Single-Cell Analysis Reveals Distinct Immune and Smooth Muscle Cell Populations that Contribute to Chronic Thromboembolic Pulmonary Hypertension.

Rationale: Chronic thromboembolic pulmonary hypertension (CTEPH) is a sequela of acute pulmonary embolism (PE) in which the PE remodels into a chronic scar in the pulmonary arteries. This results in vascular obstruction, pulmonary microvasculopathy, and pulmonary hypertension. Objectives: Our current understanding of CTEPH pathobiology is primarily derived from cell-based studies limited by the use of specific cell markers or phenotypic modulation in cell culture. Therefore, our main objective was to identify the multiple cell types that constitute CTEPH thrombusy and to study their dysfunction. Methods: Here we used single-cell RNA sequencing of tissue removed at the time of pulmonary endarterectomy surgery from five patients to identify the multiple cell types. Using in vitro assays, we analyzed differences in phenotype between CTEPH thrombus and healthy pulmonary vascular cells. We studied potential therapeutic targets in cells isolated from CTEPH thrombus. Measurements and Main Results: Single-cell RNA sequencing identified multiple cell types, including macrophages, T cells, and smooth muscle cells (SMCs), that constitute CTEPH thrombus. Notably, multiple macrophage subclusters were identified but broadly split into two categories, with the larger group characterized by an upregulation of inflammatory signaling predicted to promote pulmonary vascular remodeling. CD4+ and CD8+ T cells were identified and likely contribute to chronic inflammation in CTEPH. SMCs were a heterogeneous population, with a cluster of myofibroblasts that express markers of fibrosis and are predicted to arise from other SMC clusters based on pseudotime analysis. Additionally, cultured endothelial, smooth muscle, and myofibroblast cells isolated from CTEPH fibrothrombotic material have distinct phenotypes from control cells with regard to angiogenic potential and rates of proliferation and apoptosis. Last, our analysis identified PAR1 (protease-activated receptor 1) as a potential therapeutic target that links thrombosis to chronic PE in CTEPH, with PAR1 inhibition decreasing SMC and myofibroblast proliferation and migration. Conclusions: These findings suggest a model for CTEPH similar to atherosclerosis, with chronic inflammation promoted by macrophages and T cells driving vascular remodeling through SMC modulation, and suggest new approaches for pharmacologically targeting this disease.

Insights from healthcare academics on facilitating interprofessional education activities.

Facilitators are of paramount importance to the success of interprofessional education (IPE) activities; hence, it is crucial to explore their perspectives and experiences in delivering IPE in Qatar. Using an exploratory case study approach, semi-structured interviews were conducted, in 2018, among faculty members, who had facilitated at least one IPE activity in Qatar, from healthcare professional education programs at Qatar University Colleges of Pharmacy, Medicine, and Health Sciences, Weill Cornell Medicine in Qatar, the University of Calgary in Qatar, and the College of North Atlantic. Interviews were recorded and transcribed verbatim. Inductive thematic content analysis was implemented. Twenty-one interviews were conducted with the following professions represented: medicine (n = 6), pharmacy (n = 5), nursing (n = 4), biomedical science (n = 3), respiratory theory (n = 2) and public health (n = 1). Four main themes emerged from the interviews: drivers to facilitator involvement that included interest and commitment to IPE and awareness of collaborative practice benefits; facilitator participation which was based on facilitator attributes and preparedness and readiness for IPE facilitation; the organizational support in terms of dedicated structure for IPE and IPE design and delivery and; student participation in terms of group dynamics and student engagement. Some key recommendations include having a dedicated unit for IPE, scheduling protected time for IPE, and organizing facilitators' training and debriefing workshops. The facilitators valued and appreciated IPE in preparing students for future collaborative practice. These findings can inform the development of quality and sustainable IPE activities in the future.

The Elution Kinetics of BMP-2, BMP-4, and BMP-7 From a Commercial Human Demineralized Bone Matrix Putty.

