Search

It is generally accepted that the progressive loss of kidney function results from a pathogenic process that is independent of the original etiology, functioning as a final common pathway. Part of this response is characterized by triggering of interstitial infiltration and induction of tubular damage. As a consequence, tubular epithelial cells (TEC) can become activated and begin to express several inflammatory mediators. In the present review, we will summarize the potential role of TEC in progressive renal disease. Much emphasis will be put on studies using in vitro cultured TEC. These studies have provided more insight into the different signals involved in the regulation of the production of inflammatory mediators like complement, cytokines and chemokines, as well as progression factors like growth factors and matrix component by TEC.

Background The purpose of this study was to compare the overall effectiveness of 2 treatment strategies for inpatients with severe major depressive episode (DSM-III-R): (1) mirtazapine (phase 1) and subsequent lithium addition (phase 2) or (2) imipramine (phase 1) and subsequent lithium addition (phase 2). We previously reported the results of phase 1. Method In phase 1, patients were randomly assigned to treatment with either mirtazapine or imipramine, and doses were adjusted to obtain predefined blood drug levels. Nonresponders had lithium added to the double-blind mirtazapine or imipramine medication. The dose was adjusted to obtain a blood lithium level of 0.5-1.0 mmol/L. Treatment effects were evaluated weekly by the Montgomery-Asberg Depression Rating Scale for up to 2 weeks on this blood lithium level. Results Data for 100 patients were available for comparison of the 2 treatment strategies. 80 patients received no comedication. By the end of phase 2, 24 (48%) of 50 had responded to mirtazapine and 32 (64%) of 50 had responded to imipramine (intent-to-treat analysis). A survival analysis of the total patient group intent-to-treat showed a significant difference in favor of the treatment strategy with imipramine and subsequent lithium addition. Conclusion Efficacy of imipramine and subsequent lithium addition for nonresponders is superior to the same treatment strategy with mirtazapine. This applies to the patient sample studied, which consisted of 100 severely depressed inpatients, 29 of whom were psychotically depressed. More serious side effects of imipramine, however, led to discontinuation of imipramine in 5 patients. No serious side effects were observed during the phase of lithium addition to either imipramine or mirtazapine. We, therefore, prefer to start treatment with imipramine and test for fixed blood drug levels, and, if necessary, add lithium. In the case of prohibitive side effects, patients are switched to a modern antidepressant such as mirtazapine, and, if necessary, lithium is added to this antidepressant.

Background. The presence of viable cells may contribute to increased homograft valve durability. These cells may be of infiltrating recipient or persisting donor origin. In this study, in situ hybridization was used to assess the origin of cells in cryopreserved homograft valve explants. Methods. A total of 10 homografts with a donor-recipient gender mismatch were acquired from patients whose graft had been explanted at reoperation or at autopsy. The period of implantation varied from 14 days to 70 months. Frozen sections were made and alternately examined with hematoxylin and eosin staining and in situ hybridization. Male cells were distinguished from female using a biotinylated Y-chromosome-specific deoxyribonucleic acid probe. Results. No endothelial cells were found. Thirty percent of the leaflets showed large acellular zones and 30% were completely acellular. The homograft arterial wall was occupied by a vast majority of penetrating host fibroblasts in 80% of the studied specimens. Donor and recipient cells were coexistent in the wall in 60% of the studied specimens and in 50% of the leaflets. In 30% only host cells could be identified. Conclusions. This finding of tissue chimerism may lead to new insights in homograft pathology. The technique of in situ hybridization may provide an indispensable contribution in further homograft research.

A limited T-cell receptor (TCR) Vbeta repertoire employed by autoreactive T cells may be related to the development and course of autoimmune diseases. Vbeta repertoire skewing has been observed not only in man, but also in animal models of several human autoimmune diseases, such as MRL-lpr mice, which spontaneously develop a systemic lupus erythematosus (SLE)-like disease. Murine chronic graft-versus-host disease (GVHD) is an inducible model for SLE, involving direct interaction between donor T cells and recipient B cells. It is not known whether Vbeta-specific T-cell subsets are pathogenically involved in this model. Retroviral superantigens such as Mls-1 are known to have a profound impact on the TCR Vbeta repertoire in mice. Restriction of the peripheral TCR repertoire may result from intrathymic expression of Mls-1, which causes deletion of T cells expressing Vbeta6, -7, -8.1, or -9. Mls-1 incompatibility between donor and recipient can be used to determine the involvement of these TCR Vbeta families in GVHD. In the present study we induced GVHD in several strain combinations to investigate TCR Vbeta gene expression during GVHD, and the effect of Mls-1 incompatibility on the TCR Vbeta repertoire. TCR Vbeta gene expression was determined using an RNase protection assay. Our results indicate that T cells expressing the Vbeta2 or Vbeta16 chain play an important pathogenetic role, while T cells bearing the Vbeta1 or Vbeta6 chain may be related to self-limitation of the lupus-like disease in this model.

Basal cell carcinomas (BCC) are among the most common cancers in white subjects. Etiologic factors include ultraviolet and ionizing radiation, chemical carcinogens, and possibly infection with human papillomaviruses. Because of clinical and histologic differences, differential pathogenetic mechanisms have been suggested for different BCC subtypes. We studied the patient and tumor characteristics of all BCC diagnosed and/or treated at the departments of Dermatology and Plastic Surgery of our hospital between 1985 and 1996, and a review of the literature was carried out. Some important differences between patients with nodular BCC and patients with superficial BCC were observed. The frequency of superficial BCC was higher in females and was seen in younger patients as compared with nodular BCC. The latter occurred mainly in the head/neck region: in males they were seen more frequently on the ears, and in females they were predominantly seen on the eyelids, the lips, and in the neck. Superficial BCC occurred mainly on the trunk, and occurred significantly more often on the trunk in males than in females, where the legs were the most common site. These findings strongly suggest that the superficial subtype is a separate group within the clinical entity of BCC. Furthermore, our findings seem to support the etiologic role of sun exposure in these tumors; however, this role may be different for each subtype. Chronic sun exposure may be an etiologic factor in nodular BCC as compared with intermittent sun exposure in superficial BCC. Other factors, such as differences in site specific host factors and referral bias, may also play a role in the differences found between the subtypes.

Expansion of the glomerular mesangial matrix (MM), thickening of the glomerular basement membrane (GBM), and eventually the development of glomerulosclerosis are often seen in immunologically mediated kidney diseases. In addition to quantitative changes in the extracellular matrix (ECM), qualitative changes in ECM molecules may contribute to alterations in the composition of the glomerular matrix. The expression of collagen IV, alpha 1-5(IV) mRNA, and polypeptides was therefore investigated during the development of chronic graft-versus-host disease (GvHD) in mice, a model for lupus nephritis, and in chronic serum sickness (CSS) in rats, a model for membranous nephropathy. Immunohistochemical studies showed increased mesangial expression of alpha 1 and alpha 2 early in the disease, but only late in the GBM. In contrast, alpha 3 and alpha 4 increased in the GBM during disease, but not in the MM. The mRNA levels for all collagen IV chains were increased in isolated glomeruli before morphological alterations were detectable. The mRNA increase was earlier and more profound for alpha 3, alpha 4 and alpha 5 than for alpha 1 and alpha 2. Expression of alpha 3(IV) was greatest in GvHD, whereas expression of alpha 4 was greatest in CSS. As determined by in situ hybridization (ISH), alpha 1 mRNA was observed dispersed in the glomerulus, but alpha 3, alpha 4, and alpha 5 mRNAs were mainly located in cells at the periphery of the glomerular tuft. The changes in the relative abundance of collagen IV mRNA in disease states may perturb the collagen IV network, altering glomerular structure and function, and may thereby play a central role in the development of glomerulonephritis and glomerulosclerosis.

