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MicroRNAs (miRs) are small non-coding RNA molecules, which are involved in the development of various malignancies, including prostate cancer (PCa). miR-17-5p is considered the most prominent member of the miR-17-92 cluster, with an essential regulatory function of fundamental cellular processes. In many malignancies, up-regulation of miR-17-5p is associated with worse outcome. In PCa, miR-17-5p has been reported to increase cell proliferation and the risk of metastasis. In this study, prostatectomy specimens from 535 patients were collected. Tissue microarrays were constructed and in situ hybridization was performed, followed by scoring of miR-17-5p expression on different tumor compartments. High expression of miR-17-5p in tumor epithelium was associated with biochemical failure (BF, p p = 0.019). In multivariate analyses, high miR-17-5p expression in tumor epithelial cells was an independent negative prognostic factor for BF (HR 1.87, 95% CI 1.32–2.67, p

PURPOSE Wilms tumor (WT) is associated with (epi)genetic predisposing factors affecting a growing number of WT predisposing genes and loci, including those causing Beckwith-Wiedemann spectrum (BWSp) or WT1-related syndromes. To guide genetic counseling and testing, we need insight into the prevalence of WT predisposing (epi)genetic factors. PATIENTS AND METHODS All children diagnosed with WT in the Netherlands between 2015 and 2020 were referred to a clinical geneticist. Phenotypic data, disease characteristics, and diagnostic test results were collected. If no genetic predisposition was identified by targeted diagnostic testing, germline (trio-)whole-exome sequencing and BWSp testing on normal kidney-derived DNA were offered. RESULTS A total of 126 cases were analyzed of 128 identified patients. (Epi)genetic predisposing factors were present in 42 of 126 patients (33.3%) on the basis of a molecular diagnosis in blood-derived DNA (n = 26), normal kidney-derived DNA (n = 12), or solely a clinical diagnosis of BWSp (n = 4). Constitutional, heterozygous DIS3L2 variants were identified as a recurrent predisposing factor in five patients (4%), with a second somatic hit in 4 of 5 tumors. Twenty patients (16%) were diagnosed with BWSp while four additional patients without BWSp features harbored chromosome 11p15 methylation defects in normal kidney tissue. Remaining findings included WT1-related syndromes (n = 10), Fanconi anemia (n = 1), neurofibromatosis type 1 (n = 1), and a pathogenic REST variant (n = 1). In addition, (likely) pathogenic variants in adult-onset cancer predisposition genes ( BRCA2, PMS2, CHEK2, and MUTYH) were identified in 5 of 56 (8.9%) patients with available whole-exome sequencing data. Several candidate WT predisposition genes were identified, which require further validation. CONCLUSION (Epi)genetic WT predisposing factors, including mosaic aberrations and recurrent heterozygous DIS3L2 variants, were present in at least 33.3% of patients with WT. On the basis of these results, we encourage standard genetic testing after counseling by a clinical geneticist.

Clin Epigenetics 14, 41 (2022). doi:10.1186/s13148-022-01259-x, Published by BioMed Central, [S.l.]

Objectives: In most countries, non-invasive prenatal testing (NIPT) has been introduced commercially without any governmental guidance. In the Netherlands, prenatal screening for fetal anomaly is subject to a governmental license. NIPT has been implemented as part of the TRIDENT studies (Trial by Dutch laboratories for Evaluation of NIPT). TRIDENT-2 aims at offering NIPT to all pregnant women (∼174,000 women/year) within the national prenatal screening program. Since April 2017, women can choose NIPT as a contingent test after first-trimester combined testing (FCT), but may also choose NIPT as first-tier screening test. TheTRIDENT studies evaluate implementation and women's perspectives. Methods: All pregnant women in the Netherlands are offered prenatal screening and are counselled by certified counselors, generally midwives. A first-tier NIPT costs women € 175, comparable to the costs of FCT (∼€ 168). NIPT is performed by three Dutch university clinical genetic laboratories using an in-house validated test. Women can choose to have analysis of chromosomes 21, 18, and 13 without or with a report of incidental findings (findings other than trisomy 21, 13, 18) on the remaining autosomes, respectively, using the 'targeted' or 'whole genome' WISECONDOR pipeline. Sex chromosomes are not analyzed. Results: After 8 months of study, 48,234 tests have been performed (nationwide uptake of prenatal screening by NIPT as first-tier test was 40%), and 98.3% reports successfully issued. Failure rate was less than 2%. Mean turnaround time was 7 working days. 80% of women chose to have all autosomes analyzed. A total of 152 cases of T21 (0.3%), 32 cases of T18 (0.1%), 41 cases of T13 (0.1%), and 158 (0.3%) other chromosomal aberrations were found. First year results (and available follow-up) will be presented at the meeting. Conclusions: The Netherlands are the first country where NIPT is incorporated as a first-line test into a governmentally supported and health care funded prenatal aneuploidy screening program. The incorporation of the test in a university hospital laboratory and clinical service guarantees appropriate counselling and allows for proper follow-up. This 3-year study aims to provide all necessary information for a successful introduction of NIPT within the Dutch National prenatal screening program.

