ABSTRACT
Background: Research on depression showed that dysregulations in tryptophan (TRP), kynurenine (KYN), and its KYN pathway metabolites are key aspects in the development and maintenance of depressive symptoms. In our previous reports, we described sex-specific changes in TRP breakdown as well as changes in KYN and KYN/TRP in association with treatment response and inflammatory and metabolic parameters. However, results of treatment effects on KYN pathway metabolites as well as how pathway changes are related to treatment response remain sparse. Objective: We investigated potential changes of KYN and KYN pathway metabolites in association with therapeutic response of individuals with depression during a six-week multimodal psychiatric rehabilitation program. Methods: 87 participants were divided into treatment responders and non-responders (48 responders, 39 non-responders; 38 male, 49 female; M age = 51.09; SD age = 7.70) using scores of psychological questionnaires. KYN pathway metabolites serum concentrations as well as their ratios were collected using high performance liquid chromatography. Changes over time (time of admission (t1) vs. time of discharge (t2)) were calculated using repeated measure analyses of (co)variance. Results: Non-responders exhibited higher levels of 3-Hydroxyanthralinic acid (3-HAA), nicotinic acid (NA), and 3-HAA/KYN, independently of measurement time. NA levels decreased, while 3-HAA levels increased over time in both groups, independently of treatment response. 3-HK/KYN levels decreased, while KYN levels increased in non-responders, but not in responders over time. Discussion: The results indicate that some compounds of the KYN pathway metabolites can be altered through multimodal long-term interventions in association with treatment response. Especially the pathway degrading KYN further down to 3-HAA and 3-HK/KYN might be decisive for treatment response in depression.
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The calcineurin inhibitor tacrolimus, which is available as an immediate- or extended-release formulation, is the standard-of-care immunosuppression after kidney transplantation with low rejection rates, especially in the first year after transplantation. However, its highly variable metabolism rate, narrow therapeutic window, and nephrotoxic side effects require close drug monitoring and individual dosing. Here, we describe first the application of extended-release tacrolimus (ER-Tac) twice daily with beneficial effects in a kidney transplant recipient under extensive therapeutic drug monitoring. A 47-year-old female kidney transplant recipient, who was identified as a fast metabolizer for tacrolimus, presented with declining allograft function and low tacrolimus through levels over time and 8 years after a second kidney transplantation despite the administration of high doses of ER-Tac once daily. Therefore, the area under the concentration-time curve (AUC) showed exceedingly high blood levels of ER-Tac. The latest biopsy of the kidney transplant showed arteriolar hyalinosis with pole vessel stenosis as a sign of chronic transplant vasculopathy and transplant glomerulopathy as a sign of chronic humoral rejection. After the exclusion of other options for immunosuppressive therapy due to the patient's high immunological risk, the patient was switched from ER-Tac once daily to ER-Tac twice daily. After switching to ER-Tac twice daily, the AUC for oral tacrolimus decreased and the transplant function improved despite higher tacrolimus trough levels and a lower total dose administered. This case highlights the importance of careful therapeutic drug monitoring with the performance of an AUC in the follow-up management of kidney transplant recipients.
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OBJECTIVE: To compare the exercise intensity of walking football (WF) with walking (WA) and to describe specific movement characteristics of WF. DESIGN: Cross-sectional study. SETTING: Sports facilities Saarland University, Germany. PATIENTS: Eighteen patients with cardiovascular risk factors CVRFs and diseases (13 men and 5 women, age: 69 ± 10 years). INDEPENDENT VARIABLES: Patients completed a WF match and WA session of 2 x 10 min each. Video analysis was used to characterize movements during WF. MAIN OUTCOME MEASURES: Rate of perceived exertion (RPE, Borg Scale 6-20), % maximum heart rate (HRmax), musculoskeletal pain on a visual analog scale (VAS, 1-100 mm) before and up to 72 hours after exercise, and movement patterns during WF. RESULTS: The mean RPE during WF (12.1 ± 2.7) and WA (11.9 ± 3.0) did not differ (P = 0.63). The mean HR during WF (79 ± 12% of HRmax) was higher than during WA (71% ± 11%; P < 0.01). The HR variability coefficient of variation during WF (10.3% ± 5.8%) and WA (7.1 ± 5.5%) did not differ (P = 0.13). There was no influence of exercise mode (WF vs WA) on musculoskeletal pain perception (P = 0.96 for interaction). Injury-inciting activities such as lunges (median: 0.5 [interquartile range (IQR) 0-1.3]) and goal kicks (median: 4 [IQR: 1.8-5.3]) occurred rarely during WF. CONCLUSIONS: Walking football might represent an alternative to WA for health prevention programs in patients with CVRF and diseases as it is characterized by a manageable cardiocirculatory strain, moderate RPE, low pain induction, and a low number of injury-inciting activities.
