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1.
J Arthroplasty ; 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38823517

RESUMO

BACKGROUND: Wearable devices provide the ability for clinical teams to continuously monitor patients' rehabilitation progress with objective data. Understanding expected recovery patterns following total knee arthroplasty (TKA) enables prompt identification of patients failing to meet these milestones. The aim of this study was to establish normative values for daily functional recovery in the first 6 weeks after TKA using a wearable device. METHODS: This prospective study included patients who underwent TKA between 2020 and 2023, treated by 11 surgeons from 8 institutions. Eligible participants were aged 18 or older, had a primary unilateral TKA, and owned a smartphone. Knee range of motion, total daily steps, cadence, and device usage were measured continuously over 6 weeks. Statistical analysis included analysis of variance using post hoc Tukey honest significant difference tests. RESULTS: The cohort of 566 participants had a mean age of 65 and 69 for men and women, respectively (range, 50 to 80). Women comprised 61% (n = 345) of study participants. There were 82% of women and 90% of men who had a body mass index > 30. The average daily wear time of the device was 12 hours (±4) for a total of 45 days (±27). Recovery was nonlinear, with the greatest gains in the first 3 weeks postsurgery for all metrics. Men demonstrated greater total daily step counts and cadence when compared to women. Obese patients demonstrated poorer performance when compared to lower body mass index patients. CONCLUSIONS: To our knowledge, this study presents the first normative data for tracking daily functional recovery in TKA patients using wearable sensors. Standardizing the TKA recovery timeline allows surgeons to isolate factors affecting patients' healing processes, accurately counsel them preoperatively, and intervene more promptly postoperatively when rehabilitation is not within standard recovery parameters.

2.
Turk J Emerg Med ; 24(2): 111-116, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38766414

RESUMO

OBJECTIVE: The objective is to evaluate the outcome of early emergency intubation and early dialysis in formic acid (FA) poisoning and to determine the clinical features associated with its mortality. METHODS: It is a retrospective cohort study of 78 patients who presented to the emergency medicine department from July 2008 to June 2015 with alleged history and clinical features of FA poisoning. The outcome of early intubation and early dialysis was studied in terms of 7-day and 30-day mortality. The outcome was compared in severe and not severe groups separately. Severity was graded according to Med-Tu chart used for corrosive poisoning. RESULTS: In the severe group (n = 53), early dialysis was done in 15 patients. There was 53% (n = 8) 30-day mortality. In the group where early dialysis was not done there was a significant increase in mortality 92.1% (n = 35). This was statistically significant with a P = 0.003. In a similar fashion 7-day mortality was analyzed in the severe group where mortality was higher when early dialysis was not done. In not severe group early dialysis has minimally decreased the mortality. Early intubation in severe group did not demonstrate any mortality benefit. Patients who were intubated early and not intubated early had equally high mortality. In not severe group, intubation could not make any significant difference in mortality. CONCLUSION: In this retrospective study, we observed that early dialysis in the severe group has a better outcome in terms of 7-day and 30-day mortality.

3.
J Arthroplasty ; 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38604282

RESUMO

BACKGROUND: Wearable sensors and associated supporting technologies (ie, patient applications) can provide both objective (joint position, step counts, etc.) and subjective data (ie, pain scores and patient-reported outcome measures) to track a patient's episode of care. Establishing a subjective and objective baseline of a patient's experience may arguably be beneficial for multiple reasons, including setting recovery expectations for the patient and demonstrating the effectiveness or success of the intervention. METHODS: In this pilot study, we characterized a subset of patients (n = 82 from 7 surgeons) using a wearable sensor system at least 6 days before total knee arthroplasty and provided postsurgical data up to 50 days postintervention. The 5-day average before surgery for total step counts (activity), achieved flexion and extension on a progress test (functional limit) and visual analog scale daily pain score were calculated. The difference from baseline was then calculated for each patient for each day postsurgery and reported as averages. RESULTS: On average, a patient will experience a relative deficit of 4,000 steps immediately following surgery that will return to near-baseline levels 50 days postintervention. A 30° deficit in flexion and a 10° deficit in extension will return at a similar rate as steps. Relative pain scores will worsen with an increase of approximately 3 points immediately following surgery. However, pain will decrease by 2 points relative to baseline between 40 and 50 days. CONCLUSIONS: The results of this pilot study demonstrate a method to baseline a patient's presurgical subjective and objective data and to provide a reference for postsurgical recovery expectations. Applications for these data include benchmarking for evaluating intervention success as well as setting patient expectations.

