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Background: In the search for effective treatments for refractive obsessive-compulsive disorder (OCD), deep brain stimulation (DBS) serves as an alternative option for those with minimal response to pharmacotherapy. The rarity of reports regarding DBS use for OCD is attributed to the invasive nature of the procedure: placement of electrodes within targeted areas of the brain to provide neuromodulation. This treatment of last resort may decrease functional impairment and pharmacologic complications for a debilitating mental illness. This study compares the pharmacotherapy utilization and treatment outcomes of five treatment-refractory OCD patients after the placement of DBS with those of a matched cohort. Methods: This retrospective, single-center, case-cohort study reviewed the electronic medical records of five subjects treated with DBS for treatment-refractory OCD and compared them to a similar treatment-refractory cohort whose OCD was treated without the use of DBS. Control subjects were matched by age, sex, years since diagnosis, number of previous medication class trials, and additional clinical factors. Inclusion criteria were defined as those that are at least eighteen years of age, assigned a primary diagnosis of OCD per the ICD-10 classification, and received DBS treatment for refractory OCD. Exclusion criteria included comorbid psychotic disorders, unstable neurological or coagulation disorder(s), and/or an eating disorder diagnosis. The primary endpoint was the change in the number of psychotropic medications two years after implantation for the DBS cohort and two years after psychiatric decompensation for the comparator cohort. Secondary endpoints included: Y-BOCS (the Yale-Brown Obsessive-Compulsive Scale) changes over time, duration quantity of psychotropic medication classes prescribed, and additional symptomology scale changes. Results: Patients receiving DBS were more likely to be on fewer medications and trialed fewer medications after treatment. One out of the five patients was found to be a responder in Y-BOCS scoring after DBS treatment. A reduction in anxiety and depression symptoms was also seen in the HAM-A and HAM-D scales for those that received DBS. Conclusions : A reduction in psychiatric medications trialed during therapy was observed, as well as varying reductions in OCD, anxiety, and depression symptomology following DBS. Results from this study indicate that DBS implantation may contribute to a reduction in polypharmacy while displaying DBS's potential impact on comorbid anxiety and depression symptoms. Given that the small sample size limits generalizability, additional prospective, randomized trials comparing the efficacy of DBS for OCD-specific symptomology and its overall impact on pharmacotherapy are needed in order to further establish the role of DBS as an accepted treatment option for OCD.

Background: The aim of this study was to substantiate the ability of noninvasive low-field magnetic resonance imaging (lfMRI) to accurately depict meniscal lesions, thereby establishing lfMRI as a viable option for the diagnosis of meniscal pathology., Study Design: This was a prospective, controlled study., Materials and Methods: In each of 57 stifle joints, 5 predefined lfMRI sequences using a 0.25 T lfMRI were used. The scans were evaluated by an experienced surgeon (DECVS) and through external assessment by a radiologist (DECVDI). The patients were divided into two groups depending on their meniscal status after lfMRI. Dogs (Group 1; n = 33) without lfMRI evidence of medial meniscal pathology underwent TPLO, whereas concurrent craniomedial mini-arthrotomy was performed in patients with suspected meniscal lesions (Group 2; n = 24). Gait assessment was performed 6 weeks later and 6 months postoperatively., Results: Cohen's kappa value of 0.8571 corresponds to a high level of agreement between the observers. A significant correlation was found between preoperative lameness severity and intraoperative meniscal damage ( p < 0.04). The results showed a highly significant correlation between meniscal injuries on MRI and intraoperative findings ( p < 0.0001)., Conclusions: LfMRI appears to be a noninvasive, reliable imaging tool for the detection of medial meniscal lesions in cranial cruciate-deficient stifle joints, aiming to avoid (minimally) invasive diagnostics in healthy menisci.

