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1.
J Neurointerv Surg ; 2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38782567

RESUMEN

BACKGROUND: Internal jugular vein (IJV) stenosis has recently been recognized as a plausible source of symptom etiology in patients with cerebral venous outflow disorders (CVD). Diagnosis and determining surgical candidacy remains difficult due to a poor understanding of IJV physiology and positional symptom exacerbation often reported by these patients. METHODS: A retrospective single-center chart review was conducted on adult patients who underwent diagnostic cerebral venography with rotational IJ venography from 2022 to 2024. Patients were divided into three groups for further analysis based on symptoms and diagnostic criteria: presumed jugular stenosis, near-healthy venous outflow, and idiopathic intracranial hypertension. RESULTS: Eighty-nine patients were included in the study. Most commonly, ipsilateral rotation resulted in ipsilateral IJV stenosis and gradient development at C4-6 and contralateral stenosis and gradient appearance in the contralateral IJV at C1, with stenosis and gradient development in bilateral IJVs at C1-3 bilaterally during chin flexion. In all patients, 93.3% developed at least moderate dynamic stenosis of at least one IJV, more than two-thirds (69.7%) developed either severe or occlusive stenosis during rightward and leftward rotation, and 81.8% developed severe or occlusive stenosis with head flexion. Dynamic gradients of at least 4 mmHg were seen in 68.5% of patients, with gradients of at least 8 mmHg in 31.5% and at least 10 mmHg in 12.4%. CONCLUSION: This study is the first to document dynamic changes in IJV caliber and gradients in different head positions, offering insights into the complex nature of venous outflow and its impact on CVD.

2.
J Pak Med Assoc ; 74(5): 984-986, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38783452

RESUMEN

Acute promyelocytic leukaemia (APL) is a form of acute myelogenous leukaemia. APL is characterised by anaemia due to suppression of normal haematopoiesis and infection. Haematopoietic stem cell transplantation (HSCT) is current option for the treatment of haematopoietic malignancies and is proving to be successful. Although HSCT has been effective for the treatment of haematopoietic malignant tumours, chronic graft-versushost disease (GVHD) but secondary cancers can occur, which is a serious complication and frequently involves the oral cavity and skin. Here, we report the case of tongue cancer occurring 17 years after transplantation in a patient who developed GVHD after haematopoietic stem cell transplantation and APL remission. To the best of our knowledge, this is the first report of secondary oral cancer after HSCT with APL as the primary disease.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Promielocítica Aguda , Neoplasias de la Lengua , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Promielocítica Aguda/terapia , Neoplasias de la Lengua/cirugía , Neoplasias de la Lengua/terapia , Masculino , Enfermedad Injerto contra Huésped/etiología , Persona de Mediana Edad , Adulto , Neoplasias Primarias Secundarias/etiología
3.
Chemistry ; 30(28): e202400421, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38478466

RESUMEN

N-Heterocyclic ylides are important synthetic precursors to rapidly build molecular complexity. Pyrazolium ylides have largely been unexplored, and we demonstrate their diverse utility in this report. We show that these readily accessible building blocks can be used to construct different heterocyclic skeletons by varying the coupling partner. Indolizines can be formed via an N-deletion type mechanism when reacting pyrazolium salts with electron deficient alkynes. 1,2-Dihydropyrimidines can be formed via a rearrangement mechanism when reacting pyrazolium ylides with isocyanates. These reactions enable access to valuable heteroarenes without the need for transition metal catalysis, high temperatures, or strong bases.

