Gene-dosage- and sex-dependent differences in the prodromal-Like phase of the F344tgHD rat model for Huntington disease.

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.

Influence of the skull bone and brain tissue on the sound field in transcranial extracorporeal shock wave therapy: an ex vivo study.

OBJECTIVES: Focused ultrasound is mainly known for focal ablation and localized hyperthermia of tissue. During the last decade new treatment options were developed for neurological indications based on blood-brain-barrier opening or neuromodulation. Recently, the transcranial application of shock waves has been a subject of research. However, the mechanisms of action are not yet understood. Hence, it is necessary to know the energy that reaches the brain during the treatment and the focusing characteristics within the tissue. METHODS: The sound field of a therapeutic extracorporeal shock wave transducer was investigated after passing human skull bone (n=5) or skull bone with brain tissue (n=2) in this ex vivo study. The maximum and minimum pressure distribution and the focal pressure curves were measured at different intensity levels and penetration depths, and compared to measurements in water. RESULTS: Mean peak negative pressures of up to -4.97 MPa were reached behind the brain tissue. The positive peak pressure was attenuated by between 20.85 and 25.38 dB/cm by the skull bone. Additional damping by the brain tissue corresponded to between 0.29 and 0.83 dB/cm. Compared to the measurements in water, the pulse intensity integral in the focal spot was reduced by 84 % by the skull bone and by additional 2 % due to the brain tissue, resulting in a total damping of up to 86 %. The focal position was shifted up to 8 mm, whereas the basic shape of the pressure curves was preserved. CONCLUSIONS: Positive effects may be stimulated by transcranial shock wave therapy but damage cannot be excluded.

Management of partial-thickness rotator cuff tears with autologous adipose-derived regenerative cells is safe and more effective than injection of corticosteroid.

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".

Comparison of the Penetration Depth of 905 nm and 1064 nm Laser Light in Surface Layers of Biological Tissue Ex Vivo.

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.

Infantile human labial glands: Distribution of aquaporins and claudins in the context of paracellular and transcellular pathways.

Human labial glands consist of saliva-secreting cells which are formed by serous and predominantly mucous glandular cells. The following excretory duct system converts the isotonic saliva into a hypotonic fluid. Liquids are transported across the membrane of epithelial cells by paracellular or transcellular mode of action. We studied aquaporins (AQP) and tight junction proteins in the endpieces and duct system of human labial glands of 3-5-month-old infants for the first time. AQP1, AQP3, and AQP5 represent the transcellular transport; tight junction proteins like claudin-1, - 3, - 4, and - 7 regulate the permeability of the paracellular pathway. Specimens of 28 infants were included in this study and analyzed histologically. AQP1 was present in myoepithelial cells and in endothelial cells of small blood vessels. AQP3 showed basolateral plasmamembrane localization in glandular endpieces. AQP5 was localized at the apical cytomembrane in serous and mucous glandular cells and at the lateral membrane in serous cells. Ducts remained unstained with the antibody to AQP1, AQP3, and AQP5. Claudin-1, - 3, - 4, and - 7 were expressed mainly in the lateral plasmamembrane of serous glandular cells. In the ducts, claudin-1, - 4, and - 7 were detected at the basal cell layer, claudin-7 also at the lateral cytomembrane. Our findings provide new insights into the localization of epithelial barrier components necessary for regulating saliva-modification in infantile labial glands.

Spread of the Optical Power Emission of Three Units Each of Two Different Laser Therapy Devices Used in Sports Medicine, Which Cannot Be Assessed by the Users, Shown by Means of High-Fidelity Laser Measurement Technology.

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.

["B problems" in non-traumatic resuscitation room management]. / "B-Probleme" des nichttraumatologischen Schockraummanagements.

In the primary survey of resuscitation room management in critically ill nontrauma patients, the ABCDE (airway, breathing, circulation, disability, exposure) approach is used for immediate recognition and treatment of life-threatening conditions. "B problems" are associated with respiratory failure and require immediate treatment. The pathogenesis is diverse, especially in the nontrauma resuscitation room. Clinical examination, emergency sonography and knowledge of oxygenation techniques and ventilation are important components of diagnosis and therapy. Standardized procedures and regular training in the emergency room are of fundamental importance.

Reduced cortical neuron number and neuron density in schizophrenia with focus on area 24: a post-mortem case-control study.

