Peanut gastrointestinal delivery oral immunotherapy in adolescents: Results of the build-up phase of a randomized, double-blind, placebo-controlled trial (PITA study).

BACKGROUND: Oral immunotherapy to peanut is effective in desensitizing patients but has significant side effects including anaphylaxis and gastrointestinal symptoms. In most protocols, peanut is administered in a vehicle food. OBJECTIVE: In an exclusively adolescent population, we tested a new approach using sealed capsules of peanut (gastrointestinal delivery oral immunotherapy or GIDOIT) to bypass the upper gastrointestinal tract. The primary aim was to assess the efficacy of the oral build-up phase of GIDOIT and the secondary aim to analyse its safety. METHODS: Adolescents with a history of a clinical allergic reaction after peanut ingestion were included in a 2-armed, parallel-design, individually randomized, double-blind, placebo-controlled, multicentre trial after a positive double-blind placebo-controlled oral food challenge (DBPCFC1). A central randomization centre used computer-generated tables to allocate treatments. Peanut (or placebo) capsules were ingested daily over a period of 24 weeks with increments every 2 weeks from 2 to 400 mg of peanut protein (pp). Primary outcome was tolerance of 400 mg of pp at DBPCFC2. RESULTS: Thirty patients were included between September 2013 and May 2014. At DBPCFC2, unresponsiveness to 400 mg of pp was achieved in 17/21 peanut group patients (2 withdrawn patients) and 1/9 in the placebo group (Intention-to-treat analysis, P < .001, absolute difference = 0.7, 95%IC 0.43 0.96). Oropharyngeal symptoms were equally frequent in both groups. No dysphagia or other signs of eosinophilic oesophagitis occurred. Digestive adverse events (AE) were more frequent in the treated group (P = .02), but mild and without compliance issues. Only one severe advent event led to withdrawal in a patient who ingested twice the investigated treatment. Peanut-specific humoral immune responses were modulated. CONCLUSION: The GIDOIT protocol demonstrated clinical and immunological efficacy and had an acceptable level of safety with weak oropharyngeal symptoms, no dysphagia, mild digestive events and few severe systemic AE.

Dunnigan lipodystrophy syndrome: French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins).

Dunnigan syndrome, or Familial Partial Lipodystrophy type 2 (FPLD2; ORPHA 2348), is a rare autosomal dominant disorder due to pathogenic variants of the LMNA gene. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins), is to provide health professionals with a guide to optimal management and care of patients with FPLD2, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), is available on the French Health Authority website (in French). Dunnigan syndrome is characterized by a partial atrophy of the subcutaneous adipose tissue and by an insulin resistance syndrome, associated with a risk of metabolic, cardiovascular and muscular complications. Its prevalence, assessed at 1/100.000 in Europe, is probably considerably underestimated. Thorough clinical examination is key to diagnosis. Biochemical testing frequently shows hyperinsulinemia, abnormal glucose tolerance and hypertriglyceridemia. Elevated hepatic transaminases (hepatic steatosis) and creatine phosphokinase, and hyperandrogenism in women, are common. Molecular analysis of the LMNA gene confirms diagnosis and allows for family investigations. Regular screening and multidisciplinary monitoring of the associated complications are necessary. Diabetes frequently develops from puberty onwards. Hypertriglyceridemia may lead to acute pancreatitis. Early atherosclerosis and cardiomyopathy should be monitored. In women, polycystic ovary syndrome is common. Overall, the management of patients with Dunnigan syndrome requires the collaboration of several health care providers. The attending physician, in conjunction with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are described to provide such a support.

[Ovarian metastasis of breast cancer: a case report. Role of cytoreductive surgery]. / Métastase ovarienne du cancer du sein: à propos d'un cas. Rôle de la chirurgie cytoréductrice.

The ovaries are a common metastatic site for breast cancer. The diagnosis and treatment of ovarian masses from a metastatic breast cancer are difficult. The complete resection of these metastatic masses seems to give a benefit in terms of global survival. This benefit depends on the residual tumoral volume and on the free interval between initial breast cancer diagnosis and apparition of the metastatic ovarian masses. We discuss the treatment of a patient with ovarian metastasis as first sign of a metastatic breast cancer.

Does first-line surgery still have its place in the treatment of acromegaly?

