Jean-François Mornex

Accelerated coronary atherosclerosis and arteriosclerosis in young human-immunodeficiency-virus-positive patients.

ObjectiveTo determine the type of lesions observed in young patients infected with human immunodeficiency virus‐1 (HIV‐1). DesignExamination of coronary networks in corpses of 13 men and two women who had died aged 23–32 years after having been infected with HIV‐1 virus, having been seropositive for 2–5 years. Causes of death were infectious complications (five cases), infection with cytomegalovirus leading to gastro‐intestinal haemorrhaging (one case), infection with cytomegalovirus and Kaposis sarcoma (one case), overdoses of drugs (five cases) and sudden death (three cases). MethodsThe pathological analysis was carried out on the proximal and distal coronary networks. In order to characterize the lesions better, the cells and the cytokines involved were characterized by immunohistochemistry. ResultsIn all 15 cases we observed thickening of intima in the proximal network at least as great as that of the media, caused by a proliferation of secreting cells, phenotypically identified as smooth muscle cells, with exaggerated production of elastic fibres and in association with an increase in the expression of tumor necrosis factor‐α and interleukin‐1α. In nine cases, atherosclerosis had developed from and on the surface of this proliferation and in four cases arteriosclerosis had an unusual appearance, in the form of mamillated vegetations with endoluminal protrusions. A similar proliferation was found in the distal network in four cases, but with a significantly smaller proportion of elastic fibres ConclusionsThe lesions we examined in these young HIV‐1‐ infected patients presented particular features and were intermediate between the lesions observed during common coronary atherosclerosis and atherosclerosis associated with chronic rejection of cardiac transplants.

Genomic heterogeneity in the pol region of ovine lentiviruses obtained from bronchoalveolar cells of infected sheep from France

In order to determine the genomic heterogeneity of ovine lentiviruses, we analysed eight isolates from naturally infected sheep from one geographical region of France. A 475 nt fragment in the region of the pol gene coding for reverse transcriptase was amplified by RT-PCR from RNA directly extracted from uncultured bronchoalveolar lavage cells. The resulting PCR fragments were analysed by restriction enzyme digestion, cloned in a TA vector and sequenced. Restriction enzyme analysis showed distinct patterns from the eight isolates, and sequencing showed them to be closely related in both nucleotide (2.3-8.1% variation) and deduced amino acid (0-6.2% variation) sequences. Their amino acid sequences differed from that of visna-maedi virus complete viral genome sequence K1514 by 12.5-15.3%, but from that of caprine arthritis encephalitis virus (CAEV) viral genome sequence Co by only 4.2-6.9%. Phylogenetic analysis showed that the French isolates form a group related to CAEV Co and distant from previously reported ovine lentivirus sequences from different origins.

Lung transplantation for lymphangioleiomyomatosis: the French experience.

Background. Lymphangioleiomyomatosis (LAM) is a rare disease, leading in some cases to end-stage respiratory failure. Lung transplantation (LT) represents a therapeutic option in advanced pulmonary LAM. Methods. We conducted a retrospective multicenter study of 44 patients who underwent LT for LAM at 9 centers in France between 1988 and 2006. Results. All patients were women with a mean age of 41±10 years at LT. There were 34 single-lung transplants and 11 bilateral transplants (one retransplantation). Prior clinical events related to LAM were present in 75% of the patients and previous thoracic surgical procedures were noted in 86.6% of cases. At the latest preoperative evaluation, 30 patients had an obstructive pattern (mean forced expiratory volume in 1 second: 26%±14% of predicted) and 15 had a combined restrictive and obstructive pattern, with a mean KCO=27%±8.8% of predicted, PaO2=52.8±10.4 and PaCO2=42.6±9.8 mm Hg. Intraoperative cardiopulmonary bypass was required in 13 cases. The length of mechanical ventilation was 7.5±12.8 days. The median duration of follow-up was 37 months. The 1, 2, 5, and 10 years survival rates were 79.6%, 74.4%, 64.7%, and 52.4%, respectively. Extensive pleural adhesions were found in 21 patients leading to severe intraoperative hemorrhage. Postoperative LAM-related complications were pneumothorax in the native lung in five patients, chylothorax in six, bronchial dehiscence or stenosis in seven. There were two cases of recurrence of LAM. Conclusion. Despite a high morbidity mainly caused by previous surgical interventions and disease-related complications, LT is a satisfactory therapeutic option for end-stage respiratory failure in LAM.

