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1.
Nat Commun ; 11(1): 480, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980599

RESUMO

Mutations in the actively expressed, maternal allele of the imprinted KCNK9 gene cause Birk-Barel intellectual disability syndrome (BBIDS). Using a BBIDS mouse model, we identify here a partial rescue of the BBIDS-like behavioral and neuronal phenotypes mediated via residual expression from the paternal Kcnk9 (Kcnk9pat) allele. We further demonstrate that the second-generation HDAC inhibitor CI-994 induces enhanced expression from the paternally silenced Kcnk9 allele and leads to a full rescue of the behavioral phenotype suggesting CI-994 as a promising molecule for BBIDS therapy. Thus, these findings suggest a potential approach to improve cognitive dysfunction in a mouse model of an imprinting disorder.


Assuntos
Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Histonas/metabolismo , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Hipotonia Muscular/genética , Hipotonia Muscular/metabolismo , Canais de Potássio/genética , Animais , Comportamento Animal , Encéfalo/metabolismo , Anormalidades Craniofaciais/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Impressão Genômica , Inibidores de Histona Desacetilases/farmacologia , Humanos , Deficiência Intelectual/tratamento farmacológico , Locus Cerúleo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hipotonia Muscular/tratamento farmacológico , Mutação , Fenótipo , Fenilenodiaminas/farmacologia , Canais de Potássio/deficiência , Canais de Potássio/metabolismo , Regulação para Cima/efeitos dos fármacos
2.
Medicine (Baltimore) ; 98(51): e18075, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31860957

RESUMO

RATIONALE: Dyke-Davidoff-Masson syndrome (DDMS) is a rare syndrome commonly occurring in children and characterized by cerebral hemiatrophy, hypertrophy of the skull, epilepsy, and mental retardation. However, few have been reported in China, especially in teenagers. This case investigated its possible cause and explored a relative effective solution. PATIENT CONCERNS: A 24-year-old female came to department having experienced recurrent seizures for 12 years. DIAGNOSIS: DDMS was diagnosed from its manifestations, biochemistry indexes, and imaging (computed tomography angiography, magnetic resonance venography, and so on). INTERVENTIONS: Several drugs are used to treat the disease, including valproate, carbamazepine, topiramate, and ginkgo biloba extract. OUTCOMES: Under the medicine treatment of magnesium valproate with carbamazepine, the patient experienced partial seizures approximately once per month that lasted 30 to 60 seconds each without any complications observed during a follow-up period of 24 months. CONCLUSION: The imaging and clinical features of DDMS in this teenager were similar to those in classic infantile-onset cases. A potential cause of the disease could be brain trauma, which impaired the middle cerebral artery and reduced cerebral blood supply, leading to epilepsy and hemiatrophy. LESSONS: It was concluded early diagnosis and pharmacotherapy are the keys to preventing intellectual decline in DDMS patients. Moreover, the combination of magnesium valproate and carbamazepine could significantly reduce the frequency and duration of seizures, despite not eliminating them completely.


Assuntos
Encefalopatias/diagnóstico por imagem , Deficiência Intelectual/diagnóstico , Imagem por Ressonância Magnética/métodos , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Encefalopatias/tratamento farmacológico , Carbamazepina/uso terapêutico , China , Doença Crônica , Feminino , Humanos , Deficiência Intelectual/tratamento farmacológico , Prognóstico , Recidiva , Medição de Risco , Índice de Gravidade de Doença , Síndrome , Tomografia Computadorizada por Raios X/métodos , Ácido Valproico , Adulto Jovem
5.
BMC Cancer ; 19(1): 1040, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31684896

