Publications by authors named "Giovanni Romeo"

158 Publications

Genetic history of Calabrian Greeks reveals ancient events and long term isolation in the Aspromonte area of Southern Italy.

Sci Rep 2021 Feb 4;11(1):3045. Epub 2021 Feb 4.

Department of Cultural Heritage, University of Bologna, Ravenna, Italy.

Calabrian Greeks are an enigmatic population that have preserved and evolved a unique variety of language, Greco, survived in the isolated Aspromonte mountain area of Southern Italy. To understand their genetic ancestry and explore possible effects of geographic and cultural isolation, we genome-wide genotyped a large set of South Italian samples including both communities that still speak Greco nowadays and those that lost the use of this language earlier in time. Comparisons with modern and ancient populations highlighted ancient, long-lasting genetic links with Eastern Mediterranean and Caucasian/Near-Eastern groups as ancestral sources of Southern Italians. Our results suggest that the Aspromonte communities might be interpreted as genetically drifted remnants that departed from such ancient genetic background as a consequence of long-term isolation. Specific patterns of population structuring and higher levels of genetic drift were indeed observed in these populations, reflecting geographic isolation amplified by cultural differences in the groups that still conserve the Greco language. Isolation and drift also affected the current genetic differentiation at specific gene pathways, prompting for future genome-wide association studies aimed at exploring trait-related loci that have drifted up in frequency in these isolated groups.
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http://dx.doi.org/10.1038/s41598-021-82591-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862261PMC
February 2021

AUDACITY: A comprehensive approach for the detection and classification of Runs of Homozygosity in medical and population genomics.

Comput Struct Biotechnol J 2020 14;18:1956-1967. Epub 2020 Jul 14.

Medical Genetics Unit, Sant'Orsola-Malpighi University Hospital, Bologna, Italy.

Runs of Homozygosity (RoHs) are popular among geneticists as the footprint of demographic processes, evolutionary forces and inbreeding in shaping our genome, and are known to confer risk of Mendelian and complex diseases. Notwithstanding growing interest in their study, there is unmet need for reliable and rapid methods for genomic analyses in large data sets. AUDACITY is a tool integrating novel RoH detection algorithm and autozygosity prediction score for prioritization of mutation-surrounding regions. It processes data in VCF file format, and outperforms existing methods in identifying RoHs of any size. Simulations and analysis of real exomes/genomes show its potential to foster future RoH studies in medical and population genomics.
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http://dx.doi.org/10.1016/j.csbj.2020.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394861PMC
July 2020

Autozygosity-driven genetic diagnosis in consanguineous families from Italy and the Greater Middle East.

Hum Genet 2020 Nov 2;139(11):1429-1441. Epub 2020 Jun 2.

Medical Genetics Sant'Orsola, Malpighi University Hospital of Bologna, Via Massarenti 9, 40138, Bologna, Italy.

Autozygosity-driven exome analysis has been shown effective for identification of genes underlying recessive diseases especially in countries of the so-called Greater Middle East (GME), where high consanguinity unravels the phenotypic effects of recessive alleles and large family sizes facilitate homozygosity mapping. In Italy, as in most European countries, consanguinity is estimated low. Nonetheless, consanguineous Italian families are not uncommon in publications of genetic findings and are often key to new associations of genes with rare diseases. We collected 52 patients from 47 consanguineous families with suspected recessive diseases, 29 originated in GME countries and 18 of Italian descent. We performed autozygosity-driven exome analysis by detecting long runs of homozygosity (ROHs > 1.5 Mb) and by prioritizing candidate clinical variants within. We identified a pathogenic synonymous variant that had been previously missed in NARS2 and we increased an initial high diagnostic rate (47%) to 55% by matchmaking our candidate genes and including in the analysis shorter ROHs that may also happen to be autozygous. GME and Italian families contributed to diagnostic yield comparably. We found no significant difference either in the extension of the autozygous genome, or in the distribution of candidate clinical variants between GME and Italian families, while we showed that the average autozygous genome was larger and the mean number of candidate clinical variants was significantly higher (p = 0.003) in mutation-positive than in mutation-negative individuals, suggesting that these features influence the likelihood that the disease is autozygosity-related. We highlight the utility of autozygosity-driven genomic analysis also in countries and/or communities, where consanguinity is not widespread cultural tradition.
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http://dx.doi.org/10.1007/s00439-020-02187-7DOI Listing
November 2020

A simple method to measure the temperature and levitation height of devices rotating at cryogenic temperatures.

Rev Sci Instrum 2020 Apr;91(4):045118

Istituto Nazionale di Geofisica e Vulcanologia, Via di Vigna Murata 605, 00143 Roma, Italy.

We describe a simple system to measure the temperature and levitation height of levitating cryogenic devices in rotation. Devices of this kind are the half-wave-plates rotating on superconducting magnetic bearings used in several cryogenic polarimeters for the cosmic microwave background. The temperature measurement is important to monitor the radiative background and potential systematic effects in the polarimeter. In our implementation, the temperature sensor is a thermistor, physically mounted on the rotating device. The sensor is biased with an AC current, which is transferred from the stationary electronics to the rotating device via capacitive coupling. The levitation height sensor is a network of capacitors, similar to the one used for the capacitive coupling of the thermistor. We describe the optimization of the readout system and its performance, which has been tested on a room-temperature prototype. We show that this system reaches an accuracy better than 3% for the measurement of the thermistor resistance and an accuracy of ∼10 μm for the measurement of its levitation height.
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http://dx.doi.org/10.1063/5.0005498DOI Listing
April 2020

In silico analysis of a novel causative mutation in Cadherin23 gene identified in an Omani family with hearing loss.

