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1.
Artigo em Inglês | MEDLINE | ID: mdl-38602276

RESUMO

BACKGROUND: Primary progressive aphasia (PPA) is a neurodegenerative condition characterised by a prominent and progressive deterioration in language abilities, which significantly impacts quality of life and interpersonal relationships. Speech and language therapy plays a crucial role in offering interventions. Group intervention is one mode of delivery that could benefit communication functioning and overall wellbeing of people with PPA (pwPPA) and their care partners. Group interventions are also more efficient than one-to-one intervention and may facilitate peer support. AIMS: The aim of this review was to systematically evaluate the current evidence for the effectiveness of speech and language therapy groups for pwPPA and their care partners. Specifically, this paper considered three questions: 1.What evidence-based speech and language therapy groups for pwPPA and their care partners have been reported to date? 2.Are group communication interventions effective in improving quality of life and communication function for pwPPA and their care partners? 3.Are group communication interventions that are designed for people with communication difficulties of other aetiologies (such as stroke) effective for pwPPA? In addition, this review aimed to describe the structure and content of groups, including aims, disciplines involved, size and frequency of group meetings, and outcome measures. METHODS: MEDLINE, CINAHL and PsycINFO were used to retrieve articles of interest. A total of 10 studies published between 2009 and 2022 met the eligibility criteria and therefore were included in this study. Data were extracted from the articles regarding the structure and content of groups. MAIN CONTRIBUTION: Although evidence is currently limited, results suggest that speech and language therapy group intervention can improve specific linguistic processes, the use of communication strategies and psychosocial well-being. The importance of multidisciplinary input and care partners' involvement in groups was highlighted, along with the benefits of creative non-verbal activities as tools for self-expression. There is also initial evidence that telehealth group provision and one-off group sessions may be feasible and can benefit psychosocial well-being. Lastly, intentional recruitment and explicit education on different aphasia types are described as important when pwPPA participate in groups with mixed diagnoses. CONCLUSIONS: The literature on speech and language therapy group interventions for PPA shows promise of positive effects on communication function and psychosocial well-being of both pwPPA and their care partners. Speech and language therapists can consider these published interventions when designing and implementing similar groups, but more robust evidence is required to confirm the relative effectiveness of this approach. WHAT THIS PAPER ADDS: What is already known on this subject Speech pathology led group intervention shows some promise in benefitting communication functioning and overall well-being of pwPPA and their carers, but there has been no systematic evaluation of all the evidence regarding the efficacy of speech and language therapy led groups. Establishing feasibility, acceptability and efficacy of speech and language therapy group interventions for pwPPA and their carers may present a valuable addition for managing this progressive language disability. What this paper adds to existing knowledge Although evidence is currently limited, results from this systematic review suggest that speech and language therapy led group intervention can improve specific linguistic processes, the use of communication strategies and psychosocial well-being for pwPPA and their carers. The importance of multidisciplinary input and carers' involvement in groups was highlighted, along with the benefits of creative non-verbal activities as tools for self-expression. There is also initial evidence that telehealth group provision for carers may be feasible and can benefit psychosocial wellbeing. Lastly, intentional recruitment and explicit education on different aphasia types are described as important when pwPPA participate in groups with mixed diagnoses. What are the potential or actual clinical implications of this work? A synthesis of the evidence base for speech and language therapy led PPA groups, as well as a description of the group components and formats, will be valuable for clinical service planning, and will guide future examination of group options for pwPPA and their carers. Speech and language therapists can also consider the research findings from this systematic review when designing and implementing similar groups in their local context.

2.
J Am Chem Soc ; 145(33): 18538-18548, 2023 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-37555666

RESUMO

Recently, various metabolites derived from host microbes have been reported to modulate the immune system, with potential involvement in health or diseases. Archaea, prokaryotic organisms, are present in the human body, but their connection with the host is largely unknown when compared to other microorganisms such as bacteria. This study focused on unique glycerolipids from symbiotic methanogenic archaea and evaluated their activities toward an innate immune receptor. The results revealed that archaeal lipids were recognized by the C-type lectin receptor Mincle and induced immune responses. A concurrent structure-activity relationship study identified the key structural features of archaeal lipids required for recognition by Mincle. Subsequent gene expression profiling suggested qualitative differences between the symbiotic archaeal lipid and the pathogenic bacteria-derived lipid. These findings have broad implications for understanding the function of symbiotic archaea in host health and diseases.


