Chronic Histopathological Changes Research Articles

Accelerated involution of germinal center in palatine tonsils in IgA nephropathy.

Altered immunological responses in the palatine tonsils may be involved in the pathogenesis of IgA nephropathy (IgAN). The germinal center serves as the site for antigen-specific humoral immune responses in the palatine tonsils. Germinal center involution is frequently observed in the palatine tonsils of IgAN (IgAN tonsils). However, the pathogenic significance of these characteristic changes remains unclear. This study aimed to investigate the morphological changes in secondary lymphoid follicles in IgAN tonsils and to evaluate the correlation between the morphometric results and the clinicopathological severity of IgAN. The tonsils of age-matched patients with recurrent tonsillitis (RT tonsils) were used as controls. The correlation between the degree of lymphoid follicular involution and histopathological severities in clinical or kidney biopsy was evaluated. In total, 87 patients with IgAN were included (48% male, median age 35 years, median estimated glomerular filtration rate: 74 mL/min/1.73 m2). Compared to RT tonsils, IgAN tonsils showed smaller median sizes of lymphoid follicles and germinal centers (P < 0.001). The relative areas of lymphoid follicles (%LFA) and germinal centers (%GCA) in the total tonsillar tissue were smaller in the IgAN tonsils than in the RT tonsils (P < 0.001). In contrast, the median proportion of mantle zones in the total tonsillar tissue was comparable between the groups. A lower %LFA was associated with a longer period from the onset of urinary abnormalities to biopsy diagnosis and higher urinary protein excretion (P = 0.01). %LFA showed significant negative correlations with frequencies of glomeruli with both global and segmental sclerosis. The present study confirmed accelerated germinal center involution in the tonsils of patients with IgAN. This characteristic change in the IgAN tonsil correlates with heavy proteinuria and advanced chronic histopathological changes in the kidneys, thereby suggesting the involvement of repeated tonsillar immunoreactions during IgAN progression.

The Reemergence of Measles.

Present-day pathologists may be unfamiliar with the histopathologic features of measles, which is a reemerging disease. Awareness of these features may enable early diagnosis of measles in unsuspected cases, including those with an atypical presentation. Using archived tissue samples from historic patients, a unique source of histopathologic information about measles and other reemerging infectious diseases, we performed a comprehensive analysis of the histopathologic features of measles seen in commonly infected tissues during prodrome, active, and late phases of the disease. Subspecialty pathologists analyzed H&E-stained slides of specimens from 89 patients accessioned from 1919 to 1998 and correlated the histopathologic findings with clinical data. Measles caused acute and chronic histopathologic changes, especially in the respiratory, lymphoid (including appendix and tonsils), and central nervous systems. Bacterial infections in lung and other organs contributed significantly to adverse outcomes, especially in immunocompromised patients. Certain histopathologic features, especially Warthin-Finkeldey cells and multinucleated giant cells without inclusions, allow pathologists to diagnose or suggest the diagnosis of measles in unsuspected cases.

Demographic, clinical and laboratory characteristics of adult-onset minimal change disease in Turkey: Turkish Society of Nephrology-Glomerular Diseases (TSN-GOLD) Working Group.

In our study, diagnostic and demographic characteristics of patients diagnosed with minimal change disease (MCD) by biopsy, clinical and laboratory findings in our country were investigated. Data were obtained from the Turkish Society of Nephrology Glomerular Diseases (TSN-GOLD) Working Group database. Demographic characteristics, indications for biopsy, diagnosis of the glomerular diseases, comorbidities, laboratory and biopsy findings of all patients were recorded. The data presented are cross-sectional and includes application data for the biopsy period. Of 3875 patients, 233 patients with MCD (median age 35.0years) were included in the study, which constitutes 6.0% of the total glomerulonephritis database. Renal biopsy was performed in 196 (84.1%) patients due to nephrotic syndrome. Median serum creatinine was 0.7 (0.6-1.0) mg/dl, mean eGFR was 104 ± 33ml/min/1.73 m2 and median proteinuria 6000mg/day. The number of patients under the age of 40years was 139 (59.7%) (Group A), and the number of patients aged 40years and over was 94 (40.3%) (Group B). Compared to Group A, global sclerotic glomeruli (24 vs. 43, p < 0.001) interstitial inflammation (15 vs. 34, p < 0.001), interstitial fibrosis (20 vs. 31, p = 0.001, vascular changes (10 vs. 25, p < 0.001) and tubular atrophy (18 vs. 30, p < 0.001) were found to be significantly higher in Group B. There was no difference in immunofluorescent staining properties between the two groups. Our data are generally compatible with the literature. Chronic histopathological changes were more common in patients aged 40years and older than younger patients. Studies investigating the effects of these different features on renal survival are needed.