RESUMO

BACKGROUND: The longevity for people with intellectual disability (ID) has significantly increased in developed countries during the past decades. Consequently, the incidence of cancer is expected to increase in this group. The aim of the present study was to investigate the prescription of pain medication in older cancer patients with intellectual disability (ID) compared to older patients in the general population, surviving or living with a cancer diagnosis. METHODS: This Swedish national registry-based study, included people with ID aged 55 years or older in 2012, and alive at the end of that year (ID cohort, n = 7936). For comparisons, we used a referent cohort, one-to-one matched with the general population by year of birth and sex (gPop cohort, n = 7936). People with at least one diagnosis of cancer during 2002-2012 were identified using the Swedish National Patient Register, resulting in 555 cancer patients with ID and 877 cancer patients from the general population. These two cohorts of cancer patients were compared with respect to prescription of pain medication for the period 2006-2012. Outcome data were aggregated so that each patient was categorized as either having or not having at least one prescription of each investigated drug group during the study period, and relative risks (RRs) for prescription were estimated for prescription in the ID cohort vs the gPop cohort. RESULTS: Cancer patients with ID were less likely than cancer patients in the gPop cohort to have at least one prescription of COX inhibitors (RR 0.61) and weak opioids (RR 0.63). They were, however, more likely to be prescribed paracetamol (RR 1.16), antidepressants (RR 2.09), anxiolytics (RR 2.84), and "other hypnotics, sedatives, and neuroleptics" (RR 1.39). No statistically significant differences between the two cohorts were found for strong opioids, antiepileptics, tricyclic antidepressants, or hypnotics and sedatives. CONCLUSION: In the studied cohort of older people surviving or living with cancer, prescriptions for pain-treatment was less common in patients with ID compared to the general population. These results may suggest that pain is not sufficiently treated among cancer patients with ID, a situation that most likely would compromise the quality of life in this group.


Assuntos
Analgésicos/uso terapêutico , Prescrições de Medicamentos/estatística & dados numéricos , Deficiência Intelectual/epidemiologia , Neoplasias/epidemiologia , Dor/tratamento farmacológico , Sistema de Registros/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Sobreviventes de Câncer , Estudos de Coortes , Feminino , Humanos , Deficiência Intelectual/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Suécia/epidemiologia
6.
South Med J ; 112(8): 428-432, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31375839

RESUMO

OBJECTIVES: Individuals with intellectual disabilities (IDs) are at increased risk for low bone mass and fragility fractures, and those who are nonambulatory may be at even higher risk. Patients with IDs often are vitamin D deficient, but there is little information concerning how vitamin D treatment of patients with IDs affects markers of bone formation and resorption. METHODS: We performed a retrospective analysis of 23 institutionalized individuals with IDs who were the subject of a performance improvement continuing medical education project designed to reduce risk for fracture by optimizing serum vitamin D levels. Patients were divided into those with normal weight-bearing (NWB) physical activity (15 patients: 14 men, 1 woman) and those with low weight-bearing (LWB) physical activity (8 patients: 7 men, 1 woman). All of the subjects received 50,000 IU of vitamin D3 weekly for 4 to 8 weeks, followed by a maintenance dose of 50,000 IU monthly for 3 to 6 months. Bone turnover markers (type 1 cross-linked C-telopeptide [CTX], type 1 N-terminal propeptide [P1NP], and parathyroid hormone [PTH]) and 25(OH)-vitamin D levels were measured before and after vitamin D supplementation. RESULTS: At baseline, there were no significant differences in the serum levels of 25OH-D, PTH, P1NP, or CTX between the two groups (NWB and LWB). Vitamin D levels were increased to a higher value in LWB subjects than in NWB subjects (61 ± 4.1 vs 48.4 ± 2.2 ng/mL, P < 0.001). Vitamin D treatment suppressed PTH (20.5% ± 14.3% vs 31.4% ± 7.7%, P = not significant) and P1NP (33.0% ± 6.2% vs 29.4% ± 6.9%, P = not significant) similarly in both groups. Although CTX levels declined by 26.4% ± 5.3% (P = 0.0002) in NWB individuals (as anticipated), vitamin D supplementation resulted in an unexpected 25.8% ± 8% increase (P = 0.01) in CTX in LWB individuals, suggesting osteoclast activation. CONCLUSIONS: Although high-dose vitamin D appeared to suppress osteoclast activity in NWB adults with IDs, the increase in serum CTX levels in those with LWB activity implies activation of osteoclasts that could exacerbate their unique low bone mass and increase fracture risk. The results support the use of a lower-dose vitamin D regimen in this patient group with LWB.