Introduction: Obsessive-compulsive disorder (OCD) is marked by a high rate of treatment resistance. Patients are often left trialing medications within multiple drug classes with little response, causing heterogeneity to emerge in prescribing patterns. This analysis seeks to investigate the selection and dosing of the pharmacotherapy utilized, to portray an overview of prescribing trends in the United States., Methods: This retrospective, single center, review of electronic medical records investigated the pharmacotherapy utilization of patients with a primary diagnosis of OCD. Two hundred and ninety-five patients who received OCD treatment at an urban, academic medical center were included in the study. Patients were included in the review if they were at least eighteen years of age and were assigned a diagnosis of OCD according to DSM-5 criteria., Results: Psychotropic pharmacotherapy was integrated into the care of 93% of patients. Selective serotonin reuptake inhibitors were the most utilized medication class at 85% followed by benzodiazepines (47%) and second-generation antipsychotics (37%). Tricyclic antidepressants and first-generation antipsychotics were the two medication classes utilized the least at 13% and 2% respectively. Additionally, mood stabilizers and serotonin-norepinephrine reuptake inhibitors were utilized at rates of 8% and 16%, respectively., Conclusions: Evidence-based treatment guidelines are being followed with varying augmentation strategies widely prevalent, thus displaying the heterogeneity in treating OCD. A high rate of benzodiazepine utilization highlights a practice trend with potential ties to clinical factors, such as the latency to treatment effect of other first-line pharmacotherapies. Future prospective studies are required to determine the cultural, pharmacoeconomic and pharmacogenomic factors that contribute to the variation in prescribing practices and whether these variations influence treatment outcomes., (© 2024 John Wiley & Sons Ltd.)

Next-generation risk assessment relies on mechanistic data from new approach methods, including transcriptome data. Various technologies, such as high-throughput targeted sequencing methods and microarray technologies based on hybridization with complementary probes, are used to determine differentially expressed genes (DEGs). The integration of data from different technologies requires a good understanding of the differences arising from the use of various technologies.To better understand the differences between the TempO-Seq platform and Affymetrix chip technology, whole-genome data for the volatile compound dimethylamine were compared. Selected DEGs were also confirmed using RTqPCR validation. Although the overlap of DEGs between TempO-Seq and Affymetrix was no higher than 37%, a comparison of the gene regulation in terms of log2fold changes revealed a very high concordance. RTqPCR confirmed the majority of DEGs from either platform in the examined dataset. Only a few conflicts were found (11%), while 22% were not confirmed, and 3% were not detected.Despite the observed differences between the two platforms, both can be validated using RTqPCR. Here we highlight some of the differences between the two platforms and discuss their applications in toxicology., (© 2024. The Author(s).)

Objectives: An integrated in vitro inhalation approach was outlined to estimate potential adverse acute inhalation effects of aerosols from commercial nebulizer applications used for purposeful room conditioning such as disinfection, scenting or others. Aerosol characterization, exposure estimation and evaluation of acute biological effects by in vitro inhalation were included to generate dose-response data, allowing for determination of in vitro lowest observable adverse effect levels (LOAELs). Correlation of these to estimates of human lung deposition was included for quantitative in vitro to in vivo extrapolation approach (QIVIVE) for acute effects during human exposure., Methods: To test the proposed approach, a case study was undertaken using two realistic test materials. An acute in vitro inhalation setup with air-liquid interface A549-cells in an optimized exposure situation (P.R.I.T. ® ExpoCube ® ) was used to expose cells and analysis of relevant biological effects (viability, mitochondrial membrane potential, stress, IL-8 release) was carried out., Results: The observed dose-responsive effects in a sub-toxic dose-range could be attributed to the main component of one test material and its presence in the aerosol phase of the nebulized material. QIVIVE resulted in a factor of at least 256 between the in vitro LOAEL and the estimated acute human lung exposure for this test material., Conclusions: The case-study shows the value of the non-target in vitro inhalation testing approach especially in case of a lack of knowledge on complex product composition. It is expected that approaches like this will be of high value for product safety and environmental health in the future.

