Fibrillary (immunotactoid) glomerulopathy. A possible role for kappa light chain in its etiology and/or pathogenesis

The initial clinical manifestations, course, and immunopathologic findings of renal biopsies of nine patients with fibrillary glomerulopathy are reported. Their first symptoms and courses were variable, but proteinuria and renal failure were common. While some patients required hemodialysis soon after coming for treatment, others progressed to renal failure over several years. Three patients had monoclonal gammopathy; one of them had an isolated, transient, Bence-Jones proteinuria. The main pathologic features are glomerular enlargement, mesangial expansion, and mild hypercellularity. Congo red and thioflavin stains were negative. Kappa chain, either alone or with lambda chain and IgG, were the predominant immunoreactants. Ultrastructurally, the presence of coarse fibrils of 15-25 nm was characteristic, but there were also granular deposits in the capillary wall that occurred in a band-like pattern in the inner half of the glomerular basement membrane in a manner similar to the deposits seen in light chain deposit disease. The immunofluorescence and ultrastructural findings suggest that light chains (especially kappa) may be significant in the pathogenesis of fibrillary glomerulopathy and that there may be a relationship with light chain deposit disease.     

Urinary bladder prostanoids--their synthesis, function and possible role in the pathogenesis and treatment of disease

The present review surveys the factors governing the synthesis of prostanoids by the urinary bladder, their role in the maintenance of normal bladder function, the pattern of their secretion in bladder disease and, finally, their possible use in the treatment of bladder pathology. It should be emphasized that this area of investigation is in its infancy, and therefore the pathophysiological and clinical relevance of these observations is, to some extent, speculative. However, a certain degree of awareness is necessary to stimulate further studies in this promising field of research.     

A new mesangial triumvirate: sulfonylureas, their receptors and endosulfines.

Although sulfonylureas have long been therapeutically utilized for their hypoglycemic properties in type 2 diabetic patients, there is a paucity of clinical or experimental data that suggests that this pharmacotherapeutic class confers a benefit on the course of diabetic renal disease. Because the mesangial compartment is central to the fibrogenic response that evolves during the course of diabetic nephropathy, determining the metabolic influence of sulfonylureas on mesangial cells is important. In this article, the current knowledge regarding the metabolic and functional consequences of a mesangial triumvirate of sulfonylureas, their sulfonylurea receptors and sulfonylurea-like ligands termed endosulfines will be reviewed.     

Collagenolytic enzyme systems in human intervertebral disc: their control, mechanism, and their possible role in the initiation of biomechanical failure

Changes in the macromolecular matrix of the intervertebral disc may predispose to biomechanical failure of the disc. Such changes would involve extracellular enzymes capable of altering the collagen and proteoglycan of the disc matrix. In this study, extracts from homogenates of both annuli fibrosi and nuclei pulposi of human lumbar discs were found to contain neutral collagenolytic, gelatinolytic, and elastinolytic enzymes in all samples assayed. The specific activity of the collagenase was higher in extracts from nuclear than from annular tissue, a difference not seen with gelatinase or elastase. The collagenase was present as both a latent and active enzyme, the other enzymes being fully active. Human intervertebral discs therefore contain enzymes capable of degrading their extracellular macromolecular matrix.     

The possible role of sphincteroplasty and surgical sphincterotomy in the pathogenesis of recurrent common duct brown stones.

The hypothesis has been tested that postcholecystectomy common duct stones of the brown subtype are a consequence of three factors: bile infection, old age and previous sphincterotomy. It was found that: (i) 27 of 39 consecutive patients with recurrent common duct stones had brown stones. Nineteen of these 27 patients (70.3%) had previous sphincterotomy or sphincteroplasty: (ii) six of 15 patients with stone and bile analysis both at the time of cholecystectomy and at the second operation and who had sterile operative bile and non brown stones at the first operation, formed brown stones after T-tube drainage and after the onset of bile infection; (iii) patients with both intra and postoperative negative bile culture (n = 39 out of 137) had a lower mean age (50.5 years) and less frequently had a sphincterotomy than did individuals with a negative culture at operation, who subsequently had bile infection (n = 37; mean age 58.5 years; sphincterotomy in 88.8% of cases). In addition, in a follow up study of 105 patients with sphincterotomy and with sphincteroplasty (including ERCP or i.v. cholangiography in all cases), mean follow-up interval 6.1 years, 11.3% of patients had brown recurrent common duct stones. It is suggested that, since brown recurrent common duct stones are secondary to bile stasis and infection and the duodenum is going to be colonized by bacteria with increasing age, sphincterotomy (and subsequent stricture), facilitating bile contamination and bacterial overgrowth, could be one of the major determinants of brown recurrent common duct stones (RCS) formation. In particular, more than 11% of the patients with a sphincterotomy are going to form in the future RCS of the brown subtype.     

