A single-centre cohort of patients with systemic light chain AL-amyloidosis treated with conventional chemotherapy or with high-dose chemotherapy and autologous stem cell transplantation.

BACKGROUND High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) has been reported to confer better prognosis in systemic light chain AL-amyloidosis as compared with conventional chemotherapy. However, only limited data are available so far on treatment and outcome of AL-amyloidosis patients in Switzerland. METHODS Within a single-centre cohort of patients with biopsy confirmed AL-amyloidosis diagnosed between January 1995 and December 2012, we aimed to investigate treatment effects in patients treated with conventional chemotherapy versus HDCT with ASCT. RESULTS We identified 50 patients with AL-amyloidosis treated with conventional chemotherapy and 13 patients who received HDCT with ASCT. Clinical characteristics differed between the groups for the age of the patients (59 years for patients with ASCT/HDCT vs 69 years; p= 0.0006) and the troponin-T value (0.015 μg/l vs 0.08 μg/l; p = 0.0279). Patients with ASCT showed a trend towards better overall survival, with median survival not yet reached compared with 53 months in patients on conventional chemotherapy (p = 0.0651). CONCLUSION Our results suggest that light chain AL-amyloidosis patients considered fit to undergo HDCT and ASCT may have a better outcome than patients treated exclusively with conventional chemotherapy regimens; however, the better performance status of patients receiving HDCT may have added to this treatment effect.

Cisplatin-resistant cells in malignant pleural mesothelioma cell lines show ALDH(high)CD44(+) phenotype and sphere-forming capacity

BACKGROUND Conventional chemotherapy in malignant pleural mesothelioma (MPM) has minimal impact on patient survival due to the supposed chemoresistance of cancer stem cells (CSCs). We sought to identify a sub-population of chemoresistant cells by using putative CSC markers, aldehyde dehydrogenase (ALDH) and CD44 in three MPM cell lines; H28, H2052 and Meso4. METHODS The Aldefluor assay was used to measure ALDH activity and sort ALDH(high) and ALDH(low) cells. Drug-resistance was evaluated by cell viability, anchorage-independent sphere formation, flow-cytometry and qRT-PCR analyses. RESULTS The ALDH(high) - and ALDH(low) -sorted fractions were able to demonstrate phenotypic heterogeneity and generate spheres, the latter being less efficient, and both showed an association with CD44. Cis- diamminedichloroplatinum (II) (cisplatin) treatment failed to reduce ALDH activity and conferred only a short-term inhibition of sphere generation in both ALDH(high) and ALDH(low) fractions of the three MPM cell lines. Induction of drug sensitivity by an ALDH inhibitor, diethylaminobenzaldehyde (DEAB) resulted in significant reductions in cell viability but not a complete elimination of the sphere-forming cells, suggestive of the presence of a drug-resistant subpopulation. At the transcript level, the cisplatin + DEAB-resistant cells showed upregulated mRNA expression levels for ALDH1A2, ALDH1A3 isozymes and CD44 indicating the involvement of these markers in conferring chemoresistance in both ALDH(high) and ALDH(low) fractions of the three MPM cell lines. CONCLUSIONS Our study shows that ALDH(high) CD44(+) cells are implicated in conveying tolerance to cisplatin in the three MPM cell lines. The combined use of CD44 and ALDH widens the window for identification and targeting of a drug-resistant population which may improve the current treatment modalities in mesothelioma.

