bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of cyclin-dependent kinase 7 mitigates doxorubicin cardiotoxicity and enhances anticancer efficacy
Authors: Chen Jingrui , Wei Jing , Xia Peng , Liu Yuening , Belew Mahder Dawit , Toohill Ryan , Wu Boyang Jason , Cheng Zhaokang
Published: April 2024

Aims

The anthracycline family of anticancer agents such as doxorubicin (DOX) can induce apoptotic death of cardiomyocytes and cause cardiotoxicity. We previously reported that DOX-induced apoptosis is accompanied by cardiomyocyte cell cycle re-entry. Cell cycle progression requires cyclin-dependent kinase 7 (CDK7)-mediated activation of downstream cell cycle CDKs. This study aims to determine whether CDK7 can be targeted for cardioprotection during anthracycline chemotherapy.

Methods and results

DOX exposure induced CDK7 activation in mouse heart and isolated cardiomyocytes. Cardiac-specific ablation of Cdk7 attenuated DOX-induced cardiac dysfunction and fibrosis. Treatment with the covalent CDK7 inhibitor THZ1 also protected against DOX-induced cardiomyopathy and apoptosis. DOX treatment induced activation of the proapoptotic CDK2–FOXO1–Bim axis in a CDK7-dependent manner. In response to DOX, endogenous CDK7 directly bound and phosphorylated CDK2 at Thr160 in cardiomyocytes, leading to full CDK2 kinase activation. Importantly, inhibition of CDK7 further suppressed tumour growth when used in combination with DOX in an immunocompetent mouse model of breast cancer.

Conclusion

Activation of CDK7 is necessary for DOX-induced cardiomyocyte apoptosis and cardiomyopathy. Our findings uncover a novel proapoptotic role for CDK7 in cardiomyocytes. Moreover, this study suggests that inhibition of CDK7 attenuates DOX-induced cardiotoxicity but augments the anticancer efficacy of DOX. Therefore, combined administration of CDK7 inhibitor and DOX may exhibit diminished cardiotoxicity but superior anticancer activity.
Aquaporins enriched in endothelial vacuole membrane regulate the diameters of microvasculature in hyperglycaemia
Authors: Chen Changsheng , Qin Yinyin , Xu Yidan , Wang Xiaoning , Lei Wei , Shen Xiaozhong , Chen Lixun , Wang Linnong , Gong Jie , Wang Yongming , Hu Shijun , Liu Dong
Published: April 2024

Aims

In patients with diabetic microvascular complications, decreased perfusion or vascular occlusion, caused by reduced vascular diameter, is a common characteristic that will lead to insufficient blood supply. Yet, the regulatory mechanism and effective treatment approach remain elusive.

Methods and results

Our initial findings revealed a notable decrease in the expression of human AQP1 in both diabetic human retina samples (49 healthy vs. 54 diabetic samples) and high-glucose-treated human retinal microvascular endothelial cells. Subsequently, our investigations unveiled a reduction in vascular diameter and compromised perfusion within zebrafish embryos subjected to high glucose treatment. Further analysis indicated a significant down-regulation of two aquaporins, aqp1a.1 and aqp8a.1, which are highly enriched in ECs and are notably responsive to hyperglycaemic conditions. Intriguingly, the loss of function of aqp1a.1 and/or aqp8a.1 resulted in a reduction of intersegmental vessel diameters, effectively mirroring the phenotype observed in the hyperglycaemic zebrafish model. The overexpression of aqp1a.1/aqp8a.1 in zebrafish ECs led to notable enlargement of microvascular diameters. Moreover, the reduced vessel diameters resulting from high-glucose treatment were effectively rescued by the overexpression of these aquaporins. Additionally, both aqp1a.1 and apq8a.1 were localized in the intracellular vacuoles in cultured ECs as well as the ECs of sprouting ISVs, and the loss of Aqps caused the reduction of those vacuoles, which was required for lumenization. Notably, while the loss of AQP1 did not impact EC differentiation from human stem cells, it significantly inhibited vascular formation in differentiated ECs.

Conclusion

EC-enriched aquaporins regulate the diameter of blood vessels through an intracellular vacuole-mediated process under hyperglycaemic conditions. These findings collectively suggest that aquaporins expressed in ECs hold significant promise as potential targets for gene therapy aimed at addressing vascular perfusion defects associated with diabetes.
Mechanisms of ischaemia-induced arrhythmias in hypertrophic cardiomyopathy: a large-scale computational study
Authors: Coleman James A , Doste Ruben , Ashkir Zakariye , Coppini Raffaele , Sachetto Rafael , Watkins Hugh , Raman Betty , Bueno-Orovio Alfonso
Published: April 2024

Aims

Lethal arrhythmias in hypertrophic cardiomyopathy (HCM) are widely attributed to myocardial ischaemia and fibrosis. How these factors modulate arrhythmic risk remains largely unknown, especially as invasive mapping protocols are not routinely used in these patients. By leveraging multiscale digital twin technologies, we aim to investigate ischaemic mechanisms of increased arrhythmic risk in HCM.

