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An eight-year-old male neutered crossbreed dog presented with erosive and ulcerative cutaneous lesions in the inguinal regions, the medial aspect of both thighs, and the stifles. Hematologic assessment revealed nonregenerative anemia, thrombocytopenia, and high numbers of neoplastic mononuclear cells with a variable degree of maturation. The mononuclear neoplastic cells, with nuclei measuring 10-20 microns in diameter, accounted for 57% of the nucleated blood cells. In addition, the blood contained increased numbers of mature neutrophils and monocytes with atypical morphology. Cytologic examination of the right popliteal lymph node found high numbers of large mononuclear cells with similar morphology to those in the peripheral blood. Flow cytometry of peripheral blood revealed expression by the mononuclear neoplastic cells of the pan-leukocyte marker CD45 and myeloid markers CD14, MAC387, and myeloperoxidase (MPO). These results confirmed a diagnosis of acute myeloid leukemia (AML). Computed tomography found moderate nodular hepatosplenomegaly and multifocal bi-cavitary lymphadenopathy. Histopathologic examination of biopsies from the cutaneous lesions identified infiltration of the dermis by intermediate to large neoplastic round cells. Further treatment was declined, and the owners elected euthanasia. Postmortem examination confirmed AML involvement in the bone marrow, peripheral and intracavitary lymph nodes, heart, liver, kidney, and skin. Neoplastic cells in the bone marrow and skin showed positive immunolabeling for ionized calcium-binding adaptor protein 1 and MPO. To the best of our knowledge, this is the first report of ulcerative cutaneous lesions observed among the presenting clinical signs in a dog with AML and secondary leukemia cutis.

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OBJECTIVE: Changes in a patient's reported breast density status (dense vs nondense) trigger modifications in their cancer risk profile and supplemental screening recommendations. This study tracked the frequency and longitudinal sequence of breast density status changes among patients who received serial mammograms. METHODS: This IRB-approved, HIPAA-compliant retrospective cohort study tracked breast density changes among patients who received at least 2 mammograms over an 8-year study period. BI-RADS density assessment categories A through D, visually determined at the time of screening, were abstracted from electronic medical records and dichotomized into either nondense (categories A or B) or dense (categories C or D) status. A sequence analysis of longitudinal changes in density status was performed using Microsoft SQL. RESULTS: A total of 58 895 patients underwent 231 997 screening mammograms. Most patients maintained the same BI-RADS density category A through D (87.35% [51 444/58 895]) and density status (93.35% [54 978/58 859]) throughout the study period. Among patients whose density status changed, the majority (97% [3800/3917]) had either scattered or heterogeneously dense tissue, and over half (57% [2235/3917]) alternated between dense and nondense status multiple times. CONCLUSION: Our results suggest that many cases of density status change may be attributable to intra- and interradiologist variability rather than to true underlying changes in density. These results lend support to consideration of automated density assessment because breast density status changes can significantly impact cancer risk assessment and supplemental screening recommendations.

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PURPOSE: Exercise-nutrient timing is of interest for people with type 2 diabetes (T2D) as a potential method to optimize glycemic control. However, the optimal nutritional environment for exercise is not well understood over the long term. The Fasted Exercise for Type 2 Diabetes (FED) Trial compared 16 weeks of fasted versus postprandial morning exercise on glycated hemoglobin (HbA1c) and liver proton density fat fraction (PDFF). METHODS: Twenty adults with T2D were recruited and randomized to complete exercise after an overnight fast versus after their morning meal. Participants walked three mornings per week, progressing to 180 minutes per week over 16 weeks. RESULTS: Groups were balanced with 5 males and 5 females each. Sixteen participants completed the trial (8 in each group, 50% female). Age, HbA1c, and PDFF were 59.8 ± 9.0 years, 7.2 ± 0.7%, and 9.3 ± 4.1%, respectively. On average, both groups completed 98% of their walking sessions but there was no change in HbA1c (-0.2%, p = 0.588). However, one participant from each group had changes in their glucose lowering medication during the trial and, when excluded, the fasted training group had greater improvements in HbA1c compared to the postprandial group (-0.3% versus 0.0%, p = 0.033). There was no difference in changes in liver PDFF between groups (-1.6% versus 0.3%, p = 0.221) but visceral fat and intramuscular fat decreased to a greater extent following fasted exercise. CONCLUSIONS: Although our study had a small sample size, it suggests that exercise after an overnight fast can have high adherence and represents an option for people with T2D to improve longer-term indicators of glycemia and ectopic fat depots.

