Statin administration or blocking PCSK9 alleviates airway hyperresponsiveness and lung fibrosis in high-fat diet-induced obese mice.

BACKGROUND: Obesity is associated with airway hyperresponsiveness and lung fibrosis, which may reduce the effectiveness of standard asthma treatment in individuals suffering from both conditions. Statins and proprotein convertase subtilisin/kexin-9 inhibitors not only reduce serum cholesterol, free fatty acids but also diminish renin-angiotensin system activity and exhibit anti-inflammatory effects. These mechanisms may play a role in mitigating lung pathologies associated with obesity. METHODS: Male C57BL/6 mice were induced to develop obesity through high-fat diet for 16 weeks. Conditional TGF-ß1 transgenic mice were fed a normal diet. These mice were given either atorvastatin or proprotein convertase subtilisin/kexin-9 inhibitor (alirocumab), and the impact on airway hyperresponsiveness and lung pathologies was assessed. RESULTS: High-fat diet-induced obesity enhanced airway hyperresponsiveness, lung fibrosis, macrophages in bronchoalveolar lavage fluid, and pro-inflammatory mediators in the lung. These lipid-lowering agents attenuated airway hyperresponsiveness, macrophages in BALF, lung fibrosis, serum leptin, free fatty acids, TGF-ß1, IL-1ß, IL-6, and IL-17a in the lung. Furthermore, the increased RAS, NLRP3 inflammasome, and cholecystokinin in lung tissue of obese mice were reduced with statin or alirocumab. These agents also suppressed the pro-inflammatory immune responses and lung fibrosis in TGF-ß1 over-expressed transgenic mice with normal diet. CONCLUSIONS: Lipid-lowering treatment has the potential to alleviate obesity-induced airway hyperresponsiveness and lung fibrosis by inhibiting the NLRP3 inflammasome, RAS and cholecystokinin activity.

A stable isotopic approach for quantifying aquaculture-derived organic matter deposition dynamics in the sediment of a coastal fish farm.

The stable carbon and nitrogen isotopic compositions (δ13C and δ15N) of sedimentary organic matter (OM) in fish farms (FFs) were investigated to quantify the aquaculture-derived OM deposition dynamics in the sediment. The dual isotopic compositions of mixed OMs in surface sediments at FFs differed significantly (p < 0.05) from those at reference sites, indicating an increased deposition of fish feces or uneaten feed in the sediments. Furthermore, OM source apportionments revealed that the quantitative contribution of fish feces (23.3 mg g-1 dw) during farming activities was significantly higher than that of other natural OM sources (C3 plants and phytoplankton). After the disassembly of fish cages, the deposited fish feces may be preferentially degraded through processes that require a large amount of oxygen consumption (<0.1 kg C m-2 yr-1). Our isotopic approach may be helpful for assessing the impact of FF wastes and for taking measures to minimize environmental deterioration.

A Spontaneous Nonhuman Primate Model of Myopic Foveoschisis.

Purpose: Foveoschisis involves the pathologic splitting of retinal layers at the fovea, which may occur congenitally in X-linked retinoschisis (XLRS) or as an acquired complication of myopia. XLRS is attributed to functional loss of the retinal adhesion protein retinoschisin 1 (RS1), but the pathophysiology of myopic foveoschisis is unclear due to the lack of animal models. Here, we characterized a novel nonhuman primate model of myopic foveoschisis through clinical examination and multimodal imaging followed by morphologic, cellular, and transcriptional profiling of retinal tissues and genetic analysis. Methods: We identified a rhesus macaque with behavioral and anatomic features of myopic foveoschisis, and monitored disease progression over 14 months by fundus photography, fluorescein angiography, and optical coherence tomography (OCT). After necropsy, we evaluated anatomic and cellular changes by immunohistochemistry and transcriptomic changes using single-nuclei RNA-sequencing (snRNA-seq). Finally, we performed Sanger and whole exome sequencing with focus on the RS1 gene. Results: Affected eyes demonstrated posterior hyaloid traction and progressive splitting of the outer plexiform layer on OCT. Immunohistochemistry showed increased GFAP expression in Müller glia and loss of ramified Iba-1+ microglia, suggesting macro- and microglial activation with minimal photoreceptor alterations. SnRNA-seq revealed gene expression changes predominantly in cones and retinal ganglion cells involving chromatin modification, suggestive of cellular stress at the fovea. No defects in the RS1 gene or its expression were detected. Conclusions: This nonhuman primate model of foveoschisis reveals insights into how acquired myopic traction leads to phenotypically similar morphologic and cellular changes as congenital XLRS without alterations in RS1.

