Insight into the Effect of Submicellar Concentrations of Sodium Deoxycholate on the Structure, Stability, and Activity of Bovine and Human Serum Albumin: An Interesting Comparison between Single and Double Tryptophan Proteins.

The progressive escalation in the applications of bile salts in diverse fields has triggered research on their interaction with various biological macromolecules, especially with proteins. A proper understanding of the interaction process of bile salts, particularly in the lower concentrations range, with the serum albumin seems important since the normal serum concentration of bile salts is approximately in the micromolar range. The current study deals with a comprehensive and comparative analysis of the interaction of submicellar concentrations of sodium deoxycholate (NaDC) with two homologous transport proteins: bovine serum albumin (BSA) and human serum albumin (HSA). HSA and BSA with one and two tryptophans, respectively, provide the opportunity for an interesting comparison of tryptophan fluorescence behavior on interaction with NaDC. The study suggests a sequential interaction of NaDC in three discrete stages with the two proteins. A detailed study using warfarin and ibuprofen as site markers provides information about the sites of interaction, which is further confirmed by inclusive molecular dynamics simulation analysis. Moreover, the comparison of the thermodynamics and stability of the NaDC-serum albumin complexes confirms the stronger interaction of NaDC with BSA as compared to that with HSA. The differential interaction between the bile salt and the two serum albumins is further established from the difference in the extent of decrease in the esterase-like activity assay of the proteins in the presence of NaDC. Therefore, the present study provides important insight into the effect of submicellar concentrations of NaDC on the structure, stability, and activity of the two homologous serum albumins and thus can contribute not only to the general understanding of the complex nature of serum albumin-bile salt interactions but also to the design of more effective pharmaceutical formulations in the field of drug delivery and biomedical research.

A novel heterozygote allele in caprine melanocortin 1 receptor (MC1R) gene: an association with heat stress traits.

Climate change negatively influences the productive and reproductive abilities of goats. There is a need to understand the relationship between heat stress and genes that may aid in the development of climate-resilient goats. Melanism variation in goats plays a role in thermoregulation, in which the melanogenic genes have a pleiotropic effect on the regulation of physiological responses and behavior that are altered due to heat stress in the animals. Thus, the present study was conducted to establish a possible association between the coat color gene (MC1R) and heat stress characteristics. The physiological responses and cortisol levels were recorded in forty different coat-colored goats. The genotyping of the animals revealed four SNPs at the 183rd (C/T), 332nd (C/G), 748th (G/T), and 801st (C/G) positions, among which the black and brown goat populations had novel SNPs at the 332nd position. Eight haplotypes were constructed, and an association study revealed that haplotypes (CCGG, TCGG, and CCTC) that were linked to white animals had lower cortisol values, rectal temperature, skin temperature, and respiration rate. The multivariate and cluster analyses revealed that the white goats were distinct from the rest of the goats. In addition, the docking results revealed the residues that were forming the interaction complex, which could play a role in melanogenesis in the animals and, in turn, the heat stress ability of the goats. Altogether, the results of the present study could pave the way for more research into coat color genes and their relationship with heat stress traits.

An in vivo and in silico analysis of novel variation in TMBIM6 gene affecting cardiopulmonary traits of Indian goats.

Transmembrane Bax Inhibitor Motif-containing 6 (TMBIM6) gene acts as calcium leak channel and negatively regulates autophagy and autophagosome formation. The TMBIM6 gene was amplified and searched for variation in three different goat populations (i.e. Black Bengal, Ganjam and Raighar) of Odisha state of the India. The result indicated two substitutions i.e. 55th position (C55T) and 95th position (C95A) in the amplified region of the gene resulting in change of amino acids (Leu > Phe and Thr > Asn). The identified SNPs were combined to form haplotypes and animals were grouped accordingly. Structural analysis showed minor changes (5%) in between mutant and wild TMBIM6 protein structures. However, any functional variation could not be identified with respect to the calcium ligand and open pore state. But an alteration of calcium binding site was found. The binding interaction of calcium with the TMBIM6 protein was hydrophobic in nature in closed state whereas hydrophilic in open pore stage. The stress releasing function was the result of calcium leakage controlled by amino acids coded by exon 4 and exon 5 regions of TMBIM6 gene. The effect of breed and haplotype on cardiopulmonary traits was studied. The data on cardiopulmonary traits of body i.e. rectal temperature, skin temperature, heart rate and respiration rate were recorded when ambient temperature usually remained the highest. The statistical analysis showed, significant difference in rectal temperature, skin temperature and respiration rate among these goat populations. The haplotypes (CC and TA) were found to have a significant (P < 0.05) effect on rectal temperature, skin temperature and respiration rate. However, any such significant effect could not be identified in recorded heart rate. The objective of the present study to identify the genetic variations in TMBIM6 gene having significant effect on cardiopulmonary traits which can be further uses as the molecular markers to improve heat tolerance mechanism in goats.

