Search

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disorders ranging from hepatic steatosis [excessive accumulation of triglycerides (TG)] to nonalcoholic steatohepatitis, which can progress to cirrhosis and hepatocellular carcinoma. The molecular pathogenesis of steatosis and progression to more severe NAFLD remains unclear. Obesity and aging, two principal risk factors for NAFLD, are associated with a hyperadrenergic state. β-Adrenergic responsiveness in liver increases in animal models of obesity and aging, and in both is linked to increased hepatic expression of β(2)-adrenergic receptors (β(2)-ARs). We previously showed that in aging rodents intracellular signaling from elevated hepatic levels of β(2)-ARs may contribute to liver steatosis. In this study we demonstrate that injection of formoterol, a highly selective β(2)-AR agonist, to mice acutely results in hepatic TG accumulation. Further, we have sought to define the intrahepatic mechanisms underlying β(2)-AR mediated steatosis by investigating changes in hepatic expression and cellular localization of enzymes, transcription factors, and coactivators involved in processes of lipid accrual and disposition—and also functional aspects thereof—in livers of formoterol-treated animals. Our results suggest that β(2)-AR activation by formoterol leads to increased hepatic TG synthesis and de novo lipogenesis, increased but incomplete β-oxidation of fatty acids with accumulation of potentially toxic long-chain acylcarnitine intermediates, and reduced TG secretion—all previously invoked as contributors to fatty liver disease. Experiments are ongoing to determine whether sustained activation of hepatic β(2)-AR signaling by formoterol might be utilized to model fatty liver changes occurring in hyperadrenergic states of obesity and aging, and thereby identify novel molecular targets for the prevention or treatment of NAFLD. NEW & NOTEWORTHY Results of our study suggest that β(2)-adrenergic receptor (β(2)-AR) activation by agonist formoterol leads to increased hepatic TG synthesis and de novo lipogenesis, incomplete β-oxidation of fatty acids with accumulation of long-chain acylcarnitine intermediates, and reduced TG secretion. These findings may, for the first time, implicate a role for β(2)-AR responsive dysregulation of hepatic lipid metabolism in the pathogenetic processes underlying NAFLD in hyperadrenergic states such as obesity and aging.

This is the fourth in a series of papers detailing the terrestrial arthropods collected during an intensive survey of a site near Steel Creek campground along the Buffalo National River in Arkansas. The survey was conducted over a period of eight and a half months in 2013 using twelve trap types, including Malaise and canopy traps, Lindgren multifunnel traps, and pan traps. We provide collection records for 38 species of Asilidae and other Diptera, 7 of which are new state records for Arkansas: (Asilidae) Lasiopogon opaculus Loew, 1874; (Lygistorrhinidae) Lygistorrhina sancthecatharinae Thompson, 1975; (Stratiomyidae) Cephalochrysa nigricornis (Loew, 1866), Gowdeyana punctifera (Malloch, 1915), Sargus decorus Say, 1824; (Ulidiidae) Callopistromyia annulipes Macquart, 1855; and (Xylophagidae) Rachicerus obscuripennis Loew, 1863.

Systemic fibrosis can be induced in humans with gadolinium-based contrast, and cumulative doses correlate with severity. Bone marrow-derived fibrocytes accumulate in the dermis. Whether target organs liberate chemokines to recruit these fibrocytes or whether fibrocytes are stimulated to home to the affected tissue is unknown. Transgenic (tagged) donor rats were treated with gadolinium-based contrast. Bone marrow was obtained from diseased animals and age-matched controls. Rats with subtotal nephrectomies were lethally irradiated and underwent salvage transplantation with either the contrast-naive or contrast-exposed bone marrow. Groups were randomly assigned to control or contrast treatment. Contrast treatment led to dermal fibrosis, and this was exacerbated in recipients of contrast-exposed marrow. Fibronectin, C-C chemokine receptors (CCRs)2 and 7, and oxidative stress were all increased in skin from contrast-treated animals-all parameters more severe in recipients of contrast-treated animals. The respective ligands, monocyte chemoattractant protein and C-C motif ligand 19, were both elevated in skin from contrast-treated animals. Coadministration of gadolinium-based contrast and a CCR2 inhibitor reduced the severity of skin disease as well as dermal cellularity. The functional role of chemokines in the effects of gadolinium-based contrast was further confirmed in in situ coculture studies using neutralizing CCR2 antibodies. These data implicate dermal liberation of specific chemokines in the recruitment of circulating bone marrow-derived cells. The disease is augmented by bone marrow exposure to contrast, which explains why multiple exposures correlate with severity.-Drel, V. R., Tan, C., Barnes, J. L., Gorin, Y., Lee, D.-Y., Wagner, B. Centrality of bone marrow in the severity of gadolinium-based contrast-induced systemic fibrosis.

