RESUMO
Background and Objectives: It is well known that alterations in microvascular structure and function contribute to the development of ocular, renal, and cardiovascular diseases. Accordingly, the presence of fundus vascular changes in patients suffering from chronic kidney disease (CKD) and Balkan endemic nephropathy (BEN) may provide information of prognostic value regarding the progression of renal disease. This study aimed to examine the associations between clinical characteristics and retinal optical coherence tomography angiography (OCTA) parameters in patients with BEN and compare them with those in CKD. Materials and Methods: This pilot study, conducted from March 2021 to April 2022, included 63 patients who were divided into two groups: the first group consisted of 29 patients suffering from BEN, and the second was a control group of 34 patients with CKD. Demographic, laboratory, clinical, and medication data were noted for all the patients included in this study. Each eye underwent OCT angiography, and the results were interpreted in accordance with the practical guide for the interpretation of OCTA findings. Results: Statistically significantly higher levels of total serum protein and triglycerides were recorded in the BEN group than in the CKD group, while the level of HDL cholesterol was lower. Based on the performed urinalysis, statistically significantly higher values of total protein and creatinine were detected in patients with CKD compared to the BEN group. It was demonstrated that the OCTA vascular plexus density of certain parts of the retina was in significant association with systolic and diastolic blood pressure, creatinine clearance, urinary creatinine, total cholesterol, diabetes mellitus type 2, age, body mass index, total serum and urinary protein, sCRP, and diuretic and antihypertensive treatment. Conclusions: In comparison with CKD, BEN leads to more significant disturbances in retinal vasculature density.
Assuntos
Nefropatia dos Bálcãs , Insuficiência Renal Crônica , Doenças Vasculares , Humanos , Nefropatia dos Bálcãs/complicações , Projetos Piloto , Tomografia de Coerência Óptica/métodos , Creatinina , Retina , Insuficiência Renal Crônica/complicações , AngiografiaRESUMO
BACKGROUND: Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial kidney disease occurring in people living in along the tributaries of the Danube River. The aim of the study was to determine serum level and urinary excretion of placental growth factor (PlGF) and placental protein 13 (PP13) in patients with BEN. METHODS: Thirty patients with BEN from the South Morava River region of Serbia and 18 controls were studied. Age of patients was 74 yr (53-87) and 73 yr (66-83) in controls. RESULTS: In patients with BEN, serum creatinine was significantly higher than in controls (129.7 vs. 83.2 µmol/L, respectively), but GFR was lower in patients than in controls (40.7 vs. 54.6 mL/min). Serum PlGF was significantly higher in BEN patients than in controls (9.90 vs. 6.80 pg/mL), urinary excretion being significantly lower in patients (0.20 vs. 0.90 pg/mmol creat.). Serum PP13 was significantly lower in BEN patients (208.2 vs. 291.0 pg/mL). Urinary excretion of PP13 was also significantly lower in BEN patients than in controls (32.5 vs. 182.5 pg/mmol creat). In multivariate regression analysis BEN, sex and age were significant determinants of the observed changes in PlGF and PP13. CONCLUSION: Important changes of PlGF and PP13 in patients with BEN were demonstrated, where kidney disease, female sex, and the age have been significant determinants.
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Nefropatia dos Bálcãs/sangue , Creatinina/sangue , Galectinas/sangue , Rim/fisiopatologia , Proteínas da Gravidez/sangue , Idoso , Idoso de 80 Anos ou mais , Nefropatia dos Bálcãs/epidemiologia , Biomarcadores , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fator de Crescimento Placentário , Análise de Regressão , SérviaRESUMO
UNLABELLED: Abstract Background: Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial nephropathy present in the Danube river regions in several Balkan countries. There appears to be a polygenic susceptibility to the disease in interaction with multiple environmental factors (aristolochic acid, ochratoxin A). In a previous study SEC61G, IL17RA, HDAC11 proved to be differently methylated throughout all patient-control pairs of BEN patients from Serbia and Bulgaria. Emerging connections between DNA methylation and histone acetylation prompted the present study on histone acetylation in patients with BEN. METHODS: The study involved 39 patients with BEN, and 39 controls collected from non-endemic regions in Serbia. The EpiSeeker Histone H3 and H4 Total Acetylation Detection colorimetric Kits and specific acetylated at lysine 18 H3K18 and H3K36 acetylated at lysine 36 detection kits were used. RESULTS: It was documented that total H4 histone acetylation level was increased significantly, while total H3 histone acetylation did not differ significantly. Specific histone structure and functional properties may be affected by the observed derangement of H3 histone acetylation pattern, since H3K36 site was significantly more acetylated, while H3K18 tended to be less acetylated than in control subjects. Multiple regression analysis revealed a statistically significant relationship between H4, H3T and H3K36 in BEN patients. CONCLUSION: This preliminary study suggests that the acetylation of histone lysine residues was detectable and found increased at specific sites of H3 and total H4 histones isolated from urothelial cells of patients with BEN. Having in mind a possible mechanism and biological role of epigenetic chromatin modification in urothelial tumor development they obtained results may open opportunity for selective therapeutic interventions in patients with BEN.