Assuntos
Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/prevenção & controle , Exercício Físico/fisiologia , Deficiência Intelectual/complicações , Deficiência Intelectual/tratamento farmacológico , Vitamina D/farmacologia , Suporte de Carga/fisiologia , Adulto , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Suplementos Nutricionais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Vitaminas/farmacologia , Adulto Jovem
7.
Med Hypotheses ; 131: 109289, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443780

RESUMO

Mental retardation is a progressive condition in Down syndrome: intelligence starts to decline linearly within the first year. This phenomenon could be related to the overproduction of a toxic compound, hydrogen sulfide. Indeed, a gene located on chromosome 21 controls the production of cystathionine-ß-synthase, an enzyme involved in hydrogen sulfide production in the central nervous system. It has recently been demonstrated that excess cystathionine-ß-synthase levels are needed and sufficient to induce cognitive phenotypes in mouse models of Down syndrome. Thus, two therapeutic options might be used in Down syndrome patients: the use of a specific cystathionine ß-synthase inhibitor and the use of an effective antidote to reduce hydrogen sulfide toxicity. Prenatal treatment of Down syndrome fetuses is also suggested.


Assuntos
Cistationina beta-Sintase/fisiologia , Síndrome de Down/psicologia , Sulfeto de Hidrogênio/antagonistas & inibidores , Deficiência Intelectual/terapia , Ácido Amino-Oxiacético/uso terapêutico , Animais , Benserazida/uso terapêutico , Encéfalo/metabolismo , Cromossomos Humanos Par 21/genética , Cobamidas/uso terapêutico , Cistationina beta-Sintase/antagonistas & inibidores , Cistationina beta-Sintase/genética , Modelos Animais de Doenças , Progressão da Doença , Dissulfiram/uso terapêutico , Síndrome de Down/genética , Inibidores Enzimáticos/uso terapêutico , Dosagem de Genes , Humanos , Sulfeto de Hidrogênio/metabolismo , Recém-Nascido , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Camundongos , Mitocôndrias/metabolismo , Ratos , Nitrito de Sódio/uso terapêutico , Especificidade da Espécie , Tiossulfatos/metabolismo
8.
Pharm Res ; 36(9): 137, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332533

RESUMO

PURPOSE: Pitt Hopkins Syndrome (PTHS) is a rare genetic disorder caused by mutations of a specific gene, transcription factor 4 (TCF4), located on chromosome 18. PTHS results in individuals that have moderate to severe intellectual disability, with most exhibiting psychomotor delay. PTHS also exhibits features of autistic spectrum disorders, which are characterized by the impaired ability to communicate and socialize. PTHS is comorbid with a higher prevalence of epileptic seizures which can be present from birth or which commonly develop in childhood. Attenuated or absent TCF4 expression results in increased translation of peripheral ion channels Kv7.1 and Nav1.8 which triggers an increase in after-hyperpolarization and altered firing properties. METHODS: We now describe a high throughput screen (HTS) of 1280 approved drugs and machine learning models developed from this data. The ion channels were expressed in either CHO (KV7.1) or HEK293 (Nav1.8) cells and the HTS used either 86Rb+ efflux (KV7.1) or a FLIPR assay (Nav1.8). RESULTS: The HTS delivered 55 inhibitors of Kv7.1 (4.2% hit rate) and 93 inhibitors of Nav1.8 (7.2% hit rate) at a screening concentration of 10 µM. These datasets also enabled us to generate and validate Bayesian machine learning models for these ion channels. We also describe a structure activity relationship for several dihydropyridine compounds as inhibitors of Nav1.8. CONCLUSIONS: This work could lead to the potential repurposing of nicardipine or other dihydropyridine calcium channel antagonists as potential treatments for PTHS acting via Nav1.8, as there are currently no approved treatments for this rare disorder.


