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1.
J Anat ; 244(1): 107-119, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37646379

RESUMO

Muscle ultrasonography is frequently used to improve the understanding of musculoskeletal impairments in children with spastic cerebral palsy (SCP). So far, most studies on muscle morphology and architecture have included typically developing children and children with SCP with similar ancestry, being mainly Caucasian. Less is known about differences in muscle morphology between children with different ancestral backgrounds. Therefore, the aim of this study was to compare muscle morphology and architecture of the medial gastrocnemius in typically developing children with African, South Asian and Southeast Asian descent from Suriname. This explorative cohort study identified children as Maroon (Ghana, African descent), Hindustani (India, South Asian) or Javanese (Indonesia, Southeast Asian), aged 5-10 years. Using 3D freehand ultrasound with the subject prone, the following medial gastrocnemius parameters were defined: muscle tendon unit (MTU) length, muscle belly length, tendon length, muscle volume, muscle thickness, anatomical cross-sectional area (ACSA), fascicle length, pennation angle, and physiological cross-sectional area (PCSA). In addition, differences between ancestral groups were assessed for the length of the MTU, muscle, tendon and fascicles in two passive stretch conditions corresponding to an externally applied joint torque of 1Nm and 4Nm. One-way ANOVA with post hoc t-tests were used to investigate differences between the ancestral groups. In total, 100 Hindustani (n = 34), Javanese (n = 34) and Maroon (n = 32) children were included. For statistical analyses, we matched the children by age, which resulted in groups of 25 children per ancestral group (n = 75). There were no differences found in MTU length, muscle belly length, ACSA, PCSA and muscle volume. Tendon length, fascicle length and pennation angle were different between ancestral groups. Compared to Javanese children, tendon length was longer (p = 0.001) and pennation angle (p = 0.001) was larger in Maroon children and fascicle length was shorter in both Maroon and Hindustani children (p < 0.001). While there was a difference found in MTU length at different conditions of passive stretch between ancestries, no differences were found in the muscle, tendon and fascicles. This is the first study that investigated macroscopic morphological and architectural parameters for the medial gastrocnemius in one extended cohort of typically developing children, stratified in three ancestral subgroups. The current results imply that ancestry-specific reference data for children are needed, especially for tendon length, fascicle length and pennation angle when investigating altered muscle morphology in neurological or neuromuscular pathologies, such as SCP. Future studies should report the ancestral background when describing muscle morphology and architecture of children and ancestral specifications should be included in normative databases.


Assuntos
Paralisia Cerebral , Músculo Esquelético , Criança , Humanos , Estudos de Coortes , Músculo Esquelético/fisiologia , Tendões , Paralisia Cerebral/patologia , Ultrassonografia/métodos
2.
Dev Med Child Neurol ; 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38525657

RESUMO

AIM: To describe the aetiological risk factors, clinical characteristics, access to rehabilitation, and educational status of children with cerebral palsy (CP) in Suriname. METHOD: Hospital-based surveillance of children with CP aged younger than 18 years was conducted at the Academic Hospital Paramaribo, Suriname (known as the Suriname CP Register [SUR-CPR]). Data were collected on sociodemographic characteristics, aetiological risk factors, clinical characteristics, rehabilitation, and educational status. Registry data on aetiological risk factors were compared with available national prevalence rates in Suriname. Descriptive statistics were reported. RESULTS: Between August 2018 and March 2020, 82 children with CP (mean [SD] age 5 years 10 months [3 years 10 months]) attending the Academic Hospital Paramaribo were registered in the SUR-CPR. The mean (SD) age at diagnosis was 5 years 5 months (4 years 1 month). Spastic CP was predominant in 90.8% of children and 58.8% were classified in Gross Motor Function Classification System levels III to V. Overall, 43.9% had preterm birth compared with 13.9% reported nationally (p < 0.001) and 61.6% had birth-related complications compared with 15% reported nationally (p < 0.001). Additionally, 39.1% had birth asphyxia and 23.2% had early feeding difficulties. Sixty-two percent were admitted to the neonatal intensive care unit, 54.0% of whom required ventilation. Most children (82.5%) had CP acquired pre- or perinatally and 17.5% had CP acquired postneonatally. Seventeen percent had never received any rehabilitation services, and 31.9% of the school-aged children were not enrolled in any education system. INTERPRETATION: The high burden of known aetiological risk factors, delayed diagnosis, and severe functional impairment among children with CP registered at the Academic Hospital Paramaribo is concerning. Public health interventions targeting early diagnosis and early intervention could improve the functional outcome of children with CP in Suriname.

