Reasoning in psychosis: risky but not necessarily hasty

Introduction. A liberal acceptance (LA) threshold for hypotheses has been put forward to explain the well-replicated “jumping to conclusions” (JTC) bias in psychosis, particularly in patients with paranoid symptoms. According to this account, schizophrenia patients rest their decisions on lower subjective probability estimates. The initial formulation of the LA account also predicts an absence of the JTC bias under high task ambiguity (i.e., if more than one response option surpasses the subjective acceptance threshold).

Methods. Schizophrenia patients (n?=?62) with current or former delusions and healthy controls (n?=?30) were compared on six scenarios of a variant of the beads task paradigm. Decision-making was assessed under low and high task ambiguity. Along with decision judgments (optional), participants were required to provide probability estimates for each option in order to determine decision thresholds (i.e., the probability the individual deems sufficient for a decision).

Results. In line with the LA account, schizophrenia patients showed a lowered decision threshold compared to controls (82% vs. 93%) which predicted both more errors and less draws to decisions. Group differences on thresholds were comparable across conditions. At the same time, patients did not show hasty decision-making, reflecting overall lowered probability estimates in patients.

Conclusions. Results confirm core predictions derived from the LA account. Our results may (partly) explain why hasty decision-making is sometimes aggravated and sometimes abolished in psychosis. The proneness to make risky decisions may contribute to the pathogenesis of psychosis. A revised LA account is put forward.     

c-Fos-dependent induction of the small ras-related GTPase Rab11a in skin carcinogenesis

Malignant transformation of mouse skin by tumor promoters and chemical carcinogens, such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), is a multistage process leading to the formation of squamous cell carcinomas. It has been shown that mice lacking the AP-1 family member c-Fos exhibit an impaired transition from benign to malignant skin tumors. Here, we demonstrate enhanced expression of the small Ras-related GTPase Rab11a after short-term TPA treatment of mouse back skin. Expression of Rab11a in vivo and in vitro critically depended on c-Fos, because TPA application to the back skin of c-Fos-deficient mice and to mouse embryonic fibroblasts did not induce Rab11a mRNA or protein expression. Moreover, dexamethasone, which is a potent inhibitor of AP-1-mediated transactivation that exhibits anti-inflammatory and anti-tumor promoting activities, inhibited TPA-induced expression of Rab11a. Within the Rab11a gene promoter, we identified a functional AP-1 binding element that exhibited elevated c-Fos binding activity after TPA treatment of keratinocytes. Enhanced expression was not restricted to chemically induced mouse skin tumors but was also found in tumor specimens derived from patients with epithelial skin tumors. These data identify Rab11a as a novel, tumor-associated c-Fos/AP-1 target and may point to an as yet unrecognized function of Rab11a in the development of skin cancer.     

Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling

TLR are primary triggers of the innate immune system by recognizing various microorganisms through conserved pathogen-associated molecular patterns. TLR2 is the receptor for a functional recognition of bacterial lipopeptides (LP) and is up-regulated during various disorders such as chronic obstructive pulmonary disease and sepsis. This receptor is unique in its ability to form heteromers with TLR1 or TLR6 to mediate intracellular signaling. According to the fatty acid pattern as well as the assembling of the polypeptide tail, LP can signal through TLR2 in a TLR1- or TLR6-dependent manner. There are also di- and triacylated LP, which stimulate TLR1-deficient cells and TLR6-deficient cells. In this study, we investigated whether heterodimerization evolutionarily developed to broaden the ligand spectrum or to induce different immune responses. We analyzed the signal transduction pathways activated through the different TLR2 dimers using the three LP, palmitic acid (Pam)octanoic acid (Oct)(2)C-(VPGVG)(4)VPGKG, fibroblast-stimulating LP-1, and Pam(2)C-SK(4). Dominant-negative forms of signaling molecules, immunoblotting of MAPK, as well as microarray analysis indicate that all dimers use the same signaling cascade, leading to an identical pattern of gene activation. We conclude that heterodimerization of TLR2 with TLR1 or TLR6 evolutionarily developed to expand the ligand spectrum to enable the innate immune system to recognize the numerous, different structures of LP present in various pathogens. Thus, although mycoplasma and Gram-positive and Gram-negative bacteria may activate different TLR2 dimers, the development of different signal pathways in response to different LP does not seem to be of vital significance for the innate defense system.     

