[Pneumatosis cystoides intestinalis: a rare illness in adults]

Pneumatosis cystoides intestinalis (PCI) is a rare illness in adults with gas filled blebs found in the submucosa or subserosa of the bowel wall. The main localization is the terminal ileum although all parts of the intestine can be affected. Clinical symptoms can vary from aqueous-slimy, bloody diarrhea to constipation and/or vague abdominal pain. Patients can also be completely asymptomatic. In symptomatic patients the therapy of PI is based on the assumed pathogenesis, so that a combined treatment of metronidazole 1500 mg daily during a period of 6-8 weeks additionally and oxygen application (PaO2 of 200-350 mmHg) for 7 days is suggested. In addition, elemental diets are recommended. Complications are indicated in the literature with 3%. In particular mechanical ileus, invagination and perforation as well as substantial intestinal bleeding up to the volvolus lead to further diagnostic and therapeutic steps. A surgical intervention is reserved for rare cases.

[Periodontitis and cardiovascular disease]

The prevalence of periodontitis and cardiovascular disease (CVD) is high. A mixed infectious biofilm etiology of periodontitis is known but not fully established in CVD. Cofactors; smoking habits, stress, ethnicity, genetics, socioeconomics and age contribute to both diseases. The objectives of this report are to summarize factors in regards to CVD and periodontitis that are clinically relevant. The hypothesis behind a relationship between the two conditions can be founded in (I) shared infections etiology, (II) shared inflammatory response, (III) epidemiological and case-control studies, and (IV) periodontal studies demonstrating improvements of CVD markers. Streptococcus species in the S. mitis group, and S. anginosus group have been identified in periodontitis and are known as pathogens in endocarditis possibly transported from the oral cavity to the heart through bacteremia during dental therapies, and tooth brushing. Other periodontal bacteria such as Porphyromonas gingivalis, Fusobacterium nucleatum and Parvimonas micra are beta-lactamase producing and may contribute to antibiotic resistance (extended spectrum beta-lactamases). Other bacteria in CVD and periodontitis include Staphylococcus aureus, and Pseudomonas aeruginosa. Chlamydia pneumoniae and P. gingivalis lipopolyysaccharide capsels share homology and induce heat-shock protein activity and a cascade of proinflammatory cytokines. Associations between periodontitis and CVD have been presented in many studies when controlling for confounders. Other studies have demonstrated that periodontal therapies increase brachial artery flow rate and reduce serum inflammatory cytokine levels. Thus, physicians caring for subjects at CVD risk should consult with dentists/periodontists. Dentists must improve their medical knowledge and also learn to consult with physicians when treating patients at CVD risk.

Bothnia dystrophy is caused by domino-like rearrangements in cellular retinaldehyde-binding protein mutant R234W

Cellular retinaldehyde-binding protein (CRALBP) is essential for mammalian vision by routing 11-cis-retinoids for the conversion of photobleached opsin molecules into photosensitive visual pigments. The arginine-to-tryptophan missense mutation in position 234 (R234W) in the human gene RLBP1 encoding CRALBP compromises visual pigment regeneration and is associated with Bothnia dystrophy. Here we report the crystal structures of both wild-type human CRALBP and of its mutant R234W as binary complexes complemented with the endogenous ligand 11-cis-retinal, at 3.0 and 1.7 A resolution, respectively. Our structural model of wild-type CRALBP locates R234 to a positively charged cleft at a distance of 15 A from the hydrophobic core sequestering 11-cis-retinal. The R234W structural model reveals burial of W234 and loss of dianion-binding interactions within the cleft with physiological implications for membrane docking. The burial of W234 is accompanied by a cascade of side-chain flips that effect the intrusion of the side-chain of I238 into the ligand-binding cavity. As consequence of the intrusion, R234W displays 5-fold increased resistance to light-induced photoisomerization relative to wild-type CRALBP, indicating tighter binding to 11-cis-retinal. Overall, our results reveal an unanticipated domino-like structural transition causing Bothnia-type retinal dystrophy by the impaired release of 11-cis-retinal from R234W.