The role of dendrin in IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) and its systemic variant IgA vasculitis (IgAV) damage the glomeruli, resulting in proteinuria, hematuria and kidney impairment. Dendrin is a podocyte-specific protein suggested to be involved in the pathogenesis of IgAN. Upon cell injury, dendrin translocates from the slit diaphragm to the nucleus, where it is suggested to induce apoptosis and cytoskeletal changes, resulting in proteinuria and accelerated disease progression in mice. Here we investigated gene and protein expression of dendrin in relation to clinical and histopathological findings to further elucidate its role in IgAN/IgAV. Glomerular gene expression was measured using microarray on 30 IgAN/IgAV patients, 5 patients with membranous nephropathy (MN) and 20 deceased kidney donors. Dendrin was spatially evaluated on kidney tissue sections by immunofluorescence (IF) staining (IgAN patients, n=4; nephrectomized kidneys, n=3) and semi-quantified by immunogold electron microscopy (IgAN/IgAV patients, n=21; MN, n=5; living kidney donors, n=6). Histopathological grading was performed according to the Oxford and Banff classifications. Clinical data were collected at the time of biopsy and follow-up. Dendrin mRNA levels were higher (P=.01) in IgAN patients compared with MN patients and controls and most prominently in patients with preserved kidney function and fewer chronic histopathological changes. Whereas IF staining did not differ between groups, immunoelectron microscopy revealed that a higher relative nuclear dendrin concentration in IgAN patients was associated with a slower annual progression rate and milder histopathological changes. Dendrin messenger RNA levels and relative nuclear protein concentrations are increased and associated with a more benign phenotype and progression in IgAN/IgAV patients.

Characteristics of Epileptiform Spike-wave Discharges and Chronic Histopathology in Controlled Cortical Impact Model of Sprague-Dawley Rats.

Post-traumatic epilepsy (PTE) is a serious complication that can occur following traumatic brain injury (TBI). Sustained secondary changes after TBI promote the process of PTE. Here, we aim to evaluate changes in behavior, electrocorticogram, and histomorphology in rats following chronic TBI models. We observed intensive 7-8Hz spike-wave-discharges (SWDs) at frontal recording sites and quantified them in SD rats with different degrees of TBI and compared them with age-matched sham rats to evaluate the association between SWDs and injury severity. Notably, although SWDs were even presented in the sham group, the number and duration of events were much lower than those in the TBI groups. SWDs have numerous similarities to absence seizures, such as abrupt onset, termination, and lack of postictal suppression, which may be the nonconvulsive characteristics of PTE. Retigabine, a novel antiepileptic drug, is ineffective in reducing SWDs. In addition, we examined chronic histopathological changes in TBI rats. Rats subjected to moderate and severe TBI exhibited significantly impaired neurological function, which was accompanied by marked cortical injury, hippocampus deformation, reactive gliosis, and mossy fiber sprouting. Long-term progressive structural changes in the brain are one of the characteristics of epileptogenesis after TBI. Our study provided the potential value of epileptiform SWDs in reflecting the nonconvulsive characteristic of PTE and highlighted the vital role of chronic pathological changes, such as reactive gliosis, in promoting the epileptogenesis following TBI.

A model of chronic, transmissible Otitis Media in mice.

Infection and inflammation of the middle ears that characterizes acute and chronic otitis media (OM), is a major reason for doctor visits and antibiotic prescription, particularly among children. Nasopharyngeal pathogens that are commonly associated with OM in humans do not naturally colonize the middle ears of rodents, and experimental models in most cases involve directly injecting large numbers of human pathogens into the middle ear bullae of rodents, where they induce a short-lived acute inflammation but fail to persist. Here we report that Bordetella pseudohinzii, a respiratory pathogen of mice, naturally, efficiently and rapidly ascends the eustachian tubes to colonize the middle ears, causing acute and chronic histopathological changes with progressive decrease in hearing acuity that closely mimics otitis media in humans. Laboratory mice experimentally inoculated intranasally with very low numbers of bacteria consistently have their middle ears colonized and subsequently transmit the bacterium to cage mates. Taking advantage of the specifically engineered and well characterized immune deficiencies available in mice we conducted experiments to uncover different roles of T and B cells in controlling bacterial numbers in the middle ear during chronic OM. The iconic mouse model provides significant advantages for elucidating aspects of host-pathogen interactions in otitis media that are currently not possible using other animal models. This natural model of otitis media permits the study of transmission between hosts, efficient early colonization of the respiratory tract, ascension of the eustachian tube, as well as colonization, pathogenesis and persistence in the middle ear. It also allows the combination of the powerful tools of mouse molecular immunology and bacterial genetics to determine the mechanistic basis for these important processes.

