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1.
J Orthop Surg (Hong Kong) ; 32(1): 10225536241242086, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38589277

RESUMO

PURPOSE: This study explores the use of ultrasound-guided Hyaluronic Acid (HA) injections for Insertional Achilles Tendinopathy (IAT). METHODS: A cohort of 15 ankles diagnosed with IAT received three weekly ultrasound-guided HA injections. The Victorian Institute of Sport Assessment - Achilles (VISA-A) questionnaire scored the severity of symptoms and functional impairment before treatment, and at one and six months post-treatment. RESULTS: Significant improvement was observed in VISA-A scores post-treatment, rising from an average baseline of 34.8 ± 15.2 (11-63) to 53.6 ± 20.9 (15-77) after one month, and then to 50.7 ± 18.6 (20-75) after six months. No adverse reactions were noted, underscoring the safety of the intervention. CONCLUSION: The pilot study presents HA injections as a potentially effective treatment for IAT, while interpretation of these findings must take into account the variability in results, indicating a range of patient responses. It encourages further research to confirm these findings and to explore HA's full potential in managing IAT, despite the limitations of a small sample size and lack of control group.


Assuntos
Tendão do Calcâneo , Esportes , Tendinopatia , Humanos , Ácido Hialurônico/uso terapêutico , Projetos Piloto , Tendinopatia/diagnóstico por imagem , Tendinopatia/tratamento farmacológico , Resultado do Tratamento
2.
bioRxiv ; 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38586056

RESUMO

Human cell line models, including the neuronal precursor line LUHMES, are important for investigating developmental transcriptional dynamics within imprinted regions, particularly the 15q11-q13 Angelman (AS) and Prader-Willi (PWS) syndrome locus. AS results from loss of maternal UBE3A in neurons, where the paternal allele is silenced by a convergent antisense transcript UBE3A-ATS, a lncRNA that normally terminates at PWAR1 in non-neurons. qRTPCR analysis confirmed the exclusive and progressive increase in UBE3A-ATS in differentiating LUHMES neurons, validating their use for studying UBE3A silencing. Genome-wide transcriptome analyses revealed changes to 11,834 genes during neuronal differentiation, including the upregulation of most genes within the 15q11-q13 locus. To identify dynamic changes in chromatin loops linked to transcriptional activity, we performed a HiChIP validated by 4C, which identified two neuron-specific CTCF loops between MAGEL2-SNRPN and PWAR1-UBE3A. To determine if allele-specific differentially methylated regions (DMR) may be associated with CTCF loop anchors, whole genome long-read nanopore sequencing was performed. We identified a paternally hypomethylated DMR near the SNRPN upstream loop anchor exclusive to neurons and a paternally hypermethylated DMR near the PWAR1 CTCF anchor exclusive to undifferentiated cells, consistent with increases in neuronal transcription. Additionally, DMRs near CTCF loop anchors were observed in both cell types, indicative of allele-specific differences in chromatin loops regulating imprinted transcription. These results provide an integrated view of the 15q11-q13 epigenetic landscape during LUHMES neuronal differentiation, underscoring the complex interplay of transcription, chromatin looping, and DNA methylation. They also provide insights for future therapeutic approaches for AS and PWS.

3.
Methods Mol Biol ; 2784: 285-299, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38502493

RESUMO

To date, CRISPR-based DNA targeting approaches have typically used fusion proteins between full fluorescent reporters and catalytically inactive Cas9 (dCas9) for imaging rather than detection of endogenous genomic DNA sequences. A promising alternative strategy for DNA targeting is the direct biosensing of user-defined sequences at single copy with single-cell resolution. Our recently described DNA biosensing approach using a dual fusion protein biosensor comprised of two independently optimized fragments of NanoLuc luciferase (NLuc) directionally fused to dCas9 paired with user-defined single-guide RNAs (sgRNAs) could allow users to sensitively detect unique copies of a target sequence in individual living cells using common laboratory equipment such as a microscope or a luminescence-equipped microplate reader. Here we describe a protocol for using such a DNA biosensor noninvasively in situ.