Assuntos
Di-Hidropiridinas/farmacologia , Reposicionamento de Medicamentos/métodos , Hiperventilação/tratamento farmacológico , Deficiência Intelectual/tratamento farmacológico , Canal de Potássio KCNQ1/antagonistas & inibidores , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Animais , Teorema de Bayes , Células CHO , Cricetulus , Di-Hidropiridinas/química , Facies , Células HEK293 , Humanos , Canal de Potássio KCNQ1/metabolismo , Aprendizado de Máquina , Bloqueadores dos Canais de Potássio/química , Bibliotecas de Moléculas Pequenas/química , Bloqueadores dos Canais de Sódio/química , Relação Estrutura-Atividade , Bloqueadores do Canal de Sódio Disparado por Voltagem/química
9.
Int J Mol Sci ; 20(12)2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31234416

RESUMO

Mutations in IQSEC2 cause intellectual disability (ID), which is often accompanied by seizures and autism. A number of studies have shown that IQSEC2 is an abundant protein in excitatory synapses and plays an important role in neuronal development as well as synaptic plasticity. Here, we review neuronal IQSEC2 signaling with emphasis on those aspects likely to be involved in autism. IQSEC2 is normally bound to N-methyl-D-aspartate (NMDA)-type glutamate receptors via post synaptic density protein 95 (PSD-95). Activation of NMDA receptors results in calcium ion influx and binding to calmodulin present on the IQSEC2 IQ domain. Calcium/calmodulin induces a conformational change in IQSEC2 leading to activation of the SEC7 catalytic domain. GTP is exchanged for GDP on ADP ribosylation factor 6 (ARF6). Activated ARF6 promotes downregulation of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors through a c-jun N terminal kinase (JNK)-mediated pathway. NMDA receptors, AMPA receptors, and PSD-95 are all known to be adversely affected in autism. An IQSEC2 transgenic mouse carrying a constitutively active mutation (A350V) shows autistic features and reduced levels of surface AMPA receptor subunit GluA2. Sec7 activity and AMPA receptor recycling are presented as two targets, which may respond to drug treatment in IQSEC2-associated ID and autism.


Assuntos
Transtorno Autístico/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Deficiência Intelectual/metabolismo , Animais , Transtorno Autístico/tratamento farmacológico , Transtorno Autístico/genética , Fatores de Troca do Nucleotídeo Guanina/análise , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Terapia de Alvo Molecular , Mutação/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
10.
Neurology ; 93(2): e200-e209, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31217257

RESUMO

OBJECTIVE: To investigate whether mammalian target of rapamycin inhibitor everolimus can improve intellectual disability, autism, and other neuropsychological deficits in children with tuberous sclerosis complex (TSC). METHODS: In this 12-month, randomized, double-blind, placebo-controlled trial, we attempted to enroll 60 children with TSC and IQ <80, learning disability, special schooling, or autism, aged 4-17 years, without intractable seizures to be assigned to receive everolimus or placebo. Everolimus was titrated to blood trough levels of 5-10 ng/mL. Primary outcome was full-scale IQ; secondary outcomes included autism, neuropsychological functioning, and behavioral problems. RESULTS: Thirty-two children with TSC were randomized. Intention-to-treat analysis showed no benefit of everolimus on full-scale IQ (treatment effect -5.6 IQ points, 95% confidence interval -12.3 to 1.0). No effect was found on secondary outcomes, including autism and neuropsychological functioning, and questionnaires examining behavioral problems, social functioning, communication skills, executive functioning, sleep, quality of life, and sensory processing. All patients had adverse events. Two patients on everolimus and 2 patients on placebo discontinued treatment due to adverse events. CONCLUSIONS: Everolimus did not improve cognitive functioning, autism, or neuropsychological deficits in children with TSC. The use of everolimus in children with TSC with the aim of improving cognitive function and behavior should not be encouraged in this age group. CLINICALTRIALSGOV IDENTIFIER: NCT01730209. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for children with TSC, everolimus does not improve intellectual disability, autism, behavioral problems, or other neuropsychological deficits.


