B. Handan Ozdemir

The presence and prognostic importance of glomerular macrophage infiltration in renal allografts

Aim: The purpose of this study was to analyze the role of intraglomerular macrophage infiltration in human renal allografts by examining biopsies from kidney grafts that were dysfunctional after transplantation. Methods: Eighty-three patients (58 men, 25 women) of a mean age of 30.2 ± 1.4 years were evaluated. In all cases, biopsy specimens were examined for the presence of macrophage infiltration in the glomeruli. The infiltration of these cells was evaluated immunohistochemically using monoclonal antibody CD68, which labels macrophage cytoplasm. 10 renal allograft biopsies with normal histopathology were used as control group. The CD68-positive macrophages in all glomeruli were counted and the glomerular macrophage index (GMI) was calculated. Results: Of the 83 patients, 40 showed acute rejection (AR), 33 showed chronic rejection (CR) and 10 showed cyclosporin A (CsA) toxicity. Only the biopsies of 28 patients stained positive for CD68 in the glomeruli. Neither patients with CsA toxicity nor controls showed intraglomerular macrophages. The CD68-positive group consisted of 7/33 CR and 21/40 AR patients. We observed intraglomerular macrophages in only 6 of the 20 AR cases that responded to steroid therapy (mean GMI 0.3 ± 0.1) and in 15 of the 20 steroid-resistant AR cases (mean GMI 1.7 ± 1.2; p < 0.01). The outcome of grafts that contained intraglomerular macrophages was significantly worse than the outcomes of other grafts noticed during the follow-up. Conclusion: We conclude that the presence of glomerular macrophages can be considered a marker for rejection and is a valuable additional criterion of rejection in the histological examination of renal allograft biopsies. The presence of intraglomerular macrophages indicates that the outcome of the graft will be significantly worse than that of grafts without intraglomerular macrophage infiltration.

Eculizumab therapy in a patient with dense-deposit disease associated with partial lipodystropy.

BackgroundDense deposit disease (DDD) (also known as membranoproliferative glomerulonephritis type II) in childhood is a rare glomerulonephritis with frequent progression to end-stage renal disease (ESRD) and a high recurrence after kidney transplantation. The pathophysiologic basis of DDD is associated with the uncontrolled systemic activation of the alternative pathway (AP) of the complement cascade.Case-diagnosis/treatmentA 14-year-old girl presented with edema and nephrotic range proteinuria. Blood tests showed hypoalbuminemia, nephrotic range proteinuria, normal renal function, and a low C3 level. Renal biopsy confirmed the diagnosis of crescentic DDD. Complement analysis revealed strong AP activation (low C3), positive C3 nephritic factor (C3NeF), and a decreased complement factor H (CFH) levels with CFH polymorphisms. Therapy with eculizumab was considered after the failure of corticosteroid and plasmapheresis to modulate the ongoing massive proteinuria and persistence of low serum C3 levels. There was a marked clinical and biochemical response following the administration of eculizumab.ConclusionsOur case emphasizes the efficacy of eculizumab in the management of crescentic DDD in a patient with a normal renal function, in a short follow-up period. Considering previously reported cases, it appears that eculizumab represents a promising new approach which may prevent progression to ESRD in a subset of patients with DDD.

Early Implant Survival in Posterior Maxilla With or Without β-Tricalcium Phosphate Sinus Floor Graft

PURPOSE The sinus lift procedure provides a way to increase the amount of available bone and the placement of longer implants. The aim of this study was to evaluate and compare the survival rates of implants inserted in the posterior maxilla (without sinus lift) to simultaneous implant insertion with sinus lift. PATIENTS AND METHODS Seventy maxillary sinuses in 62 patients were augmented by beta-tricalcium phosphate and 121 implants were inserted into these augmented sinuses (study group) and 136 implants were inserted in the posterior maxilla in 65 patients (control group). Follow-up times were 29.8 and 32.3 months for the study and control groups, respectively. RESULTS One implant in the study group and 1 implant in the control group failed. All other implants in both groups were functioning well without any significant clinical finding. Implant survivals were 99.17% in the study group and 99.26% in the control group. CONCLUSION Simultaneous implant insertion and sinus lift with beta-tricalcium phosphate is a safe surgical procedure, and survival rates of implants inserted in the augmented sinus were similar to those of implants inserted in the posterior maxilla without sinus lift.

Vascular Endothelial Growth Factor Expression and Cyclosporine Toxicity in Renal Allograft Rejection

The aim of this study was to evaluate the influence of vascular endothelial growth factor (VEGF) on renal function and on development of interstitial fibrosis (IF) in renal allografts. Tubular and interstitial expressions of VEGF and TNF‐α, and density of macrophages in the interstitium were examined in 92 patients with nonrejected kidneys, acute rejection (AR), chronic allograft nephropathy (CAN), borderline changes (BC) and acute cyclosporin A (CsA) toxicity. Follow‐up biopsy specimens from patients with AR and BC were evaluated for development of IF. A significant difference in tubular and interstitial VEGF expressions was found between patients with AR, BC, CAN and CsA toxicity (p < 0.001). Macrophage infiltration was positively correlated with VEGF and TNF‐α expressions (p < 0.001). VEGF expression increased with increasing expression of TNF‐α (p < 0.001). Renal function in first 6 months after initial biopsy was better in patients with marked tubular VEGF expression (p < 0.01); however, in follow‐up, development of IF and graft loss was found earlier in these patients (p < 0.01 and p < 0.05, respectively). Increased renal VEGF expression has protective properties immediately following renal allograft but allows for increased risk of early IF, and therefore poor graft outcome in the long term.

