Early systemic microvascular damage in pigs with atherogenic diabetes mellitus coincides with renal angiopoietin dysbalance

Background: Diabetes mellitus (DM) is associated with a range of microvascular complications including diabetic nephropathy (DN). Microvascular abnormalities in the kidneys are common histopathologic findings in DN, which represent one manifestation of ongoing systemic microvascular damage. Recently, sidestream dark-field (SDF) imaging has emerged as a noninvasive tool that enables one to visualize the microcirculation. In this study, we investigated whether changes in the systemic microvasculature induced by DM and an atherogenic diet correlated spatiotemporally with renal damage. Methods: Atherosclerotic lesion development was triggered in streptozotocin-induced DM pigs (140 mg/kg body weight) by administering an atherogenic diet for approximately 11 months. Fifteen months following induction of DM, microvascular morphology was visualized in control pigs (n = 7), non-diabetic pigs fed an atherogenic diet (ATH, n = 5), and DM pigs fed an atherogenic diet (DM+ATH, n = 5) using SDF imaging of oral mucosal tissue. Subsequently, kidneys were harvested from anethesized pigs and the expression levels of well-established markers for microvascular integrity, such as Angiopoietin-1 (Angpt1) and Angiopoietin-2 (Angpt2) were determined immunohistochemically, while endothelial cell (EC) abundance was determined by immunostaining for von Willebrand factor (vWF). Results: Our study revealed an increase in the capillary tortuosity index in DM+ATH pigs (2.31±0.17) as compared to the control groups (Controls 0.89±0.08 and ATH 1.55±0.11; p<0.05). Kidney biopsies showed marked glomerular lesions consisting of mesangial expansion and podocyte lesions. Furthermore, we observed a disturbed Angpt2/ Angpt1balance in the cortex of the kidney, as evidenced by increased expression of Angpt2 in DM+ATH pigs as compared to Control pigs (p<0.05). Conclusion: In the setting of DM, atherogenesis leads to the augmentation of mucosal capillary tortuosity, indicative of systemic microvascular damage. Concomitantly, a dysbalance in renal angiopoietins was correlated with the development of diabetic nephropathy. As such, our studies strongly suggest that defects in the systemic microvasculature mirror the accumulation of microvascular damage in the kidney

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

TWO EARLY OLD BABYLONIAN “MANAN” ARCHIVES DATED TO THE LAST YEARS OF SUMU-LA-EL

In this article, two early Old Babylonian text groups are published. One group has Ea-dāpin as its protagonist, and the other Ibbi-Ilabrat. Both text groups are part of the so-called “Mananâ texts”, that were found in the area of Kish. Most of the texts are loan documents. The main interest of these two text groups lies in the fact that they are dated to the final years of the reign of Babylon’s first king, Sumu-la-El

No difference in renal vWf and VEGF-A expression.

<p>A. Representative illustrations of kidney sections stained with endothelial marker vWF (arrow: glomerulus; arrowhead: peritubular area) in Controls, ATH, and DM+ATH pigs. B. Representative images of kidney sections stained with VEGF in Controls, ATH, and DM+ATH pigs showing expression in podocytes (arrow head), parietal epithelial cells (thin arrow) and tubuli (asterix). Original magnification of A: x 200 and B: x400.</p

Early stages of atherogenic DM leads to renal damage.

<p>A: Representative illustration of PAS stained glomeruli from a DM+ATH pig, showing mesangial proliferation and matrix expansion with capillary loops lying around the mesangium as a corona, reminiscent of a beginning Kimmelstiel-Wilson nodule (left panel; thin black arrow). Dilated capillary loops with red cell fragments show intense PAI-1 staining on consecutive slides (right panel; thick black arrow). B: Mesangial expansion index in Controls (n = 7), ATH (n = 5) and DM+ATH (n = 5) pigs. C. Electron microscopy images illustrating a normal GBM architecture (left panel; thick arrow) of the Controls pig. In ATH, there is slight effacement of the podocyte pedicles (middle panel; thick arrow). In DM+ATH, marked lipid deposits were found (right panel). Data are shown as mean ± SEM. *P<0.05 compared to Controls or ATH pigs. Original magnification of A: x400 and C: x8000.</p

Correlation between capillary tortuosity and Angpt2/Angpt1balance and creatinine levels.

<p>Scatter plot showing the correlation of renal protein expression of Angpt1(A), Angpt2 (B), Angpt2/Angpt1ratio (C).</p

Model characteristics at 15 months of follow up.

<p>Model characteristics at 15 months of follow up.</p