Feasibility and potential efficacy of a guided internet- and mobile-based CBT for adolescents and young adults with chronic medical conditions and comorbid depression or anxiety symptoms (youthCOACHCD): a randomized controlled pilot trial.

BACKGROUND: Adolescents and young adults (AYA) with a chronic medical condition show an increased risk for developing mental comorbidities compared to their healthy peers. Internet- and mobile-based cognitive behavioral therapy (iCBT) might be a low-threshold treatment to support affected AYA. In this randomized controlled pilot trial, the feasibility and potential efficacy of youthCOACHCD, an iCBT targeting symptoms of anxiety and depression in AYA with chronic medical conditions, was evaluated. METHODS: A total of 30 AYA (Mage 16.13; SD= 2.34; 73% female), aged 12-21 years either suffering from cystic fibrosis, juvenile idiopathic arthritis or type 1 diabetes, were randomly assigned to either a guided version of the iCBT youthCOACHCD (IG, n=15) or to a waitlist control group (CG, n=15), receiving an unguided version of the iCBT six months post-randomization. Participants of the IG and the CG were assessed before (t0), twelve weeks after (t1) and six months after (t2) randomization. Primary outcome was the feasibility of the iCBT. Different parameters of feasibility e.g. acceptance, client satisfaction or potential side effects were evaluated. First indications of the possible efficacy with regard to the primary efficacy outcome, the Patient Health Questionnaire Anxiety and Depression Scale, and further outcome variables were evaluated using linear regression models, adjusting for baseline values. RESULTS: Regarding feasibility, intervention completion was 60%; intervention satisfaction (M = 25.42, SD = 5.85) and perceived therapeutic alliance (M = 2.83, SD = 1.25) were moderate and comparable to other iCBTs. No patterns emerged regarding subjective and objective negative side effects due to participation in youthCOACHCD. Estimates of potential efficacy showed between group differences, with a potential medium-term benefit of youthCOACHCD (ß = -0.55, 95%CI: -1.17; 0.07), but probably not short-term (ß = 0.20, 95%CI: -0.47; 0.88). CONCLUSIONS: Our results point to the feasibility of youthCOACHCD and the implementation of a future definitive randomized controlled trial addressing its effectiveness and cost-effectiveness. Due to the small sample size, conclusions are premature, however, further strategies to foster treatment adherence should be considered. TRIAL REGISTRATION: The trial was registered at the WHO International Clinical Trials Registry Platform via the German Clinical Trials Register (ID: DRKS00016714 , 25/03/2019).

Correction: Role of growth arrest-specific gene 6-mer axis in multiple myeloma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing.

In multiple myeloma malignant plasma cells expand within the bone marrow. Since this site is well-perfused, a rapid dissemination of "fitter" clones may be anticipated. However, an imbalanced distribution of multiple myeloma is frequently observed in medical imaging. Here, we perform multi-region sequencing, including iliac crest and radiology-guided focal lesion specimens from 51 patients to gain insight into the spatial clonal architecture. We demonstrate spatial genomic heterogeneity in more than 75% of patients, including inactivation of CDKN2C and TP53, and mutations affecting mitogen-activated protein kinase genes. We show that the extent of spatial heterogeneity is positively associated with the size of biopsied focal lesions consistent with regional outgrowth of advanced clones. The results support a model for multiple myeloma progression with clonal sweeps in the early phase and regional evolution in advanced disease. We suggest that multi-region investigations are critical to understanding intra-patient heterogeneity and the evolutionary processes in multiple myeloma.In multiple myeloma, malignant cells expand within bone marrow. Here, the authors use multi-region sequencing in patient samples to analyse spatial clonal architecture and heterogeneity, providing novel insight into multiple myeloma progression and evolution.

A field investigation on transport of carbon-supported nanoscale zero-valent iron (nZVI) in groundwater.

