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Background: Genome-wide association studies (GWAS) have identified new candidate genes for the occurrence of acute coronary syndrome (ACS), but possible effects of such genes on survival following ACS have yet to be investigated.
Methods: We examined 95 polymorphisms in 69 distinct gene regions identified in a GWAS for premature myocardial infarction for their association with post-ACS mortality among 811 whites recruited from university-affiliated hospitals in Kansas City, Missouri. We then sought replication of a positive genetic association in a large, racially diverse cohort of myocardial infarction patients (N = 2284) using Kaplan-Meier survival analyses and Cox regression to adjust for relevant covariates. Finally, we investigated the apparent association further in 6086 additional coronary artery disease patients.
Results: After Cox adjustment for other ACS risk factors, of 95 SNPs tested in 811 whites only the association with the rs6922269 in MTHFD1L was statistically significant, with a 2.6-fold mortality hazard (P = 0.007). The recessive A/A genotype was of borderline significance in an age- and race-adjusted analysis of the entire combined cohort (N = 3095; P = 0.052), but this finding was not confirmed in independent cohorts (N = 6086).
Conclusions: We found no support for the hypothesis that the GWAS-identified variants in this study substantially alter the probability of post-ACS survival. Large-scale, collaborative, genome-wide studies may be required in order to detect genetic variants that are robustly associated with survival in patients with coronary artery disease.
The Weissert Event ~133 million years ago marked a profound global cooling that punctuated the Early Cretaceous greenhouse. We present modelling, high-resolution bulk organic carbon isotopes and chronostratigraphically calibrated sea surface temperature (SSTs) based on an organic paleothermometer (the TEX86 proxy), which capture the Weissert Event in the semi-enclosed Weddell Sea basin, offshore Antarctica (paleolatitude ~54 °S; paleowater depth ~500 meters). We document a ~3–4 °C drop in SST coinciding with the Weissert cold end, and converge the Weddell Sea data, climate simulations and available worldwide multi-proxy based temperature data towards one unifying solution providing a best-fit between all lines of evidence. The outcome confirms a 3.0 °C ( ±1.7 °C) global mean surface cooling across the Weissert Event, which translates into a ~40% drop in atmospheric pCO2 over a period of ~700 thousand years. Consistent with geologic evidence, this pCO2 drop favoured the potential build-up of local polar ice.
The aim of the study was to obtain volumetric data of the components of the inner ear using three-dimensional reconstruction of high-resolution cone-beam computed tomography (CBCT) images. Two hundred three CBCT image series of the temporal bone from 118 anatomically normal patients (55 women and 63 men; mean age: 49.4 ± 20.4 years) with different suspected disorders were included in this study. Normative volumetric measurements of the inner ear, the cochlea, the semicircular canals (SSC), and the vestibule were determined using a semi-automated reconstruction method of the Workstation. Volumetric measurements were successfully completed in all 118 patients. Mean inner ear, cochlear, and vestibule volumes were statistically significantly larger in males than in females on both sides (p < 0.001). Regarding the semicircular canals, no statistically significant (p = 0.053) volume difference was found. The difference between the volumes on both sides was not significant. No correlation between the patient’s age and the volume of the compartments was seen (p > 0.05). There was no significant difference between mean bony inner ear volumes when the clinical diagnoses were compared (p > 0.05 for all clinical diagnoses and volumes). Our study concluded that three-dimensional reconstruction and assessment of the volumetric measurements of the inner ear can be obtained using high-resolution CBCT imaging.
Background: Glucagon-like peptide-1 receptor agonists may be a treatment option in patients with non-alcoholic fatty liver disease (NAFLD). Aims: To investigate the effects of semaglutide on liver stiffness and liver fat in subjects with NAFLD using non-invasive magnetic resonance imaging (MRI) methods. Methods: This randomised, double-blind, placebo-controlled trial enrolled subjects with liver stiffness 2.50-4.63 kPa by magnetic resonance elastography (MRE) and liver steatosis ≥10% by MRI proton density fat fraction (MRI-PDFF). The primary endpoint was change from baseline to week 48 in liver stiffness assessed by MRE. Results: Sixty-seven subjects were randomised to once-daily subcutaneous semaglutide 0.4 mg (n = 34) or placebo (n = 33). Change from baseline in liver stiffness was not significantly different between semaglutide and placebo at week 48 (estimated treatment ratio 0.96 (95% CI 0.89, 1.03; P = 0.2798); significant differences in liver stiffness were not observed at weeks 24 or 72. Reductions in liver steatosis were significantly greater with semaglutide (estimated treatment ratios: 0.70 [0.59, 0.84], P = 0.0002; 0.47 [0.36, 0.60], P < 0.0001; and 0.50 [0.39, 0.66], P < 0.0001) and more subjects achieved a ≥ 30% reduction in liver fat content with semaglutide at weeks 24, 48 and 72, (all P < 0.001). Decreases in liver enzymes, body weight and HbA1c were also observed with semaglutide. Conclusions: The change in liver stiffness in subjects with NAFLD was not significantly different between semaglutide and placebo. However, semaglutide significantly reduced liver steatosis compared with placebo which, together with improvements in liver enzymes and metabolic parameters, suggests a positive impact on disease activity and metabolic profile. ClinicalTrials.gov identifier: NCT03357380
Background: Because Endomyocardial Biopsy has low sensitivity of about 20%, it can be performed near to myocardium that presented as Late Gadolinium Enhancement (LGE) in cardiovascular magnetic resonance (CMR). However the important issue of comparing topography of CMR and histological findings has not yet been investigated. Thus the current study was performed using an animal model of myocarditis. Results: In 10 male Lewis rats Experimental Autoimmune myocarditis was induced, 10 rats served as control. On day 21 animals were examined by CMR to compare topographic distribution of LGE to histological inflammation. Sensitivity, specificity, positive and negative predictive values for LGE in diagnosing myocarditis were determined for each segment of myocardium. Latter diagnostic values varied widely depending on topographic distribution of LGE and inflammation as well as on the used CMR sequence. Sensitivity of LGE was up to 76% (left lateral myocardium) and positive predictive values were up to 85% (left lateral myocardium), whereas sensitivity and positive predictive value dropped to 0 - 33% (left inferior myocardium). Conclusions: Topographic distribution of LGE and histological inflammation seem to influence sensitivity, specifity, positive and negative predictive values. Nevertheless, positive predictive value for LGE of up to 85% indicates that Endomyocardial Biopsy should be performed "MR-guided". LGE seems to have greater sensitivity than Endomyocardial Biopsy for the diagnosis of myocarditis.
