A regional-based newborn hearing screening program: the Emilia-Romagna model after ten years of legislation.

Background: Hearing loss, occurring in 1-3/1,000 newborns in the well-babies population, is one of the most common congenital diseases, and hearing screening at birth still represents the only means for its early detection. Since 2011 the Emilia Romagna Regional Health Agency has recommended Newborn Hearing Screening for all babies at its birth points and for newborns moving to the region. The aims of this study are to analyze the results of this regional-based Newborn Hearing Screening program and to discuss the impact of the legislative endorsement on the organization. Material and methods: This is an observational retrospective chart study. The recordings of well-babies and babies at Neonatal Intensive Care Units were collected during the period from January 1st 2015 to December 31st 2020. The following data were included: Newborn Hearing Screening coverage, percentage of refer at otoacoustic emissions, prevalence and entity of hearing loss, unilateral/bilateral rate, presence of audiological risk factors. Results: More than 99% of a total of 198,396 newborns underwent the Newborn Hearing Screening test during the period January 1st 2015 to December 31st 2020, with a coverage ranging between 99.6% and 99.9%. Overall, the percentage of confirmed hearing loss cases was about 17-30 % of refer cases, 745 children received a diagnosis of hearing loss (prevalence 3.7/1,000). Considering profound hearing loss cases, these represent 13% of bilateral hearing loss. Conclusion: A regional-based Newborn Hearing Screening program is valuable and cost-effective. In our experience, the centralization of the data system and of the data control is crucial in order to implement its efficiency and effectiveness. Healthcare policies, tracking systems and public awareness are decisive for a successful programme implementation.

Heritability, genetic correlation and linkage to the 9p21.3 region of mixed platelet-leukocyte conjugates in families with and without early myocardial infarction.

BACKGROUND AND AIMS: Variations in mixed platelet-leukocyte conjugate formation in human whole blood could be genetically determined. We quantified platelet and leukocyte activation and interaction in families with or without early myocardial infarction and evaluated their heritability, genetic correlation and linkage to the 9p21.3 region. METHODS AND RESULTS: The study population included 739 subjects (≥ 15 years old) from 54 large pedigrees, 23 with and 31 without familial myocardial infarction. Mixed platelet-leukocyte conjugates and markers of platelet or leukocyte activation (P-selectin, CD11b and L-selectin surface expression) were measured both before and after in vitro blood stimulation with collagen-ADP. All traits had significant genetic components (17.5-65.3% of the phenotypic variability), while shared household effects (0-39.6%) and environmental covariates (0-10.2%) tended to be smaller. Stimulated platelet-polymorphonuclear leukocyte (PMN) and platelet-monocyte conjugates showed the highest linkage to the 9p21.3 region (LOD = 0.94 and 1.33, respectively; empirical p value = 0.017 and 0.009). PMN markers resulted strongly genetically correlated between them in bivariate analysis among pairs of quantitative traits. CONCLUSION: This study supports a genetic regulation of human mixed platelet-leukocyte conjugates.

Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly.

Holoprosencephaly (HPE) is a common, severe malformation of the brain that involves separation of the central nervous system into left and right halves. Mild HPE can consist of signs such as a single central incisor, hypotelorism, microcephaly, or other craniofacial findings that can be present with or without associated brain malformations. The aetiology of HPE is extremely heterogeneous, with the proposed participation of a minimum of 12 HPE-associated genetic loci as well as the causal involvement of specific teratogens acting at the earliest stages of neurulation. The HPE2 locus was recently characterized as a 1-Mb interval on human chromosome 2p21 that contained a gene associated with HPE. A minimal critical region was defined by a set of six overlapping deletions and three clustered translocations in HPE patients. We describe here the isolation and characterization of the human homeobox-containing SIX3 gene from the HPE2 minimal critical region (MCR). We show that at least 2 of the HPE-associated translocation breakpoints in 2p21 are less than 200 kb from the 5' end of SIX3. Mutational analysis has identified four different mutations in the homeodomain of SIX3 that are predicted to interfere with transcriptional activation and are associated with HPE. We propose that SIX3 is the HPE2 gene, essential for the development of the anterior neural plate and eye in humans.

Nucleotide diversity of a genomic sequence similar to SHATTERPROOF (PvSHP1) in domesticated and wild common bean (Phaseolus vulgaris L.).