J Genet Eng Biotechnol 2020 Mar 2;18(1). Epub 2020 Mar 2.

Department of Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, P.O. Box 35, Al-Khoud, 123, Muscat, Oman.

Background: Hereditary hearing loss is a heterogeneous group of complex disorders with an overall incidence of one in every 500 newborns presented as syndromic and non-syndromic forms. Cadherin-related 23 (CDH23) is one of the listed deafness causative genes. It is found to be expressed in the stereocilia of hair cells and in the retina photoreceptor cells. Defective CDH23 have been associated mostly with prelingual severe-to-profound sensorineural hearing loss (SNHL) in either syndromic (USH1D) or non-syndromic SNHL (DFNB12) deafness. The purpose of this study was to identify causative mutations in an Omani family diagnosed with severe-profound sensorineural hearing loss by whole exome sequencing technique and analyzing the detected variant in silico for pathogenicity using several in silico mutation prediction software.

Results: A novel homozygous missense variant, c.A7436C (p. D2479A), in exon 53 of CDH23 was detected in the family while the control samples were all negative for the detected variant. In silico mutation prediction analysis showed the novel substituted D2479A to be deleterious and protein destabilizing mutation at a conserved site on CDH23 protein.

Conclusion: In silico mutation prediction analysis might be used as a useful molecular diagnostic tool benefiting both genetic counseling and mutation verification. The aspartic acid 2479 alanine missense substitution might be the main disease-causing mutation that damages CDH23 function and could be used as a genetic hearing loss marker for this particular Omani family.
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http://dx.doi.org/10.1186/s43141-020-0021-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049540PMC
March 2020

Associations between psychoactive substance use and sensation seeking behavior among drivers in Norway.

BMC Public Health 2020 Jan 8;20(1):23. Epub 2020 Jan 8.

Department of Forensic Sciences, Oslo University Hospital, P.O. Box 4950, Nydalen, N-0424, Oslo, Norway.

Background/aim: Drug use and risky driving is associated with sensation seeking. The aim of this study was to investigate the association between use of psychoactive substances and levels of the sensation seeking personality trait as measured with the Brief Sensation Seeking Scale 4 among drivers in Norway.

Method: A cross-sectional design was applied to estimate the association between psychoactive substance use and sensation seeking behavior. Drivers in normal traffic were included in two roadside surveys: one in the north (September 2014 - October 2015) and the other in the south-east of Norway (April 2016 - April 2017). Oral fluid was analyzed for alcohol and psychoactive drugs, and data on sex, age and time of participation were recorded. Participants filled in the Brief Sensation Seeking Scale 4 questionnaire.

Results: A total of 8053 drivers were included, of which 32% were women and 62% were under 40 years. The prevalence of alcohol was 0.3%, stimulants 0.6%, tetrahydrocannabinol 1.4%, benzodiazepines and/or z-hypnotics 2.0% and polydrug use 0.6%. Associations were found between the use of tetrahydrocannabinol or benzodiazepines and/or z-hypnotics and a low score on the "thrill and adventure seeking" domain of the Brief Sensation Seeking Scale 4 (OR = 1.723, 95% C.I. = 1.001-2.966). Associations were also found between the use of stimulants and the highest scores on the "experience seeking" (OR = 2.085, 95% C.I. = 1.084-4.009) and "disinhibition" (OR = 4.791, 95% C.I. =1.748-13.135) domains of the Brief Sensation Seeking Scale 4. No associations were found between sensation seeking behavior and alcohol or polydrug use.

Conclusion: A high degree of sensation seeking was found among drivers who had used stimulating drugs, in contrast to drives who had used tetrahydrocannabinol and benzodiazepines and/or z-hypnotics who showed a low degree of sensation seeking. The combination of sensation seeking behavior and the use of stimulants might lead to increased risky behavior and thus traffic crashes.
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http://dx.doi.org/10.1186/s12889-019-8087-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950984PMC
January 2020

Medial Cuneiform Opening Wedge Osteotomy for Correction of Flexible Flatfoot Deformity: Trabecular Titanium vs. Bone Allograft Wedges.

Biomed Res Int 2019 31;2019:1472471. Epub 2019 Mar 31.

Department of Ankle and Foot Surgery, IRCCS Istituto Ortopedico Galeazzi, 20145 Milan, Italy.

Adult flatfoot is a common pathology characterized by multiplanar deformity involving hindfoot, midfoot, and forefoot. Various surgical techniques have been described for the treatment but may not adequately correct the fixed forefoot varus component. Residual forefoot supination can be addressed by a plantar flexing opening wedge osteotomy of the medial cuneiform, also known as a Cotton osteotomy. Thus, the aims of this study were to compare clinical, radiological, and functional outcome after Cotton osteotomy, in patients treated with bone allograft or metallic implant. Consequently, 36 patients treated with opening wedge osteotomy of the medial cuneiform for forefoot varus were studied retrospectively. Patients were divided into two groups: the bone allograft group (HBG) (n=18) and the metallic implant group with BIOFOAM® Cotton Wedges (TTW) (n=18). Radiographic assessment and clinical scores including American Orthopaedic Foot and Ankle Society score, Foot Function Index, and visual analogue scale for pain were collected before operation and the last follow-up. The difference between baseline and follow-up for both groups was statistically significant for all the clinical scores and radiographic angles (p < 0.05). Most participants (92%) were very satisfied after surgery. Our results showed that Cotton osteotomy with a metallic implant provided both good clinical and radiographic outcomes comparable with bone allograft.
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http://dx.doi.org/10.1155/2019/1472471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462320PMC
August 2019

Association between alcohol and drug use and arrest for driving under the influence after crash involvement in a rural area of Norway: a case-control study.

