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Cardiac rehabilitation (CR) is a multidisciplinary intervention including patient assessment and medical actions to promote stabilization, management of cardiovascular risk factors, vocational support, psychosocial management, physical activity counselling, and prescription of exercise training. Millions of people with cardiac implantable electronic devices live in Europe and their numbers are progressively increasing, therefore, large subsets of patients admitted in CR facilities have a cardiac implantable electronic device. Patients who are cardiac implantable electronic devices recipients are considered eligible for a CR programme. This is not only related to the underlying heart disease but also to specific issues, such as psychological adaptation to living with an implanted device and, in implantable cardioverter-defibrillator patients, the risk of arrhythmia, syncope, and sudden cardiac death. Therefore, these patients should receive special attention, as their needs may differ from other patients participating in CR. As evidence from studies of CR in patients with cardiac implantable electronic devices is sparse, detailed clinical practice guidelines are lacking. Here, we aim to provide practical recommendations for CR in cardiac implantable electronic devices recipients in order to increase CR implementation, efficacy, and safety in this subset of patients.
Objectives: To compare radiation dose and image quality of single-energy (SECT) and dual-energy (DECT) head and neck CT examinations performed with second- and third-generation dual-source CT (DSCT) in matched patient cohorts. Methods: 200 patients (mean age 55.1 ± 16.9 years) who underwent venous phase head and neck CT with a vendor-preset protocol were retrospectively divided into four equal groups (n = 50) matched by gender and BMI: second (Group A, SECT, 100-kV; Group B, DECT, 80/Sn140-kV), and third-generation DSCT (Group C, SECT, 100-kV; Group D, DECT, 90/Sn150-kV). Assess- ment of radiation dose was performed for an average scan length of 27 cm. Contrast-to-noise ratio measure- ments and dose-independent figure-of-merit calcu- lations of the submandibular gland, thyroid, internal jugular vein, and common carotid artery were analyzed quantitatively. Qualitative image parameters were evalu- ated regarding overall image quality, artifacts and reader confidence using 5-point Likert scales. Results: Effective radiation dose (ED) was not signifi- cantly different between SECT and DECT acquisition for each scanner generation (p = 0.10). Significantly lower effective radiation dose (p < 0.01) values were observed for third-generation DSCT groups C (1.1 ± 0.2 mSv) and D (1.0 ± 0.3 mSv) compared to second-generation DSCT groups A (1.8 ± 0.1 mSv) and B (1.6 ± 0.2 mSv). Figure-of- merit/contrast-to-noise ratio analysis revealed superior results for third-generation DECT Group D compared to all other groups. Qualitative image parameters showed non-significant differences between all groups (p > 0.06). Conclusion: Contrast-enhanced head and neck DECT can be performed with second- and third-generation DSCT systems without radiation penalty or impaired image quality compared with SECT, while third-generation DSCT is the most dose efficient acquisition method. Advances in knowledge: Differences in radiation dose between SECT and DECT of the dose-vulnerable head and neck region using DSCT systems have not been evaluated so far. Therefore, this study directly compares radiation dose and image quality of standard SECT and DECT protocols of second- and third-generation DSCT platforms.
Objectives: To determine the diagnostic accuracy of dual-energy CT (DECT) virtual noncalcium (VNCa) reconstructions for assessing thoracic disk herniation compared to standard grayscale CT. Methods: In this retrospective study, 87 patients (1131 intervertebral disks; mean age, 66 years; 47 women) who underwent third-generation dual-source DECT and 3.0-T MRI within 3 weeks between November 2016 and April 2020 were included. Five blinded radiologists analyzed standard DECT and color-coded VNCa images after a time interval of 8 weeks for the presence and degree of thoracic disk herniation and spinal nerve root impingement. Consensus reading of independently evaluated MRI series served as the reference standard, assessed by two separate experienced readers. Additionally, image ratings were carried out by using 5-point Likert scales. Results: MRI revealed a total of 133 herniated thoracic disks. Color-coded VNCa images yielded higher overall sensitivity (624/665 [94%; 95% CI, 0.89–0.96] vs 485/665 [73%; 95% CI, 0.67–0.80]), specificity (4775/4990 [96%; 95% CI, 0.90–0.98] vs 4066/4990 [82%; 95% CI, 0.79–0.84]), and accuracy (5399/5655 [96%; 95% CI, 0.93–0.98] vs 4551/5655 [81%; 95% CI, 0.74–0.86]) for the assessment of thoracic disk herniation compared to standard CT (all p < .001). Interrater agreement was excellent for VNCa and fair for standard CT (ϰ = 0.82 vs 0.37; p < .001). In addition, VNCa imaging achieved higher scores regarding diagnostic confidence, image quality, and noise compared to standard CT (all p < .001). Conclusions: Color-coded VNCa imaging yielded substantially higher diagnostic accuracy and confidence for assessing thoracic disk herniation compared to standard CT.
The objective of this pilot clinical study was to assess the safety, technical feasibility, pharmacokinetic (PK) profile and tumour response of DC Bead™ with irinotecan (DEBIRI™) delivered by intra-arterial embolisation for the treatment of metastatic colorectal cancer. Eleven patients with unresectable liver metastases from CRC, tumour burden <30% of liver volume, adequate haematological, liver and renal function, performance status of <2 were included in this study. Patients received up to 4 sessions of TACE with DEBIRI at 3-week intervals. Feasibility of the procedure, safety and tumour response were assessed after each cycle. PK was measured after the first cycle. Patients were followed up to 24 weeks. Only mild to moderate adverse events were observed. DEBIRI is a technically feasibile procedure; no technical complications were observed. Average Cmax for irinotecan and SN-38 was 194 ng/ml and 16.7 ng/ml, respectively, with average t½ of 4.6 h and 12.4 h following administration of DEBIRI. Best overall response during the study showed disease control in 9 patients (2 patients with partial response and 7 with stable disease, overall response rate of 18%). Our study shows that transarterial chemoembolisation with irinotecan-loaded DC beads (DEBIRI) is safe, technically feasible and effective with a good PK profile.
Rationale: Early reperfusion in patients experiencing acute ischemic stroke is critical, especially for patients with large vessel occlusion who have poor prognosis without revascularization. S olitaire™ stent retriever devices have been shown to immediately restore vascular perfusion safely, rapidly, and effectively in acute ischemic stroke patients with large vessel occlusions.
Aim: The aim of the study was to demonstrate that, among patients with large vessel, anterior circulation occlusion who have received intravenous tissue plasminogen activator, treatment with S olitaire revascularization devices reduces degree of disability 3 months post stroke.
Design: The study is a global multicenter, two‐arm, prospective, randomized, open, blinded end‐point trial comparing functional outcomes in acute ischemic stroke patients who are treated with either intravenous tissue plasminogen activator alone or intravenous tissue plasminogen activator in combination with the Solitaire device. Up to 833 patients will be enrolled.
Procedures:Patients who have received intravenous tissue plasminogen activator are randomized to either continue with intravenous tissue plasminogen activator alone or additionally proceed to neurothrombectomy using the S olitaire device within six‐hours of symptom onset.
Study Outcomes: The primary end‐point is 90‐day global disability, assessed with the modified R ankin S cale (mRS). Secondary outcomes include mortality at 90 days, functional independence (mRS ≤ 2) at 90 days, change in N ational I nstitutes of H ealth S troke S cale at 27 h, reperfusion at 27 h, and thrombolysis in cerebral infarction 2b/3 flow at the end of the procedure.
Analysis:Statistical analysis will be conducted using simultaneous success criteria on the overall distribution of modified R ankin S cale (R ankin shift) and proportions of subjects achieving functional independence (mRS 0–2).
Background: Computed tomography of the head (HCT) is a widely used diagnostic tool, especially for emergency and trauma patients. However, the diagnostic yield and outcomes of HCT for patients on medical intensive care units (MICUs) are largely unknown.
