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BACKGROUND: There have been few descriptions in the literature on long-term enzyme replacement therapy (ERT) in patients with advanced late-onset Pompe disease (LOPD). OBJECTIVES: This study aimed to assess the efficacy and limitations of ERT in advanced LOPD patients. METHODS: We retrospectively reviewed the clinical courses of patients with advanced LOPD (two juvenile-onset and five adult-onset patients) who were treated with recombinant human alglucosidase alfa to examine improvements achieved with and limitations of ERT until their death or when switching to avalglucosidase alfa occurred. RESULTS: All patients were non-ambulant and ventilator dependent. The duration of follow-up ranged from 3.7 to 15.0 years (median 9.0 years). All patients reported improvements in their lives during the first two or three years of ERT. Vital capacity was clearly improved in patients with relatively spared respiratory function, although it deteriorated after respiratory complications such as pneumothorax. Pinch and grip power tended to be preserved during the treatment period. Muscle CT revealed progression of atrophy and fatty replacement predominantly in the proximal limb muscles without improvement after ERT. Four patients died due to aspergillosis, respiratory failure, ileus, and sudden death of unknown cause. CONCLUSIONS: Our findings demonstrate that patients undergoing ERT show certain improvements, even in the advanced stage of Pompe disease. Respiratory complications are lethal even during ERT, and early diagnosis and induction of therapy are critical. Muscle wasting progressed more severely in the proximal limbs, even after ERT.
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The orbitofrontal cortex (OFC) is crucial for tracking various aspects of expected outcomes, thereby helping to guide choices and support learning. Our previous study showed that the effects of reward timing and size on the activity of single units in OFC were dissociable when these attributes were manipulated independently (Roesch et al., 2006). However, in real-life decision-making scenarios, outcome features often change simultaneously, so here we investigated how OFC neurons in male rats integrate information about the timing and identity (flavor) of reward and respond to changes in these features, according to whether they were changed simultaneously or separately. We found that a substantial number of OFC neurons fired differentially to immediate versus delayed reward and to the different reward flavors. However, contrary to the previous study, selectivity for timing was strongly correlated with selectivity for identity. Taken together with the previous research, these results suggest that when reward features are correlated, OFC tends to "pack" them into unitary constructs, whereas when they are independent, OFC tends to "crack" them into separate constructs. Furthermore, we found that when both reward timing and flavor were changed, reward-responsive OFC neurons showed unique activity patterns preceding and during the omission of an expected reward. Interestingly, this OFC activity is similar and slightly preceded the ventral tegmental area dopamine (VTA DA) activity that observed in a previous study (Takahashi et al., 2023), consistent with a role for OFC in providing predictive information to VTA DA neurons.Significant Statement Although multiple features of outcomes can change simultaneously in real-life decision-making scenarios, how OFC neurons integrate information about the reward timing and identity and respond to changes in these features remains unexplored. Here we found that OFC neurons integrate information about reward timing and identity when the two features changed simultaneously. Combining with prior research (Roesch et al., 2006), these findings suggest that OFC tends to integrate correlated features into unitary constructs, while segregating independent features into separate constructs. Additionally, we observed distinct activities in general reward-responsive neurons preceding the omission of an expected reward when both identity and timing changed. This implies OFC might convey predictions to VTA that track reward timing separately based on reward identity.
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Long-term depression (LTD) of synaptic transmission at parallel fiber (PF)-Purkinje cell (PC) synapses plays an important role in cerebellum-related motor coordination and learning. LTD is induced by the conjunction of PF stimulation and climbing fiber (CF) stimulation or somatic PC depolarization, while long-term potentiation (LTP) is induced by PF stimulation alone. Therefore, it is considered that different types of stimulation induce different types of synaptic plasticity. However, we found that a small number of conjunctive stimulations (PF + somatic depolarization of PC) induced LTP, but did not induce LTD of a small size. This LTP was not associated with changes in paired-pulse ratio, suggesting postsynaptic origin. Additionally this LTP was dependent on nitric oxide. This LTP was also induced by a smaller number of physiological conjunctive PF and CF stimuli. These results suggested that a larger number or longer period of conjunctive stimulation is required to induce LTD by overcoming LTP. Ca2+ transients at the PC dendritic region was measured by calcium imaging during LTD-inducing conjunctive stimulation. Peak amplitude of Ca2+ transients increased gradually during repetitive conjunctive stimulation. Instantaneous peak amplitude was not different between the early phase and late phase, but the average amplitude was larger in the later phase than in the early phase. These results show that LTD overcomes LTP, and increased Ca2+ integration or a number of stimulations is required for LTD induction.
