Letermovir breakthroughs during the French Named Patient Programme: interest of monitoring blood concentration in clinical practice.

OBJECTIVES: To analyse mechanisms of letermovir breakthrough during compassionate primary and secondary prophylaxis. METHODS: Mechanisms of letermovir breakthrough during compassionate primary and secondary prophylaxis were analysed in four patients from the French Named Patient Programme by the French National Reference Centre for Herpesviruses. RESULTS: Of three absolute resistance cases, two were associated with treatment interruption or low letermovir concentrations in blood. A fourth case of breakthrough was not associated with resistance. Next-generation sequencing (NGS) genotyping confirmed rapid emergence of resistant mutants, within 3 months of treatment initiation. CONCLUSIONS: Measurement of letermovir concentration and genotyping should be recommended for patient follow-up during letermovir therapy.

Acute enteritis associated with Coxsackievirus A19 in a kidney transplant patient.

Diarrhea is a frequent complication after kidney transplantation, with an incidence rate between 22% and 51%. In many cases, the cause remains unknown. We describe here the first case, to our knowledge, of persistent diarrhea associated with Coxsackievirus A19 (CVA19) in a kidney transplant recipient. The patient was a 46-year-old man who received a deceased-donor kidney. He experienced delayed graft function because of donor kidney donation after circulatory determination of death. Maintenance immunosuppression consisted of low-dose cyclosporine, high-dose mycophenolate mofetil (MMF) (3 g/day), and prednisone (10 mg/day). He had severe diarrhea for 2 weeks associated with acute renal failure. No pathogens were found in the stool cultures. Enterovirus detection was positive by real-time polymerase chain reaction, and sequence analysis found CVA19 (from Enterovirus C group). Area under the curve of MMF was 48 mg.h/L. Because of the persistence of diarrhea, MMF was stopped and replaced by azathioprine. The diarrhea disappeared, but serum creatinine did not return to baseline. CVA19 rarely causes gastroenteritis. This case illustrates that MMF is not always the direct cause of diarrhea, and that new clinical infectious diseases will be detected with the expansion of molecular-based DNA diagnostics.

Mutagenicity and genotoxicity of PM2.5 issued from an urbano-industrialized area of Dunkerque (France).

Epidemiological studies have demonstrated the link between chronic exposure to particulate matter (PM), especially particles with an aerodynamic diameter lesser than 2.5 µm (PM(2.5) ), and lung cancer. Mechanistic investigations focus on the contribution of the various genotoxicants adsorbed onto the particles, and more particularly on polycyclic aromatic hydrocarbons or nitroaromatics. Most of the previous studies dealing with genotoxic and/or mutagenic measurements were performed on organic extracts obtained from PM(2.5) collected in polluted areas. In contrast, we have evaluated genotoxic and mutagenic properties of urbano-industrial PM(2.5) (PM) collected in Dunkerque (France). Thermally desorbed PM(2.5) (dPM) was also comparatively studied. Suspensions of PM and dPM (5-50 µg per plate) were tested in Salmonella tester strains TA98, TA102 and YG1041 ± S9mix. Significant mutagenicity was observed for PM in YG1041 ± S9 mix. In strain TA102 - S9mix, a slight, but not significant dose-response increase was observed, for both PM and dPM. Genotoxic properties of PM and dPM were evaluated by the measurement of (1) 8-OHdG in A549 cells and (2) bulky DNA adducts on A549 cells and on human alveolar macrophages (AMs) in primary culture. A dose-dependant formation of 8-OHdG adducts was observed on A549 cells for PM and dPM, probably mainly attributed to the core of the particles. Bulky DNA adducts were observed only in AMs after exposure to PM and dPM. In conclusion, using relevant exposure models, suspension of PM(2.5) induces a combination of DNA-interaction mechanisms, which could contribute to the induction of lung cancer in exposed populations.

Acoustic correlates of vocal effort: External factors and personality traits.

