Quantification of Tumor Vessels in Glioblastoma Patients Using Time-of-Flight Angiography at 7 Tesla: A Feasibility Study

Purpose

To analyze if tumor vessels can be visualized, segmented and quantified in glioblastoma patients with time of flight (ToF) angiography at 7 Tesla and multiscale vessel enhancement filtering.

Materials and Methods

Twelve patients with newly diagnosed glioblastoma were examined with ToF angiography (TR = 15 ms, TE = 4.8 ms, flip angle = 15°, FOV = 160×210 mm², voxel size: 0.31×0.31×0.40 mm³) on a whole-body 7 T MR system. A volume of interest (VOI) was placed within the border of the contrast enhancing part on T1-weighted images of the glioblastoma and a reference VOI was placed in the non-affected contralateral white matter. Automated segmentation and quantification of vessels within the two VOIs was achieved using multiscale vessel enhancement filtering in ImageJ.

Results

Tumor vessels were clearly visible in all patients. When comparing tumor and the reference VOI, total vessel surface (45.3±13.9 mm² vs. 29.0±21.0 mm² (p<0.035)) and number of branches (3.5±1.8 vs. 1.0±0.6 (p<0.001) per cubic centimeter were significantly higher, while mean vessel branch length was significantly lower (3.8±1.5 mm vs 7.2±2.8 mm (p<0.001)) in the tumor.

Discussion

ToF angiography at 7-Tesla MRI enables characterization and quantification of the internal vascular morphology of glioblastoma and may be used for the evaluation of therapy response within future studies.     

MiRNA-1/133a Clusters Regulate Adrenergic Control of Cardiac Repolarization

The electrical properties of the heart are primarily determined by the activity of ion channels and the activity of these molecules is permanently modulated and adjusted to the physiological needs by adrenergic signaling. miRNAs are known to control the expression of many proteins and to fulfill distinct functions in the mammalian heart, though the in vivo effects of miRNAs on the electrical activity of the heart are poorly characterized. The miRNAs miR-1 and miR-133a are the most abundant miRNAs of the heart and are expressed from two miR-1/133a genomic clusters. Genetic modulation of miR-1/133a cluster expression without concomitant severe disturbance of general cardiomyocyte physiology revealed that these miRNA clusters govern cardiac muscle repolarization. Reduction of miR-1/133a dosage induced a longQT phenotype in mice especially at low heart rates. Longer action potentials in cardiomyocytes are caused by modulation of the impact of β-adrenergic signaling on the activity of the depolarizing L-type calcium channel. Pharmacological intervention to attenuate β-adrenergic signaling or L-type calcium channel activity in vivo abrogated the longQT phenotype that is caused by modulation of miR-1/133a activity. Thus, we identify the miR-1/133a miRNA clusters to be important to prevent a longQT-phenotype in the mammalian heart.     

Stable Composition of the Nano- and Picoplankton Community during the Ocean Iron Fertilization Experiment LOHAFEX

The iron fertilization experiment LOHAFEX was conducted in a cold-core eddy in the Southern Atlantic Ocean during austral summer. Within a few days after fertilization, a phytoplankton bloom developed dominated by nano- and picoplankton groups. Unlike previously reported for other iron fertilization experiments, a diatom bloom was prevented by iron and silicate co-limitation. We used 18S rRNA gene tag pyrosequencing to investigate the diversity of these morphologically similar cell types within the nano- and picoplankton and microscopically enumerated dominant clades after catalyzed reported deposition fluorescence in situ hybridization (CARD-FISH) with specific oligonucleotide probes. In addition to Phaeocystis, members of Syndiniales group II, clade 10–11, and the Micromonas clades ABC and E made up a major fraction of the tag sequences of the nano- and picoplankton community within the fertilized patch. However, the same clades were also dominant before the bloom and outside the fertilized patch. Furthermore, only little changes in diversity could be observed over the course of the experiment. These results were corroborated by CARD-FISH analysis which confirmed the presence of a stable nano- and picoplankton community dominated by Phaeocystis and Micromonas during the entire course of the experiment. Interestingly, although Syndiniales dominated the tag sequences, they could hardly be detected by CARD-FISH, possibly due to the intracellular parasitic life style of this clade. The remarkable stability of the nano- and picoplankton community points to a tight coupling of the different trophic levels within the microbial food web during LOHAFEX.     

