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High levels of pro-inflammatory substances such as cytokines have been described in the blood and cerebrospinal fluid of schizophrenia patients. Animal models of schizophrenia show that under certain conditions an immune disturbance during early life, such as an infection-triggered immune activation, might trigger lifelong increased immune reactivity. A large epidemiological study clearly demonstrated that severe infections and autoimmune disorders are risk factors for schizophrenia. Genetic studies have shown a strong signal for schizophrenia on chromosome 6p22.1, in a region related to the human leucocyte antigen (HLA) system and other immune functions. Another line of evidence demonstrates that chronic (dis)stress is associated with immune activation. The vulnerability-stress-inflammation model of schizophrenia includes the contribution of stress on the basis of increased genetic vulnerability for the pathogenesis of schizophrenia, because stress may increase pro-inflammatory cytokines and even contribute to a lasting pro-inflammatory state. Immune alterations influence the dopaminergic, serotonergic, noradrenergic, and glutamatergic neurotransmission. The activated immune system in turn activates the enzyme indoleamine 2,3-dioxygenase (IDO) of the tryptophan/kynurenine metabolism which influences the serotonergic and glutamatergic neurotransmission via neuroactive metabolites such as kynurenic acid. The described loss of central nervous system volume and the activation of microglia, both of which have been clearly demonstrated in neuroimaging studies of schizophrenia patients, match the assumption of a (low level) inflammatory neurotoxic process. Further support for the inflammatory hypothesis comes from the therapeutic benefit of anti-inflammatory medication. Metaanalyses have shown an advantageous effect of cyclo-oxygenase-2 inhibitors in early stages of schizophrenia. Moreover, intrinsic anti-inflammatory, and immunomodulatory effects of antipsychotic drugs are known since a long time. Anti-inflammatory effects of antipsychotics, therapeutic effects of anti-inflammtory compounds, genetic, biochemical, and immunological findings point to a major role of inflammation in schizophrenia.

Hernia repair is the most common surgical procedure in the world. Augmentation with synthetic meshes has gained importance in recent decades. Most of the published work about hernia meshes focuses on the surgical technique, outcome in terms of mortality and morbidity and the recurrence rate. Appropriate biomechanical and engineering terminology is frequently absent. Meshes are under continuous development but there is little knowledge in the public domain about their mechanical properties. In the presented experimental study we investigated the mechanical properties of several widely available meshes according to German Industrial Standards (DIN ISO). Six different meshes were assessed considering longitudinal and transverse direction in a uni-axial tensile test. Based on the force/displacement curve, the maximum force, breaking strain, and stiffness were computed. According to the maximum force the values were assigned to the groups weak and strong to determine a base for comparison. We discovered differences in the maximum force (11.1±6.4 to 100.9±9.4 N/cm), stiffness (0.3±0.1 to 4.6±0.5 N/mm), and breaking strain (150±6% to 340±20%) considering the direction of tension. The measured stiffness and breaking strength vary widely among available mesh materials for hernia repair, and most of the materials show significant anisotropy in their mechanical behavior. Considering the forces present in the abdominal wall, our results suggest that some meshes should be implanted in an appropriate orientation, and that information regarding the directionality of their mechanical properties should be provided by the manufacturers.

Articular cartilage (AC) is a viscoelastic tissue with a limited regenerative capability because of the lack of vasculature. Mechanical stimulation contributes to the homeostasis of functional AC since it promotes the delivery of nutrients, cytokines and growth factors between the distant chondrocytes. We hypothesized that biomechanical stimulation might enhance mobilization of endogenous mesenchymal stem/stromal cells (MSCs) from neighboring niches as the bone marrow. This study aimed to introduce a bioreactor for inducing mobilization of MSCs from one compartment to another above by mechanical stimulation in vitro. A novel mechanical system for evaluating mobilization of cells in a 3D context in vitro is presented. The system consists of a compression bioreactor able to induce loading on hydrogel-based scaffolds, custom-made software for settings management and data recording, and image based biological evaluation. Intermittent load was applied under a periodic regime with frequency of 0.3 Hz and unload phases of 10 seconds each 180 cycles over 24 hours. The mechanical stimulation acted on an alginate scaffold and a cell reservoir containing MSCs below it. The dynamic compression exerted amplitude of 200 μm as 10% strain regarding the original height of the scaffold. The bioreactor was able to stimulate the scaffolds and the cells for 24.4 (±1.7) hours, exerting compression with vertical displacements of 185.8 (±17.8) μm and a force-amplitude of 1.87 (±1.37; min 0.31, max 4.42) N. Our results suggest that continuous mechanical stimulation hampered the viability of the cells located at the cell reservoir when comparing to intermittent mechanical stimulation (34.4 ± 2.0% vs. 66.8 ± 5.9%, respectively). Functionalizing alginate scaffolds with laminin-521 (LN521) seemed to enhance the mobilization of cells from 48 (±21) to 194 (±39) cells/mm3 after applying intermittent mechanical loading. The bioreactor presented here was able to provide mechanical stimulation that seemed to induce the mobilization of MSCs into LN521-alginate scaffolds under an intermittent loading regime.

