Minimally Invasive Osteotomy for Correction of Post-Traumatic Tibia Internal Rotation Deformity: A Case Report.

Introduction: Intramedullary nailing is a commonly performed surgery for tibia diaphysis fractures. However, in selected cases, this procedure can get complicated with rotational malalignment if not checked carefully intra-operatively. Case Report: A 29 year-old male sustained polytrauma and was treated with intramedullary nailing for bilateral femur and right-side tibia fractures. Postoperatively, the patient noticed extreme in-toeing suggesting an internal rotation deformity, which caused great difficulty in walking. The patient was planned for a revision surgery to correct the internal rotation deformity, 6 months after the index surgery. A minimally invasive metaphyseal osteotomy was performed, away from his fracture site by drilling multiple holes. The distal locking bolts of the interlocking nail were removed, and two K wires used to achieve the desired correction angle. After rotating the distal fragment, locking bolts were reinserted in new holes. We kept the patient on our regular follow-up till he achieved sound union at the osteotomy site, after which we allowed him unrestricted activities. Conclusion: The presence of an intramedullary nail can hence help the surgeon in correcting such isolated rotational deformities without getting into the hassle of implant removal to achieve the same.

Modulating Helix-preference of an Axially-twisted Molecular Scaffold Through Diastereomeric Salt Formation with Tartaric Acid Stereoisomers.

Herein, we designed a chiral, axially-twisted molecular scaffold (ATMS) using pyridine-2,6-dicarboxamide (PDC) unit as pivot, chiral trans-cyclohexanediamine (CHDA) residues as linkers, and pyrene residues as fluorescent reporters. R,R-ATMS exclusively adopted M-helicity and produced differential response in UV-vis, fluorescence, and NMR upon addition of tartaric acid (TA) stereoisomers allowing naked-eye detection and enantiomeric excess determination. Circular dichroism (CD) profile of R,R-ATMS underwent unique changes during titration with TA stereoisomers - while loss of CD signal at 345 nm was observed with equimolar D-TA and meso-TA, inversion was seen with equimolar L-TA. Temperature increase weakened these interactions to partially recover the original CD signature of R,R-ATMS. 2D NMR studies also indicated the significant structural changes in R,R-ATMS in the solution state upon addition of L-TA. Single crystal X-ray diffraction (SCXRD) studies on the crystals of the R,R-ATMS⊃D-TA salt revealed the interacting partners stacked in arrays and ATMS molecules stabilized by π-π stacking between its PDC and pyrene residues. Contrastingly, tightly-packed supramolecular cages comprised of four molecules each of R,R-ATMS and L-TA were seen in R,R-ATMS⊃L-TA salt, and the ATMS molecules contorted to achieve CH-π interactions between its pyrene residues. These results may have implications in modulating the helicity of topologically-similar larger biomolecules.

Dysregulated expression of cholesterol biosynthetic genes in Alzheimer's disease alters epigenomic signatures of hippocampal neurons.

Aging is the main risk factor of cognitive neurodegenerative diseases such as Alzheimer's disease, with epigenome alterations as a contributing factor. Here, we compared transcriptomic/epigenomic changes in the hippocampus, modified by aging and by tauopathy, an AD-related feature. We show that the cholesterol biosynthesis pathway is severely impaired in hippocampal neurons of tauopathic but not of aged mice pointing to vulnerability of these neurons in the disease. At the epigenomic level, histone hyperacetylation was observed at neuronal enhancers associated with glutamatergic regulations only in the tauopathy. Lastly, a treatment of tau mice with the CSP-TTK21 epi-drug that restored expression of key cholesterol biosynthesis genes counteracted hyperacetylation at neuronal enhancers and restored object memory. As acetyl-CoA is the primary substrate of both pathways, these data suggest that the rate of the cholesterol biosynthesis in hippocampal neurons may trigger epigenetic-driven changes, that may compromise the functions of hippocampal neurons in pathological conditions.

Machine learning-empowered sleep staging classification using multi-modality signals.