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Nefropatia dos Bálcãs/metabolismo , Histona Acetiltransferases/metabolismo , Histonas/metabolismo , Urotélio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Lisina/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Balkan endemic nephropathy (BEN) represents a chronic progressive interstitial nephritis in striking correlation with uroepithelial tumours of the upper urinary tract. The disease has endemic distribution in the Danube river regions in several Balkan countries.DNA methylation is a primary epigenetic modification that is involved in major processes such as cancer, genomic imprinting, gene silencing, etc. The significance of CpG island methylation status in normal development, cell differentiation and gene expression is widely recognized, although still stays poorly understood. METHODS: We performed whole genome DNA methylation array analysis on DNA pool samples from peripheral blood from 159 affected individuals and 170 healthy individuals. This technique allowed us to determine the methylation status of 27 627 CpG islands throughout the whole genome in healthy controls and BEN patients. Thus we obtained the methylation profile of BEN patients from Bulgarian and Serbian endemic regions. RESULTS: Using specifically developed software we compared the methylation profiles of BEN patients and corresponding controls and revealed the differently methylated regions. We then compared the DMRs between all patient-control pairs to determine common changes in the epigenetic profiles.SEC61G, IL17RA, HDAC11 proved to be differently methylated throughout all patient-control pairs. The CpG islands of all 3 genes were hypomethylated compared to controls. This suggests that dysregulation of these genes involved in immunological response could be a common mechanism in BEN pathogenesis in both endemic regions and in both genders. CONCLUSION: Our data propose a new hypothesis that immunologic dysregulation has a place in BEN etiopathogenesis.
Assuntos
Nefropatia dos Bálcãs/epidemiologia , Nefropatia dos Bálcãs/genética , Metilação de DNA/genética , Doenças Endêmicas/estatística & dados numéricos , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Genoma Humano/genética , Idoso , Península Balcânica/epidemiologia , Bulgária/epidemiologia , Ilhas de CpG/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Sérvia/epidemiologiaRESUMO
Development of germ cells is a process starting in fetus and completed only in puberty. Spermatogonial stem cells maintain spermatogenesis throughout the reproductive life of mammals. They are undifferentiated cells defined by their ability to both self-renew and differentiate into mature spermatozoa. This self-renewal and differentiation in turn is tightly regulated by a combination of intrinsic gene expression as well as the extrinsic gene signals from the local tissue microenvironment. The human testis is prone to damage, either for therapeutic reasons or because of toxic agents from the environment. For preservation of fertility, patients who will undergo radiotherapy and/or chemotherapy have an attractive possibility to keep in store and afterwards make a transfer of spermatogonial stem cells. Germ cell transplantation is not yet ready for the human fertility clinic, but it may be reasonable for young cancer patients, with no other options to preserve their fertility. Whereas this technique has become an important research tool in rodents, a clinical application must still be regarded as experimental, and many aspects of the procedure need to be optimized prior to a clinical application in men. In future, a range of options for the preservation of male fertility will get a new significance.
Assuntos
Infertilidade Masculina/terapia , Espermatogônias/transplante , Transplante de Células-Tronco , Humanos , Infertilidade Masculina/etiologia , MasculinoRESUMO
BACKGROUND: Urine beta2-microglobulin (beta2-MG) was mainly used as a tubular marker of Balkan endemic nephropathy (BEN) but recently alpha1-microglobulin (alpha1-MG) was proposed for the diagnosis of BEN. In this study, the potential of urine beta2-MG, alpha1-MG, albumin, and total protein in the differentiation of BEN from healthy persons and patients with glomerulonephritis (GN) and nephrosclerosis (NS) was examined. METHODS: This study involved 47 patients with BEN, 36 with GN, 11 with NS, 30 healthy subjects from BEN families, and 46 healthy subjects from non-BEN families. RESULTS: In BEN patients area under the curve (AUC) for urine beta2-MG (0.828) and alpha1-MG (0.782) was higher than for urine albumin (0.740), but in GN patients AUC for urine protein (0.854) and albumin (0.872) was significantly higher than for the two low molecular weight proteins. AUC for all four urinary markers in NS patients was significantly lower than in BEN patients, ranging between 500 and 595. Median urine beta2-MG excretion in BEN patients was 17.5 times higher than in GN patients and 18.3 times higher than in controls; median alpha1-MG excretion was higher only 3.0 and 2.25 times, respectively. In the differentiation of BEN from healthy controls, beta2-MG had higher sensitivity and specificity at the cutoff levels (p < 0.001) than alpha1-MG (p < 0.05). In the differentiation of BEN from GN, beta2-MG was the best marker. CONCLUSION: All four urinary markers can be used for the differential diagnosis of BEN, beta2-MG being the best. Like in aristolochic acid nephropathy, beta2-MG seems to be an early marker of tubular damage in BEN.
