Hypercholesterolaemia and Atherosclerosis Induced in Vervet l\'lonkeys by Cholesterol-free, Semisynthetic Diets

Vervet monkeys (Cercopithecus aethiops pygerethrus) were fed diets containing 40% carbohydrate, 25% casein and 14% hydrogenated coconut oil for 6 months. Three carbohydrates were fed: glucose, fructose and sucrose. All three diets were cholesterolaemic, the most severe cholesterolaemias being observed in the fructose and sucrose groups. All diets led to aortic sudanophilia. The fructose diet resulted in the most severe atherosclerosis and sudanophilia. This study' demonstrates the feasibility of using semisynthetic, cholesterol-free diets for the induction of hyperlipaemia and atherosclerosis in monkeys

Personalized immunosuppression in elderly renal transplant recipients

The number of elderly people has increased considerably over the last decades, due to a rising life expectancy and ageing populations. As a result, an increased number of elderly with end-stage-renal-disease are diagnosed, for which the preferred treatment is renal transplantation. Over the past years the awareness of the elderly as a specific patient population has grown, which increases the importance of research in this group.Elderly patients often receive kidneys from elderly donors while younger donor kidneys are preferentially reserved for younger recipients. Although the rate of acute rejection after transplantation is lower in the elderly, these rejections may lead to graft loss more frequently, as kidneys from elderly donors have marginal reserve capacity. To prevent acute rejection, immunosuppressive therapy is needed. On the other hand, elderly patients have a higher risk to die from infectious complications, and thus less immunosuppression would be preferable.Immunosuppressive treatm

Usage of Tacrolimus and Mycophenolic Acid During Conception, Pregnancy, and Lactation, and Its Implications for Therapeutic Drug Monitoring: A Systematic Critical Review

BACKGROUND: Conception, pregnancy, and lactation following solid organ transplantation require appropriate management. The most frequently used immunosu

The Detection of Incipient Caries with Tracer Dyes

The purpose of this study was to determine the increase in color contrast produced by the use of a tracer dye in detection of incipient caries lesions with transillumination. Twenty four caries-free first premolars were immersed in an acid gelatin for production of artificial incipient caries lesions. After the lesions had developed, these teeth were photographed by transillumination. Two photographs were taken of each tooth. The first photograph showed the lesion without dye. A blue tracer dye was then added and absorbed by the lesion, and a second photograph was taken. The data on the color difference were obtained by use of a reflectance colorimeter and showed a four-fold increase between the lesion and surrounding area with the dye. A two-way analysis of variance was used for the statistical interpretation. The color difference between the lesion without the dye and then with the dye was significant. The use of the blue tracer dye, therefore, significantly increased the contrast in the images of the artificial incipient lesions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68289/2/10.1177_00220345890680021101.pd

Usage of tacrolimus and mycophenolic acid during conception, pregnancy, and lactation, and its implications for therapeutic drug monitoring: a systematic critical review

Background: Conception, pregnancy, and lactation following solid organ transplantation require appropriate management. The most frequently used immunosuppressive drug combination after solid organ transplantation consists of tacrolimus (Tac) plus mycophenolic acid (MPA). Here, the effects of Tac and MPA on fertility, pregnancy, and lactation are systematically reviewed, and their implications for therapeutic drug monitoring (TDM) are discussed. Methods: A systematic literature search was performed (August 19, 2019) using Ovid MEDLINE, EMBASE, the Cochrane Central Register of controlled trials, Google Scholar, and Web of Science, and 102 studies were included. Another 60 were included from the reference list of the published articles. Results: As MPA is teratogenic, women who are trying to conceive are strongly recommended to switch from MPA to azathioprine. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes. Nevertheless, in 2015, the drug label was updated with additional risk minimization measures in a pregnancy prevention program. Data on MPA pharmacokinetics during pregnancy and lactation are limited. Tac treatment during conception, pregnancy, and lactation seems to be safe in terms of the health of the mother, (unborn) child, and allograft. However, Tac may increase the risk of hypertension, preeclampsia, preterm birth, and low birth weight. Infants will ingest very small amounts of Tac via breast milk from mothers treated with Tac. However, no adverse outcomes have been reported in children exposed to Tac during lactation. During pregnancy, changes in Tac pharmacokinetics result in increased unbound to whole-blood Tac concentration ratio. To maintain Tac concentrations within the target range, increased Tac dose and intensified TDM may be required. However, it is unclear if dose adjustments during pregnancy are necessary, considering the higher concentration of (active) unbound Tac. Conclusions: Tac treatment during conception, pregnancy and lactation seems to be relatively safe. Due to pharmacokinetic changes during pregnancy, a higher Tac dose might be indicated to maintain target concentrations. However, more evidence is needed to make recommendations on both Tac dose adjustments and alternative matrices than whole-blood for TDM of Tac during pregnancy. MPA treatment in men during conception seems to have no adverse effect on pregnancy outcomes, whereas MPA use in women during conception and pregnancy is strongly discouraged.Personalised Therapeutic