Assuntos
Archaea , Lectinas Tipo C , Humanos , Archaea/metabolismo , Lectinas Tipo C/metabolismo , Receptores Imunológicos/metabolismo , Relação Estrutura-Atividade , Lipídeos
3.
Cancer Immunol Immunother ; 70(9): 2529-2543, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33570675

RESUMO

Intravesical Bovis bacillus Calmette-Guérin (BCG) therapy is the most effective immunotherapy for bladder cancer, but it sometime causes serious side effects because of its inclusion of live bacteria. It is necessary to develop a more active but less toxic immunotherapeutic agent. Trehalose 6,6'-dimycolate (TDM), the most abundant hydrophobic glycolipid of the BCG cell wall, has been reported to show various immunostimulatory activities such as granulomagenesis and adjuvant activity. Here, we developed cationic liposomes incorporating TDM purified from Mycobacterium bovis BCG Connaught, and we investigated the antitumor effect of the cationic liposome TDM (Lip-TDM). Lip-TDM exerted an antitumor effect in bladder cancer, colon cancer, and melanoma-bearing mouse models that was comparable or even superior to that of BCG, with no body weight loss or granuloma formation. The antitumor effect of Lip-TDM disappeared in two types of mice: those with depletion of CD8+ T cells, and those with knockout of macrophage-inducible C-type lectin (Mincle) which recognize TDM. Lip-TDM treatment enhanced the maturation and migration of dendritic cells in the tumor microenvironment in a Mincle-dependent manner. Our results elucidate mechanisms that underlie Lip-TDM treatment and suggest that Lip-TDM has potential as a safe and effective treatment for various cancers.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Fatores Corda/administração & dosagem , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Fatores Imunológicos/administração & dosagem , Mycobacterium bovis , Adjuvantes Imunológicos , Animais , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/isolamento & purificação , Linfócitos T CD8-Positivos/metabolismo , Fracionamento Químico , Fatores Corda/química , Fatores Corda/isolamento & purificação , Citocinas/metabolismo , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Imunofenotipagem , Infusões Parenterais , Lipossomos , Ativação Linfocitária , Camundongos , Estrutura Molecular , Mycobacterium bovis/química , Solventes , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Dysphagia ; 36(3): 362-373, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32562141

RESUMO

Niemann-Pick disease type C (NPC) is a rare, autosomal recessive neurodegenerative disease, characterized by progressive psychiatric and neurological deficits. Neurological symptoms include cognitive decline and dysphagia. Aspiration pneumonia secondary to dysphagia is a leading cause of death in NPC. Miglustat is currently the only approved disease-specific treatment shown to be effective in stabilizing neurological symptoms. Miglustat has previously been reported to halt or improve early dysphagia and cognitive symptoms. Here we examine the characteristics of dysphagia, the relationship between dysphagia and the presence of cognitive impairment, and longitudinal changes in swallowing function during miglustat treatment in adult-and-adolescent-onset NPC. Retrospective analysis of videofluoroscopic swallow studies (VFSS) was completed for ten adults with NPC (mean age 28.44 years ± 9.34 years). Participants were recruited through the Royal Melbourne Hospital in Australia between 2008 and 2015. The Bethlehem Swallowing Scale and the Penetration-Aspiration Scale were used to quantify VFSS data. Dysphagia was present in 90% of participants at baseline with reduced lingual function and a delayed swallowing reflex as the most common symptoms. Swallow impairment appeared to stabilize during miglustat therapy for periods up to 66 months, with no significant changes in scores (p > 0.05). Data were in accordance with the literature and support the use of miglustat as an efficacious treatment for reducing swallowing impairment and stabilizing cognitive function. Findings provide detailed information on the impairments experienced by patients, give context to events leading to aspiration in NPC and, importantly, inform how management of dysphagia can complement pharmaceutical treatment.