The goal is to enhance an automated sleep staging system's performance by leveraging the diverse signals captured through multi-modal polysomnography recordings. Three modalities of PSG signals, namely electroencephalogram (EEG), electrooculogram (EOG), and electromyogram (EMG), were considered to obtain the optimal fusions of the PSG signals, where 63 features were extracted. These include frequency-based, time-based, statistical-based, entropy-based, and non-linear-based features. We adopted the ReliefF (ReF) feature selection algorithms to find the suitable parts for each signal and superposition of PSG signals. Twelve top features were selected while correlated with the extracted feature sets' sleep stages. The selected features were fed into the AdaBoost with Random Forest (ADB + RF) classifier to validate the chosen segments and classify the sleep stages. This study's experiments were investigated by obtaining two testing schemes: epoch-wise testing and subject-wise testing. The suggested research was conducted using three publicly available datasets: ISRUC-Sleep subgroup1 (ISRUC-SG1), sleep-EDF(S-EDF), Physio bank CAP sleep database (PB-CAPSDB), and S-EDF-78 respectively. This work demonstrated that the proposed fusion strategy overestimates the common individual usage of PSG signals.

Oral Administration of a Specific p300/CBP Lysine Acetyltransferase Activator Induces Synaptic Plasticity and Repairs Spinal Cord Injury.

TTK21 is a small-molecule activator of p300/creb binding protein (CBP) acetyltransferase activity, which, upon conjugation with a glucose-derived carbon nanosphere (CSP), can efficiently cross the blood-brain barrier and activate histone acetylation in the brain. Its role in adult neurogenesis and retention of long-term spatial memory following intraperitoneal (IP) administration is well established. In this study, we successfully demonstrate that CSP-TTK21 can be effectively administered via oral gavage. Using a combination of molecular biology, microscopy, and electrophysiological techniques, we systematically investigate the comparative efficacy of oral administration of CSP and CSP-TTK21 in wild-type mice and evaluate their functional effects in comparison to intraperitoneal (IP) administration. Our findings indicate that CSP-TTK21, when administered orally, induces long-term potentiation in the hippocampus without significantly altering basal synaptic transmission, a response comparable to that achieved through IP injection. Remarkably, in a spinal cord injury model, oral administration of CSP-TTK21 exhibits efficacy equivalent to that of IP administration. Furthermore, our research demonstrates that oral delivery of CSP-TTK21 leads to improvements in motor function, histone acetylation dynamics, and increased expression of regeneration-associated genes (RAGs) in a spinal injury rat model, mirroring the effectiveness of IP administration. Importantly, no toxic and mutagenic effects of CSP-TTK21 are observed at a maximum tolerated dose of 1 g/kg in Sprague-Dawley (SD) rats via the oral route. Collectively, these results underscore the potential utility of CSP as an oral drug delivery system, particularly for targeting the neural system.

Simplified LIBS-based intensity-ratio approach for concentration estimation (SLICE): an approach for elemental analysis using laser induced breakdown spectroscopy.

We propose what we believe to be a new approach for elemental analysis using laser induced breakdown spectroscopy (LIBS). This method offers enhanced convenience and simplicity for elemental analysis as it eliminates the necessity of Boltzmann/ Saha-Boltzmann plot. It is an intensity-ratio based approach that provides several notable advantages. One of the key benefits is its ability to perform comprehensive elemental analysis using only a few spectral lines; specifically, only n + 1 emission lines are sufficient for a sample containing n elemental species. This offers a great flexibility in the choice of emission lines which do not suffer from self-absorption. Further, high accuracy can be obtained as many repeated estimations from a single measurement are possible. We demonstrate the theory and working procedure of this technique by experimentally recording the data of two samples (binary and ternary copper alloys). A nanosecond Nd:YAG pulsed laser of ∼7 ns pulse duration and 532 nm incident wavelength is used. The results are in good agreement with CF-LIBS and Energy-dispersive X-ray spectroscopy (EDS).

Medial versus anterior approach for open reduction of hip in children with DDH under two years - A meta-analysis of comparative studies.