OBJECTIVES: To develop an experimental protocol to study the vocal effort generated by introducing barriers to communication, and its relationship with certain personality traits. MATERIAL AND METHODS: The experimental protocol consisted of an interactive game in which the subject gave an investigator instructions to adopt various body positions (semi-directed communication situation). The Control situation included no constraints on communication. Then a Distance Constraint (increased distance between subject and investigator) and a Time Constraint (generation of performance stress by putting the subject in competition with others) were introduced. The vocal parameters studied comprised vocal intensity and fundamental frequency in the middle of the vowel of 3 target phonemes. Subjects also took the NEO FFI-R personality test. RESULTS: The study included 41 women aged between 18 and 52 years. Vocal intensity and fundamental frequency increased significantly with the introduction of the constraints (P<0.05), intensity passing from 75.5dB to 81.8dB and frequency from 249.4Hz to 335.8Hz. No correlations were found between these changes and results for the various personality traits. CONCLUSIONS: This ecological protocol enables the impact of both physical and emotional obstacles to communication to be studied. No correlations between vocal effort and personality traits emerged. A larger-scale study would be necessary to analyze the continuum between vocal effort and vocal forcing, to improve speech therapy for dysfunctional dysphonia.

DNA adduct measurements in zebra mussels, Dreissena polymorpha, Pallas. Potential use for genotoxicant biomonitoring of fresh water ecosystems.

The purpose of this study was to examine PAH accumulation and bulky DNA adduct formation in the digestive gland of zebra mussels exposed in their habitat or in controlled laboratory conditions to complex mixture of PAH. DNA adducts were measured using a 32P-postlabelling protocol with nuclease P1 enrichment adapted from Reddy and Randerath [Reddy, M.V., Randerath, K., 1986. Nuclease P1-mediated enhancement of sensitivity of 32P-postlabelling test for structurally diverse DNA adducts. Carcinogenesis 7, 1543-1551]. Specimens collected in the upper part of the Seine estuary were shown to accumulate higher levels of PAH (up to 1.6 microg g(-1) dry weight) in comparison to individuals from the reference site (0.053 microg g(-1) dry weight). The former exhibited elevated levels of DNA adducts (up to 4.0/10(8) nucleotides) and higher diversity of individual adducts with five distinct spots being specifically detected in individuals originating from the Seine estuary. Zebra mussels exposed for 5 days to 0.01% (v/v) of organic extract of sediment from the Seine estuary were shown to accumulate high amounts of PAH (up to 138 microg g(-1) dry weight) but exhibited relatively low levels of DNA adducts. Exposure to benzo[a]pyrene led to a dose-dependent accumulation of B[a]P (up to 7063 microg g(-1) dry weight) and a clear induction of DNA adduct formation in the digestive gland of mussels (up to 1.13/10(8) nucleotides). Comparisons with other bivalves exposed to the same model PAH, revealed similar levels of adducts and comparable adduct profiles with a main adduct spot and a second faint one. This study clearly demonstrated that zebra mussels are able to biotransform B[a]P and probably other PAH into reactive metabolites with DNA-binding activity. This work also demonstrated the applicability of the nuclease P1 enhanced 32P-postlabelling method for bulky adduct detection in the digestive gland of zebra mussels. DNA adduct measurement in zebra mussels could be a suitable biomarker to monitor PAH-exposure and evaluate genotoxicity in fresh water ecosystems.

Genotoxicant accumulation and cellular defence activation in bivalves chronically exposed to waterborne contaminants from the Seine River.

