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Objective: The DIRAS2 gene is associated with ADHD, but its function is largely unknown. Thus, we aimed to explore the genes and molecular pathways affected by DIRAS2. Method: Using short hairpin RNAs, we downregulated Diras2 in murine hippocampal primary cells. Gene expression was analyzed by microarray and affected pathways were identified. We used quantitative real-time polymerase chain reaction (qPCR) to confirm expression changes and analyzed enrichment of differentially expressed genes in an ADHD GWAS (genome-wide association studies) sample. Results: Diras2 knockdown altered expression of 1,612 genes, which were enriched for biological processes involved in neurodevelopment. Expression changes were confirmed for 33 out of 88 selected genes. These 33 genes showed significant enrichment in ADHD patients in a gene-set-based analysis. Conclusion: Our findings show that Diras2 affects numerous genes and thus molecular pathways that are relevant for neurodevelopmental processes. These findings may further support the hypothesis that DIRAS2 is linked to etiological processes underlying ADHD. (J. of Att. Dis. 2021; 25(4) 572-583).
Background: Inflammation is essential for the pathogenesis of multiple sclerosis (MS). While the immune system contribution to the development of neurological symptoms has been intensively studied, inflammatory biomarkers for mental symptoms such as depression are poorly understood in the context of MS. Here, we test if depression correlates with peripheral and central inflammation markers in MS patients as soon as the diagnosis is established. Methods: Forty-four patients were newly diagnosed with relapsing-remitting MS, primary progressive MS or clinically isolated syndrome. Age, gender, EDSS, C-reactive protein (CRP), albumin, white blood cells count in cerebrospinal fluid (CSF WBC), presence of gadolinium enhanced lesions (GE) on T1-weighted images and total number of typical MS lesion locations were included in linear regression models to predict Beck Depression Inventory (BDI) score and the depression dimension of the Symptoms Checklist 90-Revised (SCL90RD). Results: CRP elevation and GE predicted significantly BDI (CRP: p = 0.007; GE: p = 0.019) and SCL90RD (CRP: p = 0.004; GE: p = 0.049). The combination of both factors resulted in more pronounced depressive symptoms (p = 0.04). CSF WBC and EDSS as well as the other variables were not correlated with depressive symptoms. Conclusions: CRP elevation and GE are associated with depressive symptoms in newly diagnosed MS patients. These markers can be used to identify MS patients exhibiting a high risk for the development of depressive symptoms in early phases of the disease.
Genes encoding endocannabinoid and sphingolipid metabolism pathways were suggested to contribute to the genetic risk towards attention deficit hyperactivity disorder (ADHD). The present pilot study assessed plasma concentrations of candidate endocannabinoids, sphingolipids and ceramides in individuals with adult ADHD in comparison with healthy controls and patients with affective disorders. Targeted lipid analyses of 23 different lipid species were performed in 71 mental disorder patients and 98 healthy controls (HC). The patients were diagnosed with adult ADHD (n = 12), affective disorder (major depression, MD n = 16 or bipolar disorder, BD n = 6) or adult ADHD with comorbid affective disorders (n = 37). Canonical discriminant analysis and CHAID analyses were used to identify major components that predicted the diagnostic group. ADHD patients had increased plasma concentrations of sphingosine-1-phosphate (S1P d18:1) and sphinganine-1-phosphate (S1P d18:0). In addition, the endocannabinoids, anandamide (AEA) and arachidonoylglycerol were increased. MD/BD patients had increased long chain ceramides, most prominently Cer22:0, but low endocannabinoids in contrast to ADHD patients. Patients with ADHD and comorbid affective disorders displayed increased S1P d18:1 and increased Cer22:0, but the individual lipid levels were lower than in the non-comorbid disorders. Sphingolipid profiles differ between patients suffering from ADHD and affective disorders, with overlapping patterns in comorbid patients. The S1P d18:1 to Cer22:0 ratio may constitute a diagnostic or prognostic tool.
