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Heart valve diseases are a prevalent cardiovascular pathology worldwide, affecting nearly 2.5% of the population. Degenerative aortic stenosis is the most common form of heart valve disease. The treatment options include surgical or transcatheter procedures. There are two main categories of valve prostheses available: mechanical heart valves constructed from synthetic materials and bioprosthetic heart valves made from natural biomaterials. The choice of valve type depends on various factors, including the underlying medical condition, suitability for anticoagulation, valve durability, and the patient’s age and preferences. Mechanical heart valves have the advantage of long-term durability. However, patients receiving mechanical implants are subjected to lifelong anticoagulation therapy with an increased risk of thromboembolism and bleeding. Natural biomaterials do not require long-term anticoagulation. However, they experience degenerative changes leading to structural valve deterioration (SVD) that may require reoperation. The purpose of this article is to review the role of natural biological materials used for aortic valve replacement or repair, assess their biomedical and clinical advantages and limitations, and analyze the direction and perspectives of future development.

Abstract Symptomatic, partial-thickness rotator cuff tears (sPTRCT) are problematic. This study tested the hypothesis that management of sPTRCT with injection of fresh, uncultured, unmodified, autologous, adipose-derived regenerative cells (UA-ADRCs) is safe and more effective than injection of corticosteroid even in the long run. To this end, subjects who had completed a former randomized controlled trial were enrolled in the present study. At baseline these subjects had not responded to physical therapy treatments for at least 6 weeks, and were randomly assigned to receive respectively a single injection of UA-ADRCs (n = 11) or a single injection of methylprednisolone (n = 5). Efficacy was assessed using the ASES Total score, pain visual analogue scale (VAS), RAND Short Form-36 Health Survey and range of motion at 33.2 ± 1.0 (mean ± SD) and 40.6 ± 1.9 months post-treatment. Proton density, fat-saturated, T2-weighted MRI of the index shoulder was performed at both study visits. There were no greater risks connected with injection of UA-ADRCs than those connected with injection of corticosteroid. The subjects in the UA-ADRCs group showed statistically significantly higher mean ASES Total scores than the subjects in the corticosteroid group. The MRI scans at 6 months post-treatment allowed to “watch the UA-ADRCs at work”.

In Huntington disease (HD) the prodromal phase has been increasingly investigated and is currently in focus for early interventional treatments. Also, the influence of sex on disease progression and severity in patients is under discussion, as a sex-specific impact has been reported in transgenic rodent models for HD. To this end, we have been studying these aspects in Sprague Dawley rats transgenic for HD. Here, we took up on the congenic F344tgHD rat model, expressing a fragmented Htt construct with 51 CAG repeats on an inbred F344 rat background and characterized potential sexual dimorphism and gene-dosage effects in rats during the pre-symptomatic phase (1–8 months of age). Our study comprises a longitudinal phenotyping of motor function, emotion and sensorimotor gating, as well as screening of metabolic parameters with classical and automated assays in combination with investigation of molecular HD hallmarks (striatal cell number and volume estimation, appearance of HTT aggregates). Differences between sexes became apparent during middle age, particularly in the motor and sensorimotor domains. Female individuals were generally more active, demonstrated different gait characteristics than males and less anxiolytic-like behavior. Alterations in both the time course and affected behavioral domains varied between male and female F344tgHD rats. First subtle behavioral anomalies were detected in transgenic F344tgHD rats prior to striatal MSN cell loss, revealing a prodromal-like phase in this model. Our findings demonstrate that the congenic F344tgHD rat model shows high face-validity, closely resembling the human disease’s temporal progression, while having a relatively low number of CAG repeats, a slowly progressing pathology with a prodromal-like phase and a comparatively subtle phenotype. By differentiating the sexes regarding HD-related changes and characterizing the prodromal-like phase in this model, these findings provide a foundation for future treatment studies.

Abstract Background Recently, the management of musculoskeletal disorders with the patients' own stem cells, isolated from the walls of small blood vessels, which can be found in great numbers in the adipose tissue, has received considerable attention. On the other hand, there are still misconceptions about these adipose-derived regenerative cells (ADRCs) that contain vascular-associated pluripotent stem cells (vaPS cells) in regenerative medicine. Methods Based on our previous publications on this topic, we have developed a concept to describe the significance of the ADRCs/vaPS cells in the field of orthobiologics as briefly as possible and at the same time as precisely as possible. Results The ADRCs/vaPS cells belong to the group of orthobiologics that are based on autologous cells. Because the latter can both stimulate a patient’s body's localized self-healing power and provide new cells that can integrate into the host tissue during the healing response when the localized self-healing power is exhausted, this group of orthobiologics appears more advantageous than cell-free orthobiologics and orthobiologics that are based on allogeneic cells. Within the group of orthobiologics that are based on autologous cells, enzymatically isolated, uncultured ADRCs/vaPS cells have several advantages over non-enzymatically isolated cells/microfragmented fat as well as over uncultured bone marrow aspirate concentrate and cultured cells (adipose-derived stem cells, bone marrow-derived mesenchymal stem cells). Conclusions The use of ADRCs/vaPS cells can be seamlessly integrated into modern orthopedic treatment concepts, which can be understood as the optimization of a process which—albeit less efficiently—also takes place physiologically. Accordingly, this new safe and effective type of treatment is attractive in terms of holistic thinking and personalized medicine.

Abstract Background Radial extracorporeal shock wave therapy (rESWT) is an attractive, non-invasive therapy option to manage fracture nonunions of superficial bones, with a reported success rate of approximately 75%. Using zebra mussels (Dreissena polymorpha), we recently demonstrated that induction of biomineralization after exposure to focused extracorporeal shock waves (fESWs) is not restricted to the region of direct energy transfer into calcified tissue. This study tested the hypothesis that radial extracorporeal shock waves (rESWs) also induce biomineralization in regions not directly exposed to the shock wave energy in zebra mussels. Methods Zebra mussels were exposed on the left valve to 1000 rESWs at different air pressure (between 0 and 4 bar), followed by incubation in calcein solution for 24 h. Biomineralization was evaluated by investigating the fluorescence signal intensity found on sections of the left and right valves prepared two weeks after exposure. Results General linear model analysis demonstrated statistically significant (p

Abstract Background To investigate whether respectively radial extracoporeal shock wave therapy (rESWT) or a combination of rESWT, celecoxib and eperisone (rESWT + C + E) are superior in reducing pain in patients with chronic nonspecific low back pain (cnsLBP) compared to C + E alone (a standard treatment of this condition in China). Methods 140 patients with cnsLBP were randomly allocated to rESWT (n = 47), rESWT + C + E (n = 45) or C + E alone (n = 48) for four weeks between November 2017 and March 2019. Outcome was evaluated using the Pain Self-Efficacy Questionnaire (PSEQ), Numerical Rating Scale (NRS), Oswestry Low Back Pain Disability Questionnaire and Patient Health Questionnaire 9, collected at baseline as well as one week (W1), W2, W3, W4 and W12 after baseline. Results All scores showed a statistically significant improvement over time. The PSEQ and NRS scores showed a significant Time × Treatment effect. Patients treated with rESWT had significantly lower mean NRS values than patients treated with rESWT + C + E at W1 and W3, as well as than patients treated with C + E alone at W3 and W4. No severe adverse events were observed. Conclusions rESWT may not be inferior to respectively rESWT + C + E or C + E alone in reducing pain in patients with cnsLBP. Level of Evidence: Level I, prospective, randomized, active-controlled trial. Trial registration: Clinicaltrials.gov Identifier NCT03337607. Registered November 09, 2017, https://www.clinicaltrials.gov/ct2/show/NCT03337607 . Level of evidence Level I; prospective, randomized, controlled trial.

