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Biomedical subjects

G Neri

Publications and source records attributed to G Neri.

At least 19 recordsLinked to original sources
PubMed2006

Randomized, double-blind, placebo-controlled trial of phenylbutyrate in spinal muscular atrophy.

OBJECTIVE: To assess the efficacy of phenylbutyrate (PB) in patients with spinal muscular atrophy in a randomized, double-blind, placebo-controlled trial involving 10 Italian centers. METHODS: One hundred seven children were assigned to receive PB (500 mg/kg/day) or matching placebo on an intermittent regimen (7 days on/7 days off) for 13 weeks. The Hammersmith functional motor scale (primary outcome measure), myometry, and forced vital capacity were assessed at baseline and at weeks 5 and 13. RESULTS: Between January and September 2004, 107 patients aged 30 to 154 months were enrolled. PB was well tolerated, with only one child withdrawing because of adverse events. Mean improvement in functional score was 0.60 in the PB arm and 0.73 in placebo arm (p = 0.70). Changes in the secondary endpoints were also similar in the two study arms. CONCLUSIONS: Phenylbutyrate was not effective at the regimen, schedule, and duration used in this study.

Child↗
PubMed2006

The cardiofaciocutaneous syndrome.

The cardiofaciocutaneous (CFC) syndrome is a condition of sporadic occurrence, with patients showing multiple congenital anomalies and mental retardation. It is characterised by failure to thrive, relative macrocephaly, a distinctive face with prominent forehead, bitemporal constriction, absence of eyebrows, hypertelorism, downward-slanting palpebral fissures often with epicanthic folds, depressed nasal root and a bulbous tip of the nose. The cutaneous involvement consists of dry, hyperkeratotic, scaly skin, sparse and curly hair, and cavernous haemangiomata. Most patients have a congenital heart defect, most commonly pulmonic stenosis and hypertrophic cardiomyopathy. The developmental delay usually is moderate to severe. The syndrome is caused by gain-of-function mutations in four different genes BRAF, KRAS, mitogen-activated protein/extracellular signal-regulated kinase MEK1 and MEK2, all belonging to the same RAS-extracellular signal-regulated kinase (ERK) pathway that regulates cell differentiation, proliferation and apoptosis. The CFC syndrome is a member of a family of syndromes that includes the Noonan and Costello syndromes, presenting with phenotypic similarities. Noonan syndrome is caused by mutations in the protein tyrosine phosphatase SHP-2 gene (PTPN11), with a few people having a mutation in KRAS. Costello syndrome is caused by mutations in HRAS. The protein products of these genes also belong to the RAS-ERK pathway. Thus, the clinical overlap of these three conditions, which often poses a problem of differential diagnosis, is explained by their pathogenetic relatedness.

Abnormalities, Multiple↗
PubMed2006

Maintenance of X- and Y-inactivation of the pseudoautosomal (PAR2) gene SPRY3 is independent from DNA methylation and associated to multiple layers of epigenetic modifications.

Maintenance of X-inactivation is achieved through a combination of different repressive mechanisms, thus perpetuating the silencing message through many cell generations. The second human X-Y pseudoautosomal region 2 (PAR2) is a useful model to explore the features and internal relationships of the epigenetic circuits involved in this phenomenon. Recently, we demonstrated that DNA methylation plays an essential role for the maintenance of X- and Y-inactivation of the PAR2 gene SYBL1; here we report that the silencing of the second repressed PAR2 gene, SPRY3, appears to be independent of DNA methylation. In contrast to SYBL1, the inactive X and Y alleles of SPRY3 are not reactivated in cells treated with a DNA methylation inhibitor and in cells from ICF (immunodeficiency, centromeric instability, facial anomalies) syndrome patients, which have mutations in the DNA methyltransferase gene DNMT3B. SPRY3 X- and Y-inactivation is associated with a differential enrichment of repressive histone modifications and the recruitment of Polycomb 2 group proteins compared to the active X allele. Another major factor in SPRY3 repression is late replication; the inactive X and Y alleles of SPRY3 have delayed replication relative to the active X allele, even in ICF syndrome cells where the closely linked SYBL1 gene is reactivated and advanced in replication. The relatively stable maintenance of SPRY3 silencing compared with SYBL1 suggests that genes without CpG islands may be less prone to reactivation than previously thought and that genes with CpG islands require promoter methylation as an additional layer of repression.