5.
Am J Perinatol ; 41(S 01): e3319-e3325, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38195965

RESUMEN

OBJECTIVE: Among children born extremely preterm (EP), the antecedents of chronic kidney disease (CKD), including neonatal acute kidney injury (nAKI), are not well characterized. STUDY DESIGN: This was a retrospective cohort pilot study. Participants (n = 36) were adolescents born before 28 weeks of gestation enrolled at birth into the extremely low gestational age newborn study, between 2002 and 2004, at the University of North Carolina. Participants were stratified by the primary exposure to nAKI, defined using the modified Kidney Disease Improving Global Outcomes nAKI criteria. Baseline serum creatinine (SCr) was defined as the lowest SCr after 48 to 72 postnatal hours. The primary outcome was an abnormal kidney profile during adolescence, defined as having one or more of these outcomes: elevated blood pressure (>120/80 mm Hg), microalbuminuria (urine microalbumin/creatinine >30 µg/g), or an abnormal kidney volume measured by ultrasound (total kidney volume corrected for body surface area <10th%ile for age). RESULTS: Half of the participants had a history of nAKI. Thirteen had stage 1 nAKI, four had stage 2, and one had stage 3 nAKI. At 15 years of age, 50% were overweight/obese, 31% had elevated blood pressure (BP), 11% had abnormal kidney volumes, and 17% had microalbuminuria. The relative risk for having an abnormal kidney profile during adolescence among participants with a history of nAKI was 0.63 (95% confidence interval: 0.3-1.3, p = 0.2). CONCLUSION: In this sample of adolescents born EP, a history of nAKI was not associated with elevated BP, microalbuminuria, or abnormal kidney volume. Future studies are needed in larger samples to better characterize the relationship between nAKI and CKD in EP-born children. KEY POINTS: · Extremely preterm birth is associated with acute kidney injury.. · Extremely preterm birth is associated with chronic kidney disease.. · Neonatal acute kidney injury after extremely preterm birth was not associated with kidney outcomes..


Asunto(s)
Lesión Renal Aguda , Albuminuria , Creatinina , Recien Nacido Extremadamente Prematuro , Riñón , Humanos , Lesión Renal Aguda/etiología , Lesión Renal Aguda/epidemiología , Femenino , Estudios Retrospectivos , Adolescente , Masculino , Recién Nacido , Creatinina/sangre , Proyectos Piloto , Insuficiencia Renal Crónica/epidemiología , Hipertensión/epidemiología , Edad Gestacional , Ultrasonografía
6.
ACS Chem Biol ; 19(1): 37-47, 2024 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-38079390

RESUMEN

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by the accumulation of ß-amyloid (Aß), C99, and Tau in vulnerable areas of the brain. Despite extensive research, current strategies to lower Aß levels have shown limited efficacy in slowing the cognitive decline associated with AD. Recent findings suggest that C99 may also play a crucial role in the pathogenesis of AD. Our laboratory has discovered that CK1γ2 phosphorylates Presenilin 1 at the γ-secretase complex, leading to decreased C99 and Aß levels. Thus, CK1γ2 activation appears as a promising therapeutic target to lower both C99 and Aß levels. In this study, we demonstrate that CK1γ2 is inhibited by intramolecular autophosphorylation and describe a high-throughput screen designed to identify inhibitors of CK1γ2 autophosphorylation. We hypothesize that these inhibitors could lead to CK1γ2 activation and increased PS1-Ser367 phosphorylation, ultimately reducing C99 and Aß levels. Using cultured cells, we investigated the impact of these compounds on C99 and Aß concentrations and confirmed that CK1γ2 activation effectively reduced their levels. Our results provide proof of concept that CK1γ2 is an attractive therapeutic target for AD. Future studies should focus on the identification of specific compounds that can inhibit CK1γ2 autophosphorylation and evaluate their efficacy in preclinical models of AD. These studies will pave the way for the development of novel therapeutics for the treatment of AD.


Asunto(s)
Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Humanos , Precursor de Proteína beta-Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Encéfalo/metabolismo
7.
J Clin Med ; 12(20)2023 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-37892632

RESUMEN

We investigated the accuracy of CEUS for characterizing cystic and solid kidney lesions in patients with chronic kidney disease (CKD). Cystic lesions are assessed using Bosniak criteria for computed tomography (CT) and magnetic resonance imaging (MRI); however, in patients with moderate to severe kidney disease, CT and MRI contrast agents may be contraindicated. Contrast-enhanced ultrasound (CEUS) is a safe alternative for characterizing these lesions, but data on its performance among CKD patients are limited. We performed flash replenishment CEUS in 60 CKD patients (73 lesions). Final analysis included 53 patients (63 lesions). Four readers, blinded to true diagnosis, interpreted each lesion. Reader evaluations were compared to true lesion classifications. Performance metrics were calculated to assess malignant and benign diagnoses. Reader agreement was evaluated using Bowker's symmetry test. Combined reader sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for diagnosing malignant lesions were 71%, 75%, 45%, and 90%, respectively. Sensitivity (81%) and specificity (83%) were highest in CKD IV/V patients when grouped by CKD stage. Combined reader sensitivity, specificity, PPV, and NPV for diagnosing benign lesions were 70%, 86%, 91%, and 61%, respectively. Again, in CKD IV/V patients, sensitivity (81%), specificity (95%), and PPV (98%) were highest. Inter-reader diagnostic agreement varied from 72% to 90%. In CKD patients, CEUS is a potential low-risk option for screening kidney lesions. CEUS may be particularly beneficial for CKD IV/V patients, where kidney preservation techniques are highly relevant.