Genetics research 101, e3 (2019). doi:10.1017/S001667231900003X, Published by Hindawi, London

Background: Heterozygous missense mutations in the WT1 gene that affect the function of the wild-type allele have been identified in Denys-Drash syndrome, which is characterized by severe gonadal dysgenesis, early-onset nephropathy and a predisposition to renal and gonadal cancer. Intron 9 splice-site mutations that influence the balance between WT1 isoforms cause a nearly similar phenotype, known as Frasier syndrome. Nonsense mutations and deletions only lead to WT1 haploinsufficiency and, hence, to less severe gonadal dysgenesis and late-onset nephropathy. WT1 analysis is mandatory in 46,XY gonadal dysgenesis with renal abnormality. Patient: We describe a newborn with 46,XY severe partial gonadal dysgenesis, in whom structural renal anomalies and proteinuria were excluded. Gonadectomy was performed at the age of 1 month and the microscopy was thought to be suggestive for a gonadoblastoma. At the age of 9 months, the patient presented with a bilateral Wilms tumor. Results: We found a heterozygous WT1 whole-gene deletion but no other gene defects. Conclusions: This case description illustrates that a WT1 deletion might be associated with a more severe phenotype than previously thought. It also illustrates that, even in the absence of renal abnormality, it is recommended to test promptly for WT1 defects in 46,XY gonadal dysgenesis.

International audience; Focal dermal hypoplasia (FDH) is a rare syndrome characterized by pleiotropic features knowing to involve mostly skin and limbs. Although FDH has been described in children and adults, the cardinal signs of the fetal phenotype are not straightforward impacting the quality of the prenatal diagnosis. We describe in depth the ultrasound, radiological, macroscopical, and histological phenotype of three female fetuses with a severe form of FDH, propose a review of the literature and an attempt to delineate minimal and cardinal signs for FDH diagnosis. This report confirms the variability of FDH phenotype, highlights unreported FDH features, and allows delineating evocative clinical associations for prenatal diagnosis, namely intrauterine growth retardation, limbs malformations, anterior wall/diaphragm defects, and eye anomalies. © 2016 Wiley Periodicals, Inc.

Il Rapporto 2014 sul Sistema Agroalimentare dell'Emilia-Romagna rappresenta un importante contributo alla conoscenza di un settore fondamentale dell'economia regionale, un utile strumento per gli operatori e una guida per le politiche degli enti locali. Il Rapporto si apre con due capitoli che descrivono da un lato, lo scenario internazionale e, dall'altro le politiche comunitarie e nazionali, per il settore agroalimentare, che modificano lo scenario nel quale gli operatori saranno chiamati a muoversi dal 2014 al 2020. I principali cambiamenti congiunturali del sistema agroalimentare regionale occupano la parte central del Rapporto, con Quattro capitol dedicati all'agricoltura. Successivamente vengono affrontati gli altri aspetti rilevanti del sistema agro-alimentare regionale partendo dall'industria alimentare, con le dinamiche congiunturali e alcuni approfondimenti strutturali dell'occupazione.

Context: Ig superfamily member1 (IGSF1) deficiency was recently discovered as a novel X-linked cause of central hypothyroidism (CeH) and macro-orchidism. However, clinical and biochemical data regarding growth, puberty, and metabolic outcome, as well as features of female carriers, are scarce. Objective: Our objective was to investigate clinical and biochemical characteristics associated with IGSF1 deficiency in both sexes.Methods: All patients (n=42, 24 males) from 10 families examined in the university clinics of Leiden, Amsterdam, Cambridge, and Milan were included in this case series. Detailed clinical data were collected with an identical protocol, and biochemical measurements were performed in a central laboratory. Results: Male patients (age 0-87 years, 17 index cases and 7 from family studies) showed CeH (100%), hypoprolactinemia (n = 16, 67%), and transient partial GH deficiency (n = 3, 13%). Pubertal testosterone productionwasdelayed, aswerethe growth spurtandpubic hair development. However, testicular growth started at a normal age and attained macro-orchid size in all evaluable adults. Body mass index, percent fat, and waist circumference tended to be elevated. The metabolic syndrome was present in 4 of 5 patients over 55 years of age. Heterozygous female carriers (age 32-80 years) showed CeH in 6 of 18 cases (33%), hypoprolactinemia in 2 (11%), and GH deficiency in none. As in men, body mass index, percent fat, and waist circumference were relatively high, and the metabolic syndrome was present in 3 cases. Conclusion: In male patients, the X-linked IGSF1 deficiency syndrome is characterized by CeH, hypoprolactinemia, delayed puberty, macro-orchidism, and increased body weight. A subset of female carriers also exhibits CeH.

Beckwith–Wiedemann and Silver–Russell syndromes (BWS/SRS) are two imprinting disorders (IDs) associated with disturbances of the 11p15.5 chromosomal region. In BWS, epimutations and genomic alterations within 11p15.5 are observed in >70% of patients, whereas in SRS they are observed in about 60% of the cases. In addition, 10% of the SRS patients carry a maternal uniparental disomy of chromosome 7 11p15.5. There is an increasing demand for prenatal testing of these disorders owing to family history, indicative prenatal ultrasound findings or aberrations involving chromosomes 7 and 11. The complex molecular findings underlying these disorders are a challenge not only for laboratories offering these tests but also for geneticists counseling affected families. The scope of counseling must consider the range of detectable disturbances and their origin, the lack of precise quantitative knowledge concerning the inheritance and recurrence risks for the epigenetic abnormalities, which are hallmarks of these developmental disorders. In this paper, experts in the field of BWS and SRS, including members of the European network of congenital IDs (EUCID.net; www.imprinting-disorders.eu), put together their experience and work in the field of 11p15.5-associated IDs with a focus on prenatal testing. Altogether, prenatal tests of 160 fetuses (122 referred for BWS, 38 for SRS testing) from 5 centers were analyzed and reviewed. We summarize the current knowledge on BWS and SRS with respect to diagnostic testing, the consequences for prenatal genetic testing and counseling and our cumulative experience in dealing with these disorders.

