Search

Objectives: Adult naso-orbital-ethmoid (NOE) fractures are estimated to account for 5% of all adult facial fractures without published consensus on management. The purpose of this investigation was to assess the available literature regarding the treatment and outcomes of adult naso-orbital-ethmoid fractures., Data Sources: Cochrane Library, PubMed, Scopus, and CINAHL., Methods: Following PRISMA guidelines, databases were searched from inception through July 25, 2024 for studies pertaining to the treatment of NOE fractures. Measures of interest included patient demographics, associated fractures, type of intervention, and complications., Results: A total of 16 studies were included for meta-analysis, consisting of 459 patients. The patients included in the analysis had a mean age of 30.6 years (95% CI: 26.9-34.3 years) with a male-to-female gender ratio of 2.7:1. Operative intervention, specifically open reduction and internal fixation (ORIF) (90.1%; 95: CI: 76.6-98.1%), was the most commonly performed management. Closed reduction has been reported for all three types. The most frequently reported complications included nasolacrimal duct obstruction (38.6%; 95% CI: 10.6-71.7%), postoperative epiphora (24.9%; 95% CI: 6.4-50.4%), and telecanthus (20.9%; 95% CI: 1.7-53.5%)., Conclusions: Surgical intervention can be considered for all NOE types. Despite surgical intervention, NOE fractures remain difficult to treat, and inadequate repair may result in complications. Laryngoscope, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: The ductus arteriosus (DA) is critical in maintaining postnatal circulation in neonates with obstructed systemic circulation (OSC) and pulmonary circulation (OPC). We hypothesized that the size of the DA and aortic isthmus (AoI) undergoes adaptive growth in utero to counteract the hemodynamic challenges in these congenital heart diseases (CHD)., Methods: Postnatal echocardiograms of neonates diagnosed prenatally with ductal-dependent CHD who were started on prostaglandins within 24 h of birth were reviewed. We assessed the cross-sectional area of the aortic valve opening, pulmonary valve opening, AoI, and DA by calculating (diameter) 2 /body surface area. Neonates were classified into OSC or OPC then subgrouped depending upon the patency of semilunar valves: OSC with and without aortic atresia (OSC-AA and OSC-nAA, respectively) and OPC with and without pulmonary atresia (OPC-PA and OPC-nPA, respectively)., Results: Ninety-four cases were studied. The DA in OSC was significantly larger than OPC, and the DA in OSC-AA was significantly larger than OSC-nAA. The size of the AoI was significantly larger in OPC than OSC and larger in OSC-AA than OSC-nAA. Within the OSC-nAA group, there was no significant difference in the size of the DA, AoI, or pulmonary valve opening between those with retrograde flow (RF) at the AoI and without (nRF) except the aortic valve opening was significantly larger in nRF. All groups had comparable cross-sectional areas of systemic output., Conclusions: Our findings suggest that DA and AoI show compensatory growth to maintain critical blood flow to vital organs against primary anatomical abnormalities in ductus-dependent CHD. (249 words)., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Key Points: CRSwNP-specific mean total annual spending ranged from $5,837 (EDS-FLU) to $28,058 (dupilumab). Most CRSwNP patients receiving biologics had comorbid asthma and did not undergo sinus surgery. While biologics were covered by most Medicare Part D plans, only 37% of plans covered EDS-FLU., (© 2024 ARS‐AAOA, LLC.)

Background: Evidence supporting topical steroids for the treatment of chronic rhinosinusitis without nasal polyposis (CRSsNP) is unclear. Recent trials describe alternative topical steroid delivery modalities, including rinses and exhalation delivery system (EDS), necessitating a re-examination of the current literature., Methods: Cochrane Library, CINAHL, PubMed, and Scopus databases were searched from inception to February 13, 2024 for placebo-controlled randomized control trials on topical steroids used to treat CRSsNP, including topical spray, nasal irrigation, sinonasal catheter, and EDS modalities. Primary outcome measures included total symptom scores (TSS) (Δ) and response rates (odds ratio)., Results: Ten trials (N = 751) were included for meta-analysis, with a mean age of 47.5 years (range: 18-80 years; 95% confidence interval [CI]: 43.9-51.2 years). Topical steroids delivered by any method significantly improved TSS in CRSsNP patients (Δ0.4; 95% CI: 0.3-0.6; p < 0.0001). When stratified by allergy status, CRSsNP patients without allergy had significantly improved TSS when treated with EDS (Δ0.4; 95% CI: 0.1-0.7; p = 0.01), but not with topical spray (Δ0.04; 95% CI: -0.9 to 1.0; p = 0.94). Patients treated with EDS or sinonasal catheter responded significantly better compared to placebo (odds ratio [OR]: 3.4; 95% CI: 1.9-6.0; p < 0.0001; OR: 12.4; 95% CI: 1.8-83.8; p < 0.01), whereas patients treated with topical spray had no significant difference (OR: 1.8; 95% CI: 0.9-4.0; p = 0.12)., Conclusions: Topical steroids are effective in treating CRSsNP, especially when delivered via EDS or sinonasal catheter. Future trials comparing steroid delivery mechanisms using validated outcome measures in CRSsNP populations are needed., (© 2024 ARS‐AAOA, LLC.)

Objectives: To comprehensively examine the characteristics and prognosis of bilateral sudden sensorineural hearing loss (BSSHL) and its subtypes compared to unilateral sudden sensorineural hearing loss (USSHL)., Data Sources: PubMed, Scopus, and CINAHL., Review Methods: Databases were searched from inception to December 5, 2023, for studies reporting patient characteristics and audiometric outcomes for BSSHL and its simultaneous (Si-BSSHL) and sequential (Se-BSSHL) subtypes. Meta-analysis of continuous measures, proportions (%), mean differences (Δ), and odds ratio (OR) were performed., Results: Eleven studies were included, consisting of 368 patients with BSSHL and 2,705 patients with USSHL. The pooled prevalence among all SSHL cases was 88.1% (95% CI: 81.2%-93.6%) for USSHL and 11.9% (95% CI: 6.4% to 18.8%) for BSSHL. PTA improvement following treatment with steroids was significantly worse in patients with BSSHL (Δ15.3 dB; 95% CI: 14.6 to 15.9; p < 0.0001) compared to patients with USSHL. There was no significant difference in post-treatment PTA improvement between the BSSHL subtypes. Patients with Si-BSSHL were significantly less likely to have an idiopathic etiology (OR: 0.4; 95% CI: 0.2 to 0.8; p = 0.01) and significantly more likely to have an autoimmune disease etiology (OR: 27.4; 95% CI: 2.2 to 336.1; p = 0.01), comorbid cardiovascular disease (OR: 2.3; 95% CI: 1.1 to 5.1; p = 0.03), and comorbid hypertension (OR: 2.5; 95% CI: 1.6 to 3.8; p < 0.0001) compared to patients with USSHL., Conclusions: BSSHL is a considerably rarer form of SSHL with worse prognosis compared to USSHL. BSSHL, and Si-BSSHL in particular, has significantly greater associations with systemic pathologies compared to USSHL. Laryngoscope, 134:3883-3891, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Key Points: Utilization of orbital decompressions (ODS) increased (CAGR: +3.2%) from 2000 to 2019. FDA approved teprotumumab in January 2020; ODS utilization decreased (CAGR: -14.9%) from 2019 to 2022. In 2022, total spending was substantially higher for teprotumumab ($325 million) than surgery ($580,000)., (© 2024 ARS‐AAOA, LLC.)