8.
Genes (Basel) ; 14(9)2023 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-37761808

RESUMEN

Conjunctival melanoma (CM) is a rare but aggressive cancer. Over the past decade, molecular studies using rapidly advancing technologies have increasingly improved our understanding of CM genetics. CMs are mainly characterized by dysregulated MAPK and PI3K/AKT/mTOR pathways, driven by commonly mutated (BRAF, NRAS, NF1) or less commonly mutated (KIT, PTEN) genes. Another group of genes frequently mutated in CMs include TERT and ATRX, with known roles in telomere maintenance and chromatin remodeling/epigenetic regulation. Uveal melanoma-related genes (BAP1, SF3B1, GNAQ/11) can also be mutated in CMs, albeit infrequently. Additional CM-related mutated genes have increasingly been identified using more comprehensive genetic analyses, awaiting further confirmation in additional/larger studies. As a tumor arising in a partly sun-exposed mucosal tissue, CM exhibits a distinct genomic profile, including the frequent presence of an ultraviolet (UV) signature (and high mutational load) and also the common occurrence of large structural variations (distributed across the genome) in addition to specific gene mutations. The knowledge gained from CM genetic studies to date has led to new therapeutic avenues, including the use of targeted and/or immuno-therapies with promising outcomes in several cases. Accordingly, the implementation of tumor genetic testing into the routine clinical care of CM patients holds promise to further improve and personalize their treatments. Likewise, a growing knowledge of poor prognosis-associated genetic changes in CMs (NRAS, TERT, and uveal melanoma signature mutations and chromosome 10q deletions) may ultimately guide future strategies for prognostic testing to further improve clinical outcomes (by tailoring surveillance and considering prophylactic treatments in patients with high-risk primary tumors).


Asunto(s)
Neoplasias Óseas , Neoplasias de la Mama , Neoplasias de la Conjuntiva , Melanoma , Humanos , Femenino , Epigénesis Genética/genética , Fosfatidilinositol 3-Quinasas , Melanoma/genética , Neoplasias de la Conjuntiva/genética , Deleción Cromosómica
9.
Radiol Case Rep ; 18(9): 3188-3191, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37520397

RESUMEN

A 3-year-old boy developed otitis media, mastoiditis, papilledema, sixth nerve palsy, and increased intracranial pressure. The initial diagnosis was idiopathic intracranial hypertension, but doubt about that diagnosis at such a young age led to imaging reevaluation. When the abnormalities from multiple pulse sequences were aggregated with this clinical input, the correct diagnosis of otitic hydrocephalus emerged, allowing prompt implementation of appropriate treatment to avoid the risk of venous stroke.

10.
Biosens Bioelectron ; 237: 115545, 2023 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-37517336

RESUMEN

Temperature is the most commonly collected vital sign in all of clinical medicine; it plays a critical role in care decisions related to topics ranging from infection to inflammation, sleep, and fertility. Most assessments of body temperature occur at isolated anatomical locations (e.g. axilla, rectum, temporal artery, or oral cavity). Even this relatively primitive mode for monitoring can be challenging with vulnerable patient populations due to physical encumbrances and artifacts associated with the sizes, weights, shapes and mechanical properties of the sensors and, for continuous monitoring, their hard-wired interfaces to data collection units. Here, we introduce a simple, miniaturized, lightweight sensor as a wireless alternative, designed to address demanding applications such as those related to the care of neonates in high ambient humidity environments with radiant heating found in incubators in intensive care units. Such devices can be deployed onto specific anatomical locations of premature infants for homeostatic assessments. The estimated core body temperature aligns, to within 0.05 °C, with clinical grade, wired sensors, consistent with regulatory medical device requirements. Time-synchronized, multi-device operation across multiple body locations supports continuous, full-body measurements of spatio-temporal variations in temperature and additional modes of determining tissue health status in the context of sepsis detection and various environmental exposures. In addition to thermal sensing, these same devices support measurements of a range of other essential vital signs derived from thermo-mechanical coupling to the skin, for applications ranging from neonatal and infant care to sleep medicine and even pulmonary medicine.