Methods: We retrospectively evaluated all head CTs from patients admitted to a single-center MICU during a 5-year period for CT indications, diagnostic yield, and therapeutic consequences. Uni- and multivariate analyses for the evaluation of risk factors for positive head CT were conducted.
Results: Six hundred ninety (18.8%) of all patients during a 5-year period underwent HCT; 78.7% had negative CT results, while 21.3% of all patients had at least 1 new pathological finding. The main indication for acquiring CT scan of the head was an altered mental state (AMS) in 23.5%, followed by a new focal neurology in 20.7% and an inadequate wake up after stopping sedation in 14.9% of all patients. The most common new finding was intracerebral bleeding in 6.4%. In 6.7%, the CT scan itself led to a change of therapy of any kind. Admission after resuscitation or a new focal neurology were independent predictors of a positive CT. Psychic alteration and AMS were both independent predictors of a higher chance of a negative head CT. Positive HCT during MICU is an independent predictor of lower survival.
Conclusions: New onset of focal neurologic deficit seems to be a good predictor for a positive CT, while AMS and psychic alterations seem to be very poor predictors. A positive head CT is an independent predictor of death for MICU patients.
Borrelia burgdorferi sensu lato (Bbsl), the causative agent of Lyme disease, establishes an initial infection in the host’s skin following a tick bite, and then disseminates to distant organs, leading to multisystem manifestations. Tick-to-vertebrate host transmission requires that Bbsl survives during blood feeding. Complement is an important innate host defense in blood and interstitial fluid. Bbsl produces a polymorphic surface protein, CspA, that binds to a complement regulator, Factor H (FH) to block complement activation in vitro. However, the role that CspA plays in the Bbsl enzootic cycle remains unclear. In this study, we demonstrated that different CspA variants promote spirochete binding to FH to inactivate complement and promote serum resistance in a host-specific manner. Utilizing a tick-to-mouse transmission model, we observed that a cspA-knockout B. burgdorferi is eliminated from nymphal ticks in the first 24 hours of feeding and is unable to be transmitted to naïve mice. Conversely, ectopically producing CspA derived from B. burgdorferi or B. afzelii, but not B. garinii in a cspA-knockout strain restored spirochete survival in fed nymphs and tick-to-mouse transmission. Furthermore, a CspA point mutant, CspA-L246D that was defective in FH-binding, failed to survive in fed nymphs and at the inoculation site or bloodstream in mice. We also allowed those spirochete-infected nymphs to feed on C3-/- mice that lacked functional complement. The cspA-knockout B. burgdorferi or this mutant strain complemented with cspA variants or cspA-L246D was found at similar levels as wild type B. burgdorferi in the fed nymphs and mouse tissues. These novel findings suggest that the FH-binding activity of CspA protects spirochetes from complement-mediated killing in fed nymphal ticks, which ultimately allows Bbsl transmission to mammalian hosts.
Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers.
Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment.
Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.
Purpose: To investigate the diagnostic performance of noise-optimized virtual monoenergetic images (VMI+) in dual-energy CT (DECT) of portal vein thrombosis (PVT) compared to standard reconstructions. Method: This retrospective, single-center study included 107 patients (68 men; mean age, 60.1 ± 10.7 years) with malignant or cirrhotic liver disease and suspected PVT who had undergone contrast-enhanced portal-phase DECT of the abdomen. Linearly blended (M_0.6) and virtual monoenergetic images were calculated using both standard VMI and noise-optimized VMI+ algorithms in 20 keV increments from 40 to 100 keV. Quantitative measurements were performed in the portal vein for objective contrast-to-noise ratio (CNR) calculation. The image series showing the greatest CNR were further assessed for subjective image quality and diagnostic accuracy of PVT detection by two blinded radiologists. Results: PVT was present in 38 subjects. VMI+ reconstructions at 40 keV revealed the best objective image quality (CNR, 9.6 ± 4.3) compared to all other image reconstructions (p < 0.01). In the standard VMI series, CNR peaked at 60 keV (CNR, 4.7 ± 2.1). Qualitative image parameters showed the highest image quality rating scores for the 60 keV VMI+ series (median, 4) (p ≤ 0.03). The greatest diagnostic accuracy for the diagnosis of PVT was found for the 40 keV VMI+ series (sensitivity, 96%; specificity, 96%) compared to M_0.6 images (sensitivity, 87%; specificity, 92%), 60 keV VMI (sensitivity, 87%; specificity, 97%), and 60 keV VMI+ reconstructions (sensitivity, 92%; specificity, 97%) (p ≤ 0.01). Conclusions: Low-keV VMI+ reconstructions resulted in significantly improved diagnostic performance for the detection of PVT compared to other DECT reconstruction algorithms.
Objective: The aim of this study was to assess the potential risk of gadobutrol-enhanced magnetic resonance imaging (MRI) in patients with moderate to severe renal impairment for the development of nephrogenic systemic fibrosis (NSF).
Materials and Methods: We performed a prospective, international, multicenter, open-label study in 55 centers. Patients with moderate to severe renal impairment scheduled for any gadobutrol-enhanced MRI were included. All patients received a single intravenous bolus injection of gadobutrol at a dose of 0.1 mmol/kg body weight. The primary target variable was the number of patients who develop NSF within a 2-year follow-up period.
Results: A total of 908 patients were enrolled, including 586 with moderate and 284 with severe renal impairment who are at highest risk for developing NSF. The mean time since renal disease diagnosis was 1.83 and 5.49 years in the moderate and severe renal impairment cohort, respectively. Overall, 184 patients (20.3%) underwent further contrast-enhanced MRI with other gadolinium-based contrast agents within the 2-year follow-up. No patient developed symptoms conclusive of NSF.
Conclusions: No safety concerns with gadobutrol in patients with moderate to severe renal impairment were identified. There were no NSF cases.
Based on neurofeedback (NF) training as a neurocognitive treatment in attention-deficit/hyperactivity disorder (ADHD), we designed a randomized, controlled functional near-infrared spectroscopy (fNIRS) NF intervention embedded in an immersive virtual reality classroom in which participants learned to control overhead lighting with their dorsolateral prefrontal brain activation. We tested the efficacy of the intervention on healthy adults displaying high impulsivity as a sub-clinical population sharing common features with ADHD. Twenty participants, 10 in an experimental and 10 in a shoulder muscle-based electromyography control group, underwent eight training sessions across 2 weeks. Training was bookended by a pre- and post-test including go/no-go, n-back, and stop-signal tasks (SST). Results indicated a significant reduction in commission errors on the no-go task with a simultaneous increase in prefrontal oxygenated hemoglobin concentration for the experimental group, but not for the control group. Furthermore, the ability of the subjects to gain control over the feedback parameter correlated strongly with the reduction in commission errors for the experimental, but not for the control group, indicating the potential importance of learning feedback control in moderating behavioral outcomes. In addition, participants of the fNIRS group showed a reduction in reaction time variability on the SST. Results indicate a clear effect of our NF intervention in reducing impulsive behavior possibly via a strengthening of frontal lobe functioning. Virtual reality additions to conventional NF may be one way to improve the ecological validity and symptom-relevance of the training situation, hence positively affecting transfer of acquired skills to real life.
Background and aims: Spontaneous bacterial peritonitis (SBP) is a severe complication of decompensated cirrhosis. The prevalence of multidrug-resistant organisms (MDROs) in patients with cirrhosis is increasing. Identification of patients at risk for SBP due to MDROs (ie, SBP with the evidence of MDROs or Stenotrophomonas maltophilia in ascitic culture, MDRO-SBP) is crucial to the early adaptation of antibiotic treatment in such patients. We therefore investigated whether MDROs found in ascitic cultures can also be found in specimens determined by noninvasive screening procedures.
