Medically unexplained symptoms and between-group differences in 24-h ambulatory recording of stress physiology

People with medically unexplained symptoms (MUS) often have a comorbid history of stress and negative affect. Although the verbal-cognitive and (peripheral) physiological stress systems have shown a great degree of independence, at the same time it is claimed that chronic stress and negative affect can result in a disregulated physiological stress system, which may lead to MUS. Previous studies could not demonstrate a straightforward between subject relationship between MUS and stress physiology, supporting the view of independence. The aim of the current study was to further explore this relationship using an improved methodology based on ecologically valid 24-h real-life ambulatory recordings. Seventy-four participants (19 male; 55 female) with heterogeneous MUS were compared with 71 healthy controls (26 male; 45 females). Momentary experienced somatic complaints and mood, heart rate, cardiac autonomic activity, respiration and saliva cortisol were monitored using electronic diary and ambulatory registration devices. Participants with MUS reported much more momentary complaints and negative affect as compared to controls. Although MUS seemed to be associated with elevated heart rate and reduced low and very-low frequency heart period variability, these effects disappeared after controlling for differences in sports behaviour. No group differences were found for cardiac autonomic activity, respiration, end-tidal CO(2) and saliva cortisol. Our 24-h real-life ambulatory study did not support the existence of a connection between MUS and disregulated peripheral stress physiology. Future studies may instead focus on central measures to reveal potential abnormalities such as deviant central processing of visceral signals in MUS patients.     

Environmental determinants of atopic eczema phenotypes in relation to asthma and atopic sensitization

BACKGROUND: There is still uncertainty about the determinants of atopic eczema (AE). To explain the heterogeneity of the disease, different phenotypes of AE have been suggested. METHODS: The cross-sectional PARSIFAL study included 14 893 school-age children of farmers or children attending Steiner schools and their respective reference groups. A detailed questionnaire was completed, and house dust was collected for the measurement of endotoxin and glucans. Atopic sensitization was defined by allergen-specific IgE levels in the serum. RESULTS: In multivariate analyses, helping with haying was the only variable related to a farming environment having a consistent inverse association with both current symptoms and a doctor's diagnosis of AE [aOR = 0.65 (95% CI: 0.46-0.93) and 0.73 (0.51-1.05)], respectively. Severe lower respiratory tract infections (LRTI) in the first 2 years of life and usage of antibiotics ever were found to be positively related only to asthma-associated AE, whereas the effect of LRTI on AE without asthma had an opposite effect. Levels of beta(1-->3)-glucans in mattress dust were inversely related to a doctor's diagnosis of asthma-associated AE [aOR = 0.75 (0.57-0.98)], and endotoxin levels to current symptoms of asthma-associated AE [aOR = 0.73 (0.57-0.94)]. CONCLUSIONS: The analyses of the PARSIFAL study revealed two different phenotypes of AE, depending on the association with asthma and wheezing ever. With regard to the hygiene hypothesis, help with haying, exposure to beta(1-->3)-glucans and endotoxin were found to be inversely associated with the AE phenotype associated with asthma and wheezing.     

Feasibility and induced cognitive-emotional change of an emotional disclosure intervention adapted for home application

OBJECTIVE: Emotional engagement, cognitive restructuring, and positive future directedness are considered core elements to induce change in emotional disclosure interventions. Our aim was to examine the induction of these elements and the feasibility of an emotional disclosure intervention adapted for home application. METHODS: The intervention emphasized expression of negative and positive emotions (session 1-4), search for meaning (session 3), and a positive future-oriented ending (session 4). A randomized clinical trial in patients with rheumatoid arthritis compared the adapted intervention (n=40) with a time management control condition (n=28). Feasibility was evaluated regarding adherence, compliance with instructions, perceived viability, and clinical safety. Induction of core elements was evaluated by analysis of change in immediate affective responses and by computerized text analysis of word use. RESULTS: Feasibility criteria were successfully met. The disclosure condition produced higher immediate negative affect and use of emotion, insight, and optimism words compared to control, and induced the elements of change within sessions as intended. CONCLUSION: The adapted intervention is feasible for home application and induces change in variables that indicate emotional engagement, cognitive restructuring, and positive future directedness. PRACTICE IMPLICATIONS: Empirical support of health benefits of this emotional disclosure intervention will extend its applicability in patient self-care.     