Key Points: The original manufacturer of azelastine‒fluticasone (AZ‒FL) prevented generic availability until 2020 via patent enforcement. Following generic availability of AZ‒FL, Medicare utilization increased and spending decreased. Retail prices for generic AZ‒FL remain high due to markup by manufacturers and pharmacies., (© 2024 ARS‐AAOA, LLC.)

Objectives: To compare the efficacy of the 445-nm blue laser to the 585-nm pulsed dye laser (PDL) and 532-nm potassium-titanyl-phosphate (KTP) laser in the treatment of benign laryngeal lesions., Data Sources: Cochrane Library, PubMed, Scopus, and CINAHL., Review Methods: Following PRISMA guidelines, databases were searched from inception through January 29, 2024, for studies reporting the use of photoangiolytic lasers for treatment of benign laryngeal lesions, including the 585-nm PDL, 532-nm KTP laser, and 445-nm blue laser. Outcome measures included lesion resolution (%), mean differences (Δ) in Voice Handicap Index (VHI-10), and summed dysphonia grade, roughness, and breathiness (GRB) scale., Results: A total of 45 studies were included for meta-analysis, consisting of 348 patients treated with PDL, 550 patients with KTP laser, and 338 patients with blue laser. Treatment with blue laser resulted in the greatest lesion resolution (94.0%; 95% confidence interval [CI]: 90.2%-96.7%), followed by KTP laser (90.4%; 95% CI: 84.1%-95.2%), and PDL (86.9%; 95% CI: 62.9%-99.2%). VHI-10 improved significantly in patients following treatment with blue laser (Δ13.3; 95% CI: 10.7-16.0; p < 0.0001), KTP laser (Δ10.3; 95% CI: 7.4-13.3; p < 0.0001), and PDL (Δ7.4; 95% CI: 4.8-10.1; p < 0.0001). GRB improved significantly in patients following treatment with blue laser (Δ4.1; 95% CI: 2.9-5.2; p < 0.0001), KTP laser (Δ3.0; 95% CI: 2.0-4.0; p < 0.0001), and PDL (Δ2.5; 95% CI: 0.8-4.2; p = 0.005)., Conclusions: Photoangiolytic lasers are effective in treating benign laryngeal lesions. Blue lasers are promising for laryngeal laser surgery. Laryngoscope, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Ultraviolet-B (UV-B) irradiation has been reported to cause oxidative stress and inflammation-mediated skin photo-damage. Furthermore, mitochondrial dynamics have been implicated to play a critical role in these processes. For the first time, we describe in this study how UVB-induced aberrant mitochondrial dynamics and inflammation interact in primary human dermal fibroblasts (HDFs). Our findings demonstrated that UV-B irradiation induced -impairment in mitochondrial dynamics by increasing mitochondrial fragmentation in HDFs. Imbalanced mitochondrial dynamics lead to the activation of NFкB and pro-inflammatory cytokines. The current study further aimed to investigate the protective effect of Naringenin (a naturally occurring flavonoid isolated from Sea buckthorn fruit pulp) against UV-B-induced mitochondrial fragmentation and inflammation in HDFs and Balb/c mice. Although Naringenin has been shown to have anti-inflammatory and antioxidant potential, its effects and mechanisms of action on UVB-induced inflammation remained unclear. We observed that Naringenin restored the UV-B-induced imbalance in mitochondrial fission and fusion in HDFs. It also inhibited the phosphorylation of NFкB and reduced the generation of pro-inflammatory cytokines. Naringenin also alleviated UV-B-induced oxidative stress by scavenging the reactive oxygen species and up-regulating the cellular antioxidant enzymes (Catalase and Nrf2). Topical application of Naringenin to the dorsal skin of Balb/c mice exposed to UV-B radiation prevented mitochondrial fragmentation and progression of inflammatory responses. Naringenin treatment prevented neutrophil infiltration and epidermal thickening in mice's skin. These findings provide an understanding for further research into impaired mitochondrial dynamics as a therapeutic target for UV-B-induced inflammation. Our findings imply that Naringenin could be developed as a therapeutic remedy against UVB-induced inflammation., Competing Interests: Declaration of competing interest All authors have disclosed that they do not have any conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Skin homeostasis is predominantly compromised by exposure to UV-B irradiation, leading to several physiopathological processes at cellular and tissue levels that deteriorate skin function and integrity. The current study investigated the photo-protective role of seabuckthorn fruit pulp (SBT) extract against UV-B-induced damage in primary human skin fibroblasts (HDFs) and Balb/C mice skin. We subjected HDFs and Balb/C mice to UV-B irradiation and measured multiple cellular damage indicators. We found that UV-B-irradiated HDFs treated with SBT had a considerably greater survival rate than cells exposed to UV-B radiation alone. The UV-B irradiation-induced ROS generation led to the degradation of the extracellular matrix, inflammation, DNA damage, endoplasmic reticulum (ER) stress, and apoptosis. SBT treatment significantly reduced these manifestations. Topical application of SBT alleviated UV-B-induced epidermal thickening, leukocyte infiltration, and degradation of extracellular matrix in Balb/c mice skin. Based on our results, we conclude that SBT has the potential to be developed as a therapeutic/cosmetic remedy for the prevention of skin photo-damage., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

While better management of loco-regional prostate cancer (PC) has greatly improved survival, advanced PC remains a major cause of cancer deaths. Identification of novel targetable pathways that contribute to tumor progression in PC could open new therapeutic options. The di-ganglioside GD2 is a target of FDA-approved antibody therapies in neuroblastoma, but the role of GD2 in PC is unexplored. Here, we show that GD2 is expressed in a small subpopulation of PC cells in a subset of patients and a higher proportion of metastatic tumors. Variable levels of cell surface GD2 expression were seen on many PC cell lines, and the expression was highly upregulated by experimental induction of lineage progression or enzalutamide resistance in CRPC cell models. GD2 high cell fraction was enriched upon growth of PC cells as tumorspheres and GD2 high fraction was enriched in tumorsphere-forming ability. CRISPR-Cas9 knockout (KO) of the rate-limiting GD2 biosynthetic enzyme GD3 Synthase (GD3S) in GD2 high CRPC cell models markedly impaired the in vitro oncogenic traits and growth as bone-implanted xenograft tumors and reduced the cancer stem cell and epithelial-mesenchymal transition marker expression. Our results support the potential role of GD3S and its product GD2 in promoting PC tumorigenesis by maintaining cancer stem cells and suggest the potential for GD2 targeting in advanced PC., (© 2024. The Author(s).)

