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SARS-CoV-2 is a novel coronavirus currently causing a pandemic. We show that the majority of amino acid positions, which differ between SARS-CoV-2 and the closely related SARS-CoV, are differentially conserved suggesting differences in biological behaviour. In agreement, novel cell culture models revealed differences between the tropism of SARS-CoV-2 and SARS-CoV. Moreover, cellular ACE2 (SARS-CoV-2 receptor) and TMPRSS2 (enables virus entry via S protein cleavage) levels did not reliably indicate cell susceptibility to SARS-CoV-2. SARS-CoV-2 and SARS-CoV further differed in their drug sensitivity profiles. Thus, only drug testing using SARS-CoV-2 reliably identifies therapy candidates. Therapeutic concentrations of the approved protease inhibitor aprotinin displayed anti-SARS-CoV-2 activity. The efficacy of aprotinin and of remdesivir (currently under clinical investigation against SARS-CoV-2) were further enhanced by therapeutic concentrations of the proton pump inhibitor omeprazole (aprotinin 2.7-fold, remdesivir 10-fold). Hence, our study has also identified anti-SARS-CoV-2 therapy candidates that can be readily tested in patients.
SARS-CoV-2 and stroke characteristics: a report from the Multinational COVID-19 Stroke Study Group
(2020)
Background: Stroke is reported as a consequence of SARS-CoV-2 infection. However, there is a lack of regarding comprehensive stroke phenotype and characteristics
Methods: We conducted a multinational observational study on features of consecutive acute ischemic stroke (AIS), intracranial hemorrhage (ICH), and cerebral venous or sinus thrombosis (CVST) among SARS-CoV-2 infected patients. We further investigated the association of demographics, clinical data, geographical regions, and countries’ health expenditure among AIS patients with the risk of large vessel occlusion (LVO), stroke severity as measured by National Institute of Health stroke scale (NIHSS), and stroke subtype as measured by the TOAST criteria. Additionally, we applied unsupervised machine learning algorithms to uncover possible similarities among stroke patients.
Results: Among the 136 tertiary centers of 32 countries who participated in this study, 71 centers from 17 countries had at least one eligible stroke patient. Out of 432 patients included, 323(74.8%) had AIS, 91(21.1%) ICH, and 18(4.2%) CVST. Among 23 patients with subarachnoid hemorrhage, 16(69.5%) had no evidence of aneurysm. A total of 183(42.4%) patients were women, 104(24.1%) patients were younger than 55 years, and 105(24.4%) patients had no identifiable vascular risk factors. Among 380 patients who had known interval onset of the SARS-CoV-2 and stroke, 144(37.8%) presented to the hospital with chief complaints of stroke-related symptoms, with asymptomatic or undiagnosed SARS-CoV-2 infection. Among AIS patients 44.5% had LVO; 10% had small artery occlusion according to the TOAST criteria. We observed a lower median NIHSS (8[3-17], versus 11 [5-17]; p=0.02) and higher rate of mechanical thrombectomy (12.4% versus 2%; p<0.001) in countries with middle to high-health expenditure when compared to countries with lower health expenditure. The unsupervised machine learning identified 4 subgroups, with a relatively large group with no or limited comorbidities.
Conclusions: We observed a relatively high number of young, and asymptomatic SARS-CoV-2 infections among stroke patients. Traditional vascular risk factors were absent among a relatively large cohort of patients. Among hospitalized patients, the stroke severity was lower and rate of mechanical thrombectomy was higher among countries with middle to high-health expenditure.
Oral swabs, sputum and blood samples from 18 patients with SARS-CoV-2 infection were examined using real-time reverse transcription polymerase chain reaction (RT-PCR) testing. Whereas oral swabs or sputum from the lower respiratory tract were tested RT-PCR positive in all patients, RNAemia was neither detected in 3 patients without symptoms nor in 14 patients with flu-like symptoms, fever or pneumonia. The only patient with RNAemia suffered from acute respiratory distress syndrome (ARDS) and was artificially ventilated in an intensive care unit. Risk for SARS-CoV-2 transmission through blood components in asymptomatic SARS-CoV-2 infected individuals therefore seems negligible but further studies are needed.
Development of treatment strategies of chronic inflammatory disorders relies on on-going progress in drug discovery approaches and related molecular biologics. This study presents a gene reporter-based approach of phenotypic screening for anti-inflammatory compounds in the context of rheumatoid arthritis (RA).
CEBPD gene, used as the target gene for the screening readout, encodes CCAAT/enhancer binding protein delta (C/EBPδ) transcription factor (TF). Structural and regulatory characteristics of CEBPD gene as well as function of C/EBPδ TF in the context of inflammation satisfied assay requirements. C/EBPδ TF acts as a key regula-tor of inflammatory gene transcription in macrophages (Mϕ) and is observed to con-tribute to disease development in both a rodent model of RA and RA patient biopsies.
Despite well-described pro-inflammatory effects of C/EBPδ TF, it functions as a cell context-specific signal integrator showing also an anti-inflammatory activity. Conse-quently, both activation and inhibition of CEBPD alike may display a desired anti-inflammatory effect. The aim of this study was to develop a high-throughput screening assay for
CEBPD-modulating compounds and confirm hit compounds’ anti-inflammatory effects via gene expression analysis.
Generation and characterization of a multi-gene-reporter cassette 1.0 encoding enzy-matic secreted alkaline phosphatase (SEAP) gene reporter was a priority during the assay development. Chemiluminescent SEAP assay demonstrating high assay sensitivi-ty, broad linear range, high reproducibility and repeatability was chosen to monitor activity of the defined CEBPD promoter (CEBPD::SEAP). PMA-differentiated and M1-polarized THP-1-derived Mϕ stably expressing multi-gene-reporter cassette 1.0 were used as the assay’s cellular system. mRNA expression of both reporter CEBPD::SEAP and endogenous CEBPD mirrored each other in response to a LPS and IFN-g-triggered inflammatory stimulus (M1 treatment), even though the defined CEBPD promoter re-gion, utilized in the assay, contained only the most proximal and known regulatory se-quences. SEAP chemiluminescence in the reporter cells´ supernatant reliably correlat-ed with the M1 treatment-induced CEBPD::SEAP gene expression. The final screening protocol was developed for semi-automatic screening in the 384-well format.
In total, 2054 compounds from LOPAC®1280 and ENZO®774 libraries were screened twice
using the enzymatic SEAP readout with subsequent analysis of 18 selected compounds: nine with the highest and nine with the lowest signals, further characterized by qPCR. Gene expression levels of endogenous CEBPD, CEBPD::SEAP reporter as well as, IL-6,
IL-1β, and CCL2 as inflammatory markers were quantified. qPCR assays failed to corre-late to SEAP readout in 15 compounds within three standard deviations (SDs) from sol-vent control: nine low signal and six high signal compounds. Demonstrating both assay sensitivity and specificity, a correlation between qPCR gene expression and SEAP readout was observed for three hit compounds with signals above three SDs: BET inhib-itors (BETi) GSK 1210151A and Ro 11-1464 as well as an HDAC inhibitor (HDACi) vori-nostat. The control compound trichostatin A (TSA) that reproducibly upregulated SEAP readout is also an HDAC inhibitor with a similar structure to vorinostat and was there-fore included in the anti-inflammatory phenotype analysis.
The observed suppression of IL-6, IL-1ß, and CCL2 gene expression by hit compounds suggested their anti-inflammatory effect in THP-1 reporter Mϕ. mRNA expression of
IL-6 and CCL2 was suppressed by HDACi and BETi at both 4 and 24 hours, while BETi reduced IL-1β mRNA expression 24 hour time point. BETi significantly upregulated gene expression of both reporter CEBPD::SEAP and endogenous CEBPD, 4 hours after M1 treatment. At the same time point, HDACi completely abolished the mRNA expres-sion of the endogenous CEBPD, while simultaneously upregulating mRNA expression of the reporter CEBPD::SEAP. The use of the most proximal 300 base pairs region of en-dogenous CEBPD promoter, making the upstream regulatory elements unavailable in the assay, may account for differential expression levels of SEAP and C/EBPδ TF. This observation corroborated the need to include a longer and more extensive CEBPD´s gene regulatory area. Thus, an improved multi-gene-reporter cassette 2.0 was gener-ated to be used on the basis of a bacterial artificial chromosome (BAC) covering CE-BPD´s genomic area of about 200,000 base pairs.
The generated screening assay is flexible, reliable, and sensitive displaying potential for drug discovery and drug repurposing. The pharmacological modulation of CEBPD gene expression, first reported for GSK 1210151A, Ro 11-1464, and vorinostat, contrib-utes to the understanding of inflammatory responses in Mϕ and may have RA thera-peutic applications.
Locomotor activity patterns of laboratory mice are widely used to analyze circadian mechanisms, but most investigations have been performed under standardized laboratory conditions. Outdoors, animals are exposed to daily changes in photoperiod and other abiotic cues that might influence their circadian system. To investigate how the locomotor activity patterns under outdoor conditions compare to controlled laboratory conditions, we placed 2 laboratory mouse strains (melatonin-deficient C57Bl and melatonin-proficient C3H) in the garden of the Dr. Senckenbergische Anatomie in Frankfurt am Main. The mice were kept singly in cages equipped with an infrared locomotion detector, a hiding box, nesting material, and with food and water ad libitum. The locomotor activity of each mouse was recorded for 1 year, together with data on ambient
temperature, light, and humidity. Chronotype, chronotype stability, total daily activity, duration of the activity period, and daily diurnality indices were determined from the actograms. C3H mice showed clear seasonal differences in the chronotype, its stability, the total daily activity, and the duration of the activity period. These pronounced seasonal differences were not observed in the C57Bl. In both strains, the onset of the main activity period was mainly determinedby the evening dusk, whereas the offset was influenced by the ambient temperature. The actograms did not reveal infra-, ultradian, or lunar rhythms or a weekday/weekend pattern. Under outdoor conditions, the 2 strains retained their nocturnal locomotor identity as observed in the laboratory. Our results indicate that the chronotype displays a seasonal plasticity that may depend on the melatoninergic system. Photoperiod and ambient temperature are the most potent abiotic entraining cues. The timing of the evening dusk mainly affects the onset of the activity period; the ambient temperature during this period influences the latter’s duration. Humidity, overall light intensities, and human activities do not affect the locomotor behavior.
Purpose: Perfusion-weighted MRI (PWI) and O-(2-[18F]fluoroethyl-)-l-tyrosine ([18F]FET) PET are both applied to discriminate tumor progression (TP) from treatment-related changes (TRC) in patients with suspected recurrent glioma. While the combination of both methods has been reported to improve the diagnostic accuracy, the performance of a sequential implementation has not been further investigated. Therefore, we retrospectively analyzed the diagnostic value of consecutive PWI and [18F]FET PET.
