A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic

Carbohydrate-deficient glycoprotein syndrome (CDGS) represents a class of genetic diseases characterized by abnormal N-linked glycosylation. CDGS patients show a large number of glycoprotein abnormalities resulting in dysmorphy, encephalopathy, and other organ disorders. The majority of CDGSs described to date are related to an impaired biosynthesis of dolichyl pyrophosphate-linked Glc3Man9GlcNAc2 in the endoplasmic reticulum. Recently, we identified in four related patients a novel type of CDGS characterized by an accumulation of dolichyl pyrophosphate-linked Man9GlcNAc2. Elaborating on the analogy of this finding with the phenotype of alg5 and alg6 Saccharomyces cerevisiae strains, we have cloned and analyzed the human orthologs to the ALG5 dolichyl phosphate glucosyltransferase and ALG6 dolichyl pyrophosphate Man9GlcNAc2 alpha1,3-glucosyltransferase in four novel CDGS patients. Although ALG5 was not altered in the patients, a C-->T transition was detected in ALG6 cDNA of all four CDGS patients. The mutation cosegregated with the disease in a Mendelian recessive manner. Expression of the human ALG5 and ALG6 cDNA could partially complement the respective S. cerevisiae alg5 and alg6 deficiency. By contrast, the mutant ALG6 cDNA of CDGS patients failed to revert the hypoglycosylation observed in alg6 yeasts, thereby proving a functional relationship between the alanine to valine substitution introduced by the C-->T transition and the CDGS phenotype. The mutation in the ALG6 alpha1,3-glucosyltransferase gene defines an additional type of CDGS, which we propose to refer to as CDGS type-Ic.

Ankle joint pressure changes in a pes cavovarus model: supramalleolar valgus osteotomy versus lateralizing calcaneal osteotomy

BACKGROUND: A fixed cavovarus foot deformity can be associated with anteromedial ankle arthrosis due to elevated medial joint contact stresses. Supramalleolar valgus osteotomies (SMOT) and lateralizing calcaneal osteotomies (LCOT) are commonly used to treat symptoms by redistributing joint contact forces. In a cavovarus model, the effects of SMOT and LCOT on the lateralization of the center of force (COF) and reduction of the peak pressure in the ankle joint were compared. METHODS: A previously published cavovarus model with fixed hindfoot varus was simulated in 10 cadaver specimens. Closing wedge supramalleolar valgus osteotomies 3 cm above the ankle joint level (6 and 11 degrees) and lateral sliding calcaneal osteotomies (5 and 10 mm displacement) were analyzed at 300 N axial static load (half body weight). The COF migration and peak pressure decrease in the ankle were recorded using high-resolution TekScan pressure sensors. RESULTS: A significant lateral COF shift was observed for each osteotomy: 2.1 mm for the 6 degrees (P = .014) and 2.3 mm for the 11 degrees SMOT (P = .010). The 5 mm LCOT led to a lateral shift of 2.0 mm (P = .042) and the 10 mm LCOT to a shift of 3.0 mm (P = .006). Comparing the different osteotomies among themselves no significant differences were recorded. No significant anteroposterior COF shift was seen. A significant peak pressure reduction was recorded for each osteotomy: The SMOT led to a reduction of 29% (P = .033) for the 6 degrees and 47% (P = .003) for the 11 degrees osteotomy, and the LCOT to a reduction of 41% (P = .003) for the 5 mm and 49% (P = .002) for the 10 mm osteotomy. Similar to the COF lateralization no significant differences between the osteotomies were seen. CONCLUSION: LCOT and SMOT significantly reduced anteromedial ankle joint contact stresses in this cavovarus model. The unloading effects of both osteotomies were equivalent. More correction did not lead to significantly more lateralization of the COF or more reduction of peak pressure but a trend was seen. CLINICAL RELEVANCE: In patients with fixed cavovarus feet, both SMOT and LCOT provided equally good redistribution of elevated ankle joint contact forces. Increasing the amount of displacement did not seem to equally improve the joint pressures. The site of osteotomy could therefore be chosen on the basis of surgeon's preference, simplicity, or local factors in case of more complex reconstructions.

