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Background: Periodontitis is the sixth most prevalent chronic disease. Literature suggests a relationship between diabetes and periodontitis and when coexist may aggravate each other deleterious consequences. Therefore, we aimed to assess the effects of periodontitis treatment on glycemic control., Materials and Methods: A systematic literature search was conducted in PubMed, Cochrane Library, and the first 100 articles in Google Scholar from January 2011 to October 2021. The terms periodontitis, periodontal treatment, diabetes mellitus, nonsurgical treatment, glycated hemoglobin (HbA1c) were used, with the Protean "AND" and "OR." The titles, abstracts, and references of the included studies were screened. Any discrepancy was solved by an agreement between researchers. Out of 1059 studies retrieved, 320 stands after the removal of duplication, from them, 31 full texts were screened and only 11 studies were included in the final meta-analysis., Results: In the present meta-analysis, 11 studies (1469 patients included) were pooled, and the overall effect showed that periodontitis treatment improved the HbA1c, odd ratio, -0.024, 95% confidence interval, -0.42-.06, P value, 0.009, Chi-square, 52.99. However, substantial heterogeneity was observed, P value, < 0.001, I 2 for heterogeneity 81%., Conclusion: Periodontitis treatment improved the HbA1c among patients with diabetes and poor glycemic control. Screening of this common disease is important in diabetes holistic care., Competing Interests: None

Objective: The aim of the study is to investigate improvements in lower urinary tract symptoms in men with benign prostatic hyperplasia (BPH) treated with prostatic Aquablation., Materials and Methods: We performed a literature search of clinical trials using the MEDLINE, Embase, and Cochrane Library databases and retrieved published works on Aquablation for the treatment of BPH up to August 2021. Unpublished works, case reports, conference proceedings, editorial comments, and letters were excluded. Risk of bias was assessed using the ROBINS-I tool. Raw means and mean differences were meta-analyzed to produce summary estimates for pre- versus post-International Prostate Symptom Scores, maximum flow rate, and male sexual health questionnaire value changes. An inverse-variance weighted random effects model was used., Results: Seven studies were included in this review (n = 551 patients) that evaluated various urological parameters. At 3 months, the International Prostate Symptom Scores raw mean difference from baseline was -16.475 (95% confidence interval [CI], -15.264 to -17.686; p < 0.001), with improvements sustained for 12 months. Similarly, maximum flow rate improved by +1.96 (95% CI, 10.015 to 11.878; p < 0.001) from pre to 3 months postoperatively. In addition, the male sexual health questionnaire change pooled effect size was -0.55 (95% CI, -1.621 to 0.531; p = 0.321) from preintervention to postintervention at 3 months. Meta-analyses of some outcomes showed large statistical heterogeneity or evidence of publication bias., Conclusions: Aquablation seems to improve lower urinary tract symptoms in men with BPH while providing relatively preserved sexual function. Further research is required to confirm these preliminary results., Competing Interests: The article was created without consultation or input from PROCEPT BioRobotics, Inc. AA is an editorial board member of Current Urology., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc.)

The fungal toxin aflatoxin B1 (AB1) and its reactive intermediate, aflatoxin B1-8, 9 epoxide, could cause liver cancer by inducing DNA adducts. AB1 exposure can induce changes in the expression of several cancer-related genes. In this study, the effect of AB1 exposure on breast cancer MCF7 and normal breast MCF10A cell lines at the phenotypic and epigenetic levels was investigated to evaluate its potential in increasing the risk of breast cancer development. We hypothesized that, even at low concentrations, AB1 can cause changes in the expression of important genes involved in four pathways, i.e., p53, cancer, cell cycle, and apoptosis. The transcriptomic levels of BRCA1 , BRCA2 , p53 , HER1 , HER2 , cMyc , BCL2 , MCL1 , CCND1 , WNT3A , MAPK1 , MAPK3 , DAPK1 , Casp8 , and Casp9 were determined in MCF7 and MCF10A cells. Our results illustrate that treating both cells with AB1 induced cytotoxicity and apoptosis with reduction in cell viability in a concentration-dependent manner. Additionally, AB1 reduced reactive oxygen species levels. Phenotypically, AB1 caused cell-cycle arrest at G1, hypertrophy, and increased cell migration rates. There were changes in the expression levels of several tumor-related genes, which are known to contribute to activating cancer pathways. The effects of AB1 on the phenotype and epigenetics of both MCF7 and MCF10A cells associated with cancer development observed in this study suggest that AB1 is a potential risk factor for developing breast cancer.

