Hnf1b renal expression directed by a distal enhancer responsive to Pax8.

Xenopus provides a simple and efficient model system to study nephrogenesis and explore the mechanisms causing renal developmental defects in human. Hnf1b (hepatocyte nuclear factor 1 homeobox b), a gene whose mutations are the most commonly identified genetic cause of developmental kidney disease, is required for the acquisition of a proximo-intermediate nephron segment in Xenopus as well as in mouse. Genetic networks involved in Hnf1b expression during kidney development remain poorly understood. We decided to explore the transcriptional regulation of Hnf1b in the developing Xenopus pronephros and mammalian renal cells. Using phylogenetic footprinting, we identified an evolutionary conserved sequence (CNS1) located several kilobases (kb) upstream the Hnf1b transcription start and harboring epigenomic marks characteristics of a distal enhancer in embryonic and adult renal cells in mammals. By means of functional expression assays in Xenopus and mammalian renal cell lines we showed that CNS1 displays enhancer activity in renal tissue. Using CRISPR/cas9 editing in Xenopus tropicalis, we demonstrated the in vivo functional relevance of CNS1 in driving hnf1b expression in the pronephros. We further showed the importance of Pax8-CNS1 interaction for CNS1 enhancer activity allowing us to conclude that Hnf1b is a direct target of Pax8. Our work identified for the first time a Hnf1b renal specific enhancer and may open important perspectives into the diagnosis for congenital kidney anomalies in human, as well as modeling HNF1B-related diseases.

Air pollutants and daily number of admissions to psychiatric emergency services: evidence for detrimental mental health effects of ozone.

AIMS: Aim of the current study is to investigate the associations between daily levels of air pollutants (particulate matter, ozone, carbon monoxide, nitrogen dioxide) and daily admissions for mental disorders to the emergency department of two general hospitals in Umbria region (Italy). METHODS: We collected data about daily admissions to psychiatric emergency services of two general hospitals, air pollutants' levels and meteorological data for the time period 1 January 2015 until 31 December 2016. We assessed the impact of an increase in air pollutants on the number of daily admissions using a time-series econometric framework. RESULTS: A total of 1860 emergency department admissions for mental disorders were identified. We observed a statistically significant impact of ozone levels on daily admissions. The estimated coefficient of O3 is statistically significant at the 1% level. All other pollutants were not significantly associated with the number of daily admissions. CONCLUSIONS: Short-term exposure to ozone may be associated with increased psychiatric emergency services admissions. Findings add to previous literature on existing evidence for air pollution to have an impact on mental health. Ozone may be considered a potential environmental risk factor for impaired mental health.

Associations between common carotid artery diameter, Framingham risk score and cardiovascular events.

BACKGROUND AND AIMS: Vascular biomarkers are associated with risk burden and are capable to predict the development of future cardiovascular (CV) events; yet, their additive predictive value over and above established risk algorithms seems to be only modest. The present study evaluated the cross-sectional associations between vascular biomarkers, 10-year Framingham risk (FR) and prevalent CV events in a population with a high prevalence of hypertension and diabetes. METHODS AND RESULTS: As many as 681 subjects (419 men, age = 60 ± 10 years, 282 diabetics, 335 hypertensives, mean FR score = 22.5 ± 16.5%) underwent an integrated vascular examination including: radiofrequency-based ultrasound of common carotid artery (cca) to measure intima-media thickness (IMT), inter-adventitial diameter (IAD) and local pulse wave velocity (PWV); applanation tonometry to assess carotid pulse pressure (PP) and augmentation index (AIx); carotid-femoral PWV (cfPWV) measurement. One hundred and thirty-five subjects (19.8%) had history of CV events, and CV events were independently associated with male sex, age, antihypertensive treatment, current smoking, HDL-cholesterol and ccaIAD. In logistic regression model, only ccaIAD was associated with prevalence of CV events after adjustment for FR score, with the OR of 1.71 [1.34-2.19] (P < 0.0001) that remained unchanged when ccaIMT was included into the model (OR = 1.76 [1.36-2.27]; P < 0.0001). The association between prevalent CV events and ccaIAD was significant (OR of 1.65 [1.24-2.20]; P = 0.0005) also in a subgroup of subjects being at a high 10-year risk of CV disease (N = 330). CONCLUSIONS: In a population with a high prevalence of diabetes and hypertension, ccaIAD was the only vascular measure associated with prevalent CV events, independently of FR score.

