In the outer solar system, a growing number of giant planet satellites are now known to be abodes for global oceans hidden below an outer layer of ice. These planetary oceans are a natural laboratory for studying physical oceanographic processes in settings that challenge traditional assumptions made for Earth's oceans. While some driving mechanisms are common to both systems, such as buoyancy-driven flows and tides, others, such as libration, precession, and electromagnetic pumping, are likely more significant for moons in orbit around a host planet. Here, we review these mechanisms and how they may operate across the solar system, including their implications for ice-ocean interactions. Future studies should continue to advance our understanding of each of these processes as well as how they may act together in concert. This interplay also has strong implications for habitability as well as testing oceanic hypotheses with future missions.
Ice Cover , Moon , Oceanography
BACKGROUND AND AIM: Anti-reflux mucosal ablation (ARMA) is an emerging endoscopic treatment aimed at enhancing the gastroesophageal junction flap valve. This study aimed to evaluate its feasibility, effectiveness, and safety. METHODS: Between May 2018 and December 2022, patients with gastroesophageal reflux disease (GERD) symptoms refractory to acid suppression medications or those dependent on such medications were enrolled for ARMA. This retrospective analysis utilized prospectively collected data from an international bi-center study. GERD questionnaire, upper endoscopy, and 24-h pH monitoring were conducted at 2-6 months and 12 months post-ARMA. Clinical success was defined as a > 50% reduction in a validated GERD questionnaire. RESULTS: A total of 68 patients underwent ARMA. Definitive GERD was diagnosed in 44 (64.7%) patients, while 24 (35.3%) exhibited reflux hypersensitivity. Clinical success rates at 2-6 months and 1 year post-ARMA were 60% (39/65) and 70% (21/30), respectively. The median GERD-health-related quality of life score significantly improved from 26 to 11 at 2-6 months (P < 0.001). Among the 51 patients (71.8%) who underwent 24-h pH monitoring, the median acid exposure time decreased from 5.3% to 0.7% (P = 0.003), accompanied by a significant reduction in esophagitis rates (P < 0.001). Multivariate analysis did not identify predictors of short-term success. Nine (13.2%) patients experienced transient stenosis requiring balloon dilation. CONCLUSIONS: ARMA demonstrates both technical feasibility and reproducibility as a safe procedure that effectively ameliorates GERD symptoms in approximately two-thirds of patients during short-term follow up. Both reflux hypersensitivity and confirmed GERD patients, regardless of their response to acid suppression medication, may be suitable candidates.
Gastroesophageal Reflux , Quality of Life , Humans , Retrospective Studies , Reproducibility of Results , Gastroesophageal Reflux/complications , Endoscopy, Gastrointestinal
BACKGROUND & AIM: Peroral endoscopic myotomy (POEM) is a safe and effective endoscopic treatment for achalasia and other esophageal motility disorders, and TTJ (Triangle Tip Knife J; Olympus, Tokyo, Japan) is currently widely used in POEM. Recently, we reported a novel modification of TTJ, which was adjusted to knife length 2 mm by attaching a disposable clip (QuickClip Pro; Olympus) sheath to the tip as a hood attachment. In this study, we compared the safety and effectiveness of TTJ and TTJ with hood attachment (TTJ-H) in POEM. METHODS: In this 1:1 propensity score matched retrospective cohort study, we compared the procedure time, myotomy efficiency, number of coagulation forceps usage, adverse events, length of hospital stay after POEM, procedural success and clinical success between TTJ and TTJ-H groups. RESULTS: We examined 682 consecutive patients who underwent POEM between January 2021 and June 2023. We excluded 134 patients who had already undergone POEM or laparoscopic Heller myotomy as prior myotomy. Finally, we identified 98 propensity score-matched pairs (n = 196). The mean procedure time was shortened from 93.5 to 80.2 min (14% reduction, P = 0.012) when comparing TTJ-H group to TTJ group. The mean myotomy efficiency was improved from 2.76 to 2.32 min/cm (16% improvement, P = <0.001), and usage of coagulation forceps for hemostasis was decreased from 3.87 to 0.55 (86% reduction, P = <0.001). CONCLUSIONS: This study showed that use of TTJ-H could reduce total procedure time, improve myotomy efficiency, and reduce costs compared to TTJ.
Video 1We present a new therapeutic approach called antireflux mucoplasty for proton pump inhibitor-refractory GERD.
Video 1Demonstration of the usefulness of percutaneous cricothyrotomy and a super-soft hood for hypopharyngeal endoscopic submucosal dissection.
