Safety and feasability of ureteroscopy for pediatric stone, in children under 5 Years (SFUPA 5): A French multicentric study.

INTRODUCTION: Ureteroscopy (URS) can be proposed as first-line therapy for the management of pelvic stones from 10 to 20 mm and for lower ureteric stones in children. However, little is known about the success and the morbidity of URS in young children. Ureteroscopic treatment may present matters in young children because of the small size of the pediatric kidney and the small size of the collecting system. OBJECTIVE: To assess safety and efficacy of URS for the treatment of urinary stones in children aged of 5 years or less. STUDY DESIGN: After the institutional ethical board approval was obtained, we conducted a retrospective, analytic, multicentric study that included all URS performed between January 2016 and April 2022 in children aged of 5 years or less. In this non-comparative case series, anonymized pooled data were collected from 7 tertiary care centers of pediatric patients. Endpoints were the one-session SFR at 3 months and per and postoperatives complications. Descriptive statistics were applied to describe the cohort. RESULTS: Eighty-three patients were included. For them, 96 procedures were performed at the median age of 3.5 years (IQR: 0.8-5) and median weight of 14 Kg (6.3-23). Median stone size was 13 mm (4-45). There were 65 (67 %) renal stones treated with flexible URS, most of which were in the renal pelvis (30 %) and in the lower calix (33 %). A ureteral access sheath was used in 91 % procedures. Preoperative ureteral stent was placed in 52 (54 %) of patients. None of patients had ureteral dilatation. The single-session SFR was 67.4 % (56.3 and 89.2 % for flexible URS and semi-rigid URS respectively) and children require 1.4 procedures to achieve complete stone clearance. The overall complication rate was 18.7 %, most of them were minor (Clavien I-II). Intraoperative perirenal extravasation (Clavien IIIb) due to forniceal rupture was documented in 6.2 % of cases, related to an increased intrapelvic pressure (IPP) performed in a closed pelvicalyceal system. DISCUSSION: Pediatric urologists should be aware of forniceal rupture based on the presence of extravasation of contrast during endourological procedures especially when they have difficulties to reach lower caliceal stone in small patient. CONCLUSION: URS in patients aged of 5 years or less, is a complex minimally invasive procedure with reasonable efficacy and low morbidity. Intrarenal stones treated by RIRS in young children carries the risk of additional procedures to complete stone clearance.

Efecto del ejercicio sobre la inflamación y ferritina sérica en pacientes con obesidad y diabetes mellitus 2 / Effect of exercise on inflammation and serum ferritin in patients with obesity and type 2 diabetes mellitus

Type 2 Diabetes Mellitus (DM2) is considered a chronic inflammatory and systemic disease of low degree of intensity that promotes other pathologies such as cardiovascular disease, cancer and cognitive impairment. The relationship between inflammatory markers and insulin resistance in obese patients is known. Low-grade inflammation is an independent predictor of chronic diseases and mortality from all causes. Ferritin may be increased in DM2, but it is not clear if its cause is hyperglycemia or chronic inflammation. Objective: To evaluate the impact of a twenty-week program of exercise and diet on the markers of inflammation, metabolic control and the value of ferritin in a sample of obese patients with DM2, assisted in our National Health System. Materials and Methods: Open, controlled and randomized clinical trial in primary care patients. Of 161 patients with DM2 evaluated 35 fulfilled the inclusion criteria. They were divided into two homogeneous groups (control and intervention). Blood was taken from both groups to measure Ferritin along with other inflammatory and metabolic markers, before and after the exercise and diet program. These variables and the changes in serum Ferritin were analyzed. Results: At the beginning of the study Ferritin was elevated in 72.2% and 52.9% of the control and intervention group respectively. In the end, there was a significant difference between the groups, with benefit of the intervention group in the decrease of Interleukin-6, glycosylated hemoglobin, waist and body mass index. There was a non-significant decrease in C-reactive protein and Ferritin. This last one was not related to the other variables. The control group showed no significant decrease of any variable Conclusions: To apply a program of controlled exercise and diet, in the usual treatment of patients with DM2, improves inflammation and glucose homeostasis, discernible by the decrease in inflammatory parameters and by the improvement in the glycemic control. Serum ferritin was not useful to predict the metabolic control of these patients and assess the response to treatment.