Purpose of Review: To provide an overview of diagnosis, genetic abnormalities, clinical signs and treatment options for the major heritable renal cell carcinoma (RCC) syndromes., Recent Findings: RCC in major hereditary syndromes are disorders which are typically autosomal dominant. They predispose patients to early onset of RCC and may exhibit other extrarenal manifestations. Early recognition of these diseases allows correct screening at appropriate ages as well as early detection of RCC. Moreover, expedient identification may optimize the management of extra renal manifestations as well as allow for genetic testing and screening of at-risk relatives., Summary: The risk of RCC in these major heritable syndromes is higher than sporadic disease. They occur at earlier age groups and can be multifocal or bilateral. Tumours are observed until at least 3 cm before any intervention, while nephron sparing surgery is widely considered as the treatment of choice except for hereditary leiomyomatosis with renal cell cancer, of which radical nephrectomy is treatment of choice. Intervention should be timeous as there is a highly reported incidence of early metastasis. Molecular therapies have been used in the setting of patients with metastasis, some of which show favourable outcomes., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Algerian universities rely on total quality management. TQM is one of the most successful strategic options for improving the quality of higher education. In addition, achieving academic accreditation and progress in international rankings. The study aims to address relevant contemporary issues by examining the impact of total quality management on the quality of higher education. The data were analyzed using a mixed-method approach; the study was done as a survey, with data collected via questionnaires issued to 610 students. The questionnaire included Likert scale items that were quantitatively evaluated and modeled using structural equation modeling (SEM) using Amos to accomplish the path analysis of the research model. Furthermore, qualitative data were acquired through interviews with 24 professors who are members of the Quality Cells, and qualitative data were evaluated using content analysis with NVivo. The study findings revealed that TQM has a direct and significant impact on the quality of graduates, scientific research, and community service in Algerian universities. The main results have been presented, and recommendations for future research are made., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yahiaoui, Chergui, Aissaoui, Brika, Lamari, Musa and Almezher.)

e-Learning is a key strategy in the course of higher education to improve the results of the educational process and stimulate student motivation. The COVID-19 pandemic imposed on Algerian universities to adopt e-Learning systems to search for effectiveness and efficiency of academic approaches. This paper seeks to remedy these problems by analyzing the impact of e-Learning systems on student motivation and outcomes. A mixed-method approach was used in the data analysis. We conducted the study as a survey, with data being gathered via questionnaires distributed to 398 students. The questionnaire includes open questions that were qualitatively analyzed using content analysis with Nvivo, besides Likert scale questions were quantitatively analyzed and modeled using Structural equation modeling (SEM) with Amos to accomplish the path analysis of the research model. The results of the study showed that student motivation (Attention, Relevance, Confidence, and Satisfaction) and student outcomes (knowledge, skills, and attitudes) are significantly affected by e-Learning systems (Technical and electronic requirements, personal requirements, perceived value, and credibility of e-Learning). The key findings are discussed, and they provide recommendations for future research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yahiaoui, Aichouche, Chergui, Brika, Almezher, Musa and Lamari.)