Methods and results

Computational models of human HCM cardiomyocytes, tissue, and ventricles were used to simulate outcomes of Phase 1A acute myocardial ischaemia. Cellular response predictions were validated with patch-clamp studies of human HCM cardiomyocytes (n = 12 cells, N = 5 patients). Ventricular simulations were informed by typical distributions of subendocardial/transmural ischaemia as analysed in perfusion scans (N = 28 patients). S1-S2 pacing protocols were used to quantify arrhythmic risk for scenarios in which regions of septal obstructive hypertrophy were affected by (i) ischaemia, (ii) ischaemia and impaired repolarization, and (iii) ischaemia, impaired repolarization, and diffuse fibrosis. HCM cardiomyocytes exhibited enhanced action potential and abnormal effective refractory period shortening to ischaemic insults. Analysis of ∼75 000 re-entry induction cases revealed that the abnormal HCM cellular response enabled establishment of arrhythmia at milder ischaemia than otherwise possible in healthy myocardium, due to larger refractoriness gradients that promoted conduction block. Arrhythmias were more easily sustained in transmural than subendocardial ischaemia. Mechanisms of ischaemia–fibrosis interaction were strongly electrophysiology dependent. Fibrosis enabled asymmetric re-entry patterns and break-up into sustained ventricular tachycardia.

Conclusion

HCM ventricles exhibited an increased risk to non-sustained and sustained re-entry, largely dominated by an impaired cellular response and deleterious interactions with the diffuse fibrotic substrate.
Work Productivity Impairment in Persons with Inflammatory Bowel Diseases: A Systematic Review and Meta-analysis
Authors: Youssef Michael , Hossein-Javaheri Nariman , Hoxha Tedi , Mallouk Christina , Tandon Parul
Published: April 2024

Background and Aims

The impact of inflammatory bowel disease [IBD] on work productivity remains unclear. In this systematic review and meta-analysis, we quantify work-related outcomes and employment data among persons with IBD.

Methods

A systematic literature search was conducted in MEDLINE, EMBASE, the Cochrane library, Scopus, ProQuest, and clinicaltrials.gov from inception to February 2023, to identify studies on work productivity in persons with IBD aged > 18 years. Work productivity was defined primarily by the Work Productivity and Activity Impairment [WPAI] questionnaire which includes absenteeism, presenteeism, overall work impairment, and non-work activity impairment. In addition, we included data on employment, sick leaves, disability pensions, and indirect costs due to productivity loss. Pooled effect analysis was conducted using a random-effects model for pooled estimates of continuous and proportional data with 95% confidence intervals.

Results

Among all patients with IBD, the pooled estimates were 16.4% for absenteeism, 35.9% for presenteeism, 39.4% for overall work impairment, and 46.0% for non-work activity impairment. Indirect costs from overall work impairment were 5131.09 euros/patient/year. Only two-thirds of IBD patients were employed, and one in three lost their jobs due to IBD. Among those employed, 39.5% report sick days, 21.3% report work disability, and 12.3% receive disability pensions. Most studies demonstrate clinically meaningful improvements in work productivity with medical and/or surgical therapies.

Conclusion

Persons with IBD experience significant work impairment and associated indirect costs. This highlights the need for appropriate workplace accommodations and timely medical therapy to alleviate the burden of disease and improve work outcomes.
Bridge to transplant in single-ventricle anatomy: subpulmonary support with EXCOR ventricular assist device associated with pulmonary artery reconstruction
Authors: Domínguez del Castillo José Joaquín , Merino Cejas Carlos Manuel , Gómez Guzmán Elena , Frías Pérez Manuel Angel
Published: April 2024

Patients with a single ventricle circulation continue to be a challenge for a heart transplant. The patients in this cohort, often in poor clinical condition with frequent hepatic and renal impairment having undergone previous multiple surgical procedures, are often allosensitive and consequently have an increased risk of post-transplant complications. Although the most recently published series results are improved, this group of patients, with preserved ventricular function, continues to have a higher mortality rate. Moreover, the operation can be complicated by anatomical differences among the pulmonary arteries. This case report presents a child with tricuspid atresia and pulmonary vascular resistance contraindicating Fontan surgery, unfavourable anatomy of the central pulmonary arteries and in poor clinical condition. An EXCOR ventricular assist device (Berlin Heart) was used for sub- pulmonary mechanical circulatory support and pulmonary bifurcation reconstruction, as a bridge to a transplant.
First report from the European registry for anomalous aortic origin of coronary artery (EURO-AAOCA)
Authors: Gräni Christoph , Stark Anselm W , Lo Rito Mauro , Frigiola Alessandro , Siepe Matthias , Tchana Bertrand , Cipriani Alberto , Zorzi Alessandro , Pergola Valeria , Crea Domenico , Sarris George , Protopapas Elephterios , Sirico Domenico , Di Salvo Giovanni , Pegoraro Cinzia , Sarto Patrizio , Francois Katrien , Frigiola Alessandra , Cristofaletti Alessandra , Accord Ryan E , Gonzalez Rocafort Alvaro , Debeco Geoffroy , Padalino Massimo
Published: April 2024

OBJECTIVES

Anomalous aortic origin of a coronary artery (AAOCA) is a group of rare congenital heart defects with various clinical presentations. The lifetime-risk of an individual living with AAOCA is unknown, and data from multicentre registries are urgently needed to adapt current recommendations and guide optimal patient management. The European AAOCA Registry (EURO-AAOCA) aims to assess differences with regard to AAOCA management between centres.

METHODS

EURO-AAOCA is a prospective, multicentre registry including 13 European centres. Herein, we evaluated differences in clinical presentations and management, treatment decisions and surgical outcomes across centres from January 2019 to June 2023.