3.
Health Educ Res ; 39(2): 182-196, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38300230

RESUMO

The objectives of the study were to (i) document refugee, immigrant and migrant (RIM) communities' knowledge, attitudes and beliefs (KABs) related to the Coronavirus disease (COVID-19) vaccine and (ii) identify best practices for developing and disseminating culturally and linguistically responsive health messaging addressing those KABs. Thirteen online focus groups (OFGs) in 10 languages were conducted. Each OFG was conducted in the participants' native language. OFGs were recorded, transcribed, translated and uploaded to qualitative software for coding. A thematic analysis was conducted. Results suggest that while there was some variation between different language groups (e.g. whether religious leaders were seen as trusted sources of information about COVID), there were also important commonalities. Most language groups (i) alluded to hearing about or having gaps in knowledge about COVID-19/the COVID-19 vaccine, (ii) reported hearing negative or conflicting stories about the vaccine and (iii) shared concerns about the negative side effects of the vaccine. There continues to be a need for health messaging in RIM communities that is culturally and linguistically concordant and follows health literacy guidelines. Message content about the COVID-19 vaccine should focus on vaccine importance, effectiveness and safety, should be multimodal and should be primarily delivered by healthcare professionals and community members who have already been vaccinated.


Assuntos
COVID-19 , Emigrantes e Imigrantes , Refugiados , Migrantes , Humanos , Vacinas contra COVID-19 , Cidades , Conhecimentos, Atitudes e Prática em Saúde , COVID-19/prevenção & controle
4.
Clin Radiol ; 77(2): e170-e179, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34916047

RESUMO

Adrenal vein sampling (AVS) is a recommended if not required final diagnostic step in the investigation of primary aldosteronism, the most common cause of remediable secondary hypertension. Successful adrenal vein sampling is operator-dependent. Having performed over 600 such procedures at our centre over 20 years, our single-operator experience is described in detail for the purpose of training future radiologists as well as for use by those who are planning to start an AVS programme of their own. This updated review considers new developments in primary aldosteronism disease understanding that are relevant for AVS performance and protocols, along with technical enhancements that may be used for special cases. Detailed understanding of variant anatomy and tips for successful cannulation are keys to success, along with an endocrinology and clinical chemistry partnership for continuous quality control. A successful AVS programme offers patients a hope for cure of resistant hypertension.


Assuntos
Glândulas Suprarrenais/irrigação sanguínea , Hiperaldosteronismo/diagnóstico , Humanos , Veias
5.
J Comput Assist Tomogr ; 46(2): 308-314, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35297586

RESUMO

OBJECTIVE: This study aimed to investigate the prognostic significance of dynamic contrast-enhanced computed tomography in patients with stage IA non-small cell lung cancer (NSCLC). METHODS: We retrospectively enrolled 139 patients (77 men, 62 women; mean age, 59 years) with stage IA NSCLC who underwent dynamic contrast-enhanced computed tomography. Data on age, pathologic subtype, peak enhancement, and net enhancement of primary lung cancer were collected and correlated with 5-year survival. RESULTS: Peak enhancement had a significant correlation with overall survival in the univariable analysis (hazard ratio [HR], 1.18, confidence interval [CI], 1.01-1.38; P = 0.04) and in the multivariable analysis (HR, 1.19; CI, 1.01-1.39; P = 0.04). Patients with peak enhancement of 90 Hounsfield unit or higher had a significantly increased risk of death compared with patients with less enhancement after curative surgery (HR, 4.15; CI, 1.23-13.95; P = 0.02). CONCLUSIONS: Our study confirmed the prognostic significance of peak enhancement as an indicator for the overall survival of stage IA NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos
6.
Chem Eng J ; 433: 133783, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-34853550

