Biomedical subjects

Giovanni Neri

Publications and source records attributed to Giovanni Neri.

45 records · Page 3Linked to original sources

PubMed2003

Understanding the biological underpinnings of fragile X syndrome.

PURPOSE OF REVIEW: The purpose of this review is to present the latest findings on fragile X syndrome and to put them into perspective. Fragile X syndrome is a relatively common form of inherited mental retardation, caused by loss of function of the FMR1 gene on the long arm of the X chromosome. The molecular mechanisms underlying the syndrome are complex and continue to surprise researchers more than 12 years after the cloning of the gene. RECENT FINDINGS: We will specifically discuss the various aspects of the clinical phenotype, reassessed with the employment of functional imaging and electrophysiological techniques. The unexpected finding of a pathologic phenotype in premutation carriers is highlighted, as it represents a new and distinct condition with a different presentation in males and females. The third section deals briefly with the various functions of the FMRP protein, an RNA-binding protein interacting with multiple RNA molecules as well as proteins. It is important to realize that FMRP is probably changing partners several times, depending on its localization, on posttranslational modifications and on the available interacting proteins. In the following section, we present in short recent discoveries on the defective neuronal circuits in the fragile X syndrome. Most of these new data were made available by the study of animal models, mostly the Fmr1 knockout mouse, but also Drosophila. SUMMARY: We briefly discuss the alternative options for treating fragile X syndrome. Presently, a neuropharmacological approach acting on either critical receptors or aimed at reactivating the silenced FMR1 gene appears promising.

Child↗

PubMed2003

Immunoscintigraphic detection of the ED-B domain of fibronectin, a marker of angiogenesis, in patients with cancer.

PURPOSE: ED-B fibronectin is expressed only during angiogenic processes and in tissues undergoing growth and/or extensive remodeling. We demonstrated previously the possibility to target and selectively deliver therapeutic substances to tumor vasculature in experimental animal models using a human recombinant antibody fragment, L19, specific for the ED-B domain of fibronectin. Here we evaluate the possibility of targeting primary tumors and metastatic lesions in cancer patients through immunoscintigraphy using (123)I-labeled dimeric L19 [L19(scFv)(2)]. EXPERIMENTAL DESIGN: Twenty patients (34-79 years of age) with lung, colorectal, or brain cancer, whose tumors had been confirmed by imaging techniques and/or histologically, were admitted to the immunoscintigraphic investigation. RESULTS: The dimeric L19 antibody selectively localized in tumor lesions in aggressive types of lung cancer and colorectal cancer. Because ED-B fibronectin is expressed only during angiogenic processes and in tissues undergoing growth and/or extensive remodeling, L19(scFv)(2) is able to distinguish between quiescent and actively growing lesions. No side effects were observed. CONCLUSIONS: The ability of L19(scFv)(2) to target tumors in patients provides the foundations for new therapeutic applications, in which the L19 antibody is engineered to selectively deliver bioactive molecules to primary tumors as well as to metastases.

Adult↗

PubMed2002

Limb anomalies: Developmental and evolutionary aspects.

In this review we describe the developmental mechanisms involved in the making of a limb, by focusing on the nature and types of interactions of the molecules that play a part in the regulation of limb patterning and characterizing clinical conditions that are known to result from the abnormal function of these molecules. The latter subject is divided into sections dealing with syndromal and nonsyndromal deficiencies, polydactylies, and brachydactylies. Conditions caused by mutations in homeobox genes and fibroblast growth factors and their receptor genes are listed separately. Since the process of limb development has been conserved for more than 300 millions years, with all the necessary adaptive modifications occurring throughout evolution, we also take into consideration the evolutionary aspects of limb development in terms of genetic repertoire, molecular pathways, and morphogenetic events.

Animals↗

PubMed2002

Quantitative analysis of DNA demethylation and transcriptional reactivation of the FMR1 gene in fragile X cells treated with 5-azadeoxycytidine.

