Delayed traumatic right diaphragmatic rupture.
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Accidents, Traffic↗
Biomedical subjects
Laurent Martin
Publications and source records attributed to Laurent Martin.
Effector and memory CD8+ T cells can be generated in response to alloantigen independently of CD4+ T cell help.
There is now considerable evidence suggesting that CD8(+) T cells are able to generate effector but not functional memory T cells following pathogenic infections in the absence of CD4(+) T cells. We show that following transplantation of allogeneic skin, in the absence of CD4(+) T cells, CD8(+) T cells become activated, proliferate, and expand exclusively in the draining lymph nodes and are able to infiltrate and reject skin allografts. CD44(+)CD8(+) T cells isolated 100 days after transplantation rapidly produce IFN-gamma following restimulation with alloantigen in vitro. In vivo CD44(+)CD8(+) T cells rejected donor-type skin allografts more rapidly than naive CD8(+) T cells demonstrating the ability of these putative memory T cells to mount an effective recall response in vivo. These data form the first direct demonstration that CD8(+) T cells are able to generate memory as well as effector cells in response to alloantigen during rejection in the complete absence of CD4(+) T cells. These data have important implications for the design of therapies to combat rejection and serve to reinforce the view that CD8(+) T cell responses to allografts require manipulation in addition to CD4(+) T cell responses to completely prevent the rejection of foreign organ transplants.
Animals↗
Long-term doxycycline-regulated transgene expression in the retina of nonhuman primates following subretinal injection of recombinant AAV vectors.
Adeno-associated viral gene therapy has shown promise for the treatment of inherited and acquired retinal disorders. In most applications, regulation of expression is a critical concern for both safety and efficacy. The purpose of our study was to evaluate the ability of the tetracycline-regulatable system to establish long-term transgene regulation in the retina of nonhuman primates. Three rAAV vectors expressing the tetracycline-dependent transactivator (rtTA) under the control of either the ubiquitous CAG promoter or the specific RPE65 promoter (AAV2/5.CAG.TetOn.epo, AAV2/4.CAG.TetOn.epo, and AAV2/4.RPE65.TetOn.epo) were generated and administered subretinally to seven macaques. We demonstrated that repeated inductions of transgene expression in the nonhuman primate retina can be achieved using a Tet-inducible system via rAAV vector administration over a long period (2.5 years). Maximum erythropoietin (EPO) secretion in the anterior chamber depends upon the rAAV serotype and the nature of the promoter driving rtTA expression. We observed that the EPO isoforms produced in the retina differ from one another based on the transduced cell type of origin within the retina and also differ from both the physiological EPO isoforms and the isoforms produced by AAV-transduced skeletal muscle.
Animals↗
Facial thermography is a sensitive tool to determine antihistaminic activity: comparison of levocetirizine and fexofenadine.
AIMS: To assess the antihistaminic activity of levocetirizine and fexofenadine 2 h and 24 h after drug administration using facial thermography and to compare the results with those using well-established parameters of antihistaminic activity in the nose and skin. METHODS: This was a randomized, double-blind, three-treatment, three-period, single-dose, cross-over study in healthy males taking levocetirizine 5 mg, fexofenadine 120 mg or placebo. The primary endpoint was nasal skin temperature after nasal histamine challenge recorded for 20 min at 2 and 24 h after drug intake. The secondary endpoints were nasal symptoms and a histamine skin prick test. RESULTS: Thirty subjects were randomized. At 2 h after drug intake the inhibition of the nasal temperature increase from baseline was not significantly different between levocetirizine and fexofenadine. At 24 h it was significantly more pronounced after levocetirizine than fexofenadine (difference: least-squares mean: -0.13 degrees C; P < or = 0.024, 95% CI -0.24, -0.02). Both drugs significantly reduced (P < or = 0.001) the mean temperature increase from baseline compared with placebo at 2 and 24 h (least-squares mean increase and (95% CI): levocetirizine, -0.28 degrees C (-0.42, -0.14) and -0.32 degrees C (-0.43, -0.21); fexofenadine -0.35 degrees C (-0.49, -0.21) and -0.19 degrees C (-0.30, -0.08), respectively). Results of nasal symptom score and wheal and flare were consistent with the thermography results. CONCLUSIONS: Facial thermography is an objective, non-invasive and sensitive method to study antihistaminic activity at the nose level. Levocetirizine and fexofenadine demonstrate the same activity at 2 h after drug intake, but levocetirizine has a more sustained activity at 24 h.
