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Hypertension is prevalent in e-waste recycling areas, and elevated blood pressure in children significantly increases the risk of hypertension in adulthood. However, the associations and toxic pathways between chronic exposure to metal(loids) and elevated blood pressure are rarely investigated. In this study, we measured the levels of 29 hair metal(loids) (chronic exposure biomarkers) and blood pressure in 667 susceptible children from an e-waste recycling area to explore their relationships. Paired urine metabolomics analysis was also performed to interpret potential mechanistic pathways. Results showed that the hypertension prevalence in our recruited children (13.0 %) exceeded the average rate (9.5 %) for Chinese children aged 6-17 years. The top five abundant metal(loids), including lead, strontium, barium, and zinc, demonstrated the most profound associations with elevated systolic blood pressure. Quantile g-computation, weighted quantile sum, and Bayesian kernel machine regression analysis jointly demonstrated a significant association between chronic exposure to metal(loids) mixture and systolic blood pressure. Interestingly, selenium showed significant antagonistic interactions with these four metals, suggesting that supplementing selenium may help children resist the elevated blood pressure induced by metal(loids) exposure. Increased metal(loids) and blood pressure levels were significantly linked to changes in urine metabolomics. Structural equation model indicated that androsterone glucuronide and N-Acetyl-1-aspartylglutamic acid were the significant mediators of the associations between metal(loids) and blood pressure, with mediation effects of 77.4 % and 29.0 %, respectively, suggesting that androsterone glucuronide and N-Acetyl-1-aspartylglutamic acid may be involved in the development of metal-induced blood pressure elevating effect. Girls were more vulnerable to metal(loids)-induced hormonal imbalance, especially androsterone glucuronide, than boys. Chronic exposure to metal(loids) at e-waste recycling sites may contribute to elevated blood pressure in children through disrupting various metabolism pathways, particularly hormonal balance. Our study provides new insights into potential mechanistic pathways of metal(loids)-induced changes in children's blood pressure.
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Objective: To analyze the effectiveness of tuberosity suture combined with autogenous bone grafting in reverse total shoulder arthroplasty for elderly patients with proximal humerus fracture. Methods: A clinical data of 28 patients with fresh proximal humerus fractures, who met the selection criteria and admitted between June 2014 and April 2022, was retrospectively analyzed. There were 7 males and 21 females. Age ranged from 65 to 81 years, with an average of 73.8 years. The causes of injury were 21 cases of fall, 6 cases of traffic accident, and 1 case of falling from height. The time from injury to operation ranged from 5 to 20 days with an average of 9.2 days. There were 8 cases of Neer three-part fracture and 20 cases of four-part fracture. The reverse total shoulder arthroplasty was performed, and the greater and lesser tuberosities were sutered and reconstructed with autogenous bone grafting. After operation, the Constant score, American Society for Shoulder Surgery (ASES) score, and visual analogue scale (VAS) score were used to evaluate shoulder function and pain; and the active range of motion of the shoulder joint was recorded, including flexion, external rotation, and internal rotation. X-ray films were taken to observe the position of prosthesis. According to the evaluation criteria proposed by Boileau, the healing of greater tuberosity was evaluated, and the effectiveness was compared between the patients with healed and non-healed (displacement and absorption) greater tuberosity. Results: All incisions healed by first intention after operation. All patients were followed up 24-106 months, with an average of 60.9 months. At last follow-up, the VAS score of shoulder joint ranged from 0 to 6 (mean, 1.1). The Constant score ranged from 45 to 100 (mean, 80.1). The ASES score ranged from 57 to 100 (mean, 84.7). The active range of motions of shoulder joint were 60°-160° (mean, 118°) in flexion, 0°-50° (mean, 30°) in external rotation, and corresponding to reaching the S 5-T 8 vertebral body level in internal rotation. During follow-up, no shoulder joint re-dislocation or severe shoulder instability occurred, and no revision surgery was performed. X-ray film reexamination showed that there was no loosening of the prosthesis. According to the evaluation criteria proposed by Boileau, the greater tuberosity fused in 22 cases (78.6%), displaced in 3 cases (10.7%), and absorbed in 3 cases (10.7%). The shoulder joint function and pain related evaluation indicators in the healed group were significantly better than those in the non-healed group ( P<0.05). Conclusion: Tuberosity suture combined with autogenous bone grafting is a relatively simple procedure that provides a reliable fixation for the anatomic recovery of greater and lesser tuberosities and is beneficial for the recovery of shoulder function in elderly patients with proximal humeral fractures.