ESI-MS/MS measurement of free carnitine and its precursor γ-butyrobetaine in plasma and dried blood spots from patients with organic acidurias and fatty acid oxidation disorders

BackgroundIn patients with fatty acid oxidation disorders (FAODs) and organic acidurias (OAs) “secondary carnitine deficiency” occurs. In OAs carnitine supplementation is widely performed and dose is often adjusted to blood-free carnitine levels. Dried blood spots (DBS) are mostly used to measure carnitine status, however measurements in plasma are discussed to be more accurate. The concentration and the predictive value of the carnitine precursor γ-butyrobetaine in blood during carnitine deficiency are unknown.MethodsFree carnitine and γ-butyrobetaine were quantified by tandem mass spectrometry in plasma and DBS from supplemented patients with OAs (n = 18) and unsupplemented patients with FAODs (n = 66) and were compared with healthy controls (n = 50).ResultsCarnitine concentrations in plasma were significantly higher than in DBS. In contrast, γ-butyrobetaine concentrations in plasma were significantly lower than in DBS. Supplemented patients had high free carnitine concentrations in combination with high γ-butyrobetaine concentrations. Unsupplemented carnitine palmitoyltransferase I-deficient patients had exceptionally high free carnitine concentrations without elevated γ-butyrobetaine, however, carnitine in plasma was much lower than in DBS. In patients with low carnitine, γ-butyrobetaine in plasma is no evidence of induced carnitine biosynthesis.ConclusionsParallel measurements in plasma and DBS demonstrated that numerous patients with low values in DBS had normal values when measured in plasma, suggesting plasma to be the more appropriate medium to use for carnitine status monitoring. In contrast, diagnosis of CPT-I deficiency may be missed when analysis is performed in plasma. Carnitine supplementation presumably inhibits γ-butyrobetaine dioxygenase and results in high γ-butyrobetaine.     

Polymorphonuclear leucocytes selectively produce anti-inflammatory interleukin-1 receptor antagonist and chemokines, but fail to produce pro-inflammatory mediators

The role of neutrophils in the immune response has long been regarded as mainly phagocytic, but recent publications have indicated the production of several cytokines by polymorphonuclear leucocytes (PMN). The results of the individual reports, however, vary considerably. In this study, we established a cytokine profile of pure human neutrophils and demonstrated that minor contamination of peripheral blood mononuclear cells (PBMCs) in PMN preparations can lead to false-positive results. In our hands, peripheral blood PMN fail to produce the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha). Instead, they secrete large amounts of the chemokine IL-8 and the anti-inflammatory IL-1 receptor antagonist (IL-1ra). Additionally, PMN preparations of a high purity show production of the chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and growth-related oncogene-alpha (GRO-alpha), as well as macrophage colony-stimulating factor (M-CSF). The neutrophil therefore represents a novelty by producing the antagonist of IL-1beta (i.e. IL-1ra) in the absence of IL-1beta itself. To support our results, we differentiated stem cells from human cord blood into PMN and monocytes, respectively. These in vitro-differentiated PMN showed the same cytokine profile as peripheral blood PMN lacking IL-1beta, while differentiated monocytes produced the expected IL-1beta in addition to IL-1ra. The clear anti-inflammatory nature of their cytokine profile enables PMN to antagonize pro-inflammatory signals in experimental conditions. It is therefore possible that PMN play a key role in immune regulation by counteracting a dysregulation of the inflammatory process. Clinical studies, in which administration of recombinant G-CSF had a favourable effect on the outcome of severe infections and even sepsis without worsening inflammation, could thus be explained by our results.     