In vivo activation of alveolar macrophages in ovine lentivirus infection

Sheep infected by visna-maedi virus, a lentivirus related to the human immunodeficiency virus, develop a chronic interstitial lung disease. Since monocyte/macrophages are known to be specifically infected by visna-maedi virus, we investigated the role of macrophages in the appearance of pulmonary lesions in animals with naturally occurring disease. Alveolitis in maedi leads to a doubling in bronchoalveolar lavage total cell counts and of macrophages as compared to normal sheep. A significant increase in the relative percentage of neutrophils was also observed, accompanied by an increased spontaneous release of neutrophil chemotactic activity by alveolar macrophages of diseased animals, suggesting that they may be activated. Macrophage activation is also demonstrated by the observation of a significant (x3) increase of spontaneous fibronectin release by alveolar macrophages from maedi lungs, and furthermore by the high level expression of major histocompatibility complex class II antigens on most of these cells. Thus viral infection, although restricted to a small population of macrophages, is able to modulate extensive activation of macrophages in the lung. Activated macrophages release mediators likely to play a role in the development of the alveolitis and the parenchymal desorganization. These findings may be relevant to our understanding of the mechanisms by which human immunodeficiency virus infection leads to pulmonary disease other than that caused by opportunistic infections.

Lack of Functional Receptors Is the Only Barrier That Prevents Caprine Arthritis-Encephalitis Virus from Infecting Human Cells

ABSTRACT Barriers to replication of viruses in potential host cells may occur at several levels. Lack of suitable and functional receptors on the host cell surface, thereby precluding entry of the virus, is a frequent reason for noninfectivity, as long as no alternative way of entry (e.g., pinocytosis, antibody-dependent adsorption) can be exploited by the virus. Other barriers can intervene at later stages of the virus life cycle, with restrictions on transcription of the viral genome, incorrect translation and posttranslational processing of viral proteins, inefficient viral assembly, and release or efficient early induction of apoptosis in the infected cell. The data we present here demonstrate that replication of caprine arthritis-encephalitis virus (CAEV) is restricted in a variety of human cell lines and primary tissue cultures. This barrier was efficiently overcome by transfection of a novel infectious complete-proviral CAEV construct into the same cells. The successful infection of human cells with a vesicular stomatitis virus (VSV) G-pseudotyped Env-defective CAEV confirmed that viral entry is the major obstacle to CAEV infection of human cells. The fully efficient productive infection obtained with the VSV-G-protein-pseudotyped infectious CAEV strengthened the evidence that lack of viral entry is the only practical barrier to CAEV replication in human cells. The virus thus produced retained its original host cell specificity and acquired no propensity to propagate further in human cultures.

Relative Impact of Human Leukocyte Antigen Mismatching and Graft Ischemic Time After Lung Transplantation

BACKGROUND Recent data strongly suggest that human leukocyte antigen (HLA) mismatching has a negative impact on development of bronchiolitis obliterans syndrome (BOS) and survival after lung transplantation (LTx). Because HLA matching is sometimes achieved by extending ischemic time in other solid-organ transplantation models and ischemic time is a risk factor per se for death after LTx, we sought to compare the theoretical benefit of HLA matching with the negative impact of lengthened ischemic time. METHODS In this collaborative study we compared the relative impact of HLA mismatching and ischemic time on BOS and survival in 182 LTx recipients. RESULTS Using multivariate analyses, we observed a lower incidence of BOS (hazard ratio [HR] = 1.70, 95% confidence interval [CI]: 1.1 to 2.7, p = 0.03) and enhanced survival (HR = 1.91, 95% CI: 1.24 to 2.92, p = 0.01) in patients with zero or one HLA-A mismatch compared with those having two HLA-A mismatches. This beneficial effect on survival was equivalent to a reduction of ischemic time of 168 minutes. CONCLUSIONS We observed a reduced incidence of BOS and a better survival rate in patients well-matched at the HLA-A locus, associated with an opposite effect of an enhanced ischemic time. This suggests that graft ischemic time should be taken into account in future studies of prospective HLA matching in LTx.

Self‐expanding metal stents for the management of bronchial stenosis and bronchomalacia after lung transplantation

Background: Airway stenosis or malacia after lung transplantation, usually as a result of anastomotic ischemia, remains a major problem. Methods: The authors report their experience with the Gianturco expandable stent for the management of 23 bronchial stenoses in 18 patients following lung transplantation. Stent placement occurred an average of 5.6 months after transplantation. Results: Stents were well tolerated and produced immediate symptomatic and functional improvement. The mean follow‐up after implantation was 21 months (range, 4 to 48 mo). The authors removed five stents by endoscopy and replaced them, and removed one stent entirely. Laser resection was used to control granulomas or partial fibrosis stenosis that occurred in four stents (14.3%) after an average of 4 months. One stent broke but was still in place and effective 32 months later. One patient died of hemorrhage 4 months after stenting. Conclusion: Although it can still be improved, this expandable metal stent is suitable for the treatment of posttransplantation proximal bronchial stenosis.