Alleles↗
PubMed2005

Genitourinary anomalies in Mowat-Wilson syndrome with deletion/mutation in the zinc finger homeo box 1B gene (ZFHX1B). Report of three Italian cases with hypospadias and review.

Hypospadias, when the urethra opens on the ventral side of the penis, is a common malformation seen in about 3 per 1,000 male births. It is a complex disorder associated with genetic and environmental factors and can be part of genetic syndromes. Mowat-Wilson syndrome (MWS) is a multiple congenital anomaly syndrome characterized by a distinct facial phenotype, Hirschsprung disease, microcephaly and mental retardation. It is caused by mutations in the zinc finger homeo box 1B gene, ZFHX1B (SIP1). To date, 68 deletion/mutation-positive cases have been reported. Genitourinary anomalies are common in MWS. Here we report that hypospadias is common in males with this syndrome. In 39 patients where this information was available, hypospadias was present in 46% of patients (18/39). In the 3 Italian male cases reported here, hypospadias was always present. MWS should be considered by endocrinologists in patients with hypospadias associated with developmental delays/mental retardation, in particular in the presence of a distinct facial phenotype.

Child, Preschool↗
PubMed2005

Mutation analysis of the NSD1 gene in a group of 59 patients with congenital overgrowth.

Sotos syndrome is characterized by pre- and post-natal overgrowth, typical craniofacial features, advanced bone age, and developmental delay. Some degree of phenotypic overlap exists with other overgrowth syndromes, in particular with Weaver syndrome. Sotos syndrome is caused by haploinsufficiency of the NSD1 (nuclear receptor SET domain containing gene 1) gene. Microdeletions involving the gene are the major cause of the syndrome in Japanese patients, whereas intragenic mutations are more frequent in non-Japanese patients. NSD1 aberrations have also been described in some patients diagnosed as Weaver syndrome. Some authors have suggested a certain degree of genotype-phenotype correlation, with a milder degree of overgrowth, a more severe mental retardation, and a higher frequency of congenital anomalies in microdeleted patients. Data on larger series are needed to confirm this suggestion. We report here on microdeletion and mutation analysis of NSD1 in 59 patients with congenital overgrowth. Fourteen novel mutations, two previously described and one microdeletion were identified. All patients with a NSD1 mutation had been clinically classified as "classical Sotos," although their phenotype analysis demonstrated that some major criteria, such as overgrowth and macrocephaly, could be absent. All patients with confirmed mutations shared the typical Sotos facial gestalt. A high frequency of congenital heart defects was present in patients with intragenic mutations, supporting the relevance of the NSD1 gene in the pathogenesis of this particular defect.

Adolescent↗
PubMed2005

Preproorexin and orexin receptors are expressed in cortisol-secreting adrenocortical adenomas, and orexins stimulate in vitro cortisol secretion and growth of tumor cells.

Orexins A and B are hypothalamic peptides that originate from the proteolytic cleavage of preproorexin and act through two subtypes of receptors, named OX1-R and OX2-R. OX1-R almost exclusively binds orexin-A, whereas OX2-R is nonselective for both orexins. We previously found that orexin-A, via the OX1-R, stimulates cortisol secretion from dispersed human adrenocortical cells. In this study, we demonstrate that six of eight cortisol-secreting adenomas expressed preproorexin mRNA, and seven of 10 adenomas contained measurable amounts of orexin-A but not orexin-B. Normal adrenal cortexes neither expressed preproorexin nor contained orexins. All adenomas expressed OX1-R and OX2-R mRNAs, and real-time PCR showed that the expression of both receptors was up-regulated in adenomas, compared with normal adrenal cortex. Orexin-A concentration-dependently raised basal cortisol secretion from freshly dispersed normal and adenomatous cells, minimal and maximal effective concentrations being 10(-10) and 10(-8) m, and the peptide efficacy (percent increase elicited by 10(-8) m orexin-A) was significantly higher in adenomas than in the normal adrenal cortex. Orexin-B was ineffective, thereby indicating that orexin secretagogue action is mediated by the OX1-R. In contrast, both orexins (10(-8) m) raised the proliferative activity of cultured normal and adenomatous cells, suggesting that this effect is mediated by OX2-R or both receptor subtypes. Collectively, our findings allow us to conclude that the orexin system is overexpressed in cortisol-secreting adenomas and suggest that orexin-A may act as an autocrine-paracrine regulator of the secretory activity and growth of some of these adrenal tumors.