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibits strong stability on conventional stainless steel (SS) surface, with infectious virus detected even after two days, posing a high risk of virus transmission via surface touching in public areas. In order to mitigate the surface toughing transmission, the present study develops the first SS with excellent anti-pathogen properties against SARS-COV-2. The stabilities of SARS-CoV-2, H1N1 influenza A virus (H1N1), and Escherichia coli (E.coli) on the surfaces of Cu-contained SS, pure Cu, Ag-contained SS, and pure Ag were investigated. It is discovered that pure Ag and Ag-contained SS surfaces do not display apparent inhibitory effects on SARS-CoV-2 and H1N1. In comparison, both pure Cu and Cu-contained SS with a high Cu content exhibit significant antiviral properties. Significantly, the developed anti-pathogen SS with 20 wt% Cu can distinctly reduce 99.75% and 99.99% of viable SARS-CoV-2 on its surface within 3 and 6 h, respectively. In addition, the present anti-pathogen SS also exhibits an excellent inactivation ability for H1N1 influenza A virus (H1N1), and Escherichia coli (E.coli). Interestingly, the Cu ion concentration released from the anti-pathogen SS with 10 wt% and 20 wt% Cu was notably higher than the Ag ion concentration released from Ag and the Ag-contained SS. Lift buttons made of the present anti-pathogen SS are produced using mature powder metallurgy technique, demonstrating its potential applications in public areas and fighting the transmission of SARS-CoV-2 and other pathogens via surface touching.

7.
Int J Behav Nutr Phys Act ; 18(1): 6, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413484

RESUMO

BACKGROUND: Early childhood is a critical period for growth and development, yet the association with physical activity during this important period is unknown. The aim of this review is to critically summarize the evidence on the prospective associations between physical activity and health and development in children aged < 5 years. METHODS: A systematic search in three electronic databases (Pubmed, PsycINFO, and Sportdiscus) was conducted to identify prospective studies examining the associations between physical activity (all types; specified by quantity) and health indicators (body composition, cardiometabolic health, bone health and risks/harm) or development (motor, cognitive and social-emotional development) in young children (mean age < 5 years at baseline). Two independent researchers assessed the methodological quality using the 'Quality Assessment Tool for Quantitative Studies' (EPHPP). This tool covers eight quality criteria: selection bias, study design, confounders, blinding, data collection methods, withdrawals and drop-outs, intervention integrity and data-analysis. RESULTS: Thirty-nine studies, predominantly conducted in preschoolers (ages 3-5 years), were included of which nine were rated as high methodological quality. There was moderate evidence for a positive association between physical activity and motor (n = 11 studies) and cognitive development (n = 10 studies) based on consistent findings from studies having low-to-moderate methodological quality. There was insufficient evidence for an association between physical activity and body composition (n = 15 studies), cardiometabolic health indicators (n = 7 studies), social-emotional development (n = 2 studies) and bone health (n = 2 studies) based on inconsistent findings from studies having weak-to-high methodological quality. CONCLUSIONS: There is a need for more high-quality research in order to determine the dose-response relationship between physical activity and health and development in early childhood. Special attention should be paid to studies in children below the age of 3 years.


Assuntos
Desenvolvimento Infantil , Saúde da Criança , Exercício Físico , Saúde do Lactente , Pré-Escolar , Feminino , Humanos , Lactente , Masculino
8.
J Endocrinol Invest ; 44(12): 2809-2817, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34003462