Male Gender and Body Mass Index Are Associated With Hypertension and Reduced Kidney Function 5 or More Years After Living Kidney Donation.

BACKGROUND: The objective of this study was to evaluate renal function and to explore the relationship between some risk factors in kidney donors 12.37 ± 7.60 years after donation. PATIENTS AND METHODS: In a cross-sectional study conducted in a transplant unit, 77 nephrectomized subjects were assessed ≥5 years after donation to evaluate their renal function and the presence or absence of hypertension, dyslipidemia, and microalbuminuria. RESULTS: Twenty donors had an estimated glomerular filtration rate of <60 mL/min/1.73 m(2). Nine donors showed urinary albumin excretion of >20 µg/min (11.68%). Subjects with an EGFR of <60 mL/min were predominantly male and hypertensive and showed higher body mass index (BMI), higher uric acid, higher total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C), and logarithm of triglycerides/HDL-C (log TG/HDL-C) ratios than donors with an EGFR of >60 mL/min. Hypertensive donors were older and had higher BMI, higher UA serum values, higher TC/HDL-C and log TG/HDL-C ratios and microalbuminuria than nonhypertensive donors (P < .005). A multivariate analysis was conducted and, after final adjustment, a filtration rate of <60 mL/min was 3.05 times higher in men than women, increased 10% for each 1-unit increase in BMI and was positively associated with log (TG/HDL-C). The frequency of hypertension increased by 10% for each 1-unit increase in BMI and was positively associated with microalbuminuria. CONCLUSION: In this sample of kidney donors from a single transplant unit, ≥5 years after donation, male sex and high BMI were positively associated with the presence of kidney failure.

Immunoexpression of angiogenesis and proliferation markers in patients treated with cyclosporin A.

AIM: In the present immunohistochemical study, the expression of vascular endothelial growth factor, nitric oxide synthase 1 and 3, and Ki-67 in the gingival tissues of renal transplant patients treated with cyclosporin A was assessed. Gingival overgrowth (GO) frequently occurs in transplant patients receiving immunosuppressive drugs such as cyclosporine and this gingival inflammation might play an important role in the pathogenesis of drug-induced GO. METHODS: Twenty-eight human gingival biopsies were taken from healthy patients with chronic periodontitis (N.=14 control group), and from renal transplant recipients treated with cyclosporin A (N.=14 test group). The retrieved specimens were immunohistochemically processed and stained for vascular endothelial growth factor, nitric oxide synthase 1 and 3, and Ki-67. RESULTS: The levels of vascular endothelial growth factor, nitric oxide synthase 1 and 3, and Ki-67 were found to be significantly different among groups (P>0.001), with patients treated with cyclosporin A showing higher levels of all the analyzed markers compared to control group. CONCLUSION: In summary, the data from this pilot study suggests that the investigated factors have a role in the inflammation processes associated to immunosuppressive therapy. However, further studies with a larger sample population need to be conducted for an exhaustive knowledge of the mechanisms leading to GO.

Exercise acts as a drug; the pharmacological benefits of exercise.

The beneficial effects of regular exercise for the promotion of health and cure of diseases have been clearly shown. In this review, we would like to postulate the idea that exercise can be considered as a drug. Exercise causes a myriad of beneficial effects for health, including the promotion of health and lifespan, and these are reviewed in the first section of this paper. Then we deal with the dosing of exercise. As with many drugs, dosing is extremely important to get the beneficial effects of exercise. To this end, the organism adapts to exercise. We review the molecular signalling pathways involved in these adaptations because understanding them is of great importance to be able to prescribe exercise in an appropriate manner. Special attention must be paid to the psychological effects of exercise. These are so powerful that we would like to propose that exercise may be considered as a psychoactive drug. In moderate doses, it causes very pronounced relaxing effects on the majority of the population, but some persons may even become addicted to exercise. Finally, there may be some contraindications to exercise that arise when people are severely ill, and these are described in the final section of the review. Our general conclusion is that exercise is so effective that it should be considered as a drug, but that more attention should be paid to the dosing and to individual variations between patients.

