 7353 live births, and shows extensive genetic heterogeneity. The incidence of late infantile NCL, 9.0 per 100,000 (or 1 in 11,161) live births, is the highest reported in the world.
Assuntos
Lipofuscinoses Ceroides Neuronais/epidemiologia , Lipofuscinoses Ceroides Neuronais/genética , Adolescente , Aminopeptidases , Criança , Pré-Escolar , Análise Mutacional de DNA , Dipeptidil Peptidases e Tripeptidil Peptidases , Endopeptidases/genética , Família , Feminino , Heterogeneidade Genética , Genótipo , Humanos , Proteínas de Membrana Lisossomal , Masculino , Proteínas de Membrana/genética , Lipofuscinoses Ceroides Neuronais/diagnóstico , Terra Nova e Labrador/epidemiologia , Fenótipo , Serina Proteases , Tripeptidil-Peptidase 1Assuntos
Carcinoma , Neoplasias do Plexo Corióideo , Doenças do Cão , Carcinomatose Meníngea , Neoplasias Meníngeas , Cães , Animais , Carcinomatose Meníngea/veterinária , Neoplasias do Plexo Corióideo/diagnóstico por imagem , Neoplasias do Plexo Corióideo/cirurgia , Neoplasias do Plexo Corióideo/veterinária , Carcinoma/cirurgia , Carcinoma/veterinária , Neoplasias Meníngeas/veterinária , Doenças do Cão/diagnóstico por imagem , Doenças do Cão/cirurgiaRESUMO
Integral membrane proteins are predicted to play key roles in the biogenesis and function of nuclear pore complexes (NPCs). Revealing how the transport apparatus is assembled will be critical for understanding the mechanism of nucleocytoplasmic transport. We observed that expression of the carboxyl-terminal 200 amino acids of the nucleoporin Nup116p had no effect on wild-type yeast cells, but it rendered the nup116 null strain inviable at all temperatures and coincidentally resulted in the formation of nuclear membrane herniations at 23 degrees C. To identify factors related to NPC function, a genetic screen for high-copy suppressors of this lethal nup116-C phenotype was conducted. One gene (designated SNL1 for suppressor of nup116-C lethal) was identified whose expression was necessary and sufficient for rescuing growth. Snl1p has a predicted molecular mass of 18.3 kDa, a putative transmembrane domain, and limited sequence similarity to Pom152p, the only previously identified yeast NPC-associated integral membrane protein. By both indirect immunofluorescence microscopy and subcellular fractionation studies, Snl1p was localized to both the nuclear envelope and the endoplasmic reticulum. Membrane extraction and topology assays suggested that Snl1p was an integral membrane protein, with its carboxyl-terminal region exposed to the cytosol. With regard to genetic specificity, the nup116-C lethality was also suppressed by high-copy GLE2 and NIC96. Moreover, high-copy SNL1 suppressed the temperature sensitivity of gle2-1 and nic96-G3 mutant cells. The nic96-G3 allele was identified in a synthetic lethal genetic screen with a null allele of the closely related nucleoporin nup100. Gle2p physically associated with Nup116p in vitro, and the interaction required the N-terminal region of Nup116p. Therefore, genetic links between the role of Snl1p and at least three NPC-associated proteins were established. We suggest that Snl1p plays a stabilizing role in NPC structure and function.