Objectives: To evaluate the predictive value of volumetric bone mineral density (BMD) assessment of the lumbar spine derived from phantomless dual-energy CT (DECT)-based volumetric material decomposition as an indicator for the 2-year occurrence risk of osteoporosis-associated fractures. Methods: L1 of 92 patients (46 men, 46 women; mean age, 64 years, range, 19–103 years) who had undergone third-generation dual-source DECT between 01/2016 and 12/2018 was retrospectively analyzed. For phantomless BMD assessment, dedicated DECT postprocessing software using material decomposition was applied. Digital files of all patients were sighted for 2 years following DECT to obtain the incidence of osteoporotic fractures. Receiver operating characteristic (ROC) analysis was used to calculate cut-off values and logistic regression models were used to determine associations of BMD, sex, and age with the occurrence of osteoporotic fractures. Results: A DECT-derived BMD cut-off of 93.70 mg/cm3 yielded 85.45% sensitivity and 89.19% specificity for the prediction to sustain one or more osteoporosis-associated fractures within 2 years after BMD measurement. DECT-derived BMD was significantly associated with the occurrence of new fractures (odds ratio of 0.8710, 95% CI, 0.091–0.9375, p < .001), indicating a protective effect of increased DECT-derived BMD values. Overall AUC was 0.9373 (CI, 0.867–0.977, p < .001) for the differentiation of patients who sustained osteoporosis-associated fractures within 2 years of BMD assessment. Conclusions: Retrospective DECT-based volumetric BMD assessment can accurately predict the 2-year risk to sustain an osteoporosis-associated fracture in at-risk patients without requiring a calibration phantom. Lower DECT-based BMD values are strongly associated with an increased risk to sustain fragility fractures.
Key Points: Dual-energy CT–derived assessment of bone mineral density can identify patients at risk to sustain osteoporosis-associated fractures with a sensitivity of 85.45% and a specificity of 89.19%. The DECT-derived BMD threshold for identification of at-risk patients lies above the American College of Radiology (ACR) QCT guidelines for the identification of osteoporosis (93.70 mg/cm 3 vs 80 mg/cm 3 ).
A new species belonging to the crustacean class Remipedia is described from an anchialine cave system on the island of Cozumel (Mexico), and is illustrated and compared morphologically and molecularly (CO1 and 16S) with closely related taxa. Xibalbanus cozumelensis sp. nov., the first remipede described from Cozumel, is morphologically similar to Xibalbanus tulumensis (Yager, 1987) from the Yucatán Peninsula, but the two species are genetically separate from each other (about 10% in CO1). A phylogenetic (Bayesian) analysis of Yucatán remipede populations based on CO1 and 16S placed them in a monophyletic Xibalbanus (in Xibalbanidae fam. nov.), with X. cozumelensis as most closely related to X. tulumensis. The Yucatán Peninsula and Cozumel have been separate since approx. early Cenozoic (~65 Ma), which suggests allopatric speciation for X. cozumelensis sp. nov. and X. tulumensis. However, the comparatively low genetic divergence between the two species may indicate that there has been gene flow between ‘mainland’ Yucatán and Cozumel long after the geological separation of the two landmasses, e.g., in cave systems under the sea bed, either continuously or sporadically, for example during the Last Glacial Maximum when the sea level was about 120 m lower than today.
An important experimental program on Nuclear Astrophysics is being carried out at the n_TOF since several years, in order to address the still open issues in stellar and primordial nucleosynthesis. Several neutron capture reactions relevant to s-process nucleosynthesis have been measured so far, some of which on important branching point radioisotopes. Furthermore, the construction of a second experimental area has recently opened the way to challenging measurements of (n, charged particle) reactions on isotopes of short half-life. The Nuclear Astrophysics program of the n_TOF Collaboration is here described, with emphasis on recent results relevant for stellar nucleosynthesis, stellar neutron sources and primordial nucleosynthesis.
The 33S(n,α)30Si cross section measurement, using 10B(n,α) as reference, at the n_TOF Experimental Area 2 (EAR2) facility at CERN is presented. Data from 0.01 eV to 100 keV are provided and, for the first time, the cross section is measured in the range from 0.01 eV to 10 keV. These data may be used for a future evaluation of the cross section because present evaluations exhibit large discrepancies. The 33S(n,α)30Si reaction is of interest in medical physics because of its possible use as a cooperative target to boron in Neutron Capture Therapy (NCT).
The spent fuel of current nuclear reactors contains fissile plutonium isotopes that can be combined with 238U to make mixed oxide (MOX) fuel. In this way the Pu from spent fuel is used in a new reactor cycle, contributing to the long-term sustainability of nuclear energy. The use of MOX fuels in thermal and fast reactors requires accurate capture and fission cross sections. For the particular case of 242Pu, the previous neutron capture cross section measurements were made in the 70's, providing an uncertainty of about 35% in the keV region. In this context, the Nuclear Energy Agency recommends in its “High Priority Request List” and its report WPEC-26 that the capture cross section of 242Pu should be measured with an accuracy of at least 7–12% in the neutron energy range between 500 eV and 500 keV. This work presents a brief description of the measurement performed at n_TOF-EAR1, the data reduction process and the first ToF capture measurement on this isotope in the last 40 years, providing preliminary individual resonance parameters beyond the current energy limits in the evaluations, as well as a preliminary set of average resonance parameters.
The Cosmological Lithium Problem refers to the large discrepancy between the abundance of primordial 7Li predicted by the standard theory of Big Bang Nucleosynthesis and the value inferred from the so-called “Spite plateau” in halo stars. A possible explanation for this longstanding puzzle in Nuclear Astrophysics is related to the incorrect estimation of the destruction rate of 7Be, which is responsible for the production of 95% of primordial Lithium. While charged-particle induced reactions have mostly been ruled out, data on the 7Be(n,α) and 7Be(n,p) reactions are scarce or completely missing, so that a large uncertainty still affects the abundance of 7Li predicted by the standard theory of Big Bang Nucleosynthesis. Both reactions have been measured at the n_TOF facility at CERN, providing for the first time data in a wide neutron energy range.
The CERN n_TOF neutron beam facility is characterized by a very high instantaneous neutron flux, excellent TOF resolution at the 185 m long flight path (EAR-1), low intrinsic background and coverage of a wide range of neutron energies, from thermal to a few GeV. These characteristics provide a unique possibility to perform high-accuracy measurements of neutron-induced reaction cross-sections and angular distributions of interest for fundamental and applied Nuclear Physics. Since 2001, the n_TOF Collaboration has collected a wealth of high quality nuclear data relevant for nuclear astrophysics, nuclear reactor technology, nuclear medicine, etc. The overall efficiency of the experimental program and the range of possible measurements has been expanded with the construction of a second experimental area (EAR-2), located 20 m on the vertical of the n_TOF spallation target. This upgrade, which benefits from a neutron flux 30 times higher than in EAR-1, provides a substantial extension in measurement capabilities, opening the possibility to collect data on neutron cross-section of isotopes with short half-lives or available in very small amounts. This contribution will outline the main characteristics of the n_TOF facility, with special emphasis on the new experimental area. In particular, we will discuss the innovative features of the EAR-2 neutron beam that make possible to perform very challenging measurements on short-lived radioisotopes or sub-mg samples, out of reach up to now at other neutron facilities around the world. Finally, the future perspectives of the facility will be presented.
