The association of autosomal dominant optic atrophy and moderate deafness may be due to the R445H mutation in the OPA1 gene

PURPOSE: To examine the involvement of the optic atrophy 1 (OPA1) gene in optic atrophy associated with moderate deafness. DESIGN: Observational case report.The entire coding sequence of the OPA1 gene was directly sequenced in the case of a patient suffering from optic atrophy associated with moderate deafness. RESULTS: A de novo heterozygous mutation R445H in the OPA1 gene was found. No similar mutation was detected in either of the patient's parents or in the 100 chromosome controls. CONCLUSION: The R445H mutation in OPA1 might be the cause of the association between dominant optic atrophy and moderate deafness, a phenotype that may be currently underdiagnosed.     

Innate immunity and pathogen-host interaction

The skin and contiguous mucosal surfaces define the primary locus of interaction between host and micro-organisms. In this review, we focus on the innate immune system in the mucosa, which manages to deal with invading pathogens, the mechanisms that organisms have evolved in order to circumvent this primary defensive barrier and, finally, potential therapeutic manipulation of the innate immune system that was the focus of meeting at a Euroconference/Workshop on "Novel Strategies of Mucosal Immunisation through Exploitation of Mechanisms of Innate Immunity in Pathogen-Host Interaction", which was held in Siena, Italy, November 2002.     

Thoracic outlet: assessment with MR imaging in asymptomatic and symptomatic populations

PURPOSE: To compare the dynamic modifications of the thoracic outlet in asymptomatic volunteers and symptomatic patients and assess the presence and location of vasculonervous compressions in these two populations. MATERIALS AND METHODS: Thirty-five healthy volunteers and 54 patients with clinical symptoms of thoracic outlet syndrome (TOS) underwent magnetic resonance (MR) imaging of the thoracic outlets with their arms alongside their bodies and after a postural maneuver. Measurements were obtained at the interscalene triangle (thickness of anterior scalene muscle, interscalene angle), at the costoclavicular space (minimum costoclavicular distance, distance between inferior border of subclavius muscle and the anterior chest wall, maximum thickness of subclavius muscle, angle between first rib shaft and horizontal), and at the retropectoralis minor space (distance between posterior border of pectoralis minor muscle and posterior lining of axilla at the passage of the axillary vessels, thickness of pectoralis minor muscle). The presence and location of vasculonervous compressions were also assessed. Group data were analyzed with the Student t test. RESULTS: Patients with TOS had a smaller costoclavicular distance after the postural maneuver (P <.001), a thicker subclavius muscle in both arm positions (P <.001), and a wider retropectoralis minor space after the postural maneuver (P <.001) than did volunteers. Venous compressions after the postural maneuver were observed in 47% of volunteers and 63% of patients at the prescalene space, in 54% of volunteers and 61% of patients at the costoclavicular space, and in 27% of volunteers and 30% of patients at the retropectoralis minor space. Arterial and nervous compressions, respectively, were seen in 72% and 7% of patients. No arterial or nervous compression was seen in volunteers. Except for venous thrombosis, vasculonervous compressions were demonstrated only with arm elevation. Only three thoracic outlet measurements differed significantly in both populations. CONCLUSION: MR imaging appeared helpful in demonstrating the location and cause of arterial or nervous compressions.     

Selective abrogation of the proinvasive activity of the trefoil peptides pS2 and spasmolytic polypeptide by disruption of the EGF receptor signaling pathways in kidney and colonic cancer cells

Trefoil peptides (TFFs) are now considered as scatter factors, proinvasive and angiogenic agents acting through cyclooxygenase-2 (COX-2)- and thromboxane A2 receptor (TXA2-R)-dependent signaling pathways. As expression and activation levels of the epidermal growth factor receptor (EGFR) predict the metastatic potential of human colorectal cancers, the purpose of this study was to establish whether the EGF receptor tyrosine kinase (EGFR-TK) contributes to cellular invasion induced by TFFs in kidney and colonic cancer cells. Both the dominant negative form of the EGFR (HER-CD533) and the EGFR-TK inhibitor ZD1839 (Iressa) abrogated cellular invasion induced by pS2, spasmolytic polypeptide (SP) and the src oncogene, but not by ITF and the TXA2-R. Similarly, EGFR-TK inhibition by ZD1839 reversed the invasive phenotype promoted by the constitutively activated form of the EGFR (EGFRvIII) and the EGFR agonists transforming growth factor alpha (TGFalpha), amphiregulin and EGF. We also provide evidence that TFFs, EGFRvIII, and TGFalpha trigger common proinvasive pathways using the PI3'-kinase and Rho/Rho- kinase cascades. These findings identify the EGFR-TK as a key signaling element for pS2- and SP-mediated cellular invasion. It is concluded that although pS2, SP and ITF belong to the same family of inflammation- and cancer-associated regulatory peptides, they do not control identical signaling networks.     

