Creating oral squamous cancer cells: a cellular model of oral-esophageal carcinogenesis

Immortalization and malignant transformation are important steps in tumor development. The ability to induce these processes from normal human epithelial cells with genetic alterations frequently found in the corresponding human cancer would significantly enhance our understanding of tumor development. Alterations in several key intracellular regulatory pathways (the pRB, p53, and mitogenic signaling pathways and the telomere maintenance system) appear to be sufficient for the neoplastic transformation of normal human cells. Nevertheless, in vitro transformation models to date depend on viral oncogenes, most prominently the simian virus 40 early region, to induce immortalization and malignant transformation of normal human epithelial cells. Here, we demonstrate a transformation model creating oral-esophageal cancer cells by using a limited set of genetic alterations frequently observed in the corresponding human cancer. In a stepwise model, cyclin D1 overexpression and p53 inactivation led to immortalization of oral keratinocytes. Additional ectopic epithelial growth factor receptor overexpression followed by c-myc overexpression as well as consecutive reactivation of telomerase induced by epithelial growth factor receptor sufficed to transform oral epithelial cells, truly recapitulating the development of the corresponding human disease.     

Efficacy of malaria prophylaxis in American and Swiss travelers to Kenya

The protective effect of malaria chemoprophylaxis with either Fansidar (pyrimethamine-sulfadoxine) or chloroquine was estimated by determining the attack rates of Plasmodium falciparum infections acquired in Kenya and imported by U.S. and Swiss travelers who had used no chemoprophylaxis, who had used only chloroquine for prophylaxis, and who had used Fansidar weekly, either alone or in combination with chloroquine. The estimated attack rates were almost identical in U.S. and Swiss travelers. The attack rate per 100,000 travelers averaged 280 in those who did not use chemoprophylaxis, 162 in those who took 4-aminoquinolines (P greater than .05), and 27 in those who used Fansidar for prophylaxis (P less than .001). Non-immune travelers to Kenya have an appreciable risk of acquiring a P. falciparum infection and need to be informed of current guidelines for chemoprophylaxis. The changing drug susceptibility patterns in Africa require continuous evaluation of the efficacy of recommended drug regimens for malaria prophylaxis.     

Comparison of translocation rates of various indigenous bacteria from the gastrointestinal tract to the mesenteric lymph node

Bacterial translocation is defined as the passage of indigenous bacteria from the gastrointestinal (GI) tract through the lamina propria to the mesenteric lymph nodes (MLN) and other organs. We compared the relative abilities of various aerobic, facultatively anaerobic, and obligately anaerobic bacteria to translocate from the GI tract to the MLN in gnotobiotic mice colonized with single strains of bacteria. Indigenous gram-negative enteric bacilli translocated in large numbers to the MLN, whereas gram-positive bacteria translocated at intermediate levels and obligately anaerobic bacteria at only very low levels. Our results suggest that enteric bacilli such as Escherichia coli, Proteus, and Enterobacter are associated with a higher incidence of bacteremia in debilitated patients, because these bacteria translocate more efficiently from the GI tract than do other bacteria, especially obligate anaerobes.     

Adjunctive therapies in severe sepsis and septic shock: Current place of steroids

For more than five decades, the use of corticosteroids as an adjunctive therapy to treat severe sepsis and septic shock has incited consistent debate. Negative results of the Corticosteroid Therapy of Septic Shock (CORTICUS) study evoked a revision of Surviving Sepsis Campaign guidelines suggesting a more restricted use of low-dose hydrocortisone only in patients with severe septic shock. Hemodynamic improvement by low-dose steroids was evident and independent from adrenal insufficiency, but did not improve survival. The roles of cortisol measurement and adrenal function tests for treatment decisions have been questioned. An international task force introduced the concept of critical illness-related corticosteroid insufficiency, which challenges the predominant role of adrenal dysfunction and underscores sustained inflammation due to tissue steroid resistance. Whether moderate steroid doses induce superinfections and muscle weakness is unclear. This article reviews recent publications, actual recommendations, ongoing discussions, and future perspectives.     