It has been presupposed that the thermodynamic stability constant ( Ktherm) of gadolinium-based MRI chelates relate to the risk of precipitating nephrogenic systemic fibrosis. The present study compared low- Ktherm gadodiamide with high- Ktherm gadoteridol in cultured fibroblasts and rats with uninephrectomies. Gadolinium content was assessed using scanning electron microscopy equipped with energy-dispersive X-ray spectroscopy in paraffin-embedded tissues. In vitro, fibroblasts demonstrated dose-dependent fibronectin generation, transforming growth factor-β production, and expression of activated myofibroblast stress fiber protein α-smooth muscle actin. There were negligible differences with respect to toxicity or proliferation between the two contrast agents. In the rodent model, gadodiamide treatment led to greater skin fibrosis and dermal cellularity than gadoteridol. In the kidney, both contrast agents led to proximal tubule vacuolization and increased fibronectin accumulation. Despite large detectable gadolinium signals in the spleen, skin, muscle, and liver from the gadodiamide-treated group, contrast-induced fibrosis appeared to be limited to the skin and kidney. These findings support the hypothesis that low- Ktherm chelates have a greater propensity to elicit nephrogenic systemic fibrosis and demonstrate that certain tissues are resistant to these effects.

Malnutrition is thought to contribute to more than one-third of all childhood deaths via increased susceptibility to infection. Malnutrition is a significant risk factor for the development of visceral leishmaniasis, which results from skin inoculation of the intracellular protozoan Leishmania donovani . We previously established a murine model of childhood malnutrition and found that malnutrition decreased the lymph node barrier function and increased the early dissemination of L. donovani . In the present study, we found reduced numbers of resident dendritic cells (conventional and monocyte derived) but not migratory dermal dendritic cells in the skin-draining lymph nodes of L. donovani -infected malnourished mice. Expression of chemokines and their receptors involved in trafficking of dendritic cells and their progenitors to the lymph nodes was dysregulated. C-C chemokine receptor type 2 (CCR2) and its ligands (CCL2 and CCL7) were reduced in the lymph nodes of infected malnourished mice, as were CCR2-bearing monocytes/macrophages and monocyte-derived dendritic cells. However, CCR7 and its ligands (CCL19 and CCL21) were increased in the lymph node and CCR7 was increased in lymph node macrophages and dendritic cells. CCR2-deficient mice recapitulated the profound reduction in the number of resident (but not migratory dermal) dendritic cells in the lymph node but showed no alteration in the expression of CCL19 and CCL21. Collectively, these results suggest that the malnutrition-related reduction in the lymph node barrier to dissemination of L. donovani is related to insufficient numbers of lymph node-resident but not migratory dermal dendritic cells. This is likely driven by the altered activity of the CCR2 and CCR7 chemoattractant pathways.

For a finite subgroup $G$ of the special unitary group $SU_2$, we study the centralizer algebra $Z_k(G) = End_G(V^{\otimes k})$ of $G$ acting on the $k$-fold tensor product of its defining representation $V= \mathbb{C}^2$. These subgroups are in bijection with the simply-laced affine Dynkin diagrams. The McKay correspondence relates the representation theory of these groups to the associated Dynkin diagram, and we use this connection to show that the structure and representation theory of $Z_k(G)$ as a semisimple algebra is controlled by the combinatorics of the corresponding Dynkin diagram., 43 pages; Minor changes, final version to appear in Proceedings of the London Mathematical Society

