COVID-19 in solid organ transplant recipients: A national cohort study from Sweden

Solid organ transplant (SOT) recipients run a high risk for adverse outcomes from COVID-19, with reported mortality around 19%. We retrospectively reviewed all known Swedish SOT recipients with RT-PCR confirmed COVID-19 between March 1 and November 20, 2020 and analyzed patient characteristics, management, and outcome. We identified 230 patients with a median age of 54.0 years (13.2), who were predominantly male (64%). Most patients were hospitalized (64%), but 36% remained outpatients. Age >50 and male sex were among predictors of transition from outpatient to inpatient status. National early warning Score 2 (NEWS2) at presentation was higher in non-survivors. Thirty-day all-cause mortality was 9.6% (15.0% for inpatients), increased with age and BMI, and was higher in men. Renal function decreased during COVID-19 but recovered in most patients. SARS-CoV-2 antibodies were identified in 78% of patients at 1–2 months post-infection. Nucleocapsid-specific antibodies decreased to 38% after 6–7 months, while spike-specific antibody responses were more durable. Seroprevalence in 559 asymptomatic patients was 1.4%. Many patients can be managed on an outpatient basis aided by risk stratification with age, sex, and NEWS2 score. Factors associated with adverse outcomes include older age, male sex, greater BMI, and a higher NEWS2 score.     

Central diabetes insipidus associated with impaired renal aquaporin-1 expression in mice lacking liver X receptor β

The present study demonstrates a key role for the oxysterol receptor liver X receptor β (LXRβ) in the etiology of diabetes insipidus (DI). Given free access to water, LXRβ(-/-) but not LXRα(-/-) mice exhibited polyuria (abnormal daily excretion of highly diluted urine) and polydipsia (increased water intake), both features of diabetes insipidus. LXRβ(-/-) mice responded to 24-h dehydration with a decreased urine volume and increased urine osmolality. To determine whether the DI was of central or nephrogenic origin, we examined the responsiveness of the kidney to arginine vasopressin (AVP). An i.p. injection of AVP to LXRβ(-/-) mice revealed a partial kidney response: There was no effect on urine volume, but there was a significant increase of urine osmolality, suggesting that DI may be caused by a defect in central production of AVP. In the brain of WT mice LXRβ was expressed in the nuclei of magnocellular neurons in the supraoptic and paraventricular nuclei of the hypothalamus. In LXRβ(-/-) mice the expression of AVP was markedly decreased in the magnocellular neurons as well as in urine collected over a 24-h period. The persistent high urine volume after AVP administration was traced to a reduction in aquaporin-1 expression in the kidney of LXRβ(-/-) mice. The LXR agonist (GW3965) in WT mice elicited an increase in urine osmolality, suggesting that LXRβ is a key receptor in controlling water balance with targets in both the brain and kidney, and it could be a therapeutic target in disorders of water balance.     

Localization and ontogeny of the orphan receptor OR-1 in the rat brain

This study describes the expression of the OR-1 orphan receptor in embryonic, postnatal, and adult brain tissue studied byin situ hybridization. This newly characterized member of the nuclear receptor superfamily functions as a modulator of retinoic acid and thyroid hormone signalling by influencing gene activation by these hormones from a distinct promoter region. In the fetal brain OR-1 mRNA was observed from E13–E16 in the developing pons, tegmentum, pontine flexure, medulla, inferior and superior colliculi, cerebellum, hippocampus, thalamus, striatum, and cortical plate. At E18, OR-1 was expressed in the hippocampus, cerebellum, ventricular layer of the developing cortex and cortical plate, striatum, and olfactory bulb. In the E21 to early postnatal brain the highest expression of OR-1 mRNA was seen in the hippocampus, cerebellum, striatum, and olfactory bulb. The expression of OR-1 in the cerebellum increased during postnatal development and by d P21 OR-1 mRNA had reached the levels present in the adult in the cerebellar cortex. In the adult brain the highest expression of OR-1 mRNA was observed in the Ca1 area of the hippocampus and the cerebellar cortex. We conclude that OR-1 is widely expressed in the fetal brain, whereas in the postnatal and adult brains OR-1 mRNA is more discretely localized, and that the amount of OR-1 mRNA increases in the cerebellum during postnatal development. The results of this study suggest that, in the fetal brain, OR-1 has a spatially widespread role in modulating gene activation by retinoids and thyroid hormone, whereas in the adult brain this modulation occurs only in distinct neuronal populations.     

Tissue localization of the carcinogenic glutamic acid pyrolysis product Glu-P-1 in control and {beta}-naphthoflavone-treated mice and rats

Autoradiograms obtained after i.v. injection of the ¹⁴C-labelledcarcinogenic ghitamk acid pyrolysis product Glu-P-1 to miceand rats showed a pronounced uptake of radioactivity in theliver, kidney, thyroid and nasal mucosa. High concentrationsof radioactivity were present in the bile and intestinal contentsat short post-injection times. In the male rat, the Zymbal'sgland and the preputial gland were identified as sites of highand specific binding at all post-injection times examined. Theliver and nasal mucosa were identified as sites of retentionof non-extractable radioactivity. In the pigmented mouse, Glu-P-1and/or its metabolites were accumulated in melanin. Glu-P-1is known to be activated by cytochrome P-448. Pretreatment withß-naphthoflavone (a cytochrome P-448 inducer) didnot change the tissue localization of radioactivity in eitherspecies except for the liver where the overall labelling wasdecreased. Neither did pretreatment of mice with the glutathione-depletingagent phorone change the distribution pattern significantly.However, combined pretreatments of mice with either phoroneor ß-naphthoflavone and the cytochrome P-448 inhibitor9-hydroxyellipticine resulted in an increased overall retentionof radioactivity in the body.     