Video 1Demonstration of endoscopic mucoplasty for benign esophageal strictures (multiple Schatzki rings).
Video 1Triangle-tip jet knife with hood attachment: a novel modification over existing endoscopic knife.
OBJECTIVES: Anti-reflux mucosectomy (ARMS) and anti-reflux mucosal ablation (ARMA) were developed as interventions for proton pump inhibitor (PPI)-refractory/-dependent gastroesophageal reflux disease (GERD). Although ARMS and ARMA are established treatments for PPI-refractory GERD, reliance on natural healing for ulcer scar formation introduces uncertainty and bleeding risk. To address these issues, we introduced a novel approach called anti-reflux mucoplasty (ARM-P), which involves immediate closure of mucosal defects following mucosectomy. This pilot study aims to evaluate the safety, feasibility, and efficacy of ARM-P. METHODS: A retrospective single-center study was conducted using prospectively collected data from October 2022 to July 2023. Patients with PPI-refractory/-dependent GERD who underwent ARM-P were included. The study evaluated technical success of ARM-P, before and after ARM-P GERD-Health Related Quality of Life Questionnaire, GerdQ, and Frequency Scale for the Symptoms of GERD scores, along with PPI discontinuation and endoscopic esophagogastric junction morphology. RESULTS: A total of 20 patients with a median age of 61.5 years underwent the ARM-P procedure. The procedure achieved 100% technical success without adverse events. After ARM-P, 55.0% discontinued PPI usage and 15.0% reduced PPI dose by half. Median GERD-Health Related Quality of Life Questionnaire score improved from 21 to 6 (P = 0.0026), median GerdQ score improved from 9 to 7 (P = 0.0022), and median Frequency Scale for the Symptoms of GERD score decreased from 16 to 7 (P = 0.0003). Median Hill's Classification significantly improved from grade III to grade I (P = 0.0001). CONCLUSIONS: This study presents the first pilot report of ARM-P, demonstrating its procedural safety, technical feasibility, and short-term efficacy.
OBJECTIVES: The endoscopic pressure study integrated system (EPSIS) is a novel diagnostic tool used to evaluate lower esophageal sphincter (LES) function. EPSIS allows the measurement of intragastric pressure (IGP) during gastric insufflation through esophagogastroduodenoscopy (EGD) and records its pressure waveform. This study aimed to assess the usefulness and applicability of EPSIS as an adjunct diagnostic modality for achalasia. METHODS: This case-control study was conducted using a database of patients who underwent EGD, barium swallow (BS), high-resolution manometry (HRM), and EPSIS between January 2022 and December 2022. The achalasia (experimental) group (n = 35) consisted of patients with a definitive diagnosis of achalasia. The control group (n = 34) consisted of patients with no abnormalities in EGD, BS, or HRM and no abnormal acid reflux confirmed with 24-h pH-impedance monitoring. EPSIS findings were compared between the two groups and characterized by the waveform pattern (uphill or flat), maximum IGP (IGP-Max), pressure difference, and the gradient of the waveform. RESULTS: All patients in the achalasia group showed an uphill pattern, in contrast to 21 patients (61.8%) in the control group. IGP-Max demonstrated the best diagnostic accuracy for achalasia, with a cut-off value of 15.8 mmHg (100% sensitivity, 58.8% specificity, and area under the curve [AUC] 0.78). The pressure gradient also demonstrated good diagnostic accuracy, with a cut-off value of 0.40 mmHg/s (80% sensitivity, 61.8% specificity, and AUC 0.76). CONCLUSION: This study demonstrated that EPSIS can be applied as a diagnostic modality in patients with achalasia.
Video 1Demonstration of the Loop-10 closure technique for unintentional mucosal perforation during re-do esophageal peroral endoscopic myotomy.
With the advent of endoscopic submucosal dissection, a variety of endoscopic devices including knives and high-frequency electrosurgical unit have become available. In addition, the concept of natural orifice transluminal endoscopic surgery pushed flexible endoscopic surgery ahead. In this review, the birth of peroral endoscopic myotomy and its expansion into the field of submucosal endoscopy are reviewed.
