Psychotherapy for Alcohol Use Disorder Is Associated With Reduced Risk of Incident Alcohol-Associated Liver Disease.

BACKGROUND & AIMS: Alcohol-associated liver disease (ALD) is a devastating complication of alcohol use disorder (AUD). Once it develops, ALD is exceedingly difficult to treat; it therefore is critical to identify ways to prevent ALD. By treating the causes of increased alcohol consumption, psychotherapy may offer prophylactic benefit against the development of ALD for patients with AUD. METHODS: In this retrospective cohort study, we used International Classification of Diseases, 9th and 10th revision, codes to identify 9635 patients with AUD in the Mass General Brigham Biobank. The mean follow-up period from AUD diagnosis was 9.2 years. We used Cox regression models to generate hazard ratios (HR) for the development of ALD given the receipt or nonreceipt of psychotherapy, adjusting for a range of other contributors including the receipt of medication-assisted treatment. RESULTS: In our cohort, 60.4% of patients were men, 83.5% of patients were white, the median age was 57.0 years, and 3544 patients (36.8%) received psychotherapy. ALD developed in 1135 patients (11.8%). In multivariable analysis, psychotherapy was associated with a reduced rate of ALD (HR, 0.59; 95% CI, 0.50-0.71; P < .001). This association held for both individual psychotherapy (HR, 0.70; 95% CI, 0.56-0.86; P < .001) and group psychotherapy (HR, 0.76; 95% CI, 0.61-0.94; P = .01). Among patients with cirrhosis, psychotherapy was associated with a lower rate of hepatic decompensation (HR, 0.68; 95% CI, 0.48-0.95; P = .03). CONCLUSIONS: The receipt of psychotherapy in the setting of AUD is associated with reduced incidence and progression of ALD. Given the safety and potential benefit of psychotherapy, clinicians should consider using it to prevent the development of ALD.

Moderate-high intensity exercise associates with reduced incident alcohol-associated liver disease in high-risk patients.

BACKGROUND: Therapies to prevent alcohol-associated liver disease (ALD) in high-risk patients are needed. AIMS: In this retrospective association study, we examined whether patients with alcohol use disorder (AUD) who reported greater exercise were less likely to develop liver disease. METHODS: In this retrospective cohort study, we used the Mass General Brigham Biobank to investigate the impact of both moderate-high and light-intensity exercise on the development of ALD in patients with AUD, using clinician-provided diagnostic International Classification of Diseases 10 codes. Exercise was evaluated using a questionnaire completed after an AUD diagnosis, and before evidence of liver disease. Cox regressions were used to generate hazard ratios (HRs) for the development of ALD. RESULTS: 1987 patients met inclusion criteria. These patients were followed for an average of 10.7 years. In multivariable analyses, we found that patients that reported at least 2.5 h of moderate-high intensity exercise/week (confidence interval recommendation for exercise) were less likely to develop ALD compared to patients that did not exercise (HR: 0.26, 95%CI: 0.085-0.64, P = 0.007). Indeed, each hour of moderate-high intensity exercise was associated with progressively decreasing odds of developing ALD (HR: 0.76, 95%CI: 0.58-0.91, P = 0.02). Conversely, patients who did not engage in any moderate-high intensity exercise were more likely to develop ALD (HR: 2.76, 95%CI: 1.44-5.40, P = 0.003). CONCLUSIONS: In our cohort, patients with AUD who reported moderate-high intensity exercise showed a lower association with incidence of ALD development than patients who did not exercise.

Hepatic gap junctions amplify alcohol liver injury by propagating cGAS-mediated IRF3 activation.