Assuntos
alfa-Globulinas/urina , Nefropatia dos Bálcãs/urina , Microglobulina beta-2/urina , Adulto , Idoso , Albuminúria/urina , Nefropatia dos Bálcãs/diagnóstico , Biomarcadores/urina , Estudos de Casos e Controles , Diagnóstico Diferencial , Feminino , Glomerulonefrite/urina , Humanos , Masculino , Pessoa de Meia-Idade , Nefroesclerose/urinaRESUMO
BACKGROUND: The jugular foramen, the bony opening on the basis of skull, is an opening through which pass the ninth, tenth, and eleventh cranial nerves, two dural sinuses, and the meningeal branches of the occipital and ascending pharyngeal arteries. The increasing use of modern diagnostic procedures and new surgical approaches has created a need for much more detailed anatomical studies and explanations. This article reveals some additional features. MATERIAL/METHODS: Fifty jugular foramina of skulls of persons of unknown age and gender were examined. The morphological characteristics of all the investigated jugular foramina were described, measured, and compared, taking into consideration their side. RESULTS: All quantitative mean values, except for the width of the anteromedial compartment, were greater on the right side; of these, the lengths and widths of the posterolateral compartment were significantly greater. The bipartite form of the jugular foramen dominated. Complete bony bridging of the jugular foramen was found in 24% of cases. There is no rule of simultaneous complete bony bridging of the jugular foramen and splitting of the hypoglossal canal. CONCLUSIONS: A detailed examination of the jugular foramen anatomy was performed. The main types of jugular foramina and the frequencies of bipartite or tripartite division were established. Several dimensions of the parts of the jugular foramen were measured. Some new data could provide important information about the anatomy of the jugular foramen for reliable surgical interventions in this area.
Assuntos
Crânio/anatomia & histologia , Adulto , HumanosRESUMO
AIMS AND BACKGROUND: Upper urinary tract transitional cell carcinoma, a relatively rare tumor, is up to 100 times more frequent in regions with Balkan endemic nephropathy. Characteristics of transitional cell carcinoma in the endemic South Morava Region in Serbia in the previous 50 years were evaluated. PATIENTS: We analyzed 477 cases with pathologically confirmed transitional cell carcinoma who underwent surgery from 1957 to 2006: 91 from endemic, 106 from adjacent and 280 from control settlements. Cases in the study came from 10 endemic villages, 46 adjacent villages, 51 control villages and the city of Nis. RESULTS: The increase in number of transitional cell carcinoma from 1957 was followed by a peak between 1967 and 1978 (yearly incidence 21.9 per 100,000) and a slow decrease thereafter to 7.4 (1997-2006). In the control settlements, the increase was steady. Reduced kidney function at surgery was found in 58% of patients from endemic and in 20% from control settlements. Age at surgery has significantly increased from 52.3 and 51.5 (1957-1966) to 70.9 and 66.1 (1997-2006) for endemic and control settlements, respectively. The female sex was predominant in endemic and adjacent settlements and the male sex in control settlements. Transitional cell carcinoma from endemic settlements was of a lower grade in the period from 1957-1986, but in the period from 1987-2006 they were predominantly high grade. Low tumor stage (pTa-pT1) predominated in transitional cell carcinoma from the endemic and adjacent but not the control settlements in the period from 1957 to 1986. However, in the last 20 years, upper urinary tract transitional cell carcinoma stage increased, the highest in the period from 1997 to 2006 in all settlements studied. Conservative surgery was advocated for transitional cell carcinoma in Balkan endemic nephropathy areas up to 1996. Transitional cell carcinoma are now more malignant and more advanced than before, and a less aggressive approach is used only for absolute indications. CONCLUSIONS: An increased number of transitional cell carcinoma in endemic settlements was observed, markedly decreasing in the last decade. An increasing age and a shorter survival were recorded in patients both from Balkan endemic nephropathy and control settlements. Sporadic cases upper urinary tract transitional cell carcinoma in settlements adjacent to endemic settlements were demonstrated.