Adolescent↗
Endothelial oxidative stress induced by serum from patients with severe trauma hemorrhage.
OBJECTIVE: Shock induces oxidative stress by ischemia-reperfusion phenomenon. Endothelial cells are involved in the inflammatory response and oxidative stress responsible for microcirculation impairment and organ failure. We examined the potential of serum from patients to induce in vitro reactive oxygen species production by cultured human umbilical vein endothelial cells (HUVECs). PATIENTS: Three groups were compared: hemorrhagic shock trauma patients, isolated brain injured patients, and healthy volunteers. METHODS: In the hemorrhagic shock group we sought a correlation between reactive oxygen species production and severity of shock. Serum was separated and perfused in an in vitro model of perfused HUVECs. Ex vivo reactive oxygen species production was assessed by fluorescence microscopy using dichlorodihydrofluorescein, an intracellular dye oxidized by H2O2. Results are expressed in proportional change from baseline and normalized by protidemia to control for variation related to hemodilution. RESULTS: Reactive oxygen species production by endothelial cells exposed to serum from hemorrhagic shock patients (46.2+/-24.9%) was significantly greater than in those with brain injury (3.9+/-35.1%) and in healthy volunteers (-6.8+/-5.8%). In the hemorrhagic shock group dichlorodihydrofluorescein fluorescence was strongly correlated positively to Simplified Acute Physiology Score II and lactatemia and negatively to [HCO3-]. CONCLUSIONS: Serum from trauma patients with hemorrhagic shock induces reactive oxygen species formation in naive endothelial cells which is correlated to shock severity.
APACHE↗
Detection of anti-HLA antibodies with flow cytometry in needle core biopsies of renal transplants recipients with chronic allograft nephropathy.
The aim of this study was to assess the feasibility of detecting anti-HLA antibodies in eluates from needle core biopsies of renal transplants with chronic allograft nephropathy. Two methods of screening, the enzyme-linked immunosorbent assay (ELISA) and flow cytometry (FlowPRA) were compared. Twenty renal transplants with CAN were removed after irreversible graft failure. To assess the feasibility of detecting anti-HLA antibodies in small samples, needle core biopsies were sampled at the same place as surgical samples and at a second cortical area. Antibodies were eluted with an acid elution kit and anti-class I and class II IgG HLA antibodies detected using ELISA and flow cytometry. Flow cytometry was found to be more sensitive than ELISA for detecting anti-HLA antibodies in eluates from renal transplants with CAN (95% vs. 75% of positive cases). Detection of anti-HLA antibodies showed good agreement between surgical samples and needle core biopsies performed at the same place for anti-class I (80% vs. 65%, r=0.724 P<0.01) and anti-class II HLA antibodies (70% vs. 55%, r=0.827 P<0.01). In addition, differences in the detection of anti-class I HLA antibodies in needle core biopsies sampled at different sites suggests that immunization to class I donor antigen could be underestimated in needle core biopsy samples. These data indicate that anti-HLA antibodies can be detected in needle core biopsies from renal transplants. Provided further evaluation is done, elution might be a complementary method to detect anti-HLA antibodies when they are bound to the transplant.
Antibodies↗
Donor-specific antibodies in allograft rejection: clinical and experimental data.