Bone morphogenetic proteins (BMPs) are associated with bone extracellular matrix and impart osteoinductive properties to demineralized bone matrix (DBM) grafts. The first step of the osteoinductive process is BMP release from DBM in situ; however, this has not been characterized for human DBM. The authors investigated the release of BMPs 2, 4, and 7 from a clinical human DBM putty (Bonus II DBM, Biomet Inc, Warsaw, IN). The DBM was placed in Sorensen buffer and the BMP concentrations in the Sorensen buffer and guanidine extracts of the DBM were measured concurrently by enzymelinked immunosorbant assay for up to 7 days. The baseline DBM concentrations were BMP-2: 28.1 ±â€Š1.3 ng/g DBM, BMP-4: 0.577 ±â€Š0.056 ng/g DBM, and BMP-7: 92.9 ±â€Š7.5 ng/g DBM. Relative to baseline, the proportions released by 7 days were 11.1%, 3.9%, and 29.3%, respectively. The early (0-8 hour) and late (8-168 hours) elution rates were BMP-2: 0.16 ±â€Š0.24 and 0.0089 ±â€Š0.012 ng/(g DBM hr), and BMP-7: 1.29 ±â€Š2.1 and 0.086 ±â€Š0.039 ng/(g DBM hr), respectively. Little BMP-4 elution occurred over the first 24 hours, with the rate for the remaining interval being 0.00014 ±â€Š0.00021 ng/(g DBM hr). The apparent DBM BMP profiles were counterintuitive in that the concentrations increased from baseline for some, or all, of the 7 days instead of monotonically decreasing. Similar behavior has previously been reported in bovine studies. This provides further evidence that BMPs are associated with at least 2 compartments in DBM differing by their affinity for BMPs and that guanidine extraction of BMPs is not 100% efficient.

The extraction and measurement of bone morphogenetic protein 7 from bovine cortical bone as a function of particle size.

Bone morphogenetic proteins (BMPs), present in parts per billion in bone, endow demineralized bone matrix (DBM) with osteoinductive properties suitable for clinical use. Although BMPs are mainly associated with bone matrix, they also associate with other bone compartments as well, including the mineral phase. The purpose of this study was to gain a more complete understanding of the distribution of BMPs in undemineralized bone. Eleven discrete particle size ranges of bovine cortical bone were prepared, ranging between less than 25 µm and 600 to 710 µm for the smallest and largest sizes, respectively. The bone was extracted with 4-M guanidine-HCl/0.05-M Tris-HCl, and the amount of BMP-7 released was measured with enzyme-linked immunosorbant assay. In addition, 106- to 710-µm bone particles were demineralized and similarly extracted for comparison. The measured BMP-7 content of the DBM was 24.6 ± 1.56 ng/g. The values for bone increased nonlinearly with decreasing particle size, ranging from 1.13 ± 0.50 ng/g for the 600- to 710-µm particles to 4.18 ± 1.14 ng/g for the less than 25-µm particles (P < 0.001). However, modeling the bone particles as solid spheres to estimate total surface area showed that the extracted BMP-7 per unit area was greater for larger particle sizes. These seemingly opposing results suggest that BMPs may become proportionally damaged or altered in response to the increased forces required to generate smaller particles and, as such, may not be detectable with enzyme-linked immunosorbant assay. In addition, minimization of bone particle size is not an effective strategy to approach the BMP availability of DBM.

Comparison for efficacy of general exercises with and without mobilization therapy for the management of adhesive capsulitis of shoulder - An interventional study.

OBJECTIVE: The aim of this work was to evaluate the effectiveness of exercise with manual therapy and exercise alone in adhesive capsulitis of the shoulder. METHOD: This randomized study was conducted at institute of physical medicine and rehabilitation Dow University of Health Sciences, Karachi between January, 2014 and July, 2014. Forty four participant age between 25-40 years were recruited. Twenty two participants were allocated to exercise and manual therapy group and 22 participants were allocated to exercise only group. Exercise and manual therapy group received general exercises and Maitland mobilization on shoulder joint whereas exercise group only received general exercises. Both interventions were carried out 3 times a week for 5 consecutive weeks. Pre and post intervention scores of Visual analogue scale (VAS), range of movement and Shoulder Pain and Disability Index (SPDI) were recorded. Paired sample t-test was used to analyze the results within groups. RESULTS: After 5 weeks of intervention both groups made significant improvements in all outcome measures (p < 0.001). Intra group analysis showed no significant difference between two groups (p > 0.05). Mean VAS and SPADI difference was 2.23 and 22 in General exercise & manual therapy group and 2.33 and 23 in General exercise group respectively. CONCLUSION: Both exercises with manual therapy and exercises alone are equally effective in the management of adhesive capsulits of the shoulder joint.

