Coronary ostial aneurysms after composite graft replacement

Coronary ostial aneurysms after composite graft replacement of the ascending aorta and aortic valve is a rare complication. We report two patients with Marfan syndrome who developed coronary ostial aneurysms at the sites of the coronary anastomosis, presumably because of oversized windows made in the graft. They were successfully treated by redo composite graft replacement. To prevent this complication, it is important to consider that the hole made in the tube graft should not be larger than the diameter of the respective coronary ostium to avoid exposure of the diseased aortic wall to the circulating blood as much as possible, and that the suture used to anastomose the coronary buttons should pass through the rim of the ostium rather than through the aortic wall surrounding it.     

Redo composite valve graft replacement

BACKGROUND: Redo composite valve graft replacement remains a challenging problem, that may lead to increased surgical mortality. METHODS: In our experience from September 1976 through December 1999, eight consecutive patients (seven men and 1 woman) underwent eight redo composite valve graft replacements. The mean age at reoperation was 43.1 years (range 31 to 51 years). Seven patients had stigmata of Marfan's syndrome. Reoperation was indicated for pseudoaneurysm formation in five patients, coronary ostial aneurysms in two patients, and active fungal endocarditis in one patient. Previous root replacement had been performed in all eight patients using a composite mechanical valve. The techniques used at previous procedures were the Bentall technique in seven and Carrel's button technique in one. The mean interval between primary root replacement and redo root replacement was 10 years (range 2 to 18 years). The patient with active fungal endocarditis having a stuck valve was subjected to emergency operation. RESULTS: The techniques used at the reoperations included Carrel's button technique in five patients, the interposition technique (Phieler) in two patients, and Cabrol's technique in one patient. Aortic arch aneurysm repair was performed in five patients. There were two hospital deaths (2 [25%] of 8). One patient died on postoperative day 1 with low cardiac output and the other suffered a sudden cardiac arrest on postoperative day 14. The mean follow-up was 34.6 months (range 1 to 85 months). There was one late death. The cause of death was multiple organ failure due to recurrence of fungal endocarditis 6 months after redo composite and total arch replacement. CONCLUSION: Redo composite graft replacement can be accomplished with lower early mortality, and therefore, this operation should not be delayed given the appropriate clinical circumstances. Many causes of failure of composite valve graft replacement can be avoided if the appropriate surgical technique is chosen.     

Interleukins 4 and 13 drive lipid abnormalities in skin cells through regulation of sex steroid hormone synthesis