Evolutionary studies in plant and animal breeding are aimed at understanding the structure and organization of genetic variations of species. We have identified and characterized a genomic sequence in Phaseolus vulgaris of 1,200 bp (PvSHP1) that is homologous to SHATTERPROOF-1 (SHP1), a gene involved in control of fruit shattering in Arabidopsis thaliana. The PvSHP1 fragment was mapped to chromosome Pv06 in P. vulgaris and is linked to the flower and seed color gene V. Amplification of the PvSHP1 sequence from the most agronomically important legume species showed a high degree of interspecies diversity in the introns within the Phaseoleae, while the coding region was conserved across distant taxa. Sequencing of the PvSHP1 sequence in a sample of 91 wild and domesticated genotypes that span the geographic distribution of this species in the centers of origin showed that PvSHP1 is highly polymorphic and, therefore, particularly useful to further investigate the origin and domestication history of P. vulgaris. Our data confirm the gene pool structure seen in P. vulgaris along with independent domestication processes in the Andes and Mesoamerica; they provide additional evidence for a single domestication event in Mesoamerica. Moreover, our results support the Mesoamerican origin of this species. Finally, we have developed three indel-spanning markers that will be very useful for bean germplasm characterization, and particularly to trace the distribution of the domesticated Andean and Mesoamerican gene pools.

Congenital lung malformations: a novel application for lung ultrasound?

Congenital lung malformations (CLMs) include a group of different disorders. With widespread use of antenatal ultrasonography (aUS) and increased use of pre-natal magnetic resonance imaging (MRI), CLMs are increasingly detected, nevertheless the best postnatal imaging approach is not yet well defined: newborns usually undergo several chest X-rays and eventually computed tomography to confirm the diagnosis. In this case series, we show lung ultrasound features of three different cases of congenital lung malformations, describing prenatal and postnatal images comparing different imaging techniques.

Beans in Europe: origin and structure of the European landraces of Phaseolus vulgaris L.

This study focuses on the expansion of Phaseolus vulgaris in Europe. The pathways of distribution of beans into and across Europe were very complex, with several introductions from the New World that were combined with direct exchanges between European and other Mediterranean countries. We have analyzed here six chloroplast microsatellite (cpSSR) loci and two unlinked nuclear loci (for phaseolin types and Pv-shatterproof1). We have assessed the genetic structure and level of diversity of a large collection of European landraces of P. vulgaris (307) in comparison to 94 genotypes from the Americas that are representative of the Andean and Mesoamerican gene pools. First, we show that most of the European common bean landraces (67%) are of Andean origin, and that there are no strong differences across European regions for the proportions of the Andean and Mesoamerican gene pools. Moreover, cytoplasmic diversity is evenly distributed across European regions. Secondly, the cytoplasmic bottleneck that was due to the introduction of P. vulgaris into the Old World was very weak or nearly absent. This is in contrast to evidence from nuclear analyses that have suggested a bottleneck of greater intensity. Finally, we estimate that a relatively high proportion of the European bean germplasm (about 44%) was derived from hybridization between the Andean and Mesoamerican gene pools. Moreover, although hybrids are present everywhere in Europe, they show an uneven distribution, with high frequencies in central Europe, and low frequencies in Spain and Italy. On the basis of these data, we suggest that the entire European continent and not only some of the countries therein can be regarded as a secondary diversification center for P. vulgaris. Finally, we outline the relevance of these inter-gene pool hybrids for plant breeding.

Introgression from modern hybrid varieties into landrace populations of maize (Zea mays ssp. mays L.) in central Italy.

