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Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. Here, we screen 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, P3FI-63. RNA-seq, ATAC-seq, and docking analyses implicate histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirm the inhibition of multiple KDMs with the highest selectivity for KDM3B. Structural similarity search of P3FI-63 identifies P3FI-90 with improved solubility and potency. Biophysical binding of P3FI-90 to KDM3B is demonstrated using NMR and SPR. P3FI-90 suppresses the growth of FP-RMS in vitro and in vivo through downregulating PAX3-FOXO1 activity, and combined knockdown of KDM3B and KDM1A phenocopies P3FI-90 effects. Thus, we report KDM inhibitors P3FI-63 and P3FI-90 with the highest specificity for KDM3B. Their potent suppression of PAX3-FOXO1 activity indicates a possible therapeutic approach for FP-RMS and other transcriptionally addicted cancers., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Anti-glomerular basement membrane disease (GBM) (Goodpasture's disease) typically presents with acute manifestations of rapidly progressive glomerulonephritis often accompanied by lung haemorrhage. Anti-GBM disease is usually monophasic. However, atypical presentations with indolent renal involvement are being increasingly recognized. Herein we report a patient who presented with lung haemorrhage, minimal renal involvement, and negative result for serum anti-GBM antibody, while immunofluorescence examination of the renal biopsy provided the diagnosis leading to the institution right treatment with excellent response. Interestingly, he had presented 10 years earlier with lung hemorrhage, more significant renal involvement clinically and histologically, with positive serum anti-GBM antibody. The present case is intended to increase our awareness regarding the variable presentations of anti-GBM disease, such as with negative serology and recurrence of anti-GBM disease. The presentation of anti-GBM nephritis with non-proliferative, non-crescentic glomerulonephritis is also highlighted. The possible explanations for negative serum anti-GBM antibody are explored with a brief review of literature., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Indian Journal of Nephrology.)

A collision tumour of the kidney is a very rare condition defined by two immediately adjacent but histologically distinct neoplasms that coexist within one organ without histological admixture. We present a collision tumour in a transplant kidney treated with open partial nephrectomy. This case also highlights key surgical principles the enhanced risk of oncogenesis in transplant recipients, and some key principles for surgical resection of a tumour in a transplant kidney., Competing Interests: All authors declare no conflict of interest., (© 2020 Published by Elsevier Inc.)

Allergic asthma is a chronic pulmonary disorder fundamentally linked to immune dysfunction. Since the immune system begins developing in utero , prenatal exposures can affect immune programming and increase risk for diseases such as allergic asthma. Chronic psychosocial stress during pregnancy is one such risk factor, having been associated with increased risk for atopic diseases including allergic asthma in children. To begin to define the underlying causes of the association between maternal stress and allergic airway inflammation in offspring, we developed a mouse model of chronic heightened stress hormone during pregnancy. Continuous oral administration of corticosterone (CORT) to pregnant mice throughout the second half of pregnancy resulted in an ~2-fold increase in circulating hormone in dams with no concomitant increase in fetal circulation, similar to the human condition. To determine how prolonged heightened stress hormone affected allergic immunity in offspring, we induced allergic asthma with house dust mite (HDM) and examined the airway immune response to allergen. Female mice responded to HDM more frequently and had a more robust immune cell response compared to their male counterparts, irrespective of maternal treatment. Male offspring from CORT-treated dams had a greater number of inflammatory cells in the lung in response to HDM compared to males from control dams, while maternal treatment did not affect immune cell numbers in females. Alternatively, maternal CORT caused enhanced goblet cell hyperplasia in female offspring following HDM, an effect that was not observed in male offspring. In summary, prenatal exposure to mild, prolonged heightened stress hormone had sexually dimorphic effects on allergic inflammation in airways of adult offspring., (Copyright © 2020 Smith, Paul, McGee, Sinniah, Flom, Jackson-Humbles, Harkema and Racicot.)

Background: BK virus is a polyoma virus causing renal allograft nephropathy. Reduction of immunosuppression with the early recognition of significant BK viral loads in urine and plasma can effectively prevent BKV associated nephropathy (BKVN), however the optimal compartment and frequency of BK viral load measurement post renal transplantation are undetermined. Our purpose was to examine time to detection and viral loads in urine compared to plasma, and establish viral load cut-offs associated with histological BKVN., Methods: We performed a retrospective analysis of the BKV screening frequency and compartment(s) of 277 adult renal transplant recipients (RTR)., Results: BKVN was histologically diagnosed in 17 (6.1 %) RTR. In cases where both urine and plasma were tested fortnightly for 6 months (n = 53), BKV was detected in the urine 29 days earlier than plasma. Fortnightly (n = 72) versus 3-monthly (n = 78) testing demonstrated that BKV was detected in the urine significantly earlier (median 63 versus 97 days, p = 0.001) and at a lower level (median 3.27 versus 6.71 log10 c/mL, p < 0.001) with more frequent testing, but this difference was not evident in plasma first detection (80 versus 95 days, p = 0.536) or first positive viral load (3.18 versus 3.30 log10 c/mL, p = 0.603). The optimum cut-off BK viral load for histological diagnosis of BKVN was 4.10 log10 c/mL for the first positive urine, 3.79 log10 c/mL for the first positive plasma, 9.24 log10 c/mL for the peak urine, and 4.53 log10 c/mL for the peak plasma., Conclusions: Frequent urinary BK viral load screening for the prevention of BKVN is suggested due to its high sensitivity and earlier detection.

