Fungal adaptation to contemporary fungicide applications: the case of Botrytis cinerea populations from Champagne vineyards (France).

In addition to being one of the most acute problems impeding chemical control of fungal diseases, the evolution of fungicide resistance is an emblematic case of local adaptation to spatially heterogeneous and temporally variable selection pressures. Here we dissected the adaptation of Botrytis cinerea (the causal agent of grey mould) populations on grapes to several fungicides. We carried out a 2-year survey (four collection dates) on three treated/untreated pairs of plots from vineyards in Champagne (France) and monitored the frequency of four resistant phenotypes that are unambiguously associated with four distinct genotypes. For two loci under selection by currently used fungicides (MDR1 and MDR2), the frequencies of resistant mutations at vintage were greater in treated plots compared to untreated plots, showing that the effect of selection is detectable even at the plot scale. This effect was not detectable for two other loci under selection by previously used fungicides (BenR1 and ImiR1). We also found that treatment with currently used fungicides reduced B. cinerea effective population size, leading to a significant decrease in genic diversity and allelic richness in treated vs. untreated plots. We further highlight that even under ample drift and migration, fungal populations can present an efficient response to selection. Finally, for the four studied loci, the costs of fungicide resistance were estimated by modelling the decrease in the frequency of resistant mutations in the absence of treatment. We discuss the importance of these estimates for defining strategies for limiting or counteracting the local adaptation of pests to fungicides.

T-2 toxin inhibits the differentiation of human monocytes into dendritic cells and macrophages.

The aim of this work was to study the in vitro effect of T-2 toxin on human monocyte differentiation into macrophages and dendritic cells. Cytotoxicity of T-2 toxin on monocytes, on monocytes in differentiation process into macrophages or dendritic cells, and on immature dendritic cells and macrophages was evaluated to determine IC50. Monocytes are more sensitive to T-2 toxin than to differentiate cells. IC50 were equal to 0.11 nM for monocyte, to 45 and 30 nM for monocyte during differentiation process for 24 and 48 h of incubation, respectively, to 38 and 20 nM for immature dendritic cells after 24 and 48 h of incubation, and to 22 and 20 nM for macrophages after 24 and 48 h of incubation. T-2 toxin effects on monocyte differentiation process into macrophages have been explored: according to phenotypic expressions (CD71, CD14, CD11a, CD80, CD86, HLA-DR and CD64), endocytic capacity, phagocytosis, burst respiratory activity and TNF-alpha secretion. In the presence of 10 nM of T-2 toxin (no cytotoxic concentration), CD71 expression is downregulated compared to control. Endocytosis and phagocytosis capacities are less effective as burst respiratory activity and TNF-alpha secretion. Monocyte differentiation process into dendritic cells in the presence of 10 nM T-2 toxin is also markedly disturbed. Expression of CD1a (specific dendritic cells marker) is downregulated while that of CD14 (specific monocyte marker) is upregulated. CD11a, CD80, CD86, HLA-DR and CD64 expressions did not change. These results show that T-2 toxin disturbs human monocytes differentiation process into macrophages and dendritic cells. These results could significantly contribute to immunosuppressive properties of this alimentary toxin.

Non-conform diagnostic management of pulmonary embolism suspected patients is responsible for a higher risk of thrombotic event occurrence.

The aim of this 3-month follow-up prospective pragmatic study was to evaluate the implementation of a pulmonary embolism (PE) diagnostic strategy in clinical practice. One thousand and one hundred thirty-four consecutive in- and outpatients with clinically suspected PE were enrolled into a sequential diagnostic algorithm in which vascular medical unit plays a pivotal role in advising physicians and suggesting the most appropriate tests according to the diagnostic algorithm. In this observational study, patients that followed the proposed work-up were attributed to a so-called "conform group". Patients in whom diagnostic work-up was not according to protocol were attributed to a "non-conform group". Nine hundred and ninety-seven patients (87.9%) had a conform work-up, and 137 patients a non-conform work-up according to the proposed diagnostic algorithm. The non-conform work-up directly increased in relation to the age of the referred patients. PE was ruled out in 907 (80%) patients of whom 787 (86.8%) were in the conform group. Of the 797 patients who did not receive anticoagulant drugs, follow-up was obtained in 792 (99.4%). Among these patients, the incidence of acute thromboembolic events during the 3-month follow-up period was different in the group of patients that had a conform work-up (1%, [95% CI, 0.5-2.1%]) from the non-conform group patients (4.5%, [95% CI, 2-10.2%]. Therefore patients from the non-conform group have an independent increased risk to develop a thromboembolic event during the follow-up, adjusted odds ratio 3.3 [1.1-10, 95% CI]. Therefore we demonstrated that a non-conform diagnostic management strategy is associated with a higher risk of thrombotic event occurrence.