Digestive System Surgical Procedures , Endoscopic Mucosal Resection , Esophageal Achalasia , Natural Orifice Endoscopic Surgery , Humans , Esophageal Achalasia/surgery , Endoscopy, Gastrointestinal
The inferred density of Enceladus' core, together with evidence of hydrothermal activity within the moon, suggests that the core is porous. Tidal dissipation in an unconsolidated core has been proposed as the main source of Enceladus' geological activity. However, the tidal response of its core has generally been modeled assuming it behaves viscoelastically rather than poroviscoelastically. In this work, we analyze the poroviscoelastic response to better constrain the distribution of tidal dissipation within Enceladus. A poroviscoelastic body has a different tidal response than a viscoelastic one; pressure within the pores alters the stress field and induces a Darcian porous flow. This flow represents an additional pathway for energy dissipation. Using Biot's theory of poroviscoelasticity, we develop a new framework to obtain the tidal response of a spherically symmetric, self-gravitating moon with porous layers and apply it to Enceladus. We show that the boundary conditions at the interface of the core and overlying ocean play a key role in the tidal response. The ocean hinders the development of a large-amplitude Darcian flow, making negligible the Darcian contribution to the dissipation budget. We therefore infer that Enceladus' core can be the source of its geological activity only if it has a low rigidity and a very low viscosity. A future mission to Enceladus could test this hypothesis by measuring the phase lags of tidally induced changes of gravitational potential and surface displacements.
Delivery of adeno-associated viral vectors (AAVs) to cerebrospinal fluid (CSF) has emerged as a promising approach to achieve widespread transduction of the central nervous system (CNS) and peripheral nervous system (PNS), with direct applicability to the treatment of a wide range of neurological diseases, particularly lysosomal storage diseases. Although studies in small animal models have provided proof of concept and experiments in large animals demonstrated feasibility in bigger brains, there is not much information on long-term safety or durability of the effect. Here, we report a 7-year study in healthy beagle dogs after intra-CSF delivery of a single, clinically relevant dose (2 × 1013 vg/dog) of AAV9 vectors carrying the canine sulfamidase, the enzyme deficient in mucopolysaccharidosis type IIIA. Periodic monitoring of CSF and blood, clinical and neurological evaluations, and magnetic resonance and ultrasound imaging of target organs demonstrated no toxicity related to treatment. AAV9-mediated gene transfer resulted in detection of sulfamidase activity in CSF throughout the study. Analysis at tissue level showed widespread sulfamidase expression and activity in the absence of histological findings in any region of encephalon, spinal cord, or dorsal root ganglia. Altogether, these results provide proof of durability of expression and long-term safety for intra-CSF delivery of AAV-based gene transfer vectors encoding therapeutic proteins to the CNS.
Mucopolysaccharidosis type IVA (MPSIVA) or Morquio A disease, a lysosomal storage disorder, is caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, resulting in keratan sulfate (KS) and chondroitin-6-sulfate accumulation. Patients develop severe skeletal dysplasia, early cartilage deterioration and life-threatening heart and tracheal complications. There is no cure and enzyme replacement therapy cannot correct skeletal abnormalities. Here, using CRISPR/Cas9 technology, we generate the first MPSIVA rat model recapitulating all skeletal and non-skeletal alterations experienced by patients. Treatment of MPSIVA rats with adeno-associated viral vector serotype 9 encoding Galns (AAV9-Galns) results in widespread transduction of bones, cartilage and peripheral tissues. This led to long-term (1 year) increase of GALNS activity and whole-body correction of KS levels, thus preventing body size reduction and severe alterations of bones, teeth, joints, trachea and heart. This study demonstrates the potential of AAV9-Galns gene therapy to correct the disabling MPSIVA pathology, providing strong rationale for future clinical translation to MPSIVA patients.
Chondroitinsulfatases/genetics , Dependovirus/genetics , Disease Models, Animal , Genetic Therapy/methods , Mucopolysaccharidosis IV/therapy , Musculoskeletal System/metabolism , Animals , Cartilage, Articular/metabolism , Cartilage, Articular/pathology , Cartilage, Articular/ultrastructure , Chondroitinsulfatases/deficiency , Chondroitinsulfatases/metabolism , Gene Expression Regulation, Enzymologic , Genetic Vectors/genetics , Humans , Male , Microscopy, Electron, Transmission , Mucopolysaccharidosis IV/enzymology , Mucopolysaccharidosis IV/genetics , Musculoskeletal System/pathology , Musculoskeletal System/ultrastructure , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Treatment Outcome
Careful control of iron availability in the retina is central to maintenance of iron homeostasis, as its imbalance is associated with oxidative stress and the progression of several retinopathies. Ferritin, known for its role in iron storage and detoxification, has also been proposed as an iron-transporter protein, through its binding to Scara5 and TIM2 membrane receptors. In this study, the presence and iron-related functions of TIM2 in the mouse retina were investigated. Our results revealed for the first time the presence of TIM2 receptors in the mouse retina, mainly in Müller cells. Experimental TIM2 downregulation in the mouse retina promoted, probably due to a compensatory mechanism, Scara5 overexpression that increased retinal ferritin uptake and induced iron overload. Consecutive reactive oxygen species (ROS) overproduction and vascular endothelial growth factor (VEGF) overexpression led to impaired paracellular and transcellular endothelial transport characterized by tight junction degradation and increased caveolae number. In consequence, blood-retinal barrier (BRB) breakdown and retinal edema were observed. Altogether, these results point to TIM2 as a new modulator of retinal iron homeostasis and as a potential target to counteract retinopathy.