Background: Coronavirus disease 2019 (COVID-19) has an established impact on multiple organ systems, including the vascular and urogenital systems. Vascular effects may include venous thromboembolic disease, which could theoretically be a precursor to priapism-a urological emergency defined as an abnormal condition of prolonged penile erection lasting >4 hours. To better explore this association, we critically appraised all the published COVID-19 cases associated with priapism., Materials and Methods: After PROSPERO registration ( CRD42021245257), a systematic search of Google Scholar, Scopus, Embase, Web of Science, PubMed, Cumulative Index to Nursing and Allied Health Literature, Global Index Medicus, and Cochrane Database of Systematic Reviews was performed using specific search terms. The following study metadata were extracted: age, requirement for respiratory support, cavernous blood gas findings, management of priapism, and patient outcomes., Results: Fifteen single-patient case reports were included in this review. Of these, all of the patients presented with ischemic priapism, 9 patients (60.0%) were >60 years of age, 4 (26.7%) reported more than a single episode of priapism, 11 (73.3%) presented with pneumonia, 8 (53.3%) required mechanical ventilation, D-dimer was elevated in 5 of the 6 (83.3%) patients in whom this was reported, and among the 13 patients in whom mortality was reported, 4 (30.8%) died., Conclusions: Early reports suggest a prognostic relationship between COVID-19 and coexisting priapism. However, owing to commonalities in their pathophysiology and the small dataset reported in the literature, the probable association between COVID-19 and priapism is still theoretical. Further research is needed to confirm this association., Competing Interests: AA is an Editorial Board member of Current Urology., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc.)

This paper provides a broad bibliometric overview of the important conceptual advances that have been published during COVID-19 within "e-learning in higher education." E-learning as a concept has been widely used in the academic and professional communities and has been approved as an educational approach during COVID-19. This article starts with a literature review of e-learning. Diverse subjects have appeared on the topic of e-learning, which is indicative of the dynamic and multidisciplinary nature of the field. These include analyses of the most influential authors, of models and networks for bibliometric analysis, and progress towards the current research within the most critical areas. A bibliometric review analyzes data of 602 studies published (2020-2021) in the Web of Science (WoS) database to fully understand this field. The data were examined using VOSviewer, CiteSpace, and KnowledgeMatrix Plus to extract networks and bibliometric indicators about keywords, authors, organizations, and countries. The study concluded with several results within higher education. Many converging words or sub-fields of e-learning in higher education included distance learning, distance learning, interactive learning, online learning, virtual learning, computer-based learning, digital learning, and blended learning (hybrid learning). This research is mainly focused on pedagogical techniques, particularly e-learning and collaborative learning, but these are not the only trends developing in this area. The sub-fields of artificial intelligence, machine learning, and deep learning constitute new research directions for e-learning in light of COVID-19 and are suggestive of new approaches for further analysis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Brika, Chergui, Algamdi, Musa and Zouaghi.)

Enzymes have evolved to catalyze their precise reactions at the necessary rates, locations, and time to facilitate our development, to respond to a variety of insults and challenges, and to maintain a healthy, balanced state. Enzymes achieve this extraordinary feat through their unique kinetic parameters, myriad regulatory strategies, and their sensitivity to their surroundings, including substrate concentration and pH. The Cancer Genome Atlas (TCGA) highlights the extraordinary number of ways in which the finely tuned activities of enzymes can be disrupted, contributing to cancer development and progression often due to somatic and/or inherited genetic alterations. Rather than being limited to the domain of enzymologists, kinetic constants such as kcat, Km, and kcat/Km are highly informative parameters that can impact a cancer patient in tangible ways-these parameters can be used to sort tumor driver mutations from passenger mutations, to establish the pathways that cancer cells rely on to drive patients' tumors, to evaluate the selectivity and efficacy of anti-cancer drugs, to identify mechanisms of resistance to treatment, and more. In this review, we will discuss how changes in enzyme activity, primarily through somatic mutation, can lead to altered kinetic parameters, new activities, or changes in conformation and oligomerization. We will also address how changes in the tumor microenvironment can affect enzymatic activity, and briefly describe how enzymology, when combined with additional powerful tools, and can provide us with tremendous insight into the chemical and molecular mechanisms of cancer., (© 2022 The Author(s).)