The increasing global concern of antimicrobial resistance and shortage of new antimicrobials necessitates exploring untapped terrestrial environments for new bioactive microbiome diversity. The low-temperature and oligotrophic North Western Himalaya (NWH) region has a vast diversity of Streptomyces with potential antimicrobial properties that remain largely unexplored. This study evaluates the diversity of culturable Streptomyces from high-altitude NWH and their potential as a source of new antimicrobials through genus-specific isolation and identification. The results demonstrate a distinct phylogenetic clustering of Streptomyces from different sampling regions of NWH, site-specific variation in culturable β-diversity and species commonness with varying intersite bioactivity among different sites. Further, the study optimized the media selection for large-scale culture cultivation in antibiotic production processes and demonstrated the antimicrobial efficacy of Streptomyces against a range of pathogens through in vitro bioassays using minimum inhibitory concentration determination and antibiofilm activity. Untargeted label-free proteomic profiling also revealed variable expression of stress-response proteins and antibiotic regulators as a competitive survival strategy for selective antagonistic Streptomyces. The findings highlight the potential of NWH in augmenting antimicrobial discovery and combating antimicrobial resistance through the isolation and study of novel bioactive Streptomyces., (© The Author(s) 2024. Published by Oxford University Press on behalf of FEMS.)

Cutaneous pigmentation is an important phenotypic trait whose regulation, despite recent advances, has yet to be completely elucidated. Melanogenesis, a physiological process of melanin production, is imperative for organism survival as it provides protection against the environmental insults that majorly involve sunlight-induced skin photodamage. However, immoderate melanin synthesis can cause pigmentation disorders associated with a psychosocial impact. In this study, the hypopigmentation effect of (2-methylbutyryl)shikonin, a natural product present in the root extract of Lithospermum erythrorhizon , and the underlying mechanisms responsible for the inhibition of melanin synthesis in α-MSH-stimulated B16F10 cells and C57BL/6J mice was studied. Non-cytotoxic concentrations of (2-methylbutyryl)shikonin significantly repressed cellular tyrosinase activity and melanin synthesis in both in vitro and in vivo models (C57BL/6J mice). (2-Methylbutyryl)shikonin remarkably abolished the protein expression of MITF, tyrosinase, tyrosinase-related protein 1, and tyrosinase-related protein 2, thereby blocking the production of pigment melanin via modulating the phosphorylation status of MAPK proteins, viz., ERK1/2 and p38. In addition, specific inhibition of ERK1/2 attenuated the inhibitory effects of (2-methylbutyryl)shikonin on melanin synthesis, whereas selective inhibition of p38 augmented the inhibitory effect of BSHK on melanin synthesis. Moreover, topical application of (2-methylbutyryl)shikonin on C57BL/6J mouse tails remarkably induced tail depigmentation. In conclusion, with these findings, we, for the first time, report the hypopigmentation effect of (2-methylbutyryl)shikonin via inhibition of cellular tyrosinase enzyme activity, subsequently ameliorating the melanin production, thereby indicating that (2-methylbutyryl)shikonin is a potential natural therapy for hyperpigmentation disorders.

Objective: We used a framework to assess the value implications of thoracic surgeon operative volume within an 8-hospital health system., Methods: Surgical cases for non-small cell lung cancer were assessed from March 2015 to March 2021. High-volume (HV) surgeons performed >25 pulmonary resections annually. Metrics include length of stay, infection rates, 30-day readmission, in-hospital mortality, median 30-day charges and direct costs, and 3-year recurrence-free and overall survival. Multivariate regression-based propensity scores matched patients between groups. Metrics were graphed on radar charts to conceptualize total value., Results: All 638 lung resections were performed by 12 surgeons across 6 hospitals. Two HV surgeons performed 51% (n = 324) of operations, and 10 low-volume surgeons performed 49% (n = 314). Median follow-up was 28.8 months (14.0-42.3 months). Lobectomy was performed in 71% (n = 450) of cases. HV surgeons performed more segmentectomies (33% [n = 107] vs 3% [n = 8]; P  < .001). Patients of HV surgeons had a lower length of stay (3 [2-4] vs 5 [3-7]; P  < .001) and infection rates (0.6% [n = 1] vs 4% [n = 7]; P  = .03). Low-volume and HV surgeons had similar 30-day readmission rates (14% [n = 23] vs 7% [n = 12]; P  = .12), in-hospital mortality (0% [n = 0] vs 0.6% [n = 1]; P  = .33), and oncologic outcomes; 3-year recurrence-free survival was 95% versus 91%; P  = .44, and 3-year overall survival was 94% versus 90%; P  = 0. Charges were reduced by 28%, and direct costs were reduced by 23% (both P  < .001) in the HV cohort., Conclusions: HV surgeons provide comprehensive value across a health system. This multidomain framework can be used to help drive oncologic care decisions within a health system., Competing Interests: The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2023 The Author(s).)

Objective: Transport and Golgi Organization protein 1 (TANGO1) is a protein that regulates the export of procollagen from the endoplasmic reticulum and has a role in the organization of exit sites for general protein export. What regulates the expression of TANGO1 and the role of TANGO1 in fibrosis is poorly understood and has never been studied in the setting of systemic sclerosis (SSc). We undertook this study to determine the role of TANGO1 in SSc fibrosis., Methods: SSc (n = 15) and healthy (n = 12) primary fibroblast lung cell lines were investigated for the expression of TANGO1. Histologic analyses for TANGO1 were performed on lung biopsy samples (n = 12 SSc patient samples and n = 8 healthy control samples)., Results: SSc fibroblasts showed increased expression of TANGO1 protein in cultured fibroblasts. TANGO1 colocalizes with α-smooth muscle actin (α-SMA)-positive cells in SSc lung tissue and is highly up-regulated in the neointima of SSc vessels. TANGO1 expression was dependent on the inflammasome activation of caspase 1. It was also dependent on signaling from the interleukin-1 (IL-1) and transforming growth factor β (TGFβ) receptors. The decrease in TANGO1 down-regulated export of larger cargos including collagen and laminin. Reduced TANGO1 protein had no effect on smaller molecular weight cargoes; however, the secretion of elastin was significantly reduced., Conclusion: TANGO1 is markedly increased in SSc fibroblasts and was found to be elevated in lung tissue in association with α-SMA-positive cells. TANGO1 expression is driven by inflammasome-dependent caspase 1 activation and is mediated by IL-1 and TGFβ downstream signaling. These observations suggest that during fibrosis, caspase 1 promotes the up-regulation of TANGO1 and the organization of endoplasmic reticulum exits sites, ultimately contributing to procollagen export and fibrosis., (© 2023 American College of Rheumatology.)