Alcohol-related liver disease (ALD) accounts for the majority of cirrhosis and liver-related deaths worldwide. Activation of IFN-regulatory factor (IRF3) initiates alcohol-induced hepatocyte apoptosis, which fuels a robust secondary inflammatory response that drives ALD. The dominant molecular mechanism by which alcohol activates IRF3 and the pathways that amplify inflammatory signals in ALD remains unknown. Here we show that cytoplasmic sensor cyclic guanosine monophosphate-adenosine monophosphate (AMP) synthase (cGAS) drives IRF3 activation in both alcohol-injured hepatocytes and the neighboring parenchyma via a gap junction intercellular communication pathway. Hepatic RNA-seq analysis of patients with a wide spectrum of ALD revealed that expression of the cGAS-IRF3 pathway correlated positively with disease severity. Alcohol-fed mice demonstrated increased hepatic expression of the cGAS-IRF3 pathway. Mice genetically deficient in cGAS and IRF3 were protected against ALD. Ablation of cGAS in hepatocytes only phenocopied this hepatoprotection, highlighting the critical role of hepatocytes in fueling the cGAS-IRF3 response to alcohol. We identified connexin 32 (Cx32), the predominant hepatic gap junction, as a critical regulator of spreading cGAS-driven IRF3 activation through the liver parenchyma. Disruption of Cx32 in ALD impaired IRF3-stimulated gene expression, resulting in decreased hepatic injury despite an increase in hepatic steatosis. Taken together, these results identify cGAS and Cx32 as key factors in ALD pathogenesis and as potential therapeutic targets for hepatoprotection.

Breaking paracyclophane: the unexpected formation of non-symmetric disubstituted nitro[2.2]metaparacyclophanes.

Substituted [2.2]metaparacyclophanes are amongst the least studied of the simple cyclophanes. This is undoubtedly the result of the lengthy syntheses of these compounds. We report the simple synthesis of a rare example of a non-symmetric [2.2]metaparacyclophane. Treatment of [2.2]paracyclophane under standard nitration conditions gives a mixture of 4-nitro[2.2]paracyclophane, 4-hydroxy-5-nitro[2.2]metaparacyclophane and a cyclohexadienone cyclophane.

Loss of Response to Anti-Tumor Necrosis Factor Alpha Therapy in Crohn's Disease Is Not Associated with Emergence of Novel Inflammatory Pathways.

BACKGROUND: While monoclonal antibodies against tumor necrosis factor-α (TNFα) are effective in treating Crohn's disease (CD), approximately one-third of patients lose response. The mechanisms underlying this loss of response remain elusive. AIM: We sought to determine if novel biological pathways, including TNFα-independent inflammatory pathways, emerge in those with loss of response to anti-TNFα. METHODS: Using RNA microarray technology in 28 patients with CD, we examined the colonic gene expression differences between those with active inflammation in the setting of loss of response to TNFα-antagonist therapy ("loss of responders") compared to anti-TNFα naïve patients with active inflammation and those on anti-TNF therapy in disease remission. Pathway enrichment analyses were performed. RESULTS: We found that colonic expression of chemokines known to drive inflammation (CXCL20, CXCL9, and CXCL10) was elevated in those with loss of response compared to those in remission. Expression of genes critical to modulating oxidative stress burden (DUOX2, DUOXA2, and NOS2) was also elevated. Additionally, MMP3, MMP1, and MMP12 were elevated in those with continued inflammation. Gene enrichment analysis revealed that loss of responders exhibited dysregulation in the cysteine and methionine metabolism pathway, suggesting alteration in oxidative stress burden. There were no differences in genes or pathways between loss of responders and those who were TNFα-naïve. However, loss of response occurred despite the ability of anti-TNFα therapy to normalize APO gene expression. CONCLUSION: Our analyses suggest that loss of response to anti-TNFα is not driven by the emergence of pathways that bypass the action or induce resistance to anti-TNFα therapy.

Alternative erythropoietin-mediated signaling prevents secondary microvascular thrombosis and inflammation within cutaneous burns.