Methods: We evaluated 104 patients with WHO grade II–IV glioma and suspected TP on conventional MRI using PWI and dynamic [18F]FET PET. Leakage corrected maximum relative cerebral blood volumes (rCBVmax) were obtained from dynamic susceptibility contrast PWI. Furthermore, we calculated static (i.e., maximum tumor to brain ratios; TBRmax) and dynamic [18F]FET PET parameters (i.e., Slope). Definitive diagnoses were based on histopathology (n = 42) or clinico-radiological follow-up (n = 62). The diagnostic performance of PWI and [18F]FET PET parameters to differentiate TP from TRC was evaluated by analyzing receiver operating characteristic and area under the curve (AUC).
Results: Across all patients, the differentiation of TP from TRC using rCBVmax or [18F]FET PET parameters was moderate (AUC = 0.69–0.75; p < 0.01). A rCBVmax cutoff > 2.85 had a positive predictive value for TP of 100%, enabling a correct TP diagnosis in 44 patients. In the remaining 60 patients, combined static and dynamic [18F]FET PET parameters (TBRmax, Slope) correctly discriminated TP and TRC in a significant 78% of patients, increasing the overall accuracy to 87%. A subgroup analysis of isocitrate dehydrogenase (IDH) mutant tumors indicated a superior performance of PWI to [18F]FET PET (AUC = 0.8/< 0.62, p < 0.01/≥ 0.3).
Conclusion: While marked hyperperfusion on PWI indicated TP, [18F]FET PET proved beneficial to discriminate TP from TRC when PWI remained inconclusive. Thus, our results highlight the clinical value of sequential use of PWI and [18F]FET PET, allowing an economical use of diagnostic methods. The impact of an IDH mutation needs further investigation.
Purpose: The antifungal drugs ketoconazole and itraconazole reduce serum concentrations of 4β-hydroxycholesterol, which is a validated marker for hepatic cytochrome P450 (CYP) 3A4 activity. We tested the effect of another antifungal triazole agent, fluconazole, on serum concentrations of different sterols and oxysterols within the cholesterol metabolism to see if this inhibitory reaction is a general side effect of azole antifungal agents.
Methods: In a prospective, double-blind, placebo-controlled, two-way crossover design, we studied 17 healthy subjects (nine men, eight women) who received 400 mg fluconazole or placebo daily for 8 days. On day 1 before treatment and on day 8 after the last dose, fasting blood samples were collected. Serum cholesterol precursors and oxysterols were measured by gas chromatography-mass spectrometry-selected ion monitoring and expressed as the ratio to cholesterol (R_sterol).
Results: Under fluconazole treatment, serum R_lanosterol and R_24,25-dihydrolanosterol increased significantly without affecting serum cholesterol or metabolic downstream markers of hepatic cholesterol synthesis. Serum R_4β-, R_24S-, and R_27-hydroxycholesterol increased significantly.
Conclusion: Fluconazole inhibits the 14α-demethylation of lanosterol and 24,25-dihydrolanosterol, regulated by CYP51A1, without reduction of total cholesterol synthesis. The increased serum level of R_4β-hydroxycholesterol under fluconazole treatment is in contrast to the reductions observed under ketoconazole and itraconazole treatments. The question, whether this increase is caused by induction of CYP3A4 or by inhibition of the catabolism of 4β-hydroxycholesterol, must be answered by mechanistic in vitro and in vivo studies comparing effects of various azole antifungal agents on hepatic CYP3A4 activity.
Background: Data on the arrhythmic burden of women at risk for sudden cardiac death are limited, especially in patients using the wearable cardioverter-defibrillator (WCD).
Objective: We aimed to characterize WCD compliance, atrial and ventricular arrhythmic burden, and WCD outcomes by sex in patients enrolled in the Prospective Registry of Patients Using the Wearable Cardioverter Defibrillator (WEARIT-II U.S. Registry).
Methods: In the WEARIT-II Registry, we stratified 2000 patients by sex into women (n = 598) and men (n = 1402). WCD wear time, ventricular and atrial arrhythmic events during WCD use, and implantable cardioverter-defibrillator (ICD) implantation rates at the end of WCD use were evaluated.
Results: The mean WCD wear time was similar in women and men (94 days vs 90 days; P = .145), with longer daily use in women (21.4 h/d vs 20.7 h/d; P = .001). Burden of ventricular tachycardia or ventricular fibrillation was higher in women, with 30 events per 100 patient-years compared with 18 events per 100 patient-years in men (P = .017), with similar findings for treated and non-treated ventricular tachycardia/ventricular fibrillation. Recurrent atrial arrhythmias/sustained ventricular tachycardia was also more frequent in women than in men (167 events per 100 patient-years vs 73 events per 100 patient-years; P = .042). However, ICD implantation rate at the end of WCD use was similar in both women and men (41% vs 39%; P = .448).
Conclusion: In the WEARIT-II Registry, we have shown a higher burden of ventricular and atrial arrhythmic events in women than in men. ICD implantation rates at the end of WCD use were similar. Our findings warrant monitoring women at risk for sudden cardiac death who have a high burden of atrial and ventricular arrhythmias while using the WCD.
Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity. Especially,thedevelopmentoffibrosisandportalhypertensioninNAFLDpatientsrequirestreatment. Transgenic TGR(mREN2)27 rats overexpressing mouse renin spontaneously develop NAFLD with portal hypertension but without obesity. This study investigated the additional role of obesity in this model on the development of portal hypertension and fibrosis. Obesity was induced in twelve-week old TGR(mREN2)27 rats after receiving Western diet (WD) for two or four weeks. Liver fibrosis was assessed using standard techniques. Hepatic expression of transforming growth factor-β1 (TGF-β1), collagen type Iα1, α-smooth muscle actin, and the macrophage markers Emr1, as well as the chemoattractant Ccl2, interleukin-1β (IL1β) and tumor necrosis factor-α (TNFα) were analyzed. Assessment of portal and systemic hemodynamics was performed using the colored microsphere technique. Asexpected,WDinducedobesityandliverfibrosisasconfirmedbySiriusRedandOilRed O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were increasedduringfeedingofWD,indicatinginfiltrationofmacrophagesintotheliver,eventhoughthis increase was statistically not significant for the EGF module-containing mucin-like receptor (Emr1) mRNA expression levels. Of note, portal pressure increased with the duration of WD compared to animals that received a normal chow. Besides obesity, WD feeding increased systemic vascular resistance reflecting systemic endothelial and splanchnic vascular dysfunction. We conclude that transgenic TGR(mREN2)27 rats are a suitable model to investigate NAFLD development with liver fibrosis and portal hypertension. Tendency towards elevated expression of Emr1 is associated with macrophage activity point to a significant role of macrophages in NAFLD pathogenesis, probably due to a shift of the renin–angiotensin system towards a higher activation of the classical pathway. The hepatic injury induced by WD in TGR(mREN2)27 rats is suitable to evaluate different stages of fibrosis and portal hypertension in NAFLD with obesity.
Purpose: The primary treatment goals for advanced-stage thumb carpometacarpal (CMC) joint osteoarthritis are complete pain relief and restoration of thumb strength. The purpose of the present study was to introduce a variation of the abductor pollicis longus (APL) suspension arthroplasty using a single looping of a radial slip from the APL tendon around the flexor carpi radialis (FCR) tendon combined with RegJoint™ interposition and to determine its efficacy in the treatment of thumb CMC joint osteoarthritis.
Methods: Between 2015 and 2017, 21 patients were included. The average age was 60.8 years (range 48–79). The mean follow-up was 27.7 months (range 8–50). Evaluation included pain, radial and palmar abduction, tip pinch and grip strength, and Disabilities of the Arm, Shoulder, and Hand (DASH) score.
Results: Pain averaged 0.3 (range 0–4) at rest and 1.4 (range 0–4) on exertion. The radial and palmar abduction were 97% and 99% compared to the contralateral side. The tip pinch and grip strength were 4.1 kg (range 3–6.5) and 22 kg (range 13.3–40), respectively. The DASH score accounted for 18.5 (range 0.8–41.7).
Conclusion: The modified APL suspension interposition arthroplasty was an efficient and simplified option for the treatment of thumb CMC joint osteoarthritis, with results comparable or better than other published procedures. The APL suspension technique was easy to perform avoiding difficult bone tunneling and incision of the FCR tendon. The RegJoint™ interposition as spacer prevented impingement of the first metacarpal base on the second metacarpal base or the trapezoid bone.
The risk of increasing dengue (DEN) and chikungunya (CHIK) epidemics impacts 240 million people, health systems, and the economy in the Hindu Kush Himalayan (HKH) region. The aim of this systematic review is to monitor trends in the distribution and spread of DEN/CHIK over time and geographically for future reliable vector and disease control in the HKH region. We conducted a systematic review of the literature on the spatiotemporal distribution of DEN/CHIK in HKH published up to 23 January 2020, following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. In total, we found 61 articles that focused on the spatial and temporal distribution of 72,715 DEN and 2334 CHIK cases in the HKH region from 1951 to 2020. DEN incidence occurs in seven HKH countries, i.e., India, Nepal, Bhutan, Pakistan, Bangladesh, Afghanistan, and Myanmar, and CHIK occurs in four HKH countries, i.e., India, Nepal, Bhutan, and Myanmar, out of eight HKH countries. DEN is highly seasonal and starts with the onset of the monsoon (July in India and June in Nepal) and with the onset of spring (May in Bhutan) and peaks in the postmonsoon season (September to November). This current trend of increasing numbers of both diseases in many countries of the HKH region requires coordination of response efforts to prevent and control the future expansion of those vector-borne diseases to nonendemic areas, across national borders.
Recent studies suggested an important contribution of sphingosine-1-phospate (S1P) signaling via its specific receptors (S1PRs) in the production of pro-inflammatory mediators such as Interleukin (IL)-1β in cancer and inflammation. In an inflammation-driven cancer setting, we previously reported that myeloid S1PR1 signaling induces IL-1β production by enhancing NLRP3 (NOD-, LRR- and Pyrin Domain-Containing Protein 3) inflammasome activity. However, the autocrine role of S1P and enzymes acting on the S1P rheostat in myeloid cells are unknown. Using human and mouse macrophages with pharmacological or genetic intervention we explored the relative contribution of sphingosine kinases (SPHKs) in NLRP3 inflammasome activity regulation. We noticed redundancy in SPHK1 and SPHK2 activities towards macrophage NLRP3 inflammasome transcriptional induction and IL-1β secretion. However, pharmacological blockade of both kinases in unison completely abrogated NLRP3 inflammasome induction and IL-1β secretion. Interestingly, human and mouse macrophages demonstrate varied responses towards SPHKs inhibition and IL-1β secretion. Clinical datasets of renal cell carcinoma and psoriasis patients showed a positive correlation between enzymes affecting the S1P rheostat with NLRP3 inflammasome components expression, which corroborates our finding. Our data provide a better understanding on the role of SPHKs and de novo synthesized S1P in macrophage NLRP3 inflammasome activation
Background and purpose: Superficial siderosis of the central nervous system is a sporadic finding in magnetic resonance imaging, resulting from recurrent bleedings into the subarachnoid space. This study aimed to determine the frequency of spinal dural cerebrospinal fluid (CSF) leaks amongst patients with a symmetric infratentorial siderosis pattern. Methods: In all, 97,733 magnetic resonance images performed between 2007 and 2018 in our neurocenter were screened by a keyword search for “hemosiderosis” and “superficial siderosis.” Siderosis patterns on brain imaging were classified according to a previously published algorithm. Potential causative intracranial bleeding events were also assessed. Patients with a symmetric infratentorial siderosis pattern but without causative intracranial bleeding events in history were prospectively evaluated for spinal pathologies. Results: Forty-two patients with isolated supratentorial siderosis, 30 with symmetric infratentorial siderosis and 21 with limited (non-symmetric) infratentorial siderosis were identified. Amyloid angiopathy and subarachnoid hemorrhage were causes for isolated supratentorial siderosis. In all four patients with a symmetric infratentorial siderosis pattern but without a causative intracranial bleeding event in history, spinal dural abnormalities were detected. Dural leaks were searched for in patients with symmetric infratentorial siderosis and a history of intracranial bleeding event without known bleeding etiology, considering that spinal dural CSF leaks themselves may also cause intracranial hemorrhage, for example by inducing venous thrombosis due to low CSF pressure. Thereby, one additional spinal dural leak was detected. Conclusions: Persisting spinal dural CSF leaks can frequently be identified in patients with a symmetric infratentorial siderosis pattern. Diagnostic workup in these cases should include magnetic resonance imaging of the whole spine.