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by skin dryness, inflammation, and itch. A major hallmark of AD is an elevation of the immune cytokines IL-4 and IL-13. These cytokines lead to skin barrier disruption and lipid abnormalities in AD, yet the underlying mechanisms are unclear. Sebaceous glands are specialized sebum-producing epithelial cells that promote skin barrier function by releasing lipids and antimicrobial proteins to the skin surface. Here, we show that in AD, IL-4 and IL-13 stimulate the expression of 3β-hydroxysteroid dehydrogenase 1 (HSD3B1), a key rate-limiting enzyme in sex steroid hormone synthesis, predominantly expressed by sebaceous glands in human skin. HSD3B1 enhances androgen production in sebocytes, and IL-4 and IL-13 drive lipid abnormalities in human sebocytes and keratinocytes through HSD3B1. Consistent with our findings in cells, HSD3B1 expression is elevated in the skin of AD patients and can be restored by treatment with the IL-4Rα monoclonal antibody, Dupilumab. Androgens are also elevated in a mouse model of AD, though the mechanism in mice remains unclear. Our findings illuminate a connection between type 2 immunity and sex steroid hormone synthesis in the skin and suggest that abnormalities in sex steroid hormone synthesis may underlie the disrupted skin barrier in AD. Furthermore, targeting sex steroid hormone synthesis pathways may be a therapeutic avenue to restoring normal skin barrier function in AD patients.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by stratum corneum lipid abnormalities (1, 2) and a dysfunctional skin barrier (3). The skin is a vital organ separating the host from its environment, and thus, the barrier breakdown seen in AD has systemic consequences for the host. AD patients experience more frequent episodes of skin infection from the increased exposure to commensal microbes. Additionally, the deeper penetration of environmental allergens in AD skin promotes the sequential progression of AD to other atopic diseases, including allergic rhinitis, food allergy, and asthma (4). AD is also an increasingly common condition with up to 13% of children and 10% of adults suffering from AD, with an annual treatment cost of $5.3 billion in the United States alone (5, 6).A major hallmark of AD is the elevated production of interleukins 4 and 13 (IL-4 and IL-13), both type 2 cytokines. These cytokines are pathogenic and drive the inflammation and barrier disruption seen in AD (7). Dupilumab is a human monoclonal antibody directed against the shared alpha subunit of the IL-4 and IL-13 receptors (IL-4Rα) and has revolutionized therapy for patients with moderate to severe AD and asthma (8). It is clear that blockade of IL-4Rα signaling restores skin barrier function and skin lipid metabolism in AD patients (9–11); however; how these classical immune pathways impact the skin epithelium is less clearly defined.Sebaceous glands are composed of specialized epithelial cells called sebocytes that generate sebum—a unique oily mixture of wax esters, squalene, triglycerides, proteins, and fatty acids required for normal skin ecology (12–15). Sebum is essential for barrier function, yet few current studies have examined the impact of sebaceous glands in the pathogenesis of AD (3, 11, 16, 17). Here, we explore how human sebocytes respond to the cytokines IL-4 and IL-13 to begin to establish how these cells impact barrier dysfunction in AD. We show that IL-4 and IL-13 up-regulate the expression of 3β-hydroxysteroid dehydrogenase 1 (HSD3B1) in sebaceous glands through the activation of STAT6. HSD3B1 is the rate-limiting enzyme in the synthesis of all classes of steroid hormones in primates (18, 19). Thus, IL-4 and IL-13 stimulate the production of the sex steroids androstenedione and dihydrotestosterone in sebocytes. Consistent with our findings in culture, the expression of HSD3B1 is also highly elevated in the lesional skin of human AD patients, which can be restored by Dupilumab treatment. Furthermore, we utilized small interfering RNA (siRNA) targeting HSD3B1 and show that depletion of HSD3B1-derived sex steroids in sebocytes increases lipid synthesis machinery in sebocytes and keratinocytes. Current treatments for AD primarily focus on immunosuppression to combat type 2 inflammation (20). Our findings provide insight into the impact of type 2 cytokines on skin ecology and uncover the sex steroid hormone synthesis pathway as a potential therapeutic target for the treatment of AD in humans.     

Chronological Aging in African-American Skin: A Reliable Photonumeric Scale Demonstrates Age and Body Mass Index as Contributing Factors

Background

Increased photoprotection by natural melanin allows for African-Americans to be less impacted by photoaging than Caucasians. However, less is known about chronological aging in this population.

Helicobacter pylori activates myosin light-chain kinase to disrupt claudin-4 and claudin-5 and increase epithelial permeability