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We estimated the severity of cerebellar ataxia by analyzing gait rhythm. We measured the step times in patients with pure cerebellar ataxia and healthy controls and then analyzed the distribution of the ratios of adjacent times. Gait rhythm displayed the best adaptation when expressed as the sum of the power law and lognormal distributions in both groups, and the groups could be distinguished by the exponent of the power law distribution, reflecting the fractal property of gait rhythm. Gait rhythm might reflect different features of impairment in patients with cerebellar ataxia, making it a useful continuous scale for cerebellar ataxia.
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Background: Severe metformin intoxication can lead to lactic acidosis and vasoplegic shock, for which the optimal management strategy remains uncertain, especially in cases of severe circulatory collapse. Case Presentation: A 45-year-old diabetic woman on metformin therapy presented with impaired consciousness and seizures. She had experienced a cardiac arrest and undergone extracorporeal cardiopulmonary resuscitation. Blood gas analysis showed severe lactic acidosis. A 71-g metformin packet was found at the patient's home, suggesting an overdose. Despite extracorporeal support and blood purification, severe lactic acidosis and hypotension persisted. Methylene blue was administered 32 h from the onset, which improved her metabolic and circulatory status. We examined her blood sample throughout the case to check the transition of metformin blood concentration. Conclusion: Methylene blue may be beneficial for severe metformin toxicity, regardless of the blood concentration of metformin and the time since intoxication. However, further research is needed to establish its optimal use and effectiveness.
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Photomixotrophic growth A (PmgA) is a pleiotropic regulator essential for growth under photomixotrophic and prolonged high-light (HL) conditions in the cyanobacterium Synechocystis sp. PCC 6803. The overall similarity with the anti-sigma factor of the bacterial partner-switching system indicates that PmgA exerts a regulatory function via phosphorylation of its target proteins. In this study, we performed an in vitro phosphorylation assay and protein-protein interaction analysis and found that PmgA interacts with four anti-sigma antagonist homologs, Ssr1600, Slr1856, Slr1859, and Slr1912, but specifically phosphorylates Ssr1600. Phenotypic analyses using the set of gene disruption and overexpression strains of pmgA and ssr1600 revealed that phosphorylation by PmgA is essential for the accumulation of Ssr1600 protein in vivo. The ssr1600-disrupted mutant showed similar phenotypes as those previously reported for the pmgA-disrupted mutant, namely, no obvious phenotype just after the shift to HL, but higher chlorophyll content, 5-aminolevulinic acid synthesis activity, and psaAB transcript levels than those in the wild-type after 6â hours. These findings indicate that the phosphorylated form of Ssr1600 works as the output of the partner-switching system to coordinately repress chlorophyll biosynthesis and accumulation of photosystem I during HL acclimation.
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Gene doping is prohibited in horse sports and can involve the administration of exogenous genes, called transgenes, to postnatal animals. Quantitative polymerase chain reaction (qPCR) methods have been developed to detect gene doping; however, these generally require DNA extraction from the plasma prior to qPCR. In this study, we developed two methods, direct droplet digital PCR (ddPCR) and nested ddPCR, to detect the equine erythropoietin (EPO) transgene without DNA extraction. Direct ddPCR used pretreated plasma and PCR to detect the EPO transgene spiked at 10 copies/µL. Nested ddPCR utilised pre-amplification using nontreated plasma, purification of PCR products and PCR to detect the EPO transgene spiked at 1 copy/µL in plasma. These methods successfully detected the EPO transgene after intramuscular injection into horses. Since each method has different detection sensitivity, the combined use of direct ddPCR for screening and nested ddPCR for confirmation may complement each other and prevent the occurrence of false positives, allowing the reliable detection of gene-doped substances. One advantage of these methods is the small amount of sample required, approximately 2.2-5.0 µl, owing to the lack of a DNA extraction step. Therefore, these tests could be applied to small volume samples as an alternative to conventional gene doping tests.