Glycogenic hepatopathy (GH) is an under-recognised complication of type 1 diabetes mellitus (T1DM) not controlled to target resulting in hepatomegaly and elevated liver transaminases. We report the case of a 19-year-old man with T1DM not controlled to target who presented with abdominal pain, hepatomegaly and deranged liver transaminases. He was subsequently diagnosed with GH on liver biopsy, with the mainstay of treatment being reduction in caloric intake and insulin., (© 2015 Royal Australasian College of Physicians.)

Adalimumab (Humira) is a tumour necrosis factor α (TNF α ) inhibitor that is approved for the treatment of rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn's disease, ankylosing spondylitis, and juvenile idiopathic arthritis (Sullivan and Preda (2009), Klinkhoff (2004), and Medicare Australia). Use of TNF α inhibitors is associated with the induction of autoimmunity (systemic lupus erythematosus, vasculitis, and sarcoidosis or sarcoid-like granulomas) (Ramos-Casals et al. (2010)). We report a patient with extensive psoriasis presenting with renal failure and seropositive lupus markers without classical lupus nephritis after 18 months treatment with adalimumab. He has renal biopsy proven IgA nephritis instead. Renal biopsy is the key diagnostic tool in patients presenting with adalimumab induced nephritis and renal failure. He made a remarkable recovery after adalimumab cessation and steroid treatment. To our knowledge, this is a unique case of a psoriasis patient presenting with seropositive lupus markers without classical lupus nephritis renal failure and had renal biopsy proven IgA glomerulonephritis after receiving adalimumab.

Australia's Indigenous people have high rates of chronic kidney disease and kidney failure. To define renal disease among these people, we reviewed 643 renal biopsies on Indigenous people across Australia, and compared them with 249 biopsies of non-Indigenous patients. The intent was to reach a consensus on pathological findings and terminology, quantify glomerular size, and establish and compare regional biopsy profiles. The relative population-adjusted biopsy frequencies were 16.9, 6.6, and 1, respectively, for Aboriginal people living remotely/very remotely, for Torres Strait Islander people, and for non-remote-living Aboriginal people. Indigenous people more often had heavy proteinuria and renal failure at biopsy. No single condition defined the Indigenous biopsies and, where biopsy rates were high, all common conditions were in absolute excess. Indigenous people were more often diabetic than non-Indigenous people, but diabetic changes were still present in fewer than half their biopsies. Their biopsies also had higher rates of segmental sclerosis, post-infectious glomerulonephritis, and mixed morphologies. Among the great excess of biopsies in remote/very remote Aborigines, females predominated, with younger age at biopsy and larger mean glomerular volumes. Glomerulomegaly characterized biopsies with mesangiopathic changes only, with IgA deposition, or with diabetic change, and with focal segmental glomerulosclerosis (FSGS). This review reveals great variations in biopsy rates and findings among Indigenous Australians, and findings refute the prevailing dogma that most indigenous renal disease is due to diabetes. Glomerulomegaly in remote/very remote Aboriginal people is probably due to nephron deficiency, in part related to low birth weight, and probably contributes to the increased susceptibility to kidney disease and the predisposition to FSGS.

We report a 29 year old male cystic fibrosis patient with end stage lung disease and normal renal function who underwent a sequential double lung transplant. Medical history included: an ileal resection and pancreatic exocrine dysfunction. The postoperative period was complicated with haemorrhage and repeat surgery, requiring multiple blood transfusions and extensive antibiotic cover. Pancreatic supplements were interrupted. Acute renal failure attributed to haemodynamically-mediated acute tubular necrosis was managed expectantly. He remained dialysis dependent 8 weeks post surgery and was maintained on triple immunosuppression with tacrolimus, mycophenolate and prednisolone. A DTPA study was consistent with ATN. Renal biopsy revealed features consistent with tubular injury due to acute oxalate nephropathy (AON). Further biochemical characterization excluded primary hyperoxaluria but confirmed increased 24 hour urinary oxalate. He was maintained on enhanced frequency HDF and subsequently received an uncomplicated live related renal transplant 10 months post lung transplant with only additional basiliximab. Calcium carbonate was continued to manage post transplant hyperoxaluria and an early renal biopsy excluded recurrent oxalate injury. Enteric hyperoxaluria due to malabsorption in patients with CF especially with ileal resection, in addition to loss of gut Oxalobacter formigenes due to prolonged antimicrobials, increases the risk of AON. Increased awareness of this condition and screening prior to lung transplant is recommended., (© 2012 The Authors. Nephrology © 2012 Asian Pacific Society of Nephrology.)

We present a case of sclerosing lipogranuloma of the penis in a 25-year-old man of Burmese origin complicating injection of an unknown non-biodegradable oily foreign material into his external genitalia. Despite frequent complications, penile augmentation with exogenous paraffin material is still practised in some parts of the world. Sclerosing lipogranuloma is a rare condition in Australia that dermatologists need to consider in the differential of a genital ulcer or indurated penile mass, particularly in young men from South-East Asia. A causal relationship between the procedure and adverse events may not be made because complications are frequently delayed for many years. A high degree of clinical suspicion and a skin biopsy is essential, as a history of injection may not be disclosed., (© 2010 The Authors. Australasian Journal of Dermatology © 2010 The Australasian College of Dermatologists.)

Galloway-Mowat syndrome is a rare condition that is likely hereditary though the underlying offending gene has not been identified, and is characterized by microcephaly and severe nephrotic syndrome culminating in childhood death. Some of the reported cases have abnormalities in neuronal migration and intractable seizures, but many of the described cases focus on the renal pathology and emphasize a diversity of clinical and pathological features. The case described herein includes a thorough neuropathological description, and when the neuroradiology and neuropathology of the previously published cases is scrutinized, a fairly consistent clinical and neuropathological phenotype emerges.