Assuntos
Transtornos de Deglutição , Doenças Neurodegenerativas , Doença de Niemann-Pick Tipo C , 1-Desoxinojirimicina/análogos & derivados , Adolescente , Adulto , Deglutição , Transtornos de Deglutição/tratamento farmacológico , Transtornos de Deglutição/etiologia , Inibidores Enzimáticos , Humanos , Doença de Niemann-Pick Tipo C/complicações , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Estudos Retrospectivos
5.
J Org Chem ; 84(11): 6788-6797, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31046282

RESUMO

Mincle is a C-type lectin receptor of the innate immune system with the ability to sense pathogens and commensals through lipidic metabolites. While a growing number of bacterial glycolipids have been discovered that can signal through human Mincle, no fungal metabolites are known that can signal through the human form of this receptor. We report the total synthesis of a complex ß-1,2-mannosyloxymannitol glycolipid from Malassezia pachydermatis 44-2, which was reported to signal through the murine Mincle receptor. Assembly of 44-2 was achieved through a highly convergent route that exploits symmetry elements inherent within this molecule and delineation of conditions that maintain the delicate l-mannitol triester-triol array. We show that 44-2 is a potent agonist of human Mincle signaling and constitutes the first fungal metabolite identified that can signal through the human Mincle receptor, providing new insights into antifungal immunity.


Assuntos
Glicolipídeos/síntese química , Glicolipídeos/farmacologia , Lectinas Tipo C/metabolismo , Malassezia/efeitos dos fármacos , Malassezia/metabolismo , Manitol/análogos & derivados , Receptores Imunológicos/metabolismo , Glicolipídeos/química , Humanos , Lectinas Tipo C/química , Manitol/síntese química , Manitol/química , Manitol/farmacologia , Conformação Molecular , Receptores Imunológicos/química
6.
Vasa ; 44(1): 43-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25537057

RESUMO

BACKGROUND: The second derivative of the finger plethysmogram (SDPTG) comprises five waves termed a to e. The magnitudes of waves b-e are normalized by that of wave a for within- and between-patient comparison. In the present study, affects of meal ingestion for SDPTG in young and elderly subjects are examined. SUBJECTS AND METHODS: Mean arterial pressure and SDPTG before and after meal ingestion in young and elderly subjects were measured. For young subjects, stroke volume and pulse rate were also measured, and the total peripheral resistance (TPR) of the blood vessels was analyzed. Relationship between TPR and the ratio of the peak of SDPTG in young subjects was also analyzed. RESULTS: In young subjects, postprandial d/a was significantly larger and TPR was smaller than before intake and was linearly and significantly correlated with TPR. An increase in the postprandial d/a was also observed in the elderly subjects who were not undergoing hypertension treatment. However, this increase was not observed in elderly subjects who were treated for hypertension. CONCLUSIONS: Change in d/a is considered to be an index of change in TPR. TPR is considered to be decreased by agents for treatment of hypertension, and meal ingestion does not appear to further decrease TPR. These results are considered to be useful for understanding cardiodynamics surrounding meal ingestion.


Assuntos
Envelhecimento/fisiologia , Pletismografia/métodos , Período Pós-Prandial/fisiologia , Resistência Vascular/fisiologia , Vasodilatação/fisiologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Dedos/irrigação sanguínea , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
7.
Masui ; 64(10): 1068-71, 2015 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-26742412

RESUMO

We report a case of epidural hematoma in an elderly patient with normal coagulability and without difficulty in epidural catheterization. A 76-year-old man with a history of cervical myelopathy was scheduled for gastrojejunostomy under combined epidural and general anesthesia. He had normal bleeding time, coagulation test results, and platelet count. He underwent an epidural catheterization without difficulty. On the first postoperative day, he noticed that could not move his legs with analgesia. After stopping continuous epidural perfusion, he could move legs slightly, but paraplegia remained. On the second postoperative day, MRI of the spine demonstrated a hematoma-like lesion, and severe thoracic and lumbar spinal canal stenosis. Severe vertebral deformation, especially in cases of the elderly, is a potential risk for epidural hematoma after epidural catheterization, because a small hematoma may compress the spinal cord. A careful preoperative evaluation whether to perform epidural catheterization and postoperative observation are required for elderly patients with severe vertebral deformation.