Reconstructive Dreams: A Pragmatic Fantastic After Postmodernism

This dissertation focuses on the use of fantastic elements in the work of a young generation of writers which explore the possibilities of literary development after and beyond postmodernism. By overtly declaring the fictionality of their fantastic stories by means of frame narratives, texts like Jonathan Safran Foer’s Everything is Illuminated (2002), Michael Chabon’s The Amazing Adventures of Kavalier and Clay (2000), Mark Danielewski’s House of Leaves (2000), David Mitchell’s number9dream (2001) and Yann Martel’s Life of Pi (2001) reassess the communicative value of genre boundaries in an attempt to move beyond postmodern relativity and breakdown of communicability. This clear focus on pragmatic concerns marks a shift in the use of the fantastic which calls for a reconsideration of some of the general critical assumptions about the workings of the mode. Though the relation between reality and fiction remains a central issue, the main concern shifts away from such epistemological and ontological considerations, towards questions concerning the pragmatic function of literary fiction in general and different genres in particular. Instead of dwelling on the typically postmodern concerns about the fictionality of reality and the instability of meaning, the works under discussion emphasise the constructive role fiction plays in dealing with reality, the uses to which it can be put and the functions it fulfils in fashioning our being in the world. Drawing on Iser’s theory of the fictive, Irmtraud Huber therefore suggests a reconceptualisation of the fantastic mode, which newly foregrounds its underlying pragmatic structure. She bring this adapted understanding to bear in a close textual analysis of the above mentioned literary texts, with the aim to account for their use of the mode in their commitment to a larger literary endeavour of a new generation that engages with the inheritance of postmodernism and struggles to come into its own.

Unnatural Narration beyond Postmodernist Alterities

Postmodernism has frequently employed unnatural narration with the aim to disturb and subvert conventionalized reading practices. Postmodernist discourses thus widely associate the unnatural with alterity, marginality and the suppressed. In this paper, I caution against such a perspective, which threatens to unduly limit our understanding of the broad variety of relations between natural and unnatural narrative on the one hand, and of the multiple possible functions of unnatural narratives on the other. Taking my cue from the use of unnatural narration in a number of recent novels, like Mark Z. Danielewski’s House of Leaves (2000), Michael Chabon’s Amazing Adventures of Kavalier & Clay (2000), or Yann Martel’s Life of Pi (2001), I will argue that a postmodernist approach which foregrounds ontological and epistemological questions and emphasizes alterity and subversion remains blind to some of the pragmatic implications that are the main concern of the unnatural narratives under consideration. This not only begs the question whether and in how far such a shift from ontological and epistemological towards pragmatic concerns constitutes a move beyond postmodernism, but also calls for a reconsideration of some of our widely established theories and assumptions about unnatural narratives.

Promising anchoring groups for single-molecule conductance measurements

The understanding of the charge transport through single molecule junctions is a prerequisite for the design and building of electronic circuits based on single molecule junctions. However, reliable and robust formation of such junctions is a challenging task to achieve. In this topical review, we present a systematic investigation of the anchoring group effect on single molecule junction conductance by employing two complementary techniques, namely scanning tunneling microscopy break junction (STM-BJ) and mechanically controllable break junction (MCBJ) techniques, based on the studies published in the literature and important results from our own work. We compared conductance studies for conventional anchoring groups described earlier with the molecular junctions formed through π-interactions with the electrode surface (Au, Pt, Ag) and we also summarized recent developments in the formation of highly conducting covalent Au–C σ-bonds using oligophenyleneethynylene (OPE) and an alkane molecular backbone. Specifically, we focus on the electron transport properties of diaryloligoyne, oligophenyleneethynylene (OPE) and/or alkane molecular junctions composed of several traditional anchoring groups, (dihydrobenzo[b]thiophene (BT), 5-benzothienyl analogue (BTh), thiol (SH), pyridyl (PY), amine (NH2), cyano (CN), methyl sulphide (SMe), nitro (NO2)) and other anchoring groups at the solid/liquid interface. The qualitative and quantitative comparison of the results obtained with different anchoring groups reveals structural and mechanistic details of the different types of single molecular junctions. The results reported in this prospective may serve as a guideline for the design and synthesis of molecular systems to be used in molecule-based electronic devices.

Pestiviruses.

