Publications by authors named "Stefano Paolacci"

45 Publications

A simultaneous next-generation sequencing approach to the diagnosis of couple infertility.

Minerva Endocrinol (Torino) 2021 May 14. Epub 2021 May 14.

MAGI Euregio, Bolzano, Italy.

Background: Infertility is a disorder of the male and/or female reproductive system, characterized by failure to establish a clinical pregnancy after 12 months of regular unprotected sexual intercourse. On a world basis, about one in six couplesare affected by infertility during their reproductive lifespan. Despite a comprehensive diagnostic work-up, infertility in about 50% of couples remains idiopathic. In this context, a next-generation sequencing (NGS) approach has been suggested to increase diagnostic yield. Accordingly, this study aimed to evaluate the effectiveness of a custom-made NGS gene panel for the simultaneous genetic diagnosis of both partners of a large population of infertile couples.

Methods: We developed a custom-made NGS panel for 229 genes associated with male and female infertility. The panel targeted exons and their flanking regions and was used to screen 99 couples with idiopathic infertility.

Results: NGS sequencing revealed five pathogenic variants in six couples and 17 likely pathogenic variants or variants with uncertain significance (VUS). The pathogenic variants were identified in the following genes: GNRHR, CCDC39, DNAH5, and CCDC103; likely pathogenic variants were identified in TAC3, PROKR2, and CFTR; VUS were identified in CATSPER2, FGFR1, LRRC6, DNAH5, DNAH11, TGFBR3, and DNAI1.

Conclusions: The panel of genes designed for this study allowed the identification of pathogenetic gene mutations and the presence of VUS in 6.1% and 17.2%, respectively, of couples with idiopathic infertility. This is the first study to successfully apply an NGS-based genetic screening including 229 genes known to play a role in both male and female infertility.
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http://dx.doi.org/10.23736/S2724-6507.21.03477-1DOI Listing
May 2021

Immunophenotypical characterization of paraneoplastic neurological syndrome patients: a multicentric study.

J Biosci 2021 ;46

UOC Neurology and Stroke Unit, ASST Lecco, Merate, LC, Italy.

Paraneoplastic neurological syndromes (PNS) are a group of rare and severe immune-mediated disorders that affect the nervous system in patients with cancer. The best way to diagnose a paraneoplastic neurological disorder is to identify anti-onconeural protein antibodies that are specifically associated with various cancers. The aim of this multicentric study was to clinically and immunologically characterize patients with PNS and study their association with cancer. Patients suspected to have PNS were enrolled from various clinical centres and were characterized immunologically. This study population consisted of 112 patients. Onset of PNS was mainly subacute (76 %). PNS patients had various neurological disorders and symptoms. PNS developed before the diagnosis of cancer in 28 definite PNS patients and in six suspected PNS patients. The most frequent autoantibodies detected in PNS patients were anti-Hu and anti-Yo. One definite PNS patient with cerebellar syndrome had anti-Tr antibody and seven patients had atypical antibodies. The literature associates these antibodies with various neurological disorders and cancers. Our observations confirm the important role of autoantibodies in PNS and their importance for the early diagnosis of cancer in PNS patients.
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January 2021

Male Infertility Diagnosis: Improvement of Genetic Analysis Performance by the Introduction of Pre-Diagnostic Genes in a Next-Generation Sequencing Custom-Made Panel.

Front Endocrinol (Lausanne) 2020 26;11:605237. Epub 2021 Jan 26.

MAGI EUREGIO, Bolzano, Italy.

Background: Infertility affects about 7% of the general male population. The underlying cause of male infertility is undefined in about 50% of cases (idiopathic infertility). The number of genes involved in human spermatogenesis is over two thousand. Therefore, it is essential to analyze a large number of genes that may be involved in male infertility. This study aimed to test idiopathic male infertile patients negative for a validated panel of "diagnostic" genes, for a wide panel of genes that we have defined as "pre-diagnostic."

Methods: We developed a next-generation sequencing (NGS) gene panel including 65 pre-diagnostic genes that were used in 12 patients who were negative to a diagnostic genetic test for male infertility disorders, including primary spermatogenic failure and central hypogonadism, consisting of 110 genes.

Results: After NGS sequencing, variants in pre-diagnostic genes were identified in 10/12 patients who were negative to a diagnostic test for primary spermatogenic failure (n = 9) or central hypogonadism (n = 1) due to mutations of single genes. Two pathogenic variants of and genes and three uncertain significance variants of , , and genes were found. Moreover, three variants with high impact were found in , , and genes.

Conclusion: This study suggests that searching for pre-diagnostic genes may be of relevance to find the cause of infertility in patients with apparently idiopathic primary spermatogenic failure due to mutations of single genes and central hypogonadism.
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http://dx.doi.org/10.3389/fendo.2020.605237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872015PMC
June 2021

Genetic Determinants of the Effects of Training on Muscle and Adipose Tissue Homeostasis in Obesity Associated with Lymphedema.

Lymphat Res Biol 2020 Dec 29. Epub 2020 Dec 29.

MAGI'S Lab, Rovereto, Italy.