Performance of the Now Malaria rapid diagnostic test with returned travellers: a 2-year retrospective study in a French teaching hospital.

Malaria caused by Plasmodium falciparum remains the major life-threatening parasitic infection in the world. The number of cases in non-endemic countries continues to increase, and it is important that misdiagnosis of malaria should not occur, especially in non-immune travellers, because of the high risk of a fatal outcome. In a retrospective study of 399 sera, the Now Malaria rapid test was compared with the quantitative buffy coat (QBC) test and microbiological examination of thin blood films. Compared with the QBC test and thin blood films, the Now Malaria test had sensitivity and specificity values of 96.4% and 97%, respectively, for the detection of pure P. falciparum infection. A negative predictive value of 99.4% allows this test to be included in diagnostic strategies for patients presenting with clinical suspicion of malaria. Two false-negative results were associated with low levels of parasitaemia in the specimens. Thus, use of the Now Malaria test alone to detect P. falciparum infection in non-endemic countries could lead to misdiagnosis of malaria. This rapid diagnostic test should therefore be performed in association with another prompt traditional method such as examination of thin blood films.

[Adverse drug effects: a prospective study by Apnet performed in seven emergency care units in France: propositions for preventive measures]. / Accidents médicamenteux. (A propos d'une étude prospective de l'Apnet réalisée dans sept services d'accueil et d'urgences français). Propositions pour des mesures préventives.

Various studies have shown that adverse drug effects (ADEs) are a substantial cause of hospital admissions. However, little is known about the incidence and severity of ADEs resulting in hospital visits. To address this issue, we conducted a prospective survey in primary care and emergency departments of French public hospitals. This study was performed over two periods of one week, one in January, February and one in June 2003, in primary care and emergengy departments of four university hospitals and three general hospitals throughout France. Out of a total of 1826 patients consulting, 1663 were taking at least one drug during the previous week and were included for analysis according to the protocol. Altogether, 370 (22.2%; IC 95: 20.2-24.3%) of these patients receiving at least one drug consulted because of an ADE. From these 370 patients, 263 (15.8%) where considered as touched by a probably (12), likely (13) or very likely (14) ADE. The sex ratio was the same in both groups with or without ADE (0.88%; P=0.95). Patients with ADE were older than those without (62.4 vs 53.8 years, P=0.0016). Furthermore, ADE patients were more likely to have a higher severity score than no-ADE group (P=0.0003). The outcome seemed to be worse in patients with an ADE. The percentage of patients treated with 2 or more drugs and the number of drug exposures were significantly higher in patients with ADE than in those without (93.2% vs 84.2%, P<0.0001, and 5.8 vs 4.5 P<0.0001, respectively). The most frequent causes of visits for ADE-patients were digestive (n=38: 14.4%), neurological (n=23: 10.6%), malaise (n=48: 18,2%) events. The most frequently incriminated drug classes were (1) psychotropic agents, (including anxiolytics, hypnotics, antidepressants and antipsychotics), (2) diuretics (3) anticoagulants, (4) other cardiovascular drugs and (5) analgesics, including non steroidal anti-inflammatory agents. In 150 cases (40.8%; IC 95: 33.7% - 45%), the ADE was considered to be preventable because a contra-indication or a warning about drug use had not been respected.

Treatment of mycoses in cancer patients.