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Artroplastía de Reemplazo de Hombro , Trasplante Óseo , Rango del Movimiento Articular , Fracturas del Hombro , Articulación del Hombro , Humanos , Masculino , Femenino , Anciano , Artroplastía de Reemplazo de Hombro/métodos , Fracturas del Hombro/cirugía , Trasplante Óseo/métodos , Articulación del Hombro/cirugía , Anciano de 80 o más Años , Trasplante Autólogo , Resultado del Tratamiento , Suturas , Húmero/cirugía , Técnicas de SuturaRESUMEN
PURPOSE: To investigate the differences in survival after venous thromboembolism (VTE) and anticoagulation efficacy and safety between catheter (CRVTE) and non-catheter-related VTE (NCRVTE) in cancer patients. METHODS: A retrospective research was conducted, and consecutive cancer (digestive, respiratory, genitourinary, blood and lymphatic, and the other cancers) patients with VTE were enrolled. The anticoagulation therapies included low-molecular-weight heparin (LMWH), warfarin, new type of direct oral anticoagulants (NDOACs), LMWH combined with warfarin, and LMWH combined with NDOACs. Data were collected from the electronic medical record database of our hospital and were analyzed accordingly by Kruskal-Wallis H Test, Chi-square test, Fisher's exact test, Logistic regressions, Kaplan-Meier analysis, and Cox regressions. RESULTS: 263 patients were included, median age in years (interquartile range) was 64(56-71) and 60.5% were male. VTE recurrence rate was 16.7% in CRVTE group which was significantly lower than 34.8% in NCRVTE group (P = .032). Heart diseases were independently associated with VTE recurrence (P = .025). Kaplan-Meier survival estimates at 1, 2, and 3 years for CRVTE group were 62.5%, 60.0%, and 47.5%, respectively, compared with 47.9% (P = .130), 38.7% (P = .028), and 30.1% (P = .046), respectively, for NCRVTE group. Cox regression showed surgery (P = .003), anticoagulation therapy types (P = .009), VTE types (P = .006) and cancer types (P = .039) were independent prognostic factors for 3-year survival after VTE. Nonmajor and major bleeding were not significantly different (P = .417). Anticoagulation therapy types were independently associated with the bleeding events (P = .030). CONCLUSIONS: Cancer patients with CRVTE potentially have a better anticoagulation efficacy and survival compared to NCRVTE, and the anticoagulation safety seems no significant difference.
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Anticoagulantes , Neoplasias , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/tratamiento farmacológico , Tromboembolia Venosa/etiología , Tromboembolia Venosa/mortalidad , Neoplasias/complicaciones , Neoplasias/mortalidad , Neoplasias/tratamiento farmacológico , Masculino , Femenino , Anticoagulantes/uso terapéutico , Anticoagulantes/efectos adversos , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
While a large body of work in sentence comprehension has explored how different types of linguistic information are used to guide syntactic parsing, less is known about the effect of discourse structure. This study investigates this question, focusing on the main and subordinate discourse contrast manifested in the distinction between restrictive relative clauses (RRCs) and appositive relative clauses (ARCs) in American English. In three self-paced reading experiments, we examined whether both RRCs and ARCs interfere with the matrix clause content and give rise to the agreement attraction effect. While the standard attraction effect was consistently observed in the baseline RRC structures, the effect varied in the ARC structures. These results collectively suggest that discourse structure indeed constrains syntactic dependency resolution. Most importantly, we argue that what is at stake is not the static discourse structure properties at the global sentence level. Instead, attention should be given to the incremental update of the discourse structure in terms of which discourse questions are active at any given moment of a discourse. The current findings have implications for understanding the way discourse structure, specifically the active state of discourse questions, constrains memory retrieval.