The ability of donor-specific major histocompatibility complex alloantibodies to destroy a transplanted organ within minutes, the so-called hyperacute rejection phenomenon, has been known for a long time. It is a clear demonstration of the possible cytotoxic effect of antibodies. Apart from this particular situation, the role of antibodies in inducing acute or chronic allograft rejection remains controversial. Many clinical data have shown that transplant recipients capable of developing class I or class II anti-HLA antibodies experienced shorter survival periods than those who were not. This fact, in accordance with experimental data, only demonstrates that high antibody responders reject a transplant more easily than low responders. More interestingly, there is now increasing evidence that posttransplant appearance of donor-specific alloantibodies, and probably of alloreactive-induced autoantibodies, is strongly correlated with reduced graft survival rate, especially from chronic rejection. We demonstrated that donor-specific HLA antibodies can be found in more than 70% of transplanted kidneys with chronic allograft nephropathy, and that the intragraft presence of such antibodies is significantly correlated with high numbers of plasma cells on early biopsies and C4d deposits, a recognized marker of humoral rejection. It is likely that non-HLA antibodies also play a deleterious role in organ transplant outcome, particularly the heterogeneous group of anti-endothelial cells antibodies, anti-MIC antibodies, autoantibodies and some others with no recognized target. Convincing experimental data, especially using B cell and T cell deficient mice, strongly suggest that B cells and donor-specific antibodies are required for fully developed chronic allograft rejection. The role of antibodies in inducing the cascade of cytokines and growth factors leading to tissue lesions is of increasing interest since it is now possible to control B cell proliferation and antibody production.
Animals↗
[Urinary bovine tuberculosis in man].
Human infestation by Mycobacterium bovis has become rare since eradication of bovine tuberculosis. However, this aetiology must be envisaged, as the sensitivity of the micro-organism is variable and its demonstration requires specific techniques.
Animals↗
Influence of positive end-expiratory pressure (PEEP) on histopathological and bacteriological aspects of pneumonia during low tidal volume mechanical ventilation.
OBJECTIVE: Ventilatory strategies combining low tidal volume (V(T)) with positive end-expiratory pressure (PEEP) are considered to be lung protective. The influence of the PEEP level was investigated on bacteriology and histology in a model of ventilator-associated pneumonia. SUBJECTS: Nineteen New Zealand rabbits. INTERVENTIONS: The animals were mechanically ventilated with a positive inspiratory pressure of 15 cmH(2)O and received either a zero end-expiratory pressure (ZEEP, n=6), a 5 cmH(2)O PEEP (n=5) or a 10 cmH(2)O PEEP (n=4). An inoculum of Enterobacter aerogenes was then instilled intrabronchially. The non-ventilated pneumonia group (n=4) was composed of spontaneously breathing animals which received the same inoculum. Pneumonia was assessed 24 h later. MAIN RESULTS: The lung bacterial burden was higher in mechanically ventilated animals compared with spontaneously breathing animals. All animals from the latter group had negative spleen cultures. The spleen bacterial concentration was found to be lower in the 5 cmH(2)O PEEP group when compared to the ZEEP and 10 cmH(2)O PEEP groups (3.1+/-1.5 vs 4.9+/-1.1 and 5.0+/-1.3 log(10) cfu/g, respectively; p<0.05). Lung weight and histological score values were lower in the spontaneously breathing animals as well as in the 5 cmH(2)O PEEP group compared with the ZEEP and 10 cmH(2)O groups. CONCLUSIONS: Mechanical ventilation substantially increased the lung bacterial burden and worsened the histological aspects of pneumonia in this rabbit model. Variations in terms of lung injury and systemic spreading of infection were noted with respect to the ventilatory strategy.
Animals↗
"Genetic Doping" with erythropoietin cDNA in primate muscle is detectable.
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Animals↗
Management of hepatitis C patients: a French population-based study.