RESUMO

PURPOSE: Many patients who undergo bone marrow transplantation (BMT) in adulthood experience unexplained chronic fatigue which can have a major impact on their health-related quality of life (QoL). Pre-BMT treatment regimens increase the risk of developing acquired growth hormone deficiency (GHD), which results in a clinical syndrome with decreased energy and has additionally been linked to metabolic syndrome. METHODS: Using the gold-standard insulin hypoglycemic test (IHT), we evaluated the prevalence of GHD in 18 post-BMT adult patients with unexplained chronic fatigue, as well as the correlation between peak serum GH response and QoL scores, the metabolic syndrome, and insulin resistance. Peak serum GH cut-point less than 3.0 ug/L was used for the diagnosis of severe GHD. The Fatigue Severity Scale and Quality of Life in Adult GHD Assessment questionnaires were used to quantify fatigue symptoms. RESULTS: The prevalence of severe GHD within this sample of 18 patients was 50%. A trend between lower peak serum GH response and higher fatigue and QoL-AGHDA scores was observed. CONCLUSIONS: GHD may represent a remediable contributor to post-BMT chronic fatigue in adults, further studies are needed to evaluate the potential role of screening and GH replacement therapy in this vulnerable patient population. IMPLICATIONS FOR CANCER SURVIVORS: GHD may be a treatable explanation for disabling post-BMT fatigue pending results of intervention studies.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Síndrome de Fadiga Crônica , Hormônio do Crescimento , Síndrome Metabólica , Complicações Pós-Operatórias , Qualidade de Vida , Transplante de Medula Óssea/métodos , Sobreviventes de Câncer , Estudos Transversais , Síndrome de Fadiga Crônica/etiologia , Síndrome de Fadiga Crônica/metabolismo , Síndrome de Fadiga Crônica/psicologia , Síndrome de Fadiga Crônica/terapia , Feminino , Hormônio do Crescimento/sangue , Hormônio do Crescimento/deficiência , Terapia de Reposição Hormonal/métodos , Humanos , Resistência à Insulina , Masculino , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/etiologia , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/metabolismo , Complicações Pós-Operatórias/psicologia , Complicações Pós-Operatórias/terapia , Prevalência , Inquéritos e Questionários , Avaliação de Sintomas/métodos
9.
Proc Natl Acad Sci U S A ; 115(15): E3559-E3568, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29581270

RESUMO

A de novo mutation in the KCND2 gene, which encodes the Kv4.2 K+ channel, was identified in twin boys with intractable, infant-onset epilepsy and autism. Kv4.2 channels undergo closed-state inactivation (CSI), a mechanism by which channels inactivate without opening during subthreshold depolarizations. CSI dynamically modulates neuronal excitability and action potential back propagation in response to excitatory synaptic input, controlling Ca2+ influx into dendrites and regulating spike timing-dependent plasticity. Here, we show that the V404M mutation specifically affects the mechanism of CSI, enhancing the inactivation of channels that have not opened while dramatically impairing the inactivation of channels that have opened. The mutation gives rise to these opposing effects by increasing the stability of the inactivated state and in parallel, profoundly slowing the closure of open channels, which according to our data, is required for CSI. The larger volume of methionine compared with valine is a major factor underlying altered inactivation gating. Our results suggest that V404M increases the strength of the physical interaction between the pore gate and the voltage sensor regardless of whether the gate is open or closed. Furthermore, in contrast to previous proposals, our data strongly suggest that physical coupling between the voltage sensor and the pore gate is maintained in the inactivated state. The state-dependent effects of V404M on CSI are expected to disturb the regulation of neuronal excitability and the induction of spike timing-dependent plasticity. Our results strongly support a role for altered CSI gating in the etiology of epilepsy and autism in the affected twins.


Assuntos
Transtorno Autístico/genética , Epilepsia/genética , Canais de Potássio Shal/genética , Animais , Transtorno Autístico/metabolismo , Epilepsia/metabolismo , Feminino , Humanos , Proteínas Interatuantes com Canais de Kv/genética , Proteínas Interatuantes com Canais de Kv/metabolismo , Potenciais da Membrana/fisiologia , Mutação , Oócitos/fisiologia , Técnicas de Patch-Clamp/métodos , Polimorfismo Genético , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Canais de Potássio Shal/metabolismo , Transfecção , Xenopus laevis
10.
Br J Sports Med ; 53(13): 812, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30181323

