Mast cell activation syndrome—anesthetic challenges in two different clinical scenarios

Mast cell activation syndrome(MCAS) includes a group of disorders that result in the inappropriate release of inflammatory mediators from mast cells. These mediators can affect multiple organ systems and lead to significant morbidity, and possible fatality. Although reactions, typically in response to various nonspecific stimuli, are usually mild, they may put those with MCAS at increased risk of anaphylaxis. In this case report, we present two clinical scenarios of MCAS, and identify possible f...     

Hepatocellular Carcinoma,Alpha Fetoprotein,and Liver Allocation for Transplantation: Past,Present and Future

Hepatocellular carcinoma (HCC) is one of the leading indications for liver transplantation and has been the treatment of choice due to the oncologic benefit for patients with advanced chronic liver disease (AdvCLD) and small tumors for the last 25 years. For HCC patients undergoing liver transplantation, alpha fetoprotein (AFP) has increasingly been applied as an independent predictor for overall survival, disease free recurrence, and waitlist drop out. In addition to static AFP, newer studies evaluating the AFP dynamic response to downstaging therapy show enhanced prognostication compared to static AFP alone. While AFP has been utilized to select HCC patients for transplant, despite years of allocation policy changes, the US allocation system continues to take a uniform approach to HCC patients, without discriminating between those with favorable or unfavorable tumor biology. We aim to review the history of liver allocation for HCC in the US, the utility of AFP in liver transplantation, the implications of weaving AFP as a biomarker into policy. Based on this review, we encourage the US transplant community to revisit its HCC organ allocation model, to incorporate more precise oncologic principles for patient selection, and to adopt AFP dynamics to better stratify waitlist dropout risk.     

Peer community health workers improve HIV testing and ART linkage among key populations in Zambia: retrospective observational results from the Z‐CHECK project, 2019–2020

IntroductionZambia has made tremendous progress towards HIV epidemic control; however, gaps remain among key populations (KPs), such as female sex workers (FSWs), men who have sex with men (MSM), people who inject drugs (PWID) and people in prisons and enclosed settings due to cultural, social and legal barriers. The University of Maryland, Baltimore Zambia Community HIV Epidemic Control for Key Populations (Z‐CHECK) project aimed to improve HIV case‐finding, linkage and treatment adherence at the community level for KPs in Zambia. We describe Z‐CHECK strategies and examine HIV positivity yield and antiretroviral therapy (ART) linkage among KPs to inform ongoing programme improvement.MethodsZ‐CHECK recruited, trained and deployed peer community health workers (CHWs) for KP groups, with ongoing mentorship in community engagement. CHWs offered HIV testing in safe spaces and escorted newly HIV‐diagnosed clients for same‐day ART initiation. Z‐CHECK also reached out to KP community leaders and gatekeepers for KP mobilization and trained healthcare workers (HCWs) on KP services and sensitivity. We conducted a retrospective observational review of routinely collected aggregate data for KPs aged ≥15 years at high risk for HIV transmission across five districts in Zambia from January 2019 to December 2020.ResultsZ‐CHECK provided HIV testing for 9211 KPs, of whom 2227 were HIV positive (positivity yield, 24%). Among these, 1901 (85%) were linked to ART; linkage for MSM, FSW, PWID and people in prisons and enclosed settings was 95%, 89%, 86% and 65%, respectively. Programme strategies that contributed to high positivity yield and linkage included the use of peer KP CHWs, social network testing strategies and opportunities for same‐day ART initiation. Challenges to programme implementation included stigma and discrimination among HCWs, as well as KP CHW attrition, which may be explained by high mobility.ConclusionsPeer CHWs were highly effective at reaching KP communities, identifying persons living with HIV and linking them to care. Engaging KP community gatekeepers resulted in high diffusion of health messages and increased access to health resources. The mobility of CHWs and HCWs is a challenge for programme implementation. Innovative interventions are needed to support PWID and people in prisons and enclosed settings.     

