Staphylococcus haemolyticus superinfection of Legionella pneumonia during infliximab therapy

We present the case of a 42-year-old man affected by psoriasis with Staphylococcus Haemolyticus superinfection of Legionella pneumonia during infliximab therapy. The introduction of compounds that block TNF-\u3b1 has yielded great benefits for patients affected by selected autoimmune diseases that fail to respond to classic anti-inflammatory agents, but, on the other hand, has led to an increased susceptibility to infections, in particular of those caused by intracellular pathogens, such as L. Pneumophila. Emerging evidence suggests that legionellosis can be complicated by superinfection with other agents, including saprophytic microorganisms, among which coagulasenegative staphylococci. To our knowledge, this is the first report of systemic legionellosis with superinfection by S. haemolyticus, an emerging nosocomial multi-resistant pathogen that commonly causes septicemia, osteomyelitis or endocarditis, but has not so far been associated with necrotizing pneumonia. Despite the optimal antimicrobial therapy for Staphylococcus spp. Pneumonia is still controversial, evidence suggests that in patients with confirmed positivity for methicillin resistant strains, particularly if sensitivity to vancomycin is suboptimal, linezolid should be the first choice therapy, being superior to vancomycin and teicoplanin

The A736V TMPRSS6 Polymorphism Influences Hepatic Iron Overload in Nonalcoholic Fatty Liver Disease

AIMS: Hepatic iron accumulation due to altered trafficking is frequent in patients with nonalcoholic fatty liver disease (NAFLD), and is associated with more severe liver damage and hepatocellular carcinoma. The p.Ala736Val TMPRSS6 variant influences iron metabolism regulating the transcription of the hepatic hormone hepcidin, but its role in the pathogenesis of iron overload disorders is controversial. Aim of this study was to evaluate the whether the TMPRSS6 p.Ala736Val variant influences hepatic iron accumulation in a well-characterized series of Italian patients with histological NAFLD. METHODS: 216 patients with histological NAFLD. TMPRSS6 and HFE variants were assessed by allele specific PCR, liver histology by the NAFLD activity score and Perls' staining for iron. RESULTS: Homozygosity for the p.736Val allele previously linked to higher hepcidin did not influence transferrin saturation (TS), but was associated with lower hepatic iron stores (p\u200a=\u200a0.01), and ferritin levels (median 223 IQR 102-449 vs. 308 IQR 141-618 ng/ml; p\u200a=\u200a0.01). Homozygosity for TMPRSS6 p.736Val was nearly associated with lower ballooning (p\u200a=\u200a0.05), reflecting hepatocellular damage related to oxidative stress. The influence of TMPRSS6 on hepatic iron accumulation was more marked in patients negative for HFE genotypes predisposing to iron overload (p.Cys282Tyr + and p.His63Asp +/+; p\u200a=\u200a0.01), and the p.736Val variant was negatively associated with hepatic iron accumulation independently of age, gender, HFE genotype, and beta-thalassemia trait (OR 0.59, 0.39-0.88). CONCLUSIONS: The p.Ala736Val TMPRSS6 variant influences secondary hepatic iron accumulation in patients with NAFLD

Genetics of nonalcoholic fatty liver disease : a 2018 update

Nonalcoholic fatty liver disease (NAFLD), now the leading cause of liver damage worldwide, is epide-miologically associated with obesity, insulin resistance and type 2 diabetes, and is a potentially progressive condition to advanced liver fibrosis and hepatocellular carcinoma. However, there is huge interindividual variability in liver disease susceptibility. Inherited factors also play an important role in determining disease predisposition. During the last years, common variants in PNPLA3, TM6SF2, MBOAT7 and GCKR have been demonstrated to predispose to the full spectrum of NAFLD pathology by facilitating hepatic fat accumulation in the presence of environmental triggers. Other variants regulating inflammation and fibrogenesis then modulate liver disease progression in those at higher risk. Evidence is also accumulating that rare variants are involved in disease predisposition. In the future, evaluation of genetic risk factors may be exploited to stratify the risk of liver-related complications of the disease, and to guide hepatocellular carcinoma surveillance and choose pharmacological therapy

Beyond hereditary hemochromatosis : new insights into the relationship between iron overload and chronic liver diseases

Following the model of hereditary hemochromatosis, the possible role of iron overload as a cofactor for disease progression in acquired liver diseases has been investigated with controversial results. In recent years, progress has been made in understanding the regulation of iron metabolism, thereby allowing the evaluation of the mechanisms linking liver diseases to excessive iron accumulation. Indeed, deregulation of the transcription of hepcidin, emerging as the master regulator of systemic iron metabolism, has been implicated in the pathogenesis of hepatic iron overload in chronic liver diseases. Whatever the cause, hepatocellular iron deposition promotes liver fibrogenesis, while an emerging possible aggravating factor is represented by the strong link between iron stores and insulin resistance, a recently recognized risk factor for the progression of liver diseases. Overall, these pathogenic mechanisms, together with the known proliferative and mutagenic effect of excess iron, converge in determining an increased susceptibility to hepatocellular carcinoma. Finally, an association between serum ferritin levels and mortality in patients with end-stage liver disease has recently been reported.Prospective, randomized studies are required to evaluate whether iron depletion may reduce fibrosis progression, hepatocellular carcinoma development, and eventually mortality in patients with chronic liver diseases

The immunopathogenesis of alcoholic and nonalcoholic steatohepatitis : two triggers for one disease?

Alcoholic liver disease and nonalcoholic liver disease represent a leading cause of liver disease and share similar pathogenic mechanisms among which activation of the immune system plays a key role. The main events consist in (a) activation of Kupffer cells via TLR-4 by LPS and fatty acids (b) complement activation (c) increased release of proinflammatory mediators (d) alteration in NK and NKT cell number/activity (e) activation of the adaptive immune system. At the same time, activation of intracellular pro-inflammatory pathways by cytokines and bacterial products, inhibit insulin signaling favoring lipogenesis, metabolic alterations, and cell damag

TNFalpha promoter polymorphisms

Polymorphisms in the promoter of the tumor necrosis factor alpha (TNFalpha) gene have been reported to affect the transcription rate and the release of this cytokine. Among the best studied, the -238 and -308 polymorphisms have been associated with an increased transcriptional activity and TNFalpha release, whereas the -863 polymorphism have been associated with a reduced transcriptional activity. A growing body of evidence indicates that these polymorphisms may affect susceptibility to different diseases. Here we describe a method to detect the -238, -308, and -863 TNFalpha polymorphisms by the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Briefly, DNA is amplified by PCR using mutagenic primers containing a single base-pair mismatch adjacent to the polymorphic site to introduce a restriction site into the wild-type nucleotide sequences after amplification. The PCR products are then digested with specific restriction enzymes and analyzed by agarose gel electrophoresis