Illusions of fusions: assessing cervical vertebral fusion on lateral cephalograms, multidetector computed tomographs, and cone-beam computed tomographs

INTRODUCTION The aims of this study were to compare lateral cephalograms with other radiologic methods for diagnosing suspected fusions of the cervical spine and to validate the assessment of congenital fusions and osteoarthritic changes against the anatomic truth. METHODS Four cadaver heads were selected with fusion of vertebrae C2 and C3 seen on a lateral cephalogram. Multidetector computed tomography (MDCT) and cone-beam computed tomography (CBCT) were performed and assessed by 5 general radiologists and 5 oral radiologists, respectively. Vertebrae C2 and C3 were examined for osseous fusions, and the left and right facet joints were diagnosed for osteoarthritis. Subsequently, the C2 and C3 were macerated and appraised by a pathologist. Descriptive analysis was performed, and interrater agreements between and within the groups were computed. RESULTS All macerated specimens showed osteoarthritic findings of varying degrees, but no congenital bony fusion. All observers agreed that no fusion was found on MDCT or CBCT. They disagreed on the prevalence of osteoarthritic deformities (general radiologists/MDCT, 100%; oral radiologists/CBCT, 93.3%) and joint space assessment in the facet joints (kappa = 0.452). The agreement within the rater groups differed considerably (general radiologists/MDCT, kappa = 0.612; oral radiologists/CBCT, kappa = 0.240). CONCLUSIONS Lateral cephalograms do not provide dependable data to assess the cervical spine for fusions and cause false-positive detections. Both MDCT interpreted by general radiologists and CBCT interpreted by oral radiologists are reliable methods to exclude potential fusions. Degenerative osteoarthritic changes are diagnosed more accurately and consistently by general radiologists evaluating MDCT.

Conservative treatment of asymmetric ankle osteoarthritis

This review article summarizes the currently available (poor) evidence of conservative treatment of asymmetric ankle osteoarthritis in the literature and adds the authors' experience with the particular technique. The use of dietary supplementation, viscosupplementation, platelet-rich plasma, nonsteroidal anti-inflammotory drugs, corticosteroid injections, physical therapy, shoe modifications and orthoses, and patient's education in asymmetric ankle osteoarthritis is outlined. There definitively is a place for conservative treatment with reasonable success in patients whose ankles do not qualify anymore for joint-preserving surgery and in patients with medical or orthopedic contraindications for realignment surgery, total ankle replacement, and ankle arthrodesis.

Expert opinion on toxicity profiling--report from a NORMAN expert group meeting.

This article describes the outcome and follow-up discussions of an expert group meeting (Amsterdam, October 9, 2009) on the applicability of toxicity profiling for diagnostic environmental risk assessment. A toxicity profile was defined as a toxicological "fingerprint" of a sample, ranging from a pure compound to a complex mixture, obtained by testing the sample or its extract for its activity toward a battery of biological endpoints. The expert group concluded that toxicity profiling is an effective first tier tool for screening the integrated hazard of complex environmental mixtures with known and unknown toxicologically active constituents. In addition, toxicity profiles can be used for prioritization of sampling locations, for identification of hot spots, and--in combination with effect-directed analysis (EDA) or toxicity identification and evaluation (TIE) approaches--for establishing cause-effect relationships by identifying emerging pollutants responsible for the observed toxic potency. Small volume in vitro bioassays are especially applicable for these purposes, as they are relatively cheap and fast with costs comparable to chemical analyses, and the results are toxicologically more relevant and more suitable for realistic risk assessment. For regulatory acceptance in the European Union, toxicity profiling terminology should keep as close as possible to the European Water Framework Directive (WFD) terminology, and validation, standardization, statistical analyses, and other quality aspects of toxicity profiling should be further elaborated.

Microsurgical treatment of perimedullary spinal arteriovenous fistulas

Objective: Perimedullary arteriovenous fistulas (PMAVF) are exceptional spinal vascular malformations and their best therapeutic management remains controversial. Here the authors present their experience with PMAVF to characterize the clinical, neuroimaging and treatment data of patients operated on PMAVF and to analyse both incidence of complications and resurgery in the microsurgical therapy of PMAVF. Method: Fifteen patients (13 men, 2 women, mean age 51 years) with PMAVF identified by selective spinal angiography were microsurgically treated at our institution between 1992 and 2006. The presenting symptoms (duration 3 months to 5 years) were consistent with progressive myelopathy (13) or included isolated pain syndrome (2). Lumbar PMAVF location (6) was predominant followed by the sacral (5) and thoracic (4) site including 6 PMAVF of the filum terminale and 2 PMAVF associated with a glomerular AVM and dural arteriovenous fistula, respectively. Microsurgical PMAVF obliteration and postoperative angiography were routinely performed. All patients were available for follow-up evaluation within 6 months postoperatively. Results: Surgery with complete (12) or almost complete (3) PMAVF occlusion resulted in neurological improvement (10) or stabilization (1), 4 patients deteriorated postoperatively. Whereas no complications occured, a second operation because of residual or recanalized PMAVF was indicated in one case each. Two associated dual spinal vascular malformations could be observed and subsequently obliterated. Conclusions: Microsurgical occlusion of PMAVF appears to be a secure and adequate therapeutic option that prevents progressive neurological deterioration and results in good outcome in the majority of patients. Complications associated with surgery, recurrences and reoperations are infrequent. Therefore, in the authors experience microsurgery is the preferred therapy to treat PMAVF. Despite the rarity of PMAVF the possibility of the coincidence of associated second vascular malformations should be considered.