In fragile X syndrome, hypermethylation of the expanded CGG repeat and of the upstream promoter leads to transcriptional silencing of the FMR1 gene. Absence of the FMR1 protein results in mental retardation. We previously proved that treatment with 5-azadeoxycytidine (5-azadC) of fragile X cell lines results in reactivation of the FMR1 gene. We now show that this treatment causes passive demethylation of the FMR1 gene promoter. We employed the bisulfite-sequencing technique to detect the methylation status of individual CpG sites in the entire promoter region, upstream of the CGG repeat. Lymphoblastoid cell lines of fragile X males with full mutations of different sizes were tested before and after treatment with 5-azadC at various time points. We observed that individual cells are either completely unmethylated or not, with few relevant exceptions. We also investigated the extent of methylation in the full mutation (CGG repeat) itself by Southern blot analysis after digestion with methylation-sensitive enzymes Fnu4HI and McrBC and found that the CGG repeat remains at least partially methylated in many cells with a demethylated promoter. This may explain the quantitative discrepancy between the large extent of promoter demethylation and the limited levels of FMR1 transcriptional reactivation estimated by quantitative real-time fluorescent RT-PCR analysis.

Azacitidine↗

PubMed2002

Heterozygous submicroscopic inversions involving olfactory receptor-gene clusters mediate the recurrent t(4;8)(p16;p23) translocation.

The t(4;8)(p16;p23) translocation, in either the balanced form or the unbalanced form, has been reported several times. Taking into consideration the fact that this translocation may be undetected in routine cytogenetics, we find that it may be the most frequent translocation after t(11q;22q), which is the most common reciprocal translocation in humans. Case subjects with der(4) have the Wolf-Hirschhorn syndrome, whereas case subjects with der(8) show a milder spectrum of dysmorphic features. Two pairs of the many olfactory receptor (OR)-gene clusters are located close to each other, on both 4p16 and 8p23. Previously, we demonstrated that an inversion polymorphism of the OR region at 8p23 plays a crucial role in the generation of chromosomal imbalances through unusual meiotic exchanges. These findings prompted us to investigate whether OR-related inversion polymorphisms at 4p16 and 8p23 might also be involved in the origin of the t(4;8)(p16;p23) translocation. In seven case subjects (five of whom both represented de novo cases and were of maternal origin), including individuals with unbalanced and balanced translocations, we demonstrated that the breakpoints fell within the 4p and 8p OR-gene clusters. FISH experiments with appropriate bacterial-artificial-chromosome probes detected heterozygous submicroscopic inversions of both 4p and 8p regions in all the five mothers of the de novo case subjects. Heterozygous inversions on 4p16 and 8p23 were detected in 12.5% and 26% of control subjects, respectively, whereas 2.5% of them were scored as doubly heterozygous. These novel data emphasize the importance of segmental duplications and large-scale genomic polymorphisms in the evolution and pathology of the human genome.

Abnormalities, Multiple↗

PubMed2002

Lidocaine versus ropivacaine for topical anesthesia in cataract surgery(1).

PURPOSE: To assess the anesthetic efficacy and safety of topical ropivacaine versus topical lidocaine in cataract surgery. SETTING: Institute of Ophthalmology, University of Modena and Reggio Emilia, Modena, Italy. METHODS: This prospective controlled randomized double-blind study comprised 64 patients scheduled for planned routine cataract extraction. Patients were randomized into 2 groups; 1 received topical ropivacaine 1% and the other, topical lidocaine 4%. The duration of surgery, intraoperative and early postoperative complications, and the need for supplemental intracameral anesthesia were recorded. Intraoperative and postoperative subjective pain was quantified by patients using a scale from 1 to 10. An endothelial cell count was performed preoperatively and 2 months after surgery. RESULTS: The mean endothelial cell density decreased from 2334 cells/mm(2) +/- 496 (SD) to 2016 +/- 674 cells/mm(2) in the ropivacaine group and from 2519 +/- 404 cells/mm(2) to 1847 +/- 607 cells/mm(2) in the lidocaine group. The difference in cell density between groups was not significant before (P =.154) or after surgery (P =.329); however, the difference in mean cell loss between groups was statistically significant (P =.031). The duration of surgery and intraoperative complications were the same in both groups. Four patients in the ropivacaine group and 5 in the lidocaine group required supplemental anesthesia (P >.05). The mean subjective analog pain score was slightly higher in the lidocaine group (P >.05). The day after surgery, 12 eyes in the ropivacaine group and 6 in the lidocaine group had transient corneal edema (P =.150). CONCLUSIONS: Topical ropivacaine performed at least as well as topical lidocaine in efficacy and safety in cataract surgery. It provided sufficient and long-lasting analgesia without the need for supplemental intracameral anesthesia in most cases.