Assuntos
Técnicas Biossensoriais , RNA Guia de Sistemas CRISPR-Cas , Sequência de Bases , DNA/genética , DNA/metabolismo , Luciferases/genética , Luciferases/metabolismo , Sistemas CRISPR-Cas/genética
5.
Isr Med Assoc J ; 25(12): 804-808, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38142319

RESUMO

BACKGROUND: Hip fractures are a public health problem that disproportionately affects the elderly. Displaced femoral neck fractures were treated historically with hemiarthroplasty, but the use of total hip arthroplasty (THA) is increasing showing superior long-term results. OBJECTIVES: To assess whether THA has superior short-term results compared to bipolar hemiarthroplasty for displaced femoral neck fractures. METHODS: Two groups of active older patients underwent either cementless bipolar hemiarthroplasty or THA for displaced femoral neck fracture. All patients were operated on using the direct lateral approach to the hip joint. Patients were assessed using the Harris Hip Score at hospital discharge and at 6 weeks follow-up. RESULTS: We included 40 patients ages 65-85 years; 18 underwent bipolar hemiarthroplasty and 22 THA. The number of women in each group was similar, as was mean age: 73.1 ± 4.2 years in the hemiarthroplasty group and 71.0 ± 3.7 in THA. Harris Hip Score on hospital discharge was similar in both groups. Walking ability at discharge was better in the THA cohort and they were discharged sooner: 5.2 ± 1.3 vs. 6.4 ± 1.7 days following hemiarthroplasty (P = 0.021). At 6 weeks follow-up, the mean Harris Hip Score was higher in the THA group (78.6 ± 11 vs. 61.5 ± 17 for hemiarthroplasty, P < 0.001). Patients in the THA group walked longer distances, needed less support while walking, and reported less pain. CONCLUSIONS: Better short-term results at hospital discharge and at 6 weeks follow-up after THA contributed to earlier patient independence and shorter hospital stays.


Assuntos
Artroplastia de Quadril , Fraturas do Colo Femoral , Hemiartroplastia , Fraturas do Quadril , Humanos , Feminino , Idoso , Artroplastia de Quadril/efeitos adversos , Artroplastia de Quadril/métodos , Hemiartroplastia/métodos , Resultado do Tratamento , Fraturas do Colo Femoral/cirurgia , Fraturas do Quadril/cirurgia
6.
Bioinformation ; 19(8): 829-832, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37908613

RESUMO

Filoviruses, categorized as World Health Organization (WHO) Risk Group 4 (RG-4) pathogens, represent significant global health risks due to their extraordinary virulence. The Filoviridae family encompasses Ebola strains such as Sudan, Zaire, Bundibugyo, Tai Forest (formerly known as Ivory Coast), Reston, and Bombali, in addition to the closely related Marburg and Ravn virus strains. Filoviruses originated from a common ancestor about 10,000 years ago and displayed remarkable consistency in genetic heterogeneity until the 20th century. However, they overcame a genetic bottleneck by mid-century. Paradoxically, this resulted in the emergence of boosted virulent strains from the 1970's onward. Filovirus research is included in the NIAID Biodefense Program and utilizes the highest level specialized protective laboratories, Biosafety Laboratory (BSL)-4. The spread of Filoviruses as well as other RG-4 pathogens within Africa poses a significant health threat increasingly both in Africa and out of Africa.

7.
Front Psychol ; 14: 1273586, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37901094

RESUMO

Aim: Adolescents have been identified as the group who struggle most with successful adjustment to closed loop technology. This study aims to identify the psychological constructs that should form part of a positive psychology intervention to assist with the adjustment to closed loop technology among adolescents living with type 1 diabetes. Method: Qualitative document analysis was employed to integrate findings from two documents: a published ongoing intervention study and a recent phenomenological study by the authors. Reflexive thematic analysis was used to identify themes from the documents. Findings: The following themes were identified as important psychological constructs that aid adjustment: the importance of knowledge and education; the process of positive adjustment to closed loop technology; a positive outlook; and building a relationship with diabetes. Conclusion: Interventions are needed to assist adolescents in their adjustment to closed loop technology. The psychological constructs identified served as a starting point in designing an effective, evidence-based intervention grounded in data and theory. Knowledge and education, responsibility, identity, positive affect, gratitude, support, and trust are psychological constructs that need to be included in an intervention program.