Expression of caspase-3, p53 and Bcl-2 in generalized aggressive periodontitis

BackgroundApoptosis, or programmed cell death is a form of physiological cell death. It is increased or decreased in the presence of infection, inflammation or tissue remodelling. Previous studies suggest that apoptosis is involved in the pathogenesis of inflammatory periodontal disease. The aim of the present study was to investigate the clinical features and known indicators of apoptosis (p53, Bcl-2, Caspase-3) in patients with generalized aggressive periodontitis (GAP)MethodsEight patients with GAP, who had sites with probing depths (PD) > 5 mm, and 10 periodontally-healthy persons were included in the study. Clinical examinations and PD were performed, and the plaque index and gingival index were recorded. Gingival tissues biopsies were obtained from active site of each patient and from healthy individuals. The expression of caspase-3, Bcl-2, and p53 was evaluated by immunohistochemistryResultsThere were no significant differences between GAP and control group with respect to levels of caspase-3 and p53 expression (P > 0.05). Contrary, the frequency of grade 3 expression of Bcl-2 was higher in GAP group than the control group.ConclusionThe higher frequency of Bcl-2 expression in GAP group indicates and delayed apoptosis can lead to increasing resident inflammatory cells in periodontal tissues and resulting in progressive periodontal destruction.

Analysis of proliferative activity in oral gingival epithelium in immunosuppressive medication induced gingival overgrowth.

BackgroundDrug-induced gingival overgrowth is a frequent adverse effect associated principally with administration of the immunosuppressive drug cyclosporin A and also certain antiepileptic and antihypertensive drugs. It is characterized by a marked increase in the thickness of the epithelial layer and accumulation of excessive amounts of connective tissue. The mechanism by which the drugs cause gingival overgrowth is not yet understood. The purpose of this study was to compare proliferative activity of normal human gingiva and in cyclosporine A-induced gingival overgrowth.MethodsGingival samples were collected from 12 generally healthy individuals and 22 Cyclosporin A-medicated renal transplant recipients. Expression of proliferating cell nuclear antigen was evaluated in formalin-fixed, paraffin-embedded gingival samples using an immunoperoxidase technique and a monoclonal antibody for this antigen.ResultsThere were differences between the Cyclosporin A group and control group in regard to proliferating cell nuclear antigen and epithelial thickness. In addition, the degree of stromal inflammation was higher in the Cyclosporin A group when compared with the control group.ConclusionThe results suggest that the increased epithelial thickness observed in Cyclosporin A-induced gingival overgrowth is associated with increased proliferative activity in keratinocytes.

Interactions of systemic immune response and local wound healing in different burn depths: an experimental study on rats.

This study aimed to clarify the local and systemic immune responses at different burn depths. Thirty female Sprague–Dawley rats were divided into three groups: full-thickness (F), partial-thickness (P), and Sham (S). Burns were induced on three separate areas on the dorsums of rats. Serum levels of interferon (IFN)-&ggr;; tumor necrosis factor-&agr;; interleukin (IL)-1, IL-6, and IL-10 were measured once in controls and 1 hour after burn, 48 hours after burn, and 7 days after burn in F and P groups. Neutrophils, CD68-positive macrophages, HLA-DR-positive cells, and CD3-positive lymphocytes were graded semiquantitatively, and the wounds were examined once in shams and at 1 hour after burn, 48 hours after burn, and 7 days after burn in F and P groups. IL-6 levels were highest in F group, followed by P group 1 hour after burn. IFN-&ggr; levels were higher in the F group; IL-1 levels were higher in F and P groups at 1 hour after burn. Local accumulation of macrophages was similar in F and P groups. Lymphocytes were denser in P group at 1 hour after burn, and neutrophils were denser in F group at 7 days after burn. We suggest that early elevations of IL-6 and IFN-&ggr; prolong inflammation in full-thickness burns. Modulation of proinflammatory cytokines may improve burn wound treatment.