Age-dependent variations of human and rat colon myofibroblasts in culture: Influence on their functional interactions with colon cancer cells

Epithelial-mesenchymal interactions play a pivotal role in colon cancer invasion and metastasis. We aimed at elucidating the impact of long-term cultivation on the phenotypic and functional characteristics of primary fibroblasts and their interaction with the human colon adenocarcinoma cell line LoVoC5. We used fibroblasts from human colon tumor tissue, normal human colon mucosa, rat normal colon and 2 rat colon-derived myofibroblast cell lines, MIC316 and MG. The following parameters were studied: cell shape and size, growth curve, intermediate filament expression and extracellular matrix synthesis. Coculture models with or without cell contacts were used to test the effects on LoVoC5 cell proliferation, spreading and adhesion. Irrespective of their origin, fibroblastic cells in primary cultures presented marked phenotypic and functional changes with time. Before passage 5, they presented as large, slow-growing cells expressing vimentin and alpha-smooth muscle actin; synthesizing laminin-1, fibronectin and collagens I and IV; and inducing LoVoC5 proliferation, spreading and adhesion. After passage 15, they presented as small, fast-growing cells inconstantly expressing alpha-smooth muscle actin and synthesizing mainly type I collagen. In coculture with or without cell contacts, they inhibited LoVoC5 proliferation and allowed only limited cell spreading and adhesion. Myofibroblastic cell lines presented as large, fast-growing cells expressing vimentin and alpha-smooth muscle actin and synthesizing mainly type I collagen. They had no significant effects on LoVoC5 proliferation, spreading and adhesion. Our results underline the importance of age-dependent variations in colon mesenchymal cells in culture and for the in vitro study of epithelial-mesenchymal interactions in colon cancer.     

Chfr inactivation is not associated to chromosomal instability in colon cancers

Numerous observations suggest that chromosome instability is caused by mitotic abnormalities such as errors in the partitioning of chromosomes. Chfr was recently defined as a central component of a new mitotic checkpoint that delays chromosome condensation in response to mitotic stress. Chfr was shown to be frequently inactivated in several human neoplasms, including colon, lung and esophageal cancers. To test whether Chfr inactivation may lead or participate to chromosomal instability (CIN), we analysed the genetic and epigenetic status of the gene in a large panel of primary colon and breast cancers, as well as in colon and breast cancer cell lines displaying either a microsatellite instability or a CIN. Our results confirm that Chfr is frequently inactivated in colon cancers, through a mechanism of hypermethylation of the promoter sequences. In contrast, the loss of Chfr expression appears to be a rare event in breast cancers. Furthermore, our data demonstrate that Chfr inactivation is not associated with CIN in these frequent types of human cancers.     

Uterine scars and subsequent vaginal birth: follow-up of 73 parturients in the Central Maternity Hospital of Bangui (Central African Republic)

Uterine rupture is a threat during vaginal deliveries of women with uterine scars from previous caesarean deliveries or other surgery. Special prudence among this group has resulted in a rise of cesarean rates in developed countries but also in Africa. The lack of available data in this domain in our country led us to conduct this preliminary study, with the objectives of: determining the frequency of deliveries among these patients and of the complications associated with them; identifying some of the risk factors and assessing maternal and fetal prognosis. This should facilitate further studies to determine the management attitudes most appropriate to the realities of our health system. We conducted a cross-sectional study during the last six months of 1999 at the central maternity hospital in Bangui. We included in this study only women with previous caesarean scars giving birth again during the study period. We followed them from admission to the labour room until discharge, without intervening in their delivery. Structured questionnaires enabled us to collect data on clinical, social and demographic variables. We recorded 74 births, including one set of twins, among the 73 parturient subjects. Vaginal delivery occurred in 45 cases (60.8%), and caesarean in 29. Women with a single uterine scar gave birth by vaginal delivery significantly more often than they had caesareans. We recorded 7 cases of uterine rupture, most often associated with a birth interval less than 2 years. One uterine rupture led to the mother's death. Perinatal mortality was 10.8%: no newborn survived these uterine ruptures. Vaginal delivery remains possible for women with uterine scars when adequate monitoring of a trial of labor is available and on condition that the pelvis is normal and the birth interval exceeds two years.     