Assuntos
Transtorno Autístico/tratamento farmacológico , Everolimo/uso terapêutico , Imunossupressores/uso terapêutico , Deficiência Intelectual/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Esclerose Tuberosa/tratamento farmacológico , Adolescente , Transtorno Autístico/etiologia , Transtorno Autístico/psicologia , Criança , Comunicação , Método Duplo-Cego , Função Executiva , Feminino , Humanos , Deficiência Intelectual/etiologia , Testes de Inteligência , Masculino , Comportamento Problema , Qualidade de Vida , Sono , Comportamento Social , Esclerose Tuberosa/complicações , Esclerose Tuberosa/psicologia
11.
Int J Mol Sci ; 20(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31207912

RESUMO

The 15q11.2 BP1-BP2 microdeletion (Burnside-Butler) syndrome is an emerging disorder that encompasses four genes (NIPA1, NIPA2, CYFIP1, and TUBGCP5). When disturbed, these four genes can lead to cognitive impairment, language and/or motor delay, psychiatric/behavioral problems (attention-deficit hyperactivity, autism, dyslexia, schizophrenia/paranoid psychosis), ataxia, seizures, poor coordination, congenital anomalies, and abnormal brain imaging. This microdeletion was reported as the most common cytogenetic finding when using ultra-high- resolution chromosomal microarrays in patients presenting for genetic services due to autism with or without additional clinical features. Additionally, those individuals with Prader-Willi or Angelman syndromes having the larger typical 15q11-q13 type I deletion which includes the 15q11.2 BP1-BP2 region containing the four genes, show higher clinical severity than those having the smaller 15q11-q13 deletion where these four genes are intact. Two of the four genes (i.e., NIPA1 and NIPA2) are expressed in the brain and encode magnesium transporters. Magnesium is required in over 300 enzyme systems that are critical for multiple cellular functions, energy expenditure, protein synthesis, DNA transcription, and muscle and nerve function. Low levels of magnesium are found in those with seizures, depression, and acute or chronic brain diseases. Anecdotally, parents have administered magnesium supplements to their children with the 15q11.2 BP1-BP2 microdeletion and have observed improvement in behavior and clinical presentation. These observations require more attention from the medical community and should include controlled studies to determine if magnesium supplements could be a treatment option for this microdeletion syndrome and also for a subset of individuals with Prader-Willi and Angelman syndromes.


Assuntos
Deficiência Intelectual/tratamento farmacológico , Magnésio/uso terapêutico , Aberrações Cromossômicas , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 15/metabolismo , Suplementos Nutricionais , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Magnésio/administração & dosagem
12.
J Appl Res Intellect Disabil ; 32(6): 1389-1400, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31192534

RESUMO

BACKGROUND: Antipsychotic medications are used among 19%-58% of adults with intellectual disabilities to manage challenging behaviour against the NICE guideline recommendations. Studies show that it is possible to completely withdraw antipsychotics in about one third of adults with intellectual disabilities and a dose reduction of 50% or more in another third. METHOD: In Cornwall, over three years the present authors developed a structured pathway to withdraw antipsychotics among adults with intellectual disabilities which involved people with intellectual disabilities and their carers, GPs, community learning disability team members and pharmacists. RESULTS: The present authors managed to withdraw antipsychotics totally among 46.5% (33/71) and reduced over 50% of dosage in another 11.3% (8/71) of adults with intellectual disabilities. At three months follow-up no one required hospital admission or change in placement. CONCLUSION: It is possible to withdraw/reduce antipsychotics in a high proportion of adults with intellectual disabilities if a concerted effort is made involving all stakeholders from the outset.