Alternate erythropoietin (EPO)-mediated signaling via the heteromeric receptor composed of the EPO receptor and the ß-common receptor (CD131) exerts the tissue-protective actions of EPO in various types of injuries. Herein we investigated the effects of the EPO derivative helix beta surface peptide (synonym: ARA290), which specifically triggers alternate EPO-mediated signaling, but does not bind the erythropoietic EPO receptor homodimer, on the progression of secondary tissue damage following cutaneous burns. For this purpose, a deep partial thickness cutaneous burn injury was applied on the back of mice, followed by systemic administration of vehicle or ARA290 at 1, 12, and 24 h postburn. With vehicle-only treatment, wounds exhibited secondary microvascular thrombosis within 24 h postburn, and subsequent necrosis of the surrounding tissue, thus converting to a full-thickness injury within 48 h. On the other hand, when ARA290 was systemically administered, patency of the microvasculature was maintained. Furthermore, ARA290 mitigated the innate inflammatory response, most notably tumor necrosis factor-alpha-mediated signaling. These findings correlated with long-term recovery of initially injured yet viable tissue components. In conclusion, ARA290 may be a promising therapeutic approach to prevent the conversion of partial- to full-thickness burn injuries. In a clinical setting, the decrease in burn depth and area would likely reduce the necessity for extensive surgical debridement as well as secondary wound closure by means of skin grafting. This use of ARA290 is consistent with its tissue-protective properties previously reported in other models of injury, such as myocardial infarction and hemorrhagic shock.

Association of Use of a Mobile Tackling Dummy During College Football Practice With Reduced Sport-Related Concussion: Results of a Pilot Investigation.

Background: Considering the multifaceted consequences of improperly managed sport-related concussions (SRCs) in American football, identifying efficacious prevention measures for enhancing player safety is crucial. Purpose: To investigate the association of primary prevention measures (no-tackle practices and using a mobile tackling dummy in practice) with the frequency of SRCs within college football programs in the United States. Study Design: Descriptive epidemiology study. Methods: In this pilot study, we analyzed the frequency of new SRCs recorded during various settings (total, in preseason, in season, in practice, and game) across 14 seasons (2007-2019 and 2021) for Dartmouth College and across 7 seasons (2013-2019) for the 7 other teams in the Ivy League men's athletic football conference. Trends between seasons and the number of SRCs sustained were examined using correlations and basic descriptive statistics. We also examined SRC frequency in relation to primary prevention measures (no-tackle practices, use of mobile tackling dummies during practice) in the Dartmouth College football program, and we compared SRCs with regard to the no-tackle practice policy in the other Ivy League teams. Results: There was a statistically significant reduction in the number of SRCs over the seasons studied, with the strongest finding observed for Dartmouth College in-game SRCs (r = -0.52; P = .029). Relatedly, the strongest between-season effect was seen for the Dartmouth College practice policy on in-game SRCs (η2 = 0.510; P = .01). The use of mobile tackling dummies was found to be independently associated (adjusting for no-tackle practice) with a lower number total (ß = -0.53; P = .049), in-season (ß = -0.63; P = .023), and in-game (ß = -0.79; P = .003) SRCs. While seasons with the no-tackle practice were not meaningfully associated with SRCs for Dartmouth College, stronger trends were observed in the other Ivy League teams, such that seasons with this policy were associated with lower SRC prevalence. Conclusion: Our data indicate that the use of the mobile tackling dummy in practice was related to the reduced number of SRCs sustained at multiple settings during the football season. To a lesser extent, the no-tackle practice policy was also associated with a reduced number of SRCs.

AgRP neuron cis-regulatory analysis across hunger states reveals that IRF3 mediates leptin's acute effects.

AgRP neurons in the arcuate nucleus of the hypothalamus (ARC) coordinate homeostatic changes in appetite associated with fluctuations in food availability and leptin signaling. Identifying the relevant transcriptional regulatory pathways in these neurons has been a priority, yet such attempts have been stymied due to their low abundance and the rich cellular diversity of the ARC. Here we generated AgRP neuron-specific transcriptomic and chromatin accessibility profiles from male mice during three distinct hunger states of satiety, fasting-induced hunger, and leptin-induced hunger suppression. Cis-regulatory analysis of these integrated datasets enabled the identification of 18 putative hunger-promoting and 29 putative hunger-suppressing transcriptional regulators in AgRP neurons, 16 of which were predicted to be transcriptional effectors of leptin. Within our dataset, Interferon regulatory factor 3 (IRF3) emerged as a leading candidate mediator of leptin-induced hunger-suppression. Measures of IRF3 activation in vitro and in vivo reveal an increase in IRF3 nuclear occupancy following leptin administration. Finally, gain- and loss-of-function experiments in vivo confirm the role of IRF3 in mediating the acute satiety-evoking effects of leptin in AgRP neurons. Thus, our findings identify IRF3 as a key mediator of the acute hunger-suppressing effects of leptin in AgRP neurons.

