Arterial haptoglobin : expression, regulation and function

Several studies have demonstrated that collagen turnover is important during arterial restructuring. However, the precise mediators involved in collagen turnover are still not known. In order to develop specific inhibitors to prevent arterial restructuring, it is essential to get a better understanding of the molecular pathways involved in collagen turnover. In this thesis, we used a subtraction PCR to identify new candidate proteins that are involved in arterial restructuring and to get a better insight in these pathways. One of the identified proteins using subtraction PCR was the acute phase glycoprotein haptoglobin. Haptoglobin was found to be expressed by adventitial fibroblasts, early after flow changes. In vitro assays demonstrated that haptoglobin is a gelatinase inhibitor and important for cell migration. Furthermore, haptoglobin knockout mice demonstrated delayed arterial restructuring after flow changes. As NO plays an important role in flow-induced arterial restructuring, we investigated whether arterial haptoglobin expression was regulated via NO. Inhibition of NO synthesis by a aspecific NOS-inhibitor resulted in decreased arterial haptoglobin expression. This coincided with decreased arterial IL-6 expression, which is a well described regulator of haptoglobin expression in the liver. IL-6 knockout mice were used to confirm a regulatory role of IL-6 in arterial haptoglobin expression. However, haptoglobin expression was normal in IL-6 knockout mice, pointing to back-up mechanisms for the regulation of haptoglobin expression. Previously, sero-epidemiological studies have demonstrated that arthritis and cancer are characterized by increased serum haptoglobin levels. In this thesis, we demonstrated that local expression of haptoglobin is increased in these two pathological tissues that are characterized by enhanced cell migration and matrix turnover. As haptoglobin is present at high concentrations in the serum, the function of local haptoglobin expression is not completely understood. We therefore investigated whether alterations in haptoglobin glycosylation could explain the necessity of local haptoglobin expression. Haptoglobin expression and glycosylation was studied in balloon dilated rabbit arteries. Balloon dilation increased arterial haptoglobin expression within the first two weeks after injury whereas liver haptoglobin expression remained constant. There were no differences in arterial haptoglobin glycosylation patterns after balloon dilation. However, arterial haptoglobin was differentially glycosylated compared to liver haptoglobin and these arterial haptoglobin glycoforms could be detected in the serum. Previously, alterations in serum haptoglobin glycosylation have been associated with the progression and outcome of different diseases. As arterial haptoglobin has a characteristic glycosylation pattern, we investigated whether serum haptoglobin glycosylation patterns could serve as serum marker for atherosclerotic disease. There were, however, no differences were found in total serum haptoglobin levels or serum haptoglobin glycosylation patterns between patients with atherosclerosis and patients with only risk factors. In addition, no relation was found between total serum haptoglobin levels and glycosylation patterns with intima-media thickness in the carotid artery, which is a surrogate measure for the extent of atherosclerosis. These results indicate that serum haptoglobin glycosylation patterns are not suitable to use as serum marker for atherosclerotic diseas

The Psychiatric Case Register Middle Netherlands

<p>Abstract</p> <p>Background</p> <p>The Psychiatric Case Register Middle Netherlands (PCR-MN) registers the mental healthcare consumption of over Dutch 760,000 inhabitants in the centre of the Netherlands. In 2010 the follow-up period was over ten years. In this paper we describe the content, aims and research potential of this case register.</p> <p>Description</p> <p>All mental healthcare institutions in the middle-western part of the province of Utrecht participate in the PCR-MN case register. All in- and out-patients treated in these institutions have been included in the database from the period 2000 to 2010. Diagnosis according to DSM-IV on axis I to IV, visits to in- and out-patient clinics and basic demographics are recorded. A major advantage of this register is the possibility to link patients anonymously from the PCR-MN cohort to other databases to analyze relationships with determinants and outcomes, such as somatic healthcare consumption, mortality, and demographics, which further increases the research potential</p> <p>Conclusions</p> <p>The PCR-MN database has a large potential for scientific research because of its size, duration of follow-up and ability to link with additional databases, and is accessible for academic researchers.</p

SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids

Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human-induced pluripotent stem-cell-derived kidney organoids with SARS-CoV-2. Single-cell RNA sequencing indicated injury and dedifferentiation of infected cells with activation of profibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in long COVID

Neural correlates of intolerance of uncertainty in clinical disorders

Intolerance of uncertainty is a key contributor to anxiety-related disorders. Recent studies highlight its importance in other clinical disorders. The link between its clinical presentation and the underlying neural correlates remains unclear. This review summarizes the emerging literature on the neural correlates of intolerance of uncertainty. In conclusion, studies focusing on the neural correlates of this construct are sparse, and findings are inconsistent across disorders. Future research should identify neural correlates of intolerance of uncertainty in more detail. This may unravel the neurobiology of a wide variety of clinical disorders and pave the way for novel therapeutic targets

Bevacizumab for Intravitreal Injection: Impact of Sub-Visible Particles on the Shelf-Life of Repackaged Bevacizumab

Purpose: Bevacizumab (Avastin) is a humanized monoclonal antibody approved by the European Medicines Agency for the intravenous treatment of cancer. However, it is often used as an intravitreal injection for the treatment of macular degeneration or edema. For this purpose, bevacizumab is repackaged from glass vials into plastic syringes. The formation of particles during this compounding process as well as during storage is a source of concern. The aim of this study was to test the sub-visible particulate contamination in bevacizumab material, both in the glass vial and after repackaging into polycarbonate BD Luer-Lok™ syringes. Methods: Syringes with repackaged bevacizumab from 3 different compounding hospital pharmacies were tested for sub-visible particles at different time points during storage at 2-8°C. Results: The batches of bevacizumab starting product complied with the European Pharmacopoeia (Ph. Eur.) for small-volume parenterals. Repackaging into syringes led to an immediate increase in small particles. The number of particles ≥25 μm increased 1.3-fold, and the number of particles ≥10 μm increased 5-fold, respectively. Storage of up to 37 days did not lead to an additional increase in particle counts. All batches complied with the national criteria for particles in intravitreal solutions. Conclusions: Particle count increased due to the repackaging process, but no substantial increase was observed during storage. Formation of sub-visible particles does not impact the shelf-life of bevacizumab repackaged into BD Luer-Lok syringes