Etiology of Experimental Calcium Oxalate Monohydrate Nephrolithiasis in Rats

In a rat-model system, tubular crystal retention as a possible mechanism for the etiology of nephrolithiasis in man, was studied by conventional transmission electron microscopy. The animals were supplied for nine days with a crystal-inducing diet, with ethylene glycol plus NH4Cl in their drinking-water. After this induction period, a two day regime with fresh drinking-water was included, to allow crystals to be removed by spontaneous crystalluria. After aldehyde fixation of the rat kidneys, large crystals were seen inside the tubular lumen. The crystals were attached to cell surfaces and covered by neighboring epithelial cells. Some crystals were overgrown by several epithelial cells and underwent a process of so-called exotubulosis, resulting in free or cell-surrounded crystals in the interstitium, and possibly in crystals in Giant cells. To investigate the fate of the retained crystals, some animals were additionally exposed to a low-oxalate challenge from drinking water containing 0.1 volume per cent of ethylene glycol for 12 or 30 days, respectively. It was assumed that this would interfere with the retained intratubular or interstitial crystals, and allow the crystals to grow into mini-stones. This was not observed. After the oxalate challenge, no crystals were found to be retained in the tubules (free or covered by cells). Interstitial crystals were observed, but it remains to be demonstrated whether such crystals actually grow into mini-stones or that they are removed by the sterile inflammation process observed

Etiology of Calcium Oxalate Nephrolithiasis in Rats. I. Can This Be a Model for Human Stone Formation?

Crystal retention is studied in a rat-model system as a possible mechanism for the etiology of human nephrolithiasis. A crystal-inducing diet (CID) of ethylene glycol plus NH4Cl in their drinking-water is offered to healthy rats to generate intratubular crystals. Subsequently, the fate of retained crystals is investigated by allowing the rats a tissue recovery/crystalluria phase for three, five and ten days, respectively, on normal drinking water. The process of exotubulosis is observed in cortex and medulla of aldehyde-fixed kidneys after three days recovery. After five days, crystals are predominantly seen there in the interstitium. After ten days, cortex and medulla are virtually free of crystals. However, in the papillary regions after five and ten days recovery, three types of calcium oxalate monohydrate (COM) crystals are present: (1) free in the calycine space, (2) sub-epithelially located surrounded by interstitial cells within, and (3) covered by macrophage-like cells, outside the original papillary surface. After a CID plus three days recovery, a further thirty-seven days extra oxalate challenge with solely 0.3 vol% ethylene glycol induced intratubular and interstitial oxalate crystals. In the papillary region, large sub-epithelial crystals are seen. However, no crystals are seen in kidneys from rats given solely (0.5 or 0.8 vol.%) ethylene glycol for thirty days. An oxalate re-challenge retards crystal removal

Etiology of Calcium Oxalate Nephrolithiasis in Rats. II. The Role of the Papilla in Stone Formation

In kidneys of healthy rats submitted to a crystal-inducing diet (CID) with ethylene glycol (EG) and NH4Cl, the fate of retained crystals in the papillar region is studied during a recovery period of one, five or ten days, as model system for human nephrolithiasis. Scanning electron microscopy (SEM) shows, at papillary tips bulging into the calycine space, crystal masses covered either by the epithelium or a thin fibrous veil, or by unidentified mobile cuboidal cells. After CID plus one or five days recovery, small sub-epithelial swellings are seen of large sub-epithelial crystals at or around the papillary tip. After CID plus ten days, massive sub-surface crystal-containing micrometer-sized stones are seen in which the presence of calcium is confirmed by X-ray microanalysis. The papillary tip of rats after a re-challenge with an oxalate load from 0.1 vol% EG for twelve or forty-two days shows minor lesions. But a re-challenge with 0.3 vol% EG for thirty-seven days induces large sub-epithelial papillary millimeter-sized stones. The Von Kossa section staining converts the crystals into a black precipitate, but large peri-tubular or peri-vascular calcium deposits are absent. A new hypothesis about the etiology of an inductive calcium oxalate monohydrate nephrolithiasis is formulated which differs from the one proposed by Randall based on his deductive human kidney studies

Lectin-Cytochemistry of Experimental Rat Nephrolithiasis

Lectin reactivity in epithelial apical cell coats of normal rat kidneys was compared to that from animals subjected to crystal inducing diets (CID). The aim was to see whether the absence of lectin reactivity in cell coats is related to intratubular calcium oxalate crystal retention. In normal rat kidneys, after a pre-embedding procedure, it was observed that at the ultrastructural level, reactivity was present but that the lectin specificity for the various parts of the nephron might have to be reconsidered. There was heterogeneity between the epithelial cells with respect to the presence of coat material in the tubular cell apices. Tubular epithelial cell apices from CID rats showed no obvious changes in lectin reactivity pattern. Lectin reactivity was present at the periphery of intratubular crystals but undetectable at true crystal attachment sites or reduced at cell apices in the vicinity of recently attached crystals or agglomerates. After a post-embedding reaction procedure, wheat-germ agglutinin (WGA)-lectin reactivity confirmed the presence of coat material in the cleft between cell apex and retained crystal at crystal-attachment sites. The WGA/Au-10 nm reaction products were also seen inside epithelial cells. WGA/Au-10 nm reaction products mark a crystal matrix component inside intratubular and re-tained crystals. A similar matrix was also marked by an α-osteopontin ( αOPN/Au-10 nm) reaction product