Assuntos
Anestesia Epidural/efeitos adversos , Hematoma Epidural Espinal/etiologia , Idoso , Cateterismo/efeitos adversos , Humanos , Masculino
8.
J Biol Chem ; 288(41): 29934-42, 2013 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-24003223

RESUMO

Grb2-associated regulator of Erk/MAPK1 (GAREM) is an adaptor molecule in the EGF-mediated signaling pathway. GAREM is expressed ubiquitously in human organs and cultured cells. Two GAREM homologues are encoded by the human genome. Therefore, previously identified GAREM is named GAREM1. Here we characterized a new subtype of GAREM, GAREM2, that is specifically expressed in the mouse, rat, and human brain. Three GAREM2 tyrosines (Tyr-102, Tyr-429, and Tyr-551) are phosphorylated upon EGF stimulation and are necessary for binding to Grb2. Furthermore, GAREM2 and Shp2 regulate Erk activity in EGF-stimulated cells. These characteristics are similar to those of GAREM1. GAREM2 is expressed in some neuroblastoma cell lines and is also tyrosine-phosphorylated and bound to Grb2 after treatment with EGF. Eventually, GAREM2 regulates Erk activation in the presence of EGF or insulin like growth factor 1. GAREM2 also regulates insulin-like growth factor 1-induced neuronal differentiation of the SH-SY5Y neuroblastoma cell line. Although the structure and function of both GAREM subtypes are similar, GAREM1 is recruited into the nucleus and GAREM2 is not. Nuclear localization of GAREM1 might be controlled by a GAREM1-specific nuclear localization sequence and 14-3-3ε binding. The N-terminal 20 amino acids of GAREM1 make up its nuclear localization sequence that is also a 14-3-3ε binding site. The GAREM family is a new class of adaptor molecules with subtype-specific biological functions.


Assuntos
Encéfalo/metabolismo , Proteína Adaptadora GRB2/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Neuritos/fisiologia , Sequência de Aminoácidos , Animais , Células COS , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Chlorocebus aethiops , Fator de Crescimento Epidérmico/farmacologia , Proteína Adaptadora GRB2/genética , Proteína Adaptadora GRB2/metabolismo , Células HEK293 , Células HeLa , Humanos , Immunoblotting , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Microscopia de Fluorescência , Dados de Sequência Molecular , Neuritos/metabolismo , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Neurônios/citologia , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/fisiologia , Interferência de RNA , Ratos , Ratos Wistar , Homologia de Sequência de Aminoácidos
10.
Sci Rep ; 14(1): 11561, 2024 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773300

RESUMO

Mitochondrial diseases are mainly caused by dysfunction of mitochondrial respiratory chain complexes and have a variety of genetic variants or phenotypes. There are only a few approved treatments, and fundamental therapies are yet to be developed. Leigh syndrome (LS) is the most severe type of progressive encephalopathy. We previously reported that apomorphine, an anti- "off" agent for Parkinson's disease, has cell-protective activity in patient-derived skin fibroblasts in addition to strong dopamine agonist effect. We obtained 26 apomorphine analogs, synthesized 20 apomorphine derivatives, and determined their anti-cell death effect, dopamine agonist activity, and effects on the mitochondrial function. We found three novel apomorphine derivatives with an active hydroxy group at position 11 of the aporphine framework, with a high anti-cell death effect without emetic dopamine agonist activity. These synthetic aporphine alkaloids are potent therapeutics for mitochondrial diseases without emetic side effects and have the potential to overcome the low bioavailability of apomorphine. Moreover, they have high anti-ferroptotic activity and therefore have potential as a therapeutic agent for diseases related to ferroptosis.