The application of nanoscale zero-valent iron (nZVI) for subsurface remediation of groundwater contaminants is a promising new technology, which can be understood as alternative to the permeable reactive barrier technique using granular iron. Dechlorination of organic contaminants by zero-valent iron seems promising. Currently, one limitation to widespread deployment is the fast agglomeration and sedimentation of nZVI in colloidal suspensions, even more so when in soils and sediments, which limits the applicability for the treatment of sources and plumes of contamination. Colloid-supported nZVI shows promising characteristics to overcome these limitations. Mobility of Carbo-Iron Colloids (CIC) - a newly developed composite material based on finely ground activated carbon as a carrier for nZVI - was tested in a field application: In this study, a horizontal dipole flow field was established between two wells separated by 5.3m in a confined, natural aquifer. The injection/extraction rate was 500L/h. Approximately 1.2kg of CIC was suspended with the polyanionic stabilizer carboxymethyl cellulose. The suspension was introduced into the aquifer at the injection well. Breakthrough of CIC was observed visually and based on total particle and iron concentrations detected in samples from the extraction well. Filtration of water samples revealed a particle breakthrough of about 12% of the amount introduced. This demonstrates high mobility of CIC particles and we suggest that nZVI carried on CIC can be used for contaminant plume remediation by in-situ formation of reactive barriers.

Role of Growth arrest-specific gene 6-Mer axis in multiple myeloma.

Multiple myeloma is a mostly incurable malignancy characterized by the expansion of a malignant plasma cell (PC) clone in the human bone marrow (BM). Myeloma cells closely interact with the BM stroma, which secretes soluble factors that foster myeloma progression and therapy resistance. Growth arrest-specific gene 6 (Gas6) is produced by BM-derived stroma cells and can promote malignancy. However, the role of Gas6 and its receptors Axl, Tyro3 and Mer (TAM receptors) in myeloma is unknown. We therefore investigated their expression in myeloma cell lines and in the BM of myeloma patients and healthy donors. Gas6 showed increased expression in sorted BMPCs of myeloma patients compared with healthy controls. The fraction of Mer(+) BMPCs was increased in myeloma patients in comparison with healthy controls whereas Axl and Tyro3 were not expressed by BMPCs in the majority of patients. Downregulation of Gas6 and Mer inhibited the proliferation of different myeloma cell lines, whereas knocking down Axl or Tyro3 had no effect. Inhibition of the Gas6 receptor Mer or therapeutic targeting of Gas6 by warfarin reduced myeloma burden and improved survival in a systemic model of myeloma. Thus, the Gas6-Mer axis represents a novel candidate for therapeutic intervention in this incurable malignancy.

Cell-free carrier system for localized delivery of peripheral blood cell-derived engineered factor signaling: towards development of a one-step device for autologous angiogenic therapy.

Spatiotemporally-controlled delivery of hypoxia-induced angiogenic factor mixtures has been identified by this group as a promising strategy for overcoming the limited ability of chronically ischemic tissues to generate adaptive angiogenesis. We previously developed an implantable, as well as an injectable system for delivering fibroblast-produced factors in vivo. Here, we identify peripheral blood cells (PBCs) as the ideal factor-providing candidates, due to their autologous nature, ease of harvest and ample supply, and investigate wound-simulating biochemical and biophysical environmental parameters that can be controlled to optimize PBC angiogenic activity. It was found that hypoxia (3% O2) significantly affected the expression of a range of angiogenesis-related factors including VEGF, angiogenin and thrombospondin-1, relative to the normoxic baseline. While all three factors underwent down-regulation over time under hypoxia, there was significant variation in the temporal profile of their expression. VEGF expression was also found to be dependent on cell-scaffold material composition, with fibrin stimulating production the most, followed by collagen and polystyrene. Cell-scaffold matrix stiffness was an additional important factor, as shown by higher VEGF protein levels when PBCs were cultured on stiff vs. compliant collagen hydrogel scaffolds. Engineered PBC-derived factor mixtures could be harvested within cell-free gel and microsphere carriers. The angiogenic effectiveness of factor-loaded carriers could be demonstrated by the ability of their releasates to induce endothelial cell tubule formation and directional migration in in vitro Matrigel assays, and microvessel sprouting in the aortic ring assay. To aid the clinical translation of this approach, we propose a device design that integrates this system, and enables one-step harvesting and delivering of angiogenic factor protein mixtures from autologous peripheral blood. This will facilitate the controlled release of these factors both at the bed-side, as an angiogenic therapy in wounds and peripheral ischemic tissue, as well as pre-, intra- and post-operatively as angiogenic support for central ischemic tissue, grafts, flaps and tissue engineered implants.

Association of exercise-induced hyperinsulinaemic hypoglycaemia with MCT1-expressing insulinoma.