We saw a lack of data on the biomechanical behavior of degenerated articular cartilage (OA) compared with that of healthy cartilage, even though the susceptibility to wear and tear of articular cartilage plays a key role in the progression of osteoarthritis (OA). Therefore, we performed a comparison between naturally occurring OA and healthy cartilage from pigs, before and after tribological stress. The aim of the study was to compare OA-cartilage with healthy cartilage and to analyze the resilience to tribological shear stress, which will be measured as height loss (HL), and to friction forces of the cartilage layers. The findings will be substantiated in macro- and microscopical evaluations before and after tribological exposure. We assessed stifle joints of fifteen old and sixteen young pigs from the local abattoir radiologically, macroscopically and histologically to determine possible OA alterations. We put pins from the femoral part of the joints and plates from the corresponding tibial plateaus in a pin-on-plate tribometer under stress for about two hours with about 1108 reciprocating cycles under a pressure of approximately 1 MPa. As a surrogate criterion of wear and tear, the HL was recorded in the tribometer. The heights of the cartilage layers measured before and after the tribological exposure were compared histologically. The condition of the cartilage before and after the tribological exposure was analyzed both macroscopically with an adapted ICRS score and microscopically according to Little et al. (2010). We assessed the friction forces acting between the surfaces of the cartilage pair-specimens. Articular cartilage taken from old pigs showed significant degenerative changes compared to that taken from the young animals. The macroscopic and microscopic scores showed strong alterations of the cartilage after the tribological exposure. There was a noticeable HL of the cartilage specimens after the first 100 to 300 cycles. The HL after tribological exposure was lower in the group of the old animals with 0.52 mm ± 0.23 mm than in the group of the young animals with 0.86 mm ± 0.26 mm (p < 0.0001). The data for the HL was validated by the histological height measurements with 0.50 mm ± 0.82 mm for the old and 0.79 mm ±0.53 mm for the young animals (p = 0.133). The friction forces measured at the cartilage of the old animals were 2.25 N ± 1.15 N and 1.89 N ± 1.45 N of the young animals (p = 0.3225). Unlike articular cartilage from young pigs, articular cartilage from old pigs showed OA alterations. Tribological shear stress exposure revealed that OA cartilage showed less HL than healthy articular cartilage. Tribological stress exposure in a pin-on-plate tribometer seemed to be an appropriate way to analyze the mechanical stability of articular cartilage, and the applied protocol could reveal weaknesses of the assessed cartilage tissue. Friction and HL seemed to be independent parameters when degenerated and healthy articular cartilage were assessed under tribological exposure in a pin-on- plate tribometer.

The gut-brain communication is mostly driven by the immune, metabolic and neural pathways which remained poorly explored in patients with alcohol use disorder (AUD). The metabolites arising from the tryptophan-kynurenine pathway have gained considerable attention since they are at the interface between intestinal bacteria, host immune response and brain functions. This study described the circulating levels of kynurenine metabolites in AUD patients, at the onset (T1) and end (T2) of a 3-week detoxification program, and tested correlations between those metabolites and inflammatory markers, the gut microbiota and the psychological symptoms. Increased concentration of the neurotoxic metabolite quinolinic acid (QUIN) and decreased levels of the neuroprotector metabolite kynurenic acid (KYNA) which both modulate glutamatergic neurotransmission were observed in AUD patients, particularly at T2. The inflammatory marker hsCRP was associated with several metabolic ratios of the kynurenine pathway. Tryptophan, KYNA and QUIN were correlated with depression, alcohol craving and reaction time, respectively. Analysis of gut microbiota revealed that bacteria known as short-chain fatty acid producers, as well as bacterial metabolites including butyrate and medium-chain fatty acids were associated with some metabolites of the tryptophan-kynurenine pathway. Targeting the glutamatergic neurotransmission through the modulation of the kynurenine pathway, by manipulating the gut microbiota, might represent an interesting alternative for modulating alcohol-related behavior.

