Depression,Anxiety and Quality of Life in Long-Term Survivors of Malignant Melanoma: A Register-Based Cohort Study

Aim

The purpose of the study was to determine anxiety and depression, quality of life, and their determinants in long-term survivors of malignant melanoma.

Methods

In a state cancer registry a cohort of survivors of malignant melanoma was contacted via the physician registered. Of 1302 contactable patients, 689 (52.2%) completed a questionnaire including the Patient Health Questionnaire with generalized anxiety (GAD-7) and depression (PHQ-9) and the EORTC Quality of Life Questionnaire (EORTC QLQ 30). Based on multiple regression analysis, predictors of quality of life and distress were identified. Comparison data were assessed in two waves of representative face-to-face household surveys of the adult German population.

Results

An average of 8.4 (5.7 to 12.2) years after diagnosis, distress was higher in women compared to men and in middle adulthood (vs. older patients). Symptoms were higher in women than in men, and there was a decline of functioning and increase of symptoms across the age range of both genders. Compared to the general population, there were slightly increased depression and anxiety (only women), but no impaired global quality of life. Yet, survivors evidenced functional decline and more physical symptoms. Distress and reduced quality of life were consistently predicted by lack of social support, fear of recurrence, pessimism and self-blame. Distress was increased by a family history of melanoma, and additional mental and somatic diseases.

Conclusion

Overall, long-term survivors have adjusted well achieving a global quality of life comparable to the general population. Yet, compromised functional dimensions, physical symptoms and distress indicate the need for integrating psychooncological screening into oncological follow-up, which might be guided by predictors such as family history or social support. Further prospective study is needed to determine the course of adaptation to the disease and corroborate the risk factors identified.     

High-Throughput Assay Development for Cystine-Glutamate Antiporter (xc -) Highlights Faster Cystine Uptake than Glutamate Release in Glioma Cells

The cystine-glutamate antiporter (system x_c ^-) is a Na⁺-independent amino acid transporter that exchanges extracellular cystine for intracellular glutamate. It is thought to play a critical role in cellular redox processes through regulation of intracellular glutathione synthesis via cystine uptake. In gliomas, system x_c ^- expression is universally up-regulated while that of glutamate transporters down-regulated, leading to a progressive accumulation of extracellular glutamate and excitotoxic cell death of the surrounding non-tumorous tissue. Additionally, up-regulation of system x_c ^- in activated microglia has been implicated in the pathogenesis of several neurodegenerative disorders mediated by excess glutamate. Consequently, system x_c ^- is a new drug target for brain cancer and neuroinflammatory diseases associated with excess extracellular glutamate. Unfortunately no potent and selective small molecule system x_c ^- inhibitors exist and to our knowledge, no high throughput screening (HTS) assay has been developed to identify new scaffolds for inhibitor design. To develop such an assay, various neuronal and non-neuronal human cells were evaluated as sources of system x_c ^-. Human glioma cells were chosen based on their high system x_c ^- activity. Using these cells, [¹⁴C]-cystine uptake and cystine-induced glutamate release assays were characterized and optimized with respect to cystine and protein concentrations and time of incubation. A pilot screen of the LOPAC/NINDS libraries using glutamate release demonstrated that the logistics of the assay were in place but unfortunately, did not yield meaningful pharmacophores. A larger, HTS campaign using the 384-well cystine-induced glutamate release as primary assay and the 96-well ¹⁴C-cystine uptake as confirmatory assay is currently underway. Unexpectedly, we observed that the rate of cystine uptake was significantly faster than the rate of glutamate release in human glioma cells. This was in contrast to the same rates of cystine uptake and glutamate release previously reported in normal human fibroblast cells.     

Cerebrospinal Fluid from Patients with Subarachnoid Haemorrhage and Vasospasm Enhances Endothelin Contraction in Rat Cerebral Arteries

Introduction

Previous studies have suggested that cerebrospinal fluid from patients with subarachnoid hemorrhage (SAH) leads to pronounced vasoconstriction in isolated arteries. We hypothesized that only cerebrospinal fluid from SAH patients with vasospasm would produce an enhanced contractile response to endothelin-1 in rat cerebral arteries, involving both endothelin ET_A and ET_B receptors.

Methods

Intact rat basilar arteries were incubated for 24 hours with cerebrospinal fluid from 1) SAH patients with vasospasm, 2) SAH patients without vasospasm, and 3) control patients. Arterial segments with and without endothelium were mounted in myographs and concentration-response curves for endothelin-1 were constructed in the absence and presence of selective and combined ET_A and ET_B receptor antagonists. Endothelin concentrations in culture medium and receptor expression were measured.