Blood-Retinal Barrier/physiology , Ependymoglial Cells/metabolism , Ferritins/metabolism , Membrane Proteins/physiology , Animals , Biological Transport , Blotting, Western , Homeostasis/physiology , Immunohistochemistry , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Electron, Transmission , Ophthalmoscopy , Oxidative Stress , Reactive Oxygen Species/metabolism , Real-Time Polymerase Chain Reaction , Scavenger Receptors, Class A/metabolism , Spectrometry, X-Ray Emission , Tandem Mass Spectrometry , Vascular Endothelial Growth Factor A/metabolism
Purpose: It has been suggested that arteriolar annuli localized in retinal arterioles regulate retinal blood flow acting as sphincters. Here, the morphology and protein expression profile of arteriolar annuli have been analyzed under physiologic conditions in the retina of wild-type, ß-actin-Egfp, and Nestin-gfp transgenic mice. Additionally, to study the effect of hypertension, the KAP transgenic mouse has been used. Methods: Cellular architecture has been studied using digested whole mount retinas and transmission electron microscopy. The profile of protein expression has been analyzed on paraffin sections and whole mount retinas by immunofluorescence and histochemistry. Results: The ultrastructural analysis of arteriolar annuli showed a different cell population found between endothelial and muscle cells that matched most of the morphologic criteria established to define interstitial Cajal cells. The profile of protein expression of these vascular interstitial cells (VICs) was similar to that of interstitial Cajal cells and different from the endothelial and smooth muscle cells, because they expressed ß-actin, nestin, and CD44, but they did not express CD31 and α-SMA or scarcely express F-actin. Furthermore, VICs share with pericytes the expression of NG2 and platelet-derived growth factor receptor beta (PDGFR-ß). The high expression of Ano1 and high activity of nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase observed in VICs was diminished during hypertensive retinopathy suggesting that these cells might play a role on the motility of arteriolar annuli and that this function is altered during hypertension. Conclusions: A novel type of VICs has been described in the arteriolar annuli of mouse retina. Remarkably, these cells undergo important molecular modifications during hypertensive retinopathy and might thus be a therapeutic target against this disease.
Endothelial Cells/pathology , Hypertension/pathology , Hypertensive Retinopathy/pathology , Interstitial Cells of Cajal/pathology , Retinal Artery/pathology , Actins/metabolism , Animals , Anoctamin-1/metabolism , Arterial Pressure , Arterioles/pathology , Endothelial Cells/metabolism , Green Fluorescent Proteins/metabolism , Histocytochemistry , Hyaluronan Receptors/metabolism , Hypertensive Retinopathy/metabolism , Interstitial Cells of Cajal/metabolism , Mice , Mice, Inbred ICR , Mice, Transgenic , Microscopy, Electron, Transmission , Microscopy, Fluorescence , NADPH Dehydrogenase/metabolism , Nestin/metabolism
Genital organs from 33 nocturnal monkeys Aotus namcymaae, 29 Poeppig's woolly monkeys (Lagothrix poeppigii), 21 red uakaris (Cacajao calvus) and 11 large-headed capuchins (Sapajus macrocephalus) were histologically analyzed in order to describe the endometrial changes related to the ovarian cycle. A. nancymaae and S. macrocephalus showed histological evidence of menstrual cycle with the detachment of the most superficial endometrium and the subepithelial reabsorption of the endometrial functional layer, explaining the extensive presence of both hemosiderin and fibrin clusters in the early follicular stages. In L. poeppigii, despite the presence of fibrin clusters promoting the remodeling of the endometrium, we did not observe the detachment of the functional layer of the endometrium, suggesting that this species presents a non-menstruating cycle. Finally, C. calvus showed no histological sign of menstrual phase. This reproductive information is useful to improve assisted reproductive techniques in non-human primates, and give us opportunity for comparative studies on the evolution of animal reproductive biology, including humans.
