Chressen C. Remus

Progesterone and HMOX-1 promote fetal growth by CD8 + T cell modulation

Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies in Western societies. IUGR is a strong predictor of reduced short-term neonatal survival and impairs long-term health in children. Placental insufficiency is often associated with IUGR; however, the molecular mechanisms involved in the pathogenesis of placental insufficiency and IUGR are largely unknown. Here, we developed a mouse model of fetal-growth restriction and placental insufficiency that is induced by a midgestational stress challenge. Compared with control animals, pregnant dams subjected to gestational stress exhibited reduced progesterone levels and placental heme oxygenase 1 (Hmox1) expression and increased methylation at distinct regions of the placental Hmox1 promoter. These stress-triggered changes were accompanied by an altered CD8+ T cell response, as evidenced by a reduction of tolerogenic CD8+CD122+ T cells and an increase of cytotoxic CD8+ T cells. Using progesterone receptor- or Hmox1-deficient mice, we identified progesterone as an upstream modulator of placental Hmox1 expression. Supplementation of progesterone or depletion of CD8+ T cells revealed that progesterone suppresses CD8+ T cell cytotoxicity, whereas the generation of CD8+CD122+ T cells is supported by Hmox1 and ameliorates fetal-growth restriction in Hmox1 deficiency. These observations in mice could promote the identification of pregnancies at risk for IUGR and the generation of clinical interventional strategies.

Evaluation of four different optimized magnetic-resonance-imaging sequences for visualization of dental and maxillo-mandibular structures at 3 T

OBJECTIVES The purpose of this study was to evaluate four in-house optimized, non-contrast enhanced sequences for MRI-investigation of maxillo-mandibular and dental structures by use of 3 T. METHODS 12 volunteers with different dental status were examined by using a 3 T MRI with a 20-channel standard head-and-neck coil. All images performed were evaluated by using 3D-techniques, with different slice-thicknesses, in 3D T1- and T2-weighted sequences, as well as by using new techniques of image depictions. In addition phantom measurements were performed to estimate the extent of image artefacts caused by retainers and metal implants. RESULTS Mean age of the participants was 33 years (range, 25.5-62.75 years), and the sex ratio was 5 females to 7 males. We identified different techniques to improve osseous and dental structures, despite problems caused by dental implants, tooth crowns or braces. CONCLUSION The sequences evaluated offered excellent visualization in 2D and 3D of osseous and dental structures. Anatomical, osseous and dental structures were described at their ROI, in relation to patients with dental and head and neck pathologies. The ability to detect and distinguish pathological processes as soon as possible in 3D with excellent image quality avoiding ionizing radiation remains a challenging domain.

Application of the steepest slope model reveals different perfusion territories within the mouse placenta

OBJECTIVES The steepest slope model is a numerically robust and fast method for perfusion quantification. The purpose of this study was to evaluate if the steepest slope model can be used for quantifying placental perfusion in mice based on dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) datasets. MATERIAL AND METHODS T1-weighted DCE MRI was performed in 5 pregnant BALB/c mice on gestation day (gd) 14.5 and in 5 mice on gd 16.5 using a 7T small animal MRI scanner. The placentas were manually delineated in the DCE datasets and the arterial input function (AIF) was selected from the kidney hilus. Placental perfusion was determined on a voxel-by-voxel basis using the steepest slope model. Perfusion was averaged over the entire placenta as well as separately calculated for the high-flow compartment within the central labyrinth zone and for the remaining low-flow placenta tissue. The AIF selection was independently performed by two observers for assessment of inter-observer differences. RESULTS Mean perfusion on gd 14.5 was 135 ml/min/100 ml (standard deviation SD: 29 ml/min/100 ml placenta) and 112 ml/min/100 ml on gd 16.5 for the whole placenta (SD: 32 ml/min/100 ml). Perfusion in the high flow compartment in the central labyrinth was significantly higher (p ≤ 0.002) than in the low-flow compartment including the remaining placenta tissue: 184 ml/min/100 ml (SD: 39 ml/min/100 ml) vs. 119 ml/min/100 ml (SD 28 ml/min/100 ml) on gd 14.5 and 158 ml/min/100 ml (SD: 58 ml/min/100 ml) vs. 114 ml/min/100 ml (SD: 52 ml/min/100 ml of placenta) on gd 16.5. The mean relative inter-rater observer difference was 6%. CONCLUSION The steepest slope model is a computationally simple method, which allows perfusion quantification in the mouse placenta. Furthermore, the results of this work indicate that the different placental compartments should be analyzed separately to prevent biased results due to averaging.