The neutron capture cross section of several key unstable isotopes acting as branching points in the s-process are crucial for stellar nucleosynthesis studies, but they are very challenging to measure due to the difficult production of sufficient sample material, the high activity of the resulting samples, and the actual (n,γ) measurement, for which high neutron fluxes and effective background rejection capabilities are required. As part of a new program to measure some of these important branching points, radioactive targets of 147Pm and 171Tm have been produced by irradiation of stable isotopes at the ILL high flux reactor. Neutron capture on 146Nd and 170Er at the reactor was followed by beta decay and the resulting matrix was purified via radiochemical separation at PSI. The radioactive targets have been used for time-of-flight measurements at the CERN n_TOF facility using the 19 and 185 m beam lines during 2014 and 2015. The capture cascades were detected using a set of four C6D6 scintillators, allowing to observe the associated neutron capture resonances. The results presented in this work are the first ever determination of the resonance capture cross section of 147Pm and 171Tm. Activation experiments on the same 147Pm and 171Tm targets with a high-intensity 30 keV quasi-Maxwellian flux of neutrons will be performed using the SARAF accelerator and the Liquid-Lithium Target (LiLiT) in order to extract the corresponding Maxwellian Average Cross Section (MACS). The status of these experiments and preliminary results will be presented and discussed as well.
he study of the resonant structures in neutron-nucleus cross-sections, and therefore of the compound-nucleus reaction mechanism, requires spectroscopic measurements to determine with high accuracy the energy of the neutron interacting with the material under study.
To this purpose, the neutron time-of-flight facility n_TOF has been operating since 2001 at CERN. Its characteristics, such as the high intensity instantaneous neutron flux, the wide energy range from thermal to few GeV, and the very good energy resolution, are perfectly suited to perform high-quality measurements of neutron-induced reaction cross sections. The precise and accurate knowledge of these cross sections plays a fundamental role in nuclear technologies, nuclear astrophysics and nuclear physics.
Two different measuring stations are available at the n_TOF facility, called EAR1 and EAR2, with different characteristics of intensity of the neutron flux and energy resolution. These experimental areas, combined with advanced detection systems lead to a great flexibility in performing challenging measurement of high precision and accuracy, and allow the investigation isotopes with very low cross sections, or available only in small quantities, or with very high specific activity.
The characteristics and performances of the two experimental areas of the n_TOF facility will be presented, together with the most important measurements performed to date and their physics case. In addition, the significant upcoming measurements will be introduced.
Background: There are no blood-based molecular biomarkers of temporal lobe epilepsy (TLE) to support clinical diagnosis. MicroRNAs are short noncoding RNAs with strong biomarker potential due to their cell-specific expression, mechanistic links to brain excitability, and stable detection in biofluids. Altered levels of circulating microRNAs have been reported in human epilepsy, but most studies collected samples from one clinical site, used a single profiling platform or conducted minimal validation.
Method: Using a case-control design, we collected plasma samples from video-electroencephalogram-monitored adult TLE patients at epilepsy specialist centers in two countries, performed genome-wide PCR-based and RNA sequencing during the discovery phase and validated findings in a large (>250) cohort of samples that included patients with psychogenic non-epileptic seizures (PNES).
Findings: After profiling and validation, we identified miR-27a-3p, miR-328-3p and miR-654-3p with biomarker potential. Plasma levels of these microRNAs were also changed in a mouse model of TLE but were not different to healthy controls in PNES patients. We determined copy number of the three microRNAs in plasma and demonstrate their rapid detection using an electrochemical RNA microfluidic disk as a prototype point-of-care device. Analysis of the microRNAs within the exosome-enriched fraction provided high diagnostic accuracy while Argonaute-bound miR-328-3p selectively increased in patient samples after seizures. In situ hybridization localized miR-27a-3p and miR-328-3p within neurons in human brain and bioinformatics predicted targets linked to growth factor signaling and apoptosis.
Interpretation: This study demonstrates the biomarker potential of circulating microRNAs for epilepsy diagnosis and mechanistic links to underlying pathomechanisms.
Colorectal cancer (CRC) is one of the most common tumor entities worldwide and a common cause of cancer-associated death. Colorectal cancer liver metastases (CRLM) thereby constitute a severe life-limiting factor. The therapy of CRLM presents a major challenge and surgical resection as well as systemic chemotherapy remain the first-line treatment options. Over the years several locoregional, vascular- and image-based treatments offered by interventional radiologists have emerged when conventional therapies fail, or metastases recurrence occurs. Among such options is the conventional/traditional transarterial chemoembolization (cTACE) by local injection of a combination of chemotherapeutic- and embolic-agents. A similar treatment is the more recent irinotecan-loaded drug-eluting beads TACE (DEBIRI-TACE), which are administered using the same approach. Numerous studies have shown that these different types of chemoembolization can be applied in different clinical settings safely. Furthermore, such treatments can also be combined with other local or systemic therapies. Unfortunately, due to the incoherent patient populations of studies investigating TACE in CRLM, critics state that the definite evidence supporting positive patient outcomes is still lacking. In the following article we review studies on conventional and DEBIRI-TACE. Although highly dependent on the clinical setting, prior therapies and generally the study population, cTACE and DEBIRI-TACE show comparable results. We present the most representative studies on the different chemoembolization procedures and compare the results. Although there is compelling evidence for both approaches, further studies are necessary to determine which patients profit most from these therapies. In conclusion, we determine TACE to be a viable option in CRLM in different clinical settings. Nevertheless, a multidisciplinary approach is desired to offer patients the best possible care.
Stratospheric inorganic chlorine (Cly) is predominantly released from long-lived chlorinated source gases and, to a small extent, very short-lived chlorinated substances. Cly includes the reservoir species (HCl and ClONO2) and active chlorine species (i.e., ClOx). The active chlorine species drive catalytic cycles that deplete ozone in the polar winter stratosphere. This work presents calculations of inorganic chlorine (Cly) derived from chlorinated source gas measurements on board the High Altitude and Long Range Research Aircraft (HALO) during the Southern Hemisphere Transport, Dynamic and Chemistry (SouthTRAC) campaign in austral late winter and early spring 2019. Results are compared to Cly in the Northern Hemisphere derived from measurements of the POLSTRACC-GW-LCYCLE-SALSA (PGS) campaign in the Arctic winter of 2015/2016. A scaled correlation was used for PGS data, since not all source gases were measured. Using the SouthTRAC data, Cly from a scaled correlation was compared to directly determined Cly and agreed well. An air mass classification based on in situ N2O measurements allocates the measurements to the vortex, the vortex boundary region, and midlatitudes. Although the Antarctic vortex was weakened in 2019 compared to previous years, Cly reached 1687±19 ppt at 385 K; therefore, up to around 50 % of total chlorine was found in inorganic form inside the Antarctic vortex, whereas only 15 % of total chlorine was found in inorganic form in the southern midlatitudes. In contrast, only 40 % of total chlorine was found in inorganic form in the Arctic vortex during PGS, and roughly 20 % was found in inorganic form in the northern midlatitudes. Differences inside the two vortices reach as much as 540 ppt, with more Cly in the Antarctic vortex in 2019 than in the Arctic vortex in 2016 (at comparable distance to the local tropopause). To our knowledge, this is the first comparison of inorganic chlorine within the Antarctic and Arctic polar vortices. Based on the results of these two campaigns, the differences in Cly inside the two vortices are substantial and larger than the inter-annual variations previously reported for the Antarctic.