Patients and methods: This retrospective study was conducted at the liver center of the University Hospital Frankfurt, Germany. Between 2011 and 2016, patients with cirrhosis were included upon diagnosis of SBP and sample collection of aerobic/anaerobic ascitic cultures. Furthermore, the performance of at least one complete MDRO screening was mandatory for study inclusion.
Results: Of 133 patients diagnosed with SBP, 75 (56.4%) had culture-positive SBP and 22 (16.5%) had MDRO-SBP. Multidrug-resistant Escherichia coli (10/22; 45.5%) and vancomycin-resistant enterococci (7/22; 36.4%) resembled the major causatives of MDRO-SBP. Rectal swabs identified MDROs in 17 of 22 patients (77.3%) who developed MDRO-SBP with a time-dependent sensitivity of 77% and 87% after 30 and 90 days upon testing, while negative predictive value was 83% and 76%, respectively. The majority of patients were included from intensive care unit or intermediate care unit.
Conclusion: MDRO screening may serve as a noninvasive diagnostic tool to identify patients at risk for MDRO-SBP. Patients with decompensated cirrhosis should be screened for MDROs from the first day of inpatient treatment onward.
Intestinal carriage of multidrug-resistant bacteria among healthcare professionals in Germany
(2017)
Healthcare professionals (HCP) might be at increased risk of acquisition of multidrug-resistant bacteria (MDRB), i.e., methillicin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and multidrug-resistant gram-negative bacteria (MDRGN) and could be an unidentified source of MDRB transmission.
The aim of this study was to determine the prevalence as well as risk factors of MDRB colonization among HCP.
HCP (n=107) taking part in an antibiotic stewardship program, were voluntarily recruited to perform a rectal swab and to fill in a questionnaire to identify risk factors of MDRB carriage, i.e. being physician, gender, travel abroad within the previous 12 months, vegetarianism, regular consumption of raw meat, contact to domestic animals, household members with contact to livestock, work or fellowship abroad, as well as medical treatment abroad and antibiotic therapy within the previous 12 months.
Selective solid media were used to determine the colonization rate with MRSA, VRE and MDRGN. MDRGN were further characterized by molecular analysis of underlying β-lactamases.
None of the participants had an intestinal colonization with MRSA or VRE. 3.7% of the participants were colonized with extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, predominantly blaCTX-M type. Neither additional flouroquinolone resistance nor carbapenem resistance was detected in any of these isolates. No risk factors were identified to have a significant impact of MDRB carriage among HCP.
A colonization rate of 3.7% with ESBL-producing Enterobacteriaceae is of interest, but comparing it to previously published data with similar colonization rates in the healthy population in the same geographic area, it is probably less an occupational risk.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers potential cure to acute myeloid leukemia (AML) patients. However, infections with commensal bacteria are an important cause for non-relapse mortality (NRM). We have previously described the impact of multidrug-resistant organism (MDRO) colonization on the survival of allo-HSCT patients. In the aforementioned publication, according to consensus, we there did not consider the opportunistic gram-negative bacterium Stenotrophomonas maltophilia (S. maltophilia) to be an MDRO. Since rate of S. maltophilia colonization is increasing, and it is not known whether this poses a risk for allo-HSCT patients, we here analyzed here its effect on the previously described and now extended patient cohort. We report on 291 AML patients undergoing allo-HSCT. Twenty of 291 patients (6.9%) were colonized with S. maltophilia. Colonized patients did not differ from non-colonized patients with respect to their age, remission status before allo-HSCT, donor type and HSCT-comorbidity index. S. maltophilia colonized patients had a worse overall survival (OS) from 6 months up to 60 months (85% vs. 88.1% and 24.7% vs. 59.7%; p = 0.007) due to a higher NRM after allo-HSCT (6 months: 15% vs. 4.8% and 60 months: 40.1% vs. 16.2% p = 0.003). The main cause of mortality in colonized patients was infection (46.2% of all deaths) and in non-colonized patients relapse (58.8% of all deaths). 5/20 colonized patients developed an invasive infection with S. maltophilia. The worse OS after allo-HSCT due to higher infection related mortality might implicate the screening of allo-HSCT patients for S. maltophilia and a closer observation of colonized patients as outpatients.
A case of Lymphangioleiomyomatosis (LAM) of the lung in a patient with a history of breast cancer
(2019)
Background: Lymphangioleiomyomatosis (LAM) is a rare progressive cystic and nodular disease of the lung characterized by smooth muscle cell proliferation. LAM predominantly affects young premenopausal women. This report is of a case of LAM presenting in a 47-year-old woman with a past history of breast cancer and discusses the possibility of an association between the two conditions.
Case report: A 47-year-old woman presented as an emergency with an exacerbation of a four-month history of shortness of breath and dry cough. Her symptoms began following the start of anti-hormonal treatment with letrozole and goserelin acetate for a moderately differentiated (grade 2) invasive ductal carcinoma of the breast (pT2, pN0, M0) which was positive for expression of estrogen receptor (ER+), progesterone receptor (PR+), and human epidermal growth factor receptor 2 (HER2+). Until the previous four months, she had breast-conserving treatment with radiotherapy and tamoxifen therapy. Following hospital admission, she was found to be in type I respiratory failure. Chest X-ray, lung computed tomography (CT), and positron-emission tomography (PET) showed diffuse cystic and nodular lung lesions, consistent with a diagnosis of LAM, and antihormonal therapy was discontinued. She developed pericarditis that was treated with the anti-inflammatory agent, colchicine. Treatment with letrozole and sirolimus improved her respiratory symptoms.
Conclusions: A rare case of LAM is presented in a woman with a recent history of breast cancer. Because both tumors were hormone-dependent, this may support common underlying gene associations and signaling pathways between the two types of tumor.
Objectives: To correlate the radiological assessment of the mastoid facial canal in postoperative cochlear implant (CI) cone-beam CT (CBCT) and other possible contributing clinical or implant-related factors with postoperative facial nerve stimulation (FNS) occurrence. Methods: Two experienced radiologists evaluated retrospectively 215 postoperative post-CI CBCT examinations. The mastoid facial canal diameter, wall thickness, distance between the electrode cable and mastoid facial canal, and facial-chorda tympani angle were assessed. Additionally, the intracochlear position and the insertion angle and depth of electrodes were evaluated. Clinical data were analyzed for postoperative FNS within 1.5-year follow-up, CI type, onset, and causes for hearing loss such as otosclerosis, meningitis, and history of previous ear surgeries. Postoperative FNS was correlated with the measurements and clinical data using logistic regression. Results: Within the study population (mean age: 56 ± 18 years), ten patients presented with FNS. The correlations between FNS and facial canal diameter (p = 0.09), wall thickness (p = 0.27), distance to CI cable (p = 0.44), and angle with chorda tympani (p = 0.75) were statistically non-significant. There were statistical significances for previous history of meningitis/encephalitis (p = 0.001), extracochlear-electrode-contacts (p = 0.002), scala-vestibuli position (p = 0.02), younger patients’ age (p = 0.03), lateral-wall-electrode type (p = 0.04), and early/childhood onset hearing loss (p = 0.04). Histories of meningitis/encephalitis and extracochlear-electrode-contacts were included in the first two steps of the multivariate logistic regression. Conclusion: The mastoid-facial canal radiological assessment and the positional relationship with the CI electrode provide no predictor of postoperative FNS. Histories of meningitis/encephalitis and extracochlear-electrode-contacts are important risk factors.
hintergrund: Männer in Deutschland sterben früher als Frauen und nehmen weniger häufig Krebsvorsorgeuntersuchungen wahr.
Fragestellung: Ziel war die prospektive Evaluation einer „Movember-Gesundheitsinitiative“ am Universitätsklinikum Frankfurt (UKF) im November 2019.