AIMS: Our aim was to assess the proportion of patients in a well-defined population reaching specialized medical care after hepatitis C diagnosis. METHODS: Hepatitis C-positive patients recorded in the population-based registry of Cote-d'Or, an administrative district in France, constituted the study population. RESULTS: Between 1994 and 1999, new hepatitis C-positive serology was diagnosed in 847 patients, of whom 690 were eligible for this study. A total of 135 patients had not been given specialized medical care after diagnosis; among them, 50.4% had a normal serum alanine transferase level at diagnosis, 62.2% had risk factors related to lifestyle (drug addiction, sexual risk...), and 26.7% were current alcoholics. The 555 other patients were involved in specialized medical care after diagnosis: 42.7% had a liver biopsy and 27.0% were treated. Treatment was carried out more often in males than in females (OR: 1.67; P<0.005), and in patients less than 65 years old (OR: 2.94; P<0.0002). Nearly 30.5% of patients with a Metavir score greater than A1F1 did not undergo treatment. CONCLUSION: This study shows that in a general population at least one patient out of five with hepatitis C infection remains outside the health care system. It also reveals that management practices vary with gender. Further surveys are needed to better understand this phenomenon.
Adolescent↗
Incidence and significance of cardiac troponin I release in severe trauma patients.
BACKGROUND: The incidence and significance of troponin I release and its mechanism are unknown in severe trauma patients. The characteristics of this release were prospectively studied in such patients and correlated with presence of shock, existence of myocardial contusion, and outcome. METHODS: During a 24-month period, serial electrocardiogram recordings and troponin I measurements were performed in all trauma patients admitted at a surgical intensive care unit. The diagnosis of a significant myocardial contusion was made on electrocardiographic criteria. According to the time course of troponin I, three groups of patients were defined a priori: very transient (</= 12 h) and limited release (troponin I < 2 microg/l), transient (</= 36 h) and significant release (troponin I >/= 2 microg/l), and sustained (> 36 h) and significant release (troponin I > 2 microg/l). In the last group, coronary artery angiography was performed. RESULTS: The incidence of troponin I release was 12% (95% confidence interval [CI], 9.6-14.4%) in 728 patients. A significant myocardial contusion was found in 35 patients (5%; 95% CI, 3.4-6.6%) and may occur in the absence of chest trauma and without troponin I release. Sensitivity, specificity, and positive and negative predictive values of troponin I for the diagnosis of myocardial contusion were 63, 98, 40, and 98%, respectively. Troponin I release was observed in 54 early (> 48 h) survivors (7%; 95% CI, 5.6-9.6%) without preexisting coronary artery disease. A sustained and significant release of troponin I (17 patients) was frequently associated with chest trauma (82%) and constantly with electrocardiographic abnormalities. A coronary artery injury was found in 7 patients (2 major and 5 minor vascular injuries) (1% of the whole group; 95% CI, 0.4-2.0%). Mortality was similar in early survivors with (15%; 95% CI, 7-27%) or without (12%; 95% CI, 9-14%) troponin I release. The odds ratio for late mortality was 1.32 (95% CI, 0.61-2.85) in patients with troponin I release. CONCLUSIONS: Serial electrocardiogram recordings and troponin I assessments may be proposed for initial screening in high-risk trauma patients to detect anatomical cardiac injuries through the time course of circulating protein. Troponin I release does not have a prognosis value in trauma patients.
Accidental Falls↗
Detection of donor-specific anti-HLA antibodies with flow cytometry in eluates and sera from renal transplant recipients with chronic allograft nephropathy.
BACKGROUND: Chronic allograft nephropathy (CAN), which remains the main cause of graft loss after kidney transplantation, is still poorly understood. Because anti-HLA antibodies may be involved in the pathogenesis of CAN, this study was performed to look for donor-specific antibodies (DSA) fixed onto renal transplants with CAN. METHODS: DSA were identified after elution with flow cytometric assay and/or flow cytometric crossmatches in 20 transplants removed after irreversible graft failure caused by CAN and in control samples from 2 transplants with relapsing glomerulopathy, 2 transplants lost after vascular thrombosis, and 4 normal kidneys. The results were compared with those obtained in the serum samples 1 year after grafting, at the time of transplantectomy, and within 2 months after transplantectomy. RESULTS: IgG anti-class I, anti-class II, or both DSA were identified in 70.6% of eluates versus 73.6% of posttransplantectomy serum samples (NS), 42.1% of 1-year postgrafting serum samples (P<0.05), and 31.6% of serum samples at the time of transplantectomy (P<0.05). Our data show a good correlation between the target of anti-HLA antibodies found in both eluates and posttransplantectomy serum samples, but the precise specificity of anti-HLA antibodies is more often assigned in posttransplantectomy serum samples than in eluates. This problem needs further evaluation. CONCLUSION: This study shows that testing for anti-HLA DSA in eluates from removed kidney transplants using flow cytometry can be achieved and is highly efficient. It already suggests that both anti-class I and anti-class II HLA antibodies can be involved in CAN. Further studies are now needed to evaluate the possibility of identifying such antibodies in the eluates of transplant biopsy specimens from recipients experiencing CAN.