Spatial variability of water quality and sedimentary organic matter during winter season in coastal aquaculture zone of Korea.

We investigated the composition, source, and reactivity of sedimentary organic matter (OM) present in aquaculture systems along the Korean coast. A multi-isotopic approach was applied to 216 surface sediments from five sections: western (W)-1, W-2, southern (S)-1, S-2, and eastern (E)-1 sections. The 15N-enriched total nitrogen signatures in the surface sediments of the W-1 section may indicate that a substantial fraction of sedimentary OM has anthropogenic origins exported through the Han River. Simultaneously, the deposition of allochthonous OM is predominant in the S sections (Jinhae and Masan Bays). The 34S-depleted patterns at the S-2 section may indicate that sulfate reduction occurring at the sedimentary boundary contributes to active OM decomposition, depending on the increased sedimentation of the aquaculture-derived OM. Our results highlight that isotopic-based source tracking near aquaculture systems provide important information for identifying anthropogenic contamination in coastal marine sediments and for improving environmental management.

House dust mite-induced Akt-ERK1/2-C/EBP beta pathway triggers CCL20-mediated inflammation and epithelial-mesenchymal transition for airway remodeling.

House dust mite (HDM) allergens cause inflammatory responses and chronic allergic diseases such as bronchial asthma and atopic dermatitis. Here, we investigate the mechanism by which HDM induces C-C chemokine ligand 20 (CCL20) expression to promote chronic inflammation and airway remodeling in an HDM-induced bronchial asthma mouse model. We showed that HDM increased CCL20 levels via the Akt-ERK1/2-C/EBPß pathway. To investigate the role of CCL20 in chronic airway inflammation and remodeling, we made a mouse model of CCL20-induced bronchial asthma. Treatment of anti-CCL20Ab in this mouse model showed the reduced airway hyper-responsiveness and inflammatory cell infiltration into peribronchial region by neutralizing CCL20. In addition, CCL20 induced the Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation through NLRP3 deubiquitination and transcriptional upregulation in BEAS-2B cells. As expected, anti-CCL20Ab markedly suppressed NLRP3 activation induced by CCL20. Moreover, HDM-induced CCL20 leads to epithelial-mesenchymal transition in the lung epithelium which appears to be an important regulator of airway remodeling in allergic asthma. We also found that anti-CCL20Ab attenuates airway inflammation and remodeling in an HDM-induced mouse model of bronchial asthma. Taken together, our results suggest that HDM-induced CCL20 is required for chronic inflammation that contributes airway remodeling in a mouse model of asthma.

CRISPR-based VEGF suppression using paired guide RNAs for treatment of choroidal neovascularization.

Clustered regularly interspaced short palindromic repeats (CRISPR)-based genomic disruption of vascular endothelial growth factor A (Vegfa) with a single gRNA suppresses choroidal neovascularization (CNV) in preclinical studies, offering the prospect of long-term anti-angiogenesis therapy for neovascular age-related macular degeneration (AMD). Genome editing using CRISPR-CRISPR-associated endonucleases (Cas9) with multiple guide RNAs (gRNAs) can enhance gene-ablation efficacy by augmenting insertion-deletion (indel) mutations with gene truncations but may also increase the risk of off-target effects. In this study, we compare the effectiveness of adeno-associated virus (AAV)-mediated CRISPR-Cas9 systems using single versus paired gRNAs to target two different loci in the Vegfa gene that are conserved in human, rhesus macaque, and mouse. Paired gRNAs increased Vegfa gene-ablation rates in human cells in vitro but did not enhance VEGF suppression in mouse eyes in vivo. Genome editing using paired gRNAs also showed a similar degree of CNV suppression compared with single-gRNA systems. Unbiased genome-wide analysis using genome-wide unbiased identification of double-stranded breaks (DSBs) enabled by sequencing (GUIDE-seq) revealed weak off-target activity arising from the second gRNA. These findings suggest that in vivo CRISPR-Cas9 genome editing using two gRNAs may increase gene ablation but also the potential risk of off-target mutations, while the functional benefit of targeting an additional locus in the Vegfa gene as treatment for neovascular retinal conditions is unclear.