Abstract Background To compare lay-off times achieved by treating acute muscle injuries in elite football players with a multimodal therapy approach that includes a specific protocol of almost daily radial extracorporeal shock wave therapy (rESWT) with corresponding data reported in the literature. Methods We performed a retrospective analysis of treatments and recovery times of muscle injuries suffered by the players of an elite football team competing in the first/second German Bundesliga during one of the previous seasons. Results A total of 20 acute muscle injuries were diagnosed and treated in the aforementioned season, of which eight (40%) were diagnosed as Type 1a/muscular tightness injuries, five (25%) as Type 2b/muscle strain injuries, four (20%) as Type 3a/partial muscle tear injuries and three (15%) as contusions. All injuries were treated with the previously mentioned multimodal therapy approach. Compared with data reported by Ekstrand et al. (Br J Sports Med 47:769–774, 2013), lay-off times (median/mean) were shortened by 54% and 58%, respectively, in the case of Type 1a injuries, by 50% and 55%, respectively, in the case of Type 2b injuries as well as by 8% and 21%, respectively, in the case of Type 3a injuries. No adverse reactions were observed. Conclusions Overall, the multimodal therapy approach investigated in this study is a safe and effective treatment approach for treating Type 1a and 2b acute muscle injuries amongst elite football players and may help to prevent more severe, structural muscle injuries.

The choice of parameters for laser beams used in the treatment of musculoskeletal diseases is of great importance. First, to reach high penetration depths into biological tissue and, secondly, to achieve the required effects on a molecular level. The penetration depth depends on the wavelength since there are multiple light-absorbing and scattering molecules in tissue with different absorption spectra. The present study is the first comparing the penetration depth of 1064 nm laser light with light of a smaller wavelength (905 nm) using high-fidelity laser measurement technology. Penetration depths in two types of tissue ex vivo (porcine skin and bovine muscle) were investigated. The transmittance of 1064 nm light through both tissue types was consistently higher than of 905 nm light. The largest differences (up to 5.9%) were seen in the upper 10 mm of tissue, while the difference vanished with increasing tissue thickness. Overall, the differences in penetration depth were comparably small. These results may be of relevance in the selection of a certain wavelength in the treatment of musculoskeletal diseases with laser therapy.

BackgroundHeart-focused anxiety (HFA) raises the risk for adverse outcomes in patients with heart disease. Despite this great importance, it is rarely assessed in clinical practice. Three dimensions are commonly defined in the context of HFA: heart-related fear, avoidance, and attention. The impact of these aspects on cardiac risk factors is essentially unclear. In this study, we investigated the relationship between HFA and behavioral cardiac risk factors as well as health-related quality of life (HRQoL), which represent important treatment outcomes of inpatient psycho-cardiological rehabilitation.MethodsA prospective observational design was used to examine 238 rehabilitation inpatients with comorbidity of cardiac disease and psychiatric disorder. We assessed HFA using the Cardiac Anxiety Questionnaire (CAQ), HRQoL using the SF-12 Health Survey, exercise capacity using the 6-minute walk test, and smoking behavior, respectively at admission (t0) and discharge (t1). Physical activity was assessed at t0 and in a follow-up survey 6 months after discharge (t2) using the International Physical Activity Questionnaire (IPAQ). Multiple regression models were used to analyze the predictive value of HFA for the outcome variables at t0, t1, and t2, adjusted for socio-demographic factors and depression. Predictive values for changes over time were evaluated by the regressor variable approach.ResultsExercise capacity and physical activity were negatively predicted by baseline heart-related avoidance, both cross-sectionally and prospectively. Avoidance at t1 also negatively predicted long-term changes over time in physical activity at t2. Total HFA and the subcomponent avoidance negatively predicted physical HRQoL both cross-sectionally and prospectively. Mental HRQoL was cross-sectionally predicted by heart-focused attention at t0, and prospectively predicted by total HFA and by avoidance. Regarding changes in the course of rehabilitation, baseline avoidance negatively predicted improvement in physical HRQoL during rehabilitation. Concerning smoking behavior, no associations with HFA were found.ConclusionsHFA is a relevant inhibiting factor for the achievement of therapy goals in psycho-cardiological rehabilitation such as health behavior and HRQoL. Heart-related avoidance in particular, has a negative impact on exercise capacity, physical activity, and self-reported physical health. Its prospective negative predictive value for physical activity and physical health underlines the relevance of HFA for psycho-cardiological interventions.

Laser therapy devices (LTDs) operating with near-infrared laser light are increasingly being used in sports medicine. For several reasons, users cannot evaluate whether or not such devices emit laser beams according to the specifications provided by the manufacturer and the settings of the device. In this study, the laser beams from two different LTDs that can be used in sports medicine were thoroughly characterized by measuring the emitted power, pulse shapes and lengths and spatial intensity distributions using professional, high-fidelity laser measurement technology. This was repeated for three units of each LDT independently to distinguish problems of individual units from potential intrinsic instrument design errors. The laser beams from the units of one LTD agreed with the settings of the device, with the measured average power for these units being within 3.3% of the set power. In contrast, the laser beams from the units of the other LTD showed large deviations between the settings and the actual emitted light. This device came with three laser diodes that could be used independently and simultaneously. The average power differed greatly between the units as well as between the laser diodes within each unit. Some laser diodes emitted essentially no light, which could lead to a lack of treatment for patients. Other laser diodes emitted much more power than set at the device (up to 230%), which could result in skin irritations or burning of patients. These findings indicate a need for better standardization and consistency of therapeutic laser light sources.

Abstract Gadolinium based contrast agents (GBCAs) are widely used in clinical MRI since the mid-1980s. Recently, concerns have been raised that trace amounts of Gadolinium (Gd), detected in brains even long time after GBCA application, may cause yet unrecognized clinical consequences. We therefore assessed the behavioral phenotype, neuro-histopathology, and Gd localization after repeated administration of linear (gadodiamide) or macrocyclic (gadobutrol) GBCA in rats. While most behavioral tests revealed no difference between treatment groups, we observed a transient and reversible decrease of the startle reflex after gadodiamide application. Residual Gd in the lateral cerebellar nucleus was neither associated with a general gene expression pathway deregulation nor with neuronal cell loss, but in gadodiamide-treated rats Gd was associated with the perineuronal net protein aggrecan and segregated to high molecular weight fractions. Our behavioral finding together with Gd distribution and speciation support a substance class difference for Gd presence in the brain after GBCA application.

