Severe Cholestatic Hepatitis Secondary to SARS-CoV-2.

Liver injury is a common manifestation of coronavirus disease 2019 (COVID-19), with most injuries manifesting as transient mild hepatocellular injury. Cholestatic injury occurs less commonly and is typically mild. Severe cholestatic injury is rare, with only 4 cases reported in the literature. We present a 70-year-old woman with no known liver disease who presented with severe COVID-19 and developed severe cholestatic hepatitis. A liver biopsy was performed demonstrating bile duct injury, uncommonly reported in patients with COVID-19. This complication needs greater awareness because it has been known to cause progressive liver disease requiring transplantation.

Are We Ready to Include Prognostic Factors in Inflammatory Bowel Disease Trials?

Inflammatory bowel disease (IBD) is a chronic inflammatory disease characterized by periodic episodes of flares and remission. Treatment is aimed at healing the bowel, to ultimately decrease hospitalization rates, need for surgeries and overall disability. In more recent years, treatment has transitioned from a reactive approach to a more proactive approach focusing on treating disease earlier and preventing complications. The challenge lies in identifying patients who need more intensive treatment early and trying to determine who will respond to which medications. Biomarkers and clinical activity scoring systems can be used to help guide treatment decisions. However, IBDs are very heterogeneous and the significance of these biomarkers can be difficult to discern on an individual basis. Recently, prognostic tools have been developed to aid in determining a patient's prognosis as well as their likelihood to respond to different therapies. Despite this progress, clinical trials have not routinely adopted this approach in their study design. Tools for stratification of disease severity and to personalize treatment choices have the potential to improve our studies both by enriching the patient population and further guiding clinical decision making in practice. This review aims to discuss biomarkers, current prognosticating tools, tools that determine response to therapy and how incorporating these into clinical trials will be beneficial.

The dark side of the colon: current issues surrounding the significance, prevalence, detection, diagnosis and management of serrated polyps.

PURPOSE OF REVIEW: Hyperplastic polyps, once considered to have no malignant potential, are now recognized to be part of a larger group of polyps known as serrated polyps. Serrated polyps can progress to CRC through an epigenetic pathway known as CpG Island Methylator Phenotype (CIMP), characterized by hypermethylation of specific DNA regions such as the promoter regions of the DNA mismatch repair genes like MLH1. The CIMP pathway is tightly linked with mutations of the oncogene BRAF. There are three subtypes of serrated polyps - hyperplastic polyps, sessile serrated polyps (SSPs) and traditional serrated adenomas (TSAs). TSAs harbor cytologic dysplasia whereas hyperplastic polyps and SSPs are nondysplastic lesions. Currently, only SSPs and TSAs are believed to progress to CRC whereas hyperplastic polyps are thought to be benign with no malignant potential. This article will review the current evidence while highlighting some of the issues regarding serrated polyps. RECENT FINDINGS: One challenge has been pathologically distinguishing hyperplastic polyps from SSPs, which is an important distinction, given the potential for progression of SSPs to CRC. Other challenges regarding serrated polyps include adequate detection and resection. Surveillance guideline recommendations for some serrated polyps have been changed in current guidelines to reflect the malignant potential, recommending closer surveillance intervals than the 10-year follow-up that has been traditionally provided for hyperplastic polyps. SUMMARY: Given the difficulties in diagnosing as well as resecting, it is important for endoscopists to know how to detect, resect and manage follow-up in patients with serrated polyps.

Clinical outcomes after magnetic resonance angiography (MRA) versus computed tomographic angiography (CTA) for pulmonary embolism evaluation.

PURPOSE: To compare patient outcomes following magnetic resonance angiography (MRA) versus computed tomographic angiography (CTA) ordered for suspected pulmonary embolism (PE). METHODS: In this IRB-approved, single-center, retrospective, case-control study, we reviewed the medical records of all patients evaluated for PE with MRA during a 5-year period along with age- and sex-matched controls evaluated with CTA. Only the first instance of PE evaluation during the study period was included. After application of our exclusion criteria to both study arms, the analysis included 1173 subjects. The primary endpoint was major adverse PE-related event (MAPE), which we defined as major bleeding, venous thromboembolism, or death during the 6 months following the index imaging test (MRA or CTA), obtained through medical record review. Logistic regression, chi-square test for independence, and Fisher's exact test were used with a p < 0.05 threshold. RESULTS: The overall 6-month MAPE rate following MRA (5.4%) was lower than following CTA (13.6%, p < 0.01). Amongst outpatients, the MAPE rate was lower for MRA (3.7%) than for CTA (8.0%, p = 0.01). Accounting for age, sex, referral source, BMI, and Wells' score, patients were less likely to suffer MAPE than those who underwent CTA, with an odds ratio of 0.44 [0.24, 0.80]. Technical success rate did not differ significantly between MRA (92.6%) and CTA (90.5%) groups (p = 0.41). CONCLUSION: Within the inherent limitations of a retrospective case-controlled analysis, we observed that the rate of MAPE was lower (more favorable) for patients following pulmonary MRA for the primary evaluation of suspected PE than following CTA.