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Transfer RNA (tRNA) modifications are crucial for protein synthesis, but their position-specific physiological roles remain poorly understood. Here we investigate the impact of N4-acetylcytidine (ac4C), a highly conserved tRNA modification, using a Thumpd1 knockout mouse model. We find that loss of Thumpd1-dependent tRNA acetylation leads to reduced levels of tRNALeu, increased ribosome stalling, and activation of eIF2α phosphorylation. Thumpd1 knockout mice exhibit growth defects and sterility. Remarkably, concurrent knockout of Thumpd1 and the stress-sensing kinase Gcn2 causes penetrant postnatal lethality, indicating a critical genetic interaction. Our findings demonstrate that a modification restricted to a single position within type II cytosolic tRNAs can regulate ribosome-mediated stress signaling in mammalian organisms, with implications for our understanding of translation control as well as therapeutic interventions.

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Disruptions in circadian rhythms are associated with increased risk of developing metabolic diseases. General control nonderepressible 2 (GCN2), a primary sensor of amino acid insufficiency and activator of the integrated stress response (ISR), has emerged as a conserved regulator of the circadian clock in multiple organisms. The objective of this study was to examine diurnal patterns in hepatic ISR activation in the liver and whole-body rhythms in metabolism. We hypothesized that GCN2 activation cues hepatic ISR signaling over a natural 24 h feeding fasting cycle. To address our objective, wild type (WT) and whole body Gcn2 knockout (GCN2 KO) mice were housed in metabolic cages and provided free access to either a Control or leucine-devoid diet (LeuD) for 8-days in total darkness. On the last day, blood and livers were collected at circadian time (CT) 3 and CT15. In livers of WT mice, GCN2 phosphorylation followed a diurnal pattern that was guided by intracellular branched chain amino acid concentrations (r2=0.93). Feeding LeuD to WT mice increased hepatic ISR activation at CT15 only. Diurnal oscillation in hepatic ISR signaling, the hepatic transcriptome including lipid metabolic genes, and triglyceride concentrations were substantially reduced or absent in GCN2 KO mice. Further, mice lacking GCN2 were unable to maintain circadian rhythms in whole body energy expenditure, respiratory exchange ratio and physical activity when fed LeuD. In conclusion, GCN2 activation functions to maintain diurnal ISR activation in the liver and has a vital role in the mechanisms by which nutrient stress affects whole-body metabolism.

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Stretching an elastic material along one axis typically induces contraction along the transverse axes, a phenomenon known as the Poisson effect. From these strains, one can compute the specific volume, which generally either increases or, in the incompressible limit, remains constant as the material is stretched. However, in networks of semiflexible or stiff polymers, which are typically highly compressible yet stiffen significantly when stretched, one instead sees a significant reduction in specific volume under finite strains. This volume reduction is accompanied by increasing alignment of filaments along the strain axis and a nonlinear elastic response, with stiffening of the apparent Young's modulus. For semiflexible networks, in which entropic bending elasticity governs the linear elastic regime, the nonlinear Poisson effect is caused by the nonlinear force-extension relationship of the constituent filaments, which produces a highly asymmetric response of the constituent polymers to stretching and compression. The details of this relationship depend on the geometric and elastic properties of the underlying filaments, which can vary greatly in experimental systems. Here, we provide a comprehensive characterization of the nonlinear Poisson effect in an affine network model and explore the influence of filament properties on essential features of both microscopic and macroscopic response, including strain-driven alignment and volume reduction.