The aim of the present work was to investigate genotoxicant accumulation and biological responses of zebra mussels and blue mussels collected along a pollution gradient in the Seine estuary and in the Seine Bay. The sampling area included three contaminated and one reference sites for each species. The study focused on polyaromatic hydrocarbons (PAH), lindane, polychlorobiphenyls (PCB) and metals known to be potential genotoxicants and/or reactive oxygen species (ROS) inducers. Enzymatic activities related to cellular defence systems including the phase II enzyme glutathione S-transferase (GST) and three antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were measured in gills. DNA adducts and DNA strand breaks (Comet assay) were measured in digestive gland and hemocytes, respectively. Species differences were observed in metal accumulation (As and Pb), GPx activity and DNA adduct formation. A marked upstream-downstream gradient was reported for PAH body burden and to a lesser extent for PCB and metals with the highest values measured just downstream the industrialized area of Rouen. GST and SOD activities in gills of bivalves were positively related to PAH and metals body burden, respectively. Activation of those cellular defences may prevent accumulation of electrophilic metabolites and free radicals and thus may protect DNA and others macromolecules against oxidation and adduction. Although DNA strand breaks and bulky adducts were detected in both species, levels were relatively low and no significant site differences were observed in June 2003. Our results indicate a clear relationship between genotoxicant accumulation and positive activation of detoxification and antioxidant systems but poor consequences in term of DNA damage for wild population of mussels inhabiting the Seine estuary.

Presence of C-19 steroids in mammary Shionogi carcinoma (SC 115) in castrated mice.

Intact and castrated male DD/S mice were inoculated with androgen-dependent cells (SC 115). All intact animals developed tumors after Day 12 of inoculation; however, six of seven castrated animals presented tumors 48 days postinoculation. The levels of steroids in both tumors were then examined. In castrated mice, dehydroepiandrosterone and androst-5-ene-3 beta, 17 beta-diol levels were diminished by 30% and 70%, respectively, while the amounts of testosterone and androstenedione were reduced by more than 90%. Our data also demonstrate that androstane-3 alpha, 17 beta-diol and androstane-3 beta, 17 beta-diol were decreased to 60% and dihydrotestosterone decreased to 6% of their normal value, respectively. This latter level (0.48 nM) was sufficient to still effect a potent androgenic response in the tumor. Besides, a highly significant correlation was found in these tumors between various C-19 steroids (dehydroepiandrosterone and androstane-3 alpha, 17 beta-diol, r = 0.97, P less than 0.01), suggesting a possible conversion of C-19 precursors into potent androgens in the tumors. Determination of the plasma steroid levels in the castrated animals clearly confirmed that potent androgenic steroids and precursors were still in the circulation 3 days after castration. It thus appears that C-19 steroids from adrenal origin may be also involved in "independent" tumor growth.

Response to antiviral therapy in haematopoietic stem cell transplant recipients with cytomegalovirus (CMV) reactivation according to the donor CMV serological status.

Pre-emptive antiviral treatment efficiently prevents occurrence of cytomegalovirus (CMV) disease in allogeneic stem cell transplant recipients. However, successive treatment courses can be necessary. The current study was aimed at determining factors that could influence the response to antiviral treatment, in particular the donor CMV serostatus. A total of 147 consecutive CMV-seropositive recipients (R+) were included and prospectively monitored for 6 months after transplantation. Reactivation of CMV occurred in 111 patients, 61 of 78 with a CMV-positive donor (D+) and in 50 of 69 with a CMV-negative donor (D-) (p 0.45). Baseline viral loads and initial viral doubling times did not differ between D+/R+ and D-/R+. Fifteen D+/R+ and four D-/R+ had self-resolving CMV infections. A total of 92 patients received antiviral treatment and 81 (88%) had a significant decrease in CMV load under therapy. Repeated CMV episodes were observed in 67% of those and were significantly more frequent in D-/R+ than in D+/R+ (p <0001). Half-life of CMV under treatment was significantly longer in D-/R+ than in D+/R+. Treatment failure observed in eight recipients was associated with low leucocyte count at reactivation onset, and was significantly more frequent in D-/R+ (six patients) than in D+/R+ (two patients) (p <0.0001). CMV strains resistant to antivirals were found in two D-/R+. Donor CMV serostatus influenced neither CMV reactivation occurrence nor the kinetics of CMV DNA load in the early phase of CMV replication but had a significant impact on response to antiviral therapy. Virological drug-resistance remained rare.

Seasonal variations of DNA-adduct patterns in open field farmers handling pesticides.