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PURPOSE: To evaluate the diagnostic performance of CT-like MR images reconstructed with an algorithm combining compressed sense (CS) with deep learning (DL) in patients with suspected osseous shoulder injury compared to conventional CS-reconstructed images. METHODS: Thirty-two patients (12 women, mean age 46 ± 14.9 years) with suspected traumatic shoulder injury were prospectively enrolled into the study. All patients received MR imaging of the shoulder, including a CT-like 3D T1-weighted gradient-echo (T1 GRE) sequence and in case of suspected fracture a conventional CT. An automated DL-based algorithm, combining CS and DL (CS DL) was used to reconstruct images of the same k-space data as used for CS reconstructions. Two musculoskeletal radiologists assessed the images for osseous pathologies, image quality and visibility of anatomical landmarks using a 5-point Likert scale. Moreover, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. RESULTS: Compared to CT, all acute fractures (n = 23) and osseous pathologies were detected accurately on the CS only and CS DL images with almost perfect agreement between the CS DL and CS only images (κ 0.95 (95 %confidence interval 0.82-1.00). Image quality as well as the visibility of the fracture lines, bone fragments and glenoid borders were overall rated significantly higher for the CS DL reconstructions than the CS only images (CS DL range 3.7-4.9 and CS only range 3.2-3.8, P = 0.01-0.04). Significantly higher SNR and CNR values were observed for the CS DL reconstructions (P = 0.02-0.03). CONCLUSION: Evaluation of traumatic shoulder pathologies is feasible using a DL-based algorithm for reconstruction of high-resolution CT-like MR imaging.
Subject(s)
Deep Learning , Fractures, Bone , Shoulder Injuries , Humans , Female , Adult , Middle Aged , Shoulder , Magnetic Resonance Imaging/methods , Image Enhancement/methods , Shoulder Injuries/diagnostic imaging , Fractures, Bone/diagnostic imaging , Tomography, X-Ray Computed/methods , Imaging, Three-Dimensional/methodsABSTRACT
The clinical manifestation of sphingolipidosis leads often to misclassification between acid sphingomyelinase deficiency (ASMD) and Gaucher disease. In this multicenter, prospective study, we investigated a cohort of 31,838 individuals suspected to have Gaucher disease, due to clinical presentation, from 61 countries between 2017 and 2022. For all samples, both Acid-ß-glucocerebrosidase and acid sphingomyelinase enzyme activities were measured in dried blood spot specimens by tandem mass spectrometry followed by genetic confirmatory testing in potential positive cases. In total, 5933 symptomatic cases showed decreased enzyme activities and were submitted for genetic confirmatory testing. 1411/5933 (24%) cases were finally identified with Gaucher disease and 550/5933 (9%) with ASMD. Most of the confirmed ASMD cases were newborns and children below 2 years of age (63%). This study reveals that one in four cases suspected for Gaucher disease is diagnosed with ASMD. An early appropriate diagnostic work-up is essential because of the availability of a recently approved enzyme replacement therapy for ASMD. In conclusion, a diagnostic strategy using differential biochemical testing including genetic confirmatory testing in clinically suspected cases for sphingolipidosis is highly recommended.