Background Uretero-pelvic junction obstruction (UPJO) is a common cause of upper tract urinary obstruction. This condition is generally treated with various surgical options which include endoscopic (retrograde or anterograde), laparoscopic, open or robotic-assisted approaches. Herein, we describe a novel endoscopic retropelvic extra-luminal approach using a mini (14 Fr) nephroscope. Methods A 30-year-old male presented with symptomatic left UPJO and inferior pole renal stones, which were identified on computed tomography (CT) imaging. Mercaptuacetyltriglycine (MAG3) renogram demonstrated a functioning left kidney. With the patient positioned supine, a mini-perc (Karl-Storz) nephroscope was used to access the renal pelvis via the percutaneous route. The retropelvic space was thereafter accessed. Using a Holmium-YAG laser, the UPJO was splayed using an extra-luminal approach. Results Clear endoscopic vision, minimal bleeding, and overall satisfactory identification of the UPJO were achieved. At the 12-month follow-up, the patient remained stent and symptom-free. On follow-up CT imaging and MAG3 renogram, the system remained dilated with no obstruction noted. Conclusion Percutaneous anterograde retropelvic extra-luminal endopyelotomy is a novel approach that should be considered in patients with secondary renal calculi. This is the first report of the procedure being successfully performed utilizing the mini-perc access route., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Alhlib et al.)

Background The intensive care unit (ICU) generates more medication prescriptions per patient day than any other unit in the hospital. The dynamics of the ICU environment, coupled with the complexity of patient pathology, increases the risk of medication errors. This study aimed to evaluate the incidence and spectrum of medication errors in an adult general ICU in Johannesburg, South Africa. Methods A retrospective chart review was conducted at a 19-bed ICU in a tertiary-level hospital in Johannesburg. Data were independently collected by two of the study investigators. The doctors' prescription and the nurses' administration section of patient bedside charts were scrutinized for drug prescription and administration errors. Results Of the 656 patient days studied, 3237 drugs (5.6 drugs per patient day) were prescribed. There were a total of 359 medication errors, comprising 237 (66.0%) prescription and 122 (34.0%) administration errors. The total error rate per 1000 patient days was 621.1, while the total error rate per 1000 drug prescriptions was 110.9. The most common errors were incorrect dose prescribed (n=69, 19.2%), incorrect dosing interval prescribed (n=48, 13.4%), incorrect dose administered (n=42, 11.7%) and failure to administer the prescribed drug (n=38, 10.6%). Conclusion The overall occurrence of medication errors is high but is in keeping with general international trends. Targeted interventions should be implemented to minimize the frequency of medication errors in the ICU and consequent risk to patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Laher et al.)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Candida albicans has been reported globally as the most widespread pathogenic species contributing candidiasis from superficial to systemic infections in immunocompromised individuals. Their metabolic adaptation depends on glyoxylate cycle to survive in nutrient-limited host. The long term usage of fungistatic drugs and the lack of cidal drugs frequently result in strains that could resist commonly used antifungals and display multidrug resistance (MDR). In search of potential therapeutic intervention and novel fungicidals, we have explored a plant alkaloids, namely arborinine and graveoline for its antifungal potential. Alkaloids belongs to Rutaceae family have been reported with numerous antimicrobial activities. In this study, we aimed to isolate and identify the antifungal active alkaloids of R. angustifolia and assess antifungal effect targeting C. albicans isocitrate lyase (ICL) gene which regulates isocitrate lyase, key enzyme in glyoxylate cycle contributing to the virulence potential of C. albicans. Alkaloids were extracted by bioassay guided isolation technique which further identified by TLC profile and compared with the standard through HPLC and NMR analysis. The antifungal activities of the extracted alkaloids were quantified by means of MIC (Minimum Inhibitory Concentration). The gene expression of the targeted gene upon treatment was analysed using RT-qPCR and western blot. Additionally, this study looked at the drug-likeness and potential toxicity effect of the active alkaloid compounds in silico analysis. Spectroscopic analysis showed that the isolated active alkaloids were characterized as acridone, furoquinoline, 4-quinolone known as arborinine and graveoline. Results showed that each compound significantly inhibited the growth of C. albicans at the dose of 250 to 500 µg/mL which confirm its antifungal activity. Each alkaloid was found to successfully downregulate the expression of both ICL1 gene CaIcl1 protein. Finally, ADMET analysis suggests a good prediction of chemical properties, namely absorption, distribution, metabolism, excretion and toxicity (ADMET) that will contribute in drug discovery and development later on.