Autoantibodies↗
Subcellular expression of c-IAP1 and c-IAP2 in colorectal cancers: relationships with clinicopathological features and prognosis.
The Inhibitor of Apoptosis Protein (IAP) family includes several critical cell death inhibitors, the expression of which could be involved in colorectal carcinogenesis. Among them, c-IAP1 and c-IAP2 expression has never been investigated in colorectal cancer. The present study was designed to determine whether expression of both IAPs was related to pathological parameters and survival in sporadic colon carcinomas. Analysis of five human colon cancer cell lines by both western blotting of cell fractions and immunocytochemistry showed that the two IAPs could be expressed both in the nucleus and in the cytoplasm. Immunohistochemical analysis of a series of 46 sporadic colorectal adenocarcinomas demonstrated that c-IAP1 expression was more frequent in the nucleus (85%), and that c-IAP2 was more often expressed in the cytoplasm (82%). A significant association was identified between a strong lymphoid infiltrate in the stroma and the nuclear expression of c-IAP2 (p = 0.02). No other relationship was observed between IAP expression and pathological features. After adjusting by age and stage, the relative risk of death was lower for cytoplasmic c-IAP1, cytoplasmic c-IAP2, and nuclear c-IAP2 expression. It was higher for nuclear c-IAP1 expression. These associations were not statistically significant, but this work underlines the importance of taking into account the subcellular location of the IAP family members in the evaluation of their prognostic significance.
Adult↗
Detection of isoelectric profiles of erythropoietin in urine: differentiation of natural and administered recombinant hormones.
Erythropoietin (EPO) is normally present in urine at a low concentration (about 1IU/L, i.e., about 10ng/L) for a total protein concentration of at least 50mg/L. A method to study the isoelectric profile of this hormone from 20-ml urine aliquots without previous purification was developed. This method involves isoelectric focusing of the retentate from ultrafiltered urine. Both the ultrafiltration and the isoelectric focusing required precautionary measures to prevent EPO degradation by the proteases that are present in urine. Because classical immunoblotting gave rise to an unspecific detection of various urinary proteins in the focused retentate, it was essential to use the "double-blotting" process developed to solve this problem. Sufficient sensitivity was achieved using amplified chemiluminiscent detection after the blotting membrane was treated with dithiotreitol. The patterns that were revealed from various urinary samples proved to be highly heterogeneous as they were composed of more than 10 isoforms in a pI range of 3.7-4.7. Clear transformation of the patterns was observed in the case of treatment by the recombinant hormone, suggesting that this method can be regarded an efficient tool for indicating recombinant EPO misuse in sports. It may also open new investigations in the field of physiologic or pathologic exploration.
Blotting, Western↗
Preliminary data of the GORTEC 2000-02 phase III trial comparing intravenous and subcutaneous administration of amifostine for head and neck tumors treated by external radiotherapy.