Assuntos
Antipsicóticos/uso terapêutico , Desprescrições , Deficiência Intelectual/tratamento farmacológico , Sobremedicalização/prevenção & controle , Comportamento Problema , Inglaterra , Clínicos Gerais , Humanos , Equipe de Assistência ao Paciente , Guias de Prática Clínica como Assunto , Desenvolvimento de Programas , Avaliação de Programas e Projetos de Saúde , Participação dos Interessados
13.
J Appl Res Intellect Disabil ; 32(4): 981-993, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31038275

RESUMO

BACKGROUND: There are concerns that antipsychotics may be used inappropriately in adults with intellectual disability for problem behaviours in the absence of a diagnosed mental health condition. The aim was to examine the prevalence and patterns of antipsychotic use and their association with problem behaviours and mental health conditions in older adults with intellectual disability. METHODS: Cross-sectional data were drawn from Wave 2 (2013/2014) of the Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing (IDS-TILDA). Medication data were available for 95.6% (n = 677). Those who reported antipsychotic use and reported psychotic or other mental health conditions and those who reported problem behaviours were compared. RESULTS: In total, 45.1% (n = 305) had antipsychotics, and of those with antipsychotic use and diagnosis information (n = 282), 25.9% (73) had a psychotic disorder. 58% of those exposed to antipsychotics reported problem behaviours. CONCLUSION: Reported use of antipsychotics significantly exceeded reported doctor's diagnosis of psychotic conditions in this study.


Assuntos
Antipsicóticos/uso terapêutico , Deficiência Intelectual , Transtornos Mentais , Comportamento Problema , Adulto , Idoso , Comorbidade , Estudos Transversais , Feminino , Humanos , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/fisiopatologia , Irlanda/epidemiologia , Estudos Longitudinais , Masculino , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/epidemiologia , Transtornos Mentais/fisiopatologia , Pessoa de Meia-Idade , Prevalência
14.
Soc Psychiatry Psychiatr Epidemiol ; 54(8): 937-944, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30903237

RESUMO

PURPOSE: To describe demographic and diagnostic profiles in a national cohort of older people with intellectual disability (ID) who were prescribed antipsychotics. METHODS: Using national registers, we identified people with ID who were 55 + years in 2012 (n = 7936), as well as a subcohort with complete information on demographic factors (sex, year of birth, severity of ID, presence of behavior impairment, and residence in special housing; n = 1151). Data regarding diagnoses and prescription of antipsychotics were added for the time period 2006-2012. The potential effects of demographic factors and diagnoses on the prescription of sedating and less-sedating antipsychotics, respectively, were assessed in separate models by estimating the relative risks (RRs) of prescription. RESULTS: Of the demographic factors, severe/profound ID (RR 1.17), behavior impairment (RR 1.34), and living in special housing (RR 1.25) were associated with prescription of sedating antipsychotics, whereas only behavior impairment (RR 1.42) was associated with prescription of less-sedating antipsychotics. For both sedating and less-sedating antipsychotics, the diagnoses with the largest association (i.e., highest relative risk) were schizophrenia (RR 2.17 for sedating and RR 1.81 for less-sedating) and ID (RR 1.84 and RR 1.68, respectively), followed by disorders of psychological development (for sedating antipsychotics, RR 1.57) and organic mental disorders (for less-sedating antipsychotics, RR 1.55). CONCLUSIONS: The associations between prescription of antipsychotics and demographic factors and non-psychotic diagnoses, respectively, suggest that older people with ID may be prescribed antipsychotic medication without thorough psychiatric diagnosing. If so, there is a need for improving the abilities of health care professionals to properly diagnose and manage psychiatric illness in this population.