The Natural Course of Biopsy-Proven Isolated Microscopic Hematuria: a Single Center Experience of 350 Patients.

The increasing interest in healthcare and health screening events is revealing additional cases of asymptomatic isolated microscopic hematuria (IMH). However, a consensus of the evaluation and explanation of the IMH prognosis is controversial among physicians. Here, we present the natural course of IMH together with the pathological diagnosis and features to provide supportive data when approaching patients with IMH. We retrospectively evaluated 350 patients with IMH who underwent a renal biopsy between 2002 and 2011, and the pathological diagnosis and chronic histopathological features (glomerulosclerosis, interstitial fibrosis, and tubular atrophy) were reviewed. Deterioration of renal function was examined during follow up. The patients with IMH were evaluated for a mean of 86 months. IgA nephropathy was the most common diagnosis in 164 patients (46.9%). Chronic histopathological changes were observed in 166 (47.4%) but was not correlated with proteinuria or a decline in renal function. Ten patients developed proteinuria, and all of them had IgA nephropathy. Three patients progressed to chronic kidney disease with an estimated glomerular filtration rate < 60 mL/min/1.73 m2 but none progressed to end stage renal disease. In conclusion, IMH had a generally benign course during 7-years of observation, although IgA nephropathy should be monitored if it progresses to proteinuria. Future prospective randomized studies may help conclude the long-term prognosis and lead to a consensus for managing IMH.

Clinical Analysis of 10 Years Protocol Biopsy After Kidney Transplantation.

Purpose. The steady advances in immunosuppression have enabled control of early acute rejection, but long-term graft survival remains unchanged. Chronic histopathological changes influence graft survival rate. The aim of this study was to establish the relationship of risk factors interstitial fibrosis and tubular atrophy (IF/TA) on 10 years protocol biopsy.Methods. We assessed the histological findings obtained at 10 years protocol biopsy after living-donor kidney transplantation(KTx) of 62 patients who received kidney allografts between 1986 and 2003. Using the Banff'07 classification, we classified the patients into two groups, Group1 was less than IF/TA GradeI, Group2 was more than IF/TA GradeII. Risk factors for IF/TA were analyzed retrospectively.Results. The mean age of the recipient was 9.96±5.29 years old, 10 patients (16%) had a kidney from ABO incompatible donor. 62 patients were classified Group1 (n=36) and Group2 (n=26), there were no significant difference in original disease, recipient's age and sex, HLA mismatch, the relation of donor to recipient, CNI, CIT (Cold ischemic time) and except donor's age (38.8±6.97 years old (Group1) vs. 42.6±7.29 years old (Group2), p<0.05). But no significant difference, rate of ABO incompatible kidney transplantation (ABO-iKTx) had more Group1 than Group2 (22%(Group1) vs. 7.6%(Group2), NS). There were no significant difference evaluation of acute rejection(AR) within 1 years KTx between both Groups. We observed AR at 1 and 5 years protocol biopsy after KTx, Evaluation of AR were 22% and 8.5% of Group1, 24% and 28% of Group2. The ratio more than IF/TA GradeII were 20% in Group1 and 44% in Group2(p<0.05). eGFR post-transplantation was significantly difference between both groups (58.6±14.1(Group1) vs. 48.9±17.9(Group2)ml/min at 10 years, p<0.05).Conclusion. Chronic histopathological graft injury were established at 5 years KTx. IF/TA Grade of ABO-iKTx tend to be low, we should study that early modification of early immunosuppression may prevent the chronic histopathological graft injury and alter the long-term graft outcome.