Matrix protein accumulation is a prominent feature of diabetic nephropathy that contributes to renal fibrosis and decline in renal function. The pathogenic mechanisms of matrix accumulation are incompletely characterized. We investigated if the matrix metalloprotease a disintegrin and metalloprotease1 7 (ADAM17), known to cleave growth factors and cytokines, is activated in the kidney cortex of OVE26 type 1 diabetic mice and the potential mechanisms by which ADAM17 mediates extracellular matrix accumulation. Protein expression and activity of ADAM17 were increased in OVE26 kidney cortex. Using a pharmacological inhibitor to ADAM17, TMI-005, we determined that ADAM17 activation results in increased type IV collagen, Nox4, and NADPH oxidase activity in the kidney cortex of diabetic mice. In cultured mouse proximal tubular epithelial cells (MCTs), high glucose increases ADAM17 activity, Nox4 and fibronectin expression, cellular collagen content, and NADPH oxidase activity. These effects of glucose were inhibited when cells were pretreated with TMI-005 and/or transfected with small interfering ADAM17. Collectively, these data indicate a novel mechanism whereby hyperglycemia in diabetes increases extracellular matrix protein expression in the kidney cortex through activation of ADAM17 and enhanced oxidative stress through Nox enzyme activation. Additionally, our study is the first to provide evidence that Nox4 is downstream of ADAM17.

Naturally occurring type 2 diabetes has been found in a colony of baboons. Ongoing characterization of the baboon colony maintained at the Southwest National Primate Research Center has revealed a significant range of glucose sensitivity with some animals clearly diabetic. Seven baboons, four with diabetes and three without diabetes, underwent histopathological investigation. Three diabetic animals were diagnosed using fasting blood glucose, hemoglobin A1C, and intravenous glucose tolerance test, and a fourth one was known to have hyperglycemia. One control baboon and three baboons with diabetes had microalbuminuria. On kidney biopsy, diabetic baboons had thickening of the glomerular basement membrane and mesangial matrix expansion compared to controls. Immunohistochemistry showed the diabetic animals had increased mesangial expression of cellular fibronectin ED-A. Two diabetic animals with microalbuminuria had evidence of mesangiolysis with the formation of an early nodule. One diabetic animal had a Kimmestiel–Wilson nodule. We conclude that the baboon represents a useful primate model of diabetes and nephropathy that resembles the nephropathy associated with type 2 diabetes in humans.

Diabetes promotes protein synthesis to induce kidney hypertrophy and increase renal matrix proteins. Increased capacity for mRNA translation by way of ribosomal biogenesis facilitates sustained stimulation of protein synthesis. We tested the hypothesis that high glucose induces ribosomal biogenesis as indicated by an increase in rRNA synthesis in the setting of augmented protein synthesis. High glucose (30 mM) increased global protein synthesis, expression of matrix proteins, laminin γ1and fibronectin, and rDNA transcription in glomerular epithelial cells (GECs) compared with 5 mM glucose. High glucose induced Ser388phosphorylation of upstream binding factor (UBF), an rDNA transcription factor, along with increased phosphorylation of Erk and p70S6 kinase. Inactivation of Erk and p70S6 kinase either by their respective chemical inhibitors or by expression of their inactive mutant constructs blocked high-glucose-induced UBF phosphorylation. High glucose reduced nuclear content of p19ARF and promoted dissolution of inactive UBF-p19ARF complex. High glucose also promoted association of UBF with RPA194, a subunit of RNA polymerase I. Inhibition of Erk, p70S6 kinase, and UBF1 by transfecting GECs with their respective inactive mutants abolished laminin γ1synthesis, protein synthesis, and rDNA transcription. Renal cortex from type 1 diabetic rats and type 2 diabetic db/ db mice showed increased phosphorylation of UBF, Erk, and p70S6 kinase coinciding with renal hypertrophy and onset of matrix accumulation. Our data suggest that augmented ribosome biogenesis occurs in an UBF-dependent manner during increased protein synthesis induced by high glucose in the GECs that correlates with UBF activation and renal hypertrophy in rodents with type 1 and type 2 diabetes.