Development of a Brief Cognitive and Behavioral Intervention for the Management of Episodic Breathlessness—A Delphi Survey With International Experts

ContextEpisodic breathlessness is characterized by a severe worsening of breathlessness intensity that goes beyond usual fluctuations. Episodes are usually short; therefore, nonpharmacological strategies (cognitive and behavioral) seem most promising to be beneficial. Which strategies—delivered separately or in combination—might be most effective and feasible remains unclear.ObjectivesThe Delphi survey selects and determines different nonpharmacological strategies for coping with episodic breathlessness to develop a brief cognitive and behavioral intervention for the management of episodic breathlessness.MethodsUsing an online Delphi survey comprising three rounds, international, multidisciplinary experts in breathlessness summarized and determined cognitive and behavioral strategies. The a priori target agreement for close-ended questions was 70%.ResultsExperts (n = 41/87; n = 45/85; n = 36/85) agreed on 15 of the 31 cognitive and behavioral strategies. Based on the panellists' opinion, the final version of the cognitive and behavioral intervention comprised the following characteristics: individually tailored intervention, a high proportion of communication, short duration, the involvement of carers, and use of the Breathing, Thinking, Functioning Model of Spathis et al. Consensus upon the delivery of the subsequent strategies within the intervention was reached: handheld fan, forward lean, diaphragmatic breathing, distraction, pursed lips breathing, long breaths out, and relaxation training.ConclusionUsing the consented nonpharmacological strategies, a brief cognitive and behavioral intervention was developed that balances between individualization and standardization of the intervention.     

Caspase-6 activity predicts lower episodic memory ability in aged individuals

Caspase-6 (Casp6), a cysteinyl protease that induces axonal degeneration, is activated early in Alzheimer Disease (AD) brains. To determine whether Casp6 activation is responsible for early cognitive impairment, we investigated the abundance of Casp6 activity, paired helical filament–1 (PHF-1) phosphorylated Tau and amyloid beta peptide (Aβ) pathology by immunohistochemistry in the hippocampal formation of aged non–cognitively impaired (NCI) individuals. Casp6 activity was restricted to the entorhinal cortex (ERC) and CA1 regions of the hippocampus. Pathology scores were then correlated with cognitive scores obtained within 1 year of death. Regression analyses revealed that ERC and CA1 Casp6 activity were the main contributor to lower episodic memory performance, whereas ERC PHF-1 pathology predicted lower semantic and working memory performance. Aβ did not correlate with any of the cognitive tests. Because Casp6 activity and PHF-1 pathology are intimately associated with AD pathology and memory decline is an early event in AD, we conclude that Casp6 activity and PHF-1 immunoreactivity in ERC identifies aged individuals at risk for developing AD.     

CD40 ligand and interferon‐γ induce an antimicrobial response against Mycobacterium tuberculosis in human monocytes

The ability of T cells to activate antimicrobial pathways in infected macrophages is essential to host defence against many intracellular pathogens. Here, we compared the ability of two T‐cell‐mediated mechanisms to trigger antimicrobial responses against Mycobacterium tuberculosis in humans, CD40 activation and the release of interferon‐γ (IFN‐γ). Given that IFN‐γ activates a vitamin D‐dependent antimicrobial response, we focused on induction of the key components of this pathway. We show that activation of human monocytes via CD40 ligand (CD40L) and IFN‐γ, alone, and in combination, induces the CYP27b1‐hydroxylase, responsible for the conversion of 25‐hydroxyvitamin D (25D) to the bioactive 1,25‐dihydroxyvitamin D (1,25D), and the vitamin D receptor (VDR). The activation of the vitamin D pathway by CD40L and IFN‐γ results in up‐regulated expression of the antimicrobial peptides, cathelicidin and DEFB4, as well as induction of autophagy. Finally, activation of monocytes via CD40L and IFN‐γ results in an antimicrobial activity against intracellular M. tuberculosis. Our data suggest that at least two parallel T‐cell‐mediated mechanisms, CD40L and IFN‐γ, activate the vitamin D‐dependent antimicrobial pathway and trigger antimicrobial activity against intracellular M. tuberculosis, thereby contributing to human host defence against intracellular infection.