This case study explores the applicability of transcriptome data to characterize a common mechanism of action within groups of short-chain aliphatic α-, β-, and γ-diketones. Human reference in vivo data indicate that the α-diketone diacetyl induces bronchiolitis obliterans in workers involved in the preparation of microwave popcorn. The other three α-diketones induced inflammatory responses in preclinical in vivo animal studies, whereas beta and gamma diketones in addition caused neuronal effects. We investigated early transcriptional responses in primary human bronchiolar (PBEC) cell cultures after 24 h and 72 h of air-liquid exposure. Differentially expressed genes (DEGs) were assessed based on transcriptome data generated with the EUToxRisk gene panel of Temp-O-Seq ® . For each individual substance, genes were identified displaying a consistent differential expression across dose and exposure duration. The log fold change values of the DEG profiles indicate that α- and β-diketones are more active compared to γ-diketones. α-diketones in particular showed a highly concordant expression pattern, which may serve as a first indication of the shared mode of action. In order to gain a better mechanistic understanding, the resultant DEGs were submitted to a pathway analysis using ConsensusPathDB. The four α-diketones showed very similar results with regard to the number of activated and shared pathways. Overall, the number of signaling pathways decreased from α-to β-to γ-diketones. Additionally, we reconstructed networks of genes that interact with one another and are associated with different adverse outcomes such as fibrosis, inflammation or apoptosis using the TRANSPATH-database. Transcription factor enrichment and upstream analyses with the geneXplain platform revealed highly interacting gene products (called master regulators, MRs) per case study compound. The mapping of the resultant MRs on the reconstructed networks, visualized similar gene regulation with regard to fibrosis, inflammation and apoptosis. This analysis showed that transcriptome data can strengthen the similarity assessment of compounds, which is of particular importance, e.g., in read-across approaches. It is one important step towards grouping of compounds based on biological profiles., Competing Interests: JK was employed by GeneXplain GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Drake, Wehr, Zobl, Koschmann, De Lucca, Kühne, Hansen, Knebel, Ritter, Boei, Vrieling, Bitsch and Escher.)

A hallmark of topological phases is the occurrence of topologically protected modes at the system's boundary. Here, we find topological phases in the antisymmetric Lotka-Volterra equation (ALVE). The ALVE is a nonlinear dynamical system and describes, for example, the evolutionary dynamics of a rock-paper-scissors cycle. On a one-dimensional chain of rock-paper-scissor cycles, topological phases become manifest as robust polarization states. At the transition point between left and right polarization, solitary waves are observed. This topological phase transition lies in symmetry class D within the "tenfold way" classification as also realized by 1D topological superconductors.

Objective:  The aim of this study was to compare outcomes after tibial plateau levelling osteotomy (TPLO) and modified Maquet procedure (MMP) for the treatment of cranial cruciate ligament rupture (CCLR) in dogs using clinical and radiographic evaluation and treadmill-based force plate gait analysis., Study Design:  This study was a prospective, randomized, controlled study., Materials and Methods:  Sixty-one dogs (76 joints) with CCLR were treated with TPLO ( n  = 30 dogs, 41 joints) or MMP ( n  = 31 dogs, 35 joints) and compared with a control group of 16 healthy Labrador Retrievers. Outcomes after surgery were compared by clinical orthopaedic assessment, radiographic evaluation and force plate gait analysis performed preoperatively, and then at 6 weeks, 3 and 6 months postoperatively. For objective comparison of ground reaction forces, the data were compared with the control group. Major complications were reported., Results:  A significant improvement in ground reaction forces was reached in all surgically treated dogs. No significant difference was found between the surgical methods at any postoperative re-examination. With regard to peak vertical force (PVF), there were significantly more patients with TPLO within the reference range of healthy dogs at the 3 months re-examination than dogs with MMP. There was no significant difference in mean value comparisons between TPLO and control groups 6 months postoperatively. Compared with the control group, mean values of 93.9% (PVF) and 85.9% (vertical impulse [VI]) were reached by the TPLO group and 89.4% (PVF) and 79.9% (VI) by the MMP group, 6 months postoperatively.No significant differences were found regarding major complications or progression of osteoarthritis., Conclusions:  Although no significant differences were found between the surgical methods, TPLO patients showed superiority with regard to clinical outcome., Competing Interests: Dr. Reese reports grants from Gesellschaft zur Förderung Kynologischer Forschung e.V. (GKF), during the conduct of the study., (Georg Thieme Verlag KG Stuttgart · New York.)