Helicobacter pylori is a spiral, gram-negative bacterium that specifically and persistently infects the human stomach. In some individuals, H. pylori-induced chronic gastritis may progress to gastroduodenal ulcers and gastric cancer. Currently, the host-microbe interactions that determine the clinical outcome of infection are not well defined. H. pylori strains capable of disrupting the gastric epithelial barrier may increase the likelihood of developing serious disease. In this study, H. pylori strain SS1 increased gastric, but not small intestinal, permeability in C57BL/6 mice. H. pylori strain SS1 was able to directly increase paracellular permeability, in the absence of host inflammatory cells, by disrupting the tight-junctional proteins occludin, claudin-4, and claudin-5 in confluent nontransformed epithelial cells. H. pylori SS1 also reduced claudin-4 protein levels in human gastric AGS cells. The ability of H. pylori SS1 to increase permeability appeared to be independent of the well-characterized virulence factors vacuolating cytotoxin and CagA protein. H. pylori activated myosin light-chain kinase in epithelial cells to phosphorylate myosin light chain and increase permeability by disrupting claudin-4 and claudin-5. The bacterial factor responsible for increasing epithelial permeability was heat sensitive, membrane bound, and required apical contact with monolayers. In conclusion, disruptions of the tight junctions observed in this study implicate host cell signaling pathways, including the phosphorylation of myosin light chain and the regulation of tight-junctional proteins claudin-4 and claudin-5, in the pathogenesis of H. pylori infection.     

Illuminating the Role of Vitamin A in Skin Innate Immunity and the Skin Microbiome: A Narrative Review

Vitamin A is a fat-soluble vitamin that plays an important role in skin immunity. Deficiencies in Vitamin A have been linked to impaired immune response and increased susceptibility to skin infections and inflammatory skin disease. This narrative review summarizes recent primary evidence that elucidates the role of vitamin A and its derivatives on innate immune regulators through mechanisms that promote skin immunity and sustain the skin microbiome.     

Helicobacter pylori activates calpain via toll-like receptor 2 to disrupt adherens junctions in human gastric epithelial cells

Helicobacter pylori is a risk factor for the development of gastritis, gastroduodenal ulcers, and gastric adenocarcinoma. H. pylori-induced disruption of epithelial adherens junctions (AJs) is thought to promote the development of severe disease; however, the mechanisms whereby H. pylori alters AJ structure remain incompletely understood. The present study demonstrates that H. pylori infection in human patients is associated with elevated serum levels of an 80-kDa E-cadherin ectodomain, whose presence is independent of the presence of serum antibodies against CagA. In vitro, a heat-labile H. pylori surface component activates the host protease calpain in human gastric MKN45 cells independently of the virulence factors CagA and VacA. H. pylori-induced calpain activation results in cleavage of E-cadherin to produce a 100-kDa truncated form and induce relocalization of E-cadherin and β-catenin. Stimulation of MKN45 cells with the toll-like receptor 2 (TLR2) ligand P3C activated calpain and disrupted E-cadherin and β-catenin in a pattern similar to that induced by H. pylori. Inhibition of TLR2 prevented H. pylori-induced calpain activation and AJ disassembly. Together, these findings identify a novel pathway whereby H. pylori activates calpain via TLR2 to disrupt gastric epithelial AJ structure.     

New neostigmine-based behavioral mouse model of abdominal pain

BackgroundAnimal models of visceral pain have gained much attention as an important tool to elucidate the possible mechanisms underlying functional gastrointestinal (GI) disorders. Here we report the development of a new, minimally invasive behavioral model of abdominal pain induced by ip administration of neostigmine in mice.MethodsSpontaneous behavioral responses evoked by ip injection of neostigmine were compared to pain-related behaviors induced by acetic acid solution (ip), mustard oil (MO) and capsaicin (both ic). Pain behaviors were quantified by assessment of defined postures (licking of the abdomen, stretching, squashing of the abdomen and abdominal contractions). Neuronal activation of spinal cord was measured by determining the number of c-Fos-positive cells.ResultsNeostigmine (2.5 μg/kg, ip), acetic acid solution (ip), MO and capsaicin (both ic) induced spontaneous behavioral responses in mice, which were blocked by morphine (3 mg/kg, ip), suggesting the involvement of pain signaling pathways. Injection of neostigmine enhanced c-Fos expression in spinal cord neurons.ConclusionThe neostigmine model represents a new minimally invasive mouse model to study visceral pain. Based on the neuronal activation pattern in the spinal cord we suggest that this model may be used to study abdominal pain signaling pathways in the GI tract.