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Understanding how muscle activity changes with different surface grades during canter is essential for developing training protocols in Thoroughbreds because canter is their primary gait in training and races. We measured the spatiotemporal parameters and the activation of 12 surface muscles in the leading limb side of 7 Thoroughbreds. Horses were equipped with hoof strain gauges and cantered at 10 m/s on a treadmill set to grades of -4%, 0%, 4%, and 8%, randomly, for 30 seconds each without a lead change. Integrated electromyography (iEMG) values during stance and swing phases were calculated and normalized to mean iEMG values during stride duration at 0% grade in each muscle. The iEMG values at each grade were compared using a generalized mixed model. Stride duration significantly decreased due to shorter swing duration on an 8% grade (P < 0.001) compared to all other grades, where no significant changes were observed. Compared to a 0% grade, the normalized iEMG values during the stance phase on an 8% grade in five muscles significantly increased (Musculus infraspinatus; +9%, M. longissimus dorsi (LD); +4%, M. gluteus medius (GM); +29%, M. biceps femoris; +47%, M. flexor digitorum lateralis; +16%). During the swing phase, the normalized iEMG values in six muscles significantly increased on an 8% grade compared to a 0% grade (M. splenius; +21%, M. triceps brachii; +54%, LD; +37%, GM; +24%, M. semitendinosus; +51%, M. extensor digitorum longus; +10%). No significant changes were observed in iEMG values on -4% and 4% grades compared to the 0% grade. Although +/- 4% grades had little effect on neuromuscular responses, 8% uphill canter reduced stride duration due to decreased swing duration and required increase of muscle activation during either stance and swing phase. Canter on an 8% grade might strengthen equine muscles to increase propulsive force and stride frequency.
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Eletromiografia , Teste de Esforço , Marcha , Músculo Esquelético , Animais , Cavalos/fisiologia , Músculo Esquelético/fisiologia , Marcha/fisiologia , Fenômenos Biomecânicos , Masculino , Feminino , Condicionamento Físico Animal/fisiologiaRESUMO
Introduction: Recently, there have been a few reports of atypical post-coronavirus disease 2019 (COVID-19) myelopathy manifesting tract-specific lesions similar to those due to vitamin B12 deficiency. However, the precise characteristics of imaging or clinical course remain not well understood. Methods: A retrospective analysis of the clinical and imaging characteristics of four patients who were referred to our hospital with a unique post-COVID-19 myelopathy was performed. Results: Four-to-six weeks following COVID-19 infection in the summer of 2023, four middle-aged men developed paraparesis, hypo/dysesthesia and bladder/bowel disturbance, suggesting myelopathy. Although spinal MRI showed no abnormalities in the early stages, tract-specific longitudinal lesions along the dorsal and lateral columns became apparent as the symptoms progressed. Owing to the lack of MRI findings at the early stage, all cases were challenging to diagnose. However, the patients remained partially responsive to aggressive immunosuppressive therapies, even in the advanced stage. Discussion: We termed these tract-specific longitudinal lesions in the presented case series 'Grasshopper sign' because brain coronal and spine axial MRI findings looked like a grasshopper's antennae and face. Early identification of the characteristic MRI abnormality could allow for early intervention using intensive immunosuppressive therapy, which could improve patient outcomes.