4.
Orthop Rev (Pavia) ; 16: 116363, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38682046

RESUMO

Objective: Given the rise of martial arts within the fitness and recreational industry, it is important to study trends in injury and note that practicing martial arts comes with a risk of injury, particularly to the upper extremities. By studying consumer product-related injuries to the upper extremities and addressing the current gap in the literature, future martial arts equipment can come with increased safety features, better provide information to healthcare providers treating such injuries, and improve risk mitigation through the Consumer Product Safety Commission. Methods: The National Electronic Injury Surveillance System Database was analyzed to collect data on martial arts equipment-related injuries on the upper extremities within the last 10 years. Results: Over the most recent span of 10 years (2013-2022), there were approximately 78,680 injuries reported to the ED. The majority of them took place in 2013 (12.8%). Men were 2.4 times more likely to get injured than women. Injuries peaked in the age group 10-19-year-olds (33%) and particularly age 12 (4.8%). The upper extremity most commonly affected was the shoulder (29.1%), and the most common diagnosis group was a fracture (29.2%). Most injuries presented to the emergency department were not hospitalized (98.7%). Conclusions: This study highlights the occurrence of upper extremity injuries due to martial arts within the last 10 years and provides new information on the prevalence of such injuries. The results highlight that these injuries are usually non-severe and most commonly affect adolescent males; however, future research should explore performance-based recovery post-injury and long-term pain.

5.
Clin Endocrinol (Oxf) ; 100(5): 441-446, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38463009

RESUMO

OBJECTIVES: Various biases pertaining to stature account for a male sex predominance in growth hormone deficiency (GHD) cases diagnosed by endocrinology clinics. This manuscript will assess the sex distribution when biases are minimised. METHODS: Retrospective chart review was conducted on patients diagnosed with GHD between 3 and 16 years of age. The sex distribution of cases was ascertained according to: (1) peak GH (pGH) by groups; based on growth hormone provocative testing, (2) pituitary gland imaging results, and (3) isolated GHD (IGHD) versus multiple pituitary hormone deficiencies (MPHD). The relative frequency of each sex was compared according to these subgroups with significance evaluated at α = .05 level. RESULTS: Of the 5880 clinic referrals for short stature, there were 3709 boys (63%) and 2171 girls (37%). Of these, 20% of boys (n = 745) and 15.3% of girls (n = 332) underwent provocative testing for GHD. Of those tested, 39.2% of boys (n = 292) and 32.2% of girls (n = 107) were diagnosed with GHD, all p < .001. There was a male predominance in GHD cases based on pGH or GHD severity. Though not significant, girls were more likely than boys to have MPHD (p = .056), even across pGH groups (p = .06). Both boys and girls had a similar distribution of imaging abnormalities. CONCLUSION: Stratifying by sex, we found similar percentages of pituitary imaging abnormalities (including tumours) and the number of pituitary hormone deficiencies in boys and girls as the cause of GHD. For these classifications, we did not find the historically reported male sex predominance.


Assuntos
Nanismo Hipofisário , Hormônio do Crescimento Humano , Hipopituitarismo , Feminino , Humanos , Criança , Masculino , Estudos Retrospectivos , Hipopituitarismo/epidemiologia , Nanismo Hipofisário/epidemiologia , Hormônio do Crescimento , Distribuição por Sexo
6.
Surg Oncol ; : 102057, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38462387