Subject(s)
Gaucher Disease , Niemann-Pick Disease, Type A , Niemann-Pick Diseases , Child , Humans , Infant, Newborn , Niemann-Pick Disease, Type A/diagnosis , Niemann-Pick Disease, Type A/genetics , Gaucher Disease/diagnosis , Gaucher Disease/genetics , Prospective Studies , Niemann-Pick Diseases/diagnosis , Niemann-Pick Diseases/genetics , Sphingomyelin Phosphodiesterase/genetics , Tandem Mass Spectrometry/methodsABSTRACT
BACKGROUND: The coefficient of friction (CoF) serves as an indicator for the mechanical properties of natural and regenerated articular cartilage (AC). After tribological exposure, a height loss (HL) of the cartilage pair specimens can be measured. Our aim was to determine the CoF and HL of regenerated AC tissue and compare them with those of natural AC from non-operated joints and AC from joints where the regenerated tissues had been created after different treatments. METHODS: In partial-thickness defects of the trochleae of the stifle joints of 60 Göttingen Minipigs, regenerated AC was created. In total, 40 animals received a Col I matrix, 20 laden with autologous chondrocytes, and 20 without. The defects of 20 animals were left empty. The healing periods were 24 and 48 weeks. A total of 10 not-operated animals, delivered the "external" control specimens. Osteochondral pins were harvested from defect and non-defect areas, the latter serving as "internal" controls. Using a pin-on-plate tribometer, we measured the CoF and the HL. RESULTS: The CoF of the regenerated AC ranged from 0.0393 to 0.0688, and the HL, from 0.22 mm to 0.3 mm. The differences between the regenerated AC of the six groups and the "external" controls were significant. The comparison with the "internal" controls revealed four significant differences for the CoF and one for the HL in the operated groups. No differences were seen within the operated groups. CONCLUSIONS: The mechanical quality of the regenerated AC tissue showed inferior behavior with regard to the CoF and HL in comparison with natural AC. The comparison of regenerated AC tissue with AC from untreated joints was more promising than with AC from the treated joints.
ABSTRACT
Bipolar disorder (BD) is a complex mood disorder with a strong genetic component. Recent studies suggest that microRNAs contribute to psychiatric disorder development. In BD, specific candidate microRNAs have been implicated, in particular miR-137, miR-499a, miR-708, miR-1908 and miR-2113. The aim of the present study was to determine the contribution of these five microRNAs to BD development. For this purpose, we performed: (i) gene-based tests of the five microRNA coding genes, using data from a large genome-wide association study of BD; (ii) gene-set analyses of predicted, brain-expressed target genes of the five microRNAs; (iii) resequencing of the five microRNA coding genes in 960 BD patients and 960 controls and (iv) in silico and functional studies for selected variants. Gene-based tests revealed a significant association with BD for MIR499A, MIR708, MIR1908 and MIR2113. Gene-set analyses revealed a significant enrichment of BD associations in the brain-expressed target genes of miR-137 and miR-499a-5p. Resequencing identified 32 distinct rare variants (minor allele frequency < 1%), all of which showed a non-significant numerical overrepresentation in BD patients compared to controls (p = 0.214). Seven rare variants were identified in the predicted stem-loop sequences of MIR499A and MIR2113. These included rs142927919 in MIR2113 (pnom = 0.331) and rs140486571 in MIR499A (pnom = 0.297). In silico analyses predicted that rs140486571 might alter the miR-499a secondary structure. Functional analyses showed that rs140486571 significantly affects miR-499a processing and expression. Our results suggest that MIR499A dysregulation might contribute to BD development. Further research is warranted to elucidate the contribution of the MIR499A regulated network to BD susceptibility.
Subject(s)
Bipolar Disorder , MicroRNAs , Bipolar Disorder/genetics , Gene Frequency , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , MicroRNAs/geneticsABSTRACT
This essay studies the physical shape, character and fate of Oedipus, applying relevant and current medical scientific criteria. The abuses he suffered during childhood play an important role in this context. The name Oedipus is usually translated as "swollen foot", but according to various etymological sources, the name can be interpreted in different ways. One of these interpretations alludes to fact that it was easy for the hero to solve the riddle of the sphinx because its key message addressed an orthopedic issue as it was dealing with the function of the feet. During Oedipus' life, he suffered many injuries and disorders, which can be classified using the current ICD code. There is, for example, his blindness after he had blinded himself. In addition, we can assume that Oedipus suffered from a post-traumatic stress disorder and a borderline personality disorder following the child abuse caused by his parents who intended to kill him. Thus, the discussion about his own responsibility for his actions is again being put into question. Oedipus`s life story is once again proof that Greek mythology can reflect the reality of life.