RESULTS

A total of 262 AAOCA patients were included, with a median age of 33 years (12–53) with a bimodal distribution. One hundred thirty-nine (53.1%) were symptomatic, whereas chest pain (n = 74, 53.2%) was the most common complaint, followed by syncope (n = 21, 15.1%). Seven (5%) patients presented with a myocardial infarction, 2 (1.4%) with aborted sudden cardiac death. Right-AAOCA was most frequent (150, 57.5%), followed by left-AAOCA in 51 (19.5%), and circumflex AAOCA in 20 (7.7%). There were significant differences regarding diagnostics between age groups and across centres. Seventy-four (28.2%) patients underwent surgery with no operative deaths; minor postoperative complications occurred in 10 (3.8%) cases.

CONCLUSIONS

Currently, no uniform agreement exists among European centres with regard to diagnostic protocols and clinical management for AAOCA variants. Although surgery is a safe procedure in AAOCA, future longitudinal outcome data will hopefully shed light on how to best decide towards optimal selection of patients undergoing revascularization versus conservative treatment.
Modular Completely Dirichlet forms as Squares of Derivations
Authors: Wirth Melchior
Published: April 2024

We prove that certain closable derivations on the GNS Hilbert space associated with a non-tracial weight on a von Neumann algebra give rise to GNS-symmetric semigroups of contractive completely positive maps on the von Neumann algebra.
An Introduction to the Complete Blood Count for Clinical Chemists: Red Blood Cells
Authors: Marin Maximo J , van Wijk Xander M R , Boothe Paul D , Harris Neil S , Winter William E
Published: April 2024

Background

The most frequently ordered laboratory test worldwide is the complete blood count (CBC).

Content

In this primer, the red blood cell test components of the CBC are introduced, followed by a discussion of the laboratory evaluation of anemia and polycythemia.

As clinical chemists are increasingly tasked to direct laboratories outside of the traditional clinical chemistry sections such as hematology, expertise must be developed. This review article is a dedication to that effort.
Exposure to imipenem at sub-minimum inhibitory concentration leads to altered expression of major outer membrane proteins in Acinetobacter baumannii
Authors: Nayak Srajana , Akshay Sadanand Dangari , Deekshit Vijaya Kumar , Raj Juliet Mohan , Maiti Biswajit
Published: April 2024

Aims

Acinetobacter baumannii is a nosocomial pathogen known to be multidrug-resistant (MDR), especially to drugs of the carbapenem class. Several factors contribute to resistance, including efflux pumps, β-lactamases, alteration of target sites, and permeability defects. In addition, outer membrane proteins (OMPs), like porins are involved in the passage of antibiotics, and their alteration could lead to resistance development. This study aimed to explore the possible involvement of porins and OMPs in developing carbapenem resistance due to differential expression.

Methods and results

The antibiotic-susceptible and MDR isolates of A. baumannii were first studied for differences in their transcriptional levels of OMP expression and OMP profiles. The antibiotic-susceptible isolates were further treated with imipenem, and it was found that the omp genes were differentially expressed. Six of the nine genes studied were upregulated at 1 h of exposure to imipenem. Their expression gradually decreased with time, further confirmed by their OMP profile and two-dimensional gel electrophoresis.

Conclusions

This study could identify OMPs that were differentially expressed on exposure to imipenem. Hence, this study provides insights into the role of specific OMPs in antibiotic resistance in A. baumannii.
Breakdown of hawking evaporation opens new mass window for primordial black holes as dark matter candidate
Authors: Thoss Valentin , Burkert Andreas , Kohri Kazunori
Published: April 2024

The energy injection through Hawking evaporation has been used to put strong constraints on primordial black holes as a dark matter candidate at masses below 1017 g. However, Hawking’s semiclassical approximation breaks down at latest after half-decay. Beyond this point, the evaporation could be significantly suppressed, as was shown in recent work. In this study we review existing cosmological and astrophysical bounds on primordial black holes, taking this effect into account. We show that the constraints disappear completely for a reasonable range of parameters, which opens a new window below 1010 g for light primordial black holes as a dark matter candidate.
Comparison between South African and UK Occupational Health Nursing
Authors: O’Neill Janet G
Published: April 2024

Occupational Health nursing forms a major part of workplace health and risk management; however, both the UK and South Africa have workforce challenges. Both have different histories, support and service needs; however, recent education changes are similar. This comparison explores the uniqueness of each but also those similarities and subtle differences in education changes. The aim is to enlighten the reader but also be thought-provoking and provide the potential of learning from each other.
Cortical Network Disruption Is Minimal in Early Stages of Psychosis
Authors: Van Dyken Peter C , MacKinley Michael , Khan Ali R , Palaniyappan Lena
Published: April 2024

Background and Hypothesis

Schizophrenia is associated with white matter disruption and topological reorganization of cortical connectivity but the trajectory of these changes, from the first psychotic episode to established illness, is poorly understood. Current studies in first-episode psychosis (FEP) patients using diffusion magnetic resonance imaging (dMRI) suggest such disruption may be detectable at the onset of psychosis, but specific results vary widely, and few reports have contextualized their findings with direct comparison to young adults with established illness.

Study Design

Diffusion and T1-weighted 7T MR scans were obtained from N = 112 individuals (58 with untreated FEP, 17 with established schizophrenia, 37 healthy controls) recruited from London, Ontario. Voxel- and network-based analyses were used to detect changes in diffusion microstructural parameters. Graph theory metrics were used to probe changes in the cortical network hierarchy and to assess the vulnerability of hub regions to disruption. The analysis was replicated with N = 111 (57 patients, 54 controls) from the Human Connectome Project-Early Psychosis (HCP-EP) dataset.