RESUMO

PURPOSE: Machine learning (ML) models have been used to predict cancer survival in several sarcoma subtypes. However, none have investigated extremity leiomyosarcoma (LMS). ML is a powerful tool that has the potential to better prognosticate extremity LMS. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried for cases of histologic extremity LMS (n = 634). Patient, tumor, and treatment characteristics were recorded, and ML models were developed to predict 1-, 3-, and 5-year survival. The best performing ML model was externally validated using an institutional cohort of extremity LMS patients (n = 46). RESULTS: All ML models performed best at the 1-year time point and worst at the 5-year time point. On internal validation within the SEER cohort, the best models had c-statistics of 0.75-0.76 at the 5-year time point. The Random Forest (RF) model was the best performing model and used for external validation. This model also performed best at 1-year and worst at 5-year on external validation with c-statistics of 0.90 and 0.87, respectively. The RF model was well calibrated on external validation. This model has been made publicly available at https://rachar.shinyapps.io/lms_app/ CONCLUSIONS: ML models had excellent performance for survival prediction of extremity LMS. Future studies incorporating a larger institutional cohort may be needed to further validate the ML model for LMS prognostication.

7.
Schizophr Bull ; 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38412332

RESUMO

BACKGROUND AND HYPOTHESIS: Cognitive deficits in schizophrenia are linked to dysfunctions of the dorsolateral prefrontal cortex (DLPFC), including alterations in parvalbumin (PV)-expressing interneurons (PVIs). Redox dysregulation and oxidative stress may represent convergence points in the pathology of schizophrenia, causing dysfunction of GABAergic interneurons and loss of PV. Here, we show that the mitochondrial matrix protein cyclophilin D (CypD), a critical initiator of the mitochondrial permeability transition pore (mPTP) and modulator of the intracellular redox state, is altered in PVIs in schizophrenia. STUDY DESIGN: Western blotting was used to measure CypD protein levels in postmortem DLPFC specimens of schizophrenic patients (n = 27) and matched comparison subjects with no known history of psychiatric or neurological disorders (n = 26). In a subset of this cohort, multilabel immunofluorescent confocal microscopy with unbiased stereological sampling methods were used to quantify (1) numbers of PVI across the cortical mantle (20 unaffected comparison, 14 schizophrenia) and (2) PV and CypD protein levels from PVIs in the cortical layers 2-4 (23 unaffected comparison, 18 schizophrenia). STUDY RESULTS: In schizophrenic patients, the overall number of PVIs in the DLPFC was not significantly altered, but in individual PVIs of layers 2-4 PV protein levels decreased along a superficial-to-deep gradient when compared to unaffected comparison subjects. These laminar-specific PVI alterations were reciprocally linked to significant CypD elevations both in PVIs and total DLPFC gray matter. CONCLUSIONS: Our findings support previously reported PVI anomalies in schizophrenia and suggest that CypD-mediated mPTP formation could be a potential contributor to PVI dysfunction in schizophrenia.

8.
J Craniofac Surg ; 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38299824

RESUMO

INTRODUCTION: Recognizing and understanding risk factors for craniofacial injury in the elderly is of paramount importance in prevention. This research aims to investigate the prevalence of craniofacial injuries in connection with extrinsic preventable factors, particularly identifying common household products that pose the greatest risk for such injuries. MATERIALS AND METHODS: This study was done with the utilization of the 2013 to 2022 National Electronic Injury Surveillance System (NEISS). Data gathered included patient age, injury type, cause of injury, and year of incidence. "Elderly" was defined as an individual of 65 years of age or older. RESULTS: There was a total of 9,703,688 estimated national cases of elderly craniofacial injury from 2013 to 2022. In all, 5,888,112 (60.68%) of these occurred in females. In descending order, the 5 most common items responsible for craniofacial injury in the elderly are floors/flooring Materials (3,741,706, 30.92%), beds/bed frames (1,250,396, 10.33%), stairs/steps (907,92, 7.50%), chairs (546,697, 4.52%), and tables (453,989, 3.75%). These top 5 account for roughly 57% of all cases. The 5 most common presenting diagnoses were internal injury (2,957,095, 40.21%), lacerations (1,435,926, 19.53%), ABR (1,191,008, 16.20%), fracture (568,842, 7.74%), and hematoma (355,871, 4.84%). CONCLUSIONS: Out of the roughly 10 million cases of craniofacial injury in the last decade, ~three-fifths have happened to women. The majority of injuries occur in a home setting. The overwhelming majority of cases were related to the product code 1807-floors or flooring materials, and the largest diagnosis was internal injury by a wide margin. Evidently, there is a large population of elderly patients who suffer from craniofacial injuries related to objects and items that permeate within their living residences. The elimination of excess elderly craniofacial injury can be achieved by reducing fall risk factors in the immediate vicinity of the elderly.