RESUMO

OBJECTIVE: To optimally target exercise interventions for patients with cancer, it is important to identify which patients benefit from which interventions. DESIGN: We conducted an individual patient data meta-analysis to investigate demographic, clinical, intervention-related and exercise-related moderators of exercise intervention effects on physical fitness in patients with cancer. DATA SOURCES: We identified relevant studies via systematic searches in electronic databases (PubMed, Embase, PsycINFO and CINAHL). ELIGIBILITY CRITERIA: We analysed data from 28 randomised controlled trials investigating the effects of exercise on upper body muscle strength (UBMS) and lower body muscle strength (LBMS), lower body muscle function (LBMF) and aerobic fitness in adult patients with cancer. RESULTS: Exercise significantly improved UBMS (ß=0.20, 95% Confidence Interval (CI) 0.14 to 0.26), LBMS (ß=0.29, 95% CI 0.23 to 0.35), LBMF (ß=0.16, 95% CI 0.08 to 0.24) and aerobic fitness (ß=0.28, 95% CI 0.23 to 0.34), with larger effects for supervised interventions. Exercise effects on UBMS were larger during treatment, when supervised interventions included ≥3 sessions per week, when resistance exercises were included and when session duration was >60 min. Exercise effects on LBMS were larger for patients who were living alone, for supervised interventions including resistance exercise and when session duration was >60 min. Exercise effects on aerobic fitness were larger for younger patients and when supervised interventions included aerobic exercise. CONCLUSION: Exercise interventions during and following cancer treatment had small effects on UBMS, LBMS, LBMF and aerobic fitness. Demographic, intervention-related and exercise-related characteristics including age, marital status, intervention timing, delivery mode and frequency and type and time of exercise sessions moderated the exercise effect on UBMS, LBMS and aerobic fitness.


Assuntos
Terapia por Exercício/métodos , Força Muscular/fisiologia , Doenças Musculares/fisiopatologia , Doenças Musculares/terapia , Neoplasias/fisiopatologia , Aptidão Física/fisiologia , Humanos , Qualidade de Vida
12.
Nat Mater ; 16(2): 208-213, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27643731

RESUMO

Electronic defect states at material interfaces provide highly deleterious sources of noise in solid-state nanostructures, and even a single trapped charge can qualitatively alter the properties of short one-dimensional nanowire field-effect transistors (FET) and quantum bit (qubit) devices. Understanding the dynamics of trapped charge is thus essential for future nanotechnologies, but their direct detection and manipulation is rather challenging. Here, a transistor-based set-up is used to create and probe individual electronic defect states that can be coherently driven with microwave (MW) pulses. Strikingly, we resolve a large number of very high quality (Q ∼ 1 × 105) resonances in the transistor current as a function of MW frequency and demonstrate both long decoherence times (∼1 µs-40 µs) and coherent control of the defect-induced dynamics. Efficiently characterizing over 800 individually addressable resonances across two separate defect-hosting materials, we propose that their properties are consistent with weakly driven two-level systems.

13.
Acta Anaesthesiol Scand ; 62(6): 839-847, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29399781

RESUMO

BACKGROUND: Management of labor epidurals in obese women is difficult and extension to surgical anesthesia is not always successful. Our previous retrospective pilot study found epidural extension was more likely to fail in obese women. This study used a prospective cohort to compare the failure rate of epidural extension in obese and non-obese women and to identify risk factors for extension failure. METHODS: One hundred obese participants (Group O, body mass index ≥ 40 kg/m2 ) were prospectively identified and allocated two sequential controls (Group C, body mass index ≤ 30 kg/m2 ). All subjects utilized epidural labor analgesia and subsequently required anesthesia for cesarean section. The primary outcome measure was failure of the labor epidural to be used as the primary anesthetic technique. Risk factors for extension failure were identified using Chi-squared and logistic regression. RESULTS: The odds ratio (OR) of extension failure was 1.69 in Group O (20% vs. 13%; 95% CI: 0.88-3.21, P = 0.11). Risk factors for failure in obese women included ineffective labor analgesia requiring anesthesiologist intervention, (OR 3.94, 95% CI: 1.16-13.45, P = 0.028) and BMI > 50 kg/m2 (OR 3.42, 95% CI: 1.07-10.96, P = 0.038). CONCLUSION: The failure rate of epidural extension did not differ significantly between the groups. Further research is needed to determine the influence of body mass index > 50 kg/m2 on epidural extension for cesarean section.