Methoden: Im Rahmen der „Movember-Gesundheitsinitiative“ wurde allen männlichen Mitarbeitern des UKF ab dem 45. Lebensjahr und bei erstgradiger familiärer Vorbelastung eines Prostatakarzinoms ab dem 40. Lebensjahr im November 2019 gemäß S3-Leitlinien der Deutschen Gesellschaft für Urologie (DGU) eine Prostatakarzinom-Vorsorgeuntersuchung angeboten.
Ergebnisse: Insgesamt nahmen 14,4 % der Mitarbeiter teil. Eine familiäre Vorbelastung gaben insgesamt 14,0 % Teilnehmer an. Das mediane Alter betrug 54 Jahre. Der mediane PSA(prostataspezifisches Antigen)-Wert lag bei 0,9 ng/ml, der mediane PSA-Quotient bei 30 %. Bei 5 % (n = 6) zeigte sich ein suspekter Tastbefund in der DRU (digital-rektale Untersuchung). Nach Altersstratifizierung (≤ 50 vs. > 50 Lebensjahre) zeigten sich signifikante Unterschiede im medianen PSA-Wert (0,7 ng/ml vs. 1,0 ng/ml, p < 0,01) und der bereits zuvor durchgeführten urologischen Vorsorge (12,1 vs. 42,0 %, p < 0,01). Vier Teilnehmer (3,3 %) zeigten erhöhte Gesamt-PSA-Werte. Bei 32,2 % der Teilnehmer zeigte sich mindestens ein kontrollbedürftiger Befund. Insgesamt wurden 6 Prostatabiopsien durchgeführt. Hierbei zeigte sich in einem Fall ein intermediate-risk Prostatakarzinom (Gleason 3 + 4, pT3a, pPn1, pNx, R0).
Schlussfolgerungung: Im Rahmen der UKF-Movember-Gesundheitsinitiative 2019 konnten durch ein Vorsorgeangebot 121 Männer für eine Prostatakrebs-Vorsorge inklusive PSA-Testung gewonnen werden. Auffällige/kontrollbedürftige Befunde zeigten sich bei 32,2 %. Bei einem Mitarbeiter wurde ein therapiebedürftiges Prostatakarzinom entdeckt und therapiert.
The isolation of transcribed DNA sequences of P815 cells and the partial characterization with respect to their sequence composition and relative rates of enzymatic DNA methylation are reported in this paper. Transcribed regions were purified by affinity chromatography using immobilized heterogenous nuclear RNA of P815 cells. About 10% of total genome was found in this fraction. Reassociation analyses showed differences in sequence composition of transcribed versus non-transcribed DNA fractions. The relative proportion of inverted repeats was doubled in the transcribed fraction whereas ordinary highly repetitive sequences comprising mainly of satellite DNA were found almost exclusively in the non-transcribed regions of the P815 genome. About 70% of transcribed portions corresponds to unique and intermediary DNA sequences. After labelling of cells with L-[Methyl-3H]methionine and [14C]deoxycytidine relative rates of enzymatic DNA methylation were computed for different kinetic components of transcribed and non- transcribed portions of P815 genome. No difference was found except in inverted repeats. In transcribed DNA the relative rate of enzymatic DNA methylation was only about 40% of that of the non-transcribed ones. We have quantitated this hypomethylation and found that there is, in average, about one 5-methylcytosine residue in 100 nucleotides of transcribed inverted repeats, compared to about 2.5 5-methylcytosines in non-transcribed fractions. In view of these data we propose that the enzymatic methylation of inverted DNA repeats negatively controls the transcriptional process in a given genomic region.
A specific class of DNA sequences, the inverted repetitive sequences, forms a double-stranded structure within a single linear polynucleotide chain in denatured DNA. The reassociation process is unimolecular and occurs very fast. Quantitative analyses have shown that these sequences com-E rise about 4-5% of the nuclear DNA of various mammalian cells (P815 mouse mastocytoma, Hela, L cells, Raji and Chang cells, and human embryonic hepatocytes) and are interspersed within sequences of other degrees of repetitiveness.
After labeling the cells with L-[Metnyl-3H]methionine and [14C]deoxycytidine, relative rates of enzymic DNA methylation were computed on the basis of 3H and 14C radioactivities found in py rimidine residues of the nuclear DNA. The results indicate that DNA of inverted repetitive sequences is methylated to a level about 50% higher than the ordinary repetitive sequences and to about 300% higher than the unique and intermediary sequences.
The biological function of the inverted repeats as well as the role of their enzymic hypermethyl ation is unknown.
The sequence complexity of nuclear RNA from mouse liver, mouse spleen and highly malignant P815 mastocytoma was measured by nRNA driven hybridization to unique DNA sequences of P815 cells. The unique DNA sequences represent 63% of the total nuclear DNA of P815 cells and their availibility in hybridization experiments was found to be 76%. Of these sequences 7.8% formed hybrids with nuclear RNA of this cell, about 11.5% with mouse spleen and about 14.5% with mouse liver nuclear RNA. Assuming an asymmetrical transcription, the complexities of these transcripts are 2.8 × 108 nucleotides for mouse P815 mastocytoma, 4.3 × 108 for mouse spleen and about 5.3 × 108 nucleotides for mouse liver.
Cellular specifity of the transcribed information was analyzed in additivity experiments, in which unique DNA sequences, not complementary to the nuclear RNA of one cell were annealed to the nuclear RNAs of the two other tissues/cells. In these experiments most of the nuclear RNA se quences of P815 cells were found to be also present in the nucleus of mouse liver and spleen. Only a small portion of the unique DNA sequences of P815 mastocytoma (about 1.2% corresponding to 4.4 ×107 nucleotides) was found to be complementary only to P815 mastocytoma nuclear RNA.
Multidrug-resistant Gram-negative bacteria (MDR GNB) were found to colonise 60.8% (95% confidence interval: 52.3–68.9) of 143 refugee patients mainly from Syria (47), Afghanistan (29), and Somalia (14) admitted to the University Hospital Frankfurt, Germany, between June and December 2015. This percentage exceeds the prevalence of MDR GNB in resident patients four–fold. Healthcare personnel should be aware of this and the need to implement or adapt adequate infection control measures.
Although the 12C(n,p)12B and 12C(n,d)11B reactions are of interest in several fields of basic and applied Nuclear Physics the present knowledge of these two cross-sections is far from being accurate and reliable, with both evaluations and data showing sizable discrepancies. As part of the challenging n_TOF program on (n,cp) nuclear reactions study, the energy differential cross-sections of the 12C(n,p)12B and 12C(n,d)11 B reactions have been measured at CERN from the reaction thresholds up to 30 MeV neutron energy. Both measurements have been recently performed at the long flight-path (185 m) experimental area of the n_TOF facility at CERN using a pure (99.95%) rigid graphite target and two silicon telescopes. In this paper an overview of the experiment is presented together with a few preliminary results.
From July 2002 to March 2004 the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) aboard the European Space Agency´s Environmental Satellite (Envisat) measured nearly continuously mid infrared limb radiance spectra. These measurements are utilised to retrieve the global distribution of the chlorofluorocarbon CFC-11 by applying a new fast forward model for Envisat MIPAS and an accompanying optimal estimation retrieval processor. A detailed analysis shows that the total retrieval errors of the individual CFC-11 volume mixing ratios are typically below 10% in the altitude range 10 to 25 km and that the systematic components dominate. Contribution of a priori information to the retrieval results are less than 5 to 10% and the vertical resolution of the observations is about 3 to 4 km in the same vertical range. The data are successfully validated by comparison with several other space experiments, an air-borne in-situ instrument, measurements from ground-based networks, and independent Envisat MIPAS analyses. The retrieval results from 425 000 Envisat MIPAS limb scans are compiled to provide a new climatological data set of CFC-11. The climatology shows significantly lower CFC-11 abundances in the lower stratosphere compared with the Reference Atmospheres for MIPAS (RAMstan V3.1) climatology. Depending on the atmospheric conditions the differences between the climatologies are up to 30 to 110 ppt (45 to 150%) at 19 to 27 km altitude. Additionally, time series of CFC-11 mean abundance and variability for five latitudinal bands are presented. The observed CFC-11 distributions can be explained by the residual mean circulation and large-scale eddy-transports in the upper troposphere and lower stratosphere. The new CFC-11 data set is well suited for further scientific studies.