Study Results

Widespread microstructural changes were found in people with established illness, but changes in FEP patients were minimal. Unlike the established illness group, no appreciable topological changes in the cortical network were observed in FEP patients. These results were replicated in the early psychosis patients of the HCP-EP datasets, which were indistinguishable from controls in most metrics.

Conclusions

The white matter structural changes observed in established schizophrenia are not a prominent feature in the early stages of this illness.
Work Experience and Mental Health from Adolescence to Mid-Life
Authors: Staff Jeremy , Mortimer Jeylan T
Published: April 2024

The etiology of psychological differences among those who pursue distinct lines of work have long been of scholarly interest. A prevalent early and continuing assumption is that experiences on the job influence psychological development; contemporary analysts focus on dimensions indicative of mental health. Still, such work-related psychological differences may instead be attributable to selection processes to the extent that individuals can choose, or be selected to, different lines of work, based on their prior characteristics. Whereas much attention has been directed to employment per se as a key determinant of mental health, we consider work status (employed or not) and hours of work, as well as work quality, including both intrinsic and extrinsic dimensions among those who are employed. We also investigate differences in the effects of work experiences on mental health in distinct phases of the work career. Drawing on eleven waves of longitudinal data obtained from a cohort of ninth grade students followed prospectively to age 45–46 (54% female; 73% white), we examine whether key psychological dimensions indicative of mental health (mastery, depressive affect, and self-esteem) change in response to employment and to particular experiences on the job. The findings, based on a fixed-effects modeling strategy, indicate that observed psychological differences related to employment and work quality are not attributable to stable individual proclivities. Evidence suggests that mental health is responsive to changing experiences at work from mid-adolescence to mid-life.
The Soil Microbiomes of American Ginseng (Panax quinquefolius) Cultivated in North America Differ by Location but Not Always by Disease Status
Authors: Maggard Isabella J. , Deel Kayla B. , Gao Ying , Cahoon A. Bruce
Published: April 2024

One of the greatest challenges faced by ginseng producers is control of fungal pathogens that adversely affect harvest yields and are a contributing factor to replant failure syndrome. The goal of this project was to survey the soil microbiome of healthy versus diseased American ginseng grown in North America. Soils associated with healthy and diseased plants were collected from commercial farms in Garett County, Maryland, and Marathon County, Wisconsin. Environmental DNA metabarcoding was used to compare the bacterial and fungal microbiomes of healthy versus diseased plants from both locations. The most common bacteria occurred within the phylum Proteobacteria, Firmicutes, and Bacteroidota and the most common fungi occurred within Ascomycota, Basidiomycota, Mortierellomycota, and Glomeromycota. Overall, alpha- and beta-diversities were statistically significant between the two locations. Community analyses (beta-diversity) of the Maryland site revealed a significant difference in the bacterial composition of soils associated with healthy versus diseased plants but not in the fungi. Conversely, there was a significantly different assemblage of fungi in healthy versus diseased associated soils from the Wisconsin site, but not for bacteria. Our results, when compared to previous metabarcoding studies, suggest that there is little congruence between the soil microbiomes associated with cultivated ginseng and that we are still in the early stages of ginseng soil rhizosphere exploration.

[Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Repair and regeneration of the alveolar epithelium in lung injury
Authors: Wang Yaxuan , Wang Lan , Ma Shuaichen , Cheng Lianhui , Yu Guoying
Published: April 2024

Considerable progress has been made in understanding the function of alveolar epithelial cells in a quiescent state and regeneration mechanism after lung injury. Lung injury occurs commonly from severe viral and bacterial infections, inhalation lung injury, and indirect injury sepsis. A series of pathological mechanisms caused by excessive injury, such as apoptosis, autophagy, senescence, and ferroptosis, have been studied. Recovery from lung injury requires the integrity of the alveolar epithelial cell barrier and the realization of gas exchange function. Regeneration mechanisms include the participation of epithelial progenitor cells and various niche cells involving several signaling pathways and proteins. While alveoli are damaged, alveolar type II (AT2) cells proliferate and differentiate into alveolar type I (AT1) cells to repair the damaged alveolar epithelial layer. Alveolar epithelial cells are surrounded by various cells, such as fibroblasts, endothelial cells, and various immune cells, which affect the proliferation and differentiation of AT2 cells through paracrine during alveolar regeneration. Besides, airway epithelial cells also contribute to the repair and regeneration process of alveolar epithelium. In this review, we mainly discuss the participation of epithelial progenitor cells and various niche cells involving several signaling pathways and transcription factors.
Risankizumab as a Therapeutic Approach for Recalcitrant Pyoderma Gangrenosum
Authors: Michelucci Alessandra , Manzo Margiotta Flavia , Granieri Giammarco , Salvia Giorgia , Fidanzi Cristian , Bevilacqua Matteo , Panduri Salvatore , Romanelli Marco , Dini Valentina
Published: April 2024

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis that is challenging to diagnose and treat. Clinicians frequently use fast-acting corticosteroids, which are subsequently combined with slower-acting immunosuppressants to progressively taper the corticosteroid dosage. Current research is focused on the use of monoclonal antibodies (mAbs) directed against target molecules involved in the pathogenesis of PG. However, available data on their efficacy are based on sporadic case reports and clinical experiences, so the authors aimed to evaluate the efficacy of risankizumab, an anti-interleukin-23 mAb, in the management of two complex PG cases.