AIM: To evaluate the effect of portal vein thrombosis and arterioportal shunts on local tumor response in advanced cases of unresectable hepatocellular carcinoma treated by transarterial chemoembolization.
METHODS: A retrospective study included 39 patients (mean age: 66.4 years, range: 45-79 years, SD: 7) with unresectable hepatocellular carcinoma (HCC) who were treated with repetitive transarterial chemoembolization (TACE) in the period between March 2006 and October 2009. The effect of portal vein thrombosis (PVT) (in 19 out of 39 patients), the presence of arterioportal shunt (APS) (in 7 out of 39), the underlying liver pathology, Child-Pugh score, initial tumor volume, number of tumors and tumor margin definition on imaging were correlated with the local tumor response after TACE. The initial and end therapy local tumor responses were evaluated according to the response evaluation criteria in solid tumors (RECIST) and magnetic resonance imaging volumetric measurements.
RESULTS: The treatment protocols were well tolerated by all patients with no major complications. Local tumor response for all patients according to RECIST criteria were partial response in one patient (2.6%), stable disease in 34 patients (87.1%), and progressive disease in 4 patients (10.2%). The MR volumetric measurements showed that the PVT, APS, underlying liver pathology and tumor margin definition were statistically significant prognostic factors for the local tumor response (P = 0.018, P = 0.008, P = 0.034 and P = 0.001, respectively). The overall 6-, 12- and 18-mo survival rates from the initial TACE were 79.5%, 37.5% and 21%, respectively.
CONCLUSION: TACE may be exploited safely for palliative tumor control in patients with advanced unresectable HCC; however, tumor response is significantly affected by the presence or absence of PVT and APS.
Polygenic risk scores, based on risk variants identified in genome-wide-association-studies (GWAS), explain a considerable portion of the heritability for schizophrenia (SZ) and bipolar disorder (BD). However, little is known about the combined effects of these variants, although polygenic neuroimaging has developed into a powerful tool of translational neuroscience. In this study, we used genome wide significant SZ risk variants to test the predictive capacity of the polygenic model and explored potential associations with white matter volume, a key candidate in imaging phenotype for psychotic disorders.
By calculating the combined additive schizophrenia risk of seven SNPs (significant hits from a recent schizophrenia GWAS study), we show that increased additive genetic risk for SZ was associated with reduced white matter volume in a group of participants (n = 94) consisting of healthy individuals, SZ first-degree relatives, SZ patients and BD patients. This effect was also seen in a second independent sample of healthy individuals (n = 89). We suggest that a moderate portion of variance (~4%) of white matter volume can be explained by the seven hits from the recent schizophrenia GWAS.
These results provide evidence for associations between cumulative genetic risk for schizophrenia and intermediate neuroimaging phenotypes in models of psychosis. Our work contributes to a growing body of literature suggesting that polygenic risk may help to explain white matter alterations associated with familial risk for psychosis.
Objective: TGF-β2 (TGF-β, transforming growth factor beta), the less-investigated sibling of TGF-β1, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-β2 in biliary-derived liver diseases.
Design: As we also found upregulated TGFB2 in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-β2 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of TgfB2 silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels.
Results: TgfB2-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. TgfB2 expression in MDR2-KO mice was blunted using TgfB2-directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and αSMA expression as well as induced PparG expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on Ccl3, Ccl4, Ccl5, Mki67 and Notch3 expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, TGFB2 and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue.
Conclusions: Taken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-β2 silencing and provide a direct rationale for TGF-β2-directed drug development.
Remipedia is a stygobitic group commonly associated with coastal anchialine caves. This class consists of 12 genera, ten of which are found within the Lucayan Archipelago. Herein, we describe a new species within the genus Godzillius from Conch Sound Blue Hole, North Andros Island, Bahamas. Godzillius louriei sp. nov. is the third known remipede observed from a subseafloor marine cave, and the first from the Godzilliidae. Remipedes dwell within notoriously difficult to access cave habitats and thus integrative and comprehensive systematic studies at family or genus level are often absent in the literature. In this study, all species of Godzillius are compared using morphological and molecular approaches. Specifically, the feeding appendages of G. louriei sp. nov., G. fuchsi Gonzalez, Singpiel & Schlagner, 2013 and G. robustus Schram, Yager & Emerson, 1986 were examined using scanning electron microscopy (SEM). Species of Godzillius are identified based on the spines of maxilla 1 segment 4 and by the denticles on the lacinia mobilis of the left mandible. A molecular phylogeny using the mitochondrial 16S rRNA and nuclear histone 3 genes recovered G. louriei sp. nov. within the Godzillius clade and 16S genetic distances revealed a 13–15% difference between species of Godzillius.
Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0–T1: +3.37±2.17%), while non-responders further decreased in methylation (−2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02–0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.
Na,K-ATPase mediates net electrogenic transport by extruding three Na+ ions and importing two K+ ions across the plasma membrane during each reaction cycle. We mutated putative cation coordinating amino acids in transmembrane hairpin M5-M6 of rat Na,K-ATPase: Asp776 (Gln, Asp, Ala), Glu779 (Asp, Gln, Ala), Asp804 (Glu, Asn, Ala), and Asp808 (Glu, Asn, Ala). Electrogenic cation transport properties of these 12 mutants were analyzed in two-electrode voltage-clamp experiments on Xenopus laevis oocytes by measuring the voltage dependence of K+-stimulated stationary currents and pre-steady-state currents under electrogenic Na+/Na+ exchange conditions. Whereas mutants D804N, D804A, and D808A hardly showed any Na+/K+ pump currents, the other constructs could be classified according to the [K+] and voltage dependence of their stationary currents; mutants N776A and E779Q behaved similarly to the wild-type enzyme. Mutants E779D, E779A, D808E, and D808N had in common a decreased apparent affinity for extracellular K+. Mutants N776Q, N776D, and D804E showed large deviations from the wild-type behavior; the currents generated by mutant N776D showed weaker voltage dependence, and the current-voltage curves of mutants N776Q and D804E exhibited a negative slope. The apparent rate constants determined from transient Na+/Na+ exchange currents are rather voltage-independent and at potentials above -60 mV faster than the wild type. Thus, the characteristic voltage-dependent increase of the rate constants at hyperpolarizing potentials is almost absent in these mutants. Accordingly, dislocating the carboxamide or carboxyl group of Asn776 and Asp804, respectively, decreases the extracellular Na+ affinity.