Quantitative depth profiling of Ce 3+ in Pt/CeO 2 by in situ high-energy XPS in a hydrogen atmosphere

The redox property of ceria is a key factor in the catalytic activity of ceria-based catalysts. The oxidation state of well-defined ceria nanocubes in gas environments was analysed in situ by a novel combination of near-ambient pressure X-ray Photoelectron Spectroscopy (XPS) and high-energy XPS at a synchrotron X-ray source. In situ high-energy XPS is a promising new tool to determine the electronic structure of matter under defined conditions. The aim was to quantitatively determine the degree of cerium reduction in a nano-structured ceria-supported platinum catalyst as a function of the gas environment. To obtain a non-destructive depth profile at near-ambient pressure, in situ high-energy XPS analysis was performed by varying the kinetic energy of photoelectrons from 1 to 5 keV, and, thus, the probing depth. In ceria nanocubes doped with platinum, oxygen vacancies formed only in the uppermost layers of ceria in an atmosphere of 1 mbar hydrogen and 403 K. For pristine ceria nanocubes, no change in the cerium oxidation state in various hydrogen or oxygen atmospheres was observed as a function of probing depth. In the absence of platinum, hydrogen does not dissociate and, thus, does not lead to reduction of ceria.

Duration of unspecific prodromal and clinical high risk states, and early help-seeking in first-admission psychosis patients

PURPOSE Prevention of psychosis requires both presence of clinical high risk (CHR) criteria and early help-seeking. Previous retrospective studies of the duration of untreated illness (i.e. prodrome plus psychosis) did not distinguish between prodromal states with and without CHR symptoms. Therefore, we examined the occurrence of CHR symptoms and first help-seeking, thereby considering effects of age at illness-onset. METHODS Adult patients first admitted for psychosis (n = 126) were retrospectively assessed for early course of illness and characteristics of first help-seeking. RESULTS One-hundred and nine patients reported a prodrome, 58 with CHR symptoms. In patients with an early illness-onset before age 18 (n = 45), duration of both illness and psychosis were elongated, and CHR symptoms more frequent (68.9 vs. 33.3 %) compared to those with adult illness-onset. Only 29 patients reported help-seeking in the prodrome; this was mainly self-initiated, especially in patients with an early illness-onset. After the onset of first psychotic symptoms, help-seeking was mainly initiated by others. State- and age-independently, mental health professionals were the main first point-of-call (54.0 %). CONCLUSIONS Adult first-admission psychosis patients with an early, insidious onset of symptoms before age 18 were more likely to recall CHR symptoms as part of their prodrome. According to current psychosis-risk criteria, these CHR symptoms, in principle, would have allowed the early detection of psychosis. Furthermore, compared to patients with an adult illness-onset, patients with an early illness-onset were also more likely to seek help on their own account. Thus, future awareness strategies to improve CHR detection might be primarily related to young persons and self-perceived subtle symptoms.

Loss of bone strength in HLA-B27 transgenic rats is characterized by a high bone turnover and is mainly osteoclast-driven

Objective Although osteopenia is frequent in spondyloarthritis (SpA), the underlying cellular mechanisms and association with other symptoms are poorly understood. This study aimed to characterize bone loss during disease progression, determine cellular alterations, and assess the contribution of inflammatory bowel disease (IBD) to bone loss in HLA-B27 transgenic rats. Methods Bones of 2-, 6-, and 12-month-old non-transgenic, disease-free HLA-B7 and disease-associated HLA-B27 transgenic rats were examined using peripheral quantitative computed tomography, μCT, and nanoindentation. Cellular characteristics were determined by histomorphometry and ex vivo cultures. The impact of IBD was determined using [21-3 x 283-2]F1 rats, which develop arthritis and spondylitis, but not IBD. Results HLA-B27 transgenic rats continuously lost bone mass with increasing age and had impaired bone material properties, leading to a 3-fold decrease in bone strength at 12 months of age. Bone turnover was increased in HLA-B27 transgenic rats, as evidenced by a 3-fold increase in bone formation and a 6-fold increase in bone resorption parameters. Enhanced osteoclastic markers were associated with a larger number of precursors in the bone marrow and a stronger osteoclastogenic response to RANKL or TNFα. Further, IBD-free [21-3 x 283-2]F1 rats also displayed decreased total and trabecular bone density. Conclusions HLA-B27 transgenic rats lose an increasing amount of bone density and strength with progressing age, which is primarily mediated via increased bone remodeling in favor of bone resorption. Moreover, IBD and bone loss seem to be independent features of SpA in HLA-B27 transgenic rats.

