Group 5 Pulmonary Hypertension Associated With T-Cell Large Granular Lymphocytic Leukemia: Hemodynamics and Treatment.

Group 5 pulmonary hypertension (PH) encompasses diverse diseases, with a few cases linking it to T-cell large granular lymphocytic (LGL) leukemia. We report a case of a 76-year-old woman, diagnosed with LGL leukemia and concomitant PH, treated with oral triple pulmonary arterial hypertension (PAH) therapy. She initially presented with dyspnea on exertion; evaluation revealed severe precapillary PH. Implementing cyclophosphamide for leukemia along with tadalafil and macitentan for PH led to sustained symptomatic and hemodynamic improvement for over 3 years. At that time, deterioration in PH prompted the addition of selexipag, resulting in sustained clinical improvement for an additional 5 years. This case exemplifies the potential for sustained benefits of PAH therapy in leukemia-associated PH and highlights the need for continued research on the mechanistic relationship between LGL leukemia and PH, with the hope of identifying new management strategies.

[n]Cycloparaphenylenes as Compatible Fluorophores for Melt Electrowriting.

Fluorescent probes are an indispensable tool in the realm of bioimaging technologies, providing valuable insights into the assessment of biomaterial integrity and structural properties. However, incorporating fluorophores into scaffolds made from melt electrowriting (MEW) poses a challenge due to the sustained, elevated temperatures that this processing technique requires. In this context, [n]cycloparaphenylenes ([n]CPPs) serve as excellent fluorophores for MEW processing with the additional benefit of customizable emissions profiles with the same excitation wavelength. Three fluorescent blends are used with distinct [n]CPPs with emission wavelengths of either 466, 494, or 533 nm, identifying 0.01 wt% as the preferred concentration. It is discovered that [n]CPPs disperse well within poly(ε-caprolactone) (PCL) and maintain their fluorescence even after a week of continuous heating at 80 °C. The [n]CPP-PCL blends show no cytotoxicity and support counterstaining with commonly used DAPI (Ex/Em: 359 nm/457 nm), rhodamine- (Ex/Em: 542/565 nm), and fluorescein-tagged (Ex/Em: 490/515 nm) phalloidin stains. Using different color [n]CPP-PCL blends, different MEW fibers are sequentially deposited into a semi-woven scaffold and onto a solution electrospun membrane composed of [8]CPP-PCL as a contrasting substrate for the [10]CPP-PCL MEW fibers. In general, [n]CPPs are potent fluorophores for MEW, providing new imaging options for this technology.

Pulmonary embolism versus pulmonary vasculitis in Hughes-Stovin syndrome: Characteristic computed tomography pulmonary angiographic findings and diagnostic and therapeutic implications. HSS International Study Group.

BACKGROUND AND AIM: Hughes-Stovin syndrome (HSS) is a rare systemic vasculitis with widespread venous/arterial thrombosis and pulmonary vasculitis. Distinguishing between pulmonary embolism (PE) and in-situ thrombosis in the early stages of HSS is challenging. The aim of the study is to compare clinical, laboratory, and computed tomography pulmonary angiography (CTPA) characteristics in patients diagnosed with PE versus those with HSS. METHODS: This retrospective study included 40 HSS patients with complete CTPA studies available, previously published by the HSS study group, and 50 patients diagnosed with PE from a single center. Demographics, clinical and laboratory findings, vascular thrombotic events, were compared between both groups. The CTPA findings were reviewed, with emphasis on the distribution, adherence to the mural wall, pulmonary infarction, ground glass opacification, and intra-alveolar hemorrhage. Pulmonary artery aneurysms (PAAs) in HSS were assessed and classified. RESULTS: The mean age of HSS patients was 35 ± 12.3 years, in PE 58.4 ± 17 (p < 0.0001). Among PE 39(78 %) had co-morbidities, among HSS none. In contrast to PE, in HSS both major venous and arterial thrombotic events are seen.. Various patterns of PAAs were observed in the HSS group, which were entirely absent in PE. Parenchymal hemorrhage was also more frequent in HSS compared to PE (P < 0.001). CONCLUSION: Major vascular thrombosis with arterial aneurysms formation are characteristic of HSS. PE typically appear loosely-adherent and mobile whereas "in-situ thrombosis" seen in HSS is tightly-adherent to the mural wall. Mural wall enhancement and PAAs are distinctive pulmonary findings in HSS. The latter findings have significant therapeutic ramifications.