Assuntos
Analgesia Epidural/efeitos adversos , Analgesia Obstétrica/efeitos adversos , Obesidade/complicações , Adulto , Índice de Massa Corporal , Feminino , Humanos , Gravidez , Estudos Prospectivos
14.
Anaesthesia ; 73(4): 466-473, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29322504

RESUMO

Ultrasound assistance for neuraxial techniques may improve technical performance; however, it is unclear which populations benefit most. Our study aimed to investigate the efficacy of neuraxial ultrasound in women having caesarean section with combined spinal-epidural anaesthesia, and to identify factors associated with improved technical performance. Two-hundred and eighteen women were randomly allocated to ultrasound-assisted or control groups. All the women had a pre-procedure ultrasound, but only women in the ultrasound group had this information conveyed to the anaesthetist. Primary outcomes were first-pass success (a single needle insertion with no redirections) and procedure difficulty. Secondary outcomes were block quality, patient experience and complications. Exploratory sub-group analysis and regression analysis were used to identify factors associated with success. Data from 215 women were analysed. First-pass success was achieved in 67 (63.8%) and 42 (38.2%) women in the ultrasound and control groups, respectively (adjusted p = 0.001). Combined spinal-epidural anaesthesia was 'difficult' in 19 (18.1%) and 33 (30.0%) women in the ultrasound and control groups, respectively (adjusted p = 0.09). Secondary outcomes did not differ significantly. Anaesthetists misidentified the intervertebral level by two or more spaces in 23 (10.7%) women. Sub-group analysis demonstrated a benefit for ultrasound in women with easily palpable spinous processes (adjusted p = 0.027). Regression analysis identified use of ultrasound and easily palpable spinous processes to be associated with first-pass success.


Assuntos
Anestesia Epidural/métodos , Anestesia Obstétrica/métodos , Raquianestesia/métodos , Cesárea , Ultrassonografia de Intervenção/métodos , Adulto , Pontos de Referência Anatômicos/diagnóstico por imagem , Espaço Epidural/diagnóstico por imagem , Feminino , Humanos , Vértebras Lombares/diagnóstico por imagem , Agulhas , Gravidez , Adulto Jovem
15.
Opt Express ; 25(15): 17695-17700, 2017 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-28789261

RESUMO

We present a fiber-coupled pump-module emitting more than 1kW of mode-stripped power at 976nm from a detachable 225µm, 0.22NA fiber. The electrical-to-optical efficiency at 1kW is ~50%. Six of these pump modules attached to a (6 + 1):1 multimode combiner enable a 5-6kW, single-mode, Yb-doped fiber amplifier.

17.
Hum Mol Genet ; 23(13): 3481-9, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24501278

RESUMO

Numerous studies and case reports show comorbidity of autism and epilepsy, suggesting some common molecular underpinnings of the two phenotypes. However, the relationship between the two, on the molecular level, remains unclear. Here, whole exome sequencing was performed on a family with identical twins affected with autism and severe, intractable seizures. A de novo variant was identified in the KCND2 gene, which encodes the Kv4.2 potassium channel. Kv4.2 is a major pore-forming subunit in somatodendritic subthreshold A-type potassium current (ISA) channels. The de novo mutation p.Val404Met is novel and occurs at a highly conserved residue within the C-terminal end of the transmembrane helix S6 region of the ion permeation pathway. Functional analysis revealed the likely pathogenicity of the variant in that the p.Val404Met mutant construct showed significantly slowed inactivation, either by itself or after equimolar coexpression with the wild-type Kv4.2 channel construct consistent with a dominant effect. Further, the effect of the mutation on closed-state inactivation was evident in the presence of auxiliary subunits that associate with Kv4 subunits to form ISA channels in vivo. Discovery of a functionally relevant novel de novo variant, coupled with physiological evidence that the mutant protein disrupts potassium current inactivation, strongly supports KCND2 as the causal gene for epilepsy in this family. Interaction of KCND2 with other genes implicated in autism and the role of KCND2 in synaptic plasticity provide suggestive evidence of an etiological role in autism.