Adrenal Cortex Neoplasms↗
PubMed2005

A novel microdeletion syndrome with loss of the MSH2 locus and hereditary non-polyposis colorectal cancer.

Constitutional chromosome deletions can predispose to the development of cancer with the phenotypic characteristics of inherited cancer syndromes, when the deleted region encompasses a tumour suppressor gene. Examples of such conditions are represented by the cytogenetic deletions associated with retinoblastoma, Wilms tumour and familial adenomatous polyposis. So far, no constitutional deletions involving the genes implicated in hereditary non-polyposis colorectal cancer (HNPCC) have been identified. This may be at least partially because of the lack of distinctive phenotypic manifestations in HNPCC. We describe the first case of a constitutional microdeletion associated with HNPCC. Suspicion of a microdeletion was prompted by the association of mental retardation, postnatal growth deficiency, minor congenital anomalies and early onset (37 years) sporadic colon cancer. The patient was found to harbour a microdeletion within chromosome 2p16-p21, including the MSH2 gene. Since there are very few reports of deletions of the 2p16-p21 region, our observation sets the grounds for the definition of a novel multiple congenital anomaly/mental retardation/cancer microdeletion syndrome.

Abnormalities, Multiple↗
PubMed2004

Assisted reproductive technology and congenital overgrowth: some speculations on a case of Pallister-Killian syndrome.

We report on a boy with Pallister-Killian syndrome (PKS) who was conceived by assisted reproductive technology (ART), specifically in vitro fertilization (IVF) with parents' gametes. A prenatal diagnosis performed elsewhere by CVS failed to detect the presence of the isochromosome 12p that was demonstrated postnatally in approximately 50% of cultured skin fibroblasts. Given that the patient did not show the congenital overgrowth typical of PKS, we speculate that ART might have restricted overgrowth in this particular case. More broadly, we hypothesize that overgrowth might protect from early demise fetuses conceived by ART, a technology known to cause low and very low birth weight.

Abnormalities, Multiple↗
PubMed2004

Solitary median maxillary central incisor syndrome: clinical case with a novel mutation of sonic hedgehog.

Solitary median maxillary central incisor (SMMCI) is a rare dental anomaly. It is usually considered as a minor manifestation of holoprosencephaly (HPE). Some reported families had severe cases of HPE in some members and SMMCI in others. Mutations of Sonic Hedgehog (SHH) have been documented in these families. SMMCI has also been found as an isolated finding or together with other anomalies such as microcephaly, short stature, endocrine pathology, and choanal atresia. We describe a patient with SMMCI and a novel SHH mutation: Val332Ala.

Abnormalities, Multiple↗
PubMed2004

Nonhomologous Robertsonian translocations (NHRTs) and uniparental disomy (UPD) risk: an Italian multicentric prenatal survey.

OBJECTIVES: The risk of uniparental disomy (UPD) occurrence associated with the prenatal finding of balanced nonhomologous Robertsonian translocations (NHRTs) has been estimated only on limited empirical data. The aim of the study was to verify the estimate of the general risk, to get narrower confidence intervals by cumulating the data and to obtain risk estimates for specific translocation types. METHODS: We tested for UPD 160 prenatal specimens referred to the participant centers after the cytogenetic finding of NHRT. RESULTS: One case of upd(14)mat was found, associated with a 45,XX,der(14;22)mat fetal karyotype. The general empirical risk of UPD occurrence in NHRT carrier fetuses, corrected for the actual number of chromosomes analyzed, was 0.76% (95% CI 0.02-4.25%). Cumulative data with previous studies gives a general risk of UPD associated with NHRT of 0.80% (95% CI 0.17-2.34%). The UPD risk for the specific NHRT der(13;14) did not significantly differ from that of the other NHRTs taken together. CONCLUSION: The present survey confirms the previously estimated risk of occurrence of UPD in offspring of NHRT carriers as a low, but not negligible risk, worth being investigated in prenatal diagnosis.

Amniocentesis↗
PubMed2004

Short term microgravity effect on isometric hand grip and precision pinch force with visual and proprioceptive feedback.