Identification and Characterization of Circular Intronic RNAs Derived from Insulin Gene.

Circular RNAs (circRNAs) are a large family of noncoding RNAs that have emerged as novel regulators of gene expression. However, little is known about the function of circRNAs in pancreatic ß-cells. Here, transcriptomic analysis of mice pancreatic islet RNA-sequencing data identified 77 differentially expressed circRNAs between mice fed with a normal diet and a high-fat diet. Surprisingly, multiple circRNAs were derived from the intron 2 of the preproinsulin 2 (Ins2) gene and are termed as circular intronic (ci)-Ins2. The expression of ci-Ins2 transcripts in mouse pancreatic islets, and ßTC6 cells were confirmed by reverse transcription PCR, DNA sequencing, and RNase R treatment experiments. The level of ci-Ins2 was altered in ßTC6 cells upon exposure to elevated levels of palmitate and glucose. Computational analysis predicted the interaction of several RNA-binding proteins with ci-Ins2 and their flanking region, suggesting their role in the ci-Ins2 function or biogenesis. Additionally, bioinformatics analysis predicted the association of several microRNAs with ci-Ins2. Gene ontology and pathway analysis of genes targeted by miRNAs associated with ci-Ins2 suggested the regulation of several key biological processes. Together, our findings indicate that differential expression of circRNAs, especially ci-Ins2 transcripts, may regulate ß-cell function and may play a critical role in the development of diabetes.

Photophysical Properties of Coumarin 1 in Bile Salt Aggregates: An Insight into the Role of Bile Salt Structure on the Aggregation Behavior.

The photophysical behavior of Coumarin 1 (Cou1), a well-known 7-aminocoumarin derivative, is very sensitive to the microenvironment in which it resides. In the present study, the effect of six bile salt variants on the photophysical behavior of Cou1 has been investigated. Dihydroxy (deoxycholates) as well as trihydroxy (cholates) bile salts with conjugated and unconjugated side chains have been chosen to get insight into the role of bile salt structure on the microenvironment of Cou1. Cou1 photophysics was found to be extremely sensitive to the aggregation process of the bile salt variants. The reduced polarity of the micellar environment stabilizes the planar intramolecular charge transferred state of Cou1, resulting in significant modulation in its photophysics in the bile salt media. The changes in the fluorescence parameters such as fluorescence intensity, emission energy, fluorescence quantum yield, anisotropy, and lifetime of Cou1 reveal that there is a distinct difference in the aggregation behavior of deoxycholates from that of cholates. The deoxycholates form micelles more or less critically similar to those of conventional surfactants, whereas the cholates self-assemble rather noncritically over a wide concentration range, thus signifying the vital role of the extra hydroxyl group in the aggregation pattern of trihydroxy bile salts. The conjugated bile salts are found to provide a relatively more compact, rigid, and hydrophobic microenvironment to Cou1 as compared to their unconjugated counterparts. Considering the significant modulation in the photophysical properties of Cou1, it has been employed as a molecular reporter for monitoring the aggregation process of bile salt variants and important information could be obtained about the effect of bile salt structure on the aggregation pattern and also about the micellar properties.

Phosphatidylethanolamine and Cholesterol Promote Hemifusion Formation: A Tug of War between Membrane Interfacial Order and Intrinsic Negative Curvature of Lipids.