Factors associated with discontinuation of treatment for pulmonary arterial hypertension in the United States.

Information on factors leading to pulmonary arterial hypertension (PAH) treatment discontinuation is limited. This study analyzed 12,902 new PAH medication users to identify predictors of treatment discontinuation. Treatment by accredited pulmonary hypertension centers and combination therapy with PAH agents from different classes were less likely to result in discontinuation.

Multicolor Long-Term Single-Particle Tracking Using 10 nm Upconverting Nanoparticles.

Single-particle tracking (SPT) is a powerful technique to unveil molecular behaviors crucial to the understanding of many biological processes, but it is limited by factors such as probe photostability and spectral orthogonality. To overcome these limitations, we develop upconverting nanoparticles (UCNPs), which are photostable over several hours at the single-particle level, enabling long-term multicolor SPT. We investigate the brightness of core-shell UCNPs as a function of inert shell thickness to minimize particle size while maintaining sufficient signal for SPT. We explore different rare-earth dopants to optimize for the brightest probes and find that UCNPs doped with 2% Tm3+/30% Yb3+, 10% Er3+/90% Yb3+, and 15% Tm3+/85% Yb3+ represent the optimal probes for blue, green, and near-infrared emission, respectively. The multiplexed 10 nm probes enable three-color single-particle tracking on live HeLa cells for tens of minutes using a single, near-infrared excitation source. These photostable and multiplexed probes open new avenues for numerous biological applications.

Non-CG DNA methylation and MeCP2 stabilize repeated tuning of long genes that distinguish closely related neuron types.

The extraordinary diversity of neuron types in the mammalian brain is delineated at the highest resolution by subtle gene expression differences that may require specialized molecular mechanisms to be maintained. Neurons uniquely express the longest genes in the genome and utilize neuron-enriched non-CG DNA methylation (mCA) together with the Rett syndrome protein, MeCP2, to control gene expression, but the function of these unique gene structures and machinery in regulating finely resolved neuron type-specific gene programs has not been explored. Here, we employ epigenomic and spatial transcriptomic analyses to discover a major role for mCA and MeCP2 in maintaining neuron type-specific gene programs at the finest scale of cellular resolution. We uncover differential susceptibility to MeCP2 loss in neuronal populations depending on global mCA levels and dissect methylation patterns and intragenic enhancer repression that drive overlapping and distinct gene regulation between neuron types. Strikingly, we show that mCA and MeCP2 regulate genes that are repeatedly tuned to differentiate neuron types at the highest cellular resolution, including spatially resolved, vision-dependent gene programs in the visual cortex. These repeatedly tuned genes display genomic characteristics, including long length, numerous intragenic enhancers, and enrichment for mCA, that predispose them to regulation by MeCP2. Thus, long gene regulation by the MeCP2 pathway maintains differential gene expression between closely-related neurons to facilitate the exceptional cellular diversity in the complex mammalian brain.

Severe pulmonary hypertension-interstitial lung disease presenting as right ventricular failure: stabilisation with intravenous prostacyclin and maintenance with inhaled prostacyclin.

Background: Pulmonary hypertension (PH) leads to increased morbidity and mortality in interstitial lung disease (ILD). While the INCREASE trial highlighted the use of inhaled prostacyclin in PH-ILD patients, such therapy may be inadequate when right ventricular failure (RVF) is also present. In this study, we report the use of intravenous prostacyclin in three PH-ILD patients to stabilise right ventricular (RV) function, with a subsequent transition to maintenance therapy with inhaled prostacyclin. Methods: We evaluated three consecutive PH-ILD patients with RVF. RV afterload and pulmonary vascular resistance (PVR) were treated with intravenous prostacyclin during the induction phase of the therapy. Patients transitioned from intravenous prostacyclin to the maintenance phase of the treatment with inhaled prostacyclin once three transition criteria were met: cardiac index (CI) >2 L·min-1·m-2, PVR <7 Wood units (WU) and tricuspid annular plane systolic excursion (TAPSE) change >1 mm or TAPSE >1.6 cm. Results: Pre-treatment parameters for the three patients were a mean PVR of 14.3 WU, a mean Fick CI of 1.8 L·min-1·m-2 and a mean TAPSE of 1.4 cm. The average intravenous prostacyclin dose at the time of transition to maintenance therapy was 20.7 ng·kg-1·m-2 of treprostinil. At 3-months follow-up, the mean PVR was 6.3 WU, Fick CI 2.2 L·min-1·m-2 and TAPSE 1.7 cm. Conclusion: This case series of three PH-ILD patients with RVF introduces the concept of an initial intravenous prostacyclin induction phase, followed by a transition to maintenance therapy with inhaled prostacyclin. Further development of this treatment algorithm with a refinement of the transition criteria, potential testing in a clinical trial and a longer-term follow-up period is warranted to improve the outcomes of advanced PH-ILD patients with concomitant RVF.