Targeting vascular endothelial growth factor using retinal gene therapy.

Pharmacotherapies targeting vascular endothelial growth factor (VEGF) have revolutionized the management for neovascular retinal disorders including diabetic retinopathy and neovascular age-related macular degeneration. However, the burden of frequent injections, high cost, and treatment resistance in some patients remain unresolved. To overcome these challenges, newer generations of anti-angiogenic biological therapies, engineered proteins, implantable delivery systems, and biopolymers are currently being developed to enable more sustained, longer-lasting treatments. The use of gene therapies for pathologic angiogenesis has garnered renewed interests since the first FDA-approval of a gene therapy to treat inherited retinal diseases associated with biallelic RPE65 mutations. Newer generations of viral vectors and novel methods of intraocular injections helped overcome ocular barriers, improving the efficiency of transduction as well as safety profile. In addition, unlike current anti-VEGF gene therapy strategies which employ a biofactory approach to mimic existing pharmacotherapies, novel genome editing strategies that target pro-angiogenic factors at the DNA level offer a unique and distinct mechanistic approach that can potentially be more precise and lead to a permanent cure. Here, we review current anti-VEGF therapies and newer pharmacologic agents under development, examine technologies and progress in adapting anti-VEGF gene therapies, and explore the future application of CRISPR-Cas9 technology to suppress ocular angiogenesis.

Host Immune Responses after Suprachoroidal Delivery of AAV8 in Nonhuman Primate Eyes.

The suprachoroid is a potential space located between the sclera and choroid of the eye, which provides a novel route for ocular drug or viral vector delivery. Suprachoroidal injection of adeno-associated virus (AAV)8 using transscleral microneedles enables widespread transgene expression in eyes of nonhuman primates, but may cause intraocular inflammation. We characterized the host humoral and cellular immune responses after suprachoroidal delivery of AAV8 expressing green fluorescent protein (GFP) in rhesus macaques, and found that it can induce mild chorioretinitis that resolves after systemic corticosteroid administration, with recovery of photoreceptor morphology, but persistent immune cell infiltration after 3 months, corresponding to a loss of GFP expression from retinal pigment epithelial cells, but persistent expression in scleral fibroblasts. Suprachoroidal AAV8 triggered B cell and T cell responses against GFP, but only mild antibody responses to the viral capsid compared to intravitreal injections of the same vector and dose. Systemic biodistribution studies showed lower AAV8 levels in liver and spleen after suprachoroidal injection compared with intravitreal delivery. Our findings suggest that suprachoroidal AAV8 primarily triggers host immune responses to GFP, likely due to sustained transgene expression in scleral fibroblasts outside the blood-retinal barrier, but elicits less humoral immune reactivity to the viral capsid than intravitreal delivery due to lower egress into systemic circulation. As GFP is not native to primates and not a clinically relevant transgene, suprachoroidal AAV delivery of human transgenes may have significant translational potential for retinal gene therapy.

Obesity-induced Vitamin D Deficiency Contributes to Lung Fibrosis and Airway Hyperresponsiveness.

