Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma.

The mRNA expression of the dipeptidyl peptidase 4 (DPP4) gene family is highly upregulated in human hepatocellular carcinoma (HCC) and is associated with poor survival in HCC patients. Compounds that inhibit the DPP4 enzyme family, such as talabostat and ARI-4175, can mediate tumour regression by immune-mediated mechanisms that are believed to include NLRP1 activation. This study investigated the expression and activity of the DPP4 family during the development of HCC and evaluated the efficacy of ARI-4175 in the treatment of early HCC in mice. This first report on this enzyme family in HCC-bearing mice showed DPP9 upregulation in HCC, whereas intrahepatic DPP8/9 and DPP4 enzyme activity levels decreased with age. We demonstrated that ARI-4175 significantly lowered the total number of macroscopic liver nodules in these mice. In addition, ARI-4175 increased intrahepatic inflammatory cell infiltration, including CD8+ T cell numbers, into the HCC-bearing livers. Furthermore, ARI-4175 activated a critical component of the inflammasome pathway, caspase-1, in these HCC-bearing livers. This is the first evidence of caspase-1 activation by a pan-DPP inhibitor in the liver. Our data suggest that targeting the DPP4 enzyme family may be a novel and effective approach to promote anti-tumour immunity in HCC via caspase-1 activation.

Closed Suction Drainage after Primary Total Knee Arthroplasty: A Prospective Randomized Trial.

The discussion as to whether or not to use closed suction drainage (CSD) after total knee arthroplasty (TKA) is still ongoing. A multitude of surgical techniques makes comparison between studies difficult. The aim of the present study was to investigate the benefit of CSD versus nondrainage following primary TKA when operating after exsanguination (by means of a rubber Esmarch bandage) with a tourniquet and without any form of hemostasis. A prospective randomized trial was performed with a homogeneous sample of 36 patients with strict inclusion and exclusion criteria. Patients were evaluated preoperatively, on a daily basis during their hospital stay, and at 6 weeks, 3 months, 6 months, and 1 year postoperatively. The use of CSD led to a significantly stronger drop in hemoglobin levels by approximately 1 g/dL (p = 0.012). Knee circumference, wound secretion, wound healing, and postoperative range of motion did not show significant differences. All discharge criteria were met in both groups by day 9. Interestingly, patients without CSD reported higher pain levels during the entire postoperative inpatient stay and also at the 6-week follow-up (p = 0.012). These differences could not be observed in longer follow-up. The use of CSD after primary TKA in this study did not lead to indispensable advantages but did lead to increased postoperative blood loss. When evaluating the advantages and disadvantages of the use of CSD after TKA from the data in the literature, special attention must be paid to the operating technique, as it has a strong impact on the results obtained.

Underlying Processes of an Inverted Personalization Effect in Multimedia Learning - An Eye-Tracking Study.

One of the frequently examined design principles in multimedia learning is the personalization principle. Based on empirical evidence this principle states that using personalized messages in multimedia learning is more beneficial than using formal language (e.g., using 'you' instead of 'the'). Although there is evidence that these slight changes in regard to the language style affect learning, motivation and the perceived cognitive load, it remains unclear, (1) whether the positive effects of personalized language can be transferred to all kinds of content of learning materials (e.g., specific potentially aversive health issues) and (2) which are the underlying processes (e.g., attention allocation) of the personalization effect. German university students (N = 37) learned symptoms and causes of cerebral hemorrhages either with a formal or a personalized version of the learning material. Analysis revealed comparable results to the few existing previous studies, indicating an inverted personalization effect for potentially aversive learning material. This effect was specifically revealed in regard to decreased average fixation duration and the number of fixations exclusively on the images in the personalized compared to the formal version. These results can be seen as indicators for an inverted effect of personalization on the level of visual attention.

Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug.

The dose-limiting toxicity of chemotherapeutics, heterogeneity and drug resistance of cancer cells, and difficulties of targeted delivery to tumors all pose daunting challenges to effective cancer therapy. We report that small interfering RNA (siRNA) duplexes readily penetrate intact bacterially derived minicells previously shown to cause tumor stabilization and regression when packaged with chemotherapeutics. When targeted via antibodies to tumor-cell-surface receptors, minicells can specifically and sequentially deliver to tumor xenografts first siRNAs or short hairpin RNA (shRNA)-encoding plasmids to compromise drug resistance by knocking down a multidrug resistance protein. Subsequent administration of targeted minicells containing cytotoxic drugs eliminate formerly drug-resistant tumors. The two waves of treatment, involving minicells loaded with both types of payload, enable complete survival without toxicity in mice with tumor xenografts, while involving several thousandfold less drug, siRNA and antibody than needed for conventional systemic administration of cancer therapies.

Tacrolimus ointment causes inflammatory dendritic epidermal cell depletion but no Langerhans cell apoptosis in patients with atopic dermatitis.