Case report of rare congenital cardiovascular anomalies associated with truncus arteriosus type 2
(2022)
Truncus arteriosus (TA) is a very rare congenital anomaly with complex cardiovascular anatomy and high lethality also due to severe associated anatomical variants and pathologies. As TA has a massive impact on the survival of a newborn and usually has to be surgically treated. Thus, it is of high importance to understand this congenital cardiovascular disease and associated complications, to improve life expectancy and outcome of these patients. We recently came across a newborn female patient with a rare complex case of persistent TA type 2 associated with further complex cardiovascular anomalies, who received a contrast enhanced CT scan on the 3 rd day post-partum, showing complex cardiovascular abnormalities that were ultimately incompatible with life.
Purpose: The purpose of the study is to retrospectively evaluate the development and technological progress in local oncological treatments of hepatocellular carcinoma (HCC) by means of ablation techniques like laser interstitial thermal therapy (LITT), microwave ablation (MWA) and transarterial chemoembolization (TACE) in a multimodal application.
Method: This retrospective single-center study uses data generated between 1993 and 2020 (1,045 patients). Therapy results are evaluated using survival rates of Kaplan-Meier estimator, Cox proportional hazard regression and log-rank test.
Results: Median survival times in group LITT (25 patients) are 1.6 years, and, 2.6 years for LITT + TACE (67 patients). For LITT only treatments 1-/3-/5-year survival rates scored 64%, 24% and 20%. Results for combined LITT + TACE treatments were 84%, 37% and 14%. Median survival time in group MWA (227 patients) is 4.5 years. Estimated median survival time for MWA + TACE (108 patients) leads to a median survival time of 2.7 years. In group MWA the 1-/3-/5-year survival rates are 85%, 54%, 45%. Group MWA + TACE shows values of 79%, 41% and 25%. A separate group of 618 patients has been analyzed with TACE as monotherapy. Median survival time of 1 year was estimated in this group. 1-/3-/5-year survival rates are 48%, 15% and 8%. - Cox regression analysis showed that the different treatment methods are statistically significant predictors for survival of patients.
Conclusions: Treatments with MWA resulted in best median survival rates, followed by MWA + TACE in combination. Survival rates of MWA only are significantly higher vs. LITT, vs. LITT + TACE and vs. TACE monotherapy.
Vaccination represents one of the fundamentals in the fight against SARS-CoV-2. Myocarditis has been reported as a rare but possible adverse consequence of different vaccines, and its clinical presentation can range from mild symptoms to acute heart failure. We report a case of a 29-year-old man who presented with fever and retrosternal pain after receiving SARS-CoV-2 vaccine. Cardiac magnetic resonance imaging and laboratory data revealed typical findings of acute myocarditis.
Objectives: To compare dual-energy CT (DECT) and MRI for assessing presence and extent of traumatic bone marrow edema (BME) and fracture line depiction in acute vertebral fractures. Methods: Eighty-eight consecutive patients who underwent dual-source DECT and 3-T MRI of the spine were retrospectively analyzed. Five radiologists assessed all vertebrae for presence and extent of BME and for identification of acute fracture lines on MRI and, after 12 weeks, on DECT series. Additionally, image quality, image noise, and diagnostic confidence for overall diagnosis of acute vertebral fracture were assessed. Quantitative analysis of CT numbers was performed by a sixth radiologist. Two radiologists analyzed MRI and grayscale DECT series to define the reference standard. Results: For assessing BME presence and extent, DECT showed high sensitivity (89% and 84%, respectively) and specificity (98% in both), and similarly high diagnostic confidence compared to MRI (2.30 vs. 2.32; range 0–3) for the detection of BME (p = .72). For evaluating acute fracture lines, MRI achieved high specificity (95%), moderate sensitivity (76%), and a significantly lower diagnostic confidence compared to DECT (2.42 vs. 2.62, range 0–3) (p < .001). A cutoff value of − 0.43 HU provided a sensitivity of 89% and a specificity of 90% for diagnosing BME, with an overall AUC of 0.96. Conclusions: DECT and MRI provide high diagnostic confidence and image quality for assessing acute vertebral fractures. While DECT achieved high overall diagnostic accuracy in the analysis of BME presence and extent, MRI provided moderate sensitivity and lower confidence for evaluating fracture lines.
Objectives: To investigate the diagnostic accuracy of color-coded contrast-enhanced dual-energy CT virtual noncalcium (VNCa) reconstructions for the assessment of lumbar disk herniation compared to unenhanced VNCa imaging.
Methods: A total of 91 patients were retrospectively evaluated (65 years ± 16; 43 women) who had undergone third-generation dual-source dual-energy CT and 3.0-T MRI within an examination interval up to 3 weeks between November 2019 and December 2020. Eight weeks after assessing unenhanced color-coded VNCa reconstructions for the presence and degree of lumbar disk herniation, corresponding contrast-enhanced portal venous phase color-coded VNCa reconstructions were independently analyzed by the same five radiologists. MRI series were additionally analyzed by one highly experienced musculoskeletal radiologist and served as reference standard.
Results: MRI depicted 210 herniated lumbar disks in 91 patients. VNCa reconstructions derived from contrast-enhanced CT scans showed similar high overall sensitivity (93% vs 95%), specificity (94% vs 95%), and accuracy (94% vs 95%) for the assessment of lumbar disk herniation compared to unenhanced VNCa images (all p > .05). Interrater agreement in VNCa imaging was excellent for both, unenhanced and contrast-enhanced CT (κ = 0.84 vs κ = 0.86; p > .05). Moreover, ratings for diagnostic confidence, image quality, and noise differed not significantly between unenhanced and contrast-enhanced VNCa series (all p > .05).
Conclusions: Color-coded VNCa reconstructions derived from contrast-enhanced dual-energy CT yield similar diagnostic accuracy for the depiction of lumbar disk herniation compared to unenhanced VNCa imaging and therefore may improve opportunistic retrospective lumbar disk herniation assessment, particularly in case of staging CT examinations.
Key Points
• Color-coded dual-source dual-energy CT virtual noncalcium (VNCa) reconstructions derived from portal venous phase yield similar high diagnostic accuracy for the assessment of lumbar disk herniation compared to unenhanced VNCa CT series (94% vs 95%) with MRI serving as a standard of reference.
• Diagnostic confidence, image quality, and noise levels differ not significantly between unenhanced and contrast-enhanced portal venous phase VNCa dual-energy CT series.
• Dual-source dual-energy CT might have the potential to improve opportunistic retrospective lumbar disk herniation assessment in CT examinations performed for other indications through reconstruction of VNCa images.
Objective: To determine the early treatment response after microwave ablation (MWA) of inoperable lung neoplasms using the apparent diffusion coefficient (ADC) value calculated 24 h after the ablation.