Angiogenic effects of borate glass microfibers in a rodent model

The primary objective of this research was to evaluate the use of bioactive borate-based glass microfibers for angiogenesis in soft tissue repair applications. The effect of these fibers on growth of capillaries and small blood vessels was compared to that of 45S5 silica glass microfibers and sham implant controls. Compressed mats of three types of glass microfibers were implanted subcutaneously in rats and tissues surrounding the implant sites histologically evaluated 2-4 weeks post surgery. Bioactive borate glass 13-93B3 supplemented with 0.4 wt % copper promoted extensive angiogenesis as compared to silica glass microfibers and sham control tissues. The angiogenic responses suggest the copper-containing 13-93B3 microfibers may be effective for treating chronic soft tissue wounds. A second objective was to assess the possible systemic cytotoxicity of dissolved borate ions and other materials released from implanted borate glass microfibers. Cytotoxicity was assessed via histological evaluation of kidney tissue collected from animals 4 weeks after subcutaneously implanting high amounts of the borate glass microfibers. The evaluation of the kidney tissue from these animals showed no evidence of chronic histopathological changes in the kidney. The overall results indicate the borate glass microfibers are safe and effective for soft tissue applications.

Interstitial Fibrosis and Tubular Atrophy on Protocol Biopsies at 1 Year After Renal Transplantation

BackgroundAdvancements in immunosuppressive therapy have enabled control of early acute rejection and improved long-term kidney transplantation (KT) survival. Chronic histopathologic changes influence graft survival rate. We examined tubulointerstitial changes at 1 year after KT, focusing on the progression of interstitial fibrosis and/or tubular atrophy (IF/TA). MethodsUsing the Banff' 07 classification, we assessed the histological findings obtained at 1 year after transplantation of 38 patients who underwent the procedure between January 2008, and March 2010. In 24 cases, we obtained scores for interstitial fibrosis (ci) >1 and/or tubular atrophy (ct) > 1. We classified the patients into two groups, namely, less than borderline changes (BCs) (t0, i0, or i1; group A) versus BCs and above (t > 1, i2, or i3; group B). We compared their baseline data, renal function, and pathological scores. ResultsThe mean serum creatinine levels were 1.06 mg/dL for group A and 1.32 mg/dL for group B. The “ct” grading according to the Banff' 07 classification was 0.83 for group A and 1.50 for group B (both P < .05). No significant difference was observed with respect to the percentage of patients with IF/TA (Banff category 5). ConclusionPatients more within 1 year after KT with BCs who show irreversible tubular atrophy by biopsy experience impaired renal function. The presence of BC at the first year may not be associated with IF/TA.

Glycyrrhizin and Long-Term Histopathologic Changes in a Murine Model of Asthma

BackgroundLicorice root has been widely used to treat bronchial asthma for many years. However, the effect of this herb on lung histopathologic features is not fully understood. ObjectiveIn this study, we aimed to determine the effects of oral administration of glycyrrhizin, an active constituent of licorice root, on lung histopathologic features in BALB/c mice, in which the model of chronic asthma was established. MethodsTwenty-eight BALB/c mice were divided into 4 groups: control, placebo, dexamethasone, and glycyrrhizin. Mice in the treatment and placebo groups were sensitized with 2 intraperitoneal injections of ovalbumin and then were exposed to aerosolized ovalbumin for 30 minutes per day on 3 days each week for 8 weeks beginning on the 21st study day. In the last week of inhalational exposure, mice in the placebo group received saline and those in the treatment groups received either dexamethasone, 1 mg/kg, or glycyrrhizin, 10 mg/kg, via orogastric gavage for 7 consecutive days. Animals were humanely killed 24 hours after the last ovalbumin and drug exposure. Lung histopathologic findings were evaluated using light and electron microscopy. ResultsAs evaluated in the control, placebo, dexamethasone, and glycyrrhizin groups, respectively, the mean (SD) basement membrane thickness was 306.34 (36.91), 657.52 (98.99), 405.13 (96.1), and 465.01 (121.48) nm; subepithelial smooth muscle thickness was 7.22 (1.37), 11.24 (1.85), 5.62 (1.15), and 7.76 (1.11) μm; epithelium thickness was 19.48 (1.22), 41.62 (5.49), 22.59 (3.18), and 25.54 (4.68) μm; number of mast cells was 1.34 (0.19), 3.62 (0.5), 2.06 (0.77), and 2.77 (0.23)/16,400 μm2; and number of goblet cells was 0.32 (0.1), 4.92 (0.82), 0.66 (0.06), and 0.98 (0.15)/100 μm. Evaluation of lung histopathologic features demonstrated that the chronic asthma model of mice was successfully established, with significantly higher numbers of goblet and mast cells and increased thickness of epithelium, basement membrane, and subepithelial smooth muscle layers (P < 0.001 for all) in the asthma group compared with in the control group. The number of goblet (P < 0.001) and mast (P < 0.02) cells and the thickness of basement membrane (P < 0.001), subepithelial smooth muscle layers (P ≤ 0.001), and epithelium of the lung (P < 0.001) were found to be significantly lower in the glycyrrhizin group compared with in the placebo group. When the glycyrrhizin and dexamethasone groups were compared, there was no statistically significant difference between the 2 groups in the histopathologic parameters, including thickness of basement membrane (P = 0.514), subepithelial smooth muscle (P = 0.054), and epithelium (P = 1.0) and number of mast (P = 0.075) and goblet (P = 0.988) cells. ConclusionsThe results of this study suggest that the group receiving glycyrrhizin had amelioration of all established chronic histopathologic changes of lung in the mouse model of asthma. Further studies are needed to evaluate the efficacy of glycyrrhizin in the management of asthma.

