ABSTRACT
Background
To detect early cardiac deterioration, a simple and stable tool is needed. Measurement of time intervals in a simple 4-chamber view using color-coded tissue Doppler imaging is a ...relatively new approach to assess fetal cardiac function. The aim of this study was to evaluate the applicability of this modality and to construct reference ranges for cardiac time intervals.
Methods
We performed a prospective longitudinal cohort study in healthy fetuses. We used linear mixed models to construct age-adjusted reference ranges for shortening time (St) and lengthening time (Lt) in three cardiac regions: global heart and right and left ventricular wall. St and Lt were expressed as percentage of the cardiac cycle. Feasibility and intra- and interobserver variabilities were evaluated. We applied the technique to twin–twin transfusion syndrome (TTTS) recipients before laser therapy to test the diagnostic performance.
Results
A total of 251 recordings were obtained from 54 healthy singletons. St decreased and Lt increased with gestational age in all regions. We found a high feasibility (99.6%) and excellent intra-/interobserver variability for St (0.96/0.94) and Lt (0.99/0.96) of the global heart. Left and right ventricle performance parameters were good. In TTTS recipients, St was prolonged (
p
< 0.01) and Lt was shortened (
p
< 0.01) in all regions and the feasibility was excellent (96.6%).
Conclusions
The assessment of fetal cardiac function by measurement of cardiac time intervals is technically feasible with good reproducibility, even in difficult scanning circumstances such as TTTS. It is possible to discriminate between healthy and compromised fetuses with this technique.
Background The purpose of the study was to investigate a novel BRAF and CDK 4/6 inhibitor combination therapy in a murine model of BRAF-V600-mutant human melanoma monitored by .sup.18F-FDG-PET/CT and ...diffusion-weighted MRI (DW-MRI). Methods Human BRAF-V600-mutant melanoma (A375) xenograft-bearing balb/c nude mice (n = 21) were imaged by .sup.18F-FDG-PET/CT and DW-MRI before (day 0) and after (day 7) a 1-week BRAF and CDK 4/6 inhibitor combination therapy (n = 12; dabrafenib, 20 mg/kg/d; ribociclib, 100 mg/kg/d) or placebo (n = 9). Animals were scanned on a small animal PET after intravenous administration of 20 MBq .sup.18F-FDG. Tumor glucose uptake was calculated as the tumor-to-liver-ratio (TTL). Unenhanced CT data sets were subsequently acquired for anatomic coregistration. Tumor diffusivity was assessed by DW-MRI using the apparent diffusion coefficient (ADC). Anti-tumor therapy effects were assessed by ex vivo immunohistochemistry for validation purposes (microvascular density - CD31; tumor cell proliferation - Ki-67). Results Tumor glucose uptake was significantly suppressed under therapy (DELATTL.sub.Therapy - 1.00 + or - 0.53 vs. DELATTL.sub.Control 0.85 + or - 1.21; p 0.001). In addition, tumor diffusivity was significantly elevated following the BRAF and CDK 4/6 inhibitor combination therapy (DELAADC.sub.Therapy 0.12 + or - 0.14 x 10.sup.-3 mm.sup.2/s; DELAADC.sub.Control - 0.12 + or - 0.06 x 10.sup.-3 mm.sup.2/s; p 0.001). Immunohistochemistry revealed a significant suppression of microvascular density (CD31, 147 + or - 48 vs. 287 + or - 92; p = 0.001) and proliferation (Ki-67, 3718 + or - 998 vs. 5389 + or - 1332; p = 0.007) in the therapy compared to the control group. Conclusion A novel BRAF and CDK 4/6 inhibitor combination therapy exhibited significant anti-angiogenic and anti-proliferative effects in experimental human melanomas, monitored by .sup.18F-FDG-PET/CT and DW-MRI. Keywords: Melanoma, BRAF inhibitor, CDK inhibitor, .sup.18F-FDG-PET, Diffusion-weighted MRI, Therapy monitoring
The aim of this study was to investigate magnetic resonance imaging (MRI) with αvß3-integrin-targeted ultrasmall superparamagnetic iron oxide nanoparticles (RGD-USPIO) for the in vivo monitoring of ...early antiangiogenic therapy effects in experimental breast cancer.
