Cyclosporine Interacts with Mycophenolic Acid by Inhibiting the Multidrug Resistance-Associated Protein 2

In mycophenolate mofetil (MMF)-treated organ transplant recipients, lower mycophenolic acid (MPA) plasma concentrations have been found in cyclosporine (CsA) compared with tacrolimus (Tac)-based immunosuppressive regimens. We previously demonstrated that CsA decreases exposure to MPA and increases exposure to its metabolite MPA-glucuronide (MPAG), possibly by interfering with the biliary excretion of MPAG. To elucidate the role of the multidrug resistance-associated protein (Mrp)-2 in the interaction between MMF and CsA, we treated three groups of 10 Mrp2-deficient rats (TR- rat) for 6 days with either vehicle, CsA (8 mg/kg) or Tac (4 mg/kg) by oral gavage. Hereafter, co-administration with MMF (20 mg/kg) was started in all groups and continued through day 14. The 24-h MPA/MPAG area under the concentration-time curve (AUC) was determined after single (day 7) and multiple MMF doses (day 14). On both study days, there were no significant differences in the mean MPA and MPAG AUC between CsA and Tac-treated animals. We conclude that the pharmacokinetics of MMF are comparable in Mrp2-deficient rats receiving either CsA or Tac as co-medication. This finding suggests that CsA-mediated inhibition of the biliary excretion of MPAG by the Mrp2 transporter is the mechanism responsible for the interaction between CsA and MMF.     

Spinal cord compression in renal osteodystrophy

Summary A patient undergoing regular haemodialysis for chronic renal insufficiency developed neck pain followed by progressive spinal cord compression due to subluxation at the level C3-4. Decompression, laminectomy and osteosynthesis led to an almost complete recovery. A review of all the histological specimens suggested that hyperparathyroidism and not amyloidosis caused the vertebral destruction.     

Subcutaneous cryptococcosis due to Cryptococcus diffluens in a patient with sporotrichoid lesions case report, features of the case isolate and in vitro antifungal susceptibilities.

Environmental fungi, in particular primary pathogens and Cryptococcus spp. can be responsible for skin lesions mimicking sporotrichosis. In this paper, we report a case of subcutaneous cryptococcosis in an apparently healthy, young male patient due to a non-C. neoformans Cryptococcus species, C. diffluens. The isolate showed in vitro phenotypic switching that may affect virulence and host inflammatory and immune responses, and in vitro resistance to amphotericin B and 5-flucytosin. This species shares several phenotypic traits with C. neoformans, and, therefore, decisive diagnosis should be based on biopsy and culturing results followed by molecular identification.     

Cloning and functional characterization of a novel connexin expressed in somites of Xenopus laevis.

Connexin-containing gap junctions play an essential role in vertebrate development. More than 20 connexin isoforms have been identified in mammals. However, the number identified in Xenopus trails with only six isoforms described. Here, identification of a new connexin isoform from Xenopus laevis is described. Connexin40.4 was found by screening expressed sequence tag databases and carrying out polymerase chain reaction on genomic DNA. This new connexin has limited amino acid identity with mammalian (<50%) connexins, but conservation is higher (approximately 62%) with fish. During Xenopus laevis development, connexin40.4 was first expressed after the mid-blastula transition. There was prominent expression in the presomitic paraxial mesoderm and later in the developing somites. In adult frogs, expression was detected in kidney and stomach as well as in brain, heart, and skeletal muscle. Ectopic expression of connexin40.4 in HEK293 cells, resulted in formation of gap junction like structures at the cell interfaces. Similar ectopic expression in neural N2A cells resulted in functional electrical coupling, displaying mild, asymmetric voltage dependence. We thus cloned a novel connexin from Xenopus laevis, strongly expressed in developing somites, with no apparent orthologue in mammals.     

Computerized anatomy of the distal radius and its relevance to volar plating,research, and teaching

Distal radius fractures are common and fracture patterns and fixation can be complex. Computerized anatomy evaluation (CAE) might offer non‐invasive and enhanced anatomy assessment that might help with implant selection and placement and screw length determination. Our goal was to test the accuracy of two CAE methods for anatomical volar plate positioning and screw lengths measurement of the distal radius. We included 56 high‐resolution peripheral quantitative computed tomography scans of intact, human distal radii. Plates were placed manually onto 3D printed models (method 1), which was compared with automated computerized plate placement onto the 3D computer models (method 2). Subsequently, screw lengths were determined digitally for both methods. Screw lengths evaluations were compared via Bland–Altman plots. Both CAE methods resulted in identical volar plate selection and in anatomical plate positioning. For screw length the concordance correlation coefficient was ≥0.91, the location shift ≤0.22 mm, and the scale shift ≤0.16. The differences were smaller than ±1 mm in all samples. Both CAE methods allow for comparable plate positioning and subsequent screw length measurement in distal radius volar plating. Both can be used as a non‐invasive teaching environment for volar plate fixation. Method 2 even offers fully computerized assessments. Future studies could compare our models to other anatomical areas, post‐operative volar plate positioning, and model performance in actual distal radius fracture instead of intact radii. Clin. Anat. 32:361–368, 2019. © 2018 The Authors. Clinical Anatomy published by Wiley Periodicals, Inc. on behalf of American Association of Clinical Anatomists.     