Purpose: Open reduction (OR) is usually required in developmental dysplasia of hip (DDH) for children below 24 months of age, those who failed to achieve a satisfactory reduction by the closed method. OR in this age group can be performed either through a medial or anterior approach. However, there is a paucity of literature and a lack of more substantial evidence regarding which approach (medial versus anterior) is superior for performing OR in this age group with minimal complications. Methods: Four databases (PubMed, Embase, Scopus, and Cochrane Library) were searched for relevant articles reporting outcomes and complication rates of DDH children less than 24 months undergone OR either through medial or anterior approach using pre-defined keywords. Data on avascular necrosis (AVN) rates, further corrective surgery (FCS) rates, and clinical and radiological grading using McKay clinical criteria and Severin radiological criteria were assessed. Meta-analysis was carried out using RevMan (Review Manager 5.4) software. Results: Five comparative studies, having a minimum of two-year follow-up, were included for final analysis. According to the MINORS tool assessment, all five studies were of good to high quality. Of 257 hips, 151 and 106 underwent OR through medial and anterior approaches, respectively. Our meta-analysis showed a statistically significant (p = 0.01) number of AVN cases with the anterior approach compared to the medial approach. The overall random effect showed the odds of having AVN with an anterior approach to be 2.27 (95% CI: 1.18,4.38) times more than the same with a medial approach. Regarding FCS rates, the meta-analysis depicted no significant difference between the two groups (p = 0.63). The two groups had no statistically significant difference regarding clinical and radiological outcomes using McKay and Severin criteria, respectively. Following surgery, improvement in the acetabular index from pre-operative value showed no statistically significant difference between the two groups (p = 0.48). Conclusions: Medial approach is safe and effective for OR of the hip in DDH up to 24 months of age. Our analysis showed that AVN rates are lower with a medial approach than the anterior approach, with similar clinical and radiological outcomes and rates of FCS. However, one should consider the surgeon's expertise while choosing between these approaches.

Design and analysis of a photonic crystal nanocavity based bio-sensor for blood component detection.

A design of a photonic crystal nanocavity based bio-sensor having a footprint of 12×8µm 2 is proposed to detect different blood components. A finite difference time domain (FDTD) numerical technique has been used to characterize the sensor by evaluating its frequency response. The shift in resonant wavelength of the proposed cavity is utilized to detect blood refractive index fluctuation due to the presence of various components. The obtained numerical findings show that the maximum sensitivity for a shift in resonant wavelength is reported as 760 nm/RIU for various blood components. Moreover, the fabrication of PhC is always prone to the fabrication induced disorders. Hence, the impact of fabrication imperfections on the sensor's performance also has been included in the analysis.

Forgotten Foreign Bodies Mimicking Osteomyelitis, a Diagnostic Dilemma - A Report of Two Cases.

Introduction: The first differential diagnosis for a chronic discharging sinus on an extremity is usually chronic osteomyelitis. These patients are usually treated with surgical debridement and intravenous antibiotics. However, all discharging sinuses are not osteomyelitis. Case Report: We encountered two such cases, initially treated as osteomyelitis, which did not respond to initial surgical debridement and, on further workup, were found to have foreign bodies in situ that mimicked osteomyelitis. The first case is a 1 ½-year-old child with an intact rubber band inside the wrist, presenting with sinuses on the wrist, and the second one is a 12-year-old with an old penetrating injury to the foot through the sole of a rubber slipper. Both patients recovered completely once the foreign bodies were removed. Conclusion: We stress the importance of keeping the possibility of a foreign body in mind in patients with discharging sinuses not responding adequately to debridement and antibiotics.

ARL8B mediates lipid droplet contact and delivery to lysosomes for lipid remobilization.

Lipid droplets (LDs) play a crucial role in maintaining cellular lipid balance by storing and delivering lipids as needed. However, the intricate lipolytic pathways involved in LD turnover remain poorly described, hindering our comprehension of lipid catabolism and related disorders. Here, we show a function of the small GTPase ARL8B in mediating LD turnover in lysosomes. ARL8B-GDP localizes to LDs, while ARL8-GTP predominantly favors lysosomes. GDP binding induces a conformation with an exposed N-terminal amphipathic helix, enabling ARL8B to bind to LDs. By associating with LDs and lysosomes, and with its property to form a heterotypic complex, ARL8B mediates LD-lysosome contacts and efficient lipid transfer between these organelles. In human macrophages, this ARL8B-dependent LD turnover mechanism appears as the major lipolytic pathway. Our finding opens exciting possibilities for understanding the molecular mechanisms underlying LD degradation and its potential implications for inflammatory disorders.