Introducción: La diabetes mellitus 2 (DM2) es considerada una enfermedad inflamatoria crónica y sistémica de bajo grado de intensidad que promueve otras patologías. Es conocida la relación entre |inflamación e insulino resistencia en pacientes obesos, siendo un predictor independiente de morbimortalidad por todas las causas. Ferritina puede estar aumentada en la DM2, no es claro si su causa es la hiperglucemia o la inflamación crónica. Objetivo: Evaluar el impacto de un programa de veinte semanas de ejercicio y dieta sobre los marcadores de inflamación, control metabólico y el valor de ferritina en una muestra de pacientes con DM2 obesos. Materiales y Métodos: Ensayo clínico abierto, controlado y randomizado en pacientes del nivel primario de atención. Se evaluaron 35 pacientes con DM2 que se dividieron en dos grupos homogéneos (control e intervención). Se extrajo sangre para medir Ferritina, marcadores inflamatorios y metabólicos, antes y luego del programa de ejercicio y dieta. Analizamos los cambios de esas variables. Resultados: Ferritina estaba elevada en el 72.2% y 52.9% del grupo control e intervención respectivamente. Al final hubo una diferencia significativa entre los grupos, con beneficio del grupo intervención en el descenso de Interleucina-6, hemoglobina glicosilada, cintura e índice de masa corporal. Hubo un descenso no significativo de Ferritina y Proteína C reactiva. Ferritina no presentó relación con las demás variables. En el grupo control no hubo descenso significativo de ninguna variable. Conclusiones: Aplicar un programa de ejercicio controlado y dieta, en el tratamiento de pacientes con DM2, mejora la inflamación y la homeostasis de la glucosa, discernible por el descenso de parámetros inflamatorios y por la mejora en el control glucémico. Ferritina sérica no fue útil para predecir el control metabólico y valorar la respuesta al tratamiento.

Susceptibility genes in hypertension.

Hypertension is a complex, multifactorial disease; genetic factors represent one third to half of the inter-individual variability of blood pressure values. Among the causes of secondary hypertension are a group of disorders with a Mendelian inheritance pattern. Recent advances in molecular biology have revealed the pathogenesis of hypertension in many of these conditions. Remarkably, the mechanism in every case has proved to be upregulation of sodium Na reabsorption in the distal nephron, with accompanying expansion of extracellular volume. On the contrary in the essential hypertension the underlying pathogenetic mechanism is more complex because of interplay between several 'risk' genes and environmental factors. It is assumed that blood pressure is under the control of a large number of genes each of which has only relatively mild effects. It has therefore been difficult to discover the genes that contribute to blood pressure variation using traditional approaches including candidate gene studies and linkage studies. Recent development of genotyping technology made large scale genome-wide association studies possible. This approach and the study of monogenic forms of hypertension has led to the discovery of novel and robust candidate genes for human essential hypertension, many of which require functional analysis in experimental models. This review summarizes the current findings for candidate genes associated with blood pressure and focuses on recent advances and future potential of pharmacogenetics of hypertension, with the intent to clarify what amount of these investments in basic science research will be delivered into benefits to patients.

Prothrombotic mutations, family history and the risk of thrombosis in postmenopausal women: implications for hormone replacement therapy.

OBJECTIVE: Hormone replacement therapy (HRT) is acknowledged as the gold standard for the alleviation of climacteric vasomotor symptoms. Prothrombotic genetic variants have been suggested to increase thrombotic risk among HRT users. The aim of the study was to determine whether a positive family history may identify a genetic predisposition for thrombosis in women before prescribing HRT. METHODS: From January 2005 to May 2009, we consecutively enrolled 145 asymptomatic women (mean age 51.2 ±â€Š5.4 years) without previous episodes of venous and/or arterial thrombosis referred to our Genetics Research Unit before starting HRT. A detailed family history was reconstructed and we identified 48 women (33.1%) with a positive family history, defined as venous thromboembolism and/or stroke or heart attack, in first-degree relatives before 60 years for men and 65 years for women. A group of 121 women (mean age 54.0 ±â€Š9.1 years) with an episode of venous and/or arterial thrombosis was also included. Genetic screening for factor V Leiden, prothrombin G20210A and methylenetetrahydrofolate reductase C677T polymorphisms was performed. RESULTS: The frequency of factor V Leiden or prothrombin G20210A mutations was significantly higher both in asymptomatic women with a positive family history (16.7% vs. 2.1%, p = 0.001) and in patients with thrombosis (12.4% vs. 2.1%; p = 0.005) compared with asymptomatic women without a family history. Multivariate regression analysis showed a synergic effect between the presence of one prothrombotic mutation and family history on the risk of thrombosis (odds ratio 3.7, 95% confidence interval 1.9-7.2). CONCLUSIONS: A positive family history of thrombosis is a sensitive indicator for selected genetic testing in high-risk women before starting HRT.