Sight-threatening ocular manifestations of acute febrile neutrophilic dermatosis (Sweet's syndrome).

Sweet's syndrome is a primarily dermatologic disorder with many features of systemic inflammation. It is generally characterized by a neutrophilic dermatosis in the setting of fever and an elevated white blood cell count. Inflammation has been described to occur in many organ systems including the lung, bone, liver, spleen, brain and eye. Ocular inflammation is a well-known comorbidity that may occur in the setting of Sweet's syndrome, including conjunctivitis, episcleritis, scleritis, iritis and choroiditis, among other forms. In the current article, we have compiled a series of cases that describe three separate patients who demonstrated a rare form of ocular involvement in Sweet's syndrome, retinal vasculitis. The evidence from these three cases and other reports in recent ophthalmologic literature suggest overlapping of ocular manifestations of Sweet's syndrome and the closely related Behçet's disease. It is important to be aware of the sometimes challenging differential between these two disorders and their sight-threatening complications.

Enhancing solubility and stability of piperine using ß-cyclodextrin derivatives: computational and experimental investigations.

Piperine (PP), a natural alkaloid found in black pepper, possesses significant bioactivities. However, its use in pharmaceutical applications is hindered by low water solubility and susceptibility to UV light degradation. To overcome these challenges, we investigated the potential of ß-cyclodextrin (ßCD) and its derivatives with dimethyl (DMßCD), hydroxy-propyl (HPßCD) and sulfobutyl-ether (SBEßCD) substitutions to enhance the solubility and stability of PP. This study employed computational and experimental approaches to examine the complexation between PP and ßCDs. The results revealed the formation of two types of inclusion complexes: the P-form and M-form involving the insertion of piperidine moiety and the methylene-di-oxy-phenyl moiety, respectively. These complexes primarily rely on van der Waals interactions. Among the three derivatives, the PP/SBEßCD complex exhibited the highest stability followed by HPßCD, as attributed to maximum atom contacts and minimal solvent accessibility. Solubility studies confirmed the formation of inclusion complexes in a 1:1 ratio. Notably, the stability constant of the inclusion complex was approximately two-fold higher with SBEßCD and HPßCD compared to ßCD. The DSC thermograms provided confirmation of the formation of the inclusion complex between the host and guest. These findings highlight the potential of ßCD derivatives to effectively encapsulate PP, improving its solubility and presenting new opportunities for its pharmaceutical applications.Communicated by Ramaswamy H. Sarma.

In vitro and in silico studies of the inclusion complexation of 8-bromobaicalein with ß-cyclodextrins.

Baicalein, a flavone derived from Scutellaria baicalensis Georgi, exhibits potent anti-inflammatory, antiviral, and anticancer properties. Its derivative, known as 8-bromobaicalein (BB), has been found to have strong cytotoxic effect on MCF-7 human breast cancer cells. However, its limited solubility in water has hindered its potential for wider applications. To address this issue, we investigated the use of cyclodextrins specifically ßCD, 2,6-di-O-methyl-ß-cyclodextrin (DMßCD), and hydroxypropyl-ß-cyclodextrin (HPßCD) to improve the solubility of BB through inclusion complexation. During 250 ns molecular dynamics simulations, it was found that BB can form inclusion complexes with all ßCDs. These complexes exhibit two distinct orientations: chromone group insertion (C-form) and phenyl group insertion (P-form). The formation of these complexes is primarily driven by van der Waals interactions. DMßCD has the highest number of atom contacts with BB and the lowest solvent accessibility in the hydrophobic cavity. These results coincide with the highest binding affinity from the MM/GBSA-based free energy calculation method. Experimental phase solubility diagrams revealed a 1:1 stoichiometric ratio (AL type) between BB and ßCDs, in which BB/DMßCD showed the highest stability. The formation of inclusion complexes was confirmed by differential scanning calorimetry and scanning electron microscope methods. Additionally, the BB/DMßCD inclusion complex demonstrated significantly higher anticancer activity against MCF-7 human breast cancer cells compared to BB alone. These findings underscore the potential of DMßCD for formulating BB in pharmaceutical and medical applications.