Assuntos
Antipsicóticos/uso terapêutico , Prescrições de Medicamentos/estatística & dados numéricos , Deficiência Intelectual/tratamento farmacológico , Transtornos Neurocognitivos/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Demografia , Feminino , Habitação/estatística & dados numéricos , Humanos , Prescrição Inadequada , Deficiência Intelectual/psicologia , Masculino , Pessoa de Meia-Idade , Transtornos Neurocognitivos/tratamento farmacológico , Sistema de Registros , Esquizofrenia/tratamento farmacológico , Esquizofrenia/epidemiologia
15.
J Appl Res Intellect Disabil ; 32(4): 861-870, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30790388

RESUMO

BACKGROUND: Although there is little evidence on their efficacy regarding challenging behaviour, antipsychotics are the most used psychotropic drugs in residential intellectually disabled people. Discontinuation is possible for some residential clients with intellectual disabilities. This study aimed to gain insight into support staff's perceptions of discontinuing antipsychotics in residential clients with intellectual disabilities. METHOD: Four focus groups were conducted in this mixed-methods study, followed by a survey. RESULTS: A large majority of support staff perceive antipsychotics to be effective in controlling challenging behaviour. Support staff regarded themselves as willing to contribute to the discontinuation of antipsychotics, but were more confident about achieving reductions. CONCLUSIONS: The attitude of the majority of support staff towards discontinuation provides a good basis for regularly reviewing antipsychotics use. A reduction plan should include preliminary steps, methods of monitoring and evaluating the process, and establishing measures for dealing with possible crises.


Assuntos
Pessoal Técnico de Saúde , Antipsicóticos/uso terapêutico , Atitude do Pessoal de Saúde , Desprescrições , Deficiência Intelectual/tratamento farmacológico , Comportamento Problema , Instituições Residenciais , Adulto , Feminino , Grupos Focais , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
J Hum Genet ; 64(4): 291-296, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30692598

RESUMO

A rare form of osteogenesis imperfecta (OI) caused by Wingless-type MMTV integration site family 1 (WNT1) mutations combines central nervous system (CNS) anomalies with the characteristic increased susceptibility to fractures. We report an additional case where arachnoid cysts extend the phenotype, and that also confirms the association of intellectual disabilities with asymmetric cerebellar hypoplasia here. Interestingly, if the cerebellum is normal in this disorder, intelligence is as well, analogous to an association with similar delays in a subset of patients with sporadic unilateral cerebellar hypoplasia. Those cases typically appear to represent vascular disruptions, and we suggest that most brain anomalies in WNT1-associated OI have vascular origins related to a role for WNT1 in CNS angiogenesis. This unusual combination of benign cerebellar findings with effects on higher functions in these two situations raises the possibility that WNT1 is involved in the pathogenesis of the associated sporadic cases as well. Finally, our patient reacted poorly to pamidronate, which appears ineffective with this form of OI, so that a lack of improvement is an indication for molecular testing that includes WNT1.


Assuntos
Sistema Nervoso Central/fisiopatologia , Deficiência Intelectual/genética , Osteogênese Imperfeita/genética , Proteína Wnt1/genética , Cistos Aracnóideos/diagnóstico por imagem , Cistos Aracnóideos/fisiopatologia , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/diagnóstico por imagem , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Cerebelo/fisiopatologia , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiopatologia , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/fisiopatologia , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/fisiopatologia , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/fisiopatologia , Pamidronato/administração & dosagem , Pamidronato/efeitos adversos
17.
J Mol Neurosci ; 67(2): 305-311, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30604381

RESUMO

To study the clinical effectiveness and mechanism of GM1 acupoint injection therapy on mental retardation for children with cerebral palsy (CP). A total of 90 children with CP were divided into acupoint injection group (group A), subcutaneous injection group (group B), and control group (group C). Another 30 healthy children were set as a healthy control group (group D). The Mental Developmental Index (MDI), Psychomotor Developmental Index (PDI), and hemodynamic parameters in the cerebral arteries were measured before and after treatment. After three treatment courses, the MDI and PDI in groups A, B, and C were increased, and the increase in group A was most obvious (P < 0.05). Peak systolic velocity, mean velocity, and end-diastolic velocity were also elevated in group A, and after three treatment courses, resistance index decreased with a statistical significance (P < 0.05). However, there were no significant changes in groups B and C (P > 0.05). For all groups, neuron-specific enolase levels decreased and total superoxide dismutase increased after treatment. Acupoint injection therapy combined with conventional rehabilitation therapy demonstrated significant effects on cerebral hemodynamic conditions for children with CP.


