Author Correction: Aldo-keto reductase 1C2 (AKR1C2) as the second gene associated to non-syndromic primary lipedema: investigating activating mutation or overexpression as causative factors.

Correction to: Eur Rev Med Pharmacol Sci 2023; 27 (6 Suppl): 127-136-DOI: 10.26355/eurrev_202312_34697 After publication and following some post-publication concerns, the authors have applied the following corrections to the galley proof. -       The conflict of interest section has been amended as follows: J. Kaftalli and G. Marceddu are employees at MAGI EUREGIO. K. Donato is employee at MAGI EUREGIO and MAGISNAT. M. Bertelli is president of MAGI EUREGIO, MAGISNAT, and MAGI's LAB. G. Bonetti, K. Dhuli, A. Macchia, and P.E. Maltese are employees at MAGI's LAB. M. Bertelli, P.E. Maltese, K. Louise Herbst, Sa. Michelini, Se. Michelini, and P. Chiurazzi are patent inventors (US20220362260A1). M. Bertelli, P.E. Maltese, G. Marceddu are patent inventors (US20230173003A1). M. Bertelli, K. Dhuli and P.E. Maltese are patent inventors (WO2022079498A1). M. Bertelli, P.E. Maltese, Sa. Michelini, Se. Michelini, P. Chiurazzi, K. Louise Herbst, J. Kaftalli, K. Donato, and A. Bernini are patent applicants (Application Number 18/516,241). M. Bertelli, K. Donato, P. Chiurazzi, G. Marceddu, K. Dhuli, G. Bonetti and J. Kaftalli are patent applicants (Application Number: 18/466.879). M. Bertelli, G. Bonetti, G. Marceddu, K. Donato, K. Dhuli, J. Kaftalli, Sa. Michelini, and K. Louise Herbst are patent applicants (Application Number 63/495,155). The remaining authors have no conflict of interest to disclose. -       Figure 5 has been modified as follows to better distinguish outliers: -       The legend of Figure 5 has to be modified as follows: Relative expression of AKR1C1 and AKR1C3 in different groups (CTR = non affected controls, L = lipedema patients without overexpression of AKR1C2, L-over = Lipedema patients with overexpression of AKR1C2), showing that lipedema patients expressed AKR1C1 and AKR1C3 levels similar to the control group. Outliers are reported as black triangles. There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/34697.

AKR1C1 and hormone metabolism in lipedema pathogenesis: a computational biology approach.

OBJECTIVE: Lipedema is an autosomal dominant genetic disease that mainly affects women. It is characterized by excess deposition of subcutaneous adipose tissue, pain, and anxiety. The genetic and environmental etiology of lipedema is still largely unknown. Although considered a rare disease, this pathology has been suggested to be underdiagnosed or misdiagnosed as obesity or lymphedema. Steroid hormones seem to be involved in the pathogenesis of lipedema. Indeed, aldo-keto reductase family 1 member C1 (AKR1C1), a gene coding for a protein involved in steroid hormones metabolism, was the first proposed to be correlated with lipedema. PATIENTS AND METHODS: In this study, we employed a molecular dynamics approach to assess the pathogenicity of AKR1C1 genetic variants found in patients with lipedema. Moreover, we combined information theory and structural bioinformatics to identify AKR1C1 polymorphisms from the gnomAD database that could predispose to the development of lipedema. RESULTS: Three genetic variants in AKR1C1 found in patients with lipedema were disruptive to the protein's function. Furthermore, eight AKR1C1  variants found in the general population could predispose to the development of lipedema. CONCLUSIONS: The results of this study provide evidence that AKR1C1 may be a key gene in lipedema pathogenesis, and that common polymorphisms could predispose to lipedema development.

Aldo-keto reductase 1C2 (AKR1C2) as the second gene associated to non-syndromic primary lipedema: investigating activating mutation or overexpression as causative factors.

OBJECTIVE: Lipedema is a debilitating chronic condition predominantly affecting women, characterized by the abnormal accumulation of fat in a symmetrical, bilateral pattern in the extremities, often coinciding with hormonal imbalances. PATIENTS AND METHODS: Despite the conjectured role of sex hormones in its etiology, a definitive link has remained elusive. This study explores the case of a patient possessing a mutation deletion within the C-terminal region of Aldo-keto reductases Member C2 (AKR1C2), Ser320PheTer2, that could lead to heightened enzyme activity. A cohort of 19 additional lipedema patients and 2 additional affected family members14 were enrolled in this study. The two additional affected family members are relatives of the patient with the AKR1C1 L213Q variant, which is included in the 19 cohorts and described in literature. RESULTS: Our investigation revealed that AKR1C2 was overexpressed, as quantified by qPCR, in 5 out of 21 (24%) lipedema patients who did not possess mutations in the AKR1C2 gene. Collectively, these findings implicate AKR1C2 in the pathogenesis of lipedema, substantiating its causative role. CONCLUSIONS: This study demonstrates that the activating mutation in the enzyme or its overexpression is a causative factor in the development of lipedema. Further exploration and replication in diverse populations will bolster our understanding of this significant connection.