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Comprensión , Lenguaje , Lectura , Humanos , Lingüística , Psicolingüística , Femenino , Masculino , AdultoRESUMEN
BACKGROUND: We aimed to explore the differences and relationships in body composition, social function, and comorbidities between children with attention-deficit/hyperactivity disorder (ADHD) and subthreshold ADHD. METHODS: A case-control study was conducted to analyze the differences between children with ADHD and subthreshold ADHD. Logistic regression models were used to analyze the factors influencing social functional impairments and comorbidities. RESULTS: Children with ADHD and subthreshold ADHD had a higher fat mass index than healthy children (p < 0.05). The scores of all six social functional domains were higher in the subthreshold ADHD and ADHD groups than in the control group (p < 0.05). The prevalence of comorbidity was higher in children with subthreshold ADHD and ADHD compared to the control group (p < 0.05). Inattention and comorbid anxiety/depression increased the risk of functional impairments in children with ADHD (full syndrome/subthreshold), whereas a higher fat-free mass index reduced the risk. The severity of hyperactivity was associated with a higher risk of comorbidity in children with ADHD (full syndrome/subthreshold). CONCLUSION: Children with subthreshold ADHD and ADHD had more fat mass and higher rates of social functional impairments and comorbidities than healthy children. There were clinical correlations between body composition, social functional impairments, and comorbidities in ADHD. IMPACT: 1. Children with subthreshold ADHD and ADHD had higher fat mass levels than normal children. 2. The social function impairments and comorbidities of children with subthreshold ADHD were similar to those with ADHD. 3. Inattentiveness and anxiety/depression increased the risk of functional impairments in children with ADHD (full syndrome/subthreshold), while a higher fat-free mass index and skeletal muscle-to-body fat ratio reduced the risk.
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Li-rich layered oxides are promising candidates for high-capacity Li-ion battery cathode materials. In this study, we employ first-principles calculations to investigate the effect of F doping on Li-rich Li2MnO3 layered cathode materials. Our findings reveal that both Li2MnO3 and Li2MnO2.75F0.25 exhibit significant volume changes (greater than 10%) during deep delithiation, which could hinder the cycling of more Li ions from these two materials. For Li2MnO3, it is observed that oxygen ions lose electrons to compensate for charge during the delithiation process, leading to a relatively high voltage plateau. After F doping, oxidation occurs in both the cationic (Mn) and anionic (O) components, resulting in a lower voltage plateau at the beginning of the charge, which can be attributed to the oxidation of Mn3+ to Mn4+. Additionally, F doping can somewhat suppress the release of oxygen in Li2MnO3, improving the stability of anionic oxidation. However, the increase of the activation barriers for Li diffusion can be observed after F doping, due to stronger electrostatic interactions between F- and Li+, which adversely affects the cycling kinetics of Li2MnO2.75F0.25. This study enhances our understanding of the impact of F doping in Li2MnO3 based on theoretical calculations.
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BACKGROUND: The incidence and mortality of lung cancer have increased annually. Accurate diagnosis can help improve therapeutic efficacy of interventions and prognosis. Percutaneous lung biopsy is a reliable method for the clinical diagnosis of lung cancer. Ultrasound-guided percutaneous lung biopsy technology has been widely promoted and applied in recent years. AIM: To investigate the diagnostic value of contrast-enhanced ultrasound (CEUS)-guided percutaneous biopsy in peripheral pulmonary lesions. METHODS: We retrospectively collected data on 237 patients with peripheral thoracic focal lesions who underwent puncture biopsy at Wuxi People's Hospital. The patients were randomly divided into two groups: The CEUS-guided before lesion puncture group (contrast group) and conventional ultrasound-guided group (control group). Analyze the diagnostic efficacy of the puncture biopsy, impact of tumor size, and number of puncture needles and complications were analyzed and compared between the two groups. RESULTS: Accurate pathological results were obtained for 92.83% (220/237) of peripheral lung lesions during the first biopsy, with an accuracy rate of 95.8% (113/118) in the contrast group and 89.9% (107/119) in the control group. The difference in the area under the curve (AUC) between the contrast and the control groups was not statistically significant (0.952 vs 0.902, respectively; P > 0.05). However, when the lesion diameter ≥ 5 cm, the diagnostic AUC of the contrast group was higher than that of the control group (0.952 vs 0.902, respectively; P < 0.05). In addition, the average number of puncture needles in the contrast group was lower than that in the control group (2.58 ± 0.53 vs 2.90 ± 0.56, respectively; P < 0.05). CONCLUSION: CEUS guidance can enhance the efficiency of puncture biopsy of peripheral pulmonary lesions, especially for lesions with a diameter ≥ 5 cm. Therefore, CEUS guidance has high clinical diagnostic value in puncture biopsy of peripheral focal lung lesions.