Assuntos
Aporfinas , Doença de Leigh , Mitocôndrias , Doença de Leigh/tratamento farmacológico , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Aporfinas/farmacologia , Aporfinas/química , Aporfinas/síntese química , Aporfinas/uso terapêutico , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Apomorfina/farmacologia , Apomorfina/uso terapêutico , Apomorfina/análogos & derivados , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/uso terapêutico , Agonistas de Dopamina/química , Alcaloides/farmacologia , Alcaloides/química , Alcaloides/uso terapêutico
11.
Sci Signal ; 16(775): eabn9909, 2023 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-36881655

RESUMO

The common Fc receptor γ (FcRγ) chain is a signaling subunit common to several immune receptors, but cellular responses induced by FcRγ-coupled receptors are diverse. We investigated the mechanisms by which FcRγ generates divergent signals when coupled to Dectin-2 and Mincle, structurally similar C-type lectin receptors that induce the release of different cytokines from dendritic cells. Chronological tracing of transcriptomic and epigenetic changes upon stimulation revealed that Dectin-2 induced early and strong signaling, whereas Mincle-mediated signaling was delayed, which reflects their expression patterns. Generation of early and strong FcRγ-Syk signaling by engineered chimeric receptors was sufficient to recapitulate a Dectin-2-like gene expression profile. Early Syk signaling selectively stimulated the activity of the calcium ion-activated transcription factor NFAT, which rapidly altered the chromatin status and transcription of the Il2 gene. In contrast, proinflammatory cytokines, such as TNF, were induced regardless of FcRγ signaling kinetics. These results suggest that the strength and timing of FcRγ-Syk signaling can alter the quality of cellular responses through kinetics-sensing signaling machineries.


Assuntos
Receptores Fc , Transdução de Sinais , Cinética , Receptores de IgG/genética , Citocinas , Células Dendríticas
12.
Methods Mol Biol ; 2613: 23-31, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36587068

RESUMO

The cell envelopes of pathogens comprise a wealth of unique glycolipids, which are important modulators of the host immune responses during infection and in some cases have been used as adjuvants. Despite this abundant basic knowledge, the identities of the host immune receptors for mycobacterial lipids have long been elusive (Ishikawa et al., Trends Immunol 38:66-76, 2017). We describe the method of how to isolate glycolipids from microorganisms and how to analyze the glycolipids' potential to activate reporter cells and bone marrow-derived dendritic cells (BMDCs), such as surface marker expression and reactive oxygen species (ROS) production. Additionally, we outline an in vitro BMDC/T cell coculture model to investigate functional consequences of leukocyte activation, such as cytokine production. In this chapter, we provide a guide for extracting glycolipids from microorganisms and how to use them to activate leukocytes. We also present methods on how to generate and activate reporter cells, as well as BMDCs and how to set up BMDC/T cell cocultures. We further outline how to generate samples and how to analyze the immunomodulatory effect glycolipid exposure has on these cells, via flow cytometry, ROS production assays and ELISA.


Assuntos
Glicolipídeos , Linfócitos T , Glicolipídeos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Adjuvantes Imunológicos , Apresentação de Antígeno , Células Dendríticas
13.
Mol Genet Metab Rep ; 34: 100951, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36632326

RESUMO

Coenzyme Q10 (CoQ10) is involved in ATP production through electron transfer in the mitochondrial respiratory chain complex. CoQ10 receives electrons from respiratory chain complex I and II to become the reduced form, and then transfers electrons at complex III to become the oxidized form. The redox state of CoQ10 has been reported to be a marker of the mitochondrial metabolic state, but to our knowledge, no reports have focused on the individual quantification of reduced and oxidized CoQ10 or the ratio of reduced to total CoQ10 (reduced/total CoQ10) in patients with mitochondrial diseases. We measured reduced and oxidized CoQ10 in skin fibroblasts from 24 mitochondrial disease patients, including 5 primary CoQ10 deficiency patients and 10 respiratory chain complex deficiency patients, and determined the reduced/total CoQ10 ratio. In primary CoQ10 deficiency patients, total CoQ10 levels were significantly decreased, however, the reduced/total CoQ10 ratio was not changed. On the other hand, in mitochondrial disease patients other than primary CoQ10 deficiency patients, total CoQ10 levels did not decrease. However, the reduced/total CoQ10 ratio in patients with respiratory chain complex IV and V deficiency was higher in comparison to those with respiratory chain complex I deficiency. Measurement of CoQ10 in fibroblasts proved useful for the diagnosis of primary CoQ10 deficiency. In addition, the reduced/total CoQ10 ratio may reflect the metabolic status of mitochondrial disease.