11.
Am Surg ; 89(10): 4191-4194, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37278021

RESUMEN

BACKGROUND: Symptomatic cholelithiasis is a common disease in which the majority of patients are managed electively. There is an unknown proportion of patients who require emergency surgery for acute cholecystitis in this elective waiting period. Our study aimed to evaluate risk factors for requiring an emergency cholecystectomy during this waiting period. METHODS: This single-center retrospective observational study queried medical records for scheduled elective cholecystectomies from 2017 to 2022. We then evaluated these patients to determine who required emergency intervention via acute cholecystectomy. Patient demographics were analyzed. Patient cohort subgroups were created for patients who waited longer than 60 days and less than 60 days. RESULTS: 1086 patients from 2017 to 2022 were scheduled for an elective cholecystectomy. Of those, 48 required emergency cholecystectomy. Average wait times of those who required emergent cholecystectomy were found to be significantly higher at 60.3 d, compared to 47.3 d for the elective group (P = .03*). Subgroup analysis of patients with >60 d average wait time re-demonstrated significance with 92.1 d and 115.7 d (P = .004) for the elective and emergency subgroups, respectively. >60 d wait time showed increased odds ratio of 1.805 (P = .05) for requiring an emergency cholecystectomy. Logistic regression analysis identified >60 d waiting period (P = .01) and obesity (P = .0001) as predictors of needing emergency surgery. DISCUSSION: Wait time >60 d is associated with an increased risk of emergent cholecystectomy. Obesity was identified as a key risk factor which should be considered for stratifying patients for more urgent surgical intervention.


Asunto(s)
Colecistectomía Laparoscópica , Colelitiasis , Humanos , Colecistectomía , Colelitiasis/cirugía , Factores de Riesgo , Estudios Retrospectivos , Procedimientos Quirúrgicos Electivos , Obesidad/complicaciones , Obesidad/cirugía
12.
Schizophr Bull ; 49(6): 1614-1624, 2023 11 29.
Artículo en Inglés | MEDLINE | ID: mdl-37163675

RESUMEN

BACKGROUND AND HYPOTHESIS: Cognitive impairment is a hallmark of schizophrenia, but no effective treatment is available to date. The underlying pathophysiology includes disconnectivity between hippocampal and prefrontal brain regions. Supporting evidence comes from diffusion-weighted imaging studies that suggest abnormal organization of frontotemporal white matter pathways in schizophrenia. STUDY DESIGN: Here, we hypothesize that in schizophrenia, deficient maturation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes substantially contributes to abnormal frontotemporal macro- and micro-connectivity and subsequent cognitive deficits. STUDY RESULTS: Our postmortem studies indicate a reduced oligodendrocyte number in the cornu ammonis 4 (CA4) subregion of the hippocampus, and others have reported the same histopathological finding in the dorsolateral prefrontal cortex. Our series of studies on aerobic exercise training showed a volume increase in the hippocampus, specifically in the CA4 region, and improved cognition in individuals with schizophrenia. The cognitive effects were subsequently confirmed by meta-analyses. Cell-specific schizophrenia polygenic risk scores showed that exercise-induced CA4 volume increase significantly correlates with OPCs. From animal models, it is evident that early life stress and oligodendrocyte-related gene variants lead to schizophrenia-related behavior, cognitive deficits, impaired oligodendrocyte maturation, and reduced myelin thickness. CONCLUSIONS: Based on these findings, we propose that pro-myelinating drugs (e.g., the histamine blocker clemastine) combined with aerobic exercise training may foster the regeneration of myelin plasticity as a basis for restoring frontotemporal connectivity and cognition in schizophrenia.