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Ticagrelor is contraindicated in combination with cytochrome P450 3A4 and 3A5 enzyme (CYP3A4/5) inducers due to increased clearance, causing diminished antiplatelet effects. The emergent nature of acute coronary syndromes (ACS) may preclude scrutinization of home medications before P2Y12 inhibitor administration. The purpose of this case series is to establish the temporal impact of CYP3A4/5 enzyme induction on ticagrelor's pharmacodynamic effect by utilizing VerifyNow platelet aggregation studies. This was a retrospective case series of three patients who were taking a CYP3A4/5-inducing medication and loaded with ticagrelor for ACS. The duration of ticagrelor's antiplatelet effect was dramatically shortened in the presence of background CYP3A4/5 induction. The offset of antiplatelet effect, defined by platelet reactivity units (PRU), was 10-24 hours in the presence of CYP3A4/5 enzyme induction compared to the anticipated 36-48 hours. This was consistent across CYP3A4/5-inducing medications including carbamazepine, phenobarbital, and phenytoin. This study demonstrates rapid return of platelet function after a ticagrelor loading dose in the presence of CYP3A4/5-inducing medications. Monitoring of PRU every 6-12 hours with subsequent loading with clopidogrel or prasugrel should be considered. Larger scale studies are warranted to confirm these results.

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OBJECTIVE: Posttraumatic stress disorder (PTSD) has been linked with menopause symptoms (eg, vasomotor, urinary) and their sequelae (eg, sexual difficulties). However, PTSD is a heterogeneous disorder, and less is known about which aspects may be most associated with menopause-related health. METHODS: Using confirmatory factor analyses, we evaluated five structural models of PTSD symptoms in 208 predominately postmenopausal women veterans (aged 45-64 years). We investigated associations between PTSD-operationalized as a probable diagnosis and symptom dimensions of the best-fitting model-and common menopause-related health concerns, including (1) vasomotor, urinary, and vaginal symptoms; (2) vasomotor symptom interference; and (3) sexual functioning. RESULTS: A six-factor anhedonia model-comprising re-experiencing, avoidance, negative affect, anhedonia, anxious arousal, and dysphoric arousal-provided optimal fit. Both probable PTSD and greater symptoms across all dimensions were linked with presence of urinary and vasomotor, but not vaginal, symptoms. Comparing dimensions revealed that negative affect and dysphoric arousal were particularly associated with urinary symptoms, whereas dysphoric arousal was the factor most strongly related to vasomotor symptom interference. Associations between PTSD and sexual dysfunction were mixed; whereas there was no relation with probable diagnosis, all dimensions were linked with adverse sexual sequelae. CONCLUSIONS: PTSD-considered categorically and dimensionally-was relevant to menopause-related health in midlife women veterans. Further, symptoms of negative affect and dysphoric arousal were particularly related to urinary and vasomotor symptoms. These specific symptoms may drive associations between PTSD and these aspects of menopause-related health. Clinical interventions targeting these symptoms may promote midlife women's health.

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Intra-articular corticosteroids are a popular treatment choice for joint-associated pain and inflammation in horses despite recent work on the metabolic effects of these drugs. The goal of this project was to compare metabolic effects between intra-articular (IA) triamcinolone acetonide (TA) and an autologous protein solution (APS). Five mixed-breed geldings (4-9 years) were utilized for this project. Three identical and consecutive 28-day treatment blocks were used, with metacarpophalangeal IA treatments consisting of equal volumes of saline, a commercially available APS, or 9 mg of TA. Regular plasma and serum samples were collected for ACTH, cortisol, glucose, insulin, and thyroid hormone analysis, in addition to thyrotropin-releasing hormone (TRH) and oral sugar tests (OSTs). Significant treatment effects of IA TA were present at 48 h post-injection in both the TRH and the OST. There was also significant suppression by IA TA of baseline ACTH and cortisol between 2 h and 96 h post-treatment, hyperglycemia between 12 h and 48 h, and hyperinsulinemia at 32 h post-treatment. There were no treatment effects with respect to any measured thyroid hormones, nor were there any significant treatment effects of APS noted. Results suggest at least 2 days and up to 7 days should elapse between a single 9 mg IA TA treatment and OST and/or TRH testing. This study found that TA exhibits significant effects on ACTH, cortisol, glucose, and insulin, while the APS does not.