Acute fulminant myocarditis in children and adolescents: the role of mechanical circulatory assist

We report children and adolescents in fulminant myocarditis undergoing prolonged circulatory support with different assist devices. Between 1994 and 2004, seven children and adolescents (aged 7-18 years, mean age 13.5 years) were treated with VADs (5 Thoratec, 1 Medos, 1 Novacor) for circulatory support. Three patients underwent left ventricular support; biventricular support was necessary in four patients. Four patients (three left VADs, one bi-VAD) could be successfully bridged to heart transplantation after a mean support time of 163 days (56-258 days). One 7-year-old girl (Medos-BVAD) died after a support time of 11 days because of irreversible multiorgan failure. One 18-year-old patient was successfully weaned from Thoratec BVAD after 66 days with complete recovery of left ventricular function. As good markers, atrial and brain natriuretic peptides were found which reached normal values after recovery of myocardial function. A 15-year-old girl is still on the device. In children or adolescents with irreversible shock in fulminant myocarditis with an anticipated mortality of 100%, both successful bridging to heart transplantation and successful bridging to recovery are possible. Young patients with fulminant myocarditis should be rapidly transferred to a clinic with a mechanical circulatory support program to offer this life-saving option.     

Google Glass for Documentation of Medical Findings: Evaluation in Forensic Medicine

Background

Google Glass is a promising premarket device that includes an optical head-mounted display. Several proof of concept reports exist, but there is little scientific evidence regarding its use in a medical setting.

Objective

The objective of this study was to empirically determine the feasibility of deploying Glass in a forensics setting.

Methods

Glass was used in combination with a self-developed app that allowed for hands-free operation during autopsy and postmortem examinations of 4 decedents performed by 2 physicians. A digital single-lens reflex (DSLR) camera was used for image comparison. In addition, 6 forensic examiners (3 male, 3 female; age range 23-48 years, age mean 32.8 years, SD 9.6; mean work experience 6.2 years, SD 8.5) were asked to evaluate 159 images for image quality on a 5-point Likert scale, specifically color discrimination, brightness, sharpness, and their satisfaction with the acquired region of interest. Statistical evaluations were performed to determine how Glass compares with conventionally acquired digital images.

Results

All images received good (median 4) and very good ratings (median 5) for all 4 categories. Autopsy images taken by Glass (n=32) received significantly lower ratings than those acquired by DSLR camera (n=17) (region of interest: z=–5.154, P<.001; sharpness: z=–7.898, P<.001; color: z=–4.407, P<.001, brightness: z=–3.187, P=.001). For 110 images of postmortem examinations (Glass: n=54, DSLR camera: n=56), ratings for region of interest (z=–8.390, P<.001) and brightness (z=–540, P=.007) were significantly lower. For interrater reliability, intraclass correlation (ICC) values were good for autopsy (ICC=.723, 95% CI .667-.771, P<.001) and postmortem examination (ICC=.758, 95% CI .727-.787, P<.001). Postmortem examinations performed using Glass took 42.6 seconds longer than those done with the DSLR camera (z=–2.100, P=.04 using Wilcoxon signed rank test). The battery charge of Glass quickly decreased; an average 5.5% (SD 1.85) of its battery capacity was spent per postmortem examination (0.81% per minute or 0.79% per picture).

Conclusions

Glass was efficient for acquiring images for documentation in forensic medicine, but the image quality was inferior compared to a DSLR camera. Images taken with Glass received significantly lower ratings for all 4 categories in an autopsy setting and for region of interest and brightness in postmortem examination. The effort necessary for achieving the objectives was higher when using the device compared to the DSLR camera thus extending the postmortem examination duration. Its relative high power consumption and low battery capacity is also a disadvantage. At the current stage of development, Glass may be an adequate tool for education. For deployment in clinical care, issues such as hygiene, data protection, and privacy need to be addressed and are currently limiting chances for professional use.