Unveiling a Sour Truth: Acute Pancreatitis Linked to Apple Cider Vinegar Supplement.

Acute pancreatitis, a common gastrointestinal ailment in the United States, often lacks a clear etiology, with one-third of cases deemed idiopathic. We discuss an 84-year-old woman with acute pancreatitis possibly linked to a recently introduced weight loss supplement containing apple cider vinegar. Literature review unveils scant data regarding the risks of acute pancreatitis associated with less rigorously studied and regulated supplements, such as apple cider vinegar products. Considering the morbidity and financial burden associated with acute pancreatitis, there is a pressing need to report and disseminate awareness of diverse etiologies, encompassing drug and supplement-induced cases. This case report endeavors to address this need.

Evaluating solubility, stability, and inclusion complexation of oxyresveratrol with various ß-cyclodextrin derivatives using advanced computational techniques and experimental validation.

Oxyresveratrol (OXY), a natural stilbenoid in mulberry fruits, is known for its diverse pharmacological properties. However, its clinical use is hindered by low water solubility and limited bioavailability. In the present study, the inclusion complexes of OXY with ß-cyclodextrin (ßCD) and its three analogs, dimethyl-ß-cyclodextrin (DMßCD), hydroxypropyl-ß-cyclodextrin (HPßCD) and sulfobutylether-ß-cyclodextrin (SBEßCD), were investigated using in silico and in vitro studies. Molecular docking revealed two binding orientations of OXY, namely, 4',6'-dihydroxyphenyl (A-form) and 5,7-benzenediol ring (B-form). Molecular Dynamics simulations suggested the formation of inclusion complexes with ßCDs through two distinct orientations, with OXY/SBEßCD exhibiting maximum atom contacts and the lowest solvent-exposed area in the hydrophobic cavity. These results corresponded well with the highest binding affinity observed in OXY/SBEßCD when assessed using the MM/GBSA method. Beyond traditional simulation methods, Ligand-binding Parallel Cascade Selection Molecular Dynamics method was employed to investigate how the drug enters and accommodates within the hydrophobic cavity. The in silico results aligned with stability constants: SBEßCD (2060 M-1), HPßCD (1860 M-1), DMßCD (1700 M-1), and ßCD (1420 M-1). All complexes exhibited a 1:1 binding mode (AL type), with SBEßCD enhancing OXY solubility (25-fold). SEM micrographs, DSC thermograms, FT-IR and 1H NMR spectra confirm the inclusion complex formation, revealing novel surface morphologies, distinctive thermal behaviors, and new peaks. Notably, the inhibitory impact on the proliferation of breast cancer cell lines, MCF-7, exhibited by inclusion complexes particularly OXY/DMßCD, OXY/HPßCD, and OXY/SBEßCD were markedly superior compared to that of OXY alone.

3D Printing of Alginate/Chitosan-Based Scaffold Empowered by Tyrosol-Loaded Niosome for Wound Healing Applications: In Vitro and In Vivo Performances.

This study introduces a tyrosol-loaded niosome integrated into a chitosan-alginate scaffold (Nio-Tyro@CS-AL), employing advanced electrospinning and 3D printing techniques for wound healing applications. The niosomes, measuring 185.40 ± 6.40 nm with a polydispersity index of 0.168 ± 0.012, encapsulated tyrosol with an efficiency of 77.54 ± 1.25%. The scaffold's microsized porous structure (600-900 µm) enhances water absorption, promoting cell adhesion, migration, and proliferation. Mechanical property assessments revealed the scaffold's enhanced resilience, with niosomes increasing the compressive strength, modulus, and strain to failure, indicative of its suitability for wound healing. Controlled tyrosol release was demonstrated in vitro, essential for therapeutic efficacy. The scaffold exhibited significant antibacterial activity against Pseudomonas aeruginosa and Staphylococcus aureus, with substantial biofilm inhibition and downregulation of bacterial genes (ndvb and icab). A wound healing assay highlighted a notable increase in MMP-2 and MMP-9 mRNA expression and the wound closure area (69.35 ± 2.21%) in HFF cells treated with Nio-Tyro@CS-AL. In vivo studies in mice confirmed the scaffold's biocompatibility, showing no significant inflammatory response, hypertrophic scarring, or foreign body reaction. Histological evaluations revealed increased fibroblast and macrophage activity, enhanced re-epithelialization, and angiogenesis in wounds treated with Nio-Tyro@CS-AL, indicating effective tissue integration and repair. Overall, the Nio-Tyro@CS-AL scaffold presents a significant advancement in wound-healing materials, combining antibacterial properties with enhanced tissue regeneration, and holds promising potential for clinical applications in wound management.