Chronic kidney disease (CKD) is one component of a spectrum of chronic disease in Aboriginal Australians. CKD is marked by albuminuria, which predicts renal failure and nonrenal natural death. Rates vary greatly by community and region and are much higher in remote areas. This reflects the heterogeneous characteristics and circumstances of Aboriginal people. CKD is multideterminant, and early-life influences (notably low birth weight), infections (including poststreptococcal glomerulonephritis), metabolic/hemodynamic parameters, and epigenetic/genetic factors probably contribute. CKD is associated intimately with cardiovascular risk. Albuminuria progresses over time, with a high incidence of new onset of pathologic levels of albuminuria in all age groups. All the usual morphologic findings are found in renal biopsy specimens. However, glomerular enlargement is notable in individuals from remote regions, but not those living closer to population centers. Glomerulomegaly probably represents compensatory hypertrophy caused by low nephron number, which probably underlies the accentuated susceptibility to renal disease. In the last decade, health care services have been transformed to accommodate systematic chronic disease surveillance and management. After a relentless increase for 3 decades, rates of Aboriginal people starting renal replacement therapy, as well as chronic disease deaths, appear to be stabilizing in some regions. Official endorsement of these system changes, plus ongoing reductions in the incidence of low birth weight and infections, hold promise for continued better outcomes., (Copyright © 2010 National Kidney Foundation, Inc. All rights reserved.)

In vitro and in vivo experimental studies suggest that the transcription factor NF-kappaB plays a role in tubulointerstitial injury. We investigated possible cellular and molecular mechanisms involving NF-kappaB activation in the progression of tubulointerstitial lesions in human lupus nephritis (LN). Paraffin-embedded renal biopsies from 50 patients with LN and six control patients with minimal change disease (MCD) were examined by Southwestern histochemistry for in situ detection of active NF-kappaB and AP-1. Immunohistochemistry was performed to examine the expression of NF-kappaB, AP-1, and NF-kappaB regulatory proteins (IkappaB-alpha, p-IkappaB-alpha, and IKK-alpha proteins), as well as NF-kappaB and AP-1 downstream target proinflammatory molecules (ICAM-1, TNF-alpha, IL-1beta, IL-6, and GM-CSF) and NF-kappaB upstream signaling molecules (CD40 and CD40L). We observed extensive upregulation of activated NF-kappaB in renal tubular cells and interstitial cells, in parallel with overactivation of transcription factor AP-1 in LN, as compared with normal controls and MCD. Tubular expression of activated NF-kappaB correlated well with the degree of tubulointerstitial histopathological indices and/or renal function. Tubulointerstitial IKK-alpha expression was specifically upregulated in LN. IkappaB-alpha and p-IkappaB-alpha were detected only in interstitial cells in LN. Tubulointerstitial expression levels of NF-kappaB and AP-1 downstream inflammatory molecules and NF-kappaB upstream signaling molecules CD40 and CD40L were markedly enhanced in LN as compared with MCD or normal controls and were associated with tubulointerstitial histopathological indices and/or renal function. The results suggest that altered IKK-alpha expression and NF-kappaB activation along with AP-1 overexpression may play a pathogenic role in tubulointerstitial injury in human LN mediated through a network of downstream proinflammatory molecules.

A 35-year-old morbidly obese woman on home haemodialysis presented with painful indurated subcutaneous nodules histologically characteristic of calciphylaxis. After failing to respond to conventional treatment, she was commenced on an intravenous infusion of 25 g of sodium thiosulfate three times per week. Two weeks after commencing sodium thiosulfate, the pain resolved completely. By 12 weeks, the lesions had healed and the infusions were ceased. Two months later, skin lesions recurred, but resolved again within 3 months of recommencement of sodium thiosulfate treatment, which was continued for 8 months. The treatment was well tolerated. There has been no recurrence of lesions in the 18 months since the cessation of sodium thiosulfate. Clinical trials to determine the optimum dose and duration of therapy for sodium thiosulfate treatment of calciphylaxis should be given priority because of its high rate of success in treating what is otherwise a severe and mostly lethal condition.

Calciphylaxis is a small vessel vasculopathy with medial calcification associated with intimal proliferation, fibrosis and thrombosis. This study discusses the clinical features and treatment of calciphylaxis and assesses the prognosis of patients with calciphylaxis. All patients admitted to vascular or renal wards from January 2003 to December 2004 at Royal Perth Hospital, with diagnosis of calciphylaxis confirmed histologically were included in the study. Five patients were included in the study; four male and one female. Three patients had end stage renal failure on haemodialysis and two had normal renal function. All three patients with end-stage renal failure had secondary hyperparathyroidism associated with elevated parathormone and corrected ionised calcium. The two patients with normal renal function had normal calcium, phosphate, and parathormone levels. The diagnosis of calciphylaxis was confirmed in all patients. The wounds of four patients healed and one patient died 8 months after the diagnosis of calciphylaxis had been made. Calciphylaxis is a condition mostly present in patients with end-stage renal failure and can occur in patients with normal renal function. It usually carries a poor prognosis, but in this small series the outcome of patients was good with satisfactory healing of wounds.