Acute and Chronic Effects of Epicardial Radiofrequency Applications Delivered on Epicardial Coronary Arteries

Epicardial coronary injury is by far the most feared complication of epicardial ablation. Little information is available regarding the chronic effects of delivering radiofrequency in the vicinity of large coronary vessels, and the long-term impact of this approach for mapping and ablation on epicardial vessel integrity is poorly understood. Therefore, the aim of this study was to characterize the acute and chronic histopathologic changes produced by in vivo epicardial pulses of radiofrequency ablation on coronary artery of porcine hearts. Seven pigs underwent a left thoracotomy. The catheter was sutured adjacent to the left anterior descending artery and left circumflex artery, and 20 pulses of radiofrequency energy were applied. Radiofrequency lesions located no more than 1 mm of the vessel were used for this analysis. Three animals were euthanized 20 days (acute phase) after the procedure and 4 animals after 70 days (chronic phase). The following parameters were obtained in each vessel analyzed: (1) internal and external perimeter; (2) vessel wall thickness; (3) tunica media thickness, and (4) tunica intima thickness. The presence of adipose tissue around the coronary arteries, the distance between the artery and the epicardium, and the anatomic relationship of the artery with the coronary vein was also documented for each section. Sixteen of 20 (80%) sections analyzed, showed intimal thickening with a mean of 0.18 ± 0.14 mm compared with 0.13 ± 0.16 mm in the acute phase (P = 0.331). The mean tunica media thickness was 0.25 ± 0.10 mm in the chronic phase animals compared with 0.18 ± 0.03 mm in the acute phase animals (P = 0.021). A clear protective effect of pericardial fat and coronary veins was also present. A positive correlation between depth of radiofrequency lesion and the degree of vessel injury expressed as intimal and media thickening (P = 0.001) was present. A negative correlation was identified (r = -0.83; P = 0.002) between intimal thickening and distance between epicardium and coronary artery. In this porcine model of in vivo epicardial radiofrequency ablation in proximity to coronary arteries leads to acute and chronic histopathologic changes characterized by tunica intima and media thickening, with replacement of smooth muscle cells with extracellular matrix, but no significant stenosis was observed up to 70 days after the ablation. The absence of acute coronary occlusion or injury does not preclude subsequent significant arterial damage, which frequently occurs when epicardial radiofrequency applications are delivered in close vicinity to the vessels.

Ginseng ameliorates chronic histopathologic changes in a murine model of asthma

Currently, asthma therapies are effective in reducing inflammation but airway remodeling is poorly responsive to these agents. New therapeutic options that have fewer side effects and reverse chronic changes in the lungs are essential. This study aimed to determine the efficacy of oral administration of ginseng on lung histopathology in a murine model of chronic asthma. BALB/c mice were divided into four groups: control, placebo, ginseng, and dexamethasone. All mice except those in the control group were sensitized and challenged with ovalbumin. Then, mice in the ginseng group were given 2 gr/kg per day of ginseng and mice in the dexamethasone group received 1 mg/kg per day of dexamethasone via orogastic gavage once daily for 1 week. Lung histopathology was evaluated by using light and electron microscopy in all groups. All of the chronic changes of airways in the ginseng group were significantly ameliorated when compared with the placebo group. When compared with the dexamethasone group, the ginseng group had significantly lower numbers of mast cell count. Thicknesses of basement membrane, epithelium, and subepithelial smooth muscle were not statistically different between the ginseng and dexamethasone groups. Goblet cell numbers were much more reduced in the dexamethasone group. Ginseng is effective in resolving the established chronic histopathological changes of the lungs in the murine model of asthma.