Administration, Topical↗

PubMed2002

A novel gene, FAM11A, associated with the FRAXF CpG island is transcriptionally silent in FRAXF full mutation.

The cytogenetic expression of the FRAXF fragile site is due to an expanded, hypermethylated and unstable CGG repeat in Xq28. Normal individuals have 6-38 triplet repeats while individuals expressing the fragile site have expansions of greater than 300 triplets. Through analysis of the region adjacent to the fragile site, we have identified a approximately 2.6 kb cDNA originating from the FRAXF fragile site associated CpG island, and containing the unstable FRAXF CGG repeat in its 5' UTR region. This gene, FAM11A, comprises at least seven exons, shows alternative splicing, and extends over 35 kb of genomic DNA distal to the FRAXF fragile site. Analysis of the FAM11A cDNA sequence has identified a 1050 bp open reading frame encoding a 350 amino acid protein. We have also identified FAM11B a highly conserved (88% at the protein level) transcribed chromosome 2 retropseudogene. We show that the novel FRAXF fragile site associated gene FAM11A is transcriptionally silenced in a normal individual with a cytogenetically and molecularly detectable FRAXF CGG full mutation (fragile site). Finally, we were able to reactivate FAM11A transcription by treatment of a FRAXF lymphoblastoid cell line with the demethylating agent 5-azadeoxycytidine, thus demonstrating the critical role of FRAXF methylation in FAM11A silencing.

Alternative Splicing↗

PubMedDate not supplied

Evaluation of ecotoxicological effects of endocrine disrupters during a four-year survey of the Mediterranean population of swordfish (Xiphias gladius).

In this project we investigated the ecotoxicological effects of endocrine disrupters in a four-year survey of the Mediterranean population of swordfish (Xiphias gladius). In the Mediterranean environment, top predators, such as swordfish, accumulate high concentrations of polyhalogenated aromatic hydrocarbons (PHAHs) and toxic metals, potentially incurring high toxicological risk. The effects of organochlorines and trace elements (Hg, Cd and Pb) in 192 swordfish specimens, caught in the Strait of Messina, Sicily, Italy, were investigated using vitellogenin (Vtg), zona radiata proteins (Zrp) and CYP1A (BPMO, EROD) activities. Vtg and Zrp were found to be dramatically induced in some adult male specimens, suggesting that this species is highly exposed to estrogens in the Mediterranean Sea. A role of organochlorines in this induction phenomenon is suggested by the statistically significant correlations between Zrp in plasma and PCB concentrations in muscle (p<0.032) and Vtg in plasma and PCB concentrations in liver (p<0.034) of male specimens. Levels of trace elements in liver were in the following ranges: Hg 1-22, Cd 1-28 and Pb 0-1.6 ppm d.w. These data indicate potential reproductive alterations in large pelagic fish and suggest the need for continuous monitoring to avoid reductions in the population of this fish species of high commercial and ecological interest.

Analysis of Variance↗

PubMedDate not supplied

[Familial Mediterranean fever: an ancient hereditary disease].

Familial Mediterranean fever (FMF) is an autosomal recessive disorder that mainly affects people living around the Mediterranean sea (i.e. Turks, Armenians, Arabs and Jews), but cases of FMF are now being increasingly diagnosed in every country of the world (including Italy). Described for the first time in 1945, it has recently become more relevant, after the discovery of the responsible gene, the MEFV gene which encodes a 781-aminoacid protein called pyrin that seems to play a role in the regulation of the inflammatory process. As the prototype of an emerging group of disorders fated to become more and more popular--the hereditary auto-inflammatory disorders--FMF is an under-diagnosed cause of fever of unknown origin. Fever is the main but not the only symptom; sterile serosites are the most common associated features. The classical clinical picture is being continuously enriched. Geno-phenotype correlations and interval-free symptoms are the new clinical insights, while fundamentally important studies attempt to enlighten its obscure pathogenesis. In spite of the introduction of alternative treatments, colchicine is still the only suitable drug for the prevention of acute episodes and the development of amyloidosis.

Algorithms↗