Vitamin D (VitD) has pleiotropic effects. VitD deficiency is closely involved with obesity and may contribute to the development of lung fibrosis and aggravation of airway hyperresponsiveness (AHR). We evaluated the causal relationship between VitD deficiency and the lung pathologies associated with obesity. In vivo effects of VitD supplementation were analyzed using high-fat diet (HFD)-induced obese mice and TGF-ß1 (transforming growth factor-ß1) triple transgenic mice. Effects of VitD supplementation were also evaluated in both BEAS-2B and primary lung cells from the transgenic mice. Obese mice had decreased 25-OH VitD and VitD receptor expressions with increases of insulin resistance, renin and angiotensin-2 system (RAS) activity, and leptin. In addition, lung pathologies such as a modest increase in macrophages, enhanced TGF-ß1, IL-1ß, and IL-6 expression, lung fibrosis, and AHR were found. VitD supplementation to HFD-induced obese mice recovered these findings. TGF-ß1-overexpressing transgenic mice enhanced macrophages in BAL fluid, lung expression of RAS, epithelial-mesenchymal transition markers, AHR, and lung fibrosis. VitD supplementation also attenuated these findings in addition to the attenuation of the expressions of TGF-ß1, and phosphorylated Smad-2/3 in lung. Supplementing in vitro-stimulated BEAS-2B and primary lung cells with VitD inhibited TGF-ß1 expression, supporting the suppressive effect of VitD for TGF-ß1 expression. These results suggest that obesity leads to VitD deficiency and worsens insulin resistance while enhancing the expression of leptin, RAS, TGF-ß1, and proinflammatory cytokines. These changes may contribute to the development of lung fibrosis and AHR. VitD supplementation rescues these changes and may have therapeutic potential for asthma with obesity.

Quantitative Fundus Autofluorescence in Rhesus Macaques in Aging and Age-Related Drusen.

Purpose: To employ quantitative fundus autofluorescence (qAF) imaging in rhesus macaques to noninvasively assess retinal pigment epithelial (RPE) lipofuscin in nonhuman primates (NHPs) as a model of aging and age-related macular degeneration (AMD). Methods: The qAF imaging was performed on eyes of 26 rhesus macaques (mean age 18.8 ± 8.2 years, range 4-27 years) with normal-appearing fundus or with age-related soft drusen using a confocal scanning laser ophthalmoscope with 488 nm excitation and an internal fluorescence reference. Eyes with soft drusen also underwent spectral-domain optical coherence tomography imaging to measure drusen volume and height of individual drusen lesions. The qAF levels were measured from the perifoveal annular ring (quantitative autofluorescence 8 [qAF8]) using the Delori grid, as well as focally over individual drusen lesions in this region. The association between qAF levels and age, sex, and drusen presence and volume were determined using multivariable regression analysis. Results: Mean qAF levels increased with age (P < 0.001) and were higher in females (P = 0.047). Eyes with soft drusen exhibited reduced mean qAF compared with age-matched normal eyes (P = 0.003), with greater drusen volume showing a trend toward decreased qAF levels. However, qAF levels are focally increased over most individual drusen (P < 0.001), with larger drusen appearing more hyperautofluorescent (R2 = 0.391, P < 0.001). Conclusions: In rhesus macaques, qAF levels are increased with age and female sex, but decreased in eyes with soft drusen, similar to human AMD. However, drusen lesions appear hyperautofluorescent unlike those in humans, suggesting similarities and differences in RPE lipofuscin between humans and NHPs that may provide insight into drusen biogenesis and AMD pathogenesis.

Clinical Characteristics of Campylobacter Enterocolitis in Korean Adults: A Retrospective Study at a Single Center.