Effects of somatostatin analogues on acromegalic cardiomyopathy: results from a prospective study using cardiac magnetic resonance.

OBJECTIVE: Left ventricular (LV) hypertrophy is the main finding of patients with active acromegaly at cardiac magnetic resonance (CMR). The aim of the study was to evaluate heart changes in acromegalic patients treated with somatostatin analogues (SMSA) using CMR. DESIGN AND PATIENTS: This was a prospective study. Fourteen consecutive patients (8 women, mean age 46+/-10 yr) with untreated active acromegaly were submitted to CMR and 2D-color Doppler echocardiography before and after a 6-month SMSA course. MEASUREMENTS: LV volume, mass (LVM) and wall thickness. RESULTS: CMR: Mean LVM and LVM index (i) decreased from 151+/-17 g and 77+/-9 g/m2, to 144+/-24 g and 70+/-12 g/m2, respectively (p=0.047 and p<0.0001, respectively); LV hypertrophy reverted in 6 out of 10 patients (p=0.016). Systolic function, evaluated by measuring LV ejection fraction remained normal in all patients (67+/-11%). There was not a correlation between changes in LVMi and changes in serum IGF-I concentrations. However, patients with controlled disease had higher reduction of LVMi than those with uncontrolled acromegaly (DeltaLVMi, -8.2+/-4.2 vs 4.0+/-5.3 p<0.05). 2D-echo cardiography: Mean LVMi decreased from 110+/-24 g/m2 to 100+/-20 g/m2 (p=0.026); hypertrophy, revealed in 5 patients (36%) at baseline, reversed in 2 patients (p=0.500) after SMSA; abnormal diastolic function [evaluated by isovolumic relaxation time or early (E) to late of atrial (A) peak velocities ratio] found in 4 patients (29%) at the study entry, improved in a patient. Systolic function remained within the normal range in all patients during the study period. CONCLUSIONS: CMR detects changes in LVMi in most patients with acromegaly treated with SMSA, which are more evident if the disease is controlled.

Desmopresssin and hemodilution: implications in doping.

Blood doping improves physical performance in sport. This is the reason why the antidoping authorities subject athletes to blood tests. Plasma volume expanders are prohibited agents used to reduce an artificial increase in hematological values using different illegal practices. The aim of our study was to test whether desmopressin (DDAVP)-induced hemodilution would alter the concentration of hematological parameters used to detect blood doping in sports. This was an intra-subject crossover study. Venous blood samples were obtained from eight physically active males on two occasions. On the first occasion the subjects ingested 1.5 L of mineral water and 4.3 microg/kg of DDAVP. On the second occasion the subjects ingested 1.5 L of mineral water. The samples were analyzed for hematocrit, hemoglobin, reticulocytes, OFF Hr-Score, glucose, albumin, creatinine and total proteins. After treatment with DDAVP we found a significant decrease in the hematocrit, hemoglobin and in the OFF Hr-Score values. We also found a significant decrease in glucose, albumin, creatinine and total proteins concentration; however, in this case, all the values were significantly below the physiological levels. Treatment with DDAVP has a very effective hemodilution effect. We consider that this substance should be included in the WADA's prohibited list.

Effect of intermittent hypoxia on hematological parameters after recombinant human erythropoietin administration.

Recent publications reflect the anti-doping authorities' concern about the use of altitude simulator systems as violating the spirit of sport criterion (Levine 2006; Loland and Murray 2007; Spriggs 2005). The aim of our study was to determine whether intermittent hypoxic treatments could modify the hemoglobin, hematocrit, reticulocytes, and erythropoietic stimulation index (OFF-Hr Score) values after administration of rHuEPO-alpha. Although these hematological parameters are of secondary nature some international sport federations currently exclude athletes who show aberrant values of these parameters from competition. Ten young male Wistar rats were treated, three times a week for 2 weeks, with 500 IU of rHuEPO-alpha. After the treatment, the animals were randomly divided into two groups: normoxic and hypoxic. The normoxic group was maintained at 21% O(2) 24 h a day for 23 days. The hypoxic group was maintained 12 h at 21% O(2) and 12 h at 12% O(2) (~4,000 m) the same time period. After the rHuEPO-alpha treatment, the hypoxic group of animals had a faster recovery rate in the reticulocyte count, elevated concentrations of hemoglobin and hematocrit and a significant increase in the endogenous EPO levels when compared with the normoxic group of animals. These changes led to significant modifications in the OFF-Hr Score between the hypoxic and normoxic animals. Intermittent hypoxic treatments after rHuEPO administration can significantly modify the main hematological parameters tested by the anti-doping authorities. Our results in an animal model suggest checking the described phenomena in humans in order to reach major conclusions.

