Pharmacokinetics of gentamicin eluted from a regenerating bone graft substitute:<i>In vitro</i> and clinical release studies

OBJECTIVES: Deep bone and joint infections (DBJI) are directly intertwined with health, demographic change towards an elderly population, and wellbeing. The elderly human population is more prone to acquire infections, and the consequences such as pain, reduced quality of life, morbidity, absence from work and premature retirement due to disability place significant burdens on already strained healthcare systems and societal budgets. DBJIs are less responsive to systemic antibiotics because of poor vascular perfusion in necrotic bone, large bone defects and persistent biofilm-based infection. Emerging bacterial resistance poses a major threat and new innovative treatment modalities are urgently needed to curb its current trajectory. MATERIALS AND METHODS: We present a new biphasic ceramic bone substitute consisting of hydroxyapatite and calcium sulphate for local antibiotic delivery in combination with bone regeneration. Gentamicin release was measured in four setups: 1) in vitro elution in Ringer’s solution; 2) local elution in patients treated for trochanteric hip fractures or uncemented hip revisions; 3) local elution in patients treated with a bone tumour resection; and 4) local elution in patients treated surgically for chronic corticomedullary osteomyelitis. RESULTS: The release pattern in vitro was comparable with the obtained release in the patient studies. No recurrence was detected in the osteomyelitis group at latest follow-up (minimum 1.5 years). CONCLUSIONS: This new biphasic bone substitute containing antibiotics provides safe prevention of bone infections in a range of clinical situations. The in vitro test method predicts the in vivo performance and makes it a reliable tool in the development of future antibiotic-eluting bone-regenerating materials. Cite this article: M. Stravinskas, P. Horstmann, J. Ferguson, W. Hettwer, M. Nilsson, S. Tarasevicius, M. M. Petersen, M. A. McNally, L. Lidgren. Pharmacokinetics of gentamicin eluted from a regenerating bone graft substitute: In vitro and clinical release studies. Bone Joint Res 2016;5:427–435. DOI: 10.1302/2046-3758.59.BJR-2016-0108.R1

Bioabsorbable metal zinc differentially affects mitochondria in vascular endothelial and smooth muscle cells

Zinc is an essential trace element having various structural, catalytic and regulatory interactions with an estimated 3000 proteins. Zinc has drawn recent attention for its use, both as pure metal and alloyed, in arterial stents due to its biodegradability, biocompatibility, and low corrosion rates. Previous studies have demonstrated that zinc metal implants prevent the development of neointimal hyperplasia, which is a common cause of restenosis following coronary intervention. This suppression appears to be smooth muscle cell-specific, as reendothelization of the neointima is not inhibited. To better understand the basis of zinc\u27s differential effects on rat aortic smooth muscle (RASMC) versus endothelial (RAENDO) cells, we conducted a transcriptomic analysis of both cell types following one-week continuous treatment with 5 µM or 50 µM zinc. This analysis indicated that genes whose protein products regulate mitochondrial functions, including oxidative phosphorylation and fusion/fission, are differentially affected by zinc in the two cell types. To better understand this, we performed Seahorse metabolic flux assays and quantitative imaging of mitochondrial networks in both cell types. Zinc treatment differently affected energy metabolism and mitochondrial structure/function in the two cell types. For example, both basal and maximal oxygen consumption rates were increased by zinc in RASMC but not in RAENDO. Zinc treatment increased apparent mitochondrial fusion in RASMC cells but increased mitochondrial fission in RAENDO cells. These results provide some insight into the mechanisms by which zinc treatment differently affects the two cell types and this information is important for understanding the role of zinc treatment in vascular cells and improving its use in biodegradable metal implants

Diastolic function measurements and diagnostic consequences: a comparison of pulsed wave- and color-coded tissue Doppler imaging