含pyrin结构域NOD样受体家族3炎性小体的翻译后修饰及其在脓毒症发生发展中的作用

翻译后修饰(post-translational modification, PTM)主要包括磷酸化、泛素化、烷基化、S-亚硝基化和ADP-核糖基化等,能够通过多分子多位点调控含pyrin结构域NOD样受体家族3(NOD-like receptors family pyrin domain containing 3, NLRP3)炎性小体。NLRP3炎性小体激活将造成炎症级联反应不断扩大。而这种炎症反应紊乱是推动脓毒症进展的重要因素。文章详细阐述了NLRP3炎性小体的PTM,并介绍了NLRP3的PTM在脓毒症中的作用,以期干预NLRP3炎性小体的活化,进而调控炎症,为未来脓毒症治疗提供新思路。     

Biomechanical and morphological types of the linea alba and its possible role in the pathogenesis of midline incisional hernia.

OBJECTIVE: To review the tensile strength of the different histological types of fibres in the linea alba and correlate the anatomical features of the anterior abdominal wall with the tensile strength of the linea alba to see whether the tensile strength of the linea alba might contribute to the development of midline incisional hernias. DESIGN: Laboratory study. SETTING: University hospital, Germany. SUBJECTS: 46 cadavers in part one, and 9 freshly frozen and 38 formalin-fixed cadavers in part two. INTERVENTIONS: In the first part of the study the histological examination was by binocular dissection microscopy, magnification x10, but this was not sufficiently reproducible so in the second part we used an Olympus BX50 microscope, magnification x20, and Optimas 5.22 picture processing software. Tensile strength was measured using a Loosenhausen ZHP 1-6 tensiometer. MAIN OUTCOME MEASURES: Correlation between anatomical features and tensile strength. RESULTS: The method used in part one of the study failed to differentiate between the three types of fibres in the linea alba (weak, intermediate, and compact). In the second part of the study we found that the fibres were irregular, with no systematic crossing of the fibres of the aponeurosis. There was a significant correlation between the thickness and density of fibres in the linea alba and its tensile strength (r = 0.9). The thickness of fibres ranged from 21.9-38.2 microm and the density from 48% to 90%. The tensile strength ranged from 3-25 kp. CONCLUSION: A combination of low density and thin fibres in the linea alba could be a predisposing factor for development of midline incisional hernias     

A role for ELAM-1 in the pathogenesis of MOF during septic shock.

As a model for septic shock, LPS was infused into anesthetized Cynomolgus monkeys. Hematologic and metabolic parameters proved the induced shock response. The data presented show that administration of LPS to Cynomolgus monkeys induced a generalized inflammatory status, which was characterized by systemic release of the cytokines TNF and IL-6. Further it was demonstrated, using immune-histological methods, that a generalized expression in vivo of the endothelial leukocyte adhesion molecule (ELAM)-1 was induced on endothelial cells by LPS infusion. ELAM-1 expression was most pronounced on vasculature of lung tissue and skin. As shown in serial skin biopsies, ELAM-1 expression was induced rapidly: at 2 hr after the onset of LPS infusion, reaching maximum after 4 hr. The expression of ELAM-1 is considered to be of relevance for the mechanism which underlies the stasis of PMN in the tissues during septic shock.     

Cardiopulmonary bypass in the early puerperium: possible new role for aprotinin.

A case of successful emergency reoperation for mitral valve replacement 2 hours after a cesarean section is reported. The use of aprotinin (Trasylol; Bayer AG, Leverkusen, Germany) greatly simplified the surgical procedure and was in our opinion the most important factor in an uncomplicated outcome.     

Differential expression of chemokines and chemokine receptors in murine islet allografts: the role of CCR2 and CCR5 signaling pathways

Chemokines and their receptors play a pivotal role in the initiation and amplification of the immune response. Investigated was their differential expression after syngeneic and allogeneic islet transplantation. During the 7 d after transplantation, the chemokines MCP-1, MCP-2, RANTES, MIG, IP-10, I-TAC, and two CC chemokine receptors CCR2 and CCR5 were highly expressed in allografts when compared with isografts. Disrupting the CCR2 and CCR5 pathways individually resulted in prolongation of the survival time 16.1 +/- 0.4 and 15.8 +/- 0.9 d, respectively, of fully major histocompatibility complex-mismatched islet grafts compared with wild-type controls (11.2 +/- 1.0 d). Blockade of both receptors had no synergistic effect. Rapamycin-treated wild-type recipients rejected their grafts at 17.4 +/- 2.2 d, in contrast to rapamycin-treated CCR2-/- recipients at 38 +/- 8.6 d (P = 0.025). The disruption of the CCR2 and CCR5 signaling, alone or in combination, moderately prolong islet allograft survival. However, the combination of low-dose immunosuppression and targeting of CCR2 greatly augmented islet graft survival.     