Assuntos
Terapia por Acupuntura/métodos , Paralisia Cerebral/complicações , Gangliosídeo G(M1)/uso terapêutico , Deficiência Intelectual/terapia , Pontos de Acupuntura , Artérias Cerebrais/fisiologia , Pré-Escolar , Feminino , Gangliosídeo G(M1)/administração & dosagem , Hemodinâmica , Humanos , Lactente , Injeções Subcutâneas/métodos , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/etiologia , Masculino , Fosfopiruvato Hidratase/sangue , Superóxido Dismutase/sangue
18.
J Psychiatr Res ; 110: 83-92, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30597425

RESUMO

Recent studies have suggested an important role of de novo mutations (DNMs) in neuropsychiatric disorders. As DNMs are not subject to elimination due to evolutionary pressure, they are likely to have greater disruptions on biological functions. While a number of sequencing studies have been performed on neuropsychiatric disorders, the implications of DNMs for drug discovery remain to be explored. In this study, we employed a gene-set analysis approach to address this issue. Four neuropsychiatric disorders were studied, including schizophrenia (SCZ), autistic spectrum disorders (ASD), intellectual disability (ID) and epilepsy. We first identified gene-sets associated with different drugs, and analyzed whether the gene-set pertaining to each drug overlaps with DNMs more than expected by chance. We also assessed which medication classes are enriched among the prioritized drugs. We discovered that neuropsychiatric drug classes were indeed significantly enriched for DNMs of all four disorders; in particular, antipsychotics and antiepileptics were the most strongly enriched drug classes for SCZ and epilepsy respectively. Interestingly, we revealed enrichment of several unexpected drug classes, such as lipid-lowering agents for SCZ and anti-neoplastic agents. By inspecting individual hits, we also uncovered other interesting drug candidates or mechanisms (e.g. histone deacetylase inhibition and retinoid signaling) that might warrant further investigations. Taken together, this study provided evidence for the usefulness of DNMs in guiding drug discovery or repositioning.


Assuntos
Transtorno do Espectro Autista/genética , Descoberta de Drogas , Epilepsia/genética , Deficiência Intelectual/genética , Psicotrópicos , Esquizofrenia/genética , Transtorno do Espectro Autista/tratamento farmacológico , Biologia Computacional , Epilepsia/tratamento farmacológico , Humanos , Deficiência Intelectual/tratamento farmacológico , Mutação , Farmacogenética , Esquizofrenia/tratamento farmacológico
20.
Epidemiol Psychiatr Sci ; 28(4): 365-368, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30353794

RESUMO

Children with intellectual and developmental disabilities (IDD) are likely to receive high-risk prescribing practices, such as polypharmacy, long-term use of psychotropic medications, and overuse of antipsychotics. Behavioural interventions, such as applied behavioural analysis, are evidence-based practices for children with IDD and should be the first-line treatment. Short-term use of psychotropic medications may be helpful in reducing the severity and frequency of challenging behaviours while evidence-based behavioural interventions are pursued. In this essay, we offer practical guidelines for better care.


Assuntos
Deficiências do Desenvolvimento/tratamento farmacológico , Deficiência Intelectual/tratamento farmacológico , Sobremedicalização , Psicotrópicos/uso terapêutico , Criança , Deficiências do Desenvolvimento/diagnóstico , Medicina Baseada em Evidências , Humanos , Deficiência Intelectual/diagnóstico , Guias de Prática Clínica como Assunto , Estados Unidos
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