9.
J Natl Med Assoc ; 116(2 Pt 1): 170-173, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38220584

RESUMO

BACKGROUND/OBJECTIVE: Alzheimer's disease is a prominent neurodegenerative disorder characterized by cognitive decline and memory loss. Variations in subjective cognitive decline among Alzheimer's patients, often reported by caregiver, may stem from cultural, socioeconomic, healthcare access, and genetic factors. This study investigates racial disparities in subjective cognitive decline reported by caregivers and their implications. METHODS: In this study, data from 12,627 Alzheimer's caretakers from the CDC's Alzheimer's Disease and Healthy Aging Data Portal were analyzed using JMP software. Caregivers reported patients' cognitive decline for various racial categories: Asian/Pacific Islander, Black, Hispanic, Native American/Native Alaskan, and White. Fit model tests and distribution analyses were employed to assess disparities in symptom severity. The study focused on four key questions regarding symptom prevalence and healthcare communication to assess the degree of symptoms the patients were experiencing. RESULTS: Significant disparities in symptom severity reported by Alzheimer's caretakers were observed among the racial groups analyzed. The symptom severity ranked from least to most severe is the following: White, Asian/Pacific Islander, Black, Native American/Native Alaskan, and Hispanic patients. There was variance when it came to communication with healthcare providers, as the Asian population had the lowest communication rates. These findings underscore the need for targeted interventions considering cultural differences. It is important that tailoring healthcare approaches for different racial backgrounds is happening as a remedy to this gap in communication. CONCLUSION: Due to cultural, socioeconomic, genetic factors, and others, there were significant observed disparities. Tailoring interventions to these diverse populations is crucial to address these inequities.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Disparidades em Assistência à Saúde , Hispânico ou Latino , Grupos Raciais , Estados Unidos/epidemiologia , Brancos , Nativo Asiático-Americano do Havaí e das Ilhas do Pacífico , Negro ou Afro-Americano , Indígena Americano ou Nativo do Alasca
10.
Cureus ; 15(10): e47843, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38021602

RESUMO

Type 2 diabetes (T2DM) and obesity represent major global health burdens and economic costs to healthcare systems. T2DM management is challenging due to multiple comorbidities and limited drug efficacy. Bariatric surgery has emerged as an effective treatment approach. A 65-year-old man with refractory obesity (BMI > 35 kg/m2) and poorly controlled T2DM underwent gastric bypass surgery in 2018. Prior to surgery, medication noncompliance and dietary measures failed to achieve adequate glycemic control or weight loss. Postoperatively, the patient lost 20 kg and achieved improved T2DM control (HbA1C reduction), allowing complete cessation of diabetic medications. The patient's case demonstrates bariatric surgery's potential to significantly alter the clinical course of obesity and T2DM versus standard care. National guidelines outline eligibility criteria for bariatric referral; however, utilization rates remain low (<1%) despite over two million eligible individuals in the United Kingdom. Improved access could reduce disease burden and healthcare costs from diabetes complications over the long term. This case report provides a real-world example supporting bariatric surgery as an effective intervention for appropriately selected patients with obesity and uncontrolled T2DM, with the potential to improve clinical outcomes and lower costs associated with diabetes management.

11.
Cureus ; 15(10): e46695, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38022054

RESUMO

We report on the case of a 52-year-old male who sustained a transverse patellar fracture after tripping on uneven pavement. These fractures can be easy to miss on anteroposterior views, highlighting the importance of multiple radiographic views of the knee. Examination of the knee is also important, as initial clinical appearance can be benign. These fractures are most often seen in adolescents, which makes the current case somewhat unusual.