Role of cyclical pressure and particles in the release of M-CSF,chemokines, and PGE2 and their role in loosening of implants

A septic loosening of orthopaedic implants is usually attributed to the action of wear debris from the prosthesis. Recent studies, however, have also implicated physical pressures in the joint as a further cause of loosening. We have examined the role of both wear debris and pressure on the secretion of two chemokines, MIP-1alpha and MCP-1, together with M-CSF and PGE2, by human macrophages in vitro. The results show that pressure alone stimulated the secretion of more M-CSF and PGE2 when compared with control cultures. Particles alone stimulated the secretion of M-CSF and PGE2, when compared with unstimulated control cultures, but did not stimulate the secretion of the two chemokines. Exposure of macrophages to both stimuli simultaneously had no synergistic effect on the secretion of the chemokines, but both M-CSF and PGE2 were increased in a synergistic manner. Our findings suggest that pressure may be an initiating factor for the recruitment of cells into the periprosthetic tissue.     

Renal hemodynamics in radiocontrast medium-induced renal dysfunction: A role for dopamine-1 receptors.

BACKGROUND: Radiocontrast medium (RCM) administration induces a transient increase in renal blood flow (RBF), followed by a prolonged vasoconstriction. This vasoconstrictor phase in RBF is accompanied by a decrement in glomerular filtration rate (GFR). Nonselective dopamine (DA) receptor stimulation is known to increase RBF and GFR. Clinical studies, however, fail to demonstrate a renoprotective effect of DA following RCM administration. This lack of renoprotection may relate to nonspecific adrenergic stimulation by DA. The effect of select DA-1 receptor stimulation on renal hemodynamics following RCM administration has not been evaluated. METHODS: This study tests the hypothesis that selective DA-1 receptor stimulation blunts the declines in RBF and GFR that follow RCM injections, independent of changes in baseline RBF and GFR. Experiments were performed in six anesthetized, volume-depleted dogs. RBF was measured by an electromagnetic flow probe around the renal artery and GFR by inulin clearance. After a 60-minute equilibration period, baseline values of RBF, GFR, and arterial pressure were determined. Two separate intrarenal bolus injections of the ionic RCM Renograffin were then given in the presence of saline infusion. After a 60-minute recovery period, intra-arterial infusions of either the selective DA-1 receptor agonist fenoldopam or the selective DA-1 receptor antagonist Schering 23390 were started in random order, and experiments were repeated. RESULTS: Neither agent significantly altered baseline values of arterial pressure, RBF, or GFR rate. Fenoldopam prevented reductions in GFR (-17 +/- 2 Deltaml/min, control vs. 2 +/- 1 Deltaml/min, fenoldopam, P < 0.001). Conversely, GFR was further reduced in the presence of Schering 23390 (-15 +/- 2 Deltaml/min, control vs. -23 +/- 1 Deltaml/min, Schering 23390, P < 0.05). Similarly, the maximal reduction in RBF was blunted with fenoldopam (-71 +/- 12 Deltaml/min, control vs. -3 +/- 2 Deltaml/min, fenoldopam, P < 0. 01), whereas Schering 23390 potentiated maximal RBF reductions following the RCM injection (-85 +/- 11 Deltaml/min, control vs. -119 +/- 14 Deltaml/min, Schering 23390, P < 0.05). The duration of recovery from vasoconstriction was also prolonged in the presence of Schering 23390 (342 +/- 35 seconds, control vs. 762 +/- 56 seconds, Schering 23390, P < 0.0001). CONCLUSION: We conclude that selective DA-1 receptor stimulation protects against RCM-mediated decrements in renal hemodynamics, independent of changes in baseline GFR and RBF. Clinical trials are required to examine whether selective DA-1 receptor stimulation may have a role in prophylaxis against nephropathy development in high-risk patients undergoing procedures that require RCM.     