Tissue Doppler imaging (TDI) plays an important role in assessing diastolic function using echocardiography. However, two different methods [pulsed wave (PW-TDI) and color-coded (CC-TDI)] are currently used. We aimed to compare both measurements. We included 114 patients that were referred to our echocardiography department for evaluation of diastolic left ventricular function. In these patients, we sequentially measured tissue velocities of basal lateral and septal myocardium of the left ventricle in an apical four-chamber view with both PW-TDI and CC-TDI. Our cohort consisted of a heterogeneous group of patients with and without a history of cardiac disease. Mean age of the patients was 52 +/- A 16.7 years, and 62% were males. We found a strong correlation between PW-TDI- and CC-TDI-derived myocardial velocities (r = 0.93; p = 0.001). However, E' (mean of lateral and septal) velocities measured with PW-TDI were consistently higher compared to CC-TDI values [PW-TDI E' 10.3 +/- A 3.9 (SD) cm/s vs. CC-TDI E' 7.7 +/- A 3.1 cm/s; p <0.001]. From these data, we calculated that the relation between E' measured with PW-TDI and CC-TDI can be described as: E' (PW-TDI) = 1.25 + 1.17 x E' (CC-TDI). Consequently, E/E' measured with PW-TDI was consistently lower compared with CC-TDI (9.1 +/- A 3.1 vs. 12.5 +/- A 5.7; p <0.001) From these data, we calculated that the relation between E/E' measured with PW-TDI and CC-TDI can be described as: E/E' (PW-TDI) = 2.13 + 0.56 x E/E' (CC-TDI). Despite a strong correlation, tissue velocities measured with PW-TDI will yield higher values as compared with CC-TDI. This should be taken into account when defining cut-off values for the evaluation of diastolic function

Markedly Divergent Tree Assemblage Responses to Tropical Forest Loss and Fragmentation across a Strong Seasonality Gradient

We examine the effects of forest fragmentation on the structure and composition of tree assemblages within three seasonal and aseasonal forest types of southern Brazil, including evergreen, Araucaria, and deciduous forests. We sampled three southernmost Atlantic Forest landscapes, including the largest continuous forest protected areas within each forest type. Tree assemblages in each forest type were sampled within 10 plots of 0.1 ha in both continuous forests and 10 adjacent forest fragments. All trees within each plot were assigned to trait categories describing their regeneration strategy, vertical stratification, seed-dispersal mode, seed size, and wood density. We detected differences among both forest types and landscape contexts in terms of overall tree species richness, and the density and species richness of different functional groups in terms of regeneration strategy, seed dispersal mode and woody density. Overall, evergreen forest fragments exhibited the largest deviations from continuous forest plots in assemblage structure. Evergreen, Araucaria and deciduous forests diverge in the functional composition of tree floras, particularly in relation to regeneration strategy and stress tolerance. By supporting a more diversified light-demanding and stress-tolerant flora with reduced richness and abundance of shade-tolerant, old-growth species, both deciduous and Araucaria forest tree assemblages are more intrinsically resilient to contemporary human-disturbances, including fragmentation-induced edge effects, in terms of species erosion and functional shifts. We suggest that these intrinsic differences in the direction and magnitude of responses to changes in landscape structure between forest types should guide a wide range of conservation strategies in restoring fragmented tropical forest landscapes worldwide

Deep Neural Network Attribution Methods for Leakage Analysis and Symmetric Key Recovery

Deep Neural Networks (DNNs) have recently received significant attention in the side-channel community due to their state-of-the-art performance in security testing of embedded systems. However, research on the subject mostly focused on techniques to improve the attack efficiency in terms of the number of traces required to extract secret parameters. What has not been investigated in detail is a constructive approach of DNNs as a tool to evaluate and improve the effectiveness of countermeasures against side-channel attacks. In this work, we try to close this gap by applying attribution methods that aim for interpreting DNN decisions, in order to identify leaking operations in cryptographic implementations. In particular, we investigate three different approaches that have been proposed for feature visualization in image classification tasks and compare them regarding their suitability to reveal Points of Interests (POIs) in side-channel traces. We show by experiments with three separate data sets that Layer-wise Relevance Propagation (LRP) proposed by Bach et al. provides the best result in most cases. Finally, we demonstrate that attribution can also serve as a powerful side-channel distinguisher in DNN-based attack setups