Mice with chronic graft-versus-host disease (GvHD) induced by injection of DBA/2 lymphocytes into (DBA/2×C57BL/10) F1 hybrids (DBA/2 GvHD) develop a lupus-like glomerulonephritis with global glomerulosclerosis 12 weeks after induction of the disease. In two other strain combinations with similar H-2 incompatibilities [BALB/c into BALB/c×BL10 (BALB/c GvHD) and BALB.D2 into BALB.D2×BL10 (BALB.D2 GvHD)], GvHD induction leads to lupus nephritis without global glomerulosclerosis. This study investigated the identity of kidney-infiltrating leukocytes and their involvement in the development of glomerulosclerosis in these three strain combinations. In mice with DBA/2 GvHD, a significant increase in glomerular CD11a-positive cells was found 4 weeks after disease induction. Mice with BALB/c or BALB.D2 GvHD did not show an increase in glomerular CD11a-positive cells at any time point. In the interstitium, CD11a-positive cells were observed 4 weeks after disease induction only in mice with DBA/2 GvHD. In mice with BALB.D2 GvHD, no increase was found in interstitial CD11a-positive cells. In mice with BALB/c GvHD, interstitial CD11a-positive cells were found from week 4 onward. Further immunohistochemical analysis of the glomerular CD11a-positive cells in mice with DBA/2 GvHD showed that these cells were neither polymorphonuclear leukocytes (PMN), nor CD3-positive (T cells), B220-positive (B cells), or F4/80-positive (macrophages). They were all CD45-positive (leukocytes) and MHC class II-positive. In conclusion, we have shown in this model of chronic lupus nephritis that glomerular influx of as yet unidentified CD11a-positive leukocytes is associated with the development of glomerulosclerosis. © 1998 John Wiley & Sons, Ltd.

The purpose of this article is to review a set of recently obtained data concerning matrix and matrix adhesion molecules in renal disease. Our goal is not to cover the entire topic, but rather to focus on findings obtained with an experimental model for chronic lupus nephritis, evoked in mice by inducing graft-versus-host disease (GVHD). The overall aim of these studies was to investigate the role of adhesion molecules as targets for autoantibodies, in the recruitment of inflammatory cells, and in the accumulation of matrix in kidney disorders. In addition, we set out to discover how matrix proteins in renal diseases differ from normal matrix molecules both quantitatively, in their increased frequency, and qualitatively, in their intramolecular structure. The advances in understanding and methodology described in this review imply a substantial capability for greater insight into the pathogenesis of kidney disease; for making better use of renal biopsies, such as in applying competitive reverse-transcriptase-polymerase chain reaction (RT-PCR) in RNA analysis for matrix; and in developing more effective treatment strategies for patients with kidney disease.

SUMMARY Mice with chronic graft-versus-host disease (GVHD), induced by injection of DBA/2 lymphocytes in (C57BL10*DBA/2) F1 hybrids, develop a syndrome resembling systemic lupus erythematosus (SLE) with immune complex glomerulonephritis. In this model we evaluated the role of interactions between CD11a (LFA-1α) and CD54 (intercellular adhesion molecule-1 (ICAM-1)) molecules on leucocytes in the development of renal disease in systemic autoimmunity. Two weeks after induction of GVHD, when anti-nuclear autoantibodies were detected in the circulation and immune complexes had formed in the glomeruli, mice were injected twice per week with rat anti-CD11a and anti-CD54 MoAbs, or with their vehicle PBS, or with control rat IgG. MoAb treatment significantly lowered albuminuria and increased survival compared with control mice with GVHD. In the glomeruli of MoAb-treated mice there was markedly less binding of immunoglobulin and C3, while anti-renal tubular epithelium autoantibodies, but not anti-glomerular basement membrane autoantibodies, were significantly lowered in the circulation 4 weeks after disease induction. In addition, MoAb treatment inhibited the glomerular influx of CD11a+ cells and decreased development of histological abnormalities in the kidneys. Both rat IgG- and MoAb-treated mice developed anti-rat immunoglobulin antibodies. Furthermore, a marked splenomegaly with an increase of the T cell compartment was observed in MoAb-treated mice with GVHD. These results show that CD11a/CD54 interactions are crucial for the full-blown development of lupus nephritis in this model. Treatment aimed at blocking the activity of these molecules profoundly attenuated the development of renal disease in chronic GVHD even if started when first symptoms of SLE (i.e. anti-nuclear autoantibodies in sera and glomerular binding of immunoglobulins) were already detectable.

Preeclampsia is associated with increased levels of the circulating antiangiogenic factor sFlt-1 and with an excessive shedding of placenta-derived multinucleated syncytial aggregates into the maternal circulation. However, it remains unclear whether these aggregates are transcriptionally active in the maternal organs and can, therefore, contribute to the systemic manifestations of preeclampsia. In this study, we measured placental soluble fms-like tyrosine kinase-1 (sFlt-1) mRNA levels in preeclamptic- and control placentas and performed RNA in situ hybridization to localize the main placental expression site of sFlt-1 mRNA. Because the maternal lung is the first capillary bed that circulating syncytial aggregates traverse, we studied the presence and persistence of placental material in lungs of preeclamptic and control subjects. To confirm the placental origin of these aggregates in maternal lungs, immunohistochemistry for the placenta-specific marker hCG (human chorionic ghonadotropin) and Y chromosome in situ hybridization were performed. Using human placental tissue, we found that syncytial knots are the principal site of expression of the antiangiogenic factor sFlt-1. In addition, autopsy material obtained from women with preeclampsia (n=9) showed significantly more placenta-derived syncytial aggregates in the lungs than in control subjects (n=26). Importantly, these aggregates still contained the antiangiogenic factor sFlt-1 after their entrapment in the maternal lungs. The current study confirms the important role of syncytial knots in placental sFlt-1 mRNA production. In addition, it shows a significant association between preeclampsia and larger quantities of sFlt-1 containing syncytial aggregates in maternal lungs, suggesting that the transfer of syncytial aggregates to the maternal compartment may contribute to the systemic endothelial dysfunction that characterizes preeclampsia.

Early pancreas graft loss is usually attributed to technical failure while the possibility of antibody-mediated rejection (AMR) is generally overlooked. To investigate the role of AMR in early pancreas graft loss, we retrospectively assessed 256 patients with simultaneous pancreas-kidney transplantation (SPK) between 1985 and 2010 at our institute. We included 33 SPK patients who lost their pancreas graft1 year after transplantation. AMR was diagnosed based on donor-specific antibodies, C4d and histology in 7 cases, 8 cases were suspicious for AMR and 18 pancreas graft losses were not due to AMR. Acute AMR occurred1 month after transplantation in 6/7 cases, whereas all other causes typically led to loss1 month after transplantation. Thrombotic lesions occurred equally among the 33 cases. In 12/18 concurrent kidney specimens, the diagnostic results paralleled those of the pancreas graft. All patients with acute AMR of the pancreas graft lost their renal grafts1 year after transplantation. In the setting of a thrombotic event, histopathological analysis of early pancreas graft loss is advisable to rule out the possibility of AMR, particularly because a diagnosis of acute AMR has important consequences for renal graft outcomes.