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BACKGROUND: Alzheimer's disease is the most common type of dementia and is responsible for up to 80% of dementia diagnoses and is the sixth leading cause of death in the United States. An estimated 38,000 American Indian/Alaska Native (AI/AN) people aged ≥65 years were living with Alzheimer's disease and related dementias (ADRD) in 2020, a number expected to double by 2030 and quadruple by 2050. Administrative healthcare data from the Indian Health Service (IHS) were used to estimate ADRD among AI/AN populations. METHODS: Administrative IHS healthcare data from federal fiscal years 2016 to 2020 from the IHS National Data Warehouse were used to calculate the count and rate per 100,000 AI/AN adults aged ≥45 years with at least one ADRD diagnosis code on their medical record. RESULTS: This study identified 12,877 AI/AN adults aged ≥45 years with an ADRD diagnosis code, with an overall rate of 514 per 100,000. Of those, 1856 people were aged 45-64. Females were 1.2 times (95% confidence interval: 1.1-1.2) more likely than males to have a medical visit with an ADRD diagnosis code. CONCLUSIONS: Many AI/AN people with ADRD rely on IHS, tribal, and urban Indian health programs. The high burden of ADRD in AI/AN populations aged 45-64 utilizing IHS health services highlights the need for implementation of ADRD risk reduction strategies and assessment and diagnosis of ADRD in younger AI/AN populations. This study provides a baseline to assess future progress for efforts addressing ADRD in AI/AN communities.

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In this registered report, we propose to stress-test existing models for predicting the ideology-prejudice association, which varies in size and direction across target groups. Previous models of this relationship use the perceived ideology, status, and choice in group membership of target groups to predict the ideology-prejudice association across target groups. These analyses show that models using only the perceived ideology of the target group are more accurate and parsimonious in predicting the ideology-prejudice association than models using perceived status, choice, and all of the characteristics in a single model. Here, we stress-test the original models by testing the models' predictive utility with new measures of explicit prejudice, a comparative operationalization of prejudice, the Implicit Association Test, and additional target groups. In Study 1, we propose to directly test the previous models using an absolute measure of prejudice that closely resembles the measure used in the original study. This will tell us if the models replicate with distinct, yet conceptually similar measures of prejudice. In Study 2, we propose to develop new ideology-prejudice models for a comparative operationalization of prejudice using both explicit measures and the Implicit Association Test. We will then test these new models using data from the Ideology 2.0 project collected by Project Implicit. We do not have full access to this data yet, but upon acceptance of our Stage 1 registered report, we will gain access to the complete dataset. Currently, we have access to an exploratory subset of the data that we use to demonstrate the feasibility of the study, but its limited number of target groups prevents conclusions from being made.

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BACKGROUND: Nonfunctional pituitary neuroendocrine tumors (PitNETs) exhibit wide variability in growth pattern based on subtype. Silent corticotroph adenomas (SCAs) demonstrate aggressive growth compared with other nonfunctional pituitary adenomas (NFPAs), especially into the cavernous sinus. In this study, we sought to characterize other growth patterns of SCAs compared with NFPAs. METHODS: We performed a retrospective analysis of all patients with nonfunctional PitNETs treated with surgical resection via endoscopic endonasal approach at a single institution from August 1, 2018, to May 11, 2024. Preoperative computed tomography and magnetic resonance imaging were reviewed to determine extension into the suprasellar space, sphenoid sinus, cavernous sinus, and clivus. RESULTS: The study comprised 91 patients, including 20 SCAs and 71 NFPAs. SCAs demonstrated significantly greater rates of growth into the sphenoid sinus (55.0% vs. 23.94%, P = 0.013), clivus (65.0% vs. 16.9%, P < 0.0001), and cavernous sinus (defined as Knosp grade 3 or 4; 55.0% vs. 23.35%, P = 0.016). Other NFPAs were more likely to grow into the suprasellar space (92.96% vs. 75.0%, P = 0.038). Tumor volume was similar between groups (11.93 cm3 vs. 9.06 cm3, P = 0.2). CONCLUSIONS: Silent corticotroph PitNETs demonstrate predilection for invasion of bony structures, with higher rates of growing through the sellar floor into the sphenoid sinus, growing posteroinferiorly into the clivus and laterally into the cavernous sinuses. Other nonfunctional PitNETs tended to follow the path of least resistance, growing superiorly into the suprasellar space. These differences in growth patterns may account for some of the clinical challenges of treating silent corticotroph PitNETs.

