The psychological impact of dependency in adults withchronic fatigue syndrome/myalgic encephalomyelitis: A qualitative exploration

Chronic fatigue syndrome/myalgic encephalomyelitis can limit functional capacity, producing various degrees of disability and psychological distress. Semi-structured interviews explored the experiences of adults with chronic fatigue syndrome/myalgic encephalomyelitis being physically dependent on other people for help in daily life, and whether physical dependency affects their psychological well-being. Thematic analysis generated six themes: loss of independence and self-identity, an invisible illness, anxieties of today and the future, catch-22, internalised anger, and acceptance of the condition. The findings provide insight into the psychological impact of dependency. Implications for intervention include better education relating to chronic fatigue syndrome/myalgic encephalomyelitis for family members, carers, and friends; ways to communicate their needs to others who may not understand chronic fatigue syndrome/myalgic encephalomyelitis; and awareness that acceptance of the condition could improve psychological well-being

Validation of a Dutch Risk Score Predicting Poor Outcome in Adults with Bacterial Meningitis in Vietnam and Malawi

We have previously developed and validated a prognostic model to predict the risk for unfavorable outcome in Dutch adults with bacterial meningitis. The aim of the current study was to validate this model in adults with bacterial meningitis from two developing countries, Vietnam and Malawi. Demographic and clinical characteristics of Vietnamese (n = 426), Malawian patients (n = 465) differed substantially from those of Dutch patients (n = 696). The Dutch model underestimated the risk of poor outcome in both Malawi and Vietnam. The discrimination of the original model (c-statistic [c] 0.84; 95% confidence interval 0.81 to 0.86) fell considerably when re-estimated in the Vietnam cohort (c = 0.70) or in the Malawian cohort (c = 0.68). Our validation study shows that new prognostic models have to be developed for these countries in a sufficiently large series of unselected patients

Development of the preterm gut microbiome in twins at risk of necrotising enterocolitis and sepsis

The preterm gut microbiome is a complex dynamic community influenced by genetic and environmental factors and is implicated in the pathogenesis of necrotising enterocolitis (NEC) and sepsis. We aimed to explore the longitudinal development of the gut microbiome in preterm twins to determine how shared environmental and genetic factors may influence temporal changes and compared this to the expressed breast milk (EBM) microbiome. Stool samples (n = 173) from 27 infants (12 twin pairs and 1 triplet set) and EBM (n = 18) from 4 mothers were collected longitudinally. All samples underwent PCR-DGGE (denaturing gradient gel electrophoresis) analysis and a selected subset underwent 454 pyrosequencing. Stool and EBM shared a core microbiome dominated by Enterobacteriaceae, Enterococcaceae, and Staphylococcaceae. The gut microbiome showed greater similarity between siblings compared to unrelated individuals. Pyrosequencing revealed a reduction in diversity and increasing dominance of Escherichia sp. preceding NEC that was not observed in the healthy twin. Antibiotic treatment had a substantial effect on the gut microbiome, reducing Escherichia sp. and increasing other Enterobacteriaceae. This study demonstrates related preterm twins share similar gut microbiome development, even within the complex environment of neonatal intensive care. This is likely a result of shared genetic and immunomodulatory factors as well as exposure to the same maternal microbiome during birth, skin contact and exposure to EBM. Environmental factors including antibiotic exposure and feeding are additional significant determinants of community structure, regardless of host genetics