Susceptibility to systemic lupus erythematosus (SLE) and, in particular, lupus nephritis is strongly influenced by genetic factors. Previous studies have shown that MHC-related antigens influence the development of SLE. In the current study, we set out to investigate how non-MHC genes influence the pathogenesis of glomerulonephritis in chronic graft-versus-host disease (GVHD) in mice, a model for lupus nephritis. For the induction of GVHD we used parent-to-F1 hybrid mouse strain combinations. DBA/2, BALB/c, BALB.D2 and C57Bl/10.D2 (BL10.D2) donor lymphocytes carrying an H-2d haplotype were injected into H-2b/d F1 hybrids of BL10 mice, which differed only at non-MHC loci. Within these hybrid strains the development of immune complex glomerulonephritis was investigated by monitoring the occurrence of autoantibodies in the circulation, deposition of immunoglobulins in the glomeruli, development of albuminuria, and glomerulosclerosis. In diseased DBA/2 mice albuminuria developed 6 weeks after induction of the disease. Mice with a BALB background developed a lupus-like syndrome characterized by albuminuria starting 8 weeks after induction of the GVHD. During the development of the GVHD, polyclonal B cell activation occurred in both the DBA/2 and BALB/c strains, resulting in the formation of autoantibodies. Only the strain combination using DBA/2 mice developed anti-GBM antibodies. In DBA/2 and BALB strain combinations immune complexes were detected in a granular pattern along the glomerular capillary walls. In the DBA/2 recipients a linear pattern of immunoglobulin depositions preceded the granular phase. This study demonstrates that: (i) non-MHC genes govern the pathogenesis of immune complex nephritis in this model by influencing the autoantibody profile; and (ii) the presence of anti-GBM antibodies in the early stages of the disease is a conditio sine qua non for the development of full-blown glomerulonephritis and glomerulosclerosis in this model.

In order to relate histopathological findings of the kidney in systemic vasculitis to renal outcome, scoring of various morphological parameters is necessary. Therefore, we conducted a standardization study for evaluating renal biopsies from patients with systemic vasculitis. Four experienced renal pathologists from four European centres joined in the study. A scoring protocol was devised that required the observers to score an extensive number of histopathological lesions either quantitatively (as a percentage of the total number of glomeruli) or dichotomously (on a present/absent scale). Twenty renal biopsies were scored individually by all the observers, from which the inter-observer variability was analysed. Ten randomly chosen biopsies were scored again, in order to obtain the intra-observer variability. For inter-observer agreement, the evaluation of the quantitative variables was satisfactory for both rounds (0.55or = Kendall's Wor = 0.95 and 0.59or = Wor = 0.96, respectively, with all P0.05). However, the inter-observer agreement for the dichotomous data was poor (kappaor = 0.30 in more than half of the parameters in both rounds). Also the data on intra-observer agreement showed more favourable results for the analysis of the quantitative data (Pearson's r0.45 in more than 85% of the variables in both rounds) than for the dichotomous scoring system (kappaor = 0.30 in more than half of the variables). It is concluded that even between experienced renal pathologists discrepancies occur in scoring kidney biopsies. Inter- and intra-observer agreement is greater if a quantitative method for reviewing the biopsies is applied that requires the observers to score the tissue specimens systematically.

Spectral analysis of fluctuations in heart rate and blood pressure was employed to explore sympathetic and parasympathetic cardiovascular control mechanisms in relation to trait anxiety in major depressive disorder. Sixteen drug-free female depressed patients were divided into two groups: those who were high on trait anxiety (HTA, n = 9) and those who were normal or low on trait anxiety (LTA, n = 7). In patients and age-matched female controls (n = 10), heart rate (HR), blood pressure (BP; Finapres device) and respiration were recorded during a period of supine rest (10 min), orthostatic challenge (60 ° head-up tilting, 8 min), and post-orthostatic supine rest (8 min). Power spectra were calculated over the last 4 min of these three situations for HR, systolic BP, as well as for respiration. Spectral density was assessed for three frequency bands: low (0.02–0.06 Hz), mid (0.07–0.14 Hz) and high (0.15–0.50 Hz). Patients did not differ from controls during supine rest. During orthostatic challenge, HTA patients showed significantly more HR increase and suppression of high-frequency fluctuations of HR (suggesting stronger vagal inhibition) in comparison with the controls; this effect was accompanied by a significant increase in respiratory frequency. Both patients groups did not show the normal increase in mid-frequency band fluctuations of BP during orthostatic challenge, indicating reduced sympathetic activation. Low-frequency fluctuations of HR, as well as respiratory frequency during post-orthostatic supine rest of the HTA patients were significantly increased versus controls. This exploratory study indicates that trait anxiety may be a relevant factor when evaluating parasympathetic and sympathetic dysbalances in the state of a major depressive disorder.

Increased mRNA and protein expression of extracellular matrix (ECM) components, including fibronectin, occurs during the development of glomerulonephritis and glomerulosclerosis in immunologically mediated kidney diseases. However, in addition to these quantitative changes in ECM expression, qualitative changes in these molecules may contribute to malformations in the composition of the glomerular matrix. These qualitative changes may include alterations in the splicing pattern of the V-region of fibronectin, since this region plays a role in its accumulation. The splicing patterns of this region have been studied in chronic graft-versus-host disease (GvHD) in mice, a model of lupus nephritis, and in chronic serum sickness (CSS) in rats, a model of immune complex nephritis. Cloning of the mouse fibronectin V-region from kidney tissue revealed 96.1 per cent homology with the corresponding domain in rat fibronectin. PCR (polymerase chain reaction) analysis of RNA from isolated glomeruli revealed three isoforms of this region in both mouse and rat fibronectin, namely inclusion or exclusion of the whole region, or exclusion of only the CS1 domain. In both models, increased exclusion of the V-region was observed early in the disease. However, in GvHD the splicing pattern returned to normal, whereas in CSS the shift persisted during the course of the experiment. Differentiated expression of fibronectin isoforms may exert an important effect on the structure and biological function of the glomerulus and may thus play a role in the development of glomerulonephritis and glomerulosclerosis.

Spectral analysis of fluctuations in heart rate (HR) and blood pressure (BP) was applied to assess sympathetic and parasympathetic cardiovascular control mechanisms in patients with unipolar affective disorder before and after treatment with imipramine (IMI) or mirtazapine (MIR). In a double-blind randomized study, 10 patients received treatment with IMI and 10 patients received treatment with MIR. Cardiovascular parameters were studied before and after 4 weeks of treatment: HR and BP (Finapres) were recorded continuously during supine rest (SR) and orthostatic challenge (OC; 60-degrees head-up tilting). During SR and OC, power spectra were calculated for HR and systolic BP. Spectral density was assessed for three frequency bands: low (0.02-0.06 Hz), mid (0.07-0.14 Hz), and high (0.15-0.50 Hz). Before treatment, the depressed patients (N = 20) differed from age-matched controls (N = 20) only in their response to OC: the depressed patients showed more suppression of HR variability (both mid- and high-frequency band fluctuations), indicating stronger vagal inhibition, and a reduced increase of BP variability (mid-frequency band fluctuations), indicating reduced sympathetic activation. After 4 weeks of treatment, patients treated with either antidepressant drug showed significant changes of HR (increase) and HR variability (decrease) during SR and OC; the suppression of mid- and high-frequency fluctuations of HR was larger for IMI than for MIR. The increase in HR and decrease in HR variability may be attributed to the anticholinergic properties of IMI (strong) and MIR (weak), resulting in cardiac vagal inhibition. Whereas MIR had no effect on BP or BP variability, IMI specifically reduced mid-frequency band fluctuations of BP as the result of a suppression of central sympathetic activity. Our data confirm and extend previous observations on the presence of autonomic dysfunctions in unmedicated depressed patients: spectral analysis of HR and BP fluctuations suggested that both parasympathetic and sympathetic mechanisms are involved, specifically during OC. The preexisting autonomic cardiovascular dysfunctions were not normalized by antidepressant drugs. In fact, some of the components of the cardiovascular autonomic dysfunction were further aggravated, depending on the pharmacologic profile of the drug under investigation.