Due to the increasing need of new treatment options against bacterial lung infections, novel antimicrobial peptides (AMPs) are under development. Local bioavailability and less systemic exposure lead to the inhalation route of administration. Combining AMPs with nanocarriers (NCs) into nanosystems (NSs) might be a technique for improved results. An air-liquid interface (ALI) in vitro inhalation model was set up including a human alveolar lung cell line (A549) and an optimized exposure system (P.R.I.T.® ExpoCube®) to predict acute local lung toxicity. The approach including aerosol controls (cupper-II-sulfate and lactose) delivered lowest observable adverse effect levels (LOAELs). Different combinations of AMPs (AA139, M33) and NCs (polymeric nanoparticles (PNPs), micelles and liposomes) were tested under ALI and submerged in vitro conditions. Depending on the nature of AMP and NCs, packing of AMPs into NSs reduced the AMP-related toxicity. Large differences were found between the LOAELs determined by submerged or ALI testing with the ALI approach indicating higher sensitivity of the ALI model. Since aerosol droplet exposure is in vivo relevant, it is assumed that ALI based results represents the more significant source than submerged testing for in vivo prediction of local acute lung toxicity. In accordance with the current state-of-the-art view, this study shows that ALI in vitro inhalation models are promising tools to further develop in vitro methods in the field of inhalation toxicology., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Precision cut liver slices (PCLiS) represent a promising tool in reflecting hepatotoxic responses. However, the culture of PCLiS varies considerably between laboratories, which can affect the performance of the liver slices and thus the experimental outcome. In this study, we describe an easily accessible culture method, which ensures optimal slice viability and functionality, in order to set the basis for reproducible and comparable PCLiS studies. The quality of the incubated rat PCLiS was assessed during a 24h culture period using ten readouts, which covered viability (lactate dehydrogenase-, aspartate transaminase- and glutamate dehydrogenase-leakage, ATP content) and functionality parameters (urea, albumin production) as well as histomorphology and other descriptive characteristics (protein content, wet weight, slice thickness). The present culture method resulted in high quality liver slices for 24h. Finally, PCLiS were exposed to increasing concentrations of acetaminophen to assess the suitability of the model for the detection of hepatotoxic responses. Six out of ten readouts revealed a toxic effect and showed an excellent mutual correlation. ATP, albumin and histomorphology measurements were identified as the most sensitive readouts. In conclusion, our results indicate that rat PCLiS are a valuable liver model for hepatotoxicity studies, particularly if they are cultured under optimal standardized conditions., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Autoinducers are small signaling molecules that mediate intercellular communication in microbial populations and trigger coordinated gene expression via 'quorum sensing'. Elucidating the mechanisms that control autoinducer production is, thus, pertinent to understanding collective microbial behavior, such as virulence and bioluminescence. Recent experiments have shown a heterogeneous promoter activity of autoinducer synthase genes, suggesting that some of the isogenic cells in a population might produce autoinducers, whereas others might not. However, the mechanism underlying this phenotypic heterogeneity in quorum-sensing microbial populations has remained elusive. In our theoretical model, cells synthesize and secrete autoinducers into the environment, up-regulate their production in this self-shaped environment, and non-producers replicate faster than producers. We show that the coupling between ecological and population dynamics through quorum sensing can induce phenotypic heterogeneity in microbial populations, suggesting an alternative mechanism to stochastic gene expression in bistable gene regulatory circuits.

Interactions between hepatocytes and immune cells as well as inflammatory episodes are frequently discussed to play a critical role in the alteration of the individual susceptibility to idiosyncratic drug-induced liver injury (iDILI). To evaluate this hypothesis and to face the urgent need for predictive in vitro models, we established two co-culture systems based on two human cell lines in presence or absence of pro-inflammatory factors (LPS, TNF), i.e. hepatoma HepG2 cells co-cultured with monocytic or macrophage-like THP-1 cells. HepG2 monocultures served as control scenario. Mono- or co-cultures were treated with iDILI reference substances (Troglitazone [TGZ], Trovafloxacin [TVX], Diclofenac [DcL], Ketoconazole [KC]) or their non-iDILI partner compounds (Rosiglitazone, Levofloxacin, Acetylsalicylic Acid, Fluconazole). The liver cell viability was subsequently determined via WST-Assay. An enhanced cytotoxicity (synergy) or a hormetic response compared to the drug effect in the HepG2 monoculture was considered as iDILI positive. TGZ synergized in co-cultures with monocytes without an additional pro-inflammatory stimulus, while DcL and KC showed a hormetic response. All iDILI drugs synergized with TNF in the simple HepG2 monoculture, indicating its relevance as an initiator of iDILI. KC showed a synergy when co-exposed to both, monocytes and LPS, while TVX and DcL showed a synergy under the same conditions with macrophages. All described iDILI responses were not observed with the corresponding non-iDILI partner compounds. Our first results confirm that an inflammatory environment increases the sensitivity of liver cells towards iDILI compounds and point to an involvement of pro-inflammatory factors, especially TNF, in the development of iDILI.

