Dario Manfellotto

Maternal Diastolic Dysfunction and Left Ventricular Geometry in Gestational Hypertension

Abstract—The objective of this study was to evaluate diastolic parameters and left ventricular geometry in gestational hypertension. Twenty-one consecutive pregnant women with gestational hypertension and 21 normotensive women matched for age and gestational age were enrolled in the third trimester of gestation. Echocardiographic and uterine color Doppler evaluations were performed. Systolic, diastolic, and mean blood pressure, total vascular resistance (TVR), and uterine resistance index were higher in hypertensive women than in control subjects (P <0.01). Left atrial function and cardiac output were significantly lower in gestational hypertension (P <0.01). Patients with gestational hypertension had longer left ventricular isovolumetric relaxation time (IVRT) (P <0.0001); lower velocity-time integral of the A wave (P <0.05) and of the diastolic pulmonary vein flow (P <0.05); and higher velocity-time integral of the reverse pulmonary vein flow (P <0.05). Systolic fraction of the pulmonary vein flow was higher in women with gestational hypertension than in control subjects (P <0.01); the difference in duration of pulmonary vein flow and A wave was closer to 0 in gestational hypertension (P <0.0001). Altered left ventricular geometry was found in 100% of hypertensive patients and in 19.05% of normotensive patients (P <0.001). IVRT, left ventricular end-systolic volume, atrial function, and uterine resistance index were directly related to TVR (P <0.01); deceleration time of the E wave showed a quadratic correlation with TVR (P <0.01). Gestational hypertension is characterized by an altered cardiac geometric pattern of concentric hypertrophy. The altered geometric pattern assessed during gestational hypertension is associated, in our study, with depressed systolic function, high TVR, altered diastolic function, and left atrial dysfunction. Deceleration time of the E wave, IVRT, and left atrial fractional area change, found in concomitance with the highest TVR, may be useful in the evaluation of cardiac function and hemodynamics present in pregnancy-induced hypertension.

Human genetic variation of CYP450 superfamily: analysis of functional diversity in worldwide populations

AIM The present study aimed to investigate the human genetic diversity of the CYP450 superfamily in order to identify functional interethnic differences and analyze the role of CYP450 enzymes in human adaptation. MATERIALS & METHODS A computational analysis of genetic and functional differences of the 57 CYP450 genes was performed using the Human Genome Diversity Project and HapMap data; comprising approximately 1694 individuals belonging to 62 human populations. RESULTS Twenty-six CYP450 SNPs with F-statistics significantly different than the general distribution were identified. Some showed high differentiation among human populations, suggesting that functional interethnic differences may be present. Indeed, some of these are significantly associated with drug response or disease risk. Furthermore, our data highlighted that TBXAS1 and genes in CYP3A cluster may have a role in some processes of human adaptation. CONCLUSION Our study provided an analysis of genetic diversity of CYP450 superfamily, identifying functional differences among ethnic groups and their related clinical phenotypes.

Glutathione S-transferase gene polymorphisms and air pollution as interactive risk factors for asthma in a multicentre Italian field study: A preliminary study.

Abstract Background: Asthma is one of the most common chronic diseases. Several studies have indicated that oxidative stress impairs pulmonary function. Glutathione S-transferases (GSTs) are believed to be critical in the protection of cells from reactive oxygen species. Aim: In this case-control study we analysed the possible association between polymorphism in several cytosolic GST genes, air pollution and asthma development. Methods: Genotyping of GSTM1 and GSTT1 genes was carried out by a multiplex PCR; GSTA1, GSTO1, GSTO2, GSTP1 polymorphisms were determined using the PCR-RFLP method. Data on atmospheric pollutants were collected by the regional air-quality monitoring network. Results: Among all the polymorphisms studied, the frequencies of GSTA1, GSTM1, GSTO2 and GSTT1 genotypes found in the group of asthmatic patients seem to differ from the frequencies of those found in the control group. Air pollutants were analysed and the air quality parameters considered proved to be significantly different, and therefore suitable for this study. Conclusion: The final result of this research should hopefully lead to a better understanding of gene–environment interactions, so allowing earlier prediction and diagnosis of asthma disease and providing an efficient means of prevention.