A prospective randomized study is comparing intravenous (IV; arm A) versus subcutaneous (SC; arm B) administration of amifostine in patients receiving radiotherapy for head and neck cancer. Main eligibility criteria were newly diagnosed squamous cell head and neck cancer, inclusion of at least 75% of both parotid glands within radiation fields that would receive at least 40 Gy, and no evidence of distant metastasis. Prophylactic use of pilocarpine and concomitant chemotherapy were prohibited. Intravenous administration of amifostine is 200 mg/m2/d in a short 3-minute infusion 15 to 30 minutes before each fraction of radiotherapy. Subcutaneous administration is 500 mg/d in two, slow 1.25-mL injections at two different sites 20 to 60 minutes before each radiotherapy fraction. Antiemetic treatment and blood pressure monitoring are required in both arms. As of April 25, 2002, 111 of the 292 required patients were included. Data are available for the first 54 patients. Acute toxicity included nausea/vomiting (12% for arm A; 13% for arm B), hypotension (6% in arm A; 0% in arm B), skin rash (15% in arm A; 16% in arm B), and asthenia (4% in arm A; 0% in arm B). Compliance with amifostine administration was 70% in arm A (IV) and 80% in arm B (SC). The rate of acute xerostomia (> or = grade 2) was 23% in arm A and 19% in arm B. These preliminary results indicate that tolerance is better with SC than IV administration, particularly because of the absence of hypotension. The absence of hypotension with SC administration facilitates patient monitoring and management in radiotherapy departments. More patients and data are required to assess the long-term efficacy of SC administration on acute and late xerostomia.
Amifostine↗
New model of ventilator-associated pneumonia in immunocompetent rabbits.
OBJECTIVE: Despite the high rate of therapeutic failures in ventilator-associated pneumonia, up to now there has been no animal model specifically designed for antimicrobial evaluation. A rabbit model of ventilator-associated pneumonia is described for the first time in this study. DESIGN Prospective, randomized experimental study. SETTING: An animal research laboratory. SUBJECTS: Male New Zealand healthy rabbits (n = 44). INTERVENTIONS: After oral intubation and an hour of mechanical ventilation, animals in the ventilator-associated pneumonia group (n = 22) were infected intrabronchially with a calibrated inoculum of. The nonventilated pneumonia group (n = 22) was composed of animals that received the same inoculum in the absence of mechanical ventilation. Rabbits from both groups were randomly killed 3, 6, 12, 24, or 48 hrs after inoculation. Pneumonia evaluation was based on histologic (macroscopic and microscopic score) and bacteriologic (bacterial count) findings. MAIN RESULTS: Infected animals undergoing mechanical ventilation rapidly developed a progressive bilateral and multifocal pneumonia. Lung bacterial mean (sd) concentration was 6.48 (0.71) log10 colony-forming units (cfu) per gram of tissue at the 48th hour, whereas bacteremia occurred in most cases. In the nonventilated pneumonia group, pneumonia was less severe in terms of bacterial count (3.18 [1.86] log10 cfu/g; p <.05), and spleen cultures remained negative. In addition, microscopic examination revealed noninfectious lung injury in the ventilator-associated pneumonia group, especially hyaline membrane filling alveolar spaces. Of note, these features were never observed in the nonventilated pneumonia group. CONCLUSIONS: An animal model of ventilator-associated pneumonia was obtained in immunocompetent rabbits. Histopathologic and bacteriologic features were similar to those found in humans. Obviously, pneumonia was more severe when animals underwent mechanical ventilation, especially in terms of systemic spread. Noninfectious lung injury corresponding to ventilation-induced lung injury may explain the difference. This model emphasizes the strong impact of both mechanical ventilation and infection on lung because they seem to act synergistically when causing alveolar damage. Moreover, it seems well suited to testing antimicrobial effectiveness.
Animals↗
[Acute herpetic hepatitis: clinico-pathological study of two cases].
Two cases of acute herpetic hepatitis affecting immunocompetent adults after surgery, are reported. They point out the relevance of liver biopsy for the diagnosis of these generally unrecognized infections. Liver biopsy allows not only diagnosis but also the identification of the virus on tissue sections with immunohistochemistry or in situ hybridization. The prognosis of herpetic hepatitis which can be correlated with the extension of apoptosis, remains poor despite the appearance of antiviral drugs. An apoptosis score could represent an interesting prognostic factor whose value remains to be assessed.
Adult↗