Condensation phenomena arise through a collective behaviour of particles. They are observed in both classical and quantum systems, ranging from the formation of traffic jams in mass transport models to the macroscopic occupation of the energetic ground state in ultra-cold bosonic gases (Bose-Einstein condensation). Recently, it has been shown that a driven and dissipative system of bosons may form multiple condensates. Which states become the condensates has, however, remained elusive thus far. The dynamics of this condensation are described by coupled birth-death processes, which also occur in evolutionary game theory. Here we apply concepts from evolutionary game theory to explain the formation of multiple condensates in such driven-dissipative bosonic systems. We show that the vanishing of relative entropy production determines their selection. The condensation proceeds exponentially fast, but the system never comes to rest. Instead, the occupation numbers of condensates may oscillate, as we demonstrate for a rock-paper-scissors game of condensates.

Cranial cruciate ligament rupture is the most common cause of hindlimb disease in dogs and is often associated with an additional lesion of the medial meniscus. The exact aetiopathogenesis of this condition in dogs is unknown. Normally, the degeneration of the ligament first leads to a partial rupture which progresses to a complete rupture following an unspectacular trauma. The positive cranial drawer test confirms the cranial cruciate ligament rupture, however, in some cases, particularly in partial ligament lesions, the diagnosis is not obvious. Therefore, the reexamination of the sedated patient is recommended to generally increase the sensitivity of clinical tests. Magnetic resonance imaging and stifle joint arthroscopy are useful methods to evaluate the cruciate ligaments in indistinct cases or to assess the joint for secondary changes. The therapy of cranial cruciate ligament ruptures can be divided into extra- and intracapsular as well as tibial osteotomies. The principle of the different tibial osteotomies is the muscular compensation of stifle joint instability. The results are successful but not uncritical. This article presents a short review on the substantial problems associated with cranial cruciate ligament rupture in dogs. A more detailed description of secondary problems and complications would exceed the scope of this article and should be considered in another study.

Fluorescent proteins (FPs) are widely used in biochemistry, biology and biophysics. For quantitative analysis of gene expression FPs are often used as marking molecules. Therefore, sufficient knowledge of maturation times and their affecting factors is of high interest. Here, we investigate the maturation process of the FPs GFP and mCherry expressed by the three closely related Escherichia coli strains of the Colicin E2 system, a model system for colicinogenic interaction. One strain, the C strain produces Colicin, a toxin to which the S strain is sensitive, and against which the R strain is resistant. Under the growth conditions used in this study, the S and R strain have similar growth rates, as opposed to the C strain whose growth rate is significantly reduced due to the toxin production. In combination with theoretical modelling we studied the maturation kinetics of the two FPs in these strains and could confirm an exponential and sigmoidal maturation kinetic for GFP and mCherry, respectively. Our subsequent quantitative experimental analysis revealed a high variance in maturation times independent of the strain studied. In addition, we determined strain dependent maturation times and maturation behaviour. Firstly, FPs expressed by the S and R strain mature on similar average time-scales as opposed to FPs expressed by the C strain. Secondly, dependencies of maturation time with growth conditions are most pronounced in the GFP expressing C strain: Doubling the growth rate of this C strain results in an increased maturation time by a factor of 1.4. As maturation times can vary even between closely related strains, our data emphasize the importance of profound knowledge of individual strains' maturation times for accurate interpretation of gene expression data.