Mild Traumatic Brain Injury and the Auditory System: An Overview of the Mechanisms, Clinical Presentations, and Current Diagnostic Modalities.

The acute and long-term consequences of mild traumatic brain injury (mTBI) are far reaching. Though it may often be overlooked due to the now expansive field of research dedicated to understanding the consequences of mTBI on the brain, recent work has revealed that substantial changes in the vestibulo-auditory system can also occur due to mTBI. These changes, termed "labyrinthine" or "cochlear concussion," include hearing loss, vertigo, and tinnitus that develop after mTBI in the setting of an intact bony labyrinthine capsule (as detected on imaging). In the review that follows, we focus our discussion on the effects of mTBI on the peripheral structures and pathways of the auditory and vestibular systems. Although the effects of indirect trauma (e.g., noise and blast trauma) have been well-investigated, there exists a profound need to improve our understanding of the effects of direct head injury (such as mTBI) on the auditory and vestibular systems. Our aim is to summarize the current evidentiary foundation upon which labyrinthine and/or cochlear concussion are based to shed light on the ways in which clinicians can refine the existing modalities used to diagnose and treat patients experiencing mTBI as it relates to hearing and balance.

Disease characteristics, treatments, and outcomes of patients with pulmonary arterial hypertension treated with selexipag in real-world settings from the SPHERE registry (SelexiPag: tHe usErs dRug rEgistry).

BACKGROUND: Selexipag is an oral prostacyclin receptor agonist, indicated for pulmonary arterial hypertension to delay disease progression and reduce the risk of pulmonary arterial hypertension-related hospitalization. SelexiPag: tHe usErs dRug rEgistry (NCT03278002) was a US-based, prospective, real-world registry of selexipag-treated patients. METHODS: Adults with pulmonary hypertension (enrolled 2016-2020) prescribed selexipag were followed for ≤18 months, with data collected at routine clinic visits. Patients were defined as newly or previously initiated if they had started selexipag ≤60 days or >60 days, respectively, before enrollment. RESULTS: The registry included 829 patients (430 newly initiated, 399 previously initiated; 759 with pulmonary arterial hypertension), of whom 55.6% were World Health Organization functional class (FC) 3/4; 57.3% were intermediate or high risk per Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0. In patients with pulmonary arterial hypertension, 18-month discontinuation rates for adverse events were 22.0%, 32.0%, and 11.9%, and 18-month survival rates were 89.4%, 84.2%, and 94.5% in the overall, newly, and previously initiated patient populations, respectively. From baseline to month 18, most patients had stable or improved FC and stable or improved REVEAL 2.0 risk category status. Discontinuation for adverse events, hospitalization, and survival were similar regardless of patients' individually tolerated selexipag maintenance dose. No new safety signals were identified. CONCLUSIONS: In this real-world analysis of patients initiating selexipag, most patients had stable or improved FC and REVEAL 2.0 risk category. Similar to the GRIPHON trial, outcomes with selexipag in this real-world study were comparable across maintenance dose strata, with no new safety signals.

MeCP2 represses the activity of topoisomerase IIß in long neuronal genes.

A unique signature of neurons is the high expression of the longest genes in the genome. These genes have essential neuronal functions, and disruption of their expression has been implicated in neurological disorders. DNA topoisomerases resolve DNA topological constraints and facilitate neuronal long gene expression. Conversely, the Rett syndrome protein, methyl-CpG-binding protein 2 (MeCP2), can transcriptionally repress long genes. How these factors regulate long genes is not well understood, and whether they interact is not known. Here, we identify and map a functional interaction between MeCP2 and topoisomerase IIß (TOP2ß) in mouse neurons. We profile neuronal TOP2ß activity genome wide, detecting enrichment at regulatory regions and gene bodies of long genes, including MeCP2-regulated genes. We show that loss and overexpression of MeCP2 alter TOP2ß activity at MeCP2-regulated genes. These findings uncover a mechanism of TOP2ß inhibition by MeCP2 in neurons and implicate TOP2ß dysregulation in disorders caused by MeCP2 disruption.

Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional deficits.

Phenotypic heterogeneity in monogenic neurodevelopmental disorders can arise from differential severity of variants underlying disease, but how distinct alleles drive variable disease presentation is not well understood. Here, we investigate missense mutations in DNA methyltransferase 3A (DNMT3A), a DNA methyltransferase associated with overgrowth, intellectual disability, and autism, to uncover molecular correlates of phenotypic heterogeneity. We generate a Dnmt3aP900L/+ mouse mimicking a mutation with mild to moderate severity and compare phenotypic and epigenomic effects with a severe R878H mutation. P900L mutants exhibit core growth and behavioral phenotypes shared across models but show subtle epigenomic changes, while R878H mutants display extensive disruptions. We identify mutation-specific dysregulated genes that may contribute to variable disease severity. Shared transcriptomic disruption identified across mutations overlaps dysregulation observed in other developmental disorder models and likely drives common phenotypes. Together, our findings define central drivers of DNMT3A disorders and illustrate how variable epigenomic disruption contributes to phenotypic heterogeneity in neurodevelopmental disease.

Towards a comprehensive regulatory map of Mammalian Genomes.

Genome mapping studies have generated a nearly complete collection of genes for the human genome, but we still lack an equivalently vetted inventory of human regulatory sequences. Cis-regulatory modules (CRMs) play important roles in controlling when, where, and how much a gene is expressed. We developed a training data-free CRM-prediction algorithm, the Mammalian Regulatory MOdule Detector (MrMOD) for accurate CRM prediction in mammalian genomes. MrMOD provides genome position-fixed CRM models similar to the fixed gene models for the mouse and human genomes using only genomic sequences as the inputs with one adjustable parameter - the significance p-value. Importantly, MrMOD predicts a comprehensive set of high-resolution CRMs in the mouse and human genomes including all types of regulatory modules not limited to any tissue, cell type, developmental stage, or condition. We computationally validated MrMOD predictions used a compendium of 21 orthogonal experimental data sets including thousands of experimentally defined CRMs and millions of putative regulatory elements derived from hundreds of different tissues, cell types, and stimulus conditions obtained from multiple databases. In ovo transgenic reporter assay demonstrates the power of our prediction in guiding experimental design. We analyzed CRMs located in the chromosome 17 using unsupervised machine learning and identified groups of CRMs with multiple lines of evidence supporting their functionality, linking CRMs with upstream binding transcription factors and downstream target genes. Our work provides a comprehensive base pair resolution annotation of the functional regulatory elements and non-functional regions in the mammalian genomes.

Changes in nerve growth factor signaling in female mice with cyclophosphamide-induced cystitis.

IC/BPS is a chronic inflammatory pelvic pain syndrome characterized by lower urinary tract symptoms including unpleasant sensation (pain, pressure, or discomfort) in the suprapubic or bladder area, as well as increased urinary frequency and urgency, and decreased bladder capacity. While its etiology remains unknown, increasing evidence suggests a role for changes in nerve growth factor (NGF) signaling. However, NGF signaling is complex and highly context dependent. NGF activates two receptors, TrkA and p75NTR, which activate distinct but overlapping signaling cascades. Dependent on their coexpression, p75NTR facilitates TrkA actions. Here, we show effects of CYP treatment and pharmacological inhibition of p75NTR (via LM11A-31) and TrkA (ARRY-954) on NGF signaling-related proteins: NGF, TrkA, phosphorylated (p)-TrkA, p75NTR, p-ERK1/2, and p-JNK. Cystitis conditions were associated with increased urothelial NGF expression and decreased TrkA and p75NTR expression as well as altering their co-expression ratio; phosphorylation of ERK1/2 and JNK were also altered. Both TrkA and p75NTR inhibition affected the activation of signaling pathways downstream of TrkA, supporting the hypothesis that NGF actions during cystitis are primarily TrkA-mediated. Our findings, in tandem with our recent companion paper demonstrating the effects of TrkA, TrkB, and p75NTR inhibition on bladder function in a mouse model of cystitis, highlight a variety of potent therapeutic targets and provide further insight into the involvement of NGF signaling in sustained conditions of bladder inflammation.

The PH-ILD Detection tool: External validation and use in patients with ILD.