Pestiviruses cause economically important diseases among domestic ruminants and pigs, but they may also infect a wide spectrum of wild species of even-toed ungulates (Artiodactyla). Bovine viral diarrhea virus (BVDV) and Border disease virus of sheep infect their hosts either transiently or persistently. Cellular and humoral immunotolerance to the infecting strain is a unique feature of persistent infection (PI) by ruminant pestiviruses. Persistence, caused by transplacental infection early in fetal development, depends on virally encoded interferon antagonists that inactivate the host's innate immune response to the virus without globally interfering with its function against other viruses. At epidemiological equilibrium, approximately 1-2% of animals are PI. Successful BVDV control programs show that removal of PI animals results in viral extinction in the host population. The nucleotide sequences of ruminant pestiviruses change little during persistent infection. Nevertheless, they display large heterogeneity, pointing to a long history of virus-host coevolution in which avirulent strains are more successful.

Protease inhibitors to treat hepatitis C in the Swiss HIV Cohort Study: high efficacy but low treatment uptake

OBJECTIVES Direct-acting antiviral agents (DAAs) have become the standard of care for the treatment of chronic hepatitis C virus (HCV) infection. We aimed to assess treatment uptake and efficacy in routine clinical settings among HIV/HCV coinfected patients after the introduction of the first generation DAAs. METHODS Data on all Swiss HIV Cohort Study (SHCS) participants starting HCV protease inhibitor (PI) treatment between September 2011 and August 2013 were collected prospectively. The uptake and efficacy of HCV therapy were compared with those in the time period before the availability of PIs. RESULTS Upon approval of PI treatment in Switzerland in September 2011, 516 SHCS participants had chronic HCV genotype 1 infection. Of these, 57 (11%) started HCV treatment during the following 2 years with either telaprevir, faldaprevir or boceprevir. Twenty-seven (47%) patients were treatment-naïve, nine (16%) were patients with relapse and 21 (37%) were partial or null responders. Twenty-nine (57%) had advanced fibrosis and 15 (29%) had cirrhosis. End-of-treatment virological response was 84% in treatment-naïve patients, 88% in patients with relapse and 62% in previous nonresponders. Sustained virological response was 78%, 86% and 40% in treatment-naïve patients, patients with relapse and nonresponders, respectively. Treatment uptake was similar before (3.8 per 100 patient-years) and after (6.1 per 100 patient-years) the introduction of PIs, while treatment efficacy increased considerably after the introduction of PIs. CONCLUSIONS The introduction of PI-based HCV treatment in HIV/HCV-coinfected patients improved virological response rates, while treatment uptake remained low. Therefore, the introduction of PIs into the clinical routine was beneficial at the individual level, but had only a modest effect on the burden of HCV infection at the population level.

Can ancient colour polymorphisms explain why some cichlid lineages speciate rapidly under disruptive sexual selection?

It is not sufficiently understood why some lineages of cichlid fishes have proliferated in the Great Lakes of East Africa much more than anywhere else in the world, and much faster than other cichlid lineages or any other group of freshwater fish. Recent field and experimental work on Lake Victoria haplochromines suggests that mate choice-mediated disruptive sexual selection on coloration, that can cause speciation even in the absence of geographical isolation, may explain it. We summarize the evidence and propose a hypothesis for the genetics of coloration that may help understand the phenomenon. By detl ning colour patterns by hue and arrangement of hues on the body, we could assign almost all observed phenotypes of Lake Victoria cichlids to one of three female («plain», «orange blotched», «black and white») and three male («blue», «red-ventrum», «reddorsum») colour patterns. These patterns diagnose species but frequently eo-occur also as morphs within the same population, where they are associated with variation in mate preferences, and appear to be transient stages in speciation. Particularly the male patterns occur in almost every genus of the species flock. We propose that the patterns and their association into polymorphisms express an ancestral trait that is retained across speciation. Our model for male colour pattern assumes two structural loci. When both are switched off, the body is blue. When switched on by a cascade of polymorphic regulatory genes, one expresses a yellow to red ventrum, the other one a yellow to red dorsum. The expression of colour variation initiates speciation. The blue daughter species will inherit the variation at the regulatory genes that can, without new mutational events, purely by recombination, again expose the colour polymorphism, starting the process anew. Very similar colour patterns also dominate among the Mbuna of Lake Malawi. In contrast, similar colour polymorphisms do not exist in the lineages that have not proliferated in the Great Lakes. The colour pattern polymorphism may be an ancient trait in the lineage (or lineages) that gave rise to the two large haplochromine radiations. We propose two tests of our hypothesis.

Binary recombinase systems for high-resolution conditional mutagenesis.

Conditional mutagenesis using Cre recombinase expressed from tissue specific promoters facilitates analyses of gene function and cell lineage tracing. Here, we describe two novel dual-promoter-driven conditional mutagenesis systems designed for greater accuracy and optimal efficiency of recombination. Co-Driver employs a recombinase cascade of Dre and Dre-respondent Cre, which processes loxP-flanked alleles only when both recombinases are expressed in a predetermined temporal sequence. This unique property makes Co-Driver ideal for sequential lineage tracing studies aimed at unraveling the relationships between cellular precursors and mature cell types. Co-InCre was designed for highly efficient intersectional conditional transgenesis. It relies on highly active trans-splicing inteins and promoters with simultaneous transcriptional activity to reconstitute Cre recombinase from two inactive precursor fragments. By generating native Cre, Co-InCre attains recombination rates that exceed all other binary SSR systems evaluated in this study. Both Co-Driver and Co-InCre significantly extend the utility of existing Cre-responsive alleles.

Outcomes of patients on dual-boosted PI regimens: experience of the Swiss HIV cohort study

Dual-boosted protease inhibitors (DBPI) are an option for salvage therapy for HIV-1 resistant patients. Patients receiving a DBPI in the Swiss HIV Cohort Study between January1996 and March 2007 were studied. Outcomes of interest were viral suppression at 24 weeks. 295 patients (72.5%) were on DBPI for over 6 months. The median duration was 2.2 years. Of 287 patients who had HIV-RNA >400?copies/ml at the start of the regimen, 184 (64.1%) were ever suppressed while on DBPI and 156 (54.4%) were suppressed within 24 weeks. The median time to suppression was 101 days (95% confidence interval 90-125 days). The median number of past regimens was 6 (IQR, 3-8). The main reasons for discontinuing the regimen were patient's wish (48.3%), treatment failure (22.5%), and toxicity (15.8%). Acquisition of HIV through intravenous drug use and the use of lopinavir in combination with saquinavir or atazanavir were associated with an increased likelihood of suppression within 6 months. Patients on DBPI are heavily treatment experienced. Viral suppression within 6 months was achieved in more than half of the patients. There may be a place for DBPI regimens in settings where more expensive alternates are not available.

Fas death receptor signalling: roles of Bid and XIAP

Fas (also called CD95 or APO-1), a member of a subgroup of the tumour necrosis factor receptor superfamily that contain an intracellular death domain, can initiate apoptosis signalling and has a critical role in the regulation of the immune system. Fas-induced apoptosis requires recruitment and activation of the initiator caspase, caspase-8 (in humans also caspase-10), within the death-inducing signalling complex. In so-called type 1 cells, proteolytic activation of effector caspases (-3 and -7) by caspase-8 suffices for efficient apoptosis induction. In so-called type 2 cells, however, killing requires amplification of the caspase cascade. This can be achieved through caspase-8-mediated proteolytic activation of the pro-apoptotic Bcl-2 homology domain (BH)3-only protein BH3-interacting domain death agonist (Bid), which then causes mitochondrial outer membrane permeabilisation. This in turn leads to mitochondrial release of apoptogenic proteins, such as cytochrome c and, pertinent for Fas death receptor (DR)-induced apoptosis, Smac/DIABLO (second mitochondria-derived activator of caspase/direct IAP binding protein with low Pi), an antagonist of X-linked inhibitor of apoptosis (XIAP), which imposes a brake on effector caspases. In this review, written in honour of Juerg Tschopp who contributed so much to research on cell death and immunology, we discuss the functions of Bid and XIAP in the control of Fas DR-induced apoptosis signalling, and we speculate on how this knowledge could be exploited to develop novel regimes for treatment of cancer.