Background/Aims: Although the diarrheal disease caused by Campylobacter bacteria has been continuously increasing in Korea, there has been limited study on the clinical aspects of Campylobacter enteritis in adults in Korea. The purpose of this study was to analyze the clinical features and characteristics of adult patients with Campylobacter enteritis. Methods: This retrospective study included patients diagnosed with Campylobacter enterocolitis at Nowon Eulji University Hopsital between January 2016 and December 2017. Campylobacter enterocolitis was diagnosed through polymerase chain reaction of stools from patients with acute diarrhea. Results: Among 630 hospitalized patients with acute diarrhea, Campylobacter enterocolitis was diagnosed in 88 patients (14.0%). The mean age was 37.9±19.1 years. Campylobacter enterocolitis was most prevalent in the summer (52 patients, 59.1%). Patients exhibited more than 10 times of diarrhea in 36 (40.9%), high fever above 39°C in 19 (21.59%), and abdominal pain above 5 points on the numeric rating scale in 23 (26.14%) cases. In abdominal CT scan, pancolitis was found in 58 patients (65.9%). Small intestine was involved in 37 patients (42.4%). Mean CRP was 10.14 mg/dL (range 0.72-32.27 mg/dL). The duration of diarrhea after antibiotics treatment was 2.34±1.51 days in the ciprofloxacin treatment group and 2.26±1.71 days in the 3rd cephalosporin treatment group. Conclusions: Campylobacter enterocolitis was common during summer. Commonly healthy young adults were hospitalized due to severe symptoms of Campylobacter enterocolitis. Whole colon and small bowel were frequently involved. Most patients were treated with antibiotics, and the efficacy of 3rd cephalosporin treatment was not inferior to that of ciprofloxacin treatment.

Factors Impacting Efficacy of AAV-Mediated CRISPR-Based Genome Editing for Treatment of Choroidal Neovascularization.

Frequent injections of anti-vascular endothelial growth factor (anti-VEGF) agents are a clinical burden for patients with neovascular age-related macular degeneration (AMD). Genomic disruption of VEGF-A using adeno-associated viral (AAV) delivery of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 has the potential to permanently suppress aberrant angiogenesis, but the factors that determine the optimal efficacy are unknown. Here, we investigate two widely used Cas9 endonucleases, SpCas9 and SaCas9, and evaluate the relative contribution of AAV-delivery efficiency and genome-editing rates in vivo to determine the mechanisms that drive successful CRISPR-based suppression of VEGF-A, using a mouse model of laser-induced choroidal neovascularization (CNV). We found that SpCas9 demonstrated higher genome-editing rates, greater VEGF reduction, and more effective CNV suppression than SaCas9, despite similar AAV transduction efficiency between a dual-vector approach for SpCas9 and single-vector system for SaCas9 to deliver the Cas9 orthologs and single guide RNAs (gRNAs). Our results suggest that successful VEGF knockdown using AAV-mediated CRISPR systems may be determined more by the efficiency of genome editing rather than viral transduction and that SpCas9 may be more effective than SaCas9 as a potential therapeutic strategy for CRISPR-based treatment of CNV in neovascular AMD.

Suprachoroidal and Subretinal Injections of AAV Using Transscleral Microneedles for Retinal Gene Delivery in Nonhuman Primates.

Retinal gene therapy using adeno-associated viruses (AAVs) is constrained by the mode of viral vector delivery. Intravitreal AAV injections are impeded by the internal limiting membrane barrier, while subretinal injections require invasive surgery and produce a limited region of therapeutic effect. In this study, we introduce a novel mode of ocular gene delivery in rhesus macaques using transscleral microneedles to inject AAV8 into the subretinal or suprachoroidal space, a potential space between the choroid and scleral wall of the eye. Using in vivo imaging, we found that suprachoroidal AAV8 produces diffuse, peripheral expression in retinal pigment epithelial (RPE) cells, but it elicited local infiltration of inflammatory cells. Transscleral subretinal injection of AAV8 using microneedles leads to focal gene expression with transduction of RPE and photoreceptors, and minimal intraocular inflammation. In comparison, intravitreal AAV8 shows minimal transduction of retinal cells, but elicits greater systemic humoral immune responses. Our study introduces a novel mode of transscleral viral delivery that can be performed without vitreoretinal surgery, with focal or diffuse transgene expression patterns suitable for different applications. The decoupling of local and systemic immune responses reveals important insights into the immunological consequences of AAV delivery to different ocular compartments surrounding the blood-retinal barrier.

Long-term Evolution and Remodeling of Soft Drusen in Rhesus Macaques.

