While studies have shown significant clinical improvement after medial meniscus allograft transplantation (MMAT) with good long-term graft survivorship, progression to osteoarthritis still occurs, ...even in the presence of intact grafts. Several factors can potentially explain the lack of chondroprotection despite graft survivorship, including meniscal degeneration, tearing, and remodeling after the initial procedure. A major factor contributing to progression of osteoarthritis is meniscal extrusion, which is seen in up to 60% of patients and seems to be more of an issue in medial meniscus transplantation compared to lateral and is present even immediately postoperatively. Grafts without extrusion provide protective effects similar to the native meniscus, while greater than 3 mm of extrusion leads to nearly complete loss of the protective effects. A reconstruction of the meniscotibial ligament, in addition to standard MMAT, may significantly decrease meniscal extrusion. Optimization of graft size, quality, and meniscal root positioning is best to prevent extrusion and restore native biomechanics.
Ion channels are integral membrane proteins present on the plasma membrane as well as intracellular membranes. In the human genome, there are more than 400 known genes encoding ion channel proteins. ...Ion channels are known to regulate several cellular, organellar, and physiological processes. Any mutation or disruption in their function can result in pathological disorders, both common or rare. Ion channels present on the plasma membrane are widely acknowledged for their role in various biological processes, but in recent years, several studies have pointed out the importance of ion channels located in intracellular organelles. However, ion channels located in intracellular organelles are not well-understood in the context of physiological conditions, such as the generation of cellular excitability and ionic homeostasis. Due to the lack of information regarding their molecular identity and technical limitations of studying them, intracellular organelle ion channels have thus far been overlooked as potential therapeutic targets. In this review, we focus on a novel class of intracellular organelle ion channels, Chloride Intracellular Ion Channels (CLICs), mainly documented for their role in cardiovascular, neurophysiology, and tumor biology. CLICs have a single transmembrane domain, and in cells, they exist in cytosolic as well as membranous forms. They are predominantly present in intracellular organelles and have recently been shown to be localized to cardiomyocyte mitochondria as well as exosomes. In fact, a member of this family, CLIC5, is the first mitochondrial chloride channel to be identified on the molecular level in the inner mitochondrial membrane, while another member, CLIC4, is located predominantly in the outer mitochondrial membrane. In this review, we discuss this unique class of intracellular chloride channels, their role in pathologies, such as cardiovascular, cancer, and neurodegenerative diseases, and the recent developments concerning their usage as theraputic targets.
Iliac vein compression (LIVC) is a prevalent finding in the general population, but a smaller number of patients are symptomatic. ILVC should be considered in symptomatic patients with unexplained ...unilateral lower leg swelling. Patients typically complain of one or more of the following symptoms: lower leg pain, heaviness, venous claudication, swelling, hyperpigmentation and ulceration. ILVC can be thrombotic, combined with acute or chronic DVT, or non-thrombotic. ILVC is best diagnosed with intravascular ultrasound (IVUS), but computed tomography angiography (CTA) and magnetic resonance angiography (MRA) have emerged as valid screening tests. Venography underestimates the severity of ILVC but may provide insights into the anatomy and the presence of collaterals. Based on current available evidence, endovascular therapy with stenting remains the main treatment strategy for ILVC. Dedicated nitinol venous stents are currently under review by the Food and Drug Administration for potential approval in the United States. These stents have been released outside the US. There is no consensus to the optimal anticoagulation regimen post-ILVC stenting. Oral anticoagulants, however, remain a preferred therapy in patients with history of thrombotic ILVC.
Various biliary pathologic conditions can lead to acute abdominal pain. Specific diagnosis is not always possible clinically because many biliary diseases have overlapping signs and symptoms. Imaging ...can help narrow the differential diagnosis and lead to a specific diagnosis. Although ultrasonography (US) is the most useful imaging modality for initial evaluation of the biliary system, multidetector computed tomography (CT) is helpful when US findings are equivocal or when biliary disease is suspected. Diagnostic accuracy can be increased by optimizing the CT protocol and using multiplanar reformations to localize biliary obstruction. CT can be used to diagnose and stage acute cholecystitis, including complications such as emphysematous, gangrenous, and hemorrhagic cholecystitis; gallbladder perforation; gallstone pancreatitis; gallstone ileus; and Mirizzi syndrome. CT also can be used to evaluate acute biliary diseases such as biliary stone disease, benign and malignant biliary obstruction, acute cholangitis, pyogenic hepatic abscess, hemobilia, and biliary necrosis and iatrogenic complications such as biliary leaks and malfunctioning biliary drains and stents. Treatment includes radiologic, endoscopic, or surgical intervention. Familiarity with CT imaging appearances of emergent biliary pathologic conditions is important for prompt diagnosis and appropriate clinical referral and treatment.