The mechanisms of cell death in focal cerebral ischemia highlight neuroprotective perspectives by anti-caspase therapy

A number of studies have validated the importance of caspase activation in ischemia-induced brain damage. Caspases participate in both the initiation and execution phases of apoptosis, and play a central role in neuronal death after global cerebral ischemia. In focal ischemia, apoptosis occurs in the penumbra during the secondary phase of expansion of the lesion. However, ultrastructural and biochemical analysis have also shown signs of apoptosis in the initial lesion, or infarct core, which is traditionally considered necrotic. Specific caspase pathways are activated in the core and in the penumbra, and participate in both cytoplasmic and nuclear apoptotic events, notwithstanding their initial classification as activator or initiator caspases. This confirms previous suggestions that caspase inhibition holds tremendous neuroprotective potential in stroke and other apoptosis-related degenerative diseases. Consequently, two new approaches, aimed at treating stroke-induced brain damage by anti-apoptotic molecules, are being developed in academic and industrial laboratories. These are based, respectively, on the use of small peptide sequences corresponding to the preferred cleavage site of a caspase, and on genomic constructions derived from the fusion of endogenous anti-caspase molecules with a protein transduction domain from the human immunodeficiency virus-1. Fusion proteins containing endogenous caspases inhibitors efficiently counteract apoptosis in vitro. In in vivo models of focal cerebral ischemia, fusion proteins successfully cross the blood brain barrier and protect cells from ischemic death. This new approach by protein therapy could prove to be an interesting alternative for the reduction of the dramatic consequences of stroke, provided that the long-term efficiency of this protection in terms of functional recovery is demonstrated.     

The antibacterial properties of solid supported liposomes on Streptococcus oralis biofilms

A novel system for the delivery of drugs to bacterial biofilms has been developed. The system is based on the use of anionic and cationic liposomes as drug carriers adsorbed on the surface of zinc citrate particles. The adsorption process results in the formation of solid supported vesicles (SSVs) which aids the stabilisation of the liposomes. Anionic liposomes have been prepared by incorporation of phosphatidylinositol (PI) into dipalmitoylphosphatidylcholine (DPPC) liposomes and cationic liposomes have been prepared by incorporation of dioctadecyldimethylammonium bromide (DDAB) into DPPC plus cholesterol liposomes. The liposomes were adsorbed onto zinc citrate particle and targeted to immobilised biofilms of the oral bacterium Streptococcus oralis. The liposomes were used to carry the bactericides, Triclosan, a lipid-soluble agent, and the aqueous-soluble penicillin-G, and their ability to inhibit bacterial growth from immobilised biofilms was accessed. Zinc citrate is itself a bactericide and is used in the formulation of toothpastes. The SSVs carrying the drugs have therapeutic properties. To trace the origin of these properties, each component of the SSV was investigated alone and in combination in binary systems. Some combinations showed synergistic (or additive) antibacterial effects while others showed regressive effects compared with their components.     

Implicit learning in children and adolescents with mental retardation

The literature on implicit learning in persons with mental retardation is scarce and contradictory with respect to the relationship between degree of intellectual disability and impact of implicit-learning processes on performance. We examined children and adolescents with mild or moderate mental retardation and typically developing children matched on MA with regard to their implicit learning. Individuals with mental retardation modified their behavior after an implicit training procedure in a way similar to MA- or CA-matched controls. The impact of implicit learning did not vary as a function of IQ or age. However, some differences appeared between groups in their explicit remembering of the training conditions. The theoretical implications of these results are discussed.