Diabetes and high glucose (HG) increase the generation of NADPH oxidase-derived reactive oxygen species and induce apoptosis of glomerular epithelial cells (podocytes). Loss of podocytes contributes to albuminuria, a major risk factor for progression of kidney disease. Here, we show that HG inactivates AMP-activated protein kinase (AMPK), up-regulates Nox4, enhances NADPH oxidase activity, and induces podocyte apoptosis. Activation of AMPK blocked HG-induced expression of Nox4, NADPH oxidase activity, and apoptosis. We also identified the tumor suppressor protein p53 as a mediator of podocyte apoptosis in cells exposed to HG. Inactivation of AMPK by HG up-regulated the expression and phosphorylation of p53, and p53 acted downstream of Nox4. To investigate the mechanism of podocyte apoptosis in vivo, we used OVE26 mice, a model of type 1 diabetes. Glomeruli isolated from these mice showed decreased phosphorylation of AMPK and enhanced expression of Nox4 and p53. Pharmacologic activation of AMPK by 5-aminoimidazole-4-carboxamide-1-riboside in OVE26 mice attenuated Nox4 and p53 expression. Administration of 5-aminoimidazole-4-carboxamide-1-riboside also prevented renal hypertrophy, glomerular basement thickening, foot process effacement, and podocyte loss, resulting in marked reduction in albuminuria. Our results uncover a novel function of AMPK that integrates metabolic input to Nox4 and provide new insight for activation of p53 to induce podocyte apoptosis. The data indicate the potential therapeutic utility of AMPK activators to block Nox4 and reactive oxygen species generation and to reduce urinary albumin excretion in type 1 diabetes.

Angiotensin II (Ang II) and vascular endothelial growth factor (VEGF) are important mediators of kidney injury in diabetes. Acute hyperglycemia increased synthesis of intrarenal Ang I and Ang II and resulted in activation of both Ang II receptors, AT1 and AT2, in the kidney. Losartan (specific AT1 antagonist) or PD123319 (specific AT2 antagonist) did not affect hyperglycemia but prevented activation of renal AT1 and AT2, respectively. In murine renal cortex, acute hyperglycemia increased VEGF protein but not mRNA content after 24 h, which suggested translational regulation. Blockade of AT2, but not AT1, prevented increase in VEGF synthesis by inhibiting translation of VEGF mRNA in renal cortex. Acute hyperglycemia increased VEGF expression in wild type but not in AT2 knockout mice. Binding of heterogeneous nuclear ribonucleoprotein K to VEGF mRNA, which stimulates its translation, was prevented by blockade of AT2, but not AT1. The Akt-mTOR-p70(S6K) signaling pathway, involved in the activation of mRNA translation, was activated in hyperglycemic kidneys and was blocked by the AT2 antagonist. Elongation phase is an important step of mRNA translation that is controlled by elongation factor 1A (eEF1A) and 2 (eEF2). Expression of eEF1A and activity of eEF2 was higher in kidney cortex from hyperglycemic mice and only the AT2 antagonist prevented these changes. To assess selectivity of translational control of VEGF expression, we measured expression of fibronectin (FN) and laminin β1 (lamβ1): acute hyperglycemia increased FN expression at both protein and mRNA levels, indicating transcriptional control, and did not affect the expression of lamβ1. To confirm results obtained with PD123319, we induced hyperglycemia in AT2 knockout mice and found that in the absence of AT2, translational control of VEGF expression by hyperglycemia was abolished. Our data show that acute hyperglycemia stimulates Ang II synthesis in murine kidney cortex, this leads to AT2 activation and stimulation of VEGF mRNA translation, via the Akt-mTOR-p70(S6K) signaling pathway. Our data show that exclusive translational control of protein expression in the kidney by acute hyperglycemia is not a general phenomenon, but do not prove that it is restricted to VEGF.