Nutrigenomics: SNPs correlated to vitamins' deficiencies.

Abstract: Nutrients can influence the physiological processes in the body by interacting with molecular systems. Including nutrigenetics and nutrigenomics, nutritional genomics focuses on how bio-active food components interact with the genome. The purpose of this study is to clarify how nutrigenomics and vitamin dietary deficits relate to one another. Food tolerances among human sub-populations are known to vary due to genetic variation, which may also affect dietary needs. This raises the prospect of tailoring a person's nutritional intake for optimum health and illness prevention, based on their unique genome. To better understand the interplay between genes and nutrients and to plan tailored weight loss, nutrigenetic testing may soon become a key approach.

Nutrigenomics: SNPs correlated to physical activity, response to chiropractic treatment, mood and sleep.

Abstract: Nutrigenomics, a rapidly evolving field that bridges genetics and nutrition, explores the intricate interactions between an individual's genetic makeup and how they respond to nutrients. At its core, this discipline focuses on investigating Single Nucleotide Polymorphisms (SNPs), the most common genetic variations, which significantly influence a person's physiological status, mood regulation, and sleep patterns, thus playing a pivotal role in a wide range of health out-comes. Through decoding their functional implications, researchers are able to uncover genetic factors that impact physical fitness, pain perception, and susceptibility to mood disorders and sleep disruptions. The integration of nutrigenomics into healthcare holds the promise of transformative interventions that cater to individual well-being. Notable studies shed light on the connection between SNPs and personalized responses to exercise, as well as vulnerability to mood disorders and sleep disturbances. Understanding the intricate interplay between genetics and nutrition informs targeted dietary approaches, molding individual health trajectories. As research advances, the convergence of genetics and nourishment is on the brink of reshaping healthcare, ushering in an era of personalized health management that enhances overall life quality. Nutrigenomics charts a path toward tailored nutritional strategies, fundamentally reshaping our approach to health preservation and preventive measures.

Nutrigenomics: SNPs correlated to Food Preferences and Susceptibilities.

Background: Nutrigenomics explores the intricate interplay between single nucleotide polymorphisms (SNPs), food preferences, and susceptibilities. Methods: This study delves into the influence of SNPs on food sensitivities, allergies, tyramine intolerance, and taste preferences. Genetic factors intricately shape physiological reactions to dietary elements, with polymorphisms contributing to diverse sensitivities and immune responses. Results: Tyramine intolerance, arising from metabolic inefficiencies, unveils genetic markers exerting influence on enzyme function. SNPs transcend genetic diversity by exerting substantial impact on food sensitivities/allergies, with specific variants correlating to heightened susceptibilities. Genes accountable for digesting food components play pivotal roles. Given the rising prevalence of food sensitivities/allergies, understanding genetic foundations becomes paramount. In the realm of taste and food preferences, SNPs sculpt perception and choice, yielding variances in taste perception and preferences for sweetness, bitterness, and umami. This genetic medley extends its reach to encompass wider health implications. Conclusions: In this review article, we have focused on how polymorphisms wield significant sway over physiological responses, sensitivities, and dietary inclinations. Unraveling these intricate relationships illuminates the path to personalized nutrition, potentially revolutionizing tailored recommendations and interventions.

Bioetics Issues of Artificial Placenta and Artificial Womb Technology.

Abstract: The worldwide infertility crisis and the increase in mortality and morbidity among infants, due to preterm births and associated complications, have stimulated research into artificial placenta (AP) and artificial womb (AW) technology as novel solutions. These technologies mimic the natural environment provided in the mother's womb, using chambers that ensure the supply of nutrients to the fetus and disposal of waste substances through an appropriate mechanism. This review aims to highlight the background of AP and AW technologies, revisit their historical development and proposed applications, and discuss challenges and bioethical and moral issues. Further research is required to investigate any negative effects of these new technologies, and ethical concerns pertaining to the structure and operation of this newly developed technology must be addressed and resolved prior to its introduction to the public sphere.

In Memory of Professor Derek Pheby.

Abstract: Professor Derek Pheby's passing in November 2022 marked a profound loss for the scientific community. Professor Derek Pheby, a stalwart figure in the fields of autoimmune diseases and bioethics, was known for his dedication to scientific research and patients' support, particularly for those affected by paraneoplastic autoimmune syndromes. Professor Pheby made significant contributions to research, especially about Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). His leadership of the ME Biobank and scientific coordination of EUROMENE demonstrated his commitment to pushing boundaries and fostering international collaborations. Professor Pheby's scientific work addressed various aspects of ME/CFS, from physician education to patient needs, the development of a post-mortem tissue bank, and effective treatments. Beyond his medical career, Professor Pheby was a crucial member of the Independent Ethics Committee of MAGI, he was a poet, humanitarian, and advocate for child protection. His generosity and boundless spirit left an enduring legacy, fostering innovative research in the pursuit of combating autoimmune diseases.