Materials and methods: This retrospective study included 47 patients with 68 lung lesions, who underwent percutaneous MWA from January 2008 to December 2017. Evaluation of the lesions was done using MRI including DWI sequence with ADC value calculation pre-ablation and 24 h post-ablation. DWI-MR was performed with b values (50, 400, 800 mm2/s). The post-ablation follow-up was performed using chest CT and/or MRI within 24 h following the procedure; after 3, 6, 9, and 12 months; and every 6 months onwards to determine the local tumor response. The post-ablation ADC value changes were compared to the end response of the lesions.
Results: Forty-seven patients (mean age: 63.8 ± 14.2 years, 25 women) with 68 lesions having a mean tumor size of 1.5 ± 0.9 cm (range: 0.7–5 cm) were evaluated. Sixty-one lesions (89.7%) showed a complete treatment response, and the remaining 7 lesions (10.3%) showed a local progression (residual activity). There was a statistically significant difference regarding the ADC value measured 24 h after the ablation between the responding (1.7 ± 0.3 × 10−3 mm2/s) and non-responding groups (1.4 ± 0.3 × 10−3 mm2/s) with significantly higher values in the responding group (p = 0.001). A suggested ADC cut-off value of 1.42 could be used as a reference point for the post-ablation response prediction (sensitivity: 66.67%, specificity: 84.21%, PPV: 66.7%, and NPV: 84.2%). No significant difference was reported regarding the ADC value performed before the ablation as a factor for the prognosis of treatment response (p = 0.86).
Conclusion: ADC value assessment following ablation may allow the early prediction of treatment efficacy after MWA of inoperable lung neoplasms.
Key Points
• ADC value calculated 24 h post-treatment may allow the early prediction of MWA efficacy as a treatment of pulmonary tumors and can be used in the early immediate post-ablation imaging follow-up.
• The pre-treatment ADC value of lung neoplasms is not different between the responding and non-responding tumors.
Background: The human chromosomal region 9p21.3 has been shown to be strongly associated with Coronary Heart Disease (CHD) in several Genome-wide Association Studies (GWAS). Recently, this region has also been shown to be associated with Aggressive Periodontitis (AgP), strengthening the hypothesis that the established epidemiological association between periodontitis and CHD is caused by a shared genetic background, in addition to common environmental and behavioural risk factors. However, the size of the analyzed cohorts in this primary analysis was small compared to other association studies on complex diseases. Using our own AgP cohort, we attempted to confirm the described associations for the chromosomal region 9p21.3. Methods: We analyzed our cohort consisting of patients suffering from the most severe form of AgP, generalized AgP (gAgP) (n = 130) and appropriate periodontally healthy control individuals (n = 339) by genotyping four tagging SNPs (rs2891168, rs1333042, rs1333048 and rs496892), located in the chromosomal region 9p21.3, that have been associated with AgP. Results: The results confirmed significant associations between three of the four SNPs and gAgP. The combination of our results with those from the study which described this association for the first time in a meta-analysis of the four tagging SNPs produced clearly lower p-values compared with the results of each individual study. According to these results, the most plausible genetic model for the association of all four tested SNPs with gAgP seems to be the multiplicative one. Conclusion: We positively replicated the finding of an association between the chromosomal region 9p21.3 and gAgP. This result strengthens support for the hypothesis that shared susceptibility genes within this chromosomal locus might be involved in the pathogenesis of both CHD and gAgP.
Aims: The primary safety and efficacy endpoints of the randomized FIRE AND ICE trial have recently demonstrated non-inferiority of cryoballoon vs. radiofrequency current (RFC) catheter ablation in patients with drug-refractory symptomatic paroxysmal atrial fibrillation (AF). The aim of the current study was to assess outcome parameters that are important for the daily clinical management of patients using key secondary analyses. Specifically, reinterventions, rehospitalizations, and quality-of-life were examined in this randomized trial of cryoballoon vs. RFC catheter ablation.
Methods and results: Patients (374 subjects in the cryoballoon group and 376 subjects in the RFC group) were evaluated in the modified intention-to-treat cohort. After the index ablation, log-rank testing over 1000 days of follow-up demonstrated that there were statistically significant differences in favour of cryoballoon ablation with respect to repeat ablations (11.8% cryoballoon vs. 17.6% RFC; P = 0.03), direct-current cardioversions (3.2% cryoballoon vs. 6.4% RFC; P = 0.04), all-cause rehospitalizations (32.6% cryoballoon vs. 41.5% RFC; P = 0.01), and cardiovascular rehospitalizations (23.8% cryoballoon vs. 35.9% RFC; P < 0.01). There were no statistical differences between groups in the quality-of-life surveys (both mental and physical) as measured by the Short Form-12 health survey and the EuroQol five-dimension questionnaire. There was an improvement in both mental and physical quality-of-life in all patients that began at 6 months after the index ablation and was maintained throughout the 30 months of follow-up.
Conclusion: Patients treated with cryoballoon as opposed to RFC ablation had significantly fewer repeat ablations, direct-current cardioversions, all-cause rehospitalizations, and cardiovascular rehospitalizations during follow-up. Both patient groups improved in quality-of-life scores after AF ablation.
Clinical trial registration: ClinicalTrials.gov identifier: NCT01490814.
Modelling short-term variability in carbon and water exchange in a temperate Scots pine forest
(2015)
The vegetation–atmosphere carbon and water exchange at one particular site can strongly vary from year to year, and understanding this interannual variability in carbon and water exchange (IAVcw) is a critical factor in projecting future ecosystem changes. However, the mechanisms driving this IAVcw are not well understood. We used data on carbon and water fluxes from a multi-year eddy covariance study (1997–2009) in a Dutch Scots pine forest and forced a process-based ecosystem model (Lund–Potsdam–Jena General Ecosystem Simulator; LPJ-GUESS) with local data to, firstly, test whether the model can explain IAVcw and seasonal carbon and water exchange from direct environmental factors only. Initial model runs showed low correlations with estimated annual gross primary productivity (GPP) and annual actual evapotranspiration (AET), while monthly and daily fluxes showed high correlations. The model underestimated GPP and AET during winter and drought events. Secondly, we adapted the temperature inhibition function of photosynthesis to account for the observation that at this particular site, trees continue to assimilate at very low atmospheric temperatures (up to daily averages of −10 °C), resulting in a net carbon sink in winter. While we were able to improve daily and monthly simulations during winter by lowering the modelled minimum temperature threshold for photosynthesis, this did not increase explained IAVcw at the site. Thirdly, we implemented three alternative hypotheses concerning water uptake by plants in order to test which one best corresponds with the data. In particular, we analyse the effects during the 2003 heatwave. These simulations revealed a strong sensitivity of the modelled fluxes during dry and warm conditions, but no single formulation was consistently superior in reproducing the data for all timescales and the overall model–data match for IAVcw could not be improved. Most probably access to deep soil water leads to higher AET and GPP simulated during the heatwave of 2003. We conclude that photosynthesis at lower temperatures than assumed in most models can be important for winter carbon and water fluxes in pine forests. Furthermore, details of the model representations of water uptake, which are often overlooked, need further attention, and deep water access should be treated explicitly.