BMJ Open 2019 01 3;9(1):e023563. Epub 2019 Jan 3.

Department of Forensic Sciences, Oslo University Hospital, Oslo, Norway.

Objectives: The rate of deaths caused by road traffic crashes is particularly high in rural areas. It has been hypothesised that one factor that may contribute is differences in patterns of alcohol use. The aim was to compare the prevalence of psychoactive substances among crash-involved drivers arrested for suspicion of driving under the influence (DUI) who are tested for alcohol and drugs and recent random drivers in a rural area. Furthermore, we investigated the association between traffic crashes and driving after using alcohol, illicit or medicinal drugs either alone or in combination.

Methods: A case-control study was carried out in which the case group consisted of crash-involved drivers arrested for suspicion of DUI from 2000 to 2015. This group was compared with a control group of randomly selected drivers recruited to a roadside survey in normal traffic from 2014 to 2015. The case group consisted of 612 individuals (542 men and 70 women) and the control group of 3027 individuals (2099 men and 927 women). Drug and alcohol screening was performed on blood samples from the cases and samples of oral fluid from the controls.

Results: The proportion of psychoactive substances was 81.7% among cases and 1.6% among the controls. The prevalence of combinations of psychoactive substances was 18% among the cases and 0.3% among the controls. The multivariate regression model analysis identified significant drug interactions.

Conclusion: The prevalence of alcohol and drugs was high among the crash-involved drivers arrested for suspicion of DUI by the police. In contrast to earlier published research combinations of different psychoactive substances did not increase the OR for traffic crash involvement more than the single drug with highest OR. The statistical methodology presented in this study should be allied in future studies with greater statistical power to confirm these findings.
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http://dx.doi.org/10.1136/bmjopen-2018-023563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326312PMC
January 2019

First evidence of association between past environmental exposure to dioxin and DNA methylation of CYP1A1 and IGF2 genes in present day Vietnamese population.

Environ Pollut 2018 Nov 17;242(Pt A):976-985. Epub 2018 Jul 17.

Medical Genetics Unit, S. Orsola Hospital, University of Bologna, Italy and European School of Genetic Medicine, Italy.

During the Vietnam War, the United States military sprayed over 74 million litres of Agent Orange (AO) to destroy forest cover as a counterinsurgency tactic in Vietnam, Laos and Cambodia. The main ingredient was contaminated by 2,3,7,8-tetrachlorodibenzo-paradioxin (TCDD). DNA methylation (DNAm) differences are potential biomarker of environmental toxicants exposure. The aim of this study was to perform a preliminary investigation of the DNAm levels from peripheral blood of the present-day Vietnamese population, including individuals whose parents, according to historical data, were exposed to AO/TCDD during the war. 94 individuals from heavily sprayed areas (cases) and 94 individuals from non-sprayed areas (controls) were studied, and historical data on alleged exposure of parents collected. 94 cases were analysed considering those whose father/parents participated in the war (N = 29) and considering the place of residence of both parents (64 living in sprayed areas versus 30 in non-contaminated areas). DNAm levels in CYP1A1 and IGF2 genes were measured (MALDI-TOF technology). The analyses showed that: 1) one CpG site in the CYP1A1 and one in the IGF2 gene showed significant differences in DNAm levels between cases and controls; 2) the CYP1A1 region resulted to be hypomethylated (in 9 out of 16 sites/units; p-val<0.01) in 29 individuals whose father/parents participated in the war in the spray zones; 3) we showed that the place of residence of both parents influenced methylation levels of the CYP1A1 and IGF2 genes (p-val<0.05). In conclusion this study indicates that past environmental exposure to dioxin (AO/TCDD) shapes the DNAm profile of CYP1A1 and that the place of living for parents in former spray zones influences DNAm of CYP1A1 and IGF2 genes. These results open the way to new applications of DNAm as potential biomarker(s) of past human exposure to dioxin.
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http://dx.doi.org/10.1016/j.envpol.2018.07.015DOI Listing
November 2018

A mosaic intragenic microduplication of LAMA1 and a constitutional 18p11.32 microduplication in a patient with keratosis pilaris and intellectual disability.

Am J Med Genet A 2018 11 23;176(11):2395-2403. Epub 2018 Sep 23.

Laboratory of Cytogenetics, Research Institute of Medical Genetics, Tomsk NRMC, Tomsk, Russia.

The application of array-based comparative genomic hybridization and next-generation sequencing has identified many chromosomal microdeletions and microduplications in patients with different pathological phenotypes. Different copy number variations are described within the short arm of chromosome 18 in patients with skin diseases. In particular, full or partial monosomy 18p has also been associated with keratosis pilaris. Here, for the first time, we report a young male patient with intellectual disability, diabetes mellitus (type I), and keratosis pilaris, who exhibited a de novo 45-kb microduplication of exons 4-22 of LAMA1, located at 18p11.31, and a 432-kb 18p11.32 microduplication of paternal origin containing the genes METTL4, NDC80, and CBX3P2 and exons 1-15 of the SMCHD1 gene. The microduplication of LAMA1 was identified in skin fibroblasts but not in lymphocytes, whereas the larger microduplication was present in both tissues. We propose LAMA1 as a novel candidate gene for keratosis pilaris. Although inherited from a healthy father, the 18p11.32 microduplication, which included relevant genes, could also contribute to phenotype manifestation.
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http://dx.doi.org/10.1002/ajmg.a.40478DOI Listing
November 2018

Challenges and common weaknesses in case-control studies on drug use and road traffic injury based on drug testing of biological samples.

Ann Epidemiol 2018 11 24;28(11):812-820. Epub 2018 Aug 24.