Successful transplantation of isolated islets of Langerhans has been reported in large mammals, including man, but metabolic control has not been well-established. We studied the glucose and islet hormone response to fasting, i. v. glucose bolus infusion, i.v. arginine bolus infusion during a 35-mmol/l hyperglycaemic clamp, mixed meals, and i. v. insulin-induced hypoglycaemia up to 3 years after intrasplenic islet autotransplantation in six pancreatectomised dogs. The individual postprandial insulinogenic index (ratio of 2-h postprandial insulin to glucose levels) at 1 month post-transplant, predicted (r=0.99) the time to functional graft failure (6–175 weeks). Metabolic studies at 6 months post-transplant in four dogs demonstrated normal fasting glucose and hormone levels, except for reduced pancreatic polypeptide levels. Intravenous glucose and arginine-stimulated insulin were reduced to 15% of preoperative values. In contrast, postprandial normoin-sulinaemia was observed — albeit with moderate hyperglycaemia (approximately 10 mmol/l). Postprandial glucagon and glucose-dependent insulinotropic polypeptide (GIP) had increased. Comparison of the post-transplant insulin responses to a meal and to intravenous challenges demonstrated maximal stimulation of the graft by the meal. Post-transplant pancreatic polypeptide responses to a meal and i.v. arginine were severely reduced, and no pancreatic polypeptide response to i.v. insulin-induced hypoglycaemia was observed — indicating absence of cholinergic reinnervation. Thus, glucose regulation and both the insulin secretory capacity and life expectancy of islet grafts were best documented by meal testing. Tentatively, a postprandial hyperglycaemia-enhanced incretin effect of glucose-dependent insulinotropic polypeptide and other gut hormones may account for the difference in the insulin response to i. v. glucose and a meal. Aside from the reduced insulin secretory capacity, both a deranged pulsatile delivery of insulin, hyperglucagonaemia, and pancreatic polypeptide deficiency may have been conducive to glucose intolerance.

The physical activity (PA) intention-behaviour gap is a topic of considerable contemporary research, given that most of our models used to understand physical activity suggest that intention is the proximal antecedent of behavioural enactment. The purpose of this study was to quantify the intention-PA gap at public health guidelines with a meta-analysis of the action control framework.Systematic review and meta-analysis.Literature searches were conducted in July 2012 among five key search engines. This search yielded a total of 2,865 potentially relevant records; of these, 10 studies fulfilled the full eligibility criteria (N = 3,899).Random-effects meta-analysis procedures with correction for sampling bias were employed in the analysis for estimates of non-intenders who subsequently did not engage in physical activity (21%), non-intenders who subsequently performed physical activity (2%), intenders who were not successful at following through with their PA (36%), and successful intenders (42%). The overall intention-PA gap was 46%.These results emphasize the weakness in early intention models for understanding PA and suggest this would be a problem during intervention. Contemporary research that is validating and exploring additional constructs (e.g., self-regulation, automaticity) that augment intention or improving the measurement of motivation seems warranted.What is already known on this subject? Intention is considered the proximal antecedent of behaviour in many popular models. Intention is also an established correlate of physical activity behaviour, yet discordance is considerable in experimental research. What does this study add? This meta-analysis of studies that have assessed concordance/discordance of physical activity intention and behaviour at public health guidelines shows the intention-behaviour gap at 48% and the discordance is from intenders who do not act. The results demonstrate that discordance is not just from extreme levels of intention or behaviour (e.g., intend to exercise six times but only exercise five), but from levels that are relevant to health promotion.

Production and cytokine-mediated regulation of monocyte chemoattractant protein-1 by human proximal tubular epithelial cells. Impairment of renal function in various types of glomerular disease is associated with tubulointerstitial changes. The mechanism of mononuclear cell infiltration in the interstitium is not fully understood. Recently, monocyte chemoattractant protein-1 (MCP-1) has been identified as a monocytespecific chemotactic factor. We analyzed the presence of MCP-1 in renal biopsies from patients with various forms of glomerular disease and demonstrated that MCP-1 expression is increased in renal tubular epithelial cells during disease. Further analysis showed that various cell lines of human proximal tubular epithelial cells (PTEC) produce MCP-1 in culture under serum-free conditions and that the production is inhibited by cycloheximide. IL-lα and TNF-α enhanced the production by each cell line in a dose- and time-dependent manner as measured by radioimmunoassay. Northern blot analysis demonstrated that IL-lα and TNF-α markedly enhanced the expression of MCP-1 mRNA. Taken together these observations support the notion that MCP-1 is synthesized de novo by PTEC. MCP-1 produced by PTEC is found to be 13 kD by gel filtration chromatography. It is chemotactically active for monocytes. We conclude that in various types of glomerular disease, MCP-1 expression in tubular epithelial cells is associated with up-regulation of MCP-1 production by PTEC. These findings raise the possibility that macrophages may accumulate in renal interstitium as a consequence of MCP-1 production by PTEC.

Summary: Mediators released by glomerular macrophages may stimulate glomerular visceral epithelial cells (GVEC) to produce cytokines, growth factors or extracellular matrix components. This study describes that human GVEC produce monocyte chemoattractant protein-1 (MCP-1), a monocyte-specific chemotactic factor, and the effects of interleukin-lα (IL-1α) and tumour necrosis factor-α (TNF-a) on the production of MCP-1 by GVEC. We observed that the intensity of MCP-1 staining in GVEC is stronger in membranous nephropathy and glomerulosclerosis than in normal kidneys. Various cell lines of GVEC produced significant amounts of MCP-1, as assessed by inhibition radio-immunoassay. the presence of IL-1α and TNF-α during culture of GVEC enhanced the production of MCP-1 in a dose- and time-dependent manner. Glomerular visceral epithelial cells in culture express mRNA for MCP-1 and the expression is upregulated 2.0- and 1.4-fold in the presence of optimal concentration of IL-1α and TNF-α, respectively. De novo synthesis of MCP-1 is supported by the observation that MCP-1 production is fully inhibited by cydoheximide. Monocyte chemoattractant protein-1 isolated from GVEC supernatants exhibits a molecular size of 12 and 10 kDa as determined by gel filtration chromatography. Both sizes of MCP-1 is chemotactically active for monocytes. This study shows increased MCP-1 production by cultured human GVEC after stimulation with the inflammatory cytokines IL-1α and TNF-α. the expression of MCP-1 in GVEC was found to be upregulated in membranous nephropathy and glomerulosclerosis. These findings suggest that MCP-1 may be involved in glomerular injury in these diseases. the possible role of MCP-1 in the pathogenesis of human glomerulonephritis is discussed.

Chronic rejection of renal allografts is a major cause of late graft loss. However, time of onset, relation with acute early rejection episodes, and risk factors are largely unknown. We undertook a cohort study of 482 consecutive patients from a single center who received a cadaveric renal allograft between January 1983 and April 1991. During the first 3 months after transplantation, 76 (15.8%) patients developed vascular rejection and 1 15 (23.9%) developed interstitial rejection. One-year graft survival of patients without rejection, with interstitial rejection, and with vascular rejection was 87.8%, 87%, and 48.7%, respectively. Five-year graft survival was 73.5% for the group without rejection, 71.4% for patients with interstitial rejection, and 34.3% for patients with vascular rejection. The adjusted relative risk of graft loss was 4.92 (95% CI 3.25-7.43) for patients with vascular rejection and 1.27 (95% CI 0.80-2.02) for patients with interstitial rejection compared with patients without early rejection, taking the time dependency of the rejection events and prognostic factors into account. The incidence of vascular rejection was increased in patients with primary nonfunction (RR 1.69, 95% CI 1.01-2.84), with 1 HLA-DR mismatch (RR 2.38, 95% CI 1.44-3.93), with 2 HLA-DR mismatches (RR 3.24, 95% CI 1.25-8.42), with a prolonged cold ischemia time (RR 1.03, 95% CI 1.00-1.06 per hr), and with 1 or more previous transplantations (RR 1.76, 95% CI 1.01-3.07). Risk of developing vascular rejection was decreased in patients using CsA as compared with azathioprine (RR 0.41, 95% CI 0.24-0.67). Early vascular rejection, occurring within 3 months after transplantation, is the most important predicting variable of both early and late graft loss. Use of CsA less HLA-DR mismatching, and in cold ischemia time of short duration possibly prevent the development of vascular rejection