A novel comparative research platform designed to determine the functional significance of tree species diversity in European forests

One of the current advances in functional biodiversity research is the move away from short-lived test systems towards the exploration of diversity-ecosystem functioning relationships in structurally more complex ecosystems. In forests, assumptions about the functional significance of tree species diversity have only recently produced a new generation of research on ecosystem processes and services. Novel experimental designs have now replaced traditional forestry trials, but these comparatively young experimental plots suffer from specific difficulties that are mainly related to the tree size and longevity. Tree species diversity experiments therefore need to be complemented with comparative observational studies in existing forests. Here we present the design and implementation of a new network of forest plots along tree species diversity gradients in six major European forest types: the FunDivEUROPE Exploratory Platform. Based on a review of the deficiencies of existing observational approaches and of unresolved research questions and hypotheses, we discuss the fundamental criteria that shaped the design of our platform. Key features include the extent of the species diversity gradient with mixtures up to five species, strict avoidance of a dilution gradient, special attention to community evenness and minimal covariation with other environmental factors. The new European research platform permits the most comprehensive assessment of tree species diversity effects on forest ecosystem functioning to date since it offers a common set of research plots to groups of researchers from very different disciplines and uses the same methodological approach in contrasting forest types along an extensive environmental gradient. (C) 2013 Elsevier GmbH. All rights reserved.

The severity of neural invasion is associated with shortened survival in colon cancer

PURPOSE Neural invasion (NI) is a histopathologic feature of colon cancer that receives little consideration. Therefore, we conducted a morphologic and functional characterization of NI in colon cancer. EXPERIMENTAL DESIGN NI was investigated in 673 patients with colon cancer. Localization and severity of NI was determined and related to patient's prognosis and survival. The neuro-affinity of colon cancer cells (HT29, HCT-116, SW620, and DLD-1) was compared with pancreatic cancer (T3M4 and SU86.86) and rectal cancer cells (CMT-93) in the in vitro three-dimensional (3D)-neural-migration assay and analyzed via live-cell imaging. Immunoreactivity of the neuroplasticity marker GAP-43, and the neurotrophic-chemoattractant factors Artemin and nerve growth factor (NGF), was quantified in colon cancer and pancreatic cancer nerves. Dorsal root ganglia of newborn rats were exposed to supernatants of colon cancer, rectal cancer, and pancreatic cancer cells and neurite density was determined. RESULTS NI was detected in 210 of 673 patients (31.2%). Although increasing NI severity scores were associated with a significantly poorer survival, presence of NI was not an independent prognostic factor in colon cancer. In the 3D migration assay, colon cancer and rectal cancer cells showed much less neurite-targeted migration when compared with pancreatic cancer cells. Supernatants of pancreatic cancer and rectal cancer cells induced a much higher neurite density than those of colon cancer cells. Accordingly, NGF, Artemin, and GAP-43 were much more pronounced in nerves in pancreatic cancer than in colon cancer. CONCLUSION NI is not an independent prognostic factor in colon cancer. The lack of a considerable biologic affinity between colon cancer cells and neurons, the low expression profile of colonic nerves for chemoattractant molecules, and the absence of a major neuroplasticity in colon cancer may explain the low prevalence and impact of NI in colon cancer.

