Bioactive Scaffolds for the Controlled Formation of Complex Skeletal Tissues

Tissue Engineering may offer new treatment alternatives for organ replacement or repair deteriorated organs. Among the clinical applications of Tissue Engineering are the production of artificial skin for burn patients, tissue engineered trachea, cartilage for knee-replacement procedures, urinary bladder replacement, urethra substitutes and cellular therapies for the treatment of urinary incontinence. The Tissue Engineering approach has major advantages over traditional organ transplantation and circumvents the problem of organ shortage. Tissues reconstructed from readily available biopsy material induce only minimal or no immunogenicity when reimplanted in the patient. This book is aimed at anyone interested in the application of Tissue Engineering in different organ systems. It offers insights into a wide variety of strategies applying the principles of Tissue Engineering to tissue and organ regeneration

Coronary artery spasm and non-Q-wave myocardial infarction following intravenous ephedrine in two healthy women under spinal anaesthesia

Vasovagal episodes occur frequently in young healthy patients undergoing venous cannulation and loco-regional anaesthesia. We report two cases of severe coronary vasospasm and non-Qwave infarction in healthy young women after administration of ephedrine for vasovagal symptoms at the onset of spinal anaesthesia. In the light of unopposed vagal predominance predisposing patients to coronary vasospasm, even in young healthy patients, atrophine and not ephedrine should be the first line treatment for bradycardia with or without hypotension under spinal anaesthesi

A canine model of irreversible urethral sphincter insufficiency

OBJECTIVE To develop a canine model of external urinary sphincter insufficiency by creating irreversible damage to the sphincter, because there is a need for a reliable and reproducible large animal model for the study of stress urinary incontinence (SUI) caused by deficient sphincter function. MATERIALS AND METHODS About a quarter of the total external sphincter muscle was removed microsurgically from seven female dogs; three age-matched dogs served as normal controls. The dogs had standard urodynamic and radiographic studies before and at 1, 2, 3, 4 and 7 months after surgery. Three dogs were killed at 4 months and four at 7 months after surgery for tissue analyses. RESULTS The interventions produced a consistent outcome. Urodynamic studies showed a significant and sustained decrease in sphincter function, which included a static urethral pressure profile, stress urethral profile and detrusor leak-point pressure. Furthermore, in vivo pudendal nerve stimulation and organ-bath studies of the retrieved tissue strips confirmed the loss of sphincter tissue function. Histologically, absence of functional sphincter muscle was evident in the damaged sphincter region. CONCLUSIONS These results show that a reliable and reproducible canine model of irreversible sphincter insufficiency can be created by microsurgical removal of sphincter muscle tissue. This model of external sphincter insufficiency could be used for evaluating methods (e.g. cell therapies) for treating SUI

Noninvasive PET Imaging and Tracking of Engineered Human Muscle Precursor Cells for Skeletal Muscle Tissue Engineering

Transplantation of human muscle precursor cells (hMPCs) is envisioned for the treatment of various muscle diseases. However, a feasible noninvasive tool to monitor cell survival, migration, and integration into the host tissue is still missing. METHODS: In this study, we designed an adenoviral delivery system to genetically modify hMPCs to express a signaling-deficient form of human dopamine D2 receptor (hD2R). The gene expression levels of the receptor were evaluated by reverse transcriptase polymerase chain reaction, and infection efficiency was evaluated by fluorescent microscopy. The viability, proliferation, and differentiation capacity of the transduced cells, as well as their myogenic phenotype, were determined by flow cytometry analysis and fluorescent microscopy. (18)F-fallypride and (18)F-fluoromisonidazole, two well-established PET radioligands, were assessed for their potential to image engineered hMPCs in a mouse model and their uptakes were evaluated at different time points after cell inoculation in vivo. Biodistribution studies, autoradiography, and PET experiments were performed to determine the extent of signal specificity. To address feasibility for tracking hMPCs in an in vivo model, the safety of the adenoviral gene delivery was evaluated. Finally, the harvested tissues were histologically examined to determine whether survival of the transplanted cells was sustained at different time points. RESULTS: Adenoviral gene delivery was shown to be safe, with no detrimental effects on the primary human cells. The viability, proliferation, and differentiation capacity of the transduced cells were confirmed, and flow cytometry analysis and fluorescent microscopy showed that their myogenic phenotype was sustained. (18)F-fallypride and (18)F-fluoromisonidazole were successfully synthesized. Specific binding of (18)F-fallypride to hD2R hMPCs was demonstrated in vitro and in vivo. Furthermore, the (18)F-fluoromisonidazole signal was high at the early stages. Finally, sustained survival of the transplanted cells at different time points was confirmed histologically, with formation of muscle tissue at the site of injection. CONCLUSION: Our proposed use of a signaling-deficient hD2R as a potent reporter for in vivo hMPC PET tracking by (18)F-fallypride is a significant step toward potential noninvasive tracking of hD2R hMPCs and bioengineered muscle tissues in the clinic

Prospective multicentre study using high intensity focused ultrasound (HIFU) for the focal treatment of prostate cancer: Safety outcomes and complications

