Fatal aspergillosis complicating severe SARS-CoV-2 infection: A case report.

As aspergillosis is a well-known complication of severe influenza, we suggest that SARS-CoV-2 might be a risk factor for invasive aspergillosis (IA). We report the case of an 87 year-old woman, with no history of immune deficit, admitted in our emergency room for severe respiratory distress. Coronavirus disease 2019 (COVID-19) diagnosis was confirmed by a SARS-CoV-2 reverse transcriptase polymerase chain reaction (PCR) on nasal swab. On day 14, pulmonary examination deteriorated with haemoptysis and a major increase of inflammatory response. A computed tomography (CT) scan revealed nodules highly suggestive of IA. Aspergillus antigen was found highly positive in sputum and blood, as was Aspergillusspp PCR on serum. Sputum cultures remained negative for Aspergillus. This patient died rapidly from severe respiratory failure, despite the addition of voriconazole. Considering SARS-CoV-2 acute respiratory distress syndrome (ARDS) as an acquired immunodeficiency, we report here a new case of "probable" IA based on clinical and biological arguments, in accordance with the last consensus definition of invasive fungal disease. On a routine basis, we have detected 30% of aspergillosis carriage (positive culture and antigen in tracheal secretions) in critically ill patients with COVID-19 in our centre. Further studies will have to determine whether sputum or tracheal secretions should be systematically screened for fungal investigations in intensive care unit (ICU) COVID-19 patients to early diagnose and treat aspergillosis.

COVID-19 and andrology: Recommendations of the French-speaking society of andrology (Société d'Andrologie de langue Française SALF).

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) metamorphosed our medical practice. In early June 2020, more than 6,400,000 COVID-19 (coronavirus-19 disease) cases were diagnosed across the world and more than 380,000 deaths were linked to COVID-19. Many medical symptoms of COVID-19 were reported. We will focus, here, on potential impacts of COVID-19 on men's andrological health. Our society (French-speaking society of andrology, SALF) also emitted some recommendations in the andrological management of men infected by SARS-CoV-2. First, considering the fever and the potential presence of SARS-CoV2 in semen, SALF recommends waiting for 3 months (duration of one spermatogenesis cycle and epididymal transit) before re-starting ART in the case of men diagnosed COVID-19 positive. Whatever the nature of testosterone and COVID-19 relationships, we recommend an andrological examination, sperm parameters, and hormonal evaluation at the time of the COVID-19 is diagnosed, and several months later. Furthermore, we are concerned by the potential morbid-mortality of the COVID-19, which mainly affects men. This "andrological bias", if proven, must be reduced by specific andrological diagnosis, therapeutic and prophylactic measures. Research in this direction must be substantiated and financially supported over the next few months (years).

Le SRAS-CoV-2 (nouveau coronavirus ou coronavirus numéro 2 responsable du syndrome respiratoire aigu sévère) a métamorphosé notre pratique médicale. Début juin 2020, plus de 6,400,000 cas de COVID-19 (maladie à coronavirus 2019) ont été diagnostiqués dans le monde et plus de 380,000 décès ont été reliés à cette maladie. De nombreux symptômes médicaux de cette infection virale ont été signalés. Nous nous concentrerons, ici, sur les impacts potentiels de COVID-19 sur la santé andrologique des hommes. Notre société (Société d'andrologie de langue Française, SALF) émet ici quelques recommandations dans la prise en charge andrologique des hommes infectés par le SRAS-CoV-2. Tout d'abord, compte tenu de la fièvre et de la présence potentielle du SRAS-CoV2 dans le sperme, la SALF recommande d'attendre 3 mois (durée d'un cycle de spermatogenèse et transit épididymaire) avant de recommencer les techniques d'assistance médicale à la procréation pour les hommes diagnostiqués COVID-19 positifs. Quelle que soit la nature des relations entre la testostérone et l'infection à SARS-CoV-2, nous recommandons un examen andrologique, un examen des paramètres du sperme et une évaluation hormonale au moment du diagnostic de l'infection, ainsi qu'à distance (3­6 mois plus tard). De plus, nous sommes préoccupés par la morbidité et la mortalité potentielles de l'infection COVID-19, qui touche principalement les hommes. Ce "biais andrologique", s'il est. prouvé, doit être réduit par un diagnostic andrologique spécifique et des mesures thérapeutiques et prophylactiques. La recherche dans ce sens doit être étayée et soutenue financièrement au cours des prochains mois (années).