Primary skin fibroblasts as a model of Parkinson's disease

Parkinson's disease is the second most frequent neurodegenerative disorder. While most cases occur sporadic mutations in a growing number of genes including Parkin (PARK2) and PINK1 (PARK6) have been associated with the disease. Different animal models and cell models like patient skin fibroblasts and recombinant cell lines can be used as model systems for Parkinson's disease. Skin fibroblasts present a system with defined mutations and the cumulative cellular damage of the patients. PINK1 and Parkin genes show relevant expression levels in human fibroblasts and since both genes participate in stress response pathways, we believe fibroblasts advantageous in order to assess, e.g. the effect of stressors. Furthermore, since a bioenergetic deficit underlies early stage Parkinson's disease, while atrophy underlies later stages, the use of primary cells seems preferable over the use of tumor cell lines. The new option to use fibroblast-derived induced pluripotent stem cells redifferentiated into dopaminergic neurons is an additional benefit. However, the use of fibroblast has also some drawbacks. We have investigated PARK6 fibroblasts and they mirror closely the respiratory alterations, the expression profiles, the mitochondrial dynamics pathology and the vulnerability to proteasomal stress that has been documented in other model systems. Fibroblasts from patients with PARK2, PARK6, idiopathic Parkinson's disease, Alzheimer's disease, and spinocerebellar ataxia type 2 demonstrated a distinct and unique mRNA expression pattern of key genes in neurodegeneration. Thus, primary skin fibroblasts are a useful Parkinson's disease model, able to serve as a complement to animal mutants, transformed cell lines and patient tissues

Symptoms of somatization as a rapid screening tool for mitochondrial dysfunction in depression

<p>Abstract</p> <p>Aims</p> <p>Somatic symptomatology is common in depression, and is often attributed to the Freudian-inspired concept of "somatization". While the same somatic symptoms and depression are common in mitochondrial disease, in cases with concurrent mood symptoms the diagnosis of a mitochondrial disorder and related therapy are typically delayed for many years. A short screening tool that can identify patients with depression at high risk for having underlying mitochondrial dysfunction is presented.</p> <p>Methods</p> <p>Six items of the Karolinska Scales of Personality (KSP) were found to differentiate among 21 chronically-depressed Swedish subjects with low versus normal muscle ATP production rates. A screening tool consisting of the six KSP questions was validated in the relatives of American genetics clinic patients, including in 24 matrilineal relatives in families with maternally inherited mitochondrial disease and in 30 control relatives.</p> <p>Results</p> <p>Among the depressed Swedish patients, the screening tool was positive in 13/14 with low and 1/7 with normal mitochondrial function (P = 0.0003). Applied to the American relatives of patients, the screening tool was positive in 13/24 matrilineal relatives and in 1/30 control relatives (P = 2 × 10^-5).</p> <p>Conclusion</p> <p>Our preliminary data suggest that a small number of specific somatic-related questions can be constructed into a valid screening tool for cases at high risk for having a component of energy metabolism in their pathogenesis.</p

Fecal Microbiota in Premature Infants Prior to Necrotizing Enterocolitis

Intestinal luminal microbiota likely contribute to the etiology of necrotizing enterocolitis (NEC), a common disease in preterm infants. Microbiota development, a cascade of initial colonization events leading to the establishment of a diverse commensal microbiota, can now be studied in preterm infants using powerful molecular tools. Starting with the first stool and continuing until discharge, weekly stool specimens were collected prospectively from infants with gestational ages ≤32 completed weeks or birth weights≤1250 g. High throughput 16S rRNA sequencing was used to compare the diversity of microbiota and the prevalence of specific bacterial signatures in nine NEC infants and in nine matched controls. After removal of short and low quality reads we retained a total of 110,021 sequences. Microbiota composition differed in the matched samples collected 1 week but not <72 hours prior to NEC diagnosis. We detected a bloom (34% increase) of Proteobacteria and a decrease (32%) in Firmicutes in NEC cases between the 1 week and <72 hour samples. No significant change was identified in the controls. At both time points, molecular signatures were identified that were increased in NEC cases. One of the bacterial signatures detected more frequently in NEC cases (p<0.01) matched closest to γ-Proteobacteria. Although this sequence grouped to the well-studied Enterobacteriaceae family, it did not match any sequence in Genbank by more than 97%. Our observations suggest that abnormal patterns of microbiota and potentially a novel pathogen contribute to the etiology of NEC

FDG-PET/CT imaging for staging and target volume delineation in conformal radiotherapy of anal carcinoma