Preclinical Cardiovascular Risk Assessment in Modern Drug Development

The new guidelines including the ICH S7A and S7B (Anonymous, 2001, 2004) have brought early safety testing of new pharmaceuticals using pharmacological models into the regulatory spotlight in the past few years. Whereas this was motivated to a large extent by a single safety issue (i.e., the proarrhythmic action of drugs that slow myocardial repolarization), the intent was to provide a comprehensive safety assessment based on pharmacodynamic end points, as opposed to histopathological end points used in traditional toxicity studies. These new guidelines were explicitly designed to protect volunteers and patients involved in clinical trials of new drugs from unexpected, life-threatening effects. As such, the emphasis is on acute, functional effects as opposed to chronic histopathological changes. This important distinction was emphasized by Zbinden (1984) some years ago. However, the implications of such testing gowell beyond this primary goal and can impact on the later use of a drug in the general population and the wish to avoid any adverse effects, even if not life threatening. The clinical importance of safety pharmacological studies should be obvious, but there is also a substantial economic consequence should adverse effects be found that limit the utility of a given agent and thereby restrict its market potential or even require it to be removed from the market. Thus, safety pharmacology has found a place in modern drug discovery and development. One should not forget that cardiovascular testing of drug candidates is not a new endeavor. Testing for effects of new agents on arterial blood pressure and heart rate has been conducted routinely for decades, long before the establishment of these new ICH guidelines. The first real attempt to put together a cohesive testing system resulted in the Japanese Guidelines for Nonclinical Studies of Drugs Manual in 1995 (Anonymous, 1995). In this Japanese Guideline, not only there is a requirement for cardiovascular studies but also related effects on the autonomic nervous system and smooth muscle effects are specifically mentioned. Studies on other organ systems were also recommended in the Japanese Guideline making it a very comprehensive package of studies. One might assume that the newer regulatory requirements for safety testing would attempt to further broaden and intensify these

Immunohistochemical Expression of Activated Caspase-3 as a Marker of Apoptosis in Glomeruli of Human Lupus Nephritis

The role of apoptosis in lupus nephritis (LN) is still controversial. One of the key events in the process of apoptosis is activation of caspase-3. Studies of experimental models suggested that activated caspase-3 is a reliable indicator of apoptotic rate, with a favorable comparison against terminal transferase-mediated DNA nick-end labeling (TUNEL) assay. Our aim is to study apoptosis in various forms of LN and its relationship to histomorphological changes and selected laboratory findings by using activated caspase-3 as a novel marker of apoptosis. We investigated glomerular cell apoptosis in 51 biopsy specimens from patients with LN classified according to the International Society of Nephrology/Renal Pathology Society classification by using the TUNEL method and immunohistochemistry against activated caspase-3. In addition, activity and chronicity indices were calculated and anti-Ki-67 antibody was used to estimate proliferative activity. Activated caspase-3-positive cells were present in glomeruli of 88.2% of cases, observed in the glomerular tuft and cellular and fibrocellular crescents. In the glomerular tuft, they were found mainly in segments with active inflammatory lesions. There was good correlation between apoptotic index assessed by using activated caspase-3 immunolabeling and the TUNEL method (r = 0.72; P < 0.01). We observed a significant positive correlation between apoptotic index and LN class (P < 0.001). Apoptotic index correlated significantly with activity index, proliferation index, and daily protein excretion (P < 0.001), but not chronicity index, creatinine concentration, or anti-DNA antibody-binding activity in serum. Apoptotic rate is greater in severe active glomerular lesions in human LN, suggesting that apoptosis may be involved in augmenting inflammation in human LN.