8.
J Clin Med ; 12(15)2023 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-37568283

RESUMO

Can the financial impact of implant choice during the learning curve of inexperienced surgeons in hip fracture surgery be quantified? Hip fractures in the elderly are a significant medical concern, often requiring surgical interventions performed by orthopedic surgery residents. As healthcare costs rise, exploring cost reduction opportunities within the healthcare system becomes crucial. In this prospective analysis, we examined the financial implications of implant choices encountered by residents during their learning curve in hip fracture surgery. Our study included 278 surgically treated pertrochanteric fractures using the same locking cephalomedullary nail. Data on patients, surgeons (including their experience and seniority), and all implants charged by the hospital were collected. This encompassed documentation of any nail-related equipment that was opened on the operating table and whether it was subsequently used by the end of the procedure. By calculating the number and cost of these implants, we assessed the financial burden associated with suboptimal choices made during the learning curve. Our findings revealed that in 16.18% of surgeries, instances of suboptimal implant utilization occurred, highlighting the complexities of the learning process. Importantly, the rate of these challenges was not influenced by surgeon seniority or patient characteristics. The mean additional cost per surgery was determined to be USD 65.69 ± 157.63 for surgeries with suboptimal implant utilization, compared to USD 56.55 ± 139.13 for surgeries without such challenges. Although there was a trend towards higher implant-related costs in resident-led surgeries, the difference did not reach statistical significance. These findings underscore the feasibility of enabling residents to autonomously perform intramedullary nailing surgeries, even without specialist supervision, while incurring minimal additional expenses during the learning curve. By acknowledging the financial implications associated with the learning curve in the management of hip fractures, we can strive to optimize healthcare costs, thus addressing an important aspect of this issue.

9.
J Clin Med ; 12(15)2023 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-37568421

RESUMO

BACKGROUND: This study compared outcomes of the direct anterior approach (DAA) and direct lateral approach (DLA) for treating displaced femoral neck fractures in active elderly patients. METHODS: This retrospective study included active elderly patients who sustained a displaced femoral neck fracture and underwent a cementless total hip arthroplasty either with a supine DAA or a decubitus DLA. Patients were assessed using the Harris hip score at discharge and at a 6-week follow-up. RESULTS: A total of 41 women and 18 men were included in the study. Of those, 22 underwent DLA and 37 received DAA, all performed by the same team. In both groups, 69% were women, mean age was 70 years, and mean BMI was 25.2. Mean hemoglobin loss was 2.3 g/dl between admission and the first post-operative day in both groups. Similar numbers in each cohort were discharged home rather than to a rehabilitation center. The patients who underwent the DAA experienced a 2-day reduction in their hospital stay compared to the DLA group (4.2 ± 1.9 vs. 6.8 ± 3.7, respectively; p < 0.001). The Harris hip score in the DAA group was significantly higher at the 6-week follow-up than in the DLA group (87.23 ± 7.75 vs. 81.23 ± 7.67, respectively; p < 0.031). CONCLUSIONS: The patients who underwent THA with the DAA demonstrated better short term outcomes compared to the alternative approach for displaced femoral neck fractures in active elderly patients. DAA helped patients regain independence faster and might decrease hospitalization and rehabilitation costs. Based on these results, we recommend using the DAA for active elderly patients with a displaced femoral neck fracture.

10.
Arch Orthop Trauma Surg ; 143(10): 6105-6112, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37202550

RESUMO

BACKGROUND: The current minimally invasive distal metatarsal osteotomy for hallux valgus (HV) is V-shaped, which prevents the correction of the rotational metatarsal head deformity and reduction of the sesamoid bones. We sought to determine the optimal method for sesamoid bone reduction during HV surgery. METHODS: We reviewed the medical records of 53 patients who underwent HV surgery between 2017 and 2019 using one of three techniques: open chevron osteotomy (n = 19), minimally invasive V-shaped osteotomy (n = 18), and a modified straight minimally invasive osteotomy (n = 16). The sesamoid position was graded using the Hardy and Clapham method on weight-bearing radiographs. RESULTS: When compared to open chevron and V-shaped osteotomies, the modified osteotomy resulted in significantly lower postoperative sesamoid position scores (3.74 ± 1.48, 4.61 ± 1.09, and 1.44 ± 0.81, respectively, P < 0.001). Furthermore, the mean change in postoperative sesamoid position score was greater (P < 0.001). CONCLUSION: The modified minimally invasive osteotomy was superior to the other two techniques in correcting HV deformity in all planes, including sesamoid reduction.


