In our cohort of patients with severe rhabdomyolysis the level of serum CK predicted the development of ARF. Although our results suggest that series of CK determination might be beneficial for the evaluation of the effect of therapy, the value of CK determination as a prognostic tool is limited, given the wide range of CK levels.

Adequate responses by our innate immune system toward invading pathogens were of vital importance for surviving infections, especially before the antibiotic era. Recently, a polymorphism in Mal (Ser180Leu, TIRAP rs8177374), an important adaptor protein downstream of the Toll-like receptor (TLR) 2 and 4 pathways, has been described to provide protection against a broad range of infectious pathogens. We assessed the functional effects of this polymorphism in human experimental endotoxemia, and we demonstrate that individuals bearing the TIRAP 180L allele display an increased, innate immune response to TLR4 and TLR2 ligands, but not to TLR9 stimulation. This phenotype has been related to an increased resistance to infection. However, an overshoot in the release of proinflammatory cytokines by TIRAP 180L homozygous individuals suggests a scenario of balanced evolution. We have also investigated the worldwide distribution of the Ser180Leu polymorphism in 14 populations around the globe to correlate the genetic makeup of TIRAP with the local infectious pressures. Based on the immunological, clinical, and genetic data, we propose that this mutation might have been selected in West Eurasia during the early settlement of this region after the out-of-Africa migration of modern Homo sapiens. This combination of functional and genetic data provides unique insights to our understanding of the pathogenesis of sepsis.Innate immunity ͉ TLR4 ͉ TLR2 ͉ evolution ͉ cytokines T he nonsynonymous single nucleotide polymorphism Ser180Leu (S180L) of the TIR domain-coding adaptor protein (TIRAP) gene, also known as adaptor protein Mal (1), was found to be protective in heterozygous individuals for a broad range of infectious diseases such as malaria, tuberculosis, bacteremia, and pneumococcal disease (1). Mal is involved in the signaling pathways of Toll-like receptors (TLR) 2 and 4, which are important innate immune receptors for the recognition of a broad range of pathogenic Gram-negative and Gram-positive bacteria (2). Recognition by TLRs eventually leads to activation of NF-B and the transcription of proinflammatory genes that activate the mechanisms of host defense and the clearance of the pathogens. However, little is known about the in vivo functional consequences of the S180L polymorphism or the possible differences in the geographic distribution of the S180L polymorphism in relation to infectious pressure.In this study we hypothesized that the difference in the frequency of TIRAP 180L between the different geographical regions was due to the effects of the mutation on the function of TLR signaling, and was shaped by the pressure exerted by different infections, either during the out-of-Africa migration of early modern humans during the early Upper Paleolithic period (60-40kya) (3) or the Neolithic demic expansion from the Near East into Europe (Ϸ10,000kya) (4, 5). This pressure may have resulted in an increase of the frequency of TIRAP S180L heterozygous individuals and thereby a strong rise of the frequency of the TIRAP 180L al...

The agonist-induced change in Ca2+ sensitivity of smooth muscle myofilaments was investigated in intact and permeabilized vascular preparations isolated from the rat and the rabbit. In intact rat mesenteric artery, membrane depolarization by 80 mM K+ solution or alpha-adrenergic stimulation by norepinephrine (NE) increased tension monotonically with increasing extracellular Ca2+ concentration ([Ca2+]e). The [Ca2+]e-tension curve generated during activation by NE was located to the left of that during activation by high K+. The protein kinase C (PKC) activator 12-O-tetradecanoylphorbol-13-acetate (TPA) shifted the high K+ [Ca2+]e-tension curve to the left but did not affect the NE curve. In rat mesenteric artery permeabilized by alpha-toxin, tension was measured while the intracellular free Ca2+ concentration ([Ca2+]i) was controlled using 2 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N'N'-tetraacetic acid and Ca2+ buffer solutions. The alpha-toxin-permeabilized fibers developed tension as a function of Ca2+ concentration. TPA and guanosine 5'-[gamma-thio]triphosphate (GTP gamma S, a nonhydrolyzable GTP analogue) significantly shifted the pCa-tension curve to the left. In intact rabbit inferior vena cava, tension was recorded simultaneously with [Ca2+]i as measured by fura-2. TPA caused a gradual increase in tension without change in [Ca2+]i. In rabbit mesenteric artery permeabilized by alpha-toxin, the tissue still responded to NE, indicating that alpha-adrenergic receptors remained intact. The response to NE was augmented by GTP and inhibited by guanosine 5'-[beta-thio]diphosphate (GDP beta S, a nonhydrolyzable GDP analogue) suggesting that a G protein is coupled with the alpha-adrenergic receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Context.-The number of authors per article has increased markedly in recent years. Little is known about the hierarchical order of authorship and its change over time. Objective.-To assess the change in number and profile of authors of original articles published over a 20-year period in BMJ. It was hypothesized that the number of authors increased over this 20-year period and that it was the senior scientists who benefited most. Design.-Comparative descriptive analysis of the number and academic rank of authors who published original articles in BMJ

Purpose: Autosomal dominant hereditary diffuse gastric cancer (HDGC) is caused by germ-line E-cadherin (CDH1) gene mutations. Early detection of cancer in carri-Conclusions: We present an asymptomatic patient from a HDGC family carrying a novel CDH1 mutation in whom FDG-PET scanning facilitated early detection of HDGC. This calls for further investigation of the role of FDG-PET scan as a screening modality in HDGC.