Early abnormalities of left ventricular myocardial characteristics associated with subclinical hyperthyroidism.

The aim of the present study was to analyze heart function in subclinical hyperthyroidism (sHT) in otherwise healthy subjects by new methods using intramyocardial ultrasonic techniques. Twenty-four newly diagnosed and untreated sHT patients (20 women, 4 men; mean age: 42+/-4 yr) and 24 sex- and age-matched healthy volunteers were studied. All subjects were submitted to conventional 2D color-Doppler echocardiography, pulsed wave tissue Doppler imaging (PWTDI) for the analysis of diastolic function, color Doppler myocardial imaging (CDMI) for the analysis of regional strain and strain rate (SR) expression of regional myocardial deformability, and to integrated backscatter (IBS) for the evaluation of intrinsic contractility and tissue characterization. Regional myocardial systolic strain findings were significantly higher in sHT patients when compared with controls (p<0.001). Considering diastolic SR, the early phase of diastolic SR was compromised in sHT subjects as compared with controls (p<0.001). Cyclic variation index (CVI), expression of intrinsic contractility, was significantly higher in sHT subjects in comparison with controls (p<0.0001). IBS values were comparable between the 2 study groups. In conclusion, the present study suggests that in patients with sHT early systolic hyperdeformability and hypercontractility are present, together with impairment of both active and passive phases of diastole. On the contrary, no left ventricular hypertrophy or other structural alterations are documented.

Myocardial systolic strain abnormalities in patients with acromegaly: a prospective color Doppler imaging study.

BACKGROUND: Heart abnormalities are frequent findings in patients with acromegaly: systolic abnormalities are considered to be secondary to diastolic changes. AIM: The aim of the study was to evaluate whether early systolic abnormalities might be revealed in acromegalic patients using the high sensitive color Doppler myocardial imaging (CDMI) technique. PATIENTS AND METHODS: Twenty-two consecutive acromegalic patients with active untreated disease (ACROUNTR) were evaluated at baseline and after a 6-month course with SS analogs (SSa) (ACROSSa); 25 healthy subjects served as controls. All subjects underwent conventional 2D-color Doppler echocardiography, pulse wave tissue Doppler imaging (PW-TDI) and CDMI. RESULTS: Mean left ventricular (LV) ejection fraction did not differ in ACROUNTR and in controls; at variance, ACROUNTR patients had reduced mean LV diastolic function (E/A ratio: 0.96+/-0.3 vs controls: 1.6+/-0.3; p<0.002). Impairment of global LV diastolic function was confirmed by PW-TDI in ACROUNTR patients having a normal systolic function. Regional myocardial systolic strain (epsilon) and strain rate (SR) values, indices of regional systolic heart deformation, were lower in ACROUNTR [epsilonsys (S) -19.8+/-2.9 and epsilonsys (L): -17.7+/-2.2] than in controls [epsilonsys (S): -27.9+/-3.8; p<0.001 and epsilonsys (L): -25.3+/-2.6; p<0.001]. In addition, the early phase of diastolic function, evaluated using SR parameters, was impaired in acromegalic patients (p<0.005 vs controls). Strain and SR values were related to serum GH and IGF-I levels (p<0.02) and greatly improved after a 6-month course with SSa [epsilonsys (S) improved to -23.8+/-3.8 (p<0.05) and epsilonsys (L) improved to -24.7+/-2.4 (p<0.03)]. CONCLUSIONS: Our study confirms that ACROUNTR patients have impaired diastolic function. More important, our study clearly shows that ACROUNTR patients have an impairment of regional myocardial systolic function, which is not secondary to diastolic changes. These intramyocardial functional abnormalities improved during medical treatment of acromegaly. It is conceivable that GH-IGF-I excess has detrimental effects either on the diastolic or the systolic phases of heart function.