Subject(s)
Oedipus Complex , Orthopedics , Child , Greece , Humans , Male , MythologyABSTRACT
Novel strategies against multidrug-resistant bacteria are urgently needed in order to overcome the current silent pandemic. Manipulation of toxin production in pathogenic species serves as a promising approach to attenuate virulence and prevent infections. In many bacteria such as Staphylococcus aureus or Listeria monocyotgenes, serine protease ClpXP is a key contributor to virulence and thus represents a prime target for antimicrobial drug discovery. The limited stability of previous electrophilic warheads has prevented a sustained effect of virulence attenuation in bacterial culture. Here, we systematically tailor the stability and inhibitory potency of phenyl ester ClpXP inhibitors by steric shielding of the ester bond and fine-tuning the phenol leaving group. Out of 17 derivatives, two (MAS-19 and MAS-30) inhibited S. aureus ClpP peptidase and ClpXP protease activities by >60 % at 1â µM. Furthermore, the novel inhibitors did not exhibit pronounced cytotoxicity against human and bacterial cells. Unlike the first generation phenylester AV170, these molecules attenuated S. aureus virulence markedly and displayed increased stability in aqueous buffer compared to the previous benchmark AV170.
Subject(s)
Anti-Bacterial Agents , Endopeptidase Clp , Esters , Hemolysin Proteins , Staphylococcus aureus , Anti-Bacterial Agents/pharmacology , Bacterial Proteins , Endopeptidase Clp/antagonists & inhibitors , Endopeptidase Clp/metabolism , Esters/chemistry , Esters/pharmacology , Hemolysin Proteins/metabolism , Humans , Staphylococcus aureus/drug effects , VirulenceABSTRACT
BACKGROUND AND OBJECTIVES: The goal of this work was to investigate the association between group A streptococcal (GAS) infections and tic incidence among unaffected children with a family history of chronic tic disorders (CTDs). METHODS: In a prospective cohort study, children with no history for tics who were 3 to 10 years of age with a first-degree relative with a CTD were recruited from the European Multicentre Tics in Children Study (EMTICS) across 16 European centers. Presence of GAS infection was assessed with throat swabs, serum anti-streptolysin O titers, and anti-DNAse titers blinded to clinical status. GAS exposure was defined with 4 different definitions based on these parameters. Cox regression analyses with time-varying GAS exposure were conducted to examine the association of onset of tics and GAS exposure during follow-up. Sensitivity analyses were conducted with Cox regression and logistic regression analyses. RESULTS: A total of 259 children were recruited; 1 child was found to have tic onset before study entry and therefore was excluded. Sixty-one children (23.6%) developed tics over an average follow-up period of 1 (SD 0.7) year. There was a strong association of sex and onset of tics, with girls having an ≈60% lower risk of developing tics compared to boys (hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.2-0.7). However, there was no statistical evidence to suggest an association of any of the 4 GAS exposure definitions with tic onset (GAS exposure definition 1: HR 0.310, 95% CI 0.037-2.590; definition 2: HR 0.561, 95% CI 0.219-1.436; definition 3: HR 0.853, 95% CI 0.466-1.561; definition 4: HR 0.725, 95% CI 0.384-1.370). DISCUSSION: These results do not suggest an association between GAS exposure and development of tics. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that group A streptococcal exposure does not associate with the development of tics in children with first-degree relatives with chronic tic disorder.
Subject(s)
Streptococcal Infections , Tic Disorders , Tics , Child , Female , Humans , Incidence , Male , Prospective Studies , Streptococcal Infections/complications , Streptococcal Infections/epidemiology , Tic Disorders/epidemiology , Tics/epidemiologyABSTRACT
Unprecedented bacterial targets are urgently needed to overcome the resistance crisis. Herein we systematically mine pyridoxal phosphate-dependent enzymes (PLP-DEs) in bacteria to focus on a target class which is involved in crucial metabolic processes. For this, we tailored eight pyridoxal (PL) probes bearing modifications at various positions. Overall, the probes exceeded the performance of a previous generation and provided a detailed map of PLP-DEs in clinically relevant pathogens including challenging Gram-negative strains. Putative PLP-DEs with unknown function were exemplarily characterized via in-depth enzymatic assays. Finally, we screened a panel of PLP binders for antibiotic activity and unravelled the targets of hit molecules. Here, an uncharacterized enzyme, essential for bacterial growth, was assigned as PLP-dependent cysteine desulfurase and confirmed to be inhibited by the marketed drug phenelzine. Our approach provides a basis for deciphering novel PLP-DEs as essential antibiotic targets along with corresponding ways to decipher small molecule inhibitors.