Experiments executed on the upper limb are assuming increasing significance in the frame of the Human Physiology in space, for at least two reasons: the upper limb is the principal means of locomotion for the subject living in a space station; furthermore, fatigue can have a significant effect on the hand, for the ordinary work on board, and in particular for the extra-vehicular activities. The degradation of the performances affecting the muscular-skeletal apparatus can be easily recognized on the upper limb, by exerting specific scientific protocols, to be repeated through the permanence of the subject in weightlessness conditions. Another aspect relevant to the effect of microgravity on the upper limb is associated with the alteration of the motor control programs due to the different gravity factor, affecting not only the bio-mechanics of the subject, but in general all his/her psycho-physical conditions, induced by the totally different environment. Specific protocols on the upper limb can facilitate the studies on learning mechanisms for the motor control. The results of such experiments can be transferred to the Earth, useful for treatment of subjects with local traumas or diseases of the Central Nervous System.

Adaptation, Physiological↗
PubMed2004

ELITE-S2: the multifactorial movement analysis facility for the International Space Station.

Experimental observations of adaptation processes of the motor control system to altered gravity conditions can provide useful elements to the investigations on the mechanisms underlying motor control of human subject. The microgravity environment obtained on orbital flights represents a unique experimental condition for the monitoring of motor adaptation. The research in motor control exploits the changes caused by microgravity on the overall sensorimotor process, due to the impairment of the sensory systems whose function depends upon the presence of the gravity vector. Motor control in microgravity has been investigated during parabolic flights and short-term space missions, in particular for analysis of movement-posture co-ordination when equilibrium is no longer a constraint. Analysis of long-term adaptation would also be very interesting, calling for long-term body motion observations during the process of complete motor adaptation to the weightlessness environment. ELITE-S2 is an innovative facility for quantitative human movement analysis in weightless conditions onboard the International Space Station (ISS). ELITE-S2 is being developed by the Italian Space Agency, ASI is to be delivering the flight models to NASA to be included in an expressed rack in US Lab Module in February 2004. First mission is currently planned for summer 2004 (increment 10 ULF 2 ISS).

Adaptation, Physiological↗
PubMed2004

Fantoni's translaryngeal tracheotomy complications. Personal experience.

Tracheotomy is a surgical procedure which, in conditions of acute respiratory emergency, guarantees an adequate airway through the trachea whereas, in cases of chronic respiratory failure, it is used to improve ventilation through the reduction of the dead respiratory space. Over the last few years, surgical techniques used in tracheotomy have been considerably modified, not only to respond to the needs of clinical indications but also on account of problems related to management of the patient and tracheostomy tube, particularly in the home setting. Besides traditional surgical techniques, in fact, in the Intensive Care Unit, percutaneous dilatative procedures are being used with increasing frequency, in particular, translaryngeal tracheotomy according to Fantoni. The latter, however, according to reports in the literature, has been shown to be followed by a higher peri-operative complication rate (40%) which involves maintenance of good function of the tracheostomy, a condition which is particularly dangerous in the management of patients in the home setting. Personal experience is described in the management of 6 patients submitted to tracheotomy according to Fantoni and in combined home treatment, who, some time after the operation. presented 'embedding' of the tracheostomy tube in the tracheostomy opening. The six patients were treated at home with ventilatory support using automatic ventilation system and were submitted, in our Clinic, to a surgical review with preparation of a tracheotomy according to the conventional method. Our experience showed a particular feature of the difficulty in the management of patients presenting respiratory diseases, submitted to translaryngeal tracheotomy and, thereafter, maintained in combined home treatment: in these subjects, in fact, the presence of the tube, the difficulty in cleaning the peristomial skin, the reduced autonomy from the automatic ventilation system and the frequent coexistence of mucopurulent tracheo-bronchial inflammatory diseases, trigger micro-lesions of the stoma and, therefore, scar keloid, narrowing of the lumen and embedding of the tube itself. In conclusion, in our personal experience, we are of the opinion that translaryngeal tracheotomy, since it is easily carried out and is a slightly invasive procedure, plays a very important role in the management of the Intensive Care Unit patient but should be reserved for the few cases requiring tracheostomy for limited periods of time, in low risk patients and within the first 18 days after the acute damaging event.

Equipment Design↗
PubMed2004

Rhinopharynx endoscopy in the diagnosis of chronic otitis media with effusion in infancy.