14.
J Hum Genet ; 57(8): 508-14, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22648185

RESUMO

Dental morphology is highly diverse among individuals and between human populations. Although it is thought that genetic factors mainly determine common dental variations, only a few such genetic factors have been identified. One study demonstrated that a nonsynonymous single-nucleotide polymorphism (370V/A, rs3827760) in the ectodysplasin A receptor gene (EDAR) is associated with shoveling and double-shoveling grades of upper first incisors and tooth crown size. Here, we examined the association of EDAR 370V/A with several dental characters in Korean and Japanese subjects. A meta-analysis that combined analyses of Korean and Japanese subjects revealed that the Asian-specific 370A allele is associated with an increase in the grades of shoveling and double shoveling, as previously found. We also showed a highly significant association between EDAR 370V/A genotype and crown size, especially mesiodistal diameters of anterior teeth. Moreover, we found that the 370A allele was associated with the presence of hypoconulids of lower second molars. These results indicated that the EDAR polymorphism is responsible, in part, for the Sinodonty and Sundadonty dichotomy in Asian populations, and clearly demonstrated that the EDAR polymorphism has pleiotropic effects on tooth morphology. As the 370A allele is known to be a most likely target of positive selection in Asian populations, some phenotypes associated with the variant may be 'hitchhiking phenotypes', while others may be actual targets of selection.


Assuntos
Povo Asiático/genética , Receptor Edar/genética , Estudos de Associação Genética , Dente/anatomia & histologia , Alelos , Genótipo , Humanos , Incisivo/anatomia & histologia , Dente Molar/anatomia & histologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Coroa do Dente/anatomia & histologia
15.
Brain Dev ; 43(2): 308-313, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33139125

RESUMO

BACKGROUND: ECHS1 is a key enzyme of the valine catabolic pathway and oxidation of fatty acids. In ECHS1 deficiency (ECHS1D), accumulation of toxic intermediates from the valine induces neurodegeneration, which presents Leigh syndrome (LS). Therefore, valine restriction is suggested as an effective therapy. Further, cysteamine may detoxify the toxic metabolites themselves and N-acetylcysteine (NAC) is a potent antioxidant preventing neurological affect. Herein, we report the therapeutic effects of dietary therapy, cysteamine, and NAC in two siblings with ECHS1D, including their clinical, neuroradiological, and chemical aspects. CASE REPORT: The elder sister was the proband and was diagnosed as LS at 13 months of age. Gene analysis identified compound heterozygous ECHS1 mutations. Her psychomotor development was regressed, and she became bedridden. At 4 years old she started a low protein diet (LPD), but with no obvious neurological change. The younger brother was confirmed early with ECHS1D and received cysteamine and NAC treatment from 5 months of age, which could not prevent him developing LS at 7 months of age. Thus, we started a LPD at 14 months of age, with which he regained his ability to roll over, then we proceeded to a valine-restricted diet. The brain magnetic resonance image hyperintensity was diminished, and the lactate peak on magnetic resonance spectroscopy decreased. His neurological outcome is better than his elder sister. In both cases, excretion of valine metabolites decreased after dietary therapy without obvious adverse effects. CONCLUSION: Early initiation of dietary therapy may reduce neurological sequelae in patients with ECHS1D.


