The transverse aortic constriction heart failure animal model: a systematic review and meta-analysis

Heart Failure Reviews - The transverse aortic constriction (TAC) model is frequently used to study adverse cardiac remodeling upon pressure overload. We set out to define the most important...     

Competitive clonal hematopoiesis in mouse chimeras explained by a stochastic model of stem cell organization

Many current experimental results show the necessity of new conceptual approaches to understand hematopoietic stem cell organization. Recently, we proposed a novel theoretical concept and a corresponding quantitative model based on microenvironment-dependent stem cell plasticity. The objective of our present work is to subject this model to an experimental test for the situation of chimeric hematopoiesis. Investigating clonal competition processes in DBA/2-C57BL/6 mouse chimeras, we observed biphasic chimerism development with initially increasing but long-term declining DBA/2 contribution. These experimental results were used to select the parameters of the mathematical model. To validate the model beyond this specific situation, we fixed the obtained parameter configuration to simulate further experimental settings comprising variations of transplanted DBA/2-C57BL/6 proportions, secondary transplantations, and perturbation of stabilized chimeras by cytokine and cytotoxic treatment. We show that the proposed model is able to consistently describe the situation of chimeric hematopoiesis. Our results strongly support the view that the relative growth advantage of strain-specific stem cells is not a fixed cellular property but is sensitively dependent on the actual state of the entire system. We conclude that hematopoietic stem cell organization should be understood as a flexible, self-organized rather than a fixed, preprogrammed process.     

Selective hepatobiliary transport of nordeoxycholate side chain conjugates in mutant rats with a canalicular transport defect

Canalicular transport of bilirubin diglucuronide, dibromosulfophthalein and several glutathione conjugates is deficient in mutant TR- rats. In contrast, transport of cholyltaurine (taurocholate), a conjugated bile acid, is normal. Previous studies using normal rats have shown that C23 nor-dihydroxy bile acids are conjugated with sulfate or glucuronide during hepatic transport in contrast to the natural C24 bile acids, which are amidated with glycine or taurine. Studies were performed to test the hypothesis that (a) in the TR- rat, nordeoxycholate would be conjugated with glucuronate or sulfate just as in the normal rat, and (b) that such conjugates would have defective biliary secretion. [C23-14C]Nordeoxycholate was administered intravenously to bile fistula rats (TR- and normal), and the biliary recovery of metabolites was assessed by chromatography and mass spectrometry. In both groups of rats, the major biotransformation product of nordeoxycholate was the side chain (23-ester) glucuronide. Conjugation on the nucleus with sulfate and glucuronide at the 3-position (ethereal linkage) also occurred, as well as amidation at the C23 carboxylic acid group. In the mutant rats, biliary secretion of the 3-sulfate and 3-glucuronide conjugates was less than 10% and 1%, respectively, of that of normal rats, whereas biliary secretion of the 23-ester glucuronide and the 23-taurine amidate, as well as unchanged nordeoxycholate, was not decreased. Canalicular secretion of nor-bile acid 3-ether glucuronides and 3-sulfates appears to involve the "bilirubin transport system," which is deficient in mutant rats. Canalicular secretion of unconjugated, amidated or esterified nordeoxycholate is mediated via another pathway, probably the "bile acid transport system."(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of chest tube administration of tissue plasminogen activator to treat retained hemothorax

Background

When retained hemothorax occurs, video-assisted thoracoscopy or thoracotomy is performed, but recently, tissue plasminogen activator (tPA) has been used. This study evaluated intrapleural tPA use for retained traumatic hemothoraces.

Methods

A retrospective review was conducted of trauma patients treated with intrapleural tPA for retained hemothorax. Data included demographics, past medical and surgical histories, injury details, treatment details, and outcomes.

Results

Seven patients (median age = 47 years, male = 6, blunt trauma = 6) met study criteria. All patients received a chest tube. Six patients later received computed tomography-guided drains for tPA infusion. Number of tPA treatments per patient varied from 1 to 5. Median total tPA dosage was 24 mg. Median time from injury to chest tube placement was 11 days and from chest tube placement to first tPA treatment was 4 days. No patients required a video-assisted thoracoscopy; however, 1 patient required thoracotomy. There were no deaths or bleeding complications attributed to intrapleural tPA.

Conclusion

Although future studies are needed to identify optimum treatment guidelines, intrapleural tPA appears to be a safe and efficacious treatment option.     

A longitudinal VBM study in paediatric obsessive–compulsive disorder at 2-year follow-up after cognitive behavioural therapy

Objectives. To identify neurodevelopmental differences in regional brain volume between medication-free paediatric obsessive–compulsive disorder (OCD) patients and controls at 2-year follow-up after cognitive behavioural therapy. Methods. We assessed 17 medication-free paediatric OCD patients (mean age 13.8 years; SD = 2.8; range 8.2–19.0) and 20 controls, matched on age and gender, with T1-weighted MR scans in a repeated measures design at three time points with intervals of 6 months and 2 years. Voxel based morphometry (VBM) was used to test whole brain voxel-wise for the effects of diagnosis and time on regional grey matter (GM) and white matter volumes. Results. GM volume of the orbitofrontal cortex showed a group × time interaction effect, driven by an increase of GM volume over the whole time period in OCD patients and a decrease in controls. When splitting the groups in two age groups (8–12 and 13–19 years) this interaction effect was only seen in the youngest age group. Conclusions. Neuroimaging findings in paediatric OCD after 6 months of CBT in the GM volume of the orbital frontal cortex are still present at 2-year follow-up.     

