Circadian Rhythm Perturbation Aggravates Gut Microbiota Dysbiosis in Dextran Sulfate Sodium-Induced Colitis in Mice.

Circadian rhythm disruption is increasingly considered an environmental risk factor for the development and exacerbation of inflammatory bowel disease. We have reported in a previous study that nychthemeral dysregulation is associated with an increase in intestinal barrier permeability and inflammation in mice with dextran sulfate sodium (DSS)-induced colitis. To investigate the effect of circadian rhythm disruption on the composition and diversity of the gut microbiota (GM), sixty male C57BL/6J mice were initially divided to two groups, with the shifted group (n = 30) exposed to circadian shifts for three months and the non-shifted group (n = 30) kept under a normal light-dark cycle. The mice of the shifted group were cyclically housed for five days under the normal 12:12 h light-dark cycle, followed by another five days under a reversed light-dark cycle. At the end of the three months, a colitis was induced by 2% DSS given in the drinking water of 30 mice. Animals were then divided into four groups (n = 15 per group): sham group non-shifted (Sham-NS), sham group shifted (Sham-S), DSS non-shifted (DSS-NS) and DSS shifted (DSS-S). Fecal samples were collected from rectal content to investigate changes in GM composition via DNA extraction, followed by high-throughput sequencing of the bacterial 16S rRNA gene. The mouse GM was dominated by three phyla: Firmicutes, Bacteroidetes and Actinobacteria. The Firmicutes/Bacteroidetes ratio decreased in mice with induced colitis. The richness and diversity of the GM were reduced in the colitis group, especially in the group with inverted circadian rhythm. Moreover, the GM composition was modified in the inverted circadian rhythm group, with an increase in Alloprevotella, Turicibacter, Bacteroides and Streptococcus genera. Circadian rhythm inversion exacerbates GM dysbiosis to a less rich and diversified extent in a DSS-induced colitis model. These findings show possible interplay between circadian rhythm disruption, GM dynamics and colitis pathogenesis.

Increasing surgeon experience and cumulative institutional experience drive decreasing hospital mortality after reoperative cardiac surgery.

OBJECTIVE: The study objective was to identify the effects of surgeon experience and age, in the context of cumulative institutional experience, on risk-adjusted hospital mortality after cardiac reoperations. METHODS: From 1951 to 2020, 36 surgeons performed 160,338 cardiac operations, including 32,871 reoperations. Hospital death was modeled using a novel tree-bagged, generalized varying-coefficient method with 6 variables reflecting cumulative surgeon and institutional experience up to each cardiac operation: (1) number of total and (2) reoperative cardiac operations performed by a surgeon, (3) cumulative institutional number of total and (4) reoperative cardiac operations, (5) year of surgery, and (6) surgeon age at each operation. These were adjusted for 46 patient characteristics and surgical components. RESULTS: There were 1470 hospital deaths after cardiac reoperations (4.5%). At the institutional level, hospital death decreased exponentially and became less variable, leveling at 1.2% after approximately 14,000 cardiac reoperations. For all surgeons as a group, hospital death decreased rapidly over the first 750 reoperations and then gradually decreased with increasing experience to less than 1% after approximately 4000 reoperations. Surgeon age up to 75 years was associated with ever-decreasing hospital death. CONCLUSIONS: Surgeon age and experience have been implicated in adverse surgical outcomes, particularly after complex cardiac operations, with young surgeons being novices and older surgeons having declining ability. However, at Cleveland Clinic, outcomes of cardiac reoperations improved with increasing primary surgeon experience, without any suggestion to mid-70s of an age cutoff. Patients were protected by the cumulative background of institutional experience that created a culture of safety and teamwork that mitigated adverse events after cardiac surgery.

Artificial Intelligence, Computational Simulations, and Extended Reality in Cardiovascular Interventions.