The mechanism of renal cell apoptosis involves transcriptional activation of the inducible nitric oxide synthase (iNOS) gene by nuclear factor (NF)-kappaB. The role of apoptosis in mediating tubulointerstitial injury in human lupus nephritis (LN) remains unclear. We examined the relationship between alterations in NF-kappaB activation and iNOS expression levels and the degree of apoptosis in both glomerular and tubulointerstitial compartments of subjects with LN. Studies were done in renal biopsies from 49 patients with LN and 10 normal kidney tissues. Apoptotic and proliferating cells were identified by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and staining with anti-proliferating cell nuclear antigen antibody, respectively. Nuclear factor-kappaB and iNOS expression was examined by Southwestern histochemistry and immunohistochemistry, respectively. Glomerular cell apoptosis and proliferation increased concomitantly in LN. Glomerular apoptosis correlated with the activity index, the degree of proliferation, and the level of glomerular overexpression of iNOS and activated NF-kappaB in LN. Tubular cell apoptosis correlated with the activity and chronicity indices, the degree of tubular atrophy, and decline in renal function at the time of biopsy. Tubular expression of iNOS and activated NF-kappaB correlated with tubular cell proliferation in LN. Nuclear factor-kappaB activation accompanied overexpression of iNOS in both glomerular and tubulointerstitium compartments in LN. Apoptosis of renal cells associated with NF-kappaB activation and iNOS overexpression may play an important role in mediating chronic renal injury, especially tubulointerstitial lesions that may manifest clinically as progressive renal insufficiency.

We report a rare presentation of a nested variant of urothelial carcinoma with liver and bone metastases in a 74-year-old man admitted to the hospital with bilateral hydronephrosis and acute renal failure. At cystoscopy, both ureters were obstructed, with the right ureter narrowed along its entire length. Subsequent histopathologic examination from the ureteral resection revealed nested variant of urothelial carcinoma. Bilateral stents were placed, and the patient survived 12 months with a good partial response to chemotherapy. A total of 76 cases of nested variant of urothelial carcinoma have been reported worldwide. Our patient was the first, to our knowledge, to present with bilateral hydronephrosis and tumor extension along one ureter.

Nuclear Factor-kappaB (NF-kappaB) has been suggested to play a role in the cellular and molecular mechanisms underlying glomerular injury. We investigated the potential role of NF-kappaB activation in the pathogenesis of glomerular injury in 31 patients with class III-V lupus nephritis (LN), 14 patients with non-proliferative proteinuric glomerulopathy and six normal controls. The expression of NF-kappaB subunits p65 and p50, and the NF-kappaB regulated proinflammatory mediators tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) as well as CD68 and synaptopodin was examined by Southwestern histochemistry (SWH) or immunohistochemistry. In contrast to non-proliferative glomerulopathy and normal controls, NF-kappaB activation (both p65 and p50) was enhanced in glomerular endothelial, mesangial cells or infiltrating cells in class IV LN, along with upregulation of TNF-alpha, IL-1beta, IL-6 and ICAM-1 expression. Glomerular endothelial and mesangial activation of NF-kappaB and mesangial ICAM-1 expression correlated with disease activity and the level of glomerular macrophage infiltration. Podocyte NF-kappaB overactivation (predominantly p65) paralleled podocyte expression of TNF-alpha and IL-1beta in patients with LN and non-proliferative glomerulopathy. Podocyte staining scores of NF-kappaB and p65 were positively correlated with the severity of proteinuria in LN and non-proliferative glomerulopathy. These results suggest a pathogenic role for NF-kappaB in glomerular injury by multiple mechanisms.

The activities of cell cycle regulatory proteins have been reported to be associated with the development of pathological lesions in glomerulonephritis. To assess the cellular mechanisms underlying the mesangial cell proliferation and glomerulosclerosis in progressive human IgA nephropathy (IgAN), we examined the expression of E2F1, Rb, c-Myc, proliferating cell nuclear antigen (PCNA), cyclins (D1, E and A), cyclin-dependent kinase 2 (CDK2) and CDK inhibitors (p21(waf1), p27(kip1), 57(kip2) and p16(ink4a)) by immunohistochemistry in renal biopsy specimens. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) was also performed to detect the presence of apoptosis. In total, 51 cases of IgAN were categorized into four subgroups according to histological severity. A dramatic upregulation of E2F1 expression in mesangial cells was identified in proliferating glomeruli, which correlated well with the proliferation index. High endogenous expression of p27(kip1) and p57(kip2) by podocytes in normal glomeruli and glomeruli with minor lesions was observed to decrease in proliferating and sclerosing glomeruli; this pattern displayed a strong inverse correlation with the mean glomerulosclerosis score and the index of glomerular lesion. Increased apoptotic activity was identified in progressive glomerular lesions of advanced IgAN, which correlated with the proliferative activity in these lesions as assessed by total expression levels of PCNA and CDK2 in glomeruli, E2F1 expression levels in the mesangium, cyclin D1 expression levels in endothelium and the c-Myc glomerular staining score. Our results suggest that the onset and magnitude of mesangial cell proliferation and glomerulosclerosis is associated with the upregulation of E2F1 by mesangial cells and the downregulation of p27(kip1) and p57(kip2) by glomerular epithelial cells. The cell type-specific and coordinated regulation of proliferative and proapoptotic activities of cell cycle regulatory proteins may play an important role in mediating progressive glomerular injury in human IgAN.

In situ hybridization, immunohistochemistry, and TUNEL staining were applied to renal biopsy specimens of immunoglobulin A nephropathy (IgAN) patients to determine the expression of nitric oxide synthase (iNOS) (mRNA and protein), p53, and their potential roles in renal cell apoptosis in relation to the development of pathologic lesions. Fifty-one cases were categorized into four subgroups (A-D) according to the presence of progressive histopathological features. A cell type-specific and differential overexpression of iNOS mRNA and protein was demonstrated in glomerular cells in subgroups (A-C) and was found to correlate well with the upregulation of p53 protein by glomerular endothelium and epithelium in early- and advanced-stage disease. In the tubulointerstitium, induction of iNOS products was evident in damaged tubules in late-stage disease, in parallel with the upregulation of p53 protein levels in these tubules. Increased TUNEL staining observed in glomeruli with progressive lesions and tubules with degenerative changes positively correlated with the expression levels of iNOS and p53 in glomerular endothelium, epithelium, and their overexpression in damaged tubules. Clinicopathologic correlations demonstrated that induction of iNOS products in renal cells was associated with indices of poor renal prognosis in human IgAN. The coupled induction of iNOS and p53 upregulation in intrinsic renal cells of IgAN may be linked with both pro- and anti-apoptotic activities, thus playing an important role in mediating progressive renal injury and determining renal outcome in human IgAN.