Excreted/secreted Trichuris suis products reduce barrier function and suppress inflammatory cytokine production of intestinal epithelial cells

The administration of helminths is considered a promising strategy for the treatment of autoimmune diseases due to their immunomodulatory properties. Currently, the application of the helminth Trichuris suis as a treatment for Crohn's disease is being studied in large multi-center clinical trials. The intestinal epithelium forms an efficient barrier between the intestinal lumen containing the microbial flora and helminths, and dendritic cells (DCs) present in the lamina propria that determine the T_H response. Here, we investigated how excreted/secreted (E/S) products of T. suis affect the barrier function of intestinal epithelial cells (IECs) in order to reach the DCs and modulate the immune response. We show that T. suis E/S products reduce the barrier function and the expression of the tight junction proteins EMP-1 and claudin-4 in IEC CMT93/69 monolayers in a glycan-dependent manner. This resulted in an increased passage of soluble compounds to the basolateral side that affected DC function. In addition, T. suis E/S suppressed LPS-induced pro-inflammatory cytokine production by CMT93/69 cells, whereas the production of the T_H2 response-inducing cytokine thymic stromal lymphopoietin (TSLP) was induced. Our studies indicate that T. suis E/S glycans affect the function of the intestinal epithelium in order to modulate DC function. Identification of the T. suis E/S glycans that modulate IEC and DC function may lead to a strategy to reduce symptoms of autoimmune and allergic immune diseases by orally administrated helminth-derived factors without the need of infection with live helminths.     

Long-term outcome after fetal transfusion for hydrops associated with parvovirus B19 infection

OBJECTIVE: To evaluate neurodevelopmental status of children treated with intrauterine red blood cell and platelet transfusion for fetal hydrops caused by parvovirus B19. METHODS: Maternal and neonatal records of all intrauterine transfusions for congenital parvovirus B19 infection in our center between 1997 and 2005 were reviewed. Congenital B19 virus infection was confirmed by the presence of parvovirus B19-specific immunoglobulin M or parvovirus B19 DNA in fetal blood samples. All children underwent a general pediatric and neurological examination. Primary outcome measure was neurodevelopmental status (developmental index by Bayley Scales of Infant Development or Snijders-Oomen test). Secondary outcome measure was general health status of surviving children. RESULTS: A total of 25 intrauterine transfusions were performed in 24 hydropic fetuses. Median fetal hemoglobin concentration, platelet count, and blood pH before intrauterine transfusions were 4.5 g/dL (range 2.4-11.4 g/dL), 79x10(9)/L (range 37-238x10(9)/L) and 7.36 (range 7.31-7.51), respectively. Sixteen survivors aged 6 months to 8 years were included in the follow-up study. Eleven children (68%) were normal, and 5 children (32%) demonstrated a delayed psychomotor development with an suboptimal neurological examination (mild delay n=3, severe delay n=2). Neurodevelopmental status did not correlate with pre-intrauterine transfusion hemoglobin, platelet, or blood pH values. Growth and general health status were normal in all. Two children had minor congenital defects. CONCLUSION: Neurodevelopmental status was abnormal in 5 of 16 survivors and was not related to the severity of fetal anemia and acidemia. We hypothesize that fetal parvovirus B19 infection may induce central nervous system damage. LEVEL OF EVIDENCE: III.     

Reforms in VUmc School of Medical Sciences Amsterdam: Student engagement,a Minor elective semester and stakeholder collaboration in improving the quality of assessments

Abstract

Background: At VUmc School of Medical Sciences, major curricular reforms occurred in 2005 and 2015, related to the introduction of a Bachelor-Master structure, a new legislation from the Ministry of Education, the changing societal context, and taking note of students’ and teachers’ needs.

Summary of work: Along with the introduction of the Bachelor-Master system, the period between 2005 and 2009 saw the movement from traditional lecture-based teaching to small group teaching in a competency-based curriculum, in which the students were responsible for their learning. Student engagement grew through students’ designing learning modules and conducting some of the teaching. In the Bachelor program, an elective “Minor”, was designed to broaden and deepen the knowledge of our students beyond the core learning outcomes, in a discipline of their choice. The examination board (EB), responsible for maintaining the quality of assessment, was split into the General EB, which handled overall strategy issues, and the Executive EB, which handled student requests and monitored the quality of assessments.

Lessons learned: Students develop a sense of what education is about if they are provided opportunities in designing teaching and conducting it. A Minor elective in the medical study can provide the students with an opportunity to learn outside the medical field. Collaborative working between different stakeholders in a medical school is crucial for safeguarding the quality of assessments. Curricular reforms need time to be accepted and integrated into the culture of the medical school. The educational vision needs to be refreshed regularly in alignment with the changing societal context.