 The authors enrolled two patients with PG who were already treated with immunosuppressive therapies. Their management was based on the off-label use of an mAb directed against the p19 subunit of interleukin-23: risankizumab. Patients received subcutaneous injections of 150 mg at the start of treatment, at week 4, and then every 10 weeks thereafter. Systemic therapy was combined with local management of ulcers, based on the principles of TIME (tissue, infection, moisture balance, and epithelialization) applied to the inflammatory and noninflammatory phases of PG.

 Clinical resolution was obtained at week 24 for patient 1 and week 16 for patient 2 and was maintained until week 40, without adverse effects or disease recurrence. These clinical cases demonstrate that risankizumab is a valid tool in terms of efficacy and safety for complicated cases of multirefractory PG when provided in parallel with local personalized wound management.
Follicular (Infundibular–Tricholemmal) Squamous Cell Carcinoma: A New WHO Entity. Clinicopathological Features in 103 Cases, Including Follow-Up and Implications for Patient Management
Authors: Carr Richard A. , Wiggins James , Slater David N.
Published: April 2024

Aims:

Cutaneous follicular (infundibular–tricholemmal) squamous cell carcinoma (FSCC) is a new World Health Organization entity. We present the largest series of published cases, summarizing clinical data, diagnostic criteria, differential diagnosis, and implications for patient management.

Methods:

Cases were identified from 2004 to 2011. Inclusion criteria included discrete attachment(s) of the tumor to the overlying epidermis via follicular infundibula, tricholemmal keratinization, and cellular pleomorphism. Keratoacanthoma and lesions with adjacent bowenoid epidermal dysplasia were excluded.

Results:

One hundred three cases of FSCC identified. 48.5% demonstrated completely circumscript borders (in situ for practical purposes), 12.6% uncertain for invasion (overwhelmingly pushing borders), and only 38.8% as clearly invasive. Follicular mucin in acantholytic spaces within tumor epithelium was a distinctive finding in 57.2% of cases. Clinical data indicated predominance in elderly (median 78.5 years) men (70.4%), with preferential head and neck location (81.6%). Many were clinically suspected as squamous cell carcinoma (48.5%). However, a significant minority were clinically diagnosed as basal cell carcinoma (40.8%). This may reflect that FSCC commonly presented as a papule or nodule (51.3%). By contrast, keratoacanthoma was less frequently suggested (17.2%) and still fewer lesions were suspected to be actinic keratosis/Bowen's disease (13.6%). Follow-up in 82 cases (median 26.5 months, range 3–144) identified 5 (6.1%) local recurrences. There was no instance of metastasis in the subgroup of lesions with completely circumscript borders. Three of 45 (6.7%) patients, with follow-up, considered to have tumors with invasive pushing, and/or infiltrative borders developed lymph node metastases.

Conclusions:

FSCC is identified as a common skin cancer, incorporating historical entities, such as infundibular carcinoma and tricholemmal carcinoma, with readily identifiable histologic features. Correct diagnosis has implications for patient management; a significant subgroup of lesions show completely circumscript borders that are considered in situ for practical purposes.
Junctional Epidermolysis Bullosa Linked to Homozygous Mutation in LAMC2 Gene: A Case Report With Eosinophil-Rich Inflammatory Infiltrate
Authors: Haskoloğlu Şule , Öztürk Gökcan , Deveci Demirbaş Nazlı , Akal Can , İslamoğlu Candan , Baskın Kübra , Heper Aylin , Erdeve Ömer , Ceylaner Serdar , Doğu Figen , İkincioğulları Aydan
Published: April 2024

Junctional epidermolysis bullosa (JEB) is a rare, incurable, devastating, and mostly fatal congenital genetic disorder characterized by painful blistering of the skin and mucous membranes in response to minor trauma or pressure. JEB is classified roughly into 2 subtypes: JEB-Herlitz is caused by mutations on genes encoding laminin-332. The authors present a patient consulted with a suspicion of primary immunodeficiency due to skin sores that started at the age of 1 month and a history of 3 siblings who died with similar sores, who was diagnosed with JEB-Herlitz after detecting a homozygous LAMC2 gene mutation in WES analysis. Microscopic evaluation of hematoxylin and eosin–stained sections showed vesicle formation with subepidermal separation, which is accompanied by striking neutrophil and eosinophil leukocyte infiltration both in the vesicle and papillary dermis (eosinophil-rich inflammatory infiltrate). Such a histopathological finding has been rarely reported in this condition.
Blau Syndrome With Delayed Cutaneous Manifestations: A Case Report
Authors: Panah Elnaz , Garfield Erin , Zahirsha Zisansha , Muhlbauer Aaron , Lake Eden , Speiser Jodi
Published: April 2024

Blau syndrome is a rare familial autoinflammatory disorder characterized by the triad of granulomatous dermatitis, polyarthritis, and uveitis. Blau syndrome exhibits an autosomal dominant inheritance pattern and can be caused by a gain-of-function mutation in nucleotide-binding oligomerization domain 2 (NOD2), a member of the NOD-like receptor family of pattern recognition receptors. Mutations in NOD2 cause upregulation of inflammatory cytokines and resultant autoinflammation. Because of the rarity of this condition and early onset of symptoms, Blau syndrome may be misdiagnosed as juvenile idiopathic arthritis. We present a case of a 37-year-old male patient with a long-documented history of juvenile idiopathic arthritis and uveitis, who developed an asymptomatic eruption of pink papules on the trunk and upper extremities. A biopsy demonstrated noncaseating, well-formed dermal granulomas with relatively sparse lymphocytic inflammation and Langerhans-type giant cells. Genetic testing confirmed a mutation in NOD2. Based on the patient's clinical history, histologic findings, genetic testing, the diagnosis of Blau syndrome was made.
Rhabdomyomatous Mesenchymal Hamartoma: Report of 4 Cases With Histochemical and Immunohistochemical Findings and Emphasis on Potential Pitfalls
Authors: AbdullGaffar Badr , Keloth Tasnim
Published: April 2024