Division of Health Data and Digitalization, Norwegian Institute of Public Health, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Purpose: To determine and discuss common weaknesses and errors in case-control studies on the association between drug use and road traffic crash injury among drivers and recommend improvements for future studies.

Methods: A search for case-control studies published between 2000 and 2016 was performed using PubMed and other databases in addition to manual search. The used methodologies were compared with requirements and recommendations for case-control studies as well as current knowledge on the interpretation of drug concentrations in biological samples.

Results: Seventeen studies were identified. The major difficulties in the studies were related to likely selection bias, information bias, and confounding. In some studies, the definition of drug exposure was different for controls than for cases, generating potentially serious errors in the odds ratio estimations. Other weaknesses include lacking explanation of the assessment of drug exposure, missing covariates, lacking description of statistical methods, and lack of discussion of bias and confounding.

Conclusions: Many of the observed challenges and weaknesses can be overcome or reduced. Recommendations for future studies are presented.
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http://dx.doi.org/10.1016/j.annepidem.2018.08.006DOI Listing
November 2018

Mutant MYO1F alters the mitochondrial network and induces tumor proliferation in thyroid cancer.

Int J Cancer 2018 10 7;143(7):1706-1719. Epub 2018 May 7.

Department of Medical and Surgical Sciences, DIMEC, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

Familial aggregation is a significant risk factor for the development of thyroid cancer and familial non-medullary thyroid cancer (FNMTC) accounts for 5-7% of all NMTC. Whole exome sequencing analysis in the family affected by FNMTC with oncocytic features where our group previously identified a predisposing locus on chromosome 19p13.2, revealed a novel heterozygous mutation (c.400G > A, NM_012335; p.Gly134Ser) in exon 5 of MYO1F, mapping to the linkage locus. In the thyroid FRTL-5 cell model stably expressing the mutant MYO1F p.Gly134Ser protein, we observed an altered mitochondrial network, with increased mitochondrial mass and a significant increase in both intracellular and extracellular reactive oxygen species, compared to cells expressing the wild-type (wt) protein or carrying the empty vector. The mutation conferred a significant advantage in colony formation, invasion and anchorage-independent growth. These data were corroborated by in vivo studies in zebrafish, since we demonstrated that the mutant MYO1F p.Gly134Ser, when overexpressed, can induce proliferation in whole vertebrate embryos, compared to the wt one. MYO1F screening in additional 192 FNMTC families identified another variant in exon 7, which leads to exon skipping, and is predicted to alter the ATP-binding domain in MYO1F. Our study identified for the first time a role for MYO1F in NMTC.
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http://dx.doi.org/10.1002/ijc.31548DOI Listing
October 2018

Posterior tibial tendon dysfunction: Clinical and magnetic resonance imaging findings having histology as reference standard.

Eur J Radiol 2018 Feb 11;99:55-61. Epub 2017 Dec 11.

Department of Biomedical Sciences for Health, University of Milano, Via Pascal 36, 20135, Milano, Italy; Unit of Diagnostic and Interventional Radiology, IRCCS Istituto Ortopedico Galeazzi, Via R. Galeazzi 4, 20166, Milano, Italy. Electronic address:

Objective: To investigate the correlation between MRI, clinical tests, histopathologic features of posterior tibial tendon (PTT) dysfunction in patients with acquired adult flatfoot deformity surgically treated with medializing calcaneal osteotomy and flexor digitorum longus tendon transposition.

Materials And Methods: Nineteen patients (11 females; age: 46 ± 15 year, range 18-75) were pre-operatively evaluated using the single heel rise (HR) and the first metatarsal rise (FMR) sign tests. Two reviewers graded the PTT tears on a I-III scale and measured the hindfoot valgus angle on the pre-operative MRI of the ankle. The specimens of the removed portion of PTT were histologically analysed by two pathologists using the Bonar and Movin score. Linear regression, Spearman's rank-order, and intraclass correlation coefficient (ICC) statistics were used.

Results: ICC for MRI was excellent (0.952). Correlation between FMR and HR tests was at limit of significance (r = 0.454; P = 0.051). The HR and FMR tests were significantly correlated to the Movin score (r = 0.581; P = 0.009 and r = 0.538; P = 0.018, respectively) and were not significantly correlated to the Bonar score (both with a r = 0.424; P = 0.070). PTT tendinopathy grading at MRI was significantly correlated to the FMR test (p = 0.041) but not to the hindfoot valgus angle (p = 0.496), the HR test (p = 0.943), the Bonar score (p = 0.937), and the Movin score (p = 0.436). The hindfoot angle was not correlated to any of the other variables (p > 0.264).

Conclusion: For PTT dysfunction, there is high correlation between HR and FMR test and histology evaluated using the Movin score, while no correlation was seen for the Bonar score. Semiquantitative grading of PTT dysfunction at MRI only correlates to the FMR and not to histology. The hindfoot valgus angle is not correlated to any of the considered variables.
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http://dx.doi.org/10.1016/j.ejrad.2017.12.005DOI Listing
February 2018

Vascular Risk Factors, Vascular Diseases, and Imaging Findings in a Hospital-based Cohort of Mild Cognitive Impairment Types.

Curr Alzheimer Res 2018 ;15(7):679-690

Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Italy.

Background: Mild Cognitive Impairment (MCI) is a transitional state between normal cognition and dementia.

Objective: The aim of this study is to investigate the role of vascular risk factors, vascular diseases, cerebrovascular disease and brain atrophy in a large hospital-based cohort of MCI types including 471 amnestic MCI (a-MCI), 693 amnestic MCI multiple domain (a-MCImd), 322 single non-memory MCI (snm-MCI), and 202 non amnestic MCI multiple domain (na-MCImd). For comparison, 1,005 neurologically and cognitively healthy subjects were also evaluated.