Goltz-Gorlin syndrome is a highly variable disorder affecting many body parts of meso-ectodermal origin. Mutations in X-linked PORCN have been identified in almost all patients with a classical Goltz-Gorlin phenotype. The pentalogy of Cantrell is an infrequently described congenital disorder characterized by the combination of five anomalies: a midline supra-umbilical abdominal wall defect; absent or cleft lower part of the sternum; deficiency of the diaphragmatic pericardium; deficiency of the anterior diaphragm; and congenital heart anomalies. Etiology and pathogenesis are unknown. We report on an infant with findings fitting both Goltz-Gorlin syndrome (sparse hair; anophthalmia; clefting; bifid nose; irregular vermillion of both lips; asymmetrical limb malformations; caudal appendage; linear aplastic skin defects; unilateral hearing loss) and the pentalogy of Cantrell (absent lower sternum; anterior diaphragmatic hernia; ectopia cordis; omphalocele). The clinical diagnosis Goltz-Gorlin syndrome was confirmed molecularly by a point mutation in PORCN (c.727C > T). The presence of molecularly confirmed Goltz-Gorlin syndrome and pentalogy of Cantrell in a single patient has been reported twice before. The present patient confirms that the pentalogy of Cantrell can be caused in some patients by a PORCN mutation. It remains at present uncertain whether this can be explained by the type or localization of the mutation within PORCN, or whether the co-occurrence of the two entities is additionally determined by mutations or polymorphisms in other genes, environmental factors, and/or epigenetic influences. (C) 2011 Wiley-Liss, Inc

Background: Goltz-Gorlin syndrome or focal dermal hypoplasia is a highly variable, X-linked dominant syndrome with abnormalities of ectodermal and mesodermal origin. In 2007, mutations in the PORCN gene were found to be causative in Goltz-Gorlin syndrome.Method: A series of 17 patients with Goltz-Gorlin syndrome is reported on, and their phenotype and genotype are described.Results: In 14 patients (13 females and one male), a PORCN mutation was found. Mutations included nonsense (n = 5), frameshift (n = 2), aberrant splicing (n = 2) and missense (n = 5) mutations. No genotype-phenotype correlation was found. All patients with the classical features of the syndrome had a detectable mutation. In three females with atypical signs, no mutation was found. The male patient had classical features and showed mosaicism for a PORCN nonsense mutation in fibroblasts. Two affected sisters had a mutation not detectable in their parents, supporting germline mosaicism. Their father had undergone radiation for testicular cancer in the past. Two classically affected females had three severely affected female fetuses which all had midline thoracic and abdominal wall defects, resembling the pentalogy of Cantrell and the limb-body wall complex. Thoracic and abdominal wall defects were also present in two surviving patients. PORCN mutations can possibly cause pentalogy of Cantrell and limb-body wall complexes as well. Therefore, particularly in cases with limb defects, it seems useful to search for these.Conclusions: PORCN mutations can be found in all classically affected cases of Goltz-Gorlin syndrome, including males. Somatic and germline mosaicism occur. There is no evident genotype-phenotype correlation.

The molecular aetiology of male subfertility is still unknown in the majority of cases and it is thought that multiple genes are involved. One of the genes that might play a role in male reproductive function is the protein C inhibitor (PCI) gene. In mice the presence of PCI is an absolute requirement for reproduction. In this study we performed a mutation screen of the PCI gene in subfertile men with severe teratozoospermia or idiopathic azoospermia. Male partners of subfertile couples with idiopathic azoospermia (n = 27) or teratozoospermia (n = 34) and men with normozoospermia (n = 34) were screened for mutations in the PCI gene by direct sequencing. Nine nucleotide variants found in the patients were not present in the initial control group and were therefore screened in an additional control group of 80 men with normozoospermia by restriction fragment length polymorphism analysis. In addition, PCI antigen levels were measured in the seminal plasma of the patients in which a potential mutation was found. In total, three new variants were exclusively present in men with idiopathic azoospermia, but are not likely to have caused the patients' phenotypes. In addition, the PCI antigen levels in seminal plasma of these three patients were not decreased. The fact that we were not able to detect causal mutations in the PCI gene does not necessarily lead to the conclusion that the PCI protein is not involved in human male fertility, but the results of our study indicate that mutations in the human PCI gene are not a common cause of reduced semen parameters in men.