A role for two-pore potassium (K2P) channels in endometrial epithelial function.

The human endometrial epithelium is pivotal to menstrual cycle progression, implantation and early pregnancy. Endometrial function is directly regulated by local factors that include pH, oxygen tension and ion concentrations to generate an environment conducive to fertilization. A superfamily of potassium channels characterized by two-pore domains (K2P) and encoded by KCNK genes is implicated in the control of the cell resting membrane potential through the generation of leak currents and modulation by various physicochemical stimuli. The aims of the study were to determine the expression and function of K2P channel subtypes in proliferative and secretory phase endometrium obtained from normo-ovulatory women and in an endometrial cancer cell line. Using immunochemical methods, real-time qRT-PCR proliferation assays and electrophysiology. Our results demonstrate mRNA for several K2P channel subtypes in human endometrium with molecular expression of TREK-1 shown to be higher in proliferative than secretory phase endometrium (P < 0.001). The K2P channel blockers methanandamide, lidocaine, zinc and curcumin had antiproliferative effects (P < 0.01) in an endometrial epithelial cancer cell line indicating a role for TASK and TREK-1 channels in proliferation. Tetraethylammonium- and 4-aminopyridine-insensitive outwards currents were inhibited at all voltages by reducing extracellular pH from 7.4 to 6.6. Higher expression of TREK-1 expression in proliferative phase endometrium may, in part, underlie linked to increased cell division. The effects of pH and a lack of effect of non-specific channel blockers of voltage-gated potassium channels imply a role for K2P channels in the regulation of human endometrial function.

Resolvin D2 prevents secondary thrombosis and necrosis in a mouse burn wound model.

Deep partial thickness burns are subject to delayed necrosis of initially viable tissues surrounding the primary zone of thermally induced coagulation, which results in an expansion of the burn wound, both in area and depth, within 48 hours postburn. Neutrophil sequestration and activation leading to microvascular damage is thought to mediate this secondary tissue damage. Resolvins, a class of endogenous mediators derived from omega-3 polyunsaturated fatty acids, have been shown to regulate the resolution of inflammation. We hypothesized that exogenous resolvins could mitigate the deleterious impact of the inflammatory response in burn wounds. Using two different mouse burn injury models involving significant partial thickness injuries, we found that a systemically administered single dose of resolvin D2 (RvD2) as low as 25 pg/g bw given within an interval of up to 4 hours postburn effectively prevented thrombosis of the deep dermal vascular network and subsequent dermal necrosis. By preserving the microvascular network, RvD2 enhanced neutrophil access to the dermis, but prevented neutrophil-mediated damage through other anti-inflammatory actions, including inhibition of tumor necrosis factor-α, interleukin-1ß, and neutrophil platelet-endothelial cell adhesion molecule-1. In a clinical context, RvD2 may be therapeutically useful by reducing the need for surgical debridement and the area requiring skin grafting.

A Novel Case of Multicentric Reticulohistiocytosis Associated with Renal Cell Carcinoma Successfully Treated with Infliximab and Methotrexate.

Multicentric reticulohistiocytosis (MRH) is categorized as a rare non-Langerhans cell histiocytosis most commonly seen in women in the fourth to fifth decade of life. This systemic inflammatory condition affects multiple organ systems and can result in severe joint destruction which can progress to arthritis mutilans. To date, various underlying malignancies have been discovered in patients with MRH including breast, gastric, thymic, hepatic, and melanoma. There has been 1 case of underlying renal cell carcinoma reported in a patient diagnosed with MRH. Additionally, there is no consistently recognized treatment for MRH described in the literature. The rarity of the disease contributes to the difficulty in defining a standardized treatment. We present the case of a patient with extensive joint and skin involvement who was successfully treated with infliximab and methotrexate, experienced clinical improvement, and was later diagnosed with clear cell renal cell carcinoma. The synergistic effects of infliximab and methotrexate, in combination with the low side-effect profile, appear to be promising in the setting of MRH and in our patient resulted in the resolution of symptoms and cutaneous manifestations. We suggest this regimen as an effective combination therapy. We emphasize thorough and continuous screening for underlying malignancy associated with MRH, despite clinical improvement or negative malignancy work-up upon initial diagnosis.