Haplorhini/physiology , Menstrual Cycle/physiology , Animals , Female , Species Specificity , Uterus/anatomy & histology , Uterus/physiology
Prevalence of type 2 diabetes (T2D) and obesity is increasing worldwide. Currently available therapies are not suited for all patients in the heterogeneous obese/T2D population, hence the need for novel treatments. Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent for T2D/obesity. Native FGF21 has, however, poor pharmacokinetic properties, making gene therapy an attractive strategy to achieve sustained circulating levels of this protein. Here, adeno-associated viral vectors (AAV) were used to genetically engineer liver, adipose tissue, or skeletal muscle to secrete FGF21. Treatment of animals under long-term high-fat diet feeding or of ob/ob mice resulted in marked reductions in body weight, adipose tissue hypertrophy and inflammation, hepatic steatosis, inflammation and fibrosis, and insulin resistance for > 1 year. This therapeutic effect was achieved in the absence of side effects despite continuously elevated serum FGF21. Furthermore, FGF21 overproduction in healthy animals fed a standard diet prevented the increase in weight and insulin resistance associated with aging. Our study underscores the potential of FGF21 gene therapy to treat obesity, insulin resistance, and T2D.
Diabetes Mellitus, Type 2/therapy , Fibroblast Growth Factors/genetics , Genetic Therapy , Insulin Resistance , Obesity/therapy , Adipocytes/metabolism , Adipose Tissue, White/drug effects , Adipose Tissue, White/metabolism , Animals , Body Weight , Diabetes Mellitus, Type 2/genetics , Diet, High-Fat , Energy Metabolism , Fatty Liver/therapy , Fibroblast Growth Factors/metabolism , Fibrosis/therapy , Gene Transfer Techniques , Hyperplasia/therapy , Liver/metabolism , Liver/pathology , Male , Mice , Muscle, Skeletal/metabolism , Obesity/genetics , Pancreatitis/therapy
The marine portion of the West Antarctic Ice Sheet (WAIS) in the Amundsen Sea Embayment (ASE) accounts for one-fourth of the cryospheric contribution to global sea-level rise and is vulnerable to catastrophic collapse. The bedrock response to ice mass loss, glacial isostatic adjustment (GIA), was thought to occur on a time scale of 10,000 years. We used new GPS measurements, which show a rapid (41 millimeters per year) uplift of the ASE, to estimate the viscosity of the mantle underneath. We found a much lower viscosity (4 × 1018 pascal-second) than global average, and this shortens the GIA response time scale from tens to hundreds of years. Our finding requires an upward revision of ice mass loss from gravity data of 10% and increases the potential stability of the WAIS against catastrophic collapse.
Cerebrospinal fluid analyses are important for diagnosis of neurologic problems in rabbits and for translational research projects using rabbits as models. Blind puncture of the cisterna magna is the current standard technique for sampling cerebrospinal fluid in this species. However, the complexity and small size of the cisterna magna and surrounding structures are limitations of this technique. Aims of this prospective, anatomic, pilot study were to (1) describe the normal anatomy of the atlanto-occipital region, (2) describe ultrasonographic anatomic landmarks, and (3) develop and evaluate a technique for ultrasound-guided puncture of the cisterna magna for cerebrospinal fluid sampling in rabbits. Thirty healthy rabbits were included and the study was conducted in three stages. Three rabbit cadavers were used for the first stage of the study. Then, the second stage was completed using 13 rabbit cadavers. Finally, the third stage was completed in 14 live rabbits. The ultrasound-guided puncture performed in 13 cadavers was successful at the first attempt in 10 cases, and at the second attempt in the remaining three cases. In the in vivo study, the ultrasound-guided puncture was successful in all 14 cases, without signs of complications. Findings supported the use of ultrasound-guided puncture of the cisterna magna as a safe technique that may be used routinely or when the sample of cerebrospinal fluid cannot be obtained with the blind technique in rabbits.
Arthrocentesis/veterinary , Atlanto-Occipital Joint/diagnostic imaging , Cerebrospinal Fluid/diagnostic imaging , Cisterna Magna/diagnostic imaging , Ultrasonography/veterinary , Animals , Cadaver , Female , Male , Pilot Projects , Prospective Studies , Rabbits , Reference Values