The aetiology of impaired spermatogenesis is unknown in the majority of subfertile men. From several studies of concordance for involuntary childlessness among men, we can conclude that there is a substantial familial component in male subfertility and that shared loci segregating through families can be assumed. We now know that deletions on the Y chromosome, which do not penetrate fully, account for some of these cases. There are good reasons to suspect that other cases result from mutations in genes located elsewhere in the genome. In this article, we discuss different approaches to unravelling the molecular basis of impaired spermatogenesis originating from genetic abnormalities in chromosomes other than the Y chromosome. Genetic mapping studies are in general a good approach to detect disease-causing genes that are segregating through a population; they can provide a short-cut to unravelling the biochemistry of a disease. In this paper, we explain our reasons for arguing that linkage and association studies are no promising means to identify the genes causing impaired spermatogenesis. We conclude that direct screening of candidate genes for mutations will be necessary to detect genes involved in impaired spermatogenesis. However, this approach requires studies of the biochemical pathways of normal and abnormal spermatogenesis. Since we have a poor understanding of these pathways, more research is needed into the biochemistry of spermatogenesis

Heterozygous missense mutations in the WT1 gene that affect the function of the wild-type allele have been identified in Denys-Drash syndrome, which is characterized by severe gonadal dysgenesis, early-onset nephropathy and a predisposition to renal and gonadal cancer. Intron 9 splice-site mutations that influence the balance between WT1 isoforms cause a nearly similar phenotype, known as Frasier syndrome. Nonsense mutations and deletions only lead to WT1 haploinsufficiency and, hence, to less severe gonadal dysgenesis and late-onset nephropathy. WT1 analysis is mandatory in 46,XY gonadal dysgenesis with renal abnormality.We describe a newborn with 46,XY severe partial gonadal dysgenesis, in whom structural renal anomalies and proteinuria were excluded. Gonadectomy was performed at the age of 1 month and the microscopy was thought to be suggestive for a gonadoblastoma. At the age of 9 months, the patient presented with a bilateral Wilms tumor.We found a heterozygous WT1 whole-gene deletion but no other gene defects.This case description illustrates that a WT1 deletion might be associated with a more severe phenotype than previously thought. It also illustrates that, even in the absence of renal abnormality, it is recommended to test promptly for WT1 defects in 46,XY gonadal dysgenesis.

Mutations in the LDL receptor are responsible for familial hypercholesterolemia (FH). At present, more than 600 mutations of the LDL receptor gene are known to underlie FH. However, the array of mutations varies considerably in different populations. Therefore, the delineation of essentially all LDL receptor gene mutations in a population represents a prerequisite for the implementation of nation-wide genetic testing for FH. In this study, the frequency and geographical distribution of 13 known mutations were evaluated in a cohort of 1223 FH patients. We identified 358 mutation carriers, representing 29% of the FH cohort. Four mutations (N543H-2393de19, 1359--1G-->A, 313 + 1 G-->A and W23X) occurred with a relatively high frequency, accounting for 22.4% of the entire study cohort. Two of these common FH mutations (N543H-2393de19 and 1359 - 1G-->A) showed a preferential geographic distribution. Second, to further expand the array of LDL receptor gene mutations, we conducted mutation analysis by denaturing gradient gel electrophoresis (DGGE) in 141 children with definite FH. A mutation was identified in 111 patients, involving 16 new single base substitutions and four small deletions and insertions, which brings the number of different FH-causing mutations in our country up to 61. Our data indicate that an estimate of the prevalence of specific mutations, as well as the compilation of a database of all FH-causing mutations in a given country, can facilitate selection of the most appropriate molecular diagnostic approach.

[Author Affiliation]Marco Pozzi. 1 Istituto Di Ricovero e Cura a Carattere Scientifico ( IRCCS) Eugenio Medea, Lecco, Italy.Simone Pisano. 2 Department of Medicine and Public Health, Second University of Naples, Naples, Italy.Silvana Bertella. 1 Istituto Di Ricovero e Cura a Carattere Scientifico ( IRCCS) Eugenio Medea, Lecco, Italy.Paola Lombardi. 2 Department of Medicine and Public Health, Second University of Naples, Naples, Italy.Paolo Pellegrino. 3 Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, Universita di Milano, Milan, Italy.Massimo Molteni. 1 Istituto Di Ricovero e Cura a Carattere Scientifico ( IRCCS) Eugenio Medea, Lecco, Italy.Emilio Clementi. 1 Istituto Di Ricovero e Cura a Carattere Scientifico ( IRCCS) Eugenio Medea, Lecco, Italy. 4 Unit of Clinical Pharmacology, National Research Council ( CNR) Institute of Neuroscience, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, Universita di Milano, Milan, Italy.Carmela Bravaccio. 5 Department of Translational Medical Sciences, University Federico II of Naples, Naples, Italy.Sonia Radice. 3 Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, "Luigi Sacco" University Hospital, Universita di Milano, Milan, Italy.* The first two authors contributed equally.Funding: This work was supported by Agenzia Italiana del Farmaco (AIFA) and by the Italian Ministry of Health (Ricerca Corrente 2015, to E.C.). The funding public institutions had no role in any part of the work.Address correspondence to: Emilio Clementi, PhD, Department of Biomedical and Clinical Sciences, University of Milano, Via GB Grassi 74, 20157 Milano, Italy, E-mail: emilio.clementi@unimi.itTo The Editor:Renewed interest in the relationship between autoimmune diseases and psychiatric disorders has been raised by a recent consensus paper describing pediatric acute-onset neuropsychiatric syndrome (PANS) (Chang et al. 2014), which also includes the previously known pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) (Swedo et al. 1998). Although the diagnostic process is still debated and differential diagnosis may be challenging, several features of both disorders have been described. PANDAS is characterized by an infection-mediated (by group A-β hemolytic Streptococcus) abrupt, dramatic onset of neuropsychiatric symptoms mainly including, but not limited to, tics and obsessive-compulsive behaviors, whereas PANS may be caused by several triggers, not only postinfectious ones, and may present, together with obsessive-compulsive behaviors, with the predominant feature of acute-onset food refusal, rather than tics (Murphy et al. 2014). Anti-streptolysin O (ASO) titration is supportive of the diagnosis of PANDAS or PANS, and should be performed when they are suspected (Kiessling et al. 1993; Murphy et al. 2015; Pozzi et al. 2014). In the case of isolated measurements, the diagnostic threshold has been set at 400 U/mL, whereas the normality threshold is generally 200 U/mL, although it may be adjusted by age (Chang et al. 2014). It is also known that elevated ASO titers may be linked with a plurality of conditions that are not always pathological; however, scant data are available on the possible association of group A Streptococcus and ASO titers with the occurrence of neuropsychiatric manifestations other than Sydenham's chorea and PANDAS or PANS (Pozzi et al. 2014).Autoimmunity-based etiological hypotheses are increasingly being probed for neuropsychiatric diseases, such as autism spectrum disorders (ASD) (Keil et al. 2010). We have explored the distribution of ASO titers in a wide pediatric neuropsychiatric population, aiming to check for differences among groups of patients with different psychiatric diagnoses. …