In schizophrenia and depression, opposite patterns of type-1 – type-2 immune response seem to be associated with differences in the activation of the enzyme indoleamine 2,3-dioxygenase (IDO) and in the tryptophan - kynurenine metabolism resulting in increased production of kynurenic acid in schizophrenia and decreased production of kynurenic acid in depression. These differences are associated with an imbalance in the glutamatergic neurotransmission, which may contribute to an overweight of N-methyl-D-aspartate (NMDA) agonism in depression and of NMDA antagonism in schizophrenia. The differential activation of microglia cells and astrocytes may be an additional mechanism contributing to this imbalance. The immunological imbalance results both in schizophrenia and in depression in an increased Prostaglandin E2 (PGE2) production and probably also in an increased Cyclo-oxygenase-2 (COX-2) expression. Although there is strong evidence for the view, that the interactions of the immune system, IDO, the serotonergic system, and the glutamatergic neurotransmission play a key role in schizophrenia and in depression, several gaps, e.g. the roles of genetics, disease course, sex, different psychopathological states, etc. have to be bridged by intense further research. There are already hints that anti-inflammatory therapy may have beneficial effects in schizophrenia and major depression. COX-2 inhibititors have been tested in animal models of depression and in preliminary clinical trials, the latter showing favourable effects compared to placebo, both, in schizophrenia and in major depression. The effects of COX-2 inhibition in the central nervous system (CNS) as well as the different components of the inflammatory system, the kynurenine-metabolism and the glutamatergic neurotransmission, however, still need careful further validation including clinical studies with sufficient sample size.

Background Locking plate fixation combined with coracoclavicular (CC) augmentation using a suspensory fixation system is a widely accepted technique for unstable lateral clavicle fractures. Elective hardware removal is commonly performed due to mechanical irritation or discomfort, yet data on radiographic and clinical outcomes following implant removal remain limited. The purpose of this study was to evaluate immediate radiographic loss of reduction and long-term clinical outcomes after removal of the locking plate and CC augmentation in patients with lateral clavicle fractures. It was hypothesized that a measurable loss of reduction occurs following hardware removal, and that clinical outcomes would nevertheless remain excellent, with no residual patient complaints. Methods A total of 41 patients with lateral clavicle fractures treated with locking plate fixation and CC augmentation underwent implant removal between 2013 and 2022. Coracoclavicular distance (CCD) was measured pre- and immediately post-removal. Clavicular drill tunnel (CDT) diameters were measured post-removal. Clinical outcomes were assessed using PROMs (CMS, DASH, SPADI, SSV, VAS), as well as return to work and sports, and re-operation rates. Results The mean CCD increased from 9.1 ± 3.2 mm to 10.0 ± 3.0 mm after implant removal ( p < .0001). A loss of reduction ≥ 10% was observed in 54% of cases, and a substantial loss (≥ 6 mm) in 12%. CDT measurements showed significant tunnel widening toward the inferior cortex compared to the superior and mid-clavicular cortex ( p < .0001). Clinically, 23 patients were included after a mean follow-up of 71 months. Patients achieved excellent outcomes with a mean CMS of 88.5 ± 10.5, DASH of 5.4 ± 7.6, SPADI of 93.4 ± 7.9, SSV of 95.4 ± 6.9, and VAS of 0.6 ± 1.1. PROMs did not differ between patients with or without radiographic loss of reduction. All patients returned to work and sports, with no reoperations required. Conclusions Although 54% of patients showed a measurable radiographic loss of reduction following implant removal, substantial displacement was uncommon (12%). Radiographic loss of reduction was not associated with inferior clinical outcomes. Patients demonstrated excellent long-term function, with a full return to work and sports.