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BACKGROUND: Mechanical insufflation-exsufflation (MI-E) facilitates extubation. However, its potential to reduce the duration of ventilator use remains unclear. Therefore, the present study investigated whether the use of MI-E shortened the duration of mechanical ventilation in patients with high sputum retention. METHODS: A randomized open-label trial was conducted at a single intensive care unit (ICU) in Japan between November 2017 and June 2019. Ventilated subjects requiring suctioning at least once every hour due to sputum retention were randomly assigned to the MI-E group or conventional care group. The primary endpoint was the number of ventilator-free days on day 28. Secondary endpoints were ventilator days in surviving subjects, the length of ICU stay, and mortality and tracheostomy rates among survivors. RESULTS: Forty-eight subjects (81% males) with a median age of 72 years (interquartile range [IQR], 65-85 years) were enrolled. There were 27 subjects in the MI-E group and 21 in the control group. The median number of ventilator-free days was 21 (IQR, 13-24) and 18, respectively (IQR, 0-23) (P = .38). No significant differences were observed in the ICU length of stay (median, 10 days (IQR, 7-12) vs 12 days (IQR, 6-15); P = .31), mortality rate (19% vs 15%; odds ratio [OR], 1.36 [0.28-6.50]; P = .69), or tracheostomy rate among survivors (14% vs 28%; OR, 0.40 [0.08-1.91]; P = .25). CONCLUSION: In ventilated subjects in the ICU with high sputum retention, the use of MI-E did not significantly increase the number of ventilator-free days over that with conventional care.
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Insuflação , Unidades de Terapia Intensiva , Tempo de Internação , Respiração Artificial , Escarro , Humanos , Masculino , Feminino , Idoso , Respiração Artificial/métodos , Idoso de 80 Anos ou mais , Insuflação/métodos , Traqueostomia , Japão , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Photo-based measurement methods are used to assess axial postural abnormalities (PA) in Parkinson's disease (PD). However, they capture only moments in time. We developed the 2-minute standing endurance test (2â¯M-SET), which specifically captures temporal changes in posture, as a novel dynamic method for measuring axial PA in patients with PD. RESEARCH QUESTION: This study aimed to verify the effectiveness and validity of the 2â¯M-SET for capturing temporal changes in axial PA in patients with PD. METHODS: Twenty-eight patients with PD participated. The participants attempted to maintain an upright posture for 2â¯minutes during three tasks: standing, stepping in place, and walking. The rate of change in postural angle was recorded at 10-second intervals. Based on the results, the 2â¯M-SET was developed. Therapists evaluated the 2â¯M-SET using the NeuroPostureApp© to measure anterior trunk flexion (ATF) angles and lateral trunk flexion (LTF) angles at 0, 10, 30, 60, and 120â¯seconds. To assess reliability, the congruence between the measurements obtained by the therapists and those obtained using a three-dimensional motion-analysis system was examined. For validity, we assessed whether the ATF and LTF angles measured by the therapists could accurately capture postural changes at regular intervals over time. RESULTS: The average postural changes over 2â¯minutes for the standing, stepping in place, and gait tasks were 59.2±83.5%, 37.6±30.7%, and 45.4±50.6%, respectively. The intraclass correlation coefficients showed high reliability, with values of 0.985 and 0.970 for the ATF and LTF angles, respectively. SIGNIFICANCE: The results of our proposed 2â¯M-SET method, which uses temporal photo-based measurements to assess the patient's ability to maintain an upright standing position for 2â¯minutes, demonstrate the potential to capture temporal changes in axial PA. DATA AVAILABILITY STATEMENT: The data supporting the findings of this study are available upon reasonable request and approval from the local ethics committee.
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Doença de Parkinson , Equilíbrio Postural , Posição Ortostática , Humanos , Doença de Parkinson/fisiopatologia , Masculino , Feminino , Idoso , Equilíbrio Postural/fisiologia , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Fenômenos Biomecânicos , Postura/fisiologiaRESUMO
PURPOSE: Trichomonas vaginalis is a causative agent of common non-viral sexually transmitted infections worldwide. However, the biological features, such as genotypes and endosymbionts, of T. vaginalis isolated in Japan remain unclear. The aim of this study was to characterize the actin-based genotypes and the endosymbionts of T. vaginalis isolated in Sapporo, Japan. METHODS: Three T. vaginalis clinical strains were isolated in Sapporo, Japan between 2019 and 2022. Actin-based genotyping was conducted by sequencing and phylogenetic analyses. The endosymbionts, such as Mycoplasma sp. and Trichomonasvirus, were detected using PCR and RT-PCR, respectively. Furthermore, the detected Mycoplasma spp. were identified using 16S rRNA gene sequencing. RESULTS: Of the three T. vaginalis strains, two belonged to genotype E, whereas one was genotype G as determined by actin-based genotyping. Two of the T. vaginalis strains harbored Mycoplasma spp. Using nearly full-length 16S rRNA gene sequencing, both were identified as Candidatus Mycoplasma girerdii. In contrast, the Trichomonasvirus was not found in the T. vaginalis strains. CONCLUSION: To our knowledge, this is the first report on the characterization of actin-based genotypes and the presence of endosymbiotic Ca. M. girerdii in T. vaginalis strains in Japan. Thus, this study will provide an important impetus for future research.