Intranasal and intragastric allergen immunotherapy prevented chronic histopathologic changes in a murine model of asthma

Rationale Mucosal tolerance is suggested to be one of the most promising therapeutic approaches in treatment of asthma. Methods In order to test whether the administration of antigen OVA intranasally (IN) and by intragastric (IG) route before the establishment of chronic asthma model could reverse the characteristic features of lung histopathology, BALB/c mice were divided into 4 groups. Group I received 100 μg ovalbumin (OVA) intranasally on consecutive days 15-20. Group II received 5 mg of ovalbumin (OVA) intragastrically on each alternate days (days 28-31-34). Chronic asthma model was established in groups I, II and III as per protocol. Group IV served as controls. In day 92 lungs were taken out for histopathologic evaluation. Results All of the histopathological parameters in small, medium and large airways were significantly more in group III when compared to controls, indicating that chronic asthma model was successfully established. All of the histopathological parameters evaluated in small, medium and large airways showed significant reduction in Group I when compared to Group III. Furthermore, no significant difference in any of those parameters was detected when compared with control mice. Comparisons of histopathological parameters of mice in Group II were less than that of Group III. There was no significant difference in any of the evaluated airway histopathological parameters evaluated in the comparison of Group I and Group II. Conclusions We concluded that low dose intranasal allergen immunotherapy is a very effective potential strategy for primary prevention of chronic asthma development in mouse model.

Elevated serum C-reactive protein associates with deterioration of renal function in transplant recipients.

Since t he elevated concentration of serum C-reactive protein (CRP) is a sensitive indicator of underlying inflammation, we investigated the association between serum CRP during the initial 6 post-transplantation months and histopathological changes in the 6-month protocol biopsies in 79 patients. We stained the biopsies for CRP and C3 to elucidate a possible role of CRP in renal injuries. Forty patients showed no or minimal (Grade 0-1) tubular atrophy or interstitial fibrosis and 39 patients mild to moderate (Grade > or = 2) chronic histopathological changes. The latter group had had higher concentration of CRP during the first 6 post-transplant months. Because the histopathological changes predict poor long-term prognosis, we followed--from 6th month onwards--40 patients who had no or minimal histopathologic changes, and analyzed the association between CRP elevation and development of chronic allograft dysfunction. During this follow-up period (mean 51, range 14-72 months), 23 of 40 patients retained normal CRP level (Group A, mean CRP 1.12 mg/l), and 17 patients had elevated CRP concentrations (Group B, mean CRP 4.16 mg/l); 24-hour creatinine clearance improved or remained the same in all Group A patients, whereas it decreased in 7 of 17 (41%) of Group B patients (p < 0.001). In Group B patients, the annual change of creatinine clearance correlated inversely with the mean CRP concentration (r = -0.682, p < 0.01). Our results show that histological changes in 6-month biopsies were more prominent in patients with more transplantation-associated complications, infections and frequently higher CRP levels during the initial 6 post-transplant months than in those with lower CRP levels. During post-biopsy follow-up, we found low-grade systemic inflammation--measured as elevated CRP--to associate with impairment of graft function in patients with no or minimal histological findings in 6-month biopsies, and permanently low CRP to rule out chronic allograft dysfunction.

The role of the protocol biopsies in renal allograft recipients

Subclinical rejection and long-term cyclosporine nephrotoxicity are well-known risk factors of chronic allograft nephropathy. In a prospective study 32 low-risk patients were randomized to either a reduced CsA dose (5 mg/kg/d) and daclizumab (group A, n = 16) for 7 months posttransplant with subsequent CsA tapering/withdrawal, or to a normal CsA dose (10 mg/kg/day) without daclizumab (group B, n = 16). Both groups received MMF and prednisone. Protocol biopsies were obtained at engraftment and 3 and 12 months after Tx. The number of rejection episodes was the primary endpoint. The secondary endpoints were: renal function, histological parameters related to CsA, and serum levels of TGF-β and PDGF-BB. A low incidence of clinically suspected rejection episodes was observed (19% in group A and 12.4% in group B; P = NS). Although protocol biopsies showed 12 subclinical rejection episodes (six in group A, six in group B), serum creatinine levels were not different between the examined groups at 3 months. However, at 12 months, there was a statistically improved mean creatinine level in group A patients (1.2 mg/dL ± 0.5 in group A vs 1.54 mg/dL in group B; P < .05). Chronic histopathologic changes were significant for biopsies at 3 and 12 months in both groups compared to the baseline findings for protocol biopsies (with no differences between groups, or between 3 and 12 months in both groups). Serum TGF-β and PDGF-BB did not differ between the groups. Protocol biopsies may be useful to monitor safety and efficiency of new immunosuppressive protocols. Immunosuppressive regimens with low CsA doses followed by the drug's complete withdrawal seem to be efficient and safe in low-risk kidney allograft recipients.