Background and Purpose: A new neurological implant, the Sensor-Reservoir, was developed to provide a relative measurement of ICP, which permits a noninvasive technique to detect and localize occlusions in ventricular drainage systems and, thus, to identify mechanical damage to shunt valves. The "reservoir" of this device can be used to administer medication or a contrast agent, to extract cerebral spinal fluid (CSF), and with the possibility of directly measuring ICP. The Sensor-Reservoir was evaluated to identify possible MRI-related issues at 1.5-T/64-MHz and 3-T/128-MHz., Materials and Methods: Standard testing techniques were utilized to evaluate magnetic field interactions (i.e., translational attraction and torque), MRI-related heating, and artifacts at 3-T for the Sensor-Reservoir. In addition, 12 samples of the Sensor-Reservoir underwent testing to determine if the function of these devices was affected by exposures to various MRI conditions at 1.5-T/64-MHz and 3-T/128-MHz., Results: Magnetic field interactions for the Sensor-Reservoir were not substantial. The heating results indicated a highest temperature rise of 1.8 °C, which poses no patient risks. Artifacts were relatively small in relation to the size and shape of the Sensor-Reservoir, but may interfere diagnostically if the area of interest is near the device. All devices were unaffected by exposures to MRI conditions at 1.5-T/64-MHz and 3-T/128-MHz., Conclusion: When specific guidelines are followed, the Sensor-Reservoir is "MR conditional" for patients undergoing MRI examinations at 3-T or less., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Analyzing coexistence and survival scenarios of Lotka-Volterra (LV) networks in which the total biomass is conserved is of vital importance for the characterization of long-term dynamics of ecological communities. Here, we introduce a classification scheme for coexistence scenarios in these conservative LV models and quantify the extinction process by employing the Pfaffian of the network's interaction matrix. We illustrate our findings on global stability properties for general systems of four and five species and find a generalized scaling law for the extinction time.

Higher throughput methods, high content analysis and automated screening methods are of highest demand in drug development today. In toxicology, these strategies are becoming increasingly important, as well. Therefore, an integrated higher throughput method for the comet assay is addressed by the development presented here. The sensitivity, specificity and relevance of the comet assay as a method for determination of DNA damage in vivo and in vitro have been highlighted in many studies. Actually, efforts are made to include it in a panel of genotoxicity tests for regulatory purposes. However, the standard comet assay is a time consuming procedure due to the specific methods needed. The improvements presented here lead to a faster and easier slide-production, a smaller amount of cells needed, a higher amount of comets quantified, a fully automated analysis of comets including reanalysis, storing, visualisation and documentation possibilities using standard comet quantification models such as tail length or tail moment, and - by introduction of clearly definable selection criteria based on image analysis algorithms - clearly improve objectivity and standardization of the analysis procedure. Results prove the high reproducibility, flexibility, efficiency and suitability of the procedure as a fully automated analysis method in higher throughput genotoxicity testing in vitro.

Testis-specific gene A (TSGA) was originally identified in rat and shown to be expressed within the testes. Here, we have cloned the murine homolog [also known as jumonji domain-containing 1a (Jmjd1a)] and for the first time characterized the TSGA protein and its functions. Although murine TSGA is expressed in testes, its mRNA is also present in many other tissues, including heart, thymus, liver, and skin. Immunostaining revealed that TSGA is a nuclear protein, whose N-terminus contains a putative nuclear localization signal. TSGA displays significant homology to a suspected tumor suppressor and coactivator (5qNCA), to a thyroid hormone receptor interacting protein (TRIP8) and to the corepressor Hairless, pointing at a role of TSGA in transcription regulation. Indeed, TSGA contains several functional transcription repression domains. In addition, TSGA interacts both in vitro and in vivo with ER71 (ETS related 71), a transcription factor that is expressed in the testes of adult mice and during embryogenesis. Specifically, the N-terminus of TSGA and the C-terminus of ER71 are primarily engaged in their complex formation. Furthermore, TSGA impairs the ability of ER71 to activate transcription from the matrix metalloproteinase-1 promoter. Thus, TSGA may modulate the function of ER71 and thereby affect spermatogenesis as well as embryonic development.