Assuntos
Hallux Valgus , Ossos do Metatarso , Ossos Sesamoides , Humanos , Hallux Valgus/diagnóstico por imagem , Hallux Valgus/cirurgia , Estudos Retrospectivos , Osteotomia/métodos , Ossos Sesamoides/diagnóstico por imagem , Ossos Sesamoides/cirurgia , Ossos do Metatarso/cirurgia , Resultado do Tratamento
11.
Mol Cell ; 83(10): 1677-1692.e8, 2023 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-37207626

RESUMO

PERIOD (PER) and Casein Kinase 1δ regulate circadian rhythms through a phosphoswitch that controls PER stability and repressive activity in the molecular clock. CK1δ phosphorylation of the familial advanced sleep phase (FASP) serine cluster embedded within the Casein Kinase 1 binding domain (CK1BD) of mammalian PER1/2 inhibits its activity on phosphodegrons to stabilize PER and extend circadian period. Here, we show that the phosphorylated FASP region (pFASP) of PER2 directly interacts with and inhibits CK1δ. Co-crystal structures in conjunction with molecular dynamics simulations reveal how pFASP phosphoserines dock into conserved anion binding sites near the active site of CK1δ. Limiting phosphorylation of the FASP serine cluster reduces product inhibition, decreasing PER2 stability and shortening circadian period in human cells. We found that Drosophila PER also regulates CK1δ via feedback inhibition through the phosphorylated PER-Short domain, revealing a conserved mechanism by which PER phosphorylation near the CK1BD regulates CK1 kinase activity.


Assuntos
Relógios Circadianos , Proteínas Circadianas Period , Animais , Humanos , Fosforilação , Retroalimentação , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Caseína Quinase I/genética , Caseína Quinase I/metabolismo , Ritmo Circadiano/genética , Drosophila/metabolismo , Serina/metabolismo , Mamíferos/metabolismo
12.
J Child Orthop ; 17(2): 156-163, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37034194

RESUMO

Introduction: Proximal third diaphyseal fractures of the radius and ulna represent an onerous fracture pattern due to difficulty maintaining acceptable alignment with nonoperative management. Our aim was to identify the factors that increase the odds for a surgical treatment of these fractures. Recognizing these factors can raise awareness to patients who are more likely to require additional care and assist clinicians in counseling families, targeting treatment plans, and constructing follow-up protocols. We hypothesized that the age of the patient, the amount of initial fracture displacement, and the angulation of the fracture would predict the need for operative treatment. Methods: We retrospectively reviewed 276 proximal third diaphyseal forearm fractures at a single tertiary care institution. All patients underwent a nonoperative treatment trial, and if failed continued to surgery. Following a univariate analysis, we constructed a binary multivariate logistic regression model that included age, initial translation, and initial angulation to assess the association between the tested variables. Results: A regression model revealed that age (10 years and older, odds ratio: 8.2, 95% confidence interval: 3.9-17.24, p < 0.001) and radius translation of more than 100% (odds ratio: 7.06, 95% confidence interval: 2.69-18.52, p < 0.001) were associated with the need for surgical treatment. Initial fracture angulation lacked an association with a surgical treatment (odds ratio: 0.81 95% confidence interval: 0.38-1.74, p = 0.59). Conclusion: Age above 10 years and 100% initial translation of the radius fracture increased the odds for an ultimate decision to perform a surgery. Initial angulation, although often being the most remarkable radiographic feature, was not associated with a nonoperative treatment failure. We recommend an initial reduction attempt after counseling patients and their families that there is a high rate of conversion to operative treatment when the above features are met. Level of evidence: level III.

13.
Afr J Prim Health Care Fam Med ; 15(1): e1-e6, 2023 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-37042539

RESUMO

BACKGROUND: Managing diabetes is especially challenging for adolescents, and they often struggle to believe they can manage the condition. Illness perception has been widely associated with better diabetes management outcomes, but the influence of continuous glucose monitoring (CGM) on adolescents has been largely neglected. AIM: The study aimed to explore the illness perception of a group of adolescents living with type 1 diabetes (T1D) using CGM. SETTING: The study was conducted at a medical centre that provides diabetes care services to youth living with T1D in Parktown, South Africa. METHODS: A qualitative research approach using semi-structured online interviews was used to gather data that was thematically analysed. RESULTS: Themes emerging from the data confirmed that CGM creates a sense of control over diabetes management as blood glucose measures were more visible. A sense of normalcy was established as CGM influences a new routine and a way of life, integrating diabetes into a young person's identity. Despite the users' awareness of being different due to diabetes management, CGM assisted in creating a sense of belonging, contributing to developing a better quality of life. CONCLUSION: Findings of this study support the use of CGM as a means of empowering adolescents struggling with diabetes management to achieve better treatment outcomes. The important role of illness perception in facilitating this change was also evident.Contribution: By listening to the adolescent's voice, CGM was identified as a possible intervention to empower adolescents to improve diabetes management.