Subject(s)
Anti-Bacterial Agents , Pyridoxal , Anti-Bacterial Agents/pharmacology , Bacteria/metabolism , Pyridoxal/pharmacology , Pyridoxal Phosphate/metabolismABSTRACT
This study investigated whether vitamin D is associated with the presence or severity of chronic tic disorders and their psychiatric comorbidities. This cross-sectional study compared serum 25-hydroxyvitamin D [25(OH)D] (ng/ml) levels among three groups: children and adolescents (3-16 years) with CTD (n = 327); first-degree relatives (3-10 years) of individuals with CTD who were assessed for a period of up to 7 years for possible onset of tics and developed tics within this period (n = 31); and first-degree relatives who did not develop tics and were ≥ 10 years old at their last assessment (n = 93). The relationship between 25(OH)D and the presence and severity of tics, as well as comorbid obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD), were analysed controlling for age, sex, season, centre, latitude, family relatedness, and comorbidities. When comparing the CTD cohort to the unaffected cohort, the observed result was contrary to the one expected: a 10 ng/ml increase in 25(OH)D was associated with higher odds of having CTD (OR 2.08, 95% CI 1.27-3.42, p < 0.01). There was no association between 25(OH)D and tic severity. However, a 10 ng/ml increase in 25(OH)D was associated with lower odds of having comorbid ADHD within the CTD cohort (OR 0.55, 95% CI 0.36-0.84, p = 0.01) and was inversely associated with ADHD symptom severity (ß = - 2.52, 95% CI - 4.16-0.88, p < 0.01). In conclusion, lower vitamin D levels were not associated with a higher presence or severity of tics but were associated with the presence and severity of comorbid ADHD in children and adolescents with CTD.
Subject(s)
Tic Disorders , Tics , Vitamin D , Adolescent , Attention Deficit Disorder with Hyperactivity/psychology , Child , Comorbidity , Cross-Sectional Studies , Humans , Obsessive-Compulsive Disorder/epidemiology , Obsessive-Compulsive Disorder/psychology , Severity of Illness Index , Tic Disorders/metabolism , Tic Disorders/psychology , Tics/complications , Tics/metabolism , Tourette Syndrome/psychology , Vitamin D/metabolismABSTRACT
Infectious pathogens may represent an environmental risk factor for chronic tic disorders (CTD). This cross-sectional study aimed to determine whether Mycoplasma pneumoniae (M. pneumoniae) IgG positivity is associated with the presence or severity of tics. We compared M. pneumoniae IgG positivity across three groups: children and adolescents (3-16â¯years) with CTD (CTD group; nâ¯=â¯302); siblings (3-10â¯years) of people with CTD who developed tics within a seven-year follow-up period (tic onset group; nâ¯=â¯51); siblings (4-10â¯years) who did not develop tics within the study period and were ≥10-years-old at their last assessment (unaffected group; nâ¯=â¯88). The relationship between M. pneumoniae IgG positivity and the presence and severity of tics was analysed using multilevel models controlling for site, family relatedness, sex, age, presence of comorbid obsessive-compulsive and/or attention-deficit/hyperactivity disorder and use of psychotropic medication. M. pneumoniae IgG positivity was not associated with the presence of CTD, or the first onset of tics as compared to siblings who remained unaffected. M. pneumoniae IgG positivity was associated with a higher tic severity score within the CTD group (ßâ¯=â¯2.64, s.e.â¯=â¯1.15, pâ¯=â¯0.02). It is possible that M. pneumoniae infection influences tic severity in CTD or, that having more severe tics, increases the risk of infection. However, it is more likely that the association observed in this study reflects a propensity toward enhanced immune responses in people with CTD and that, rather than a causal relationship, infection and greater tic severity are indirectly linked via shared underlying immune mechanisms.
Subject(s)
Tic Disorders , Tics , Tourette Syndrome , Adolescent , Child , Cross-Sectional Studies , Humans , Immunoglobulin G , Mycoplasma pneumoniae , Severity of Illness Index , Tic Disorders/complications , Tics/complicationsABSTRACT
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.
