Scleroderma pulmonary arterial hypertension: the same as idiopathic pulmonary arterial hypertension?

PURPOSE OF REVIEW: Pulmonary arterial hypertension (PAH) is a common complication of systemic sclerosis (SSc), which confers significant morbidity and mortality. The current therapies and treatment strategies for SSc-associated PAH (SSc-PAH) are informed by those used to treat patients with idiopathic PAH (IPAH). There are, however, important differences between these two diseases that impact diagnosis, treatment, and outcomes. RECENT FINDINGS: Both SSc-PAH and IPAH are incompletely understood with ongoing research into the underlying cellular biology that characterize and differentiate the two diseases. Additional research seeks to improve identification among SSc patients in order to diagnose patients earlier in the course of their disease. Novel therapies specifically for SSc-PAH such as rituximab and dimethyl fumarate are under investigation. SUMMARY: Although patients with SSc-PAH and IPAH present with similar symptoms, there are significant differences between these two forms of PAH that warrant further investigation and characterization of optimal detection strategies, treatment algorithms, and outcomes assessment.

Barriers to frostbite treatment at an academic medical center.

The treatment of frostbite injuries has undergone a radical change over the past decade with a shift from supportive therapy and observation towards early and aggressive medical intervention with thrombolytics and vasodilators. Institutions that have implemented evidence-based protocols have significantly decreased their amputation rates (Bruen et al., 2007; Lindford et al., 2017a; Twomey et al., 2005). We present the case of a middle-aged male treated for frostbite of multiple fingers on both hands. Because there was no treatment protocol at our institution, there were multiple delays in the patient's care including imaging and initiation of intravenous (IV) prostanoids. This case illustrates the deleterious effects of delays in treatment and strongly suggests that all facilities located in areas of cold exposure should have protocols in place for such an occurrence.

Allelic polymorphism of GIGANTEA is responsible for naturally occurring variation in circadian period in Brassica rapa.

GIGANTEA (GI) was originally identified by a late-flowering mutant in Arabidopsis, but subsequently has been shown to act in circadian period determination, light inhibition of hypocotyl elongation, and responses to multiple abiotic stresses, including tolerance to high salt and cold (freezing) temperature. Genetic mapping and analysis of families of heterogeneous inbred lines showed that natural variation in GI is responsible for a major quantitative trait locus in circadian period in Brassica rapa. We confirmed this conclusion by transgenic rescue of an Arabidopsis gi-201 loss of function mutant. The two B. rapa GI alleles each fully rescued the delayed flowering of Arabidopsis gi-201 but showed differential rescue of perturbations in red light inhibition of hypocotyl elongation and altered cold and salt tolerance. The B. rapa R500 GI allele, which failed to rescue the hypocotyl and abiotic stress phenotypes, disrupted circadian period determination in Arabidopsis. Analysis of chimeric B. rapa GI alleles identified the causal nucleotide polymorphism, which results in an amino acid substitution (S264A) between the two GI proteins. This polymorphism underlies variation in circadian period, cold and salt tolerance, and red light inhibition of hypocotyl elongation. Loss-of-function mutations of B. rapa GI confer delayed flowering, perturbed circadian rhythms in leaf movement, and increased freezing and increased salt tolerance, consistent with effects of similar mutations in Arabidopsis. Collectively, these data suggest that allelic variation of GI-and possibly of clock genes in general-offers an attractive target for molecular breeding for enhanced stress tolerance and potentially for improved crop yield.

Single-cell transcriptomics reveal diverging pathobiology and opportunities for precision targeting in scleroderma-associated versus idiopathic pulmonary arterial hypertension.

Introduction: Pulmonary arterial hypertension (PAH) involves progressive cellular and molecular change within the pulmonary vasculature, leading to increased vascular resistance. Current therapies targeting nitric oxide (NO), endothelin, and prostacyclin pathways yield variable treatment responses. Patients with systemic sclerosis-associated PAH (SSc-PAH) often experience worse outcomes than those with idiopathic PAH (IPAH). Methods: Lung tissue samples from four SSc-PAH, four IPAH, and four failed donor specimens were obtained from the Pulmonary Hypertension Breakthrough Initiative (PHBI) lung tissue bank. Single-cell RNA sequencing (scRNAseq) was performed using the 10X Genomics Chromium Flex platform. Data normalization, clustering, and differential expression analysis were conducted using Seurat. Additional analyses included gene set enrichment analysis (GSEA), transcription factor activity analysis, and ligand-receptor signaling. Pharmacotranscriptomic screening was performed using the Connectivity Map. Results: SSc-PAH samples showed a higher proportion of fibroblasts and dendritic cells/macrophages compared to IPAH and donor samples. GSEA revealed enriched pathways related to epithelial-to-mesenchymal transition (EMT), apoptosis, and vascular remodeling in SSc-PAH samples. There was pronounced differential gene expression across diverse pulmonary vascular cell types and in various epithelial cell types in both IPAH and SSc-PAH, with epithelial to endothelial cell signaling observed. Macrophage to endothelial cell signaling was particularly pronounced in SSc-PAH. Pharmacotranscriptomic screening identified TIE2, GSK-3, and PKC inhibitors, among other compounds, as potential drug candidates for reversing SSc-PAH gene expression signatures. Discussion: Overlapping and distinct gene expression patterns exist in SSc-PAH versus IPAH, with significant molecular differences suggesting unique pathogenic mechanisms in SSc-PAH. These findings highlight the potential for precision-targeted therapies to improve SSc-PAH patient outcomes. Future studies should validate these targets clinically and explore their therapeutic efficacy.

A case report describing diverticulosis of the appendix presenting as acute appendicitis.

INTRODUCTION: Diverticulosis of the appendix (DA) is a rare clinical finding which is often confused with acute or chronic appendicitis and is usually only identified during or after appendectomy. The symptoms of DA can last for up to two weeks and laboratory studies tend to reflect a more chronic inflammation. Distinguishing the two entities is important as DA has a higher risk for perforation and may be associated with an underlying malignancy. PRESENTATION OF CASE: A 54--year old African--American male presented with three--days of right sided abdominal pain, nausea, and vomiting. Physical exam and abdominal CT imaging were concerning for early acute appendicitis. The patient was taken emergently to the operating room for laparoscopic appendectomy. Extensive adhesions were found around the Appendix which was grossly abnormal with multiple diverticula. The patient had an uneventful recovery. DISCUSSION: Patients with DA are often misdiagnosed with chronic or acute appendicitis based on their presenting symptoms and imaging. While appendectomy is the definitive treatment, diagnosing DA before surgery is important in determining the patient's risks and potential complications. CONCLUSION: Diverticulosis of the Appendix is a rare clinical entity which is often misdiagnosed. Better imaging techniques and higher indices of clinical suspicion are needed to make the appropriate diagnoses before patients are taken for surgery.