Landraces are domesticated local plant varieties that did not experience a deliberate and intensive selection during a formal breeding programme. In Europe, maize landraces are still cultivated, particularly in marginal areas where traditional farming is often practiced. Here, we have studied the evolution of flint maize landraces from central Italy over 50 years of on-farm cultivation, when dent hybrid varieties were introduced and their use was widespread. We have compared an 'old' collection, obtained during the 1950s, before the introduction of hybrids, and a recent collection of maize landraces. For comparison, a sample of maize landraces from north Italy, and of improved germplasm, including hybrids and inbred lines were also used. A total of 296 genotypes were analysed using 21 microsatellites. Our results show that the maize landraces collected in the last 5-10 years have evolved directly from the flint landrace gene pool cultivated in central Italy before the introduction of modern hybrids. The population structure, diversity and linkage disequilibrium analyses indicate a significant amount of introgression from hybrid varieties into the recent landrace populations. No evidence of genetic erosion of the maize landraces was seen, suggesting that in situ conservation of landraces is an efficient strategy for preserving genetic diversity. Finally, the level of introgression detected was very variable among recent landraces, with most of them showing a low level of introgression; this suggests that coexistence between different types of agriculture is possible, with the adoption of correct practices that are aimed at avoiding introgression from undesired genetic sources.

Evolved feature weighting for random subspace classifier.

The problem addressed in this letter concerns the multiclassifier generation by a random subspace method (RSM). In the RSM, the classifiers are constructed in random subspaces of the data feature space. In this letter, we propose an evolved feature weighting approach: in each subspace, the features are multiplied by a weight factor for minimizing the error rate in the training set. An efficient method based on particle swarm optimization (PSO) is here proposed for finding a set of weights for each feature in each subspace. The performance improvement with respect to the state-of-the-art approaches is validated through experiments with several benchmark data sets.

[Initial experience of an alternative surgical strategy for stenosis post- urethroplasty using dorsal buccal mucosa graft]. / Estrategia quirúirgica alternativa en las estenosis posturetroplastia con técnica de colgajo prepucial tubulizado: experiencia inicial.

In the early '80s, tubularized preputial flap has been intensively used for proximal hypospadias. Even if not yet used today, there are a conspicuous number of patients treated in that time that today present with obstructive symptoms. In this paper, authors propose an initial experience of an alternative strategy to the complete re-do. Three patients (6, 9 and 27 years old) were diagnosed of stenosis at the junction of the tubularized preputial flap and the native urethra. Proximal and distal urethra was normal at the urethrogram in all cases. A augmentation was performed. One year follow up is free of obstructive symptoms and flowmetry is normal. The technique proposed seems to be the best balanced owing to a minimal invasivity and better results along time.

Late-presenting right congenital diaphragmatic hernia with severe hypotrophy of the right lobe of the liver.

INTRODUCTION: Congenital diaphragmatic hernia (CDH) presenting after 30 days of life is unusual and has a variant pattern of presentation. PRESENTATION OF CASE: We present a death case occurred to a 34-days-old infant. The infant arrived to our emergency department in cardiac arrest after having suffered from intermittent acute abdominal pain. Autopsy confirmed the presence of a right CDH, with herniation of the right lobe of the liver into the thorax. DISCUSSION: Most of the cases of CDH are diagnosed prenatally or in the neonatal period. However, some patients do not develop symptoms until after the neonatal period. The relevance of our case is the co-existence of right CDH and important hypotrophy of the right lobe of the liver. CONCLUSIONS: Evidence of this phenomenon represents an absolute novelty in the extant scientific literature. Even if rare, we suggest to suspect the presence of CDH in fetus with disparity in right and left liver lobe at prenatal ultrasound.

Molecular genetics of holoprosencephaly.

Holoprosencephaly (HPE) is a common developmental defect of the human forebrain and midface. Pathological studies have identified different categories of severity of the brain and craniofacial malformations observed in HPE, although the variable clinical spectrum of HPE extends in unbroken sequence from alobar HPE and cyclopia to clinically unaffected carriers in familial HPE. The etiology of HPE is extremely heterogeneous including both environmental and genetic causes. Here we focus on molecular aspects of HPE in light of the recent identification of some of the genes causing human HPE and other candidate genes involved in forebrain development, through different approaches, such as positional cloning and functional cloning, based on animal models. These approaches will aid in the identification of additional genes involved in HPE and in a better understanding of the molecular genetics of brain development.

Holoprosencephaly: molecular study of a California population.