Steatohepatitis is a significant risk factor for end-stage liver disease. In this study, the therapeutic potential of Glabridin (GBD), an isoflavan derived from Glycyrrhiza glabra, is investigated in in-vitro and in-vivo models against palmitic acid (PA) or fast food (FF) diet + alcohol (EtOH). Mouse hepatocytes (AML-12 cells) were treated with PA; 250 μM + EtOH; 250 μM ± GBD (10 μM and 25 μM) for 24 h. C57BL/6J mice fed with standard chow (SC) diet, fast food (FF) diet + intermittent oral ingestion of EtOH (10-50%v/v) ± GBD (20 mg/kg and 40 mg/kg) for eight (8) weeks, were analyzed for histological features of steatohepatitis and fibrosis, biochemical indexes, and protein and gene expression studies related to oxidative stress, inflammation, lipogenesis, fibrosis, and apoptosis. GBD therapy considerably reduced intracellular events in AML-12 cells exposed to PA + EtOH. GBD treatments significantly improved body metrics, biochemical indexes, and histological features in C57BL/6J mice compared to FF + EtOH. Moreover, protein and gene expression investigations revealed a strong therapeutic effects on oxidative stress, inflammation, steatosis, fibrosis, and apoptosis -related molecular signaling cascades. In conclusion, these findings suggest that GBD has a strong therapeutic potential to be developed as anti-steatohepatitis/fibrosis medicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Overexpression of the EPS15 Homology Domain containing 1 (EHD1) protein has been linked to tumorigenesis but whether its core function as a regulator of intracellular traffic of cell surface receptors plays a role in oncogenesis remains unknown. We establish that EHD1 is overexpressed in Ewing sarcoma (EWS), with high EHD1 mRNA expression specifying shorter patient survival. ShRNA-knockdown and CRISPR-knockout with mouse Ehd1 rescue established a requirement of EHD1 for tumorigenesis and metastasis. RTK antibody arrays identified IGF-1R as a target of EHD1 regulation in EWS. Mechanistically, we demonstrate a requirement of EHD1 for endocytic recycling and Golgi to plasma membrane traffic of IGF-1R to maintain its surface expression and downstream signaling. Conversely, EHD1 overexpression-dependent exaggerated oncogenic traits require IGF-1R expression and kinase activity. Our findings define the RTK traffic regulation as a proximal mechanism of EHD1 overexpression-dependent oncogenesis that impinges on IGF-1R in EWS, supporting the potential of IGF-1R and EHD1 co-targeting., (© 2023. The Author(s).)

Chronic exposure to Ultraviolet B radiation (UV-B) evokes a myriad of toxic signalling events in the irradiated skin. One of such response is ER stress, which is known to exacerbate photodamage responses. Also, recent literature has highlighted the adverse impact of environmental toxicants on mitochondrial dynamics and mitophagy. Impaired mitochondrial dynamics escalates oxidative damage and causes apoptosis. There have been evidences that support crosstalk between ER stress and mitochondrial dysfunction. However, mechanistic clarification is still needed to verify the interactions between UPR responses and mitochondrial dynamics impairment in UV-B-induced photodamage models. Lastly, plant-based natural agents have garnered attention as therapeutic agents against skin photodamage. Thus, gaining mechanistic insights of plant-based natural agents is required for their application and feasibility in clinical settings. With this aim in view, this study was performed in primary human dermal fibroblasts (HDFs) and Balb/C mice. Different parameters regarding mitochondrial dynamics, ER stress, intracellular damage and histological damage were analyzed using western blot, rt-PCR and microscopy. We demonstrated that UV-B exposure leads to induction of UPR responses, upregulation of Drp-1 and inhibition of mitophagy. Further, 4-PBA treatment leads to reversal of these noxious stimuli in irradiated HDF cells, thereby, indicating an upstream role of UPR induction in mitophagy inhibition. Also, we explored the therapeutic effect of Rosmarinic acid (RA) against ER stress and impaired mitophagy in photodamage models. RA prevents intracellular damage via alleviation of ER stress and mitophagic responses in HDFs and irradiated Balb/C mice skin. The current study summarizes the mechanistic insights into UVB-mediated intracellular damage and role of natural plant-based agent (RA) in ameliorating these toxic responses., (© 2023 John Wiley & Sons Ltd.)

Melanoma, the most serious yet uncommon type of cancer, originates in melanocytes. Risk factors include UV radiation, genetic factors, tanning lamps and beds. Here, we described the synthesis and selective anti melanoma activity of [3,2- b ]indole fused 18β-glycyrrhetinic acid, a derivative of 18β-glycyrrhetinic acid in murine B16F10 and A375 human melanoma cell lines. Among the 14 molecules, GPD-12 showed significant selective cytotoxic activity against A375 and B16F10 cell lines with IC50 of 13.38 μM and 15.20 μM respectively. GPD 12 induced the formation of reactive oxygen species in A375 cells that could trigger oxidative stress mediated cell death as is evident from the increased expression of apoptosis related proteins such as caspase-9 and caspase-3 and the increased ratio of Bax to Bcl2. The results showed that GPD 12 can be used as an effective therapeutic agent against melanoma., Competing Interests: The authors declare that there is no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Background: Gastric cancer has been ranked the third leading cause of cancer death worldwide. Its detection at the early stage is difficult because patients mostly experience vague and non-specific symptoms in the early stages. Methods : The RNA-seq datasets of both gastric cancer and normal samples were considered and processed. The obtained differentially expressed genes were then subjected to functional enrichment analysis and pathway analysis. An implicit atomistic molecular dynamics simulation was executed on the selected protein receptor for 50 ns. The electrostatics, surface potential, radius of gyration, and macromolecular energy frustration landscape were computed. Results : We obtained a large number of DEGs; most of them were down-regulated, while few were up-regulated. A DAVID analysis showed that most of the genes were prominent in the KEGG and Reactome pathways. The most prominent GAD disease classes were cancer, metabolic, chemdependency, and infection. After an implicit atomistic molecular dynamics simulation, we observed that DLC1 is electrostatically optimized, stable, and has a reliable energy frustration landscape, with only a few maximum energy frustrations in the loop regions. It has a good functional and binding affinity mechanism. Conclusions : Our study revealed that DLC1 could be used as a potential druggable target for specific subsets of gastric cancer.

With nearly all cancer deaths a result of metastasis, elucidating novel pro-metastatic cellular adaptations could provide new therapeutic targets. Here, we show that overexpression of the EPS15-Homology Domain-containing 2 (EHD2) protein in a large subset of breast cancers (BCs), especially the triple-negative (TNBC) and HER2+ subtypes, correlates with shorter patient survival. The mRNAs for EHD2 and Caveolin-1/2, structural components of caveolae, show co-overexpression across breast tumors, predicting shorter survival in basal-like BC. EHD2 shRNA knockdown and CRISPR-Cas9 knockout with mouse Ehd2 rescue, in TNBC cell line models demonstrate a major positive role of EHD2 in promoting tumorigenesis and metastasis. Mechanistically, we link these roles of EHD2 to store-operated calcium entry (SOCE), with EHD2-dependent stabilization of plasma membrane caveolae ensuring high cell surface expression of the SOCE-linked calcium channel Orai1. The novel EHD2-SOCE oncogenic axis represents a potential therapeutic target in EHD2- and CAV1/2-overexpressing BC., Competing Interests: HL, TB, BM, NI, IM, AB, SM, SC, MR, MS, MT, JM, WT, DC, ER No competing interests declared, VB, HB received funding from Nimbus Therapeutics for an unrelated project, (© 2023, Luan, Bielecki, Mohapatra et al.)