Early detection of pulp necrosis and dental vitality after traumatic dental injuries in children and adolescents by 3-Tesla magnetic resonance imaging

OBJECTIVES More than 50% of all children suffer a traumatic dental injury (TDI) during childhood. In many cases, dentists apply root canal treatment (RCT), which is performed on an average of 7-10 days after replantation. Our aim was to evaluate whether RCT is necessary in many cases, and whether revitalization of affected teeth is possible and measurable by visualization using 3T magnetic resonance imaging (MRI). MATERIAL AND METHODS Seven healthy children with TDI were treated by repositioning of the affected teeth and reduction of alveolar process fractures followed by splinting. Two weeks after initial treatment, splints were removed. After 6 weeks, all children received 3-Tesla (3T), three-dimensional, high-resolution MRI with a 20-channel standard head and neck coil. The mean age of the children (male/female = 5:2) was 10.8 years (range, 8-17 years). In addition, all children received conventional dental examination for tooth vitality and dental sensitivity to cold and tenderness on percussion. RESULTS 3T MRI provided excellent images that allowed fine discrimination between dental pulp and adjacent tooth. Using four in-house optimized, non-contrast-enhanced sequences, including panoramic reconstruction, the assessment and analysis of the dental pulp was sufficiently feasible. We could demonstrate reperfusion and thus vitality of the affected teeth in 11 sites. In one child, MRI was able to detect nonreperfusion after TDI of the affected tooth. MRI results were confirmed by clinical examination in all cases. As a consequence of this expectant management and proof of reperfusion and tooth vitality by 3T MRI, only one child had to be treated by RCT. CONCLUSION 3T MRI is a very promising tool for visualization and detection in the field of dental and oromaxillofacial diseases. By using new 3T MRI sequences in children with TDI, we could demonstrate that RCT are not necessary in every case, and thus could prevent unnecessary treatment of children in the future. Larger studies should follow to confirm the potential benefit in clinical practice.

Intraindividual comparison of preoperative 99mTc-MDP SPECT/CT and intraoperative and histopathological findings in patients with bisphosphonate- or denosumab-related osteonecrosis of the jaw

PURPOSE Bisphosphonate- or denosumab-related osteonecrosis of the jaw (BRONJ/DRONJ) requires reliable preoperative assessment of the extent of disease for surgical planning. The aim of this study was to compare the extent of BRONJ/DRONJ as detected by Tc-99m-methylene diphosphonate (MDP) bone scintigraphy with intraoperative and histopathological findings, and to assess the additional value of hybrid single photon emission computed tomography/computed tomography (SPECT/CT) for evaluation of disease. MATERIAL AND METHODS Twenty-one patients with BRONJ/DRONJ underwent three-phase bone scintigraphy including SPECT/CT. The diagnostic certainty using conventional SPECT or fused SPECT/CT imaging was compared. Location and extent of disease on scintigraphic imaging and pre- and intra-operative clinical assessment were compared. Intraoperative and histopathological findings served as reference standard. RESULTS A total of 29 sites of BRONJ/DRONJ were histopathologically confirmed in 21 patients. Bone scintigraphy demonstrated increased perfusion in 57.1% of patients, increased blood pool in 76.2%, and increased tracer accumulation at the metabolic phase in all patients. The intensity of tracer accumulation at the metabolic phase correlated significantly with clinical stage of disease (rs = 0.47, p = 0.03). Clinical examination (p < 0.0001), but not SPECT (p = 0.19), underestimated the extent of disease as determined by surgical evaluation. SPECT/CT offered a significantly higher diagnostic certainty (p < 0.0001). CONCLUSION In patients with BRONJ/DRONJ, the true extent of osseous lesions as determined by surgery is significantly underestimated by clinical examination. Tc-99m-MDP bone scintigraphy can reliably predict the extent of disease. Hybrid SPECT/CT may significantly increase the diagnostic certainty of anatomical localization.

DCE MRI reveals early decreased and later increased placenta perfusion after a stress challenge during pregnancy in a mouse model

OBJECTIVES Stress during pregnancy is known to have negative effects on fetal outcome. The purpose of this exploratory study was to examine placental perfusion alterations after stress challenge during pregnancy in a mouse model. MATERIAL AND METHODS Seven Tesla MRI was performed on pregnant mice at embrionic day (ED) 14.5 and 16.5. Twenty dams were exposed to an established acoustic stress challenge model while twenty non-exposed dams served as controls. Placental perfusion was analyzed in dynamic contrast-enhanced (DCE) MRI using the steepest slope model. The two functional placental compartments, the highly vascularized labyrinth and the endocrine junctional zone, were assessed separately. RESULTS Statistical analysis revealed decreased perfusion levels in the stress group at ED 14.5 compared to controls in both placenta compartments. On ED 16.5, the perfusion level increased significantly in the stress group while placenta perfusion in controls remained similar or even slightly decreased leading to an overall increased perfusion in the stress group on ED 16.5 compared to controls. CONCLUSION MR imaging allows noninvasive placenta perfusion assessment in this fetal stress mimicking animal model. In this exploratory study, we demonstrated that stress challenge during pregnancy leads to an initial reduction followed by an increase of placenta perfusion.