Method: Several vascular risk factors and vascular diseases were assessed. All participants underwent neurological, neuropsychological and behavioural assessments as well as carotid ultrasonography and standard brain MRI. Multinomial logistic regression models on the MCI cohort with the NCH group and a-MCI type as reference categories were used to assess the effects of the variables evaluated on the estimated probability of one of the four MCI types.

Results: This study demonstrates that cerebrovascular disease contributes substantially to the risk of non-memory MCI types and a-MCImd type, and that brain atrophy is present in all MCI types and is greater in multiple domain types particularly in the na-MCI type.

Conclusion: Improving detection and control of cerebrovascular disease in aging individuals should be mandatory. Since the incidence of MCI and dementia will be expected to rise because of the progressive life expectancy, a better management of cerebrovascular disease could indeed prevent or delay the onset of MCI, or could delay progression of MCI to dementia.
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http://dx.doi.org/10.2174/1567205015666180119110712DOI Listing
May 2019

The early years of the ESHG leading to the reform of 1988 and the spirit of the Sestri Levante school.

Eur J Hum Genet 2017 12;25(s2):S6-S12

Human Cancer Genetics Program, The Ohio State University, Columbus, Ohio, USA.

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http://dx.doi.org/10.1038/ejhg.2017.142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763252PMC
December 2017

Outcome of ankle arthrodesis and ankle prosthesis: a review of the current status.

Br Med Bull 2017 Dec;124(1):91-112

Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University, Via Alvaro del Portillo, 200, 00128 Trigoria, Rome, Italy.

Introduction: In advanced stages of ankle osteoarthritis (OA), ankle arthrodesis (AA) or total ankle arthroplasty (TAR) may be necessary. Our purpose is to compare AA and total ankle replacement for the surgical management of end stage ankle OA.

Sources Of Data: We conducted a literature search of PubMed, Medline, CINAHL, Cochrane, Embase and Google Scholar databases using the terms 'ankle' in combination with 'OA', 'arthrodesis', 'arthroplasty', 'joint fusion', 'joint replacement'. Studies where treatment was exclusively total ankle replacement or AA were excluded. Treatment characteristics and outcome parameters (overall postoperative outcome and complication rate) were reviewed.

Areas Of Agreement: When counseling patients who are considering their options with regard to ankle arthritis treatment, surgeons should determine on an individual basis which procedure is more suitable.

Areas Of Controversy: TAR has become an accepted treatment for end-stage OA, but revision rates for TAR are significant higher than for AA (odds ratio 2.28 95% confidence interval [CI], 1.63-3.19; P < 0.0001).

Growing Points: The results of TAA are gradually improving, but the procedure cannot yet be recommended for the routine management of ankle OA.

Areas Timely For Developing Research: Although there is some evidence to support TAR to conserve ankle motion and offer improved function and decreased pain with high satisfaction rates, revision rates for TAR are significantly higher than revision rates for AA. Proper patient selection should be better addressed in future studies for successful treatment of end-stage ankle OA.

Level Of Evidence: Systematic review, level III.
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http://dx.doi.org/10.1093/bmb/ldx042DOI Listing
December 2017

Whole Exome Sequencing allows the identification of two novel groups of Xeroderma pigmentosum in Tunisia, XP-D and XP-E: Impact on molecular diagnosis.

J Dermatol Sci 2018 Feb 2;89(2):172-180. Epub 2017 Nov 2.

Laboratory of Biomedical Genomics and Oncogenetics (LR11IPT05), Institut Pasteur de Tunis, Université Tunis El Manar, El Manar I, 2092 Tunis, Tunisia.

Background: Skin cancers (SC) are complex diseases that develop from complex combinations of genetic and environmental risk factors. One of the most severe and rare genetic diseases predisposing to SC is the Xeroderma pigmentosum (XP) syndrome.

Objectives: First, to identify the genetic etiology of XP and to better classify affected patients. Second, to provide early molecular diagnosis for pre-symptomatic patient and finally to offer genetic counseling for related individuals.

Methods: Whole Exome Sequencing (WES) and Run Of Homozygosity (ROH) were performed for two patients belonging to two different multiplex consanguineous families. The identified mutations were confirmed by Sanger sequencing and researched in ten Tunisian families including a total of 25 affected individuals previously suspected as having XP group V (XP-V) form. All patients had mild dermatological manifestations, absence of neurological abnormalities and late onset of skin tumors.

Results: Screening for functional variations showed the presence of the ERCC2 p.Arg683Gln in XP14KA-2 patient and a novel mutation, DDB2 p. (Lys381Argfs*2), in XP51-MAH-1 patient. Sanger sequencing and familial segregation showed that the ERCC2 mutation is present at a homozygous state in 10 affected patients belonging to 3 families. The second mutation in DDB2, is present at a homozygous state in 5 affected cases belonging to the same family. These two mutations are absent in the remaining 10 affected patients. The ERCC2 c.2048G > A mutation is present in a medium ROH region (class B) suggesting that it mostly arises from ancient relatedness within individuals. However, the c.1138delG DDB2 mutation is present in a large ROH region (class C) suggesting that it arises from recent relatedness.

Conclusion: To our knowledge, this is the first study that identifies XP-D and XP-E complementation groups in Tunisia. These two groups are very rare and under-diagnosed in the world and were not reported in North Africa.
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http://dx.doi.org/10.1016/j.jdermsci.2017.10.015DOI Listing
February 2018

Serendipitous discovery of potent human head and neck squamous cell carcinoma anti-cancer molecules: A fortunate failure of a rational molecular design.