[Reduction of multiple pregnancies in ART with large SET procedures over the period 2001-2010]. / Réduction des grossesses multiples en AMP par un usage large du SET (Single Embryo Transfer) sur la période 2001-2010.

OBJECTIVE: To evaluate delivery rate and multiple pregnancy rates in ART (assisted reproductive techniques) following introduction of an elective single embryo tranfer (eSET) policy. This strategy was started in 2002 including transfer of one embryo for women less than 35 years with a least two good quality embryo during their first or second attempts. PATIENTS AND METHODS: Retrospective study including all IVF cycles performed in the IVF centre of Clermont-Ferrand University Hospital from 01/01/2001 to 31/12/2010. Main outcome measures were number of embryos transferred, cumulative delivery and multiple pregnancy rates (including fresh and frozen embryo transfers). A subgroup analysis including patients' age was done. RESULTS: Cumulative delivery rate reached 27,3% in 2010 with a significant drop in multiple pregnancy rate: from 30% in 2001 to 7,9% in 2010. The average number of transferred embryo decreased from 2.29 to 1.55 in the same period. In our centre, eSET was performed in 85% of first IVF attempt and in 34,4% of second attempts for women less than 35 years. CONCLUSION: The implementation of an eSET policy does not change the delivery rate but significantly decrease the number of multiple pregnancies compared to double embryo transfer. eSET should be carried out during the 1st and 2nd attempts in patients under 35 years when at least two good quality embryos were obtained.

[Effects of mycophenolate mofetil in ischemic acute renal failure in rats]. / Efectos del micofenolato mofetil en la insuficiencia renal aguda isquémica en ratas.

Mycophenolate mofetil (MMF) is a purine synthesis inhibitor commonly used as immunosupresive agent in transplantation. Kidney grafts undergo more or less prolonged cold ischemia after harvesting which results in variable degrees of ischemia reperfusion injury. To determine whether the inhibition of early events of cellular infiltration may influence the severity of damage induced by ischemic acute renal failure, 45 Sprague Dawley rats were given MMF at a dose of 20mg/kg/day (MMF-rats) by gavage 2 days before (pre-MMF group, n=15) or after (post-MMF group, n=15) clamping the left renal artery for 40 minutes followed by rigt-sided nephrectomy. (control group, n=15) received vehicle. Serum Creatinine (Screat) was measured daily in all groups. On the 2nd post-ischemic day Screat was significantly lower (p=0.001) in pre-MMF group compared with post-MMF group and control group (4 +/- 2mg/dl post-MMF group vs 1.7 +/- 1.2 mg/dl pre-MMF group, control group 5+/-2, p< 0.05). Kidney biopsies shown that the histologic damage was 54 +/- 28% in post-MMF group vs 34+/- 22% in pre-MMF group and 61 +/- 25% in control group (pre-MMF vs post-MMF, p NS). On the 5th day post-ischemic, MMF-rats showed more severe tubulointerstitial necrosis (pre-MMF group: 17 +/- 20 %, post-MMF group: 33 +/- 27%) than controls (4 +/- 5%). The severity of ATN was significantly higher in post-MMF group compared with controls (p=0.01). Tubulointersticial T-lymphocyte (T CD 5) and monocyte (ED 1) infiltration evaluated on the 2nd post-ischemic day was less intense in group I (T CD5: 3 +/- 3, ED 1: 10 +/- 9, cel/mm2) compared to post-MMF group (T CD 5: 10 +/- 4, ED 1: 55 +/- 40) and to control group (T CD 5: 10+/- 4, ED 1: 64 +/- 46). However, on the 5th post-ischemia day, ED 1 infiltration was significantly higher in post-MMF group (24 +/- 18%) compared to pre-MMF group (5 +/- 5, p NS) and also in pre-MMF group vs control group (31 +/- 33, p< 0.05). Our results suggest that MMF given before a renal ischemic insult may reduce the severity of histologic damage resulting from ischemia reperfusion injury.