Membrane fusion is an important process for the survival of eukaryotes. The shape of lipids plays an important role in fusion by stabilizing nonlamellar fusion intermediates. Lipids with intrinsic positive curvature such as lysophosphatidylcholine and others inhibit hemifusion formation, whereas lipids having intrinsic negative curvature, e.g., phosphatidylethanolamine and cholesterol (CH), are known to promote hemifusion formation. In this work, we have measured the effect of dioleoylphosphatidylethanolamine (DOPE) and CH on the depth-dependent organization, dynamics, and fusion of dioleoylphosphatidylcholine membranes. Both DOPE and CH promote hemifusion formation despite their ability to order the interfacial and acyl chain region of the membrane and block water percolation at these regions. Generally, membrane ordering and inhibition of water percolation at the acyl chain region are detrimental to membrane fusion. This clearly emphasizes the importance of intrinsic negative curvature of lipids in membrane fusion. Interestingly, DOPE and CH show differential effects on the rate of hemifusion formation, which might be owing to their ability to induce order at the interfacial region and intrinsic negative curvature. Overall, our result is significant in understanding the role of lipidic shape in membrane fusion.

Identification of potential proteins translated from circular RNA splice variants.

Circular RNAs (circRNAs) are covalently closed RNA molecules generated from precursor RNAs by the head-to-tail backsplicing of exons. Hundreds of studies demonstrated that circRNAs are ubiquitously expressed and regulate cellular events by modulating microRNA (miRNA) and RNA-binding protein (RBP) activities. A few circRNAs are also known to translate into functional polypeptides regulating cellular physiology. All these functions primarily depend on the full-length sequence of the circRNAs. CircRNA backsplice junction sequence is the key to identifying circRNAs and their full-length mature sequence. However, some multi-exonic circRNAs exist in different isoforms sharing identical backsplice junction sequences and are termed circRNA splice variants. Here, we analyzed the previously published HeLa cell RNA-seq datasets to identify circRNA splice variants using the de novo module of the CIRCexplorer2 circRNA annotation pipeline. A subset of circRNAs with splice variants was validated by the circRNA-rolling circle amplification (circRNA-RCA) method. Interestingly, several validated circRNAs were predicted to translate into proteins by the riboCIRC database. Furthermore, polyribosome fractionation followed by quantitative PCR confirmed the association of a subset of circRNAs with polyribosome supporting their protein-coding potential. Finally, bioinformatics analysis of proteins derived from splice variants of circCORO1C and circASPH suggested altered protein sequences and structures that could affect their physiological functions. Together, our study identified novel circRNA splice variants and their potential translation into protein isoforms which may regulate various physiological processes.

The Surrogacy Regulation Act of 2021: A Right Step Towards an Egalitarian and Inclusive Society?

With the advent of major scientific and technological advancements in obstetrics and gynecology, surrogacy is quickly becoming a viable alternative to enable people of all genders to become parents. However, its path toward reality is still fraught with legal and ethical dilemmas. With the Surrogacy Act of 2021 coming into effect earlier this year, the present article aims to dissect the various legal nuances involved while also considering the societal norms governing the actual scenario at ground zero. Our review discusses the aspects of eligibility criteria, the health implications, the rights of the surrogate mother and the child born, the financial burden, and compensation. We aimed to bring attention to this act and its implications on marginalized segments of society, with an attempt to bring beneficial changes for them. In this review, we provide viable alternatives adopted across the globe to solve the identified issues to make the present act non-discriminatory and more rewarding to all involved beneficiaries.

Understanding the Association Between Obesity and Obstructive Sleep Apnea Syndrome: A Case-Control Study.

Introduction Obstructive sleep apnea (OSA) represents a sleep-related impairment linked to upper airway function. The question of whether OSA drives obesity or if shared underlying factors contribute to both conditions remains unresolved. Hence, this present study aims to understand the interplay between obstructive sleep apnea syndrome (OSAS) and obesity through in-depth analysis of anthropometric data within control subjects and OSA patients. Methodology A case-control study was conducted, which included 40 cases and 40 matched healthy controls. Study participants with reported symptoms of snoring, daytime drowsiness, or both were included in the study. All the study participants underwent comprehensive anthropometric assessments such as height, weight, body mass index (BMI), neck circumference, waist circumference, hip circumference, waist-to-hip ratio, skin-fold thickness, and thickness measurements of biceps, triceps, suprailiac, and subscapular muscles. Results Within the OSA group, significant disparities emerged in mean age, waist circumference, waist-to-hip ratio, and diverse fat accumulations encompassing visceral, subcutaneous, trunk, and subcutaneous leg fat. Notably, skin-fold thickness at specific sites - biceps, triceps, subscapula, and suprailiac - demonstrated considerable augmentation relative to the control group. Furthermore, mean values associated with height, weight, BMI, neck circumference, fat percentage, subcutaneous arm fat, entire arm composition, and trunk skeletal muscle either equaled or exceeded those in the control group. However, statistical significance was not attained in these comparisons. Conclusion This investigation underscored a pronounced correlation between numerous endpoints characterizing OSA patients and markers of obesity. Consequently, addressing altered levels of obesity-linked anthropometric variables through pharmacological interventions might hold promise as a pivotal strategy for improving symptoms associated with OSA.