Relationship between preclinical abnormalities of global and regional left ventricular function and insulin resistance in severe obesity: a Color Doppler Imaging Study.

BACKGROUND: The aim of this study was to evaluate the relationship between insulin resistance and preclinical abnormalities of the left ventricular structure and function detected in severe obesity by Color Doppler Myocardial Imaging (CDMI). Forty-eight consecutive severely obese patients (Group O) (11 males, 37 females, mean age 32.8+/-7 years) were enrolled. Forty-eight sex- and age-matched non-obese healthy subjects were also recruited as controls (Group C). All subjects underwent conventional 2D-Color Doppler echocardiography and CDMI. The homeostasis model assessment insulin resistance index (HOMA-IR) was used to assess insulin resistance results. Obese subjects had a greater left ventricular mass index (by height) (58.8+/-14 g/m(2.7)) than controls (37+/-8 g/m(2.7)) (P<0.0001), owing to compensation response to volume overload caused by a greater cardiac output (P<0.02). Preload reserve was increased in obese subjects, as demonstrated by a significant increase in left atrial dimension (P<0.0001). Obese patients had a slightly reduced LV diastolic function (transmitral E/A ratio: Group O, 1.1+/-0.8 vs Group C, 1.5 +/-0.5; P<0.002). Cardiac deformation assessed by regional myocardial systolic strain and strain rate (SR) values was significantly lower (abnormal) in obese patients than in controls, both at the septum and lateral wall level. These strain and SR abnormalities were significantly related to body mass index. In addition, the early phase of diastolic function, evaluated using SR, was compromised in obese patients (P<0.001). The HOMA-IR values in obese patients were significantly higher (3.09+/-1.6) than those determined in the control group (0.92+/-0.5) (P<0.0001). The HOMA-IR values, in the obese group, were significantly related to systolic strain and SR values sampled at the septum level (P<0.0001). CONCLUSION: In conclusion, this study has demonstrated that obese patients pointed out systolic structural and functional abnormalities at a preclinical stage, in particular through strain and SR analysis; on the other hand, those altered CDMI parameters well distinguish obese subjects as compared with the control group. Furthermore, another main finding of the study was that myocardial deformation (systolic strain) could have a correlation with insulin resistance level.

[Site specific mutagenesis by homologous recombination in embryonic stem cells]. / Mutagenèse dirigée par recombinaison homologue dans les cellules ES.

Twenty years ago, the production of mice whose genomes have been deliberatly modified revolutionised biology. Indeed, it is now possible to eliminate a gene's expression to various levels in desired locations, and also to broadcast these genetic modifications created in vitro to the progeny. The isolation and culture of embryonic stem cells (ES) and the discovery of the mechanism of homologous recombination between two sequences of DNA in the 80's, have contributed to the development of site-directed mutagenesis. Today, site specific mutagenesis by homologous recombination in embryonic stem cells is a powerful technique and is widely used throughout the world. In parallel, new techniques to invalidate targeted genes are emerging. These genetics tools, which we will introduce, allow for a better understanding of a gene's function both in fundamental and clinical research. It is now possible to create murine models of human genetic diseases including Lesch-Nhyan syndrome, Adenomatous Polyposis and Duchenne muscular dystrophy which we will discuss as examples.

Quantification methods in contrast echocardiography.

New technologies and the availability of new echo-contrast agents have resulted in advances of diagnostic and prognostic indications of left ventricular opacification (LVO) and myocardial perfusion. The clinical diagnostic value of ultrasound contrast media for LVO and its impact on the clinical decision-making process has been demonstrated in several studies. Recent research aims at developing new quantitative software to improve the delineation of the endocardial border, to assess 3D myocardial perfusion for more accurate regional/global LV function measurements, and to evaluate 4D intra-cardiac flow dynamics. Furthermore, a general consensus has been reached on the incremental value of myocardial contrast echocardiography (MCE) for obtaining additional information in both chronic and acute coronary artery disease (CAD) patients and on the possibility to make quantitative measurements of microvascular damage. Q-contrast is a new software system which provides quantitative measurements to generate parametric images of microcirculatory flow. In a research project including 120 patients, Q-contrast software has been tested to assess the role of contrast in AMI (Acute Myocardial Infarction Contrast Imaging (A.M.I.C.I. Study); good agreement between parametric MCE and SPECT has been found. Preliminary results further confirm that quantitative MCE may provide additional clinical value over qualitative information for the assessment of LV function and of the effects of coronary artery disease on the myocardial microcirculation (viability, ischemia or infarct).