It is widely accepted that metabolic changes associated with training are influenced by a person's genetic background. In this review, we explore the polymorphisms underlying interindividual variability in response to training of weight loss and muscle mass increase in obese individuals, with or without lymphedema, and in normal-weight subjects. We searched PubMed for articles in English published up to May 2019 using the following keywords: (((physical training[Title/Abstract] OR sport activity[Title/Abstract]) AND predisposition[Title/Abstract]) AND polymorphism [Title/Abstract]). We identified 38 single-nucleotide polymorphisms that may modulate the genetic adaptive response to training. The identification of genetic marker(s) that improve the beneficial effects of training may in perspective make it possible to assess training programs, which in combination with dietary intervention can optimize body weight reduction in obese subjects, with or without lymphedema. This is particularly important for patients with lymphedema because obesity can worsen the clinical status, and therefore, a personalized approach that could reduce obesity would be fundamental in the clinical management of lymphedema.
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http://dx.doi.org/10.1089/lrb.2020.0057DOI Listing
December 2020

Prenatal genetic diagnosis: Fetal therapy as a possible solution to a positive test.

Acta Biomed 2020 11 9;91(13-S):e2020021. Epub 2020 Nov 9.

MAGI EUREGIO, Bolzano, Italy; MAGI'S LAB, Rovereto (TN), Italy; EBTNA-LAB, Rovereto (TN), Italy.

Background: Fetal abnormalities cause 20% of perinatal deaths. Advances in prenatal genetic and other types of screening offer great opportunities for identifying high risk pregnancies.

Methods: Through a literature search, here we summarise what are the prenatal diagnostic technique that are being used and how those techniques may allow for prenatal interventions.

Results: Next generation sequencing and non-invasive prenatal testing are fundamental for clinical diagnostics because of their sensitivity and accuracy in identifying point mutations, aneuploidies, and microdeletions, respectively. Timely identification of genetic disorders and other fetal abnormalities enables early intervention, such as in-utero gene therapy, fetal drug therapy and prenatal surgery.

Conclusion: Prenatal intervention is mainly focused on conditions that may cause death or lifelong disabilities, like spina bifida, congenital diaphragm hernia and sacrococcygeal teratoma; and may be an alternative therapeutic option to termination of pregnancy. However, it is not yet widely available, due to lack of specialized centers.
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http://dx.doi.org/10.23750/abm.v91i13-S.10534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023142PMC
November 2020

Complications related to in vitro reproductive techniques support the implementation of natural procreative technologies.

Acta Biomed 2020 11 9;91(13-S):e2020018. Epub 2020 Nov 9.

MAGI EUREGIO, Bolzano, Italy; MAGI'S LAB, Rovereto (TN), Italy; EBTNA-LAB, Rovereto (TN), Italy.

Background And Aim: Infertility affects ~20% of the couples in the world. Assisted reproductive technologies (ARTs) are currently the most common treatment option for infertility. Nevertheless, ARTs may be associated with complications for mothers and/or offspring. Natural procreative technology (NaProTechnology) is a natural treatment which minimizes these risks by seeking to identify the causes of infertility to enable better treatments. This narrative review summarizes the complications related to ARTs and clarifies how the NaProTechnology approach can help ARTs to achieve better results or be used in alternative to ARTs.

Methods: Data in the literature indicate that NaProTechnology is a natural approach for treating infertility.

Results: The percentage of live births obtained by NaProTechnology is similar to that of ARTs.

Conclusions: An extensive search for the genetic defects causing infertility or subfertility through genetic testing can help both ARTs and NaProTechnology to achieve successful pregnancies. By discovering the underlying causes of infertility, genetic tests enable better family counseling, like the implications of transmitting risk- and disease-alleles to future generations.
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http://dx.doi.org/10.23750/abm.v91i13-S.10525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023144PMC
November 2020

A pilot study on the preventative potential of alpha-cyclodextrin and hydroxytyrosol against SARS-CoV-2 transmission.

Acta Biomed 2020 11 9;91(13-S):e2020022. Epub 2020 Nov 9.

DESAM Institute, Near East University, Nicosia, Cyprus.

Background And Aim Of The Work: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current pandemics. This virus attacks the cells by binding to the transmembrane angiotensin I converting enzyme 2. In this study, we experimented a food supplement containing alpha-cyclodextrin and hydroxytyrosol for the improvement of the defenses against the SARS-CoV-2. Hydroxytyrosol has anti-viral properties and is able to reduce the serum lipids in mice. α-cyclodextrin has the ability to deplete sphingolipids and phospholipids from the cellular membranes. The aim of the present preliminary open non-controlled interventional study was to evaluate the efficacy of alpha-cyclodextrin and hydroxytyrosol in improving defenses against SARS-CoV-2.

Methods: Fifty healthy volunteers at a higher risk of SARS-CoV-2 infection from Northern Cyprus and six positive individuals for SARS-CoV-2 were enrolled in this study. The in silico prediction was performed using D3DOCKING to evaluate the interactions of hydroxytyrosol and alpha-cyclodextrin with proteins involved in the SARS-CoV-2 endocytosis.

Results: The 50 volunteers did not become positive in 15 days for SARS-CoV-2 after the administration of the compound for two weeks, despite they were at higher risk of infection than the general population. Interestingly, in the cohort of six positive patients, two patients were administered the spray and became negative after five days, despite the viral load was higher in the treated subjects than the untreated patients who became negative after ten days. In addition, we identified possible interactions among hydroxytyrosol and alpha-cyclodextrin with the protein Spike and the human proteins ACE2 and TMPRSS2.

Conclusions: We reported on the results of the possible role of alpha-cyclodextrin and hydroxytyrosol in improving defenses against SARS-CoV-2. The next step will be the administration of the compound to a larger cohort in a controlled study to confirm the reduction of the infection rate of SARS-CoV-2 in the treated subjects.
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http://dx.doi.org/10.23750/abm.v91i13-S.10817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023124PMC
November 2020

Pilot study for the evaluation of safety profile of a potential inhibitor of SARS-CoV-2 endocytosis.