Causes of maladaptation
(2019)
Evolutionary biologists tend to approach the study of the natural world within a framework of adaptation, inspired perhaps by the power of natural selection to produce fitness advantages that drive population persistence and biological diversity. In contrast, evolution has rarely been studied through the lens of adaptation's complement, maladaptation. This contrast is surprising because maladaptation is a prevalent feature of evolution: population trait values are rarely distributed optimally; local populations often have lower fitness than imported ones; populations decline; and local and global extinctions are common. Yet we lack a general framework for understanding maladaptation; for instance in terms of distribution, severity, and dynamics. Similar uncertainties apply to the causes of maladaptation. We suggest that incorporating maladaptation‐based perspectives into evolutionary biology would facilitate better understanding of the natural world. Approaches within a maladaptation framework might be especially profitable in applied evolution contexts – where reductions in fitness are common. Toward advancing a more balanced study of evolution, here we present a conceptual framework describing causes of maladaptation. As the introductory article for a Special Feature on maladaptation, we also summarize the studies in this Issue, highlighting the causes of maladaptation in each study. We hope that our framework and the papers in this Special Issue will help catalyze the study of maladaptation in applied evolution, supporting greater understanding of evolutionary dynamics in our rapidly changing world.
Background: The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC. Methods: The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 3-year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating. Discussion: If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC. (trial registered at www.clinicaltrials.gov: NCT00355862) (EudraCT Number: 2005-005362-36)
Purpose: The aim of this study was to prospectively compare the therapy response and safety of microwave (MWA) and radiofrequency ablation (RFA) for the treatment of liver metastases using a dual ablation system.
Methods: Fifty patients with liver metastases (23 men, mean age: 62.8 ± 11.8 years) were randomly assigned to MWA or RFA for thermal ablation using a one generator dual ablation system. Magnetic resonance imaging (MRI) was acquired before treatment and 24 h post ablation. The morphologic responses to treatment regarding size, volume, necrotic areas, and diffusion characteristics were evaluated by MRI. Imaging follow-up was obtained for one year in three months intervals, whereas clinical follow-up was obtained for two years in all patients.
Results: Twenty-six patients received MWA and 24 patients received RFA (mean diameter: 1.6 cm, MWA: 1.7 cm, RFA: 1.5 cm). The mean volume 24 h after ablation was 37.0 cm3 (MWA: 50.5 cm3, RFA: 22.9 cm3, P < 0.01). The local recurrence rate was 0% (0/26) in the MWA-group and 8.3% (2/24) in the RFA-group (P = 0.09). The rate of newly developed malignant formations was 38.0% (19/50) for both groups (MWA: 38.4%, RFA: 37.5%, P = 0.07). The overall survival rate was 70.0% (35/50) after two years (MWA: 76.9%, RFA: 62.5%, P = 0.60). No major complications were reported.
Conclusion: In conclusion, MWA and RFA are both safe and effective methods for the treatment of liver metastases with MWA generating greater volumes of ablation. No significant differences were found for overall survival, rate of neoplasm, or major complications between both groups.
Three groups of beetles inhabit cones of cycads (Cycadales) in the northern hemisphere and are believed to be involved in their pollination. The primitive weevil subtribe Allocorynina (Coleoptera: Belidae) is restricted to the New World cycad genera Dioon Lindl. and Zamia L. One group of weevils (Curculionidae), found only in Cycas L., appears to be a relatively recent colonizer of northern hemisphere cycads. Members of the beetle subfamily Pharaxonothinae (Erotylidae) occur in all Asian and New World cycad genera. Phylogenetic trees of these beetles, based on DNA analysis and supported with morphological studies, are compared to patterns of continental drift and cycad phylogenies. Laurasian origins are suggested for these beetle groups with high latitude dispersal for at least one of these groups during periods of global warm climates.
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.
Single-molecule super-resolution microscopy allows imaging of fluorescently-tagged proteins in live cells with a precision well below that of the diffraction limit. Here, we demonstrate 3D sectioning with single-molecule super-resolution microscopy by making use of the fitting information that is usually discarded to reject fluorophores that emit from above or below a virtual-'light-sheet', a thin volume centred on the focal plane of the microscope. We describe an easy-to-use routine (implemented as an open-source ImageJ plug-in) to quickly analyse a calibration sample to define and use such a virtual light-sheet. In addition, the plug-in is easily usable on almost any existing 2D super-resolution instrumentation. This optical sectioning of super-resolution images is achieved by applying well-characterised width and amplitude thresholds to diffraction-limited spots that can be used to tune the thickness of the virtual light-sheet. This allows qualitative and quantitative imaging improvements: by rejecting out-of-focus fluorophores, the super-resolution image gains contrast and local features may be revealed; by retaining only fluorophores close to the focal plane, virtual-'light-sheet' single-molecule localisation microscopy improves the probability that all emitting fluorophores will be detected, fitted and quantitatively evaluated.
Lenalidomide (LEN) maintenance (MT) post autologous stem cell transplantation (ASCT) is standard of care in newly diagnosed multiple myeloma (MM) but has not been compared to other agents in clinical trials. We retrospectively compared bortezomib (BTZ; n = 138) or LEN (n = 183) MT from two subsequent GMMG phase III trials. All patients received three cycles of BTZ-based triplet induction and post-ASCT MT. BTZ MT (1.3 mg/m2 i.v.) was administered every 2 weeks for 2 years. LEN MT included two consolidation cycles (25 mg p.o., days 1–21 of 28 day cycles) followed by 10–15 mg/day for 2 years. The BTZ cohort more frequently received tandem ASCT (91% vs. 33%) due to different tandem ASCT strategies. In the LEN and BTZ cohort, 43% and 46% of patients completed 2 years of MT as intended (p = 0.57). Progression-free survival (PFS; HR = 0.83, p = 0.18) and overall survival (OS; HR = 0.70, p = 0.15) did not differ significantly with LEN vs. BTZ MT. Patients with <nCR after first ASCT were assigned tandem ASCT in both trials. In patients with <nCR and tandem ASCT (LEN: n = 54 vs. BTZ: n = 84), LEN MT significantly improved PFS (HR = 0.61, p = 0.04) but not OS (HR = 0.46, p = 0.09). In conclusion, the significant PFS benefit after eliminating the impact of different tandem ASCT rates supports the current standard of LEN MT after ASCT.
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.
The idea of slow-neutron capture nucleosynthesis formulated in 1957 triggered a tremendous experimental effort in different laboratories worldwide to measure the relevant nuclear physics input quantities, namely (n,γ) cross sections over the stellar temperature range (from few eV up to several hundred keV) for most of the isotopes involved from Fe up to Bi. A brief historical review focused on total energy detectors will be presented to illustrate how, advances in instrumentation have led, over the years, to the assessment and discovery of many new aspects of s-process nucleosynthesis and to the progressive refinement of theoretical models of stellar evolution. A summary will be presented on current efforts to develop new detection concepts, such as the Total-Energy Detector with γ-ray imaging capability (i-TED). The latter is based on the simultaneous combination of Compton imaging with neutron time-of-flight (TOF) techniques, in order to achieve a superior level of sensitivity and selectivity in the measurement of stellar neutron capture rates.
Fission program at n_TOF
(2019)
Since its start in 2001 the n_TOF collaboration developed a measurement program on fission, in view of advanced fuels in new generation reactors. A special effort was made on measurement of cross sections of actinides, exploiting the peculiarity of the n_TOF neutron beam which spans a huge energy domain, from the thermal region up to GeV. Moreover fission fragment angular distributions have also been measured. An overview of the cross section results achieved with different detectors is presented, including a discussion of the 237Np case where discrepancies showed up between different detector systems. The results on the anisotropy of the fission fragments and its implication on the mechanism of neutron absorption, and in applications, are also shown.