Background and purpose: Superficial siderosis of the central nervous system is a sporadic finding in magnetic resonance imaging, resulting from recurrent bleedings into the subarachnoid space. This study aimed to determine the frequency of spinal dural cerebrospinal fluid (CSF) leaks amongst patients with a symmetric infratentorial siderosis pattern. Methods: In all, 97,733 magnetic resonance images performed between 2007 and 2018 in our neurocenter were screened by a keyword search for “hemosiderosis” and “superficial siderosis.” Siderosis patterns on brain imaging were classified according to a previously published algorithm. Potential causative intracranial bleeding events were also assessed. Patients with a symmetric infratentorial siderosis pattern but without causative intracranial bleeding events in history were prospectively evaluated for spinal pathologies. Results: Forty-two patients with isolated supratentorial siderosis, 30 with symmetric infratentorial siderosis and 21 with limited (non-symmetric) infratentorial siderosis were identified. Amyloid angiopathy and subarachnoid hemorrhage were causes for isolated supratentorial siderosis. In all four patients with a symmetric infratentorial siderosis pattern but without a causative intracranial bleeding event in history, spinal dural abnormalities were detected. Dural leaks were searched for in patients with symmetric infratentorial siderosis and a history of intracranial bleeding event without known bleeding etiology, considering that spinal dural CSF leaks themselves may also cause intracranial hemorrhage, for example by inducing venous thrombosis due to low CSF pressure. Thereby, one additional spinal dural leak was detected. Conclusions: Persisting spinal dural CSF leaks can frequently be identified in patients with a symmetric infratentorial siderosis pattern. Diagnostic workup in these cases should include magnetic resonance imaging of the whole spine.
Objective: To assess the influence of biphasic calcium phosphate materials with different surface topographies on bone formation and osseointegration of titanium implants in standardized alveolar ridge defects.
Materials and methods: Standardized alveolar ridge defects (6 × 6 mm) were created in the mandible of 8 minipigs and filled with three biphasic calcium phosphate materials (BCP1–3, 90% tricalcium phosphate/10% hydroxyapatite) with different surface properties (micro- and macroporosities) as well as a bovine-derived natural bone mineral (NBM) as a control. At 12 weeks, implants were placed into the augmented defects. After further 8 weeks of healing, dissected blocks were processed for histological analysis (e.g., mineralized (MT), residual bone graft material (BS), bone-to-implant contact (BIC)).
Results: All four biomaterials showed well-integrated graft particles and new bone formation within the defect area. MT values were comparable in all groups. BS values were highest in the NBM group (21.25 ± 13.52%) and markedly reduced in the different BCP groups, reaching statistical significance at BCP1-treated sites (9.2 ± 3.28%). All test and control groups investigated revealed comparable and statistically not significant different BIC values, ranging from 73.38 ± 20.5% (BCP2) to 84.11 ± 7.84% (BCP1), respectively.
Conclusion* All bone graft materials facilitated new bone formation and osseointegration after 12 + 8 weeks of healing.
Background: To detect deviations from a normal postural control, standard values can be helpful for comparison purposes. Since the postural control is influenced by gender and age, the aim of the present study was the collection of standard values for women between 31 and 40 years of age.
Methods: For the study, 106 female, subjectively healthy, German subjects aged between 31 and 40 years (35 ± 2.98 years) were measured using a pressure measuring platform.
Results: Their average BMI was 21.60 ± 4.65 kg/m2. The load distribution between left and right foot was almost evenly balanced with a median 51.46% load on the left [tolerance interval (TR) 37.02%/65.90%; confidence interval (CI) 50.06/52.85%] and 48.54% [TR 43.10/62.97%; CI 47.14/49.93%] on the right foot. The median forefoot load was 33.84% [TR 20.68/54.73%; CI 31.67/37.33%] and the rearfoot load was measured at 66.16% [TR 45.27/79.33%; CI 62.67/68.33%]. The median/mean body sway in the sagittal plane was measured 12 mm [TR 5.45/23.44 mm; CI 11.00/14.00 mm] and 8.17 mm in the frontal plane [TR 3.33/19.08 mm; CI 7.67/9.33 mm]. The median of the ellipse area is 0.72 cm2 [TR 0.15/3.69 cm2; CI 0.54/0.89°]. The ellipse width has a median of 0.66 cm [TR 0.30/1.77 cm; CI 0.61/0.78 cm] and the height of 0.33 cm [TR 0.13/0.71 cm; CI 0.30/0.37 cm]. The ellipse angle (sway, left forefoot to right rearfoot) has a mean of − 19.34° [TR − 59.21/− 0.44°; CI − 22.52/− 16.16°] and the ellipse angle sway from right forefoot to left rearfoot has a mean of 12.75° [TR 0.09/59.09°; CI 9.00/16.33°].
Conclusion: The right-to-left ratio is balanced. The forefoot-to-rearfoot ratio is approximately 1:2. Also, the body sway can be classified with 12 and 8 mm as normal. The direction of fluctuation is either approx. 19° from the left forefoot to the right rearfoot or approx. 13° the opposite. Body weight, height, and BMI were comparable to the German average of women in a similar age group, so that the measured standard values are representative and might serve as baseline for the normal function of the balance system in order to support the diagnosis of possible dysfunctions in postural control.
Background: The aim of this study was to collect standard reference values of the weight and the maximum pressure distribution in healthy adults aged 18–65 years and to investigate the influence of constitutional parameters on it.
Methods: A total of 416 healthy subjects (208 male / 208 female) aged between 18 and 65 years (Ø 38.3 ± 14.1 years) participated in this study, conducted 2015–2019 in Heidelberg. The age-specific evaluation is based on 4 age groups (G1, 18–30 years; G2, 31–40 years; G3, 41–50 years; G4, 51–65 years). A pressure measuring plate FDM-S (Zebris/Isny/Germany) was used to collect body weight distribution and maximum pressure distribution of the right and left foot and left and right forefoot/rearfoot, respectively.
Results: Body weight distribution of the left (50.07%) and right (50.12%) foot was balanced. There was higher load on the rearfoot (left 54.14%; right 55.09%) than on the forefoot (left 45.49%; right 44.26%). The pressure in the rearfoot was higher than in the forefoot (rearfoot left 9.60 N/cm2, rearfoot right 9.51 N/cm2/forefoot left 8.23 N/cm2, forefoot right 8.59 N/cm2). With increasing age, the load in the left foot shifted from the rearfoot to the forefoot as well as the maximum pressure (p ≤ 0.02 and 0.03; poor effect size). With increasing BMI, the body weight shifted to the left and right rearfoot (p ≤ 0.001, poor effect size). As BMI increased, so did the maximum pressure in all areas (p ≤ 0.001 and 0.03, weak to moderate effect size). There were significant differences in weight and maximum pressure distribution in the forefoot and rearfoot in the different age groups, especially between younger (18–40 years) and older (41–65 years) subjects.
Discussion: Healthy individuals aged from 18 to 65 years were found to have a balanced weight distribution in an aspect ratio, with a 20% greater load of the rearfoot. Age and BMI were found to be influencing factors of the weight and maximum pressure distribution, especially between younger and elder subjects. The collected standard reference values allow comparisons with other studies and can serve as a guideline in clinical practice and scientific studies.
Hintergrund: Die Analyse krankheitsspezifischer Kosten gewinnt in einem zunehmend ökonomisch ausgerichteten Gesundheitssystem an Relevanz, wobei vor allem chronische Erkrankungen aufgrund der langen Krankheitsdauer sowie häufiger Hospitalisierung und Arztbesuche von besonderem Interesse sind. Epilepsien stellen eine häufige neurologische Erkrankung dar, welche mit paroxysmal auftretenden epileptischen Anfällen und häufig hiermit assoziierten Verletzungen einhergeht und alle Altersgruppen betrifft.
Ziel: Ziel der Arbeit ist die Aufarbeitung der stationären Behandlungskosten anfallsbedingter Verletzungen sowie die Analyse hinsichtlich relevanter kostenverursachender Faktoren. Mittels alternativer Kalkulation der Versorgungskosten soll zusätzlich der Frage nach potenziellen Vergütungsproblemen im aktuellen DRG-System („diagnosis related groups“) nachgegangen werden.
Methoden: Grundlage dieser monozentrischen, retrospektiven Analyse ist der tatsächliche Erlös der stationären Behandlung von 62 Patienten, die zwischen 01/2010 und 01/2018 im Universitätsklinikum Frankfurt aufgrund von Verletzungen im Rahmen epileptischer Anfälle erfolgte. Die Analyse potenzieller kostenverursachender Faktoren bezog sich auf relevante soziodemographische und klinische Aspekte, die alternative Kalkulation der Versorgungskosten wurde mit gängigen gesundheitsökonomischen Methoden durchgeführt.
Ergebnisse: Der mittlere DRG-Erlös betrug 7408 € (±8993 €, Median 5086 €, Spanne 563–44.519 €), die mittleren kalkulierten Kosten 9423 € (±11.113 €, 5626 €, Spanne 587–49.830 €). Als signifikant kostenverursachender Faktor konnte eine Liegedauer ≥7 Tage (p = 0,014) identifiziert werden. Aufgrund des signifikanten Unterschieds (p < 0,001) zwischen Erlös und kalkulierten Kosten erfolgte eine Analyse nach Faktoren für potenzielle Vergütungsprobleme, welche für eine Aufenthaltsdauer von ≥7 Tagen (p = 0,014) sowie für eine Behandlung auf Intensivstation (p = 0,019) signifikant verblieb.