Parton energy loss and momentum broadening at NLO in high temperature QCD plasmas

We present an overview of a perturbative-kinetic approach to jet propagation, energy loss, and momentum broadening in a high temperature quark–gluon plasma. The leading-order kinetic equations describe the interactions between energetic jet-particles and a non-abelian plasma, consisting of on-shell thermal excitations and soft gluonic fields. These interactions include ↔ scatterings, collinear bremsstrahlung, and drag and momentum diffusion. We show how the contribution from the soft gluonic fields can be factorized into a set of Wilson line correlators on the light-cone. We review recent field-theoretical developments, rooted in the causal properties of these correlators, which simplify the calculation of the appropriate Wilson lines in thermal field theory. With these simplifications lattice measurements of transverse momentum broadening have become possible, and the kinetic equations describing parton transport have been extended to next-to-leading order in the coupling g.

Comparison of homeopathic globules prepared from high and ultra-high dilutions of various starting materials by ultraviolet light spectroscopy

Objective Homeopathic globules are commonly used in clinical practice, while research focuses on liquid potencies. Sequential dilution and succussion in their production process has been proposed to change the physico-chemical properties of the solvent(s). It has been reported that aqueous potencies of various starting materials showed significant differences in ultraviolet light transmission compared to controls and between different dilution levels. The aim of the present study was to repeat and expand these experiments to homeopathic globules. Methods Globules were specially produced for this study by Spagyros AG (Gümligen, Switzerland) from 6 starting materials (Aconitum napellus, Atropa belladonna, phosphorus, sulfur, Apis mellifica, quartz) and for 6 dilution levels (6x, 12x, 30c, 200c, 200CF (centesimal discontinuous fluxion), 10,000CF). Native globules and globules impregnated with solvents were used as controls. Globules were dissolved in ultrapure water, and absorbance in the ultraviolet range was measured. The average absorbance from 200 to 340 nm was calculated and corrected for differences between measurement days and instrumental drift. Results Statistically significant differences were found for A. napellus, sulfur, and A. mellifica when normalized average absorbance of the various dilution levels from the same starting material (including control and solvent control globules) was compared. Additionally, absorbance within dilution levels was compared among the various starting materials. Statistically significant differences were found among 30c, 200c and 200CF dilutions. Conclusion This study has expanded previous findings from aqueous potencies to globules and may indicate that characteristics of aqueous high dilutions may be preserved and detectable in dissolved globules.

Fatal hyperammonemia and carbamoyl phosphate synthetase 1 (CPS1) deficiency following high-dose chemotherapy and autologous hematopoietic stem cell transplantation

Fatal hyperammonemia secondary to chemotherapy for hematological malignancies or following bone marrow transplantation has been described in few patients so far. In these, the pathogenesis of hyperammonemia remained unclear and was suggested to be multifactorial. We observed severe hyperammonemia (maximum 475 μmol/L) in a 2-year-old male patient, who underwent high-dose chemotherapy with carboplatin, etoposide and melphalan, and autologous hematopoietic stem cell transplantation for a neuroblastoma stage IV. Despite intensive care treatment, hyperammonemia persisted and the patient died due to cerebral edema. The biochemical profile with elevations of ammonia and glutamine (maximum 1757 μmol/L) suggested urea cycle dysfunction. In liver homogenates, enzymatic activity and protein expression of the urea cycle enzyme carbamoyl phosphate synthetase 1 (CPS1) were virtually absent. However, no mutation was found in CPS1 cDNA from liver and CPS1 mRNA expression was only slightly decreased. We therefore hypothesized that the acute onset of hyperammonemia was due to an acquired, chemotherapy-induced (posttranscriptional) CPS1 deficiency. This was further supported by in vitro experiments in HepG2 cells treated with carboplatin and etoposide showing a dose-dependent decrease in CPS1 protein expression. Due to severe hyperlactatemia, we analysed oxidative phosphorylation complexes in liver tissue and found reduced activities of complexes I and V, which suggested a more general mitochondrial dysfunction. This study adds to the understanding of chemotherapy-induced hyperammonemia as drug-induced CPS1 deficiency is suggested. Moreover, we highlight the need for urgent diagnostic and therapeutic strategies addressing a possible secondary urea cycle failure in future patients with hyperammonemia during chemotherapy and stem cell transplantation.