Neuroendocrine tumors (NETs) are a rare group of malignancies which are aggressive and widely metastatic. Cardiac metastases (CMs) are rarely reported because of NET. We aim to analyze the available ...literature to study the proportional prevalence of CM because of NET and its location and effect on the ejection fraction (EF) and survival rate. Our search strategy and meta-analysis are in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) AMSTAR-2 (Assessing the methodological quality of systematic Reviews-2) Guidelines. A literature search was conducted on MEDLINE (EMBASE and PubMed) for randomized clinical trials, pilot trials, and retrospective and prospective studies. Statistical analysis was performed using the CRAN-R software (https://CRAN.R-project.org/doc/FAQ/R-FAQ.html). The quality assessment of the included articles was performed using the Cochrane Risk of Bias and Newcastle-Ottawa Scale. A total of 16,685 patients were included in the study. The mean age of patients included in the study was 61.28 ± SD 9.89 years. Of these, 257 patients had a total of 283 CM. Metastasis was mainly located in the left ventricle with a pooled proportion of 0.48, 95% confidence interval (CI) 0.4 to 0.56, pericardium: 0.34, 95% CI 0.19 to 0.53, right ventricle 0.28, 95% CI 0.16 to 0.44, interventricular septum 0.25, 95% CI 0.16 to 0.37, left atrium 0.1, 95% CI 0.03 to 0.26 and right atrium 0.05, 95% CI 0.01 to 0.20. Decrease in EF at the time of CM diagnosis was the effect most consistently reported in patients with CM. Pooled mean survival was 35.89, 95% CI 8.27 to 155.68 months after the diagnosis of CM. CM due to NET was <2% and the left ventricle is the most common metastatic location, followed by the pericardium. Decreased EF was the most common clinical picture observed. Further studies are needed to analyze the clinical impact of NET CM.
The aim of this study was to evaluate outcomes using total corneal astigmatism (TCA) to calculate arcuate keratotomy(ies) (AK) parameters performed with femtosecond laser-assisted cataract surgery to ...reduce low corneal astigmatism.
Patients who had femtosecond laser-assisted cataract surgery and AK with 0.50 diopter (D) to 1.30 D of TCA were included. Exclusion criteria were intraoperative complications, preexisting corneal surgery, and comorbidities that might adversely affect outcomes. Corneal tomography (Galilei G4, Zeimer Ophthalmic Systems AG) was performed preoperatively and 1 month postoperatively. TCA was input into the Donnenfeld limbal relaxing incisions nomogram to calculate the AK parameters. Preoperative and postoperative tomographic and subjective refractive measurements were compared. The Alpins method for vector analysis evaluated results.
Eighty-two eyes of 82 patients were included. Mean preoperative TCA was significantly reduced from 0.80 ± 0.19 D to 0.51 D ± 0.26 D (P < 0.001). Preoperative posterior corneal astigmatism, -0.28 ± 0.13 D, was unchanged, postoperative posterior corneal astigmatism, -0.28 ± 0.14 D (P = 0.653). Target-induced astigmatism arithmetic mean (0.82 ± 0.21 D) was greater than that of the surgically induced astigmatism (0.70 ± 0.40 D), resulting in an arithmetic mean difference vector of 0.51 ± 0.27 D with a summated mean at 0.16 D at 20 degrees. The correction index was 0.87, indicating undercorrection. Angle of error arithmetic mean, -1.27 ± 23.27 degrees, indicated good alignment.
Inputting TCA for calculation of femtosecond laser AK parameters can reduce low amounts of preoperative corneal astigmatism, thereby improving uncorrected vision.
Background/Aims: Systemic hyperlipidemia and intracellular lipid accumulation induced by chronic high fat diet (HFD) leads to enhanced fatty acid oxidation (FAO) and ketogenesis. The present study ...was aimed to determine whether activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) by surplus free fatty acids (FA) in hyperlipidemic condition, has a positive feedback regulation over FAO and ketogenic enzymes controlling lipotoxicity and cardiac apoptosis. Methods: 8 weeks old C57BL/6 wild type (WT) or PPAR-γ-/- mice were challenged with 16 weeks 60% HFD to induce obesity mediated type 2 diabetes mellitus (T2DM) and diabetic cardiomyopathy. Treatment course was followed by echocardiographic measurements, glycemic and lipid profiling, immunoblot, qPCR and immunohistochemistry (IHC) analysis of PPAR-γ and following mitochondrial metabolic enzymes 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2), mitochondrial β- hydroxy butyrate dehydrogenase (BDH1) and pyruvate dehydrogenase kinase isoform 4 (PDK4). In vivo model was translated in vitro, with neonatal rat cardiomyocytes (NRCM) treated with PPAR-γ agonist/antagonist and PPAR-γ overexpression adenovirus in presence of palmitic acid (PA). Apoptosis was determined in vivo from left ventricular heart by TUNEL assay and immunoblot analysis. Results: We found exaggerated circulating ketone bodies production and expressions of the related mitochondrial enzymes HMGCS2, BDH1 and PDK4 in HFD-induced diabetic hearts and in PA-treated NRCM. As a mechanistic approach we found HFD mediated activation of PPAR-γ is associated with the above-mentioned mitochondrial enzymes. HFD-fed PPAR-γ-/-mice display decreased hyperglycemia, hyperlipidemia associated with increased insulin responsiveness as compared to HFD-fed WT mice PPAR-γ-/–HFD mice demonstrated a more robust functional recovery after diabetes induction, as well as significantly reduced myocyte apoptosis and improved cardiac function. Conclusions: PPAR-γ has been described previously to regulate lipid metabolism and adipogenesis. The present study suggests for the first time that increased PPAR-γ expression by HFD is responsible for cardiac dysfunction via upregulation of mitochondrial enzymes HMGCS2, BDH1 and PDK4. Targeting PPAR-γ and its downstream mitochondrial enzymes will provide novel strategies in preventing metabolic and myocardial dysfunction in diabetes mellitus.