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Actinas , Genótipo , Mycoplasma , Filogenia , RNA Ribossômico 16S , Simbiose , Trichomonas vaginalis , Trichomonas vaginalis/genética , Trichomonas vaginalis/isolamento & purificação , Japão , Mycoplasma/genética , Mycoplasma/isolamento & purificação , Mycoplasma/classificação , Actinas/genética , Humanos , RNA Ribossômico 16S/genética , Feminino , Vaginite por Trichomonas/parasitologiaRESUMO
This study aimed to determine whether heat acclimation could induce adaptations in exercise performance, thermoregulation, and the expression of proteins associated with heat stress in the skeletal muscles of Thoroughbreds. Thirteen trained Thoroughbreds performed 3 weeks of training protocols, consisting of cantering at 90% maximal oxygen consumption (VO2max) for 2 min 2 days/week and cantering at 7 m/s for 3 min 1 day/week, followed by a 20-min walk in either a control group (CON; Wet Bulb Globe Temperature [WBGT] 12-13°C; n = 6) or a heat acclimation group (HA; WBGT 29-30°C; n = 7). Before and after heat acclimation, standardized exercise tests (SET) were conducted, cantering at 7 m/s for 90 s and at 115% VO2max until fatigue in hot conditions. Increases in run time (p = 0.0301), peak cardiac output (p = 0.0248), and peak stroke volume (p = 0.0113) were greater in HA than in CON. Pulmonary artery temperature at 7 m/s was lower in HA than in CON (p = 0.0332). The expression of heat shock protein 70 (p = 0.0201) and 90 (p = 0.0167) increased in HA, but not in CON. These results suggest that heat acclimation elicits improvements in exercise performance and thermoregulation under hot conditions, with a protective adaptation to heat stress in equine skeletal muscles.
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Aclimatação , Proteínas de Choque Térmico HSP70 , Músculo Esquelético , Condicionamento Físico Animal , Animais , Cavalos/fisiologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Condicionamento Físico Animal/métodos , Condicionamento Físico Animal/fisiologia , Proteínas de Choque Térmico HSP70/metabolismo , Aclimatação/fisiologia , Masculino , Temperatura Alta , Regulação da Temperatura Corporal/fisiologia , Consumo de Oxigênio/fisiologia , Resposta ao Choque Térmico/fisiologiaRESUMO
BACKGROUND: Comparatively little is known regarding the initial cardiorespiratory response of young racehorses to training. The objectives were to compare physiological parameters before and after introductory training and determine whether young Thoroughbreds show endoscopic signs of exercise-induced pulmonary hemorrhage (EIPH). Ten Thoroughbreds (20-23 months) underwent 12-weeks of introductory training, including weekly speed sessions. Two 600 m high-speed exercise tests (HSET) were performed following weeks 4 and 12 while wearing a validated ergospirometry facemask. Peak oxygen consumption (VÌO2pk) and ventilatory parameters (tidal volume, VT; peak inspiratory and expiratory flow, PkVÌI, PkVÌE; respiratory frequency, Rf; minute ventilation, VÌE) were measured. The ventilatory equivalent of oxygen (VÌE/VÌO2) and the aerobic and anaerobic contributions to energy production were calculated. Maximal heart rate (HRmax) and HR at maximal speed (HRVmax) were determined. Post-exercise hematocrit, plasma ammonia and blood lactate were measured. Evidence of EIPH was investigated via tracheobronchoscopy post-exercise. Results were compared (paired t-test, P < 0.05). RESULTS: Horses were faster following training (P < 0.001) and VÌO2pk increased 28 ml/(kg total mass.min) (28 ± 16%; P < 0.001). Ventilatory (VÌE, P = 0.0015; Rf, P < 0.001; PkVÌI, P < 0.001; PkVÌE, P < 0.001) and cardiovascular parameters (HRmax, P = 0.03; HRVmax, P = 0.04) increased. The increase in VÌE was due to greater Rf, but not VT. VÌE/VÌO2 was lower (26 ± 3.6 vs 23 ± 3.7; P = 0.02), indicating improved ventilatory efficiency. Anaerobic contribution to total energy production increased from 15.6 ± 6.1% to 18.5 ± 6.3% (P = 0.02). Post-exercise hematocrit (P < 0.001), plasma ammonia (P = 0.03) and blood lactate (P = 0.001) increased following training. Horses showed no signs of EIPH. CONCLUSIONS: Young two-year-old Thoroughbreds responded well to introductory training without developing tracheobronchoscopic evidence of EIPH.