Nonadhesive liquid embolic agent for cerebral arteriovenous malformations: preliminary histopathological studies in swine rete mirabile.

To assess acute and chronic histopathological changes observed in a swine arteriovenous malformation model after endovascular delivery of Embolyx E (Micro Therapeutics Inc., San Clemente, CA) and its organic solvent dimethyl sulfoxide (DMSO). To develop standard endovascular delivery techniques of Embolyx through microcatheters into swine rete mirabile (RMB). Forty RMBs in 22 swine were used to analyze acute and chronic angiographic and histological changes after superselective delivery of Embolyx E and/or its organic solvent (DMSO). Four RMBs (two for DMSO and two for Embolyx E study) were used as control specimens. Angiographic and histological evaluations were obtained 18 days, 1 month, 3 months, and 6 months after the procedure. Particular attention was paid to the presence of focal or diffuse angionecrosis, arterial revascularization, and perivascular inflammatory response. Staged and/or continuous delivery of Embolyx E were performed through the DMSO-compatible microcatheters without untoward catheter "gluing." All subacute/chronic specimens embolized with Embolyx E showed no evidence of angiographic recanalization. Twelve RMBs were used in acute studies, and all specimens showed no evidence of angionecrosis or aggressive inflammatory reaction. Subacute and chronic (total, n = 14) histological examinations of the RMBs showed mild inflammatory response manifested by monocellular infiltration and scattered foreign body giant cell reaction. In the 9 of 14 subacute and chronic specimens, focal disruption of elastica was observed along with embolic materials. Fourteen RMBs in eight swine were used to determine the safety range for DMSO injection. Two RMBs were used as control specimens. Rapid intra-arterial delivery (0.5 ml/5-15 s, n = 6) of DMSO caused angiographic vasospasm and histological endothelial necrosis. Slow injection (0.5 ml/30-120 s, n = 8) of DMSO showed minimum or no angiographic vasospasm, minimal adventitial inflammatory response, and no clinical complications. Embolyx E, an occlusive and nonadhesive embolic agent, is capable of producing permanent occlusion of swine RMB with the development of mild intra- and perivascular inflammatory changes and no clinical complications. The slow endovascular delivery of DMSO produces no untoward angiographic, pathological, or clinical changes. A fast injection of DMSO causes endothelial necrosis and severe inflammatory response in the arterial wall. This embolic material seems to have appropriate biochemical, anatomic, and histopathological characteristics to be used in the treatment of cerebral arteriovenous malformations or vascular cranial base tumors.

Sequential analysis of subacute and chronic neuronal, astrocytic and microglial alterations after transient global ischemia in rats.

Recent experimental investigations have emphasized the importance of assessing both acute and chronic histopathological changes occurring after cerebral ischemia. The purpose of this study was to evaluate the temporal profile of neuronal, astrocytic and microglial alterations within vulnerable regions (striatum and CA1 sector of hippocampus) following transient global ischemia. Anesthetized Wistar rats underwent 10 min of normothermic (37 degrees C) ischemia induced by bilateral carotid ligations plus hypotension (45-50 mm Hg) and were allowed to survive for periods ranging from 1 to 10 weeks (n=4-6/group) prior to quantitative histopathological analysis. Adjacent sections were examined by hematoxylin-and-eosin histopathology, immunostaining for glial fibrillary acidic protein, and B4-isolectin immunochemistry for microglia. In the striatum, normal-neuron counts were first decreased significantly at 2 weeks after the ischemic insult. Neuronal loss was associated with the proliferation of reactive microglia, which peaked at 1 week. By contrast, reactive astrocytosis displayed a more protracted pattern, with peak activation at 2 weeks. In the CA1 hippocampus, a decreased number of normal neurons was seen at 1 week post ischemia, together with a significant increase in immunoreactive microglia at that time; the latter normalized after 2 weeks. Reactive astrocytes in the CA1 hippocampus were significantly increased at 1-2 weeks after ischemia. In a subgroup of severely injured animals, foci of frank striatal infarction were associated with early and severe microglial and astrocytic proliferation at week 4 or later. Finally, cerebrovascular changes included endothelial disruption within affected areas. These observations document a subacute and chronic sequence of cellular responses following brief periods of global ischemia, involving both neurons, glia and vascular endothelium.