Holoprosencephaly (HPE) is a common developmental anomaly of the forebrain and midface in which the cerebral hemispheres fail to separate into distinct left and right halves. HPE is extremely heterogeneous. In addition to teratogenic agents, several genes are implicated in the cause of HPE. Using samples from a population-based birth defects registry in California, we performed a mutational analysis of the known HPE genes Sonic Hedgehog (SHH), ZIC2, and SIX3, in addition to two HPE candidate genes, TG-interacting factor (TGIF), and Patched (PTC), on a group of sporadic HPE patients. This is the first molecular study of HPE in a population-based sample of patients. Among these patients, a deletion in the homeodomain of SIX3 and several polymorphisms in SIX3 and TGIF were identified. No sequence changes were detected in SHH, ZIC2, and PTC. Our results suggest that mutations in the currently recognized HPE genes may explain <5% of all sporadic HPE cases.

SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature.

Solitary median maxillary central incisor (SMMCI) or single central incisor is a rare dental anomaly. It has been reported in holoprosencephaly (HPE) cases with severe facial anomalies or as a microform in autosomal dominant HPE (ADHPE). In our review of the literature, we note that SMMCI may also occur as an isolated finding or in association with other systemic abnormalities. These anomalies include short stature, pituitary insufficiency, microcephaly, choanal atresia, midnasal stenosis, and congenital nasal pyriform aperture stenosis. SMMCI can also be a feature of recognized syndromes or associations or a finding in patients with specific chromosomal abnormalities. We performed a molecular study on a cohort of 13 SMMCI patients who did not have HPE. We studied two genes, Sonic Hedgehog (SHH) and SIX3, in which mutations have been reported in patients showing SMMCI as part of the HPE spectrum. A new missense mutation in SHH (I111F), segregating in one SMMCI family, was identified. Our results suggest that this mutation may be specific for the SMMCI phenotype since it has not been found in the HPE population or in normal controls. Published 2001 Wiley-Liss, Inc.

A split hand-split foot (SHFM3) gene is located at 10q24-->25.

The split hand-split foot (SHSF) malformation affects the central rays of the upper and lower limbs. It presents either as an isolated defect or in association with other skeletal or non-skeletal abnormalities. An autosomal SHSF locus (SHFM1) was previously mapped to 7q22.1. We report the mapping of a second autosomal SHSF locus to 10q24-->25. A panel of families was tested with 17 marker loci mapped to the 10q24-->25 region. Maximum lod scores of 3.73, 4.33 and 4.33 at a recombination fraction of zero were obtained for the loci D10S198, PAX2 and D10S1239, respectively. An 19 cM critical region could be defined by haplotype analysis and several genes with a potential role in limb morphogenesis are located in this region. Heterogeneity testing indicates the existence of at least one additional autosomal SHSF locus.

Molecular phylogeny of Anthyllis spp.

For the genus Anthyllis (Fam. Fabaceae, tribe Loteae), with few exceptions, little information is available on the genetic variation among and within species. This genus contains 20 species distributed throughout Europe, Africa, and the Mediterranean basin. The most widespread species is A. vulneraria, and over 30 intraspecies taxa have been identified based on plant morphology. To study the molecular phylogeny of the genus, the sequences of the internal transcribed spacers ITS1 and ITS2 of the nuclear ribosomal DNA of 10 Anthyllis species, including 11 subspecies of A. vulneraria and three subspecies of A. montana, were obtained and analysed together with sequences of five other species of the genus obtained from GenBank. Our results suggest that the genus Anthyllis is not monophyletic and is divided in two main clades: the Anthyllis sensu strictu and the "tetraphylla clade". The former includes most of the Anthyllis species, and the latter includes three annual species more closely related to Lotus. All the taxa were also analysed according to seven chloroplast microsatellites, and these data closely confirm the results obtained with the ITS phylogeny.

Combination of paclitaxel and etoposide in the treatment of advanced non-small cell lung cancer: a phase I-II study.