Substance P and calcitonin gene-related peptide increase IL-1 beta, IL-6 and TNF alpha secretion from human peripheral blood mononuclear cells.

We found that substance P (SP) and calcitonin gene-related peptide (CGRP) (0.3-1 microM) increased, in a concentration-dependent manner, the basal secretion of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF alpha) from cultured lymphocyte-enriched mononuclear cells isolated from human peripheral blood. SP and CGRP (0.1 microM) synergistically increased basal TNF alpha secretion. Dynorphin A((1-17)) (0.1-1 microM) did not modify basal cytokine secretion. Lipopolysaccharide (10 ng/ml)-induced cytokine secretion and [(3)H]thymidine uptake were not altered by any neuropeptide (at 0.1 microM). Thus, SP and CGRP stimulate the production of pro-inflammatory cytokines from lymphocytes only at high concentrations, similar to those reached during tissue damage.

Melatonin treatment enhances the efficiency of mice immunization with Venezuelan equine encephalomyelitis virus TC-83.

To determine whether treatment with melatonin (MLT) improves the efficiency of immunization against Venezuelan equine encephalomyelitis (VEE) virus, mice were vaccinated with TC-83 VEE virus and treated daily with MLT (1 or 5 mg/kg) starting 3 days before immunization, until 10 days after. IgM antibody titers were determined at days 7, 14, and 21 post-immunization. IL-10 levels were assayed at day 14 postvaccination. Treatment with MLT increased antibody titers 14 days after the immunization. IL-10 levels also increased with MLT treatment (1 and 5 mg/kg). Mice were challenged with live VEE virus at day 21 postimmunization, and viral titers were plaque assayed in chicken embryo fibroblasts 4 days after the infection. Following this challenge brain virus levels were significantly reduced. The results suggest that MLT treatment enhances the efficiency of mice immunization against VEE virus.

Mycophenolate mofetil prevents salt-sensitive hypertension resulting from angiotensin II exposure.

BACKGROUND: Interstitial mononuclear cell infiltration is a feature of experimental models of salt-sensitive hypertension (SSHTN). Since several products of these cells are capable of modifying local vascular reactivity and sodium reabsorption, we investigated whether mycophenolate mofetil (MMF), a drug known to inhibit infiltration and proliferation of immune cells, would modify the SSHTN induced by angiotensin II (Ang II) infusion. METHODS: Sprague-Dawley rats received Ang II for two weeks using subcutaneous minipumps. A high-sodium (4% NaCl) diet was started on the third week and was maintained until the eighth week. MMF (30 mg/kg, N = 15), an immunosuppressive drug, or vehicle (N = 15) was given daily by gastric gavage during the initial three weeks. Sham-operated rats (N = 9) were used as controls. Body weight, blood pressure (tail-cuff plethysmography), and serum creatinine were determined weekly. Urinary malondialdehyde (MDA) excretion, renal histology, and immunohistology, including the presence of Ang II and superoxide-producing cells, were analyzed at the end of Ang II infusion and at eight weeks. RESULTS: MMF treatment did not modify hypertension induced during exogenous Ang II infusion, but prevented the subsequent SSHTN. Tubulointerstitial injury resulting from Ang II infusion was significantly reduced by MMF treatment, as were proliferative activity, T-cell infiltration and activation (interleukin-2 receptor expression), superoxide-producing cells, and urinary MDA excretion. Ang II-producing cells were present in the renal tubulointerstitium of rats with SSHTN (60 +/- 30 Ang II-positive cells/mm(2) at 8 weeks) and were reduced by two thirds in the MMF-treated group. Forty percent of lymphocytes infiltrating the tubulointerstitium stained positive for Ang II. The expression of Ang II receptors in the kidney was unmodified. CONCLUSIONS: SSHTN resulting from Ang II infusion is associated with infiltration and activation of immune cells that produce Ang II. MMF treatment reduces these features and prevents the development of SSHTN.

Mycophenolate mofetil prevents salt-sensitive hypertension resulting from nitric oxide synthesis inhibition.