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OBJECTIVE: Huntington's disease (HD) is a neurodegenerative disease caused by a triplet repeat expansion within the gene huntingtin (HTT). Antagonistic pleiotropy is a theory of aging that posits that some genes, facilitating individual fitness early in life through adaptive evolutionary changes, also augment detrimental aging-related processes. Antagonistic pleiotropy theory may explain a positive evolutionary pressure toward functionally advantageous brain development that is vulnerable to rapid degeneration. The current study investigated antagonistic pleiotropy in HD using a years-to-onset paradigm in a unique sample of children and young adults at risk for HD. METHODS: Cognitive, behavioral, motor, and brain structural measures from premanifest gene-expanded (n = 79) and gene nonexpanded (n = 112) participants (6-21 years) in the Kids-HD study were examined. All measures in the gene-expanded group were modeled using a mixed-effects regression approach to assess years-to-onset-based changes while controlling for normal growth. Simultaneously, structure-function associations were also examined. RESULTS: Decades from motor onset, gene-expanded participants showed significantly better cognitive, behavioral, and motor scores versus gene nonexpanded controls, along with larger cerebral volumes and cortical features. After this initial peak, a prolonged deterioration was observed in both functional and structural measures. Far from onset, brain measures were positively correlated with functional measures, supporting the view that functional advantages were mediated by structural differences. INTERPRETATION: Mutant HTT may drive the development of a larger than normal brain that subserves superior early-life function. These findings support the antagonistic pleiotropy theory of HTT in HD, where this gene drives early advantage followed by accelerated aging processes. ANN NEUROL 2024.

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Background: Hospice services for patients with Huntington's disease (HD) are likely beneficial in relieving significant burdens and minimizing costly hospitalizations at the end of life, though there has been little study or clinical guidance on hospice enrollment for patients with HD. Objectives: The primary objective of this study was to identify clinical, sociodemographic, and system-level factors associated with discharges to hospice compared to other dispositions for hospitalized patients with late-stage HD. Methods: These analyses used data from the Nationwide Inpatient Sample between the years 2007 and 2011. Weighted logistic regression with a forward selection approach was performed to identify factors associated with discharge to hospice compared to discharge to home, facility, other locations, and death in hospital. Results: These analyses included 6544 hospitalizations of patients with late-stage HD. There was a significant increasing trend in discharges to hospice over the study period (P < 0.001). After adjustment, multiple clinical, sociodemographic, and system-level variables were identified as being associated with discharges to hospice. Patients with aspiration pneumonia and non-aspiration pneumonias had lower odds of being discharged to hospice compared to dying in the hospital. When comparing to discharges to facilities and home, weight loss and palliative care consultation were associated with greater odds of discharge to hospice. Conclusions: Our findings serve as a foundation for future studies on these factors, and thus help clinician decision-making on when to start advance care planning or end-of-life care for patients with HD. These results also support studies developing hospice referral criteria specific to patients with HD.

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Endoplasmic reticulum (ER) stress induces the repression of protein synthesis throughout the cell. Attempts to understand how localized stress leads to widespread repression have been limited by difficulties in resolving translation rates at the subcellular level. Here, using live-cell imaging of reporter mRNA translation, we unexpectedly found that during ER stress, active translation at mitochondria was significantly protected. The mitochondrial protein ATPase family AAA domain-containing protein 3A (ATAD3A) interacted with protein kinase RNA-like endoplasmic reticulum kinase (PERK) and mediated this effect on localized translation by competing for binding with PERK's target, eukaryotic initiation factor 2 (eIF2). PERK-ATAD3A interactions increased during ER stress, forming mitochondria-ER contact sites. Furthermore, ATAD3A binding attenuated local PERK signaling and rescued the expression of some mitochondrial proteins. Thus, PERK-ATAD3A interactions can control translational repression at a subcellular level, mitigating the impact of ER stress on the cell.