Invasive fungal infections are becoming increasingly frequent among immunocompromised patients and especially among cancer patients. The most common pathogens identified are Candida species, Aspergillus species, Cryptococcus neoformans, and Mucor species. Amphotericin B remains the mainstay of antifungal therapy. However, the toxicity of this drug may limit its use and, in addition, both failures and relapses have been reported. 5-Fluorocytosine and imidazoles, such as miconazole and ketoconazole, have been shown to be active, mainly on yeast organisms. The emergence of 5-fluorocytosine-resistant strains warrants caution for its administration as a single agent. The specific role of ketoconazole has not yet been established in large studies. In our experience, ketoconazole seems to be effective in the treatment of severe oral candidiasis in non-neutropenic cancer patients. Moreover, ketoconazole administered prophylactically to neutropenic patients decreases the number of positive surveillance cultures in these patients. The rare incidence of major toxicity and the ability to administer ketoconazole orally represent also major arguments for further investigation of ketoconazole activity by prospective controlled studies.

Symposium on infectious complications of neoplastic disease (Part II). Chemoprophylaxis of fungal infections.

As invasive fungal infection remains a common problem in the management of cancer patients, chemoprophylaxis of these opportunistic infections is desperately needed. The most frequently investigated antifungal agents have been nystatin, amphotericin B, and ketoconazole. In placebo-controlled studies, high doses of antifungal agents decreased the positive results from surveillance cultures, and there is some suggestion that such chemoprophylaxis may reduce the incidence of invasive candidiasis in neutropenic cancer patients. However, no oral chemoprophylaxis has effectively prevented aspergillosis or mucormycoses in these patients. There are still many areas of controversy, and the most adequate regimens, if any, remain to be defined.

Fungemia in the immunocompromised host. Changing patterns, antigenemia, high mortality.

Fungemias were reviewed in 110 immunocompromised patients hospitalized between November 1, 1974, and December 31, 1977, a Memorial Sloan-Kettering Cancer Center (MSKCC). The incidence of Candida tropicalis fungemia increased each year. Seventy-six percent of the patients with C. tropicalis fungemia and 32.5 percent of those with C. albicans fungemia had either leukemia or lymphoma. Seventy-seven percent of the C. parapsilosis fungemias were related to total parenteral nutrition. Thirty-seven percent of the patients with C. albicans fungemia were receiving oral prophylactic nystatin therapy. The source of fungemia was often difficult to determine: in 60 percent of the patients, only blood cultures were positive for C. tropicalis or Torulopsis glabrata; no cultures were positive for the fungus from any other site before the episode occurred. Serologic tests, including a highly sensitive passive hemagglutination test, showed fourfold increases in titer only inconsistently. A passive hemagglutination-inhibition test for circulating antigen was positive in 50.9 percent of 57 patients with fungemia who were tested and may be a valid indication for treatment. Fungemia usually represented a severe and often fatal disease. The over-all mortality of the 110 patients with fungemia was 79 percent whereas only 23 percent of the patients with C. parapsilosis fungemia died. Among the patients who received more than 200 mg of amphotericin B, 71 percent died despite treatment.

Endotracheal antibiotics for the prevention of tracheobronchial infections in tracheotomized unconscious patients. A comparative study of gentamicin and aminosidin-polymyxin B combination.

Endotracheal administration of gentamicin has been compared to the endotracheal administration of aminosidin plus polymyxin B as a preventive measure against tracheobronchial infections in 25 and 22 tracheotomized patients respectively who had been admitted to a neurosurgical unit. Both series were comparable as far as underlying disease, duration of hospitalization, surgical therapy. Both regimens were similarly effective from the bacteriologic and clinical points of view. Both regimens were similarly effective in preventing colonization of bronchial secretions by potential pathogens and were associated with a similar frequency of infectious episodes (eight in each group). The use of aminosidin-polymyxin B combination was associated with a lower incidence of emergence of gentamicin resistant strains, but the endotracheal administration of gentamicin was better tolerated than that of the combination. It is concluded that the combination of aminosidin-polymyxin is a useful alternative to gentamicin for the prevention of bronchopulmonary infections in unconscious tracheotomized patients.

Effect of parenteral nutrition on muscle amino acid output and 3-methylhistidine excretion in septic patients.