Optimizing training adaptations by manipulating glycogen

For decades, glycogen has been recognized as a storage form of glucose within the liver and muscles. Only recently has a greater role for glycogen as a regulator of metabolic signalling been suggested. Glycogen either directly or indirectly regulates a number of signalling proteins, including the adenosine-5\u27-phosphate- (AMP-) activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK). AMPK and p38 MAPK play a significant role in controlling the expression and activity of the peroxisome proliferator activated receptor &gamma; coactivators (PGCs), respectively. The PGCs can directly increase muscle mitochondrial mass and endurance exercise performance. As low muscle glycogen is generally associated with greater activation of these pathways, the concept of training with low glycogen to maximize the physiological adaptations to endurance exercise is gaining acceptance in the scientific community. In this review, we evaluate the scientific basis for this philosophy and propose some practical applications of this philosophy for the general population as well as elite endurance athletes.<br /

Differential metabolic effects of oral butyrate treatment in lean versus metabolic syndrome subjects

Background: Gut microbiota-derived short-chain fatty acids (SCFAs) have been associated with beneficial metabolic effects. However, the direct effect of oral butyrate on metabolic parameters in humans has never been studied. In this first in men pilot study, we thus treated both lean and metabolic syndrome male subjects with oral sodium butyrate and investigated the effect on metabolism. Methods: Healthy lean males (n = 9) and metabolic syndrome males (n = 10) were treated with oral 4 g of sodium butyrate daily for 4 weeks. Before and after treatment, insulin sensitivity was determined by a two-step hyperinsulinemic euglycemic clamp using [6,6-2H2]-glucose. Brown adipose tissue (BAT) uptake of glucose was visualized using 18F-FDG PET-CT. Fecal SCFA and bile acid concentrations as well as microbiota composition were determined before and after treatment. Results: Oral butyrate had no effect on plasma and fecal butyrate levels after treatment, but did alter other SCFAs in both plasma and feces. Moreover, only in healthy lean subjects a significant improvement was observed in both peripheral (median Rd: from 71 to 82 μmol/kg min, p < 0.05) and hepatic insulin sensitivity (EGP suppression from 75 to 82% p < 0.05). Although BAT activity was significantly higher at baseline in lean (SUVmax: 12.4 ± 1.8) compared with metabolic syndrome subjects (SUVmax: 0.3 ± 0.8, p < 0.01), no significant effect following butyrate treatment on BAT was observed in either group (SUVmax lean to 13.3 ± 2.4 versus metabolic syndrome subjects to 1.2 ± 4.1). Conclusions: Oral butyrate treatment beneficially affects glucose metabolism in lean but not metabolic syndrome subjects, presumably due to an altered SCFA handling in insulin-resistant subjects. Although preliminary, these first in men findings argue against oral butyrate supplementation as treatment for glucose regulation in human subjects with type 2 diabetes mellitus

Aortic stiffness is associated with cardiac function and cerebral small vessel disease in patients with type 1 diabetes mellitus: assessment by magnetic resonance imaging

To evaluate, with the use of magnetic resonance imaging (MRI), whether aortic pulse wave velocity (PWV) is associated with cardiac left ventricular (LV) function and mass as well as with cerebral small vessel disease in patients with type 1 diabetes mellitus (DM). We included 86 consecutive type 1 DM patients (49 male, mean age 46.9 +/- 11.7 years) in a prospective, cross-sectional study. Exclusion criteria included aortic/heart disease and general MRI contra-indications. MRI of the aorta, heart and brain was performed for assessment of aortic PWV, as a marker of aortic stiffness, systolic LV function and mass, as well as for the presence of cerebral white matter hyperintensities (WMHs), microbleeds and lacunar infarcts. Multivariate linear or logistic regression was performed to analyse the association between aortic PWV and outcome parameters, with covariates defined as age, gender, mean arterial pressure, heart rate, BMI, smoking, DM duration and hypertension. Mean aortic PWV was 7.1 +/- 2.5 m/s. Aortic PWV was independently associated with LV ejection fraction ( = -0.406, P = 0.006), LV stroke volume ( = -0.407, P = 0.001), LV cardiac output ( = -0.458, P = 0.001), and with cerebral WMHs (P < 0.05). There were no independent associations between aortic stiffness and LV mass, cerebral microbleeds or lacunar infarcts. Aortic stiffness is independently associated with systolic LV function and cerebral WMHs in patients with type 1 DM.Neuro Imaging Researc

Dynamic coordination in brain and mind

Our goal here is to clarify the concept of 'dynamic coordination', and to note major issues that it raises for the cognitive neurosciences. In general, coordinating interactions are those that produce coherent and relevant overall patterns of activity, while preserving the essential individual identities and functions of the activities coordinated. 'Dynamic coordination' is the coordination that is created on a moment-by-moment basis so as to deal effectively with unpredictable aspects of the current situation. We distinguish different computational goals for dynamic coordination, and outline issues that arise concerning local cortical circuits, brain systems, cognition, and evolution. Our focus here is on dynamic coordination by widely distributed processes of self-organisation, but we also discuss the role of central executive processes