Liver and spleen stiffness in patients with extrahepatic portal vein obstruction.

PURPOSE: To evaluate liver stiffness (LS) and spleen stiffness (SS) in patients with extrahepatic portal vein obstruction (EHPVO). MATERIALS AND METHODS: Institutional research board approval and informed consent were obtained. LS and SS were measured in 65 consecutive patients with EHPVO. Patients underwent endoscopy, liver biopsy, liver function tests, abdominal ultrasonography, a detailed history, and examination. LS and SS measurements were also obtained in 50 age-matched healthy control subjects. Comparisons were made by using the Student t test, Mann-Whitney test for quantitative data, and χ(2) or Fisher exact test for qualitative data. RESULTS: Sixty-five patients with EHPVO (with a bleed, n = 45; without a bleed, n = 20; mean age, 25.4 years ± 10.7 [standard deviation]; 29 men, 36 women) were enrolled. Twenty-two (34%) had hypersplenism. LS (P = .001) and SS (P = .01) were higher in patients with EHPVO (6.7 kPa ± 2.3 and 51.7 kPa ± 21.5, respectively) than in control subjects (4.6 kPa ± 0.7 and 16.0 kPa ± 3.0, respectively). Patients who had a bleed had higher SS than did those without a bleed (60.4 kPa ± 5.4 vs 30.3 kPa ± 14.2, P = .01). There was no significant difference in age (26.7 years ± 10.4 vs 22.5 years ± 9.8, P = .8) and median duration of disease (4.5 years [range, 1-26 years] vs 6.0 years [range, 1-22 years], P = .23) in patients with a bleed versus those without. With a cutoff of 5.9 kPa for LS, sensitivity and specificity for detection of a variceal bleed were 67% and 75%, respectively. An SS cutoff of 42.8 kPa yielded sensitivity and specificity of 88% and 94%, respectively. CONCLUSION: LS and SS were higher in patients with EHPVO than in control subjects, and patients with a history of a bleed had a higher SS than did those without a bleed.

Outcome and complications of endoscopic ultrasound guided pancreatic pseudocyst drainage using combined endoprosthesis and naso-cystic drain.

BACKGROUND AND AIM: Endoscopic ultrasound guided pancreatic pseudocyst drainage (EUS-PPD) is increasingly being used for management of pancreatic pseudocysts. We evaluated the outcome and complications of EUS-PPD with modified combined technique by inserting both endoprosthesis and naso-cystic drain. METHODS: Forty patients referred between August 2007 and January 2010 for EUS-PPD were prospectively studied. EUS-PPD was attempted for symptomatic pancreatic pseudocysts which were; (i) resistant to conservative treatment, (ii) in contact with the gastric or duodenal wall on EUS and (iii) having no bulge seen on endoscopy. Controlled radial expansion wire guided balloon dilation of the puncture tract was performed followed by insertion of a 10 French double pigtail stent and 7-Fr naso-biliary drain. The early and late outcome and complications of EUS-PPD were analyzed. RESULTS: Thirty-two patients had non-infected and eight had infected pseudocysts. EUS-PPD was technically successful in all. Pseudocysts resolved completely in 39 patients, while one with infected pseudocyst underwent surgical resection for bleeding in the cyst. Naso-cystic drain was removed in 39 patients after median duration of 13 days. Thereafter, the double pigtail stent was removed in all cases after median duration of 10 weeks. Pseudocyst recurred in one patient requiring a second session of EUS-PPD. All 32 patients without cystic infection were successfully treated by EUS-PPD. Seven out of eight patients (87%) with cystic infection were successfully treated by EUS-PPD. CONCLUSION: Endoscopic ultrasound guided pancreatic pseudocyst drainage with modified combined technique is safe and is associated with high success rate.

Pathogenicity and virulence of Rickettsia.