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Brain-machine interface (BMI) controlled functional electrical stimulation (FES) is a promising treatment to restore hand movements to people with cervical spinal cord injury. Recent intracortical BMIs have shown unprecedented successes in decoding user intentions, however the hand movements restored by FES have largely been limited to predetermined grasps. Restoring dexterous hand movements will require continuous control of many biomechanically linked degrees-of-freedom in the hand, such as wrist and finger flexion, that would form the basis of those movements. Here we investigate the ability to restore simultaneous wrist and finger flexion, which would enable grasping with a controlled hand posture and assist in manipulating objects once grasped. We demonstrate that intramuscular FES can enable monkeys with temporarily paralyzed hands to move their fingers and wrist across a functional range of motion, spanning an average 88.6 degrees at the metacarpophalangeal joint flexion and 71.3 degrees of wrist flexion, and intramuscular FES can control both joints simultaneously in a real-time task. Additionally, we demonstrate a monkey using an intracortical BMI to control the wrist and finger flexion in a virtual hand, both before and after the hand is temporarily paralyzed, even achieving success rates and acquisition times equivalent to able-bodied control with BMI control after temporary paralysis in two sessions. Together, this outlines a method using an artificial brain-to-body interface that could restore continuous wrist and finger movements after spinal cord injury.

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The transcriptional coactivators EP300 and CREBBP are critical regulators of gene expression that share high sequence identity but exhibit nonredundant functions in basal and pathological contexts. Here, we report the development of a bifunctional small molecule, MC-1, capable of selectively degrading EP300 over CREBBP. Using a potent aminopyridine-based inhibitor of the EP300/CREBBP catalytic domain in combination with a VHL ligand, we demonstrate that MC-1 preferentially degrades EP300 in a proteasome-dependent manner. Mechanistic studies reveal that selective degradation cannot be predicted solely by target engagement or ternary complex formation, suggesting additional factors govern paralogue-specific degradation. MC-1 inhibits cell proliferation in a subset of cancer cell lines and provides a new tool to investigate the noncatalytic functions of EP300 and CREBBP. Our findings expand the repertoire of EP300/CREBBP-targeting chemical probes and offer insights into the determinants of selective degradation of highly homologous proteins.

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Although the green alga Chlamydomonas reinhardtii has long served as a reference organism, few studies have interrogated its role as a primary producer in microbial interactions. Here, we quantitatively investigated C. reinhardtii's capacity to support a heterotrophic microbe using the established coculture system with Mesorhizobium japonicum, a vitamin B12-producing α-proteobacterium. Using stable isotope probing and nanoscale secondary ion mass spectrometry (nanoSIMS), we tracked the flow of photosynthetic fixed carbon and consequent bacterial biomass synthesis under continuous and diurnal light with single-cell resolution. We found that more 13C fixed by the alga was taken up by bacterial cells under continuous light, invalidating the hypothesis that the alga's fermentative degradation of starch reserves during the night would boost M. japonicum heterotrophy. 15NH4 assimilation rates and changes in cell size revealed that M. japonicum cells reduced new biomass synthesis in coculture with the alga but continued to divide-a hallmark of nutrient limitation often referred to as reductive division. Despite this sign of starvation, the bacterium still synthesized vitamin B12 and supported the growth of a B12-dependent C. reinhardtii mutant. Finally, we showed that bacterial proliferation could be supported solely by the algal lysis that occurred in coculture, highlighting the role of necromass in carbon cycling. Collectively, these results reveal the scarcity of fixed carbon in this microbial trophic relationship (particularly under environmentally relevant light regimes), demonstrate B12 exchange even during bacterial starvation, and underscore the importance of quantitative approaches for assessing metabolic coupling in algal-bacterial interactions.

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