Rhabdomyomatous mesenchymal hamartoma (RMH) typically presents as a congenital midline head and neck cutaneous polyp in infants. Perianal and mucocutaneous lesions have been reported, and recently, acquired adult-onset variants have been proposed. This makes the true prevalence, etiopathogenesis, and clinicopathologic distribution and classification of RMHs in children compared with those in adults uncertain. We performed a retrospective review to highlight the salient histopathologic, histochemical, and immunohistochemical features in RMHs and to emphasize their specific clinicopathologic criteria to avoid diagnostic pitfalls. We found 4 (0.3%) infants [2 female infants and 2 male infants, average age: 4 months] with mental, nasal, lingual, and perianal midline RMHs (average size: 1.0 cm) of 1303 patients with cutaneous polypoid lesions. Three were isolated, and 1 was associated with Goldenhar syndrome. The cutaneous polyps demonstrated intermixed skeletal muscle, adipose, and fibrocollagenous core stroma that extended into the dermis and around the dermal appendages. The lingual lesion demonstrated skeletal muscle and fibrocollagenous stroma with prominent nerve bundles and little adipose tissue. All showed interstitial loose mesenchyme. Masson trichome demarcated the triphasic stromal components. Alcian blue demonstrated the loose myxoid mesenchyme. Elastic van Gieson did not show elastic fibers. Desmin demonstrated the skeletal muscle bundles, S100 highlighted the adipose tissue lobules and the nerve bundles, and CD34 displayed the mesenchymal stroma. Ki67 showed a low proliferation index in the loose mesenchyme. Smooth muscle actin did not reveal smooth muscle bundles, but with CD31, they highlighted the thick blood vessels. CD117 revealed prominent mast cells. From our retrospective review series, 4 cases that originally diagnosed as RMHs were excluded. Likewise, we found some examples of the reported cases in the English literature that might have been mistaken for RMHs. This is because they did not fulfill the diagnostic clinicopathologic criteria. RMH constitutes a rare entity with specific clinicopathologic features. Most lesions are isolated. Some are associated with congenital anomalies and syndromes. Strict clinicopathologic diagnostic criteria should be applied to avoid mislabeling look-alike lesions for RMHs.
Age-Related Changes in Vancomycin Protein Binding: Is It Time to Take It Seriously?
Authors: Gadsby Jessica , Stachow Lucy , Mulla Hussain
Published: April 2024

Background:

Vancomycin (VAN) protein binding in plasma is influenced by illness and age; hence, doses titrated according to total concentrations are fraught. In this study, model-estimated free VAN concentrations (EFVC) were compared with assumed free VAN concentrations (AFVC) in neonates, children, and adults in the intensive care unit and those on dialysis.

Methods:

Patient cohorts were identified from the hospital database. Demographics, clinical characteristics, total VAN concentrations, and laboratory variables were obtained from electronic health records. EFVC was derived from 6 models identified in the literature. For all models, total VAN concentration was the most important predictor; other predictors included albumin, total protein, and dialysis status. The AFVC was calculated as 50% of the total concentration (ie, assumption of 50% bound).

Results:

Differences between EFVC and AFVC in adults were insignificant; however, differences in pediatric intensive care unit patients, according to 2 different models, were significant: mean ± SD = 4.1 ± 1.58 mg/L and 4.7 ± 2.46 mg/L (P< 0.001); the percentages within the free VAN trough range = 30.4% versus 55.1% and 30% versus 55.1%; and the supratherapeutic percentages = 65.2% versus 31.9% and 66.7% versus 31.9%, respectively. In neonates, the difference between EFVC and AFVC was mean ± SD = 6.9 ± 1.95 mg/L (P< 0.001); the percentages within the free VAN trough range for continuous and intermediate dosing were 0% versus 81.3% and 14.3% versus 71.4%, and the supratherapeutic percentages were 100% versus 6.25% and 71.4% versus 0%, respectively.

Conclusions:

The fraction of free unbound VAN is higher in sick children and neonates than in adults. Therefore, total VAN concentrations do not correlate with the pharmacologically active free VAN concentrations in the same manner as in adults. Adjusting VAN doses in neonates and children to target the same total VAN concentration as the recommended therapeutic range for adults may result in toxicfree concentrations.
Follow the Area Under the Curve Not the Trough Concentration: A Case Study of Tacrolimus Monitoring in a Kidney Transplant Recipient Cotreated With Phenobarbital
Authors: Izarn Oscar , Morin Marie-Pascale , Ntobe-Bunkete Beni , Golbin Léonard , Ferrand-Sorre Marie-José , Tron Camille , Lemaitre Florian
Published: April 2024

The authors described tacrolimus dosing in a kidney transplant patient concurrently treated with phenobarbital, where measuring the tacrolimus area under the curve was necessary to achieve adequate drug exposure and improve kidney function.
IL-4 attenuates myocardial infarction injury by promoting M2 macrophage polarization
Authors: Lu Da , Fan Jiajia , Lin Yang , Yang Kai , Zheng Fuzhen , Ma Teng , Zhu Feng
Published: April 2024