Leaflet durability and costs restrict contemporary trans-catheter aortic valve replacement (TAVR) largely to elderly patients in affluent countries. TAVR that are easily deployable, avoid secondary procedures and are also suitable for younger patients and non-calcific aortic regurgitation (AR) would significantly expand their global reach. Recognizing the reduced need for post-implantation pacemakers in balloon-expandable (BE) TAVR and the recent advances with potentially superior leaflet materials, a trans-catheter BE-system was developed that allows tactile, non-occlusive deployment without rapid pacing, direct attachment of both bioprosthetic and polymer leaflets onto a shape-stabilized scallop and anchorage achieved by plastic deformation even in the absence of calcification. Three sizes were developed from nickel-cobalt-chromium MP35N alloy tubes: Small/23 mm, Medium/26 mm and Large/29 mm. Crimp-diameters of valves with both bioprosthetic (sandwich-crosslinked decellularized pericardium) and polymer leaflets (triblock polyurethane combining siloxane and carbonate segments) match those of modern clinically used BE TAVR. Balloon expansion favors the wing-structures of the stent thereby creating supra-annular anchors whose diameter exceeds the outer diameter at the waist level by a quarter. In the pulse duplicator, polymer and bioprosthetic TAVR showed equivalent fluid dynamics with excellent EOA, pressure gradients and regurgitation volumes. Post-deployment fatigue resistance surpassed ISO requirements. The radial force of the helical deployment balloon at different filling pressures resulted in a fully developed anchorage profile of the valves from two thirds of their maximum deployment diameter onwards. By combining a unique balloon-expandable TAVR system that also caters for non-calcific AR with polymer leaflets, a powerful, potentially disruptive technology for heart valve disease has been incorporated into a TAVR that addresses global needs. While fulfilling key prerequisites for expanding the scope of TAVR to the vast number of patients of low- to middle income countries living with rheumatic heart disease the system may eventually also bring hope to patients of high-income countries presently excluded from TAVR for being too young.

Abstract Background This study tested the hypothesis that treatment of symptomatic, partial-thickness rotator cuff tears (sPTRCT) with fresh, uncultured, unmodified, autologous adipose-derived regenerative cells (UA-ADRCs) isolated from lipoaspirate at the point of care is safe and more effective than corticosteroid injection. Methods Subjects aged between 30 and 75 years with sPTRCT who did not respond to physical therapy treatments for at least 6 weeks were randomly assigned to receive a single injection of an average 11.4 × 106 UA-ADRCs (in 5 mL liquid; mean cell viability: 88%) (n = 11; modified intention-to-treat (mITT) population) or a single injection of 80 mg of methylprednisolone (40 mg/mL; 2 mL) plus 3 mL of 0.25% bupivacaine (n = 5; mITT population), respectively. Safety and efficacy were assessed using the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), RAND Short Form-36 Health Survey, and pain visual analogue scale (VAS) at baseline (BL) as well as 3 weeks (W3), W6, W9, W12, W24, W32, W40, and W52 post treatment. Fat-saturated T2-weighted magnetic resonance imaging of the shoulder was performed at BL as well as at W24 and W52 post treatment. Results No severe adverse events related to the injection of UA-ADRCs were observed in the 12 months post treatment. The risks connected with treatment of sPTRCT with UA-ADRCs were not greater than those connected with treatment of sPTRCT with corticosteroid injection. However, one subject in the corticosteroid group developed a full rotator cuff tear during the course of this pilot study. Despite the small number of subjects in this pilot study, those in the UA-ADRCs group showed statistically significantly higher mean ASES total scores at W24 and W52 post treatment than those in the corticosteroid group (p < 0.05). Discussion This pilot study suggests that the use of UA-ADRCs in subjects with sPTRCT is safe and leads to improved shoulder function without adverse effects. To verify the results of this initial safety and feasibility pilot study in a larger patient population, a randomized controlled trial on 246 patients suffering from sPTRCT is currently ongoing. Trial registration Clinicaltrials.gov ID NCT02918136. Registered September 28, 2016, https://clinicaltrials.gov/ct2/show/NCT02918136 . Level of evidence Level I; prospective, randomized, controlled trial.

There is increasing interest in the application of near-infrared (NIR) laser light for the treatment of various musculoskeletal disorders. The present study thoroughly examined the physical characteristics of laser beams from two different laser therapy devices that are commercially available for the treatment of musculoskeletal disorders. Then, these laser beams were used to measure the penetration depth in various biological tissues from different animal species. The key result of the present study was the finding that for all investigated tissues, most of the initial light energy was lost in the first one to two millimeters, more than 90% of the light energy was absorbed within the first ten millimeters, and there was hardly any light energy left after 15–20 mm of tissue. Furthermore, the investigated laser therapy devices fundamentally differed in several laser beam parameters that can have an influence on how light is transmitted through tissue. Overall, the present study showed that a laser therapy device that is supposed to reach deep layers of tissue for treatments of musculoskeletal disorders should operate with a wavelength between 800 nm and 905 nm, a top-hat beam profile, and it should emit very short pulses with a large peak power.

Uncultured, unmodified, autologous, adipose-derived regenerative cells (UA-ADRCs) are a safe and effective treatment option for various musculoskeletal pathologies. However, it is unknown whether the composition of the final cell suspension systematically varies with the subject’s individual age, sex, body mass index and ethnicity. UA-ADRCs were isolated from lipoaspirate from n = 232 subjects undergoing elective lipoplasty using the Transpose RT system (InGeneron, Inc.; Houston, TX, USA). The UA-ADRCs were assessed for the number of nucleated cells, cell viability and the number of viable nucleated cells per gram of adipose tissue harvested. Cells from n = 37 subjects were further characterized using four-channel flow cytometry. The present study shows, for the first time, that key characteristics of UA-ADRCs can be independent of the subject’s age, sex, BMI and ethnicity. This result has important implications for the general applicability of UA-ADRCs in regeneration of musculoskeletal tissue. Future studies must determine whether the independence of key characteristics of UA-ADRCs of the subject’s individual age, sex, BMI and ethnicity only applies to the system used in the present study, or also to others of the more than 25 different experimental methods and commercially available systems used to isolate UA-ADRCs from lipoaspirate that have been described in the literature.

Hippocampus-related cognitive deficits in working and verbal memory are frequent in schizophrenia, and hippocampal volume loss, particularly in the cornu ammonis (CA) subregions, was shown by magnetic resonance imaging studies. However, the underlying cellular alterations remain elusive. By using unbiased design-based stereology, we reported a reduction in oligodendrocyte number in CA4 in schizophrenia and of granular neurons in the dentate gyrus (DG). Here, we aimed to replicate these findings in an independent sample. We used a stereological approach to investigate the numbers and densities of neurons, oligodendrocytes, and astrocytes in CA4 and of granular neurons in the DG of left and right hemispheres in 11 brains from men with schizophrenia and 11 brains from age- and sex-matched healthy controls. In schizophrenia, a decreased number and density of oligodendrocytes was detected in the left and right CA4, whereas mean volumes of CA4 and the DG and the numbers and density of neurons, astrocytes, and granular neurons were not different in patients and controls, even after adjustment of variables because of positive correlations with postmortem interval and age. Our results replicate the previously described decrease in oligodendrocytes bilaterally in CA4 in schizophrenia and point to a deficit in oligodendrocyte maturation or a loss of mature oligodendrocytes. These changes result in impaired myelination and neuronal decoupling, both of which are linked to altered functional connectivity and subsequent cognitive dysfunction in schizophrenia.