Several studies have reported reprogramming of fibroblasts into induced cardiomyocytes; however, reprogramming into proliferative induced cardiac progenitor cells (iCPCs) remains to be accomplished. ...Here we report that a combination of 11 or 5 cardiac factors along with canonical Wnt and JAK/STAT signaling reprogrammed adult mouse cardiac, lung, and tail tip fibroblasts into iCPCs. The iCPCs were cardiac mesoderm-restricted progenitors that could be expanded extensively while maintaining multipotency to differentiate into cardiomyocytes, smooth muscle cells, and endothelial cells in vitro. Moreover, iCPCs injected into the cardiac crescent of mouse embryos differentiated into cardiomyocytes. iCPCs transplanted into the post-myocardial infarction mouse heart improved survival and differentiated into cardiomyocytes, smooth muscle cells, and endothelial cells. Lineage reprogramming of adult somatic cells into iCPCs provides a scalable cell source for drug discovery, disease modeling, and cardiac regenerative therapy.
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•Cardiac factors reprogram fibroblasts into induced cardiac progenitors cells (iCPCs)•Wnt and JAK/STAT signaling enables robust expansion of iCPCs•iCPCs differentiate into cardiomyocytes, smooth muscle cells, and endothelial cells•Injected iCPCs generate myocardium in the embryonic and adult post-MI mouse heart
Lalit et al. report that a combination of cardiac factors and signaling molecules reprogram adult mouse fibroblasts into expandable induced cardiac progenitor cells (iCPCs). iCPCs are multipotent and can differentiate into cardiomyocytes, smooth muscle, and endothelial cells. Moreover, iCPCs generate myocardium when injected into the embryonic and adult post-MI mouse heart.
Recent studies have shown that cigarette smoke (CS)-induced oxidative stress impairs autophagy, resulting in aggresome-formation that correlates with severity of chronic obstructive pulmonary disease ...(COPD)-emphysema, although the specific step in autophagy pathway that is impaired is unknown. Hence, in this study, we aimed to evaluate the role of master autophagy transcription factor EB (TFEB) in CS-induced COPD-emphysema pathogenesis.
We first observed that TFEB accumulates in perinuclear spaces as aggresome-bodies in COPD lung tissues of tobacco smokers and severe emphysema subjects, compared with non-emphysema or nonsmoker controls. Next, Beas2b cells and C57BL/6 mice were exposed to either cigarette smoke extract (CSE) or subchronic-CS (sc-CS), followed by treatment with potent TFEB-inducing drug, gemfibrozil (GEM, or fisetin as an alternate), to experimentally verify the role of TFEB in COPD. Our in vitro results indicate that GEM/fisetin-mediated TFEB induction significantly (p < 0.05) decreases CSE-induced autophagy-impairment (Ub/LC3B reporter and autophagy flux assay) and resulting aggresome-formation (Ub/p62 coexpression/accumulation; immunoblotting and staining) by controlling reactive oxygen species (ROS) activity. Intriguingly, we observed that CS induces TFEB accumulation in the insoluble protein fractions of Beas2b cells, which shows a partial rescue with GEM treatment. Moreover, TFEB knockdown induces oxidative stress, autophagy-impairment, and senescence, which can all be mitigated by GEM-mediated TFEB induction. Finally, in vivo studies were used to verify that CS-induced autophagy-impairment (increased Ub, p62, and valosin-containing protein in the insoluble protein fractions of lung/cell lysates), inflammation (interleukin-6 IL-6 levels in bronchoalveolar lavage fluid and iNOS expression in lung sections), apoptosis (caspase-3/7), and resulting emphysema (hematoxylin and eosin H&E) can be controlled by GEM-mediated TFEB induction (p < 0.05).
CS exposure impairs autophagy in COPD-emphysema by inducing perinuclear localization of master autophagy regulator, TFEB, to aggresome-bodies.
TFEB-inducing drug(s) can control CS-induced TFEB/autophagy-impairment and COPD-emphysema pathogenesis. Antioxid. Redox Signal. 27, 150-167.
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