Bcl-2 defines a new class of proto-oncogenes that block cell death without promoting cell proliferation. To elucidate the role of Bcl-2 in the development of glomerular lesions in human IgA nephropathy (IgAN), we applied immunohistochemistry coupled with in situ hybridization to detect the expression of Bcl-2 products and their association with Bax, p27(kip1), and p57(kip2) in modulating the apoptotic, proliferative, and sclerotic events in progressive glomerular injury. Glomerular cell apoptosis was examined by TdT-mediated dUTP-biotin nick-end labeling (TUNEL) staining. A total of 51 IgAN cases were categorized into four subgroups (A to D) according to the severity of their histopathological lesions. Creatinine levels, creatinine clearance, and magnitude of proteinuria based on 24-h urine collections at the time of diagnostic renal biopsy were available for the majority of subjects. Bcl-2 expression was observed predominantly in podocytes in IgAN. Podocyte expression of Bcl-2 was found to be upregulated in early-stage disease and downregulated in late-stage disease. Bcl-2 downregulation in progressive IgAN was associated with an increased Bax/Bcl-2 ratio in glomerular epithelial cells and correlated with the downregulation of high endogenous podocyte p27(kip1) and p57(kip2) expression. Bax/Bcl-2 ratios positively correlated with glomerular cell apoptosis and the degree of glomerulosclerosis, whereas p27(kip1) and p57(kip2) expression levels were inversely correlated with mesangial hypercellularity and glomerulosclerosis. Clinicopathologic correlations demonstrated that downregulation of Bcl-2 protein expression was associated with indices of poor renal prognosis in human IgAN. The results suggest that Bcl-2 expression by podocytes may exert modulatory effects on cellular processes that contribute to progressive glomerular injury and play an important role in determining renal outcome in human IgA nephropathy.

Interleukin-12 (IL12) is a cytokine that is secreted by activated phagocytes and dendritic cells and that induces interferon-gamma production by natural-killer and T lymphocytes. It consists of two subunits, p35 and p40, which are encoded by IL12A and IL12B, respectively. The first reported patient with a genetic cytokine disorder was a Pakistani child, who was homozygous for a large loss-of-function deletion (g.482+82&#95;856-854del) in IL12B. This IL12-deficient child suffered from infections caused by bacille Calmette-Guérin (BCG) and Salmonella enteritidis. We herein report 12 additional patients from five other kindreds. In one kindred from India, the same large deletion that was described elsewhere (g.482+82&#95;856-854del) was identified. In four kindreds from Saudi Arabia, a recessive loss-of-function frameshift insertion (g.315&#95;316insA) was found. A conserved haplotype encompassing the IL12B gene suggested that a founder effect accounted for the recurrence of each mutation. The two founder mutational events-g.482+82&#95;856-854del and g.315&#95;316insA-were estimated to have occurred approximately 700 and approximately 1,100 years ago, respectively. Among a total of 13 patients with IL12 deficiency, 1 child had salmonellosis only and 12 suffered from clinical disease due to BCG or environmental nontuberculous mycobacteria. One patient also had clinical disease caused by virulent Mycobacterium tuberculosis, five patients had clinical disease caused by Salmonella serotypes, and one patient had clinical disease caused by Nocardia asteroides. The clinical outcome varies from case to case, since five patients (aged 2-11 years) died of overwhelming infection, whereas eight patients (aged 3-12 years) are still in good health and are not currently taking antibiotics. In conclusion, IL12 deficiency is not limited to a single kindred, shows significant variability of outcome, and should be considered in the genetic diagnosis of patients with mycobacteriosis and/or salmonellosis. To date, two founder IL12B mutations have been identified, accounting for the recurrence of a large deletion and a small insertion within populations from the Indian subcontinent and from the Arabian Peninsula, respectively.

The antiphospholipid antibody syndrome (APS) is characterized by recurrent thrombosis, fetal loss, multiorgan involvement, and the presence of lupus anticoagulant and/or anticardiolipin antibody. When not associated with systemic lupus erythematosus, other collagen diseases, or ingestion of medications, the condition is called primary APS. The kidney may be involved in the APS syndrome with acute nephritis and renal failure. The cases with renal biopsy studies have shown variable glomerular morphology, ranging from mild mesangial changes to a diffuse endocapillary proliferative glomerulonephritis. The most frequent lesion is thrombotic microangiopathy or features seen in the hemolytic uremic syndrome. Apart from fibrin thrombus deposition, only a few cases have shown focal and segmental deposits of IgG and/or IgM and/or C3. We describe a patient with primary APS who had thrombosis with lower limb amputation and acute renal failure. The renal biopsy specimen showed a focal proliferative glomerulonephritis with endothelial proliferation and damage, with diffuse heavy mesangial deposits of IgA and fibrinogen. This case with diabetes mellitus, but without diabetic nephropathy, represents the occurrence of primary APS and mesangial IgA nephropathy which potentiated the renal injury, leading to acute renal failure. The relationship to the Henoch-Schönlein syndrome is discussed., (Copyright 2001 S. Karger AG, Basel)

Mefenamic acid ingestion, usually in excess and over prolonged period is known to produce interstitial nephritis, or less commonly papillary necrosis, with acute renal failure. However, it is not dose-dependent for the induction of tubulointerstitial damage. Excess iodine ingestion is known to produce toxicity and possible death, but acute renal failure is rare. There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells. Iodine has not been documented to produce red cell hemolysis and hemoglobinuria. We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets. These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy, probably from the iodine, and renal dysfunction from alteration of renal perfusion by selective COX-1 inhibition of prostaglandin production, and induction of acute interstitial nephritis from mefenamic acid, leading to acute renal failure which was reversible by hemodialysis and supportive therapy.