Schlussfolgerung: Die stationären Versorgungskosten von Patienten mit Frakturen aufgrund epileptischer Anfälle sind hoch und daher gesundheitsökonomisch relevant. Generell scheint die auf Fallpauschalen basierende Vergütung nach G‑DRG die tatsächlichen Kosten zu decken, bei Patienten mit einer langen Liegedauer oder einen Aufenthalt auf Intensivstation können jedoch Vergütungsprobleme bestehen.
Bei Kindern mit akuter lymphoblastischer Leukämie ist eine möglichst frühe und genaue Diagnostik der Infiltration des Zentralen Nervensystems für die Festlegung der weiteren Therapie von essenzieller Bedeutung. Ziel dieser Studie war es, die diagnostische Wertigkeit der Schädel-MRT im Vergleich zum Standarddiagnostikum Lumbalpunktion bezüglich einer leukämischen Beteiligung des ZNS zu untersuchen. Außerdem sollte die Häufigkeit relevanter Zufallsbefunde festgestellt werden, um den Nutzen einer zusätzlich zur Lumbalpunktion durchgeführten MRT zu beurteilen. Es erfolgte eine retrospektive Analyse der Daten von 277 Patienten mit Erstdiagnose und 56 Patienten mit Rezidiv einer ALL, die zwischen 1998 und 2016 an der Klinik für Kinder- und Jugendmedizin des Universitätsklinikums Frankfurt am Main behandelt worden waren. Sie hatten im Rahmen der initialen Diagnostik zusätzlich zur Lumbalpunktion eine Schädel-MRT mit Kontrastmittel erhalten.
Der durchschnittliche zeitliche Abstand zwischen Diagnosestellung und MRT betrug 11 Tage (39,5 Tage bei Rezidivpatienten). Die Sensitivitäten und Spezifitäten der beiden diagnostischen Mittel MRT und Liquor wurden berechnet.
Dazu diente als Goldstandard die endgültige Diagnose des ZNS-Status, die entweder durch die Liquordiagnostik, die Bildgebung oder die Klinik (RetinaInfiltration, Fazialisparese) gestellt wurde.
Insgesamt fanden sich bei 14 der 277 Patienten mit Erstdiagnose Leukämie eine Infiltration des ZNS. Davon waren 2 Patienten in der MRT, 11 Patienten in der Lumbalpunktion und 2 Patienten durch eine Retina-Infiltration als positiv diagnostiziert worden. Nur ein Patient, der in der MRT positiv befundet worden war, hatte in der Liquordiagnostik ein negatives Ergebnis. Bei den 56 Patienten mit Rezidiv ergab die MRT 6 positive Befunde und die Liquordiagnostik zeigte 13 positive Befunde. 3 Patienten waren zudem klinisch mit Fazialisparese (n=2) und retinaler Infiltration (n=1) positiv zu werten. Diese 3 hatten jedoch auch in der Lumbalpunktion ein positives Ergebnis. Von den Patienten, die in der MRT positiv befundet wurden, hatte 1 Patient ein negatives Ergebnis in der Lumbalpunktion.
Dieser zeigte allerdings Symptome und hätte somit die Bildgebung ohnehin erhalten. Für die MRT ergibt sich bei den Patienten mit Erstdiagnose eine Sensitivität von 14,3%, bei den Rezidivpatienten eine Sensitivität von 43%. Die Spezifität liegt bei den Patienten mit Erstdiagnose ALL bei 99,6% und bei den Rezidivpatienten bei 100%. Für die Lumbalpunktion errechnet sich bei den Patienten mit Erstdiagnose eine Sensitivität von 78,6% und bei den Rezidivpatienten eine Sensitivität von 92,9%, mit einer Falsch-negativ-Rate von 21,4% und 7,1%. Die Spezifität der Lumbalpunktion liegt in beiden Gruppen bei 100%.
Bezüglich relevanter Zufallsbefunde ist bei den Patienten mit Erstdiagnose eine Sinusvenenthrombose bei einer klinisch unauffälligen Patientin zu nennen.
Weitere Nebenbefunde, die keine Auswirkungen auf die Therapie hatten, waren Schleimhautschwellungen der Nasennebenhöhlen (n=188), Verlegung der Mastoidzellen (n=45), Hirnvolumenminderung (n=27), Blutungen ohne Therapiebedürftigkeit (n=5), Zysten (n=11) und angeborene Fehlbildungen (n=7). Außerdem wurde bei 6 Rezidivpatienten eine chronische therapieassoziierte Leukenzephalopathie diagnostiziert.
Die vorliegende Studie stellt unseres Wissens nach die bisher umfangreichste Schädel-MRT-Studie bei Kindern mit ALL unter dieser Fragestellung dar. Ihre Nachteile ergeben sich durch die retrospektive Betrachtung und dadurch bedingte eingeschränkte Einheitlichkeit.
Aus unseren Ergebnissen lässt sich schlussfolgern, dass die Schädel-MRT keinen zusätzlichen Nutzen zur alleinigen Lumbalpunktion bringt. Nur ein einziger Patient hatte in der MRT ein positives Ergebnis, welches weder durch die Lumbalpunktion noch durch die Klinik erkannt worden war. Auch in Hinblick auf die geringe Rate an relevanten Nebenbefunden bei asymptomatischen Patienten ergibt sich keine grundsätzliche Notwendigkeit zur Durchführung dieser Bildgebung. Die zusätzliche Belastung einer kontrastmittelgestützten MRT, für die bei kleinen Kindern zudem häufig eine Sedierung erforderlich ist, kann klinisch neurologisch unauffälligen Patienten mit ALL also erspart werden.
Stellenwert der Teststreifen-basierten Analyse der INR für die Behandlung von Blutungskomplikationen
(2020)
Das Ziel der hier vorliegenden Studie war es einen Zusammenhang zwischen den Ergebnissen von konventioneller versus Teststreifen-basierter INR-Messung zu untersuchen und die Analysedauern der beiden Methoden zu vergleichen. Wir haben in dieser prospektiven Mono-Center Studie 24 hämorrhagische Patienten und Patientinnen inkludiert und aus infrastrukturellen Gesichtspunkten in zwei Gruppenkollektive aufgeteilt. Das eine Studienkollektiv bildeten 12 hämorrhagische Patientinnen der Klinik für Gynäkologie und Geburtshilfe des Universitätsklinikums Frankfurt. Die Blutproben dieser Patientinnen wurden mittels einem personengebundenen Transportdienst in das Zentrallabor der Universitätsklinik geliefert. Das zweite Gruppenkollektiv bildeten 12 Patienten aus dem Schockraum der zentralen Notaufnahme. Die Blutproben dieses Kollektivs wurden mittels Rohrpost direkt in das Zentrallabor übermittelt. Wir untersuchten mittels konventioneller Gerinnungsdiagnostik und mittels Teststreifen-basierter POC-Diagnostik (CoaguChek II Pro®, PT Test, Roche Diagnostics AG) die INR eines jeden Patienten. Zudem erfolgte die Erfassung von Transport- und Analysedauer. Für die Auswertung der Daten errechneten wir die Spearman-Korrelationskoeffizienten sowohl auf Gruppenebene als auch für das Gesamtkollektiv und führten eine Bland-Altman Analyse zum direkten Methodenvergleich durch.
Es zeigte sich, dass die mittels POCT ermittelte INR im Gesamtkollektiv signifikant mit den im Zentrallabor gemessenen Werten korreliert (r=0,79). Auch auf Gruppenebene zeigte sich in Gruppe 1 (Schockraum) r=0,91 und in Gruppe 2 (Kreißsaal) r=0,83 eine signifikante Korrelation. Die Bland-Altmann Analyse ergab, dass die Ergebnisse der Teststreifen-basierten POC-Methode um 0,082 (SD±0,19) niedriger waren als die Ergebnisse der konventionellen Gerinnungstests. Die Untersuchung der Analyse- und Transportzeiten brachte hervor, dass die Bereitstellungsdauer der POC-Messmethode signifikant kürzer war (2 (1,04/2,85) Minuten) als die Dauer bis zur elektronischen Ergebnisbereitstellung nach laboranalytischen Untersuchungen (58,2 (38,28/88) Minuten). Es ergab sich zudem, dass die Transportdauer mittels Rohrpost mit 8 (3,25/10,1) Minuten signifikant kürzer war als die des personengebundenen Transportdienstes 18,5 (14,5/33) Minuten (p<0,001).Die in der Studie ermittelten konsistenten Ergebnisse lassen vermuten, dass Teststreifen-basierte Systeme als Methoden zur Notfalldiagnostik hämorrhagischer Patienten geeignet sein können, weil ihre Messergebnisse verglichen mit der klassischen Gerinnungsdiagnostik im Zentrallabor deutlich schneller und mit vergleichbarer Ergebnisqualität vorliegen. Die Teststreifen-basierten Methoden können als diagnostische Elemente in Hämotherapie-Algorithmen eingesetzt werden und dazu beitragen, eine zeitnahe und zielgerichtete Hämotherapie umzusetzen, die sich positiv auf das klinische Ergebnis der Patienten auswirken kann.
Introduction: Quinolone prophylaxis is recommended for patients with advanced cirrhosis at high risk of spontaneous bacterial peritonitis (SBP) or with prior SBP. Yet, the impact of long-term antibiotic prophylaxis on the microbiome of these patients is poorly characterized.
Methods: Patients with liver cirrhosis receiving long-term quinolone prophylaxis to prevent SBP were prospectively included and sputum and stool samples were obtained at baseline, 1, 4 and 12 weeks thereafter. Both bacterial DNA and RNA were assessed with 16S rRNA sequencing. Relative abundance, alpha and beta diversity were calculated and correlated with clinical outcome.
Results: Overall, 35 stool and 19 sputum samples were obtained from 11 patients. Two patients died (day 9 and 12) all others were followed for 180 days. Reduction of Shannon diversity and bacterial richness was insignificant after initiation of quinolone prophylaxis (p > 0.05). Gut microbiota were significantly different between patients (p < 0.001) but non-significantly altered between the different time points before and after initiation of antibiotic prophylaxis (p > 0.05). A high relative abundance of Enterobacteriaceae > 20% during quinolone prophylaxis was found in three patients. Specific clinical scenarios (development of secondary infections during antibiotic prophylaxis or the detection of multidrug-resistant Enterobacteriaceae) characterized these patients. Sputum microbiota were not significantly altered in individuals during prophylaxis.
Conclusion: The present exploratory study with small sample size showed that inter-individual differences in diversity of gut microbiota were high at baseline, yet quinolone prophylaxis had only a moderate impact. High relative abundances of Enterobacteriaceae during follow-up might indicate failure of or non-adherence to quinolone prophylaxis. However, our results may not be clinically significant given the limitations of the study and therefore future studies are needed to further investigate this phenomenon.