12.
Cureus ; 15(9): e45563, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37868471

RESUMO

The authors present the case of a man with a relatively benign clinical presentation who had a computed tomography scan that revealed a "geographic liver" pattern. The radiologic appearance of hepatic steatosis, its significance, and its association with metabolic syndrome highlight the importance of this radiologic finding.

13.
BMC Res Notes ; 16(1): 263, 2023 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-37814301

RESUMO

OBJECTIVE: This article presents the dataset titled "Do you know how to Stop The Bleed®? [1]" The dataset contains the survey responses of 200 US persons aged 16 years and above regarding their knowledge of hemorrhage control, based on the American College of Surgeons Stop The Bleed® (STB) course [2]. RESULTS: Two hundred adults in the United States completed this web-based survey, which consisted of a quiz to assess STB knowledge. Factors that were not statistically correlated to STB knowledge retention included age, sex, race and education level up to college level. On the other hand, resuscitation coursework (p = 0.004) and income (p = 0.049) were important determinants of Stop the Bleed® knowledge. In particular, participants with CPR certification (p = 0.020) and/or a postgraduate degree (p = 0.015) scored higher than their counterparts in this sample cohort.


Assuntos
Hemorragia , Adulto , Humanos , Inquéritos e Questionários , Estados Unidos
14.
J Natl Med Assoc ; 115(6): 589-592, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37845146

RESUMO

OBJECTIVE: To determine if there is a racial disparity in satisfaction with maternal healthcare, and examine the quality of care mothers of color receive. METHODS: An online survey of women in the United States who had been pregnant at least once was conducted. The study received an exempt determination by our Institution's Review Board. RESULTS: Race, age, income, were all significant indicators for whether a woman was satisfied with maternal healthcare measures. CONCLUSION: Race is one of many indicators for dissatisfaction with maternal healthcare. More in-depth research on patient perception of care is recommended.


Assuntos
Negro ou Afro-Americano , Hispânico ou Latino , Gravidez , Feminino , Humanos , Estados Unidos/epidemiologia , Disparidades em Assistência à Saúde , Mães , Satisfação Pessoal
15.
Cancers (Basel) ; 15(13)2023 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-37444395

RESUMO

VIP (vasoactive intestinal peptide) is a 28-amino acid peptide hormone expressed by cancer and the healthy nervous system, digestive tract, cardiovascular, and immune cell tissues. Many cancers express VIP and its surface receptors VPAC1 and VPAC2, but the role of autocrine VIP signaling in cancer as a targetable prognostic and predictive biomarker remains poorly understood. Therefore, we conducted an in silico gene expression analysis to study the mechanisms of autocrine VIP signaling in cancer. VIP expression from TCGA PANCAN tissue samples was analyzed against the expression levels of 760 cancer-associated genes. Of the 760 genes, 10 (MAPK3, ZEB1, TEK, NOS2, PTCH1 EIF4G1, GMPS, CDK2, RUVBL1, and TIMELESS) showed statistically meaningful associations with the VIP (Pearson's R-coefficient > |0.3|; p < 0.05) across all cancer histologies. The strongest association with the VIP was for the epithelial-mesenchymal transition regulator ZEB1 in gastrointestinal malignancies. Similar positive correlations between the VIP and ZEB1 expression were also observed in healthy gastrointestinal tissues. Gene set analysis indicates the VIP is involved in the EMT and cell cycle pathways, and a high VIP and ZEB1 expression is associated with higher median estimate and stromal scores These findings uncover novel mechanisms for VIP- signaling in cancer and specifically suggest a role for VIP as a biomarker of ZEB1-mediated EMT. Further studies are warranted to characterize the specific mechanism of this interaction.