Structural and functional abnormalities of the anterior cingulate cortex (ACC) have frequently been identified in schizophrenia. Alterations of von Economo neurons (VENs), a class of specialized projection neurons, have been found in different neuropsychiatric disorders and are also suspected in schizophrenia. To date, however, no definitive conclusions can be drawn about quantitative histologic changes in the ACC in schizophrenia because of a lack of rigorous, design-based stereologic studies. In the present study, the volume, total neuron number and total number of VENs in layer V of area 24 were determined in both hemispheres of postmortem brains from 12 male patients with schizophrenia and 11 age-matched male controls. To distinguish global from local effects, volume and total neuron number were also determined in the whole area 24 and whole cortical gray matter (CGM). Measurements were adjusted for hemisphere, age, postmortem interval and fixation time using an ANCOVA model. Compared to controls, patients with schizophrenia showed alterations, with lower mean total neuron number in CGM (- 14.9%, P = 0.007) and in layer V of area 24 (- 21.1%, P = 0.002), and lower mean total number of VENs (- 28.3%, P = 0.027). These data provide evidence for ACC involvement in the pathophysiology of schizophrenia, and complement neuroimaging findings of impaired ACC connectivity in schizophrenia. Furthermore, these results support the hypothesis that the clinical presentation of schizophrenia, particularly deficits in social cognition, is associated with pathology of VENs.

More than Ninety Percent of the Light Energy Emitted by Near-Infrared Laser Therapy Devices Used to Treat Musculoskeletal Disorders Is Absorbed within the First Ten Millimeters of Biological Tissue.

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.

Decreased Oligodendrocyte Number in Hippocampal Subfield CA4 in Schizophrenia: A Replication Study.

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.

Fächerübergreifende psychokardiologische Rehabilitation: vom Modellprojekt zur Blaupause des dualen Rehabilitationskonzeptes ­ von Erfahrungswerten zu wissenschaftlichen Daten.

The development and course of heart disease can be decisively influenced by psychological comorbidities (especially depression, anxiety disorder or post-traumatic stress disorder). An acute or chronic cardiological disease can in turn trigger or exacerbate mental disorders. These relationships are of considerable importance for cardiac rehabilitation, since psychological comorbidities often limit activity and participation more than organic heart disease. In monodisciplinary rehabilitation procedures (cardiological or psychosomatic), however, in the case of comorbidity, one clinical picture cannot be adequately treated and assessed by socio-medical experts. Interdisciplinary rehabilitation concepts are required here.In the first part of this article, the development and implementation of an interdisciplinary psychocardiological rehabilitation concept from the model phase to the establishment and expansion to other disciplines as well as the first research results are described. After initial positive evaluation data and good acceptance by the rehabilitants, the German Pension Insurance (DRV) is expanding the concept to other specialist areas under the name "dual rehabilitation" in order to promote interdisciplinary cooperation in the case of psychological and somatic comorbidity.In the second part of the work, the concept and first data from the controlled EvaPK study (Evaluation of the effectiveness of psychocardiological rehabilitation) funded by the DRV Bund are presented. These show that the comorbid patients are particularly stressed in terms of activity and participation (recorded in the Mini-ICF-APP-S) and that psychocardiological rehabilitation is also effective in this highly stressed group. However, the evaluations of the catamnesis and the cardiac function parameters are still missing.Both the pilot study and the first data from the EvaPK study show that psychocardiological rehabilitation meets the needs of comorbid patients and is well accepted by them. However, successful psychocardiological rehabilitation according to the concept presented here requires higher personnel costs and intensive, equal cooperation. Further research on this is necessary.

Safety and efficacy of treating post-burn pathological scars with extracorporeal shock wave therapy: A meta-analysis of randomised controlled trials.

The clinical application of shockwave therapy has expanded to the treatment of pathological scars. The objective of this systematic review and meta-analysis is to quantitatively evaluate the efficacy and safety of extracorporeal shockwave therapy combined with comprehensive rehabilitation therapy on post-burn pathological scars compared to comprehensive rehabilitation therapy alone. The randomised controlled trials of extracorporeal shockwave therapy for post-burn pathological scars published in English and Chinese languages before October 2021 were included. The methodological quality and risk of bias of the selected articles were assessed with the Cochrane Collaboration's 'risk of bias' tool. RevMan software was applied for data analysis. This is the first systematic review and meta-analysis considering the effectiveness and safety of extracorporeal shockwave therapy on post-burn pathological scars. And nine randomised controlled trials involving 422 patients were included in this meta-analysis. The meta-analysis results showed that, compared with comprehensive rehabilitation therapy alone, extracorporeal shockwave therapy combined with comprehensive rehabilitation therapy was more effective in relieving pain (standardized mean difference [SMD] = -0.59, 95% confidence interval [CI]: [-0.87 to -0.31], p < 0.0001) and pruritus related to pathological scars (SMD = -0.94; 95% CI: [-1.25 to -0.63], p = 0.004), improving scars' appearance (SMD = -1.78, 95% CI: [-3.37 to -0.19], p = 0.03) and elasticity (SMD = 0.25, 95% CI: [0.29-0.21], p < 0.00001), decreasing scars thickness (SMD = -0.13, 95% CI: [-0.25 to -0.01], p = 0.04) and promoting the maturation status of scars (SMD = -2.86, 95% CI: [-3.96 to -1.76], p < 0.00001). There were no reported serious adverse events during and after extracorporeal shockwave therapy in the included studies. Available data preliminarily suggested that the combination of extracorporeal shockwave therapy and comprehensive rehabilitation therapy had better therapeutic effect on post-burn pathological scars than comprehensive rehabilitation therapy alone, without obvious side effects. However, further clinical well-controlled randomised controlled trials are needed. Systematic review registration ID: PROSPERO CRD42022297573.