Pathologic data indicate that human cytomegalovirus (HCMV) infection might be associated with the pathogenesis of several human malignancies. However, no definitive evidence of a causal link between HCMV infection and cancer dissemination has been established to date. This study describes the modulation of the invasive behavior of NCAM-expressing tumor cell lines by HCMV. Neuroblastoma (NB) cells, persistently infected with the HCMV strain AD169 (UKF-NB-4AD169 and MHH-NB-11AD169), were added to endothelial cell monolayers and adhesion and penetration kinetics were measured. The 140- and 180-kDa isoforms of the adhesion receptor NCAM were evaluated by flow cytometry, Western blot, and reverse transcriptionpolymerase chain reaction (RT-PCR). The relevance of NCAM for tumor cell binding was proven by treating NB with NCAM antisense oligonucleotides or NCAM transfection. HCMV infection profoundly increased the number of adherent and penetrated NB, compared to controls. Surface expression of NCAM was significantly lower on UKF-NB-4AD169 and MHH-NB-11AD169, compared to mock-infected cells. Western-blot and RT-PCR demonstrated reduced protein and RNA levels of the 140- and 180-kDa isoform. An inverse correlation between NCAM expression and adhesion capacity of NB has been shown by antisense and transfection experiments. We conclude that HCMV infection leads to downregulation of NCAM receptors, which is associated with enhanced tumor cell invasiveness.
Serum GFAP for stroke diagnosis in regions with limited access to brain imaging (BE FAST India)
(2021)
Introduction: Despite a high burden of stroke, access to rapid brain imaging is limited in many middle- and low-income countries. Previous studies have described the astroglial protein GFAP (glial fibrillary acidic protein) as a biomarker of intracerebral hemorrhage. The aim of this study was to test the diagnostic accuracy of GFAP for ruling out intracranial hemorrhage in a prospective cohort of Indian stroke patients. Patients and methods: This study was conducted in an Indian tertiary hospital (Christian Medical College, Ludhiana). Patients with symptoms suggestive of acute stroke admitted within 12 h of symptom onset were enrolled. Blood samples were collected at hospital admission. Single Molecule Array technology was used for determining serum GFAP concentrations. Results: A total number of 155 patients were included (70 intracranial hemorrhage, 75 ischemic stroke, 10 stroke mimics). GFAP serum concentrations were elevated in intracranial hemorrhage patients compared to ischemic stroke patients [median (interquartile range) 2.36 µg/L (0.61–7.16) vs. 0.18 µg/L (0.11–0.38), p < 0.001]. Stroke mimics patients had a median GFAP serum level of 0.14 µg/L (0.09–0.26). GFAP values below the cut-off of 0.33 µg/L (area under the curve 0.871) ruled out intracranial hemorrhage with a negative predictive value of 89.7%, (at a sensitivity for detecting intracranial hemorrhage of 90.0%). Discussion: The high negative predictive value of a GFAP test system allows ruling out patients with intracranial hemorrhage. Conclusion: In settings where immediate brain imaging is not available, this would enable to implement secondary prevention (e.g., aspirin) in suspected ischemic stroke patients as soon as possible.
Background: Understanding which factors influence dietary intake, particularly in daily life, is crucial given the impact diet has on physical as well as mental health. However, a factor might influence whether but not how much an individual eats and vice versa or a factor’s importance may differ across these two facets. Distinguishing between these two facets, hence, studying dietary intake as a dual process is conceptually promising and not only allows further insights, but also solves a statistical issue. When assessing the association between a predictor (e.g. momentary affect) and subsequent dietary intake in daily life through ecological momentary assessment (EMA), the outcome variable (e.g. energy intake within a predefined time-interval) is semicontinuous. That is, one part is equal to zero (i.e. no dietary intake occurred) and the other contains right-skewed positive values (i.e. dietary intake occurred, but often only small amounts are consumed). However, linear multilevel modelling which is commonly used for EMA data to account for repeated measures within individuals cannot be applied to semicontinuous outcomes. A highly informative statistical approach for semicontinuous outcomes is multilevel two-part modelling which treats the outcome as generated by a dual process, combining a multilevel logistic/probit regression for zeros and a multilevel (generalized) linear regression for nonzero values. Methods: A multilevel two-part model combining a multilevel logistic regression to predict whether an individual eats and a multilevel gamma regression to predict how much is eaten, if an individual eats, is proposed. Its general implementation in R, a widely used and freely available statistical software, using the R-package brms is described. To illustrate its practical application, the analytical approach is applied exemplary to data from the Eat2beNICE-APPetite-study. Results: Results highlight that the proposed multilevel two-part model reveals process-specific associations which cannot be detected through traditional multilevel modelling. Conclusions: This paper is the first to introduce multilevel two-part modelling as a novel analytical approach to study dietary intake in daily life. Studying dietary intake through multilevel two-part modelling is conceptually as well as methodologically promising. Findings can be translated to tailored nutritional interventions targeting either the occurrence or the amount of dietary intake.