Purpose: To characterize the evolution and structure of soft drusen in aged rhesus macaques using in vivo multimodal retinal imaging and ex vivo histologic and ultrastructural analyses as a nonhuman primate model of early age-related macular degeneration (AMD). Methods: Multimodal imaging including fundus photography, spectral domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) were used to characterize and track individual drusen lesions in 20 aged rhesus macaques (mean age 23.3 ± 2.7 years) with drusenoid lesions over 2 years, followed by semithin histologic analysis and transmission electron microscopy (TEM). Results: Although most drusen gradually increased in size, a portion spontaneously regressed or collapsed over 2 years. Histologic analyses showed that soft drusen exhibit hypertrophy and dysmorphia of overlying retinal pigment epithelium (RPE), as seen in early and intermediate AMD, but do not exhibit RPE atrophy, RPE migration, or photoreceptor degeneration characteristic of advanced AMD. Ultrastructure of soft drusen showed abundant lipid particles within Bruch's membrane and AMD-related basal linear deposits (BlinD) resembling those in human drusen. Conclusions: The dynamic remodeling, histologic findings, and ultrastructural features of soft drusen in aged rhesus macaques support nonhuman primates as an animal model of early AMD and reveal important insights into drusen biogenesis and AMD development.

CRISPR Technology for Ocular Angiogenesis.

Among genome engineering tools, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based approaches have been widely adopted for translational studies due to their robustness, precision, and ease of use. When delivered to diseased tissues with a viral vector such as adeno-associated virus, direct genome editing can be efficiently achieved in vivo to treat different ophthalmic conditions. While CRISPR has been actively explored as a strategy for treating inherited retinal diseases, with the first human trial recently initiated, its applications for complex, multifactorial conditions such as ocular angiogenesis has been relatively limited. Currently, neovascular retinal diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and neovascular age-related macular degeneration, which together constitute the majority of blindness in developed countries, are managed with frequent and costly injections of anti-vascular endothelial growth factor (anti-VEGF) agents that are short-lived and burdensome for patients. By contrast, CRISPR technology has the potential to suppress angiogenesis permanently, with the added benefit of targeting intracellular signals or regulatory elements, cell-specific delivery, and multiplexing to disrupt different pro-angiogenic factors simultaneously. However, the prospect of permanently suppressing physiologic pathways, the unpredictability of gene editing efficacy, and concerns for off-target effects have limited enthusiasm for these approaches. Here, we review the evolution of gene therapy and advances in adapting CRISPR platforms to suppress retinal angiogenesis. We discuss different Cas9 orthologs, delivery strategies, and different genomic targets including VEGF, VEGF receptor, and HIF-1α, as well as the advantages and disadvantages of genome editing vs. conventional gene therapies for multifactorial disease processes as compared to inherited monogenic retinal disorders. Lastly, we describe barriers that must be overcome to enable effective adoption of CRISPR-based strategies for the management of ocular angiogenesis.

Differentiation of Retinal Glial Cells From Human Embryonic Stem Cells by Promoting the Notch Signaling Pathway.

Dysfunction of retinal glial cells, particularly Müller cells, has been implicated in several retinal diseases. Despite their important contribution to retinal homeostasis, a specific way to differentiate retinal glial cells from human pluripotent stem cells has not yet been described. Here, we report a method to differentiate retinal glial cells from human embryonic stem cells (hESCs) through promoting the Notch signaling pathway. We first generated retinal progenitor cells (RPCs) from hESCs then promoted the Notch signaling pathway using Notch ligands, including Delta-like ligand 4 and Jagged-1. We validated glial cell differentiation with qRT-PCR, immunocytochemistry, western blots and fluorescence-activated cell sorting as we promoted Notch signaling in RPCs. We found that promoting Notch signaling in RPCs for 2 weeks led to upregulation of glial cell markers, including glial fibrillary acidic protein (GFAP), glutamine synthetase, vimentin and cellular retinaldehyde-binding protein (CRALBP). Of these markers, we found the greatest increase in expression of the pan glial cell marker, GFAP. Conversely, we also found that inhibition of Notch signaling in RPCs led to upregulation of retinal neuronal markers including cone-rod homeobox (CRX) and orthodenticle homeobox 2 (OTX2) but with little expression of GFAP. This retinal glial differentiation method will help advance the generation of stem cell disease models to study the pathogenesis of retinal diseases associated with glial dysfunction such as macular telangiectasia type 2. This method may also be useful for the development of future therapeutics such as drug screening and gene editing using patient-derived retinal glial cells.