U1-RNP and Toll-like receptors in the pathogenesis of mixed connective tissue diseasePart II. Endosomal TLRs and their biological significance in the pathogenesis of mixed connective tissue disease

Mixed connective tissue disease (MCTD) is a chronic autoimmune immunopathological disease of unknown etiology, which is characterized by the presence of various clinical symptoms and the presence of autoantibodies against U1-RNP particles. The U1-RNP component engages immune cells and their receptors in a complex network of interactions that ultimately lead to autoimmunity, inflammation, and tissue injury. The anti-U1-RNP autoantibodies form an immune complex with self-RNA, present in MCTD serum, which can act as endosomal Toll-like receptor (TLR) ligands. Inhibition of TLRs by nucleic acids is a promising area of research for the development of novel therapeutic strategies against pathogenic infection, tumorigenesis and autoimmunity. In this review we summarize current knowledge of endogenous TLRs and discuss their biological significance in the pathogenesis of MCTD. In part I we described the structure, biological function and significance of the U1-RNP complex in MCTD.     

Tyrosine isomers and hormonal signaling:A possible role for the hydroxyl free radical in insulin resistance

Oxidative stress processes play a major role in the development of the complications associated with diabetes and other diseases via non-enzymatic glycation,the hexosamine pathway,the polyol pathway and diacylglycerol-protein kinase C.Oxidative stress may lead to the production of hydroxyl free radicals,which can attack macromolecules,such as lipids,nucleic acids or amino acids.Phenylalanine(Phe) can be enzymatically converted to the physiological para-tyrosine(p-Tyr);however,a hydroxyl free radical attack on Phe may yield meta-and ortho-tyrosine(m-and o-Tyr,respectively) in addition to p-Tyr.Hence,m-and o-Tyr may be regarded as markers of hydroxyl free radical-induced damage.Their accumulation has been described;e.g.,this accumulation has been found in the urine of patients with diabetes mellitus(DM) and/or chronic kidney disease,in cataract lenses,in vessel walls,in irradiated food and in amniotic fluid,and it may serve as an indicator of oxidative stress.The use of resveratrol to treat patients with type 2 DM led to a decrease in the urinary excretion of o-Tyr and concomitantly led to an improvement in insulin signaling and insulin sensitivity.Literature data also suggest that m-and o-Tyr may interfere with intracellular signaling.Our group has shown that erythropoietin(EPO) has insulin-like metabolic effects on fat cells in addition to its ability to promote the proliferation of erythroid precursor cells.We have shown that the supplementation of cell culture medium with m-and o-Tyr inhibits erythroblast cell proliferation,which could be ameliorated by p-Tyr.Additionally,in vivo,the o-Tyr/p-Tyr ratio is higher in patients with renal replacement therapy and a greater need for EPO.However,the o-Tyr/p-Tyr ratio was an independent determinant of EPO-resistance indices in our human study.The o-Tyr content of blood vessel walls inversely correlates with insulin-and acetylcholineinduced vasodilation,which could be further impaired by artificial oxidative stress and improved by the use of antioxidants.In rats that receive o-Tyr supplements,decreased vasorelaxation is detected in response to insulin.Additionally,o-Tyr supplementation led to the incorporation of the unnatural amino acid into cellular proteins and caused a decrease in the insulin-induced phosphorylation of endothelial nitric oxide synthase.Our data suggest that m-and o-Tyr may not only be markers of oxidative stress;instead,they may also be incorporated into cellular proteins,leading to resistance to insulin,EPO and acetylcholine.     

Anterior and posterior pituitary function in brain-stem-dead donors. A possible role for hormonal replacement therapy

Blood samples were obtained, at the time of organ donation, from 31 consecutive brain-stem-dead (BSD) donors referred to one transplant coordinator during a 9-month period. Twenty-four cases (77%) had clinical diabetes insipidus (DI), which was poorly controlled with marked dehydration in a majority of cases (serum osmolality range 268-357; median 302 mOSM/kg). Serum triiodothyronine (T3) was subnormal in 25 (81%); all had normal or high serum reverse T3; and the serum free thyroxine (T4) index was subnormal in 9 (29%), and TSH was subnormal in 7 (23%). In no case were T4 and TSH both subnormal and results were typical of the sick euthyroid syndrome rather than TSH deficiency. Of 21 cases not receiving corticosteroids, 5 (24%) had a serum cortisol above 550 nmol/L (20 micrograms/dl), excluding ACTH deficiency, and only 1 had undetectable cortisol levels. Those with severe hypotension did not have significantly lower serum cortisol (mean 354 vs. 416; P greater than 0.5). Levels of prolactin, growth hormone, gonadotrophins, and gonadal steroids were variable, but only a minority were frankly deficient in these hormones. BSD donors frequently have DI, which is often managed poorly by nonspecialists and requires appropriate replacement therapy. In contrast most patients are not totally deficient in anterior pituitary hormones. Routine hormonal therapy with cortisol and T3 cannot, therefore, be justified on endocrinological grounds. Widespread introduction of such treatment should only follow controlled trials that clearly demonstrate clinically significant improvement in the transplanted organ function, without detriment to the donor.