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Hemorragia , Consumo de Oxigênio , Condicionamento Físico Animal , Animais , Cavalos , Hemorragia/veterinária , Masculino , Pneumopatias/veterinária , Frequência Cardíaca , Feminino , Adaptação Fisiológica , Doenças dos Cavalos/fisiopatologiaRESUMO
Eomesodermin-expressing (Eomes+) T-helper (Th) cells show cytotoxic characteristics in secondary progressive multiple sclerosis. We found that Eomes+ Th cell frequency was increased in the peripheral blood of amyotrophic lateral sclerosis and Alzheimer's disease patients. Furthermore, granzyme B production by Th cells from such patients was high compared with controls. A high frequency of Eomes+ Th cells was observed in the initial (acutely progressive) stage of amyotrophic lateral sclerosis, and a positive correlation between Eomes+ Th cell frequency and cognitive decline was observed in Alzheimer's disease patients. Therefore, Eomes+ Th cells may be involved in the pathology of amyotrophic lateral sclerosis and Alzheimer's disease. ANN NEUROL 2024;95:1093-1098.
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Doenças Neurodegenerativas , Proteínas com Domínio T , Linfócitos T Auxiliares-Indutores , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Esclerose Lateral Amiotrófica/imunologia , Granzimas/metabolismo , Doenças Neurodegenerativas/imunologia , Proteínas com Domínio T/metabolismo , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
Objective We aimed to reveal detailed on-treatment lipid profiles, lipid-related surrogate markers, and factors predicting failure to achieve the guideline-recommended lipid management goal following guideline-recommended statin treatment in Japanese patients with acute myocardial infarction (AMI). Methods and Results Sixty AMI patients who underwent coronary intervention and had received rosuvastatin 10 mg/day since the start of their hospitalization were assessed for on-treatment lipid-related profiles, including high-sensitivity C-reactive protein, small dense low-density lipoprotein cholesterol (sd LDL-C), and lipoprotein (a), at the 12-week follow-up. Patients who failed to achieve the guideline-recommended lipid management at 12 weeks were defined as the "unachieved group." Univariate and multivariate logistic regression analyses were performed to evaluate the predictors of inclusion in the unachieved group after high-dose statin treatment. Despite the use of high-dose rosuvastatin, 61.7% of the enrolled AMI patients were included in the unachieved group. In addition, the unachieved group had higher sd LDL-C and lipoprotein (a) levels than the achieved group. Logistic regression analyses demonstrated that low baseline high-density lipoprotein cholesterol (HDL-C) levels and the absence of diabetes were predictors of inclusion in the unachieved group. Conclusion More than half of the Japanese AMI patients treated with rosuvastatin 10 mg/day did not achieve the guideline-recommended goal of lipid management and still had lipid-related residual risk at 12 weeks. Particular attention should be paid to patients with low baseline HDL-C levels and those without diabetes with regard to their on-treatment lipid profiles.