SpeckleCam: high-resolution computational speckle contrast tomography for deep blood flow imaging.

Laser speckle contrast imaging is widely used in clinical studies to monitor blood flow distribution. Speckle contrast tomography, similar to diffuse optical tomography, extends speckle contrast imaging to provide deep tissue blood flow information. However, the current speckle contrast tomography techniques suffer from poor spatial resolution and involve both computation and memory intensive reconstruction algorithms. In this work, we present SpeckleCam, a camera-based system to reconstruct high resolution 3D blood flow distribution deep inside the skin. Our approach replaces the traditional forward model using diffuse approximations with Monte-Carlo simulations-based convolutional forward model, which enables us to develop an improved deep tissue blood flow reconstruction algorithm. We show that our proposed approach can recover complex structures up to 6 mm deep inside a tissue-like scattering medium in the reflection geometry. We also conduct human experiments to demonstrate that our approach can detect reduced flow in major blood vessels during vascular occlusion.

Recombinant VEGF-C (Cys156Ser) improves mesenteric lymphatic drainage and gut immune surveillance in experimental cirrhosis.

Background & Aims: Lymphatic vessels (LVs) are crucial for maintaining abdominal fluid homoeostasis and immunity. In cirrhosis, mesenteric LVs (mLVs) are dilated and dysfunctional. Given the established role of vascular endothelial growth factor-C (VEGF-C) in improving LVs, we hypothesised that VEGF-C treatment could ameliorate the functions of mLVs in cirrhosis. Methods: In this study, we developed a nanoformulation comprising LV-specific growth factor, recombinant human VEGF-C (Cys156Ser) protein (E-VEGF-C) and delivered it orally in different models of rat cirrhosis to target mLVs. Cirrhotic rats were given nanoformulation without VEGF-C served as vehicles. Drainage of mLVs was analysed using tracer dye. Portal and systemic physiological assessments and computed tomography were performed to measure portal pressures and ascites. Gene expression and permeability of primary mesenteric lymphatic endothelial cells (LyECs) was studied. Immune cells in mesenteric lymph nodes (MLNs) were quantified by flow cytometry. Endogenous and exogenous gut bacterial translocation to MLNs was examined. Results: In cirrhotic rats, mLVs were dilated and leaky with impaired drainage. Treatment with E-VEGF-C induced proliferation of mLVs, reduced their diameter, and improved functional drainage. Ascites and portal pressures were significantly reduced in E-VEGF-C rats compared with vehicle rats. In MLNs of E-VEGF-C animals, CD8+CD134+ T cells were increased, whereas CD25+ regulatory T cells were decreased. Both endogenous and exogenous bacterial translocation were limited to MLNs in E-VEGF-C rats with reduced levels of endotoxins in ascites and blood in comparison with those in vehicle rats. E-VEGF-C treatment upregulated the expression of vascular endothelial-cadherin in LyECs and functionally improved the permeability of these cells. Conclusions: E-VEGF-C treatment ameliorates mesenteric lymph drainage and portal pressure and strengthens cytotoxic T-cell immunity in MLNs in experimental cirrhosis. It may thus serve as a promising therapy to manage ascites and reduce pathogenic gut bacterial translocation in cirrhosis. Impact and Implications: A human recombinant pro-lymphangiogenic growth factor, VEGF-C, was encapsulated in nanolipocarriers (E-VEGF-C) and orally delivered in different models of rat liver cirrhosis to facilitate its gut lymphatic vessel uptake. E-VEGF-C administration significantly increased mesenteric lymphatic vessel proliferation and improved lymph drainage, attenuating abdominal ascites and portal pressures in the animal models. E-VEGF-C treatment limited bacterial translocation to MLNs only with reduced gut bacterial load and ascitic endotoxins. E-VEGF-C therapy thus holds the potential to manage ascites and portal pressure and reduce gut bacterial translocation in patients with cirrhosis.

Effect of mineral elements on the formation of gallbladder stones using spectroscopic techniques.