Converting cyclosporine A from intravenous to oral administration in hematopoietic stem cell transplant recipients and the role of azole antifungals

Purpose: Cyclosporine A (CsA) is the most widely used immunosuppressive agent after a hematopoietic stem cell transplantation (HSCT). Although recommendations for CsA dose conversion from intravenous to oral administration differ from 1:1 to 1:3, most studies did not consider the role of azole antifungals as an important confounder. Therefore, we assess the optimal conversion rate of CsA from intravenous to oral administration in HSCT recipients, taking into account the concomitant use of azole antifungals. Methods: We retrospectively included patients from a large database of 483 patients who underwent a HSCT and received intravenous CsA as part of the conditioning regimen and peritransplant immunosuppression. All patients were converted from intravenous to oral administration in a 1:1 conversion rate. We collected for each patient three CsA trough concentrations during intravenous and oral administration, directly before and after conversion to oral administration. Results: We included 71 patients; 50 patients co-treated with fluconazole, 10 with voriconazole, and 11 without azole co-medication. In patients with voriconazole, the dose-corrected CsA concentration (CsA concentration divided by CsA dosage) was not different between intravenous and oral administration (2.6% difference, p = 0.754), suggesting a CsA oral bioavailability of nearly 100%. In patients with fluconazole and without azole co-medication, the dose-corrected CsA concentration was respectively 21.5% (p < 0.001) and 25.2% (p = 0.069) lower during oral administration. Conclusions: In patients with voriconazole, CsA should be converted 1:1 from intravenous to oral administration. In patients with fluconazole and without azole co-medication, a 1:1.3 substitution is advised to prevent subtherapeutic CsA concentrations

Bridging the gap between stellar-mass black holes and ultraluminous X-ray sources

The X-ray spectral and timing properties of ultraluminous X-ray sources (ULXs) have many similarities with the very high state of stellar-mass black holes (power-law dominated, at accretion rates greater than the Eddington rate). On the other hand, their cool disk components, large characteristic inner-disk radii and low characteristic timescales have been interpreted as evidence of black hole masses ~ 1000 Msun (intermediate-mass black holes). Here we re-examine the physical interpretation of the cool disk model, in the context of accretion states of stellar-mass black holes. In particular, XTE J1550-564 can be considered the missing link between ULXs and stellar-mass black holes, because it exhibits a high-accretion-rate, low-disk-temperature state (ultraluminous branch). On the ultraluminous branch, the accretion rate is positively correlated with the disk truncation radius and the bolometric disk luminosity, while it is anti-correlated with the peak temperature and the frequency of quasi-periodic-oscillations. Two prototypical ULXs (NGC1313 X-1 and X-2) also seem to move along that branch. We use a phenomenological model to show how the different range of spectral and timing parameters found in the two classes of accreting black holes depends on both their masses and accretion rates. We suggest that ULXs are consistent with black hole masses ~ 50-100 Msun, moderately inefficiently accreting at ~20 times Eddington.Comment: 11 pages, accepted for publication in Astrophysics and Space Science. Based on work presented at the Fifth Stromlo Symposium, Australian National University, Dec 200