Diverse extracellular signals induce plasma membrane translocation of sphingosine kinase-1 (SphK1), thereby enabling inside-out signaling of sphingosine-1-phosphate. We have shown before that Gq-coupled receptors and constitutively active Gαq/11 specifically induced a rapid and long-lasting SphK1 translocation, independently of canonical Gq/phospholipase C (PLC) signaling. Here, we further characterized Gq/11 regulation of SphK1. SphK1 translocation by the M3 receptor in HEK-293 cells was delayed by expression of catalytically inactive G-protein-coupled receptor kinase-2, p63Rho guanine nucleotide exchange factor (p63RhoGEF), and catalytically inactive PLCβ3, but accelerated by wild-type PLCβ3 and the PLCδ PH domain. Both wild-type SphK1 and catalytically inactive SphK1-G82D reduced M3 receptor-stimulated inositol phosphate production, suggesting competition at Gαq. Embryonic fibroblasts from Gαq/11 double-deficient mice were used to show that amino acids W263 and T257 of Gαq, which interact directly with PLCβ3 and p63RhoGEF, were important for bradykinin B2 receptor-induced SphK1 translocation. Finally, an AIXXPL motif was identified in vertebrate SphK1 (positions 100–105 in human SphK1a), which resembles the Gαq binding motif, ALXXPI, in PLCβ and p63RhoGEF. After M3 receptor stimulation, SphK1-A100E-I101E and SphK1-P104A-L105A translocated in only 25% and 56% of cells, respectively, and translocation efficiency was significantly reduced. The data suggest that both the AIXXPL motif and currently unknown consequences of PLCβ/PLCδ(PH) expression are important for regulation of SphK1 by Gq/11.
Einleitung: Für die meisten Patienten mit HCC ist die LTX die einzige kurative Behandlungsoption. Bei diesen Patienten scheint eine Kontrolle der Erkrankung durch lokale Verfahren im Intervall bis zur LTX zu erreichen zu sein. Als das beste Verfahren gilt die transarterielle Chemoembolisation (TACE). Die Effektivität ist jedoch umstritten. Möglicherweise kann sie aber Patienten startifizieren, die ein hohes Rezidivrisiko haben.
Material und Methoden: Im Zeitraum zwischen 1995 und 2005 wurden n=27 Patienten mit HCC im Alter zwischen 22 und 69 Jahren transplantiert. Hiervon erhielten n=15 Patienten eine Vorbehandlung in Form einer alleinigen TACE oder kombiniert mit PEI [n=1] bzw. LITT [n=1]. Retrospektiv wurde das Gesamtüberleben sowie das „Event-free-survival“ (Rezidiv, Reinfektion und Tod) analysiert.
Ergebnisse: Die mittlere Wartezeit betrug bei Patienten in der TACE-Gruppe 214 Tage, bei Patienten ohne Vorbehandlung 133 Tage. Bei einem mittleren Nachbeobachtungszeitraum von 1097 ± 1193 Tagen für TACE-Patienten und 1674 ± 966 Tagen für non-TACE-Patienten betrug das Überleben für Patienten, die mit TACE vorbehandelt wurden 83,3%, für Patienten, die keine TACE erhielten 86.7% (p=0,5693). Gleiches fand sich für das Event-free-survival (p=0,8823). Das Gesamtüberleben der Patienten, die auf der Warteliste einen Tumorprogress hatten lag bei 77%, während Patienten mit stabiler Tumorgröße oder Regredienz der Tumore ein Überleben von 93% aufwiesen (p=0,0153). Unter TACE-Behandlung zeigten 5/15 Patienten eine zunehmende Anzahl an Herden im histologischen Präparat verglichen mit der Ausgangsbildgebung. Nur bei einem Patienten zeigte sich der Progress der Erkrankung bereits in der präoperativen Bildgebung. Patienten mit einem Progress der Erkrankung hatten ein Gesamtüberleben von 60%, während Patienten mit „stable disease“ oder Rückgang der Herde ein Gesamtüberleben von 100% hatten (p=0,0180).
Schlussfolgerung: Unseren Ergebnisse zufolge ist der Effekt der TACE als Bridgingverfahren auf das Überleben der Patienten fraglich. Allerdings scheint die TACE zur Riskostratifizierung geeignet zu sein. In unserem Patientenkollektiv hatten Patienten, die eine Progredienz der Erkrankung auf der Warteliste zeigten ein signifikant schlechteres Gesamtüberleben. Dies gilt auch bei ausschließlicher Betrachtung der Patienten mit TACE.
Objective: To investigate the accuracy, efficiency and radiation dose of a novel laser navigation system (LNS) compared to those of free-handed punctures on computed tomography (CT).
Materials and methods: Sixty punctures were performed using a phantom body to compare accuracy, timely effort, and radiation dose of the conventional free-handed procedure to those of the LNS-guided method. An additional 20 LNS-guided interventions were performed on another phantom to confirm accuracy. Ten patients subsequently underwent LNS-guided punctures.
Results: The phantom 1-LNS group showed a target point accuracy of 4.0 ± 2.7 mm (freehand, 6.3 ± 3.6 mm; p = 0.008), entrance point accuracy of 0.8 ± 0.6 mm (freehand, 6.1 ± 4.7 mm), needle angulation accuracy of 1.3 ± 0.9° (freehand, 3.4 ± 3.1°; p < 0.001), intervention time of 7.03 ± 5.18 minutes (freehand, 8.38 ± 4.09 minutes; p = 0.006), and 4.2 ± 3.6 CT images (freehand, 7.9 ± 5.1; p < 0.001). These results show significant improvement in 60 punctures compared to freehand. The phantom 2-LNS group showed a target point accuracy of 3.6 ± 2.5 mm, entrance point accuracy of 1.4 ± 2.0 mm, needle angulation accuracy of 1.0 ± 1.2°, intervention time of 1.44 ± 0.22 minutes, and 3.4 ± 1.7 CT images. The LNS group achieved target point accuracy of 5.0 ± 1.2 mm, entrance point accuracy of 2.0 ± 1.5 mm, needle angulation accuracy of 1.5 ± 0.3°, intervention time of 12.08 ± 3.07 minutes, and used 5.7 ± 1.6 CT-images for the first experience with patients.
Conclusion: Laser navigation system improved accuracy, duration of intervention, and radiation dose of CT-guided interventions.
To analyze prospectively the interventional and clinical aspects of computed tomography-guided direct intratumoural injection of a novel chemotherapeutic administration and the parenchymal changes of tumour and necrosis in malignant liver tumours. Eight patients with 17 colorectal liver metastases were treated with a mean of 5.1 injections and nine patients with 13 hepatocellular carcinoma nodules with a mean of 3.1 treatments with computed tomography guided local applications of a novel cisplatin/epinephrine gel. This application provides a higher local and lower systemic drug concentration. Volumes of tumour and necrosis prior and after treatment were measured by computer generated volumetric analysis. Contrast enhanced studies verified pretherapeutic viable tumour volumes with a value of 77.4 ml in the metastases and 29.2 ml in the hepatocellular carcinoma nodules. Intratumoural drug application resulted in a significant increase of necrosis and a decrease in viable tumour volume to be 68.3 ml in metastases and 14.5 ml in hepatocellular carcinoma. Local therapy control rate for the follow up to 6 months was 38 and 71% for the group of metastases and hepatocellular carcinoma, respectively. Direct intratumoural injection of cisplatin/epinepthrine injectable gel is a feasible and good tolerated method and results in the development of a statistically significant increase in necrosis in malignant liver tumours. For hepatocellular carcinoma a higher local therapy control rate compared to colorectal metastases can be reported.
During the measurement campaign FROST 2 (FReezing Of duST 2), the Leipzig Aerosol Cloud Interaction Simulator (LACIS) was used to investigate the influence of various surface modifications on the ice nucleating ability of Arizona Test Dust (ATD) particles in the immersion freezing mode. The dust particles were exposed to sulfuric acid vapor, to water vapor with and without the addition of ammonia gas, and heat using a thermodenuder operating at 250 °C. Size selected, quasi monodisperse particles with a mobility diameter of 300 nm were fed into LACIS and droplets grew on these particles such that each droplet contained a single particle. Temperature dependent frozen fractions of these droplets were determined in a temperature range between −40 °C ≤T≤−28 °C. The pure ATD particles nucleated ice over a broad temperature range with their freezing behavior being separated into two freezing branches characterized through different slopes in the frozen fraction vs. temperature curves. Coating the ATD particles with sulfuric acid resulted in the particles' IN potential significantly decreasing in the first freezing branch (T>−35 °C) and a slight increase in the second branch (T≤−35 °C). The addition of water vapor after the sulfuric acid coating caused the disappearance of the first freezing branch and a strong reduction of the IN ability in the second freezing branch. The presence of ammonia gas during water vapor exposure had a negligible effect on the particles' IN ability compared to the effect of water vapor. Heating in the thermodenuder led to a decreased IN ability of the sulfuric acid coated particles for both branches but the additional heat did not or only slightly change the IN ability of the pure ATD and the water vapor exposed sulfuric acid coated particles. In other words, the combination of both sulfuric acid and water vapor being present is a main cause for the ice active surface features of the ATD particles being destroyed. A possible explanation could be the chemical transformation of ice active metal silicates to metal sulfates. The strongly enhanced reaction between sulfuric acid and dust in the presence of water vapor and the resulting significant reductions in IN potential are of importance for atmospheric ice cloud formation. Our findings suggest that the IN concentration can decrease by up to one order of magnitude for the conditions investigated.
During the measurement campaign FROST 2 (FReezing Of duST 2), the Leipzig Aerosol Cloud Interaction Simulator (LACIS) was used to investigate the influences of various surface modifications on the immersion freezing behavior of Arizona Test Dust (ATD) particles. The dust particles were exposed to sulfuric acid vapor, to water vapor with and without the addition of ammonia gas, and heat using a thermodenuder operating at 250 °C. Size selected, quasi monodisperse particles with a mobility diameter of 300 nm were fed into LACIS and droplets grew on these particles such that each droplet contained a single particle. Temperature dependent frozen fractions of these droplets were determined in a temperature range between −40 °C ≤ T ≤ −28 °C. The pure ATD particles nucleated ice over a~broad temperature range with their freezing behavior being separated into two freezing branches characterized through different slopes in the frozen fraction vs. temperature curves. Coating the ATD particles with sulfuric acid resulted in the particles' IN potential significantly decreasing in the first freezing branch (T > −35 °C) and a slight increase in the second branch (T≤ −35 °C). The addition of water vapor after the sulfuric acid coating caused the disappearance of the first freezing branch and a strong reduction of the IN ability in the second freezing branch. The presence of ammonia gas during water vapor exposure had a negligible effect on the particles' IN ability compared to the effect of water vapor. Heating in the thermodenuder led to a decreased IN ability of the sulfuric acid coated particles for both branches but the additional heat did not or only slightly change the IN ability of the pure ATD and the water vapor exposed sulfuric acid coated particles. In other words, the combination of both sulfuric acid and water vapor being present is a main cause for the ice active surface features of the ATD particles being destroyed. A possible explanation could be the chemical transformation of ice active metal silicates to metal sulfates. From an atmospheric point of view, and here specifically the influences of atmospheric aging on the IN ability of dust particles, the strongly enhanced reaction between sulfuric acid and dust in the presence of water vapor, and the resulting significant reductions in IN potential, are certainly very interesting.
The slow neutron capture process (s-process) is responsible for producing about half of the elemental abundances heavier than iron in the universe. Neutron capture cross sections on stable isotopes are a key nuclear physics input for s-process studies. The 72Ge(n, γ) cross section has an important influence on production of isotopes between Ge and Zr during s-process in massive stars and therefore experimental data are urgently required. 72Ge(n, γ) was measured at the neutron time-of-flight facility n_TOF (CERN) for the first time at stellar energies. The measurement was performed using an enriched 72GeO2 sample at a flight path of 185m with a set of liquid scintillation detectors (C6D6). The motivation, experiment and current status of the data analysis are reported.
Developments in managing CF continue to drive dramatic improvements in survival. As newborn screening rolls-out across Europe, CF centres are increasingly caring for cohorts of patients who have minimal lung disease on diagnosis. With the introduction of mutation-specific therapies and the prospect of truly personalised medicine, patients have the potential to enjoy good quality of life in adulthood with ever-increasing life expectancy. The landmark Standards of Care published in 2005 set out what high quality CF care is and how it can be delivered throughout Europe. This underwent a fundamental re-write in 2014, resulting in three documents; center framework, quality management and best practice guidelines. This document is a revision of the latter, updating standards for best practice in key aspects of CF care, in the context of a fast-moving and dynamic field.
In continuing to give a broad overview of the standards expected for newborn screening, diagnosis, preventative treatment of lung disease, nutrition, complications, transplant/end of life care and psychological support, this consensus on best practice is expected to prove useful to clinical teams both in countries where CF care is developing and those with established CF centres. The document is an ECFS product and endorsed by the CF Network in ERN LUNG and CF Europe.
A mild synthetic method for N-formyl-Met-Leu-Phe-OH (1) is described. After Fmoc solid phase peptide synthesis, on-bead formylation and HPLC purification, more than 30 mg of the fully 13C/15N-labelled tripeptide 1 could be isolated in a typical batch. This peptide can be easily crystallised and is therefore well suited as a standard sample for setting up solid-state NMR experiments.
The purpose of this study is to compare the efficacy and safety of microwave ablation (MWA) versus laser-induced thermotherapy (LITT) as a local treatment for hepatocellular carcinoma (HCC,) with regard to therapy response, survival rates, and complication rates as measurable outcomes. This retrospective study included 250 patients (52 females and 198 males; mean age: 66 ± 10 years) with 435 tumors that were treated by MWA and 53 patients (12 females and 41 males; mean age: 67.5 ± 8 years) with 75 tumors that were treated by LITT. Tumor response was evaluated using CEMRI (contrast-enhanced magnetic resonance imaging). Overall, 445 MWA sessions and 76 LITT sessions were performed. The rate of local tumor progression (LTP) and the rate of intrahepatic distant recurrence (IDR) were 6% (15/250) and 46% (115/250) in the MWA-group and 3.8% (2/53) and 64.2% (34/53) in the LITT-group, respectively. The 1-, 3-, and 5-year overall survival (OS) rates calculated from the date of diagnosis were 94.3%, 65.4%, and 49.1% in the MWA-group and 96.2%, 54.7%, and 30.2% in the LITT-group, respectively (p-value: 0.002). The 1-, 2-, and 3-year disease-free survival (DFS) rates were 45.9%, 30.6%, and 24.8% in the MWA-group and 54.7%, 30.2%, and 17% in the LITT-group, respectively (p-value: 0.719). Initial complete ablation rate was 97.7% (425/435) in the MWA-group and 98.7% (74/75) in the LITT-group (p-value > 0.99). The overall complication rate was 2.9% (13/445) in the MWA-group and 7.9% (6/76) in the LITT-group (p-value: 0.045). Based on the results, MWA and LITT thermal ablation techniques are well-tolerated, effective, and safe for the local treatment of HCC. However, MWA is recommended over LITT for the treatment of HCC, since the patients in the MWA-group had higher survival rates.