Pulmonary hypertension (PH) results in increased morbidity and mortality in patients with interstitial lung disease (ILD). Early recognition of PH in this population is essential for planning diagnostic testing, initiating therapy, and evaluating for lung transplantation. The previously developed PH-ILD Detection tool has significant potential in the evaluation and treatment of ILD patients; the aim of this study was to validate the tool in an independent, multicenter cohort of patients. We conducted a retrospective review of prospectively collected data from 161 ILD patients. Patients were stratified into low- (n = 78, 48.4%), intermediate- (n = 54, 33.5%), and high-risk (n = 29, 18.0%) groups based on the score obtained with the tool. Intermediate- and high-risk patients underwent follow-up echocardiogram (TTE); 49.4% (n = 41) had an abnormal TTE suggestive of underlying PH. These patients underwent right heart catheterization; PH-ILD was diagnosed in 73.2% (n = 30) of these cases. The PH-ILD Detection tool has a sensitivity of 93.3%, specificity of 90.9%, and area-under-the-curve of 0.921 for diagnosing PH in ILD patients, validating the findings from the original study and establishing the tool as a fundamental resource for early recognition of PH in ILD patients.

Cogan Syndrome: A Case Study and Review of the Literature.

Cogan syndrome is an autoimmune disease characterized by vestibular symptoms, bilateral sensorineural hearing loss, and inflammatory ocular manifestations, which may be accompanied by systemic vasculitis. We herein present the case of a patient with bilateral sensorineural hearing loss who presented with pain over her cochlear implantation incision site. She was later found to have evidence of ocular disease and underlying vasculitis leading to a diagnosis of Cogan syndrome.

Characteristics of patients with pulmonary arterial hypertension from an innovative, comprehensive real-world patient data repository.

Pulmonary arterial hypertension (PAH) is a rare, life-limiting disease. PAH registries provide real-world data that complement clinical trial data and inform treatment decisions. The TRIO comprehensive, integrated patient data repository (TRIO CIPDR), is an innovative US repository capturing data on contemporary patients diagnosed with pulmonary hypertension and receiving US Food and Drug Administration-approved PAH therapies. This repository uniquely combines clinical data from electronic medical records with the ability to track drug-prescription and drug-dispensing characteristics, and includes 946 adult patients with PAH (data collected January 2019 to December 2020) enrolled from nine representative US specialist tertiary care centers. Potentially eligible patients were identified based on dispensing data from specialty pharmacies. Hemodynamic and clinical data, as well as dispensing information on prescribed PAH medications, were provided by tertiary centers. At enrollment, 75% of patients were female, 67% were White, median age at PAH diagnosis was 53 years (median time from diagnosis to enrollment was 5 years), and 37% were obese. Comorbidity profiles were as expected for a PAH population, although the proportion with atrial fibrillation (34%) was higher than expected. Overall, 38% of patients had idiopathic PAH and 30% had connective tissue disease-related PAH. Among 917 patients receiving PAH-specific therapy, 40% were on monotherapy, 43% on dual therapy, and 17% on triple therapy. Longitudinal data from this repository will allow tracking of the PAH treatment journey in relation to clinical characteristics and outcomes.

A proposed association between subjective nonpulsatile tinnitus and migraine.

Objective: Tinnitus is defined as the perception of sound in the absence of an external source. We propose the hypothesis that migraine can cause exacerbation of tinnitus in some patients. Methods: English literature from PubMed has been reviewed. Results: Studies have reported a high prevalence of cochlear symptoms in patients with migraine headaches and up to 45% of tinnitus patients have been shown to concomitantly suffer from migraine. Both conditions are thought to stem from central nervous system disturbances, involving disruption of the auditory and trigeminal nerve pathways. One proposed mechanism of this association is the modulation of sound sensitivity by trigeminal nerve activation of the auditory cortex during migraine attacks, resulting in tinnitus fluctuation in some patients. Increased brain and inner ear vascular permeability resulting from trigeminal nerve inflammation, can also cause observed headache and auditory symptoms. Tinnitus and migraine also share a number of symptom triggers including stress, sleep disturbances, and dietary factors. These shared features may help explain promising results of migraine therapies for the treatment of tinnitus. Conclusion: Given the complex association between tinnitus and migraine, further investigation is needed to identify the underlying mechanisms and determine the optimal treatment strategies for managing migraine-related tinnitus patients.