Increasing evidence suggests that preeclampsia is associated with complement dysregulation. The origin of complement dysregulation in preeclampsia is unknown, and further unraveling this mechanism could provide both diagnostic tools and therapeutic targets. Because the placenta is believed to play a crucial role in the pathogenesis of preeclampsia, we investigated placentas from preeclamptic women (n=28) and controls (n=44) for the presence of complement activation products. Immunohistochemistry was performed for C1q, mannose-binding lectin, properdin, and C4d. Staining patterns were related to pregnancy outcome. Possible causes of complement activation were investigated, including the presence of immune deposits at the syncytiotrophoblast and changes in the placental mRNA expression of complement regulatory proteins. C4d was rarely present in placentas from healthy controls (3%), whereas it was observed in 50% of placentas obtained from preeclamptic women ( P= 0.001). In these placentas, C4d was observed in a focal (9/14) or diffuse (5/14) staining pattern at the syncytiotrophoblast. With respect to C1q, mannose-binding lectin, and properdin, no differences were observed between cases and controls. In preeclamptic women, diffuse placental C4d was associated with a significantly lower gestational age at delivery. Furthermore, the mRNA expression of the complement regulatory proteins CD55 and CD59 was significantly upregulated in preeclampsia. In conclusion, there is evidence for increased classical pathway activation and altered complement regulation in preeclampsia. The relation between C4d and lower gestational age at birth suggests that the extent of complement dysregulation is associated with the severity of preeclampsia. Inhibiting excessive complement activation may be a promising therapeutic approach in the management of preeclampsia.

Although research has shown that whether people talk about health issues influences health campaign effects, no evidence exists on whether conversational valence fulfils a mediating role within health campaign effects. In the context of alcohol consumption, this two-wave experimental research studies the effects of exposure to an anti-alcohol message on conversational valence about alcohol. Further, it investigates whether valence subsequently affects alcohol consumption intentions.Eighty-four undergraduate students, in dyads, were randomly assigned to one of two conditions (anti-alcohol message vs. no alcohol message exposure).A baseline measure of the intention to refrain from binge drinking was assessed in advance. Two weeks later, half of the participants were exposed to an anti-alcohol message, after which all pairs engaged in a conversation about alcohol and binge drinking followed by an assessment of conversational valence and again the intention to refrain from binge drinking.An indirect effect of health message exposure on the intention to refrain from binge drinking through conversational valence was revealed. When participants viewed an anti-alcohol message, they reported significantly more negative conversations about alcohol. Subsequently, a more negative conversational valence about alcohol increased the intention to refrain from binge drinking.These findings suggest that conversational valence is relevant for health campaign effects. By demonstrating that health messages can influence this valence, important implications arise in terms of health promotion. Future research should focus on how to design effective health campaigns that are able to guide conversational valence in the desired direction.

The introduction of C4d in daily clinical practice in the late nineties aroused an ever-increasing interest in the role of antibody-mediated mechanisms in allograft rejection. As a marker of classical complement activation, C4d made it possible to visualize the direct link between anti-donor antibodies and tissue injury at sites of antibody binding in a graft. With the expanding use of C4d worldwide several limitations of C4d were identified. For instance, in ABO-incompatible transplantations C4d is present in the majority of grafts but this seems to point at ‘graft accommodation’ rather than antibody-mediated rejection. C4d is now increasingly recognized as a potential biomarker in other fields where antibodies can cause tissue damage, such as systemic autoimmune diseases and pregnancy. In all these fields, C4d holds promise to detect patients at risk for the consequences of antibody-mediated disease. Moreover, the emergence of new therapeutics that block complement activation makes C4d a marker with potential to identify patients who may possibly benefit from these drugs. This review provides an overview of the past, present, and future perspectives of C4d as a biomarker, focusing on its use in solid organ transplantation and discussing its possible new roles in autoimmunity and pregnancy.

Summary points Vasculitides associated with antineutrophil cytoplasmic antibodies (ANCAs) are systemic autoimmune diseases of unknown cause that affect small to medium sized blood vessels. They include granulomatosis with polyangiitis (formerly Wegener’s granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome). This review mainly focuses on granulomatosis with polyangiitis and microscopic polyangiitis. Although they are relatively rare, they must be diagnosed and treated early because untreated disease may rapidly develop into multiple organ failure and death. With modern treatment, these diseases are no longer fatal but chronic. Early diagnosis and treatment may prevent progression to end organ damage and lengthen healthier life. A recent large survey of patients with ANCA associated vasculitis found a lag of three to 12 months between disease onset and diagnosis, suggesting that diagnostic delay is a problem.1 We review the diagnosis and management of ANCA associated vasculitides for the generalist reader, drawing on the findings of observational studies, randomised controlled trials, and meta-analyses. #### Sources and selection criteria We searched PubMed (original search performed in August 2011, updated in December 2011) for relevant articles on epidemiology, diagnosis, and management of antineutrophil cytoplasmic antibody (ANCA) associated vasculitis. Where possible, we sought data from …

We characterized beta 1 integrin subunit expression on three different cultures of benign human nevomelanocytes (NMC) and on four different cell cultures of human dysplastic nevus (DN) cells by flow cytometry analysis and examined their role in mediating cell spreading and migration on collagen type IV (CN IV) and laminin (LN) coated substrates by using a quantitative video image analysis system. The seven human NMC and DNC cultures expressed heterogeneous levels of beta 1, alpha 2, alpha 3 and alpha 6 integrin subunits. Image analysis showed that a significant increase (P < 0.001) in cell spreading and migration of the DN cells was induced on increasing coating concentrations of CN IV and LN. However, the NMC did not show an increase in cell spreading or migration on these substrates when compared to the substrates coated with denatured BSA only. The CN IV-induced cell spreading of the DN cells was significantly inhibited by anti-beta 1 mAb (AIIB2), anti-alpha 2 mAb (P1E6), or anti-alpha 3 mAb (P1B5), but not by mAb against alpha 6 integrin subunit (GoH3). The DN cell spreading on LN was not significantly inhibited by these mAbs. In contrast, the migration of the DN on CN IV and LN was significantly inhibited by anti-beta 1 mAb, anti-alpha 2 mAb, anti-alpha 3 mAb and anti-alpha 6 mAb. These data suggest that the alpha 2 and alpha 3 subunit are important for cell spreading of the DN on CN IV, although they are less important in cell spreading on the extracellular matrix component LN.(ABSTRACT TRUNCATED AT 250 WORDS)

In a previous study, susceptibility for Trypanosoma brucei-related glomerulopathy in mice was shown to be dependent on non-major histocompatibility complex genes. Glomerular disease in this model could not be explained by the production of autoantibodies alone. In order to analyze which part of the defense system, in addition to the B-cell compartment, is involved in the development of this infection-related glomerular disease, groups of athymic (BALB/c rnu/rnu), splenectomized, or macrophage-depleted BALB/c mice were inoculated with T. brucei parasites. Polyclonal B-cell activation, invariably observed in infected BALB/c mice, was absent in BALB/c rnu/rnu mice. Glomerular disease in athymic mice, however, as defined by albuminuria and deposition of immune complexes, was not different from that seen in euthymic infected BALB/c mice. Splenectomy prior to inoculation of parasites led to a decreased incidence of albuminuria in 40% of the animals, whereas splenectomy 21 days after inoculation reduced albuminuria significantly, suggesting a role for spleen cells in the induction of glomerular disease. After macrophage depletion with liposome-encapsulated dichlorodimethylene-diphosphonate, infected BALB/c mice developed significantly higher albuminuria levels for a period up to 2 weeks after depletion. Therefore, it was concluded that the development of T. brucei-related glomerular disease is independent of thymus-matured T cells, while the involvement of macrophages in the development of proteinuria is inhibitory rather than disease inducing. Spleen cells other than thymus-dependent T cells, B cells, and macrophages should be investigated for their role in the pathogenesis of this glomerulopathy.