Assuntos
Glicemia , Diabetes Mellitus Tipo 1 , Humanos , Adolescente , Diabetes Mellitus Tipo 1/terapia , Automonitorização da Glicemia , Qualidade de Vida , Resultado do Tratamento
14.
J Am Mosq Control Assoc ; 39(1): 18-30, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-37043608

RESUMO

Near-infrared spectroscopy (NIRS), coupled with modeling and chemometrics, has been used to age grade anopheline and aedine mosquitoes; however, NIRS has not been widely used in field studies to assign mosquitoes to age classes. One reason is the relative cost of NIRS spectrometers. We developed a spectrometer system incorporating a miniature optical engine generating spectra in the shortwave infrared region, calibrated it using laboratory-reared Aedes aegypti, and evaluated its utility to age grade wild-caught cattail mosquitoes, Coquillettidia perturbans. As a refinement of the method, we compared a scoring system based on spectral data point outliers with the typical chemometrics that have been used with NIRS. This inexpensive system (<$3,600) could reliably discriminate between age cohorts of mosquitoes and has the potential for more detailed age grading. Laboratory-reared Ae. aegypti demonstrated a decline in the fraction of spectral outliers with age, and field-collected Cq. perturbans similarly demonstrated such a decline (greater in newly emerged mosquitoes) with date of collection, consistent with their univoltine demography in Massachusetts. We conclude that an economical NIRS system may be able to provide a quantitative dichotomous (young versus old) assessment of field-collected mosquito samples, and thereby may be used to complement abundance-based analyses of the efficacy of adulticiding applications.


Assuntos
Aedes , Animais , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Massachusetts
15.
J Clin Med ; 12(4)2023 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-36835842

RESUMO

Introduction: Anticoagulation use in the elderly is common for patients undergoing femoral neck hip surgery. However, its use presents a challenge to balance it with associated comorbidities and benefits for the patients. As such, we attempted to compare the risk factors, perioperative outcomes, and postoperative outcomes of patients who used warfarin preoperatively and patients who used therapeutic enoxaparin. Methods: From 2003 through 2014, we queried our database to determine the cohorts of patients who used warfarin preoperatively and the patients who used therapeutic enoxaparin. Risk factors included age, gender, Body Mass Index (BMI) > 30, Atrial Fibrillation (AF), Chronic Heart Failure (CHF), and Chronic Renal Failure (CRF). Postoperative outcomes were also collected at each of the patients' follow-up visits, including number of hospitalization days, delays to theatre, and mortality rate. Results: The minimum follow-up was 24 months and the average follow-up was 39 months (range: 24-60 months). In the warfarin cohort, there were 140 patients and 2055 patients in the therapeutic enoxaparin cohort. Number of hospitalization days (8.7 vs. 9.8, p = 0.02), mortality rate (58.7% vs. 71.4%, p = 0.003), and delays to theatre (1.70 vs. 2.86, p < 0.0001) were significantly longer for the anticoagulant cohort than the therapeutic enoxaparin cohort. Warfarin use best predicted number of hospitalization days (p = 0.00) and delays to theatre (p = 0.01), while CHF was the best predictor of mortality rate (p = 0.00). Postoperative complications, such as Pulmonary Embolism (PE) (p = 0.90), Deep Vein Thrombosis (DVT) (p = 0.31), and Cerebrovascular Accidents (CVA) (p = 0.72), pain levels (p = 0.95), full weight-bearing status (p = 0.08), and rehabilitation use (p = 0.34) were similar between the cohorts. Conclusion: Warfarin use is associated with increased number of hospitalization days and delays to theatre, but does not affect the postoperative outcome, including DVT, CVA, and pain levels compared to therapeutic enoxaparin use. Warfarin use proved to be the best predictor of hospitalization days and delays to theatre while CHF predicted mortality rate.