Die Kurzversion der NMR Skala (NMR-SF) zur Erfassung der selbsteingeschätzten Fähigkeit zur Regulation negativer Stimmungen: Überblick und Konstruktvalidierung

Die NMR-SF ist die Kurzversion der NMR Skala. Die NMR-SF misst die selbsteingeschätze Fähigkeit zur Regulation negativer Stimmungen. Das von der NMR-SF erfasste Konstrukt spielt in der Ätiologie und Psychotherapie psychischer Störungen eine wichtige Rolle. Die vorliegende Studie untersucht die Konstruktvalidität des Verfahrens in 2 nicht-klinischen und einer depressiven Stichprobe. Die NMR-SF korreliert positiv mit funktionalen Strategien zum Umgang mit negativen Stimmungen und negativ mit dysfunktionalen Strategien. Hohe Werte in der NMR-SF gehen weiterhin mit weniger psychischen Beschwerden einher. Die NMR-SF korreliert leicht positiv mit sozialer Erwünschtheit. Die Ergebnisse der aktuellen Studie unterstützen die Kon­struktvalidität der NMR-SF. Die NMR-SF stellt sich als ein psychometrisch gutes Verfahren zur Messung von NMR-Erwartungen dar. Aufgrund ihrer Ökonomie empfiehlt sich die NMR-SF für die Anwendung in klinischen Stichproben, insbesondere im Rahmen von Verlaufsmessungen.

Neonatal Fc receptor expression in dendritic cells mediates protective immunity against colorectal cancer

Cancers arising in mucosal tissues account for a disproportionately large fraction of malignancies. Immunoglobulin G (IgG) and the neonatal Fc receptor for IgG (FcRn) have an important function in the mucosal immune system that we have now shown extends to the induction of CD8(+) T cell-mediated antitumor immunity. We demonstrate that FcRn within dendritic cells (DCs) was critical for homeostatic activation of mucosal CD8(+) T cells that drove protection against the development of colorectal cancers and lung metastases. FcRn-mediated tumor protection was driven by DCs activation of endogenous tumor-reactive CD8(+) T cells via the cross-presentation of IgG complexed antigens (IgG IC), as well as the induction of cytotoxicity-promoting cytokine secretion, particularly interleukin-12, both of which were independently triggered by the FcRn-IgG IC interaction in murine and human DCs. FcRn thus has a primary role within mucosal tissues in activating local immune responses that are critical for priming efficient anti-tumor immunosurveillance.

Internetbasierte geleitete Selbsthilfeansätze bei Angststörungen und Depressionen

Das Spektrum internetbasierter psychologischer Behandlungsangebote bei psychischen Problemen und Erkrankungen bewegt sich zwischen webbasierten Selbsthilfeprogrammen, die das Internet als Informationsmedium verwenden, und Email-, Chat- und Video-Therapien, in welchen das Internet zu Kommunikationszwecken zwischen Hilfesuchenden und Professionellen genutzt wird. Dieser Beitrag fokussiert auf eine Beratungs- und Therapieform, die die Möglichkeiten des Internets als Informations- und Kommunikationsmedium in sogenannten geleiteten Selbsthilfeansätzen kombiniert. Internetbasierte geleitete Selbsthilfeansätze, in welchen Klienten während der Bearbeitung eines Selbsthilfeprogramms von Therapeuten via Internet (z.B. Email) unterstützt werden, wurden in den letzten Jahren intensiv erforscht. Im Bereich von Angststörungen und Depressionen liegen besonders viele Studien vor. Verschiedene Forschergruppen haben hier in der Regel große Behandlungseffekte gefunden, die mit der Wirkung von Face-to-Face-Therapien vergleichbar sind. In diesem Beitrag wird der geleitete Selbsthilfeansatz dargestellt und die empirische Evidenz diskutiert.

Metabolomic tissue signature in human non-alcoholic fatty liver disease identifies protective candidate metabolites

Background Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in industrialized countries, yet its pathophysiology is incompletely understood. Small-molecule metabolite screens may offer new insights into disease mechanisms and reveal new treatment targets. Methods Discovery (N = 33) and replication (N = 66) of liver biopsies spanning the range from normal liver histology to non-alcoholic steatohepatitis (NASH) were ascertained ensuring rapid freezing under 30 s in patients. 252 metabolites were assessed using GC/MS. Replicated metabolites were evaluated in a murine high-fat diet model of NAFLD. Results In a two-stage metabolic screening, hydroquinone (HQ, pcombined = 3.0 × 10−4) and nicotinic acid (NA, pcombined = 3.9 × 10−9) were inversely correlated with histological NAFLD severity. A murine high-fat diet model of NAFLD demonstrated a protective effect of these two substances against NAFLD: Supplementation with 1% HQ reduced only liver steatosis, whereas 0.6% NA reduced both liver fat content and serum transaminase levels and induced a complex regulatory network of genes linked to NALFD pathogenesis in a global expression pathway analysis. Human nutritional intake of NA equivalent was also consistent with a protective effect of NA against NASH progression. Conclusion This first small-molecular screen of human liver tissue identified two replicated protective metabolites. Either the use of NA or targeting its regulatory pathways might be explored to treat or prevent human NAFLD.