Assuntos
Nefropatia dos Bálcãs/epidemiologia , Carcinoma de Células de Transição/diagnóstico , Carcinoma de Células de Transição/epidemiologia , Doenças Endêmicas , Neoplasias Urológicas/diagnóstico , Neoplasias Urológicas/epidemiologia , Adulto , Distribuição por Idade , Idoso , Nefropatia dos Bálcãs/patologia , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Sérvia/epidemiologiaRESUMO
Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease frequently accompanied by urothelial carcinoma (UC). In light of the increased UC incidence and the markers observed in BEN patients with developed UC, the aim of the current case-control study is to assess survivin, p53 protein, growth factors and receptors (VEGF, VEGFR1, IGF I, IGF-1R and IGFBP5), tumor marker (TF)/CD142, circulating soluble Fas receptor and neopterin, as potentially predictive markers for UC in patients with BEN (52 patients), compared to healthy, age-matched subjects (40). A threefold increase was registered in both circulating and urinary survivin level in BEN patients. Especially noticeable was the ratio of U survivin/U Cr level five times the ratio of BEN patients associated with standard renal markers in multivariate regression models. The concentrations of VEGF, VEGFR1, (TF)/CD142, (sFas) were not significantly different in BEN patients, while urinary/plasma level demonstrated a significant decrease for VEGF. The levels of IGF I, IGFBP5 and IGF-1R were significantly reduced in the urine of BEN patients. Plasma concentration of neopterin was significantly higher, while urinary neopterin value was significantly lower in BEN patients compared to healthy controls, which reflected a significantly lower urine/plasma ratio and low local predictive value. As BEN is a slow-progressing chronic kidney disease, early detection of survivin may be proposed as potential predictor for malignant alteration and screening tool in BEN patients without the diagnosis of UC.
RESUMO
Balkan endemic nephropathy (BEN) represents a chronic tubulointerstitial nephropathy which is followed by the progression of kidney fibrosis to end-stage kidney failure. The critical involvement of poisons in food (aristolochic acid (AA), ochratoxin, and heavy metals) and selenium deficiency are among nutritive factors which contribute to the pathogenesis of BEN, due to reactive oxygen species (ROS) liberation and/or decreased antioxidative defence system. The aim of the study is to distinguish a possible systemic and local origin of ROS through the measurement of xanthine oxidase (XO) activity in urine and plasma, along with the determination of the oxidative changes in lipids and proteins. The study included 50 patients with BEN and 38 control healthy subjects. We noted increased levels of both thiobarbituric acid-reactive substances (TBARS) and advanced oxidation protein products (AOPPs) in the plasma of patients with BEN, compared to the control group (p < 0.001). The urinary levels of AOPPs were higher in patients with BEN in comparison to the control (p < 0.001). The specific activity of XO was significantly lower in plasma and urine in BEN samples, compared to controls (p < 0.005). Based on these results, we hypothesize that XO might not be considered a direct systemic or local contributor to ROS production in BEN, most probably because of the diminished kidney functional tissue mass and/or AA-induced changes in purine nucleotide conformation. The increased AOPP and TBARS level in both plasma and urine in BEN may predict ROS systemic liberation with toxic local effects.
Assuntos
Nefropatia dos Bálcãs/enzimologia , Nefropatia dos Bálcãs/patologia , Estresse Oxidativo , Xantina Oxidase/metabolismo , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredução , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Balkan nephropathy (BN) has not been described in children; however, some previous studies in children from families with BN have revealed abnormalities of the urinary tract. In this study, urinary excretion of beta2-microglobulin, N-acetyl-beta-D-glucosaminidase (NAG) and gamma-glutamyl transpeptidase (GGT) was studied three times a year: spring, autumn, and winter, during a 3-year period, in 703 healthy children, initial age 9-13, from endemic and nonendemic settlements around the South Morava River. Beta-2-microglobulin excretion in urine, in all three seasons, was highest in children from families with BN compared with the excretion in children from the city, nonendemic villages, and those from nonendemic families. Increased urinary GGT excretion in children from endemic villages in October was higher than in children from the city and control villages, being the same in both endemic and nonendemic families. However, in February, it was similar in children from the city, endemic, and control villages. In conclusion, children from families with BN excreted significantly more beta2-microglobulin in all three seasons (spring, autumn, winter) of the study, in multivariate analysis significant for family status, gender, and the season (p < 0.001). NAG emerged as a potentially useful marker for seasonal exposure to an environmental nephrotoxin.