Results

Compared to the other groups, the following was observed in arteries exposed to cerebrospinal fluid from patients with vasospasm: 1) larger contractions at lower endothelin concentrations (p<0.05); 2) the increased endothelin contraction was absent in arteries without endothelium; 3) higher levels of endothelin secretion in the culture medium (p<0.05); 4) there was expression of ET_A receptors and new expression of ET_B receptors was apparent; 5) reduction in the enhanced response to endothelin after ET_B blockade in the low range and after ET_A blockade in the high range of endothelin concentrations; 6) after combined ET_A and ET_B blockade a complete inhibition of endothelin contraction was observed.

Conclusions

Our experimental findings showed that in intact rat basilar arteries exposed to cerebrospinal fluid from patients with vasospasm endothelin contraction was enhanced in an endothelium-dependent manner and was blocked by combined ET_A and ET_B receptor antagonism. Therefore we suggest that combined blockade of both receptors may play a role in counteracting vasospasm in patients with SAH.     

Cladribine Exposure Results in a Sustained Modulation of the Cytokine Response in Human Peripheral Blood Mononuclear Cells

Background and Objectives

Cladribine is a cytotoxic drug which ameliorates the clinical course of relapsing-remitting multiple sclerosis. In addition to cytotoxicity, the mode of action may include immunomodulatory mechanisms. This in vitro study was designed to investigate cladribine’s effects on cell function after the removal of cladribine to distinguish cytotoxic versus immunomodulatory effects.

Methods

Cells were incubated in the absence or presence of cladribine (1×10^-8 M to 1×10^-5 M) for 72 h. Cladribine was removed from the cell culture and surviving peripheral blood mononuclear cells were cultured up to 58 days to determine the immunomodulatory effects of cladribine on cell function (e.g., proliferation and cytokine release).

Results

In the long-term, brief cladribine exposure did not impair the proliferation of surviving peripheral blood mononuclear cells. However, it induced an anti-inflammatory shift in the cytokine milieu with significantly enhanced release of IL-4 (Days 9 and 44, p<0.01; Day 58, p<0.05) and IL-5 (Day 9, p<0.01), resulting in an increased IL-4/INF-gamma ratio (Days 9 and 44, p<0.01; Day 58, p<0.05). Additionally, a trend towards an increased IL-10 production was observed. No changes were found in the production of IFN-gamma, TNF-alpha, IL-6, IL-8, IL-17A, IL-23 or NGF-beta.

Conclusions

In vitro cladribine exposure induces a sustained anti-inflammatory shift in the cytokine profile of surviving peripheral blood mononuclear cells. This immunomodulatory action might contribute to cladribine’s beneficial effects in the treatment of multiple sclerosis.     

Persistent High IgG Phase I Antibody Levels against Coxiella burnetii among Veterinarians Compared to Patients Previously Diagnosed with Acute Q Fever after Three Years of Follow-Up

Background

Little is known about the development of chronic Q fever in occupational risk groups. The aim of this study was to perform long-term follow-up of Coxiella burnetii seropositive veterinarians and investigate the course of IgG phase I and phase II antibodies against C. burnetii antigens and to compare this course with that in patients previously diagnosed with acute Q fever.

Methods

Veterinarians with IgG phase I ≥1:256 (immunofluorescence assay) that participated in a previous seroprevalence study were asked to provide a second blood sample three years later. IgG antibody profiles were compared to a group of acute Q fever patients who had IgG phase I ≥1:256 twelve months after diagnosis.

Results

IgG phase I was detected in all veterinarians (n = 76) and in 85% of Q fever patients (n = 98) after three years (p<0.001). IgG phase I ≥1:1,024, indicating possible chronic Q fever, was found in 36% of veterinarians and 12% of patients (OR 3.95, 95% CI: 1.84–8.49).

Conclusions

IgG phase I persists among veterinarians presumably because of continuous exposure to C. burnetii during their work. Serological and clinical follow-up of occupationally exposed risk groups should be considered.     

Membrane Cholesterol Modulates LOX-1 Shedding in Endothelial Cells

The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor responsible for ox-LDL recognition, binding and internalization, which is up-regulated during atherogenesis. Its activation triggers endothelium dysfunction and induces inflammation. A soluble form of LOX-1 has been identified in the human blood and its presence considered a biomarker of cardiovascular diseases. We recently showed that cholesterol-lowering drugs inhibit ox-LDL binding and internalization, rescuing the ox-LDL induced apoptotic phenotype in primary endothelial cells. Here we have investigated the molecular bases of human LOX-1 shedding by metalloproteinases and the role of cell membrane cholesterol on the regulation of this event by modulating its level with MβCD and statins. We report that membrane cholesterol affects the release of different forms of LOX-1 in cells transiently and stably expressing human LOX-1 and in a human endothelial cell line (EA.hy926). In particular, our data show that i) cholesterol depletion triggers the release of LOX-1 in exosomes as a full-length transmembrane isoform and as a truncated ectodomain soluble fragment (sLOX-1); ii) endothelial cells secrete a soluble metalloproteinase which induces LOX-1 ectodomain shedding and iii) long term statins treatment enhances sLOX-1 proteolytic shedding.     