Exacerbated pathology of viral encephalitis in mice with central nervous system-specific autoantibodies

We examine here the outcome of viral encephalomyelitis [mouse hepatitis virus (MHV) A59, Theiler's encephalomyelitis virus, and Coxsackievirus B3] in mice with autoantibodies to a central nervous system (CNS)-specific antigen, myelin oligodendrocyte glycoprotein, that usually develop no clinical disease. Morbidity and mortality of the acute viral CNS disease was augmented by the presence of the autoantibodies in all three viral infections. Transfer of serum containing the autoantibodies at the time of infection with MHV was sufficient to reproduce the exacerbated disease. The presence of the autoantibodies was found to result in increased infiltration of mononuclear cells into the brain. Early demyelination was severely augmented in brains and spinal cords of MHV-infected mice with CNS-specific autoantibodies. The antibody-mediated exacerbation was shown to be independent of the complement system but to require expression of Fc receptors, because it was observed in C'-3-deficient but not in Fc receptor-deficient mice. Our study illustrates the possibility that infections can lead to much more profound immunopathology in the presence of an otherwise latent autoimmune condition.     

Performance of the Sebia CAPILLARYS 2 for detection and immunotyping of serum monoclonal paraproteins

We evaluated the performance of the CAPILLARYS 2 (Sebia, Norcross, GA) capillary electrophoresis system for detection and identification of monoclonal proteins in serum samples. We analyzed 104 serum specimens by Sebia Hydragel serum protein electrophoresis (agarose gel electrophoresis [AGE]/immunofixation electrophoresis [IFE]) and CAPILLARYS 2 capillary zone electrophoresis (CZE)/immunosubtraction. AGE and CZE had sensitivities of 90% and 81%, respectively, based on IFE as the "gold standard," and all bands detected were confirmed by IFE (100% specificity). AGE and CZE had an overall agreement of 91% on serum protein electrophoresis. In the population tested, IgG was detected in 29% of samples by IFE and 30% using immunosubtraction. Similarly IgA was detected in 9% of cases by IFE and 8% by immunosubtraction. IgM and light chains were detected in 6% and 3% of cases, respectively, by IFE, whereas CZE/immunosubtraction did not detect any IgM or light chains. In our hands, AGE and CZE had the same specificity for detection of monoclonal proteins; however, CZE/immunosubtraction seems to be less sensitive than IFE for the detection of IgM and, possibly, serum light chains.     

SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome

Background

Heterozygous gain‐of‐function mutations in various genes encoding proteins of the Ras‐MAPK signalling cascade have been identified as the genetic basis of Noonan syndrome (NS) and cardio‐facio‐cutaneous syndrome (CFCS). Mutations of SOS1, the gene encoding a guanine nucleotide exchange factor for Ras, have been the most recent discoveries in patients with NS, but this gene has not been studied in patients with CFCS.

Methods and results

We investigated SOS1 in a large cohort of patients with disorders of the NS–CFCS spectrum, who had previously tested negative for mutations in PTPN11, KRAS, BRAF, MEK1 and MEK2. Missense mutations of SOS1 were discovered in 28% of patients with NS. In contrast, none of the patients classified as having CFCS was found to carry a pathogenic sequence change in this gene.

Conclusion

We have confirmed SOS1 as the second major gene for NS. Patients carrying mutations in this gene have a distinctive phenotype with frequent ectodermal anomalies such as keratosis pilaris and curly hair. However, the clinical picture associated with SOS1 mutations is different from that of CFCS. These findings corroborate that, despite being caused by gain‐of‐function mutations in molecules belonging to the same pathway, NS and CFCS scarcely overlap genotypically.     

