Aerobic capacity and skeletal muscle characteristics in glycogen storage disease IIIa: an observational study

Background: Individuals with glycogen storage disease IIIa (GSD IIIa) (OMIM #232400) experience muscle weakness and exercise limitation that worsen through adulthood. However, normative data for markers of physical capacity, such as strength and cardiovascular fitness, are limited. Furthermore, the impact of the disease on muscle size and quality is unstudied in weight bearing skeletal muscle, a key predictor of physical function. We aim to produce normative reference values of aerobic capacity and strength in individuals with GSD IIIa, and to investigate the role of muscle size and quality on exercise impairment. Results: Peak oxygen uptake (V̇O2peak) was lower in the individuals with GSD IIIa than predicted based on demographic data (17.0 (9.0) ml/kg/min, 53 (24)% of predicted, p = 0.001). Knee extension maximum voluntary contraction (MVC) was also substantially lower than age matched predicted values (MVC: 146 (116) Nm, 57% predicted, p = 0.045), though no difference was found in MVC relative to body mass (1.88 (2.74) Nm/kg, 61% of predicted, p = 0.263). There was a strong association between aerobic capacity and maximal leg strength (r = 0.920; p = 0.003). Substantial inter-individual variation was present, with a high physical capacity group that had normal leg strength (MVC), and relatively high V̇O2peak, and a low physical capacity that display impaired strength and substantially lower V̇O2peak. The higher physical capacity sub-group were younger, had larger Vastus Lateralis (VL) muscles, greater muscle quality, undertook more physical activity (PA), and reported higher health-related quality of life. Conclusions: V̇O2peak and knee extension strength are lower in individuals with GSD IIIa than predicted based on their demographic data. Patients with higher physical capacity have superior muscle size and structure characteristics and higher health-related quality of life, than those with lower physical capacity. This study provides normative values of these important markers of physical capacity

Validation of a perioperative population factor VIII pharmacokinetic model with a large cohort of pediatric hemophilia a patients

AIMS: Population pharmacokinetic (PK) models are increasingly applied to perform individualized dosing of factor VIII (FVIII) concentrates in haemophilia A patients. To guarantee accurate performance of a population PK model in dose individualization, validation studies are of importance. However, external validation of population PK models requires independent data sets and is, therefore, seldomly performed. Therefore, this study aimed to validate a previously published population PK model for FVIII concentrates administrated perioperatively. METHODS: A previously published population PK model for FVIII concentrate during surgery was validated using independent data from 87 children with severe haemophilia A with a median (range) age of 2.6 years (0.03–15.2) and body weight of 14 kg (4–57). First, the predictive performance of the previous model was evaluated with MAP Bayesian analysis using NONMEM v7.4. Subsequently, the model parameters were (re)estimated using a combined dataset consisting of the previous modelling data and the data available for the external validation. RESULTS: The previous model underpredicted the measured FVIII levels with a median of 0.17 IU mL(−1). Combining the new, independent and original data, a dataset comprising 206 patients with a mean age of 7.8 years (0.03–77.6) and body weight of 30 kg (4–111) was obtained. Population PK modelling provided estimates for CL, V1, V2, and Q: 171 mL h(−1) 68 kg(−1), 2930 mL 68 kg(−1), 1810 mL 68 kg(−1), and 172 mL h(−1) 68 kg(−1), respectively. This model adequately described all collected FVIII levels, with a slight median overprediction of 0.02 IU mL(−1). CONCLUSIONS: This study emphasizes the importance of external validation of population PK models using real‐life data

Relevance of BCAR4 in tamoxifen resistance and tumour aggressiveness of human breast cancer