Abstract Background Acute injuries of the hamstring muscle complex (HMC) type 3b (interfascicle/bundle-tear) are frequently observed in various sports disciplines both in elite and recreational sport. The treatment of choice of acute HMC injuries type 3b is a progressive physiotherapeutic exercise programme. Besides this, there is currently only insufficient scientific evidence to support other treatment methods, including local infiltrations and injections of platelet-rich-plasma. Very recently, it was demonstrated that extracorporeal shock wave therapy (ESWT) may accelerate regeneration after acute skeletal muscle injury. The aim of the present study is to test the hypothesis that the combination of radial ESWT (rESWT) and a specific rehabilitation program (RP) is effective and safe in treatment of acute HMC injury type 3b in athletes, and is statistically significantly more effective than the combination of sham-rESWT and RP. Methods We will perform a double blind, randomized, sham-controlled clinical trial at the clinic KinEf Kinesiología Deportiva, Ciudad Autónoma de Buenos Aires, Argentina. Forty patients with acute HMC injury type 3b will be randomly allocated to receive either rESWT (nine rESWT sessions; three sessions per week; 2500 radial extracorporeal shock waves (rESWs) per session; energy density depending on what the patient tolerates) or sham-rESWT. In addition, all patients will receive a specific rehabilitation program that will last for 8 weeks. The primary outcome measure will be the individual time (days) necessary to return to play. Secondary outcomes will include the presence or absence of reinjury during a time period of 6 months after inclusion into the study. Discussion Because of the lack of adequate treatment options for acute HMC injury type 3b in athletes and particularly the high reinjury rate, we hypothesize that the results of this trial will be of importance and have impact on clinical practice. Trial registration ClinicalTrials.gov ID NCT03473899. Registered March 22, 2018.

Extracorporeal shock wave therapy (ESWT) is a safe and effective treatment option for various pathologies of the musculoskeletal system. Many studies address the molecular and cellular mechanisms of action of ESWT. However, to date, no uniform concept could be established on this matter. In the present study, we perform a systematic review of the effects of exposure of musculoskeletal tissue to extracorporeal shock waves (ESWs) reported in the literature. The key results are as follows: (i) compared to the effects of many other forms of therapy, the clinical benefit of ESWT does not appear to be based on a single mechanism; (ii) different tissues respond to the same mechanical stimulus in different ways; (iii) just because a mechanism of action of ESWT is described in a study does not automatically mean that this mechanism is relevant to the observed clinical effect; (iv) focused ESWs and radial ESWs seem to act in a similar way; and (v) even the most sophisticated research into the effects of exposure of musculoskeletal tissue to ESWs cannot substitute clinical research in order to determine the optimum intensity, treatment frequency and localization of ESWT.

Mussels have been used as animal models for studying ecotoxicology, biomineralization, and bio-adhesion for many years. Despite a wealth of studies on their shell matrix and byssus proteins, few studies have focused on the extracellular matrix molecules in mussel soft tissues. Extracellular matrix molecules may play important roles in biomineralization, immune reaction, and tissue homeostasis. In the present study, extracellular matrix and mineralization-related molecules in zebra mussel soft tissue were immunolocalized using well-characterized monoclonal antibodies. Our results demonstrate specific immunolocalization for collagen IV, fibronectin, and keratan sulfate in hemocytes; collagen IV in peripheral nerves; and aggrecan, link protein, and collagen XVIII in foot tissue. Laminin, decorin, and osteonectin were also broadly immunolocalized in mussel soft tissues. The distributions of these extracellular matrix molecules in mussel tissues are in line with the cell-mediated shell mineralization hypothesis, providing evidence for the molecules involved in the peripheral nervous system and byssus formation, and explaining the conservation of extracellular matrix molecules during evolution. These results further contribute to establishing zebra mussels as an attractive animal model in biomedical research.

Background and Objectives: This study tested the hypothesis that treatment of myofascial trigger points (MTrPs) in the upper trapezius muscle (UTM) with repeated injection of 1% lidocaine results in better alleviation of muscular stiffness and soreness as well as improved metabolism in the hypercontracted MTrP area than treatment with radial extracorporeal shock wave therapy (rESWT). Materials and Methods: A single-blinded, prospective, randomized controlled trial was conducted on patients suffering from MTrPs in the UTM. Thirty patients were treated with repeated injection of 2 mL of 1% lidocaine (three injections; one injection per week). Another 30 patients were treated with rESWT (three treatment sessions; one treatment session per week; 2000 radial extracorporeal shock waves per treatment session; positive energy flux density = 0.10 mJ/mm2). The primary outcome measure was pain severity using the VAS score. The secondary outcome measures included muscle elasticity index, pressure pain threshold and neck disability index. Evaluation was performed at baseline (T1), 15–30 min after the first treatment in order to register immediate treatment effects (T2), before the second treatment (i.e., one week after baseline) (T3) and one week after the third treatment (i.e., four weeks after baseline) (T4). Results: There were no statistically significant differences in the primary and secondary outcome measures between the patients in the lidocaine arm and the patients in the rESWT arm at T1 and T4. Within the arms, the mean differences of all outcomes were statistically significant (p < 0.001) when comparing the data obtained at T1 with the data obtained at T3 and the data obtained at T4. Conclusions: The results of this pilot study suggest that the use of rESWT in patients with MTrPs in the UTM is safe and leads to reduced pain and improved muscle elasticity, pressure pain threshold and neck disability index, without adverse effects. Larger trials are necessary to verify this. Clinicians should consider rESWT instead of injections of lidocaine in the treatment of MTrPs in the UTM.

(1) Background: Conclusions of meta-analyses of clinical studies may substantially influence opinions of prospective patients and stakeholders in healthcare. Nineteen meta-analyses of clinical studies on the management of primary knee osteoarthritis (pkOA) with stem cells, published between January 2020 and July 2021, came to inconsistent conclusions regarding the efficacy of this treatment modality. It is possible that a separate meta-analysis based on an independent, systematic assessment of clinical studies on the management of pkOA with stem cells may reach a different conclusion. (2) Methods: PubMed, Web of Science, and the Cochrane Library were systematically searched for clinical studies and meta-analyses of clinical studies on the management of pkOA with stem cells. All clinical studies and meta-analyses identified were evaluated in detail, as were all sub-analyses included in the meta-analyses. (3) Results: The inconsistent conclusions regarding the efficacy of treating pkOA with stem cells in the 19 assessed meta-analyses were most probably based on substantial differences in literature search strategies among different authors, misconceptions about meta-analyses themselves, and misconceptions about the comparability of different types of stem cells with regard to their safety and regenerative potential. An independent, systematic review of the literature yielded a total of 183 studies, of which 33 were randomized clinical trials, including a total of 6860 patients with pkOA. However, it was not possible to perform a scientifically sound meta-analysis. (4) Conclusions: Clinicians should interpret the results of the 19 assessed meta-analyses of clinical studies on the management of pkOA with stem cells with caution and should be cautious of the conclusions drawn therein. Clinicians and researchers should strive to participate in FDA and/or EMA reviewed and approved clinical trials to provide clinically and statistically valid efficacy.