BACKGROUND: The topical immunomodulators tacrolimus and pimecrolimus are novel therapeutic options for atopic dermatitis (AD). The inhibition of nuclear factor of activated T cell-dependent proinflammatory cytokine production in cutaneous lymphocytes is an established effect of topical immunomodulators, which additionally influence mast cells, eosinophils, and dendritic cells (DCs). The latter include a reduced expression of the high-affinity IgE receptor FcepsilonRI, a reduced stimulatory capacity of lesional DCs, and a selective depletion of the inflammatory dendritic epidermal cells (IDECs) but not of Langerhans cells (LCs) from the lesional skin. OBJECTIVE: Because induction of apoptosis in lymphocytes is a reported tacrolimus effect, we asked whether tacrolimus ointment induces apoptosis of LCs or IDECs in AD lesions. METHODS: Epidermal single-cell suspensions were prepared from AD lesions of 9 tacrolimus-treated and 5 hydrocortisone butyrate-treated patients with AD before and after 1 week of treatment. Cell numbers, apoptosis rate, and immunophenotype were assessed by using the standardized FACS technique with terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, Annexin V, and 3-color immunophenotyping. Freshly isolated LCs and monocyte-derived DCs served as in vitro controls. RESULTS: Tacrolimus and steroid ointment induced a selective depletion of IDECs from the epidermis and reduced the expression of the costimulatory molecules CD80 and CD86. Tacrolimus ointment did not increase the rate of apoptotic DCs, whereas steroid ointment did so. The isolation-induced high apoptosis rate of freshly isolated LCs was unaffected by both drugs. CONCLUSION: Tacrolimus ointment selectively depletes IDECs and alters the immunophenotype of epidermal DCs in AD lesions, but there is no evidence for tacrolimus-induced DC apoptosis in this phenomenon.

Eczema molluscatum in tacrolimus treated atopic dermatitis.

Eczema molluscatum describes the occurrence of molluscum contagiosum virus infection in a patient with underlying atopic dermatitis. Novel, safe and effective treatment options in atopic dermatitis are the topical immunomodulators tacrolimus and pimecrolimus. One major advantage over corticosteroids is that they do not induce skin atrophy. Some physicians fear that topical immunomodulators may predispose patients to skin infections. We observed a patient with atopic dermatitis who developed eczema molluscatum during treatment with tacrolimus 0.1% ointment. After withdrawal of tacrolimus, the lesions resolved spontaneously over 3 weeks.

Viral infections in atopic dermatitis: pathogenic aspects and clinical management.

A number of different widespread and disseminated viral infections can occur in patients with atopic dermatitis. Eczema molluscatum is troublesome but not dangerous. Although eczema vaccinatum is rare, it is life-threatening and of increased concern as smallpox vaccinations are reintroduced as a response to possible bioterrorism. There is little information on the course of smallpox itself in atopic dermatitis. Eczema herpeticum is the most common member of this group; recent advances in understanding its pathogenesis might contribute to a more successful management of this serious complication.

Predisposing factors and clinical features of eczema herpeticum: a retrospective analysis of 100 cases.

BACKGROUND: Eczema herpeticum (EH) is a widespread herpes simplex virus infection of inflamed skin, most often occurring in patients with atopic dermatitis (AD). A monomorphic eruption of dome-shaped blisters and pustules in the eczematous lesions along with severe systemic illness lead to the clinical diagnosis, but atypical variants with disseminated slits may also occur. Topical use of corticosteroids is alleged to be a pathogenetic factor for EH, but predisposing factors for EH are largely unknown. Objective and methods We sought to characterize the clinical features and predisposing factors for EH. A retrospective analysis of 100 patients with EH seen from 1980 through 1996 and of 105 control patients with AD was performed. RESULTS: Fever and lymphopenia were associated with EH, whereas an increased erythrocyte sedimentation rate was frequently seen in patients with EH and control patients who were impetiginized. In 100 patients with EH, primary herpes simplex virus infection was likely in 20 patients, and a secondary herpes simplex virus infection was suggestive in 26 patients. In all, 13 patients had a second EH, whereas 3 patients had a third EH. Patients with EH had a significantly earlier onset of AD and a significantly higher total serum IgE level than the control patients. More than 75% of the patients with EH had not received corticosteroid treatment in the 4 weeks before onset of EH. CONCLUSIONS: The characteristics of patients with EH are those associated with severe manifestations of AD. The majority of EH occurs in patients with untreated AD, arguing against a role for topical corticosteroids in the development of EH.

Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with distinct role in inflammatory skin diseases.

Epidermal dendritic cells found in inflamed skin include Langerhans cells and the recently identified population of inflammatory dendritic epidermal cells. Another subset of dendritic cells in humans is the plasmacytoid dendritic cell in peripheral blood, which is characterized by the production of large amounts of type I interferon (interferon-alpha and interferon-beta) upon viral infection. We hypothesized that plasmacytoid dendritic cells might be involved in anti-viral defense mechanisms of the skin. Here we investigated plasmacytoid dendritic cells, inflammatory dendritic epidermal cells, and Langerhans cells in epidermal single cell suspensions of normal looking skin from healthy volunteers and of lesional skin from patients with different inflammatory skin diseases. Langerhans cells were found in normal and in inflamed skin samples. In normal skin, plasmacytoid dendritic cells and inflammatory dendritic epidermal cells were low or absent. Lesional skin samples from patients with psoriasis vulgaris and contact dermatitis contained relatively high numbers of both inflammatory dendritic epidermal cells and plasmacytoid dendritic cells. In contrast, many inflammatory dendritic epidermal cells but only very few plasmacytoid dendritic cells could be detected in atopic dermatitis lesions. Lupus erythematosus was characterized by high numbers of plasmacytoid dendritic cells but low numbers of inflammatory dendritic epidermal cells. These results demonstrate that in addition to resident Langerhans cells, plasmacytoid dendritic cells and inflammatory dendritic epidermal cells are selectively recruited to the skin lesions depending on the type of skin disease. The lack of plasmacytoid dendritic cells in atopic dermatitis may predispose atopic dermatitis patients to viral infections such as eczema herpeticum, a secondary infection of atopic dermatitis lesions with herpes simplex virus. The composition of dendritic cell subsets may help to clarify the etiology of inflammatory skin diseases and forms the basis for therapeutic intervention with selective microbial molecules such as immunostimulatory CpG oligonucleotides.