Background: The role of the voiding cystourethrogram (VCUG) in the follow-up of children with posterior urethral valves (PUVs) post-ablation has been considered a standard practice. The urethral ratio and gradient of change have proven to be useful., Objectives: We aimed to review the role of the 'ideal' ratio on predicting residual PUV post-ablation., Methods: A systematic review of the PubMed, SCOPUS and Web of Science databases was performed (April 2019). The search terms included 'Urethral Ratio and Posterior urethral valve ablation'. All cited reference lists were further evaluated for additional inclusive studies., Results: Eleven studies were identified, of which nine were relevant to the topic. Case reports, comments and adult and animal studies were excluded, leaving four studies for critical review. In total, 338 patients were assessed. The control group consisted of 167 age-matched, male children. Study regions included India and Australia. The ages ranged from 15 days to 3.4 years. Ablation methods included the use of a resectoscope with cutting diathermy, cold knife or Bugbee electrode. The mean urethral ratios in the control group ranged from 1.04 to 1.73. The suggested predictive urethral cut-off ratios recommended include 2.2 ( p = 0.001), 2.5-3 and 3.5., Conclusion: Although the precise cut-off ratio could not be clearly defined in this review, a urethral ratio less than a range of 2.2-3.5 has proven to be a beneficial predictor of ablation success and should thus be incorporated into standard VCUG reporting templates in the follow-up of PUVs in male children in resource-limited settings., Competing Interests: The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article., (© 2020. The Authors.)

Background: There is an increasing awareness of the perceived stress and approach to learning effects on academic achievement., Objective: This study aimed to assess the educational environment and approach to learning in clinical phase medical students., Methods: This comparative cross-sectional study was conducted among fifty-nine clinical stage medical students at Omdurman Islamic University (Khartoum, Sudan) during the period from June to August 2016. All the participants signed a written informed consent, then responded to a structured questionnaire to collect demographic data, the two process study questionnaires and the perceived stress questionnaire. The ethical committee of Omdurman Islamic University approved the research, and the Statistical Package for Social Sciences was used to compare the students based on sex, class, and their grades. Data were analyzed by SPSS version 22, using descriptive statistics and t-test., Results: There were fifty-nine medical students, of whom 41.5% were males with a mean age of 22.62±1.84 years. Stress was evident in the majority of medical students (88.1%). The students are using the deep approach to learning more than the superficial approach (The total score was 29.49±6.39 for the deep approach, while it was 20.81±6.94 for the superficial approach). In the current study, no differences were found regarding sex, class, or grades apart from the superficial approach which was used less among women., Conclusion: The perceived stress was prevalent among medical students in Omdurman Islamic University, Sudan, the students used the deep approach to learning more than the superficial, no differences were evident in the perceived stress and the learning approach in relation to sex, class level or grades apart from less superficial approach among women., Competing Interests: Conflict of Interest: There is no conflict of interest to be declared.

Systemic Lupus Erythrematosus (SLE) is an inflammatory autoimmune disorder that may affect multiple organ systems. The clinical course is marked by spontaneous remission and relapses. Severity may vary from mild episodic disorder to a rapidly fulminant life threatening illness. Clinical manifestations of Lupus Nephritis (LN) are varied according to the renal pathologic lesions. Treatment of LN remains controversial. As a chronic disease with periods of remission and relapses, it is unclear whether relapses should be treated as the initial presentation of the disease. This prospective study was designed to compare between three different modalities of therapy for treating LN patients. The study includes all systemic lupus patients seen in Alexandria University Hospital since January 2004 for 6 months. Forty-three patients with SLE were presented to us by SLE, only 31 had LN and 22 were included in the study. The patients were classified randomly into 3 arms. All patients received steroid therapy plus from the beginning either Cyclophosphamide (CYP) [Group I, n=7], or Cyclosporine (CsA) [Group II, n=7], or Azathioprine (AZA) [Group III, n=8], Full history and examination were done. Laboratory investigations included routine and immunological studies of ANA, Anti-DNA, C3 and C4. Renal biopsy was done in all patients. After 6 months of follow up; Serum creatinine was stationary in CYP group from 2.2 +/- 1.1 to 2.1 +/- 1.7; while significantly decreased in CsA from 2.8+1.7 to 1.0 +/- 0.5 mg/dl. Moreover; while proteinuria decreased in CYP from 2.7 +/- 0.7 to 1.8 +/- 2.2; there was more pronounced decreased from 6.9 +/- 10.0 to 2.4 +/- 1.2 g/24 hr in CsA group despite very huge increase in glomerular filtration rate (GFR). 2 out 7 cases of CsA group; while 2 of 6 of CYP group did not show improvement. Moreover; 3 of 6 of CYP group and 1 of 6 of AZA group needed to be shifted to CsA group because of side effects and/or no response to CYP and showed good response. These patients were either class V or IV. However; only one case in this study with signs of acute CsA toxicity was reversed by monitoring the dose. In conclusion, CsA in this study proved to be superior over CYP in LN at least in the short term follow up; provided to be given with appropriate doses even if it is used in class IV, which was thought to be very responsive to CYP.