Replications of fundamental research models in ultra high dilutions 1994 and 2015 - update on a bibliometric study

INTRODUCTION This paper focuses exclusively on experimental models with ultra high dilutions (i.e. beyond 10(-23)) that have been submitted to replication scrutiny. It updates previous surveys, considers suggestions made by the research community and compares the state of replication in 1994 with that in 2015. METHODS Following literature research, biochemical, immunological, botanical, cell biological and zoological studies on ultra high dilutions (potencies) were included. Reports were grouped into initial studies, laboratory-internal, multicentre and external replications. Repetition could yield either comparable, or zero, or opposite results. The null-hypothesis was that test and control groups would not be distinguishable (zero effect). RESULTS A total of 126 studies were found. From these, 28 were initial studies. When all 98 replicative studies were considered, 70.4% (i.e. 69) reported a result comparable to that of the initial study, 20.4% (20) zero effect and 9.2% (9) an opposite result. Both for the studies until 1994 and the studies 1995-2015 the null-hypothesis (dominance of zero results) should be rejected. Furthermore, the odds of finding a comparable result are generally higher than of finding an opposite result. Although this is true for all three types of replication studies, the fraction of comparable studies diminishes from laboratory-internal (total 82.9%) to multicentre (total 75%) to external (total 48.3%), while the fraction of opposite results was 4.9%, 10.7% and 13.8%. Furthermore, it became obvious that the probability of an external replication producing comparable results is bigger for models that had already been further scrutinized by the initial researchers. CONCLUSIONS We found 28 experimental models which underwent replication. In total, 24 models were replicated with comparable results, 12 models with zero effect, and 6 models with opposite results. Five models were externally reproduced with comparable results. We encourage further replications of studies in order to learn more about the model systems used.

Treatment intensification with insulin glargine in patients with inadequately controlled type 2 diabetes improves glycaemic control with a high treatment satisfaction and no weight gain

PRINCIPLES We aimed to evaluate the efficacy of, and treatment satisfaction with, insulin glargine administered with SoloSTAR® or ClikSTAR® pens in patients with type 2 diabetes mellitus managed by primary care physicians in Switzerland. METHODS A total of 327 patients with inadequately controlled type 2 diabetes were enrolled by 72 physicians in this prospective observational study, which aimed to evaluate the efficacy of a 6-month course of insulin glargine therapy measured as development of glycaemic control (glycosylated haemoglobin [HbA1c] and fasting plasma glucose [FPG]) and weight change. We also assessed preference for reusable or disposable pens, and treatment satisfaction. RESULTS After 6 months, the mean daily dose of insulin glargine was 27.7±14.3 U, and dose titration was completed in 228 (72.4%) patients. Mean HbA1c decreased from 8.9%±1.6% (n=327) to 7.3%±1.0% (n=315) (p<0.0001), and 138 (43.8%) patients achieved an HbA1c≤7.0%. Mean FPG decreased from 10.9±4.5 to 7.3±1.8 mmol/l (p<0.0001). Mean body weight did not change (85.4±17.2 kg vs 85.0±16.5 kg; p=0.11). Patients' preference was in favour of the disposable SoloStar® pen (80%), as compared with the reusable ClickStar® pen (20%). Overall, 92.6% of physicians and 96.3% of patients were satisfied or very satisfied with the insulin glargine therapy. CONCLUSIONS In patients with type 2 diabetes insulin glargine administered by SoloSTAR® or ClikSTAR® pens, education on insulin injection and on self-management of diabetes was associated with clinically meaningful improvements in HbA1c and FPG without a mean collective weight gain. The vast majority of both patients and primary care physicians were satisfied with the treatment intensification.