Assuntos
Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Complexo de Proteínas Formadoras de Poros Nucleares , Proteínas Nucleares/genética , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/citologia , Sequência de Aminoácidos , Clonagem Molecular , Retículo Endoplasmático/química , Proteínas Fúngicas/metabolismo , Genes Fúngicos/genética , Genes Letais/genética , Genes Supressores/genética , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/genética , Proteínas de Membrana/análise , Proteínas de Membrana/metabolismo , Chaperonas Moleculares , Dados de Sequência Molecular , Membrana Nuclear/química , Membrana Nuclear/ultraestrutura , Poro Nuclear , Proteínas Nucleares/análise , Proteínas Nucleares/metabolismo , Fenótipo , Saccharomyces cerevisiae/genética , Alinhamento de Sequência , Homologia de Sequência de AminoácidosAssuntos
Doenças do Cão , Degeneração do Disco Intervertebral , Deslocamento do Disco Intervertebral , Disco Intervertebral , Animais , Doenças do Cão/diagnóstico por imagem , Cães , Disco Intervertebral/diagnóstico por imagem , Degeneração do Disco Intervertebral/diagnóstico por imagem , Degeneração do Disco Intervertebral/veterinária , Deslocamento do Disco Intervertebral/diagnóstico por imagem , Deslocamento do Disco Intervertebral/cirurgia , Deslocamento do Disco Intervertebral/veterinária , Imageamento por Ressonância Magnética/veterináriaRESUMO
BACKGROUND: Intranasal administration of benzodiazepines has shown superiority over rectal administration for terminating emergency epileptic seizures in human trials. No such clinical trials have been performed in dogs. OBJECTIVE: To evaluate the clinical efficacy of intranasal midazolam (IN-MDZ), via a mucosal atomization device, as a first-line management option for canine status epilepticus and compare it to rectal administration of diazepam (R-DZP) for controlling status epilepticus before intravenous access is available. ANIMALS: Client-owned dogs with idiopathic or structural epilepsy manifesting status epilepticus within a hospital environment were used. Dogs were randomly allocated to treatment with IN-MDZ (n = 20) or R-DZP (n = 15). METHODS: Randomized parallel-group clinical trial. Seizure cessation time and adverse effects were recorded. For each dog, treatment was considered successful if the seizure ceased within 5 minutes and did not recur within 10 minutes after administration. The 95% confidence interval was used to detect the true population of dogs that were successfully treated. The Fisher's 2-tailed exact test was used to compare the 2 groups, and the results were considered statistically significant if P < .05. RESULTS: IN-MDZ and R-DZP terminated status epilepticus in 70% (14/20) and 20% (3/15) of cases, respectively (P = .0059). All dogs showed sedation and ataxia. CONCLUSIONS AND CLINICAL IMPORTANCE: IN-MDZ is a quick, safe and effective first-line medication for controlling status epilepticus in dogs and appears superior to R-DZP. IN-MDZ might be a valuable treatment option when intravenous access is not available and for treatment of status epilepticus in dogs at home.
Assuntos
Anticonvulsivantes/uso terapêutico , Diazepam/uso terapêutico , Doenças do Cão/tratamento farmacológico , Midazolam/uso terapêutico , Estado Epiléptico/veterinária , Administração Intranasal/veterinária , Administração Retal , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Diazepam/administração & dosagem , Diazepam/efeitos adversos , Cães , Feminino , Masculino , Midazolam/administração & dosagem , Midazolam/efeitos adversos , Estado Epiléptico/tratamento farmacológicoRESUMO
A questionnaire-based study was used to investigate the association between the findings on magnetic resonance imaging (MRI) screening for syringomyelia (SM) in 79 asymptomatic Cavalier King Charles spaniels (CKCS) and the subsequent development of clinical signs consistent with SM in later life. Owners reported clinical signs consistent with SM in 13/79 (16%) dogs at the time of the questionnaire. A significantly greater proportion of CKCS with a syrinx visible on MRI screening showed clinical signs in later life (9/25, 36%) than dogs without a visible syrinx (4/54, 7%; odds ratio 6.9). Whether the findings of MRI screening can be used to indicate the likelihood of an asymptomatic CKCS developing clinical signs consistent with SM in later life warrants further prospective study in a larger cohort of dogs.
Assuntos
Doenças do Cão/diagnóstico , Imageamento por Ressonância Magnética/veterinária , Siringomielia/veterinária , Animais , Coleta de Dados , Doenças do Cão/patologia , Cães , Razão de Chances , Fatores de Risco , Inquéritos e Questionários , Siringomielia/diagnósticoRESUMO
In a highly consanguineous, predominantly Cree Indian community in northern Saskatchewan, Canada, 14 similarly malformed babies have been born to eight different mothers since 1953. Six of these infants are reported to assist delineation of the syndrome. The major manifestations of the condition are: Intrauterine growth retardation, perinatal death, marked microcephaly, and severe malformations of the limbs, especially the arms. Elbows are fused, forearms are greatly shortened and usually contain only a single bone, and the hands are very abnormal with only two to four malformed digits. Parental consanguinity, a sex ratio close to one, and a 25% segregation ratio all support autosomal recessive inheritance of this syndrome.