Acta Biomed 2020 11 9;91(13-S):e2020009. Epub 2020 Nov 9.

MAGI'S LAB, Rovereto (TN), Italy; MAGI EUREGIO, Bolzano, Italy; EBTNA-LAB, Rovereto (TN), Italy.

Background And Aim Of The Work: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current pandemics of coronavirus disease. This virus is able to attack the cells of the airway epithelium by binding to the transmembrane angiotensin I converting enzyme 2 (ACE2). We developed an oral spray that could inhibit the SARS-CoV-2 endocytosis. The spray contains hydroxytyrosol for its anti-viral, anti-inflammatory and anti-oxidant properties, and α-cyclodextrin for its ability to deplete sphingolipids, that form the lipid rafts where ACE2 localizes. The aim of the present pilot multi-centric open non-controlled observational study was to evaluate the safety profile of the "Endovir Stop" spray.

Methods: An MTT test was performed to evaluate cytotoxicity of the spray in two human cell lines. An oxygen radical absorbance capacity assay was performed to evaluate the antioxidant capacity of the spray. The spray was also tested on 87 healthy subjects on a voluntary basis.

Results: The MTT test revealed that the spray is not cytotoxic. The ORAC assay showed a good antioxidant capacity for the spray. Endovir Stop tested on healthy volunteers showed the total absence of side effects and drug interactions during the treatment.

Conclusions: We demonstrated that Endovir Stop spray is safe. The next step would be the administration of the efficacy of the spray by testing it to a wider range of people and see whether there is a reduced infection rate of SARS-CoV-2 in the treated subjects than in the non-treated individuals.
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http://dx.doi.org/10.23750/abm.v91i13-S.10583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023122PMC
November 2020

Genetic and physiological autonomic nervous system factors involved in failed back surgery syndrome: A review of the literature and report of nine cases treated with pulsed radiofrequency.

Acta Biomed 2020 11 9;91(13-S):e2020020. Epub 2020 Nov 9.

MAGI EUREGIO, Bolzano, Italy; EBTNA-LAB, Rovereto (TN), Italy; MAGI'S LAB, Rovereto (TN), Italy.

Background And Aim: failed back surgery syndrome is one of the most important causes of chronic low back pain that involve the physiology of autonomic nervous system factors. Some genetic and molecular factor can be determinant in the development of failed back surgery syndrome and novel therapy are needed. Pulsed radiofrequency treatment could be an innovative treatment option for this syndrome.

Methods: 44 patients classified with failed back surgery syndrome from the Poliambulanza Foundation Hospital of Brescia patients were treated with standard therapy for six months; 9 of these patients who showed no improvement were candidates for pulsed radiofrequency therapy for three months.

Results And Conclusions: reduction of lumbar and radicular pain, disability and number of drug classes prescribed improved significantly (p <0.001) in patients treated with pulsed radiofrequency compared to whom that follow only the standard therapy. The role of the nervous system is important for understanding how pulsed radiofrequency can improve the health of patients with back pain. We suggest that some genetic and molecular studies are needed for better understand the role of this therapy in back pain.
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http://dx.doi.org/10.23750/abm.v91i13-S.10533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023133PMC
November 2020

Chiropractic care for hypertension: Review of the literature and study of biological and genetic bases.

Acta Biomed 2020 11 9;91(13-S):e2020017. Epub 2020 Nov 9.

MAGI'S LAB, Rovereto (TN), Italy; MAGI EUREGIO, Bolzano, Italy; EBTNA-LAB, Rovereto (TN), Italy.

Background And Aim: Hypertension is a multifactorial condition that is among the leading causes of mortality worldwide. Regulation of blood pressure greatly depends upon the activity of the autonomic nervous system. Alterations in the autonomic nervous system can lead to hypertension. In addition to nervous system control and individual physiologic state, various genes can directly influence autonomic responses. The complexity of blood pressure control is reflected in the 20-30% of individuals resistant to traditional pharmacological treatment, this indicates the need for alternative interventions. This article provides an integrative review and discussion of the key neurophysiologic and genetic factors that contribute to blood pressure regulation, the autonomic nervous system (ANS) and manual therapy literature, and the manual therapy and blood pressure literature.

Methods: To assess the effects of chiropractic on the management of hypertension we searched articles published from 1980 to 2019 in PubMed, the Index to Chiropractic Literature and CINAHL, using the keywords: chiropractic, spinal manipulation, hypertension, and blood pressure.

Results: We found 38 original studies that analyzed the effect of chiropractic therapy on hypertension. Of these studies, 10 were case reports and the statistical significance of the effects of chiropractic on blood pressure was not evaluated on these articles, so we focused on the remaining 28 articles.

Conclusions: The results of the review relative to chiropractic care were promising, but often contradictory, suggesting more research should be done. In consideration of the complexity of ANS blood pressure control, an evaluation of patient presenting physiologic and genetic characteristics is recommended and could provide valuable insight relative to the likelihood of patient blood pressure related responsiveness to care.
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http://dx.doi.org/10.23750/abm.v91i13-S.10524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023135PMC
November 2020

Neurobiological basis of chiropractic manipulative treatment of the spine in the care of major depression.

Acta Biomed 2020 11 9;91(13-S):e2020006. Epub 2020 Nov 9.