High glucose-induced protein synthesis in the glomerular epithelial cell (GEC) is partly dependent on reduction in phosphorylation of AMP-activated protein kinase (AMPK). We evaluated the effect of resveratrol, a phytophenol known to stimulate AMPK, on protein synthesis. Resveratrol completely inhibited high glucose stimulation of protein synthesis and synthesis of fibronectin, an important matrix protein, at 3 days. Resveratrol dose-dependently increased AMPK phosphorylation and abolished high glucose-induced reduction in its phosphorylation. We examined the effect of resveratrol on critical steps in mRNA translation, a critical event in protein synthesis. Resveratrol inhibited high glucose-induced changes in association of eIF4E with eIF4G, phosphorylation of eIF4E, eEF2, eEF2 kinase and, p70S6 kinase, indicating that it affects important events in both initiation and elongation phases of mRNA translation. Upstream regulators of AMPK in high glucose-treated GEC were explored. High glucose augmented acetylation of LKB1, the upstream kinase for AMPK, and inhibited its activity. Resveratrol prevented acetylation of LKB1 and restored its activity in high glucose-treated cells; this action did not appear to depend on SIRT1, a class III histone deacetylase. Our data show that resveratrol ameliorates protein synthesis by regulating the LKB1-AMPK axis.

Kidney development is regulated by a coordinated reciprocal induction of metanephric mesenchymal (MM) and ureteric bud (UB) cells. Here, established MM and UB progenitor cell lines were recombined in three-dimensional Matrigel implants in SCID mice. Differentiation potential was examined for changes in phenotype, organization, and the presence of specialized proteins using immunofluorescence and bright-field and electron microscopy. Both cell types, when grown alone, did not develop into specialized structures. When combined, the cells organized into simple organoid structures of polarized epithelia with lumens surrounded by capillary-like structures. Tracker experiments indicated the UB cells formed the tubuloid structures, and the MM cells were the source of the capillary-like cells. The epithelial cells stained positive for pancytokeratin, the junctional complex protein ZO-1, collagen type IV, as well as UB and collecting duct markers, rearranged during transfection (RET), Dolichos biflorus lectin, EndoA cytokeratin, and aquaporin 2. The surrounding cells expressed α-smooth muscle actin, vimentin, platelet endothelial cell adhesion molecule 1 (PECAM), and aquaporin 1, a marker of vasculogenesis. The epithelium exhibited apical vacuoles, microvilli, junctional complexes, and linear basement membranes. Capillary-like structures showed endothelial features with occasional pericytes. UB cell epithelialization was augmented in the presence of MM cell–derived conditioned medium, glial-derived neurotrophic factor (GDNF), hepatocyte growth factor (HGF), or fibronectin. MM cells grown in the presence of UB-derived conditioned medium failed to undergo differentiation. However, UB cell–derived conditioned medium induced MM cell migration. These studies indicate that tubulogenesis and vasculogenesis can be partially recapitulated by recombining individual MM and UB cell lineages, providing a new model system to study organogenesis ex vivo .

Rat mesangial α-endosulfine. Background Sulfonylurea agents exert their physiologic effects via binding to specific sulfonylurea receptors (SUR) in adenosine triphosphate-sensitive potassium (K ATP ) channels. Mesangial cells express K ATP and respond to sulfonylureas by altering glucose metabolism, elevating intracellular calcium and contracting. A putative endogenous sulfonylurea, α-endosulfine, has been demonstrated in diverse tissues and is a member of the cyclic adenosine monophosphate (cAMP)-regulated family of phosphoproteins. This study investigates mesangial cell expression of ENSA , the gene encoding α-endosulfine, and its regulation by glucose. Methods Expression of rat glomerular and mesangial ENSA was examined by reverse transcription-polymerase chain reaction (RT-PCR) and Northern analysis. In situ hybridization studies were carried out to investigate the presence and distribution of ENSA in kidney cortex. Expression of mesangial cell α-endosulfine was studied by immunoblotting, immunofluorescence, and confocal microscopy. Results RT-PCR with gene-specific primers and Northern blotting disclosed abundant expression of two major ENSA transcripts at 2.4kb and 1.2kb in whole rat kidney, kidney cortex, and mesangial cells. In situ hybridization of rat kidney demonstrated renal ENSA expression, particularly within glomeruli. Confocal microscopy revealed a diffusely granular, cytosolic distribution of α-endosulfine. High glucose concentrations increased ENSA expression by 24hours, an effect that persisted for at least 10days. Protein expression paralleled gene expression. Conclusion. ENSA and α-endosulfine are expressed in rat glomeruli and mesangial cell and gene and protein expression are up-regulated by a high glucose environment. α -Endosulfine has potential roles as a regulator of metabolism and contractility via mesangial cell K ATP .