What is new in adnexal tumors of the skin?

This article reviews the recent dermatopathology literature regarding cutaneous adnexal neoplasms, with emphasis on new and underrecognized entities, "old entities" with new findings, advances in immunohistochemistry, and new findings in relation to inherited disorders associated with cutaneous adnexal neoplasms.

Skin pH: from basic science to basic skin care.

The "acid mantle" is a topic not only of historical interest, but also of clinical significance and has recently been linked to vital stratum corneum function. Despite compelling basic science evidence placing skin pH as a key factor in barrier homeostasis, stratum corneum integrity, and antimicrobial defense, application of the acid mantle concept in clinical care is lacking. We review recent basic science investigations into skin pH, discuss skin disorders characterized by aberrant pH, and finally discuss practical application for preservation of the acid mantle. Recognizing factors that alter skin pH and selecting products that preserve the acid mantle is of prime importance in treating dermatologic patients.

Knowledge and attitude regarding euthanasia among medical students in the public and private medical schools of Karachi.

OBJECTIVE: To assess the awareness about and perception of euthanasia among medical students of Karachi. METHOD: The cross-sectional study was conducted from December 2011 to March 2012 among students of private-sector and one public-sector medical college in Karachi. Data was analysed using SPSS version 17, and associations were worked out using chi-square test. RESULTS: Out of the 493 students, 226 (46%) were from the matriculation system and 194 (39%) from the Cambridge system, while the remaining 15% were from the American High School. The male-female ratio was 1:3. There were 284 (58%) students from the private medical college. Majority of the private medical school students (n = 284; 99.6%) knew about euthanasia, compared to the public-sector facility where only 161 (77%) knew of it. Of the total, 405 (82%) students agreed that it is physician-assisted suicide; 255 (52%) agreed to the idea of palliative care, claiming it was sufficient to maintain life; 226 (54%) disagreed that a doctor should not be allowed to administer a lethal dose while only 162 (33%) agreed to the idea of it; 285 (58%) disagreed that a law regarding the practice of euthanasia should not be introduced, whereas 134 (27%) agreed to it; 70 (14%) agreed to the practice of euthanasia, while 311 (63%) disagreed, mostly for religious reasons. CONCLUSION: The awareness of euthanasia was high, but a very small proportion of students approved of it. There is need to include palliative care and euthanasia in the Behavioural Science module in the under-graduation programme of both public and private medical schools.

Cellular mechanisms in the pathogenesis of interstitial lung diseases.

The interstitial lung diseases (ILDs) are a large, heterogeneous group of several hundred generally rare pulmonary pathologies, which show injury, inflammation and/or scarring in the lung. Although the aetiology of these disorders remains largely unknown, various cellular mechanisms have an important role in pathogenesis of fibrosis on the background of occupational, environmental and genetic factors. We have tried to provide new insights into the interactions and cellular contributions, analysing the roles of various cells in the pathogenesis of idiopathic pulmonary fibrosis.

Decentering the use of police: An abolitionist approach to safety planning in psychotherapy.

