Extensive hepatic infarction in severe preeclampsia as part of the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): Evolution of CT findings and successful treatment with plasma exchange therapy

AbstractObjectiveWe describe the serial computed tomography (CT) findings of extensive hepatic infarction and successful plasma exchange therapy in a severe preeclamptic woman with postpartum HELLP syndrome.Case ReportA 38 year-old woman presented with elevated blood pressure of 140–180/90–120 mmHg and 3+ proteinuria at 28 weeks of gestation. Two days after admission, the patient suddenly complained of severe epigastric pain and headache. Her blood pressure rose sharply to 195/120 mmHg. A 980 g female was delivered by emergency cesarean section. Following delivery, the patient's clinical condition and laboratory values deteriorated, with progressive liver insufficiency (peak AST level = 4246 IU/L, ALT = 3685 IU/L, LDH = 6237 IU/L, platelets = 72,000/mm3). Two consecutive plasma exchanges (PEX) were undertaken on the 3rd and 4th postpartum day. A contrast-enhanced CT of the abdomen performed 8 days postpartum showed geographically wedge-shaped areas of low attenuation, with a mottled appearance in the right hepatic lobe. Shortly thereafter, the patient recovered and all laboratory parameters gradually normalized 3 weeks after delivery. Follow-up CT-scan of the liver 2 months postpartum showed no evidence of infarction, with complete recovery.ConclusionWe recommend that severely ill patients with HELLP syndrome having epigastric pain should undergo CT imaging of the liver. A trial of postpartum PEX therapy should be considered for treatment of the HELLP syndrome complicated with hepatic infarction, which is recalcitrant to conventional medical management, and fails to abate within 72–96 hours of delivery

Stonin1 mediates endocytosis of the proteoglycan NG2 and regulates focal adhesion dynamics and cell motility

Cellular functions, ranging from focal adhesion (FA) dynamics and cell motility to tumour growth, are orchestrated by signals cells receive from outside via cell surface receptors. Signalling is fine-tuned by the exo-endocytic cycling of these receptors to control cellular responses such as FA dynamics, which determine cell motility. How precisely endocytosis regulates turnover of the various cell surface receptors remains unclear. Here we identify Stonin1, an endocytic adaptor of unknown function, as a regulator of FA dynamics and cell motility, and demonstrate that it facilitates the internalization of the oncogenic proteoglycan NG2, a co-receptor of integrins and platelet-derived growth factor receptor. Embryonic fibroblasts obtained from Stonin1-deficient mice display a marked surface accumulation of NG2, increased cellular signalling and defective FA disassembly as well as altered cellular motility. These data establish Stonin1 as a specific adaptor for the endocytosis of NG2 and as an important factor for FA dynamics and cell migration

Stonin1 mediates endocytosis of the proteoglycan NG2 and regulates focal adhesion dynamics and cell motility

Cellular functions, ranging from focal adhesion (FA) dynamics and cell motility to tumour growth, are orchestrated by signals cells receive from outside via cell surface receptors. Signalling is fine-tuned by the exo-endocytic cycling of these receptors to control cellular responses such as FA dynamics, which determine cell motility. How precisely endocytosis regulates turnover of the various cell surface receptors remains unclear. Here we identify Stonin1, an endocytic adaptor of unknown function, as a regulator of FA dynamics and cell motility, and demonstrate that it facilitates the internalization of the oncogenic proteoglycan NG2, a co-receptor of integrins and platelet-derived growth factor receptor. Embryonic fibroblasts obtained from Stonin1-deficient mice display a marked surface accumulation of NG2, increased cellular signalling and defective FA disassembly as well as altered cellular motility. These data establish Stonin1 as a specific adaptor for the endocytosis of NG2 and as an important factor for FA dynamics and cell migration

Controlled Release of Therapeutics from Thermoresponsive Nanogels: A Thermal Magnetic Resonance Feasibility Study

Thermal magnetic resonance (ThermalMR) accommodates radio frequency (RF)-induced temperature modulation, thermometry, anatomic and functional imaging, and (nano)molecular probing in an integrated RF applicator. This study examines the feasibility of ThermalMR for the controlled release of a model therapeutics from thermoresponsive nanogels using a 7.0-tesla whole-body MR scanner en route to local drug-delivery-based anticancer treatments. The capacity of ThermalMR is demonstrated in a model system involving the release of fluorescein-labeled bovine serum albumin (BSA-FITC, a model therapeutic) from nanometer-scale polymeric networks. These networks contain thermoresponsive polymers that bestow environmental responsiveness to physiologically relevant changes in temperature. The release profile obtained for the reference data derived from a water bath setup used for temperature stimulation is in accordance with the release kinetics deduced from the ThermalMR setup. In conclusion, ThermalMR adds a thermal intervention dimension to an MRI device and provides an ideal testbed for the study of the temperature-induced release of drugs, magnetic resonance (MR) probes, and other agents from thermoresponsive carriers. Integrating diagnostic imaging, temperature intervention, and temperature response control, ThermalMR is conceptually appealing for the study of the role of temperature in biology and disease and for the pursuit of personalized therapeutic drug delivery approaches for better patient care