Assuntos
Acetilglucosaminidase/urina , Nefropatia dos Bálcãs/epidemiologia , Nefropatia dos Bálcãs/urina , Doenças Endêmicas , Microglobulina beta-2/urina , gama-Glutamiltransferase/urina , Adolescente , Biomarcadores/urina , Bósnia e Herzegóvina/epidemiologia , Bulgária/epidemiologia , Estudos de Casos e Controles , Criança , Creatinina/urina , Croácia/epidemiologia , Família , Feminino , Humanos , Masculino , Estudos Retrospectivos , Romênia/epidemiologia , Saúde da População Rural , Estações do Ano , Sérvia/epidemiologia , Saúde da População UrbanaRESUMO
Upper urothelial carcinoma (UUC), a rare neoplasm, occurs more frequently in some regions of Balkan countries than in other areas in the world. The aim of this study is to compare phenotypic morphological characteristics of UUC in Balkan endemic nephropathy (BEN) region and control rural and city populations free of BEN, and to determine the characteristic(s) that could discriminate tumors in endemic and non-endemic regions. The authors analyzed biopsies from 88 patients with UUC, 40 patients who live in Balkan endemic (BEN) settlements and 48 control subjects. The histological sections were used to assess morphological variables: histologic grade, pathologic stage (pT), growth pattern, pattern of invasion, lympho-vascular invasion (LVI), presence of necrosis and metaplastic changes (squamous or glandular) within the tumor. Statistically significant differences between the groups were found concerning tumor grade, pattern of invasion, growth pattern and metaplastic changes. High-grade tumors and trabecular/infiltrative patterns of invasion were more frequent in the group of BEN tumors (chi(2)=4.583, p<0.05; chi(2)=8.064, p<0.05). Moreover, solid growth and metaplastic changes are significant in BEN tumor, chi(2)=9.696, p<0.01; chi(2)=9.35, p<0.01, respectively. Discriminant analysis of morphological variables had indicated that BEN and control tumors are significantly different (Wilks' lambda=0.833, chi(2)=15.044 and p<0.05). The best characteristic that differentiated them was growth pattern; i.e., solid growth for BEN tumors and papillary for control tumors.
Assuntos
Nefropatia dos Bálcãs/patologia , Neoplasias Renais/patologia , Neoplasias Ureterais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Nefropatia dos Bálcãs/complicações , Nefropatia dos Bálcãs/epidemiologia , Feminino , Humanos , Neoplasias Renais/complicações , Neoplasias Renais/epidemiologia , Pelve Renal/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ureterais/complicações , Neoplasias Ureterais/epidemiologiaRESUMO
Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease associated with urothelial cancer, which affects people living in the alluvial plains along the tributaries of the Danube River. Challenges of studying BEN using the epidemiological method are multiple. The natural history from exposure to occurrence of the disease may take many years. The early stages of BEN are not easily detectable clinically, as the disease is asymptomatic until a significant decline in function occurs, and even then symptoms are usually non-specific. The natural history of BEN is complex, possibly with multiple risk factors operating both at the stage of initiation of renal damage and in its progression. In BEN, genetic susceptibility is due to multiple genes of small effects, gene-gene interactions, and gene-environment interactions of complex nature that are difficult to assess with current study designs. BEN is now kidney disease of the old people, and many risk factors for disease such as smoking, alcohol consumption, obesity, and diabetes could contribute to the kidney damage. Evidence is presented that environmental rather than genetic factors play a decisive role in the etiopathogenesis of BEN. Aristolochic acid, described as a culprit of BEN in 1959, is confirmed in 2007 by the molecular biology methods. Mycotoxins and polycyclic aromatic hydrocarbons, leached from lignites and found in the vicinity of endemic settlements, deserve further investigation. Despite advances in understanding the epidemiology of BEN, more research is needed on the patterns of BEN over time and between places, and on identifying the contributions of modifiable risk factors in initiating and hastening progression of BEN in order to improve the scope for preventing BEN. Primary prevention is still at the beginning. Knowledge accumulated in the fifty years of BEN research and new data about prevention and treatment of chronic kidney disease reveal several effective methods in secondary and tertiary prevention of BEN. Genetic epidemiology could establish the relative size of the genetic effect in relation to other sources of variation in disease risk (i.e., environmental effects such as intrauterine environment, physical and chemical effects, as well as behavioral and social aspects). Public health authorities in the several countries having aristolochic acid nephropathy should take immediate measures for reducing dietary exposure of residents to Aristolochia.