Recent studies have suggested that subtle microvascular and tubulointerstitial injury in the kidney can cause salt-sensitive hypertension. To test this hypothesis, we determined whether the mild renal disease induced by transient blockade of nitric oxide (NO) synthesis would result in salt-sensitive hypertension and whether prevention of the renal injury by coadministration of the immunosuppressive agent mycophenolate mofetil (MMF) would block the development of salt sensitivity. N(omega)-nitro-L-arginine-methyl ester (L-NAME; 70 mg/100 ml in the drinking water) was administered for 3 wk to rats with or without MMF (30 mg x kg(-1) x day(-1) by gastric gavage), followed by a 1-wk "washout" period in which the MMF was continued, which was followed in turn by placement on a high-salt (4% NaCl) diet for an additional 4 wk. Renal histology was examined at 3 and 8 wk, and blood pressure was measured serially. L-NAME treatment resulted in acute hypertension and the development of mild renal injury. During the washout period, blood pressure returned to normal, only to return to the hypertensive range on exposure of the animals to a high-salt diet. MMF treatment prevented the development of hypertension in response to a high-salt diet. This correlated with the ability of MMF to inhibit specific aspects of the renal injury, including the development of segmental glomerulosclerosis, the infiltration of T cells and ANG II-positive cells, and the thickening of afferent arterioles.

Melatonin prolongs survival of immunodepressed mice infected with the Venezuelan equine encephalomyelitis virus.

Male albino mice immunodepressed after the injection of dexamethasone (DEX) were inoculated intraperitoneally with the Guajira strain of Venezuelan equine encephalomyelitis (VEE) virus. Melatonin (MLT) was administered daily, at a dose of 500 micrograms/kg bodyweight, for 3 days before virus inoculation and 10 days after. Serum levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) were determined in all the experimental groups (control, DEX, DEX + MLT, DEX + VEE, DEX + VEE + MLT, VEE and MLT). At day 6 after the virus inoculation, the survival rate was significantly increased from 0% in group DEX + VEE to 32.5% in the group of immunodepressed infected mice treated with MLT (DEX + VEE + MLT). By day 10 a survival rate of 10% was found in group DEX + VEE + MLT and 0% in group VEE. No alterations in IL-2 serum levels were observed. MLT increased GM-CSF in control and in DEX-treated mice. In the VEE virus-infected mice treated with DEX, serum levels of GM-CSF increased progressively from day 1 to 5 postinoculation. In contrast, the levels of GM-CSF in infected immunodepressed mice treated with MLT decreased significantly from day 1 to 5 postinoculation. At day 5 after viral inoculation, no differences were detected in the cerebral viral titres in groups VEE, DEX + VEE and DEX + MLT + VEE. These results show that MLT does not inhibit VEE viral replication in the brain of immunodepressed mice.

Role of immunocompetent cells in nonimmune renal diseases.

Renal infiltration with macrophages and monocytes is a well-recognized feature of not only immune, but also nonimmune kidney disease. This review focuses on the investigations that have shown accumulation of immunocompetent cells in experimental models of acute and chronic ischemia, protein overload, hypercholesterolemia, renal ablation, obstructive uropathy, polycystic kidney disease, diabetes, aging, murine hypertension, and nephrotoxicity. We examine the mechanisms of infiltration of immunocompetent cells and their participation in the self-perpetuating cycle of activation of the angiotensin system, generation of reactive oxygen species, and further recruitment of monocytes and lymphocytes. We also discuss the possibility of antigen-dependent and antigen-independent mechanisms of immune cell activation in these animal models. Finally, we review the recent studies in which suppression of cellular immunity with mycophenolate mofetil has proven beneficial in attenuating or preventing the progression of renal functional and histologic damage in experimental conditions of nonimmune nature.

Mycophenolate mofetil treatment reduces cholesterol-induced atherosclerosis in the rabbit.