MAGI EUREGIO, Bolzano, Italy; MAGI'S LAB, Rovereto (TN), Italy; EBTNA-LAB, Rovereto (TN), Italy.

Background And Aim: Major depressive disorder is associated with an autonomic nervous system imbalance. All the symptoms of depression (high cortisol, high adrenalin, insomnia, agitation, anxiety) can probably be attributed to over-activation of the sympathetic nervous system. We performed this review in order to highlight the possible links between chiropractic intervention, its potential molecular effects and its possible outcomes on patients with depression.

Methods: We performed a literature search for all the relevant manuscript regarding the effects of chiropractic and depression on the autonomic nervous system.

Results: Chiropractic care and spinal manipulation regulate the autonomic nervous system at peripheral level and its projections to the central nervous system. In particular, they may activate the parasympathetic system to counterbalance the activity of the sympathetic system. Vagal parasympathetic stimulation is also considered an effective therapy for major depression as it releases neurotrophins essential for anti-depressive therapies, including brain-derived neurotrophic factor and nerve growth factor.

Conclusion: Chiropractic and spinal manipulative therapies along with vagal nerve stimulation may therefore be regarded as treatment options for depression.
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http://dx.doi.org/10.23750/abm.v91i13-S.10536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023121PMC
November 2020

Genetic analysis of intellectual disability and autism.

Acta Biomed 2020 11 9;91(13-S):e2020003. Epub 2020 Nov 9.

MAGI EUREGIO, Bolzano, Italy; MAGI'S LAB, Rovereto (TN), Italy; EBTNA-LAB, Rovereto (TN), Italy.

Background And Aim: Intellectual disability (ID) and autism spectrum disorders (ASD) are neurodevelopmental conditions that often co-exist and affect children from birth, impacting on their cognition and adaptive behaviour. Social interaction and communication ability are also severely impaired in ASD. Almost 1-3% of the population is affected and it has been estimated that approximately 30% of intellectual disability and autism is caused by genetic factors. The aim of this review is to summarize monogenic conditions characterized by intellectual disability and/or autism for which the causative genes have been identified.

Methods And Results: We identified monogenic ID/ASD conditions through PubMed and other NCBI databases. Many such genes are located on the X chromosome (>150 out of 900 X-linked protein-coding genes), but at least 2000 human genes are estimated to be involved in ID/ASD. We selected 174 genes (64 X-linked and 110 autosomal) for an NGS panel in order to screen patients with ID and/or ASD, after fragile X syndrome and significant Copy Number Variants have been excluded.

Conclusions: Accurate clinical and genetic diagnosis is required for precise treatment of these disorders, but due to their genetic heterogeneity, most cases remain undiagnosed. Next generation sequencing technologies have greatly enhanced the identification of new genes associated with intellectual disability and autism, ultimately leading to the development of better treatment options.
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http://dx.doi.org/10.23750/abm.v91i13-S.10684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023126PMC
November 2020

Genetic test for the personalization of sport training.

Acta Biomed 2020 11 9;91(13-S):e2020012. Epub 2020 Nov 9.

MAGI'S LAB, Rovereto (TN), Italy; EBTNA-LAB, Rovereto (TN), Italy; MAGI EUREGIO, Bolzano, Italy.

Genetic variants may contribute to confer elite athlete status. However, this does not mean that a person with favourable genetic traits would become a champion because multiple genetic interactions and epigenetic contributions coupled with confounding environmental factors shape the overall phenotype. This opens up a new area in sports genetics with respect to commercial genetic testing. The analysis of genetic polymorphisms linked to sport performance would provide insights into the potential of becoming an elite endurance or power performer. This mini-review aims to highlight genetic interactions that are associated with performance phenotypes and their potentials to be used as markers for talent identification and trainability.
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http://dx.doi.org/10.23750/abm.v91i13-S.10593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023127PMC
November 2020

Somatic Variant Analysis Identifies Targets for Tailored Therapies in Patients with Vascular Malformations.

J Clin Med 2020 Oct 22;9(11). Epub 2020 Oct 22.

MAGI'S LAB, Via delle Maioliche, 57/D, 38068 Rovereto, TN, Italy.

Vascular malformations include various disorders characterized by morphological, structural and/or functional alterations of blood and lymph vessels. Most are sporadic, due to somatic mutations. Here, we report a cohort of patients with sporadic and/or unifocal vascular malformations, in whom we carried out next generation sequencing analysis of a panel of genes associated with vascular malformations. The 115 patients analyzed were from different clinical centres. In 37 patients (32%), we found pathogenic mutations: most of these were gain-of-function mutations in (18%, 21/115) and (13/115, 11%). We also found mutations in , and . Identifying pathogenic variants in patients with vascular malformations can help improve management, particularly in cases with activating mutations that cause an increase in cell proliferation. Personalized pharmacological treatment, if possible, is now considered preferable to surgery and can help prevent recurrences, i.e., long-term complications of residual malformation or regrowth of tumors. For instance, rapamycin is currently being investigated for the treatment of various vascular malformations associated with hyperactivation of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway.
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http://dx.doi.org/10.3390/jcm9113387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690376PMC
October 2020

Paraneoplastic Neurological Syndromes: Study of Prevalence in a Province of the Lombardy Region, Italy.

J Clin Med 2020 Sep 25;9(10). Epub 2020 Sep 25.

MAGI EUREGIO, 39100 Bolzano, Italy.