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Nefropatia dos Bálcãs/epidemiologia , Nefropatia dos Bálcãs/etiologia , Exposição Ambiental/efeitos adversos , Predisposição Genética para Doença/epidemiologia , Nefropatia dos Bálcãs/fisiopatologia , Progressão da Doença , Métodos Epidemiológicos , Feminino , Humanos , Incidência , Masculino , Avaliação das Necessidades , Intoxicação por Plantas , Compostos Policíclicos , Polimorfismo Genético , Prognóstico , Medição de Risco , Sérvia/epidemiologia , Índice de Gravidade de DoençaRESUMO
Myelinated nerve fibers suffer from different degrees of atrophy with age. The success of subsequent regeneration varies. The aim of this research was to analyze myelinated fibers of the human sciatic nerve during the aging process. Morphometric analysis was performed on 17 cases with an age range from 9 to 93 years. The outer and inner diameter of 100 randomly selected nerve fibers was measured in each of the cases evaluated, and the g-ratio (axonal diameter/outer diameter of the whole nerve fiber) of each was calculated. Scatter plots of the diameters and g-ratios of the analyzed fibers were then analyzed. Nerve fibers of each case were classified into three groups according to the g-ratio values: group I (g-ratio lower than 0.6), group II (g-ratio from 0.6 to 0.7) and group III (g-ratio higher than 0.7). Afterwards, nerve fibers of group II were further classified into small and large subgroups. The percentages of each group of nerve fibers were computed for each case and these values were used for correlational and bivariate linear regression analysis. The percentage of myelinated nerve fibers with large diameter and optimal g-ratio of the sciatic nerve declines significantly with age. This is accompanied by a simultaneous significant increase in the percentage of small myelinated fibers with g-ratio values close to 1 that occupy the upper left quadrant of the scatter plot. It can be concluded that aging of the sciatic nerve is associated with significant atrophy of large myelinated fibers. Additionally, a significant increase in regenerated nerve fibers with thinner myelin sheath is observed with age, which, together with the large myelinated fiber atrophy, might be the cause of the age-related decline in conduction velocity. A better understanding of the changes in aging peripheral nerves might improve interpretation of their pathological changes, as well as comprehension of their regeneration in individuals of different age.
Assuntos
Envelhecimento/patologia , Fibras Nervosas Mielinizadas/patologia , Nervo Isquiático/anatomia & histologia , Nervo Isquiático/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Atrofia , Criança , Humanos , Pessoa de Meia-Idade , Regeneração Nervosa , Nervo Isquiático/citologia , Adulto JovemRESUMO
Balkan endemic nephropathy (BEN) is a disease that affects people that live in the alluvial plains along the tributaries of the Danube River in the Balkan region. BEN is a chronic tubulointerstitial disease with a slow progression to terminal renal failure and has strong association with upper tract urothelial carcinoma (UTUC). There are several hypotheses about the etiology of BEN, but only the toxic effect of aristolochic acid has been confirmed as a risk factor in the occurrence of the disease. Aberrantly expressed miRNAs have been shown to be associated with many types of cancers. A number of studies have investigated the expression of microRNAs in urothelial carcinoma, mainly on urothelial bladder cancer, and only a few have included patients with UTUC. Here we present the first study of microRNA profiling in UTUC tissues from patients with BEN (BEN-UTUC) and patients with UTUC from nonendemic Balkan regions (non-BEN-UTUC) in comparison to normal kidney tissues. We found 10 miRNAs that were differentially expressed in patients with BEN-UTUC and 15 miRNAs in patients with non-BEN-UTUC. miRNA signature determined in BEN-UTUC patients differs from the non-BEN-UTUC patients; only miR-205-5p was mutual in both groups.