BACKGROUND The process of multistep tumor development has been studied thoroughly in the development of malignant melanomas. The authors investigated the expression of cellular adhesion molecules in nevomelanocytic lesions to explore a postulated role of adhesion molecules in cell-cell and cell-matrix interactions during tumor development. METHODS Sections of 20 nevocellular nevi, 35 dysplastic nevi, 6 melanomas in situ, and 20 malignant melanomas were investigated with respect to their expression of intercellular adhesion molecule-1 (ICAM-1), inducible cell adhesion molecule-110 (INCAM-110)/vascular cell adhesion molecule-1 (VCAM-1), E-selectin, lymphocyte function-associated antigen-1 (LFA-1), and the integrins for very late antigen-(VLA) alpha-(alpha) 2 and VLA-alpha 6; for these studies, monoclonal antibodies were used and indirect immunoperoxidase and immunofluorescence staining methods were performed. RESULTS In the transformation from benign to malignant neoplasms, the expression of ICAM-1 was upregulated strongly. The expression of VLA-alpha 2 on tumor cells increased whereas that of VLA-alpha 6 decreased; these alterations corresponded to changes previously observed in their ligands within the extracellular matrix. These results were statistically significant. In addition, ICAM-1, INCAM-110/VCAM-1, and E-selectin were detected in activated endothelial cells, probably as a result of cytokine activation. The ligand for ICAM-1, LFA-1, was confined to mononuclear cells. CONCLUSIONS The increase in ICAM-1 and VLA-alpha 2 expression and the decrease of VLA-alpha 6 expression may, in combination with specific matrix alterations, lead to a change in cell-cell and cell-matrix interaction, thereby contributing to the invasive property of melanocytic tumor cells. The neoexpression of INCAM-110/VCAM-1 and E-selectin in pigmented skin lesions may play a role in both infiltrative growth and the generation of a host reaction toward these tumors.

Background. A randomized trial was undertaken comparing the Western R1 resection with limited N1-level lymphadenectomy and the Japanese R2 resection with extended lymphadenectomy, including the N2-level for curative resection of gastric cancer patients. After 389 patients were entered in the trial, protocol deviations were observed that reduced the intended distinction between the two types of lymphadenectomy: noncompliance, i.e., no substantiation of lymphadenectomy by nodal yields at indicated stations, and contamination, i.e., extension of lymphadenectomy outside the allocated level of nodal clearance. Methods. To identify factors underlying these protocol deviations, the authors analyzed the influence of six patient-, tumor, and treatment-related characteristics on the magnitude of deviations per patient, and on the incidence of deviations per lymph node station. Results. Protocol deviations were influenced by the following station-specific factors: (1) the number of nodes per station; (2) the clarity of anatomical station definition; (3) the location of stations; (4) local conventions on the type of gastrectomy; and (5) technical features to allow complete en bloc dissection. Furthermore, nonspecific factors such as inadequate retrieval of nodes, incomplete dissection, and careful selection of clinically overt metastases outside the allocated level of nodal clearance were randomly distributed over stations, and they, too, contributed to the deviations. Conclusions. Based on the findings, the authors took additional steps to preserve the distinction between limited and extended lymphadenectomy and to improve the accuracy of nodal staging. These factors should be considered when standardization of both surgicopathologic trials and clinical protocols for the treatment of gastric cancer is pursued. Cancer 1994; 73:1544–51.

In recent years the interaction between tumour cells and the surrounding extracellular matrix in the process of tumour development, invasion and metastasis has been a focus of interest. We studied frozen sections of nine naevocellular naevi (junctional, compound and intradermal), 40 dysplastic naevi, six pagetoid in situ melanomas and 12 superficial spreading melanomas in order to determine the expression of: the basement membrane proteins collagen type IV and laminin, the interstitial collagen types I, III and VI, and fibronectin and tenascin. An indirect immunoperoxidase technique was used. In the various stages of melanocytic tumour progression we observed: 1 loss of type IV collagen and laminin within dermal melanocytic cell nests; 2 de novo expression of basement membrane type IV collagen and increased expression of the interstitial collagen types I, III and VI, as well as tenascin and fibronectin in the dermal stroma surrounding dysplastic naevus cells and melanoma cells; 3 presence of extracellular matrix components in close association with intra-epidermally located invading atypical melanocytes. These data demonstrate the complex alterations of the composition of the extracellular matrix from bland naevi through lesions with progressive atypia to invasive melanoma. The changes described result in a molecular environment which melanocytes with an altered adhesion molecule profile are able to invade.

Glomerulonephritis in BALB/c mice following infection with Trypanosoma brucei is characterized by albuminuria and glomerular deposition of immunoglobulins. Electron-dense deposits are present in the mesangium, as well as subendothelially and subepithelially along the glomerular capillary wall. In this study the nature of intracytoplasmic, electron-dense, round structures observed in glomerular endothelial cells was investigated by immunoelectron-microscopy and enzyme histochemistry. The presence of these structures was related in time with the development of proteinuria. Mice from the C57BL10 strain, which upon infection develop glomerular immune complexes without proteinuria, were examined as well. The results demonstrated that the first endothelial changes, occurring 3-4 weeks after infection, were swelling of endothelial cells containing intracytoplasmic, electron-dense, round structures. These changes were seen prior to the onset of proteinuria, and were not present in glomeruli of mice that did not develop proteinuria. The endothelial granules were shown to contain immunoglobulins and typical lysosomal enzymes, providing evidence for phagocytosis by the glomerular endothelial cells. Liver endothelial cells did not show comparable changes. Thus, local phagocytosis by glomerular endothelial cells is shown to be a specific event in the development of glomerular disease.

Repeated action can lead to the formation of habits and identification as 'the kind of person' that performs the behaviour. This has led to the suggestion that identity-relevance is a facet of habit. This study explores conceptual overlap between habit and identity, and examines where the two constructs fit into an extended Theory of Planned Behaviour (TPB) model of binge-drinking among university students.Prospective, questionnaire-based correlational design.A total of 167 UK university students completed baseline measures of past behaviour, self-identity, the Self-Report Habit Index (SRHI), and TPB constructs. One week later, 128 participants completed a follow-up behaviour measure.Factor analyses of the SRHI and four identity items revealed two correlated but distinct factors, relating to habit and identity, respectively. Hierarchical regression analyses of intention and behaviour showed that identity contributed over and above TPB constructs to the prediction of intention, whereas habit predicted behaviour directly, and interacted with intentions in predicting behaviour. Habits unexpectedly strengthened the intention-behaviour relation, such that strong intenders were more likely to binge-drink where they also had strong habits.Identity and habit are conceptually discrete and impact differently on binge-drinking. Findings have implications for habit theory and measurement. Recommendations for student alcohol consumption reduction initiatives are offered.

An implicit association test (IAT) was used to investigate how habit strength, implicit attitudes and fruit consumption interrelate. Fifty-two participants completed a computerized IAT and provided measures of fruit consumption and related habit strength. Implicit attitudes moderated the habit strength—fruit consumption relationship; stronger relationships were observed when implicit attitudes were more positive. Amongst those with strong fruit habits, more positive associations with fruit were found for those who had recently consumed sufficient fruits compared to those who had not. Findings demonstrate the relevance of implicit positive associations in understanding the relationship between fruit consumption habits and subsequent fruit consumption.

The first Banff proposal for the diagnosis of pancreas rejection (Am J Transplant 2008; 8: 237) dealt primarily with the diagnosis of acute T-cell-mediated rejection (ACMR), while only tentatively addressing issues pertaining to antibody-mediated rejection (AMR). This document presents comprehensive guidelines for the diagnosis of AMR, first proposed at the 10th Banff Conference on Allograft Pathology and refined by a broad-based multidisciplinary panel. Pancreatic AMR is best identified by a combination of serological and immunohistopathological findings consisting of (i) identification of circulating donor-specific antibodies, and histopathological data including (ii) morphological evidence of microvascular tissue injury and (iii) C4d staining in interacinar capillaries. Acute AMR is diagnosed conclusively if these three elements are present, whereas a diagnosis of suspicious for AMR is rendered if only two elements are identified. The identification of only one diagnostic element is not sufficient for the diagnosis of AMR but should prompt heightened clinical vigilance. AMR and ACMR may coexist, and should be recognized and graded independently. This proposal is based on our current knowledge of the pathogenesis of pancreas rejection and currently available tools for diagnosis. A systematized clinicopathological approach to AMR is essential for the development and assessment of much needed therapeutic interventions.