Human Cloning: Biology, Ethics, and Social Implications.

Abstract: This scholarly article delves into the multifaceted domains of human cloning, encompassing its biological underpinnings, ethical dimensions, and broader societal implications. The exposition commences with a succinct historical and contextual overview of human cloning, segueing into an in-depth exploration of its biological intri-cacies. Central to this biological scrutiny is a comprehensive analysis of somatic cell nuclear transfer (SCNT) and its assorted iterations. The accomplishments and discoveries in cloning technology, such as successful animal cloning operations and advances in the efficiency and viability of cloned embryos, are reviewed. Future improvements, such as reprogramming procedures and gene editing technology, are also discussed. The discourse extends to ethical quandaries intrinsic to human cloning, entailing an extensive contemplation of values such as human dignity, autonomy, and safety. Furthermore, the ramifications of human cloning on a societal plane are subjected to scrutiny, with a dedicated emphasis on ramifications encompassing personal identity, kinship connections, and the fundamental notion of maternity. Culminating the analysis is a reiteration of the imperative to develop and govern human cloning technology judiciously and conscientiously. Finally, it discusses several ethical and practical issues, such as safety concerns, the possibility of exploitation, and the erosion of human dignity, and emphasizes the significance of carefully considering these issues.

Targeting Mast Cells: Sodium Cromoglycate as a Possible Treatment of Lipedema.

Background: Mast cells are immune cells that mediate hypersensi-tivity and allergic reactions in the body, secreting histamine and other inflammatory molecules. They have been associated with different inflammatory conditions such as obesity and other adipose tissue di-sorders. Lipedema is a chronic disease characterized by an abnormal accumulation of adipose tissue on the legs and arms, pain, and other symptoms. Mast cells may play a role in the pathology of lipedema. Objective: Pilot study to determine levels of histamine and its metabolites in lipedema subcutaneous adipose tissue (SAT) biopsy samples, and to test sodium cromoglycate for the treatment of mast cells in women with lipedema. Methods: Biopsies from lipedema and control SAT were collected and analyzed histologically for the presence of mast cells. Mass spec-trometry was used to measure the levels of histamine, a key marker of mast cells, and its metabolites in SAT in women with lipedema and controls, and after a group of women with lipedema were administered oral and topical doses of sodium cromoglycate for two weeks. Results: Histological examination of biopsies from lipedema patients confirmed the presence of mast cells. Metabolomic analysis revealed high levels of histamine and its metabolites in samples from women with lipedema compared to controls. Following a two-week treatment period, lipedema tissue samples exhibited reduced levels of histamine, suggesting a reduction of mast cell activity. Conclusion: Sodium cromoglycate has the ability to stabilize mast cells and reduce histamine levels in lipedema patients, which could be useful in lowering the symptoms of lipedema.

Characterization of somatic mutations in the pathogenesis of lipedema.

Background: Lipedema, a complex and enigmatic adipose tissue disorder, remains poorly understood despite its significant impact on the patients' quality of life. Genetic investigations have uncovered potential contributors to its pathogenesis, including somatic mutations, which are nonheritable genetic alterations that can play a pivotal role in the development of this disease. Aim: This review aims to elucidate the role of somatic mutations in the etiology of lipedema by examining their implications in adipose tissue biology, inflammation, and metabolic dysfunction. Results: Studies focusing on leukocyte clones, genetic alterations like TET2 and DNMT3A, and the intricate interplay between adipose tissue and other organs have shed light on the underlying mechanisms driving lipedema. From the study of the scientific literature, mutations to genes correlated to three main pathways could be involved in the somatic development of lipedema: genes related to mitochondrial activity, genes related to localized disorders of subcutaneous adipose tissue, and genes of leukocyte clones. Conclusions: The insights gained from these diverse studies converge to highlight the complex genetic underpinnings of lipedema and offer potential avenues for therapeutic interventions targeting somatic mutations to alleviate the burden of this condition on affected individuals.

The orchestration of gene expression and the editing role of microRNA.

In this short educational communication the ESPU Research Committee presents the role of non-coding RNA and how these can affect gene expression. In particular we discuss the role of microRNA on post transcriptional changes and how these may cause pathological conditions within Pediatric Urology and how microRNA could be useful in future clinical practice.

Genetics of fat deposition.