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Nefropatia dos Bálcãs/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células de Transição/metabolismo , MicroRNAs/metabolismo , Neoplasias Ureterais/metabolismo , Adulto , Idoso , Nefropatia dos Bálcãs/epidemiologia , Península Balcânica/epidemiologia , Carcinoma de Células de Transição/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ureterais/epidemiologiaRESUMO
AIM: The aim of this study was to examine the ocular fundus pathology in patients with Balkan endemic nephropathy (BN) and chronic kidney diseases (CKD). METHODS: The study included 51 patients with BN from the South Morava River region in Serbia, and 102 subjects with different stages of chronic renal diseases, matched according to age and gender, obtained from a database used in a recently published study. All patients had visited Outpatient Department of the Clinic of Nephrology, Clinical Center Nis. All patients underwent routine ophthalmic examinations. RESULTS: There were significantly more (P < 0.001) patients with age-related macular degeneration (AMD) in the group with BN (31.37 %) than in those with CKD (5.88 %). Multivariate logistic regression analysis confirmed that the significant factors related to AMD in the group with BN were albuminuria (P < 0.05) and proteinuria (P < 0.05); in CKD patients, the level of HDL (P < 0.05), while negative correlation with the level of triglyceride was registered (P < 0.05). There was no association between estimated glomerular filtration rate and AMD. The significant factors related to retinopathy in the group with BN are age (P < 0.05) and serum creatinine values (P < 0.05), in patients with CKD increasing age (P < 0.001) and DM (P < 0.05). CONCLUSION: Ocular fundus pathology in patients with BN is similar to the pathology of other CKD, but with significantly more AMD (about four times), probably related to the genetic/epigenetic factors.
Assuntos
Nefropatia dos Bálcãs/epidemiologia , Degeneração Macular/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Albuminúria/etiologia , Nefropatia dos Bálcãs/sangue , HDL-Colesterol/sangue , Creatinina/sangue , Creatinina/urina , Diabetes Mellitus/epidemiologia , Feminino , Fundo de Olho , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Fatores de Risco , Sérvia/epidemiologia , Triglicerídeos/sangueRESUMO
BACKGROUND: Balkan endemic nephropathy (BEN) has not been described in children, however some previous studies of children from families with BEN have revealed abnormalities of the urinary tract including an increased urinary protein excretion. METHODS: In the present study, urinary excretion of total protein was studied in 703 healthy children, aged 9-13, from endemic and non-endemic settlements around the South Morava River. Since BEN is an environmentally induced disease, with possible seasonal variation of toxin(s), children were studied three times a year: in spring, autumn and winter, during a 3-year period. After a water load of 15 ml/kg body weight, a 3-hour urine sample was collected, from 7 to 10 a.m. RESULTS: Protein excretion in urine was highest in children from families with BEN compared with the excretion in children from the city, non-endemic villages, and those from non-endemic families living in the same settlements. This was the case during all three periods investigated in the second year of the study. In the autumn term of all three years of the study, protein excretion was significantly higher in children from families with BEN than in children from the city and from non- endemic families living in the same settlements. If the upper limit of protein excretion is set at 34 mg/mmol creatinine, then increased protein excretion in autumn was found in the first year of study in 9/229 children from endemic settlements and in only 4/474 children from non-endemic areas (p = 0.004); in the second year in 5/229 and 3/474 children (p = 0.069), and in the third year in 10/229 and 4/474 children (p = 0.002), respectively. CONCLUSIONS: We have presented evidence that children from families with BEN and endemic villages consistently excreted significantly more protein in the autumn, and in three seasons (spring, autumn, winter) in 1 year of our study. These results are consistent with seasonal variations in exposure to an environmental toxin(s).
Assuntos
Nefropatia dos Bálcãs/epidemiologia , Proteinúria/epidemiologia , Adolescente , Nefropatia dos Bálcãs/patologia , Criança , Humanos , Saúde da População Rural , Estações do Ano , Saúde da População Urbana , Sistema Urinário/anormalidadesRESUMO
Endemic nephropathy (EN) is a chronic tubulointerstitial nephropathy with an early insidious and slow development into terminal renal failure. Proteomics is the systematic study of a proteome, which is the total protein content of a cell, organism or body fluids. Application of proteomic technologies in nephrology has enabled more detailed analyses of protein functions and examined their importance in various physiological and pathological states. Biomarkers with high specificity and sensitivity to early diagnosis are needed for a better understanding of the mechanisms of EN development and its consequences. Urine beta2-microglobulin (B2M) was mainly used as a tubular marker of EN but recently alpha1-microglobulin (AMBP) was proposed for the diagnosis of EN. We studied the urine proteins of 360 patients with EN, diabetic nephropathy (DN) and acute kidney injury (AKI) and the healthy population using proteomic tools. Protein maps from the urine of patients with EN showed significant differences in comparison to the healthy subjects and patients with DN and AKI. Our study highlights six proteins in urine that were differentially excreted in the urine of EN patients compared with the other groups and have potential to be markers for EN prediction. In one of our studies, using routine biomarkers, we investigated the potential of urine B2M, AMBP, albumin and total protein as diagnostic markers for EN, in comparison to glomerulonephritis, nephrosclerosis and a healthy state. Modern proteomic technologies are still robust investigation tools, but can access a vast amount of information from one set of experiments in comparison to a classic diagnostic approach.