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The mechanism by which aging induces aortic aneurysm and dissection (AAD) remains unclear. A total of 430 participants were recruited for the screening of differentially expressed plasma microRNAs (miRNAs). We found that miR-1204 is significantly increased in both the plasma and aorta of elder patients with AAD and is positively correlated with age. Cell senescence induces the expression of miR-1204 through p53 interaction with plasmacytoma variant translocation 1, and miR-1204 induces vascular smooth muscle cell (VSMC) senescence to form a positive feedback loop. Furthermore, miR-1204 aggravates angiotensin II-induced AAD formation, and inhibition of miR-1204 attenuates ß-aminopropionitrile monofumarate-induced AAD development in mice. Mechanistically, miR-1204 directly targets myosin light chain kinase (MYLK), leading to the acquisition of a senescence-associated secretory phenotype (SASP) by VSMCs and loss of their contractile phenotype. MYLK overexpression reverses miR-1204-induced VSMC senescence, SASP and contractile phenotypic changes, and the decrease of transforming growth factor-ß signaling pathway. Our findings suggest that aging aggravates AAD via the miR-1204-MYLK signaling axis.
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Envejecimiento , Aneurisma de la Aorta , Disección Aórtica , Senescencia Celular , MicroARNs , Músculo Liso Vascular , Quinasa de Cadena Ligera de Miosina , Transducción de Señal , Animales , Femenino , Humanos , Masculino , Ratones , Envejecimiento/genética , Envejecimiento/metabolismo , Angiotensina II/metabolismo , Aneurisma de la Aorta/metabolismo , Aneurisma de la Aorta/genética , Aneurisma de la Aorta/patología , Disección Aórtica/metabolismo , Disección Aórtica/genética , Disección Aórtica/patología , Proteínas de Unión al Calcio , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Quinasa de Cadena Ligera de Miosina/metabolismo , Quinasa de Cadena Ligera de Miosina/genética , Factor de Crecimiento Transformador beta/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Ganoderic acids (GAs) are major functional components of Ganoderma lucidum. The study aimed to breed a new G. lucidum strain with increased contents of individual GAs. Two mating-compatible monokaryotic strains, G. 260125 and G. 260124, were successfully isolated from the dikaryotic G. lucidum CGMCC 5.0026 via protoplast formation and regeneration. The Vitreoscilla hemoglobin gene (vgb) and squalene synthase gene (sqs) were overexpressed in the monokaryotic G. 260124 and G. 260125 strain, respectively. Mating between the G. 260124 strain overexpressing vgb and the G. 260125 strain overexpressing sqs resulted in the formation of the new hybrid dikaryotic G. lucidum strain sqs-vgb. The maximum contents of ganoderic acid (GA)-T, GA-Me, and GA-P in the fruiting body of the mated sqs-vgb strain were 23.1, 15.3, and 39.8 µg/g dry weight (DW), respectively, 2.23-, 1.75-, and 2.69-fold greater than those in G. lucidum 5.0026. The squalene and lanosterol contents increased 2.35- and 1.75-fold, respectively, in the fruiting body of the mated sqs-vgb strain compared with those in the G. lucidum 5.0026. In addition, the maximum expression levels of the sqs and lanosterol synthase gene (ls) were increased 3.23- and 2.13-fold, respectively, in the mated sqs-vgb strain. In summary, we developed a new G. lucidum strain with higher contents of individual GAs in the fruiting body by integrating genetic engineering and mono-mono crossing.