Although immune checkpoint inhibitors such as anti-PD-1 antibodies have shown remarkable clinical success in many different tumor types, the proportion of patients benefiting from this treatment option remains low. Therefore, there is a need to sensitize tumors for immune checkpoint blockade. In this study two approaches were tested, a chemoimmunotherapy approach combining PD-1 checkpoint blockade with doxorubicin (DOX) chemotherapy, and ablation of the sphingosine-1-phosphate (S1P) receptor (S1PR4) based on the following rationale. Chemotherapy was shown to induce immune paralysis which contributes to tumor relapse, while PD-1 signaling was shown to facilitate the acquisition of chemoresistance. Thus, combinatorial chemoimmunotherapy is expected to be beneficial by maintaining or even activating anti-tumor immunity during chemotherapy. S1PR4 is an immune cell specific receptor, whose ablation slowed tumor progression by activating anti-tumor immunity in a mouse model that was previously insensitive to anti-PD-1 monotherapy. This suggested that S1PR4 ablation might pre-activate immunity to sensitize for anti-PD-1 therapy.
To test these combinatorial approaches, two tumor mouse models were employed, namely the MC38 murine adenocarcinoma model as well as the transgenic polyoma middle T oncogene (PyMT) breast cancer model. In the MC38 model, a mild synergistic effect of PD-1 immune checkpoint blockade and S1PR4 ablation was observed, indicated by improved tumor progression and survival as compared to the WT control, and an increased number of tumor-free mice compared to anti-PD-1 therapy alone in WT mice. These observations correlated with an enhanced natural killer (NK) cell infiltrate and increased CXCL9 and CXCL10 production in anti-PD-1 treated S1PR4 KO tumors. As noted before, the PyMT model was largely resistant to anti-PD-1 monotherapy in a therapeutic setting. S1PR4 ablation alone showed significant tumor reduction that was not further enhanced by anti-PD-1 treatment. The same was observed when chemotherapy with DOX was added, where WT tumors relapsed, while S1PR4 KO tumor did not. Addition of anti-PD-1 did only mildly increase tumor control in S1PR4 KO mice, indicating that S1PR4 KO per se very efficiently re-activated anti-tumor immunity. Since S1PR4 KO induces type I 12 interferon (IFN-1) over-production in S1PR4 KO PyMT tumors, a link between high IFN-1 levels and tumor immunity was tested by using mice deficient in the IFN-1 receptor (IFNAR1). Unexpectedly, DOX chemotherapy was most efficient in mice with IFNAR ablation only as compared to WT, S1PR4 KO or S1PR4 and IFNAR1 double KO mice, although deficiency in IFNAR signaling is predominantly regarded as tumor promoting. The underlying mechanisms need to be tested in future studies. Interestingly, chemoimmunotherapy in WT mice prevented tumor relapse to a similar extent than S1PR4 KO and was superior to chemotherapy or immune checkpoint blockade alone. To investigate mechanisms of chemoimmunotherapy success compared to monotherapy, whole transcriptome analysis was used, which identified a set of genes that were upregulated specifically upon chemoimmunotherapy. This gene signature and, more specifically, a condensed four-gene signature predicted favorable survival of human mammary carcinoma patients in the METABRIC cohort.
Moreover, PyMT tumors treated with chemoimmunotherapy contained higher levels of cytotoxic lymphocytes, particularly NK cells. Gene set enrichment analysis and ELISA measurements revealed increased IL-27 production and signaling in PyMT tumors upon chemoimmunotherapy. Moreover, IL-27 improved NK cell cytotoxicity against PyMT cells in vitro. These data supported recent clinical observations indicating a benefit of chemoimmunotherapy compared to monotherapy in breast cancer and suggested potential underlying mechanisms.
Taken together the present work revealed new strategies to reactivate tumor immunity leading to improved chemotherapy response, namely a combination with immune checkpoint blockade and ablation of S1PR4, which activated different lymphocyte compartments within tumors.
The firing pattern of ventral midbrain dopamine neurons is controlled by afferent and intrinsic activity to generate prediction error signals that are essential for reward-based learning. Given the absence of intracellular in vivo recordings in the last three decades, the subthreshold membrane potential events that cause changes in dopamine neuron firing patterns remain unknown. By establishing stable in vivo whole-cell recordings of >100 spontaneously active midbrain dopamine neurons in anaesthetized mice, we identified the repertoire of subthreshold membrane potential signatures associated with distinct in vivo firing patterns. We demonstrate that dopamine neuron in vivo activity deviates from a single spike pacemaker pattern by eliciting transient increases in firing rate generated by at least two diametrically opposing biophysical mechanisms: a transient depolarization resulting in high frequency plateau bursts associated with a reactive, depolarizing shift in action potential threshold; and a prolonged hyperpolarization preceding slower rebound bursts characterized by a predictive, hyperpolarizing shift in action potential threshold. Our findings therefore illustrate a framework for the biophysical implementation of prediction error and sensory cue coding in dopamine neurons by tuning action potential threshold dynamics.
Purpose of Review: To provide an overview of current surgical peri-implantitis treatment options.
Recent Findings: Surgical procedures for peri-implantitis treatment include two main approaches: non-augmentative and augmentative therapy. Open flap debridement (OFD) and resective treatment are non-augmentative techniques that are indicated in the presence of horizontal bone loss in aesthetically nondemanding areas. Implantoplasty performed adjunctively at supracrestally and buccally exposed rough implant surfaces has been shown to efficiently attenuate soft tissue inflammation compared to control sites. However, this was followed by more pronounced soft tissue recession. Adjunctive augmentative measures are recommended at peri-implantitis sites exhibiting intrabony defects with a minimum depth of 3 mm and in the presence of keratinized mucosa. In more advanced cases with combined defect configurations, a combination of augmentative therapy and implantoplasty at exposed rough implant surfaces beyond the bony envelope is feasible.
Summary: For the time being, no particular surgical protocol or material can be considered as superior in terms of long-term peri-implant tissue stability.
Background: Temporary occlusal changes and their influence on the upper body statics are still controversially discussed. Furthermore, concrete statements on whether age- or gender-specific differences in neurophysiological reactions exist are missing. Therefore, it is the aim of this study to evaluate the immediate effects of a symmetrical occlusion blocking on the upper body posture. These effects shall be investigated for both genders and for a larger age range.
Methods: In this study, 800 (407f/393 m) subjects volunteered aged from 21 to 60 years. Both genders were divided into four age groups according to decades. The three-dimensional upper body posture was measured by using the rasterstereography (ABW-Bodymapper). The habitual static posture was measured in two dental occlusion conditions (a) in rest position and (b) symmetrical blocking in the bicuspid region by cotton rolls.
Results: A significant reduction of the trunk length (0.72 mm; p < 0.001), an increase of the lumbar (0.30°; p < 0.001) and the thoracic bending angle (0.14°; p = 0.001), a reduction of the spinal forward decline (0.16°; p < 0.001) and a reduction of the scapular distance (0.36 mm; p = 0.001) was found. Gender-specific reactions can only be recorded in scapular distance, in that regard men reduce this distance while over all age groups women did not show a significant change.
Discussion: Slight gender- and age-independent reactions due to a symmetric occlusion blockade are shown: A gender independent reaction of the spinal related variables in the sagittal plane (thoracic and lumbar flexion angle, trunk length, spinal forward decline). In addition, a gender specific change of the shoulder blade distance could be observed, where men reduced the distance while female did not show a change. However, since these reactions are of a minimum amount, it can be concluded that neurophysiological compensation mechanisms work equally well regardless of age and sex, and the upper body posture of healthy people changes only very slightly due to a temporarily symmetrical altered bite position.
It becomes more and more obvious that deregulation of host metabolism play an important role in SARS-CoV-2 pathogenesis with implication for increased risk of severe course of COVID-19. Furthermore, it is expected that COVID-19 patients recovered from severe disease may experience long-term metabolic disorders. Thereby understanding the consequences of SARS-CoV-2 infection on host metabolism can facilitate efforts for effective treatment option. We have previously shown that SARS-CoV-2-infected cells undergo a shift towards glycolysis and that 2-deoxy-D-glucose (2DG) inhibits SARS-CoV-2 replication. Here, we show that also pentose phosphate pathway (PPP) is remarkably deregulated. Since PPP supplies ribonucleotides for SARS-CoV-2 replication, this could represent an attractive target for an intervention. On that account, we employed the transketolase inhibitor benfooxythiamine and showed dose-dependent inhibition of SARS-CoV-2 in non-toxic concentrations. Importantly, the antiviral efficacy of benfooxythiamine was further increased in combination with 2DG.
The nuclear factor kappa beta (NFκB) signaling pathway plays an important role in liver homeostasis and cancer development. Tax1-binding protein 1 (Tax1BP1) is a regulator of the NFκB signaling pathway, but its role in the liver and hepatocellular carcinoma (HCC) is presently unknown. Here we investigated the role of Tax1BP1 in liver cells and murine models of HCC and liver fibrosis. We applied the diethylnitrosamine (DEN) model of experimental hepatocarcinogenesis in Tax1BP1+/+ and Tax1BP1−/− mice. The amount and subsets of non-parenchymal liver cells in in Tax1BP1+/+ and Tax1BP1−/− mice were determined and activation of NFκB and stress induced signaling pathways were assessed. Differential expression of mRNA and miRNA was determined. Tax1BP1−/− mice showed increased numbers of inflammatory cells in the liver. Furthermore, a sustained activation of the NFκB signaling pathway was found in hepatocytes as well as increased transcription of proinflammatory cytokines in isolated Kupffer cells from Tax1BP1−/− mice. Several differentially expressed mRNAs and miRNAs in livers of Tax1BP1−/− mice were found, which are regulators of inflammation or are involved in cancer development or progression. Furthermore, Tax1BP1−/− mice developed more HCCs than their Tax1BP1+/+ littermates. We conclude that Tax1BP1 protects from liver cancer development by limiting proinflammatory signaling.
The survivin suppressant YM155 is a drug candidate for neuroblastoma. Here, we tested YM155 in 101 neuroblastoma cell lines (19 parental cell lines, 82 drug-adapted sublines). 77 cell lines displayed YM155 IC50s in the range of clinical YM155 concentrations. ABCB1 was an important determinant of YM155 resistance. The activity of the ABCB1 inhibitor zosuquidar ranged from being similar to that of the structurally different ABCB1 inhibitor verapamil to being 65-fold higher. ABCB1 sequence variations may be responsible for this, suggesting that the design of variant-specific ABCB1 inhibitors may be possible. Further, we showed that ABCC1 confers YM155 resistance. Previously, p53 depletion had resulted in decreased YM155 sensitivity. However, TP53-mutant cells were not generally less sensitive to YM155 than TP53 wild-type cells in this study. Finally, YM155 cross-resistance profiles differed between cells adapted to drugs as similar as cisplatin and carboplatin. In conclusion, the large cell line panel was necessary to reveal an unanticipated complexity of the YM155 response in neuroblastoma cell lines with acquired drug resistance. Novel findings include that ABCC1 mediates YM155 resistance and that YM155 cross-resistance profiles differ between cell lines adapted to drugs as similar as cisplatin and carboplatin.