Assuntos
Enoil-CoA Hidratase/deficiência , Valina/metabolismo , Acetilcisteína/farmacologia , Cisteamina/farmacologia , Dietoterapia/métodos , Enoil-CoA Hidratase/genética , Enoil-CoA Hidratase/metabolismo , Enoil-CoA Hidratase/fisiologia , Família , Feminino , Testes Genéticos/métodos , Humanos , Lactente , Japão , Doença de Leigh/genética , Doença de Leigh/prevenção & controle , Imageamento por Ressonância Magnética/métodos , Masculino , Mutação/genética , Linhagem , Irmãos , Resultado do Tratamento , Valina/deficiência , Valina/genética
16.
Mol Genet Metab Rep ; 29: 100809, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34667719

RESUMO

Short-chain enoyl-CoA hydratase (ECHS1) is involved in amino acid and fatty acid catabolism in mitochondria and its deficiency causes Leigh syndrome or exercise-induced dystonia. More than 60 patients with this condition have been reported till date. The accumulation of intermediate metabolites of valine is assumed to be responsible for the cytotoxicity. Since protein restriction, including valine reportedly improves neurological symptoms, it is essential to consider the possible incidence of and diagnose ECHS1 syndrome in the earlier stages. This study reported the liquid chromatography with tandem mass spectrometry (LC-MS/MS) urine and plasma metabolite analysis in six cases, including four new cases with ECHS1 deficiency. The values of urine cysteine/cysteamine conjugates from valine metabolites, S-(2-carboxypropyl) cysteine/cysteamine from methacrylyl-CoA, and S-(2-carboxyethyl) cysteine/cysteamine from acryloyl-CoA were separated between six patients and six normal controls. The LC-MS/MS analysis revealed that these metabolites can be used for the early diagnosis and evaluation of diet therapy.

17.
Methods Mol Biol ; 2132: 119-128, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32306320

RESUMO

C-type lectins bind to carbohydrate structures in a Ca2+-dependent manner. Some transmembrane forms of lectins act as innate immune receptors and induce signal transduction pathways in macrophages and dendritic cells (DCs). Expressing these receptors in cells bearing a reporter gene is a useful tool to investigate ligand binding and recognition. However, it cannot be used to quantify the precise affinity of the interaction, and the involvement of other proteins remains a possibility. Direct binding between a receptor and its ligand can be investigated using an immunoglobulin receptor (Ig)-fused soluble protein. This binding can be assessed using enzyme-linked immunosorbent assays and flow cytometry, and the fusion protein may also be used in a glycan array. In this chapter, we explain the generation of Ig fusion proteins and subsequent binding assays using these proteins.


Assuntos
Fragmentos Fc das Imunoglobulinas/metabolismo , Lectinas Tipo C/metabolismo , Polissacarídeos/metabolismo , Animais , Cálcio/metabolismo , Humanos , Lectinas Tipo C/genética , Ligantes , Ligação Proteica , Engenharia de Proteínas , Proteínas Recombinantes/metabolismo
18.
Gan To Kagaku Ryoho ; 36(10): 1691-6, 2009 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-19838029

RESUMO

Chemotherapy-induced nausea and vomiting (CINV) is one of the side effects causing significant psychological and physical suffering in patients receiving chemotherapy. Because CINV often impairs patients' quality of life and leads to cessation of treatments, antiemetic therapy has been thought important. Recently, the development of new antiemetic agents and the antiemetic guidelines provided by ASCO, NCCN, and MASCC etc. allow us to palliate CINV with appropriate antiemetic therapy. For appropriate antiemetic therapy, the patient must obtain accurate CINV information, particularly regarding whether it will be acute or delayed. MASCC first developed and posted the MASCC Antiemesis Tool (MAT) in 2004. The MAT is an eight-term scale for the assessment of acute and delayed nausea and vomiting, and is completed once per chemotherapy course. Although it is now validated in the US and UK and used worldwide, few reports have been available in Japan to use assessment tools including the MAT for acute and delayed CINV. We prospectively investigated the utility of the MAT. Fifteen ambulatory patients with breast cancer were subjected to evaluation, aged 29 to 73(median 58)years. In the results, the MAT allowed us to easily find patients treated with inappropriate antiemetic therapy. At the same time, it was easy to determine acute or delayed CINV, resulting in more appropriate treatment. The scale questions were unfamiliar to patients, but they clearly understood by means of a detailed explanation. Thus, it was suggested that the MAT is useful to assess antiemetic therapy. Consequently, it could contribute to completion of the chemotherapy.