Immunosuppressive therapy has been shown to either improve or, more frequently, enhance the development of atherosclerosis. We tested the effect of mycophenolate mofetil (MMF), an inhibitor of nucleotide synthesis widely used in transplant therapy, in diet-induced atherosclerosis in the rabbit. Two groups (n=10 each) of New Zealand White (NZW) rabbits were fed a 1% cholesterol diet for 12 weeks. One group received MMF (CHOL+MMF group) by gastric gavage (30 mg/kg daily) and the other group (CHOL) received the same volume of saline by the same route. There were no differences in the serum cholesterol (mean values > or =30 mmol/l in both groups after 2 weeks) or in the triglyceride, blood sugar, total protein, and albumin serum levels and weight gain in both groups of animals. The cholesterol-fed untreated rabbits had atherosclerotic plaques covering 43.9.1+/-SD 16.40% of their thoracic aorta and 41.9+/-22. 59% of their abdominal aorta, while the MMF treated group had 18. 5+/-7.17% and 17.7+/-9.71%, respectively (P<0.01). The cholesterol content of the aorta (mg/g) in the cholesterol-fed untreated group was 4.61+/-SD 1.21 in the thoracic aorta and 4.54+/-2.07 in the abdominal aorta, whereas the MMF treated group had and 2.83+/-0.84 and 2.77+/-1.44, respectively (P<0.01). Infiltrating macrophages (RAM 11 positive cells/100 nuclei) in the intimal layer of the aorta were 58.4+/-SD26.16 in the CHOL group and 8.5+/-5.51 in the CHOL+MMF group: (P<0.001). CD18 positive cells/100 nuclei were 27.4+/-17.6 in the CHOL group and 5.3+/-3.82 in the CHOL+MMF group (P<0.01), and the intima/media ratio was 0.66+/-0.11 in the CHOL group and 0. 30+/-0.09 in the MMF treated rabbits (P<0.001). MMF also reduced proliferating smooth muscle cells (HHF35 positive) infiltrating between the macrophages. These results indicate that MMF ameliorates importantly the atherogenic potential of a high cholesterol diet and this effect is associated with a reduction in macrophage and foam cell infiltration and smooth muscle cell proliferation and infiltration. Since chronic treatment with this drug is given routinely in various clinical conditions with relatively minor side effects, consideration may be given to its use as adjuvant therapy in atherosclerotic cardiovascular disease.

Melatonin protects mice infected with Venezuelan equine encephalomyelitis virus.

We investigated whether the administration of melatonin (MLT) reduces the death rate and evolution of the disease in mice infected with Venezuelan equine encephalomyelitis (VEE) virus. Our results show that, MLT protects mice infected with the virus. The mortality rate was reduced from 100% to 16% merely by increasing the dose from 0 to 1000 micrograms/MLT per kg body weight MLT significantly postponed the onset of the disease and death by several days. In surviving mice very high titres of VEE virus IgM antibodies were found seven weeks after virus inoculation. MLT significantly reduced VEE virus levels in blood and brain of infected mice and increased the survival rate when the length of pretreatment was augmented from 3 to 7 or 10 days before virus inoculation. Serum levels of interleukin-2 were not affected by MLT administration. In control mice receiving MLT as well as in infected mice treated or non-treated with MLT, interferon gamma levels in sera were increased. Interleukin-4 concentrations were found to be elevated in sera of non-infected mice receiving MLT, but did not differ from controls in infected mice treated or non-treated with the hormone. MLT reduced the degree of cell destruction produced by VEE virus in culture plates of chicken embryo fibroblasts. The protective effect of MLT warrants further investigation of the possibility of using this hormone for the treatment of humans and equines infected with VEE virus.

The epidemiological information system of the French national electricity and gas company: the SI-EPI project.

SI-EPI is epidemiological information system set up in 1978 in the national electricity and gas company, Electricité de France-Gaz de France (EDF-GDF). The worker population comprises about 150,000 individuals, involved in production, transmission and distribution of energy. SI-EPI was developed by the epidemiologists of the Occupational Health Department (180 physicians), and of the Sécurité Sociale Department (120 physicians). Several data bases constitute SI-EPI. The population data base contains demographic, socioeconomic and professional data about each worker. The health data base is an exhaustive register of sick leave, accidents, permanent disabilities, compensated diseases, causes of death and cancer incidence among active workers. The Occupational Exposure and Working Conditions data base includes the MATEX job-exposure matrix (30 potentially carcinogenic agents) and FINDEX files which record data obtained from the systematic individual surveillance of workers. The GAZEL cohort data base concerns a sample of more than 20,000 volunteer workers, followed since 1989; in addition to data from the data bases, it contains information collected from other different sources, including self-questionnaires. Numerous epidemiological studies based on SI-EPI data have been conducted by in-house epidemiologists as well as by external research groups. They include mortality and morbidity studies and address various topics and health problems. Their results are used for internal information, as well as for epidemiological research purposes.