Aims: In primary central nervous system tumours, epithelial-to-mesenchymal transition (EMT) gene expression is associated with increased malignancy. However, it has also been shown that EMT factors in gliomas are almost exclusively expressed by glioma vessel-associated pericytes (GA-Peris). In this study, we aimed to identify the mechanism of EMT in GA-Peris and its impact on angiogenic processes.
Methods; In glioma patients, vascular density and the expression of the pericytic markers platelet derived growth factor receptor (PDGFR)-β and smooth muscle actin (αSMA) were examined in relation to the expression of the EMT transcription factor SLUG and were correlated with survival of patients with glioblastoma (GBM). Functional mechanisms of SLUG regulation and the effects on primary human brain vascular pericytes (HBVP) were studied in vitro by measuring proliferation, cell motility and growth characteristics.
Results: The number of PDGFR-β- and αSMA-positive pericytes did not change with increased malignancy nor showed an association with the survival of GBM patients. However, SLUG-expressing pericytes displayed considerable morphological changes in GBM-associated vessels, and TGF-β induced SLUG upregulation led to enhanced proliferation, motility and altered growth patterns in HBVP. Downregulation of SLUG or addition of a TGF-β antagonising antibody abolished these effects.
Conclusions: We provide evidence that in GA-Peris, elevated SLUG expression is mediated by TGF-β, a cytokine secreted by most glioma cells, indicating that the latter actively modulate neovascularisation not only by modulating endothelial cells, but also by influencing pericytes. This process might be responsible for the formation of an unstructured tumour vasculature as well as for the breakdown of the blood–brain barrier in GBM.
Background: With refinements in diagnosis and therapy of gliomas, the importance of survival time as the sole outcome parameter has decreased, and patient-centered outcome parameters have gained interest. Pursuing a profession is an indispensable component of human happiness. The aim of this study was to analyze the professional outcomes besides their neuro-oncological and functional evaluation after surgery for gliomas in eloquent areas.
Methods: We assessed neuro-oncological and functional outcomes of patients with gliomas WHO grades II and III undergoing surgery between 2012 and 2018. All patients underwent routine follow-up and adjuvant treatment. Treatment and survival parameters were collected prospectively. Repercussions of the disease on the patients’ professional status, socio-economic situation, and neurocognitive function were evaluated retrospectively with questionnaires.
Results: We analyzed data of 58 patients with gliomas (WHO II: 9; III: 49). Median patient age was 35.8 years (range 21–63 years). Awake surgery techniques were applied in 32 patients (55.2%). Gross total and subtotal tumor resections were achieved in 33 (56.9%) and 17 (29.3%) patients, respectively, whereas in 8 patients (13.8%) resection had to remain partial. Most patients (n = 46; 79.3%) received adjuvant treatment. Median follow up was 43.8 months (range 11–82 months). After treatment 41 patients (70.7%) were able to resume a working life. Median time until returning to work was 8.0 months (range 0.2–22.0 months). To be younger than 40 at the time of the surgery was associated with a higher probability to return to work (p < .001). Multivariable regression analysis showed that patient age < 40 years as well as occupational group and self-reported fatigue were factors independently associated with the ability to return to work.
Conclusion: The ability to resume professional activities following brain tumor surgery is an important patient-oriented outcome parameter. We found that the majority of patients with gliomas were able to return to work following surgical and adjuvant treatment. Preservation of neurological function is of utmost relevance for individual patients´ quality of life.
In the application of range of motion (ROM) tests there is little agreement on the number of repetitions to be measured and the number of preceding warm-up protocols. In stretch training a plateau in ROM gains can be seen after four to five repetitions. With increasing number of repetitions, the gain in ROM is reduced. This study examines the question of whether such an effect occurs in common ROM tests. Twenty-two healthy sport students (10 m/12 f.) with an average age of 25.3 ± 1.94 years (average height 174.1 ± 9.8 cm; weight 66.6 ± 11.3 kg and BMI 21.9 ± 2.0 kg/cm2) volunteered in this study. Each subject performed five ROM tests in a randomized order—measured either via a tape measure or a digital inclinometer: Tape measure was used to evaluate the Fingertip-to-Floor test (FtF) and the Lateral Inclination test (LI). Retroflexion of the trunk modified after Janda (RF), Thomas test (TT) and a Shoulder test modified after Janda (ST) were evaluated with a digital inclinometer. In order to show general acute effects within 20 repetitions we performed ANOVA/Friedman-test with multiple comparisons. A non-linear regression was then performed to identify a plateau formation. Significance level was set at 5%. In seven out of eight ROM tests (five tests in total with three tests measured both left and right sides) significant flexibility gains were observed (FtF: p < 0.001; LI-left/right: p < 0.001/0.001; RF: p = 0.009; ST-left/right: p < 0.001/p = 0.003; TT-left: p < 0.001). A non-linear regression with random effects was successfully applied on FtF, RF, LI-left/right, ST-left and TT-left and thus, indicate a gradual decline in the amount of gained ROM. An acute effect was observed in most ROM tests, which is characterized by a gradual decline of ROM gain. For those tests, we can state that the acute effect described in the stretching literature also applies to the performance of typical ROM tests. Since a non-linear behavior was shown, it is the decision of the practitioner to weigh up between measurement accuracy and expenditure. Researchers and practitioners should consider this when applying ROM assessments to healthy young adults.
Aim: The aim of this study is to utilize the niche measurement guidelines outlined by Jordans et al. in order to establish normal values and accurate description of caesarean section scars in a normal population. After defining the normal distribution, abnormal pregestational scar characteristics will be identified for predicting adverse pregnancy outcomes. Methods: This is a prospective observational multicenter clinical study where women with a history of only one caesarean section and yet open family planning are enrolled. The uterine length, cervical length, niche length, niche depth, niche width, residual myometrial thickness, endometrial thickness, scar to internal os distance, anterior myometrial thickness superior and inferior to the scar and the posterior myometrial thickness opposite the scar, superior and inferior to it are measured in a pregestational uterus. The lower uterine segment is measured over a length of 3 cm during subsequent pregnancy and followed up until delivery. Results: Data from 500 patients will yield normal distribution curves for all predefined measurements. Establishing a correlation between deviations from the normal measures and adverse events would be instrumental for counseling women regarding subsequent pregnancy and mode of delivery.
Conclusion: This study will demonstrate the changes of the post-caesarean scar from a non-pregnant uterus until delivery and can confirm the importance of the scar characteristics in predicting pregnancy outcome.
Based on Eysenck’s pioneering work, CNS arousal has long been considered an encouraging biological candidate that may explain individual differences in human personality. Yet, results from empirical studies remained inconclusive. Notably, the vast majority of published results have been derived from small samples, and EEG alpha power has usually served as exclusive indicator for CNS arousal. In this study, we selected N = 468 individuals of the LIFE-Adult cohort and investigated the associations between the Big Five personality traits and CNS arousal by using the low-resolution electromagnetic tomography-based analysis tool VIGALL. Our analyses revealed that subjects who reported higher levels of extraversion and openness to experience, respectively, exhibited lower levels of CNS arousal in the resting state. Bayesian and frequentist analysis results were especially convincing for openness to experience. Among the lower-order personality traits, we obtained strongest evidence for neuroticism facet ‘impulsivity’ and reduced CNS arousal. We regard these findings as well in line with the postulations of Eysenck and Zuckerman and consistent with the assumptions of the ‘arousal regulation model’. Our results also agree with meta-analytically derived effect sizes in the field of individual differences research, highlighting the need for large studies with at least several hundreds of subjects.
Selective sympathetic and parasympathetic pathways that act on target organs represent the terminal actors in the neurobiology of homeostasis and often become compromised during a range of neurodegenerative and traumatic disorders. Here, we delineate several neurotransmitter and neuromodulator phenotypes found in diverse parasympathetic and sympathetic ganglia in humans and rodent species. The comparative approach reveals evolutionarily conserved and non-conserved phenotypic marker constellations. A developmental analysis examining the acquisition of selected neurotransmitter properties has provided a detailed, but still incomplete, understanding of the origins of a set of noradrenergic and cholinergic sympathetic neuron populations, found in the cervical and trunk region. A corresponding analysis examining cholinergic and nitrergic parasympathetic neurons in the head, and a range of pelvic neuron populations, with noradrenergic, cholinergic, nitrergic, and mixed transmitter phenotypes, remains open. Of particular interest are the molecular mechanisms and nuclear processes that are responsible for the correlated expression of the various genes required to achieve the noradrenergic phenotype, the segregation of cholinergic locus gene expression, and the regulation of genes that are necessary to generate a nitrergic phenotype. Unraveling the neuron population-specific expression of adhesion molecules, which are involved in axonal outgrowth, pathway selection, and synaptic organization, will advance the study of target-selective autonomic pathway generation.
Nitro fatty acids (NFAs) are endogenously generated lipid mediators deriving from reactions of unsaturated electrophilic fatty acids with reactive nitrogen species. Furthermore, Mediterranean diets can be a source of NFA. These highly electrophilic fatty acids can undergo Michael addition reaction with cysteine residues, leading to post-translational modifications (PTM) of selected regulatory proteins. Such modifications are capable of changing target protein function during cell signaling or in biosynthetic pathways. NFA target proteins include the peroxisome proliferator-activated receptor γ (PPAR-γ), the pro-inflammatory and tumorigenic nuclear factor-κB (NF-κB) signaling pathway, the pro-inflammatory 5-lipoxygenases (5-LO) biosynthesis pathway as well as soluble epoxide hydrolase (sEH), which is essentially involved in the regulation of vascular tone. In several animal models of inflammation and cancer, the therapeutic efficacy of well-tolerated NFA has been demonstrated. This has already led to clinical phase II studies investigating possible therapeutic effects of NFA in subjects with pulmonary arterial hypertension. Albeit Michael acceptors feature a broad spectrum of bioactivity, they have for a rather long time been avoided as drug candidates owing to their presumed unselective reactivity and toxicity. However, targeted covalent modification of regulatory proteins by Michael acceptors became recognized as a promising approach to drug discovery with the recent FDA approvals of the cancer therapeutics, afatanib (2013), ibrutinib (2013), and osimertinib (2015). Furthermore, the Michael acceptor, neratinib, a dual inhibitor of the human epidermal growth factor receptor 2 and epidermal growth factor receptor, was recently approved by the FDA (2017) and by the EMA (2018) for the treatment of breast cancer. Finally, a number of further Michael acceptor drug candidates are currently under clinical investigation for pharmacotherapy of inflammation and cancer. In this review, we focus on the pharmacology of NFA and other Michael acceptor drugs, summarizing their potential as an emerging class of future antiphlogistics and adjuvant in tumor therapeutics.