Anionization of an antigen promotes glomerular binding and immune complex formation. Bovine serum albumin (BSA, pI 4.9) was maleylated to yield highly anionic MBSA (pI 3.0). Maleylation of BSA lead to an expansion of molecular size of native BSA from an effective molecular radius (EMR) of 37 A to 57 A for MBSA as assessed by gel filtration chromatography. MBSA, but not BSA, bound to the peripheral capillary wall (PCW) and mesangium in vitro in frozen sections, and in vivo following i.v. injection (0.006 mg/g body wt), examined by immunofluorescence. When similarly injected rats or controls were given antibodies to either MBSA or BSA following injection of antigen, immune complexes were observed in glomeruli by immunofluorescence and EM only in MBSA injected rats. Deposits occurred in the mesangium and subendothelium in the PCW. In frozen sections, bound MBSA could be partially removed from tissue sections by high ionic strength buffer. Also, binding of MBSA was diminished by prior treatment of sections with synthetic polyanions. Maleylated bovine gamma-globulin and succinylated BSA showed identical binding patterns as described for MBSA, indicating that binding was not unique to the modified BSA molecule nor to the form of anionization. These results indicate that charge interactions between circulating highly anionic macromolecules and cationic domains within glomerular structures are responsible, in part, for MBSA binding and subsequent localization of immune complexes. Furthermore, it is inferred that the selective binding of MBSA to glomeruli and formation of immune complexes occurred by a mechanism not related to difference in size between MBSA and BSA. These findings are different from conventionally understood charge interactions in glomerular immune complex formation.

Size and charge selective permeability defects induced in glomerular basement membrane by a polycation. Polyethyleneimine (PEI) was given intravenously to rats followed by native ferritin or one of three cationic ferritins. After 15 min kidneys were fixed for electron microscopy. Controls (C) received vehicle without PEI, followed by the appropriate ferritin. PEI-induced permeability change was measured as the ratio (PEI/C) of counted ferritin particles within the glomerular basement membrane (GBM) in the corresponding PEI and control groups. The ratio PEI/C for each tracer was: NF (pI = 4.5–4.8)–107; CF (pI = 7.5–8.2)–3.3; CF (pI = 8.0–8.7)–1.7; and CF (pI = 8.7–9.0)–0.9. When ferritin localization in the subendothelial layer of the GBM was examined separately, PEI/C was increased for all ferritins including the most cationic species. After PEI, GFR and RBF decreased proportionately by half; thus, filtration fraction remained constant. Reduction of renal perfusion pressure to 40 mm Hg showed no alteration of ferritin permeation into the GBM. Thus, PEI effects on ferritin localization in the GBM could not be ascribed to renal hemodynamic perturbations. If the effect of PEI on GBM permeability were to be mediated exclusively by neutralization of the charge barrier, the index PEI/C should be increased for NF, but decreased for all CF. The results show a marked effect of PEI on the charge barrier (PEI/C > 100 for NF). But, PEI also enhanced total GBM permeation by CF (7.5–8.2) and CF (8.0–8.7), and increased subendothelial GBM permeation for CF (8.7–9.0). An inverse relationship of the effect of PEI to the cationic charge on CF was evident. These paradoxical results can be explained if polycations (including CF) not only neutralize anionic sites, but distort GBM gel structure, thereby altering porosity. Defauts de permeabilite selective sur la taille et la charge induits dans la membrane basale glomerulaire par un polycation. Du polyethyleneimine (PEI) a ete donne par voie intraveineuse a des rats et suivi par de la ferritine native, ou par l'une de trois ferritines cationiques. Apres 15 min, les reins ont ete fixes pour microscopie electronique. Les controles (C) recevaient du vehicule sans PEI, suivi par la ferritine appropriee. La modification de permeabilite induite par le PEI etait mesuree par le rapport (PEI/C) des particules de ferritine comptees a l'interieur de la membrane basale glomerulaire (GBM) dans les groupes PEI correspondants et controles. Le rapport PEI/C pour chaque traceur etait: NF (pI = 4,5–4,8)–107; CF (pI = 7,5–8,2)–3,3; CF (pI = 8,0–8,7)–1,7; et CF (pI = 8,7–9,0)–0,9. Quand la localisation de la ferritine dans la couche sous endotheliale de la GBM etait examinee separement, PEI/C etait augmente pour toutes les ferritines, y compris les especes les plus cationiques. Apres PEI, le GFR et le RBF ont diminue proportionnellement de moitie; ainsi la fraction de filtration est restee constante. La reduction de la pression de perfusion renale a 40 mm Hg n'a pas montre d'alteration de la permeabilite a la ferritine dans la GBM. Ainsi, les effets de PEI sur la localisation de la ferritine dans la GBM ne pouvaient etre expliques par des perturbations de l'hemodynamique renale. Si l'effet de PEI sur la permeabilite de la GBM avait pour mediateur exclusif une neutralisation de la barriere de charge, l'index PEI/C devrait etre augmente pour NF, mais diminue pour toutes les CF. Les resultats indiquent un effet marque de PEI sur la barriere de charge (PEI/C > 100 pour NF). Cependant, PEI a egalement stimule la permeabilite de GBM totale pour FC (7,5–8,2) et CF (8,0–8,7) et a augmente la permeabilite sous-endotheliale de GBM pour CF (8,7–9,0). Une relation inverse entre l'effet de PEI et la charge cationique de CF etait evidente. Ces resultats paradoxaux peuvent etre expliques si les polycations (y compris CF) neutralisent non seulement les sites anioniques, mais modifient aussi la structure du gel de la GBM, alterant ainsi sa porosite.