Assuntos
Antieméticos/farmacologia , Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Náusea/prevenção & controle , Vômito/prevenção & controle , Adulto , Idoso , Antineoplásicos/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Qualidade de Vida , Inquéritos e Questionários
19.
PLoS One ; 14(1): e0209196, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30608942

RESUMO

Intravesical therapy using Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the most established cancer immunotherapy for bladder cancer. However, its underlying mechanisms are unknown. Mycolic acid (MA), the most abundant lipid of the BCG cell wall, is suspected to be one of the essential active components of this immunogenicity. Here, we developed cationic liposomes incorporating three subclasses (α, keto, and methoxy) of MA purified separately from BCG, using the dendron-bearing lipid D22. The cationic liposomes using D22 were efficiently taken up by the murine bladder cancer cell line MB49 in vitro, but the non-cationic liposomes were not. Lip-kMA, a cationic liposome containing keto-MA, presented strong antitumor activity in two murine syngeneic graft models using the murine bladder cancer cell lines MB49 and MBT-2 in comparison to both Lip-aMA and Lip-mMA, which contained α-MA and methoxy-MA, respectively. Interestingly, Lip-kMA(D12), which was made of D12 instead of D22, did not exhibit antitumor activity in the murine syngeneic graft model using MB49 cells, although it was successfully taken up by MB49 cells in vitro. Histologically, compared to the number of infiltrating CD4 lymphocytes, the number of CD8 lymphocytes was higher in the tumors treated with Lip-kMA. Antitumor effects of Lip-kMA were not observed in nude mice, whereas weak but significant effects were observed in beige mice with natural killer activity deficiency. Thus, a cationized liposome containing keto-MA derived from BCG induced in vivo antitumor immunity. These findings will provide new insights into lipid immunogenicity and the underlying mechanisms of BCG immunotherapy.


Assuntos
Vacina BCG/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Ácidos Micólicos/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/imunologia , Animais , Vacina BCG/administração & dosagem , Vacina BCG/química , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/química , Linhagem Celular Tumoral , Feminino , Humanos , Imunoterapia , Cetoácidos/administração & dosagem , Cetoácidos/isolamento & purificação , Cetoácidos/uso terapêutico , Lipossomos/administração & dosagem , Lipossomos/química , Lipossomos/ultraestrutura , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Nus , Estrutura Molecular , Ácidos Micólicos/administração & dosagem , Ácidos Micólicos/isolamento & purificação , Tamanho da Partícula , Neoplasias da Bexiga Urinária/patologia
20.
Gan To Kagaku Ryoho ; 35(8): 1361-5, 2008 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-18701849

RESUMO

The efficacy of adjuvant chemotherapy using S-1 for one year after curative surgical treatment for patients with gastric cancer of stage II or III was reported as the result of randomized controlled trial named ACTS-GC in 2007. Therefore the number of patients undergoing this adjuvant chemotherapy is predicted to be rapidly increasing in near future. On the other hand, the government promotes to construct the liaison-clinical pathway for patients with major carcinoma as a policy in 2007. According to these two backgrounds, liaison-clinical pathway for patients with gastric cancer undergoing adjuvant chemotherapy using S-1 after curative gastrectomy has been induced in our institute from November 2007. Not only alliance among doctors, nurses and pharmacologist in our institute but also communication with clinic is important to construct and manage this pathway. Three patients have been undergoing this pathway until now. All of them are satisfied with this pathway because of reliable feelings supported by intensive alliance between our institute and local clinic.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Procedimentos Clínicos , Gastrectomia , Ácido Oxônico/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Tegafur/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia Adjuvante , Combinação de Medicamentos , Humanos , Ácido Oxônico/efeitos adversos , Neoplasias Gástricas/cirurgia , Tegafur/efeitos adversos
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