Mutation screening of the BOULE gene in 156 men with azoospermia or severe oligozoospermia revealed no relevant mutations; thus, mutations in BOULE can be eliminated as a major cause of impaired spemiatogenesis. (C)2005 by American Society for Reproductive Medicine

Focal dermal hypoplasia (FDH; Goltz-Gorlin syndrome) is an X-linked dominant disorder affecting mainly tissues of ectodermal and mesodermal origin. The phenotype is characterized by hypoplastic linear skin lesions, eye malformations, hair and teeth anomalies, and multiple limbs malformations. The disorder is caused by PORCN mutations. Here we describe a mother and daughter with FDH in whom a c.938T>G in PORCN was detected. Neither of the two had FDH, but otherwise the phenotype was classical. Focal skin hypoplasia is a hallmark of FDH but the present family indicates that FDH should also be considered in absence of this skin manifestation.

Background— Sudden cardiac death is often caused by inherited arrhythmia syndromes, particularly if it occurs at a young age. In 1996, we started a cardiogenetics clinic aimed at diagnosing such syndromes and providing timely (often presymptomatic) treatment to families in which such syndromes or sudden cardiac death existed. We studied the yield of DNA testing for these syndromes using a candidate-gene approach over our 15 years of experience. Methods and Results— We analyzed the yield of DNA testing. In subanalyses, we studied differences in the yield of DNA testing over time, between probands with isolated or familial cases and between probands with or without clear disease-specific clinical characteristics. In cases of sudden unexplained death (antemortem or postmortem analysis of the deceased not performed or providing no diagnosis), we analyzed the yield of cardiological investigations. Among 7021 individuals who were counseled, 6944 from 2298 different families (aged 41±19 years; 49% male) were analyzed. In 702 families (31%), a possible disease-causing mutation was detected. Most mutations were found in families with long-QT syndrome (47%) or hypertrophic cardiomyopathy (46%). Cascade screening revealed 1539 mutation-positive subjects. The mutation detection rate decreased over time, in part because probands with a less severe phenotype were studied, and was significantly higher in familial than in isolated cases. We counseled 372 families after sudden unexplained death; in 29% of them (n=108), an inherited arrhythmia syndrome was diagnosed. Conclusions— The proportion of disease-causing mutations found decreased over time, in part because probands with a less severe phenotype were studied. Systematic screening of families identified many (often presymptomatic) mutation-positive subjects.

International audience; Mutations in the PORCN gene were first identified in Goltz-Gorlin syndrome patients in 2007. Since then several reports have been published describing a large variety of genetic defects resulting in the Goltz-Gorlin syndrome, and mutations or deletions were also reported in angioma serpiginosum, the pentalogy of Cantrell and Limb-Body Wall Complex. Here we present a review of the published mutations in the PORCN gene to date and report on 7 new mutations together with the corresponding clinical data. Based on the review we have created a web-based locus specific database which lists all identified variants and allows the inclusion of future reports. The database is based on the Leiden Open (source) Variation Database (LOVD) software and is accessible online at http://www.lovd.nl/porcn. At present the database contains 106 variants, representing 68 different mutations, scattered along the whole coding sequence of the PORCN gene, and 12 large gene rearrangements, which brings up to 80 the number of unique mutations identified in Goltz-Gorlin syndrome patients.

The goal of this study was to assess the mortality of hypertrophic cardiomyopathy (HCM), partly in times when the disease was not elucidated and patients were untreated.HCM is feared for the risk of sudden cardiac death (SCD). Insight in the natural history of the disorder is needed to design proper screening strategies for families with HCM.In 6 large, 200-year multigenerational pedigrees (identified by using genealogical searches) and in 140 small (contemporary) pedigrees (first-degree relatives of the proband) with HCM caused by a truncating mutation in the myosin-binding protein C gene (n = 1,118), we determined all-cause mortality using the family tree mortality ratio method. The study's main outcome measure was the standardized mortality ratio (SMR).In the large pedigrees, overall mortality was not increased (SMR 0.86 [95% confidence interval (CI): 0.72 to 1.03]), but significant excess mortality occurred between 10 and 19 years (SMR 2.7 [95% CI: 1.2 to 5.2]). In the small families, the SMR was increased (SMR 1.5 [95% CI: 1.3 to 1.6]) [corrected] and excess mortality was observed between 10 and 39 years (SMR 3.2 [95% CI: 2.3 to 4.3]) and 50 and 59 years (SMR 1.9 [95% CI: 1.4 to 2.5]).We identified specific age categories with increased mortality risks in HCM families. The small, referred pedigrees had higher mortality risks than the large 200-year multigenerational pedigrees. Our findings support the strategy of starting cardiological and genetic screening in the first-degree relatives of a proband from 10 years onward and including persons in the screening at least until the age of 60 years. Screening of more distant relatives is probably most efficient between 10 and 19 years.