Rickettsiae include diverse Gram-negative microbial species that exhibit obligatory intracellular lifecycles between mammalian hosts and arthropod vectors. Human infections with arthropod-borne Rickettsia continue to cause significant morbidity and mortality as recent environmental changes foster the proliferation of arthropod vectors and increased exposure to humans. However, the technical difficulties in working with Rickettsia have delayed our progress in understanding the molecular mechanisms involved in rickettsial pathogenesis and disease transmission. Recent advances in developing genetic tools for Rickettsia have enabled investigators to identify virulence genes, uncover molecular functions, and characterize host responses to rickettsial determinants. Therefore, continued efforts to determine virulence genes and their biological functions will help us understand the underlying mechanisms associated with arthropod-borne rickettsioses.

PanCircBase: An online resource for the exploration of circular RNAs in pancreatic islets.

Circular RNAs (circRNAs) are a novel class of covalently closed RNA molecules that recently emerged as a critical regulator of gene expression in development and diseases. Recent research has highlighted the importance of novel circRNAs in the biosynthesis and secretion of insulin from ß-cells of pancreatic islets. However, all circRNAs expressed in pancreatic islets or ß-cells are not readily available in the database. In this study, we analyzed publicly available RNA-sequencing datasets of the pancreatic islets to catalog all circRNAs expressed in pancreatic islets to construct the PanCircBase (https://www.pancircbase.net/) database that provides the following resources: 1) pancreatic islet circRNA annotation details (genomic position, host gene, exon information, splice length, sequence, other database IDs, cross-species conservation), 2) divergent primers for PCR analysis of circRNAs, 3) siRNAs for silencing of target circRNAs, 4) miRNAs associated with circRNAs, 5) possible protein-coding circRNAs and their polypeptides. In summary, this is a comprehensive online resource for exploring circRNA expression and its possible function in pancreatic ß-cells.

Health research in the state of Odisha, India: A decadal bibliometric analysis (2011-2020).

Background: Bibliometric analyses are an important tool for evaluating health research outputs in terms of their distribution, trends, contributors, focus, and funding sources. The transition from millennium to sustainable development goals has led to a gradual shift in the health policy, and possibly, research priorities of low-income settings in the Empowered Action Group (EAG) states lagging in socioeconomic and health parameters, and also ranking low on innovations and research. In this study, we depict the recent trends, quantity, type, focus, and sources of health-related research in the EAG state of Odisha, India. Methods: Peer-reviewed published original research articles related to human health published between 1 January, 2011 and 31 December, 2020 and where the study population was the residents of Odisha, or the study site was in Odisha, exclusively or partially, were analyzed. The publication characteristics were tabulated, including the title, journal name, open access, date of publication, number of authors, designation of the authors, number of institutes involved, and name of the institute of the first author. The details of the study setting, study site, ethical clearance, and funding source were also analyzed. Results: The study identified 2,285 articles from database searches and included 666 articles after screening for bibliometric analysis. Most of the manuscripts had between three and six authors (43.5%). Two institutes from the state, the Regional Medical Research Center (ICMR-RMRC) and Kalinga Institute of Industrial Technology (KIIT), together contributed to 22.4% of the published manuscripts. Nearly 45.9% of the studies were community-based while 45.3% were hospital-based. While most of the published work was on infectious diseases, the proportion came down with time. An overwhelming majority of the studies were observational and less than 10% were experimental in design. Conclusions: The analysis shows a substantial increase in the number of publications in this decade. Priority setting of healthcare problems, increased funding, and capacity-building can give a much-necessitated impetus to more quality- and evidence-based research for aiding policy implementation and improvement of the overall health.

Phenotypic and genetic changes associated with the seesaw effect in MRSA strain N315 in a bioreactor model.

OBJECTIVES: Over the past decade, daptomycin treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections has led to the emergence of daptomycin nonsusceptible (DAP-NS) MRSA strains and a subsequent interest in combinatorial antibiotic therapies. We investigated the phenotypic and genetic changes associated with the seesaw effect, which describes the correlation between daptomycin resistance and increased ß-lactam susceptibility in DAP-NS MRSA and the reverse phenomenon of DAP-NS strains acquiring renewed susceptibility to daptomycin after ß-lactam exposure. METHODS: A continuous bioreactor model was used to study the effects of incremental doses of daptomycin followed by oxacillin on MRSA strain N315. Minimum inhibitory concentrations for daptomycin and oxacillin were determined for the bioreactor-derived samples. Transmission electron microscopy and cytochrome C binding assays were used to measure cell wall thickness and cell membrane charge, respectively, in the bioreactor-derived samples. Whole-genome sequencing was used to identify mutations associated with the seesaw effect. RESULTS: Although daptomycin resistance conferred enhanced susceptibility to oxacillin, oxacillin treatment of DAP-NS strains was accompanied by a lowered minimum inhibitory concentration for daptomycin. Additionally, there was a reduction in relative positive cell surface charge and cell wall thickness. However, the mutations acquired in our DAP-NS populations were not accompanied by additional genomic changes after treatment with oxacillin, implicating alternative mechanisms for the seesaw effect. CONCLUSION: In this study, we successfully produced and characterized the seesaw effect in MRSA strain N315 in a unique bioreactor model.