Subject(s)
Alcoholism , Gastrointestinal Microbiome , Humans , Inflammation , Kynurenic Acid , Kynurenine , Quinolinic AcidABSTRACT
BACKGROUND: The macrophage theory of depression states that macrophages play an important role in Major Depressive Disorder (MDD). METHODS: MDD patients (N = 140) and healthy controls (N = 120) participated in a cross-sectional study investigating the expression of apoptosis/growth and lipid/cholesterol pathway genes (BAX, BCL10, EGR1, EGR2, HB-EGF, NR1H3, ABCA1, ABCG1, MVK, CD163, HMOX1) in monocytes (macrophage/microglia precursors). Gene expressions were correlated to a set of previously determined and reported inflammation-regulating genes and analyzed with respect to various clinical parameters. RESULTS: MDD monocytes showed an overexpression of the apoptosis/growth/cholesterol and the TNF genes forming an inter-correlating gene cluster (cluster 3) separate from the previously described inflammation-related gene clusters (containing IL1 and IL6). While upregulation of monocyte gene cluster 3 was a hallmark of monocytes of all MDD patients, upregulation of the inflammation-related clusters was confirmed to be found only in the monocytes of patients with childhood adversity. The latter group also showed a downregulation of the cholesterol metabolism gene MVK, which is known to play an important role in trained immunity and proneness to inflammation. CONCLUSIONS: The upregulation of cluster 3 genes in monocytes of all MDD patients suggests a premature aging of the cells, i.e. mitochondrial apoptotic dysfunction and TNF "inflammaging", as a general feature of MDD. The overexpression of the IL-1/IL-6 containing inflammation clusters and the downregulation of MVK in monocytes of patients with childhood adversity indicates a shift in this condition to a more severe inflammation form (pyroptosis) of the cells, additional to the signs of premature aging and inflammaging.
Subject(s)
Depressive Disorder, Major/genetics , Gene Expression , Inflammation , Mitochondria/metabolism , Monocytes/metabolism , Pyroptosis , Adult , Adverse Childhood Experiences/psychology , Cross-Sectional Studies , Depressive Disorder, Major/complications , Female , Humans , Inflammation/genetics , Inflammation/metabolism , Macrophages/metabolism , Male , Microglia/metabolismABSTRACT
INTRODUCTION: 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. AIM: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.
Subject(s)
Cartilage, Articular/pathology , Knee Joint/pathology , Osteoarthritis/pathology , Aging , Animals , Biomechanical Phenomena , Bone Plates , Cartilage, Articular/diagnostic imaging , Friction , Knee Joint/diagnostic imaging , Osteoarthritis/diagnostic imaging , SwineABSTRACT
OBJECTIVE: To examine prospectively the association between group A Streptococcus (GAS) pharyngeal exposures and exacerbations of tics in a large multicenter population of youth with chronic tic disorders (CTD) across Europe. METHODS: We followed up 715 children with CTD (age 10.7 ± 2.8 years, 76.8% boys), recruited by 16 specialist clinics from 9 countries, and followed up for 16 months on average. Tic, obsessive-compulsive symptom (OCS), and attention-deficit/hyperactivity disorder (ADHD) severity was assessed during 4-monthly study visits and telephone interviews. GAS exposures were analyzed using 4 possible combinations of measures based on pharyngeal swab and serologic testing. The associations between GAS exposures and tic exacerbations or changes of tic, OC, and ADHD symptom severity were measured, respectively, using multivariate logistic regression plus multiple failure time analyses and mixed effects linear regression. RESULTS: A total of 405 exacerbations occurred in 308 of 715 (43%) participants. The proportion of exacerbations temporally associated with GAS exposure ranged from 5.5% to 12.9%, depending on GAS exposure definition. We did not detect any significant association of any of the 4 GAS exposure definitions with tic exacerbations (odds ratios ranging between 1.006 and 1.235, all p values >0.3). GAS exposures were associated with longitudinal changes of hyperactivity-impulsivity symptom severity ranging from 17% to 21%, depending on GAS exposure definition. CONCLUSIONS: This study does not support GAS exposures as contributing factors for tic exacerbations in children with CTD. Specific workup or active management of GAS infections is unlikely to help modify the course of tics in CTD and is therefore not recommended.