Chronic colitis due to an epithelial barrier defect: the role of kindlin-1 isoforms

Kindlin-1 is an epithelium-specific phosphoprotein and focal adhesion adaptor component. Mutations in the corresponding gene (KIND1) cause Kindler syndrome (KS), which is manifested by skin blistering, poikiloderma, photosensitivity and carcinogenesis. Some patients also exhibit gastrointestinal symptoms, but it has remained unclear whether these represent a feature of Kindler syndrome or a coincidence. We examined kindlin-1 in human gastrointestinal epithelia and showed that it is involved in the aetiopathology of Kindler syndrome-associated colitis. Kindlin-1 expression was assessed by indirect immunofluorescence, western blot and RT-PCR. Kindlin-1 is expressed in oral mucosa, colon and rectum. Both the full-length 74 kDa kindlin-1 protein and a 43 kDa isoform were detected in CaCo2 cells, the latter resulting from alternative splicing. In the first months of life, patients (homozygous for null mutations) had severe intestinal involvement with haemorrhagic diarrhoea and showed morphological features of severe ulcerative colitis. Later in childhood, histopathology demonstrated focal detachment of the epithelium in all segments of the colon, chronic inflammation and mucosal atrophy. These findings define an intestinal phenotype for Kindler syndrome as a consequence of a primary epithelial barrier defect. The different clinical intestinal manifestations in Kindler syndrome patients may be explained by partial functional compensation of kindlin-1 deficiency by the intestinal isoform or by the presence of truncated mutant kindlin-1.     

An oncogenetic tree model in gastrointestinal stromal tumours (GISTs) identifies different pathways of cytogenetic evolution with prognostic implications

To model the cytogenetic evolution in gastrointestinal stromal tumour (GIST), an oncogenetic tree model was reconstructed using comparative genomic hybridization data from 203 primary GISTs (116 gastric and 87 intestinal GISTs, including 151 newly analysed cases), with follow-up available in 173 cases (mean 40 months; maximum 133 months). The oncogenetic tree model identified three major cytogenetic pathways: one initiated by -14q, one by -1p, and another by -22q. The -14q pathway mainly characterized gastric tumours with predominantly stable karyotypes and more favourable clinical course. On the other hand, the -1p pathway was more characteristic of intestinal GISTs, with an increased capacity for cytogenetic complexity and more aggressive clinical course. Loss of 22q, more closely associated with -1p than -14q, appeared to initiate the critical transition to an unfavourable cytogenetic subpathway. This -22q pathway included accumulation of +8q, -9p, and -9q, which could all predict disease-free survival in addition to tumour site. Thus, insights into the cytogenetic evolution obtained from oncogenetic tree models may eventually help to gain a better understanding of the heterogeneous site-dependent biological behaviour of GISTs.     

High-resolution CT by diffraction-enhanced x-ray imaging: mapping of breast tissue samples and comparison with their histo-pathology

The aim of this study was to introduce high-resolution computed tomography (CT) of breast tumours using the diffraction-enhanced x-ray imaging (DEI) technique and to compare results with radiological and histo-pathological examinations. X-ray CT images of tumour-bearing breast tissue samples were acquired by monochromatic synchrotron radiation (SR). Due to the narrow beam and a large sample-to-detector distance scattering is rejected in the absorption contrast images (SR-CT). Large contrast enhancement is achieved by the use of the DEI-CT method, where the effects of refraction and scatter rejection are analysed by crystal optics. Clinical mammograms and CT images were recorded as reference material for a radiological examination. Three malignant and benign samples were studied in detail. Their radiographs were compared with optical images of stained histological sections. The DEI-CT images map accurately the morphology of the samples, including collagen strands and micro-calcifications of dimensions less than 0.1 mm. Histo-pathological examination and reading of the radiographs were done independently, and the conclusions were in general agreement. High-resolution DEI-CT images show strong contrast and permit visualization of details invisible in clinical radiographs. The radiation dose may be reduced by an order of magnitude without compromising image quality, which would make possible clinical in vivo DEI-CT with future compact SR sources.