Clinicians' and patients' assessment of activity overuse and underuse and its relation to physical capacity

To explore clinicians' and patients' (self)-assessment of activity overuse and underuse, and its relationship with physical capacity in patients with chronic musculoskeletal pain (CMP). Study design was cross-sectional. Participants included patients with CMP, admitted to a multidisciplinary outpatient pain rehabilitation program. The main measures used were as follows: a five-point scale to rate overuse and underuse, filled out by clinicians and patients; a five-point scale to rate physical capacity, filled out by clinicians and patients; and lifting and aerobic capacity. Cohen's kappa were calculated to test the agreement between assessments. Depending on the normality, a t-test or a Mann-Whitney U-test was used to test differences between the results of a capacity test and patients' and clinicians' assessments of capacity. A total of 141 patients were included: 42% were men, and 60% had back pain, 21% had neck pain, 19% had pain in a different location. Six percent of the patients rated themselves as underusers; clinicians rated 23% of the patients as underusers. Clinicians and patients fairly agreed (61%; kappa = 0.23) in their assessments of overuse and underuse. Differences in the physical capacity of overuse and underusers, as assessed by clinicians and patients, were all nonsignificant (P > 0.05). The physical capacity of overusers did not differ from that of underusers (P < 0.05). In conclusion, although clinicians and patients with CMP fairly agree on their assessment of activity overuse and underuse, the physical capacity of overusers was not different from that of underusers

Hypothalamically-Induced Insulin Release and its Potentiation During Oral and Intravenous Glucose Loads

Male Wistar rats were provided with bilateral cannulas in the lateral hypothalamic area (LHA) and cannulas in the left and right jugular vein. Freely moving rats provided in this way with cannulas were infused with transmitters in the LHA and with various substances in the blood circulation during simultaneous sampling of blood without disturbing the animals. Infusion of norepinephrine (NE) in the LHA resulted in increased insulin levels while plasma glucagon and blood glucose were nearly not affected. This LHA mediated insulin release was suppressed by atropine injection in the blood circulation suggesting a vagal contribution to the observed phenomenon. Administration of either an oral or i.v. glucose load during noradrenergic stimulation of the LHA elicited an exaggerated insulin response when compared to their controls. This LHA potentiated insulin response during an oral and i.v. glucose load could be suppressed by atropinization of the rats. It is concluded that meal-related stimuli are relayed to the NE-stimulated area of the LHA and that these stimuli modulate the output from this area of the LHA that is concerned with the release of insulin.

Effect of wound healing period and temperature, irradiation and post irradiation storage temperature on the keeping quality of potatoes

The effect of irradiation doses, wound healing temperature, post harvest irradiation time (wound healing period) and storage temperature on a number of quality parameters such as loss of weight, sprout inhibition and rot incidence, chemical parameters such as sugar and vitamin e content, sensory parameters taste and colour and also wound healing ability were investigated. The potatoes were irradiated with a dose range of 50 to 100 Gy, after a wound healing period varying from 0 to 6 weeks at 15 or 20 °C. The product was stored at 10 and 20 °C and 90% relative humidity

Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status

Chondrosarcomas are chemo- and radiotherapy resistant and frequently harbor mutationsin isocitrate dehydrogenase (IDH1 or IDH2), causing increased levels of D-2-hydroxyglutarate(D-2-HG). DNA repair defects and synthetic lethality with poly(ADP-ribose) polymerase (PARP)inhibition occur in IDH mutant glioma and leukemia models. Here we evaluated DNA repairand PARP inhibition, alone or combined with chemo- or radiotherapy, in chondrosarcoma celllines with or without endogenous IDH mutations. Chondrosarcoma cell lines treated with thePARP inhibitor talazoparib were examined for dose–response relationships, as well as underlyingcell death mechanisms and DNA repair functionality. Talazoparib was combined with chemo- orradiotherapy to evaluate potential synergy. Cell lines treated long termwith an inhibitor normalizingD-2-HG levels were investigated for synthetic lethality with talazoparib. We report that talazoparibsensitivity was variable and irrespective of IDH mutation status. All cell lines expressed AtaxiaTelangiectasia Mutated (ATM), but a subset was impaired in poly(ADP-ribosyl)ation (PARylation)capacity, homologous recombination, andO-6-methylguanine-DNAmethyltransferase (MGMT) expression.Talazoparib synergized with temozolomide or radiation, independent of IDH1 mutant inhibition.This study suggests that talazoparib combined with temozolomide or radiation are promisingtherapeutic strategies for chondrosarcoma, irrespective of IDH mutation status. A subset ofchondrosarcomas may be deficient in nonclassical DNA repair pathways, suggesting that PARPinhibitor sensitivity is multifactorial in chondrosarcoma.Toxicolog

Functional analysis of novel androgen receptor mutations in a unique cohort of Indonesian patients with a disorder of sex development

Mutations in the androgen receptor (AR) gene, rendering the AR protein partially or completely inactive, cause androgen insensitivity syndrome, which is a form of a 46,XY disorder of sex development (DSD). We present 3 novel AR variants found in a cohort of Indonesian DSD patients: p.I603N, p.P671S, and p.Q738R. The aim of this study was to determine the possible pathogenic nature of these newly found unclassified variants. To investigate the effect of these variants on AR function, we studied their impact on transcription activation, AR ligand-binding domain interaction with an FxxLF motif containing peptide, AR subcellular localization, and AR nuclear dynamics and DNA-binding. AR-I603N had completely lost its transcriptional activity due to disturbed DNA-binding capacity and did not show the 114-kDa hyperphosphorylated AR protein band normally detectable after hormone binding. The patient with AR-I603N displays a partial androgen insensitivity syndrome phenotype, which is explained by somatic mosaicism. A strongly reduced transcriptional activity was observed for AR-Q738R, together with diminished interaction with an FxxLF motif containing peptide. AR-P671S also showed reduced transactivation ability, but no change in DNA- or FxxLF-binding capacity and interferes with transcriptional activity for as yet unclear reasons

High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth

MTG6Molecular tumour pathology - and tumour genetic

Targeting survivin as a potential new treatment for chondrosarcoma of bone

Chondrosarcomas are malignant cartilage-forming bone tumors, which are intrinsically resistant to chemo- and radiotherapy, leaving surgical removal as the only curative treatment option. Therefore, our aim was to identify genes involved in chondrosarcoma cell survival that could serve as a target for therapy. siRNA screening for 51 apoptosis-related genes in JJ012 chondrosarcoma cells identified BIRC5, encoding survivin, as essential for chondrosarcoma survival. Using immunohistochemistry, nuclear as well as cytoplasmic survivin expression was analyzed in 207 chondrosarcomas of different subtypes. Nuclear survivin has been implicated in cell-cycle regulation while cytoplasmic localization is important for its anti-apoptotic function. RT-PCR was performed to determine expression of the most common survivin isoforms. Sensitivity to YM155, a survivin inhibitor currently in phase I/II clinical trial for other tumors, was examined in 10 chondrosarcoma cell lines using viability assay, apoptosis assay and cell-cycle analysis. Survivin expression was found in all chondrosarcoma patient samples. Higher expression of nuclear and cytoplasmic survivin was observed with increasing histological grade in central chondrosarcomas. Inhibition of survivin using YM155 showed that especially TP53 mutant cell lines were sensitive, but no caspase 3/7 or PARP cleavage was observed. Rather, YM155 treatment resulted in a block in S phase in two out of three chondrosarcoma cell lines, indicating that survivin is more involved in cell-cycle regulation than in apoptosis. Thus, survivin is important for chondrosarcoma survival and chondrosarcoma patients might benefit from survivin inhibition using YM155, for which TP53 mutational status can serve as a predictive biomarker.Toxicolog