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OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a devastating, incurable neurodegenerative disease. A subset of ALS patients manifests with early-onset and complex clinical phenotypes. We aimed to elucidate the genetic basis of these cases to enhance our understanding of disease etiology and facilitate the development of targeted therapies. METHODS: Our research commenced with an in-depth genetic and biochemical investigation of two specific families, each with a member diagnosed with early-onset ALS (onset age of <40 years). This involved whole-exome sequencing, trio analysis, protein structure analysis, and sphingolipid measurements. Subsequently, we expanded our analysis to 62 probands with early-onset ALS and further included 440 patients with adult-onset ALS and 1163 healthy controls to assess the prevalence of identified genetic variants. RESULTS: We identified heterozygous variants in the serine palmitoyltransferase long chain base subunit 2 (SPTLC2) gene in patients with early-onset ALS. These variants, located in a region closely adjacent to ORMDL3, bear similarities to SPTLC1 variants previously implicated in early-onset ALS. Patients with ALS carrying these SPTLC2 variants displayed elevated plasma ceramide levels, indicative of increased serine palmitoyltransferase (SPT) activity leading to sphingolipid overproduction. INTERPRETATION: Our study revealed novel SPTLC2 variants in patients with early-onset ALS exhibiting frontotemporal dementia. The combination of genetic evidence and the observed elevation in plasma ceramide levels establishes a crucial link between dysregulated sphingolipid metabolism and ALS pathogenesis. These findings expand our understanding of ALS's genetic diversity and highlight the distinct roles of gene defects within SPT subunits in its development.
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Esclerose Lateral Amiotrófica , Demência Frontotemporal , Doenças Neurodegenerativas , Adulto , Humanos , Demência Frontotemporal/genética , Esclerose Lateral Amiotrófica/genética , Serina C-Palmitoiltransferase/genética , Esfingolipídeos , CeramidasRESUMO
We investigated outcomes of clinic-based hand therapy combined with a home-based exercise programme after anterior plating for distal radial fractures. A total of 102 patients were randomly assigned to one of three groups: a home-based exercise programme alone; a home-based exercise programme combined with four hand therapy sessions in the clinic; and a home-based exercise programme with seven sessions in the clinic. Mean Patient-Rated Wrist Evaluation scores at 6 weeks were significantly better for the group of patients with seven sessions in the clinic than in those with only home exercises (12 vs. 30), but the difference was no longer significant at 12 weeks. Grip strength was significantly better at 6 and 12 weeks. Combined home- and clinic-based hand therapy may facilitate an earlier return of function after anterior plating for distal radius fractures.Level of evidence: II.
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Activating transcription factor 5 (ATF5) is a transcription factor that belongs to the cAMP-response element-binding protein/ATF family and is essential for the differentiation and survival of sensory neurons in mouse olfactory organs. However, transcriptional target genes for ATF5 have yet to be identified. In the present study, chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) experiments were performed to verify ATF5 target genes in the main olfactory epithelium and vomeronasal organ in the postnatal pups. ChIP-qPCR was conducted using hemagglutinin (HA)-tagged ATF5 knock-in olfactory organs. The results obtained demonstrated that ATF5-HA fusion proteins bound to the CCAAT/enhancer-binding protein-ATF response element (CARE) site in the enhancer region of nescient helix-loop-helix 1 (Nhlh1), a transcription factor expressed in differentiating olfactory and vomeronasal sensory neurons. Nhlh1 mRNA expression was downregulated in ATF5-deficient (ATF5-/-) olfactory organs. The LIM/homeobox protein transcription factor Lhx2 co-localized with ATF5 in the nuclei of olfactory and vomeronasal sensory neurons and bound to the homeodomain site proximal to the CARE site in the Nhlh1 gene. The CARE region of the Nhlh1 gene was enriched by the active enhancer marker, acetyl-histone H3 (Lys27). The present study identified Nhlh1 as a novel target gene for ATF5 in murine olfactory organs. ATF5 may upregulate Nhlh1 expression in concert with Lhx2, thereby promoting the differentiation of olfactory and vomeronasal sensory neurons.