Asunto(s)
Disfunción Cognitiva , Esquizofrenia , Animales , Humanos , Esquizofrenia/patología , Oligodendroglía/metabolismo , Vaina de Mielina/metabolismo , Vaina de Mielina/patología , Disfunción Cognitiva/patología , Hipocampo/diagnóstico por imagen , Hipocampo/patología
13.
Graefes Arch Clin Exp Ophthalmol ; 261(9): 2679-2687, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37010593

RESUMEN

PURPOSE: The goal of this study was to compare the efficacy of intraarterial chemotherapy (IAC) for retinoblastoma delivered via the ophthalmic artery (OA) division of the internal carotid artery (ICA) versus alternative branches of the external carotid artery (ECA). METHODS: We performed a retrospective chart review of patients receiving IAC for retinoblastoma at a single institution. Subjects were divided into three groups: those that received IAC solely through the OA branch of the ICA, those that initially received IAC through the OA branch of the ICA but were later switched to the ECA, and those that only received IAC through the ECA. The main outcomes compared included globe salvage rate and reduction in tumor thickness and size. RESULTS: A total of 30 eyes from 26 patients were included. A total of 91 (58%) sessions of IAC were performed through the OA division of the ICA and 65 (42%) were performed through branches of the ECA. Eleven eyes (37%) solely received IAC through the OA branch of the ICA, 16 eyes (53%) were converted to ECA treatment, and 3 eyes solely received IAC through branches of the ECA. Statistical analysis did not show any significant difference in globe salvage rate or reduction in tumor thickness and size. CONCLUSION: The use of alternative approaches for IAC when the OA branch of the ICA catheterization is not feasible allows for safe continued delivery of highly effective IAC, leading to similar outcomes in terms of globe salvage and reduction in tumor size.


Asunto(s)
Neoplasias de la Retina , Retinoblastoma , Humanos , Retinoblastoma/diagnóstico , Retinoblastoma/tratamiento farmacológico , Neoplasias de la Retina/diagnóstico , Neoplasias de la Retina/tratamiento farmacológico , Arteria Carótida Externa , Estudios Retrospectivos , Infusiones Intraarteriales , Resultado del Tratamiento , Arteria Carótida Interna
14.
Artículo en Inglés | MEDLINE | ID: mdl-36834079

RESUMEN

Breast cancer is the most commonly diagnosed cancer among Chinese American women. Knowing the BRCA1 and BRCA2 (BRCA1/2) gene mutation status can improve breast cancer patients' health outcomes by guiding targeted treatment towards preventing breast cancer recurrence and other BRCA-related cancers. Nevertheless, it is unclear if there is a disparity in knowledge and use of BRCA testing among Chinese American breast cancer patients. This cross-sectional study investigated the possible presence of differences in the knowledge and the use of BRCA testing between Chinese American and Non-Hispanic White (NHW) breast cancer patients. We surveyed 45 Chinese American and 48 NHW adult breast cancer patients who had been diagnosed with breast cancer within the previous two years through telephone interviews. The results showed that race was not statistically related to the use of BRCA testing. BRCA testing utilization was associated with family history (p < 0.05) and age (p < 0.05). However, Chinese American participants' understanding of BRCA testing was significantly lower than that of NHW participants (p = 0.030). Our findings suggest that a disparity exists in BRCA testing knowledge between Chinese American and NHW breast cancer patients. Genetic education and counseling are needed to improve BRCA testing knowledge and uptake among Chinese American breast cancer patients.


Asunto(s)
Neoplasias de la Mama , Adulto , Femenino , Humanos , Neoplasias de la Mama/diagnóstico , Estudios Transversales , Pueblos del Este de Asia , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Mutación , Recurrencia Local de Neoplasia/genética , Blanco , Conocimientos, Actitudes y Práctica en Salud
15.
Ultrasound Med Biol ; 49(3): 761-772, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36463005