Objective: To find novel genetic causes of asthenozoospermia by comprehensively screening known candidate genes derived from mouse models. Design: Case-control study. Setting: A fertility center based in an academic hospital. Patient(s): Thirty men with isolated asthenozoospermia. Intervention(s): Screening nine candidate genes for mutations: ADCY10, AKAP4, CATSPER1, CATSPER2, CATSPER3, CATSPER4, GAPDHS, PLA2G6, and SLC9A10. To account for a possible effect of heterozygous mutations, assessing imprinting of all candidate genes by studying the expression pattern of heterozygous SNPs in testis biopsies of five unrelated men. Main Outcome Measure(s): Mutations found in patients only. Result(s): We identified 10 heterozygous asthenozoospermia-specific mutations inADYC10 (n = 2), AKAP4 (n = 1), CATSPER1 (n = 1), CATSPER2 (n = 1), CATSPER3 (n = 1), CATSPER4 (n = 3), and PLA2G6 (n = 1). These mutations were distributed over six patients. In silico analysis showed that 8 of the 10 mutations either had a negative BLOSUM score, were located in conserved residues, and/or were located in a functional domain. Expression analysis demonstrated that CATSPER1 and CATSPER4 are imprinted. Conclusion(s): Given their putative effect on protein structure, their location in conserved sequences or functional domains, and their absence in controls, the identified mutations may be a cause of asthenozoospermia in humans. (Fertil Steril (R) 2011;95:1020-24. (C) 2011 by American Society for Reproductive Medicine.)

Summary The effect of lovastatin on the low density lipoprotein metabolism in bypassed rabbits was investigated. Partial ileal bypass effectively reduced total and low density lipoprotein (LDL) cholesterol by 44 and 48% respectively. The LDL drop was due to an increased fractional catabolic rate (FCR) of apolipoprotein B (apo B) from 0.74 to 1.27 pools per day with no effect on the apo B absolute catabolic rate and an increased expression of liver LDL receptors (+71%). Association of lovastatin with PIB resulted in a further decrease of total and LDL cholesterol (56 and 75% respectively) as compared to bypassed animals, without effects on the LDL FCR (1.27 ± 0.11 versus 1.42 ± 0.13 pools/day) or the expression of LDL receptors by the liver. The reduction of LDL was due to a decrease of the apolipoprotein B absolute synthetic rate (8.5 ± 1.7 versus 13.6 ± 1.7 mg/day). From these data we conclude that in bypassed rabbits lovastatin lowers total and LDL cholesterol mainly by reducing apolipoprotein B production rate.

Familial hypercholesterolemia (FH) has been identified as a major risk factor for coronary vascular disease and is associated with mutations in the low-density liporotein receptor (LDLR) and apolipoprotein B (APOB) gene. The molecular basis of FH in the Dutch population is well understood. Approximately 160 different LDLR and APOB gene defects have been identified with a panel of 9 LDLR gene and 1 APOB gene frequently occurring mutations accounting for approximately 30% of all clinically diagnosed FH cases. As molecular diagnosis of FH is becoming increasingly widely applied, a variety of mutation detection rates is reported, ranging from as low as 30% and up to 80%. This variability appears to depend on the clinical criteria applied to identify patients with FH and on the strategies and methodologies used for mutation screening. In this study we describe the application of a stepwise screening approach, combining different methodologies, to detect mutations of the LDLR gene and APOB gene in 1465 patients with FH. A mutation was found in approximately 44% of the patients, which demonstrates that this is an effective strategy for the molecular diagnosis of FH.