IL-4, an immunoregulatory cytokine, plays a role in various cellular pathways and is known to regulate M2 macrophage polarization. Numerous studies have suggested that promoting the polarization of macrophages toward the M2 phenotype is beneficial for myocardial infarction (MI) recovery. However, whether IL-4 can achieve therapeutic effects in MI by regulating M2 macrophage polarization remains unclear. In this study, the authors observed that IL-4 increased the proportion of M2 macrophages in the ischemic myocardium compared to the PBS group. Additionally, IL-4 reduced the infiltration of inflammatory cells and the expression of proinflammatory-related proteins, while enhancing the expression of genes associated with tissue repair. Furthermore, IL-4 facilitated the recovery of cardiac function and reduced fibrosis in the post-MI phase. Importantly, when macrophages were depleted, the therapeutic benefits of IL-4 mentioned above were attenuated. These findings provide evidence for the effectiveness of IL-4 in treating MI through the regulation of M2 macrophage polarization, thereby encouraging further development of this therapeutic approach.
Updates in the management of hypertension
Authors: Ramdani Sara , Haddiya Intissar
Published: April 2024

Hypertension is the leading cause of cardiovascular diseases and nephropathies. Its treatment and management require long-term follow-up which can be facilitated by the emergence of device-based therapies. Novel recommendations have been well described in the latest ESH guidelines as well as new risk factors have been identified. The authors summarized the published evidence on hypertension management. The authors also cited in this review novel treatment approaches in different settings and the intervention of medication adherence in treatment success. Such non-communicable disease requires long-term follow-up and monitoring, which is quite facilitated in the era of digitalization by cuff-less devices based on prediction tools.
Understanding the effects of COVID-19 on patients with diabetic nephropathy: a systematic review
Authors: Altoukhi Samar M. , Zamkah Mariam M. , Alharbi Reman A. , Alghamdi Shatha K. , Aldawsari Lama S. , Tarabulsi Muyassar , Rizk Hisham , Sandokji Yousif
Published: April 2024

Background:

Diabetic nephropathy is one of the consequences of diabetes mellitus that causes a continuous decline in the eGFR. After the COVID-19 pandemic, studies have shown that patients with diabetic nephropathy who had contracted COVID-19 have higher rates of morbidity and disease progression. The aim of this study was to systematically review the literature to determine and understand the effects and complications of SARS-CoV-2 on patients with diabetic nephropathy.

Materials and methods:

The authors’ research protocol encompassed the study selection process, search strategy, inclusion/exclusion criteria, and a data extraction plan. A systematic review was conducted by a team of five reviewers, with an additional reviewer assigned to address any discrepancies. To ensure comprehensive coverage, the authors employed multiple search engines including PubMed, ResearchGate, ScienceDirect, SDL, Ovid, and Google Scholar.

Results:

A total of 14 articles meeting the inclusion criteria revealed that COVID-19 directly affects the kidneys by utilizing ACE2 receptors for cell entry, which is significant because ACE2 receptors are widely expressed in the kidney.

Conclusion:

COVID-19 affects kidney health, especially in individuals with diabetic nephropathy. The mechanisms include direct viral infection and immune-mediated injury. Early recognition and management are vital for improving the outcomes.
Network pharmacology prediction and experiment validation of anti-liver cancer activity of Curcumae Rhizoma and Hedyotis diffusa Willd
Authors: Tie Songyan , Tong Tianhao , Zhan Gangxiang , Li Xin , Ouyang Dan , Cao Jianzhong
Published: April 2024

Objective:

This study aims to elucidate anti-liver cancer components and potential mechanisms of Curcumae Rhizoma and Hedyotis diffusa Willd (CR-HDW).

Methods:

Effective components and targets of CR-HDW were identified from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Liver cancer-related genes were collected from GeneCards, Gene-Disease Association (DisGeNET), and National Center for Biotechnology Information (NCBI). Protein-protein interaction networks, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were conducted to analyze the identified genes. Molecular docking was used to simulate binding of the active components and their target proteins. Cell activity assay, western blot, and senescence-associated β-galactosidase (SA-β-gal) experiments were conducted to validate core targets identified from molecular docking.

Results:

Ten active compounds of CR-HDW were identified including quercetin, 3-epioleanic acid and hederagenin. The primary core proteins comprised Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Protein Kinase B(AKT1), etc. The pathways for Phosphoinositide 3-kinase (PI3K)/ AKT, cellular senescence, Fork head boxO (FOXO) were revealed as important for anti-cancer activity of CR-HDW. Molecular docking demonstrated strong binding between liver cancer target proteins and major active components of CR-HDW. In-vitro experiments confirmed that hederagenin and 3-epioleolic acid inhibited HuH-7 cell growth, reduced expression of PI3K, AKT, and mechanistic target of rapamycin (mTOR) proteins. Hederagenin also induced HuH-7 senescence.

Conclusions:

In summary, The authors’ results suggest that the CR-HDW component (Hederagenin, 3-epoxy-olanolic acid) can inhibit the proliferation of HuH-7 cells by decreasing PI3K, AKT, and mTOR. Hederagenin also induced HuH-7 senescence.
Association of Lateral Pelvic Lymph Nodes with Disease Recurrence and Organ Preservation in Patients with Distal Rectal Adenocarcinoma Treated with Total Neoadjuvant Therapy
Authors: Beets Nathalie R. A. , Verheij Floris S. , Williams Hannah , Omer Dana M. , Lin Sabrina T. , Qin Li-Xuan , Beets Geerard L. , Beets-Tan Regina G. H. , Wei Iris H. , Widmar Maria , Pappou Emmanouil P. , Weiser Martin R. , Nash Garrett M. , Smith J. Joshua , Paty Philip B. , Miranda Joao , Kim Tae-Hyung , Gollub Marc J. , Garcia-Aguilar Julio
Published: April 2024

Objective:

Assess the significance of enlarged lateral lymph nodes (LLN) for disease recurrence, metastasis, and organ preservation in patients with rectal cancer.