Artificial intelligence, computational simulations, and extended reality, among other 21st century computational technologies, are changing the health care system. To collectively highlight the most recent advances and benefits of artificial intelligence, computational simulations, and extended reality in cardiovascular therapies, we coined the abbreviation AISER. The review particularly focuses on the following applications of AISER: 1) preprocedural planning and clinical decision making; 2) virtual clinical trials, and cardiovascular device research, development, and regulatory approval; and 3) education and training of interventional health care professionals and medical technology innovators. We also discuss the obstacles and constraints associated with the application of AISER technologies, as well as the proposed solutions. Interventional health care professionals, computer scientists, biomedical engineers, experts in bioinformatics and visualization, the device industry, ethics committees, and regulatory agencies are expected to streamline the use of AISER technologies in cardiovascular interventions and medicine in general.

TRPC3 Regulates Islet Beta-Cell Insulin Secretion.

Insulin release is tightly controlled by glucose-stimulated calcium (GSCa) through hitherto equivocal pathways. This study investigates TRPC3, a non-selective cation channel, as a critical regulator of insulin secretion and glucose control. TRPC3's involvement in glucose-stimulated insulin secretion (GSIS) is studied in human and animal islets. TRPC3-dependent in vivo insulin secretion is investigated using pharmacological tools and Trpc3-/- mice. TRPC3's involvement in islet glucose uptake and GSCa is explored using fluorescent glucose analogue 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose and calcium imaging. TRPC3 modulation by a small-molecule activator, GSK1702934A, is evaluated in type 2 diabetic mice. TRPC3 is functionally expressed in human and mouse islet beta cells. TRPC3-controlled insulin secretion is KATP -independent and primarily mediated by diacylglycerol channel regulation of the cytosolic calcium oscillations following glucose stimulation. Conversely, glucose uptake in islets is independent of TRPC3. TRPC3 pharmacologic inhibition and knockout in mice lead to defective insulin secretion and glucose intolerance. Subsequently, TRPC3 activation through targeted small-molecule enhances insulin secretion and alleviates diabetes hallmarks in animals. This study imputes a function for TRPC3 at the onset of GSIS. These insights strengthen one's knowledge of insulin secretion physiology and set forth the TRPC3 channel as an appealing candidate for drug development in the treatment of diabetes.

Triggering receptor expressed on myeloid cells-1 (TREM-1) inhibition in atherosclerosis.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a transmembrane protein expressed on endothelial cells, white blood cells, smooth muscle cells and platelets. TREM-1 plays an important role in innate immunity. TREM-1 activation pathways are implicated both in sepsis and in non-infectious inflammatory conditions, including atherosclerosis. TREM-1 enhances the subendothelial lipid accumulation and expression of pro-inflammatory cytokines and matrix-degrading enzymes, thereby promoting inflammation and plaque destabilization. TREM-1 inhibitors attenuate the inflammatory process in the atherosclerotic plaque, leading to plaque stabilization. This review focuses on the role of TREM-1 in the pathophysiology of atherosclerosis and the effects of TREM-1 inhibition in the natural history of the disease.

Blood Donation in Lebanon: A Six-Year Retrospective Study of a Decentralized Fragmented Blood Management System.

Introduction In developing countries, the lack of a sufficient and safe blood supply is a significant impediment to providing health care. Lebanon is notable for its absence of a Donor Management System to ensure continuous donor recruitment and scheduling. Herein, we report the findings of Lebanon's first large retrospective population-based study to investigate blood types and donation that is critical for managing community blood supply. Methods The non-remunerated voluntary blood donors were recruited by the non-profit organization "Donner Sang Compter". The study spanned six years, from August 2015 to May 2021, and included 36,002 people from 18 districts throughout Lebanon's nine governorates. Results The most prevalent blood type was A (42%), followed by O (37.48%), B (13.86%), and the AB group (6.84%). RhD+ groups were predominant (88.45%), with A+ being the most (37.84%) and AB- being the least prevalent (1.05%). Furthermore, blood type and donation profiling revealed a substantial geographical variation in the frequency of blood groups, despite the relatively small country's area. As for blood donation, when gender and age were considered, young male donors dominated the pool across the country. Conclusion This study on blood type prevalence and blood donor demographics may pave the way for the development of a more coherent and integrated blood management system in Lebanon, as opposed to the fragmented and decentralized system now in existence. These findings also provide crucial clinical information for the country's future transfusion medicine policies and practices, which is vital in such a precarious part of the world.