Paraneoplastic neurological syndromes (PNSs) are a heterogeneous group of rare immune-mediated diseases associated with cancer. The aim of this study was to investigate the prevalence of PNSs in the province of Brescia. PNS prevalence was calculated using the Lombardy regional hospital admission records from 1998 to 2003. We used the website "Epidemiologic and Economic Atlas of Hospital Activities in Lombardy" and the "International Statistical Classification of Diseases and Related Health Problems". In the province of Brescia, we found 54 cases of PNSs, 29 with subacute neuropathies, five with paraneoplastic cerebellar degeneration and 20 with encephalomyelitis. Peripheral nervous system diseases were the most frequent neurological disorders. In Lombardy, the number of PNS patients admitted was 322 (133 with encephalomyelitis, 21 with paraneoplastic cerebellar degeneration, 166 with polyneuropathies and two with optic degeneration). In Lombardy, the prevalence of PNSs was 25 in 100,000 hospital admissions and 5.92 in 100,000 for the Lombardy population. Our results show a discrete presence of PNS patients in the province of Brescia and in the Lombardy region as a whole.
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http://dx.doi.org/10.3390/jcm9103105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599932PMC
September 2020

Etiopathogenesis of sacroiliitis: implications for assessment and management.

Korean J Pain 2020 Oct;33(4):294-304

MAGI's Lab, Rovereto, Italy.

The sacroiliac joints connect the base of the sacrum to the ilium. When inflamed, they are suspected to cause low back pain. Inflammation of the sacroiliac joints is called sacroiliitis. The severity of the pain varies and depends on the degree of inflammation. Sacroiliitis is a hallmark of seronegative spondyloarthropathies. The presence or absence of chronic sacroiliitis is an important clue in the diagnosis of low back pain. This article aims to provide a concise overview of the anatomy, physiology, and molecular biology of sacroiliitis to aid clinicians in the assessment and management of sacroiliitis. For this narrative review, we evaluated articles in English published before August 2019 in PubMed. Then, we selected articles related to the painful manifestations of the sacroiliac joint. From the retrieved articles, we found that chronic sacroiliitis may be caused by various forms of spondyloarthritis, such as ankylosing spondyloarthritis. Sacroiliitis can also be associated with inflammatory bowel disease, Crohn's disease, gout, tuberculosis, brucellosis, and osteoarthritis, indicating common underlying etiological factors. The pathophysiology of sacroiliitis is complex and may involve internal, environmental, immunological, and genetic factors. Finally, genetic factors may also play a central role in progression of the disease. Knowing the genetic pre-disposition for sacroiliitis can be useful for diagnosis and for formulating treatment regimens, and may lead to a substantial reduction in disease severity and duration and to improved patient performance.
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http://dx.doi.org/10.3344/kjp.2020.33.4.294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532300PMC
October 2020

Next-generation sequencing: toward an increase in the diagnostic yield in patients with apparently idiopathic spermatogenic failure.

Asian J Androl 2021 Jan-Feb;23(1):24-29

Department of Clinical and Experimental Medicine, University of Catania, Catania 95123, Italy.

A large proportion of patients with idiopathic spermatogenic failure (SPGF; oligozoospermia or nonobstructive azoospermia [NOA]) do not receive a diagnosis despite an extensive diagnostic workup. Recent evidence has shown that the etiology remains undefined in up to 75% of these patients. A number of genes involved in germ-cell proliferation, spermatocyte meiotic divisions, and spermatid development have been called into play in the pathogenesis of idiopathic oligozoospermia or NOA. However, this evidence mainly comes from case reports. Therefore, this study was undertaken to identify the molecular causes of SPGF. To accomplish this, 15 genes (USP9Y, NR5A1, KLHL10, ZMYND15, PLK4, TEX15, TEX11, MEIOB, SOHLH1, HSF2, SYCP3, TAF4B, NANOS1, SYCE1, and RHOXF2) involved in idiopathic SPGF were simultaneously analyzed in a cohort of 25 patients with idiopathic oligozoospermia or NOA, accurately selected after a thorough diagnostic workup. After next-generation sequencing (NGS) analysis, we identified the presence of rare variants in the NR5A1 and TEX11 genes with a pathogenic role in 3/25 (12.0%) patients. Seventeen other different variants were identified, and among them, 13 have never been reported before. Eleven out of 17 variants were likely pathogenic and deserve functional or segregation studies. The genes most frequently mutated were MEIOB, followed by USP9Y, KLHL10, NR5A1, and SOHLH1. No alterations were found in the SYCP3, TAF4B, NANOS1, SYCE1, or RHOXF2 genes. In conclusion, NGS technology, by screening a specific custom-made panel of genes, could help increase the diagnostic rate in patients with idiopathic oligozoospermia or NOA.
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http://dx.doi.org/10.4103/aja.aja_25_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831827PMC
July 2020

Unique combination and in silico modeling of biallelic POLR3A variants as a cause of Wiedemann-Rautenstrauch syndrome.

Eur J Hum Genet 2020 12 18;28(12):1675-1680. Epub 2020 Jun 18.

MAGI's LAB S.r.l., Rovereto, Italy.

Neonatal progeroid syndrome or Wiedemann-Rautenstrauch syndrome (WRS; MIM 264090) is a rare genetic disorder that has clinical symptoms including premature aging, lipodystrophy, and variable mental impairment. Until recently genetic background of the disease was unclear. However, recent studies have indicated that WRS patients have compound heterozygote variations in the POLR3A (RNA polymerase III subunit 3A; MIM 614258) gene that might be responsible for the disease phenotype. In this study we report a WRS patient that has compound heterozygote variations in the POLR3A gene. One of the reported variations in our patient, c.3568C>T, p.(Gln1190Ter), is a novel variation that was not reported before. The other variant, c.3337-11T>C, was previously shown in WRS patients in trans with other variations.
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http://dx.doi.org/10.1038/s41431-020-0673-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784914PMC
December 2020

Genetic contributions to the etiology of anorexia nervosa: New perspectives in molecular diagnosis and treatment.