Chronic otitis media with effusion is an inflammatory process of the mucosa of the middle ear persisting for more than 3 months, being most frequent in infancy, and is correlated with marked tube obstruction. In infancy, the most frequent cause of this obstruction is adenoid hypertrophy and diagnosis, clinical or radiological, is often not confirmed by rhinopharynx fiberendoscopy. Since, in these cases, treatment is often surgical, it is possible that small patients may be submitted, unnecessarily, to adenoidectomy. In collaboration with the Paediatric Clinic, the present study on an infant outpatient population with nasal respiratory difficulty, associated with chronic otitis media with effusion, was, therefore, aimed at standardizing the endoscopic diagnosis of patients with suspected adenoid hypertrophy. Between October and December 2002, 32 consecutive patients, aged between 4 and 11 years, all oral breathers with OME, were sent to our attention from the Paediatric Clinic. All those patients, with indication for adenoidectomy, have been enrolled in the study and submitted to fiberendoscopic examination of the external ear and nose. Nasal respiration was confirmed with active anterior rhinomanometry. Endoscopic evaluation of the rhinopharynx, aimed at assessing adenoid dimensions and their relationship with the auditory tube, has been expressed in four degrees of increasing severity and adenoidectomy was indicated in those cases, classified, by us, as third and fourth degree. In our experience, endoscopic examination of the rhinopharynx has, however, shown that only 9 children (28.2%) presented an absolute need to undergo adenoidectomy since they were carriers of massive adenoid hypertrophy with tubal obstruction and consequent bilateral glue ear (3rd and 4th degree) while, in all other cases (71.8%), the clinical and radiological findings did not correspond to endoscopic data. Diagnostic accuracy that characterizes rhinopharyngeal fiberendoscopy is, therefore, in our opinion, of fundamental importance to avoid these errors, as far as possible, and in establishing an appropriate therapeutic programme.

Adenoidectomy↗
PubMed2003

Influence of genetic polymorphisms of CYP1A1 and GSTM1 on the urinary levels of 1-hydroxypyrene.

The aim of the present study is to evaluate the influence of the genetic polymorphism of two enzymes involved in the biotransformation of xenobiotics, cytochrome P450 1A1 (CYP1A1) and glutathione-S-transferase M1 (GSTM1), on the urinary levels of 1-hydroxypyrene (1-OH-P) in workers exposed to polycyclic aromatic hydrocarbons (PAHs) and in unexposed workers (controls). The study group consisted of 30 controls recruited among employees of a service company and 171 PAHs-exposed workers from two electric steel plants and an iron foundry (all males, ranging between 18 and 60 years of age). Determination of airborne PAHs and urinary 1-OH-P was performed by high-performance liquid chromatography (HPLC) with fluorimetric detection. Polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) was used to determine the genetic polymorphisms of CYP1A1 (CYP1A1*2A and CYP1A1*2B) and GSTM1. No influence of the genetic polymorphism of CYP1A1 and GSTM1 on the urinary levels of 1-OH-P was observed in this study.

Adolescent↗
PubMed2003

Absence of 12q21.2q22 deletions and subtelomeric rearrangements in cardiofaciocutaneous (CFC) syndrome patients.

Recent publications described two patients with a CFC-like phenotype and the same deletion of chromosome region 12q21.2q22 [Rauen et al., 2000, 2002]. The patients did not have the classical CFC phenotype and presented other signs not usually seen in CFC patients: the first patient had hydrocephalus, and the second, a history of olygohydramnios, normal stature, pyloric stenosis, cutaneous syndactyly of toes and bilateral transverse palmar creases. In order to verify if classic CFC patients with normal chromosomes in conventional preparations have microdeletions within the 12q21.2q22 chromosome region, we performed FISH analysis using 12 BAC probes to screen this area. The average interval between the probes was of approximately 1 Mb. No deletions were found in any of the 17 classical CFC patients we examined. We conclude that the region 12q21.2q22 is not a candidate region for CFC syndrome and that the patients described by Rauen et al. [2000, 2002] probably have a different condition, i.e., an aneuploidy syndrome, with some phenotypic resemblance to the CFC syndrome. To further evaluate the possibility of other chromosome imbalances, we performed a subtelomeric analysis, by FISH technique, of all chromosomes, and did not find any subtelomeric rearrangements.

Adolescent↗