Background: Microalbuminuria is an early sign of kidney disease in diabetes and indicates cardiovascular risk. We tested if a prespecified urinary proteomic risk classifier (CKD273) was associated with development of microalbuminuria and if progression to microalbuminuria could be prevented with the mineralocorticoid receptor antagonist spironolactone. Methods: Prospective multicentre study in people with type 2 diabetes, normal urinary albumin excretion and preserved renal function in 15 European specialist centres. High-risk individuals determined by CKD273 were randomised 1:1 (interactive web response system) in a double-blind randomised controlled trial comparing spironolactone 25 mg o.d. to placebo. Primary endpoint was development of confirmed microalbuminuria in all individuals with available data. Secondary endpoints included reduction in incidence of microalbuminuria with spironolactone and association between CKD273 and impaired renal function defined as a glomerular filtration rate < 60 ml/min per 1•73 m 2. This study is registered with ClinicalTrials.gov: NCT02040441 and is completed. Findings: From March 25, 2014 to September 30, 2018 we followed 1775 participants, 12% (n=216) had high-risk urinary proteomic pattern of which 209 were included in the trial and assigned spironolactone (n=102) or placebo (n=107). Median follow-up time was 2•51 years (IQR 2•0-3•0). Progression to microalbuminuria was seen in 28•2% of high-risk and 8•9% of low-risk people (P< 0•001) (hazard ratio (HR), 2•48; 95% confidence interval [CI], 1•80 to 3•42 P<0•001, independent of baseline clinical characteristics). A 30% decline in eGFR from baseline was seen in 42 (19•4 %) high-risk participants compared to 62 (3•9 %) low-risk participants, HR 5•15; 95 % CI (3•41 to 7•76; p<0.0001). Development of microalbuminuria was seen in 35 (33%) randomised to placebo and 26 (25%) randomised to spironolactone treatment (HR 0•81, 95% CI, 0•49 to 1•34, P=0•41). Harms: hyperkalaemia was seen in 13 versus 4, and gynaecomastia in 3 versus 0 subjects on spironolactone and placebo, respectively. Interpretation: In people with type 2 diabetes and normoalbuminuria, the urinary proteomic classifier CKD273 was associated with a 2•5 times increased risk for progression to microalbuminuria over a median of 2•5 years, independent of clinical characteristics. Spironolactone did not prevent progression to microalbuminuria in high-risk subjects.

No abstract

Background: Inhibitors of the sodium-glucose cotransporter 2 (SGLT2) slow the progression of diabetic kidney disease, possibly by reducing the proximal tubule transport workload with subsequent improvement of renal oxygenation. We aimed to test this hypothesis in individuals with type 1 diabetes and albuminuria. Methods: A randomised, double-blind, placebo-controlled, crossover trial with a single 50 mg dose of the SGLT2 inhibitor dapagliflozin and placebo in random order, separated by a two-week washout period. Magnetic resonance imaging (MRI) was used to assess renal R 2 * (a low value corresponds to a high tissue oxygenation), renal perfusion (arterial spin labelling) and renal artery flow (phase contrast imaging) at baseline, three-and six hours from tablet ingestion. Exploratory outcomes, including baroreflex sensitivity, peripheral blood oxygen saturation, peripheral blood mononuclear cell mitochondrial oxygen consumption rate, and biomarkers of inflammation were evaluated at baseline and 12 h from medication. The study is registered in the EU Clinical Trials Register (EudraCT 2019À004,557À92), on ClinicalTrials.gov (NCT04193566), and is completed. Findings: Between February 3, 2020 and October 23, 2020, 31 individuals were screened, and 19 eligible individuals were randomised. Three dropped out before receiving any of the interventions and one dropped out after receiving only placebo. We included 15 individuals (33% female) in the per-protocol analysis with a mean age of 58 (SD 14) years, median urinary albumin creatinine ratio of 46 [IQR 21À58] mg/g and an eGFR of 73 (32) ml/min/1¢73m 2 . The mean changes in renal cortical R 2 * from baseline to six hours were for dapagliflozin -1¢1 (SD 0¢7) s À1 and for placebo +1¢3 (0¢7) s À1 , resulting in a difference between interventions of -2¢3 s À1 [95% CI -4¢0 to -0¢6]; p = 0¢012. No between-intervention differences were found in any other MRI outcomes, physiological parameters or exploratory outcomes. There were no adverse events. Interpretation: A single dose of 50 mg dapagliflozin acutely improved renal cortical R 2 * without changing renal perfusion or blood flow. This suggests improved renal cortical oxygenation due to a reduced tubular transport workload in the proximal tubules. Such improved oxygenation may in part explain the long-term beneficial renal effects seen with SGLT2 inhibitors, but it remains to be determined whether the observed effects can be achieved with lower doses, with chronic treatment and if they occur in type 2 diabetes as well.