Eur J Med Chem 2017 Dec 5;141:188-196. Epub 2017 Oct 5.

Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, V.le A. Doria, 95125 Catania, Italy. Electronic address:

Histone deacetylase inhibitors (HDACis) play an important role as valuable drugs targeted to cancer therapy: several HDACis are currently being tested in clinical trials. Two new potential HDACis 1a and 1d, characterized by the presence of a biphenyl-4-sulfonamide group as a connection unit between the N-{4-[(E)-(2-formylhydrazinylidene)methyl]-3-hydroxyphenyl} and the 2-hydroxy-N-(trifluoroacetyl)benzamide moiety, respectively, as two zinc-binding group (ZBG), have been designed, synthesized and tested for their biological activity. Surprisingly, compounds 1a and 12, this last exclusively obtained in place of 1d, exhibited a very low HDAC inhibitory activity. A serendipitous assay of these two compounds, conducted on three chemoresistant cell lines of head and neck squamous cell carcinoma (HNSCC), showed their antiproliferative activity at low nanomolar concentrations, better than cisplatin. In vitro, biological assays indicated that compounds 1a and 12 are able to increase acetylation of histone H3 and to interfere with the PI3K/Akt/mTOR pathway by inducing the accumulation of PTEN protein.
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http://dx.doi.org/10.1016/j.ejmech.2017.09.075DOI Listing
December 2017

Distal renal tubular acidosis in a Libyan patient: Evidence for digenic inheritance.

Eur J Med Genet 2018 Jan 9;61(1):1-7. Epub 2017 Oct 9.

Institut Pasteur de Tunis, Laboratoire de Génomique Biomédicale et Oncogénétique (LR11IPT05), 1002 Tunis, Tunisia.

Aim Of The Study: Recent advances in understanding the underlying molecular mechanism for distal renal tubular acidosis (dRTA), led to an increased attention towards the primary and the familial forms of the disease. Mutations in ATP6V1B1 and ATP6V0A4 are usually responsible for the recessive form of the disease. Mutations in gene AE1 encoding the Cl-/HCO3- exchanger, usually present as dominant dRTA, but a recessive pattern has been recently described. Our objective is to identify the mutational spectrum responsible of dRTA in a consanguineous Libyan family.

Materials And Methods: Both ATP6V0A4 and ATP6V1B1 genes were preferentially screened in our patient. Additional whole exome sequencing (WES) in the same patient, offered a wider view on potential chromosomal rearrangements as well as the mutational spectrum of other genes involved in this disease.

Results: The patient is a heterozygote for two different mutations, one in each of the genes ATP6V0A4 and ATP6V1B1, while no deleterious variation was detected in the remaining genes responsible for the recessive form of dRTA. Homozygosity mapping and WES confirmed our findings and supported the hypothesis of a digenic inheritance model existing as an explanation for dRTA.

Conclusions: To our knowledge, this is the first report describing a Libyan patient with dRTA who suffered from early-onset sensorineural hearing loss, with a digenic mode of inheritance, supported by the identification of two novel mutations. This study increases the understanding of how dRTA is genetically transmitted, while offers a good outline towards the molecular diagnostics and genetic counseling for dRTA in Lybians.
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http://dx.doi.org/10.1016/j.ejmg.2017.10.002DOI Listing
January 2018

Lactase persistence in Tunisia as a result of admixture with other Mediterranean populations.

Genes Nutr 2017 24;12:20. Epub 2017 Aug 24.

Laboratory of Molecular Anthropology and Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences (BiGeA), University of Bologna, 40126 Bologna, Italy.

Background: The ability to digest lactose after weaning, namely, lactase persistence (LP), is encoded by polymorphisms in the gene and varies widely in frequency among different human populations. Although, evolution of LP-related genetic variants was investigated in many groups of Sub-Saharan African, Middle Eastern, and European ancestry, only few studies have focused on populations from North Africa and no data are especially available from the Tunisian one. For this reason, there is an urgent need to investigate the frequency patterns at these loci in Tunisia since this adaptive trait is implicated in health.

Methods: Forty SNPs covering the genes and including the two functional variants - 13,910 C > T and - 22,018 G > A were genotyped in 117 Tunisian individuals using the Sequenom Mass Array technology. The observed nucleotide and haplotype patterns of variation were then compared with those of several African, European, and Mediterranean human groups for which comparable data were publicly available. Admixture analysis on a 5 Mb genomic region surrounding the loci was also performed by extracting genotypes from a previously generated genome-wide dataset in order to deepen the reconstruction of the evolutionary history of these loci.

Results: We found that lactase non-persistence (LNP)-related alleles and haplotypes were predominantly present in the examined population. A clear differentiation between Tunisian, African, and North European/North Italian samples was found, while the Tunisian population showed more genetic affinity to Central and South Italian groups.

Conclusions: Our study provided a first report of LP-associated alleles and haplotypes in the Tunisian population. We highlighted a gradient followed by LP diffusion from Europe to North Africa. Based on the rich historic background of Tunisia, we suggest that this adaptive trait was introduced in that geographic region by a relatively recent gene flow.
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http://dx.doi.org/10.1186/s12263-017-0573-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571577PMC
August 2017

Reply: Purifying selection on mitochondrial DNA: a strategy for the oocyte to preserve competence.

Hum Reprod 2017 09;32(9):1949-1950

Reproductive Medicine Unit, S.I.S.Me.R., Via Mazzini, 12, Bologna 40138, Italy.

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http://dx.doi.org/10.1093/humrep/dex255DOI Listing
September 2017

Model-based bootstrapping when correcting for measurement error with application to logistic regression.