Mol Genet Genomic Med 2020 07 5;8(7):e1244. Epub 2020 May 5.

MAGI'S LAB, Rovereto, Trento, Italy.

Background: Anorexia nervosa is a multifactorial eating disorder that manifests with self-starvation, extreme anxiety, hyperactivity, and amenorrhea. Long-term effects include organ failure, disability, and in extreme cases, even death.

Methods: Through a literature search, here we summarize what is known about the molecular etiology of anorexia nervosa and propose genetic testing for this condition.

Results: Anorexia nervosa often has a familial background and shows strong heritability. Various genetic studies along with genome-wide association studies have identified several genetic loci involved in molecular pathways that might lead to anorexia.

Conclusion: Anorexia nervosa is an eating disorder with a strong genetic component that contributes to its etiology. Various genetic approaches might help in the molecular diagnosis of this disease and in devising novel therapeutic options.
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http://dx.doi.org/10.1002/mgg3.1244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336737PMC
July 2020

Molecular Aspects of Regional Pain Syndrome.

Pain Res Manag 2020 11;2020:7697214. Epub 2020 Apr 11.

MAGI's Lab, Via delle Maioliche. 57/D, 38068 Rovereto, TN, Italy.

The purpose of this review is to summarize the pathophysiology of complex regional pain syndrome (CRPS), the underlying molecular mechanisms, and potential treatment options for its management. CRPS is a multifactorial pain condition. CRPS is characterized by prolonged or excessive pain and changes in skin color and temperature, and/or swelling in the affected area, and is generally caused by stimuli that lead to tissue damage. An inflammatory response involving various cytokines and autoantibodies is generated in response to acute trauma/stress. Chronic phase pathophysiology is more complex, involving the central and peripheral nervous systems. Various genetic factors involved in the chronicity of pain have been identified in CRPS patients. As with other diseases of complex pathology, CRPS is difficult to treat and no single treatment regimen is the same for two patients. Stimulation of the vagus nerve is a promising technique being tested for different gastrointestinal and inflammatory diseases. CRPS is more frequent in individuals of 61-70 years of age with a female to male ratio of 3 : 1. Menopause, migraine, osteoporosis, and asthma all represent risk factors for CRPS and in smokers the prognosis appears to be more severe. The pathophysiological mechanisms underlying CRPS involve both inflammatory and neurological pathways. Understanding the molecular basis of CRPS is important for its diagnosis, management, and treatment. For instance, vagal nerve stimulation might have the potential for treating CRPS through the cholinergic anti-inflammatory pathway.
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http://dx.doi.org/10.1155/2020/7697214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171689PMC
October 2020

Adult-onset glutaric aciduria type I: rare presentation of a treatable disorder.

Neurogenetics 2020 07 18;21(3):179-186. Epub 2020 Apr 18.

Department of Medical Biology, Faculty of Medicine, Near East University, Nicosia, Cyprus.

Glutaric aciduria type I (GA1; OMIM #231670) is an autosomal recessively inherited and treatable disorder characterized by the accumulation and irregular excretion of glutaric acid due to a defect in the glutaryl-CoA dehydrogenase enzyme involved in the catabolic pathways of L-lysine, L-hydroxylysine, and L-tryptophan. Glutaryl-CoA dehydrogenase is encoded by the GCDH gene (OMIM #608801), and several mutations in this gene are known to result in GA1. GA1 usually presents in the first 18-36 months of life with mild or severe acute encephalopathy, movement disorders, and striatal degeneration. Few cases of adult-onset GA1 have been described so far in the literature, often with non-specific and sometimes longstanding neurological symptoms. Since a preventive metabolic treatment is available, neurologists must be aware of this rare but likely underdiagnosed presentation, especially when typical neuroimaging features are identified. Here, we describe 35-year-old presenting with headache and subjective memory problems. There was no history of dystonic movement disorders. Neurological examination and neurocognitive tests were normal. Brain MRI scan revealed white matter abnormalities associated with subependymal nodules and mild frontotemporal hypoplasia suggestive of glutaric aciduria type 1 (GA1). Genetic testing confirmed the presence of homozygous c.1204C > T (p.R402W) variant in the GCDH gene, inherited from heterozygous parents.
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http://dx.doi.org/10.1007/s10048-020-00610-9DOI Listing
July 2020

CRB1-Related Cystic Maculopathy in Twins Conceived Through Heterologous Fertilization With Variant-Carrying Oocytes.

J Pediatr Ophthalmol Strabismus 2020 Mar 12;57:e19-e24. Epub 2020 Mar 12.