Risk Factors for Asymptomatic Colon Diverticulosis.

BACKGROUNDS/AIMS: The etiology of colon diverticulosis is related to a range of genetic, biological, and environmental factors, but the risk factors for asymptomatic diverticulosis of the colon are unclear. This study examined the risk factors for asymptomatic colon diverticulosis. METHODS: This retrospective study included examinees who underwent a colonoscopy for screening at the health check-up center of SAM Hospital between January 2016 and December 2016. The examinees with colon diverticulosis found by colonoscopy were compared with those without diverticulosis. The comparison factors were age, gender, alcohol consumption, smoking status, medical history, lipid profile, body mass index, visceral fat area, waist-hip ratio, and severity of a fatty liver. RESULTS: This study included 937 examinees and the overall prevalence of diverticulosis was 8.1% (76/937). Fatty liver was found in 69.7% (53/76) in cases of colon diverticulosis and 50.3% (433/861) in the control group (p=0.001). The average waist-hip ratio was 0.92±0.051 in colon diverticulosis and 0.90±0.052 in the control group (p=0.052). Multivariate analysis revealed the waist-hip ratio (OR=1.035, 95% CI 1.000-1.070, p=0.043), moderate fatty liver (OR=2.238, 95% CI 1.026-4.882, p=0.043), and severe fatty liver (OR=5.519, 95% CI 1.236-21.803, p=0.025) to be associated with an increased risk of asymptomatic colon diverticulosis. CONCLUSIONS: The waist-hip ratio, moderate fatty liver, and severe fatty liver are risk factors for asymptomatic colon diverticulosis. Central obesity, which can be estimated by the waist-hip ratio, and fatty liver might affect the pathogenesis of asymptomatic colon diverticulosis.

Innervation of the Flexor Digitorum Profundus: A Systematic Review.

PURPOSE: The aim of this study was to review the innervation of the flexor digitorum profundus (FDP). METHODS: In PubMed and Scopus, terms (Flexor digitorum profundus OR FDP) AND (innervation OR nerve) were used, resulting in 233 and 281 papers, respectively. After excluding 142 duplicates, 73 abstracts were reviewed. Forty-seven abstracts were excluded, 26 full papers were reviewed, and 17 papers were analyzed. RESULTS: In most cases (97.6%), the index FDP was innervated by the anterior interosseous nerve (AIN). Dual innervation from the AIN and ulnar nerve (UN) was observed in 2.4% of papers. In majority (76.8%), the middle FDP received dual innervation from the AIN and the UN. The rest was innervated by the AIN only (22.0%) or the UN only (1.2%). In most cases (85.4%), the ring FDP was innervated by the UN only. The rest (14.6%) received dual innervation from the AIN and the UN. In majority of cases (64.6%), the little FDP was innervated by the UN only. The rest (35.4%) received dual innervation from the AIN and the UN. The AIN entered the FDP at 107.63 (8.80) mm from the elbow, corresponding to 26.75% (2.17%) of the forearm length, measured proximally. The average number of AIN branches to the FDP was 2.27 (1.33). The average number of UN branches to the FDP was 1.37 (0.94). In 8.8% of limbs, a communicating branch supplied the FDP. Among the limbs with a communicating branch, 32.3% had branches supplying the FDP. CONCLUSION: The results of this study may be useful in managing nerve injury patients.