Effects of oxygen (O2) tension in the gas atmosphere during in vitro maturation (IVM), in vitro fertilization (IVF) and in vitro culture (IVC) on the efficiency of in vitro production of mouse embryos were examined. Mouse oocytes recovered from large antral follicles were subjected to IVM in Waymouth medium for 15, 16 and 17 hr under 5 or 20% O2 and then subjected to IVF and IVC under 5 or 20% O2 tension. Lowering the O2 tension in the gas atmosphere for IVM from 20 to 5% improved the cleavage rate after IVF when the oocytes were subjected to IVM for 15 hr; however, no improvement in the cleavage rate was observed when the culture period for IVM was extended to 16 and 17 hr. Lowering the O2 tension to 5% for IVM and IVC improved the development of the cleaved oocytes to the blastocyst stage, regardless of the culture period for IVM. However, the O2 tension for IVF had no remarkable effect on the subsequent embryonic development. These results demonstrate that 5% O2 is superior to 20% O2 for IVM and IVC, and suggest that 20% O2 for IVM may delay oocyte maturation and/or the acquisition of fertilizability and impair the developmental competence of oocytes.

The balance between endothelial nitric oxide (NO) and angiotensin II (Ang II) maintains the homeostasis of the cardiovascular and renal systems. We tested the hypothesis that increased oxidant stress linked to a functional imbalance between NO and Ang II might play a central pathogenetic role in salt-sensitive (SS) hypertension. We studied Dahl SS (DS) rats during the prehypertensive (5 days) and hypertensive (12 weeks) phases of a high-salt (4% NaCl) diet. Control rats received a normal-salt (0.5% NaCl, [NS]) diet. Prehypertensive DS rats (systolic blood pressure [SBP] 138+/-2 mm Hg) manifested a 35% increase (P<0.05) in aortic superoxide (O2-) production without evidence of end-organ damage. Hypertensive DS rats (SBP 214+/-11 mm Hg) had impaired endothelium-dependent relaxation (EDR) and increased aortic O2- production (320%), urinary isoprostane excretion (83%), aortic (20%) and left ventricular (LVH, 21%) hypertrophy, and proteinuria (124%). In prehypertensive DS rats, candesartan (10 mg x kg(-1) x d(-1)) an Ang II type 1 receptor blocker (ARB), normalized O2- production. In hypertensive DS rats, the ARB decreased aortic O2- production by 71% and normalized EDR without affecting SBP (212+/-8 mm Hg), aortic hypertrophy, LVH, or proteinuria. Switching hypertensive DS rats to an NS diet did not affect SBP (208+/-8 mm Hg), LVH, aortic hypertrophy, or proteinuria and had minimal effects on O2- and EDR. Concomitant ARB administration plus a switch to an NS diet normalized SBP (138+/-8 mm Hg) as well as end-organ damage. Dahl salt-resistant rats fed an HS diet for 12 weeks did not show hypertension or increased O2- production. Thus, SS hypertension might represent a specific vascular diathesis linked to functional upregulation of Ang II action (increased O2- synthesis) accompanied by insufficient NO bioavailability, which promotes severe endothelial dysfunction.