Seasonal variations of DNA-adduct levels in peripheral blood cells were evaluated in open field farmers (n=26) by use of the 32P-postlabelling assay. Samples were collected before (sample S0) and during (sample S4) the period of intensive pesticide use. A similar sampling procedure was applied to a referent group (n=29). Exposure to pesticides was estimated via a detailed questionnaire. For the group of farmers, an increase in mean adduct level was observed during the season (mean RALS0=3.9+/-3.4 x 10(-10), mean RALS4=13.3+/-15.7 x 10(-10); p=0.008; RAL=relative adduct level). The mean adduct levels were significantly different between farmers and referents only in the S4 samples, with higher levels for farmers (p=0.02). The number of different adducts per individual was higher for farmers at S4 when compared with S0 (p=0.02) and compared with the referents at S4 (p=0.03). However, the increase of the adduct level in farmers did not seem to be attributable to the occurrence of specific new adducts in S4 as compared with S0, but was supposedly due to intensification of pre-existing spots and/or appearance of new unspecific ones. This would be in agreement with indirect genotoxic (epigenetic) effects known for several pesticides, even though a direct mechanism cannot be ruled out definitively. The implication of the pesticides used by the farmers in the modulation of DNA-adduct patterns was explored by analysis of exposure data obtained from the questionnaire.

(De)phosphorylation agents influence 5 alpha-reduction of testosterone in human prostate.

The effects of ATP and of 2,4-dinitrophenol (DNP) on the kinetics of 5 alpha-reductase were studied in a microsomal preparation from hyperplastic human prostates. DNP decreased and ATP increased enzyme activity in a dose-dependent manner. Furthermore, in one and the same prostate, activity was inversely correlated to prostatic acid phosphatase (PAP) concentration. These observations provide strong support for the contention that in the human prostate 5 alpha-reductase activity and, consequently, dihydrotestosterone (DHT) production may be energy dependent and involve a phosphorylation step.

Metabolism of tritiated C19 steroids by Shionogi mouse mammary tumors.

In the present report, the metabolism of dehydroepiandrosterone, 5-androstene-3 beta, 17 beta-diol and androstenedione has been studied in two different Shionogi tumors, one is androgen-dependent ("androgen sensitive") and grows in intact male mice and the other is apparently androgen-independent ("androgen insensitive") since the cells continue to grow in castrated antiandrogen (Flutamide) treated male animals. Our data clearly show that both the sensitive and insensitive tumors contain 3 beta-hydroxysteroid delta 5-delta 4 isomerase which causes the transformation of C19 steroids into potent androgenic steroids. However, the androgen sensitive tumor is able to convert 5-androstene-3 beta, 17 beta-diol into 2-hydroxyestrogens while the rate of conversion is extremely low in the insensitive tumor. Most interestingly, the production of 5 alpha-reduced steroids observed in both tissues was clearly higher in insensitive tumor homogenates.

Nonlinear discriminant analysis and prognostic factor classification in node-negative primary breast cancer using probabilistic neural networks.

BACKGROUND: We used non-linear kernel discriminant analysis (KDA) to predict the outcome of 134 axillary node-negative primary breast cancer patients not treated with adjuvant therapy in a non censored database. MATERIAL: Posterior probabilities of relapse at 5 years were estimated using probabilistic neural networks (PNN) and a cross-validation (leave-one-out) technique to avoid overfitting the data. A stepwise method was used to construct the models to define the best combination of risk factors among eleven prognostic factors: age, menopausal status, Scarff-Bloom-Richardson grade, clinical tumor size, pathological tumor size, estrogen and progesterone receptor status, urokinase-type plasminogen activator, p53 protein level, c-erbB-2 protein and epidermal growth factor receptor. The different variables were tested individually and in combination to determine their prognostic power using a ROC indicator, which measures the separation between the probability distributions of the output neuron activations under the null hypothesis (no recurrence at 5 years) and under the alternative hypothesis (recurrence at 5 years). RESULTS: The best predictive one-dimensional model was obtained with uPA (ROC indicator = 0.75). A two-factor model including uPA and clinical tumor size (T) gave the best discrimination between recurrence and non recurrence at 5 years (ROC indicator = 0.84). Additional variables did not improve the accuracy of the prediction. The uPA-T model generated a map useful in predicting the posterior probability of cancer recurrence in a given patient. This representation allows the entire database to be easily visualized and each patient can be compared with the entire database. CONCLUSION: This is a powerful approach to analyze the impact of prognostic factors and it could find clinical applications in breast cancer.