Cystic maculopathy has been associated with genetic disorders such as retinitis pigmentosa, X-linked retinoschisis, cone dystrophy, and foveal retinoschisis. Familial foveal retinoschisis was recently described as a rare disease caused by CRB1 variants. The authors report the phenotype-genotype pattern of a pair of dizygotic twins with early-onset cystic maculopathy due to CRB1 pathogenic variants. The twins were conceived by heterologous fertilization with variant-carrying oocytes. The probands were monitored for a period of 4 years. Next generation sequencing of a panel of genes responsible for retinal dystrophies was performed. Both children carried three pathogenic variants in CRB1: a novel heterozygous truncating variant p.(Val855*) inherited from the father and two known heterozygous missense variants, p.[(Phe144Val; Thr745Met)], inherited from the oocyte donor. The findings confirm that CRB1 variants can be responsible for foveal retinoschisis with variable clinical expressivity ranging from schitic macular alteration to early-onset forms of cystic maculopathy. The authors highlight the importance of exome analysis of gamete donors to assess the likelihood of recessively inherited disorders by means of a prediction algorithm able to combine parent and donor exome data. [J Pediatr Ophthalmol Strabismus. 2020;57:e19-e24.].
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http://dx.doi.org/10.3928/01913913-20200204-02DOI Listing
March 2020

Hydroxytyrosol: A natural compound with promising pharmacological activities.

J Biotechnol 2020 Feb 26;309:29-33. Epub 2019 Dec 26.

Department of Vascular Rehabilitation, San Giovanni Battista Hospital, Via Luigi Ercole Morselli, 13, 00148, Rome, Italy. Electronic address:

Hydroxytyrosol is a phenolic phytochemical with antioxidant properties in vitro. It is a natural compound that can be found in olive leaves and oil. The main dietary source of hydroxytyrosol is extra virgin olive oil. Due to its bioavailability, chemical properties and easy formulation along with its lack of toxicity, hydroxytyrosol is considered an excellent food supplement by the nutraceutical and food industries. The purpose of this review is to discuss the potential therapeutic effects of hydroxytyrosol in vivo. To do so, we conducted an electronic search in PubMed and other literature databases using "hydroxytyrosol", "beneficial effect/s", "pharmacology" as key-words. From this search, we found that hydroxytyrosol has anti-inflammatory, anti-tumor, antiviral, antibacterial and antifungal properties. Hydroxytyrosol also improves endothelial dysfunction, decreases oxidative stress, and is neuro- and cardio-protective. Due to all these biological properties, hydroxytyrosol is currently the most actively investigated natural phenol. The evidence presented in this review suggests that hydroxytyrosol has great pharmacological potential.
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http://dx.doi.org/10.1016/j.jbiotec.2019.12.016DOI Listing
February 2020

Molecular pathways involved in lymphedema: Hydroxytyrosol as a candidate natural compound for treating the effects of lymph accumulation.

J Biotechnol 2020 Jan 30;308:82-86. Epub 2019 Nov 30.

Department of Vascular Rehabilitation, San Giovanni Battista Hospital, Via Luigi Ercole Morselli, 13, 00148, Rome, Italy. Electronic address:

Lymphedema is a chronic accumulation of interstitial fluid due to inefficient lymph drainage. Major causes of lymphedema are malformations of lymphatic vessels, trauma, toxic damage and surgery. The swelling typically affects the limbs. Lymphedema may be primary, caused by genetic mutations and relatively rare, or secondary (acquired), due to external causes such as infections or surgery. Fluid accumulation induces pathological changes: activation of the inflammatory cascade, immune cell infiltration, tissue fibrosis, adipose accumulation. We focused on the inflammatory phenotype mediated by leukotriene B4, a lipid mediator of the inflammatory pathway, and the potential therapeutic effect of hydroxytyrosol. We conducted an electronic search in PubMed using "lymphedema", "lymphedema pathway", "hydroxytyrosol" as keywords. We found that lymphedema deregulates at least six molecular pathways and that hydroxytyrosol, a compound with antioxidant activity, can improve endothelial dysfunction, hemostatic and lipid profiles, and decrease oxidative stress and inflammation through inhibition of leukotriene B4 activity. This review is the first to highlight the possibility of using hydroxytyrosol to treat the secondary effects of lymphedema, especially inflammation. The possible effects of hydroxytyrosol on lymphedema should be tested in vitro and in vivo to find the best way to treat patients with lymphedema in order to improve their health status.
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http://dx.doi.org/10.1016/j.jbiotec.2019.11.017DOI Listing
January 2020

Prenatal whole exome sequencing detects a new homozygous fukutin (FKTN) mutation in a fetus with an ultrasound suspicion of familial Dandy-Walker malformation.

Mol Genet Genomic Med 2020 01 22;8(1):e1054. Epub 2019 Nov 22.

Fondazione IRCCS Casa Sollievo della Sofferenza, Laboratory of Clinical Genomics, San Giovanni Rotondo (FG), Italy.

Background: Posterior fossa malformations are among the most diagnosed central nervous system (CNS) anomalies detected by ultrasound (US) in prenatal age. We identified the pathogenic gene mutation in a male fetus of 17 weeks of gestation with US suspicion of familial Dandy-Walker spectrum malformation, using Next Generation Sequencing approach in prenatal diagnosis.

Methods: Whole exome sequencing (WES) approach has been performed on fetal genomic DNA. After reads preprocessing, mapping, variant calling, and annotation, a filtering strategy based on allelic frequency, recessive inheritance, and phenotypic ontologies has been applied. A fetal magnetic resonance imaging (MRI) at 18 weeks of gestation has been performed. An in silico analysis of a potential causative missense variant in the fukutin protein has been carried out through a structural modeling approach.