Background Children with attention-deficit/hyperactivity disorder (ADHD) show a marked temporal variability in their display of symptoms and neuropsychological performance. This could be explained in terms of an impaired glial supply of energy to support neuronal activity. Method We pursued one test of the idea with measures of a neurotrophin reflecting glial integrity (S100B) and the influences of 8 cytokines on the metabolism of amino-acids, and of tryptophan/kynurenine to neuroprotective or potentially toxic products that could modulate glial function. Serum samples from 21 medication-naïve children with ADHD, 21 typically-developing controls, 14 medicated children with ADHD and 7 healthy siblings were analysed in this preliminary exploration of group differences and associations. Results There were no marked group differences in levels of S100B, no major imbalance in the ratios of pro- to anti-inflammatory interleukins nor in the metabolism of kynurenine to toxic metabolites in ADHD. However, four trends are described that may be worthy of closer examination in a more extensive study. First, S100B levels tended to be lower in ADHD children that did not show oppositional/conduct problems. Second, in medicated children raised interleukin levels showed a trend to normalisation. Third, while across all children the sensitivity to allergy reflected increased levels of IL-16 and IL-10, the latter showed a significant inverse relationship to measures of S100B in the ADHD group. Fourthly, against expectations healthy controls tended to show higher levels of toxic 3-hydroxykynurenine (3 HK) than those with ADHD. Conclusions Thus, there were no clear signs (S100B) that the glial functions were compromised in ADHD. However, other markers of glial function require examination. Nonetheless there is preliminary evidence that a minor imbalance of the immunological system was improved on medication. Finally, if lower levels of the potentially toxic 3 HK in ADHD children were confirmed this could reflect a reduction of normal pruning processes in the brain that would be consistent with delayed maturation (supported here by associations with amino-acid metabolism) and a reduced metabolic source of energy.

The characterization of regenerated articular cartilage (AC) can be based on various methods, as there is an unambiguous accepted criterion neither for the natural cartilage tissue nor for regenerates. Biomechanical aspects should be considered as well, leading to the need for more equivalent samples. The aim of the study was to describe a large animal model where 8 specimens of regenerated AC can be created in one animal plus the impact of two surgeries on the welfare of the animals. The usefulness of the inclusion of a group of untreated animals (NAT) was to analyzed. Based on the histological results the conditions of the regenerates were to be described and the impact on knee joints were to be explored in terms of degenerative changes of the cartilage. The usefulness of the statistical term \"effect size\" (ES) will be explained with histological results. We analyzed an animal model where 8 AC regenerates were obtained from one Göttingen Minipig, on both sides of the trochleae. 60 animals were divided into 6 groups of 10 each, where the partial thickness defects in the trochlea were filled with matrices made of Collagen I with or without autologous chondrocytes or left empty over the healing periods of 24 and 48 weeks. One additional control group consisting of 10 untreated animals was used to provide untouched \"external\" cartilage. We harvested 560 samples of regenerated tissue and \"external\" controls, besides that, twice the number of further samples from other parts of the joints referred to as \"internal\" controls were also harvested. The animals recovered faster after the 1st operation when the defects were set compared to the 2nd operation when the defects were treated. 9% of all animals were lost. Other complications were for example superficial infections, seroma, diarrhea, febrile state and an injury of a claw. The histological results of the treatments proved the robustness of the study design where we included an \"external\" control group (NAT) in which the animals were not operated. Comparable significant differences between treated groups and the NAT group were detected both after ½ year and after 1 year. Spontaneous regenerated AC as control revealed differences after an observation time of nearly 1 year. The impact of the treatment on cartilage adjacent to the defect as well as the remaining knee joint was low. The ES was helpful for planning the study as it is shown that the power of a statistical comparison seems to be more influenced by the ES than by the sample size. The ranking of the ES was done exemplarily, listing the results according to their magnitude, thus making the results comparable. We were able to follow the 3 R requirements also in terms of a numerical reduction of animals due to the introduction of a group of untreated animals. This makes the model cost effective. The presented study may contribute as an improvement of the standardization of large animal models for research and regulatory requirements for regenerative therapies of AC.

Increased degradation of tryptophan (TRP) through the kynurenine (KYN) pathway (KP) is known to be involved in the molecular mechanisms resulting in the neuropathogenesis of Alzheimer’s disease (AD). Activation of the KP leads to the production of neurotoxic metabolites 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) by immune cells and neuroprotective derivates kynurenic acid (KYNA) and picolinic acid (PIC) by astrocytes and neurons. We therefore investigated whether an imbalance between neurotoxic and neuroprotective kynurenine metabolites could be detected in patients with AD. We measured serum levels of TRP, KYNA, 3-HK, PIC and QUIN in 20 patients with AD and for comparison in 20 patients with major depression, and 19 subjectively cognitive impaired subjects. Serum levels of 3-HK were markedly increased in AD patients compared to the comparison groups ( p  < .0001). Serum levels of the other KP metabolites were not significantly different between groups. Our data indicate an increased production of the neurotoxic KP metabolite 3-HK in AD. In contrast to its downstream metabolites QUIN and PIC, 3-HK can cross the blood–brain barrier via an active transport process. Our data therefore indicate an enhanced availability of 3-HK in the brain of AD patients, which may be related to the previously reported higher production of QUIN in AD brains.