Genome-Wide Association Study Reveals a Polymorphism in the Podocyte Receptor RANK for the Decline of Renal Function in Coronary Patients

Impaired kidney function is a significant health problem and a major concern in clinical routine and is routinely determined by decreased glomerular filtration rate (GFR). In contrast to single assessment of a patients'' kidney function providing only limited information on patients'' health, serial measurements of GFR clearly improves the validity of diagnosis. The decline of kidney function has recently been reported to be predictive for mortality and vascular events in coronary patients. However, it has not been investigated for genetic association in GWA studies. This study investigates for the first time the association of cardiometabolic polymorphisms with the decline of estimated GFR during a 4 year follow up in 583 coronary patients, using the Cardio-Metabo Chip. We revealed a suggestive association with 3 polymorphisms, surpassing genome-wide significance (p = 4.0 e-7). The top hit rs17069906 (p = 5.6 e-10) is located within the genomic region of RANK, recently demonstrated to be an important player in the adaptive recovery response in podocytes and suggested as a promising therapeutic target in glomerular diseases.     

Quantitative Stain-Free and Continuous Multimodal Monitoring of Wound Healing In Vitro with Digital Holographic Microscopy

Impaired epithelial wound healing has significant pathophysiological implications in several conditions including gastrointestinal ulcers, anastomotic leakage and venous or diabetic skin ulcers. Promising drug candidates for accelerating wound closure are commonly evaluated in in vitro wound assays. However, staining procedures and discontinuous monitoring are major drawbacks hampering accurate assessment of wound assays. We therefore investigated digital holographic microscopy (DHM) to appropriately monitor wound healing in vitro and secondly, to provide multimodal quantitative information on morphological and functional cell alterations as well as on motility changes upon cytokine stimulation. Wound closure as reflected by proliferation and migration of Caco-2 cells in wound healing assays was studied and assessed in time-lapse series for 40 h in the presence of stimulating epidermal growth factor (EGF) and inhibiting mitomycin c. Therefore, digital holograms were recorded continuously every thirty minutes. Morphological changes including cell thickness, dry mass and tissue density were analyzed by data from quantitative digital holographic phase microscopy. Stimulation of Caco-2 cells with EGF or mitomycin c resulted in significant morphological changes during wound healing compared to control cells. In conclusion, DHM allows accurate, stain-free and continuous multimodal quantitative monitoring of wound healing in vitro and could be a promising new technique for assessment of wound healing.     

CT-Angiography–Based Evaluation of the Aortic Annulus for Prosthesis Sizing in Transcatheter Aortic Valve Implantation (TAVI)–Predictive Value and Optimal Thresholds for Major Anatomic Parameters

Background/Objectives

To evaluate the predictive value of CT-derived measurements of the aortic annulus for prosthesis sizing in transcatheter aortic valve implantation (TAVI) and to calculate optimal cutoff values for the selection of various prosthesis sizes.

Methods

The local IRB waived approval for this single-center retrospective analysis. Of 441 consecutive TAVI-patients, 90 were excluded (death within 30 days: 13; more than mild aortic regurgitation: 10; other reasons: 67). In the remaining 351 patients, the CoreValve (Medtronic) and the Edwards Sapien XT valve (Edwards Lifesciences) were implanted in 235 and 116 patients. Optimal prosthesis size was determined during TAVI by inflation of a balloon catheter at the aortic annulus. All patients had undergone CT-angiography of the heart or body trunk prior to TAVI. Using these datasets, the diameter of the long and short axis as well as the circumference and the area of the aortic annulus were measured. Multi-Class Receiver-Operator-Curve analyses were used to determine the predictive value of all variables and to define optimal cutoff-values.

Results

Differences between patients who underwent implantation of the small, medium or large prosthesis were significant for all except the large vs. medium CoreValve (all p’s<0.05). Furthermore, mean diameter, annulus area and circumference had equally high predictive value for prosthesis size for both manufacturers (multi-class AUC’s: 0.80, 0.88, 0.91, 0.88, 0.88, 0.89). Using the calculated optimal cutoff-values, prosthesis size is predicted correctly in 85% of cases.

Conclusion

CT-based aortic root measurements permit excellent prediction of the prosthesis size considered optimal during TAVI.     

Rapid Rebound of the Treg Compartment in DEREG Mice Limits the Impact of Treg Depletion on Mycobacterial Burden,but Prevents Autoimmunity

The development of an effective vaccine against tuberculosis (Tb) represents one of the major medical challenges of this century. Mycobacterium bovis Bacille Calmette-Guerin (BCG), the only vaccine available at present, is mostly effective at preventing disseminated Tb in children, but shows variable protection against pulmonary Tb, the most common form in adults. The reasons for this poor efficacy are not completely understood, but there is evidence that T regulatory cells (Tregs) might be involved. Similarly, Tregs have been associated with the immunosuppression observed in patients infected with Tb and are therefore believed to play a role in pathogen persistence. Thus, Treg depletion has been postulated as a novel strategy to potentiate M. bovis BCG vaccination on one side, while on the other, employed as a therapeutic approach during chronic Tb infection. Yet since Tregs are critically involved in controlling autoimmune inflammation, elimination of Tregs may therefore also incur the danger of an excessive inflammatory immune response. Thus, understanding the dynamics and function of Tregs during mycobacterial infection is crucial to evaluate the potential of Treg depletion as a medical option. To address this, we depleted Tregs after infection with M. bovis BCG or Mycobacterium tuberculosis (Mtb) using DEREG mice, which express the diphtheria toxin (DT) receptor under the control of the FoxP3 locus, thereby allowing the selective depletion of FoxP3⁺ Tregs. Our results show that after depletion, the Treg niche is rapidly refilled by a population of DT-insensitive Tregs (diTregs) and bacterial load remains unchanged. On the contrary, impaired rebound of Tregs in DEREG × FoxP3^GFP mice improves pathogen burden, but is accompanied by detrimental autoimmune inflammation. Therefore, our study provides the proof-of-principle that, although a high degree of Treg depletion may contribute to the control of mycobacterial infection, it carries the risk of autoimmunity.     