Results: We identified a new homozygous missense mutation in fukutin gene (FKTN, NM_006731.2: c.898G>A; NP_006722.2: p.Gly300Arg). Fetal MRI supported molecular findings. Structural modeling analyses indicated a potential pathogenetic mechanism of the variant, through a reduced activation of the sugar moieties, which in turn impairs transfer to dystroglycan and thus its glycosylation. These findings pointed to a redefinition of the US suspicion of recurrence of Dandy-Walker malformation (DWM) to a muscular dystrophy-dystroglycanopathy type A4.

Conclusions: The present case confirmed WES as a reliable tool for the prenatal identification of the molecular bases of early-detected CNS malformations.
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http://dx.doi.org/10.1002/mgg3.1054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978243PMC
January 2020

Electrical Stimulation in the Treatment of Lymphedema and Associated Skin Ulcers.

Lymphat Res Biol 2020 06 20;18(3):270-276. Epub 2019 Nov 20.

Research Unit, EBTNA-Lab, Rovereto, Italy.

Lymphedema is a disorder in which lymph accumulates in the interstitial spaces due to poor lymphatic flow resulting from hypoplasia or aplasia of the lymphatic vessels, or to morpho-functional alterations that impair lymphatic flow. Lymphedema is a debilitating condition associated initially with inflammation that then degenerates into hardening of affected tissues and the formation of ulcers on the skin of affected limbs. No definitive treatment is available. The only therapy for lymphedema consists of physiotherapy, surgery, and compression to reduce impairment, which only treats the symptoms, not the causes. A possible new therapy that could reinforce the treatment of lymphedema progression and complications is electrical stimulation (ES). Many studies underline the effects of electric currents on the different cell mechanisms associated with disease. In this review, we summarize the effects of ES on the molecular and cellular processes involved in the pathophysiology of lymphedema, highlighting their therapeutic potential for edema reduction, ulcer repair, and restoration of lymphatic flow and . ES exerts its effect on the main stages that characterize lymphedema, from its onset to ulcer formation. There are few evidences on lymphatic models and more molecular studies are needed to understand the mechanism of action of this application in the treatment of lymphedema.
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http://dx.doi.org/10.1089/lrb.2019.0052DOI Listing
June 2020

Genetic syndromes with localized subcutaneous fat tissue accumulation.

Acta Biomed 2019 09 30;90(10-S):90-92. Epub 2019 Sep 30.

MAGI Euregio, Bolzano, Italy.

Syndromes with localized accumulation of subcutaneous fatty tissue belong to a group of genetically and phenotypically heterogeneous disorders. These diseases may show some common signs, such as nodular fat, symmetrical fat masses, obesity, fatigue, lymphedema and symmetrical lipomas (painful or otherwise). Other symptoms may be specific for the different clinical entities, enabling correct differential diagnosis. Disorders belonging to this spectrum are lipedema, generalized diffuse or nodular forms of Dercum disease, localized nodular Dercum disease and multiple symmetric lipomatosis. Here we summarize the genes involved in syndromes with localized accumulation of subcutaneous fat and the test we use for genetic analysis.
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http://dx.doi.org/10.23750/abm.v90i10-S.8767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233643PMC
September 2019

Mendelian non-syndromic obesity.

Acta Biomed 2019 09 30;90(10-S):87-89. Epub 2019 Sep 30.

MAGI'S LAB.

Obesity is highly heritable and arises from the interplay of many genes and environmental factors. It can be defined as the result of prolonged imbalance between calorie intake and energy utilization. About 5% of cases of non-syndromic obesity are monogenic (Mendelian obesity). The amount of adipose tissue in the body is mainly regulated by leptin, a hormone produced by adipocytes, and Mendelian obesity is mainly caused by mutations that disrupt the leptin/melanocortin pathway. In this article, we summarize the genes involved in genetic obesity and the test we use for genetic analysis.
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http://dx.doi.org/10.23750/abm.v90i10-S.8766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233639PMC
September 2019

Combined use of medically-assisted reproductive techniques: a new bioethical issue.

Acta Biomed 2019 09 30;90(10-S):58-61. Epub 2019 Sep 30.

MAGI Euregio, Bolzano, Italy.

Background And Aim: The studies of Nobel laureate Robert Geoffrey Edwards led to the first in vitro fertilization and embryo transfer in 1978. Since then, reproductive medicine has made huge advances. Methods available to sterile couples now include: purchasing oocytes and sperm, uterus surrogacy, pre-implantation or pre-natal diagnosis, embryo/fetal selection. Here we highlight the fact that combinations of existing technologies could threaten the non-marketability of human life.

Methods: We searched PubMed and websites to find articles regarding assisted reproduction techniques.

Results: These methods, taken separately, provide support for natural fertilization, but when used together, they may lead to genuine "baby factories". In poor countries, such "factories" exist and often act illegally.

Conclusions: We highlight the need for deeper bioethical studies and better legislation regarding the combined use of medically-assisted reproductive techniques.
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http://dx.doi.org/10.23750/abm.v90i10-S.8761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233638PMC
September 2019

Cardiac conduction defects.

Acta Biomed 2019 09 30;90(10-S):20-29. Epub 2019 Sep 30.

MAGI's Lab, Rovereto (TN), Italy.

Defects in cardiac electric impulse formation or conduction can lead to an irregular beat (arrhythmia) that can cause sudden death without any apparent cause or after stress. In the following sections, we describe the genetic disorders associated with primary cardiac conduction defects, primarily caused by mutations in ion channel genes. Primary indicates that these disorders are not caused by drugs and are not secondary to other disorders like cardiomyopathies (described in the next section).
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http://dx.doi.org/10.23750/abm.v90i10-S.8751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233635PMC
September 2019