Cumulative patient effective dose in cardiology.

Medical radiation from X-rays and nuclear medicine is the largest non-natural (man-made) source of radiation exposure in Western countries. The aim of this study was to assess the individual cumulative effective dose in patients admitted to our cardiology ward. We collected a cumulative radiological history from a structured questionnaire and access to hospital records in 50 consecutive adult patients (36 males; age, 66.7+/-10.8 years) admitted to the Institute of Clinical Physiology in Pisa. The cumulative effective dose was assessed as an indicator of stochastic risk of cancer. We derived the effective dose for each individual examination from the Medical Imaging Guidelines of the European Commission (2001). On average, each patient underwent a median of 36 examinations (interquartile range, 23-46). The median cumulative effective dose was 60.6 mSv. Three types of procedures were responsible for approximately 86% of the total collective effective dose: (i) arteriography and interventional cardiology (12% of examinations, 48% of average dose per patient); (ii) nuclear medicine (5% of examinations, 21% of average dose per patient); and (iii) CT (4% of examinations, 17% of average dose per patient). The median estimated extra risk of cancer was approximately 1 in 200 exposed subjects. In conclusion, the average contemporary cardiological patient is exposed to a significant cumulative effective dose from diagnostic and therapeutic interventions. It is important to log cumulative dose for each patient at the time of each examination. Every effort should be made to justify the indications and to optimize the doses.

Oxidative stress and its association with coronary artery disease and different atherogenic risk factors.

OBJECTIVE: It is well known that free radicals contribute to endothelial dysfunction and are involved in the pathogenesis and development of cardiovascular diseases, such as atherosclerosis. The aim of this study was to provide evidence for enhanced oxidative stress in coronary artery disease (CAD). METHODS: Plasma levels of 8-isoprostane (8-epiPGF(2alpha)), marker of lipid peroxidation, were measured in 68 subjects (age: 60 +/- 2 years, mean +/- SEM). Subjects included 30 healthy control subjects and 38 patients with angiographically proven CAD. In addition, the total antioxidant power (PAO) was evaluated in a subgroup (40 subjects, 12 healthy and 28 CAD). RESULTS: Levels of 8-epiPGF(2alpha) increased with the number of affected vessels (one- and multi-vessel disease versus control subjects, P < 0.001) and considering different risk determinants for atherosclerosis (i.e. hypertension, gender, hypercholesterolaemia, P < 0.01). In multivariate regression models the number of affected vessels was independently correlated with 8-epiPGF(2alpha) (P < 0.05). PAO values significantly decreased with increased number of affected vessels (P < 0.05) and in hypertensive patients when compared with those without hypertension (P < 0.05). In multivariate regression models the number of affected vessels resulted an independent determinant for PAO (P < 0.05). Concentration of 8-epiPGF(2alpha) and PAO also correlated with the number of cardiovascular risk factors (P < 0.01 and P = 0.07, respectively). CONCLUSION: These findings indicate that elevated levels of plasma 8-epiPGF(2alpha) and reduced antioxidant capacity are associated with the extent and the severity of CAD and with the occurrence and number of different atherogenic risk factors. This observation may assist in providing more information as to how oxidative stress may predispose to atherogenesis and suggest attractive therapeutic strategies in the prevention and treatment of cardiovascular disease.

Evidence for association of a common variant of the endothelial nitric oxide synthase gene (Glu298-->Asp polymorphism) to the presence, extent, and severity of coronary artery disease.

BACKGROUND: Genetic variants of endothelial nitric oxide synthase (eNOS) could influence individual susceptibility to coronary artery disease. OBJECTIVE: To assess whether Glu298-->Asp polymorphism of the eNOS gene is associated with the occurrence and severity of angiographically defined coronary artery disease in the Italian population. METHODS: Polymerase chain reaction/restriction fragment length polymorphism analysis was done to detect the Glu298-->Asp variant of the eNOS gene in 201 patients with coronary artery disease and 114 controls. The severity of coronary artery disease was expressed by the number of affected vessels and by the Duke scoring system. RESULTS: The frequencies of the eNOS Glu/Glu, Glu/Asp, and Asp/Asp genotypes in the coronary artery disease group were significantly different from those of controls (45.3%, 38.8%, and 15.9% v 42.1%, 51.8%, and 6.1%, respectively; chi2 = 8.589, p = 0.0136). In comparison with subjects who had a Glu298 allele in the eNOS gene, the risk of coronary artery disease was increased among Asp/Asp carriers (odds ratio 2.9, 95% confidence interval 1.2 to 6.8, p = 0.01) and was independent of the other common risk factors (p = 0.04). There was a significant association between the eNOS Glu298-->Asp variant and both the number of stenosed vessels (mean (SEM), 2.3 (0.1) for Asp/Asp v 1.9 (0.1) and 1.8 (0.1) for Glu/Glu and Glu/Asp, respectively; p = 0.01) and the Duke score (56.1 (3.1) for Asp/Asp v 46.7 (2.0) and 46.1 (1.9) for Glu/Glu and Glu/Asp, respectively; p = 0.02). CONCLUSIONS: Glu298-->Asp polymorphism of the eNOS gene appears to be associated with the presence, extent, and severity of angiographically assessed coronary artery disease.