In the 1970s assessment, and examinations in particular, were the focus of world-wide university student protest. In Australian tertiary institutions, greater use was consequently made of “continuous assessment”. After a period of quietude assessment re-emerged a decade later as a “hot” national issue in North America and as the subject of research and discussion in England. In Australia, a report for the Commonwealth Tertiary Education Commission published in 1987 (the “Pearce Report”), discussed at length the question of assessment in Australian law schools. These more recent debates reflected in part the fact that assessment practices in at least the law schools of Australian universities had not fundamentally changed since the seventies revolt. While assessment modes had in the meantime diversified greatly, according to the Pearce Report the problem-type, written examination remained the dominant mode in Australian law schools. In the early 1990s) universities are undergoing a period of rapid change spurred on by Federal government initiatives. One important consequence of this re-evaluation is the affirmation that teaching is the university’s primary function. It is with this ultimate goal in mind that this article is written. The basic premise is that assessment not only serves as a means of certification. It also performs, inevitably, an important teaching function. It is submitted that assessment still suffers from being the “grand afterthought of the educational process”. As is commonly observed, law teachers tend to repeat the methods of instruction that are familiar to them from their student days. In one study most academics surveyed saw assessment only in terms of it providing an incentive to make students work, and to enable their intellectual abilities to be measured. Students (including law students) in another study also viewed it in similar terms. Surveys conducted by the Pearce Inquiry reported widespread dissatisfaction with methods of assessment. Why assessment has been ignored from an educational viewpoint is a complex question. Possible explanations include the influence of the legal profession on teaching; teacher apathy; few incentives; external constraints (such as scarce resources) and the lack of training in and knowledge of educational theory. There is not space to analyse all of these causes. This article’s main concern is more elementary — to remedy the lack of scrutiny of law school assessment as an educational tool. Assessment needs to be re-examined in the light of its teaching and certification functions, but especially the former. To understand what we do or fail to do when we implement assessment schemes, it firstly elaborates on the teaching and certification functions which may be fulfilled and are inevitably fulfilled by student assessment. Current assessment practices are then subjected to a critical analysis. The article concludes by providing a check-list of considerations for the thoughtful law assessor: considerations which, it is submitted, should form the basis of assessment practice.