RESUMEN

Early stages of diabetic kidney disease (DKD) are difficult to diagnose in patients with type 2 diabetes. This work was aimed at identifying contrast-enhanced ultrasound (CEUS) perfusion parameters, a microcirculatory biomarker indicative of early DKD progression. CEUS kidney flash-replenishment data were acquired in control, insulin resistant and diabetic vervet monkeys (N = 16). By use of a mono-exponential model, time-intensity curve parameters related to blood volume (A), velocity (ß) and flow rate (perfusion index [PI]) were extracted from 10 concentric kidney layers to study spatial perfusion patterns that could serve as strong indicators of disease. Mean squared error (MSE) was used to assess model performance. Features calculated from the perfusion parameters were inputs for the linear regression models to determine which features could distinguish between cohorts. The mono-exponential model performed well, with average MSEs (±standard deviation) of 0.0254 (±0.0210), 0.0321 (±0.0242) and 0.0287 (±0.0130) for the control, insulin resistant and diabetic cohorts, respectively. Perfusion index features, with blood pressure, were the best classifiers between cohorts (p < 0.05). CEUS has the potential to detect early microvascular changes, providing insight into disease-related structural changes in the kidney. The sensitivity of this technique should be explored further by assessing various stages of DKD.


Asunto(s)
Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Insulinas , Animales , Chlorocebus aethiops , Medios de Contraste , Microcirculación , Riñón/irrigación sanguínea , Ultrasonografía/métodos , Nefropatías Diabéticas/diagnóstico por imagen , Perfusión
16.
Front Neurol ; 14: 1305972, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38269002

RESUMEN

Background: There is increasing recognition of connective tissue disorders and their influence on disease in the general population. A conserved clinical phenotype involving connective tissue disorders and idiopathic intracranial hypertension (IIH) and associated cerebral venous outflow disorders (CVD) has not been previously described. Methods: A single-institution retrospective review of a prospectively maintained database of patients with connective tissue disorders and CVD was performed. Results: A total of 86 patients were identified. The majority of these patients carried a diagnosis of Ehlers-Danlos syndrome (55%) and most were non-obese (mean body mass index 29.7 kg/m2), Caucasian (90%) females (87%). Most prevalent presenting symptoms included pressure headache (98%), dizziness (90%), tinnitus (92%), and cognitive dysfunction (69%). Aside from CVD and IIH, the most common associated conditions were postural orthostatic tachycardia syndrome (POTS; 55.8%), cerebrospinal fluid (CSF) leaks (51.2%), dysautonomia (45.3%), cranio-cervical instability (37.2%), mast cell activation syndrome (25.6%), and tethered cord syndrome (23.3%). Allergies to medications (87.2%) and surgical tape (19.8%) were also frequent. Despite significantly lower opening pressures on lumbar puncture, headache severity and quality of life scores were reported with the same severity of classic IIH patients, suggesting an underlying hypersensitivity to intracranial pressures and cerebral venous congestion. Conclusion: There is a rare but conserved clinical phenotype that has not been described previously that presents with severe IIH symptoms in predominantly young, non-obese Caucasian women with a high associated incidence of dysautonomia, POTS, craniocervical instability, and CSF leaks, among others.

17.
PLoS Genet ; 18(12): e1010309, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36480547

RESUMEN

DNA replication is a vulnerable time for genome stability maintenance. Intrinsic stressors, as well as oncogenic stress, can challenge replication by fostering conflicts with transcription and stabilizing DNA:RNA hybrids. RAD18 is an E3 ubiquitin ligase for PCNA that is involved in coordinating DNA damage tolerance pathways to preserve genome stability during replication. In this study, we show that RAD18 deficient cells have higher levels of transcription-replication conflicts and accumulate DNA:RNA hybrids that induce DNA double strand breaks and replication stress. We find that these effects are driven in part by failure to recruit the Fanconi Anemia protein FANCD2 at difficult to replicate and R-loop prone genomic sites. FANCD2 activation caused by splicing inhibition or aphidicolin treatment is critically dependent on RAD18 activity. Thus, we highlight a RAD18-dependent pathway promoting FANCD2-mediated suppression of R-loops and transcription-replication conflicts.