We studied the response of urinary protein overload on preexisting tubulointerstitial nephritis (TIN), which was induced in male Sprague Dawley rats by hexachloro-1,3-butadiene (HCBD). Five days after the development of TIN, puromycin aminonucleoside (PAN) was administered to induce urinary protein overload. Urinary laminin and kallikrein were measured. Urine specimens were collected daily for 14 days and on day 21; and tissue specimens were collected on days 1, 4, 7, 10, 14 and 21. Urinalysis was correlated with the renal pathology at the light microscopic level. Laminin excretion was increased on day 4; one day before total protein, indicating damage to the basement membrane. Kallikrein levels also fell early indicating distal tubular damage. There is clear evidence that urine protein overload in a previously damaged kidney with tubulointerstitial injury leads to accelerated and more severe renal damage. Laminin and kallikrein are early and sensitive markers of renal injury.

Mice deficient of functional interferon regulatory factor-1 (IRF-1-/-) by targeted gene disruption infected with a lethal murine malaria strain, Plasmodium berghei ANKA survived longer than its wild-type littermates despite the inability to induce appreciable amounts of interferon-gamma (IFN-gamma) and nitric oxide. In addition, infected IRF-1-/- mice displayed less organ injury with reduced necrosis and inflammation. Both wild-type and IRF-1-/- mice treated with exogenous interleukin-12 (IL-12) suffered extensive organ damage with corresponding up regulation of IFN-gamma, suggesting the pathogenic potential of IL-12 and IFN-gamma. IL-10 is a cytokine produced by CD4+ T lymphocytes belonging to the Th2 subset. Expression of IL-10 in the wild-type mice correlated with the severity of the infection, with higher mRNA expression towards the later stage of infection. In contrast to the wild-type mice, IL-10 levels in the IRF-1-/- mice were induced early in the infection and decreased gradually as the infection progressed. Both untreated and IL-12 treated wild-type mice appeared to follow a Th1-like immune response early in the infection and a Th2-like immune response later in the infection. However, the IRF-1-/- mice were able to launch an altered immune response with a Th2-like immune response early in the infection. These findings suggest that IL-10 expression in the IRF-1-/- mice during the early stage of P. berghei ANKA infection could play an important role in suppressing pathogenic effects of a cell mediated immune response and promoting protective immunity against the parasite.

The diversity of renal arteriole diameters in different cortical regions has important consequences for control of glomerular capillary pressure. We examined whether intrarenal angiotensin II (ANG II; 0.1, 1, or 5 ng. kg(-1). min(-1)) in anesthetized rabbits acts preferentially on pre- or postglomerular vessels using vascular casting. ANG II produced dose-related reductions in afferent and efferent diameters in the outer, mid, and inner cortex, without effecting arterial pressure. Afferent diameter decreased more than efferent in the outer and mid cortex (P < 0.05) but by a similar extent in juxtamedullary nephrons (P = 0.58). Calculated efferent resistance increased more than afferent, especially in the outer cortex (127 vs. 24 units; 5 ng. kg(-1). min(-1) ANG II). ANG II produced significant dose-related increases in the distance between the arterioles at the entrance to the glomerular pole in all regions. Thus afferent diameter decreased more in response to ANG II, but efferent resistance rose more due to smaller resting luminal dimensions. The results also indicate that glomerular pole dimensions change in response to ANG II.

Renal disease is a common complication in malaria infection. In acute falciparum malaria renal involvement is usually mild, but in severe disease acute renal failure is a major problem. Acute renal failure has been attributed to ischaemic tubular necrosis from hypovolaemia resulting from vasodilatation due to endothelial injury. Though myositis is recorded as a common manifestation in falciparum malaria, only 1 case with myositis and myoglobinuria with acute renal failure has been documented; but no renal biopsy was performed in the patient. In the present study we examined the case of a 17-year-old man with severe falciparum malaria with myositis and myoglobinuria who developed acute renal failure requiring dialysis. Muscle biopsy revealed severe myositis with macrophages and T lymphocytes including CD4+ cells. The kidney biopsy showed scanty T cells and macrophages in the glomeruli which were only mildly hypercellular. The renal tubules showed myoglobin casts in the lumen and foci of interstitial inflammatory cells, including macrophages and T lymphocytes but no CD4+ cells. Rhabdomyolysis induced by macrophages and T cells with myoglobinuria and acute renal failure is a problem in severe falciparum malaria infection., (Copyright 2000 S. Karger AG, Basel)

Injury to renal tubules and interstitium occur in various glomerular diseases, leading to functional impairment. Tubular basement membrane (TBM) is an important component in maintaining tubular epithelial cell integrity. Because ultrastructural changes in these structures had not been studied in detail, the authors analyzed 30 patients with various types of glomerular diseases, including minimal change disease (MCD), focal segmental glomerular sclerosis, IgA nephropathy, diffuse proliferative glomerulonephritis, membranous nephropathy, and lupus nephritis, by light, electron, and immunofluorescence microscopy. Ultrastructural changes in the TBM were studied and morphometric measurements were performed. The tubular basement membranes showed membranous structures, lucent or lytic areas, and tubular epithelial detachment. There was significant linear correlation between these tubular basement membrane changes and terminal complement complex neoantigens. The interstitial widening was due to banded collagen fibers, with anchoring fibers in the TBM. The various glomerular diseases lead to tubulointerstitial damage via changes in the TBM, leading to renal dysfunction.

