RESUMEN
A man in his 90s presented with acute monocular loss of vision; the emergency department triage alerted the stroke team. He underwent urgent parallel assessments by the stroke and ophthalmology teams and was diagnosed with central retinal artery occlusion. The ultimate decision was made to manage him conservatively, rather than with intravenous thrombolysis, and his visual function has remained poor. We discuss the current evidence for using intravenous thrombolysis in people with central retinal artery occlusion and use this case to exemplify the practical issues that must be overcome if ongoing randomised clinical trials of central retinal artery occlusion confirm a definite benefit from using intravenous thrombolysis.
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Oclusión de la Arteria Retiniana , Accidente Cerebrovascular , Humanos , Masculino , Oclusión de la Arteria Retiniana/terapia , Oclusión de la Arteria Retiniana/diagnóstico , Accidente Cerebrovascular/terapia , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico , Anciano de 80 o más Años , Trastornos de la Visión/diagnóstico , Trastornos de la Visión/terapia , Terapia Trombolítica/métodos , Ceguera/etiologíaRESUMEN
Hatha yoga is commonly practiced in Western countries and is claimed to reduce risk of cardiovascular disease. The purpose of this study was to evaluate and compare time-domain and frequency-domain metrics of heart rate variability (HRV) in Hatha yoga practitioners and healthy controls. This cross-sectional study, which was conducted at a regional university and community wellness center, included convenience sampling of 19 Hatha yoga practitioners and 8 healthy controls. Using a lead II ECG system, 10 minutes of electrocardiogram (ECG) recording was collected for each participant. Artifact-free, 5-minute signals were used to derive time-domain and frequency-domain measures of HRV. The mean duration of Hatha yoga practice among practitioners was 11.47 ± 8 years. Demographic and anthropometric characteristics did not differ significantly between groups. Compared with the control group, the yoga group had significantly greater mean high frequency (HF) power (859.2 ± 1342.1 vs 175.5 ± 121.1; P = .04) and mean HF normalized units (nu) (57.0 ± 16.6 vs 36.7 ± 13.4; P = .02) and a significantly lower low frequency (LF)/HF ratio (1.1 ± 0.5 vs 2.2 ± 1.1; P = .01). No significant intergroup differences were observed for LF power, LF nu, or any time-domain measures of HRV. These results lack generalizability due to small sample size and lack of blinded assessment of outcome measures. Hatha yoga practitioners showed parasympathetic predominance compared with healthy controls. Analyzing frequency-domain HRV metrics enables detecting changes in cardiac autonomic function earlier than by analysis of time-domain metrics. Parasympathetic predominance demonstrated in the yoga group suggests Hatha yoga practitioners may be at lower risk for stress-related comorbidities.
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Enfermedades Cardiovasculares , Yoga , Humanos , Enfermedades Cardiovasculares/prevención & control , Frecuencia Cardíaca/fisiología , Estudios Transversales , Factores de Riesgo , Factores de Riesgo de Enfermedad CardiacaRESUMEN
The hereditary spastic paraplegias (HSP) are among the most genetically diverse of all Mendelian disorders. They comprise a large group of neurodegenerative diseases that may be divided into 'pure HSP' in forms of the disease primarily entailing progressive lower-limb weakness and spasticity, and 'complex HSP' when these features are accompanied by other neurological (or non-neurological) clinical signs. Here, we identified biallelic variants in the transmembrane protein 63C (TMEM63C) gene, encoding a predicted osmosensitive calcium-permeable cation channel, in individuals with hereditary spastic paraplegias associated with mild intellectual disability in some, but not all cases. Biochemical and microscopy analyses revealed that TMEM63C is an endoplasmic reticulum-localized protein, which is particularly enriched at mitochondria-endoplasmic reticulum contact sites. Functional in cellula studies indicate a role for TMEM63C in regulating both endoplasmic reticulum and mitochondrial morphologies. Together, these findings identify autosomal recessive TMEM63C variants as a cause of pure and complex HSP and add to the growing evidence of a fundamental pathomolecular role of perturbed mitochondrial-endoplasmic reticulum dynamics in motor neurone degenerative diseases.
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Canales de Calcio , Mitocondrias , Paraplejía Espástica Hereditaria , Canales de Calcio/genética , Retículo Endoplásmico/genética , Humanos , Mitocondrias/patología , Mutación , Paraplejía Espástica Hereditaria/genéticaRESUMEN
Digital health technologies (DHTs) have great potential for use as clinical trial outcomes; however, practical issues need to be addressed in order to maximise their benefit. We describe our experience of incorporating two DHTs as secondary/exploratory outcome measures in PD STAT, a randomised clinical trial of simvastatin in people with Parkinson's disease. We found much higher rates of missing data in the DHTs than the traditional outcome measures, in particular due to technical and software difficulties. We discuss methods to address these obstacles in terms of protocol design, workforce training and data management.