The Effects of the Exposure of Musculoskeletal Tissue to Extracorporeal Shock Waves.

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.

Heart-Focused Anxiety Affects Behavioral Cardiac Risk Factors and Quality of Life: A Follow-Up Study Using a Psycho-Cardiological Rehabilitation Concept.

Background: Heart-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. Methods: A 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. Results: Exercise 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. Conclusions: HFA 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.

Effects of Repeated Injection of 1% Lidocaine vs. Radial Extracorporeal Shock Wave Therapy for Treating Myofascial Trigger Points: A Randomized Controlled Trial.

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.

Transmembrane protein 119 is neither a specific nor a reliable marker for microglia.

Microglia are the resident innate immune cells of the central nervous system (CNS) parenchyma. To determine the impact of microglia on disease development and progression in neurodegenerative and neuroinflammatory diseases, it is essential to distinguish microglia from peripheral macrophages/monocytes, which are eventually equally recruited. It has been suggested that transmembrane protein 119 (TMEM119) serves as a reliable microglia marker that discriminates resident microglia from blood-derived macrophages in the human and murine brain. Here, we investigated the validity of TMEM119 as a microglia marker in four in vivo models (cuprizone intoxication, experimental autoimmune encephalomyelitis (EAE), permanent filament middle cerebral artery occlusion (fMCAo), and intracerebral 6-hydroxydopamine (6-OHDA) injections) as well as post mortem multiple sclerosis (MS) brain tissues. In all applied animal models and post mortem MS tissues, we found increased densities of ionized calcium-binding adapter molecule 1+ (IBA1+ ) cells, paralleled by a significant decrease in TMEM119 expression. In addition, other cell types in peripheral tissues (i.e., follicular dendritic cells and brown adipose tissue) were also found to express TMEM119. In summary, this study demonstrates that TMEM119 is not exclusively expressed by microglia nor does it label all microglia, especially under cellular stress conditions. Since novel transgenic lines have been developed to label microglia using the TMEM119 promotor, downregulation of TMEM119 expression might interfere with the results and should, thus, be considered when working with these transgenic mouse models.

Disrupted biomineralization in zebra mussels after exposure to bisphenol-A: Potential implications for molar-incisor hypomineralization.

OBJECTIVE: The aetiology of molar-incisor hypomineralization (MIH) is currently unclear. A major hurdle in MIH research is the lack of adequate model systems. The study investigated the feasibility of zebra mussel (Dreissena polymorpha) as a novel model to screen potential MIH-related factors. METHODS: In four experiments with overall 46 groups (n = 7 mussels/group), six groups per experiment were incubated with 100 mg/l calcein (mineralization marker) solution for 96 h to evaluate the dynamics of shell biomineralization, another six groups with tap water only (controls). Then zebra mussels with and without calcein pre-incubation were exposed to cadmium sulfate hydrate (3CdSO4•8H2O) (positive control; 0, 0.01, 0.1, 1, 10 and 100 mg/l), possible aetiological factors of MIH including bisphenol-A (BPA; 0, 0.02, 0.2, 2, 20 and 200 mg/l) and erythromycin (0, 0.1, 1, 10, 100 and 1000 mg/l) as mineralization "disruptors", and doxycycline (0, 0.1, 1, 10, 100 and 1000 mg/l) for 96 h, respectively. After two weeks, the mussels were sacrificed and shells were embedded in methylmethacrylate for fluorescence intensity analysis. RESULTS: Mortality rate was 100% after 20, 200 mg/l BPA and 10, 100 mg/l 3CdSO4•8H2O exposure. Thereby, the median lethal concentration (96 h-LC50) of BPA was 6.3 mg/l (95% CI, 1.3-34.4 mg/l), and that of cadmium was 3.1 mg/l (95% CI, 0.7-10.5 mg/l). Notably, calcein fluorescence in shells significantly decreased (p < 0.05) after 2 mg/l BPA and 1 mg/l 3CdSO4•8H2O exposure. SIGNIFICANCE: These findings suggest that BPA may disrupt biomineralization. Biomineralization in zebra mussels seems to be an effective model for investigating potential MIH-related factors.

Methodological Flaws in Meta-Analyses of Clinical Studies on the Management of Knee Osteoarthritis with Stem Cells: A Systematic Review.

(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.