Diese Studie beschäftigt sich mit zwei Inschriften, einem römischen Militärdiplom und einer griechischsprachigen Grabinschrift, die aus Aleria bzw. dem Umland der Stadt stammen. Das vollständig erhaltene Diplom erwähnt eine bereits bekannte Konstitution vom 18. Februar des Jahres 129. In der Urkunde wird das Bürgerrecht verliehen an einen M. Cominius Cubesti f(ilius) Vielo, Korsen aus Cobas und einfachen Angehörigen der Flotte von Misenum. Unser Kommentar bietet verschiedene Beobachtungen zur Prosopographie der erwähnten Personen und zu römischen Militärangehörigen korsischer Herkunft. Im Anhang geben wir eine Liste der korsischen classiarii der Flotte von Misenum, der Flotte von Ravenna und einer unbestimmten Flotte, ferner eine Liste der übrigen auf Korsika bezeugten classiarii sowie ein Verzeichnis einheimischer korsischer Namen. Die nicht vor das späte dritte Jahrhundert n. Chr. datierbare griechische Inschrift ist eine Privaturkunde aus dem Grabzusammenhang. Der Text bezieht sich auf eine Griechin und wurde von ihrem Gatten, ebenfalls Griechen, veranlasst. Zwei Aspekte sind an dem Dokument von besonderem Interesse, nämlich zum einen die Präsenz einer griechisch schreibenden Person auf Korsika während dieses relativ späten Zeitabschnitts, und zum anderen die Androhung einer an den hierotaton tamion zu entrichtenden Geldbuβe im Falle der Beschädigung der Grabstätte. Beides findet seine Erklärung in der Anwesenheit von Seeleuten griechisch-orientalischer Herkunft als Angehörige der Flotte von Misenum in Aleria. Übersetzung : Stefan WlRTH, The article concerns two inscriptions from Aleria, and its territory : a military diploma and a Greek funerary text. The diploma, entire, mentions a constitution already known, from 18 February 129. Rights are given to a seaman of Misene fleet, M. Cominius Cubesti f(ilius) Vielo a Corsican from Cobas (?). The commentary includes several observations on the prosopography of the individuals mentioned and on the soldiers from Corsica. An appendix gives the list of the classiarii of the Misenan and Ravenna fleets and of an indeterminate fleet, the list of other classiarii attested in Corsica, and an index of indigenous Corsican names. The inscription in Greek (dated at least at the end of the 3rd century AD) is a private funerary document for a Greek woman from her husband, himself Greek. The interesting part of this text is the presence in Corsica in a rather late period of somebody writing in Greek and the indication of a funerary fine to pay to the hierotaton tamion in case of a violation of the tomb. These two aspects can been explained by the presence in Aleria of seamen of the Misenan fleet of Greco-oriental origin. Translation : Isabelle FAUDUET, L'étude concerne deux inscriptions provenant d'Aleria et son territoire : un diplôme militaire et un texte funéraire en grec. Le diplôme, entier, mentionne une constitution déjà connue, celle du 18 février 129 ; les droits sont octroyés à un marin de la flotte de Misène, M. Cominius Cubesti f(ilius) Vielo, corse de Gobas (?). Le commentaire contient plusieurs observations sur la prosopographie des personnages mentionnés, ainsi que sur les militaires d'origine corse. Une annexe donne la liste des classiarii corses de la flotte de Misène, de la flotte de Ravenne et d'une flotte indéterminée ; la liste d'autres classiarii attestés en Corse ; un index des noms corses indigènes. L'inscription en grec (datable au plus tôt de la fin du IIIe s. apr. J.-C.) est un document privé, funéraire, dédié à une femme par son époux, tous deux grecs. Les éléments d'intérêt du document sont, d'une part, la présence en Corse, à une époque assez tardive, d'un personnage écrivant en grec et, d'autre part, la mention d'une amende funéraire à verser au hierotaton tamion en cas de violation du tombeau. Ces deux éléments trouvent une explication dans la présence à Aleria de marins de la flotte de Misène, d'origine gréco-orientale., Lombardi Paola, Vismara Cinzia. Deux inscriptions d'Aléria (Haute-Corse). In: Gallia, tome 62, 2005. pp. 279-292.

BACKGROUND: The aetiology of impaired spermatogenesis is unknown in the majority of cases. Evidence of a contribution of genetic factors is still scarce. Therefore, the aim of our study was to assess whether male factor subfertility due to impaired spermatogenesis has a familial component and to test different genetic models of inheritance. METHODS: Cases were all men with severe idiopathic impaired spermatogenesis attending our fertility clinic from January 1998 until December 2001. Controls were all men with normozoospermia attending our fertility clinic in the same period. Family data were collected from the medical records and by additional interviews of the probands. If subfertility of a first-degree relative was mentioned, permission was sought to contact the affected family member in order to obtain all medical information available, including the results of semen analyses. RESULTS: In total, 160 patients and 285 controls were included in the analysis. Family size and number of brothers and sisters were equally distributed in both groups. In the patient group, 1.63% of the brothers who had tried to father a child were mentioned to be subfertile compared to 5.8% in the control group [odds ratio 3.18 (95% confidence interval 1.59‐6.37)]. The subfertility among the brothers in the patient group was more often due to reduced semen parameters compared to the control group. The data did not fit with frequent autosomal dominant or recessive segregation. CONCLUSION: Male factor subfertility due to impaired spermatogenesis appears to cluster in families. Our data suggests that heritable genetic factors play a role in a limited number of cases. Impaired spermatogenesis is not caused by a common genetic defect, but is most likely a complex disease in which several different factors play a role.

Item does not contain fulltext The molecular aetiology of male factor subfertility, due to impaired spermatogenesis, is still unknown in the majority of cases. It is thought to be a complex disorder in which multiple genes are implicated. Cryptorchidism and reduced fecundity are symptoms in male Beckwith-Wiedemann patients and the ZNF214 and ZNF215 genes, localized on chromosomal region 11p15, are associated with this syndrome. We hypothesized that the ZNF214 and ZNF215 genes, which are predominantly expressed in the testis, could be involved in male factor subfertility in patients with idiopathic impaired spermatogenesis or in patients with impaired spermatogenesis due to cryptorchidism. Male partners of subfertile couples with idiopathic azoo- or severe oligozoospermia, male partners with azoo- or severe oligozoospermia and cryptorchidism in their medical history and men with normozoospermia were screened for nine single nucleotide polymorphisms in the ZNF214 and ZNF215 genes. An association study was performed based on allele and estimated haplotype frequencies. Statistically significant differences in allele frequencies and in estimated haplotype frequencies were found in both patient groups compared with controls. Thereafter, both genes were screened for mutations in all patients by PCR and single strand conformation polymorphism analysis. Aberrant patterns were confirmed by DNA sequencing. Mutation analysis in ZNF214 and ZNF215 revealed five new variants in the patients that were not present in the controls. At least three of these mutations were inherited from the mother. Our results suggest that chromosomal region 11p15 is associated with male factor subfertility due to impaired spermatogenesis with and without cryptorchidism.