The dominant narrative in much of the world, but especially the West, is that public safety and security are provided by policing. Psychotherapy invests in this dominant narrative via its reliance on emergency services provided by the state, such as 911 and police, to pursue the safety of clients and the larger society. However, the long-documented history of oppressive systems of policing suggest that these dominant narratives operate to protect powerful groups while surveilling and policing marginalized people, but particularly Black and Brown communities. As such, critical and abolitionist movements have rejected the idea that policing provides safety and have sought out alternative methods for ensuring community wellness and safety. Although the field of psychology has broadly expressed interest in growing its critical lens and interrupting systems of power, very little has directly addressed how carceral logics influence psychotherapy practice, and how this influences the client's sense of safety in therapy. This manuscript argues for an abolitionist approach to informed consent and safety planning in psychotherapy to address the disparate ways that clients, and especially marginalized clients such as Black and Brown people, experience psychotherapy's traditional use of systems of policing and state authority. Clinical illustrations are provided and future directions are discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Enhancing solubility and stability of sorafenib through cyclodextrin-based inclusion complexation: in silico and in vitro studies.

Sorafenib (SOR) is an oral multikinase inhibitor that effectively hampers the growth and spread of cancer cells by targeting angiogenesis and proliferation. However, SOR tablets (Nexavar) have limited oral bioavailability, ranging from 38% to 49%, due to their low water solubility. To address this issue, cyclodextrins (CDs), widely used to enhance the solubility and stability of lipophilic drugs by encapsulating them within their molecular structure, were considered in this study. We focused on ß-cyclodextrin (ßCD) and its derivatives, including hydroxypropyl-ß-cyclodextrin (HPßCD), dimethyl-ß-cyclodextrin (DMßCD), sulfobutylether-ß-cyclodextrin (SBEßCD), and compared them with γ-cyclodextrin (γCD) for generating inclusion complexes with SOR. The 200 ns molecular dynamics simulations revealed that SOR could form inclusion complexes with all CDs in two possible orientations: pyridine group insertion (P-form) and chlorobenzotrifluoride group insertion (C-form), primarily driven by van der Waals interactions. Among the four ßCD derivatives studied, SOR exhibited the highest number of atom contacts with SBEßCD and demonstrated the lowest solvent accessibility within the hydrophobic cavity of SBEßCD. These findings correlated with the highest binding affinity of SOR/SBEßCD complex determined by SIE, MM/GBSA, and MM/PBSA methods. Experimental results further supported our computational predictions, in which SBEßCD exhibited a stability constant of 940 M-1 at 25 °C, surpassing ßCD's stability constant of 210 M-1. Taken together, our results suggest that the modified CDs, particularly SBEßCD, hold promising potential as an efficient molecular encapsulating agent for SOR, offering improved solubility and stability for this lipophilic drug.

A systematic review: Virtual-reality-based techniques for human exercises and health improvement.

Virtual Reality (VR) has emerged as a new safe and efficient tool for the rehabilitation of many childhood and adulthood illnesses. VR-based therapies have the potential to improve both motor and functional skills in a wide range of age groups through cortical reorganization and the activation of various neuronal connections. Recently, the potential for using serious VR-based games that combine perceptual learning and dichoptic stimulation has been explored for the rehabilitation of ophthalmological and neurological disorders. In ophthalmology, several clinical studies have demonstrated the ability to use VR training to enhance stereopsis, contrast sensitivity, and visual acuity. The use of VR technology provides a significant advantage in training each eye individually without requiring occlusion or penalty. In neurological disorders, the majority of patients undergo recurrent episodes (relapses) of neurological impairment, however, in a few cases (60-80%), the illness progresses over time and becomes chronic, consequential in cumulated motor disability and cognitive deficits. Current research on memory restoration has been spurred by theories about brain plasticity and findings concerning the nervous system's capacity to reconstruct cellular synapses as a result of interaction with enriched environments. Therefore, the use of VR training can play an important role in the improvement of cognitive function and motor disability. Although there are several reviews in the community employing relevant Artificial Intelligence in healthcare, VR has not yet been thoroughly examined in this regard. In this systematic review, we examine the key ideas of VR-based training for prevention and control measurements in ocular diseases such as Myopia, Amblyopia, Presbyopia, and Age-related Macular Degeneration (AMD), and neurological disorders such as Alzheimer, Multiple Sclerosis (MS) Epilepsy and Autism spectrum disorder. This review highlights the fundamentals of VR technologies regarding their clinical research in healthcare. Moreover, these findings will raise community awareness of using VR training and help researchers to learn new techniques to prevent and cure different diseases. We further discuss the current challenges of using VR devices, as well as the future prospects of human training.