[Diagnostic approach to prolonged fevers amongst adults in primary care]. / Approche diagnostique des fièvres traînantes de l'adulte en médecine de première ligne.

The article seeks to explore: (1) the necessity to import hospital-based fever management tactics into general practice; and (2) the soundness of the principle of parsimony in clinical medicine. The discussion expands on the obstacles leading to an unexplained fever by emphasising on White's Law and the limitations of academic definitions. The article tries to keep a practical orientation by recalling the difficulty of "functional hyperthermia" as well as the choice of routine diagnostic examinations. The discussion also focuses on the modes of inference in general medicine, on clinical inertia and "substantialism" as a standard of care.

L'article s'interroge : (1) sur la nécessité d'importer ou non en médecine générale les tactiques hospitalières de prise en charge de la fièvre; (2) sur le bien-fondé du principe d'économie des hypothèses en médecine clinique. La discussion s'étend sur les obstacles permettant de conclure à une fièvre inexpliquée en insistant sur la loi de White et sur les limites des définitions académiques. L'article essaye de conserver une orientation pratique en rappelant la difficulté que constituent les «hyperthermies fonctionnelles¼ tout comme le choix des examens diagnostiques. La discussion porte également sur les modes d'inférences en médecine générale, l'inertie clinique et le «substantialisme¼ comme norme de soin.

Early life stress in mice is a suitable model for Irritable Bowel Syndrome but does not predispose to colitis nor increase susceptibility to enteric infections.

Neonatal period is characterized by an immature intestinal barrier. Scattered evidence suggests that early life stressful events induce long lasting alterations of intestinal homeostasis mimicking Irritable Bowel Syndrome (IBS). Those observations highlighting defect of intestinal barrier by early life stress questioned its potential role as a risk factor for gastrointestinal disorders such as colitis and infections. In this study, we aimed to analyze if maternal separation (MS) in mice mimicks IBS main features. We next addressed whether MS could trigger or exacerbate colitis in genetically predisposed mice and/or enhance susceptibility to gastrointestinal infections in wild type mice. MS induced main features of IBS in adult wild type male mice i.e. intestinal hyperpermeability, visceral hypersensitivity, microbiota dysbiosis, bile acid malabsorption and low grade inflammation in intestine associated with a defect of Paneth cells and the ILC3 population. This breach in mucosal barrier functions in adults was associated with a systemic IgG response against commensal E. coli and increased IFNγ secretion by splenocytes. However, in IL10-/- mice, MS did not trigger nor worsen colitis. Furthermore, wild type mice submitted to MS did not show increase susceptibility to gastrointestinal infections (S. Typhimurium, L. monocytogenes or T. gondii) compared to controls. Altogether, our results identify MS in mice as a good experimental model for IBS mimicking all the main features. In addition, early life stress, even though it has long lasting consequences on intestinal homeostasis, does not constitute a facilitating factor to colitis in predisposed individuals nor to gastrointestinal infections in wild type mice.

Safety and immunogenicity of neoadjuvant treatment using WT1-immunotherapeutic in combination with standard therapy in patients with WT1-positive Stage II/III breast cancer: a randomized Phase I study.

PURPOSE: This Phase I, multicenter, randomized study (ClinicalTrials.gov NCT01220128) evaluated the safety and immunogenicity of recombinant Wilms' tumor 1 (WT1) protein combined with the immunostimulant AS15 (WT1-immunotherapeutic) as neoadjuvant therapy administered concurrently with standard treatments in WT1-positive breast cancer patients. METHODS: Patients were treated in 4 cohorts according to neoadjuvant treatment (A: post-menopausal, hormone receptor [HR]-positive patients receiving aromatase inhibitors; B: patients receiving chemotherapy; C: HER2-overexpressing patients on trastuzumab-chemotherapy combination; D: HR-positive/HER2-negative patients on chemotherapy). Patients (cohorts A-C) were randomized (2:1) to receive 6 or 8 doses of WT1-immunotherapeutic or placebo together with standard neoadjuvant treatment in a double-blind manner; cohort D patients received WT1-immunotherapeutic in an open manner. Safety was assessed throughout the study. WT1-specific antibodies were assessed pre- and post-vaccination. RESULTS: Sixty-two patients were randomized; 60 received ≥ one dose of WT1-immunotherapeutic. Two severe toxicities were reported: diarrhea (cohort C; also reported as a grade 3 serious adverse event) and decreased left ventricular ejection fraction (cohort B; also reported as a grade 2 adverse event). Post-dose 4 of WT1-immunotherapeutic, 10/10 patients from cohort A, 0/8 patients from cohort B, 6/11 patients from cohort C, and 2/3 patients from cohort D were humoral responders. The sponsor elected to close the trial prematurely. CONCLUSIONS: Concurrent administration of WT1-immunotherapeutic and standard neoadjuvant therapy was well tolerated and induced WT1-specific antibodies in patients receiving neoadjuvant aromatase inhibitors. In patients on neoadjuvant chemotherapy or trastuzumab-chemotherapy combination, the humoral response was impaired or blunted, likely due to either co-administration of corticosteroids and/or the chemotherapies themselves.

Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma: results of a phase I dose escalation study.

PURPOSE: The PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment. PATIENTS AND METHODS: Patients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points. Cellular immune responses were evaluated using in vitro assays. RESULTS: 66 patients were treated (20, 24 and 22 in the respective cohorts). AEs considered by the investigator to be causally related were mostly grade 1 or 2 injection site symptoms, fatigue, chills, fever and headache. Two DLTs (grade 3 brain oedema and proteinuria) were recorded in two patients in two cohorts (cohorts 2 and 3). All patients had detectable anti-PRAME antibodies after four immunisations. Percentages of patients with predefined PRAME-specific-CD4+T-cell responses after four immunisations were similar in each cohort. No CD8+ T-cell responses were detected. CONCLUSIONS: The PRAME immunotherapeutic had an acceptable safety profile and induced similar anti-PRAME-specific humoral and cellular immune responses in all cohorts. As per protocol, the phase II study segment was initiated to further evaluate the 500 µg PRAME immunotherapeutic dose. TRIAL REGISTRATION NUMBER: NCT01149343, Results.

Quality of documentation on antibiotic therapy in medical records: evaluation of combined interventions in a teaching hospital by repeated point prevalence survey.

This study aimed to improve the quality of documentation on antibiotic therapy in the computerized medical records of inpatients. A prospective, uncontrolled, interrupted time series (ITS) study was conducted by repeated point prevalence survey (PPS) to audit the quality of documentation on antibiotic therapy in the medical records before and after a combined intervention strategy (implementation of guidelines, distribution of educational materials, educational outreach visits, group educational interactive sessions) from the antimicrobial stewardship team (AST) in the academic teaching hospital (CHU) of Liège, Belgium. The primary outcome measure was the documentation rate on three quality indicators in the computerized medical records: (1) indication for treatment, (2) antibiotics prescribed, and (3) duration or review date. Segmented regression analysis was used to analyze the ITS. The medical records of 2306 patients receiving antibiotics for an infection (1177 in the pre-intervention period and 1129 in the post-intervention period) were analyzed. A significant increase in mean percentages in the post-intervention period was observed as compared with the pre-intervention period for the three quality indicators (indication documented 83.4 ± 10.4 % vs. 90.3 ± 6.6 %, p = 0.0013; antibiotics documented 87.9 ± 9.0 % vs. 95.6 ± 5.1 %, p < 0.0001; and duration or review date documented 31.9 ± 15.4 % vs. 67.7 ± 15.2 %, p < 0.0001). The study demonstrated the successful implementation of a combined intervention strategy from the AST. This strategy was associated with significant changes in the documentation rate in the computerized medical records for the three quality indicators.

Anti-nociceptive effect of Faecalibacterium prausnitzii in non-inflammatory IBS-like models.

Visceral pain and intestinal dysbiosis are associated with Irritable Bowel Syndrome (IBS), a common functional gastrointestinal disorder without available efficient therapies. In this study, a decrease of Faecalibacterium prausnitzii presence has been observed in an IBS-like rodent model induced by a neonatal maternal separation (NMS) stress. Moreover, it was investigated whether F. prausnitzii may have an impact on colonic sensitivity. The A2-165 reference strain, but not its supernatant, significantly decreased colonic hypersensitivity induced by either NMS in mice or partial restraint stress in rats. This effect was associated with a reinforcement of intestinal epithelial barrier. Thus, F. prausnitzii exhibits anti-nociceptive properties, indicating its potential to treat abdominal pain in IBS patients.

Anti-PSMA antibody-coupled gold nanorods detection by optical and electron microscopies.