Straight Back Syndrome: positive response to spinal manipulation and adjunctive therapy – A case report

Straight Back Syndrome (SBS) has been recognized for over 50 years. Not to be confused with flat back syndrome in the lumbar spine, SBS patients present with an obvious loss of the thoracic kyphosis accompanied by apparent heart symptoms. The main purpose of this article is to describe a patient diagnosed with SBS, whose symptoms were successfully managed using spinal manipulative therapy as well as ancillary modalities. The use of diagnostic and laboratory tests are essential to differentially diagnose cardiac disease from SBS. Genesis and incidence of this condition is also discussed as well as roentgenometric analysis. A suggested diagnostic algorithm is presented as well.     

The mosquito protein AEG12 displays both cytolytic and antiviral properties via a common lipid transfer mechanism

The mosquito protein AEG12 is up-regulated in response to blood meals and flavivirus infection though its function remained elusive. Here, we determine the three-dimensional structure of AEG12 and describe the binding specificity of acyl-chain ligands within its large central hydrophobic cavity. We show that AEG12 displays hemolytic and cytolytic activity by selectively delivering unsaturated fatty acid cargoes into phosphatidylcholine-rich lipid bilayers. This property of AEG12 also enables it to inhibit replication of enveloped viruses such as Dengue and Zika viruses at low micromolar concentrations. Weaker inhibition was observed against more distantly related coronaviruses and lentivirus, while no inhibition was observed against the nonenveloped virus adeno-associated virus. Together, our results uncover the mechanistic understanding of AEG12 function and provide the necessary implications for its use as a broad-spectrum therapeutic against cellular and viral targets.

Mosquito-borne flaviviruses such as Dengue and Zika represent a major public health risk; 96 million new cases of Dengue infection are reported every year (1), while the Zika infection can cause neurological sequleae and microencephaly (2). Vaccines have had limited success in preventing human flavivirus infections, demonstrating the need for new therapeutic approaches (2). Like humans, mosquitos mount a robust anti-viral immune response against flaviviruses. For example, the mosquito protein AEG12 and its homologs have been shown to be up-regulated in Aedes aegypti in response to Zika virus, West Nile virus, dengue, and Yellow Fever virus infection via JAK-STAT pathways (3–7). AEG12 homologs are also up-regulated upon infection by the parasite Brugia malayi (8), suggesting a role against a wide range of viral- and cell-based targets. Previous sequence analysis of AEG12 revealed it to be a member of the major allergy (MA) protein family, so named because the prototypical protein for this family (Bla g 1) is a major human allergen (9). While many insects contain MA proteins, the family is significantly expanded in Aedes (∼20) and Culex (∼8) mosquitoes; both are major vectors of arboviruses (9, 10). Elucidating the molecular basis for this antiviral activity may provide valuable insight into the development of novel flavivirus and broad-spectrum therapeutic strategies.Curiously, AEG12 was initially described not in the context of flavivirus infection but digestion. Here, AEG12 proteins were found to be highly up-regulated in the midgut of female A. aegypti and subsequently localized to the microvilli following a blood feed but not a sugar feed (9, 11, 12). A similar expression pattern was observed in the AcG12 homolog from Anopheles cilicifacies, suggesting a conserved function across mosquito species (13). In cockroaches, suppression of Bla g 1 expression significantly hindered digestion, resulting in starvation despite adequate food intake suggesting a broader role for MA domain proteins in breaking down and absorbing nutrients from both blood and nonblood food materials (14, 15). However, the function and mechanistic roles of AEG12 proteins remains unknown.The structure of Bla g 1 consists of two consecutive units, each containing five helices (α1 to α5) arranged in a pentagon with the sixth helix (α6) stacking on top. The two pentagonal structures come together to enclose an exceptionally large hydrophobic cavity of ∼3,800 ų that can accommodate up to eight fatty acid ligands (16, 17). Bla g 1 isolated from its natural allergen source was found to contain a mixture of palmitate, oleate, and stearate fatty acids (nMix), the presence of which significantly enhanced Bla g 1 thermostability (16, 17). We hypothesize that these lipid cargoes play a key role in the biological function of both Bla g 1 and AEG12 in digestion and antiviral activity. Indeed, previous studies showed that free fatty acids have viricidal effects against enveloped viruses because of their ability to permeabilize and disrupt their lipid membranes (18–21). Additionally, both free fatty acids and fatty acid–protein conjugates have been shown to destabilize and lyse mammalian cells membranes (22, 23). The ability of AEG12 to mobilize and deliver a range of fatty acid cargoes could provide a common mechanism through which it fulfills both putative functions.Here, we demonstrate that AEG12 adopts a similar structure as Bla g 1, enabling it to bind a range of fatty acid ligands within its central hydrophobic cavity. Selective delivery of these fatty acid cargoes into phosphatidylcholine (PC) lipid bilayers results in membrane destabilization and cytotoxicity against eukaryotic cells consistent with a role in erythrocyte digestion. Similarly, AEG12 displayed antiviral activity against a range of enveloped, but not nonenveloped viruses suggesting that both putative functions of AEG12 share a common mechanism of action centered on lipid exchange resulting in membrane destabilization.     

SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK

Heat-shock protein 90 (Hsp90) acts as a molecular chaperone required for maintaining the conformational stability of client proteins regulating cell proliferation, survival, and apoptosis. Here we investigate the biologic significance of Hsp90 inhibition in multiple myeloma (MM) and other hematologic tumors using an orally available novel small molecule inhibitor SNX-2112, which exhibits unique activities relative to 17-allyamino-17-demethoxy-geldanamycin (17-AAG). SNX-2112 triggers growth inhibition and is more potent than 17-AAG against MM and other malignancies. It induces apoptosis via caspase-8, -9, -3, and poly (ADP-ribose) polymerase cleavage. SNX-2112 inhibits cytokine-induced Akt and extracellular signal-related kinase (ERK) activation and also overcomes the growth advantages conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cells. Importantly, SNX-2112 inhibits tube formation by human umbilical vein endothelial cells via abrogation of eNOS/Akt pathway and markedly inhibits osteoclast formation via down-regulation of ERK/c-fos and PU.1. Finally, SNX-2112, delivered by its prodrug SNX-5422, inhibits MM cell growth and prolongs survival in a xenograft murine model. Our results indicate that blockade of Hsp90 by SNX-2112 not only inhibits MM cell growth but also acts in the bone marrow microenvironment to block angiogenesis and osteoclastogenesis. Taken together, our data provide the framework for clinical studies of SNX-2112 to improve patient outcome in MM and other hematologic malignancies.     

Longitudinal gut microbiome changes in alcohol use disorder are influenced by abstinence and drinking quantity

ABSTRACT

Many patients with alcohol use disorder (AUD) consume alcohol chronically and in large amounts that alter intestinal microbiota, damage the gastrointestinal tract, and thereby injure other organs via malabsorption and intestinal inflammation. We hypothesized that alcohol consumption and subsequent abstinence would change the gut microbiome in adults admitted to a treatment program. Stool and oral specimens, diet data, gastrointestinal assessment scores, anxiety, depression measures and drinking amounts were collected longitudinally for up to 4 weeks in 22 newly abstinent inpatients with AUD who were dichotomized as less heavy drinkers (LHD, <10 drinks/d) and very heavy drinkers (VHD, 10 or more drinks/d). Next-generation 16 S rRNA gene sequencing was performed to measure the gut and oral microbiome at up to ten time points/subject and LHD and VHD were compared for change in principal components, Shannon diversity index and specific genera. The first three principal components explained 46.7% of the variance in gut microbiome diversity across time and all study subjects, indicating the change in gut microbiome following abstinence. The first time point was an outlier in three-dimensional principal component space versus all other time points. The gut microbiota in LHD and VHD were significantly dissimilar in change from day 1 to day 5 (p = .03) and from day 1 to week 3 (p = .02). The VHD drinking group displayed greater change from baseline. The Shannon diversity index of the gut microbiome changed significantly during abstinence in five participants. In both groups, the Shannon diversity was lower in the oral microbiome than gut. Ten total genera were shared between oral and stool in the AUD participants. These data were compared with healthy controls from the Human Microbiome Project to investigate the concept of a core microbiome. Rapid changes in gut microbiome following abstinence from alcohol suggest resilience of the gut microbiome in AUD and reflects the benefits of refraining from the highest levels of alcohol and potential benefits of abstinence.