Long-standing gallbladder stones have been recognized as one of the highest risk factors for gallbladder cancer. However, the growth and progression of gallbladder stones are still not well-known, and their uncovering requires accurate information on the formation/nucleation and complex compositional information of gallstones. Multiple and single gallstones are analyzed using laser-induced breakdown spectroscopy (LIBS), photoacoustic spectroscopy (PAS), and Fourier transform infrared spectroscopy (FTIR). Spectral signatures as well as spatial variation in the spectral intensities of different elements are observed in the LIBS spectra of the gallstones. In the multiple-type gallstones, the concentration of inorganic content increases from core to periphery, whereas a single gallstone shows the opposite trend from the point of nucleation/core. It is suggested that the concentration of inorganic elements (Mg, Ca, K, and Na) plays an important role in the nucleation and growth of gallstones; thus, accordingly, multiple- and single-type gallstones are found in the gallbladder. The presence of different electronic bands of molecules, such as CH, C2, CN, and NH, is confirmed by LIBS and FTIR. PAS has identified molecules, such as cholesterol, calcium carbonate, and calcium phosphate, in different gallstone samples. These results show that PAS combined with LIBS is a promising candidate for the compositional analysis of gallstones. Furthermore, principal component analysis (PCA) is used to discriminate different layers present in the gallstones.

An Augmented Modulated Deep Learning Based Intelligent Predictive Model for Brain Tumor Detection Using GAN Ensemble.

Brain tumor detection in the initial stage is becoming an intricate task for clinicians worldwide. The diagnosis of brain tumor patients is rigorous in the later stages, which is a serious concern. Although there are related pragmatic clinical tools and multiple models based on machine learning (ML) for the effective diagnosis of patients, these models still provide less accuracy and take immense time for patient screening during the diagnosis process. Hence, there is still a need to develop a more precise model for more accurate screening of patients to detect brain tumors in the beginning stages and aid clinicians in diagnosis, making the brain tumor assessment more reliable. In this research, a performance analysis of the impact of different generative adversarial networks (GAN) on the early detection of brain tumors is presented. Based on it, a novel hybrid enhanced predictive convolution neural network (CNN) model using a hybrid GAN ensemble is proposed. Brain tumor image data is augmented using a GAN ensemble, which is fed for classification using a hybrid modulated CNN technique. The outcome is generated through a soft voting approach where the final prediction is based on the GAN, which computes the highest value for different performance metrics. This analysis demonstrated that evaluation with a progressive-growing generative adversarial network (PGGAN) architecture produced the best result. In the analysis, PGGAN outperformed others, computing the accuracy, precision, recall, F1-score, and negative predictive value (NPV) to be 98.85, 98.45%, 97.2%, 98.11%, and 98.09%, respectively. Additionally, a very low latency of 3.4 s is determined with PGGAN. The PGGAN model enhanced the overall performance of the identification of brain cell tissues in real time. Therefore, it may be inferred to suggest that brain tumor detection in patients using PGGAN augmentation with the proposed modulated CNN technique generates the optimum performance using the soft voting approach.

Myricetin encapsulated chitosan nanoformulation for management of type 2 diabetes: Preparation, optimization, characterization and in vivo activity.

Type 2 diabetes mellitus (T2DM) is a serious and alarming disease attracting widespread attention. It is not a single metabolic disease; over time, it leads to serious disorders, namely, diabetic nephropathy, neuropathy, retinopathy and several cardiovascular, hepatocellular complications. The increase in T2DM cases in recent times has attracted significant attention. Currently, the medications available have side effects, and injectables are painful, causing trauma to the patients. Therefore, it is imperative to come up with oral delivery. In this background we report here a nanoformulation carrying natural small molecule Myricetin (MYR) encapsulated within Chitosan nanoparticles (CHT-NPs). MYR-CHT-NPs were prepared by ionic gelation method and evaluated using different characterization techniques. The in vitro release of MYR from CHT NPs in different physiological media showed pH dependence. in vivo pharmacodynamic study followed by oral administration in Albino Wistar rats showed better glycaemic control than existing drug. Further, the optimized nanoparticles also exhibited controlled increase in weight as compared to Metformin. The biochemistry profile of rats treated with nanoformulation reduced the levels of several pathological biomarkers, indicating additional benefits of MYR. Histopathological images exhibited no toxicity or changes in the major organs section in contrast to normal control, suggesting safe oral administration of the encapsulated MYR. Thus, we conclude that MYR-CHT-NPs represent an attractive delivery vehicle in improving the blood glucose level with controlled weight and have the potential to be safely administered orally for the management of T2DM.