The mirine plant bug Tropidosteptes forestierae, new species (Hemiptera: Miridae) is described from
Collier County, Florida, where it was found causing serious injury to an extensive ornamental hedge of Florida swampprivet, Forestiera segregata (Jacq.) Krug and Urb. (Oleaceae). Adult male and female, fifth instar, and egg are described. Color images of the adults, nymph, egg, and injury; scanning photomicrographs of selected adult structures; and illustrations of male genitalia are provided. A key to help distinguish the 16 species of Tropidosteptes known to occur in the southeastern United States is given.
Lichen-forming fungi are symbiotic organisms that synthesize unique natural products with potential for new drug leads. Here, we explored the pharmacological activity of six lichen extracts (Evernia prunastri, Pseudevernia furfuracea, Umbilicaria pustulata, Umbilicaria crustulosa, Flavoparmelia caperata, Platismatia glauca) in the context of cancer and inflammation using a comprehensive set of 11 functional and biochemical in vitro screening assays. We assayed intracellular Ca2+ levels and cell migration. For cancer, we measured tumor cell proliferation, cell cycle distribution and apoptosis, as well as the angiogenesis-associated proliferation of endothelial cells (ECs). Targeting inflammation, we assayed leukocyte adhesion onto ECs, EC adhesion molecule expression, as well as nitric oxide production and prostaglandin (PG)E2 synthesis in leukocytes. Remarkably, none of the lichen extracts showed any detrimental influence on the viability of ECs. We showed for the first time that extracts of F. caperata induce Ca2+ signaling. Furthermore, extracts from E. prunastri, P. furfuracea, F. caperata, and P. glauca reduced cell migration. Interestingly, F. caperata extracts strongly decreased tumor cell survival. The proliferation of ECs was significantly reduced by E. prunastri, P. furfuracea, and F. caperata extracts. The extracts did not inhibit the activity of inflammatory processes in ECs. However, the pro-inflammatory activation of leukocytes was inhibited by extracts from E. prunastri, P. furfuracea, F. caperata, and P. glauca. After revealing the potential biological activities of lichen extracts by an array of screening tests, a correlation analysis was performed to evaluate particular roles of abundant lichen secondary metabolites, such as atranorin, physodic acid, and protocetraric acid as well as usnic acid in various combinations. Overall, some of the lichen extracts tested in this study exhibit significant pharmacological activity in the context of inflammation and/or cancer, indicating that the group lichen-forming fungi includes promising members for further testing.
High-resolution cryo-EM structures of respiratory complex I: Mechanism, assembly, and disease
(2019)
Respiratory complex I is a redox-driven proton pump, accounting for a large part of the electrochemical gradient that powers mitochondrial adenosine triphosphate synthesis. Complex I dysfunction is associated with severe human diseases. Assembly of the one-megadalton complex I in the inner mitochondrial membrane requires assembly factors and chaperones. We have determined the structure of complex I from the aerobic yeast Yarrowia lipolytica by electron cryo-microscopy at 3.2-Å resolution. A ubiquinone molecule was identified in the access path to the active site. The electron cryo-microscopy structure indicated an unusual lipid-protein arrangement at the junction of membrane and matrix arms that was confirmed by molecular simulations. The structure of a complex I mutant and an assembly intermediate provide detailed molecular insights into the cause of a hereditary complex I-linked disease and complex I assembly in the inner mitochondrial membrane.
While interleukin (IL)-1β is a potent pro-inflammatory cytokine involved in host defense, high levels can cause life-threatening sterile inflammation including systemic inflammatory response syndrome. Hence, the control of IL-1β secretion is of outstanding biomedical importance. In response to a first inflammatory stimulus such as lipopolysaccharide, pro-IL-1β is synthesized as a cytoplasmic inactive pro-form. Extracellular ATP originating from injured cells is a prototypical second signal for inflammasome-dependent maturation and release of IL-1β. The human anti-protease alpha-1 antitrypsin (AAT) and IL-1β regulate each other via mechanisms that are only partially understood. Here, we demonstrate that physiological concentrations of AAT efficiently inhibit ATP-induced release of IL-1β from primary human blood mononuclear cells, monocytic U937 cells, and rat lung tissue, whereas ATP-independent IL-1β release is not impaired. Both, native and oxidized AAT are active, suggesting that the inhibition of IL-1β release is independent of the anti-elastase activity of AAT. Signaling of AAT in monocytic cells involves the lipid scavenger receptor CD36, calcium-independent phospholipase A2β, and the release of a small soluble mediator. This mediator leads to the activation of nicotinic acetylcholine receptors, which efficiently inhibit ATP-induced P2X7 receptor activation and inflammasome assembly. We suggest that AAT controls ATP-induced IL-1β release from human mononuclear blood cells by a novel triple-membrane-passing signaling pathway. This pathway may have clinical implications for the prevention of sterile pulmonary and systemic inflammation.
The change in allele frequencies within a population over time represents a fundamental process of evolution. By monitoring allele frequencies, we can analyze the effects of natural selection and genetic drift on populations. To efficiently track time-resolved genetic change, large experimental or wild populations can be sequenced as pools of individuals sampled over time using high-throughput genome sequencing (called the Evolve & Resequence approach, E&R). Here, we present a set of experiments using hundreds of natural genotypes of the model plant Arabidopsis thaliana to showcase the power of this approach to study rapid evolution at large scale. First, we validate that sequencing DNA directly extracted from pools of flowers from multiple plants -- organs that are relatively consistent in size and easy to sample -- produces comparable results to other, more expensive state-of-the-art approaches such as sampling and sequencing of individual leaves. Sequencing pools of flowers from 25-50 individuals at ∼40X coverage recovers genome-wide frequencies in diverse populations with accuracy r > 0.95. Secondly, to enable analyses of evolutionary adaptation using E&R approaches of plants in highly replicated environments, we provide open source tools that streamline sequencing data curation and calculate various population genetic statistics two orders of magnitude faster than current software. To directly demonstrate the usefulness of our method, we conducted a two-year outdoor evolution experiment with A. thaliana to show signals of rapid evolution in multiple genomic regions. We demonstrate how these laboratory and computational Pool-seq-based methods can be scaled to study hundreds of populations across many climates.
The aim of this study was to detect a response difference in primary (PLC) and secondary liver tumors (SLC) with magnetic resonance elastography (MRE) after TACE therapy. Thirty-one patients (25/31 male; mean age 69.6 years [range: 39–85 years]) with repeated TACE therapy of HCC were compared with twenty-seven patients (27/27 female; mean age 61.2 years [range 39–81 years]) with repeated TACE therapy of metastatic liver disease due to breast cancer. Both groups underwent either one (n = 31) or two (n = 27) repetitive magnetic resonance imaging (MRI) and MRE exams in 4- to 6-week intervals using a 1.5-T-scanner. MRE-based liver stiffness and size measurements were evaluated in tumorous lesions and in healthy liver lobe controls. PLC showed a significantly larger tumor size compared to SLC (26.4 cm2 vs. 11 cm2, p = 0.007) and a higher degree of stiffness (5.8 kPa vs. 5.1 kPa, p = 0.04). Both tumors decreased in size during the cycles (PLC: p = 0.8 and SLC: p < 0.0001) and lesions showed an increase in stiffness (PLC: p = 0.002 and SLC: p = 0.006). MRE demonstrates that PLC and SLC have similar responses to TACE therapy. PLC had a greater increase in stiffness and SLC got smaller. An increasing stiffness and decrease in size could show a good response.