Micropropagation and elicited production of triterpenoid saponin glycosides and stigmasterol via precursor and elicitor feeding in Bacopa floribunda (R.Br.) Wettst.-A potential nootropic herb.

Bacopa floribunda (Family: Plantaginaceae) is used in folklore medicines for the management of cognitive dysfunction. It has nootropic, antiaging, anti-inflammatory, anti-cholinesterase, and antioxidant properties. We developed an efficient and reproducible protocol for in vitro propagation of B. floribunda using the nodal explants. We assessed the effects of Murashige and Skoog (MS) medium fortified with various plant growth regulatory substances (PGRs), a precursor, and elicitors and their optimal combinations on regeneration and production of total saponins, triterpenoid saponin glycosides (bacoside A3, bacopaside X, bacopaside II, and bacosaponin C), and stigmasterol content in in vitro grown biomass of B. floribunda. The growth of the shoots and roots was stimulated by MS + 2.0 mg/l BAP + 2.0 mg/l KIN and MS + 0.5 mg/l IAA + 0.5 mg/l IBA + 1.0 mg/l NAA, respectively. After 10 weeks of acclimatization, plantlets of B. floribunda had a survival rate of 95%. The highest total saponin content (35.95 ± 0.022 mg DE/g DW) was noted in the treatment of MS + 2.0 mg/l BAP + 1.5 µM SQ. Similarly, total triterpenoid saponin glycosides and stigmasterol were found maximum in biomass derived from MS + 2.0 mg/l BAP + 1.5 µM SQ and MS + 2.0 mg/l BAP, respectively. At the same treatments, bacoside A3 (1.01 ± 0.195 mg/g DW), bacopaside II (43.62 ± 0.657 mg/g DW), bacopaside X (1.23 ± 0.570 mg/g DW), bacosaponin C (0.19 ± 0.195 mg/g DW), and stigmasterol (7.69 ± 0.102 mg/g DW) were reported. The present findings will help to highlight B. floribunda as a potent memory-enhancing herb, and in future also, it could be a potential substitute to B. monnieri. The current work is the first to describe the micropropagation and the elicited production of bioactive metabolites from the in vitro grown biomass of B. floribunda. In addition, further research is needed on production of bioactives, their pharmacological effects, and the elicited production using callus, cell suspension, and hairy root cultures.

Persistent Bleeding after Coil Embolization of a Pancreatic Transplant Pseudoaneurysm: Should Covered Stents Be the Primary Management?

Life-threatening arterial complications after pancreatic transplantation can be dire. Pseudoaneurysms can be challenging to treat. There are multiple strategies to treat such complications. We present a case of pancreatic pseudoaneurysm which was initially treated by coiling followed by subsequent covered stent placement for a more durable outcome. We advocate for a "stent first" approach to these lesions if feasible.

Streptococcus pneumoniae Serotype 23B Causing Asymptomatic Sinusitis Complicated by Endocarditis and Meningitis: Sequela of a Non-vaccine Serotype.

We describe a rare case of a Streptococcus pneumoniae (S. pneumoniae) infection causing mitral valve endocarditis and bacterial meningitis in a previously healthy young adult male in his 20s who presented with altered mentation. Though our patient did not endorse any respiratory issues, we suspected the paranasal sinuses to have been the cryptic primary source of disseminated infection into the respiratory system and meninges due to incidental mucosal thickening being found on imaging. Blood and cerebrospinal fluid analyses and cultures revealed the proliferation of S. pneumoniae serotype 23B, despite our patient having previously received appropriate pneumococcal vaccinations in his childhood without delinquency. Ultimately, surgical replacement of the mitral valve, as well as a course of ceftriaxone, was indicated for this patient, in which full resolution of symptoms was achieved upon discharge.