Purpose To investigate focal therapy using High Intensity Focused Ultrasound (HIFU) for the treatment of localized prostate cancer (CaP), we analyzed the safety and complications of this procedure. Methods Patients (pts) eligible for this multicenter prospective cohort study suffered from low to intermediate risk localized CaP with no prior treatment. After tumor identification on multiparametric MRI and in prostate biopsy, the lesions were treated with HIFU observing a safety margin of 8 to 10 mm. Adverse events (AE) after 30 and 90 days, as well as the required interventions were assessed and stratified for treatment localizations. Results Of the 98 men included in the study in two European centers, 35 (35.7%) experienced AEs in the first 30 days after HIFU intervention with Clavien-Dindo grade ≤ II: 15 pts (15.3%) had a postoperative urinary tract infection and 26 pts (26.5%) a urinary retention. Four pts (4.1%) underwent subsequent intervention (Clavien-Dindo grade IIIa/b). The number of late postoperative complications occurring between 30 and 90 days after intervention was low (2.0%). The highest complication rate was associated with tumors located at the anterior base (50.0%). The inclusion of the urethra in the ablation zone led to AEs in 20 out of 41 cases (48.8%) and represented a significant risk factor for complications within 30 days (odds ratio = 2.53; 95% confidence interval: 1.08–5.96; P = 0.033). Conclusions Focal therapy of CaP lesions with a robotic HIFU-probe is safe and renders an acceptable rate of minor early AEs. The inclusion of the urethra in the ablation zone leads to an increase in early complications and should be avoided whenever possible

Multi-proxy constraints on the significance of covariant δ13C values in carbonate and organic carbon during the early Mississippian

This study investigates the covariation between carbonate and organic δ13C values in a proximal to distal transect of four outcrops in the Madison Limestone in the Western United States Rockies, combined with δ34S values of carbonate associated sulphate, the concentration of acid-insoluble material and measurements of total organic carbon. These new geochemical datasets not only allow for an evaluation of carbon isotope covariance during one of the largest perturbations to the global carbon cycle over the past 550 Myr, but also constrain the cause of the excursion in carbonate δ13C values. The results support the hypothesis that a period of anoxia did not play a role in generating the positive carbonate δ13C values, but rather favour interpretations by previous workers that the proliferation of land plants destabilized the Carboniferous carbon cycle, setting the stage for a significant change in the carbonate δ13C values of contemporaneous marine carbonates. These results also demonstrate that one of the largest perturbations to the global carbon cycle did not produce synchronous variations in carbonate and organic δ13C values, emphasizing the importance of local depositional controls on carbon isotope covariance in the geological record in both modern and ancient environments

Infiltrative growth pattern of prostate cancer is associated with lower uptake on PSMA PET and reduced diffusion restriction on mpMRI

Purpose: Recently, a significant association was shown between novel growth patterns on histopathology of prostate cancer (PCa) and prostate-specific membrane antigen (PSMA) uptake on [68Ga]PSMA-PET. It is the aim of this study to evaluate the association between these growth patterns and ADC (mm2/1000 s) values in comparison to [68Ga]PSMA uptake on PET/MRI. Methods: We retrospectively evaluated patients who underwent [68Ga]PSMA PET/MRI for staging or biopsy guidance, followed by radical prostatectomy at our institution between 07/2016 and 01/2020. The dominant lesion per patient was selected based on histopathology and correlated to PET/MRI in a multidisciplinary meeting, and quantified using SUVmax for PSMA uptake and ADCmean for diffusion restriction. PCa growth pattern was classified as expansive (EXP) or infiltrative (INF) according to its properties of forming a tumoral mass or infiltrating diffusely between benign glands by two independent pathologists. Furthermore, the corresponding WHO2016 ISUP tumor grade was evaluated. The t test was used to compare means, Pearson's test for categorical correlation, Cohen's kappa test for interrater agreement, and ROC curve to determine the best cutoff. Results: Sixty-two patients were included (mean PSA 11.7 ± 12.5). The interrater agreement between both pathologists was almost perfect with κ = 0.81. While 25 lesions had an EXP-growth with an ADCmean of 0.777 ± 0.109, 37 showed an INF-growth with a significantly higher ADCmean of 1.079 ± 0.262 (p < 0.001). We also observed a significant difference regarding PSMA SUVmax for the EXP-growth (19.2 ± 10.9) versus the INF-growth (9.4 ± 6.2, p < 0.001). Within the lesions encompassing the EXP- or the INF-growth, no significant correlation between the ISUP groups and ADCmean could be observed (p = 0.982 and p = 0.861, respectively). Conclusion: PCa with INF-growth showed significantly lower SUVmax and higher ADCmean values compared to PCa with EXP-growth. Within the growth groups, ADCmean values were independent from ISUP grading. Keywords: Diffusion-weighted imaging; MRI; PSMA PET/MRI; Prostate cancer; Radical prostatectom

Environmental forcing of the Campeche cold-water coral province, southern Gulf of Mexico

With an extension of >40 km2 the recently discovered Campeche cold-water coral province located at the northeastern rim of the Campeche Bank in the southern Gulf of Mexico belongs to the largest coherent cold-water coral areas discovered so far. The Campeche province consists of numerous 20 to 40 m high coral ridges that are developed in intermediate water depths of 500 to 600 m. The ridges are colonized by a vivid cold-water coral ecosystem that covers the upper flanks and summits. The rich coral community is dominated by the framework-building scleractinia Enallopsammia profunda and Lophelia pertusa while the associated benthic megafauna shows a rather scarce occurrence. The recent environmental setting is characterized by a high surface water production caused by a local upwelling center and a dynamic bottom water regime comprising vigorous bottom currents, internal waves and strong density contrasts, which all together provide optimal conditions for the growth of cold-water corals. The strong hydrodynamics – potentially supported by the diel vertical migration of zooplankton in the Campeche area – drive the delivering of food particles to the corals. The Campeche cold-water coral province is, thus, an excellent example highlighting the importance of the hydrographic setting in securing the food supply for the development of large and vivid cold-water coral ecosystems