Dr. Heiner Schnelling (58) ist Anglist und Germanist. Zuletzt Leiter der Universitätt- und Landesbibiiothek in Halle an der Saale, wird er zum 1. Oktober Nachfolger von Dr. Berndt Dugall als Leiter der Unibibliothek Frankfurt. Thomas J. Schmidt hat mit ihm über den Umzug der UB und die Zukunft des Buchs gesprochen.
Background: Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography.
Methods: In a systematic review of OVID MEDLINE—with additional hand-searching of relevant studies' bibliographies— from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5–24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known.
Findings: Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56–76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36–0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46–11·60; p<0·0001), antiplatelet use (1·68, 1·06–2·66; p=0·026), and anticoagulant use (3·48, 1·96–6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75–0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95–6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03–0·07).
Interpretation: In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials.
Funding: UK Medical Research Council and British Heart Foundation.
Iran is a huge but understudied Middle Eastern country with a rich but chronically understudied bee fauna, including for the highly-speciose bee genus Andrena. Examination of unidentified museum material combined with recent field collections and a critical review of the literature has revealed a total of 197 species of Andrena in the Iranian fauna, of which 65 are newly reported for the country, with an additional 16 species new for science. Andrena (Aciandrena) deminuta Wood sp. nov., Andrena (Euandrena) boustaniae Wood sp. nov., Andrena (Euandrena) oblata sp. nov., Andrena (Euandrena) sani sp. nov., Andrena (Micrandrena) elam Wood sp. nov., Andrena (Micrandrena) subviridula Wood sp. nov., Andrena (Notandrena) idigna Wood sp. nov., Andrena (Planiandrena) flagrans Wood sp. nov., Andrena (Planiandrena) sella Wood sp. nov., Andrena (Ulandrena) bulbosa Wood sp. nov., Andrena (incertae sedis) hosseiniiae Wood & Monfared sp. nov., and Andrena (incertae sedis) rostamiae sp. nov. are described from Iran, Andrena (Micrandrena) extenuata sp. nov. is described from Iran and Syria, Andrena (Micrandrena) tabula Wood sp. nov. and Andrena (Micrandrena) obsidiana Wood sp. nov. are described from Iran and Turkey, and Andrena (Planiandrena) huma sp. nov. is described from Iran, Syria, and the Golan Heights. Eight taxa are synonymised (valid name first): Andrena (Melandrena) assimilis Radoszkowski, 1876 = Andrena (Melandrena) gallica Schmiedeknecht, 1883 syn. nov.; Andrena (Notandrena) emesiana Pérez, 1911 stat. resurr. = Andrena (Notandrena) recurvirostra Warncke, 1975 syn. nov.; Andrena (Plastandrena) eversmanni Radoszkowski, 1867 = Andrena (Plastandrena) peshinica Nurse, 1904 syn. nov.; Andrena (incertae sedis) hieroglyphica Morawitz, 1876 = Andrena (Carandrena) cara Nurse, 1904 syn. nov. and Andrena (Carandrena) halictoides Nurse, 1904 syn. nov.; Andrena (Melandrena) induta Morawitz, 1894 = Andrena (Melandrena) patella Nurse, 1903 syn. nov.; Andrena (incertae sedis) minor Warncke, 1975 stat. nov. = Andrena (Carandrena) splendula Osytshnjuk, 1984 syn. nov.; Andrena (Notandrena) zostera Warncke, 1975 = Andrena (Carandrena) subsmaragdina Osytshnjuk, 1984 syn. nov. Overall, these results considerably improve our understanding of the Iranian Andrena fauna, and suggest that overall bee diversity in this country is substantially more than 1000 species.
Chlamydia are obligate intracellular bacteria that cause variety of human diseases. Host cells infected with Chlamydia are protected against many different apoptotic stimuli. The induction of apoptosis resistance is thought to be an important immune escape mechanism allowing Chlamydia to replicate inside the host cell. Infection with C. trachomatis activates the Raf/MEK/ERK pathway and the PI3K/AKT pathway. Here we show that inhibition of these two pathways by chemical inhibitors sensitized C. trachomatis infected cells to granzyme B-mediated cell death. Infection leads to the Raf/MEK/ERK-mediated up-regulation and PI3K-dependent stabilization of the anti-apoptotic Bcl-2 family member Mcl-1. Consistently, interfering with Mcl-1 up-regulation sensitized infected cells for apoptosis induced via the TNF receptor, DNA damage, granzyme B and stress. Our data suggest that Mcl-1 up-regulation is primarily required to maintain apoptosis resistance in C. trachomatis-infected cells.
Bibliothek statt Tankstelle : Dezernent bringt neuen Standort für Uni-Bibliothek ins Gespräch
(2018)
Correlation of lumbar lateral recess stenosis in magnetic resonance imaging and clinical symptoms
(2017)
Aim: To assess the correlation of lateral recess stenosis (LRS) of lumbar segments L4/5 and L5/S1 and the Oswestry Disability Index (ODI).
Methods: Nine hundred and twenty-seven patients with history of low back pain were included in this uncontrolled study. On magnetic resonance images (MRI) the lateral recesses (LR) at lumbar levels L4/5 and L5/S1 were evaluated and each nerve root was classified into a 4-point grading scale (Grade 0-3) as normal, not deviated, deviated or compressed. Patient symptoms and disability were assessed using ODI. The Spearman’s rank correlation coefficient was used for statistical analysis (P < 0.05).
Results: Approximately half of the LR revealed stenosis (grade 1-3; 52% at level L4/5 and 42% at level L5/S1) with 2.2% and 1.9% respectively reveal a nerve root compression. The ODI score ranged from 0%-91.11% with an arithmetic mean of 34.06% ± 16.89%. We observed a very weak statistically significant positive correlation between ODI and LRS at lumbar levels L4/5 and L5/S1, each bilaterally (L4/5 left: rho < 0.105, P < 0.01; L4/5 right: rho < 0.111, P < 0.01; L5/S1 left: rho 0.128, P < 0.01; L5/S1 right: rho < 0.157, P < 0.001).
Conclusion: Although MRI is the standard imaging tool for diagnosing lumbar spinal stenosis, this study showed only a weak correlation of LRS on MRI and clinical findings. This can be attributed to a number of reasons outlined in this study, underlining that imaging findings alone are not sufficient to establish a reliable diagnosis for patients with LRS.