Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects 15 to 30% of children and ~5% of adults in industrialized countries1. Although the pathogenesis of AD is not fully understood, the disease is mediated by an abnormal immunoglobulin E (IgE) immune response in the setting of skin barrier dysfunction2. Mast cells (MCs) contribute to IgE-mediated allergic disorders including AD3. Upon activation, MCs release their membrane-bound cytosolic granules leading to the release of multiple molecules that are important in the pathogenesis of AD and host defense4. More than 90% of AD patients are colonized with Staphylococcus aureus in the lesional skin whereas most healthy individuals do not harbor the pathogen5. Several Staphylococcal exotoxins (SEs) can act as superantigens and/or antigens in models of AD6. However, the role of these SEs in disease pathogenesis remains unclear. Here, we report that culture supernatants of S. aureus contain potent MC degranulation activity. Biochemical analysis identified δ-toxin as the MC degranulation-inducing factor produced by S. aureus. MC degranulation induced by δ-toxin depended on phosphoinositide 3-kinase (PI3K) and calcium (Ca2+) influx, but unlike that mediated by IgE crosslinking, it did not require the spleen tyrosine kinase (Syk). In addition, IgE enhanced δ-toxin-induced MC degranulation in the absence of antigen. Furthermore, S. aureus isolates recovered from AD patients produced high levels of δ-toxin. Importantly, skin colonization with S. aureus, but not a mutant deficient in δ-toxin, promoted IgE and IL-4 production, as well as inflammatory skin disease. Furthermore, enhancement of IgE production and dermatitis by δ-toxin was abrogated in KitW-sh/W-sh MC-deficient mice and restored by MC reconstitution. These studies identify δ-toxin as a potent inducer of MC degranulation and suggest a mechanistic link between S. aureus colonization and allergic skin disease.

Human endogenous retroviruses (HERVs) make up 8% of the human genome. The HERV-K (HML-2) family is the most recent group of these viruses to have inserted into the genome, and we have detected the activation of HERV-K (HML-2) proviruses in the blood of patients with HIV-1 infection. We report that HIV-1 infection activates expression of a novel HERV-K (HML-2) provirus, termed K111, present in multiple copies in the centromeres of chromosomes throughout the human genome yet not annotated in the most recent human genome assembly. Infection with HIV-1 or stimulation with the HIV-1 Tat protein leads to the activation of K111 proviruses. K111 is present as a single copy in the genome of the chimpanzee, yet K111 is not found in the genomes of other primates. Remarkably, K111 proviruses appear in the genomes of the extinct Neanderthal and Denisovan, while modern humans have at least 100 K111 proviruses spread across the centromeres of 15 chromosomes. Our studies suggest that the progenitor K111 integrated before the Homo-Pan divergence and expanded in copy number during the evolution of hominins, perhaps by recombination. The expansion of K111 provides sequence evidence suggesting that recombination between the centromeres of various chromosomes took place during the evolution of humans. K111 proviruses show significant sequence variations in each individual centromere, which may serve as markers in future efforts to annotate human centromere sequences. Further, this work is an example of the potential to discover previously unknown genomic sequences through the analysis of nucleic acids found in the blood of patients.

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The present study demonstrates that patients with cirrhosis had biventricular dilatation and impaired biventricular systolic strain compared with controls. Following LTx, biventricular dilatation reduced and biventricular systolic strain improved. In contrast, patients who did not undergo LTx experienced a further increase in LV mass.

Liver transplantation for hepatocellular carcinoma (HCC) is restricted by the scarcity of cadaver grafts. Living donor liver transplantation (LDLT) may potentially increase the applicability but its role and limitation are not clear. We studied the outcome of a cohort of 51 patients with unresectable HCC who were accepted on list for both options of deceased donor liver transplantation (DDLT) and LDLT. Twenty-five of 51 (49%) patients had voluntary living donors (group 1) and 26 did not (group 2). Patients in group 1 were younger, and more often had a MELD score more than 20 or blood group other than O. Twenty-one patients of group 1 underwent LDLT after a median waiting time of 24 days (range, 2-126 days), but 4 did not because the donors were not suitable (HBsAg-positive, 2; ABO-incompatible, 1; liver dysfunction, 1). Of the 30 patients who remained on list, only 6 underwent DDLT after a median waiting time of 344 days (range, 22-1359 days, P < .005). Nineteen died before transplantation and 2 were alive but taken off the list because of disease progression (drop-out rate, 70%). One patient was alive on list and 2 had undergone transplantation outside Hong Kong. The 1-, 2-, 3-, and 4-year intention-to-treat survival rates were 88%, 76%, 66%, and 66%, respectively, for group 1 and 72%, 46%, 38%, and 31%, respectively, for group 2 (relative risk of death for group 1, 0.35; 95% CI, 0.14 to 0.90; P ‫؍‬ .029). In conclusion, although complicated factors such as donor voluntarism and selection criteria limit the role of LDLT for HCC, LDLT allows more patients to undergo early transplantation and results in a better outcome. L iver transplantation offers the best chance of cure for unresectable hepatocellular carcinoma (HCC), 1-3 but the scarcity of cadaver liver grafts has seriously limited its role. To justify organ allocation, candidacy is restricted only to patients with early tumors who fulfill strict selection criteria 1,4 so that the survival is comparable to that with non-neoplastic disease. Unfortunately, the prolonged waiting time results in drop-outs because of tumor progression and adversely affects the outcome of these patients. 5,6 In addition, the unpredictable timing of a deceased donor graft makes it difficult if not impossible to accurately stage the disease and to plan any study for neoadjuvant therapy before transplantation.With the recent advances in adult living donor liver transplantation (LDLT), [7][8][9] there is potentially a drastic change in the role of liver transplantation. Studies on hypothetical decision analytic models 10,11 have demonstrated the theoretical survival benefit of LDLT over deceased donor liver transplantation (DDLT) which depends largely on the waiting time and drop-out rate. In parts of Asia including Hong Kong where there is a high incidence of HCC and a low deceased donor rate, LDLT is likely to generate a great benefit. Nonetheless, although LDLT is not restricted by the system of deceased donor organ allocation and waiting time, many other factors such as donor vol...

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There is a strong need for a new broad-spectrum antiinfluenza therapeutic, as vaccination and existing treatments are only moderately effective. We previously engineered a lectin, H84T banana lectin (H84T), to retain broad-spectrum activity against multiple influenza strains, including pandemic and avian, while largely eliminating the potentially harmful mitogenicity of the parent compound. The amino acid mutation at position 84 from histidine to threonine minimizes the mitogenicity of the wild-type lectin while maintaining antiinfluenza activity in vitro. We now report that in a lethal mouse model H84T is indeed nonmitogenic, and both early and delayed therapeutic administration of H84T intraperitoneally are highly protective, as is H84T administered subcutaneously. Mechanistically, attachment, which we anticipated to be inhibited by H84T, was only somewhat decreased by the lectin. Instead, H84T is internalized into the late endosomal/lysosomal compartment and inhibits virus-endosome fusion. These studies reveal that H84T is efficacious against influenza virus in vivo, and that the loss of mitogenicity seen previously in tissue culture is also seen in vivo, underscoring the potential utility of H84T as a broad-spectrum antiinfluenza agent.influenza virus | hemagglutinin | membrane fusion | lectin | antiviral