Biometrics 2018 03 30;74(1):135-144. Epub 2017 May 30.

Department of Biostatistics, Oslo Centre for Biostatistics and Epidemiology, University of Oslo, Norway.

When fitting regression models, measurement error in any of the predictors typically leads to biased coefficients and incorrect inferences. A plethora of methods have been proposed to correct for this. Obtaining standard errors and confidence intervals using the corrected estimators can be challenging and, in addition, there is concern about remaining bias in the corrected estimators. The bootstrap, which is one option to address these problems, has received limited attention in this context. It has usually been employed by simply resampling observations, which, while suitable in some situations, is not always formally justified. In addition, the simple bootstrap does not allow for estimating bias in non-linear models, including logistic regression. Model-based bootstrapping, which can potentially estimate bias in addition to being robust to the original sampling or whether the measurement error variance is constant or not, has received limited attention. However, it faces challenges that are not present in handling regression models with no measurement error. This article develops new methods for model-based bootstrapping when correcting for measurement error in logistic regression with replicate measures. The methodology is illustrated using two examples, and a series of simulations are carried out to assess and compare the simple and model-based bootstrap methods, as well as other standard methods. While not always perfect, the model-based approaches offer some distinct improvements over the other methods.
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http://dx.doi.org/10.1111/biom.12730DOI Listing
March 2018

Intra-individual purifying selection on mitochondrial DNA variants during human oogenesis.

Hum Reprod 2017 05;32(5):1100-1107

Medical Genetics Unit, S. Orsola Hospital, University of Bologna, Bologna 40126, Italy.

Study Question: Does selection for mtDNA mutations occur in human oocytes?

Summary Answer: We provide statistical evidence in favor of the existence of purifying selection for mtDNA mutations in human oocytes acting between the expulsion of the first and second polar bodies (PBs).

What Is Known Already: Several lines of evidence in Metazoa, including humans, indicate that variation within the germline of mitochondrial genomes is under purifying selection. The presence of this internal selection filter in the germline has important consequences for the evolutionary trajectory of mtDNA. However, the nature and localization of this internal filter are still unclear while several hypotheses are proposed in the literature.

Study Design, Size, Duration: In this study, 60 mitochondrial genomes were sequenced from 17 sets of oocytes, first and second PBs, and peripheral blood taken from nine women between 38 and 43 years of age.

Participants/materials, Setting, Methods: Whole genome amplification was performed only on the single cell samples and Sanger sequencing was performed on amplicons. The comparison of variant profiles between first and second PB sequences showed no difference in substitution rates but displayed instead a sharp difference in pathogenicity scores of protein-coding sequences using three different metrics (MutPred, Polyphen and SNPs&GO).

Main Results And The Role Of Chance: Unlike the first, second PBs showed no significant differences in pathogenic scores with blood and oocyte sequences. This suggests that a filtering mechanism for disadvantageous variants operates during oocyte development between the expulsion of the first and second PB.

Large Scale Data: N/A.

Limitations, Reasons For Caution: The sample size is small and further studies are needed before this approach can be used in clinical practice. Studies on a model organism would allow the sample size to be increased.

Wider Implications Of The Findings: This work opens the way to the study of the correlation between mtDNA mutations, mitochondrial capacity and viability of oocytes.

Study Funding/competing Interest(s): This work was supported by a SISMER grant. Laboratory facilities and skills were freely provided by SISMER, and by the Alma Mater Studiorum, University of Bologna. The authors have no conflict of interest to disclose.
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http://dx.doi.org/10.1093/humrep/dex051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850138PMC
May 2017

Return to sport activities after subtalar arthroereisis for correction of pediatric flexible flatfoot.

J Pediatr Orthop B 2018 Jan;27(1):82-87

Department of Foot and Ankle Surgery, Galeazzi Hospital, Milan, Italy.

The aim of this study was to establish whether children treated with subtalar arthroereisis for flexible flatfoot were able to return to sport activities. We reviewed 49 patients with a mean age at the time of surgery of 10.7 years. The type of sport activities, the number of sessions per week, the time dedicated to each session, and the level achieved were assessed preoperatively and at the last follow-up. Overall, 45 patients returned to sports after surgery. Surgery did not alter the duration, frequency, and type of sporting activities, but the participation in physical activities as well as the emotional status and footwear issues improved.
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http://dx.doi.org/10.1097/BPB.0000000000000449DOI Listing
January 2018

A novel founder MYO15A frameshift duplication is the major cause of genetic hearing loss in Oman.

J Hum Genet 2017 Feb 13;62(2):259-264. Epub 2016 Oct 13.

Medical Genetics Unit, Department of Medical and Surgical Sciences, Polyclinic Sant'Orsola-Malpighi, University of Bologna, Bologna, Italy.

The increased risk for autosomal recessive disorders is one of the most well-known medical implications of consanguinity. In the Sultanate of Oman, a country characterized by one of the highest rates of consanguineous marriages worldwide, prevalence of genetic hearing loss (GHL) is estimated to be 6/10 000. Families of GHL patients have higher consanguinity rates than the general Omani population, indicating a major role for recessive forms. Mutations in GJB2, the most commonly mutated GHL gene, have been sporadically described. We collected 97 DNA samples of GHL probands, affected/unaffected siblings and parents from 26 Omani consanguineous families. Analyzing a first family by whole-exome sequencing, we identified a novel homozygous frameshift duplication (c.1171_1177dupGCCATCT) in MYO15A, the gene linked to the deafness locus DFNB3. This duplication was then found in a total of 8/26 (28%) families, within a 849 kb founder haplotype. Reconstruction of haplotype structure at MYO15A surrounding genomic regions indicated that the founder haplotype branched out in the past two to three centuries from a haplotype present worldwide. The MYO15A duplication emerges as the major cause of GHL in Oman. These findings have major implications for the design of GHL diagnosis and prevention policies in Oman.
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http://dx.doi.org/10.1038/jhg.2016.120DOI Listing
February 2017

Positive selection of lactase persistence among people of Southern Arabia.