[A case of polypoid solitary colonic plasmocytoma]. / Un cas de plasmocytome solitaire du côlon à forme polypoïde.

One case of polypoid solitary plasmacytoma in the sigmoid colon of a 60 year-old woman is presented. Plasmacytomas are rarely observed in the gastrointestinal tract and are especially uncommon in the côlon. Eight cases were published since 1972. They show a mean age of 46.3 years, a sex-ratio of 1/1, varying revealing symptoms, and no preferential colonic location. Two differential diagnosis must be discussed: an inflammatory pseudotumor, and a multiple myeloma related tumor. Multiple myeloma must be ruled out by a complete radiographic and biological research. Surgery is the only therapy described and seems to be efficient.

[Antidepressants and sexual stimulation: the correlation]. / Antidépresseurs et stimulation sexuelle: la part des choses.

The purpose of this study is to correlate antidepressant treatment with sexual stimulation. The first part of this paper tries to describe some physiologic aspects of the sexual function. This complex subject includes several neuromediators which belong to adrenergic, cholinergic, dopaminergic and serotoninergic systems. A double-blind study shows that viloxazine, an atypical antidepressant, could act specifically on sex drive by desinhibiting effect. A precise study concludes that moclobemide improve significantly all components of sexual function. The numerous side effects of doxépine is a hindrance to its prescription. More precise studies about viloxazine and moclobemide suggest that both could have a specific effect on different components of sexual activity. In the second part of this paper, we consider the concept of "corrector". These drugs are numerous, however their prescriptions are not very wide spread: yohimbine, cyproheptadine, amantadine, bethanechol.

[Treatments of inguinal hernias by celioscopy. Preliminary results apropos of 162 cases]. / Cures de hernies de l'aine par coelioscopie. Résultats préliminaires à propos de 162 cas.

Mesch insertion is a reliable means for repairing inguinal hernias. Results in 162 patients treated laparoscopically via an intraperitoneal approach are reviewed herein. Analgesics were not required after the first postoperative day in 71% of patients. Fourteen patients were treated on a day-care basis. There were two recurrences due to inadequate fixation of the mesch to Cooper's ligament. The two patients who developed an infection did not require removal of the patch and had a strong, completely healed wall at the follow-up evaluation after four and ten months, respectively. The number of patients and duration of follow-up are still inadequate. However, these preliminary data warrant continued use and evaluation of this technique.

[Rectal stenosis. A rare complication of chronic salpingitis caused by an intrauterine device]. / La sténose rectale. Une complication rare des salpingites chroniques sur dispositifs intra-utérins.

The authors describe one case of rectal stenosis complicating chronic salpingitis in a patient carrying an intrauterine device. This observation is peculiar in that the inflammatory fibrous reaction is very intense, spreading all over the pelvis and forming a pseudotumoral mass sheathing the rectum. The clinical signs were mainly digestive, including a rectal syndrome: cramplike pelvic pain before defecation, tenesmus, constipation, abdominal pain and induration of the anterior aspect of the rectum observed during the clinical examination. Radiological examinations (barium enema, ultrasound, CT) show a tissue mass within the pelvis, with considerable thickening of the rectal wall. Ultrasound-guided biopsy in the pelvis yielded only nonspecific inflammatory signs with dominant fibrosis. The diagnosis of rectal stenosis caused by chronic salpingitis complicating the presence of an IUD was made only during surgery.

[A case of pulmonary distomiasis (author's transl)]. / Distomatose pulmonaire: une observation.

Pulmonary distomiasis due to Paragonimus westermani was discovered in a young 21-year-old patient from Thailand following several bouts of hemoptysis. The authors review the published literature and outline the principal characteristics of this affection, emphasizing the radiological appearances and the possible value of bronchial arteriography.