The continental expression of global cooling during the Miocene Climate Transition in Central Asia is poorly documented, as the tectonically active setting complicates the correlation of Neogene regional and global climatic developments. This study presents new geochemical data (CaSO4 content, carbonate δ13C and δ18O) from the endorheic alluvial‐lacustrine Aktau succession (Ili Basin, south‐east Kazakhstan) combined with findings from the previously published facies evolution. Time series analysis revealed long‐eccentricity forcing of the paleohydrology throughout the entire succession, split into several facies‐dependent segments. Orbital tuning, constrained by new laser ablation U‐Pb dates and a preexisting magnetostratigraphy, places the succession in a 5.0 Ma long interval in the middle to late Miocene (15.6 to 10.6 Ma). The long‐term water accumulation in the Ili Basin followed the timing of the Miocene Climate Transition, suggesting increased precipitation in the catchment area in response to climate cooling and stronger westerly winds. This was paced by minima of the 2.4 Ma eccentricity cycle, which favored the establishment of a discharge playa (~14.3 Ma) and a perennial lake (12.6 to 11.8 Ma). Furthermore, low obliquity amplitudes (nodes) caused a transient weakening of the westerlies at ~13.7 to 13.5 Ma and at ~12.7 Ma, resulting in negative hydrological budgets and salinization. Flooding of the windward Ili Basin coeval with aridification in the leeward basins suggests that the Tian Shan was a climate boundary already in the middle Miocene. Our results emphasize the impact of climate fluctuations on the westerlies' strength and thus on Central Asian hydrology.
BACKGROUND: In the heart, cytoplasmic actin networks are thought to have important roles in mechanical support, myofibrillogenesis, and ion channel function. However, subcellular localization of cytoplasmic actin isoforms and proteins involved in the modulation of the cytoplasmic actin networks are elusive. Mena and VASP are important regulators of actin dynamics. Due to the lethal phenotype of mice with combined deficiency in Mena and VASP, however, distinct cardiac roles of the proteins remain speculative. In the present study, we analyzed the physiological functions of Mena and VASP in the heart and also investigated the role of the proteins in the organization of cytoplasmic actin networks.
RESULTS: We generated a mouse model, which simultaneously lacks Mena and VASP in the heart. Mena/VASP double-deficiency induced dilated cardiomyopathy and conduction abnormalities. In wild-type mice, Mena and VASP specifically interacted with a distinct αII-Spectrin splice variant (SH3i), which is in cardiomyocytes exclusively localized at Z- and intercalated discs. At Z- and intercalated discs, Mena and β-actin localized to the edges of the sarcomeres, where the thin filaments are anchored. In Mena/VASP double-deficient mice, β-actin networks were disrupted and the integrity of Z- and intercalated discs was markedly impaired.
CONCLUSIONS: Together, our data suggest that Mena, VASP, and αII-Spectrin assemble cardiac multi-protein complexes, which regulate cytoplasmic actin networks. Conversely, Mena/VASP deficiency results in disrupted β-actin assembly, Z- and intercalated disc malformation, and induces dilated cardiomyopathy and conduction abnormalities.
A biodiversity inventory of the Lepidoptera of Pico Bonito National Park and vicinity, in the Department of Atlantida of northern Honduras, was initiated in 2009 to obtain baseline data. We present a revised checklist of Honduran butterfly species (updated from the initial 1967 lists), as well as the first comprehensive list of Honduran moths. Our updated list includes 550 species of Papilionoidea, 311 Hesperioidea, and 1,441 moth species.
Introduction: MDRO-colonization has been shown to impair survival in patients with hematological malignancies and solid tumors as well as in patients with liver disease. Despite the increasing spread of multidrug-resistant organisms (MDRO), its impact on patients with hepatocellular carcinoma (HCC) has not been studied. We conducted this retrospective study to analyze the impact of MDRO-colonization on overall prognosis in HCC patients.
Materials and methods: All patients with confirmed HCC diagnosed between January 2008 and December 2017 at the University Hospital Frankfurt were included in this study. HCC patients with a positive MDRO screening before or within the first 90 days after diagnosis of HCC were defined as colonized HCC patients, HCC patients with a negative MDRO screening were defined as noncolonized HCC patients.
Results: 59 (6%) colonized and 895 (94%) noncolonized HCC patients were included. Enterobacterales with extended-spectrum β-lactamase-like phenotype with or without resistance to fluoroquinolones (ESBL/ ± FQ) were the most frequently found MDRO with 59%, followed by vancomycin-resistant Enterococcus faecium with 37%. Colonized HCC patients had more severe cirrhosis and more advanced HCC stage compared to noncolonized HCC patients. Colonized HCC patients showed an impaired survival with a median OS of 189 days (6.3 months) compared to a median OS of 1001 days (33.4 months) in noncolonized HCC patients. MDRO-colonization was identified as an independent risk factor associated with survival in multivariate analysis.
Conclusion: MDRO-colonization is an independent risk factor for survival in patients with HCC highlighting the importance of regular MDRO screening, isolation measures as well as interdisciplinary antibiotic steward-ship programs to guide responsible use of antibiotic agents.
Introduction: The global spread of multidrug-resistant organisms (MDRO) complicates treatment and isolation measures in hospitals and has shown to increase mortality. Patients with disease- or therapy-related immunodeficiency are especially at risk for fatal infections caused by MDRO. The impact of MDRO colonization on the clinical course of AML patients undergoing intensive induction chemotherapy—a potentially curative but highly toxic treatment option—has not been systematically studied.
Materials & methods: 312 AML patients undergoing intensive induction chemotherapy between 2007 and 2015 were examined for MDRO colonization. Patients with evidence for MDRO before or during the hospital stay of induction chemotherapy were defined as colonized, patients who never had a positive swab for MDRO were defined as noncolonized.
Results: Of 312 AML patients 90 were colonized and 130 were noncolonized. Colonized patients suffered from significantly more days with fever, spent more days on the intensive care unit and had a higher median C-reactive protein value during the hospital stay. These findings did not result in a prolonged length of hospital stay or an increased mortality rate for colonized patients. However, in a subgroup analysis, patients colonized with carbapenem-resistant enterobacteriaceae (CRE) had a significantly reduced 60- and 90-day, as well as 1- and 2-year survival rates when compared to noncolonized patients.
Conclusion: Our analysis highlights the importance of intensive MDRO screening especially in patients with febrile neutropenia since persisting fever can be a sign of MDRO-colonization. CRE-colonized patients require special surveillance, since they seem to be at risk for death.
Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.
The translation eukaryotic elongation factor 1alpha (eEF1A) is a monomeric GTPase involved in protein synthesis. In addition, this protein is thought to participate in other cellular functions such as actin bundling, cell cycle regulation, and apoptosis. Here we show that eEF1A is associated with the alpha2 subunit of the inhibitory glycine receptor in pulldown experiments with rat brain extracts. Moreover, additional proteins involved in translation like ribosomal S6 protein and p70 ribosomal S6 protein kinase as well as ERK1/2 and calcineurin were identified in the same pulldown approaches. Glycine receptor activation in spinal cord neurons cultured for 1 week resulted in an increased phosphorylation of ribosomal S6 protein. Immunocytochemistry showed that eEF1A and ribosomal S6 protein are localized in the soma, dendrites, and at synapses of cultured hippocampal and spinal cord neurons. Consistent with our biochemical data, immunoreactivities of both proteins were partially overlapping with glycine receptor immunoreactivity in cultured spinal cord and hippocampal neurons. After 5 weeks in culture, eEF1A immunoreactivity was redistributed to the cytoskeleton in about 45% of neurons. Interestingly, the degree of redistribution could be increased at earlier stages of in vitro differentiation by inhibition of either the ERK1/2 pathway or glycine receptors and simultaneous N-methyl-D-aspartate receptor activation. Our findings suggest a functional coupling of eEF1A with both inhibitory and excitatory receptors, possibly involving the ERK-signaling pathway.