Driving Aggressively or Conservatively? Investigating the Effects of Automated Vehicle Interaction Type and Road Event on Drivers' Trust and Preferred Driving Style.

OBJECTIVE: This study aimed to investigate the impact of automated vehicle (AV) interaction mode on drivers' trust and preferred driving styles in response to pedestrian- and traffic-related road events. BACKGROUND: The rising popularity of AVs highlights the need for a deeper understanding of the factors that influence trust in AV. Trust is a crucial element, particularly because current AVs are only partially automated and may require manual takeover; miscalibrated trust could have an adverse effect on safe driver-vehicle interaction. However, before attempting to calibrate trust, it is vital to comprehend the factors that contribute to trust in automation. METHODS: Thirty-six individuals participated in the experiment. Driving scenarios incorporated adaptive SAE Level 2 AV algorithms, driven by participants' event-based trust in AVs and preferences for AV driving styles. The study measured participants' trust, preferences, and the number of takeover behaviors. RESULTS: Higher levels of trust and preference for more aggressive AV driving styles were found in response to pedestrian-related events compared to traffic-related events. Furthermore, drivers preferred the trust-based adaptive mode and had fewer takeover behaviors than the preference-based adaptive and fixed modes. Lastly, participants with higher trust in AVs favored more aggressive driving styles and made fewer takeover attempts. CONCLUSION: Adaptive AV interaction modes that depend on real-time event-based trust and event types may represent a promising approach to human-automation interaction in vehicles. APPLICATION: Findings from this study can support future driver- and situation-aware AVs that can adapt their behavior for improved driver-vehicle interaction.

Overcoming Challenges and Innovations in Orthopedic Prosthesis Design: An Interdisciplinary Perspective.

Recent advances in the orthopedic prostheses design have significantly improved the quality of life for individuals with orthopedic disabilities. However, there are still critical challenges that need to be addressed to further enhance the functionality of orthopedic prostheses improving biocompatibility to promote better integration with natural tissues, enhancing durability to withstand the demands of daily use, and improving sensory feedback for better control of movement are the most pressing issues. To address these challenges, promising emerging solutions such as smart prosthetics, 3D printing, regenerative medicine, and artificial intelligence have been developed. These innovative technologies hold the potential to significantly enhance the functionality of orthopedic prostheses. Realizing the full potential of these next-generation orthopedic prostheses requires addressing several critical factors. These include interdisciplinary collaboration between experts in orthopedics, materials science, biology, and engineering, increased investment in research and development, standardization of components to ensure quality and reliability, and improved access to prosthetics. A comprehensive review of these challenges and considerations for future orthopedic prosthesis design is s provided in this paper addressing the further advances to the field. By addressing these issues, we can continue to improve the lives of individuals with orthopedic disabilities and further enhance the field of orthopedic prosthetics.

The future of mobility-as-a-service: trust transfer across automated mobilities, from road to sidewalk.

While trust in different types of automated vehicles has been a major focus for researchers and vehicle manufacturers, few studies have explored how people trust automated vehicles that are not cars, nor how their trust may transfer across different mobilities enabled with automation. To address this objective, a dual mobility study was designed to measure how trust in an automated vehicle with a familiar form factor-a car-compares to, and influences, trust in a novel automated vehicle-termed sidewalk mobility. A mixed-method approach involving both surveys and a semi-structured interview was used to characterize trust in these automated mobilities. Results found that the type of mobility had little to no effect on the different dimensions of trust that were studied, suggesting that trust can grow and evolve across different mobilities when the user is unfamiliar with a novel automated driving-enabled (AD-enabled) mobility. These results have important implications for the design of novel mobilities.

Hepatopulmonary syndrome is associated with low sphingosine-1-phosphate levels and can be ameliorated by the functional agonist fingolimod.