Comparative study between prison- and community-based treatment satisfaction for opioid use disorder in Lebanon.

PURPOSE: Opioid substitution treatment (OST), such as Buprenorphine, has become a well-established evidence-based approach for the treatment of inmates with opioid use disorder (OUD) in most of the developed world. However, its application in Lebanon remains mainly as a community-based intervention. The purpose of this paper is to highlight the need of its implementation within the Lebanese correctional system. DESIGN/METHODOLOGY/APPROACH: The work is a pilot cross-sectional study that compares two groups: 30 male adult prisoners with OUD convictions receiving symptomatic treatment and 30 male adult community patients with OUD receiving Buprenorphine. The objective was to measure the difference in the patients' general perception and satisfaction of the treatments available. OUD was diagnosed using the Diagnostic and Statistical Manual of Mental Disorders 5th Edition criteria and the level of satisfaction was measured by "Treatment Perceptions Questionnaire (TPQ)." FINDINGS: The prison group reported significantly lower satisfaction when compared to the community group (total TPQ mean scores: M=34.73, SD =4.12 and M=16.67, SD =4.78, respectively, with t (56.76) =15.68, p=0.000). Furthermore, age, marital status, education level and elapsed time in treatment had no significant interactions with the total TPQ score. ORIGINALITY/VALUE: The major principles of the ethics of care and evidence-based safe practices will be proposed for the introduction of Buprenorphine to Lebanese prisons. This work provides an opportunity for the expansion of the Lebanese OST program and consequently other countries in the region could benefit from this experience.

Circadian Rhythm Disruption Aggravates DSS-Induced Colitis in Mice with Fecal Calprotectin as a Marker of Colitis Severity.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic immunologically mediated pathology that remains a major health burden. Circadian rhythm disruption leads to a deregulation in the immune system which is a major risk factor for IBD. AIMS: Since fecal calprotectin (FC) has been a useful tool for monitoring IBD, we aimed to evaluate the effect of circadian rhythm alteration on gut inflammation status and whether FC is associated with the severity of colitis. METHODS: C57BL/6J mice were exposed to circadian shifts for 3 months, and then colitis was induced by 2% dextran sulfate sodium (DSS). Colitis was evaluated according to clinical symptoms and histological scoring. Plasma and intestinal inflammatory and permeability markers as well as fecal and intestinal calprotectin were assessed. RESULTS: Circadian shifts aggravated DSS-induced colitis with increased diarrhea, flatulence, and fecal blood associated with decreased colon length. In addition, intestinal cryptic architecture was lost with the presence of increased inflammation, mucosal muscle thickening, and cryptic abscesses. Plasma tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and C-reactive protein upregulations were paralleled by the deterioration of intestinal permeability. Calprotectin expression and distribution increased in the intestines and feces of shifted animals, and levels highly correlated with the increases in intestinal inflammation and permeability. CONCLUSIONS: Circadian rhythm disruption aggravates DSS-induced colitis, whereas fecal and intestinal calprotectin associates with the severity of disease. Calprotectin might be a useful marker and tool for assessing patients at risk of IBD due to lifestyles with disruptive sleep patterns.

VEGF-C attenuates renal damage in salt-sensitive hypertension.

Salt-sensitive hypertension is a major risk factor for renal impairment leading to chronic kidney disease. High-salt diet leads to hypertonic skin interstitial volume retention enhancing the activation of the tonicity-responsive enhancer-binding protein (TonEBP) within macrophages leading to vascular endothelial growth factor C (VEGF-C) secretion and NOS3 modulation. This promotes skin lymphangiogenesis and blood pressure regulation. Whether VEGF-C administration enhances renal and skin lymphangiogenesis and attenuates renal damage in salt-sensitive hypertension remains to be elucidated. Hypertension was induced in BALB/c mice by a high-salt diet. VEGF-C was administered subcutaneously to high-salt-treated mice as well as control animals. Analyses of kidney injury, inflammation, fibrosis, and biochemical markers were performed in vivo. VEGF-C reduced plasma inflammatory markers in salt-treated mice. In addition, VEGF-C exhibited a renal anti-inflammatory effect with the induction of macrophage M2 phenotype, followed by reductions in interstitial fibrosis. Antioxidant enzymes within the kidney as well as urinary RNA/DNA damage markers were all revelatory of abolished oxidative stress under VEGF-C. Furthermore, VEGF-C decreased the urinary albumin/creatinine ratio and blood pressure as well as glomerular and tubular damages. These improvements were associated with enhanced TonEBP, NOS3, and lymphangiogenesis within the kidney and skin. Our data show that VEGF-C administration plays a major role in preserving renal histology and reducing blood pressure. VEGF-C might constitute an interesting potential therapeutic target for improving renal remodeling in salt-sensitive hypertension.