Electrothermal soft manipulator enabling safe transport and handling of thin cell/tissue sheets and bioelectronic devices

“Living” cell sheets or bioelectronic chips have great potentials to improve the quality of diagnostics and therapies. However, handling these thin and delicate materials remains a grand challenge because the external force applied for gripping and releasing can easily deform or damage the materials. This study presents a soft manipulator that can manipulate and transport cell/tissue sheets and ultrathin wearable biosensing devices seamlessly by recapitulating how a cephalopod’s suction cup works. The soft manipulator consists of an ultrafast thermo-responsive, microchanneled hydrogel layer with tissue-like softness and an electric heater layer. The electric current to the manipulator drives microchannels of the gel to shrink/expand and results in a pressure change through the microchannels. The manipulator can lift/detach an object within 10 s and can be used repeatedly over 50 times. This soft manipulator would be highly useful for safe and reliable assembly and implantation of therapeutic cell/tissue sheets and biosensing devices

Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1

Susceptibility to obesity is linked to genes regulating neurotransmission, pancreatic beta-cell function and energy homeostasis. Genome-wide association studies have identified associations between body mass index and two loci near cell adhesion molecule 1 (CADM1) and cell adhesion molecule 2 (CADM2), which encode membrane proteins that mediate synaptic assembly. We found that these respective risk variants associate with increased CADM1 and CADM2 expression in the hypothalamus of human subjects. Expression of both genes was elevated in obese mice, and induction of Cadm1 in excitatory neurons facilitated weight gain while exacerbating energy expenditure. Loss of Cadm1 protected mice from obesity, and tract-tracing analysis revealed Cadm1-positive innervation of POMC neurons via afferent projections originating from beyond the arcuate nucleus. Reducing Cadm1 expression in the hypothalamus and hippocampus promoted a negative energy balance and weight loss. These data identify essential roles for Cadm1-mediated neuronal input in weight regulation and provide insight into the central pathways contributing to human obesity.</p

Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations

We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) 1-3 of esophageal squamous cell carcinoma (ESCC) in ethnic Chinese (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study, and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% CI 0.82-0.88; P=7.72x10−20) and rs1642764 at 17p13.1 (per-allele OR= 0.88, 95% CI 0.85-0.91; P=3.10x10−13). rs7447927 is a synonymous single nucleotide polymorphism (SNP) in TMEM173 and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR=1.33, 95% CI 1.22-1.46; P=1.99x10−10). Our joint analysis identified new ESCC susceptibility loci overall as well as a new locus unique to the ESCC high risk Taihang Mountain region

Durch lösliche Faktoren vermittelte Interaktion zwischen Gliomzellen und intrinsischen Hirnzellen