The effects of adequate total parenteral nutrition (TPN) on nitrogen excretion, urea N percentage, 3-methylhistidine excretion, and leg amino acid output, were studied during the ten-day period following abdominal surgery for generalized peritonitis in nine patients. The first two postoperative days were without nutritional intake, TPN was started on the third postoperative day (57 cal/KgBW--40% as Intralipid--0.30 g of N/KgBW). Leg amino acid outputs were done before TPN (DO), then two days (D2) and eight days (D8) after TPN. Total nitrogen and urea N percentage did not significantly differ before and after TPN. Between DO and D2 there was a significant reduction of urinary 3-methylhistidine (467 +/- 37 to 280 +/- 29 mumol/24 h-P less than 0.001) and leg amino acid release (604 +/- 103 to 254 +/- 87 nmol/mn/100 g of calf muscle--P less than 0.01) reflecting reduction in muscle hypercatabolism despite the persistence of the septic state. Between D2 and D8, 3-methylhistidine remained stable while leg amino acid release continued to decrease (254 +/- 87 to 68 +/- 40 nmol/mn/100 g--P less than 0.05). This association suggests an increased muscle protein synthesis. A closer examination of the clinical evolution of these patients, especially concerning their septic evolution, shows that only improved patients with recovery from sepsis increased their muscle protein synthesis. Thus, in septic hypercatabolic patients TPN seems to be able to reduce muscle catabolism while the increase in protein synthesis is mainly the consequence of recovery from the septic state. In such patients TPN should be used as a preventive therapeutic measure.

Comparative study of three routes of administration of sisomicin.

A comparative study was performed using three routes of administration of sisomicin (1 mg/kg as single dose): intramuscular injection, intravenous rapid injection, and 1-hour infusion. Intravenous administration resulted in higher blood levels immediately after the injections than by the intramuscular route; however, later, the intramuscular injection resulted in optimal blood levels. High levels of sisomicin which were bactericidal for most Gram-negative bacilli were found in the urine of the treated patients. The antimicrobial activity of the serum obtained 1 hour after administration of sisomicin, as determined against 20 strains of Gram-negative microorganisms isolated from blood cultures, was identical with all three routes of administration of sisomicin.

Comparative trial of single-dose versus twice-daily sisomicin in bacteriuric patients.

Sisomicin was administered as a single daily intramuscular injection (160 mg) or as two daily injections (80 mg) to 50 patients with bacteriuria superimposed on chronic urologic diseases in a randomized controlled fashion. The administration of two daily doses was significantly more effective (P less than 0.01) in achieving cure than the injection of a single daily dose. The renal function, as expressed by creatinine clearance, became impaired significantly more often (P less than 0.05) in the patients receiving the single daily dose of sisomicin.

Significance of antimicrobial synergism for the outcome of gram negative sepsis.

Amikacin plus penicillin (A+P) was compared to amikacin plus carbenicillin (A+C) in a double-blind study. Therapy with one of these combinations was given, as soon as servere infection was suspected, to 117 patients with proved gram negative infection, none of whom was granulocytopenic. Gram negative bacteremia was documented retrospectively in 52 patients; 25 had received A+P and 27 had been treated with A+C. All the isolated gram negative pathogens were sensitive to amikacin (MIC less than 12 microng/ml). In the A+P group, 55 per cent of the patients responded favorably while in the A+C group 63 per cent did respond; the difference was more striking for bacteremic patients: 52 per cent responded in the A+P group and 70 per cent in the A+C group. This difference, however, was not statistically significant. The outcome of patients whose infection was treated by synergistic combinations against the offending pathogen was better (66 per cent) than that observed in patients who received nonsynergistic combinations (48 per cent) (p less than 0.05). Once again the results were more striking in the bacteremic patients (p less than 0.01). A favorable outcome was associated also with a high (larger than or equal to 1/8) bactericidal activity of the diluted serum of the treated patient against the offending pathogen (p less than 0.05). This study suggests that the optimal therapy in gram negative septicemia might be the administration of synergistic combinations of antibiotics.

[Short emergency hospitalization]. / L'hospitalisation de courte durée à l'urgence.