Orthotopic human breast cancer (MDA-MB-231) xenograft-bearing severe combined immunodeficiency mice were imaged before and after a 1-week therapy with the vascular endothelial growth factor receptor-antibody bevacizumab or placebo (n = 10 per group, daily intraperitoneal injections of bevacizumab or a volume-equivalent placebo solution, respectively) on a clinical 3 T scanner (Magnetom Skyra; Siemens Healthcare, Erlangen, Germany) before and 60 minutes after the intravenous injection of RGD-USPIO (P04000; Guerbet, Villepinte, France). R2 relaxometry employing a T2-weighted spin-echo sequence with 4 echo times (echo time, 20/40/60/80 milliseconds; repetition time, 3800 milliseconds; matrix, 128 × 128; field of view, 50 × 50; slice thickness, 1.2 mm; time to acquisition, 25 minutes) was used as semiquantitative measure to determine RGD-USPIO endothelial binding. In addition, the T2-weighted images were used to perform volumetric tumor response assessments. Imaging results were validated by ex vivo multiparametric immunohistochemistry with regard to αvß3-integrin expression, microvascular density (CD31), proliferation (Ki-67), and apoptosis (TUNEL).
RGD-USPIO endothelial binding was significantly reduced after vascular endothelial growth factor inhibition, compared with the control group in which an increased endothelial binding was detected (INCREMENTR2Therapy = -0.80 ± 0.78 s; INCREMENTR2Control = +0.27 ± 0.59 s; P = 0.002). Correspondingly, immunohistochemistry revealed a significantly lower αvß3-integrin expression (91 ± 30 vs 357 ± 72; P < 0.001), microvascular density (CD31, 109 ± 46 vs 440 ± 208; P < 0.001), tumor cell proliferation (Ki-67, 4040 ± 1373 vs 6530 ± 1217; P < 0.001), as well as significantly higher apoptosis (TUNEL, 11186 ± 4387 vs 4017 ± 1191; P = 0.004) in the therapy compared with the control group. Contrary to the changes in αvß3-integrin expression detected by RGD-USPIO MRI, morphology-based tumor response assessments did not show a significant intergroup difference in tumor volume development over the course of the experiment (ΔVolTherapy +71 ± 40 μL vs ΔVolControl +125 ± 81 μL; P > 0.05).
RGD-USPIO MRI allows for the noninvasive assessment of αvß3-integrin expression in the investigated breast cancer model. RGD-USPIO MRI may be applicable for the in vivo monitoring of early antiangiogenic therapy effects in experimental breast cancer, generating possible complementary molecular imaging biomarkers to morphology-based tumor response assessments.
Somatostatin analogues (SSA) are frequently used in the treatment of neuroendocrine tumours. Recently,
FSiTATE entered the field of somatostatin receptor (SSR) positron emission tomography ...(PET)/computed tomography (CT) imaging. The purpose of this study was to compare the SSR-expression of differentiated gastroentero-pancreatic neuroendocrine tumours (GEP-NET) measured by 18FSiTATE-PET/CT in patients with and without previous treatment with long-acting SSAs to evaluate if SSA treatment needs to be paused prior to 18FSiTATE-PET/CT.
77 patients were examined with standardised 18FSiTATE-PET/CT within clinical routine: 40 patients with long-acting SSAs up to 28 days prior to PET/CT examination and 37 patients without pre-treatment with SSAs. Maximum and mean standardized uptake values (SUVmax and SUVmean) of tumours and metastases (liver, lymphnode, mesenteric/peritoneal and bones) as well as representative background tissues (liver, spleen, adrenal gland, blood pool, small intestine, lung, bone) were measured, SUV ratios (SUVR) were calculated between tumours/metastases and liver, likewise between tumours/metastases and corresponding specific background, and compared between the two groups.
SUVmean of liver (5.4 ± 1.5 vs. 6.8 ± 1.8) and spleen (17.5 ± 6.8 vs. 36.7 ± 10.3) were significantly lower (p < 0.001) and SUVmean of blood pool (1.7 ± 0.6 vs. 1.3 ± 0.3) was significantly higher (p < 0.001) in patients with SSA pre-treatment compared to patients without. No significant differences between tumour-to-liver and specific tumour-to-background SUVRs were observed between both groups (all p > 0.05).
In patients previously treated with SSAs, a significantly lower SSR expression (18FSiTATE uptake) in normal liver and spleen tissue was observed, as previously reported for 68Ga-labelled SSAs, without significant reduction of tumour-to-background contrast. Therefore, there is no evidence that SSA treatment needs to be paused prior to 18FSiTATE-PET/CT.