Adipose tissue distribution usually varies among men and women. In men, adipose tissue is known to accumulate in the abdominal region surrounding the visceral organs (android fat distribution) whereas, in women, the accumulation of adipose tissue generally occurs in the gluteal-femoral regions (gynoid fat distribution). In some cases, however, android distribution can be found in women and gynoid distribution can be found in men. The regulation of adipose tissue accumulation involves interaction of a variety of genetic and environmental factors. This review examines genetic factors that cause differential distribution of adipose tissue in different depots of the body, between men and women and between different ethnicities. Genome-wide association studies can be used to identify genetic associations with the distribution and accumulation of adipose tissue. Insight into adipose tissue accumulation and distribution mechanisms could lead to development of personalized interventions for people who develop increased fat mass.

Steroid-converting enzymes in human adipose tissues and fat deposition with a focus on AKR1C enzymes.

Adipocytes express various enzymes, such as aldo-keto reductases (AKR1C), 11ß-hydroxysteroid dehydrogenase (11ß-HSD), aromatase, 5α-reductases, 3ß-HSD, and 17ß-HSDs involved in steroid hormone metabolism in adipose tissues. Increased activity of AKR1C enzymes and their expression in mature adipocytes might indicate the association of these enzymes with subcutaneous adipose tissue deposition. The inactivation of androgens by AKR1C enzymes increases adipogenesis and fat mass, particularly subcutaneous fat. AKR1C also causes reduction of estrone, a weak estrogen, to produce 17ß-estradiol, a potent estrogen and, in addition, it plays a role in progesterone metabolism. Functional impairments of adipose tissue and imbalance of steroid biosynthesis could lead to metabolic disturbances. In this review, we will focus on the enzymes involved in steroid metabolism and fat tissue deposition.

COVID-19 and research in pediatric urology.

COVID-19 began in December 2019 then spread worldwide. Providers, including pediatric urologists, had to adapt their clinical processes, and many non-covid research activities were suspended. COVID-19 impacts how research is financed, performed, and published, and is itself the subject of intense research. We present current research and publications specifically related to the urinary tract and the pediatric population.

Clinical outcomes after first-line HIV treatment failure in South Africa: the next cascade of care.

INTRODUCTION: There is limited literature on the appropriateness of viral load (VL) monitoring and management of detectable VL in public health settings in rural South Africa. METHODS: We analysed data captured in the electronic patient register from HIV-positive patients ≥ 15 years old initiating antiretroviral therapy (ART) in 17 public sector clinics in rural KwaZulu-Natal, during 2010-2016. We estimated the completion rate for VL monitoring at 6, 12, and 24 months. We described the cascade of care for those with any VL measurement ≥ 1000 HIV-1 RNA copies/mL after ≥ 20 weeks on ART, including the following proportions: (1) repeat VL within 6 months; (2) re-suppressed; (3) switched to second-line regimen. RESULTS: There were 29 384 individuals who initiated ART during the period [69% female, median age 31 years (interquartile range 25-39)]. Of those in care at 6, 12, and 24 months, 40.7% (9861/24 199), 34% (7765/22 807), and 25.5% (4334/16 965) had a VL test at each recommended time-point, respectively. The VL results were documented at all recommended time-points for 12% (2730/22 807) and 6.2% (1054/16 965) of ART-treated patients for 12 and 24 months, respectively. Only 391 (18.3%) of 2135 individuals with VL ≥ 1000 copies/mL on first-line ART had a repeat VL documenting re-suppression or were appropriately changed to second-line with persistent failure. Completion of the treatment failure cascade occurred a median of 338 days after failure was detected. CONCLUSION: We found suboptimal VL monitoring and poor responses to virologic failure in public-sector ART clinics in rural South Arica. Implications include increased likelihood of morbidity and transmission of drug-resistant HIV.

Pheromone receptors and their putative ligands: possible role in humans.

Pheromones are ectohormones that play an important role in communication and behavior. Pheromones and pheromone receptor genes are important in mice and other mammals that rely heavily on pheromone cues to survive. Although there is controversy about whether pheromones and pheromone receptor genes have the same importance or are even active in humans, there are some hints that they might have roles in sociosexual behavior and mental disorders. The aim of this qualitative review was to provide an overview of the state of the art regarding pheromones and pheromone receptors in humans and their possible implications in human physiology and pathology. An electronic search was conducted in MEDLINE, PubMed and Scopus databases for articles published in English up to December 2018. The search concerned a possible role of pheromones and pheromone receptors in humans with implications for sociosexual behavior, mental disorders, the menstrual cycle and nutrition. Pheromone communication in humans has not been definitively demonstrated. However, the potential ability of putative pheromones to activate the hypothalamus, which controls the release of many hormones, suggests they could have a role in systemic functions in humans. Future confirmation of the effects of pheromones and pheromone receptors in humans could be useful in the prevention and treatment of various human disorders.