Experimental renal scarring indicates that tissue transglutaminase (tTg) may be associated with the accumulation of extracellular matrix (ECM), both indirectly via TGF-beta1 activation and directly by the formation of epsilon(gamma-glutamyl) lysine dipeptide bonds within the ECM. The latter potentially accelerates deposition and confers the ECM with resistance to proteolytic digestion. Studied were 136 human renal biopsy samples from a range of chronic renal diseases (CRD) to determine changes in tTg and epsilon(gamma-glutamyl) lysine crosslinking. Immunofluorescence for insoluble tTg showed a 14-fold increase in the kidneys of CRD patients (5.3 +/- 0.5 versus 76 +/- 54 mV/cm(2)), which was shown to be active by a similar 11-fold increase in the epsilon(gamma-glutamyl) lysine crosslink (1.8 +/- 0.2 versus 19.3 +/- 14.2 mV/cm(2)). Correlations were obtained with renal function for tTg and crosslink. In situ hybridization for tTg mRNA showed that tubular epithelial cells were the major source of tTg; however, both mesangial and interstitial cells also contributed to elevated levels in CRD. This mRNA pattern was consistent with immunohistochemistry for soluble tTg. Changes in renal tTg and its product, the epsilon(gamma-glutamyl) lysine crosslink, occur in progressive renal scarring in humans independently of the original etiology and in a similar manner to experimental models. tTg may therefore play a role in the pathogenesis of renal scarring and fibrosis in patients with CRD and can therefore be considered a potential therapeutic target.

Background: Progression of renal diseases is related to the abnormal regulation of cellular and extracellular matrix turnover. Other factors in addition to schistosomal antigens may be relevant to the progression of schistosomal nephropathy (SN). The validity of markers of fibroblastic differentiation, alpha smooth muscle actin (alphaSMA), and vimentin, as well as the regenerative activity (PCNA/apoptosis index) in determination of progression of SN in comparison to other forms of non-schistosomal nephropathy (non-SN) is investigated., Methods: Three groups were included; group I pure SN (n=16), group II a diverse group of non-schistosomal patients with comparable pathologic changes on renal biopsy (n=40) and a control group (n=5). Immunohistochemical staining of myofibroblasts (alphaSMA and vimentin) and proliferating cells (PCNA) and histomorphometric analysis was done. In situ end labelling (ISEL) of DNA was used to evaluate apoptosis., Results: No differences in the patterns of distribution of positivity of the different studied markers were observed between the different nephropathy groups. Both alphaSMA and vimentin were detected in glomerular mesangial, tubular epithelial, interstitial inflammatory fibroblast-like cells and occasionally endothelial cells. PCNA and apoptotic cells were detected in tubular epithelial and interstitial cells with paucity of positive cells in the glomerulus. Significant positive correlations were detected in group I between glomerular sclerosis and interstitial markers including interstitial alphaSMA (r=0.609, P=0.001), interstitial vimentin (r=0.812, P=0.00) and interstitial apoptosis (r=0.733, P=0.001). On the other hand, glomerulosclerosis in group II showed significant positive correlations with predominantly the glomerular markers; glomerular alphaSMA (r=0.475, P=0.002), glomerular apoptosis (r=0.684, P=0.00) and glomerular PCNA (r=0.691, P=0.00). Interstitial fibrosis correlated significantly with interstitial markers in group I including interstitial alphaSMA (r=0.837, P=0.00) interstitial vimentin (r=0.929, P=0.00), interstitial apoptosis (r=0.807, P=0.00) and interstitial PCNA (r=0.617, P=0.01), while in group II it correlated with both interstitial and glomerular markers. In addition, the tubulo-interstitial ratio was significantly higher in group I in comparison with group II (P=0.024), with no difference between groups II and III., Conclusions: Although SN may start as glomerulopathy associated with increased mesangial cellularity, the interstitial rather than the glomerular markers of myofibroblastic differentiation and those of cell turnover are playing a crucial role in late stages of schistosomal, but not in non-schistosomal nephropathies.