Background:Breast cancer anti-oestrogen resistance 4 (BCAR4) was identified in a search for genes involved in anti-oestrogen resistance in breast cancer. We explored whether BCAR4 is predictive for tamoxifen resistance and prognostic for tumour aggressiveness, and studied its function.Methods:BCAR4 mRNA levels were measured in primary breast tumours, and evaluated for association with progression-free survival (PFS) and clinical benefit in patients with oestrogen receptor (ERα)-positive tumours receiving tamoxifen as first-line monotherapy for advanced disease. In a separate cohort of patients with lymph node-negative, ERα-positive cancer, and not receiving systemic adjuvant therapy, BCAR4 levels were evaluated for association with distant metastasis-free survival (MFS). The function of BCAR4 was studied with immunoblotting and RNA interference in a cell model.Results:Multivariate analyses established high BCAR4 mRNA levels as an independent predictive factor for poor PFS after start of tamoxifen therapy for recurrent disease. High BCAR4 mRNA levels were associated with poor MFS and overall survival, reflecting tumour aggressiveness. In BCAR4-expressing cells, phosphorylation of v-erb-b2 erythroblastic leukaemia viral oncogene homolog (ERBB)2, ERBB3, and their downstream mediators extracellular signal-regulated kinase 1/2 and v-akt murine thymoma viral oncogene homolog (AKT) 1/2, was increased. Selective knockdown of ERBB2 or ERBB3 inhibited proliferation, confirming their role in BCAR4-induced tamoxifen resistance.Conclusion:BCAR4 may have clinical relevance for tumour aggressiveness and tamoxifen resistance. Our cell model suggests that BCAR4-positive breast tumours are driven by ERBB2/ERBB3 signalling. Patients with such tumours may benefit from ERBB-targeted therapy

Имитация распределенной обработки информации в вычислительных системах и локальных вычислительных сетях

Предложено использовать для анализа вариантов организации распределенной обработки информации в вычислительных системах и локальных вычислительных сетях вероятностный граф реализации вычислительного процесса с явными связями типа вероятностных сетевых графиков.Запропоновано використовувати для аналізу варіантів організації розподіленої обробки інформації в обчислювальних системах і в локальних обчислювальних мережах імовірнісний граф реалізації обчислювального процесу з явними зв’язками типу імовірнісних сіткових графіків.It іs оffered to use for analyzing variants of organization of distributed information processing in computing systems and local computing networks a probabilistic graph for realizing a computing process with evident relationships of the type probabilistic network diagrams

Erythropoietin overrides the triggering effect of DNA platination products in a mouse model of Cisplatin-induced neuropathy

<p>Abstract</p> <p>Background</p> <p>Cisplatin mediates its antineoplastic activity by formation of distinct DNA intrastrand cross links. The clinical efficacy and desirable dose escalations of cisplatin are restricted by the accumulation of DNA lesions in dorsal root ganglion (DRG) cells leading to sensory polyneuropathy (PNP). We investigated in a mouse model by which mechanism recombinant erythropoietin (rhEPO) protects the peripheral nervous system from structural and functional damage caused by cisplatin treatment with special emphasis on DNA damage burden.</p> <p>Results</p> <p>A cumulative dose of 16 mg cisplatin/kg resulted in clear electrophysiological signs of neuropathy, which were significantly attenuated by concomitant erythropoietin (cisplatin 32,48 m/s ± 1,68 m/s; cisplatin + rhEPO 49,66 m/s ± 1,26 m/s; control 55,01 m/s ± 1,88 m/s; p < 0,001). The co-application of rhEPO, however, did not alter the level of unrepaired cisplatin-DNA lesions accumulating in DRG target cells. Micro-morphological analyses of the sciatic nerve from cisplatin-exposed mice showed damaged myelin sheaths and mitochondria. Co-administered rhEPO inhibited myelin sheaths from structural injuries and resulted in an increased number of intact mitochondria.</p> <p>Conclusion</p> <p>The protective effect of recombinant erythropoietin is not mediated by reducing the burden of DNA platination in the target cells, but it is likely to be due to a higher resistance of the target cells to the adverse effect of DNA damage. The increased frequency of intact mitochondria might also contribute to this protective role.</p

Use of Arthropod Rarity for Area Prioritisation: Insights from the Azorean Islands

We investigated the conservation concern of Azorean forest fragments and the entire Terceira Island surface using arthropod species vulnerability as defined by the Kattan index, which is based on species rarity. Species rarity was evaluated according to geographical distribution (endemic vs. non endemic species), habitat specialization (distribution across biotopes) and population size (individuals collected in standardized samples). Geographical rarity was considered at ‘global’ scale (species endemic to the Azorean islands) and ‘regional’ scale (single island endemics)