Am J Phys Anthropol 2016 12 18;161(4):676-684. Epub 2016 Aug 18.

Laboratory of Molecular Anthropology and Centre for Genome Biology, Department of Biological, Geological and Environmental Sciences, University of Bologna, 40126, Italy.

Objective: Frequency patterns of the lactase persistence (LP)-associated -13,915 G allele and archaeological records pointing to substantial role played by southern regions in the peopling and domestication processes that involved the Arabian Peninsula suggest that Southern Arabia plausibly represented the center of diffusion of such adaptive variant. Nevertheless, a well-defined scenario for evolution of Arabian LP is still to be elucidated and the burgeoning archaeological picture of complex human migrations occurred through the peninsula is not matched by an equivalent high-resolution description of genetic variation underlying this adaptive trait. To fill this gap, we investigated diversity at a wide genomic interval surrounding the LCT gene in different Southern Arabian populations.

Methods: 40 SNPs were genotyped to characterize LCT profiles of 630 Omani and Yemeni individuals to perform population structure, linkage disequilibrium, population differentiation-based and haplotype-based analyses.

Results: Typical Arabian LP-related variation was found in Dhofaris and Yemenis, being characterized by private haplotypes carrying the -13,915 G allele, unusual differentiation with respect to northern groups and conserved homozygous haplotype-blocks, suggesting that the adaptive allele was likely introduced in the Arabian gene pool in southern populations and was then subjected to prolonged selective pressure.

Conclusion: By pointing to Yemen as one of the best candidate centers of diffusion of the Arabian-specific adaptive variant, obtained results indicate the spread of indigenous groups as the main process underlying dispersal of LP along the Arabian Peninsula, supporting a refugia model for Arabian demic movements occurred during the Terminal Pleistocene and Early Holocene.
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http://dx.doi.org/10.1002/ajpa.23072DOI Listing
December 2016

Different versions of the Italian Foot Function Index.

J Sports Med Phys Fitness 2016 09;56(9):1092

Foot and Ankle Unit, Galeazzi Hospital, Milan, Italy -

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September 2016

Cytogenetic and molecular characterization of a recombinant X chromosome in a family with a severe neurologic phenotype and macular degeneration.

Mol Cytogenet 2015 1;8:58. Epub 2015 Aug 1.

U.O. Genetica Medica, Policlinico Sant'Orsola-Malpighi, DIMEC, Università di Bologna, via Massarenti, 9, Bologna, 40138 Italy.

Background: Duplications of MECP2 gene in males cause a syndrome characterized by distinctive clinical features, including severe to profound mental retardation, infantile hypotonia, mild dysmorphic features, poor speech development, autistic features, seizures, progressive spasticity and recurrent infections. Patients with complex chromosome rearrangements, leading to Xq28 duplication, share most of the clinical features of individuals with tandem duplications, in particular neurologic problems, suggesting a major pathogenetic role of MECP2 overexpression.

Results: We performed cytogenetic and molecular cytogenetic studies in a previously described family with affected males showing congenital ataxia, late-onset progressive myoclonic encephalopathy and selective macular degeneration. Microsatellite, FISH and array-CGH analyses identified a recombinant X chromosome with a deletion of the PAR1 region, encompassing SHOX, replaced by a duplicated segment of the Xq28 terminal portion, including MECP2.

Conclusions: Our report describes the identification of the actual genetic cause underlying a severe syndrome that previous preliminary analyses erroneously associated to a terminal Xp22.33 region. In the present family as well as in previously reported patients with similar rearrangements, the observed neurologic phenotype is ascribable to MECP2 duplication, with an undefined contribution of the other involved genes. Maculopathy, presented by affected males reported here, could be a novel clinical feature associated to Xq28 disomy due to recombinant X chromosomes, but at present the underlying pathogenetic mechanism is unknown and this potential clinical correlation should be confirmed through the collection of additional patients.
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http://dx.doi.org/10.1186/s13039-015-0164-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522089PMC
August 2015

Recreational Sports Activities After Calcaneal Fractures and Subsequent Subtalar Joint Arthrodesis.

J Foot Ankle Surg 2015 Nov-Dec;54(6):1057-61. Epub 2015 Jul 23.

Department of Ankle and Foot Surgery, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.

Subtalar joint arthrodesis is a common treatment for the management of hindfoot pathologic entities. Despite pain reduction, hindfoot stiffness is a common concern of active patients, who wish to continue or start exercising for fitness. The purpose of the present retrospective observational clinical study was to assess the rate and type of recreational sports activities in patients before and after subtalar joint arthrodesis and to correlate the clinical outcome and the level of sports activities. In 33 patients (22 males, 11 females) treated with subtalar joint arthrodesis, the pre- and postoperative participation in sports and recreational activities was evaluated. The American Orthopaedic Foot and Ankle Society hindfoot scale score, 36-item Short Form Health Survey, and a visual analog scale for pain were used as clinical outcome measures. The weekly session number, session time, and interval to activity recovery after surgery were registered. Patients with a subtalar joint arthrodesis returned to a satisfactory level of activity postoperatively. The sports participation almost reached levels similar to those preoperatively but with a shift from high- to low-impact activities.
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http://dx.doi.org/10.1053/j.jfas.2015.05.003DOI Listing
August 2016