Assuntos
Ectromelia/genética , Genes Recessivos , Microcefalia/genética , Consanguinidade , Feminino , Transtornos do Crescimento/genética , Humanos , Indígenas Norte-Americanos , Recém-Nascido , Masculino , Linhagem , Fenótipo , Saskatchewan , SíndromeRESUMO
Concordance for Goldenhar anomaly has been described in monozygotic (MZ) twins on 2 occasions but never in dizygotic (DZ) twins. In both cases the twins were similarly, although not identically, affected. We report on a pair of probably monozygotic twins (8% probability of DZ) who presented with extremely diverse manifestations of this anomaly complex. One of them required a tracheostomy because of obstructive apnea due to severe micrognathia and subsequently died. This twin had a midline lower lip cleft which has not previously been described in the Goldenhar anomaly.
Assuntos
Doenças em Gêmeos , Síndrome de Goldenhar/genética , Disostose Mandibulofacial/genética , Gêmeos Monozigóticos , Gêmeos , Feminino , Humanos , Recém-Nascido , Desenvolvimento MaxilofacialRESUMO
We present the second case of monochorionic diamniotic (MC/DA) conjoined twins. There was minimal conjunction, which was predominantly extrafetal and confined to the periumbilical ventral region. The omphalopagus twins, attached to a single forked umbilical cord, were connected by a shared umbilical hernia containing the ileum of twin B. The only visceral conjunction, located just within the belly of twin A, was midileal with the 2 separate ileums converging toward a short segment of shared muscularis propria and of side-to-side fistulization. Gastrointestinal and musculoskeletal anomalies were present in both twins with severe amyoplasia and arthrogryposis multiplex in twin A. Possible mechanisms underlying this unusual form of MZ twinning are discussed.
Assuntos
Anormalidades Múltiplas/patologia , Doenças em Gêmeos , Gêmeos Unidos/patologia , Gêmeos Monozigóticos , Artrogripose/patologia , Feminino , Hérnia Umbilical/patologia , Humanos , Recém-Nascido , Intestinos/anormalidades , Masculino , Placenta/anormalidades , GravidezRESUMO
A gene responsible for X-linked mental retardation with macrocephaly and seizures (MRX38) in a family with five affected males in three generations was localized to Xp21.1-p22.13 by linkage analysis. Recombination events placed the gene between DXS1226 distally and DXS1238 proximally, defining an interval of approximately 14 cM. A peak lod score of 2.71 was found with several loci in Xp21.1 (DXS992, DXS1236, DXS997, and DXS1036) at a recombination fraction of zero. The map intervals of 5 X-linked mental retardation loci, MRX2 (Xp22.1-p22.2), MRX19 (Xp22), MRX21 (Xp21.1-p22.3), MRX29 (Xp21.2-p22.1), and MRX32 (Xp21.2-p22.1), and two syndromal mental retardation loci, Partington syndrome (PRTS; Xp22) and Coffin-Lowry syndrome (CLS; Xp22.13-p22.2), overlap this region. As none of these display the same phenotype seen in the family reported here, this X-linked mental retardation locus may represent a new entity.
Assuntos
Mapeamento Cromossômico , Deficiência Intelectual/genética , Cromossomo X , Adolescente , Adulto , Encéfalo/anormalidades , Feminino , Ligação Genética , Humanos , Masculino , Linhagem , Recombinação Genética , Convulsões/genéticaRESUMO
We present 5 cases of a short-limb dwarfism syndrome whose manifestations overlap those of atelosteogenesis and oto-palato-digital syndrome Type II. Clinical, radiographic, genetic, and histologic data are presented which demonstrate differences between our patients and previously reported cases of these other conditions. We conclude that the disorder seen in these children represents a distinct chondrodysplasia for which we propose the name atelosteogenesis Type III.