Assuntos
Nefropatia dos Bálcãs/diagnóstico , Proteômica/métodos , Biomarcadores/análise , HumanosRESUMO
Some evidence has suggested that, with age, the hypothalamic-pituitary-adrenal (HPA) axis becomes less resilient, leading to higher glucocorticoids nocturnal levels and a flattening of the circadian profiles. Such age-related changes in the activity of the HPA axis has overexposed the brain and peripheral organs to the effects of the glucocorticoids, increasing the morbidity and mortality rates of the elderly. Debate among scientists regarding the contributions of HPA axis age-related changes of impaired feedback regulation vs. direct overactivation persists. Supporters of impaired feedback regulation assumed that this effect might be the consequence of the hippocampal age-related neuronal loss and the reduction of the number of mineralocorticoid and glucocorticoid receptors. On the other hand, healthy elderly individuals are characterized by an increase of proinflammatory cytokines, including IL-1, IL-6, and TNF-α, and the development of a chronic low-grade inflammatory state, known as inflammaging. Cytokines central to inflammaging send signals to the brain, activate HPA axis, and, by increased cortisol secretion, down-regulate inflammaging in a process known as anti-inflammaging. Even as these cytokines act at the level of the hypothalamic paraventricular nucleus, they are hampered by the intact blood-brain barrier. Further, the corticotropes in the anterior pituitary do not express cytokine receptors, and the density of folliculo-stellate cells generally increases with age. Therefore, we assumed that folliculo-stellate cells were the target structures through which the elevated levels of cytokines, as a part of the inflammaging phenomenon, would cause the overactivation of the HPA axis in healthy elderly individuals. Folliculo-stellate cells are non-endocrine cells that were originally considered to act as supporting cells for the endocrine cells. Despite the fact that FS cells do not produce any of the established hormones of the anterior pituitary, they secrete paracrine agents that act locally to modulate pituitary responses to hypothalamic and peripheral signals. There is evidence of cytokines characteristically involved in inflammaging. For example, IL-1 and TNF-α are thought to stimulate folliculo-stellate cells to release various paracrine agents, including IL-6, IL-11, leukemia inhibitory factor, and macrophage migration inhibitory factor. Through different mechanisms, these agents induce ACTH release by corticotropes. Therefore, it can be concluded that folliculo-stellate cells may act as potent mediators of the age-related HPA axis hyperactivity induced by cytokines characteristic of the inflammaging phenomenon in healthy elderly individuals.
Assuntos
Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Idoso , HumanosRESUMO
The goal of this study was to examine, the relationship between chronic kidney disease (CKD) and glaucomatous optic disc neuropathy in a cohort of patients from the south-east Serbia and to determine whether limited screening for glaucoma in specific subgroups of patients with CKD is reasonable and justifiable. This cross-sectional study included 328 subjects with various stages of CKD. All patients had visited the Outpatient Department of the Nephrology Clinic, Clinical Center Nis, Serbia. All patients underwent routine ophthalmic examinations. Glaucoma diagnosis based on elevated intraocular pressure (IOP), the presence of excavation of the optic nerve head (C/D ratio), and characteristic glaucomatous visual field loss (MD-mean deviation, PSD-pattern standard deviation). CKD was defined as kidney damage or glomerular filtration rate (GFR) of <60 ml/min/1.73 m(2) for >3 months. A total number of 328 CKD patients, 33 (10.1 %) with primary open angle glaucoma and 28 (8.5 %) with ocular hypertension (OH), were included in the study. Patients with CKD and glaucoma had significantly higher mean values of C/D ratio (0.59), visual field mean deviations (dB)-MD (p < 0.001), and visual field pattern standard deviations (dB)-PSD (p < 0.001) than patients with CKD and OH. Stepwise multivariate linear regression analysis confirmed that the most significant factors related to IOP are age (p < 0.05), AHT (p = 0.01), and eGFR (p = 0.001). Multivariate regression analysis also confirmed that the most significant factors related to cup-to-disc ratio are number of years of smoking (p < 0.05), AHT, and sCr (p < 0.01). In conclusion, the prevalence of glaucoma among CKD patients in the cohort from south-east Serbia is 10.1 %. Patients with CKD and glaucoma, eGFR and current cigarette smoking are associated with IOP level, MD, and PSD of visual field and C/D ratio.