High grade gliomas (HG-glioma) are the most common primary brain tumors. Their malignancy depends on complex crosstalk between different cell types in the CNS. Our group has previously shown that endogenous neural progenitor cells (NPC) contribute to glioma regression; conversely, brain resident immune cells (microglia) infiltrate gliomas and contribute to their growth progression. Thus, understanding the component of glioma microenvironment is a crucial goal for glioma therapy. In this thesis, I aimed to identify soluble factors secreted by glioma cells which could mediate glioma-CNS cells interaction. To identify these factors, I established a protocol to encapsulate glioma cells into a hollow fiber (HF) which allows the passage of diffusible molecules, but not cells. By utilizing the HF model, I first demonstrated the infiltration of microglia and NPC although glioma cells were entrapped in isolated fiber while NG2 cells were not affected. Astrocytes surrounding the HF showed increased GFAP immunoreactivity, a marker of astrogliosis. Furthermore, human glioma cells can also be encapsulated in HF and were similarly effective in attracting microglial cells or increasing astrogliosis in mouse brain. I showed here for the first time that GDNF is a chemo-attractant for microglia. Data from various migration assays and in vivo test suggest that GDNF, a known neurotrophic factor for neurons, which is released by glioma cells, has chemotaxis effect on microglia. Further reducing GDNF secretion from glioma cells by siRNA approach, the recruitment of microglia toward glioma HF was significantly diminished while astrogliosis was not affected. Conversely, forced secretion of GDNF from fibroblast cells increased microglia infiltration. All together, I found that GDNF plays a pivotal role in microglia infiltration but not astrocytes. Finally, to confirm if attenuation of microglia migration can further influence glioma growth, stable GDNF knockdown in glioma by shRNA method was conducted. When implanting GDNF knockdown glioma cells into mouse brain, smaller tumor was formed and the survival of mice improved. In conclusion, I identified GDNF as a HG-glioma released factor which specifically leads to microglial attraction and thereby serves a tumor promoting role. This study supports the idea that microglia play an important role in tumor growth, invasion and progression and thus can become a novel target for therapeutic strategies.Das Glioblastoma multiforme (GBM) zählt zu den häufigsten primären Hirntumoren, deren Malignität von komplexen Wechselwirkungen zwischen verschiedenen Zelltypen des Zentralen Nervensystems abhängt. In vorangegangenen Arbeiten konnte unsere Gruppe zeigen, das Endogene Neuronale Progenitorzellen zur Gliom Regression beiträgt. Im Gegensatz dazu infiltrieren Immunzellen des Gehirns, sogenannte Gliazellen, Gliome und tragen zur Tumorprogression bei. Daher ist es unerlässlich die Gliom-Umgebung und deren Wechselwirkungen genauer zu verstehen um Gliom-Therapien zu verbessern. Das Ziel dieser vorgelegten Doktorarbeit ist es, Faktoren zu identifizieren, die von Gliom-Zellen sezerniert werden und eine Wechselwirkung zwischen Gliom- Zellen und Zellen des Zentralen Nervensystems vermitteln. Um diese Faktoren zu identifizieren, habe ich ein Protokoll etabliert, bei dem Gliom-Zellen in eine Hohlfaser (HF) eingekapselt werden. Die HF erlaubt den Austausch löslicher Stoffe, verhindert aber den Austritt von Zellen und somit einen direkten Zell- Kontakt. Mit der Anwendung des HF Modells konnte ich zeigen, dass eingekapselte und ins Mausgehirn transplantierte Gliom-Zellen zu einer Infiltrierung durch Mikroglia und Neuronale Progenitorzellen führen. Eine Infiltrierung durch NG2 Zellen wurde nicht beobachtet. Astrozyten die die transplantierte HF umgeben wiesen eine erhöhte GFAP Immunoreaktivität auf, einem Marker für Astrogliose. Außerdem führte die Einkapselung von humanen Gliom-Zellen im gleichen Maße zur Infiltrierung durch Mikroglia und Astrogliose führten. Im Weiteren konnte ich erstmals zeigen, das GDNF ein Chemotaktischer Faktor für Mikroglia ist. Verschiedene Migrations-Assay und in vivo Experimente haben verdeutlicht, dass GDNF, ein bekannter neurotropischer Faktor für Neuronen der von Gliom-Zellen sezerniert wird, einen Chemotaktischen Einfluss auf Mikroglia hat. Die Reduzierung der GDNF Sekretion von Gliom-Zellen durch siRNAs führte zur Reduzierung der Mikroglia- Infiltrierung, wobei die Astrogliose unverändert blieb. Im Gegensatz dazu führte die Überexpression von GDNF in Fibroblasten zu einer erhöhten Infiltrierung durch Mikroglia. In dieser Studie konnte ich zeigen, dass GDNF eine zentrale Rolle bei der Infiltrierung durch Mikroglia spielt, die Astrogliose jedoch nicht beeinflusst. Um zuletzt zu zeigen, dass die verminderte Infiltrierung durch Mikroglia das Gliom-Wachstum beeinflusst, wurde die GDNF Sekretion in Gliom-Zellen mittels shRNA stabil vermindert. Die Implantation von GDNF Knockdown Gliom-Zellen ins Mausgehirn, resultierte in kleineren Tumoren und das Überleben der Maus wurde verlängert. Zusammenfassend bleibt festzuhalten, dass ich GDNF als Gliom-sezernierten Faktor identifiziert habe, der spezifisch zur Attraktion von Mikroglia führt und somit zum Tumorwachstum beiträgt. Diese Arbeit verdeutlicht die Rolle von Mikroglia beim Wachstum, der Invasion und der Progression von Tumoren und stellt daher einen neuartigen potentiellen Therapieansatz da

Myocardial T2* Mapping with Ultrahigh Field Magnetic Resonance: Physics and Frontier Applications

Cardiovascular magnetic resonance imaging (CMR) has become an indispensable clinical tool for the assessment of morphology, function and structure of the heart muscle. By exploiting quantification of the effective transverse relaxation time (T2*) CMR also affords myocardial tissue characterization and probing of cardiac physiology, both being in the focus of ongoing research. These developments are fueled by the move to ultrahigh magnetic field strengths, which permits enhanced sensitivity and spatial resolution that help to overcome limitations of current clinical MR systems with the goal to contribute to a better understanding of myocardial (patho)physiology in vivo. In this context, the aim of this report is to introduce myocardial T2* mapping at ultrahigh magnetic fields as a promising technique to non-invasively assess myocardial (patho)physiology. For this purpose the basic principles of T2* assessment, the biophysical mechanisms determining T2* and (pre)clinical applications of myocardial T2* mapping are presented. Technological challenges and solutions for T2* sensitized CMR at ultrahigh magnetic field strengths are discussed followed by a review of acquisition techniques and post-processing approaches. Preliminary results derived from myocardial T2* mapping in healthy subjects and cardiac patients at 7.0 T are presented. A concluding section discusses remaining questions and challenges and provides an outlook on future developments and potential clinical applications