In France, the number of admissions to emergency departments increase by 5 to 10 per cent per year. Traditionally, patients who require services beyond the first hours in the emergency department have been admitted to the acute care hospital. Observation unit are becoming common in hospitals because they allow an additional option to admission or discharge. In France, 60 per cent of emergency departments have observation units. Five to ten per cent of patients seen in an emergency department are transferred to the observation unit. These observation units are staffed with emergency personnel specifically assigned to the function of the unit. The average period of observation is less than 48 h. Of the patients observed, 50 per cent are discharged after extended observation and treatment. These observation units can be a safe, effective and cost-saving way of ensuring that patients who are considered to be in an intermediate category receive appropriate care.

[Implication of emergency departments in the regulation of public hospitalizations]. / Place des services d'urgences dans la régulation des hospitalisations publiques.

PURPOSE: Emergency departments become a useful way to access to hospital care. Since these last years difficulties of hospitalization, mainly of the elderly, after visit to the emergency department, are on the increase. CURRENT KNOWLEDGE AND KEY POINTS: Emergency departments are an important mode of recruitment for hospital units, 4 patients to 10 are hospitalized from emergency departments. The difficulties of hospitalization starting at the emergency department are more important for the elderly. Actually, there are 2 type of hospital care, planed and non planed care. The development of observation units specific to the emergency departments allowed to resolve some of these difficulties. But they are limited by their small number of beds and the duration of hospitalization below to 36 h. Some hospitals developed polyvalent emergency short stay unit to hospitalize patients who visited emergency department without necessity to give them a specialized care. FUTURE PROSPECTS AND PROJECTS: This situation must allow us to purpose a better regulation of hospitalizations which includes emergency departments in a network system including the different hospital ways of taking care. A downstream way of care adapted to the emergency hospitalizations would be developed. This could include the emergency department, the observation unit and the emergency short stay unit in interface with internal medicine and general medicine units, geriatric unit and specialized units, all of them will be included in a town-hospital care network.

[Symptomatic bladder or ureteral endometriosis: report of 8 cases and review of the literature]. / Endométriose vésicale ou urétérale, symptomatique: à propos de 8 cas et revue de la littérature.

OBJECTIVES: The aim of this study was to determine the symptoms of bladder and ureteral endometriosis and to review the treatment approaches. MATERIALS AND METHODS: We conducted a retrospective studyover the period November 1989-July 2000. We reviewed the medical data of all women with bladder or utereral endometriosis who underwent a major surgery (ureteral reimplementation on psoas bladder, partial resection of the ureter, partial cystectomy). RESULTS: Eight women met the defined selection criterion, three with bladder injuryand five with ureteral injury. The only adverse postoperative complication was a passive ureteral reflux following ureteral reimplementation on psoas bladder. No recurrence on the urinary tract were reported. CONCLUSION: Surgical treatment is indicated for patient suffering from symptomatic bladder or ureteral endometriosis. Isolated bladder injuries due to endometriosis are mostly treated by laparoscopic surgery. Ureteral endometriosis may deteriorate the renal function. The initial step of the treatment may include an uterolysis by coelioscopy or an ureteral dilatation by ureteroscopy together with a medical treatment. The renal function must be closely monitored. In case of persistent or recurrent endometriosis, an ureteral resection would be justified.

[MR cholangiopancreatography]. / Cholangio-wirsungographie par IRM.

MR cholangiopancreatography (MRCP) is a new technique allowing noninvasive investigation of the bile ducts and pancreatic duct. Due to the extremely intense signal of water on T2-weighting, MR sequences can be obtained only demonstrating liquids. The bile and pancreatic ducts can therefore be studied spontaneously even in the case of major cholestasis. The contraindications of MR cholangiography are exclusively those of MR. MRCP can visualize the level of a bile duct obstruction and often the nature of this obstruction (stone, tumour). Complementary axial T1- and T2-weighted sequences can also visualize the parenchyma around the ducts. MR cholangiography therefore appears to be a technique of the future for noninvasive investigation of the bile ducts.

[Digestive complications of oral contraceptives: a case of extensive digestive necrosis in a young woman]. / Les accidents digestifs des contraceptifs oraux: un cas de nécrose digestive étendue chez une femme jeune.