Substance P and Chronic Pain in Patients with Chronic Inflammation of Connective Tissue

Objective

Evidence suggests that substance P (SP) is involved in chronic joint inflammation, such as the pathogenesis of rheumatoid arthritis and osteoarthritis. The goal of the research was to evaluate the correlation between chronic pain and changes in the SP level in patients with chronic inflammation of the connective tissue.

Methods

Patients with osteoarthritis and rheumatoid arthritis were enrolled in this study. The relationship between chronic pain intensity and the serum SP concentration was evaluated in these groups of patients with osteoarthritis and rheumatoid arthritis.

Results

The results showed a positive correlation between the serum SP concentrations and chronic pain intensity.

Conclusions

1. The SP serum concentration was significantly different between the groups of patients with OA and RA. 2. There was a positive correlation between the serum SP concentration and chronic pain intensity in OA and RA patients.     

Cognitive Functions in Elite and Sub-Elite Youth Soccer Players Aged 13 to 17 Years

Soccer players are required to anticipate and react continuously in a changing, relatively unpredictable situation in the field. Cognitive functions might be important to be successful in soccer. The current study investigated the relationship between cognitive functions and performance level in elite and sub-elite youth soccer players aged 13–17 years. A total of 47 elite youth soccer players (mean age 15.5 years, SD = 0.9) and 41 sub-elite youth soccer players (mean age 15.2 years, SD = 1.2) performed tasks for “higher-level” cognitive functions measuring working memory (i.e., Visual Memory Span), inhibitory control (i.e., Stop-Signal Task), cognitive flexibility (i.e., Trail Making Test), and metacognition (i.e., Delis-Kaplan Executive Function System Design Fluency Test). “Lower-level” cognitive processes, i.e., reaction time and visuo-perceptual abilities, were also measured with the previous tasks. ANOVA’s showed that elite players outscored sub-elite players at the “higher-level” cognitive tasks only, especially on metacognition (p < .05). Using stepwise discriminant analysis, 62.5% of subjects was correctly assigned to one of the groups based on their metacognition, inhibitory control and cognitive flexibility performance. Controlling for training hours and academic level, MANCOVA’s showed differences in favor of the elite youth soccer players on inhibitory control (p = .001), and cognitive flexibility (p = .042), but not on metacognition (p = .27). No differences were found concerning working memory nor the “lower-level” cognitive processes (p > .05). In conclusion, elite youth soccer players have better inhibitory control, cognitive flexibility, and especially metacognition than their sub-elite counterparts. However, when training hours are taken into account, differences between elite and sub-elite youth soccer players remain apparent on inhibitory control and cognitive flexibility in contrast to metacognition. This highlights the need for longitudinal studies to further investigate the importance of “higher-level” cognitive functions for talent identification, talent development and performance in soccer.     

VGF Peptide Profiles in Type 2 Diabetic Patients’ Plasma and in Obese Mice

To address the possible involvement of VGF peptides in obesity and diabetes, we studied type 2 diabetes (T2D) and obese patients, and high-fat diet induced obese mice. Two VGF peptides (NAPP-19 and QQET-30) were identified in human plasma by HPLC-ESI-MS. The VGF C-terminus, the above two cleaved peptides, and the TLQP-21 related peptide/s were studied using ELISA and immunohistochemistry. In euglycemic patients, plasma NAPPE and TLQP like peptides were significantly reduced with obesity (74±10 vs. 167±28, and 92±10 vs. 191±19 pmol/ml, mean+SEM, n = 10 and 6, obese vs. normal BMI, respectively, p<0.03). Upon a standard glucose load, a distinct response was shown for VGF C-terminus, TLQP and QQET-like (ERVW immunoreactive) peptides in euglycemic normal BMI patients, but was virtually abolished in euglycemic obese, and in T2D patients independently of BMI. High-fat diet induced obese mice showed reduced plasma VGF C-terminus, NAPPE and QQET-like (ERVW) peptide/s (3±0.2 vs. 4.6±0.3, 22±3.5 vs. 34±1.3, and 48±7 vs. 100±7 pmol/ml, mean+SEM, n = 8/group, obese vs. slim, respectively, p<0.03), with a loss of the response to glucose for all VGF peptides studied. In immunohistochemistry, TLQP and/or VGF C-terminus antibodies labelled VGF containing perikarya in mouse celiac ganglia, pancreatic islet cells and thin beaded nerve fibres in brown adipose tissues, with fewer in white adipose tissue. Upon the glucose load, tyrosine hydroxylase and VGF C-terminus immunoreactive axons became apparent in pancreatic islets of slim animals, but not in obese animals. Alltogether, a significant loss of VGF peptide immunoreactivity and/or their response to glucose was demonstrated in obese patients, with or without T2D, in parallel with a similar loss in high-fat diet induced obese mice. An involvement of VGF in metabolic regulations, including those of brown and/or white adipose tissues is underlined, and may point out specific VGF peptides as potential targets for diagnosis and/or treatment.