The severe acute respiratory syndrome coronavirus 2 that causes coronavirus disease 2019 (COVID-19) disrupted the normal functioning throughout the world since early 2020 and it continues to do so. Nonetheless, the global pandemic was taken up as a challenge by researchers across the globe to discover an effective cure, either in the form of a drug or vaccine. This resulted in an unprecedented surge of experimental and computational data and publications, which often translated their findings in the form of databases (DBs) and tools. Over 160 such DBs and more than 80 software tools were developed, which are uncharacterized, unannotated, deployed at different universal resource locators and are challenging to reach out through a normal web search. Besides, most of the DBs/tools are present on preprints and are either underutilized or unrecognized because of their inability to make it to top Google search hits. Henceforth, there was a need to crawl and characterize these DBs and create a compendium for easy referencing. The current article is one such concerted effort in this direction to create a COVID-19 resource compendium (COVIDium) that would facilitate the researchers to find suitable DBs and tools for their research studies. COVIDium tries to classify the DBs and tools into 11 broad categories for quick navigation. It also provides end-users some generic hit terms to filter the DB entries for quick access to the resources. Additionally, the DB provides Tracker Dashboard, Neuro Resources, references to COVID-19 datasets and protein-protein interactions. This compendium will be periodically updated to accommodate new resources. Database URL: The COVIDium is accessible through http://kraza.in/covidium/., (© The Author(s) 2021. Published by Oxford University Press.)

Overexpression of the epidermal growth factor receptor (EGFR) family member ErbB2 (HER2) drives oncogenesis in up to 25% of invasive breast cancers. ErbB2 expression at the cell surface is required for oncogenesis but mechanisms that ensure the optimal cell surface display of overexpressed ErbB2 following its biosynthesis in the endoplasmic reticulum are poorly understood. ErbB2 is dependent on continuous association with HSP90 molecular chaperone for its stability and function as an oncogenic driver. Here, we use knockdown and overexpression studies to show that the HSP90/HSC70-interacting negative co-chaperone CHIP (C-terminus of HSC70-Interacting protein)/STUB1 (STIP1-homologous U-Box containing protein 1) targets the newly synthesized, HSP90/HSC70-associated, ErbB2 for ubiquitin/proteasome-dependent degradation in the endoplasmic reticulum and Golgi, thus identifying a novel mechanism that negatively regulates cell surface ErbB2 levels in breast cancer cells, consistent with frequent loss of CHIP expression previously reported in ErbB2-overexpressing breast cancers. ErbB2-overexpressing breast cancer cells with low CHIP expression exhibited higher endoplasmic reticulum stress inducibility. Accordingly, the endoplasmic reticulum stress-inducing anticancer drug Bortezomib combined with ErbB2-targeted humanized antibody Trastuzumab showed synergistic inhibition of ErbB2-overexpressing breast cancer cell proliferation. Our findings reveal new insights into mechanisms that control the surface expression of overexpressed ErbB2 and suggest that reduced CHIP expression may specify ErbB2-overexpressing breast cancers suitable for combined treatment with Trastuzumab and ER stress inducing agents.

Information on bio-type profile of Mycobacterium avium subspecies paratubeculosis (MAP) in sheep flocks and goat herds of Himalayan region is not reported earlier. The aim of our study was to determine the bio-type of MAP infecting livestock of this region. A total of 71 faecal samples (sheep-57, goats-14) were screened by Ziehl-Neelsen (ZN) staining and IS900 PCR, and then processed for culture on Herrold's egg yolk medium (HEYM) having mycobactin J (MJ). Out of 71 faecal samples, MAP colonies were seen only in four samples (sheep-3 and goat-1). Isolates were confirmed as MAP on the basis of slow growth, acid fastness, MJ dependency, IS900 and IS1311 PCR. All the IS900 and IS1311 PCR positive samples were bio-typed by IS1311 PCR-REA (restriction endonuclease analysis), which confirmed all four isolates as 'bison type.' In IS1311 based phylogeny of MAP isolates by ClustalW method of the MegAlign program of DNASTAR Lasergene software, the four sequences of MAP isolates (NCBI sequence nos. MH988763, MH988765, MH988766 and MH988764) did not show any distinct clustering/grouping pattern. However, these four isolates showed a bit of closeness to the MAP sequences (KC990353.1 and KC990352.1) of 'bison type' isolated from wood bison in Canada. In conclusion, this is the first report on isolation and bio-type profile of MAP infecting sheep and goats of Himalayan region. Study will help in devising prevention and control strategies against spread of MAP infection in livestock population of Himalayan region.

Elective closure of atrial septal defect (ASD) is usually recommended during preschool ages. However, ASD may contribute to deteriorating health in the presence of significant comorbidity and, thus, may need earlier closure. There is a lack of clarity regarding the indications for and outcomes after ASD closure in infancy and early childhood. We investigated the benefits and safety of surgical ASD closure in symptomatic patients under 2 years of age. Retrospective chart review was conducted in patients who underwent surgical ASD closure within the first 2 years of life. Of 31 symptomatic ASD patients, 22 had persistent respiratory symptoms, 24 failure to thrive, and 9 pulmonary hypertension. Overall, 26 patients (84.0%) showed clinical improvement after ASD closure, including improved respiratory status (17/22; 77.3%), resumption of normal growth (15/24; 62.5%), and resolution of pulmonary hypertension (7/7; 100%, 2 patients unable to assess postoperatively). Two medically complicated patients died a few months after surgery unrelated to surgical complications. Four out of 8 ventilator-dependent patients were weaned from mechanical ventilation within 1 month after ASD closure. Closure of ASD did not improve those patients with highly advanced lung disease and/or medically complex conditions including underlying genetic abnormalities. Surgical complications were uncommon. Postoperative hospital stay was 4 to 298 days (median 8 days). The majority of our patients demonstrated significant clinical improvement after ASD closure. Early ASD closure is safe and beneficial for symptomatic infants and young children with associated underlying pulmonary abnormalities, especially bronchopulmonary dysplasia.