Metallothioneins (MTs) are low molecular weight proteins that control cell proliferation via their metalloregulatory function. Several studies in various tumors have shown their influence in determining response to chemotherapy and prognosis. Because there has been no such study pertaining to ovarian tumors, we investigated MT expression and nuclear size in mucinous ovarian neoplasms (12 benign, 6 borderline, and 8 malignant). The percentage of MT-positive stained cells was significantly higher in the borderline than in the benign tumors, but lower than in the malignant tumors. Single layers of cells in the borderline tumors showed mild immunostaining in 50% of the cells and moderate staining in the remaining 50%, while 83.3% of cells within multilayered epithelium showed moderate to strong immunostaining. In the carcinomas, 87.5% of tumors showed moderate to strong staining in single-layered epithelium and moderate to strong staining of all the cells in multilayered epithelium. Morphometry measurements showed that the mean nuclear area of cells in the carcinomas was significantly larger than in the borderline or benign tumors. The nuclear area of cells in the carcinomas with early recurrence or metastasis was also significantly larger than in carcinomas without recurrence or metastasis. It is concluded that MT protein expression and nuclear size are possible markers for the evaluation of the progression of malignancy in mucinous ovarian tumors.

Metallothioneins (MTs) are low-molecular-weight proteins involved in metalloregulatory functions such as cell proliferation, growth, and differentiation. In recent years, MT expression has been linked with carcinogenesis, resistance to cancer therapy, and tumour progression. However, the significance of MT expression in ovarian cancers is at present inadequately documented. In this study, MT immunohistochemistry was performed in 12 benign, 14 borderline, and eight malignant serous tumours of the ovary. The intensity of the immunostaining was evaluated by image analysis. There was a significantly higher number of MT-immunopositive cells in the multilayered epithelial cells of borderline serous tumours (atypical proliferative serous tumours) than in the single layered epithelial cells within the same tumour, and in the single cell layer of benign serous tumours. There was no difference in the expression of MTs in the single layered tumour cells of benign and borderline serous tumours. Significantly higher numbers of MT-immunopositive cells were observed in both the single and the multilayered epithelial cells of serous carcinomas, the highest number being observed in the multiple layers of serous carcinomas. The positively stained malignant tumour cells in both single and multiple layers were larger than the negatively stained cells in benign, borderline, and malignant serous ovarian tumours. There was moderate to intense staining. These findings indicate that there is increased expression of MTs in the progression of malignancy, which could be used as a marker in grading the three groups of ovarian serous tumours and for determining prognosis., (Copyright 1999 John Wiley & Sons, Ltd.)

Malaria infections often cause glomerulonephritis (GN), and multiple factors have been implicated in the pathogenesis of glomerular injury. The role of cytokines in malaria associated glomerulonephritis has not been clearly defined. To study the importance of cytokines in malarial nephritis, we investigated the expression of tumour necrosis factor-alpha (TNF-alpha), interleukin-1alpha (IL-1alpha), IL-6, IL-10 and granulocyte macrophage-colony stimulating factor (GM-CSF) in kidneys acutely infected with murine malaria parasite Plasmodium berghei ANKA in C57BL/6 J mice. Groups of six mice sacrificed on days 5, 8-10, 15, and 20 postinfection, and normal controls were used for cytokine analysis. Elevated levels of messenger RNA (mRNA) specific for these cytokines in infected kidneys after day 5 postinfection were demonstrated by reverse transcription-polymerase chain reaction (RT-PCR) analysis. Kidney sections stained with specific antibodies against TNF-alpha, IL-1alpha, IL-6, IL-10 and GM-CSF by immunohistochemistry showed that the staining for these cytokines on the glomeruli was positive from day 10 postinfection, and increased progressively, mainly in the infiltrating macrophages and the glomerular mesangium. Strong correlation was found between the expression of TNF-alpha with IL-6, and IL-1alpha with IL-6. The expression of TNF-alpha, IL-1alpha, IL-6, and IL-10 also strongly correlated with the severity of proteinuria. Our findings show that there is up-regulation of cytokines in the pathogenesis of glomerulonephritis associated with murine malaria infection.

The importance of immune complexes in the pathogenesis of malarial nephritis is well established. The expression was studied of major histocompatibility complex (MHC) class I and class II antigens and the infiltration of inflammatory cells, with their possible roles in cellular immune reactions in the pathogenesis of nephritis in a murine malaria model. Thirty-six kidney sections obtained on days 5, 8-10, 15, and 20 from C57BL/6J mice acutely infected with Plasmodium berghei and uninfected control mice were stained with specific antibodies for cellular immune markers by immunohistochemistry. From day 10 post-infection, markedly enhanced expression of both MHC class I and class II (Ia) antigens was observed in the kidneys. In the glomeruli, the expression was in the mesangium and along the capillaries. MHC class II was strongly expressed in the proximal tubules. Enhanced expression of MHC class I and class II was found in the endothelium of blood vessels, especially the peritubular capillaries. In addition, immune cells positive for CD4+ and CD8a+ markers, and class I and class II antigens were present around small arteries, or in focal areas of the interstitium. There were strong correlations between MHC class I expression in the glomeruli; MHC class II expression in the glomeruli/proximal tubules; and CD4+, CD8a+ infiltrates in the tubulointerstitium; with the severity of renal dysfunction (proteinuria). These findings indicate the importance of cellular immune reactions in the pathogenesis of acute murine malarial nephritis.