Assuntos
Transtorno Autístico/genética , Exoma/genética , Mutação de Sentido Incorreto/genética , Canais de Potássio/metabolismo , Convulsões/genética , Canais de Potássio Shal/genética , Eletrofisiologia , Feminino , Humanos , Masculino , Mutação , Linhagem , Canais de Potássio/genética , Canais de Potássio Shal/metabolismo
18.
Diabetes Obes Metab ; 18(11): 1128-1133, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27403645

RESUMO

AIMS: Greater reductions in glycated haemoglobin (HbA1c) with saxagliptin, a dipeptidyl peptidase-4 inhibitor, versus placebo add-on in patients with type 2 diabetes who had inadequate glycaemic control with dapagliflozin 10 mg/d plus metformin were demonstrated after 24 weeks of treatment. Results over 52 weeks of treatment were assessed in this analysis. MATERIALS AND METHODS: Patients (mean baseline HbA1c 7.9%) receiving open-label dapagliflozin 10 mg/d plus metformin were randomized to double-blind saxagliptin 5 mg/d or placebo add-on. RESULTS: The adjusted mean change from baseline to week 52 in HbA1c was greater with saxagliptin than with placebo add-on -0.38% vs 0.05%; difference -0.42% (95% confidence interval -0.64, -0.20)]. More patients achieved the HbA1c target of <7% with saxagliptin than with placebo add-on (29% vs 13%), and fewer patients were rescued or discontinued the study for lack of glycaemic control with saxagliptin than with placebo add-on (19% vs 28%). Reductions from baseline in body weight (≤1.5 kg) occurred in both groups. Similar proportions of patients reported ≥1 adverse event with saxagliptin (58.2%) and placebo add-on (58.0%); no new safety signals were detected. Hypoglycaemia was infrequent in both treatment groups (≤2.5%), with no major episodes. The rate of urinary tract infections was similar in the saxagliptin and placebo add-on groups (7.8% vs 7.4%). The incidence of genital infections was 3.3% with saxagliptin versus 6.2% with placebo add-on. CONCLUSIONS: Triple therapy with saxagliptin add-on to dapagliflozin plus metformin for 52 weeks resulted in sustained improvements in glycaemic control without an increase in body weight or increased risk of hypoglycaemia.


Assuntos
Adamantano/análogos & derivados , Compostos Benzidrílicos/administração & dosagem , Dipeptídeos/administração & dosagem , Glucosídeos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Adamantano/administração & dosagem , Adamantano/efeitos adversos , Adulto , Idoso , Compostos Benzidrílicos/efeitos adversos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptídeos/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Feminino , Glucosídeos/efeitos adversos , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemia/sangue , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Masculino , Metformina/efeitos adversos , Pessoa de Meia-Idade , Resultado do Tratamento
19.
Cell Mol Life Sci ; 72(17): 3387-99, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25854634

RESUMO

The dominantly inherited cerebellar ataxias are a heterogeneous group of neurodegenerative disorders caused by Purkinje cell loss in the cerebellum. Recently, we identified loss-of-function mutations in the KCND3 gene as the cause of spinocerebellar ataxia type 19/22 (SCA19/22), revealing a previously unknown role for the voltage-gated potassium channel, Kv4.3, in Purkinje cell survival. However, how mutant Kv4.3 affects wild-type Kv4.3 channel functioning remains unknown. We provide evidence that SCA19/22-mutant Kv4.3 exerts a dominant negative effect on the trafficking and surface expression of wild-type Kv4.3 in the absence of its regulatory subunit, KChIP2. Notably, this dominant negative effect can be rescued by the presence of KChIP2. We also found that all SCA19/22-mutant subunits either suppress wild-type Kv4.3 current amplitude or alter channel gating in a dominant manner. Our findings suggest that altered Kv4.3 channel localization and/or functioning resulting from SCA19/22 mutations may lead to Purkinje cell loss, neurodegeneration and ataxia.