Purpose: Negative surgical margins (NSMs) have favorable prognostic implications in breast tumor resection surgery. Fluorescence image-guided surgery (FIGS) has the ability to delineate surgical margins in real time, potentially improving the completeness of tumor resection. We have recently developed indocyanine green (ICG)-loaded self-assembled hyaluronic acid (HA) nanoparticles (NanoICG) for solid tumor imaging, which were shown to enhance intraoperative contrast., Procedures: This study sought to assess the efficacy of NanoICG on completeness of breast tumor resection and post-surgical survival. BALB/c mice bearing iRFP + /luciferase + 4T1 syngeneic breast tumors were administered NanoICG or ICG, underwent FIGS, and were compared to bright light surgery (BLS) and sham controls., Results: NanoICG increased the number of complete resections and improved tumor-free survival. This was a product of improved intraoperative contrast enhancement and the identification of a greater number of small, occult lesions than ICG and BLS. Additionally, NanoICG identified chest wall invasion and predicted recurrence in a model of late-stage breast cancer., Conclusions: NanoICG is an efficacious intraoperative contrast agent and could potentially improve surgical outcomes in breast cancer.

Epidermal growth factor receptor (EGFR) is a prototype receptor tyrosine kinase and an oncoprotein in many solid tumors. Cell surface display of EGFR is essential for cellular responses to its ligands. While postactivation endocytic trafficking of EGFR has been well elucidated, little is known about mechanisms of basal/preactivation surface display of EGFR. Here, we identify a novel role of the endocytic regulator EHD1 and a potential EHD1 partner, RUSC2, in cell surface display of EGFR. EHD1 and RUSC2 colocalize with EGFR in vesicular/tubular structures and at the Golgi compartment. Inducible EHD1 knockdown reduced the cell surface EGFR expression with accumulation at the Golgi compartment, a phenotype rescued by exogenous EHD1. RUSC2 knockdown phenocopied the EHD1 depletion effects. EHD1 or RUSC2 depletion impaired the EGF-induced cell proliferation, demonstrating that the novel, EHD1- and RUSC2-dependent transport of unstimulated EGFR from the Golgi compartment to the cell surface that we describe is functionally important, with implications for physiologic and oncogenic roles of EGFR and targeted cancer therapies., (Copyright © 2020 American Society for Microbiology.)

Ladakh is the high altitude (11,184 ft above sea level) cold desert region in the state of Jammu & Kashmir (India), where winter temperature goes below - 35 °C. A total of 37 faecal samples were collected from local Changthangi and Russian merino sheep of the Leh region of Ladakh, having the history of diarrhoea and emaciation, followed by death. Of the 37 samples collected, 20 (54.05%) showed presence of Cryptosporidium sp. infection on faecal smear examination after Ziehl-Neelsen staining. The number of samples positive for Cryptosporidium sp. infection on faecal smear examination was 7 and 13 for Russian Merino and local Changthangi sheep, respectively. The occurrence of Cryptosporidium sp. infection was similar in both sexes, 11/20 (55%) in females and 9/20 (45%) for males. The Age-wise occurrence of Cryptosporidium sp. infection in different age groups was found to be: 50% in less than 2 year age group and 50% in more than 2 year age group. To the best of our knowledge, this is the first report of Cryptosporidium sp. infection in adult sheep from India. The survival of the parasite at such freezing temperature gives the insight about its cold-resistant nature., Competing Interests: Conflict of interestThe authors declare no conflicts of interest regarding the information provided in this manuscript.

The incidence of late coronary complications is reported around 8% after arterial switch operation (ASO) for d-transposition of the great arteries, but the affected patients are usually asymptomatic. Exercise stress test (EST) and myocardial perfusion imaging (MPI) are common non-invasive modalities to screen for silent myocardial ischemia, but their diagnostic reliability in children after ASO is unclear. We retrospectively reviewed asymptomatic patients following ASO with EST, MPI, and coronary imaging studies (CIS) and examined the reliability of each test in identifying abnormal coronary lesions responsible for myocardial ischemia. Thirty-seven asymptomatic patients (24 males; ages 12.7 ± 3.7 years) had EST, in which 27 and 33 patients also underwent MPI and CIS, respectively. Exercise capacity was comparable to the age- and sex-matched 37 controls. In seven patients with angiographically proven moderate to severe coronary abnormalities, only two patients had positive EST and/or MPI, and five patients were negative including one patient who later developed exercise-induced cardiac arrest due to severe proximal left coronary artery stenosis. Two patients with positive EST or MPI showed no corresponding coronary abnormalities by CIS. Occurrence of acquired late coronary abnormalities did not correlate with the original coronary anatomy or initial surgical procedures. There is no single reliable method to identify the risk of myocardial ischemia after ASO. Although CIS are regarded as a gold standard, multidisciplinary studies are essential to risk-stratify the potential life-threatening coronary lesions after ASO in children.

Aim: This study was conducted to evaluate the incidence of clinical mastitis in bovines of Jammu region, to identify the infectious organisms responsible for it, and the antimicrobial sensitivity of isolated pathogens., Materials and Methods: The study was conducted on cases that were presented to the Medicine Division of Teaching Veterinary Clinical Complex, Faculty of Veterinary Sciences and Animal Husbandry, R.S. Pura, Jammu, Jammu and Kashmir. A total of 260 cases of bovines were presented from June 30, 2012, to July 01, 2013, out of which 30 cases were of clinical mastitis. The diagnosis of clinical mastitis was made on the basis of history and clinical examination of affected animals., Results: Animal and quarter-wise incidence of clinical mastitis were found to be 11.5% and 5.76%, respectively. Of the 23 isolates obtained, Staphylococcus aureus (60.87%) was the most frequently isolated organism, followed by coagulase negative Staphylococci (13.04%), Streptococcus uberis (4.35%), Streptococcus dysgalactiae (8.69%), and Escherichia coli (13.04%). The antimicrobial sensitivity of isolates revealed maximum sensitivity to enrofloxacin, gentamicin, amoxicillin/sulbactam, ceftriaxone/tazobactam, ceftizoxime, ampicillin/sulbactam and least sensitivity for oxytetracycline and penicillin., Conclusion: Staphylococcus spp. is the major causative agent of clinical mastitis in bovines of Jammu region. The causative agents of the clinical mastitis were most sensitive to enrofloxacin and gentamicin.

Background: The prevalence of ventricular septal defects (VSDs), a birth defect in which there is an opening in the wall that separates the left and right ventricles of the heart, seemed to be substantially higher in Delaware compared with the National Birth Defects Prevention Network (NBDPN). The Delaware Birth Defects Registry (BDR) noted their high prevalence of VSDs in comparison with other states., Methods: A subset of children with a VSD born in 2007 through 2010 was identified from the complete reportable statewide defect list that the BDR creates each year. VSDs were categorized by type of VSD (muscular, perimembranous, conotruncal, or atrioventricular septal defect), by either isolated or complex, and then by spontaneously closed, surgically closed, open but clinically insignificant, lost to follow-up, fetal or neonatal death., Results: The BDR team found a prevalence of VSD of 83.4 per 10,000 including fetal/neonatal deaths. Excluding fetal and neonatal deaths the prevalence was 78.7 per 10,000 live births. Excluding small muscular VSDs, the prevalence in Delaware falls to 25.7 per 10,000., Conclusion: The BDR team chose to include all babies with all types of VSDs. Using these criteria Delaware's prevalence of 78.7 was higher than that reported by other states (whose prevalence ranges from 1.6 to 70.0 per 10,000 live births) (National Birth Defects Prevention Network, ). Delaware's prevalence is similar to other states when small muscular VSDs are excluded. Birth Defects Research (Part A) 106:888-893, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Screening for kidney diseases by urinalysis in school children is being conducted in many parts of the world with inexpensive tools such as urinary dipsticks. We conducted this study to know the prevalence of asymptomatic proteinuria in school children (age group 12-14 years) in Kashmir valley as no previous study is available. After applying exclusion criteria, 2068 children were screened for proteinuria by dipstick method. Another test was performed in the children with abnormal findings in the first sample with dipstick of the same brand, after a period of one-month. These children were also assessed by timed urine collection (i.e., 24 h urinary protein). In the first dipstick test, the prevalence of proteinuria in the studied population was 6.2% which persisted in 2.17% after second dipstick examination. No child in the studied group was found to have glycosuria. In our study, no statistically significant association was found between proteinuria and gender, body mass index, or hypertension. In our study, the prevalence of persistent proteinuria in school children (age group 12-14 years) in Kashmir valley was almost similar to the studies conducted in different parts of the world.