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Enfermedad de Parkinson , Tecnología Biomédica , Humanos , Evaluación de Resultado en la Atención de Salud , Enfermedad de Parkinson/terapiaRESUMEN
The highly evolutionarily conserved transport protein particle (TRAPP) complexes (TRAPP II and III) perform fundamental roles in subcellular trafficking pathways. Here we identified biallelic variants in TRAPPC10, a component of the TRAPP II complex, in individuals with a severe microcephalic neurodevelopmental disorder. Molecular studies revealed a weakened interaction between mutant TRAPPC10 and its putative adaptor protein TRAPPC2L. Studies of patient lymphoblastoid cells revealed an absence of TRAPPC10 alongside a concomitant absence of TRAPPC9, another key TRAPP II complex component associated with a clinically overlapping neurodevelopmental disorder. The TRAPPC9/10 reduction phenotype was recapitulated in TRAPPC10-/- knockout cells, which also displayed a membrane trafficking defect. Notably, both the reduction in TRAPPC9 levels and the trafficking defect in these cells could be rescued by wild type but not mutant TRAPPC10 gene constructs. Moreover, studies of Trappc10-/- knockout mice revealed neuroanatomical brain defects and microcephaly, paralleling findings seen in the human condition as well as in a Trappc9-/- mouse model. Together these studies confirm autosomal recessive TRAPPC10 variants as a cause of human disease and define TRAPP-mediated pathomolecular outcomes of importance to TRAPPC9 and TRAPPC10 mediated neurodevelopmental disorders in humans and mice.
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Microcefalia , Trastornos del Neurodesarrollo , Animales , Humanos , Ratones , Microcefalia/genética , Trastornos del Neurodesarrollo/genética , FenotipoRESUMEN
The genetic landscape of Parkinson's disease (PD) is characterised by rare high penetrance pathogenic variants causing familial disease, genetic risk factor variants driving PD risk in a significant minority in PD cases and high frequency, low penetrance variants, which contribute a small increase of the risk of developing sporadic PD. This knowledge has the potential to have a major impact in the clinical care of people with PD. We summarise these genetic influences and discuss the implications for therapeutics and clinical trial design.
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Predisposición Genética a la Enfermedad , Mutación , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/terapia , Polimorfismo de Nucleótido Simple , Humanos , Enfermedad de Parkinson/genética , PenetranciaRESUMEN
OBJECTIVE: Central nervous system (CNS) features in children with permanent neonatal diabetes (PNDM) due to KCNJ11 mutations have a major impact on affected families. Sulfonylurea therapy achieves outstanding metabolic control but only partial improvement in CNS features. The effects of KCNJ11 mutations on the adult brain and their functional impact are not well understood. We aimed to characterize the CNS features in adults with KCNJ11 PNDM compared with adults with INS PNDM. RESEARCH DESIGN AND METHODS: Adults with PNDM due to KCNJ11 mutations (n = 8) or INS mutations (n = 4) underwent a neurological examination and completed standardized neuropsychological tests/questionnaires about development/behavior. Four individuals in each group underwent a brain MRI scan. Test scores were converted to Z scores using normative data, and outcomes were compared between groups. RESULTS: In individuals with KCNJ11 mutations, neurological examination was abnormal in seven of eight; predominant features were subtle deficits in coordination/motor sequencing. All had delayed developmental milestones and/or required learning support/special schooling. Half had features and/or a clinical diagnosis of autism spectrum disorder. KCNJ11 mutations were also associated with impaired attention, working memory, and perceptual reasoning and reduced intelligence quotient (IQ) (median IQ KCNJ11 vs. INS mutations 76 vs. 111, respectively; P = 0.02). However, no structural brain abnormalities were noted on MRI. The severity of these features was related to the specific mutation, and they were absent in individuals with INS mutations. CONCLUSIONS: KCNJ11 PNDM is associated with specific CNS features that are not due to long-standing diabetes, persist into adulthood despite sulfonylurea therapy, and represent the major burden from KCNJ11 mutations.