A capillary-scale particle beam interface was used to detect 18 phenolic compounds in red wine samples. This technique allows reproducible, library searchable electron ionization spectra at only 1 microliter/min mobile phase flow-rate for a sensitive detection of the analytes in complex matrices. The method makes use of a narrow bore, reversed-phase packed capillary column for sample separation. Detection limits were in the low picogram range for most compounds. Sensitivity and response linearity were evaluated for eight phenolic acids, which are often encountered in red wines. The phenolic compound composition was outlined in two red wines obtained using different aging processes.

A new simplified technique for 1D non-uniform dose delivery using a single dynamic absorber, driven by a computer system, has been recently proposed together with a simple analytic algorithm. This technique uses an optimized 'stepped' absorber's speed profile and the generated fluence profile is an approximation of the desired radiation beam. In the case of non-uniform beam profiles with multiple maxima/minima, the original proposed 'stepping algorithm' has some limitations and produces a too rough approximation of the desired profiles. In order to increase the agreement between desired and generated profiles, more sophisticated optimization schemes are required. In this paper we have applied a variant of simulated annealing (SA) as a statistical optimization algorithm to further investigate the possibilities and the limits of the single-absorber technique in the field of 1D intensity modulation. In the current application the cost function used is the mean square root of the percentage differences between desired and generated profiles, the absorber's resting times have been chosen as optimization variables and at each iteration just one variable is randomly changed, adding an incremental 'grain'. A Cauchy generating function is used, different cooling schedules are evaluated; constraints related to our apparatus are introduced and starting annealing parameters are set after some initial optimization tests. The method is tested in reproducing theoretical non-uniform beams, by comparing desired modulated fluence profiles with calculated fluence profiles obtainable with the single absorber after the derivation of optimized speed profiles by the proposed SA approach. The results of these simulations show that the application of the SA method optimizes the single absorber's performance and that clinically important modulated beams useful for conformal radiotherapy can be accurately reproduced.

Familial hypercholesterolemia (FH) is an autosomal semi-dominant disorder caused by defects in the low density lipoprotein receptor (LDLR) gene and is a well-documented risk factor for developing cardiovascular disease. The LDLR genes of five Swedish children with FH were examined in this study. Initial mutation screening was performed by denaturing gradient gel electrophoresis (DGGE) with enzymatically amplified exon-sized fragments, each containing a tailing GC-rich requence. The GC-clamped fragments had been synthesized with a restriction site adjacent to the intron-corresponding sequence to allow detachment of the clamps, thereby rendering the fragments suitable for subsequent analysis by single-strand conformation polymorphism (SSCP) analysis of samples from patients with no DGGE-detectable mutations. In addition, all the LDLR genes of the patients were screened for large alterations by restriction fragment length polymorphism analysis. Following this strategy, seven different, potentially disease-causing mutations were detected in the five children with FH. Six of the alterations, five single-base substitutions and one dinucleotide deletion, have not previously been described. DGGE detected six of the mutations and SSCP the seventh.

We have studied the uptake of 125 I-labelled low-density lipoprotein (LDL) by seven experimental murine tumours in vivo. Four tumours (Lewis Lung carcinoma, B-16, MS-2 and Colon 26) showed a higher relative uptake of lipoprotein as compared to the liver, two (L-1210 and P-388) had a very low lipoprotein uptake, while lipoprotein uptake by tumour M5 was similar to that of the liver. The data was confirmed by tracing tissue uptake of lipoproteins using [ 14 C]sucrose-labeled LDL. These in vivo findings correlated well with the in vitro specific binding of 125 I-β-VLDL to membranes prepared from tumours, thus suggesting that the expression of the LDL receptor in the tumours is related to the in vivo uptake of lipoprotein. Further analysis of the LDL receptor by ligand blotting showed that the tumor receptor has several of the liver LDL receptor characteristics (including apparent M r , sensitivity to proteinases, and Ca 2+ requirement for lipoprotein binding). In summary, our data show that experimental murine tumours express the LDL receptor and suggest that the high relative in vivo uptake of LDL is determined by the elevated LDL-receptor expression in the tumours.

The theme of women scholars’ role and their contribution to initially promote social and environmental accounting and reporting is relatively new. Consequently there are many gaps to fill in concerning several topics developed within the aforementioned emerging research strand. Starting from this premise, the aim of this paper is to present a discussion about women “master pioneers” of social accounting in Italy. The research design develops through a deductive and inductive approach. The deductive approach is based on a literature review concerning social and environmental accounting and gender accounting. The inductive approach is empirically constructed and focused on the scientific and academic career of two Italian female scholars. The comparative analysis of the two cases helps to point out the relevance of women’s contribution as well as to “disclose” their role in promoting social and environmental accounting and reporting in Italy.

Il capitolo esamina l'organizzazione amministrativa preposta alla tutela dei beni culturali, nella sua articolazione centrale e periferica, e le relative competenze, la circolazione dei beni culturali ed il regime dei beni archeologici.