Background:

Optimal treatment of rectal adenocarcinoma involving LLN is subject to debate.

Methods:

A post hoc analysis of the OPRA trial, a multicenter study of patients with rectal cancer treated with total neoadjuvant therapy (TNT) followed by total mesorectal excision or watch-and-wait management. We analyzed the association of visible LLN (LLN+), LLN≥7 mm (short axis) on baseline MRI, and LLN≥4 mm on restaging MRI with recurrence, metastasis, and rectum preservation.

Results:

At baseline, 57 out of 324 (18%) patients had LLN+. In 30 (53%) of 57 patients with LLN+ on baseline MRI, the LLN disappeared after TNT. Disease recurrence in LLN was rare (3.5% of patients with LLN+ and 0.4% of patients with LLN−). All patients with recurrence in LLN also had distant metastasis. The rate of organ preservation was significantly lower in patients with LLN≥4 mm on restaging MRI (P=0.013). We found no significant differences in rates of local recurrence or metastasis between patients with LLN+ vs. LLN− and in patients with LLN≥7 vs.<7 mm on baseline MRI. LLN dissection was performed in 3 patients; 2 of them died of distant metastasis.

Conclusions:

LLN involvement is not associated with disease recurrence or metastasis, but persistence of LLN≥4 mm after TNT is negatively associated with rectum preservation in patients with locally advanced rectal cancer treated with TNT. Dissection of lateral nodes likely benefits few patients.
Periprosthetic Femoral Fractures in Total Hip Arthroplasty
Authors: Dauder-Gallego Cristina , López-Hualda Alvaro , Ferreño-Márquez David Manuel , Sosa-Reina María Dolores , Villafañe Jorge Hugo , Martínez-Martín Javier
Published: April 2024

Objective:

This study aimed to analyze the occurrence of periprosthetic fractures (PPFs) in patients who underwent total hip arthroplasty.

Methods:

The researchers conducted a retrospective review of 447 patients (494 hips) who received a hip replacement with an ESOP stem. The average follow-up period was 12.33 ± 5.2 years. The study population comprised 248 men with 276 hips and 203 women with 220 hips, with a mean age of 65.7 ± 11.6 years.

Results:

We found 42 PPFs, 15 of them taking place intraoperatively. Regarding the postoperative fractures, 3 of them happened during the first month and the rest of them afterward. There were 3 deaths directly related to the PPF episode. We found a higher risk of fractures among the female, population older than 65 years, and among those with total hip arthroplasty following hip fracture. This population showed a higher incidence of complications and mortality rate. The cumulative percentage probability of periprosthetic femoral fracture was 3.2% (95% confidence interval, 2-5.6) at 10 years, and 10.3% (95% confidence interval, 7-20) at 20 years after surgery.

Conclusions:

Our findings indicate that periprosthetic femoral fracture incidence increases significantly after the first decade. The use of modular stems did not modify this behavior, similar to other nonmodular or anatomical stems.
Efficacy of Rehabilitative Intervention on Pain and Function in Patients With Upper Limb Complex Regional Pain Syndrome
Authors: Buraschi Riccardo , Ranica Giorgia , Nicassio Filippo , Falso Maurizio Vincenzo , Pollet Joel
Published: April 2024

Aim:

Investigate the efficacy of physical therapy in the management of complex regional pain syndrome (CRPS)

Methods:

We conducted a systematic review on 3 databases: MEDLINE, EMBASE, and CENTRAL. The applied methods are stated in the protocol and registered in OSF: 10.17605/OSF.IO/SF49B.

Results:

At the end of the screening process, 12 RCTs were included. Included studies presented heterogeneous and multicomponent interventions. Physical therapy interventions resulted valuable in the management of CRPS. Motor imagery and some physical agents therapies are effective in reducing pain and for functional improvements.

Conclusion:

Physiotherapy is a central treatment for patients with CRPS.
Lifting the curse from high dimensional data: Automated projection pursuit clustering for the variety of biological data modalities
Authors: Simpson Claire , Tabatsky Evgeniy , Rahil Zainab , Eddins Devon J. , Tkachev Sasha , Georgescauld Florian , Papalegis Derek , Culka Martin , Levy Tyler , Gregoretti Ivan , Chernyshev Andrei , Koeppen Hartmut , Walther Guenther , Ghosn Eliver E. B. , Orlova Darya
Published: April 2024

Unsupervised clustering is a powerful machine-learning technique widely used to analyze high-dimensional biological data. It plays a crucial role in uncovering patterns, structure, and inherent relationships within complex datasets without relying on predefined labels. In the context of biology, high-dimensional data may include transcriptomics, proteomics, and a variety of single-cell omics data. Most existing clustering algorithms operate directly in the high-dimensional space, and their performance may be negatively affected by the phenomenon known as the curse of dimensionality. Here, we show an alternative clustering approach that alleviates the curse by sequentially projecting high-dimensional data into a low-dimensional representation. We validated the effectiveness of our approach, named APP, across various biological data modalities, including flow and mass cytometry data, scRNA-seq, multiplex imaging data, and T-cell receptor repertoire data. APP efficiently recapitulated experimentally validated cell-type definitions and revealed new biologically meaningful patterns.