16.
Mol Ther ; 31(4): 1088-1105, 2023 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-36641623

RESUMO

Angelman syndrome (AS) is a neurogenetic disorder caused by the loss of ubiquitin ligase E3A (UBE3A) gene expression in the brain. The UBE3A gene is paternally imprinted in brain neurons. Clinical features of AS are primarily due to the loss of maternally expressed UBE3A in the brain. A healthy copy of paternal UBE3A is present in the brain but is silenced by a long non-coding antisense transcript (UBE3A-ATS). Here, we demonstrate that an artificial transcription factor (ATF-S1K) can silence Ube3a-ATS in an adult mouse model of Angelman syndrome (AS) and restore endogenous physiological expression of paternal Ube3a. A single injection of adeno-associated virus (AAV) expressing ATF-S1K (AAV-S1K) into the tail vein enabled whole-brain transduction and restored UBE3A protein in neurons to ∼25% of wild-type protein. The ATF-S1K treatment was highly specific to the target site with no detectable inflammatory response 5 weeks after AAV-S1K administration. AAV-S1K treatment of AS mice showed behavioral rescue in exploratory locomotion, a task involving gross and fine motor abilities, similar to low ambulation and velocity in AS patients. The specificity and tolerability of a single injection of AAV-S1K therapy for AS demonstrate the use of ATFs as a promising translational approach for AS.


Assuntos
Síndrome de Angelman , Animais , Camundongos , Síndrome de Angelman/genética , Síndrome de Angelman/terapia , Síndrome de Angelman/metabolismo , Encéfalo/metabolismo , Regulação da Expressão Gênica , Fatores de Transcrição/genética , Fenótipo , Ubiquitina-Proteína Ligases/genética
17.
mSystems ; 8(1): e0060822, 2023 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-36598241

RESUMO

A large subset of patients with Angelman syndrome (AS) suffer from concurrent gastrointestinal (GI) issues, including constipation, poor feeding, and reflux. AS is caused by the loss of ubiquitin ligase E3A (UBE3A) gene expression in the brain. Clinical features of AS, which include developmental delays, intellectual disability, microcephaly, and seizures, are primarily due to the deficient expression or function of the maternally inherited UBE3A allele. The association between neurodevelopmental delay and GI disorders is part of the increasing evidence suggesting a link between the brain and the gut microbiome via the microbiota-gut-brain axis. To investigate the associations between colonization of the gut microbiota in AS, we characterized the fecal microbiome in three animal models of AS involving maternal deletions of Ube3A, including mouse, rat, and pig, using 16S rRNA amplicon sequencing. Overall, we identified changes in bacterial abundance across all three animal models of AS. Specific bacterial groups were significantly increased across all animal models, including Lachnospiraceae Incertae sedis, Desulfovibrios sp., and Odoribacter, which have been correlated with neuropsychiatric disorders. Taken together, these findings suggest that specific changes to the local environment in the gut are driven by a Ube3a maternal deletion, unaffected by varying housing conditions, and are prominent and detectable across multiple small and large animal model species. These findings begin to uncover the underlying mechanistic causes of GI disorders in AS patients and provide future therapeutic options for AS patients. IMPORTANCE Angelman syndrome (AS)-associated gastrointestinal (GI) symptoms significantly impact quality of life in patients. In AS models in mouse, rat, and pig, AS animals showed impaired colonization of the gut microbiota compared to wild-type (healthy) control animals. Common changes in AS microbiomes across all three animal models may play a causal effect for GI symptoms and may help to identify ways to treat these comorbidities in patients in the future.


Assuntos
Síndrome de Angelman , Gastroenteropatias , Microbioma Gastrointestinal , Camundongos , Ratos , Animais , Suínos , Síndrome de Angelman/genética , Microbioma Gastrointestinal/genética , RNA Ribossômico 16S/genética , Qualidade de Vida , Modelos Animais de Doenças , Ubiquitina-Proteína Ligases/genética
18.
Nucleic Acids Res ; 51(4): e23, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-36625266