The Impact of Kidney Development on the Life Course: A Consensus Document for Action

Hypertension and chronic kidney disease (CKD) have a significant impact on global morbidity and mortality. The Low Birth Weight and Nephron Number Working Group has prepared a consensus document aimed to address the relatively neglected issue for the developmental programming of hypertension and CKD. It emerged from a workshop held on April 2, 2016, including eminent internationally recognized experts in the field of obstetrics, neonatology, and nephrology. Through multidisciplinary engagement, the goal of the workshop was to highlight the association between fetal and childhood development and an increased risk of adult diseases, focusing on hypertension and CKD, and to suggest possible practical solutions for the future. The recommendations for action of the consensus workshop are the results of combined clinical experience, shared research expertise, and a review of the literature. They highlight the need to act early to prevent CKD and other related noncommunicable diseases later in life by reducing low birth weight, small for gestational age, prematurity, and low nephron numbers at birth through coordinated interventions. Meeting the current unmet needs would help to define the most cost-effective strategies and to optimize interventions to limit or interrupt the developmental programming cycle of CKD later in life, especially in the poorest part of the world.

GSTO1*E155del polymorphism associated with increased risk for late-onset Alzheimer's disease: association hypothesis for an uncommon genetic variant

Glutathione S-transferases are multifunctional enzymes involved in cellular detoxification. A genetic linkage was found between Alzheimers Disease (AD) and the chromosome 10q, where the GSTO1 and GSTO2 genes are located, leading to the hypothesis that GST Omega class (GSTO) genes may be an AD risk factor. Since it is still controversial, we decided to explore GSTO polymorphisms in Italian cohorts. We analyzed 119 AD patients and 114 healthy controls for the GSTO gene polymorphisms. In particular we investigated two common polymorphisms (GSTO1*A140D, GSTO2*N142D) and two uncommon variants (GSTO1*E155del, GSTO1*E208K) to find loci associated with AD risk. Detection of GSTO1*A140D and GSTO2*N142D was performed by PCR-RFLP, while GSTO1*E155del and GSTO1*E208K were detected using confronting two-pair primer and allele specific PCR, respectively. While GSTO1*A140D, GSTO1*E208K and GSTO2*N142D polymorphisms did not show significant outcomes, the GSTO1*E155del polymorphism is associated with AD [P=0.003; adjusted OR=3.70 (1.57-8.75)]. Our results suggest that GSTO1-1 plays a role in AD since the GSTO1*del155 variant is involved in changes in GSTO1-1 activities decreasing in enzyme stability. Specifically, three hypotheses may explain the role of GSTO1-1 in the pathophysiology of AD: the antioxidant activity of GSTO1-1 may protect brain tissue against oxidative stress; GSTO1-1 activity regulate interleukin-1β activation and its genetic variation may act to modulate inflammation in AD; GSTO1-1 is involved in the arsenic biotransformation pathway and gene polymorphisms may be implicated in the modulation of arsenic neurotoxicity. In conclusion, we hypothesized that GSTO1*E155del is an uncommon genetic variant associated with AD risk.

GSTM1 null genotype as risk factor for late-onset Alzheimer's disease in Italian patients

Alzheimers disease (AD) is the most common form of dementia in the elderly. The causes of AD are very complex but there is general agreement about the existence of a link between Alzheimers disease and oxidative stress. The Glutathione S-transferases (GSTs) act to detoxify products of oxidation that cause damage to macromolecules. Particular attention has been focused on GST genes because polymorphisms are important determinants of disease risk. To evaluate if GSTA1, GSTM1, GSTP1, and GSTT1 genes are associated with LOAD we screened a case-control population (n=311). Differences in genotype distributions between AD patients and controls were found only for the GSTM1 null genotype (P<0.001). In addition, a logistic regression analysis also conferred a positive association between the GSTM1 null genotype and LOAD after adjustment for age and gender (OR=2.09; 95%CI=1.31-3.35). The GSTM1 enzyme detoxifies substances such as exogenous and endogenous metabolites and plays a regulatory role in cellular signaling. Previous studies have highlighted that GSTM1 has a role in neurodegenerative disorders, but no data have associated the GSTM1 gene with AD risk. Our outcome suggests that the GSTM1 null genotype is a risk factor for AD in Italian patients.