The expression of intercellular adhesion molecule-1 (ICAM-1), the ligand leucocyte function antigen-1 (LFA-1, CD11a), and complement receptor type 3 (CR3, or Mac-1, CD11b) has been studied in murine kidneys acutely infected with the fatal malaria parasite Plasmodium berghei ANKA. Thirty-six kidney sections from five groups of C57BL/6J mice on day 5, 10, 15, and 20 post-infection, and normal controls, were stained with monoclonal antibodies against ICAM-1, LFA-1, and Mac-1. There was markedly enhanced expression of ICAM-1 in the glomerular mesangium and the endothelium of blood vessels from day 10 post-infection. ICAM-1 was also found in the proximal tubular epithelial cells in an apical location, with a linear pattern. In addition, the glomeruli showed positive staining for LFA-1 and Mac-1 on day 10 post-infection, mainly in the infiltrating inflammatory cells. Mesangial cells and inflammatory cells in the cortical tubulointerstitium showed positive staining for ICAM-1, LFA-1, and Mac-1 at the later stages of infection. There were strong correlations between ICAM-1 expression on endothelial cells of glomerular/peritubular capillaries with inflammatory cells positive for LFA-1 and Mac-1, which correlated with proteinuria. These findings show that several adhesion molecules are up-regulated in murine malaria-associated nephritis. The expression of ICAM-1 on endothelial cells correlated with the severity of inflammatory responses, indicating the relationship between the expression of adhesion molecules and cell-mediated immune renal injury. It is suggested that adhesion molecules play an important role in the pathogenesis of murine nephritis. Better knowledge of the function of these molecules in malaria infection may open new approaches to antimalarial therapy.

We examined the circulating levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 alpha, IL-6, granulocyte macrophage-colony stimulating factor (GM-CSF), and the anti-inflammatory cytokine IL-10, and their expression in kidneys acutely infected with murine malaria parasite P. berghei ANKA in C57BL/6J mice. Groups of six mice sacrificed on days 5, 10, 15, and 20, and normal controls were used for cytokine analysis. High concentrations of TNF-alpha and IL-10 were detected in plasma as shown by ELISA, and elevated levels of mRNA specific for TNF-alpha and IL-10 in infected kidneys were demonstrated by reverse transcription-polymerase chain reaction (RT-PCR) analysis. Kidney sections stained with antibodies against TNF-alpha, IL-1 alpha, IL-6, GM-CSF and IL-10 for immunohistochemistry showed markedly enhanced staining for TNF-alpha, and progressively increased staining for IL-1 alpha and IL-6 both in the tubules and the walls of arteries during the course of infection. The endothelia of blood vessels and inflammatory cells located around small arteries showed positive staining for GM-CSF from day 10 onwards. Unlike the staining for proinflammatory cytokines, the anti-inflammatory cytokine IL-10 showed strongly positive staining in normal tubules and walls of arteries, especially in the brush border of proximal tubules, but the staining intensity decreased dramatically after day 15 post-infection. A strongly positive correlation was found between the antibody staining for TNF-alpha/IL-1 alpha in tubules, and the severity of proteinuria. In contrast, there was an inverse correlation between the staining for IL-10 with TNF-alpha/IL-1 alpha, and the degree of proteinuria. Plenty of pigmented macrophages showed positive staining both for proinflammatory and anti-inflammatory cytokines in the tubulointerstitium. Our findings imply that the up-regulation of proinflammatory cytokines and the dysregulation of anti-inflammatory cytokines are involved in the pathogenesis of tubulointerstitial nephritis associated with malaria.

The use of computers for the automated image analysis of tissue sections is becoming increasingly important. The paper presents an overview of current methodologies and summarizes developments in this field. A brief introduction followed by a survey is provided in each of these areas: image transformation, image segmentation and classification.

We report a case of mucoepidermoid carcinoma of the middle ear, a site which does not appear to have been previously described. A discussion of four possible theories of pathogenesis are presented.

Deposition of immunoglobulins, complement proteins C1q, C3c, C3d, C4, C5, C6, C7, C8, C9, and terminal complement complex neoantigens in the renal tubulointerstitium was studied in serial sections by immunofluorescence microscopy. Renal tissue from 45 cases with various glomerular diseases, including 8 controls, was studied. The patients were divided into groups; one with tubulointerstitial lesions (24 cases) and the other without (13 cases). The immunoproteins were deposited mainly in the tubular basement membrane and blood vessels. Compared with controls there was a significantly increased staining score for C5 to C9 in the tubular basement membrane in both disease groups. However, the increase in terminal complement complex neoantigens score was significant only in the disease group with tubulo interstitial lesions. The changes in C3d score were not significant. Serial sections showed consistent and heavy ribbon-like deposits of complement proteins C3d, C5 to C9, and terminal complement complex neoantigens in corresponding locations of the segments of tubular basement membrane, mainly in the disease group with tubulointerstitial lesions and especially in the damaged tubules. These findings suggest that in situ activation of the complement cascade leads to the deposition of terminal complement complex neoantigens. Complement activation in the basal area of the tubules may, therefore, be an important pathogenetic mechanism in tubulointerstitial damage.

Chondroblastoma represents approximately one per cent of all primary bone tumours. It is even rarer in the temporal bone and so far only 34 cases have been reported. We report here two cases with chondroblastoma of the temporal bone. The first case was discovered as a small lesion of the attic and root of zygoma. It was removed via mastoidectomy and reconstruction of the bony defect achieved normal external ear canal anatomy and hearing post-operatively. The second case presented as an advanced tumour involving the infratemporal fossa and parapharyngeal space. It was treated surgically via the infratemporal fossa approach. As clear surgical margins were not obtained, post-operative radiotherapy was also given to minimize the chance of recurrence.