RESUMO

The discovery of cancer driver mutations is a fundamental goal in cancer research. While many cancer driver mutations have been discovered in the protein-coding genome, research into potential cancer drivers in the non-coding regions showed limited success so far. Here, we present a novel comprehensive framework Dr.Nod for detection of non-coding cis-regulatory candidate driver mutations that are associated with dysregulated gene expression using tissue-matched enhancer-gene annotations. Applying the framework to data from over 1500 tumours across eight tissues revealed a 4.4-fold enrichment of candidate driver mutations in regulatory regions of known cancer driver genes. An overarching conclusion that emerges is that the non-coding driver mutations contribute to cancer by significantly altering transcription factor binding sites, leading to upregulation of tissue-matched oncogenes and down-regulation of tumour-suppressor genes. Interestingly, more than half of the detected cancer-promoting non-coding regulatory driver mutations are over 20 kb distant from the cancer-associated genes they regulate. Our results show the importance of tissue-matched enhancer-gene maps, functional impact of mutations, and complex background mutagenesis model for the prediction of non-coding regulatory drivers. In conclusion, our study demonstrates that non-coding mutations in enhancers play a previously underappreciated role in cancer and dysregulation of clinically relevant target genes.


Assuntos
Neoplasias , Oncogenes , Sequências Reguladoras de Ácido Nucleico , Humanos , Mutação , Neoplasias/genética
19.
J Clin Med ; 12(2)2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36675385

RESUMO

Background: The assessment and identification of elderly patients with proximal femur fractures (PFF) who are at high risk of postoperative mortality may influence the treatment decision-making process. The purpose of this study was to determine whether the neutrophil-to-lymphocyte ratio (NLR) could be used to predict postoperative mortality in the elderly population. Methods: A four-year retrospective cohort study of electronic medical records was conducted at a single tertiary care hospital between 2015 and 2018. Data from 1551 patients aged 65 years and older who underwent surgical treatment for PFF were collected and analyzed. The data included complete blood counts at admission, demographic information, underlying illnesses, type of surgery, and postoperative mortality and complications during the first year of follow-up. A survival analysis model was utilized. Results: The mean age was 90.76 ± 1.88 years, 1066 (68.7%) women. Forty-four (2.8%) patients experienced postoperative infection. A higher NLR0 was independently associated with higher all-cause mortality rates in patients who underwent surgical treatment for PFF (p = 0.041). Moreover, the mean NLR0 value was higher when the death occurred earlier after surgery (p < 0.001). Conclusions: When combined with other clinical and laboratory findings, NLR0 levels may serve as a potentially valuable, inexpensive, and reliable prognostic biomarker to improve risk stratification for elderly patients who are candidates for PFF surgery. Furthermore, with additional research, we could potentially develop a treatment algorithm to identify patients at high risk of postoperative mortality.

20.
Clin Pediatr (Phila) ; 62(2): 107-114, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-35883262

RESUMO

Adolescents with overweight/obesity are at risk for vitamin D insufficiency and deficiency. Both overweight/obesity and vitamin D insufficiency/deficiency may predispose to fractures. We enrolled 103 participants (53.3% females, 15.9 ± 2.2 years) in a retrospective case-control study to determine whether an association exists between fractures and a low 25-hydroxyvitamin D (25[OH]D) among adolescents whose body mass index (BMI) ≥ 85 percentile. Cases (n = 28) sustaining a low/medium impact fracture were matched to controls (n = 75) without a fracture history. A conditional-logistic regression analysis addressing the common vitamin D insufficiency/deficiency cutoffs was used. Overweight, obesity, and significant obesity rates were 10.7%, 53.4%, and 35.9%, respectively. Mean (±SD) 25(OH)D was 16.5 ± 6.4 ng/mL. In all, 25(OH)D insufficiency rates (level <20 ng/mL) were 70.5%. Matched cases and controls had similar 25(OH)D insufficiency/deficiency rates (P > .05). Controlling for race and seasonality showed no association between fractures and 25(OH)D insufficiency/deficiency (P > .05). These data suggest that fractures are not associated with low 25(OH)D levels among adolescents whose BMI ≥ 85th percentile.


Assuntos
Fraturas Ósseas , Raquitismo , Deficiência de Vitamina D , Feminino , Humanos , Adolescente , Masculino , Sobrepeso/complicações , Sobrepeso/epidemiologia , Estudos Retrospectivos , Estudos de Casos e Controles , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Vitamina D , Fraturas Ósseas/etiologia , Fraturas Ósseas/complicações , Índice de Massa Corporal
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