[Role of the practitioner after accidents related to ionizing radiation]. / Rôle du médecin après un accident lié aux rayonnements ionisants.

Accidents due to ionizing radiations can be nuclear accidents, concerning a large part of the population, or radiological accidents which may, at higher doses, irradiate a limited number of persons. In case of nuclear accident, radioactive rejections lead to an irradiation and/or a contamination, and induce the "préfet" to take public health measures. According to the dose possibly received by the population, measures can be the continuation of normal life, confinement, distribution of stable iodine, restriction of certain food consummation, evacuation being the ultimate measure. General practitioner will be an important actor in the information of the populations. When a radiological accident occurs, the management will depend on the type of accident and the dose emitted. This treatment of medico-surgical emergency is an absolute priority, if traumatic lesions are associated, on nuclear risk, especially when prognosis for life is involved. Lesions associated to radiolesions worsen the prognosis.

[Molecular diagnosis of Duchenne/Becker muscular dystrophy in Venezuelan patients with the polymerase chain reaction]. / Diagnóstico molecular en pacientes venezolanos con distrofia muscular de Duchenne/Becker mediante la reacción en cadena de la polimerasa.

Duchenne and Becker muscular dystrophy (DMD/BMD) are recessive X-linked neuromuscular diseases produced by allelic mutations in the human dystrophin gen. In the present study we determined the 14-deletion prone exons by multiplex PCR in 24 no related venezuelan patients with clinical diagnosis of DMD/BMD. We found 37% of intragenic deletions of which 77% were located at the "hot spot" deletion region that includes exons 44 to 55. The present study show that deletion frequency observed in venezuelan patients resembles some Asian populations and is lower than that observed in Europe and North America. The explanation of the low frequency detected in our patients is beyond the present study, but it is likely that different mutations, ocurring at other regions of the gene is determining a molecular heterogeneity of the DMD/BMD disease in Venezuela.

A modified colorimetric method for the measurement of phagocytosis and antibody-dependent cell cytotoxicity using 2,7-diaminofluorene.

A sensitive and rapid colorimetric method for the in vitro determination of phagocytic activity and antibody-dependent cell-mediated cytotoxicity (ADCC) is described. The assay uses red blood cells (RBC) as target cells and relies on the specific oxidation of 2,7-diaminofluorene (DAF) by the pseudoperoxidase activity of hemoglobin (Hb). Generation of fluorene blue (FB), the chromophore formed upon oxidation of DAF, was a linear function of erythrocyte concentration. The oxidation of DAF by peritoneal macrophages (M phi) containing myeloperoxidase was negligible, confirming that the development of color was exclusively due to the pseudoperoxidase activity of Hb. A positive correlation was observed between FB formation and increased phagocytosis of opsonized erythrocytes. Phagocytosis increased as a function of time, reaching a maximum at 90 min of incubation. The phagocytosis of IgG-opsonized erythrocytes was greater than non-opsonized erythrocytes and was inhibited by high concentrations of non-specific human or mouse IgG, showing that phagocytosis was mediated by the Fc gamma receptor of macrophages. The interaction between opsonized RBC and macrophages also evoked an antibody-dependent extracellular lysis, however this process was slower than ingestion. The DAF phagocytosis assay has shown to be very sensitive, simple, rapid and safe.

Interaction of iron polymers with blood mononuclear cells and its detection with the Prussian Blue reaction.

An inhibitory effect of iron salts on various immune functions in vitro has been reported in several laboratories during the last few years. This study confirms and extends those observations by showing that iron citrate inhibits the mitogen-induced (PHA, Con A and PWM) lymphocyte proliferation. Such inhibition is observed in the presence of ferric citrate with a metal-to-ligand molar ratio of 1:1 but not with ferric citrate with metal-to-ligand molar ratio 1:20 in which the formation of polynuclear iron complexes is prevented. Increasing the concentration of serum in the culture medium diminished the inhibitory effect of 1:1 ferric citrate. Using the Prussian Blue reaction the presence of ferric iron was observed on the cell surface. It is proposed that the deposition of polynuclear iron complexes on the lymphocytes membrane is one of the possible factors determining the iron inhibitory effect.