Transplantation Tolerance Induction: Cell Therapies and Their Mechanisms.

Cell-based therapies have been studied extensively in the context of transplantation tolerance induction. The most successful protocols have relied on transfusion of bone marrow prior to the transplantation of a renal allograft. However, it is not clear that stem cells found in bone marrow are required in order to render a transplant candidate immunologically tolerant. Accordingly, mesenchymal stem cells, regulatory myeloid cells, T regulatory cells, and other cell types are being tested as possible routes to tolerance induction, in the absence of donor-derived stem cells. Early data with each of these cell types have been encouraging. However, the induction regimen capable of achieving consistent tolerance, while avoiding unwanted sided effects, and which is scalable to the human patient, has yet to be identified. Here, we present the status of investigations of various tolerogenic cell types and the mechanistic rationale for their use in tolerance induction protocols.

A high-fat diet decreases AMPK activity in multiple tissues in the absence of hyperglycemia or systemic inflammation in rats

Consumption of a high-fat diet (HFD) in experimental animal models initiates a series of molecular events and outcomes, including insulin resistance and obesity, that mimic the metabolic syndrome in humans. The relationship among, and order of, the molecular events linking a diet high in fat to pathologies is often unclear. In the present study, we provide several novel insights into the relationship between a HFD and AMP-activated protein kinase (AMPK), a key regulator of cellular metabolism and whole-body energy balance. HFD substantially decreased the activities of both isoforms of AMPK in white adipose tissue, heart, and liver. These decreases in AMPK activity occurred in the absence of decreased AMPK transcription, systemic inflammation, hyperglycemia, or elevated levels of free fatty acids. The HFD-induced decrease in AMPK activity was associated with systemic insulin resistance and hyperleptinemia. In blood, >98 % of AMPK activity was localized in agranulocytes as the á1 isoform. In contrast to the solid tissues studied, AMPK activities were not altered by HFD in granulocytes or agranulocytes. We conclude that HFD-induced obesity causes a broad, non-tissue, or isoform-specific lowering of AMPK activity. Given the central position AMPK plays in whole-body energy balance, this decreased AMPK activity may play a previously unrecognized role in obesity and its associated pathologies (AU)

A high-fat diet decreases AMPK activity in multiple tissues in the absence of hyperglycemia or systemic inflammation in rats.

Consumption of a high-fat diet (HFD) in experimental animal models initiates a series of molecular events and outcomes, including insulin resistance and obesity, that mimic the metabolic syndrome in humans. The relationship among, and order of, the molecular events linking a diet high in fat to pathologies is often unclear. In the present study, we provide several novel insights into the relationship between a HFD and AMP-activated protein kinase (AMPK), a key regulator of cellular metabolism and whole-body energy balance. HFD substantially decreased the activities of both isoforms of AMPK in white adipose tissue, heart, and liver. These decreases in AMPK activity occurred in the absence of decreased AMPK transcription, systemic inflammation, hyperglycemia, or elevated levels of free fatty acids. The HFD-induced decrease in AMPK activity was associated with systemic insulin resistance and hyperleptinemia. In blood, >98 % of AMPK activity was localized in agranulocytes as the α1 isoform. In contrast to the solid tissues studied, AMPK activities were not altered by HFD in granulocytes or agranulocytes. We conclude that HFD-induced obesity causes a broad, non-tissue, or isoform-specific lowering of AMPK activity. Given the central position AMPK plays in whole-body energy balance, this decreased AMPK activity may play a previously unrecognized role in obesity and its associated pathologies.

Cold tolerance, cold-induced hyperphagia, and nonshivering thermogenesis are normal in α1-AMPK-/- mice.

Recent studies indicate that a substantial amount of metabolically active brown adipose tissue (BAT) exists in adult humans. Given the unique ability of BAT to convert calories to heat, there is intense interest in understanding the regulation of BAT metabolism in hopes that its manipulation might be an effective way of expending excess calories. Because of the established role of AMP-activated protein kinase (AMPK) as a "metabolic master switch" and its extremely high levels of activity in BAT, it was hypothesized that AMPK might play a central role in regulating BAT metabolism. To test this hypothesis, whole body α(1)-AMPK(-/-) (knockout) and wild-type mice were studied 1) under control (room temperature) conditions, 2) during chronic cold exposure (14 days at 4°C), and 3) during acute nonshivering thermogenesis (injection of a ß(3)-adrenergic agonist). Under control conditions, loss of α(1)-AMPK resulted in downregulation of two important prothermogenic genes in BAT, thyrotropin-releasing hormone (-9.2-fold) and ciliary neurotrophic factor (-8.7-fold). Additionally, it caused significant upregulation of α(2)-AMPK activity in BAT, white adipose tissue, and liver, but not cardiac or skeletal muscle. During acute nonshivering thermogenesis and chronic cold exposure, body temperature was indistinguishable in the α(1)-AMPK(-/-) and wild-type mice. Similarly, the degree of cold-induced hyperphagia was identical in the two groups. We conclude that α(1)-AMPK does not play an obligatory role in these processes and that adaptations to chronic loss of α(1)-AMPK are able to compensate for its loss via several mechanisms.