Primary prophylaxis of gastric variceal bleeding comparing cyanoacrylate injection and beta-blockers: a randomized controlled trial.

BACKGROUND & AIMS: Gastric variceal bleeding is severe and is associated with high mortality. We compared the efficacy of cyanoacrylate injection and beta-blockers in primary prophylaxis of gastric variceal bleeding. METHODS: Cirrhotics with large gastroesophageal varices type 2 with eradicated esophageal varices or large isolated gastric varix type 1, who had never bled from gastric varix, were randomised to cyanoacrylate injection (Group I, n=30), beta-blockers (Group II, n=29) or no treatment (Group III, n=30). Primary end-points were bleeding from gastric varix or death. RESULTS: The actuarial probability of bleeding from gastric varices over a median follow-up of 26 months was 13% in Group I, 28% in Group II (p=0.039), and 45% in Group III (p=0.003). The actuarial probability of survival was higher in the cyanoacrylate compared to the no-treatment group (90% vs. 72%, p=0.048). The median hepatic venous pressure gradient (HVPG) was increased in Group I (14-15 mm Hg, p=0.001) and III (14-16 mm Hg, p=0.001) but decreased in Group II (14 to 12 mm Hg, p=0.001) during follow-up. Size of gastric varix >20 mm, a MELD score ≥17, and presence of portal hypertensive gastropathy predicted 'high risk' of first bleeding from gastric varices. CONCLUSIONS: Primary prophylaxis is recommended in patients with large and high risk gastric varices to reduce the risk of first bleeding and mortality. Cyanoacrylate injection is more effective than beta-blocker therapy in preventing first gastric variceal bleeding.

Equal efficacy of endoscopic variceal ligation and propranolol in preventing variceal bleeding in patients with noncirrhotic portal hypertension.

BACKGROUND & AIMS: Variceal bleeding increases morbidity and mortality among patients with noncirrhotic portal hypertension (NCPH). Blockers of ß-adrenergic receptor signaling and endoscopic variceal ligation (EVL) have been used to prevent recurrence of bleeding, based on data from cirrhotic patients. We compared the efficacy and safety of the ß-blocker propranolol with that of EVL in preventing the recurrence of variceal bleeding in patients with NCPH. METHODS: Consecutive patients with NCPH with a history of variceal bleeding in the past 6 weeks were assigned randomly to groups treated every 3 weeks with EVL (n = 51) or propranolol (until they had a resting heart rate of 55 beats per minute or to a maximum of 320 mg/day; n = 50). Primary end points were recurrence of variceal bleeding or death. Secondary end points were complications of EVL in patients given EVL, variceal eradication after EVL, variceal recurrence after EVL, or a decrease in variceal grade in patients given propranolol. RESULTS: After a median follow-up period of 23 months, rates of recurrence of bleeding were similar between the groups (EVL, 23.5%; propranolol, 18%; P = .625). The actuarial probability of remaining free of bleeding recurrence was similar between the groups. No deaths occurred in either group. Of the patients given propranolol, 47% had a decrease in the grade of varices and none experienced bleeding. Adverse events were minor and comparable between groups (EVL, 12%; propranolol, 18%; P = .635). CONCLUSIONS: EVL was not more effective than the ß-blocker propranolol for the secondary prophylaxis of variceal bleeding in patients with NCPH.

Endoscopic cyanoacrylate injection versus beta-blocker for secondary prophylaxis of gastric variceal bleed: a randomised controlled trial.