Background: FDG-PET/CT imaging has an emerging role in staging and treatment planning of various tumor locations and a number of literature studies show that also the carcinoma of the anal canal may benefit from this diagnostic approach. We analyzed the potential impact of FDG-PET/CT in stage definition and target volume delineation of patients affected by carcinoma of the anal canal and candidates for curative radiotherapy. Methods: Twenty seven patients with biopsy proven anal carcinoma were enrolled. Pathology was squamous cell carcinoma in 20 cases, cloacogenic carcinoma in 3, adenocarcinoma in 2, and basal cell carcinoma in 2. Simulation was performed by PET/CT imaging with patient in treatment position. Gross Tumor Volume (GTV) and Clinical Target Volume (CTV) were drawn on CT and on PET/CT fused images. PET-GTV and PET-CTV were respectively compared to CT-GTV and CT-CTV by Wilcoxon rank test for paired data. Results: PET/CT fused images led to change the stage in 5/27 cases (18.5%): 3 cases from N0 to N2 and 2 from M0 to M1 leading to change the treatment intent from curative to palliative in a case. Based on PET/CT imaging, GTV and CTV contours changed in 15/27 (55.6%) and in 10/27 cases (37.0%) respectively. PET-GTV and PET-CTV resulted significantly smaller than CT-GTV (p = 1.2 7 10-4) and CT-CTV (p = 2.9 7 10-4). PET/CT-GTV and PET/CT-CTV, that were used for clinical purposes, were significantly greater than CT-GTV (p = 6 7 10-5) and CT-CTV (p = 6 7 10-5). Conclusions: FDG-PET/CT has a potential relevant impact in staging and target volume delineation of the carcinoma of the anal canal. Clinical stage variation occurred in 18.5% of cases with change of treatment intent in 3.7%. The GTV and the CTV changed in shape and in size based on PET/CT imaging

Involvement of mTOR in CXCL12 Mediated T Cell Signaling and Migration

CXCL12 is a pleiotropic chemokine involved in multiple different processes such as immune regulation, inflammatory responses, and cancer development. CXCL12 is also a potent chemokine involved in chemoattraction of T cells to the site of infection or inflammation. Mammalian target of rapamycin (mTOR) is a serine-threonine kinase that modulates different cellular processes, such as metabolism, nutrient sensing, protein translation, and cell growth. The role of mTOR in CXCL12-mediated resting T cell migration has yet to be elucidated.Rapamycin, an inhibitor of mTOR, significantly inhibits CXCL12 mediated migration of both primary human resting T cells and human T cell leukemia cell line CEM. p70(S6K1), an effector molecule of mTOR signaling pathway, was knocked down by shRNA in CEM cells using a lentiviral gene transfer system. Using p70(S6K1) knock down cells, we demonstrate the role of mTOR signaling in T cell migration both in vitro and in vivo.Our data demonstrate a new role for mTOR in CXCL12-induced T cell migration, and enrich the current knowledge regarding the clinical use of rapamycin

Renin, endothelial no synthase and endothelin gene expression in the 2Kidney-1clip goldblatt model of long-term renovascular hypertension

<p>Abstract</p> <p>Objective</p> <p>Numerous reports have shown the influence of renin, nitric oxide (NO) and the endothelin (ET) systems for regulation of blood pressure and renal function. Furthermore, interactions between these peptides have been reported. Aim of our study was to investigate the relative contribution of these compounds in long-term renovascular hypertension/renal ischemia.</p> <p>Methods</p> <p>Hypertension/left-sided renal ischemia was induced using the 2K1C-Goldblatt rat model. Renal renin, ET-1, ET-3 and endothelial NO synthase (eNOS) gene expression was measured by means of RNAse protection assay at different timepoints up to 10 weeks after induction of renal artery stenosis.</p> <p>Results</p> <p>Plasma renin activity and renal renin gene expression in the left kidney were increased in the clipped animals while eNOS expression was unchanged. Furthermore, an increase in ET-1 expression and a decrease of ET-3 expression was detected in early stenosis.</p> <p>Conclusions</p> <p>While renin is obviously involved in regulation of blood pressure and renal function in unilateral renal artery stenosis, ET-1, ET-3 and endothelium derived NO do not appear to play an important role in renal adaptation processes in long-term renal artery stenosis, although ET-1 and ET-3 might be involved in short-term adaptation processes.</p