Subject(s)
Streptococcal Infections/epidemiology , Tic Disorders/epidemiology , Adolescent , Child , Child, Preschool , Cohort Studies , Europe/epidemiology , Female , Humans , Male , Prospective Studies , Symptom Flare UpABSTRACT
It is unclear how the tryptophan (TRP) breakdown pathway relates to the activated inflammatory state of patients with major depressive disorder (MDD). We determined in two different cohorts of patients with MDD (n = 281) and healthy controls (HCs) (n = 206) collected for the EU-MOODINFLAME project: We then correlated outcomes to each other, and to the clinical characteristics of patients. Both cohorts of patients differed clinically; patients of the Munich cohort (n = 50) were less overweight, less medicated, were less in the current episode and showed a higher HAM-D 17 score as compared with patients of the Muenster cohort (n = 231). An increased expression of ICCGs was found in the circulating monocytes of patients of both cohorts; this was in particular evident in the Munich cohort. In contrast, ISGs monocyte expression levels tended to be reduced (both cohorts). TRP serum levels were linked to the pro-inflammatory (ICCGs) monocyte state of patients; a decrease in TRP serum levels was found in the Munich cohort; TRP levels correlated negatively to patient's HAM-D 17 score. Contrary to what expected, KYN serum levels were not increased in patients (both cohorts); and an increased KYN/TRP ratio was only found in the Munich patients (who showed the lowest TRP serum levels). IDO-1 monocyte expression levels were decreased in patients (both cohorts) and negatively associated to their pro-inflammatory (ICCGs) monocyte state. Thus, a depletion of TRP via an ICCGs-inflammatory IDO activation is not likely in MDD. Downstream from KYN, and regarding compounds influencing glutamate receptors (GR), reduced serum levels of KYNA (NMDA-R antagonist), 3-HK (NMDA-R agonist), and XA (mGlu2/3 agonist) were found in patients of both cohorts; PIC serum levels (NMDA-R antagonist) were increased in patients of both cohorts. Reduced QUIN serum levels (NMDA-R agonist) were found in patients of the Muenster cohort,only. 3-HK levels correlated to the monocyte inflammatory ICCG state of patients. The ultimate effect on brain glutamate receptor triggering of this altered equilibrium between peripheral agonists and antagonists remains to be elucidated.
Subject(s)
Depressive Disorder, Major/blood , Depressive Disorder, Major/epidemiology , Inflammation Mediators/blood , Monocytes/metabolism , Signal Transduction/physiology , Tryptophan/blood , Adult , Cohort Studies , Depressive Disorder, Major/immunology , Female , Germany/epidemiology , Humans , Inflammation Mediators/immunology , Male , Middle Aged , Monocytes/immunology , Tryptophan/immunologyABSTRACT
OBJETIVO: La Monitorización Terapéutica de Drogas (llamada en inglés TDM: therapeutic drug monitoring) combina la cuantificación de las concentraciones de medicamentos en la sangre, la interpretación farmacológica y las directrices de tratamiento. La TDM introduce una herramienta de medicina de precisión en una ípoca de gran conciencia de la necesidad de tratamientos personalizados en neurología y psiquiatría. Las indicaciones claras de la TDM incluyen la ausencia de respuesta clínica en el rango de dosis terapéuticas, la evaluación de la adherencia farmacológica, problemas de tolerancia e interacciones medicamentosas. MÉTODOS: Basándose en la literatura existente, se describieron los rangos de referencia terapéutica recomendables, los valores críticos de laboratorio y los niveles de recomendación para usar la TDM para la optimización de dosis sin indicaciones específicas, se calcularon los factores de conversión, los factores para el cálculo de concentraciones medicamentosas relacionadas con la dosis (en inglés DRC dose-to-ratioconcentration) y el cociente entre el metabolito y el compuesto original (en inglés se llama MPR: metabolite-to-parent ratio). RESULTADOS: Este resumen de las guías actualizadas del consenso por la Task Force del TDM del Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie, ofrece el conocimiento práctico y teórico para la integración de la TDM como parte de la farmacoterapia con medicamentos neuropsiquiátricos en la práctica clínica rutinaria. CONCLUSIONES: La presente traducción en español, de la guía para la aplicación del TDM en medicamentos neuropsiquiátricos, tiene como objetivo ayudar a los clínicos a mejorar la seguridad y la eficacia de los tratamientos
OBJECTIVES: Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation, and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalised treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities, and forensic patients. Clear indications for TDM include lack of clinical response in the therapeutic dose range, assessment of drug adherence, tolerability issues, and drug-drug interactions. METHODS: Based upon existing literature, recommended therapeutic reference ranges, laboratory alert levels, and levels of recommendation to use TDM for dosage optimisation without specific indications, conversion factors, factors for calculation of dose-related drug concentrations, and metabolite-to-parent ratios were calculated. RESULTS: This summary of the updated consensus guidelines by the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) offers the practical and theoretical knowledge for the integration of TDM as part of pharmacotherapy with neuro- psychiatric agents into clinical routine. CONCLUSIONS: The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment