Epithelial NAIPs protect against colonic tumorigenesis.

NLR family apoptosis inhibitory proteins (NAIPs) belong to both the Nod-like receptor (NLR) and the inhibitor of apoptosis (IAP) families. NAIPs are known to form an inflammasome with NLRC4, but other in vivo functions remain unexplored. Using mice deficient for all NAIP paralogs (Naip1-6(Δ/Δ)), we show that NAIPs are key regulators of colorectal tumorigenesis. Naip1-6(Δ/Δ) mice developed increased colorectal tumors, in an epithelial-intrinsic manner, in a model of colitis-associated cancer. Increased tumorigenesis, however, was not driven by an exacerbated inflammatory response. Instead, Naip1-6(Δ/Δ) mice were protected from severe colitis and displayed increased antiapoptotic and proliferation-related gene expression. Naip1-6(Δ/Δ) mice also displayed increased tumorigenesis in an inflammation-independent model of colorectal cancer. Moreover, Naip1-6(Δ/Δ) mice, but not Nlrc4-null mice, displayed hyper-activation of STAT3 and failed to activate p53 18 h after carcinogen exposure. This suggests that NAIPs protect against tumor initiation in the colon by promoting the removal of carcinogen-elicited epithelium, likely in a NLRC4 inflammasome-independent manner. Collectively, we demonstrate a novel epithelial-intrinsic function of NAIPs in protecting the colonic epithelium against tumorigenesis.

Phosphate disorders: hyperphosphatemia or pseudohyperphosphatemia?

We report the case of a 79 year old woman presenting with progressive confusion and drowsiness. Renal insufficiency with hyperkalemia as well as hypercalcemia and severe hyperphosphatemia were diagnosed. Renal insufficiency improved with treatment. However, hyperphosphatemia persisted without apparent explanation. We discuss possible causes of hyper- and pseudohyperphosphatemia. Specifically, phosphate analysis may be disturbed by the paraproteins in patients with multiple myeloma, resulting in pseudohyperphosphatemia. We review the standard laboratory phosphate measurement and the mechanisms of interference with paraproteins.

Do we need antiplatelet therapy in thrombocytosis? Pro. Diagnostic and pathophysiologic considerations for a treatment choice.

Thrombocytosis (defined as platelets >450 x 10(9)/l) has several aetiologies. After having excluded spurious thrombocytosis (e. g., due to microspherocytes, schistocytes, cryoglobulins, or bacteria), the differential diagnosis of true thrombocytosis encompasses secondary causes (as diverse as inflammation, infection, malignancy, iron deficiency, or asplenia), primary hereditary (rare forms of familial thrombocytosis) and primary acquired entities (either in the context of a myelodysplastic syndrome or more frequently a myeloproliferative neoplasia). This manuscript addresses the following aspects: 1) diagnostic approach to thrombocytosis; 2) various mechanisms leading to a high platelet count; 3) potential of some of these mechanisms to modulate platelet function, producing hyper-reactive platelets and thus exerting a direct impact on the thrombotic risk; 4) indication of anti-thrombotic treatment in patients with thrombocytosis. There is a single prospective randomized clinical trial showing the benefit of acetyl-salicylic acid in polycythaemia vera. For other types of primary thrombocytosis and for secondary forms, treatment decisions have to be individualized according to the patient thrombotic and bleeding risks, taking into account the mechanism causing thrombocytosis. This manuscript discusses experimental and clinical data suggesting that besides patients with essential thrombocythaemia and other forms of primary thrombocytosis also those with thrombocytosis in the context of chronic inflammation, malignancy, or exposure to high altitude might benefit from anti-platelet treatment.

Ein Autor von ›hypertropher Virilität‹. Geschlecht in der Musil-Rezeption der 1920er und 1930er Jahre

Adopting "The Man Without Qualities" as a decisively masculine novel, contemporary literary criticism passed on a trope with which reviewers such as Alfred Döblin, Robert Müller and Franz Blei had already characterised Musil’s earlier texts. The reviews of the novel are therefore typical of how evaluations in terms of originality in the literary-critical and poetological debates of the 20s and 30s were regularly translated into the established gender hierarchy. The need to make such judgements can be seen as much as the symptom of a modern consciousness of crisis in masculinity as the hyper-athletics of the novel’s hero himself and the pitiful figure cut by the other men in "The Man Without Qualities".

First report of a multidrug-resistant Klebsiella pneumoniae of sequence type 11 causing sepsis in a free-ranging beaver (Castor fiber).