CoreValve Double Jeopardy: Embolized Valve Capture With Subsequent Valve.

During transcatheter aortic valve replacement with a self-expanding prosthesis, prosthesis embolization represents a rare but severe complication. Etiologies of prosthesis embolization include improper sizing and malpositioning, specifically high deployment with respect to the aortic annulus. Treatment of embolization into the aorta relies upon repositioning of the prosthesis using endovascular snares or removal with open surgery. Patients with prosthesis embolization have a high risk of mortality and morbidity including stroke and aortic dissection associated with manipulation of the prosthesis in the ascending aorta. We describe a case of self-expanding prosthesis embolization and present a solution using a second prosthesis to capture the embolized one.

Mifepristone reduces hypothalamo-pituitary-adrenal axis activation and restores weight loss in rats subjected to dietary restriction and methylphenidate administration.

This study evaluates the efficacy of mifepristone on weight restoration in rats subjected to dietary restriction and methylphenidate administration. 25 female rats aged between 9 and 12 months were divided into 2 groups: 5 controls (exposed only to dietary restriction) and 20 rats that were administered 5 mg/kg/d of methylphenidate before meal exposure, for 36 days. Among rats who responded to methylphenidate (weight loss of 15-25%) weeks after its administration, a group of 6 rats continued to receive only methylphenidate ("Met" group), and another group received 10 mg/kg/d of mifepristone in addition to methylphenidate for 18 days ("Met+Mif" group; n = 6). The mean weight of the "Met+Mif" group remained significantly lower when compared to the control group (87.63 ±â€¯2.83% vs 96.29 ±â€¯3.26%; p < 0.001 respectively) but was significantly higher than that of the "Met" group (87.63 ±â€¯2.83% vs. 80.61 ±â€¯3.52%; p < 0.001 respectively). Plasma concentrations of adiponectin and gene expression of its receptors in rats brain were significantly higher in the "Met" group as compared to the "Met+Mif" and control groups (p < 0.01). Accordingly, mifepristone reduces HPA axis activation and restores weight through adipose tissue recovering. It might be considered a promising treatment for anorexia nervosa patients in future studies.

An optimized protocol for purification of functional islets of Langerhans.

Islets of Langerhans and ß-cell isolation constitute routinely used cell models for diabetic research, and refining islet isolation protocols and cell quality assessment is a high priority. Numerous protocols have been published describing isolate of islets, but often rigorous and systematic assessment of their integrity is lacking. Herein, we propose a new protocol for optimal generation of islets. Pancreases from mice and rats were excised and digested using a low-activity collagenase solution and islets were then purified by a series of sedimentations and a Percoll gradient. Islets were maintained in culture for 5 days, during which viability, pro/antiapoptotic, and islet-specific genes, glucose-stimulated calcium entry, glucose uptake, and insulin secretion were assessed. The commonly used islet isolation technique by collagenase injection through the common bile duct (CBD) was also performed and compared with the present approach. This new protocol produced islets that retained a healthy status as demonstrated by the yield of stable living cells. Furthermore, calcium oscillation, glucose uptake, and insulin secretion remained intact in the islet cultures. This was reproducible when many rodent species were used, and neither sex nor age affected the cells behavior. When compared with the CBD technique, islet physiology was similar. Finally, this approach was used to uncover new ion channel candidates implicated in insulin secretion. In conclusion, this study outlines an efficient protocol for islet preparation that may support research into new therapeutic targets in diabetes research.