BH3 mimetics are novel anticancer therapeutics that induce apoptosis by targeting anti‐apoptotic BCL‐2 proteins. Highly specific inhibitors of the main anti-apoptotic proteins BCL-2, BCL‐XL and MCL‐1 promise new opportunities for the treatment of AML. However, it is currently unclear which of these anti-apoptotic BCL-2 proteins represents the most promising target in AML. Therefore, we investigated the effect of BH3 mimetics targeting either BCL-2 (ABT-199, S55746), BCL-XL (A-1331852) or MCL-1 (S63845) on eleven AML cell lines. Drug sensitivity screening revealed heterogeneous sensitivity towards the different BH3 mimetics, with the best responses observed upon targeting of MCL-1. Selected cell lines that displayed sensitivity towards the specific BH3 mimetics underwent intrinsic apoptosis, which was characterized by loss of mitochondrial membrane potential, exposure of phosphatidylserine and activation of caspases. Furthermore, S63845 turned out to displace BIMS and NOXA from MCL-1 to induce apoptotic cell death. Importantly, the translational relevance of this study was demonstrated by experiments in primary AML blasts, which displayed similar sensitivity towards BH3 mimetics as the cell lines did. Additionally, experiments with nonmalignant cells could confirm the clinical relevance of the MCL-1 inhibitor. There we could show, that S63845 does not cause cytotoxicity on HPCs at efficacious doses.
In conclusion, our findings reveal that the inhibition of BCL-2 proteins, especially MCL-1, by BH3 mimetics can be a promising strategy in AML treatment.
Study design: Systematic review. Background and objectives: Preoperative neuromuscular function is predictive for knee function and return to sports (RTS) after reconstruction of the anterior cruciate ligament (ACL). The aim of this review was to examine the potential benefits of prehabilitation on pre-/postoperative objective, self-reported and RTS-specific outcomes. Methods: A systematic search was conducted within three databases. From the 1.071 studies screened, two randomized control trials (RCTs), two control trials (CTs) and two cohort studies (CS) met the inclusion criteria. Methodological quality rating adopted the PEDro- (RCT, CT) or Newcastle-Ottawa-Scale (CS). Results and conclusions: Methodological quality of the included studies was moderate (PEDro score: 6.5 ± 1.7; range 4 to 9). Two studies reported higher increases of the maximal quadriceps torque from baseline to pre-reconstruction: one study in the limb symmetry index (LSI), and one in both legs of the prehabilitation group compared to the controls. At 12-weeks post-reconstruction, one study (from two) indicated that the prehabilitation group had a lesser post-operative decline in the single-leg-hop for distance LSI (clinically meaningful). Similar findings were found in terms of quadriceps strength LSI (one study). At both pre-reconstruction (three studies) and two-year post-surgery (two studies), the prehabilitation groups reached significantly higher self-reported knee function (clinically meaningful) than the controls. RTS tended to be faster (one study). At two years post-surgery, RTS rates (one study) were higher in the prehabilitation groups. The results provide evidence for the relevance of prehabilitation prior to ACL-reconstruction to improve neuromuscular and self-reported knee function as well as RTS. More high quality confirmatory RCTs are warranted.
Class I and II histone deacetylases (HDAC) are considered important regulators of immunity and inflammation. Modulation of HDAC expression and activity is associated with altered inflammatory responses but reports are controversial and the specific impact of single HDACs is not clear. We examined class I and II HDACs in TLR-4 signaling pathways in murine macrophages with a focus on IκB kinase epsilon (IKKε) which has not been investigated in this context before. Therefore, we applied the pan-HDAC inhibitors (HDACi) trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) as well as HDAC-specific siRNA. Administration of HDACi reduced HDAC activity and decreased expression of IKKε although its acetylation was increased. Other pro-inflammatory genes (IL-1β, iNOS, TNFα) also decreased while COX-2 expression increased. HDAC 2, 3 and 4, respectively, might be involved in IKKε and iNOS downregulation with potential participation of NF-κB transcription factor inhibition. Suppression of HDAC 1–3, activation of NF-κB and RNA stabilization mechanisms might contribute to increased COX-2 expression. In conclusion, our results indicate that TSA and SAHA exert a number of histone- and HDAC-independent functions. Furthermore, the data show that different HDAC enzymes fulfill different functions in macrophages and might lead to both pro- and anti-inflammatory effects which have to be considered in therapeutic approaches.