Klebsiella pneumoniae of sequence type (ST) 11 is a hyper-epidemic nosocomial clone spreading worldwide among humans and also emerging in pets. In this report, we describe a clinical case of fatal sepsis due to this multidrug-resistant (MDR) pathogen in a Eurasian beaver. The isolate showed resistance to six different classes of antimicrobials including third generation cephalosporins and fluoroquinolones. This is the first report describing the detection of a MDR K. pneumoniae ST11 in a free-ranging animal. Our finding highlights the potential for environmental dissemination of hyper-epidemic clones of K. pneumoniae and possible spread in wildlife and cause epizootics.

Real-time ultra-high optical coherence tomography monitoring of optical tissue effects caused by selective retina therapy

Purpose: Selective retina therapy (SRT) has shown great promise compared to conventional retinal laser photocoagulation as it avoids collateral damage and selectively targets the retinal pigment epithelium (RPE). Its use, however, is challenging in terms of therapy monitoring and dosage because an immediate tissue reaction is not biomicroscopically discernibel. To overcome these limitations, real-time optical coherence tomography (OCT) might be useful to monitor retinal tissue during laser application. We have thus evaluated a proprietary OCT system for its capability of mapping optical changes introduced by SRT in retinal tissue. Methods: Freshly enucleated porcine eyes, covered in DMEM upon collection were utilized and a total of 175 scans from ex-vivo porcine eyes were analyzed. The porcine eyes were used as an ex-vivo model and results compared to two time-resolved OCT scans, recorded from a patient undergoing SRT treatment (SRT Vario, Medical Laser Center Lübeck). In addition to OCT, fluorescin angiography and fundus photography were performed on the patient and OCT scans were subsequently investigated for optical tissue changes linked to laser application. Results: Biomicroscopically invisible SRT lesions were detectable in OCT by changes in the RPE / Bruch's complex both in vivo and the porcine ex-vivo model. Laser application produced clearly visible optical effects such as hyperreflectivity and tissue distortion in the treated retina. Tissue effects were even discernible in time-resolved OCT imaging when no hyper-reflectivity persisted after treatment. Data from ex-vivo porcine eyes showed similar to identical optical changes while effects visible in OCT appeared to correlate with applied pulse energy, leading to an additional reflective layer when lesions became visible in indirect ophthalmoscopy. Conclusions: Our results support the hypothesis that real-time high-resolution OCT may be a promising modality to obtain additional information about the extent of tissue damage caused by SRT treatment. Data shows that our exvivo porcine model adequately reproduces the effects occurring in-vivo, and thus can be used to further investigate this promising imaging technique.

Mechanical restoration and failure analyses of a hydrogel and scaffold composite strategy for annulus fibrosus repair

Unrepaired defects in the annulus fibrosus of intervertebral disks are associated with degeneration and persistent back pain. A clinical need exists for a disk repair strategy that can seal annular defects, be easily delivered during surgical procedures, and restore biomechanics with low risk of herniation. Multiple annulus repair strategies were developed using poly(trimethylene carbonate) scaffolds optimized for cell delivery, polyurethane membranes designed to prevent herniation, and fibrin-genipin adhesive tuned to annulus fibrosus shear properties. This three-part study evaluated repair strategies for biomechanical restoration, herniation risk and failure mode in torsion, bending and compression at physiological and hyper-physiological loads using a bovine injury model. Fibrin-genipin hydrogel restored some torsional stiffness, bending ROM and disk height loss, with negligible herniation risk and failure was observed histologically at the fibrin-genipin mid-substance following rigorous loading. Scaffold-based repairs partially restored biomechanics, but had high herniation risk even when stabilized with sutured membranes and failure was observed histologically at the interface between scaffold and fibrin-genipin adhesive. Fibrin-genipin was the simplest annulus fibrosus repair solution evaluated that involved an easily deliverable adhesive that filled irregularly-shaped annular defects and partially restored disk biomechanics with low herniation risk, suggesting further evaluation for disk repair may be warranted. Statement of significance Lower back pain is the leading cause of global disability and commonly caused by defects and failure of intervertebral disk tissues resulting in herniation and compression of adjacent nerves. Annulus fibrosus repair materials and techniques have not been successful due to the challenging mechanical and chemical microenvironment and the needs to restore biomechanical behaviors and promote healing with negligible herniation risk while being delivered during surgical procedures. This work addressed this challenging biomaterial and clinical problem using novel materials including an adhesive hydrogel, a scaffold capable of cell delivery, and a membrane to prevent herniation. Composite repair strategies were evaluated and optimized in quantitative three-part study that rigorously evaluated disk repair and provided a framework for evaluating alternate repair techniques.

Erosive tooth wear and wedge-shaped defects in 1996 and 2006: cross- sectional surveys of Swiss army recruits.

The purpose of this study was to determine the prevalence and possible etiological factors of erosive tooth wear and wedge-shaped defects in Swiss Army recruits and compare the findings with those of an analogous study conducted in 1996. In 2006, 621 recruits between 18 and 25 years of age (1996: 417 recruits; ages 19 to 25) were examined for erosive tooth wear and wedge-shaped defects. Additional data was acquired using a questionnaire about personal details, education, dentitions subjective condition, oral hygiene, eating and drinking habits, medications used, and general medical problems. In 2006, 60.1% of those examined exhibited occlusal erosive tooth wear not involving the dentin (1996: 82.0%) and 23.0% involving the dentin (1996: 30.7%). Vestibular erosive tooth wear without dentin involvement was seen in 7.7% in 2006 vs. 14.4% in 1996. Vestibular erosive tooth wear with dentin involvement was rare in both years (0.5%). Oral erosive tooth wear lacking exposed dentin was also rare in those years, although more teeth were affected in 2006 (2.1%) than in 1996 (0.7%). The examinations in 2006 found one or more initial wedge-shaped lesions in 8.5% of the recruits, while 20.4% of the study participants exhibited such in 1996. In 1996, 53% consumed acidic foods and beverages more than 5 times/day; in 2006, 83.9% did so. In neither study did multivariate regression analyses show any significant correlations between occurrence and location of erosive tooth wear and wedge-shaped defects and various other parameters, e.g., eating and hygiene habits, or dentin hyper-sensitivity. Despite a significant increase in consumption of acidic products between 1996 and 2006, the latter study found both fewer erosive tooth wear and fewer wedge-shaped defects (i.e., fewer non-carious lesions.).

Hypercoagulation and hyperkinetic blood pressure indicative of physiological loss-of-control despite behavioural control in Africans: The SABPA study.

OBJECTIVES A dissociation between behavioural (in-control) and physiological parameters (indicating loss-of-control) is associated with cardiovascular risk in defensive coping (DefS) Africans. We evaluated relationships between DefS, sub-clinical atherosclerosis, low-grade inflammation and hypercoagulation in a bi-ethnic sex cohort. METHODS Black (Africans) and white Africans (Caucasians) (n = 375; aged 44.6 ± 9.7 years) were included. Ambulatory BP, vascular structure (left carotid cross-sectional wall area (L-CSWA) and plaque counts), and markers of coagulation and inflammation were quantified. Ethnicity/coping style interaction was revealed only in DefS participants. RESULTS A hypertensive state, less plaque, low-grade inflammation, and hypercoagulation were more prevalent in DefS Africans (27-84%) than DefS Caucasians (18-41%). Regression analyses demonstrated associations between L-CSWA and 24 hour systolic BP (R(2) = 0.38; β = 0.78; p < 0.05) in DefS African men but not in DefS African women or Caucasians. No associations between L-CSWA and coagulation markers were evident. CONCLUSION Novel findings revealed hypercoagulation, low-grade inflammation and hyperkinetic BP (physiological loss-of-control responses) in DefS African men. Coupled to a self-reported in-control DefS behavioural profile, this reflects dissociation between behaviour and physiology. It may explain changes in vascular structure, increasing cerebrovascular disease risk in a state of hyper-vigilant coping.

Calcium Disorders in the Emergency Department: Independent Risk Factors for Mortality.

BACKGROUND Calcium disorders are common in both intensive care units and in patients with chronic kidney disease and are associated with increased morbidity and mortality. It is unknown whether calcium abnormalities in unselected emergency department admissions have an impact on in-hospital mortality. METHODS This cross-sectional analysis included all admissions to the Emergency Department at the Inselspital Bern, Switzerland from 2010 to 2011. For hyper- and hypocalcaemic patients with a Mann-Whitney U-test, the differences between subgroups divided by age, length of hospital stay, creatinine, sodium, chloride, phosphate, potassium and magnesium were compared. Associations between calcium disorders and 28-day in-hospital mortality were assessed using the Cox proportional hazard regression model. RESULTS 8,270 patients with calcium measurements were included in our study. Overall 264 (3.2%) patients died. 150 patients (6.13%) with hypocalcaemia and 7 patients with hypercalcaemia (6.19%) died, in contrast to 104 normocalcaemic patients (1.82%). In univariate analysis, calcium serum levels were associated with sex, mortality and pre-existing diuretic therapy (all p<0.05). In multivariate Cox regression analysis, hypocalcaemia and hypercalcaemia were independent risk factors for mortality (HR 2.00 and HR 1.88, respectively; both p<0.01). CONCLUSION Both hypocalcaemia and hypercalcaemia are associated with increased 28-day in-hospital mortality in unselected emergency department admissions.

New associations of classic acute macular neuroretinopathy

PURPOSE: To describe novel underlying associations of classic acute macular neuroretinopathy (AMN). METHODS: Multimodal imaging case series evaluating patients with classic AMN lesions and previously unreported underlying aetiologies. RESULTS: Six patients were included (five women, one man, mean age 30±7 years). Mean distance best corrected visual acuity at initial presentation was 0.21±0.3 logMAR (mean Snellen acuity: 20/30, range 20/15-20/100) and at last follow-up visit 0.09±0.17 logMAR (Snellen acuity: 20/20, range 20/15-20/60). All cases but one had bilateral lesions and showed typical parafoveal hyporeflective lesions on infrared imaging, which corresponded to the hyper-reflectivity in the Henle's layer with attenuation of the external limiting membrane, the ellipsoid zone and interdigitation zone. Underlying diseases included thrombocytopenia and anaemia associated with dengue fever, acute lymphoblastic leukaemia, chronic kidney disease and ulcerative colitis, while Valsalva-like manoeuvre was found to be a potential trigger. Other novel associations included the use of lisdexamphetamine. CONCLUSIONS: Classic AMN may be associated with leukaemia, dengue fever, ulcerative colitis and chronic kidney disease, probably as a result of chorioretinal hypoxia in the setting of thrombocytopenia and anaemia. Adrenergic agonists such as lisdexamphetamine may also contribute to the manifestation of AMN.

Heisenberg symmetry and hypermultiplet manifolds

We study the emergence of Heisenberg (Bianchi II) algebra in hyper-Kähler and quaternionic spaces. This is motivated by the rôle these spaces with this symmetry play in N = 2 hypermultiplet scalar manifolds. We show how to construct related pairs of hyper-Kähler and quaternionic spaces under general symmetry assumptions, the former being a zooming-in limit of the latter at vanishing scalar curvature. We further apply this method for the two hyper-Kähler spaces with Heisenberg algebra, which is reduced to U (1) × U (1) at the quaternionic level. We also show that no quaternionic spaces exist with a strict Heisenberg symmetry – as opposed to Heisenberg U (1). We finally discuss the realization of the latter by gauging appropriate Sp(2, 4) generators in N = 2 conformal supergravity.

Enhanced depth imaging optical coherence tomography of congenital cavitary optic disc anomaly (CODA).

AIM To report the finding of extension of the 4th hyper-reflective band and retinal tissue into the optic disc in patients with cavitary optic disc anomalies (CODAs). METHODS In this observational study, 10 patients (18 eyes) with sporadic or autosomal dominant CODA were evaluated with enhanced depth imaging optical coherence tomography (EDI-OCT) and colour fundus images for the presence of 4th hyper-reflective band extension into the optic disc. RESULTS Of 10 CODA patients (18 eyes), five patients (8 eyes) showed a definite 4th hyper-reflective band (presumed retinal pigment epithelium (RPE)) extension into the optic disc. In these five patients (seven eyes), the inner retinal layers also extended with the 4th hyper-reflective band into the optic disc. Best corrected visual acuity ranged from 20/20 to 20/200. In three patients (four eyes), retinal splitting/schisis was present and in two patients (two eyes), the macula was involved. In all cases, the 4th hyper-reflective band extended far beyond the termination of the choroid into the optic disc. The RPE extension was found either temporally or nasally in areas of optic nerve head excavation, most often adjacent to peripapillary pigment. Compared with eyes without RPE extension, eyes with RPE extension were more myopic (mean dioptres -0.9±2.6 vs -8.8±5, p=0.043). CONCLUSIONS The RPE usually stops near the optic nerve border separated by a border tissue. With CODA, extension of this hyper-reflective band and retinal tissue into the disc is possible and best evaluable using EDI-OCT or analogous image modalities. Whether this is a finding specific for CODA, linked to specific gene loci or is also seen in patients with other optic disc abnormalities needs further evaluation.