Understanding the Nuances of Hepatic Portal Venous Gas in Pneumatosis Intestinalis: An Indication of Bowel Ischemia?

Pneumatosis intestinalis (PI) is a relatively rare gastrointestinal finding that has a wide variety of causes - ranging from benign to life-threatening. It is described as the pathological presence of gas within the bowel wall with multiple hypotheses emerging as to the likely mechanism. An important indicator of a life-threatening source of PI is the presence of gas within the hepatic portal vein, referred to as hepatic portal venous gas (HPVG). While non-specific for isolated PI, HPVG has been reported in PI patients to be associated with bowel ischemia and is thereby considered an indication for emergent management. Herein we report a case involving an atypical presentation of altered mental status in which the patient was found to have PI with contemporaneous HPVG. These findings have been reported to have a high mortality rate. Our patient rapidly deteriorated during their hospital course, expiring shortly after being deemed a poor surgical candidate due to their severe co-morbidity burden. Through this case, we review evidence supporting the management of patients with PI and concurrent HPVG from an extensive review of available literature. While PI is a non-specific finding and commonly a source of diagnostic confusion, a better understanding of its natural course and potentially unorthodox sequela may afford more directed and crucial care for critically ill patients, in which time is often a precious commodity.

The treatment of refractory periorbital dermatitis.

Purpose: Refractory periorbital dermatitis has a chronic course with exacerbations leading to discomfort and cosmetic issues, yet characterization of treatment options is limited. Aims: The objective was to present comprehensive demographic data and medical management of a series of patients with refractory periorbital dermatitis. Settings and Design: Retrospective review identified patients treated at a single institution from January 2010 to August 2020. Methods: Descriptive analyses were performed. Demographic data and treatment history were reviewed and data including medication, use, date of use and discontinued use, reason for discontinuation (if applicable), refractory status, formulation, concentration, and dose frequency were extracted. Statistical Analysis Used: Descriptive analyses. Results: Forty-five patients were included. The average age at first diagnosis was 60.3 years (sd 14.9). 82.2% were women and 84.4% identified as Caucasian. Triamcinolone cream was most frequently used followed by tobramycin-dexamethasone, tacrolimus, and neomycin-polymyxin-dexamethasone. Less than 30% of patients on triamcinolone were refractory. 13.3% of patients used topical hydrocortisone, with over 80% of these patients experiencing refractory episodes of persistent irritation and erythema. Most patients were refractory during initial use or the first recurrence of periorbital dermatitis flare. Conclusions: By better characterizing the diverse treatment regimens in a unique subset of refractory patients, we hope to better inform potential courses of medical management for periorbital dermatitis.

DNA-triggered innate immune responses are propagated by gap junction communication.

Cells respond to infection by sensing pathogens and communicating danger signals to noninfected neighbors; however, little is known about this complex spatiotemporal process. Here we show that activation of the innate immune system by double-stranded DNA (dsDNA) triggers intercellular communication through a gap junction-dependent signaling pathway, recruiting colonies of cells to collectively secrete antiviral and inflammatory cytokines for the propagation of danger signals across the tissue at large. By using live-cell imaging of a stable IRF3-sensitive GFP reporter, we demonstrate that dsDNA sensing leads to multicellular colonies of IRF3-activated cells that express the majority of secreted cytokines, including IFNbeta and TNFalpha. Inhibiting gap junctions decreases dsDNA-induced IRF3 activation, cytokine production, and the resulting tissue-wide antiviral state, indicating that this immune response propagation pathway lies upstream of the paracrine action of secreted cytokines and may represent a host-derived mechanism for evading viral antiinterferon strategies.

The concise synthesis and resolution of planar chiral [2.2]paracyclophane oxazolines by C-H activation.

Planar chiral [2.2]paracyclophanes are resolved through the direct C-H arylation of enantiopure oxazolines, providing a convenient route to ligands and chiral materials. Preliminary results show that hydrolysis followed by decarboxylative phosphorylation leads to enantiopure [2.2]paracyclophane derivatives that are otherwise challenging to prepare.