A developmental approach to the prevention of hypertension and kidney disease: a report from the Low Birth Weight and Nephron Number Working Group

In 2008, the World Health Assembly endorsed the Global Noncommunicable Disease (NCD) Action Plan based on the realization that NCDs caused more deaths than communicable diseases worldwide. 1 This plan strongly advocates prevention as the most effective strategy to curb NCDs. The “Life Course Approach”, also recently highlighted in the Minsk Declaration, reflects the increasing recognition that early development impacts later-life health and disease. 1,2 Optimization of early development offers the opportunity for true primary prevention of NCDs. Developmental programming in the kidney has been recognized for over 2 decades but its contribution to the global burden of kidney diseases remains underappreciated by policy makers. 3 Given the many factors known to impact fetal kidney development, including maternal health and nutrition, exposure to stress, poverty, pollutants, drugs and infections during gestation, 3 a holistic strategy to prevent such programming effects is consistent with the “Life-Course” approach and aligns with the United Nations Sustainable Development Goals (SDG) to foster health. 2,4 Chronic kidney disease (CKD) is an important contributor to the NCD burden that has been relatively neglected in the Global NCD Action Plan, despite CKD being a major cause of hypertension, and a major risk multiplier of cardiovascular disease 1,5 While the prevalence of CKD in many lower-income countries remains unknown, CKD is more prevalent among disadvantaged populations within industrialized nations, e.g. African Americans and Aboriginal Australians. 6 People receiving dialysis or transplantation are projected to double from 2.6 million in 2010 to 5.4 million in 2030. 7 Between 2.3 and 7.1 million adult people died from lack of access to dialysis and transplantation in lower-income countries in 2010. 7 Given the clinical consequences and often prohibitively high costs of treatment, prevention and early detection are the only sustainable solutions to address this growing global burden. To address the neglected issue of developmental programming of kidney disease and hypertension, a multidisciplinary workgroup, including international expert obstetricians, neonatologists and nephrologists (see Appendix), was convened. We argue that the Global NCD Action Plan does not adequately address the impact of developmental origins of NCDs which is globally but is particularly important in low- and middle-income countries (LMICs) where developmental risk is highest and the burden of NCDs is growing fastest. 8 The working group identified the need to raise awareness of the role of developmental programming in renal disease, and suggests locally adapted preventive strategies that could have long-term benefits on health and heath cost savings worldwide, integrating obstetrical, neonatal and nephrology perspectives.

Glutathione S-transferase genes and the risk of recurrent miscarriage in Italian women.

OBJECTIVE To investigate the role of glutathione S-transferases (GSTs) in the pathogenesis of recurrent miscarriage (RM). DESIGN Genetic association study. SETTING University of Rome, Tor Vergata and San Giovanni Calibita, Fatebenefratelli Hospital. PATIENT(S) One hundred twenty-one women with RM and 113 women without pregnancy complications. INTERVENTION(S) Genomic DNA extracted from buccal cells and screening of positive/null genotypes of GSTM1 and GSTT1 genes and single nucleotide polymorphisms of GSTA1, GSTO2, and GSTP1 genes. MAIN OUTCOME MEASURE(S) Occurrence of GST polymorphisms. RESULT(S) Women with at least one GSTA1*-69T allele are more frequent in the RM group than in the control group: 67% vs. 48%, respectively. Significant outcomes were obtained considering different genetic models: codominant, dominant, and log-additive. In addition, the combined analysis suggests that GSTA1 and GSTM1 variants have a significant interaction in RM risk. CONCLUSION(S) Our study highlighted a significant association between the GSTA1 gene and an increased risk of RM. In particular, the -69T allele in the GSTA1 gene may be considered as a predisposing factor of RM.

GSTA1, GSTO1 and GSTO2 gene polymorphisms in Italian asthma patients

1. Previous studies have established that genetic alterations in glutathione S‐transferase enzymes may change the ability of the airway to deal with toxic substances and increase the risk of asthma. The present study analysed the association between asthma and GSTA1, GSTO1 and GSTO2 gene polymorphisms.

Further Evidence on the Role of Thyroid Autoimmunity in Women with Recurrent Miscarriage

It has been twenty years since the first paper reporting the association between thyroid antibodies (TAIs) and spontaneous miscarriage was published. Following this observation, several studies have clearly demonstrated an increased prevalence of TAI in patients with recurrent miscarriage (RM). However, the exact mechanism underlying this association remains a matter of debate. The aim of the present study was to evaluate the thyroid function, throughout a specific test, in patient with RM and TAI focusing on the hypothesis that TAI should be an indirect sign of a mild thyroid dysfunction. 46 patients with RM and TAI were included in the study. All patients underwent short TRH stimulation test showing an abnormal response in the vast majority of cases (65%). Normal FT4 and FT3 mean values were found whereas TSH values were in the upper normal range (2.64 ± 1.3 mUI/L). Our data support the hypothesis that in patients with RM the presence of TAI is an indirect sign of a subtle thyroid dysfunction detectable by a specific test. This test give the possibility to identify women with RM in which specific therapeutic approaches could effectively improve the possibility for a successful pregnancy.