SPECTRUM OF LIVER DAMAGE AND CORRELATION WITH CLINICAL AND LABORATORY PARAMETERS IN HCV INFECTED HEMODIALYSIS PATIENTS

There are conflicting results in studies concerning the best marker for liver histopathological features of HCV infection in HD patients. We planned a prospective study to follow HCV viremia and laboratory parameters of HD patients and correlate these with clinic features and histopathological findings. We included 68 HCV infected patients (45 male, 23 female, age: 39.8 ± 11.9 years, HD duration: 58.2 ± 36.4 months) in our study. The follow-up period after the biopsy was 33.2 ± 20.3 months. Patients liver enzyme (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT)) levels were determined monthly and ferritin levels every three months, and the mean value was recorded. We also screened patients for HCV RNA. During the follow-up period, 22 (32.4%) of the patients had positive RNA, 26 (38.2%) negative RNA, 20 (29.4%) had intermittent RNA positivity. The patients with high grade of portal necroinflammatory activity had significantly higher AST and ALT levels. In addition patients with high grade lobular activity had significantly shorter HD and HCV infection duration and higher AST, ALT and ferritin levels. AST levels were negatively correlated with duration of HD and HCV infection, and positively correlated with GGT and ferritin levels. Additionally, we found that ALT levels were negatively correlated with HD duration and positively correlated with GGT levels. ALT levels higher than 30 U/L were reflected necroinflammatory activity more significantly than levels higher than 40 U/L. Cirrhosis was detected in 5.9% of the patients, and we could not find any laboratory parameter that was correlated with stage of fibrosis. Although there is a high degree of liver involvement, cirrhosis is a relatively less frequent finding in HD patients. Serum aminotransferases and ferritin levels but not the pattern of HCV viremia are predictors of necroinflammatory activity in liver biopsy specimens. Liver biopsy obligatory to assess the disease activity in HD patients.

Relationship of HLA‐DR Expression to Rejection and Mononuclear Cell Infiltration in Renal Allograft Biopsies

Research on renal biopsies has shown that HLA class I antigens are distributed throughout the renal parenchyma, but that the distribution of HLA‐DR varies greatly. We investigated HLA‐DR expression in biopsies of 90 renal transplants, and also semiquantitatively assessed the proportions of CD68‐, CD3‐, and HLA‐DR‐positive infiltrating cells by immunohistochemistry. The relationships between tubular DR expression and interstitial lymphocyte and macrophage infiltration were examined. Forty of the biopsies showed acute rejection (AR), 33 showed chronic rejection (CR), 10 showed suspected rejection (SR), and 7 showed no evidence of rejection (NR). HLA‐DR expression was noted in 35/40 (87.5%) of the AR cases, 22/33 (66.6%) of the CR cases, and 6/10 (60%) of the SR cases. Only 1 (14.3%) of the NR cases exhibited HLA‐DR antigen expression in the renal tubules. The proportions of lymphocyte and macrophage infiltration observed in the interstitium were significantly correlated with tubular DR expression in all cases (p < 0.01). At 6 months after biopsy was done, 24/35 (68.6%) of the AR patients with tubular DR expression had showed second episode of rejection or showed deteriorated renal function. The remaining 11 AR cases with tubular DR expression had stable renal function at this stage. The cases that had no significant tubular DR expression had no problems with rejection or functional deterioration. These findings are consistent with the theory that expression of HLA‐DR antigens on renal tubular cells may be a marker of rejection and poor graft outcome.

Protective Role of Simvastatin on Lung Damage Caused by Burn and Cotton Smoke Inhalation in Rats

BACKGROUND Smoke inhalation injury is a major comorbid factor in patients with thermal injury and occurs in about 30% of patients with major burns. In addition, inhalation injury reportedly accounts for 20%-84% of the mortality in burned individuals and is associated with higher mortality rates for every age and burn size category. The aim of the present study was to investigate the effects of simvastatin on lung damage with burn and cotton smoke inhalation. METHODS Wistar rats were randomly assigned to three groups: saline treated control group, via an orogastric route (group 1, n = 6), burn (30%) and cotton smoke inhalated group (group 2, n = 6), and simvastatin treated (25 mg/kg/d, via an orogastric route) burn (30%) and cotton smoke inhalated group (group 3, n = 6). Rats were sacrificed at 48 h of the treatments and the trachea and lungs were removed completely. Tissue samples were taken for histopathologic, immunohistopathologic, and biochemical analyses. Univariate analysis of variance coupled with Duncans post-hoc test was performed for statistical evaluation. RESULTS Lung parenchymal and tracheoepithelial damage was confirmed in group 2 by histopathologic examination. Lung malonedialdehyde (MDA) levels were significantly decreased (P < 0.001), while glutathione (GSH) concentration did not alter in group 2 compared with group 1. Also, immunopathologic data revealed that epithelial iNOS level was elevated, while no modulation was detected in the level of myeloperoxidase (MPO). Simvastatin administration resulted in decreasing the lung parenchymal and tracheoepithelial damage. Tissue MDA levels were decreased significantly (P < 0.001), whereas GSH concentrations were elevated in group 3 compared with group 1 and group 2 (P < 0.001). Simvastatin treatment caused a decrease in epithelial iNOS levels, while MPO levels were not modulated. In addition, simvastatin significantly reduced pulmonary apoptosis in lung injury. CONCLUSIONS Our results have indicated that simvastatin administration seems to play beneficial role in lung injury of rats promoted by combined burn and smoke inhalation. Thus, simvastatin may represent a potential approach to prevent smoke inhalation-associated lung dysfunction. However, the significant decrease in basal oxidant production may cause impairment in cellular signalling processes.