BACKGROUND & AIMS: Hepatopulmonary syndrome (HPS) is characterised by a defect in arterial oxygenation induced by pulmonary vascular dilatation in patients with liver disease. Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator, suppresses vasodilation by reducing nitric oxide (NO) production. We investigated the role of S1P in patients with HPS and the role of fingolimod as a therapeutic option in an experimental model of HPS. METHODS: Patients with cirrhosis with HPS (n = 44) and without HPS (n = 89) and 25 healthy controls were studied. Plasma levels of S1P, NO, and markers of systemic inflammation were studied. In a murine model of common bile duct ligation (CBDL), variations in pulmonary vasculature, arterial oxygenation, liver fibrosis, and inflammation were estimated before and after administration of S1P and fingolimod. RESULTS: Log of plasma S1P levels was significantly lower in patients with HPS than in those without HPS (3.1 ± 1.4 vs. 4.6 ± 0.2; p <0.001) and more so in severe intrapulmonary shunting than in mild and moderate intrapulmonary shunting (p <0.001). Plasma tumour necrosis factor-α (76.5 [30.3-91.6] vs. 52.9 [25.2-82.8]; p = 0.02) and NO (152.9 ± 41.2 vs. 79.2 ± 29.2; p = 0.001) levels were higher in patients with HPS than in those without HPS. An increase in Th17 (p <0.001) and T regulatory cells (p <0.001) was observed; the latter inversely correlated with plasma S1P levels. In the CBDL HPS model, fingolimod restored pulmonary vascular injury by increasing the arterial blood gas exchange and reducing systemic and pulmonary inflammation, resulting in improved survival (p = 0.02). Compared with vehicle treatment, fingolimod reduced portal pressure (p <0.05) and hepatic fibrosis and improved hepatocyte proliferation. It also induced apoptotic death in hepatic stellate cells and reduced collagen formation. CONCLUSIONS: Plasma S1P levels are low in patients with HPS and even more so in severe cases. Fingolimod, by improving pulmonary vascular tone and oxygenation, improves survival in a murine CBDL HPS model. IMPACT AND IMPLICATIONS: A low level of plasma sphingosine-1-phosphate (S1P) is associated with severe pulmonary vascular shunting, and hence, it can serve as a marker of disease severity in patients with hepatopulmonary syndrome (HPS). Fingolimod, a functional agonist of S1P, reduces hepatic inflammation, improves vascular tone, and thus retards the progression of fibrosis in a preclinical animal model of HPS. Fingolimod is being proposed as a potential novel therapy for management of patients with HPS.

A diet-independent zebrafish model for NAFLD recapitulates patient lipid profiles and offers a system for small molecule screening.

Non-alcoholic Fatty Liver Disease (NAFLD) or pathological hepatic lipid overload, is considered to affect obese individuals. However, NAFLD in lean individuals is prevalent, especially in South Asian population. The pathophysiology of lean NAFLD is not well understood and most animal models of NAFLD use the high-fat diet paradigm. To bridge this gap, we have developed a diet-independent model of NAFLD in zebrafish. We have previously shown that chronic systemic inflammation causes metabolic changes in the liver leading to hepatic fat accumulation in an IL6 overexpressing (IL6-OE) zebrafish model. In the present study, we compared the hepatic lipid composition of adult IL6-OE zebrafish to the controls and found an accumulation of saturated triacylglycerols and a reduction in the unsaturated triacylglycerol species reminiscent of NAFLD patients. Zebrafish is an ideal system for chemical genetic screens. We tested whether the hepatic lipid accumulation in the IL6-OE is responsive to chemical treatment. We found that PPAR-gamma agonist Rosiglitazone, known to reduce lipid overload in the high-fat diet models of NAFLD, could ameliorate the fatty liver phenotype of the IL6-OE fish. Rosiglitazone treatment reduced the accumulation of saturated lipids and showed a concomitant increase in unsaturated TAG species in our inflammation-induced NAFLD model. Our observations suggest that the IL6-OE model can be effective for small molecule screening to identify compounds that can reverse hepatic lipid accumulation, especially relevant to lean NAFLD.