Objectives: To investigate whether botulinum toxin type A (BTX-A) injection is more effective than radial extracorporeal shock wave therapy in reducing plantar flexor muscle spasticity in subjects with cerebral palsy. Methods: A total of 68 subjects with cerebral palsy were randomly allocated to BTX-A injection (Group 1) or radial extracorporeal shock wave therapy (Group 2) (first experiment; E1). Outcome was evaluated using the Tardieu V1 and V3 stretches, at 3 weeks, 2 months (M2) and M3 after baseline. At M6 subjects in Group 1 received radial extracorporeal shock wave therapy and subjects in Group 2 received BTX-A injection (second experiment; E2); outcome was evaluated as in E1. Treatment success was defined as improvement in foot dorsiflexion ≥10° when performing the V3 stretch at M2 in both experiments. Results: In both experiments mean V1 and V3 significantly improved over time. In E1 both treatments resulted in similar treatment success. In E2 fewer subjects treated with BTX-A injection reached the criteria of treatment success than did subjects treated with radial extracorporeal shock wave therapy, which was due to a carry-over effect from E1. No significant complications were observed. Conclusion: BTX-A injection is not superior to radial extracorporeal shock wave therapy in the treatment of plantar flexor muscle spasticity in subjects with cerebral palsy.

Accumulating evidence suggests that a degenerative processes within the brain can trigger the formation of new, focal inflammatory lesions in Multiple Sclerosis (MS). Here, we used a novel pre-clinical MS animal model to test whether the amelioration of degenerative brain events reduces the secondary recruitment of peripheral immune cells and, in consequence, inflammatory lesion development.Neural degeneration was induced by a 3 weeks cuprizone intoxication period. To mitigate the cuprizone-induced pathology, animals were treated with Laquinimod (25 mg/kg) during the cuprizone-intoxication period. At the beginning of week 6, encephalitogenic T cell development in peripheral lymphoid organs was induced by the immunization with myelin oligodendrocyte glycoprotein 35–55 peptide (i.e., Cup/EAE). Demyelination, axonal injury and reactive gliosis were determined by immunohistochemistry. Positron emission tomography (PET) imaging was performed to analyze glia activation in vivo.Vehicle-treated cuprizone mice displayed extensive callosal demyelination, glia activation and enhanced TSPO-ligand binding. This cuprizone-induced pathology was profoundly ameliorated in mice treated with Laquinimod. In vehicle-treated Cup/EAE mice, the cuprizone-induced pathology triggered massive peripheral immune cell recruitment into the forebrain, evidenced by multifocal perivascular inflammation, glia activation and neuro-axonal injury. While anti myelin oligodendrocyte glycoprotein 35–55 peptide immune responses were comparable in vehicle- and Laquinimod-treated Cup/EAE mice, the cuprizone-triggered immune cell recruitment was ameliorated by the Laquinimod treatment.This study clearly illustrates that amelioration of a primary brain-intrinsic degenerative process secondary halts peripheral immune cell recruitment and, in consequence, inflammatory lesion development. These findings have important consequences for the interpretation of the results of clinical studies.

Abstract Blast-related mild traumatic brain injury induces significant long-term health issues, yet treatment procedures remain underdeveloped. Therapeutic hypothermia has been postulated as a potentially effective therapy. In a Caenorhabditis elegans model, we demonstrate a dose-dependent reduction in lifespan following exposure to blast-like shock waves. Using polyvinyl alcohol, we show that cavitation is a key injurious factor in the damaging shock wave component. Short and long lifespan C. elegans mutants demonstrated the interaction of genetic and environmental longevity-determining factors. Hypothermia reduced the long term effect of shock wave exposure. Thus, we present an effective C. elegans model of long term effects of blast-related mild traumatic brain injury, as well as evidence of the merit of therapeutic hypothermia as a therapy option following blast exposure.

Abstract Background Recent clinical and animal studies have shown that extracorporeal shock wave therapy has a promoting influence on the healing process of musculoskeletal disorders. However, the underlying biological effects of extracorporeal shock wave therapy on human skeletal muscle cells have not yet been investigated. Methods In this study, we investigated human skeletal muscle cells after exposure to radial extracorporeal shock waves in a standardized in vitro setup. Cells were isolated from muscle specimens taken from adult patients undergoing spine surgery. Primary muscle cells were exposed once or twice to radial extracorporeal shock waves in vitro with different energy flux densities. Cell viability and gene expression of the paired box protein 7 (Pax7), neural cell adhesion molecule (NCAM), and myogenic factor 5 (Myf5) and MyoD as muscle cell markers were compared to non-treated muscle cells that served as controls. Results Isolated muscle cells were positive for the hallmark protein of satellite cells, Pax7, as well as for the muscle cell markers NCAM, MyoD, and Myf5. Exposure to radial extracorporeal shock waves at low energy flux densities enhanced cell viability, whereas higher energy flux densities had no further significant impact. Gene expression analyses of muscle specific genes (Pax7, NCAM, Myf5, and MyoD) demonstrated a significant increase after single exposure to the highest EFD (4 bar, 0.19 mJ/mm2) and after double exposure with the medium EFDs (2 and 3 bar; 0.09 and 0.14 mJ/mm2, respectively). Double exposure of the highest EFD, however, results in a significant down-regulation when compared to single exposure with this EFD. Conclusions This is the first study demonstrating that radial extracorporal shock wave therapy has the potential to modulate the biological function of human skeletal muscle cells. Based on our experimental findings, we hypothesize that radial extracorporal shock wave therapy could be a promising therapeutic modality to improve the healing process of sports-related structural muscle injuries.