16.
Health Psychol Res ; 11: 74120, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37405315

RESUMO

Background: Dysmenorrhea, or painful menstrual periods, is one of the most common gynecological complaints. Most reports of uterine contractions range between moderate to severe pain, and patients often elect to cope with their discomfort without assistance from a physician. In the process, women experiencing dysmenorrhea are more likely to report absenteeism from work and school. Objectives: This study measures the reported impact of dysmenorrhea on patients' lives and elucidates a relationship between income and access to oral contraceptives. Methods: Two hundred women completed a survey about their symptoms, level of pain, treatments, and the extent to which dysmenorrhea affected day-to-day obligations. Most questions were multiple-choice while others permitted several answer selections or were free response. The data was analyzed using JMP statistical software. Results: Eighty-four percent of respondents reported moderate to severe pain during menstruation. This discomfort has caused 65.5% of the cohort to miss work and 68% to avoid participating in social gatherings. Pain relief medications are most often used as treatment - 143 respondents took ibuprofen, 93 took acetaminophen, and 51 took naproxen. 29.5% of respondents are prescribed birth control for cramps and blood flow. Income (p = 0.049), age (p = 0.002), and education (p = 0.002) were significant predictors for oral contraceptive pill (OCP) use. The lowest income groups were found to use OCPs at less than half the rate as the highest income respondents. Conclusion: Dysmenorrhea affected most participants in the cohort with an impact that extends beyond professional obligations. Income was found to be positively correlated with increased OCP use, whereas education level was inversely correlated. Clinicians should consider how patients' backgrounds influence their access to OCP options. An improvement on this study's findings would be to establish a causal relationship between these demographic factors and access to OCPs.

17.
J Clin Endocrinol Metab ; 108(11): 3009-3021, 2023 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-37246615

RESUMO

CONTEXT: Pathologies attributed to perturbations of the GH/IGF-I axis are among the most common referrals received by pediatric endocrinologists. AIM: In this article, distinctive cased-based presentations are used to provide a practical and pragmatic approach to the management of pediatric growth hormone deficiency (GHD). CASES: We present 4 case vignettes based on actual patients that illustrate (1) congenital GHD, (2) childhood GHD presenting as failure to thrive, (3) childhood GHD presenting in adolescence as growth deceleration, and (4) childhood-onset GHD manifesting as metabolic complications in adolescence. We review patient presentation and a management approach that aims to highlight diagnostic considerations for treatment based on current clinical guidelines, with mention of new therapeutic and diagnostic modalities being used in the field. CONCLUSION: Pediatric GHD is diverse in etiology and clinical presentation. Timely management has the potential not only to improve growth but can also ameliorate or even mitigate adverse metabolic outcomes, which can be directly attributed to a GH deficient state.


Assuntos
Nanismo Hipofisário , Hormônio do Crescimento Humano , Hipopituitarismo , Adolescente , Criança , Humanos , Nanismo Hipofisário/terapia , Nanismo Hipofisário/tratamento farmacológico , Hormônio do Crescimento/metabolismo , Hormônio do Crescimento Humano/uso terapêutico , Hipopituitarismo/diagnóstico , Hipopituitarismo/etiologia , Hipopituitarismo/terapia , Fator de Crescimento Insulin-Like I/metabolismo
18.
J Biol Chem ; 299(8): 104803, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37172723

RESUMO

Interleukin-1ß is one of the most potent inducers of beta cell inflammation in the lead-up to type 1 diabetes. We have previously reported that IL1ß-stimulated pancreatic islets from mice with genetic ablation of stress-induced pseudokinase TRB3(TRB3KO) show attenuated activation kinetics for the MAP3K MLK3 and JNK stress kinases. However, JNK signaling constitutes only a portion of the cytokine-induced inflammatory response. Here we report that TRB3KO islets also show a decrease in amplitude and duration of IL1ß-induced phosphorylation of TAK1 and IKK, kinases that drive the potent NF-κB proinflammatory signaling pathway. We observed that TRB3KO islets display decreased cytokine-induced beta cell death, preceded by a decrease in select downstream NF-κB targets, including iNOS/NOS2 (inducible nitric oxide synthase), a mediator of beta cell dysfunction and death. Thus, loss of TRB3 attenuates both pathways required for a cytokine-inducible, proapoptotic response in beta cells. In order to better understand the molecular basis of TRB3-enhanced, post-receptor IL1ß signaling, we interrogated the TRB3 interactome using coimmunoprecipitation followed by mass spectrometry to identify immunomodulatory protein Flightless homolog 1 (Fli1) as a novel, TRB3-interacting protein. We show that TRB3 binds and disrupts Fli1-dependent sequestration of MyD88, thereby increasing availability of this most proximal adaptor required for IL1ß receptor-dependent signaling. Fli1 sequesters MyD88 in a multiprotein complex resulting in a brake on the assembly of downstream signaling complexes. By interacting with Fli1, we propose that TRB3 lifts the brake on IL1ß signaling to augment the proinflammatory response in beta cells.