Objectives: The ongoing coronavirus pandemic is challenging, especially in severely affected patients who require intubation and sedation. Although the potential benefits of sedation with volatile anesthetics in coronavirus disease 2019 patients are currently being discussed, the use of isoflurane in patients with coronavirus disease 2019–induced acute respiratory distress syndrome has not yet been reported. Design: We performed a retrospective analysis of critically ill patients with hypoxemic respiratory failure requiring mechanical ventilation. Setting: The study was conducted with patients admitted between April 4 and May 15, 2020 to our ICU. Patients: We included five patients who were previously diagnosed with severe acute respiratory syndrome coronavirus 2 infection. Intervention: Even with high doses of several IV sedatives, the targeted level of sedation could not be achieved. Therefore, the sedation regimen was switched to inhalational isoflurane. Clinical data were recorded using a patient data management system. We recorded demographical data, laboratory results, ventilation variables, sedative dosages, sedation level, prone positioning, duration of volatile sedation and outcomes. Measurements & Main Results: Mean age (four men, one women) was 53.0 (± 12.7) years. The mean duration of isoflurane sedation was 103.2 (± 66.2) hours. Our data demonstrate a substantial improvement in the oxygenation ratio when using isoflurane sedation. Deep sedation as assessed by the Richmond Agitation and Sedation Scale was rapidly and closely controlled in all patients, and the subsequent discontinuation of IV sedation was possible within the first 30 minutes. No adverse events were detected. Conclusions: Our findings demonstrate the feasibility of isoflurane sedation in five patients suffering from severe coronavirus disease 2019 infection. Volatile isoflurane was able to achieve the required deep sedation and reduced the need for IV sedation.
Background: Gait kinematics after total hip replacement only partly explain the differences in the joint moments in the frontal plane between hip osteoarthritis patients after hip replacement and healthy controls. The goal of this study was to determine if total hip replacement surgery affects radiological leg alignment (Hip-Knee-Shaft-Angle, femoral offset, Neck-Shaft-Angle and varus/valgus alignment) and which of these parameters can explain the joint moments, additionally to the gait kinematics.
Methods: 22 unilateral hip osteoarthritis patients who were scheduled for total hip replacement were included in the study. Preoperatively and 1 year postoperatively all patients had biplanar radiographic examinations and 3D gait analysis.
Results: The operated leg showed significantly (P < 0.05) more varus (1.1°) as well as a larger femoral offset (+ 8 mm) and a larger Hip-Knee-Shaft-Angle (+ 1.3°) after total hip replacement; however no significant differences in the joint moments in the frontal plane compared to healthy controls were found. The hip moment (first half of stance) and the knee moments (first and second half of stance) were mostly determined by the varus/valgus alignment (29% and respectively 36% and 35%). The combination with a kinematic parameter (knee range of motion, foot progression angle) increased the predictive value for the knee moments.
Conclusion: In our patient group the joint moments after total hip replacement did not differ from healthy controls, whereas radiological leg alignment parameters changed significantly after the total hip replacement. A combination of these radiological leg parameters, especially the varus alignment, and the deviating kinematics explain the joint moments in the frontal plane during gait after total hip replacement surgery. For surgeons it is important not to create too much of a structural varus alignment by implanting the new hip joint as varus alignment can increase the knee adduction moment and the risk for osteoarthritis of the medial knee compartment.
Trial registration: This study was retrospectively registered with DRKS (German Clinical Trials Register) under the number DRKS00015053. Registered 1st of August 2018.
Background: Non-clear cell renal cell cancers (nccRCC) are rare entities, and the optimal therapy in metastatic disease has still to be defined. Methods: In this small prospectively randomized phase IIa multicenter trial, we investigated temsirolimus (TEM) versus sunitinib (SUN) as first-line therapy in patients with metastatic nccRCC. The patients were randomized 1:1 to either TEM in a dose of 25 mg i.v. once a week or SUN with 50 mg p.o. daily for 4 weeks on and 2 weeks off. Primary endpoint was progression-free survival (PFS). In total, 22 patients were included with predominantly papillary RCC (16/22) followed by chromophobe RCC and others. Results: The male to female ratio was 16:6. The tumor control rate (CR + PR + SD) was 58% for TEM and 90% for SUN-treated patients. There was also a trend for improved PFS with 9.3 versus 13.2 months (HR 1.64; 95% CI 0.65–4.18) in favor of SUN. There was no trend for overall survival. Conclusions: Despite this trial had to be terminated earlier due to low recruitment, the results match the other studies published so far with the mTOR inhibitor everolimus and SUN, which show a trend in favor of SUN for ORR and PFS.
Postoperative Psychosen
(1916)