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Conducta/fisiología , Sistema Nervioso Central/fisiología , Cognición/fisiología , Diabetes Mellitus/genética , Diabetes Mellitus/psicología , Canales de Potasio de Rectificación Interna/genética , Adolescente , Adulto , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/etiología , Encéfalo/diagnóstico por imagen , Sistema Nervioso Central/diagnóstico por imagen , Sistema Nervioso Central/fisiopatología , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Femenino , Humanos , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación/fisiología , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/epidemiología , Enfermedades del Sistema Nervioso/etiología , Examen Neurológico , Adulto JovenRESUMEN
Reactive sulfur species (RSS) are biologically important molecules. Among them, H2 S, hydrogen polysulfides (H2 Sn, n>1), persulfides (RSSH), and HSNO are believed to play regulatory roles in sulfur-related redox biology. However, these molecules are unstable and difficult to handle. Having access to their reliable and controllable precursors (or donors) is the prerequisite for the study of these sulfur species. Reported in this work is the preparation and evaluation of a series of O-silyl-mercaptan-based sulfur-containing molecules which undergo pH- or F- -mediated desilylation to release the corresponding H2 S, H2 Sn , RSSH, and HSNO in a controlled fashion. This OâS relay deprotection serves as a general strategy for the design of pH- or F- -triggered RSS donors. Moreover, we have demonstrated that the O-silyl groups in the donors could be changed into other protecting groups like esters. This work should allow the development of RSS donors with other activation mechanisms (such as esterase-activated donors).
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Oxígeno/química , Azufre/química , Concentración de Iones de Hidrógeno , Estructura MolecularRESUMEN
Near-infrared (NIR) fluorescent dyes with favorable photophysical properties are highly useful for bioimaging, but such dyes are still rare. The development of a unique class of NIR dyes via modifying the rhodol scaffold with fused tetrahydroquinoxaline rings is described. These new dyes showed large Stokes shifts (>110â nm). Among them, WR3, WR4, WR5, and WR6 displayed high fluorescence quantum yields and excellent photostability in aqueous solutions. Moreover, their fluorescence properties were tunable by easy modifications on the phenolic hydroxy group. Based on WR6, two NIR fluorescent turn-on probes, WSP-NIR and SeSP-NIR, were devised for the detection of H2 S. The probe SeSP-NIR was applied in visualizing intracellular H2 S. These dyes are expected to be useful fluorophore scaffolds in the development of new NIR probes for bioimaging.
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Colorantes Fluorescentes/química , Sulfuro de Hidrógeno/análisis , Espectroscopía Infrarroja Corta , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Microscopía Fluorescente , Xantonas/químicaAsunto(s)
Malformación de Arnold-Chiari/complicaciones , Malformación de Arnold-Chiari/diagnóstico por imagen , Cefaleas Secundarias/etiología , Parestesia/etiología , Siringomielia/complicaciones , Siringomielia/diagnóstico por imagen , Vértigo/etiología , Adulto , Vértebras Cervicales/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Médula Espinal/diagnóstico por imagenRESUMEN
As an important endogenous gaseous signaling molecule, hydrogen sulfide (H2S) exerts various effects in the body. A variety of pathological changes, such as cancer, glycometabolic disorders, and diabetes, are associated with altered endogenous levels of H2S, especially decreased. Therefore, the supplement of H2S is of great significance for the treatment of diseases containing the above pathological changes. At present, many efforts have been made to increase the in vivo levels of H2S by administration of gaseous H2S, simple inorganic sulfide salts, sophisticated synthetic slow-releasing controllable H2S donors or materials, and using H2S stimulating agents. In this article, we reviewed the recent development of H2S releasing/stimulating reagents and their potential applications in two common pathological processes including cancer and glycometabolic disorders.
RESUMEN
Sulfinic acids are commonly encountered intermediates found in natural product synthesis and medicinal chemistry. However, because of high reactivity, instability, and harsh reaction conditions, they are difficult to synthesize. Herein we have developed an oxidation-free method to produce sulfinic acids and sulfinate salts using 2-sulfinyl benzothiazole (BTS). We have also demonstrated the synthetic usefulness by developing one-pot syntheses of sulfones and sulfonamides.
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Benzotiazoles/química , Indicadores y Reactivos , Estructura Molecular , Oxidación-Reducción , Ácidos SulfínicosRESUMEN
Here we report the model studies of the reactions between NADH models (using HEH and BNAH) and sulfane sulfurs (using polysulfides). Such reactions could lead to the oxidation of NADH models and the production of hydrogen sulfide (H2S). Kinetics of the reaction between BNAH and elemental sulfur S8 were determined in ethanol and the second-order rate constant was found to be 0.074M-1min-1 (at 37°C) suggesting this is a slow process.
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Sulfuro de Hidrógeno/síntesis química , NAD/química , Compuestos de Azufre/química , Sulfuro de Hidrógeno/química , Estructura Molecular , Oxidación-ReducciónRESUMEN
Hydrogen sulfide (H2 S) and hydrogen polysulfides (H2 Sn , n>1) are endogenous regulators of many physiological processes. In order to better understand the symbiotic relationship and cellular cross-talk between H2 S and H2 Sn , it is highly desirable to develop single fluorescent probes which enable dual-channel discrimination between H2 S and H2 Sn . Herein, we report the rational design, synthesis, and evaluation of the first dual-detection fluorescent probe DDP-1 that can visualize H2 S and H2 Sn with different fluorescence signals. The probe showed high selectivity and sensitivity to H2 S and H2 Sn in aqueous media and in cells.
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Fluorescencia , Colorantes Fluorescentes/química , Sulfuro de Hidrógeno/análisis , Sulfuros/análisis , Células HeLa , Humanos , Estructura Molecular , Espectrometría de FluorescenciaRESUMEN
Sulfur dioxide (SO2) has long been considered a toxic environmental pollutant and byproduct of industrial processing. Recently it has become evident that SO2 may also have regulatory functions in mammalian pulmonary systems. However, the study of these effects has proven to be challenging due to the difficulty in administering SO2 in a reliable manner. In this work, we report the discovery of a new pH-dependent and water-soluble SO2 donor, benzothiazole sulfinate (BTS). We have found BTS to have slow and sustained SO2 release at physiological pH. Additionally, we have explored its vasorelaxation properties as compared to the authentic SO2 gas solutions. The slow release of BTS should make it a useful tool for the study of endogenously generated SO2.
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Benzotiazoles/farmacología , Fármacos Cardiovasculares/farmacología , Ácidos Sulfínicos/farmacología , Dióxido de Azufre/metabolismo , Vasodilatadores/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Benzotiazoles/síntesis química , Fármacos Cardiovasculares/síntesis química , Fármacos Cardiovasculares/química , Línea Celular , Concentración de Iones de Hidrógeno , Masculino , Ratones , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Norepinefrina/farmacología , Ratas Wistar , Solubilidad , Ácidos Sulfínicos/síntesis química , Dióxido de Azufre/farmacología , Porcinos , Vasodilatadores/síntesis químicaRESUMEN
The development of a functional disulfide, FmSSPy-A (Fm = 9-fluorenylmethyl; Py = pyridinyl), is reported. It can effectively convert small molecule and protein thiols (-SH) to form -S-SFm adducts under mild conditions. This method allows for a H2S-free and biomimetic protocol to generate highly reactive persulfides (in their anionic forms). The high nucleophilicity of persulfides toward a number of thiol-blocking reagents is also demonstrated. The method holds promise for further understanding the chemical biology of persulfides and S-sulfhydration.
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Disulfuros/química , Fluorenos/química , Sulfuros/química , Biomimética , Estructura MolecularRESUMEN
Recent studies conducted in hydrogen sulfide (H2S) signaling have revealed potential importance of persulfides (RSSH) in redox biology. The inherent instability of RSSH makes these species difficult to study and sometimes controversial results are reported. In this review article we summarize known knowledge about both small molecule persulfides and protein persulfides. Their fundamental physical and chemical properties such as preparation/formation and reactivity are discussed. The biological implications of persulfides and their detection methods are also discussed.
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Sulfuros/metabolismo , Animales , Antioxidantes/química , Antioxidantes/metabolismo , Vías Biosintéticas , Humanos , Oxidación-Reducción , Transducción de Señal , Sulfuros/químicaRESUMEN
Excessive checking is a common, debilitating symptom of obsessive-compulsive disorder (OCD). In an established rodent model of OCD checking behaviour, quinpirole (dopamine D2/3-receptor agonist) increased checking in open-field tests, indicating dopaminergic modulation of checking-like behaviours. We designed a novel operant paradigm for rats (observing response task (ORT)) to further examine cognitive processes underpinning checking behaviour and clarify how and why checking develops. We investigated i) how quinpirole increases checking, ii) dependence of these effects on D2/3 receptor function (following treatment with D2/3 receptor antagonist sulpiride) and iii) effects of reward uncertainty. In the ORT, rats pressed an 'observing' lever for information about the location of an 'active' lever that provided food reinforcement. High- and low-checkers (defined from baseline observing) received quinpirole (0.5mg/kg, 10 treatments) or vehicle. Parametric task manipulations assessed observing/checking under increasing task demands relating to reinforcement uncertainty (variable response requirement and active-lever location switching). Treatment with sulpiride further probed the pharmacological basis of long-term behavioural changes. Quinpirole selectively increased checking, both functional observing lever presses (OLPs) and non-functional extra OLPs (EOLPs). The increase in OLPs and EOLPs was long-lasting, without further quinpirole administration. Quinpirole did not affect the immediate ability to use information from checking. Vehicle and quinpirole-treated rats (VEH and QNP respectively) were selectively sensitive to different forms of uncertainty. Sulpiride reduced non-functional EOLPs in QNP rats but had no effect on functional OLPs. These data have implications for treatment of compulsive checking in OCD, particularly for serotonin-reuptake-inhibitor treatment-refractory cases, where supplementation with dopamine receptor antagonists may be beneficial.