Detection of the 2,3,7,8-tetpachlorodibenzo-p-dioxin (TCDD) receptor in rat liver by isoelectric focusing in polyacrylamide gels

A stereospecific, high-affinity binding protein (receptor protein) for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rat liver cytosol can be demonstrated using isoelectric focusing in polyacrylamide gels. In its native form, the receptor protein focuses at a varying pI possibly due to aggregation. However, if limited proteolysis of the receptor is carried out, the trypsinized receptor focuses as a single sharp peak at pI 5.15–5.25. Using this method the receptor can be separated from a serum TCDD-binding protein (pI 5.7–5.8) that is resistant to dextran-coated charcoal (DCC) treatment. The binding of [³H] TCDD to the receptor is competed for by 2,3,7,8-tetrachlorodibenzofuran (TCDBF), 3-methylcholanthrene (MC), and ?-naphthoflavone (?NF) but not by phenobarbital (PhB) or pregnenolone-16α-carbonitrile (PCN). The method described can be used for detection and quantitation of the TCDD receptor.     

Pituitary involvement in the sexual differentiation and 3-methylcholanthrene induction of rat liver microsomal monooxygenases

Liver microsomal monooxygenase activities with several drugs and model substrates were determined for male rats, that had been given a pituitary implant or which had been hypophysectomized and injected with 3-methylcholanthrene. The effect of implanting a male or female rat pituitary into an immature male rat was to cause a change to a more typically female pattern of monooxygenase activities, i.e. ethylmorphine and aminopyrine N-demethylases and ethoxycoumarin O-deethylase, which are less active in adult female than male rats, were suppressed and ethoxyresorufin O-deethylase, which is more active in females, was induced. The effects of pituitary implantation on the biphenyl and benzo(a)pyrene hydroxylases were apparently unrelated to sex-differences in the activities of these enzymes. The inducibility by 3-methylcholanthrene of cytochrome P448-catalysed reactions was decreased 2–3-fold by prior hypophysectomy of adult male rats.     

Influence of clofibrate on liver microsomal hydroxylation of cholesterol and androstenedione

The liver microsomal metabolism of 4-[4-¹⁴C]androstene-3,17-dione and [4-¹⁴C]cholesterol was studied in control and clofibrate-treated rats.In the control rat 25 per cent of androstenedione metabolites were hydroxylated at the 6β-position. Another 25 per cent were recovered as 16-oxygenated derivatives and minor amounts (5 per cent) were hydroxylated at the 6α- or a 7α-position. Clofibrate stimulated all the hydroxylation reactions of this compound. The 6β-hydroxylation was elevated by 100 per cent, the 7α-hydroxylation by 70 per cent, and the 6α- and 16α-hydroxylations by 50 per cent. Furthermore, following treatment with clofibrate, the ratio between 17β-hydroxy-4-androstene-3,16-dione and 16α-hydroxy-5-androstene-3, 17-dione increased from 0.15 to 0.68. The activity of the 17β-hydroxysteroid oxido-reductase increased by 100 per cent, whereas the 3β-hydroxysteroid oxidoreductase and 5α-reductase activities were only slightly affected.The 7α-hydroxylation of labelled cholesterol was uninfluenced by treatment with clofibrate.It is suggested that clofibrate stimulates the activity of the enzyme system involved in the hydroxylation of drugs in the liver.     

Gene Deletion of NF-κB p105 Enhances Neointima Formation in a Mouse Model of Carotid Artery Injury

Summary The role of nuclear factor kappa-B (NF-κB) p105 for vascular inflammatory gene expression and neointima formation after arterial injury was studied. Mice carotid arteries were injured by ligation. Vascular NF-κB activation was monitored using a NF-κB luciferase reporter mouse. Mice with gene deletion of the NF-κB p105 subunit (p50 precursor) and the corresponding wild types were assessed for vascular gene expression and neointimal hyperplasia. NF-κB was activated in the injured vessel wall in wild type mice, and this was accompanied by increased expression of the proinflammatory genes tumor necrosis factor alpha, interleukin 1 beta, and inducible nitric oxide synthase. In contrast, NF-κB p105 knockout mice had reduced expression of the inflammatory genes and enhanced neointima formation four weeks after ligation. Basic fibroblast growth factor (bFGF) gene expression increased after arterial ligation. A higher percentage of bFGF positive cells were found in lesions from NF-κB p105 knock out mice. These data indicate that the p105 subunit of NF-κB plays an essential role in vascular healing, and defects in NF-κB p105 promote neointima hyperplasia.