Chronic long-term nitrate therapy: possible cytogenetic effect in humans?

Nitrates act as donors of nitric oxide (NO), a molecule with a recognized potential for genotoxicity. In order to assess whether chronic long-term nitrate therapy may increase genotoxicity, we evaluated chromosomal damage in peripheral lymphocytes of 27 ischaemic patients undergoing chronic nitrate treatment for vertical line4 years (7.9 +/- 3.1, mean +/- SD) and 18 age- and sex-matched subjects without any previous nitrate treatment. At the same time, after treatment in vitro with 0-20 microM sodium nitroprusside as NO donor, micronucleus induction and cell proliferation were also evaluated using blood from six different healthy donors. The results showed that the frequency of structural chromosomal aberrations was not significantly higher in the drug-treated group than the control [2.1 +/- 1.4 versus 1.6 +/- 1.2 (mean +/- SD); P = 0.23]. The frequency of micronucleated lymphocytes was higher in the nitrate group than in the control group (6.5 +/- 4.6 versus 3.5 +/- 2.9, P=0.01). In vitro treatment indicated a dose-dependent increase in the frequency of micronucleated lymphocytes with increasing SNP concentrations. Cytotoxicity and cell cycle delay, with a statistically significant difference with respect to control culture, were also observed. Our results suggest a possible genotoxic activity of nitrate therapy. Further studies focusing on the possible link between nitrate therapy and genotoxicity are warranted at this point.

Evidence for DNA damage in patients with coronary artery disease.

According to the "monoclonal hypothesis" of atherosclerosis, several studies suggest that cancer and atherosclerosis may have several fundamental biological mechanisms in common. Therefore, an increase in the mutation rate may be involved in the pathogenesis of atherosclerotic plaques. The aim of the study was to verify the presence of chromosomal damage in peripheral blood lymphocytes in patients with coronary artery disease by using micronucleus (MN) test, a reliable biomarker in genetic and cancer risk assessment. Subjects included 53 patients with documented coronary ischemic heart disease (group I); 10 patients with valvular heart disease in absence of atherosclerotic lesions of the coronary arteries (group II) and 16 healthy subjects, age- and sex-matched (group III) were studied as controls. For each subject, two separate cultures were performed and 1000 binucleated cells were scored for the evaluation of MN frequency. The mean (+/-S.E.M.) of MN frequency were 11.9+/-1.7, 5.9+/-1.2 and 3.6+/-0.7 in groups I, II and III, respectively. The MN frequency of group I was significantly higher than that of group III (P=0.02). In group I, MN frequency increased with the number of affected vessels (6.3+/-0.7, 13.9+/-1.6, 14.9+/-5.3 for one-, two-, and three-vessel disease, respectively). Scheffe's test showed that MN frequency was significantly higher in two-vessel compared with one-vessel disease (P=0.0077). Moreover, a positive relationship was found between MN levels and the severity of the disease, calculated by the Duke scoring system (R=0.28, P=0.032), as well as the systolic blood pressure (R=0.34, P=0.009). These results suggest that coronary artery disease in humans is a condition characterized by an increase of DNA damage, positively correlated with the severity of the atherosclerotic disease.

Spontaneous and induced chromosome damage in somatic cells of sporadic and familial Alzheimer's disease patients.