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The microscopic stress field inhomogeneity in the interfacial region adjacent to the liquid surface is the fundamental origin of the liquid surface tension, but because of broadening due to capillary fluctuations, a detailed molecular level understanding of the stress field remains elusive. In this work, we deconvolute the capillary fluctuations to reveal the intrinsic stress field and show that the atomic-level contributions to the surface tension are similar in functional form across a variety of monatomic systems. These contributions are confined to an interfacial region approximately 1.5±0.1 times the particle diameter for all systems studied. In addition, the intrinsic density and stress profiles show a strong spatial correlation that should be useful in the development of a statistical mechanical theory for the prediction of surface stress and surface tension.
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BACKGROUND: The comparative effectiveness of volatile anaesthesia and total intravenous anaesthesia (TIVA) in terms of patient outcomes after cardiac surgery remains a topic of debate. METHODS: Multicentre randomised trial in 16 tertiary hospitals in China. Adult patients undergoing elective cardiac surgery were randomised in a 1:1 ratio to receive volatile anaesthesia (sevoflurane or desflurane) or propofol-based TIVA. The primary outcome was a composite of predefined major complications during hospitalisation and mortality 30 days after surgery. RESULTS: Of the 3123 randomised patients, 3083 (98.7%; mean age 55 yr; 1419 [46.0%] women) were included in the modified intention-to-treat analysis. The composite primary outcome was met by a similar number of patients in both groups (volatile group: 517 of 1531 (33.8%) patients vs TIVA group: 515 of 1552 (33.2%) patients; relative risk 1.02 [0.92-1.12]; P=0.76; adjusted odds ratio 1.05 [0.90-1.22]; P=0.57). Secondary outcomes including 6-month and 1-yr mortality, duration of mechanical ventilation, length of ICU and hospital stay, and healthcare costs, were also similar for the two groups. CONCLUSIONS: Among adults undergoing cardiac surgery, we found no difference in the clinical effectiveness of volatile anaesthesia and propofol-based TIVA. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-IOR-17013578).
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Anestésicos por Inhalación , Anestésicos Intravenosos , Procedimientos Quirúrgicos Cardíacos , Desflurano , Complicaciones Posoperatorias , Propofol , Humanos , Propofol/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Procedimientos Quirúrgicos Cardíacos/mortalidad , Anestésicos Intravenosos/efectos adversos , Anestésicos por Inhalación/efectos adversos , Anciano , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/prevención & control , Adulto , Sevoflurano/efectos adversos , Anestesia Intravenosa/métodos , China/epidemiología , Tiempo de Internación/estadística & datos numéricos , Anestesia por Inhalación/métodos , Anestesia por Inhalación/efectos adversos , Resultado del TratamientoRESUMEN
To address the epidemic, such as COVID-19, the government may implement the home quarantine policy for the infected residents. The logistics company is required to control the risk of epidemic spreading while delivering goods to residents. In this case, the logistics company often uses vehicles and unmanned aerial vehicles (UAVs) for delivery. This paper studies the distribution issue of cold chain logistics by integrating UAV logistics with epidemic risk management innovatively. At first, a "vehicle-UAV" joint distribution mode including vehicles, small UAVs and large UAVs, is proposed. The green cost for vehicles and UAVs is calculated, respectively. The formula for infection risk due to large numbers of residents gathering at distribution centers to pick up goods is then derived. Furthermore, based on the control of infection risk, an optimization model is developed to minimize the total logistics cost. A modified ant colony algorithm is designed to solve the model. The numerical results show that the maximum acceptable risk and the crowd management level of distribution centers both have significant effects on the distribution network, logistics cost and number of new infections. Our study provides a new management method and technical idea for ensuring the needs of residents during the epidemic.