While cancer is one of the greatest challenges to public health care, prostate cancer was chosen as cancer model to develop a more accurate imaging assessment than those currently available. Indeed, an efficient imaging technique which considerably improves the sensitivity and specificity of the diagnostic and predicting the cancer behavior would be extremely valuable. The concept of optoacoustic imaging using home-made functionalized gold nanoparticles coupled to an antibody targeting PSMA (prostate specific membrane antigen) was evaluated on different cancer cell lines to demonstrate the specificity of the designed platform. Two commonly used microscopy techniques (indirect fluorescence and scanning electron microscopy) showed their straightforwardness and versatility for the nanoparticle binding investigations regardless the composition of the investigated nanoobjects. Moreover most of the research laboratories and centers are equipped with fluorescence microscopes, so indirect fluorescence using Quantum dots can be used for any active targeting nanocarriers (polymers, ceramics, metals, etc.). The second technique based on backscattered electron is not only limited to gold nanoparticles but also suits for any study of metallic nanoparticles as the electronic density difference between the nanoparticles and binding surface stays high enough. Optoacoustic imaging was finally performed on a 3D cellular model to assess and prove the concept of the developed platform.

Ondansetron use during pregnancy: a case series.

This is a descriptive retrospective case series of 14 pregnant women treated with ondansetron for hyperemesis gravidarum (HG) at CHU Sainte-Justine, from January 2002 to October 2011. Two of the patients received ondansetron during two separate pregnancies. Both pregnancies were analyzed separately for the purposes of this study. Another woman had twins who were included in the analysis. Therefore, the outcomes of 16 pregnancies and 17 newborns are presented. The patients were on average 28.1 ± 4.6 years old and were admitted to the hospital 5.0 ± 4.0 times. All patients who received ondansetron had previously been treated using the standard HG protocol to which they had not optimally responded. Ondansetron was initiated on average at 11.8 ± 4.8 weeks' gestation. In seven cases, administration was carried out during organogenesis. We observed 16 live births, including a set of twins, and one minor birth defect (isolated atrial and ventricular septal defects) reported after a second trimester exposure. Mean gestational age at birth was 36.9 ± 3.4 weeks and mean birth weight was 2.85±0.86 kg. We also noted six other pregnancy or neonatal outcomes (intrauterine growth retardation [IUGR] for each twin and a in a single pregnancy, a transient tachypnea, a mild hydrocele, and an extrarenal pelvis). Furthermore, we noted two premature births, one at 24 weeks of gestation and her infant died in the first weeks of life due to complications of prematurity and a second birth at 36 2/7 weeks of gestation. Teratogenicity associated with the use of ondansetron has so far not been shown in humans. This case series adds information on ondansetron use during pregnancy. However, until we have more published data, ondansetron should be used as a second-line agent for the management of HG.

Isomerization of vaccenic acid to cis and trans C18:1 isomers during biohydrogenation by rumen microbes.

In ruminants, cis and trans C18:1 isomers are intermediates of fatty acid transformations in the rumen and their relative amounts shape the nutritional quality of ruminant products. However, their exact synthetic pathways are unclear and their proportions change with the forage:concentrate ratio in ruminant diets. This study traced the metabolism of vaccenic acid, the main trans C18:1 isomer found in the rumen, through the incubation of labeled vaccenic acid with mixed ruminal microbes adapted to different diets. [1-(13)C]trans-11 C18:1 was added to in vitro cultures with ruminal fluids of sheep fed either a forage or a concentrate diet. (13)C enrichment in fatty acids was analyzed by gas-chromatography-mass spectrometry after 0, 5 and 24 h of incubation. (13)C enrichment was found in stearic acid and in all cis and trans C18:1 isomers. Amounts of (13)C found in fatty acids showed that 95% of vaccenic acid was saturated to stearic acid after 5 h of incubation with the concentrate diet, against 78% with the forage diet. We conclude that most vaccenic acid is saturated to stearic acid, but some is isomerized to all cis and trans C18:1 isomers, with probably more isomerization in sheep fed a forage diet.

Novel post-digest isotope coded protein labeling method for phospho- and glycoproteome analysis.

In the field of proteomics there is an apparent lack of reliable methodology for quantification of posttranslational modifications. Present study offers a novel post-digest ICPL quantification strategy directed towards characterization of phosphorylated and glycosylated proteins. The value of the method is demonstrated based on the comparison of two prostate related metastatic cell lines originating from two distinct metastasis sites (PC3 and LNCaP). The method consists of protein digestion, ICPL labeling, mixing of the samples, PTM enrichment and MS-analysis. Phosphorylated peptides were isolated using TiO(2), whereas the enrichment of glycosylated peptides was performed using hydrazide based chemistry. Isolated PTM peptides were analyzed along with non enriched sample using 2D-(SCX-RP)-Nano-HPLC-MS/MS instrumentation. Taken together the novel ICPL labeling method offered a significant improvement of the number of identified (∼600 individual proteins) and quantified proteins (>95%) in comparison to the classical ICPL method. The results were validated using alternative protein quantification strategies as well as label-free MS quantification method. On the biological level, the comparison of PC3 and LNCaP cells has shown specific modulation of proteins implicated in the fundamental process related to metastasis dissemination. Finally, a preliminary study involving clinically relevant autopsy cases reiterated the potential biological value of the discovered proteins.