Abstract Objectives This study evaluated the clinical outcome of all-ceramic resin-bonded fixed partial dentures (RBFPDs) with a cantilevered single-retainer design. Methods Thirty anterior zirconia ...ceramic RBFPDs were inserted using either a phosphate monomer containing resin (Panavia 21 TC; N = 16) or an adhesive bonding system with a phosphoric acid acrylate primer (Multilink–Automix with Metal/Zirconia primer; N = 14). Results During a mean observation time of 41.7 months one debonding occurred in each group. Both RBFPDs could be rebonded successfully resulting in a three-year survival rate of 100%. Conclusion Independent of the bonding system cantilevered zirconia ceramic RBFPDs showed promising results during the first three years. Clinical significance Single-retainer zirconia ceramic RBFPD present an alternative treatment option offering good aesthetics, a minimal invasive preparation, a high biocompatibility and can even be used to treat juvenile patients who do not yet come into consideration for implant placement. No significant influence of the bonding system used was detected so far.
The H.E.S.S. Galactic plane survey Angüner, E. O.; Arakawa, M.; Aubert, P. ...
Astronomy & astrophysics,
04/2018, Volume:
612
Journal Article
Peer reviewed
Open access
We present the results of the most comprehensive survey of the Galactic plane in very high-energy (VHE) γ-rays, including a public release of Galactic sky maps, a catalog of VHE sources, and the ...discovery of 16 new sources of VHE γ-rays. The High Energy Spectroscopic System (H.E.S.S.) Galactic plane survey (HGPS) was a decade-long observation program carried out by the H.E.S.S. I array of Cherenkov telescopes in Namibia from 2004 to 2013. The observations amount to nearly 2700 h of quality-selected data, covering the Galactic plane at longitudes from ℓ = 250° to 65° and latitudes |b|≤ 3°. In addition to the unprecedented spatial coverage, the HGPS also features a relatively high angular resolution (0.08° ≈ 5 arcmin mean point spread function 68% containment radius), sensitivity (≲1.5% Crab flux for point-like sources), and energy range (0.2–100 TeV). We constructed a catalog of VHE γ-ray sources from the HGPS data set with a systematic procedure for both source detection and characterization of morphology and spectrum. We present this likelihood-based method in detail, including the introduction of a model component to account for unresolved, large-scale emission along the Galactic plane. In total, the resulting HGPS catalog contains 78 VHE sources, of which 14 are not reanalyzed here, for example, due to their complex morphology, namely shell-like sources and the Galactic center region. Where possible, we provide a firm identification of the VHE source or plausible associations with sources in other astronomical catalogs. We also studied the characteristics of the VHE sources with source parameter distributions. 16 new sources were previously unknown or unpublished, and we individually discuss their identifications or possible associations. We firmly identified 31 sources as pulsar wind nebulae (PWNe), supernova remnants (SNRs), composite SNRs, or gamma-ray binaries. Among the 47 sources not yet identified, most of them (36) have possible associations with cataloged objects, notably PWNe and energetic pulsars that could power VHE PWNe.
Objective: To examine zinc-protoporphyrin (ZPP) and haemoglobin levels, and to determine predictors of iron deficiency anaemia (IDA) in Zambian infants. Subjects and methods: Ninety-one women and ...their normal birth weight (NBW) infants were followed bi-monthly during the first 6 months of life, and iron status, food intake, malaria parasitaemia and growth were monitored. At 4 months, the infants were divided into two groups, and the data were analysed according to whether or not they were exclusively breastfed. Results: Almost two-third of infants were born with low iron stores as defined by ZPP levels, and this proportion increased with age. Over 50% had developed IDA by 6 months. Exclusive breastfeeding at 4 months could be a protective factor for IDA (odds ratio (OR): 0.2; 95% confidence interval (CI): 0.0-1.1). Exclusively breastfed infants had higher haemoglobin values at 4 and 6 months (mean difference 0.6; 95% CI: 0.1-1.2 g/dl and mean difference 0.9; 95% CI: 0.2-1.7 g/dl, respectively), compared with infants with early complementary feeding. In univariate analysis, past or chronic placental malaria appeared to be a predictor of IDA at 4 and 6 months, but the significance was lost in multivariate analysis. Conclusions: Zambian NBW infants are born with low iron stores and have a high risk to develop IDA in the first 6 months of life. Continuation of exclusive breastfeeding after 4 months is associated with a reduction of anaemia. The effect of placental malaria infection on increased risk of infant IDA could not be proven.