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COVID-19 , Humanos , COVID-19/epidemiología , COVID-19/prevención & control , COVID-19/economía , COVID-19/transmisión , Algoritmos , Cuarentena/economía , Dispositivos Aéreos No Tripulados , SARS-CoV-2 , Epidemias/prevención & control , Epidemias/economía , Gestión de Riesgos/métodosRESUMEN
Tacrolimus, one of the macrolide calcineurin inhibitors, is the most frequently used immunosuppressant after transplantation. Long-term administration of tacrolimus leads to dyslipidemia and affects liver lipid metabolism. In this study, we investigated the mode of action and underlying mechanisms of this adverse reaction. Mice were administered tacrolimus (2.5 mg·kg-1·d-1, i.g.) for 10 weeks, then euthanized; the blood samples and liver tissues were collected for analyses. We showed that tacrolimus administration induced significant dyslipidemia and lipid deposition in mouse liver. Dyslipidemia was also observed in heart or kidney transplantation patients treated with tacrolimus. We demonstrated that tacrolimus did not directly induce de novo synthesis of fatty acids, but markedly decreased fatty acid oxidation (FAO) in AML12 cells. Furthermore, we showed that tacrolimus dramatically decreased the expression of HMGCS2, the rate-limiting enzyme of ketogenesis, with decreased ketogenesis in AML12 cells, which was responsible for lipid deposition in normal hepatocytes. Moreover, we revealed that tacrolimus inhibited forkhead box protein O1 (FoxO1) nuclear translocation by promoting FKBP51-FoxO1 complex formation, thus reducing FoxO1 binding to the HMGCS2 promoter and its transcription ability in AML12 cells. The loss of HMGCS2 induced by tacrolimus caused decreased ketogenesis and increased acetyl-CoA accumulation, which promoted mitochondrial protein acetylation, thereby resulting in FAO function inhibition. Liver-specific HMGCS2 overexpression via tail intravenous injection of AAV8-TBG-HMGCS2 construct reversed tacrolimus-induced mitochondrial protein acetylation and FAO inhibition, thus removing the lipid deposition in hepatocytes. Collectively, this study demonstrates a novel mechanism of liver lipid deposition and hyperlipidemia induced by long-term administration of tacrolimus, resulted from the loss of HMGCS2-mediated ketogenesis and subsequent FAO inhibition, providing an alternative target for reversing tacrolimus-induced adverse reaction.
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Hidroximetilglutaril-CoA Sintasa , Hígado , Ratones Endogámicos C57BL , Tacrolimus , Animales , Tacrolimus/farmacología , Ratones , Masculino , Hidroximetilglutaril-CoA Sintasa/metabolismo , Hidroximetilglutaril-CoA Sintasa/genética , Humanos , Hígado/metabolismo , Hígado/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Proteína Forkhead Box O1/metabolismo , Inmunosupresores/farmacología , Trastornos del Metabolismo de los Lípidos/metabolismo , Trastornos del Metabolismo de los Lípidos/inducido químicamente , Trastornos del Metabolismo de los Lípidos/tratamiento farmacológico , Línea CelularRESUMEN
BACKGROUND: We report a rare case of primary clinical presentation featuring elevated creatine kinase (CK) levels in a neonate, which is associated with the LAMA2 gene. In this case, a heterozygous mutation in exon5 of the LAMA2 gene, c.715C>G (resulting in a change of nucleotide number 715 in the coding region from cytosine to guanine), induced an amino acid alteration p.R239G (No. 239) in the patient, representing a missense mutation. This observation may be elucidated by the neonatal creatine monitoring mechanism, a phenomenon not previously reported. CASE SUMMARY: We analysed the case of a neonate presenting solely with elevated CK levels who was eventually discharged after supportive treatment. The chief complaint was identification of increased CK levels for 15 d and higher CK values for 1 d. Admission occurred at 18 d of age, and despite prolonged treatment with creatine and vitamin C, the elevated CK levels showed limited improvement. Whole exome sequencing revealed the presence of a c.715C>G mutation in LAMA2 in the newborn, correlating with a clinical phenotype. However, the available information offers insufficient evidence for clinical pathogenicity. CONCLUSION: Mutations in LAMA2 are associated with the clinical phenotype of increased neonatal CK levels, for which no specific treatment exists. Whole genome sequencing facilitates early diagnosis.