Constraints on the Local Sources of Ultra High-Energy Cosmic Rays

Ultra high-energy cosmic rays (UHECRs) are believed to be protons accelerated in magnetized plasma outflows of extra-Galactic sources. The acceleration of protons to ~10^{20} eV requires a source power L>10^{47} erg/s. The absence of steady sources of sufficient power within the GZK horizon of 100 Mpc, implies that UHECR sources are transient. We show that UHECR "flares" should be accompanied by strong X-ray and gamma-ray emission, and that X-ray and gamma-ray surveys constrain flares which last less than a decade to satisfy at least one of the following conditions: (i) L>10^{50} erg/s; (ii) the power carried by accelerated electrons is lower by a factor >10^2 than the power carried by magnetic fields or by >10^3 than the power in accelerated protons; or (iii) the sources exist only at low redshifts, z<<1. The implausibility of requirements (ii) and (iii) argue in favor of transient sources with L>10^{50} erg/s.Comment: 7 pages, 1 figure, submitted to JCA

Interbeobachter-Reproduzierbarkeit der Beurteilung des Schweregrads von Beschwerden, der Griffstärke und der Druckschmerzschwelle bei Patienten mit lateraler Epikondylitis

The aim of the study was to evaluate the reproducibility of the assessment of severity of complaints, grip strength, and pressure pain threshold in patients with lateral epicondylitis in primary care. The interobserver reliability of severity of complaints and grip strength was excellent. The measurement of pressure pain threshold showed unsatisfactory reliability. Grip strength and the overall assessment of the severity of complaints are useful and reliable measures for the assessment of lateral epicondylitis. (aut.ref.

A CRISPR-Cas9-engineered mouse model for GPI anchor deficiency mirrors human phenotype and shows hippocampal synaptic dysfunctions

Pathogenic germline mutations in PIGV lead to glycosylphosphatidylinositol biosynthesis deficiency. Individuals with pathogenic biallelic mutations in genes of the glycosylphosphatidylinositol anchor pathway show cognitive impairments, a motor delay and in many cases epilepsy. Thus far, the pathophysiology underlying the disease remains unclear and suitable rodent models that mirror human pathophysiology have not been available. We therefore generated a mouse model using CRISPR-Cas9 to introduce the most prevalent hypomorphic missense mutation in European patients, at a site that is also conserved in mice, Pigv:c.1022C>A (p.A341E). Reflecting the human pathology mutant Pigv(341E) mice showed deficits in motor coordination and cognitive impairment with poorer long-term spatial memory than wild-type mice, as well as alterations in sociability and sleep patterns. Furthermore, immunohistochemistry showed decreased synaptophysin-immunoreactivity and electrophysiology recordings demonstrated reduced hippocampal synaptic transmission in Pigv(341E) mice that may underlie impaired memory formation. To gain a deeper and broader molecular understanding of the consequences of glycosylphosphatidylinositol anchor deficiency, we performed single-cell RNA sequencing on acutely isolated hippocampal cells of Pigv(341E) and wild-type mice. We found that hippocampal cells from adult Pigv(341E) mice exhibited changes in gene expression, most prominently in a subtype of microglia and subicular neurons. A significant reduction of Abl1 transcripts in several cell clusters suggests a link to the signaling pathway of glycosylphosphatidylinositol-anchored ephrins. We also observed increased levels of Hdc that might affect histamine metabolism with consequences in circadian rhythm. In summary, we present here the first mouse model with a patient-specific hypomorphic mutation that mirrors the human phenotype and shows a hippocampal synaptic defect. This new mouse model will not only open the doors for further investigation into the pathophysiology of glycosylphosphatidylinositol biosynthesis deficiency in future studies, but will also deepen our understanding in the role of glycosylphosphatidylinositol-anchor related pathways in brain development