A study of tungsten oxide nanowires self-organized on mica support.

Self-organized straight nanowires of WO3 have been epitaxially grown on muscovite mica in low super-saturation conditions. Morphology, structure and chemical composition of the prepared nanostructures have been investigated by scanning electron microscopy (SEM), x-ray diffraction (XRD) and x-ray photoelectron spectroscopy (XPS). SEM permits us to observe nanowire networks and substrate electron channeling patterns (ECP) simultaneously and thus to determine crystallographic direction of nanowire growth. The experimental results show that straight WO3 nanowires are orientated preferentially parallel to two of three high symmetry crystallographic directions of mica [100] and [110] or [100] and [Formula: see text]. XRD and XPS measurements indicated self-assembly of very thin nanowires of hexagonal tungsten bronze in the first stage of growth followed by the formation of stoichiometric WO3. The growth mechanism has been studied as a function of different preparation conditions with special focus on the role of potassium ions present on the mica surface. Based on obtained results a growth model of tungsten oxide nanowires on mica is proposed.

Intra-arterial hepatic fotemustine for the treatment of liver metastases from uveal melanoma: experience in 101 patients.

BACKGROUND: Exclusive liver metastases occur in up to 40% of patients with uveal melanoma associated with a median survival of 2-7 months. Single agent response rates with commonly available chemotherapy are below 10%. We have investigated the use of fotemustine via direct intra-arterial hepatic (i.a.h.) administration in patients with uveal melanoma metastases. PATIENTS AND METHODS: A total of 101 patients from seven centers were treated with i.a.h. fotemustine, administered intra-arterially weekly for a 4-week induction period, and then as a maintenance treatment every 3 weeks until disease progression, unacceptable toxicity or patient refusal. RESULTS: A median of eight fotemustine infusions per patient were delivered (range 1-26). Catheter related complications occurred in 23% of patients; however, this required treatment discontinuation in only 10% of the patients. The overall response rate was 36% with a median overall survival of 15 months and a 2-year survival rate of 29%. LDH, time between diagnosis and treatment start and gender were significant predictors of survival. CONCLUSIONS: Locoregional treatment with fotemustine is well tolerated and seems to improve outcome of this poor prognosis patient population. Median survival rates are among the longest reported and one-third of the patients are still alive at 2 years.

[Rupture of hepatic focal nodular hyperplasia. About two cases]. / Rupture d'une hyperplasie nodulaire focale. A propos de deux cas.

The diagnostics of focal nodular hyperplasia is reached through the use of imaging. When the diagnostic is certain, surgical abstention is the rule. Nevertheless, we were confronted with two cases of a rare complication; that of intraperitoneal rupture. In this situation, we suggest to first do an arteriography to control the bleeding, then to perform surgery when the patient has reached hemodynamic stability. Spontaneous rupture as a complication of benign nodular hyperplasia remains a rare event and only five cases were reported in litterature.

Induction of apoptosis in human promyelocytic leukemia cells by a natural trachylobane diterpene.

BACKGROUND: Trachylobane diterpenes are secondary metabolites, quite rare in nature, and their bioactivities are poorly understood. Recently, we have described the cytotoxic activity of ent-trachyloban-3beta-ol isolated from the leaves of Croton zambesicus, a plant used in African folk medicine. MATERIALS AND METHODS: Cell viability on several cell lines, cell morphology, DNA laddering, annexin Vand caspase-3 activation experiments were undertaken in order to analyse the cytotoxicty of trachylobane diterpene and to determine if this compound is able to induce apoptosis. RESULTS: ent-Trachyloban-3beta-ol exerts a dose-dependent cytotoxic effect, which varies between cell lines. Induction of apoptosis in HL-60 cells could be detected at a concentration of 50 microM after 24-h treatment. CONCLUSION: We show here, for the first time, that a trachylobane diterpene is able to induce apoptosis in human promyelocytic leukemia cells via caspase-3 activation in a concentration-dependent manner.

Cystic pneumatosis of the colon after liver transplantation.