Abstract Background A substantial body of evidence supports the use of focused extracorporeal shock wave therapy (fESWT) in the non-invasive treatment of fracture nonunions. On the other hand, virtually no studies exist on the use of radial extracorporeal shock wave therapy (rESWT) for this indication. Methods We retrospectively analyzed 22 patients treated with rESWT for fracture nonunions of superficial bones that failed to heal despite initial surgical fixation in most cases. Radial extracorporeal shock wave therapy was applied without anesthesia in three rESWT sessions on average, with one rESWT session per week and 3000 radial extracorporeal shock waves at an energy flux density of 0.18 mJ/mm2 per session. Treatment success was monitored with radiographs and clinical examinations. Results Six months after rESWT radiographic union was confirmed in 16 out of 22 patients (73%), which is similar to the success rate achieved in comparable studies using fESWT. There were no side effects. The tibia was the most common treatment site (10/22) and 70% of tibia nonunions healed within 6 months after rESWT. Overall, successfully treated patients showed a mean time interval of 8.8 ± 0.8 (mean ± standard error of the mean) months between initial fracture and commencement of rESWT whereas in unsuccessfully treated patients the mean interval was 26.0 ± 10.1 months (p

A certain cell type can be isolated from different organs in the adult body that can differentiate into ectoderm, mesoderm, and endoderm, providing significant support for the existence of a certain type of small, vascular-associated, pluripotent stem cell ubiquitously distributed in all organs in the adult body (vaPS cells). These vaPS cells fundamentally differ from embryonic stem cells and induced pluripotent stem cells in that the latter possess the necessary genetic guidance that makes them intrinsically pluripotent. In contrast, vaPS cells do not have this intrinsic genetic guidance, but are able to differentiate into somatic cells of all three lineages under guidance of the microenvironment they are located in, independent from the original tissue or organ where they had resided. These vaPS cells are of high relevance for clinical application because they are contained in unmodified, autologous, adipose-derived regenerative cells (UA-ADRCs). The latter can be obtained from and re-applied to the same patient at the point of care, without the need for further processing, manipulation, and culturing. These findings as well as various clinical examples presented in this paper demonstrate the potential of UA-ADRCs for enabling an entirely new generation of medicine for the benefit of patients and healthcare systems.

Resistive switching in metal oxides is related to the migration of donor defects. Here Baeumer et al. use in operandoX-ray spectromicroscopy to quantify the doping locally and show that small local variations in the donor concentration result in large variations in the device resistance.

The water channel protein aquaporin-4 (AQP4) is required for a normal rate of water exchange across the blood–brain interface. Following the discovery that AQP4 is a possible autoantigen in neuromyelitis optica, the function of AQP4 in health and disease has become a research focus. While several studies have addressed the expression and function of AQP4 during inflammatory demyelination, relatively little is known about its expression during non-autoimmune-mediated myelin damage. In this study, we used the toxin-induced demyelination model cuprizone as well as a combination of metabolic and autoimmune myelin injury (i.e., Cup/EAE) to investigate AQP4 pathology. We show that during toxin-induced demyelination, diffuse AQP4 expression increases, while polarized AQP4 expression at the astrocyte endfeet decreases. The diffuse increased expression of AQP4 was verified in chronic-active multiple sclerosis lesions. Around inflammatory brain lesions, AQP4 expression dramatically decreased, especially at sites where peripheral immune cells penetrate the brain parenchyma. Humoral immune responses appear not to be involved in this process since no anti-AQP4 antibodies were detected in the serum of the experimental mice. We provide strong evidence that the diffuse increase in anti-AQP4 staining intensity is due to a metabolic injury to the brain, whereas the focal, perivascular loss of anti-AQP4 immunoreactivity is mediated by peripheral immune cells.

It has become practically impossible to survey the literature on cells derived from adipose tissue for regenerative medicine. The aim of this paper is to provide a comprehensive and translational understanding of the potential of UA-ADRCs (uncultured, unmodified, fresh, autologous adipose derived regenerative cells isolated at the point of care) and its application in regenerative medicine. We provide profound basic and clinical evidence demonstrating that tissue regeneration with UA-ADRCs is safe and effective. ADRCs are neither ‘fat stem cells’ nor could they exclusively be isolated from adipose tissue. ADRCs contain the same adult stem cells ubiquitously present in the walls of blood vessels that are able to differentiate into cells of all three germ layers. Of note, the specific isolation procedure used has a significant impact on the number and viability of cells and hence on safety and efficacy of UA-ADRCs. Furthermore, there is no need to specifically isolate and separate stem cells from the initial mixture of progenitor and stem cells found in ADRCs. Most importantly, UA-ADRCs have the physiological capacity to adequately regenerate tissue without need for more than minimally manipulating, stimulating and/or (genetically) reprogramming the cells for a broad range of clinical applications. Tissue regeneration with UA-ADRCs fulfills the criteria of homologous use as defined by the regulatory authorities.

The analysis of electronic and structural properties of surfaces has been greatly advanced by photoemission electron microscopy and spectroscopy techniques. To further improve lateral and energy resolution of the instruments, it is necessary to optimize parameters of the radiation sources employed for photoemission studies (e.g. photon flux, pulse duration, spot size etc). We studied space charge effects observed in an energy-filtering photoemission electron microscope operated with a compact laboratory-scale gas-discharge extreme ultraviolet light source. In this system, we found limits of spatial- and energy-resolution controlled by the source radiation parameters. The pulse repetition rate can be varied in the kHz range and the duration of the EUV emission was measured to be several tens of nanoseconds long, and thereby very different from the standard synchrotron sources typically used for similar experiments. The spatial resolution could be improved by a factor of 5, but only on the expense of the photon density per pulse, which had to be decreased by a factor of 17 in order to reduce the image blur due to space charge effects. Furthermore, we found broadening of the x-ray photoelectron spectroscopy peaks for high photon fluxes. We have also performed a n -body Monte Carlo simulation to evaluate the difference between core-level photoelectrons and secondary electrons with respect to space charge.

The success rate of extracorporeal shock wave therapy (ESWT) for fracture nonunions in human medicine (i.e. radiographic union at 6 months after ESWT) is only approximately 75%. Detailed knowledge regarding the underlying mechanisms that induce bio-calcification after ESWT is limited. We analyzed the biological response within mineralized tissue of a new invertebrate model organism, the zebra mussel Dreissena polymorpha, after exposure with extracorporeal shock waves (ESWs). Mussels were exposed to ESWs with positive energy density of 0.4 mJ/mm2 (A) or were sham exposed (B). Detection of newly calcified tissue was performed by exposing the mussels to fluorescent markers. Two weeks later, the A-mussels showed a higher mean fluorescence signal intensity within the shell zone than the B-mussels (P

Recent design-based stereologic studies have shown that the early postnatal (

Inflammatory demyelination, which is a characteristic of multiple sclerosis lesions, leads to acute functional deficits and, in the long term, to progressive axonal degeneration. While remyelination is believed to protect axons, the endogenous-regenerative processes are often incomplete or even completely fail in many multiple sclerosis patients. Although it is currently unknown why remyelination fails, recurrent demyelination of previously demyelinated white matter areas is one contributing factor. In this study, we investigated whether laquinimod, which has demonstrated protective effects in active multiple sclerosis patients, protects against recurrent demyelination. To address this, male mice were intoxicated with cuprizone for up to eight weeks and treated with either a vehicle solution or laquinimod at the beginning of week 5, where remyelination was ongoing. The brains were harvested and analyzed by immunohistochemistry. At the time-point of laquinimod treatment initiation, oligodendrocyte progenitor cells proliferated and maturated despite ongoing demyelination activity. In the following weeks, myelination recovered in the laquinimod- but not vehicle-treated mice, despite continued cuprizone intoxication. Myelin recovery was paralleled by less severe microgliosis and acute axonal injury. In this study, we were able to demonstrate that laquinimod, which has previously been shown to protect against cuprizone-induced oligodendrocyte degeneration, exerts protective effects during oligodendrocyte progenitor differentiation as well. By this mechanism, laquinimod allows remyelination in non-supportive environments. These results should encourage further clinical studies in progressive multiple sclerosis patients.