AIMS/HYPOTHESIS: Exercise-induced hyperinsulinism (EIHI) is a hypoglycaemic disorder characterised by inappropriate insulin secretion following anaerobic exercise or pyruvate load. Activating promoter mutations in the MCT1 gene (also known as SCLA16A1), coding for monocarboxylate transporter 1 (MCT1), were shown to associate with EIHI. Recently, transgenic Mct1 expression in pancreatic beta cells was shown to introduce EIHI symptoms in mice. To date, MCT1 has not been demonstrated in insulin-producing cells from an EIHI patient. METHODS: In vivo insulin secretion was studied during an exercise test before and after the resection of an insulinoma. The presence of MCT1 was analysed using immunohistochemistry followed by laser scanning microscopy, western blot analysis and real-time RT-PCR of MCT1. The presence of MCT1 protein was analysed in four additional insulinoma patients. RESULTS: Clinical testing revealed massive insulin secretion induced by anaerobic exercise preoperatively, but not postoperatively. MCT1 protein was not detected in the patient's normal islets. In contrast, immunoreactivity was clearly observed in the insulinoma tissue. Western blot analysis and real-time RT-PCR showed a four- to fivefold increase in MCT1 in the insulinoma tissue of the EIHI patient compared with human pancreatic islets. MCT1 protein was detected in three of four additional insulinomas. CONCLUSIONS/INTERPRETATION: We show for the first time that an MCT1-expressing insulinoma was associated with EIHI and that MCT1 might be present in most insulinomas. Our data suggest that MCT1 expression in human insulin-producing cells can lead to EIHI and warrant further studies on the role of MCT1 in human insulinoma patients.

[Infantile hemangioma. Successful treatment with propranolol]. / Infantiles Hämangiom. Erfolgreiche Behandlung mit Propranolol.

We report on an infant, aged four months, suffering from a severe hemangioma of the left labium majus. We induced systemic treatment with propranolol in off-label-use over a period of 5 1/2 months. A few weeks after onset of the treatment, the size and color of hemangioma was obviously reduced; finally there was an almost complete regression. This result underlines the role of propranolol in treatment of problematic hemangioma.

Bloody nipple discharge (BND) in an 8 months old girl and a 9 months old male--rational diagnostic approach.

Bloody nipple discharge in adults is, in men as well as in women, often a symptom of an underlying malignant disease. In respect of this, multiple invasive and mutilating diagnostic procedures have been performed in infants and older children. Apart from individual cases in older and pubertal children, in childhood benign conditions are most common and can be diagnosed by non-invasive diagnostic procedures. Here we discuss a rational diagnostic approach on the basis of 2 patients with bloody nipple discharge at the age of 8 and 9 months which resolved spontaneously without treatment after 3 and 6 months, respectively.

Bone morphogenic protein 6: a member of a novel class of prognostic factors expressed by normal and malignant plasma cells inhibiting proliferation and angiogenesis.

Pathogenesis of multiple myeloma is associated with an aberrant expression of pro-proliferative, pro-angiogenic and bone-metabolism-modifying factors by malignant plasma cells. Given the frequently long time span from diagnosis of early-stage plasma cell dyscrasias to overt myeloma and the mostly low proliferation rate of malignant plasma cells, we hypothesize these to similarly express a novel class of inhibitory factors of potential prognostic relevance. Bone morphogenic proteins (BMPs) represent possible candidates as they inhibit proliferation, stimulate bone formation and have an effect on the survival of cancer patients. We assessed the expression of BMPs and their receptors by Affymetrix DNA microarrays (n=779) including CD138-purified primary myeloma cell samples (n=635) of previously untreated patients. BMP6 is the only BMP expressed by malignant and normal plasma cells. Its expression is significantly lower in proliferating myeloma cells, myeloma cell lines or plasmablasts. BMP6 significantly inhibits the proliferation of myeloma cell lines, survival of primary myeloma cells and in vitro angiogenesis. A high BMP6 expression in primary myeloma cell samples delineates significantly superior overall survival for patients undergoing high-dose chemotherapy independent of conventional prognostic factors (International Staging System (ISS) stage, beta(2) microglobulin).

Acute metabolic crisis with extreme deficiency of glutathione in combination with decreased levels of leukotriene C4 in a patient with glutathione synthetase deficiency.

