Apoptosis and proliferation kinetics of T cells in patients having experienced antiretroviral treatment interruptions

Multiple failures of antiretroviral treatments, as a result of multidrug-resistant virus, have led to a proposal for structured therapeutic interruptions (STI). However, a significant decrease in CD4+ T cells may occur. The aim of our study was to determine the kinetics of T cell subpopulation changes, T cell apoptosis and peripheral blood mononuclear cell proliferation after STI. The impact of resistance mutation disappearance on T cell apoptosis was also studied. Ten patients were enrolled prospectively, and blood sampling was performed at weeks 0, 2, 4, 6, 8 and 12. The mean increase in viral load was 1.3 log(10) copies/ml, ranging from 0.1 to 3.2. CD4+ T cell count decreased to a mean of 80 cells/mm(3) from baseline to week 12. In the same period, CD8+ T cells decreased to a mean of 139 cells/mm(3). A significant increase in both T cell apoptosis and proliferation of mononuclear cells was observed. However, proliferation was an early and brief event. The increase in CD4+ T cell apoptosis was obvious in patients exhibiting complete reversion of resistance mutations to antiviral drugs. Our results suggest that during STI, apoptosis is an overwhelming phenomenon compared with proliferation, and may explain the limited immunological impact of this therapeutic option.     

Prevalence and prognostic significance of psychiatric disorders in patients evaluated for recurrent unexplained syncope

We aimed to assess the psychiatric profile and prognostic value of psychiatric disorders (PDs) in patients presenting with unexplained syncope. Forty patients with recurrent unexplained syncope referred for head-up tilt testing were compared with age- and sex-matched patients free of known chronic PDs referred for arrhythmia. All patients underwent a semistandardized psychiatry questionnaire (Mini-International Neuropsychiatric Interview) to assess their profile. Additional stress coping was performed to study adaptational processes to stressful situations. After tilt testing and psychiatric evaluation, a drug-free follow-up was performed in patients with syncope. Of the 80 patients who referred to the psychiatric interview, 40 had evidence of at least 1 psychiatric disorder. They were 26 patients (65%) in the syncope group and 14 patients (35%) in the control group (p = 0.01). Detailed analysis revealed a more frequent subprofile of anxiety and panic disorders in patients with syncope than in controls (30% vs 12% and 20% vs 10%, respectively), whereas the subprofile of depression was similar in both groups. Moreover, those with syncope were more likely to have a high anxiety index (25 +/- 5 vs 22 +/- 4, p = 0.004), and were more prone to avoidance-oriented coping strategies when experiencing undesirable life events than controls. Considering syncope patients, no difference could be found between the 25 with a positive tilt test and the 15 with a negative tilt test with respect to the number of syncopal episodes and psychiatric profile. After a 3-year drug-free follow-up, 15 patients (37.5%) had at least 1 recurrent syncope. The recurrence rate was similar in patients with positive and negative head-up tilt test results (9 of 25 vs 6 of 15, respectively). In contrast, the syncopal recurrence rate was higher in patients who fulfilled criteria for affective disorders (13 of 26 vs 2 of 14, 95% confidence interval 1.09 to 2.55, relative risk 1.7, p = 0.04). Thus, patients with recurrent unexplained syncope are more anxious and are more prone to panic disorders and avoidance-oriented coping strategies than control patients with arrhythmia. The presence of a psychiatric disorder is associated with an increased risk of recurrence. The outcome of such patients may be improved with recognition and treatment of PDs.     

The Aging Males' Symptoms (AMS) scale: Update and compilation of international versions

Background

The interest of clinical research in aging males increased in recent years and thereby the interest to measure health-related quality of life (HRQoL) and symptoms of aging men. The Aging Males' Symptoms scale (AMS) became the most commonly used scale to measure HRQoL and symptoms in aging males in many countries worldwide. The aim of this paper is to review the current state of the instrument particularly concerning versions of the scale in different languages in the light of the quality of the translation process.

AMS versions available

Most of the translations were performed following international methodological recommendations for linguistic & cultural adaptation of HRQoL instruments. Mainly the English version was used as source language for the translation into Dutch, Spanish, Portuguese, Italian, Swedish, and Japanese (attached as additional PDF-files). Preliminary versions that were derived only from forward translations are of secondary quality and available in Finnish, Flemish, and Russian. It is recommended to complete the translation process for the latter languages before using them in international studies.

Translations in process

The AMS scale is in the process of consensus finding of two existing French versions, and the versions in the Korean, Thai, and Indonesian languages have not yet been completed in the translation process.

Conclusion

The AMS scale is obviously a valuable tool for assessing health related quality of life in aging men, because it is used worldwide. It is a standardized scale according to psychometric norms. Most of the currently available language versions were translated following international standards for linguistic and cultural translation of quality of life scales. Assistance is offered to help interested parties in the translation process.     

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.