Endocannabinoids are important lipid-signaling mediators. Both protective and deleterious effects of endocannabinoids in the cardiovascular system have been reported but the mechanistic basis for these contradicting observations is unclear. We set out to identify anti-inflammatory mechanisms of endocannabinoids in the murine aorta and in human vascular smooth muscle cells (hVSMC). In response to combined stimulation with cytokines, IL-1β and TNFα, the murine aorta released several endocannabinoids, with anandamide (AEA) levels being the most significantly increased. AEA pretreatment had profound effects on cytokine-induced gene expression in hVSMC and murine aorta. As revealed by RNA-Seq analysis, the induction of a subset of 21 inflammatory target genes, including the important cytokine CCL2 was blocked by AEA. This effect was not mediated through AEA-dependent interference of the AP-1 or NF-κB pathways but rather through an epigenetic mechanism. In the presence of AEA, ATAC-Seq analysis and chromatin-immunoprecipitations revealed that CCL2 induction was blocked due to increased levels of H3K27me3 and a decrease of H3K27ac leading to compacted chromatin structure in the CCL2 promoter. These effects were mediated by recruitment of HDAC4 and the nuclear corepressor NCoR1 to the CCL2 promoter. This study therefore establishes a novel anti-inflammatory mechanism for the endogenous endocannabinoid AEA in vascular smooth muscle cells. Furthermore, this work provides a link between endogenous endocannabinoid signaling and epigenetic regulation.
Background: The current COVID-19 pandemic has led to a surge of research activity. While this research provides important insights, the multitude of studies results in an increasing fragmentation of information. To ensure comparability across projects and institutions, standard datasets are needed. Here, we introduce the “German Corona Consensus Dataset” (GECCO), a uniform dataset that uses international terminologies and health IT standards to improve interoperability of COVID-19 data, in particular for university medicine.
Methods: Based on previous work (e.g., the ISARIC-WHO COVID-19 case report form) and in coordination with experts from university hospitals, professional associations and research initiatives, data elements relevant for COVID-19 research were collected, prioritized and consolidated into a compact core dataset. The dataset was mapped to international terminologies, and the Fast Healthcare Interoperability Resources (FHIR) standard was used to define interoperable, machine-readable data formats.
Results: A core dataset consisting of 81 data elements with 281 response options was defined, including information about, for example, demography, medical history, symptoms, therapy, medications or laboratory values of COVID-19 patients. Data elements and response options were mapped to SNOMED CT, LOINC, UCUM, ICD-10-GM and ATC, and FHIR profiles for interoperable data exchange were defined.
Conclusion: GECCO provides a compact, interoperable dataset that can help to make COVID-19 research data more comparable across studies and institutions. The dataset will be further refined in the future by adding domain-specific extension modules for more specialized use cases.
Background: The current COVID-19 pandemic has led to a surge of research activity. While this research provides important insights, the multitude of studies results in an increasing segmentation of information. To ensure comparability across projects and institutions, standard datasets are needed. Here, we introduce the “German Corona Consensus Dataset” (GECCO), a uniform dataset that uses international terminologies and health IT standards to improve interoperability of COVID-19 data.
Methods: Based on previous work (e.g., the ISARIC-WHO COVID-19 case report form) and in coordination with experts from university hospitals, professional associations and research initiatives, data elements relevant for COVID-19 research were collected, prioritized and consolidated into a compact core dataset. The dataset was mapped to international terminologies, and the Fast Healthcare Interoperability Resources (FHIR) standard was used to define interoperable, machine-readable data formats.
Results: A core dataset consisting of 81 data elements with 281 response options was defined, including information about, for example, demography, anamnesis, symptoms, therapy, medications or laboratory values of COVID-19 patients. Data elements and response options were mapped to SNOMED CT, LOINC, UCUM, ICD-10-GM and ATC, and FHIR profiles for interoperable data exchange were defined.
Conclusion: GECCO provides a compact, interoperable dataset that can help to make COVID-19 research data more comparable across studies and institutions. The dataset will be further refined in the future by adding domain-specific extension modules for more specialized use cases.
The C-type lectin-like receptor NKG2D contributes to the immunosurveillance of virally infected and malignant cells by cytotoxic lymphocytes. A peculiar and puzzling feature of the NKG2D-based immunorecognition system is the high number of ligands for this single immunoreceptor. In humans, there are a total of eight NKG2D ligands (NKG2DL) comprising two members of the MIC (MICA, MICB) and six members of the ULBP family of glycoproteins (ULBP1 to ULBP6). While MICA has been extensively studied with regard to its biochemistry, cellular expression and function, very little is known about the NKG2DL ULBP4. This is, at least in part, due to its rather restricted expression by very few cell lines and tissues. Recently, constitutive ULBP4 expression by human monocytes was reported, questioning the view of tissue-restricted ULBP4 expression. Here, we scrutinized ULBP4 expression by human peripheral blood mononuclear cells and monocytes by analyzing ULBP4 transcripts and ULBP4 surface expression. In contrast to MICA, there was no ULBP4 expression detectable, neither by freshly isolated monocytes nor by PAMP-activated monocytes. However, a commercial antibody erroneously indicated surface ULBP4 on monocytes due to a non-ULBP4-specific binding activity, emphasizing the critical importance of validated reagents for life sciences. Collectively, our data show that ULBP4 is not expressed by monocytes, and likely also not by other peripheral blood immune cells, and therefore exhibits an expression pattern rather distinct from other human NKG2DL.
Age-related diseases pose great challenges to health care systems worldwide. During aging, endothelial senescence increases the risk for cardiovascular disease. Recently, it was described that Phosphatase 1 Nuclear Targeting Subunit (PNUTS) has a central role in cardiomyocyte aging and homeostasis. Here, we determined the role of PNUTS in endothelial cell aging. We confirmed that PNUTS is repressed in senescent endothelial cells (ECs). Moreover, PNUTS silencing elicits several of the hallmarks of endothelial aging: senescence, reduced angiogenesis and loss of barrier function. To validate our findings in vivo, we generated an endothelial-specific inducible PNUTS-deficient mouse line (Cdh5-CreERT2;PNUTSfl/fl), termed PNUTSEC-KO. Two weeks after PNUTS deletion, PNUTSEC-KO mice presented severe multiorgan failure and vascular leakage. We showed that the PNUTS binding motif for protein phosphatase 1 (PP1) is essential to maintain endothelial barrier function. Transcriptomic analysis of PNUTS-silenced HUVECs and lungs of PNUTSEC-KO mice revealed that the PNUTS-PP1 axis tightly regulates the expression of semaphorin 3B (SEMA3B). Indeed, silencing of SEMA3B completely restored barrier function after PNUTS loss-of-function. These results reveal a pivotal role for PNUTS in endothelial homeostasis through a PP1-SEMA3B downstream pathway that provides a potential target against the effects of aging in ECs.
Caspase-8 is an aspartate-specific cysteine protease, which is best known for its apoptotic functions. Caspase-8 is placed at central nodes of multiple signal pathways, regulating not only the cell cycle but also the invasive and metastatic cell behavior, the immune cell homeostasis and cytokine production, which are the two major components of the tumor microenvironment (TME). Ovarian cancer often has dysregulated caspase-8 expression, leading to imbalance between its apoptotic and non-apoptotic functions within the tumor and the surrounding milieu. The downregulation of caspase-8 in ovarian cancer seems to be linked to high aggressiveness with chronic inflammation, immunoediting, and immune resistance. Caspase-8 plays therefore an essential role not only in the primary tumor cells but also in the TME by regulating the immune response, B and T lymphocyte activation, and macrophage differentiation and polarization. The switch between M1 and M2 macrophages is possibly associated with changes in the caspase-8 expression. In this review, we are discussing the non-apoptotic functions of caspase-8, highlighting this protein as a modulator of the immune response and the cytokine composition in the TME. Considering the low survival rate among ovarian cancer patients, it is urgently necessary to develop new therapeutic strategies to optimize the response to the standard treatment. The TME is highly heterogenous and provides a variety of opportunities for new drug targets. Given the variety of roles of caspase-8 in the TME, we should focus on this protein in the development of new therapeutic strategies against the TME of ovarian cancer.
MicroRNAs (miRNAs) have emerged as critical posttranscriptional regulators of the immune system, including function and development of regulatory T (Treg) cells. Although this critical role has been firmly demonstrated through genetic models, key mechanisms of miRNA function in vivo remain elusive. Here, we review the role of miRNAs in Treg cell development and function. In particular, we focus on the question what the study of miRNAs in this context reveals about miRNA biology in general, including context-dependent function and the role of individual targets vs. complex co-targeting networks. In addition, we highlight potential technical pitfalls and state-of-the-art approaches to improve the mechanistic understanding of miRNA biology in a physiological context.
The identification of unknown bodies is the fulfilment of a moral obligation towards the deceased, serves to maintain legal security within a society, and gives families the certainty they need to mourn. Taking into account respective local conditions, the aim should always be to achieve a secure and quick identification. To achieve this goal, a functioning cooperation between investigating authorities and forensic sciences is essential. The main objective of this study was to clarify the potential role of tattoos in the identification process of unknown deceased persons in the state of Jalisco, Mexico. Post-mortem data of 2045 bodies from the Instituto Jaliscience de Ciencias Forenses in Guadalajara were evaluated. Of the deceased 46% were tattooed (male: 47%, female: 39%), with 29% of all bodies (male: 29%, female: 26%) showing tattoos at body locations usually visible in everyday life (i.e. head and neck, forearms and hands). The male bodies were most frequently tattooed on the shoulders and upper arms, followed by the forearms and hands and the torso. Female bodies mostly showed tattoos on the forearms and hands, followed by the torso and legs. Taking local tattooing habits into account, the authors developed a classification for tattoo motives. With decreasing frequency, the following keywords could be assigned to the motives: letters and/or numbers, human, symbol (other), plant, symbol (religious), animal, object, tribal/ornament/geometry, fantasy/demon/comic, other. Results of the study indicate the great importance of tattoos as a possible mean of identification in Jalisco, Mexico – either as a stand-alone identification method, as a complementary tool or for planning and prioritizing subsequent investigations.
Aims: Stroke is a major complication after transcatheter aortic valve implantation (TAVI). Although multifactorial, it remains unknown whether the valve deployment system itself has an impact on the incidence of early stroke. We performed a meta- and network analysis to investigate the 30-day stroke incidence of self-expandable (SEV) and balloon-expandable (BEV) valves after transfemoral TAVI.
Methods and results: Overall, 2723 articles were searched directly comparing the performance of SEV and BEV after transfemoral TAVI, from which 9 were included (3086 patients). Random effects models were used for meta- and network meta-analysis based on a frequentist framework. Thirty-day incidence of stroke was 1.8% in SEV and 3.1% in BEV (risk ratio of 0.62, 95% confidence interval (CI) 0.49–0.80, p = 0.004). Treatment ranking based on network analysis (P-score) revealed CoreValve with the best performance for 30-day stroke incidence (75.2%), whereas SAPIEN had the worst (19.0%). However, network analysis showed no inferiority of SAPIEN compared with CoreValve (odds ratio 2.24, 95% CI 0.70–7.2).