BACKGROUND AND AIMS: Bleeding from gastric varices is often severe and difficult to manage. Endoscopic injection of gastric varices with cyanoacrylate is effective in prevention of rebleeding. The efficacy of beta-blockers in secondary prophylaxis of gastric variceal bleed has not been well studied. A comparison of the efficacy of beta-blocker treatment and cyanoacrylate injection for the prevention of gastric variceal rebleeding was carried out. METHODS: Patients with gastro-oesophageal varices type 2 (GOV2) with eradicated oesophageal varices or isolated gastric varices type 1 (IGV1) who had bled from gastric varices were randomised to cyanoacrylate injection (n=33) or beta-blocker treatment (n=34). Baseline and follow-up upper gastrointestinal endoscopy and hepatic venous pressure gradient (HVPG) measurements were performed. Primary end points were gastric variceal rebleeding or death. RESULTS: The probability of gastric variceal rebleeding rate in the cyanoacrylate group was significantly lower than in the beta-blocker group (15% vs 55%, p=0.004) and the mortality rate was lower (3% vs 25%, p=0.026) during a median follow-up of 26 months. The median baseline and follow-up HVPG in the cyanoacrylate group were 15 (10-23) and 17 (11-24) mm Hg (p=0.001) and for the beta-blocker group 14 (11-24) and 13 (8-25) mm Hg (p=0.003). While no patient showed reduction of HVPG in the cyanoacrylate group, in the beta-blocker group 12 of 28 (42%) patients were responders, of which 5 (41% of responders) bled. On multivariate analysis, treatment method, portal hypertensive gastropathy and size of the gastric varix >20 mm independently correlated with gastric variceal rebleeding. Gastric variceal rebleeding independently correlated with mortality. CONCLUSIONS: Cyanoacrylate injection is more effective than beta-blocker treatment for the prevention of gastric variceal rebleeding and improving survival.

Identification of Potential circRNA-microRNA-mRNA Regulatory Network in Skeletal Muscle.

Circular RNAs (circRNAs) are a newly discovered family of regulatory RNAs generated through backsplicing. Genome-wide profiling of circRNAs found that circRNAs are ubiquitously expressed and regulate gene expression by acting as a sponge for RNA-binding proteins (RBPs) and microRNAs (miRNAs). To identify circRNAs expressed in mouse skeletal muscle, we performed high-throughput RNA-sequencing of circRNA-enriched gastrocnemius muscle RNA samples, which identified more than 1,200 circRNAs. In addition, we have identified more than 14,000 and 15,000 circRNAs in aging human skeletal muscle tissue and satellite cells, respectively. A subset of abundant circRNAs was analyzed by RT-PCR, Sanger sequencing, and RNase R digestion assays to validate their expression in mouse skeletal muscle tissues. Analysis of the circRNA-miRNA-mRNA regulatory network revealed that conserved circNfix might associate with miR-204-5p, a suppressor of myocyte enhancer factor 2c (Mef2c) expression. To support the hypothesis that circNfix might regulate myogenesis by controlling Mef2c expression, silencing circNfix moderately reduced Mef2c mRNA expression and inhibited C2C12 differentiation. We propose that circNfix promotes MEF2C expression during muscle cell differentiation in part by acting as a sponge for miR-204-5p.

Virulence potential of Rickettsia amblyommatis for spotted fever pathogenesis in mice.

Rickettsia amblyommatis belongs to the spotted fever group of Rickettsia and infects Amblyomma americanum (Lone Star ticks) for transmission to offspring and mammals. Historically, the geographic range of A. americanum was restricted to the southeastern USA. However, recent tick surveys identified the progressive northward invasion of A. americanum, contributing to the increased number of patients with febrile illnesses of unknown etiology after a tick bite in the northeastern USA. While serological evidence strongly suggests that patients are infected with R. amblyommatis, the virulence potential of R. amblyommatis is not well established. Here, we performed a bioinformatic analysis of three genome sequences of R. amblyommatis and identified the presence of multiple putative virulence genes whose products are implicated for spotted fever pathogenesis. Similar to other pathogenic spotted fever rickettsiae, R. amblyommatis replicated intracellularly within the cytoplasm of tissue culture cells. Interestingly, R. amblyommatis displayed defective attachment to microvascular endothelial cells. The attachment defect and slow growth rate of R. amblyommatis required relatively high intravenous infectious doses to produce dose-dependent morbidity and mortality in C3H mice. In summary, our results corroborate clinical evidence that R. amblyommatis can cause mild disease manifestation in some patients.