OBJECTIF: La présente étude visait à analyser l'innervation du tendon fléchisseur profond (TFP). MÉTHODOLOGIE: Dans PubMed et Scopus, les chercheurs ont utilisé les termes Flexor digitorum profundus OU FDP ET innervation OU nerve et ont obtenu 233 et 281 articles, respectivement. Après avoir exclu 142 articles dédoublés, ils ont examiné 73 résumés et en ont exclu 47. Ils ont parcouru 26 articles complets et en ont analysé 17. RÉSULTATS: Dans la plupart des cas (97.6%), le TFP de l'index était innervé par le nerf interosseux antérieur (NIA). Les chercheurs ont observé la double innervation par le NIA et le nerf ulnaire (NU) dans 2.4% des cas. Le TFP du majeur était doublement innervé par le NIA et le NU dans la majorité des cas (76.8%). Les autres cas étaient innervés seulement par le NIA (22.0%) ou par le NU (1.2%). Dans la plupart des cas (85.4%), le TFP de l'annulaire était seulement innervé par le NU. Les autres (14.6%) étaient doublement innervés par le NIA et le NU. Le TFP de l'auriculaire était seulement innervé par le NU dans la majorité des cas (64.6%). Les autres (35.4%) étaient doublement innervés par le NIA et le NU. Le NIA pénétrait dans le TFP à 107.63 (8.80) mm du coude, ce qui correspond à une mesure proximale de 26.75% (2.17%) de la longueur de l'avant-bras. Il y avait une moyenne de 2.27 (1.33) ramifications du NIA vers le TFP et de 1.37 (0.94) ramification du NU vers le TFP. Dans 8.8% des membres, une ramification communicante alimentait le TFP; 32.3% étaient alors dotés de ramifications alimentant le TFP. CONCLUSION: Les résultats de la présente étude peuvent être utiles pour la prise en charge des patients ayant une lésion nerveuse.

Transforming Growth Factor-ß Promotes Liver Tumorigenesis in Mice via Up-regulation of Snail.

BACKGROUND & AIMS: Transforming growth factor beta (TGF-ß) suppresses early stages of tumorigenesis, but also contributes to migration and metastasis of cancer cells. A large number of human tumors contain mutations that inactivate its receptors, or downstream proteins such as Smad transcription factors, indicating that the TGF-ß signaling pathway prevents tumor growth. We investigated the effects of TGF-ß inhibition on liver tumorigenesis in mice. METHODS: C57BL/6 mice received hydrodynamic tail-vein injections of transposons encoding HRASG12V and a short hairpin RNA (shRNA) to down-regulate p53, or those encoding HRASG12V and MYC, or those encoding HRASG12V and TAZS89A, to induce liver tumor formation; mice were also given injections of transposons encoding SMAD7 or shRNA against SMAD2, SMAD3, SMAD4, or SNAI1 (Snail), with or without ectopic expression of Snail. Survival times were compared, and livers were weighted and examined for tumors. Liver tumor tissues were analyzed by quantitative reverse-transcription PCR, RNA sequencing, immunoblots, and immunohistochemistry. We analyzed gene expression levels in human hepatocellular carcinoma samples deposited in The Cancer Genome Atlas. A cell proliferation assay was performed using human liver cancer cell lines (HepG2 and Huh7) stably expressing Snail or shRNA against Snail. RESULTS: TGF-ß inhibition via overexpression of SMAD7 (or knockdown of SMAD2, SMAD3, or SMAD4) consistently reduced formation and growth of liver tumors in mice that expressed activated RAS plus shRNA against p53, or in mice that expressed activated RAS and TAZ. TGF-ß signaling activated transcription of the Snail gene in liver tumors induced by HRASG12V and shRNA against p53, and by activated RAS and TAZ. Knockdown of Snail reduced liver tumor formation in both tumor models. Ectopic expression of Snail restored liver tumorigenesis suppressed by disruption of TGF-ß signaling. In human hepatocellular carcinoma, Snail expression correlated with TGF-ß activation. Ectopic expression of Snail increased cellular proliferation, whereas Snail knockdown led to reduced proliferation in human hepatocellular carcinoma cells. CONCLUSIONS: In analyses of transgenic mice, we found TGF-ß signaling to be required for formation of liver tumors upon expression of activated RAS and shRNA down-regulating p53, and upon expression of activated RAS and TAZ. Snail is the TGF-ß target that is required for hepatic tumorigenesis in these models.