Cystic pneumatosis (CP) is an uncommon but significant condition in adults in which gas is found in a linear or cystic form in the submucosa or the subserosa of the bowel wall. The diagnosis was made by conventional X-ray and confirmed by abdominal computed tomography. Benign pneumoperitoneum due to CP should be considered in the differential diagnosis of free intra-abdominal air after chemotherapeutic or immunosuppressive therapy. As such, pneumatosis intestinalis is only a sign and must be interpreted in light of the clinical findings because it may be found in various scenarios: in patients who are otherwise healthy, and associated with pyloric stenosis, jejunoileal bypass, progressive systemic sclerosis, transplantation, chemotherapy, immunosuppression (including AIDS), obstructive pulmonary disease and finally, as in our case, after liver transplantation. Since there were no signs of secondary complications such as peritonitis, ischemia, or perforation, conservative treatment with broad-spectrum antibiotics and parenteral nutrition was initiated.

Impaired insulin response after oral but not intravenous glucose in heart- and liver-transplant recipients.

BACKGROUND: The prevalence of diabetes is high after transplantation. We hypothesized that liver transplantation induces additional alterations of glucose homeostasis because of liver denervation. METHODS: Nondiabetic patients with a heart (n=9) or liver (n=9) transplant and healthy subjects (n=8) were assessed using a two-step hyperglycemic clamp (7.5 and 10 mmol/L). Thereafter, an oral glucose load (0.65 g/kg fat free mass) was administered while glucose was clamped at 10 mmol/L. Glucose appearance from the gut was calculated as the difference between glucose appearance (6,6 2H2 glucose) and exogenous glucose infusion. Plasma insulin, glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide(GIP) concentrations were compared after intravenous and oral glucose. RESULTS: After oral glucose, the glucose appearance from the gut was increased 52% and 81% in liver- and heart-transplant recipients (P<0.05). First-pass splanchnic glucose uptake was reduced by 39% in liver-transplant and 64% in heart-transplant patients (P<0.05). After oral but not intravenous glucose, there was an impairment of insulin secretion in both transplant groups relative to the controls. Plasma concentrations of GIP and GLP-1 increased similarly in all three groups after oral glucose. CONCLUSIONS: First-pass hepatic glucose extraction is decreased after heart and liver transplant. Insulin secretion elicited by oral, but not intravenous glucose, is significantly reduced in both groups of patients. There was no difference between liver- and heart-transplant recipients, indicating that hepatic denervation was not involved. These data suggest an impairment in the beta-cell response to neural factors or incretin hormones secondary to immunosuppressive treatment.

[Agenesis of the gallbladder]. / Agénésie de la vésicule biliaire.

Isolated agenesis of the gallbladder (AG) is a rare anomaly. Twenty-three percent of the patients are symptomatic and present with right upper abdominal pain, nausea and fatty food intolerance. The condition is frequently mistaken with excluded or sclero-atrophic gallbladder, regardless of the imaging modality used. Consequently, AG leads often to unnecessary and potentially dangerous surgery. During laparoscopy, the absence of normal anatomical structures and the impossibility of pulling on the gallbladder to dissect the triangle of Callot represent an increased risk of iatrogenic injury to biliary or portal structures. The aim of this study is to discuss the pitfalls of the available radiological exams and the management of this rare condition. We describe two cases of AG, with a review of the literature. A high index of suspicion is necessary when interpreting the radiological images. In case of doubt, a MRI-cholangiography is mandatory. Because of possible inherited transmission, relatives with a history of biliary symptoms should be investigated, even when asymptomatic.

Cytotoxic aporphine alkaloids from Cassytha filiformis.

Purification of a cytotoxic crude alkaloid extract of Cassytha filiformis led to the isolation of four known aporphine alkaloids: neolitsine, dicentrine, cassythine (= cassyfiline) and actinodaphnine. Their structures were determined by analysis of spectroscopic data. All isolated alkaloids were tested for their cytotoxic activities on cancer and non-cancer cell lines in vitro. Neolitsine was the most active against HeLa and 3T3 cells (IC 50 :21.6 microM, and 21.4 microM, respectively). Cassythine and actinodaphnine showed the highest activity against Mel-5 (IC 50 : 24.3 microM and 25.7 microM, respectively) and HL-60 (IC 50 : 19.9 microM and 15.4 microM, respectively). This is the first report on the cytotoxic activity of C. filiformis extract and of neolitsine and cassythine. Furthermore, the complete NMR data of cassythine and actinodaphnine are given here for the first time.