Health behaviour models typically neglect habitual action. The Self-Report Habit Index (SRHI) permits synthesis of evidence of the influence of habit on behaviour. The purpose of this study is to review evidence around mean habit strength, habit–behaviour correlations, and habit × intention interactions, from applications of the SRHI to dietary, physical activity, and active travel behaviour. Electronic database searches identified 126 potentially relevant papers. Twenty-two papers (21 datasets) passed eligibility screening. Mean scores and correlations were meta-analysed using fixed, random and mixed effects, and interactions were synthesised via narrative review. Twenty-three habit–behaviour correlations and nine habit × intention interaction tests were found. Typical habit strength was located around the SRHI midpoint. Weighted habit–behaviour effects were medium-to-strong (fixed: r + = 0.44; random: r + = 0.46). Eight tests found that habit moderated the intention–behaviour relation. More comprehensive understanding of nutrition and activity behaviours will be achieved by accounting for habitual responses to contextual cues.

Summary Background and objectives Diffuse C4d staining in peritubular capillaries (PTCs) during an acute rejection episode (ARE) is the footprint of antibody-mediated rejection. In current clinical practice, diffuse C4d+ staining during acute rejection is regarded as an inferior prognostic sign. This case-control study investigated the prognostic role of mere C4d staining for graft outcome during an ARE in a well defined cohort of similarly ARE-treated patients. Design, setting, participants, & measurements All kidney transplant recipients in the authors9 center from January 1, 1995 to December 31, 2005 were reviewed. From these patients, 151 had a clinical ARE. Paraffin and/or frozen material was available for 128 patients showing a histologically proven ARE within the first 6 months after transplantation. All ARE patients were treated similarly with high-dose pulse steroids and in the case of steroid unresponsiveness with anti-thymocyte globulin. Biopsies were scored according to Banff criteria. Frozen and paraffin sections were stained by immunofluorescence (IF) and immunohistochemistry (IHC) for C4d, respectively, and scored for PTC positivity. Results Diffuse C4d+ staining in PTCs was found in 12.5% and 4.2% sections stained by IF or by IHC, respectively. Four patients showed diffuse positive staining with both methods but showed no different risk profile from other patients. No relation between C4d staining and clinical parameters at baseline was found. C4d staining was not associated with steroid responsiveness, graft, or patient survival. Conclusions This study shows that C4d staining is not related to clinical outcome in this cohort of histologically proven early AREs.

Both type 1 and type 2 diabetes are associated with severe complications including diabetic nephropathy. With the rapidly rising number of patients with diabetes worldwide, diabetic nephropathy is becoming one of the most common causes of renal disease. Much research effort is being put into how to identify diabetic nephropathy in patients with diabetes. A considerable number of biomarker studies were recently published on markers in plasma or urine, either with the aim to distinguish patients with or without diabetic nephropathy, or with the aim to predict renal outcome in those patients with diabetic nephropathy. We review the most recent findings on this subject and discuss the lack of histologically proven diabetic nephropathy in the majority of these studies.Most conspicuous in the field of diabetic nephropathy was the recent identification of a number of biomarkers used either in the diagnosis of diabetic nephropathy or in the evaluation of therapies meant to prevent, slow down, or reverse the processes causing diabetic nephropathy. For the histopathology of diabetic nephropathy, a new classification system was launched in 2010, which will be discussed together with future perspectives.Combining histopathological grading of and biomarkers for diabetic nephropathy will further our understanding of this complex disease manifestation.

Aims/hypothesis This meta-analysis assessed the pooled effect of each genetic variant reproducibly associated with diabetic nephropathy. Methods PubMed, EMBASE and Web of Science were searched for articles assessing the association between genes and diabetic nephropathy. All genetic variants statistically associated with diabetic nephropathy in an initial study, then independently reproduced in at least one additional study, were selected. Subsequently, all studies assessing these variants were included. The association between these variants and diabetic nephropathy (defined as macroalbuminuria/proteinuria or end-stage renal disease [ESRD]) was calculated at the allele level and the main measure of effect was a pooled odds ratio. Pre-specified subgroup analyses were performed, stratifying for type 1/type 2 diabetes mellitus, proteinuria/ESRD and ethnic group. Results The literature search yielded 3,455 citations, of which 671 were genetic association studies investigating diabetic nephropathy. We identified 34 replicated genetic variants. Of these, 21 remained significantly associated with diabetic nephropathy in a random-effects meta-analysis. These variants were in or near the following genes: ACE, AKR1B1 (two variants), APOC1, APOE, EPO, NOS3 (two variants), HSPG2, VEGFA, FRMD3 (two variants), CARS (two variants), UNC13B, CPVL and CHN2, and GREM1, plus four variants not near genes. The odds ratios of associated genetic variants ranged from 0.48 to 1.70. Additional variants were detected in subgroup analyses: ELMO1 (Asians), CCR5 (Asians) and CNDP1 (type 2 diabetes). Conclusions/interpretation This meta-analysis found 24 genetic variants associated with diabetic nephropathy. The relative contribution and relevance of the identified genes in the pathogenesis of diabetic nephropathy should be the focus of future studies. Electronic supplementary material The online version of this article (doi:10.1007/s00125-010-1996-1) contains supplementary material, which is available to authorised users.

Purpose. Habits may be a mechanism linking environmental variables with active commuting. This study investigated the role of habit strength in the explanation of active commuting across profiles based on current active commuting, motivation, and habit strength within the framework of the theory of planned behavior (TPB). Design. Cross-sectional survey using validated questionnaires. Setting. Undergraduate students who participated for course credits. Subjects. Five hundred and thirty-eight students (mean age = 21.19 [SD = 2.57]; 28.45% males; response rate = 86.36%). Measures. Questionnaire included TPB items, underlying beliefs, and a validated measure of habit strength. Active commuting was assessed with relevant items from the International Physical Activity Questionnaire. Analysis. Hierarchical regression and interaction analyses, discriminant function analysis, and analyses of variance. Results. Habit strength was the strongest correlate of active commuting and interacted with intention: at low and medium levels of habit strength, the intention–bicycle use relationship was more than twice as strong as at high levels. Beliefs regarding situational barriers were amongst the most discriminating beliefs, whereas beliefs regarding health benefits did not distinguish profiles. Conclusions. Stronger active commuting habits are associated with a lower association between intention and bicycle use. Persuasive health campaigns might more usefully instill a sense of confidence in various commuting situations rather than merely emphasizing health benefits of active commuting. (Am J Health Promot 2011;25[3]:e27–e36.)