A 32-year-old man with glutathione synthetase deficiency developing an acute metabolic crisis is described. During this acute episode, intracellular glutathione content in erythrocytes was below the detection limit (<0.3 mmol/L). Leukotriene C4 in CSF and urinary leukotriene E4 were massively decreased, indicating an imparied synthesis of cysteinyl leukotrienes. Clinical recovery after one week was accompanied by a clear improvement of these biochemical parameters. The highly disturbed glutathione synthesis is postulated to be the reason for a deficient synthesis of cysteinyl leukotrienes, which may at least in part be responsible for the severe clinical symptoms.

Isotachophoretic determination of phosphate splitting from Amifostine and p-nitrophenyl phosphate in serum and neuroblastoma cells.

Amifostine [WR-2721; H2N-(CH2)3-NH-(CH2)2-S-PO3H2] is used as a protecting agent in the chemotherapy of neuroblastoma. It is supposed that Amifostine will be transformed into its active form, the free thiol (WR-1065), easier by normal cells than by tumour cells. Analytical capillary isotachophoresis was used to determine the dephosphorylation of Amifostine in serum and on neuroblastoma cells and peripheral blood cells. Furthermore, the biological effects of Amifostine and its free thiol, on cell proliferation of neuroblastoma cells were measured in combination with Carboplatin. It was found that neuroblastoma cells did not split phosphate less efficiently than normal peripheral blood cells. Furthermore, neither Amifostine (as expected) nor the free thiol (not expected according to the theory) were able to inhibit the effects of Carboplatin. Therefore, the current hypothesis concerning the mode of action of Amifostine must be questioned.

Protein catabolism in fibroblasts cultured from patients with mucolipidosis II and other lysosomal disorders.

Protein catabolism in fibroblasts cultured from the skin of normal individuals and of patients with mucolipidosis II (I-cell disease) and several other lysosomal storage diseases was examined by metabolic labelling with [3H]leucine and following the fate of radioactive proteins in pulse-chase experiments. In mucolipidosis II cells, overall protein degradative rates were found to be distinctly lower than in normal control cells. To distinguish lysosomal from non-lysosomal degradation, labelling experiments were carried out in the presence and absence of 10 mM NH4Cl, an inhibitor of lysosomal function. It was found that mucolipidosis II fibroblasts exhibited a markedly reduced rate of lysosomal protein degradation, whereas the rate of nonlysosomal degradation appeared normal. Serum and amino acid starvation led to a marked increase in lysosomal protein degradation in normal cells, but had only a minimal effect on that in mucolipidosis II fibroblasts. The specific activities of cathepsins B, H and L were profoundly diminished in all mucolipidosis II cell lines tested. Lysosomal protein degradation in a mucolipidosis III cell line was impaired to a similar degree as in mucolipidosis II cells, whereas it was decreased to a lesser extent in fibroblasts from patients with mucopolysaccharidoses I and VI, galactosialidosis and GM1-gangliosidosis. We conclude that fibroblasts from patients with mucolipidosis II and III have a severely compromised capacity for endogenous lysosomal protein degradation that appears to result from multiple cathepsin deficiency. This lysosomal defect is likely to have pathophysiological consequences.

In vivo cytochrome P 450 interactions of the newly developed H+/K(+)-ATPase inhibitor pantoprazole (BY 1023/SK&F 96022) compared to other antiulcer drugs.

Almost 10% of adverse drug reactions observed in clinical patients are due to interactions of two or more therapeutic agents (18). The aim of the present study was to investigate in vivo interactions of the H2-blocker cimetidine and three newly developed H+/K(+)-ATPase inhibitors, omeprazole, lansoprazole and pantoprazole (BY 1023/SK&F 96022) with cytochrome P 450 in rats. Because diazepam is a drug used very often as comedication in ulcer patients, the duration of the effects of diazepam on muscle coordination were used to evaluate the drug interactions on metabolic enzymes. The present data indicate a clear rank order of the antiulcer drugs' potency for interaction with diazepam: 1) lansoprazole with a 50% prolongation of diazepam effect at 170 mumol/kg, 2) cimetidine and omeprazole at 281 and 288 mumol/kg, respectively and 3) pantoprazole at greater than 1000 mumol/kg. Because the three H+/K(+)-ATPase inhibitors are approximately equipotent with respect to inhibition of gastric acid secretion, it can be concluded that pantoprazole is superior to omeprazole and lansoprazole when unwanted adverse effects with drug metabolizing enzymes are considered. This may be an advantage in clinical use of the drug.