The present study was aimed to determine the effect on liver, associated oxidative stress, trace element and vitamin alteration in dogs with sarcoptic mange. A total of 24 dogs with clinically established diagnosis of sarcoptic mange, divided into two groups, severely infested group (n=9) and mild/moderately infested group (n=15), according to the extent of skin lesions caused by sarcoptic mange and 6 dogs as control group were included in the present study. In comparison to healthy control hemoglobin, PCV, and TEC were significantly (P<0.05) decreased in dogs with sarcoptic mange however, significant increase in TLC along with neutrophilia and lymphopenia was observed only in severely infested dogs. The albumin, glucose and cholesterol were significantly (P<0.05) decreased and globulin, ALT, AST and bilirubin were significantly (P<0.05) increased in severely infested dogs when compared to other two groups. Malondialdehyde (MDA) levels were significantly (P<0.01) higher in dogs with sarcoptic mange, with levels highest in severely infested groups. Activity of superoxide dismutase (SOD) (P<0.05) and catalase were significantly (P<0.01) lower in sarcoptic infested dogs when compared with the healthy control group. Zinc and copper levels in dogs with sarcoptic mange were significantly (P<0.05) lower when compared with healthy control group with the levels lowest in severely infested group. Vitamin A and vitamin C levels were significantly (P<0.05) lower in sarcoptic infested dogs when compared to healthy control. From the present study, it was concluded that sarcoptic mange in dogs affects the liver and the infestation is associated with oxidant/anti-oxidant imbalance, significant alteration in trace elements and vitamins., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Exosomes carry cell type-specific molecular cargo to extracellular destinations and therefore act as lateral vectors of intercellular communication and transfer of genetic information from one cell to the other. We have shown previously that the small heat shock protein αB-crystallin (αB) is exported out of the adult human retinal pigment epithelial cells (ARPE19) packaged in exosomes. Here, we demonstrate that inhibition of the expression of αB via shRNA inhibits exosome secretion from ARPE19 cells indicating that exosomal cargo may have a role in exosome biogenesis (synthesis and/or secretion). Sucrose density gradient fractionation of the culture medium and cellular extracts suggests continued synthesis of exosomes but an inhibition of exosome secretion. In cells where αB expression was inhibited, the distribution of CD63 (LAMP3), an exosome marker, is markedly altered from the normal dispersed pattern to a stacked perinuclear presence. Interestingly, the total anti-CD63(LAMP3) immunofluorescence in the native and αB-inhibited cells remains unchanged suggesting continued exosome synthesis under conditions of impaired exosome secretion. Importantly, inhibition of the expression of αB results in a phenotype of the RPE cell that contains an increased number of vacuoles and enlarged (fused) vesicles that show increased presence of CD63(LAMP3) and LAMP1 indicating enhancement of the endolysosomal compartment. This is further corroborated by increased Rab7 labeling of this compartment (RabGTPase 7 is known to be associated with late endosome maturation). These data collectively point to a regulatory role for αB in exosome biogenesis possibly via its involvement at a branch point in the endocytic pathway that facilitates secretion of exosomes., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Objectives: This study sought to assess the mechanistic effect of rotational atherectomy (RA) and orbital atherectomy (OA) on heavily calcified coronary lesions and subsequent stent placement using optical coherence tomography (OCT)., Background: RA and OA are two main approaches to ablate coronary calcium. While small case reports have described the mechanistic effect of RA in calcified coronary lesions, there has been no imaging study to assess the effect of OA on coronary artery architecture and/or compare the effects of two atherectomy devices., Methods: This study analyzed 20 consecutive patients with OCT imaging performed after atherectomy and after stent implantation, RA (n = 10) and OA (n = 10)., Results: Postatherectomy OCT analysis identified tissue modification with deep dissections in around a third of lesions after RA and OA; however, post OA dissections ("lacunae") were significantly deeper (1.14 vs. 0.82 mm, P = 0.048). Post OA/RA lesions with dissections had significantly higher percentage of lipid rich plaques and smaller calcification arcs as compared to plaques without dissections. Stents after OA were associated with a significantly lower percent of stent strut malapposition than post RA stents (4.36 vs. 8.02%, P = 0.038)., Conclusions: Although the incidence of dissections was comparable between RA and OA cases, OA resulted in deeper tissue modifications (lacunae) as shown by OCT imaging. The finding might provide an explanation for a better stent apposition after OA as compared to RA. Their impact on long-term outcome needs to be determined., (© 2015 Wiley Periodicals, Inc.)