Context/objectivePrevious studies have demonstrated that various subtypes of the metabotropic glutamate receptors (mGluRs) are expressed in the dorsal root ganglion (DRG) of the peripheral nervous system (PNS), implicating that glutamate potentially contributes to sensory transmission through these receptors. While mGluR expression has been investigated largely in the DRG, the present study focused on mGluR expression on neurons and satellite glial cells (SGCs) of the trigeminal ganglion (TG). Materials and methods: To address the presence of mGluRs in rat TG neurons and their corresponding SGCs, the trigeminal ganglia from six adult male Wistar rats were isolated and immunohistochemistry and immunocytochemistry were performed. The expression of mGluR1α-, mGluR2/3- and mGluR8 on TG neurons and SGCs was investigated in tissue slices and isolated cells. Results: 35.1 ± 6.0% of the TG neurons were positive for mGluR1α, whereas 39.9 ± 7.7% and 55.5 ± 6.3% were positive for mGluR2/3 and mGluR8, respectively. Immunoreactive neurons expressing mGluRs were mainly medium- to large sized, with a smaller population of small-sized neurons showing immunoreactivity. The SGCs showed immunoreactivity toward mGluR1α and mGluR8, but not mGluR2/3, both in the tissue and in isolated cells. Conclusions: Findings from the present study showed that trigeminal neurons express mGluR1α, mGluR2/3 and mGluR8, while SGCs only express mGluR1α and mGluR8. This novel evidence may advance investigations on a possible role of mGluRs in relation to trigeminal pain transmission within the craniofacial region.

Small aerosol particles have for a long time been known to be harmful to humans, and are today regarded to cause a larger number of deaths than traffic accidents globally. Energy dispersive x-ray fluorescence (EDXRF) is a well known method that has been used for identification of toxic as well as non-toxic elements in the particles. The combination of elements will together with other information help to identify the sources and predict the effects of particles on environment and human health.The present work was conducted in Kwabenya, a suburb of the capital Accra of Ghana, which is frequently exposed to Harmattan dust from the Sahara-Sahel region. In total 171 filters each of PM2.5 and PM(2.5-10) were collected during 1 year. Levels of elements, black carbon (BC) and mass, were determined for both particle sizes. Principal component analysis (PCA) was performed on the datasets from Harmattan and non-Harmattan periods.The daily average of PM10 was very high, 179 µg m −3 and the BC contents were 4 µg m −3 . The presence of crustal elements was large in PM(2.5-10) as well as in PM2.5, and had a more than tenfold increase in PM(2.5-10) during the Harmattan period. Major characteristic elements for different sources were identified from correlation coefficients and regression analysis of the data. Sahara sand aerosol was the major source in both study periods, but influence from biomass burning, sea-spray and metal industries was also observed.

ABSTRACT— Trace elements (Fe, Cu, Zn, Se, Mn, Ti, Pb) were measured by X‐ray fluorescence spectrometry in normal liver tissue obtained at autopsy from 74 subjects (44 ♀, 30 ♂), median age 62 years (range 20–87), and in tissue from 27 cirrhotic livers (14 alcoholic, 13 non‐alcoholic cirrhosis). The element content (median and 5–95 percentile interval) in normal livers in mmol/kg dry tissue was: Fe, 16.51 (7.82–39.03); Cu, 0.378 (0.189–0.629); Zn, 4.01 (2.59–9.33); Se, 0.018 (<0.004–0.035); Mn, <0.055 (<0.055–0.237); Ti, <0.146 (<0.146–0.919); Pb, <0.0005 (<0.0005–0.0154). Only copper content showed a sex difference, being higher in males than in females (P<0.04). In both groups of cirrhotic liver, Fe content was within normal, Cu content above normal (P<0.05, P<0.02), and Se content below normal (P<0.0001, P<0.04). Alcoholic cirrhotic livers had lower Zn levels (P<0.02), higher Mn levels (P<0.06), and higher Pb levels (P<0.03) than normal livers.

No abstract

Ash from pig manure treated by combustion and thermal gasification was characterized and compared in terms of nutrient, i.e., potassium (K), phosphorus (P) and heavy metal, i.e., cadmium (Cd), chromium (Cr), copper (Cu), nickel (Ni) and zinc (Zn) contents. Total nutrient and metal concentrations were measured using energy dispersive X-ray fluorescence analysis. Acid (HNO3, H2SO4) and water-extractable concentrations were also measured both in non-classified ash and in selected ash particle size fractions using flame atomic absorption spectrometry and colorimetric spectrometry. Results indicate that ash from gasified manure contained more water-extractable K in comparison with combusted manure whereas the opposite was the case with respect to P. Heavy metals Ni, Cr and Cd were present in higher concentrations in the fine particle size fractions (< 30 microm of particle diameter), whereas K, P, Zn and Cu exhibited higher concentrations in the coarser particle size fractions (> 30 microm).