Pharmacokinetic profile of nomegestrol acetate and 17β-estradiol after multiple and single dosing in healthy women

BackgroundThe pharmacokinetics of the monophasic oral contraceptive nomegestrol acetate (NOMAC) plus 17β-estradiol (E₂) were investigated after a single dose and multiple dosing.Study designNOMAC/E₂ (2.5 mg/1.5 mg) was administered daily to healthy women (18–50 years, n= 23) for 24 days; blood samples for pharmacokinetic analysis were obtained on Day 24 and again, after a 10-day pill-free interval, on Day 35 after a single dose.ResultsNOMAC reached steady state after 5 days with mean ± standard deviation (SD) trough NOMAC concentration (C_av) of 4.4±1.4 ng/mL. On Day 24, mean±SD peak NOMAC concentration (C_max, 12.3±3.5 ng/mL) was reached in mean 1.5 h (t_max); the mean±SD elimination half-life (t_½) was 45.9±15.3 h. After a single dose, NOMAC mean±SD C_max was 7.2±2.0 ng/mL and mean±SD t_½ was 41.9±16.2 h. On Day 24, E₂ mean±SD C_av was 50.3±25.7 pg/mL; mean±SD C_max was 86.0±51.3 pg/mL. After a single dose, mean±SD E₂ C_max was 253±179 pg/mL.ConclusionsThese data demonstrate that NOMAC/E₂ has a pharmacokinetic profile consistent with once-daily dosing.     

NetB-producing and beta2-producing Clostridium perfringens associated with subclinical necrotic enteritis in laying hens in the Netherlands

Since 2006 increasing numbers of laying hen flocks with decreased production have been reported in the Netherlands. At necropsy, birds from affected flocks showed multifocal areas of necrosis in the duodenum. Histologically the duodenum had moderate to marked villus atrophy and fusion with crypt hyperplasia and a mixed inflammatory infiltrate within the lamina propria underlying focal areas of degenerative epithelium. Multifocally, free within the intestinal lumen and associated with epithelial necrosis, were marked numbers of large rod-shaped bacteria. Anaerobic culturing and subsequent toxin typing revealed, in 19 out of 73 affected birds, the presence of Clostridium perfringens strains, either type A or type C harbouring the atypical allele of cpb2 and netB. Eighteen out of these 19 birds carried C. perfringens strains capable of producing beta2 toxin in vitro and all of these birds harboured C. perfringens strains capable of producing NetB toxin in vitro. In contrast, specific pathogen free (SPF) birds lacked gross or histological lesions in their duodenum, and C. perfringens type C was isolated from four out of 15 SPF birds tested. One of these isolates harboured the consensus three allele of cpb2 that produced beta2 toxin in vitro. None of the C. perfringens isolates originating from SPF birds harboured netB. These findings might indicate that the NetB toxin produced by C. perfringens is associated with subclinical necrotic enteritis in layers, whereas the involvement of beta2 toxin in subclinical necrotic enteritis, if any, might be variant dependent.     

Clinical effects of antiplatelet drugs and statins on D‐dimer levels

Background

Acute pulmonary embolism may be ruled out by combining nonhigh clinical probability and a normal D‐dimer level. Both antiplatelet drugs and HMG‐CoA reductase inhibitors (statins) have been associated with effects on thrombus formation, potentially influencing D‐dimer levels in this setting, leading to a higher rate of false‐negative tests. Therefore, we determined whether D‐dimer levels in patients with suspected pulmonary embolism are affected by concomitant use of antiplatelet drugs and/or statins and evaluated whether the effect of antiplatelet drugs or statins might affect diagnostic accuracy.

Materials and methods

We performed a posthoc analysis in the YEARS diagnostic study, comparing age‐ and sex‐adjusted D‐dimer levels among users of antiplatelet drugs, statins and nonusers. We then reclassified patients within the YEARS algorithm by developing a model in which we adjusted D‐dimer cut‐offs for statin use and evaluated diagnostic accuracy.

Results

We included 156 statins users, 147 antiplatelet drugs users and 726 nonusers of either drugs, all with suspected pulmonary embolism . Use of antiplatelet drugs did not have a significant effect, whereas statin use was associated with 15% decrease in D‐dimer levels (95% CI, ?28% to ?0.6%). An algorithm with lower D‐dimer thresholds in statin users yielded lower specificity (0.42 compared to 0.33) with no difference in false‐negative tests.

Conclusions

We conclude that use of statins but not of antiplatelet agents is associated with a modest decrease in D‐dimer levels. Adjusting D‐dimer cut‐offs for statin use did, however, not result in a safer diagnostic strategy in our cohort.