Objectives: The aim of this study is to compare the relative merits of optical coherence tomography (OCT), intravascular ultrasound (IVUS), and near infrared spectroscopy (NIRS) in patients with coronary artery disease for the prediction of periprocedural myocardial infarction (MI)., Background: Although several individual intravascular imaging modalities have been employed to predict periprocedural MI, it is unclear which of the imaging tools would best allow prediction of this complication., Methods: We retrospectively analyzed 110 patients who underwent OCT, IVUS, and NIRS. Periprocedural MI was defined as a post-procedural cardiac troponin I (cTnI) elevation above 3× the upper limit of normal; analysis was also performed for cTnI ≥5× the upper limit of normal., Results: cTnI ≥3× was observed in 10 patients (9%) and 8 patients had cTnI ≥5×. By OCT, minimum cap thickness was significantly lower (55 vs. 90 μm, p < 0.01), and the plaque burden by IVUS (84 ± 9% vs. 77 ± 8%, p < 0.01) and maximum 4-mm lipid core burden index by NIRS (556 vs. 339, p < 0.01) were greater in the cTnI ≥3× group. Multivariate logistic regression analysis identified cap thickness as the only independent predictor for cTnI ≥3× the upper limit of normal (odds ratio [OR]: 0.90, p = 0.02) or cTnI ≥5× (OR: 0.91, p = 0.04). If OCT findings were excluded from the analysis, plaque burden (OR: 1.13, p = 0.045) and maximum 4-mm lipid core burden index (OR: 1.003, p = 0.037) emerged to be the independent predictors., Conclusions: OCT-based fibrous cap thickness is the most important predictor of periprocedural MI. In the absence of information about cap thickness, NIRS lipid core or IVUS plaque burden best determined the likelihood of the periprocedural event., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The incidence of late coronary artery abnormalities after arterial switch operation (ASO) for d-loop transposition of the great arteries may be underestimated., Methods and results: We retrospectively reviewed coronary artery morphology in 40 of 97 patients who survived the first year after ASO. Seven asymptomatic patients developed significant late coronary artery abnormalities. One patient died suddenly at home with severe left coronary artery (LCA) ostial stenosis at age 3.8 years. The second patient collapsed during exercise at age 9.6 years due to ventricular fibrillation and severe LCA ostial stenosis despite prior negative exercise stress test (EST) and myocardial perfusion imaging (MPI). The third patient was found to have moderate ostial stenosis of the LCA with negative EST and MPI. The fourth patient with exercise-induced ST-T depression and myocardial perfusion defect was shown to have complete LCA occlusion with collateral vessel formation. Three other patients had complete proximal obliteration of either of the coronary arteries with collateral supply. An additional 4 asymptomatic patients had trivial-mild narrowing of the LCA on routine selective coronary angiogram., Conclusions: Incidence of late coronary stenosis or occlusion was not infrequent after ASO (11.3%) and presented usually without preceding symptoms and often after negative non-invasive screening. We advocate routine coronary imaging in all patients after ASO before they participate in competitive sports.

The p.Arg116His mutation in the heat shock transcription factor-4 (HSF4) has been associated with age-related cataracts, but it is also seen in 2% of the normal population, indicating either reduced penetrance or that the normal subjects were not old enough to express the phenotype. Based on the proximity of p.Arg116His to two known mutations in the DNA-binding domain of HSF4, namely, p.Leu114Pro and p.Arg119Cys, which segregate with childhood lamellar cataract, we tested the possibility that this phenotype may have been missed by the ophthalmologist and/or that it did not spread to the visual axis so as to affect vision significantly. Here, we demonstrate via BAC (bacterial artificial chromosome) transgenesis that p.Arg116His recreates the childhood lamellar cataract in mice suggesting that incomplete penetrance associated with early cataracts may not be an absence but a limitation of the detection of the phenotype., (© 2014 WILEY PERIODICALS, INC.)

Purpose: The clinical management of cataracts in infancy involves surgical removal of the lens to ensure transmission of light to the retina, which is essential for normal neural development of the infant. This surgery, however, entails a lifelong follow-up and impaired vision. To our knowledge, no animal models recapitulate human lamellar opacities, the most prevalent form of early childhood cataracts. We present data on the recreation of the human lamellar cataract phenotype in transgenic mice., Methods: Mutations in the DNA binding domain (DBD) of the heat shock transcription factor 4 (HSF4) are known to be associated with early childhood autosomal dominant lamellar cataract. We used bacterial artificial chromosome (BAC) transgenesis to express a hybrid gene: Hsf4 (DBD)-enhanced green fluorescent protein (EGFP), by recombineering EGFP sequences into the DBD of the Hsf4 gene, to interfere with the DNA binding properties of Hsf4., Results: We recapitulated the human lamellar cataract, in its temporal as well as spatial presentation, within the transgenic mouse lens. This phenotype was reproduced faithfully using four different BACs, indicating that EGFP can be used to target transcription factor function in transgenic mice. Molecular and cell biological examination of early postnatal transgenic lens reveals impairment of secondary fiber cell differentiation., Conclusions: Recreation of the human lamellar cataract phenotype in mice allows investigation of this human pathology at a level not possible previously and points to the relevance of fiber cell heterogeneity dictated by fiber cell-specific gene activity in the biogenesis of the lamellar cataract., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Aneurysms-osteoarthritis syndrome (AOS) caused by haploinsufficiency of SMAD3 is a recently described cause of syndromic familial thoracic aortic aneurysm and dissection (TAAD). We identified a novel SMAD3 mutation in a patient with hypoplastic left heart syndrome (HLHS) who developed progressive aortic aneurysm requiring surgical replacement of the neoaortic root, ascending aorta, and proximal aortic arch. Family screening for the mutation revealed that his father, who has vascular and skeletal features of AOS, and his brother, who is asymptomatic, also have the pathogenic mutation. This is the first case report of a SMAD3 mutation in a patient with hypoplastic left heart syndrome. This case highlights the importance of genetic testing for known causes of aneurysm in patients with congenital heart disease who develop aneurysmal disease as it may significantly impact the management of those patients and their family members.

Insulin is known to attenuate septic shock-induced myocardial depression. Possible mechanisms include an anti-inflammatory or inotropic effect of insulin. The objective of this study was to determine whether the mechanism of action of insulin in attenuating septic shock-induced myocardial depression is through an immunomodulatory effect. Fourteen pigs were assigned to one of two groups. Both groups received a 4-h infusion of lipopolysaccharide endotoxin from Escherichia coli 0111:B4. Group 2 additionally received insulin at 1.5 U/kg/h with infusions of D50 normal saline and KCl to maintain normal serum glucose and potassium levels. Cardiac function was measured with shortening fraction using transthoracic echocardiogram. Plasma TNF-α, IL-1β, and IL-6 levels were obtained every 30 min. Postmortem cytokine analysis and histomorphology were performed on the heart tissue. Although insulin attenuated septic shock-induced myocardial depression, this was not due to an anti-inflammatory effect and, therefore, likely resulted from an inotropic effect of insulin.

Background: Early repair of a complete common atrioventricular canal defect (CCAVCD) may benefit patients who exhibit congestive heart failure and failure to thrive. However, concern about increased risk and fragility of valve tissue has commonly led to delaying the surgical repair until the patients achieve a predetermined weight. We report our experience with a strategy of early repair independent of age or weight., Methods: Between 2003 and 2009, 32 patients underwent two-patch repair of CCAVCD at our institution; 22 patients weighed between 2.5 and 4 kg (group #1) and 10 weighed more than 4 kg (group #2). Medical records and echocardiographic studies were reviewed to determine whether there was a difference in the incidence of mortality, rate of reintervention, and complications between the two groups., Results: Operative mortality was 3.1% (1 of 32), with one additional death two years after repair, for an overall mortality of 6.25%. Median duration of mechanical ventilation, median hospital stay, and intropic score was similar between both groups. Freedom from valve reintervention was 91% in group #1 (20 of 22), and 89% in group #2 (8 of 9, p = 1.00)., Conclusions: Complete common atrioventricular canal defect can be repaired safely and effectively in patients under 4 kg. Although mortality was not increased, smaller patients have a tendency for longer intensive care and hospital stay as well as a higher incidence of atrioventricular valve regurgitation. However, valve function improved during the period of follow-up and did not impact the freedom from reintervention.