Molusco contagioso: infección oportunista del VIH/SIDA / Molluscum contagiosum: an HIV/AIDS oportunistic infection

En el presente trabajo se realizó una revisión de la literatura sobre el molusco contagioso asociado a infecciones oportunistas del virus de inmunodeficiencia humana y el síndrome de inmunodeficiencia adquirida (VIH/SIDA). Este trabajo se realizó con la finalidad de compartir con la comunidad odontológica la información recolectada

Chagas seropositive donors in kidney transplantation.

Among 239 kidney transplantations between September 1992 and September 1997, nine recipients' kidneys were obtained from Chagas seropositive donors. All of these patients were treated with benznidazole (5 mg/kg/d) for 14 days starting on day 0. None of them experienced acute Chagas disease or seroconversion even after 10 years follow-up. We concluded that, due to cadaver shortage, donors with positive serology for Chagas disease should not be excluded.

Blood pressure independent association of microalbuminuria and left ventricular hypertrophy in hypertensive men.

BACKGROUND: Rather unique amongst the prognostic predictors, microalbuminuria (MA, albuminuria: 15-200 microg min-1) is associated with several cardiovascular risk factors including left ventricular hypertrophy (LVH). The relationship, usually assumed to reflect an increased blood pressure (BP) load on the heart and the kidney, may, however, represent more than a haemodynamic correlate. METHODS: To evaluate this possibility, we related MA to left ventricular mass index (LVMI) and other functional and structural echocardiographic parameters, office and 24-h BP, weight, lipids and smoking status in 330 never treated nondiabetic hypertensive men. RESULTS: The risk of MA increased linearly by ascending quartiles of LVMI and was 2.3-fold higher in the presence of LVH after adjustment for age, left atrial size, mean fractional shortening. Systolic BP, either office or 24 h, and smoking status were the only additional independent predictors in multivariate logistic regression models. The BP-adjusted risk of MA was about twofold higher in patients with LVH, either concentric or eccentric, and neutral in those with concentric remodelling compared with normal geometry. CONCLUSIONS: The association between elevated LVMI and MA independent of several other potential confounders, systolic BP in particular, is consistent with the existence of cardiac albuminuric factors, possibly of hormonal nature, which are to be identified more precisely. The extent to which LVH explains the predictive power of MA for morbid events independent of the BP load remains unknown.

Coronary microcirculation into different models of left ventricular hypertrophy-hypertensive and athlete's heart: a contrast echocardiographic study.

The study was carried out in two different models of left ventricular hypertrophy: athlete's heart and essential arterial hypertension. Three groups of strictly age-matched males were studied: one group of 10 young adult untreated essential hypertensive patients (H), a second group of 10 athletes (A), and a group of 10 healthy individuals as controls (C). A Sonos 5500 echograph with S4 harmonic transducer was used with Levovist (ultrasonic tracer) before and after dipyridamole injection; digitised images of quantitative myocardial contrast echocardiography were collected with Power Harmonic Doppler. Angio images were analysed using dedicated PC software by placing a region-of-interest on the septum. Peak intensity, half-time (HT), the area under the curve of appearance and disappearance of microbubbles at 2/3 of PI, both in absolute and indexed values (/LVMi), were sampled. The per cent increase of PI after dipyridamole was significantly higher in C (+73%, P < 0.01) than in H (+31%) and in A (+33%) (P < 0.05). The area of appearance was significantly lower in H in comparison with C and A, both at rest and after vasodilatation. The disappearance area after dipyridamole was significantly higher in C and in A (+124%) than in H (+104%) (P < 0.05). Some hypothesis could be made: an impairment in the coronary microcirculatory function in hypertensive patients could be because of an in-crease in the arteriolar resistance. Angiogenesis and several different functional adaptations are the mechanisms that allow an optimal distribution of oxygen and of substrates to the hypertrophied myocardium of the athletes.