Assuntos
Proteínas de Ciclo Celular , Interleucina-1beta , Transdução de Sinais , Animais , Camundongos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Citocinas/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais/genética , Inibidores Enzimáticos/farmacologia , Apoptose/efeitos dos fármacos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/fisiologia , Ativação Transcricional/genética
19.
PNAS Nexus ; 2(4): pgad085, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37113978

RESUMO

Neurodevelopmental disorders (NDDs) are a widespread and growing public health challenge, affecting as many as 17% of children in the United States. Recent epidemiological studies have implicated ambient exposure to pyrethroid pesticides during pregnancy in the risk for NDDs in the unborn child. Using a litter-based, independent discovery-replication cohort design, we exposed mouse dams orally during pregnancy and lactation to the Environmental Protection Agency's reference pyrethroid, deltamethrin, at 3 mg/kg, a concentration well below the benchmark dose used for regulatory guidance. The resulting offspring were tested using behavioral and molecular methods targeting behavioral phenotypes relevant to autism and NDD, as well as changes to the striatal dopamine system. Low-dose developmental exposure to the pyrethroid deltamethrin (DPE) decreased pup vocalizations, increased repetitive behaviors, and impaired both fear conditioning and operant conditioning. Compared with control mice, DPE mice had greater total striatal dopamine, dopamine metabolites, and stimulated dopamine release, but no difference in vesicular dopamine capacity or protein markers of dopamine vesicles. Dopamine transporter protein levels were increased in DPE mice, but not temporal dopamine reuptake. Striatal medium spiny neurons showed changes in electrophysiological properties consistent with a compensatory decrease in neuronal excitability. Combined with previous findings, these results implicate DPE as a direct cause of an NDD-relevant behavioral phenotype and striatal dopamine dysfunction in mice and implicate the cytosolic compartment as the location of excess striatal dopamine.

20.
Clin Endocrinol (Oxf) ; 98(6): 779-787, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36859827

RESUMO

OBJECTIVES: While it has been established within the first 4 months of life that there is no circadian rhythm, what is unclear is the usefulness of a random serum cortisol (rSC) level in determining neonatal central adrenal insufficiency (CAI). The objective of the study is to determine the utility of using rSC in infants less than 4 months old in the evaluation of CAI. DESIGN AND PATIENTS: Retrospective chart review of infants who underwent a low dose cosyntropin stimulation test ≤4 months of life with rSC taken as baseline cortisol before stimulation. Infants were divided into three groups: those diagnosed with CAI, those at risk for CAI (ARF-CAI) and a non-CAI group. Mean rSC for each group was compared, and ROC analysis was used to identify rSC cut-off for the diagnosis of CAI. RESULTS: Two hundred and fifty one infants with the mean age of 50.5 ± 38.08 days, and 37% of these were born at term gestation. The mean rSC were lower in the CAI group (1.98 ± 1.88 mcg/dl) as compared to the ARF-CAI (6.27 ± 5.48 mcg/dl, p = .002) and non-CAI (4.6 ± 4.02 mcg/dl, p = .007) groups. ROC analysis identified a cut-off of rSC level of 5.6 mcg/dL is associated with 42.6% sensitivity and 100% specificity for the diagnosis of CAI in term infants. CONCLUSIONS: This study demonstrates that though an rSC can be used within the first 4 months of life, its value is best when done ≤30 days of life. Moreover, a diagnostic cut-off for CAI using rSC levels was identified for term infants.


Assuntos
Insuficiência Adrenal , Hidrocortisona , Lactente , Recém-Nascido , Humanos , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Sensibilidade e Especificidade , Insuficiência Adrenal/diagnóstico , Cosintropina
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