Alzheimer's disease (AD) is a neurodegenerative disorder of the elderly with a complex etiology due to the interaction between genetic and environmental factors. At least 15% of cases are inherited as an autosomal dominant mutation, but the majority are sporadic. We evaluated cytogenetic alterations, both spontaneous and chemical-induced [aluminium (Al) and griseofulvin (GF)], by means of the micronucleus (MN) test in lymphocytes or skin fibroblasts of 14 patients with sporadic and eight with familial Alzheimer's disease (FAD), respectively. The spontaneous MN frequencies of sporadic (20.8 +/- 9.2) and familial (20.7 +/- 4.6) AD patients are significantly higher than those of the respective control groups (9.0 +/- 6.8 and 6.7 +/- 3.4). In all AD patients, GF significantly increased the spontaneous MN frequency of somatic cells to a lesser extent (P < 0.05) as compared with the control group. Al treatment did not induce MN in AD patients. The results of the present study indicate that different types of somatic cells from sporadic and familial AD patients show comparable levels of spontaneous cytogenetic anomalies, and MN induction is partially reduced or lacking according to the type of chemical treatments.

Molecular characterization of chromosome 22 deletions by short tandem repeat polymorphism (STRP) in patients with conotruncal heart defects.

The haploinsufficiency of chromosome 22q11.2 can cause both DiGeorge and velocardiofacial syndromes, both of which are characterized by conotruncal heart defects as well as a wide range of other extracardiac anomalies. Several studies have demonstrated that approximately 10-20% of patients with conotruncal heart defects have a 22q11.2 deletion. In clinical laboratories, the deletion is usually detected by fluorescent in situ hybridization (FISH). We set up a polymerase chain reaction-based non-radioactive method for molecular analysis of the 22q11.2 region in conotruncal cardiac patients with conotruncal defects. Sixty-four children with conotruncal defects and their parents were genotyped by polymerase chain reaction, using fifteen polymorphic markers. We identified nine deletions (confirmed by FISH): eight were "de novo" and one familial, maternally inherited. Six deletions were of paternal and three of maternal origin. There were seven deletions of 3 Mb and the other two were of 1.5 Mb. This method is a cost-effective means of characterizing the 22q11.2 region and it can be applied for a rapid screening of 22q11.2 deletion in patients at risk. In agreement with previously published data, we found no correlation between the sizes and the parental origin of deletions and cardiac or extra-cardiac phenotypes.

Genetic instability and atherosclerosis: can somatic mutations account for the development of cardiovascular diseases?

Several observations suggest that cancer and atherosclerosis may entail fundamentally common biological mechanisms. The accumulation of lipids and the proliferation of smooth muscle cells (SMCs) are the main histological features of sclerotic plaque formation. The most prominent theory concerning the pathophysiological mechanisms of atherosclerotic plaque formation is the "inflammatory response to injury" hypothesis, which states that SMC proliferation is an inflammation-fibroproliferative reaction to different insults to the artery wall. However, recent evidence suggests that alterations at the DNA level may contribute significantly to the development of the disease. In accordance with these findings, the "monoclonal" hypothesis of atherosclerosis has been suggested. This hypothesis proposes that atherosclerosis begins as a mutation or viral infection, transforming a single, isolated smooth muscle cell into the progenitor of a proliferative clone, as seen in carcinogenesis. Studies of DNA damage in atherosclerotic tissues are lacking. Biological evidence for the hypothesis that cancer and atherosclerosis may share pathological mechanisms is discussed, emphasizing the need to perform studies investigating the involvement of somatic mutations in heart diseases.

Preferential occurrence of chromosome 21 malsegregation in peripheral blood lymphocytes of Alzheimer disease patients.

To further investigate our finding of high levels of spontaneous aneuploidy in somatic cells of Alzheimer's disease (AD) patients (Migliore et al. 1997), we studied the molecular cytogenetics of eight patients with sporadic AD and six healthy controls of similar age. Cytochalasin B-blocked binucleated peripheral blood lymphocytes from the AD patients and unaffected controls were used to measure micronucleus induction or other aneuploidy events, such as the presence of malsegregation in interphase nuclei (representing chromosome loss and gain). Dual-color fluorescence in situ hybridization (FISH) with differential labeled DNA probes was applied. We used a probe specific for the centromeres of chromosomes 13 and 21 combined with a single cosmid for the Down's syndrome region (21q22.2) to obtain information on spontaneous chromosome loss and gain frequencies for both chromosomes (13 and 21). FISH data showed that AD lymphocytes had higher frequencies of chromosome loss (evaluated as fluorescently labeled micronuclei) for both chromosomes, as well as higher frequencies of aneuploid interphase nuclei, again involving both chromosomes, compared to control lymphocytes. However, aneuploidy for chromosome 21 was more frequent than for chromosome 13 in AD patients. This preferential occurrence of chromosome 21 in malsegregation in somatic cells of AD patients raises the hypothesis that mosaicism for trisomy of chromosome 21 could underlie the dementia phenotype in AD patients, as well as in elderly Down's syndrome patients.