Thirty-six patients (pts) with unpretreated advanced non-small cell lung cancer (NSCLC) stages IIIB and IV were enrolled in this two-stage phase I-II study aimed to establish the maximum tolerated dose (MTD) of paclitaxel and to evaluate the efficacy and safety of paclitaxel combined with etoposide every 3 weeks for a maximum of 6 courses, increasing the dose of paclitaxel according to a modified Fibonacci scheme. Nineteen pts were enrolled in the first stage and 17 pts in the second stage. The characteristics of the pts were as follows: median age 56 years (40-70), median Karnofsky's Performance Status 80% (70-80), 11 pts were stage IIIB and 25 pts stage IV. The doses of etoposide administered were 50 mg/m2 for 15 pts and 100 mg/m2 for 21 pts. MTD has not been reached and the study proceeded with the dose of paclitaxel 250 mg/m2. We obtained 9 (25%) partial remissions (PR) and 11 (31%) stable disease (SD) in 33 objectively evaluable pts. Median time to progression (TTP) was 4 months (0.3-21), median survival was 9.3 months (0.3-27). The main toxicity was neutropenia and neurotoxicity, while the gastrointestinal toxicity was mild. Two pts deceased after the first course. The causes of death were necrotizing enteritis in the first pt and congestive heart failure in the second pt. A total of 156 courses were administered at 7 dose levels, with a median of 4 courses per patient (1-6). The results seem to support the use of this combination in advanced non-small cell lung cancer.

Endoscopic treatment of chronic idiopathic pancreatitis in children.

The purpose of this study was to analyze the preliminary results obtained with endoscopic treatment of children with chronic idiopathic pancreatitis. The disease appears to be caused by a deficit of pancreatic stabilizing proteins that leads to precipitation of solutes contained in the pancreatic secretions; these precipitates are the cause of inflammation. The possible role of a congenital malformation in the pathogenesis of this disease is being regarded with increasing scepticism. Between October 1991 and April 1994, five cases of chronic pancreatitis were referred to the Division of Pediatric Surgery of the Policlinico "A. Gemelli" of Rome. The age range of the patients (3 boys, 2 girls) was 3 to 14 years (mean, 10.8 years); all had a history of acute attacks and had blood chemistry findings compatible with pancreatitis. None of the patients' families had a history of pancreatic disease. All diagnoses were confirmed by endoscopic retrograde cholangiopancreatography, and the disease was staged according to the criteria of Cremer et al. Endoscopic pancreatic sphincterotomy, with or without removal of calculi, was performed in four cases (2 in the authors' hospital, 2 in another institution). Three of the children have had no further symptoms (mean follow-up period, 20 months), and their growth and weight gain have been normal. The fourth child, a 3-year-old girl, has had two episodes of pain since treatment. These attacks, both of which subsided spontaneously, probably were caused by the passage of protein plugs through the sphincterotomy. The fifth patient received no treatment because she had remained asymptomatic since the first examination (28 months ago). The short-term effects observed in these children indicate that endoscopic treatment of chronic idiopathic pancreatitis is associated with a high rate of success with respect to pain control. Because of the short follow-up, the effects on endocrine and exocrine function have not been assessed. No deaths or complications occurred. Conservative treatment of this type can be repeated if pain recurs, an important factor given the chronic nature and early onset of this disease, and it does not preclude the possibility of subsequent surgery. The authors' experience indicates that this approach should be considered the initial treatment of choice for children with chronic pancreatitis.

Treatment of intraosseous arteriovenous fistulas of the extremities.

Intraosseous arteriovenous fistulas of the extremities are rare malformations frequently associated with severe systemic hemodynamic alterations. In many cases, it is quite difficult to eliminate these anomalous vascular structures, but the possibilities for successful treatment are much greater when surgery is combined with interventional radiology. Selective embolization of the malformed vessels can be produced with a variety of agents that are injected into afferent arteries, via percutaneous puncture or through direct surgical access. The intraosseous portion of the fistula should be resected at the time of embolization or later. The authors describe the successful treatment of three patients having intraosseous arteriovenous fistulas of the upper extremities, who have had follow-up for 2 to 10 years.

Accessory lower limb in a newborn with multiple malformations.

Accessory lower limbs are rare anomalies that are associated with other severe malformations. The authors describe a case of this type and discuss the pathogenetic and classification problems surrounding these malformations in the light of the limited number of the other cases reported in the literature.

H-type rectovaginal fistula associated with the Currarino triad.

We describe a case of H-type rectovaginal fistula associated with the Currarino triad (anorectal stenosis, sacral defect, presacral mass). Presenting symptoms included passage of feces per vaginam, signs of intestinal subocclusion without perianal inflammation, left leg paresis and foul-smelling urine. An anterior sacral meningocele was repaired at the age of three months. At age 18 months the fistula was excised through a perineal approach after creation of a protective colostomy. Diagnostic and therapeutic aspects of this malformation are discussed.