Conclusion: Our analysis indicates higher 30-day stroke incidence after transfemoral TAVI with BEV compared to SEV. We could not find evidence for superiority of a specific valve system. More randomized controlled trials with head-to-head comparison of SEV and BEV are needed to address this open question.
Hintergrund: Die Tiefe Hirnstimulation ist eine etablierte Therapieoption zur Behandlung von Bewegungsstörungen. Um ein möglichst gutes Ansprechen bei geringen Nebenwirkungen zu erreichen, ist eine optimale Platzierung der Stimulationselektrode unverzichtbar. Für die Optimierung der Elektrodenposition wird in vielen Zentren eine Makrostimulation durchgeführt, die jedoch abhängig von der Mitarbeit des Patienten ist und eine Operation im Wachzustand erfordert.
Fragestellung: Ziel dieser Arbeit war es herauszufinden, ob die intraoperativ gemessenen Nebenwirkungsschwellen durch MEP oder Traktographie vorausgesagt werden können und eine Korrelation zur postoperativen Nebenwirkungsschwelle nachgewiesen werden kann.
Methoden: Eingeschlossen wurden die Daten von 42 Patienten, die sich einer Tiefen Hirnstimulation unterzogen hatten. Intraoperativ erfolge neben der Ableitung der Nebenwirkungsschwelle bei der Makrostimulation die Erfassung von MEP. Zusätzlich wurde eine Traktographie zur Darstellung der motorischen Faserbahnen durchgeführt, wobei auch die Daten der nTMS genutzt wurden. Anschließend erfolgte eine Abstandsmessung zwischen der Stimulationselektrode und der motorischen Faserbahn. Wenige Tage postoperativ wurden die Nebenwirkungsschwellen erneut im Rahmen der Ersteinstellung des Neurostimulators erhoben. Die Daten der intraoperativ gemessenen Nebenwirkungsschwelle wurden mit den Daten der MEP-Schwellenwerte, dem Faserbahnabstand und den postoperativen Schwellenwerten mittels einer linearen
Regressionsanalyse korreliert.
Ergebnisse: Eine Korrelation zwischen intraoperativer Nebenwirkungsschwelle und MEP konnte nicht nachgewiesen werden. Es ergab sich ein signifikanter Zusammenhang der Abstände der Stimulationselektrode zur motorischen Faserbahn. Die Korrelation mit den postoperativen Nebenwirkungsschwellen ergab einen signifikanten Zusammenhang.
Schlussfolgerung: Die intraoperativen Nebenwirkungsschwellen konnten durch MEP in dieser Studie nicht vorhergesagt werden. Jedoch kann die Traktographie die Makrostimulation ergänzen. Außerdem sollten die intraoperativ gemessenen Nebenwirkungsschwellen mit Vorsicht betrachtet werden, da diese zu einer Überschätzung des therapeutischen Fensters beitragen können.
Limb stump pain after amputation, due to sensitized neuromas, is a common condition that can cause a great deal of suffering in affected patients. Treatment is difficult, requiring a multidisciplinary approach that is often unsatisfactory. One treatment used to mitigate pain is electrical stimulation (EStim), administered using several different therapeutic approaches. The research described in this dissertation sought to characterize changes in peripheral nerve morphology, and neuroma formation, following limb amputation, with an eye toward developing better treatment strategies, that intervene before neuromas are fully formed. Another focus of this study was to evaluate the effect EStim has on changes in peripheral nerve morphology, and neuroma formation, following limb amputation.
Right forelimbs of 42 male Sprague Dawley rats were amputated. At 3, 7, 28, 60 and 90 days post amputation (DPA) 6 limb stumps, in each group, were harvested and changes in peripheral nerve morphology, and neuroma formation were measured. In addition, limb stumps of 6 EStim treated, 6 sham-treated (deactivated EStim devices), and 6 non-treated rats were harvested at 28 DPA.
Analysis revealed six distinct morphological characteristics of peripheral nerves during nerve regrowth and neuroma development; 1) normal nerve, 2) degenerating axons, 3) axonal sprouts, 4) unorganized bundles of axons in connective tissue, 5) unorganized axon growth into muscles, and 6) unorganized axon growth into fibrotic tissue (neuroma). At the early stages (3 & 7 DPA), normal nerves could be identified throughout the limb stump tissues and small areas of axonal sprouts were present near the distal tip of the stumps. Signs of degenerating axons were evident from 7 to 90 DPA. From day 28 on, variability of nerve characteristics, with signs of unorganized axon growth into muscle and fibrotic tissue, and neuroma formation, became visible in multiple areas of stump tissue. These pathological features became more evident at 60 and 90 DPA. EStim treated stumps revealed neuroma formation in 1 out of 6 animals, whereas in sham and controls, neuroma formation was seen in 4 out of 6 stumps respectively.
We were able to identify 6 separate histological stages of peripheral nerve regrowth and neuroma formation over 90 days following amputation. Axonal regrowth was observed as early as 3 DPA, and signs of unorganized axonal growth and neuroma formation were evident by 28 DPA. Our observations suggest that EStim-based treatment and/or other prevention strategies might be more effective if administered in the initial dynamic stages of neuroma development.
Background: Marked sex differences in autism prevalence accentuate the need to understand the role of biological sex-related factors in autism. Efforts to unravel sex differences in the brain organization of autism have, however, been challenged by the limited availability of female data.
Methods: We addressed this gap by using a large sample of males and females with autism and neurotypical (NT) control individuals (ABIDE; Autism: 362 males, 82 females; NT: 409 males, 166 females; 7-18 years). Discovery analyses examined main effects of diagnosis, sex and their interaction across five resting-state fMRI (R-fMRI) metrics (voxel-level Z > 3.1, cluster-level P < 0.01, gaussian random field corrected). Secondary analyses assessed the robustness of the results to different pre-processing approaches and their replicability in two independent samples: the EU-AIMS Longitudinal European Autism Project (LEAP) and the Gender Explorations of Neurogenetics and Development to Advance Autism Research (GENDAAR).
Results: Discovery analyses in ABIDE revealed significant main effects across the intrinsic functional connectivity (iFC) of the posterior cingulate cortex, regional homogeneity and voxel-mirrored homotopic connectivity (VMHC) in several cortical regions, largely converging in the default network midline. Sex-by-diagnosis interactions were confined to the dorsolateral occipital cortex, with reduced VMHC in females with autism. All findings were robust to different pre-processing steps. Replicability in independent samples varied by R-fMRI measures and effects with the targeted sex-by-diagnosis interaction being replicated in the larger of the two replication samples – EU-AIMS LEAP.
Limitations: Given the lack of a priori harmonization among the discovery and replication datasets available to date, sample-related variation remained and may have affected replicability.
Conclusions: Atypical cross-hemispheric interactions are neurobiologically relevant to autism. They likely result from the combination of sex-dependent and sex-independent factors with a differential effect across functional cortical networks. Systematic assessments of the factors contributing to replicability are needed and necessitate coordinated large-scale data collection across studies.
Competing Interest Statement: ADM receives royalties from the publication of the Italian version of the Social Responsiveness Scale Child Version by Organization Speciali, Italy. JKB has been a consultant to, advisory board member of, and a speaker for Takeda/Shire, Medice, Roche, and Servier. He is not an employee of any of these companies and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, or royalties. CFB is director and shareholder in SBGneuro Ltd. TC has received consultancy from Roche and Servier and received book royalties from Guildford Press and Sage. DM has been a consultant to, and advisory board member, for Roche and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. TB served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire, and Infectopharm. He received conference support or speakers fee by Lilly, Medice, and Shire. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the present work is unrelated to these relationships. JT is a consultant to Roche. The remaining authors declare no competing interests.
Die Gattungen Nicotiana tabacum und Nicotiana rustica der Tabakpflanze sind von großer wirtschaftlicher Bedeutung. Aus ihnen wird Tabak hergestellt, der mit Alkohol zur weltweit am häufigsten konsumierten Genussdroge zählt. Aufgrund seiner Legalität wird die Toxizität trotz steigender Warnung und Aufklärung immer noch unterschätzt. Die Toxizität der Tabakpflanze ist vor allem auf das Alkaloid Nikotin zurückzuführen. Dass es selten zu einer Vergiftung durch die reine Pflanze kommt, liegt daran, dass sie optisch kaum zum Verzehr anregt. Häufiger dagegen ist eine Vergiftung durch z. B. verschluckte Zigarettenstummel, die vor allem für Kinder sehr gefährlich sein kann. Eine weitere Gefahr der Vergiftung entsteht bei der Tabakernte. Nikotin wird auch über die Haut aufgenommen und kann so zu der Green Tobacco Sickness bei Tabakplantagenarbeitern führen. Im Ernstfall existiert kein Antidot. Aktivkohle sollte so schnell wie möglich gegeben werden, um die Resorption zu vermindern. Ansonsten muss das Nikotin mit einer Magenwäsche aus dem Körper gefiltert werden. Präventiv sollten deshalb verstärkt auf die Gefahren des Tabaks aufmerksam gemacht werden.
Pulmonary failure is the main cause of morbidity and mortality in the human chromosomal instability syndrome Ataxia-telangiectasia (A-T). Major phenotypes include recurrent respiratory tract infections and bronchiectasis, aspiration, respiratory muscle abnormalities, interstitial lung disease, and pulmonary fibrosis. At present, no effective pulmonary therapy for A-T exists. Cell therapy using adipose-derived mesenchymal stromal/stem cells (ASCs) might be a promising approach for tissue regeneration. The aim of the present project was to investigate whether ASCs migrate into the injured lung parenchyma of Atm-deficient mice as an indication of incipient tissue damage during A-T. Therefore, ASCs isolated from luciferase transgenic mice (mASCs) were intravenously transplanted into Atm-deficient and wild-type mice. Retention kinetics of the cells were monitored using in vivo bioluminescence imaging (BLI) and completed by subsequent verification using quantitative real-time polymerase chain reaction (qRT-PCR). The in vivo imaging and the qPCR results demonstrated migration accompanied by a significantly longer retention time of transplanted mASCs in the lung parenchyma of Atm-deficient mice compared to wild type mice. In conclusion, our study suggests incipient damage in the lung parenchyma of Atm-deficient mice. In addition, our data further demonstrate that a combination of luciferase-based PCR together with BLI is a pivotal tool for tracking mASCs after transplantation in models of inflammatory lung diseases such as A-T.
Congenital diaphragmatic hernia (CDH) is a relatively common and life-threatening birth defect, characterized by incomplete formation of the diaphragm. Because CDH herniation occurs at the same time as preacinar airway branching, normal lung development becomes severely disrupted, resulting almost invariably in pulmonary hypoplasia. Despite various research efforts over the past decades, the pathogenesis of CDH and associated lung hypoplasia remains poorly understood. With the advent of molecular techniques, transgenic animal models of CDH have generated a large number of candidate genes, thus providing a novel basis for future research and treatment. This review article offers a comprehensive overview of genes and signaling pathways implicated in CDH etiology, whilst also discussing strengths and limitations of transgenic animal models in relation to the human condition.