The nine-year H.E.S.S. Galactic Plane Survey (HGPS) has yielded the most uniform observation scan of the inner Milky Way in the TeV gamma-ray band to date. The sky maps and source catalogue of the ...HGPS allow for a systematic study of the population of TeV pulsar wind nebulae found throughout the last decade. To investigate the nature and evolution of pulsar wind nebulae, for the first time we also present several upper limits for regions around pulsars without a detected TeV wind nebula. Our data exhibit a correlation of TeV surface brightness with pulsar spin-down power Ė. This seems to be caused both by an increase of extension with decreasing Ė, and hence with time, compatible with a power law RPWN(Ė) ~Ė−0.65±0.20, and by a mild decrease of TeV gamma-ray luminosity with decreasing Ė, compatible with L1−10 TeV ~Ė0.59±0.21. We also find that the offsets of pulsars with respect to the wind nebula centre with ages around 10 kyr are frequently larger than can be plausibly explained by pulsar proper motion and could be due to an asymmetric environment. In the present data, it seems that a large pulsar offset is correlated with a high apparent TeV efficiency L1−10 TeV∕Ė. In addition to 14 HGPS sources considered firmly identified pulsar wind nebulae and 5 additional pulsar wind nebulae taken from literature, we find 10 HGPS sources that are likely TeV pulsar wind nebula candidates. Using a model that subsumes the present common understanding of the very high-energy radiative evolution of pulsar wind nebulae, we find that the trends and variations of the TeV observables and limits can be reproduced to a good level, drawing a consistent picture of present-day TeV data and theory.
Abstract Objectives The purpose of this prospective study was to evaluate the clinical outcome of crown-retained fixed dental prostheses (FDPs) made from a lithium-disilicate glass–ceramic (IPS e.max ...Press, Ivoclar-Vivadent). Methods Thirty-six three-unit FDPs were placed in 28 patients. The FDPs replaced teeth in the anterior (16%) and posterior (84%) regions. All teeth were prepared following a standardized protocol. The size of the proximal connector of the FDPs was 12 mm2 (anterior) or 16 mm2 (posterior). FDPs were cemented either with glass-ionomer cement ( n = 19) or composite resin ( n = 17). The following parameters were evaluated at baseline, 6 months after cementation and then annually (at abutment and contralateral teeth): probing pocket depth, plaque index, bleeding on probing, and tooth vitality. Results Three FDPs were defined as drop-out. The mean observation period of the remaining 33 FDPs was 86 months (range: 67–98 months): two FDPs in two patients had to be replaced (6%) because of fractures. The 8-year survival rate according to Kaplan–Meier was 93%. In addition, chipping of the veneering material was found in two FDPs (6%). Two abutments (3%) of two restorations had to be treated endodontically; and two FDPs (6%) lost retention and had to be recemented. These complications did not affect the function of the involved restorations clinically. There were no significant differences between the periodontal parameters of the test and control teeth. Significance Short-span crown-retained three-unit FDPs made from lithium-disilicate glass–ceramic can be used clinically irrespective of an adhesive or conventional cementation.
Treatment, for 1 h, of cultured Chinese hamster V79 cells, human liver HepG2 cells, and human colon HT-29 cells with theAlternaria toxins alternariol (AOH) and alternariol methyl ether (AME) caused a ...concentration-dependent induction of DNA strand breaks at concentrations ranging from 5 to 50 micromolar. After treatment for 24 h, DNA strand breaks were observed in HepG2 but not HT-29 cells. Analysis of the 24 h-incubation media of HT-29 cells showed that both toxins were completely conjugated, whereas 75% were still present as unconjugated compounds in the 24 h-media of HepG2 cells. Lysates of both cell types fortified with UDPGA were found to convert both toxins into two glucuronides each, but HT-29 cells exhibited a much high activity than HepG2 cells and gave rise to a different ratio of glucuronides. It is concluded that glucuronidation eliminates the DNA strandbreaking potential of AOH and AME, and that the two glucuronides of eachAlternaria toxin are generated by different UGT isoforms.
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