Brain volume measurement is one of the most frequently used biomarkers to establish neuroprotective effects during pre-clinical multiple sclerosis (MS) studies. Furthermore, whole-brain atrophy estimates in MS correlate more robustly with clinical disability than traditional, lesion-based metrics. However, the underlying mechanisms leading to brain atrophy are poorly understood, partly due to the lack of appropriate animal models to study this aspect of the disease. The purpose of this study was to assess brain volumes and neuro-axonal degeneration after acute and chronic cuprizone-induced demyelination. C57BL/6 male mice were intoxicated with cuprizone for up to 12 weeks. Brain volume, as well as total numbers and densities of neurons, were determined using design-based stereology. After five weeks of cuprizone intoxication, despite severe demyelination, brain volumes were not altered at this time point. After 12 weeks of cuprizone intoxication, a significant volume reduction was found in the corpus callosum and diverse subcortical areas, particularly the internal capsule and the thalamus. Thalamic volume loss was accompanied by glucose hypermetabolism, analyzed by [18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron-emission tomography. This study demonstrates region-specific brain atrophy of different subcortical brain regions after chronic cuprizone-induced demyelination. The chronic cuprizone demyelination model in male mice is, thus, a useful tool to study the underlying mechanisms of subcortical brain atrophy and to investigate the effectiveness of therapeutic interventions.

Positron emission tomography (PET) ligands targeting the translocator protein (TSPO) represent promising tools to visualize neuroinflammation in multiple sclerosis (MS). Although it is known that TSPO is expressed in the outer mitochondria membrane, its cellular localization in the central nervous system under physiological and pathological conditions is not entirely clear. The purpose of this study was to assess the feasibility of utilizing PET imaging with the TSPO tracer, [18F]-GE180, to detect histopathological changes during experimental demyelination, and to determine which cell types express TSPO. C57BL/6 mice were fed with cuprizone for up to 5 weeks to induce demyelination. Groups of mice were investigated by [18F]-GE180 PET imaging at week 5. Recruitment of peripheral immune cells was triggered by combining cuprizone intoxication with MOG35⁻55 immunization (i.e., Cup/EAE). Immunofluorescence double-labelling and transgene mice were used to determine which cell types express TSPO. [18F]-GE180-PET reliably detected the cuprizone-induced pathology in various white and grey matter regions, including the corpus callosum, cortex, hippocampus, thalamus and caudoputamen. Cuprizone-induced demyelination was paralleled by an increase in TSPO expression, glia activation and axonal injury. Most of the microglia and around one-third of the astrocytes expressed TSPO. TSPO expression induction was more severe in the white matter corpus callosum compared to the grey matter cortex. Although mitochondria accumulate at sites of focal axonal injury, these mitochondria do not express TSPO. In Cup/EAE mice, both microglia and recruited monocytes contribute to the TSPO expressing cell populations. These findings support the notion that TSPO is a valuable marker for the in vivo visualization and quantification of neuropathological changes in the MS brain. The pathological substrate of an increase in TSPO-ligand binding might be diverse including microglia activation, peripheral monocyte recruitment, or astrocytosis, but not axonal injury.

After myocardial infarction, the implantation of stem cell seeded scaffolds on the ischemic zone represents a promising strategy for restoration of heart function. However, mechanical integrity and functionality of tissue engineered constructs need to be determined prior to implantation. Therefore, in this study a novel pulsatile bioreactor mimicking the myocardial contraction was developed to analyze the behavior of mesenchymal stem cells derived from umbilical cord tissue (UCMSC) colonized on titanium-coated polytetrafluorethylene scaffolds to friction stress. The design of the bioreactor enables a simple handling and defined mechanical forces on three seeded scaffolds at physiological conditions. The compact system made of acrylic glass, Teflon®, silicone, and stainless steel allows the comparison of different media, cells and scaffolds. The bioreactor can be gas sterilized and actuated in a standard incubator. Macroscopic observations and pressure-measurements showed a uniformly sinusoidal pulsation, indicating that the bioreactor performed well. Preliminary experiments to determine the adherence rate and morphology of UCMSC after mechanical loadings showed an almost confluent cellular coating without damage on the cell surface. In summary, the bioreactor is an adequate tool for the mechanical stress of seeded scaffolds and offers dynamic stimuli for pre-conditioning of cardiac tissue engineered constructs in vitro.

Abstract Extracorporeal shock wave therapy has been reported as an effective treatment for lower limb ulceration. The aim of this systematic review was to investigate the effectiveness of extracorporeal shock wave therapy for the treatment of lower limb ulceration. Five electronic databases (Ovid MEDLINE, CINAHL, Web of Knowledge, Scopus and Ovid AMED) and reference lists from relevant studies were searched in December 2013. All study designs, with the exception of case‐reports, were eligible for inclusion in this review. Assessment of each study's methodological quality was performed using the Quality Index tool. The effectiveness of studies was measured by calculating effect sizes (Cohen's d) from means and standard deviations. Five studies, including; three randomised controlled trials, one quasi‐experimental study and one case‐series design met our inclusion criteria and were reviewed. Quality assessment scores ranged from 38 to 63% (mean 53%). Improvements in wound healing were identified in these studies following extracorporeal shock wave therapy. The majority of wounds assessed were associated with diabetes and the effectiveness of ESWT as an addition to standard care has only been assessed in one randomised controlled trial. Considering the limited evidence identified, further research is needed to support the use of extracorporeal shock wave therapy in the treatment of lower limb ulceration.

The aim of the current study was to develop a method to detect peptide-linked nanoparticles in blood plasma.A convenient enzyme linked immunosorbent assay (ELISA) was developed for the detection of peptides functionalized with biotin and fluorescein groups. As a proof of principle, polymerized pentafluorophenyl methacrylate nanoparticles linked to biotin-carboxyfluorescein labeled peptides were intravenously injected in Wistar rats. Serial blood plasma samples were analyzed by ELISA and by liquid chromatography mass spectrometry (LC/MS) technology.The ELISA based method for the detection of FITC labeled peptides had a detection limit of 1 ng/mL. We were able to accurately measure peptides bound to pentafluorophenyl methacrylate nanoparticles in blood plasma of rats, and similar results were obtained by LC/MS.We detected FITC-labeled peptides on pentafluorophenyl methacrylate nanoparticles after injection in vivo. This method can be extended to detect nanoparticles with different chemical compositions.