Assuntos
Mutação/genética , Células de Purkinje/metabolismo , Canais de Potássio Shal/metabolismo , Degenerações Espinocerebelares/genética , Análise de Variância , Cicloeximida , Primers do DNA/genética , Células HeLa , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Mutagênese Sítio-Dirigida , Canais de Potássio Shal/genética
20.
Clin Otolaryngol ; 41(3): 259-75, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26264703

RESUMO

BACKGROUND: The Glasgow Benefit Inventory (GBI) is a validated, generic patient-recorded outcome measure widely used in otolaryngology to report change in quality of life post-intervention. OBJECTIVES OF REVIEW: To date, no systematic review has made (i) a quality assessment of reporting of Glasgow Benefit Inventory outcomes; (ii) a comparison between Glasgow Benefit Inventory outcomes for different interventions and objectives; (iii) an evaluation of subscales in describing the area of benefit; (iv) commented on its value in clinical practice and research. TYPE OF REVIEW: Systematic review. SEARCH STRATEGY: 'Glasgow Benefit Inventory' and 'GBI' were used as keywords to search for published, unpublished and ongoing trials in PubMed, EMBASE, CINAHL and Google in addition to an ISI citation search for the original validating Glasgow Benefit Inventory paper between 1996 and January 2015. EVALUATION METHOD: Papers were assessed for study type and quality graded by a predesigned scale, by two authors independently. Papers with sufficient quality Glasgow Benefit Inventory data were identified for statistical comparisons. Papers with <50% follow-up were excluded. RESULTS: A total of 118 eligible papers were identified for inclusion. A national audit paper (n = 4325) showed that the Glasgow Benefit Inventory gave a range of scores across the specialty, being greater for surgical intervention than medical intervention or 'reassurance'. Fourteen papers compared one form of surgery versus another form of surgery. In all but one study, there was no difference between the Glasgow Benefit Inventory scores (or of any other outcome). The most likely reason was lack of power. Two papers took an epidemiological approach and used the Glasgow Benefit Inventory scores to predict benefit. One was for tonsillectomy where duration of sore throat episodes and days with fever were identified on multivariate analysis to predict benefit albeit the precision was low. However, the traditional factor of number of episodes of sore throat was not predictive. The other was surgery for chronic rhinosinusitis where those with polyps on univariate analysis had greater benefit than those without. Forty-three papers had a response rate of >50% and gave sufficient Glasgow Benefit Inventory total and subscales for meta-analysis. For five of the 11 operation categories (vestibular schwannoma, tonsillectomy, cochlear implant, middle ear implant and stapes surgery) that were most likely to have a single clear clinical objective, score data had low-to-moderate heterogeneity. The value in the Glasgow Benefit Inventory having both positive and negative scores was shown by an overall negative score for the management of vestibular schwannoma. The other six operations gave considerable heterogeneity with rhinoplasty and septoplasty giving the greatest percentages (98% and 99%) most likely because of the considerable variations in patient selection. The data from these operations should not be used for comparative purposes. Five papers also reported the number of patients that had no or negative benefit, a potentially a more clinically useful outcome to report. Glasgow Benefit Inventory subscores for tonsillectomy were significantly different from ear surgery suggesting different areas of benefit CONCLUSIONS: The Glasgow Benefit Inventory has been shown to differentiate the benefit between surgical and medical otolaryngology interventions as well as 'reassurance'. Reporting benefit as percentages with negative, no and positive benefit would enable better comparisons between different interventions with varying objectives and pathology. This could also allow easier evaluation of factors that predict benefit. Meta-analysis data are now available for comparison purposes for vestibular schwannoma, tonsillectomy, cochlear implant, middle ear implant and stapes surgery. Fuller report of the Glasgow Benefit Inventory outcomes for non-surgical otolaryngology interventions is encouraged.


Assuntos
Otolaringologia , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Humanos
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