Prognostic value of right ventricular ejection fraction in pulmonary arterial hypertension

Right ventricle ejection fraction (RVEF) evaluated with magnetic resonance imaging is a strong determinant of patient outcomes in pulmonary arterial hypertension. We evaluated the prognostic value of RVEF assessed with conventional planar equilibrium radionuclide angiography at baseline and change 3–6 months after initiating pulmonary arterial hypertension-specific therapy. In a prospective cohort of newly diagnosed patients with idiopathic, heritable or anorexigen-associated pulmonary arterial hypertension, RVEF was measured at baseline (n=100) and 3–6 months after initiation of therapy (n=78). After a median follow-up of 4.1 years, 41 deaths occurred, including 35 from cardiovascular causes. Patients with a (median) baseline RVEF >25% had better survival than those with a RVEF <25% using Kaplan–Meier analysis (p=0.010). RVEF at baseline was an independent predictor of all-cause and cardiovascular mortality in adjusted Cox regression model (p=0.002 and p=0.007, respectively; HR 0.93 for both). Patients with stable or increased RVEF at 3–6 months had a trend for improved all-cause survival (HR 2.43, p=0.086) and had less cardiovascular mortality (HR 3.25, p=0.034) than those in whom RVEF decreased despite therapy. RVEF assessed with conventional planar equilibrium radionuclide angiography at baseline and change in RVEF 3–6 months after therapy initiation independently predict outcomes in patients with pulmonary arterial hypertension. RVEF assessed with CPERA at baseline, and its changes on therapy, independently predict outcome in patients with PAH http://ow.ly/DsCS4

Chromosomal Distribution of Endogenous Jaagsiekte Sheep Retrovirus Proviral Sequences in the Sheep Genome

ABSTRACT A family of endogenous retroviruses (enJSRV) closely related to Jaagsiekte sheep retrovirus (JSRV) is ubiquitous in domestic and wild sheep and goats. Southern blot hybridization studies indicate that there is little active replication or movement of the enJSRV proviruses in these species. Two approaches were used to investigate the distribution of proviral loci in the sheep genome. Fluorescence in situ hybridization (FISH) to metaphase chromosome spreads using viral DNA probes was used to detect loci on chromosomes. Hybridization signals were reproducibly detected on seven sheep chromosomes and eight goat chromosomes in seven cell lines. In addition, a panel of 30 sheep-hamster hybrid cell lines, each of which carries one or more sheep chromosomes and which collectively contain the whole sheep genome, was examined for enJSRV sequences. DNA from each of the lines was used as a template for PCR with JSRV gag-specific primers. A PCR product was amplified from 27 of the hybrid lines, indicating that JSRV gag sequences are found on at least 15 of the 28 sheep chromosomes, including those identified by FISH. Thus, enJSRV proviruses are essentially randomly distributed among the chromosomes of sheep and goats. FISH and/or Southern blot hybridization on DNA from several of the sheep-hamster hybrid cell lines suggests that loci containing multiple copies of enJSRV are present on chromosomes 6 and 9. The origin and functional significance of these arrays is not known.

Factors associated with early graft dysfunction in cystic fibrosis patients receiving primary bilateral lung transplantation

OBJECTIVES Primary graft dysfunction (PGD) occurs in 10-25% of cases and remains responsible for significant morbidity and mortality after lung transplantation. Our goal was to explore donor and recipient variables and procedure factors that could be related to early graft failure in cystic fibrosis patients receiving bilateral lung transplantation, the PGD grade being derived from the PaO(2)/FiO(2) ratio measured at the sixth post-operative hour. METHODS Data from 122 cystic fibrosis patients having undergone lung transplantation in six transplant centres in France were retrospectively analysed. Donor and recipient variables, procedure characteristics and anaesthesia management items were recorded and analysed with regard to the PaO(2)/FiO(2) ratio at the sixth post-operative hour. Recipients were divided into three groups according to this ratio: Grade I PGD, when PaO(2)/FiO(2) >300 mmHg or extubated patients, Grade II, when PaO(2)/FiO(2) = 200-300 mmHg, and Grade III, when PaO(2)/FiO(2) <200 mmHg or extracorporeal membrane oxygenation still required. RESULTS Forty-eight patients were Grade I, 32 patients Grade II and 42 patients Grade III PGD. Otos donor score, recipient variables and procedure characteristics were not statistically linked to PaO(2)/FiO(2) at the sixth post-operative hour. Ischaemic time of the last implanted graft and the lactate level at the end of the procedure are the only factors related to Grade III PGD in this group. CONCLUSIONS Hyperlactataemia most probably reflects the severity of early PGD, which leaves graft ischaemic time as the only factor predicting early PGD in a multicentre population of cystic fibrosis lung graft recipients.