PIP: A case of acute intestinal vascular necrosis in a 19-year-old user of oral contraceptives (OCs) is described, and hypotheses explaining the digestive complications of synthetic estrogens are reviewed. The patient had originally presented with a violent gastric pain that subsequently spread to the entire abdomen. An abrupt worsening of her condition involved cardiovascular collapse associated with a peritoneal syndrome, vomiting and dehydration, and hyperleukocytosis. Emergency opening of the peritoneum was followed by evacuation of a large quantity of fetid gas and alimentary debris, and observation of a completely necrosed stomach. A careful lavage of the entire intestinal cavity led to temporary improvement, but it became clear during an attempt at gastrectomy that further treatment would be unavailing and the patient died shortly thereafter. Estrogens were believed to be responsible for the digestive necrosis because it occurred in a young woman who had used an estrogen-rich OC for 3 years and who smoked; a hapatic biopsy confirmed the diagnosis. No traces of other risk factors such as hypertension, hyperlipidemia, diabetes, neoplasia, or obesity were observed. Recent publications indicate that OCs are responsible for a certain number of digestive problems, which may include acceleration of intestinal transit, severe diarrhea, rectorrhagia, ischemic or ulcerative colitis, intestinal infarct which is usually localized, and hepatocellular problems ranging from moderate hepatic insufficiency to malignant tumor and Budd-Chiari syndrome. OCs do not modify hemodynamic regimes, but they may cause elevation of fibrinogen and thrombin, diminution of antithrombin III acitivty, increased platelet adhesivity, and decreased fibrinolysis leading to hypercoagulability. These modifications in hemostasis occur in all OC users and are not statistically correlated with occurence of thrombotic accidents. OCs are probably responsible for parietal vascular lesions; experimental injection of synthetic estrogens is associated with both arterial and venous lesions. The most characteristic anomaly is at the level of the intima, with proliferation of smooth muscle cells and increased conjunctive tissue fibers associated with proliferation of the media or the endothelium. The absence of lipid deposits, the simultaneous appearance of arterial and venous lesions, and other evidence argues against and atheromatous origin of parietal lesions. A significant correlation has been found between high levels of anti-synthetic ethinyl estradiol antibodies and the presence of vascular lesions. It is hypothesized that these circulating immune complexes penetrate the vascular walls of OC users and produce lesions, which may depend on factors such as smoking.^ieng

[Delay of the formation of retroperitoneal fibrosis after lymphadenectomy. An experimental study]. / Délai de formation de la fibrose rétropéritonéale après lymphadénectomie. Etude expérimentale.

The goal of our study was to evaluate peritoneal and retroperitoneal healing and therefore to assess the optimal date for surgery after laparoscopic lymphadenectomy. A para-aortic lymphadenectomy was carried out in 5 groups of 5 New Zealand female rabbits. The perivascular cicatricial tissue was dissected after specific delay for each group (48 hours, 1 week, 2 weeks, 4 weeks, and 6 weeks). Peritoneal reconstruction was observed in 80% of the "48 h" group, and in 100% in the other groups (from 1 to 6 weeks). Vascular injury complicated dissection in 40% for the "1 week" group, in 80% for the "2 weeks" group, and in 20% for the "6 weeks" group. No vascular complication was observed in the "48 h" and "4 weeks" groups. The results of "1 week" and "2 weeks" were combined. The results of the "4 weeks" group were compared, with the Fisher test, to the results of a "1 week" and "2 weeks" combined group as well as to the results of the "six weeks" group. Four weeks seem to be the optimal date for a possible surgical excision after a laparoscopic lymphadenectomy.

[Unexpected outcome of a twin transfusion syndrome. A case report]. / Evolution inattendue d'un syndrome transfuseur-transfusé. A propos d'un cas.

A monochorial biamniotic twin pregnancy was uneventful until 24-weeks amenorrhoea when severe donor-recipient transfusion syndrome occurred. Unexpectedly, the situation stabilised spontaneously with regression of amniotic fluid anomalies. Pathology examination of the placenta revealed that a central placental cotyledon had undergone ischaemic necrosis which could have led to interruption of fetal-fetal transfusion at about 23 weeks amenorrhoea.