Hanneke de Kort, research fellow1, Eelco J de Koning, associate professor, head of clinical islet transplantation programme234, Ton J Rabelink, professor of medicine, chair of department of nephrology2, Jan A Bruijn, professor immunopathology1, Ingeborg M Bajema, renal and transplantation pathologist11Department of Pathology, Leiden University Medical Centre, 2300 RC Leiden, Netherlands2Department of Nephrology, Leiden University Medical Centre3Department of Endocrinology, Leiden University Medical Centre4Hubrecht Institute, Uppsalalaan 8, 3584 CT Utrecht, NetherlandsCorrespondence to: E J P de Koning e.dekoning{at}lumc.nlAccepted 10 December 2010Summary pointsIslet of Langerhans transplantation is used in a select group of patients with type 1 diabetes with severe glycaemic lability, recurrent hypoglycaemia, and hypoglycaemia unawarenessThe procedure is minimally invasive, with few procedure related complicationsTwo to three islet infusions are usually needed to achieve insulin independenceMost patients need insulin by five years post-transplantation owing to declining graft function; beneficial effects on the frequency of hypoglycaemic episodes and hypoglycaemia awareness remainMost long term complications are related to systemic immunosuppressionThe risk-benefit ratio of islet transplantation should be carefully weighed by the treating physician and the potential recipient, who should be given adequate informationA clinical review in the BMJ in 2001 anticipated that by 2010 transplantation of islets of Langerhans would be the treatment of choice for most patients with type 1 diabetes.1 Currently, islet transplantation is an option for a specific group of patients with type 1 diabetes only—those with severe glycaemic lability, recurrent hypoglycaemia, and hypoglycaemia unawareness. Patients with type 1 diabetes—who must deal with daily subcutaneous insulin injections, regular finger pricks for glucose measurements, and worries about hypoglycaemic episodes and long term complications of diabetes, hope for a cure for their disease and may ask their doctors about islet transplantation. Therefore, doctors who treat such patients should understand the potential benefits of islet transplantation as well as the hurdles that need to be overcome before it is widely used (box 1).Sources and selection criteriaWe searched PubMed, Embase, Web of Science, Cochrane, CINAHL, Academic Search Premier, and ScienceDirect using the keyword “islet transplantation”. We limited our search to the English language and to human studies. We found no randomised controlled trials, and most publications lacked an appropriate control group that was intensively managed by insulin using modern treatment regimens. Data were mainly derived from case series, follow-up …

Shared idiotypes in mesangial deposits in IgA nephropathy are not disease-specific. The antigenic specificity of the mesangial IgA in IgA nephropathy (IgAN) remains unknown. Because shared antigenic specificities may be reflected in the usage of shared idiotypes, we prepared five monoclonal anti-idiotypic antibodies (MoAbs) specific for the mesangial IgA eluted from the kidney of an IgAN patient. All five MoAbs reacted with the same idiotype, which proved to be of a public nature. Although the idiotype could be identified in the mesangial deposits of the majority of IgAN patients studied, it was not specific for the disease because it was also found in the glomerular deposits of other types of glomerulonephritis. The idiotype was also expressed in polyethylene glycol precipitates of sera and in pokeweed mitogen-induced plasma cells from both IgAN patients and healthy controls. The conclusion that no disease-specific idiotypes are present in the renal eluate was further supported by the failure to produce polyclonal anti-idiotypic antibodies by immunizing a rabbit with the eluted mesangial IgA. Our results support the concept that mesangial IgA deposits in IgAN are of a polyclonal nature.

Susceptibility for infection-related glomerulopathy depends on non-MHC genes. BALB/c mice infected with Trypanosoma brucei and treated seven days after inoculation with Diminazene aceturate develop polyclonal B-cell stimulation, including production of antibodies to known nephritogenic autoantigens and glomerular disease associated with severe albuminuria. To investigate if the susceptibility for glomerular disease in this model is linked to MHC or non-MHC genes, we studied this disease in six mouse strains that were partly congenic for their MHC and partly congenic for their non-MHC genes. The course of the infection was measured by parasitemia and related to (auto)antibody production, proteinuria and glomerular deposition of immunoglobulins. The mouse strains could be divided into two groups. The first group consisted of the C57BL/6 (H-2 b ), C57BL/10 (H-2 b ) and B10.D2 (H-2 d ) strains, which proved to be relatively resistant to infection with Trypanosoma brucei (that is, spontaneous survival >25 days). In sera of these mice antibodies to a broad range of antigens could be found 14 days after inoculation; no proteinuria was observed. The second group consisted of the BALB/c (H-2 d ), BALB.B (H-2 b ) and DBA/2 (H-2 d ) strains, which were relatively susceptible to the infection. In these animals proteinuria occurred and a broad polyclonal B-cell stimulation was seen 42 days after inoculation. No correlation was found between the specificity of circulating antibodies and the occurrence of proteinuria or a glomerular fluorescence pattern. These results indicate that in this model non-MHC genes govern the outcome of the infection as well as the development of polyclonal B-cell stimulation and proteinuria. Concerning the glomerulopathy, a discrepancy is observed between glomerular immunoglobulin staining patterns and the development of proteinuria. Therefore, an additional pathogenetic role for non-immunoglobulin humoral factors must be considered.

SUMMARY Autoimmune diseases are far more common in women than in men. In the incidence of systemic lupus erythematosus (SLE), the female-to-male ratio is as high as 10:1. This suggests that sex hormones may play a fundamental role in determining the susceptibility to these diseases. In order to investigate the sex-related differences in the inducibility of chronic graft-versus-host disease-related experimental lupus nephritis, lymphocytes from female DBA/2 donor mice were administered to either male or female (C57BL10 × DBA/2)F1 recipients. An additional group of male recipients received lymphocytes from male DBA/2 donors. After four cell transfers, female recipients developed a significantly higher albuminuria than both male groups. Serum concentrations of autoantibodies against glomerular basement membrane (GBM). collagen IV, and laminin were significantly higher in females 2–4 weeks after induction. Levels of circulating autoantibodies against renal tubular epithelial antigens (RTE) and nuclear antigens were not different between the sexes. In transfer studies, the necessity of the presence of anti-GBM and anti-RTE autoantibodies for the development of glomerulonephritis was confirmed. These findings indicate that: (i) in this model of lupus nephritis, susceptibility to glomerulonephritis is strongly influenced by sex-related genes; and (ii) among the variety of autoantibodies occurring in this model of SLE, both anti-GBM and anti-RTE autoantibodies play a key role in the pathogenesis of glomerulonephritis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is the most common cause of rapidly progressive glomerulonephritis worldwide, and the renal biopsy is the gold standard for establishing the diagnosis. Although the prognostic value of the renal biopsy in ANCA-associated glomerulonephritis is widely recognized, there is no consensus regarding its pathologic classification. We present here such a pathologic classification developed by an international working group of renal pathologists. Our classification proposes four general categories of lesions: Focal, crescentic, mixed, and sclerotic. To determine whether these lesions have predictive value for renal outcome, we performed a validation study on 100 biopsies from patients with clinically and histologically confirmed ANCA-associated glomerulonephritis. Two independent pathologists, blinded to patient data, scored all biopsies according to a standardized protocol. Results show that the proposed classification system is of prognostic value for 1- and 5-year renal outcomes. We believe this pathologic classification will aid in the prognostication of patients at the time of diagnosis and facilitate uniform reporting between centers. This classification at some point might also provide means to guide therapy.

C4d+ antibody-mediated rejection following pancreas transplantation has not been well characterized. Therefore, we assessed the outcomes of 27 pancreas transplantation patients (28 biopsies), with both C4d staining and donor-specific antibodies (DSA) determined, from a cohort of 257 patients. The median follow-up was 50 (interquartile range [IQR] 8-118) months. Patients were categorized into 3 groups: group 1, patients with minimal or no C4d staining and no DSA (n = 13); group 2, patients with either DSA present but no C4d, diffuse C4d+ and no DSA or focal C4d+ and DSA (n = 6); group 3, patients with diffuse C4d+ staining and DSA (n = 9). Active septal inflammation, acinar inflammation and acinar cell injury/necrosis were significantly more abundant in group 3 than in group 2 (respective p-values: 0.009; 0.033; 0.025) and in group 1 (respective p-values: 0.034; 0.009; 0.002). The overall uncensored pancreas graft survival rate for groups 1, 2 and 3 were 53.3%, 66.7% and 34.6%, respectively (p = 0.044). In conclusion, recipients of pancreas transplants with no C4d or DSA had excellent long-term graft survival in comparison with patients with both C4d+ and DSA present. Hence, C4d should be used as an additional marker in combination with DSA in the evaluation of pancreas transplant biopsies.