Asunto(s)
Reparación del ADN , Anemia de Fanconi , Humanos , Reparación del ADN/genética , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/metabolismo , ADN/genética , Daño del ADN/genética , Replicación del ADN/genética , ARN , Inestabilidad Genómica/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo
18.
Cureus ; 14(6): e26260, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35911322

RESUMEN

Gitelman syndrome is an autosomal recessive inherited disorder that impairs the function of thiazide-sensitive sodium-chloride cotransporters in the distal convoluted tubule of the nephron. During labor and delivery, avoidance of sympathetic overactivity, meticulous hemodynamic monitoring, and expedited repletion of potassium and magnesium are required to avoid adverse outcomes. We present a parturient with severe Gitelman syndrome, requiring continuous electrolyte and fluid infusions, who underwent successful cesarean delivery. Potential severe morbidity was avoided with multidisciplinary planning and management.

19.
Kidney360 ; 3(4): 647-656, 2022 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-35721623

RESUMEN

Background: Individuals with chronic kidney disease (CKD) have decreased kidney cortical microvascular perfusion, which may lead to worsening kidney function over time, but methods to quantify kidney cortical microvascular perfusion are not feasible to incorporate into clinical practice. Contrast-enhanced ultrasound (CEUS) may quantify kidney cortical microvascular perfusion, which requires further investigation in individuals across the spectrum of kidney function. Methods: We performed CEUS on a native kidney of 83 individuals across the spectrum of kidney function and calculated quantitative CEUS-derived kidney cortical microvascular perfusion biomarkers. Participants had a continuous infusion of the microbubble contrast agent (Definity) with a flash-replenishment sequence during their CEUS scan. Lower values of the microbubble velocity (ß) and perfusion index (ß×A) may represent lower kidney cortical microvascular perfusion. Multivariable linear regression models tested the associations of the microbubble velocity (ß) and perfusion index (ß×A) with estimated glomerular filtration rate (eGFR). Results: Thirty-eight individuals with CKD (mean age±SD 65.2±12.6 years, median [IQR] eGFR 31.5 [18.9-41.5] ml/min per 1.73 m2), 37 individuals with end stage kidney disease (ESKD; age 54.8±12.3 years), and eight healthy volunteers (age 44.1±15.0 years, eGFR 117 [106-120] ml/min per 1.73 m2) underwent CEUS without side effects. Individuals with ESKD had the lowest microbubble velocity (ß) and perfusion index (ß×A) compared with individuals with CKD and healthy volunteers. The microbubble velocity (ß) and perfusion index (ß×A) had moderate positive correlations with eGFR (ß: rs=0.44, P<0.001; ß×A: rs=0.50, P<0.001). After multivariable adjustment, microbubble velocity (ß) and perfusion index (ß×A) remained significantly associated with eGFR (change in natural log transformed eGFR per 1 unit increase in natural log transformed biomarker: ß, 0.38 [95%, CI 0.17 to 0.59]; ß×A, 0.79 [95% CI, 0.45 to 1.13]). Conclusions: CEUS-derived kidney cortical microvascular perfusion biomarkers are associated with eGFR. Future studies are needed to determine if CEUS-derived kidney cortical microvascular perfusion biomarkers have prognostic value.


Asunto(s)
Riñón , Insuficiencia Renal Crónica , Adulto , Anciano , Biomarcadores , Humanos , Riñón/diagnóstico por imagen , Persona de Mediana Edad , Perfusión , Insuficiencia Renal Crónica/diagnóstico por imagen , Ultrasonografía/métodos
20.
West J Nurs Res ; 44(3): 239-249, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34865588

RESUMEN

Stress is a significant part of daily life, and systemic social inequities, such as racism and discrimination, are well-established contributors of chronic stress for African Americans. Added exposure to the stress of caregiving may exacerbate adverse health outcomes. This secondary analysis describes subjective and objective stress in African American family caregivers, and relationships of subjective and objective stress to health outcomes. Baseline data from 142 African American dementia family caregivers from the "Great Village" study were described using means and frequencies; regression models and Pearson's correlation were used to examine associations between demographics, social determinants of health, and health outcomes. Mixed models were used to examine change and change variation in cortisol. Most caregivers had moderate degrees of stress. Stress was associated with sleep disruption and depressive symptoms, and discrimination appeared to be an independent contributor to depressive symptoms. This work provides a foundation for interpreting subjective and objective indicators of stress to tailor existing multicomponent interventions.


Asunto(s)
Negro o Afroamericano , Demencia , Cuidadores , Humanos , Hidrocortisona , Estrés Psicológico
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