PRO-C3-Levels in Patients with HIV/HCV-Co-Infection Reflect Fibrosis Stage and Degree of Portal Hypertension

Background

Liver-related deaths represent the leading cause of mortality among patients with HIV/HCV-co-infection, and are mainly related to complications of fibrosis and portal hypertension. In this study, we aimed to evaluate the structural changes by the assessment of extracellular matrix (ECM) derived degradation fragments in peripheral blood as biomarkers for fibrosis and portal hypertension in patients with HIV/HCV co-infection.

Methods

Fifty-eight patients (67% male, mean age: 36.5 years) with HIV/HCV-co-infection were included in the study. Hepatic venous pressure gradient (HVPG) was measured in forty-three patients. The fibrosis stage was determined using FIB4 -Score. ECM degraded products in peripheral blood were measured using specific ELISAs (C4M, MMP-2/9 degraded type IV collagen; C5M, MMP-2/9 degraded type V collagen; PRO-C3, MMP degraded n-terminal propeptide of type III collagen).

Results

As expected, HVPG showed strong and significant correlations with FIB4-index (r_s = 0.628; p = 7*10⁻⁷). Interestingly, PRO-C3 significantly correlated with HVPG (r_s = 0.354; p = 0.02), alanine aminotransferase (r_s = 0.30; p = 0.038), as well as with FIB4-index (r_s = 0.3230; p = 0.035). C4M and C5M levels were higher in patients with portal hypertension (HVPG>5 mmHg).

Conclusion

PRO-C3 levels reflect liver injury, stage of liver fibrosis and degree of portal hypertension in HIV/HCV-co-infected patients. Furthermore, C4M and C5M were associated with increased portal pressure. Circulating markers of hepatic ECM remodeling might be helpful in the diagnosis and management of liver disease and portal hypertension in patients with HIV/HCV coinfection.     

Associations between Depression and Diabetes in the Community: Do Symptom Dimensions Matter? Results from the Gutenberg Health Study

Objectives

While a bidirectional relationship between diabetes and depression has been established, there is little knowledge if the associations are due to somatic-affective or cognitive-affective dimensions of depression.

Research Design and Methods

In a population-based, representative survey of 15.010 participants we therefore studied the associations of the two dimensions of depression with diabetes and health care utilization among depressed and diabetic participants. Depression was assessed by the Patient Health Questionnaire PHQ-9.

Results

We found a linear and consistent association between the intensity of depression and the presence of diabetes increasing from 6.9% in no or minimal depression to 7.6% in mild, 9% in moderate and 10.5% in severe depression. There was a strong positive association between somatic-affective symptoms but not with cognitive-affective symptoms and diabetes. Depression and diabetes were both independently related to somatic health care utilisation.

Conclusions

Diabetes and depression are associated, and the association is primarily driven by the somatic-affective component of depression. The main limitation of our study pertains to the cross-sectional data acquisition. Further longitudinal work on the relationship of obesity and diabetes should differentiate the somatic and the cognitive symptoms of depression.     

Murine Endoscopy for In Vivo Multimodal Imaging of Carcinogenesis and Assessment of Intestinal Wound Healing and Inflammation

Mouse models are widely used to study pathogenesis of human diseases and to evaluate diagnostic procedures as well as therapeutic interventions preclinically. However, valid assessment of pathological alterations often requires histological analysis, and when performed ex vivo, necessitates death of the animal. Therefore in conventional experimental settings, intra-individual follow-up examinations are rarely possible. Thus, development of murine endoscopy in live mice enables investigators for the first time to both directly visualize the gastrointestinal mucosa and also repeat the procedure to monitor for alterations. Numerous applications for in vivo murine endoscopy exist, including studying intestinal inflammation or wound healing, obtaining mucosal biopsies repeatedly, and to locally administer diagnostic or therapeutic agents using miniature injection catheters. Most recently, molecular imaging has extended diagnostic imaging modalities allowing specific detection of distinct target molecules using specific photoprobes. In conclusion, murine endoscopy has emerged as a novel cutting-edge technology for diagnostic experimental in vivo imaging and may significantly impact on preclinical research in various fields.