Conflicting reports in the literature have raised the question whether radial extracorporeal shock wave therapy (rESWT) devices and vibrating massage devices have similar energy signatures and, hence, cause similar bioeffects in treated tissues.We used laser fiber optic probe hydrophone (FOPH) measurements, high-speed imaging and x-ray film analysis to compare fundamental elements of the energy signatures of two rESWT devices (Swiss DolorClast; Electro Medical Systems, Nyon, Switzerland; D-Actor 200; Storz Medical, Tägerwillen, Switzerland) and a vibrating massage device (Vibracare; G5/General Physiotherapy, Inc., Earth City, MO, USA). To assert potential bioeffects of these treatment modalities we investigated the influence of rESWT and vibrating massage devices on locomotion ability of Caenorhabditis elegans (C. elegans) worms.FOPH measurements demonstrated that both rESWT devices generated acoustic waves with comparable pressure and energy flux density. Furthermore, both rESWT devices generated cavitation as evidenced by high-speed imaging and caused mechanical damage on the surface of x-ray film. The vibrating massage device did not show any of these characteristics. Moreover, locomotion ability of C. elegans was statistically significantly impaired after exposure to radial extracorporeal shock waves but was unaffected after exposure of worms to the vibrating massage device.The results of the present study indicate that both energy signature and bioeffects of rESWT devices are fundamentally different from those of vibrating massage devices.Prior ESWT studies have shown that tissues treated with sufficient quantities of acoustic sound waves undergo cavitation build-up, mechanotransduction, and ultimately, a biological alteration that "kick-starts" the healing response. Due to their different treatment indications and contra-indications rESWT devices cannot be equated to vibrating massage devices and should be used with due caution in clinical practice.

Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by selective striatal neuron loss and motor, cognitive and affective disturbances. The present study aimed to test the hypothesis of adult-onset neuron loss in striatum and frontal cortical layer V as well as alterations in behavior pointing to impaired striatal function in a recently developed transgenic rat model of HD (tgHD rats) exhibiting enlarged ventricles, striatal atrophy and pycnotic pyramidal cells in frontal cortical layer V. High-precision design-based stereological analysis revealed a reduced mean total number of neurons in the striatum but not in frontal cortical layer V of 12-month-old tgHD rats compared with age-matched wild-type controls. No alterations in mean total numbers of striatal neurons were found in 6-month-old animals. Testing 14-month-old animals in a choice reaction time task indicated impaired striatal function of tgHD rats compared with controls.

Previous studies in the literature have resulted in conflicting reports on the potential neurotoxicity of the β-cleaved Alzheimer’s disease C-terminal fragment (β-CTF) of β-amyloid precursor protein in vivo. To readdress this question by rigorous quantitative methods, we analyzed transgenic mice expressing human β-CTF with the I45F mutation (SPA4CT) under control of the prion protein promoter by stereological techniques. The transgene was expressed in hippocampus and cortex in large pyramidal neurons and in dentate gyrus granule cells. Proteolytic processing of β-CTF released Aβ. However, most of it remained uncleaved. Neurodegeneration was evaluated by investigating the numbers of hippocampal pyramidal and granule neurons, as well as the number of synaptophysin-immunopositive presynaptic boutons in the hippocampus of 15-month-old SPA4CT mice with design-based stereological techniques. The analyses showed that a fourfold higher expression of the transgene compared to murine APP levels had no effect on the numbers of both neurons and synaptophysin-immunopositive presynaptic boutons. These data implicate that expression of β-CTF per se is not neurotoxic, and that other mechanisms are responsible for the neurotoxic events in Alzheimer’s disease brain.

BACKGROUND: It has been hypothesized in the literature that exposure to extremely low frequency electromagnetic fields (50 or 60 Hz) may lead to human health effects such as childhood leukemia or brain tumors. In a previous study investigating multiple types of cells from brain and kidney of the mouse (Acta Neuropathologica 2004; 107: 257-264), we found increased unrepaired nuclear DNA single strand breaks (nDNA SSB) only in epithelial cells of the choroid plexus in the brain using autoradiographic methods after a continuous eight-week 50 Hz magnetic field (MF) exposure of adult mice with flux density of 1.5 mT. METHODS: In the present study we tested the hypothesis that MF exposure with lower flux densities (0.1 mT, i.e., the actual exposure limit for the population in most European countries, and 1.0 mT) shows similar results to those in the previous study. Experiments and data analysis were carried out in a similar way as in our previous study. RESULTS: Continuous eight-week 50 Hz MF exposure with 0.1 mT or 1.0 mT did not result in increased persisting unrepaired nDNA SSB in distinct types of cells in the brain, kidney, and liver of adult mice. MF exposure with 1.0 mT led to reduced unscheduled DNA synthesis (UDS) in epithelial cells in the choroid plexus of the fourth ventricle in the brain (EC-CP) and epithelial cells of the cortical collecting duct in the kidney, as well as to reduced mtDNA synthesis in neurons of the caudate nucleus in the brain and in EC-CP. CONCLUSION: No evidence was found for increased persisting unrepaired nDNA SSB in distinct types of cells in the brain, kidney, and liver of adult mice after continuous eight-week 50 Hz magnetic field exposure with flux density of 0.1 mT or 1.0 mT.

BACKGROUND/OBJECTIVES:To evaluate the predictive value of CT-derived measurements of the aortic annulus for prosthesis sizing in transcatheter aortic valve implantation (TAVI) and to calculate optimal cutoff values for the selection of various prosthesis sizes. METHODS:The local IRB waived approval for this single-center retrospective analysis. Of 441 consecutive TAVI-patients, 90 were excluded (death within 30 days: 13; more than mild aortic regurgitation: 10; other reasons: 67). In the remaining 351 patients, the CoreValve (Medtronic) and the Edwards Sapien XT valve (Edwards Lifesciences) were implanted in 235 and 116 patients. Optimal prosthesis size was determined during TAVI by inflation of a balloon catheter at the aortic annulus. All patients had undergone CT-angiography of the heart or body trunk prior to TAVI. Using these datasets, the diameter of the long and short axis as well as the circumference and the area of the aortic annulus were measured. Multi-Class Receiver-Operator-Curve analyses were used to determine the predictive value of all variables and to define optimal cutoff-values. RESULTS:Differences between patients who underwent implantation of the small, medium or large prosthesis were significant for all except the large vs. medium CoreValve (all p's

Livestock farming is the world’s largest land use sector and utilizes around 60% of the global biomass harvest. Over the coming decades, climate change will affect the natural resource base of livestock production, especially the productivity of rangeland and feed crops. Based on a comprehensive impact modeling chain, we assess implications of different climate projections for agricultural production costs and land use change and explore the effectiveness of livestock system transitions as an adaptation strategy. Simulated climate impacts on crop yields and rangeland productivity generate adaptation costs amounting to 3% of total agricultural production costs in 2045 (i.e. 145 billion US$). Shifts in livestock production towards mixed crop-livestock systems represent a resource- and cost-efficient adaptation option, reducing agricultural adaptation costs to 0.3% of total production costs and simultaneously abating deforestation by about 76 million ha globally. The relatively positive climate impacts on grass yields compared with crop yields favor grazing systems inter alia in South Asia and North America. Incomplete transitions in production systems already have a strong adaptive and cost reducing effect: a 50% shift to mixed systems lowers agricultural adaptation costs to 0.8%. General responses of production costs to system transitions are robust across different global climate and crop models as well as regarding assumptions on CO _2 fertilization, but simulated values show a large variation. In the face of these uncertainties, public policy support for transforming livestock production systems provides an important lever to improve agricultural resource management and lower adaptation costs, possibly even contributing to emission reduction.