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2,2',6-Tribromobisphenol A (Tri-BBPA), the main debrominated congener of tetrabromobisphenol A (TBBPA), is ubiquitous in the environment and human body but with unknown toxicity. Tri-BBPA was synthesized and applied to investigate its sub-chronic exposure effects on 28 organ coefficients and clinical health indicators related to liver function, kidney function, and cardiovascular system function in female mice. Results showed that the liver was the targeted organ of Tri-BBPA exposure. Compared to the control group, the changes in liver coefficient, cholinesterase, total protein, albumin, γ-glutamyl transpeptidase, lactate dehydrogenase, and creatine kinase levels ranged from -61.2 % to 35.5 % in the high-exposed group. Creatine kinase was identified as a critical effect indicator of Tri-BBPA exposure. Using the Bayesian benchmark dose derivation method, a lower reference dose than TBBPA was established for Tri-BBPA (10.6 µg/kg-day). Serum metabolomics revealed that Tri-BBPA exposure may primarily damage the liver by disrupting tryptophan metabolism related to L-alanine, tryptamine, 5-hydroxyindoleacetic acid, and 5-methoxyindoleacetate in liver cells and leading to liver dysfunction. Notably, epilepsy, schizophrenia, early preeclampsia, and late-onset preeclampsia were the top six enriched diseases, suggesting that the nervous system may be particularly affected by Tri-BBPA exposure. Our findings hinted a non-negligible health risk of exposure to debrominated products of TBBPA.
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Bifenilos Polibrominados , Animales , Ratones , Femenino , Bifenilos Polibrominados/toxicidad , Redes y Vías Metabólicas/efectos de los fármacos , Hígado/metabolismo , Hígado/efectos de los fármacos , Contaminantes Ambientales/toxicidadRESUMEN
Evidence increasingly suggests molybdenum exposure at environmental levels is still associated with adverse human health, emphasizing the necessity to establish a more protective reference dose (RfD). Herein, we conducted a study measuring 15 urinary metals and 30 clinical health indicators in 2267 participants residing near chemical enterprises across 11 Chinese provinces to investigate their relationships. The kidney and cystatin-C emerged as the most sensitive organ and critical effect indicator of molybdenum exposure, respectively. Odds of cystatin-C-defined chronic kidney disease (CKD) in the highest quantile of molybdenum exposure significantly increased by 133.5% (odds ratio [OR]: 2.34, 95% CI: 1.78, 3.11) and 75.8% (OR: 1.76, 95% CI: 1.24, 2.49) before and after adjusting for urinary 14 metals, respectively. Intriguingly, cystatin-C significantly mediated 15.9-89.5% of molybdenum's impacts on liver and lung function, suggesting nephrotoxicity from molybdenum exposure may trigger hepatotoxicity and pulmonary toxicity. We derived a new RfD for molybdenum exposure (0.87⯵g/kg-day) based on cystatin-C-defined estimated glomerular filtration rate by employing Bayesian Benchmark Dose modeling analysis. This RfD is significantly lower than current exposure guidance values (5-30⯵g/kg-day). Remarkably, >90% of participants exceeded the new RfD, underscoring the significant health impacts of environmental molybdenum exposure on populations in industrial regions of China.
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Molibdeno , Molibdeno/orina , Molibdeno/toxicidad , Molibdeno/análisis , Humanos , China/epidemiología , Femenino , Masculino , Adulto , Persona de Mediana Edad , Exposición a Riesgos Ambientales/estadística & datos numéricos , Exposición a Riesgos Ambientales/análisis , Cistatina C , Medición de Riesgo , Contaminantes Ambientales/orina , Contaminantes Ambientales/análisis , Adulto Joven , Teorema de Bayes , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/inducido químicamente , Anciano , Industria Química , Riñón/efectos de los fármacos , Tasa de Filtración Glomerular/efectos de los fármacosRESUMEN
Sex differences in mammalian complex traits are prevalent and are intimately associated with androgens1-7. However, a molecular and cellular profile of sex differences and their modulation by androgens is still lacking. Here we constructed a high-dimensional single-cell transcriptomic atlas comprising over 2.3 million cells from 17 tissues in Mus musculus and explored the effects of sex and androgens on the molecular programs and cellular populations. In particular, we found that sex-biased immune gene expression and immune cell populations, such as group 2 innate lymphoid cells, were modulated by androgens. Integration with the UK Biobank dataset revealed potential cellular targets and risk gene enrichment in antigen presentation for sex-biased diseases. This study lays the groundwork for understanding the sex differences orchestrated by androgens and provides important evidence for targeting the androgen pathway as a broad therapeutic strategy for sex-biased diseases.