Transsphenoidal surgery is currently the first-line treatment of acromegaly. Remission is observed in 80 to 90% microadenomas, 50 to 60% non-invasive macroadenomas, and less than 20% invasive macroadenomas. Predictive factors include age, maximal size of the adenoma, cavernous sinus invasion, initial hormone levels and neurosurgeon's experience. Complications are rare, with about 5% definitive diabetes insipidus and 10% of new anterior pituitary hormone deficits. Somatostatin agonist pretreatment can be proposed as it decreases tumor volume in about 25% cases and might reduce the rate of immediate postsurgical complications; however, there is no obvious difference in surgical remission rate whether patients are pretreated or not. Debulking surgery can also be proposed in very large macroadenomas incompletely controlled by somatostatin agonists or resistant to medical treatment, as it was shown to facilitate somatostatin agonist efficacy in more than 50% cases.

[A myocardial infarction during pregnancy treated by percutaneous transluminal coronary angioplasty and stent implantation. Case report]. / Infarctus myocardique durant la grossesse: à propos d'un cas traité par angioplastie transluminale percutanée et implantation d'un stent coronarien.

Acute myocardial infarction is an un-frequent event during pregnancy. It clearly causes an increase in both maternal and fetal mortality. We describe a case of pregnancy complicated during the second trimester by an acute myocardial infarction witch was treated by percutaneous transluminal coronary angioplasty combined with stenting. The challenge involved in managing this condition during pregnancy is briefly discussed.

226Ra, 222Rn AND PERMEABILITY OF BELGIAN SOILS IN RELATION WITH INDOOR RADON RISK.

Knowing the concentration of 226Ra in soil and of 222Rn in soil gas is important for the analysis of indoor radon data and the prediction of radon-prone areas. Except for soil Rn in Ardenne, the data concerning these two radionuclides in Belgian soils are very scarce. In the context of Master theses and international courses, students made 92 measurements of 226Ra in soil samples, 105 of 222Rn in soil gas, and 74 of soil permeability, a significant addition to the existing similar data. The data are analysed in relation with soil texture, geological units and indoor radon risk. There is no clear correlation between radium in soil and indoor radon risk, the most important factor of risk being soil permeability.

Compared expression levels of ornithine transcarbamylase and carbamylphosphate synthetase in liver and small intestine of normal and mutant mice.

Enzymatic assay, electrophoretic immunoblotting and RNA dot-blot techniques were employed to investigate the expression of the ornithine transcarbamylase (OTC) gene in liver and small intestine of Sparse fur mice with abnormal skin and hair (Spf-ash) and Sparse fur mice (Spf) which exhibit an X-linked OTC deficiency. We found a reduced OTC activity in these two tissues. We now show that this reduction is less pronounced in the intestine than in the liver of the Spf-ash strain. During the first 2 weeks of life, the deficiency appears to be less severe than in the adult mice. The enzymatic activity of carbamylphosphate synthetase I (CPS), another enzyme of the urea cycle, is significantly modified in the Spf mutant strain only.

[Analysis of two year heroin seizures in the Liege area]. / Deux ans d'analyse de saisies d'héroïne en région liégeoise.

The results of heroin analysis from seizures in the Liege area during the last two years are presented in this article. Between January 2003 and January 2005, 50 samples were analysed in the Laboratory of Clinical Toxicology and Forensic Toxicology of the University of Liege. Mean heroin concentration was 14,7%. Noscapine and papaverine, other opium alcaloïds, were simultaneously present with heroin. As diluents, we only identified caffein and acetaminophen.

Carbocyclic analogues of 5-fluorouracil nucleosides.

The carbocyclic analogues of 5-fluoro-2'-deoxyuridine (5-FdUrd, 1), 5-fluorouridine, and 5-fluoro-3 alpha-deoxyuridine were prepared by fluorination of the uracil nucleoside analogues with elemental fluorine. The 5-FdUrd analogue (C-5-F-2'-dUrd, 6) was enzymatically phosphorylated to the analogue of 5-FdUrd 5'-phosphate and inhibited the incorporation of 2'-deoxyuridine into DNA of murine colon 26 tumor cells and L-1210 cells in culture. Biochemical studies also indicated that C-5-F-2'-Urd (6) was a less potent inhibitor of DNA synthesis in tumor cells than was 5-FdUrd (1). C-5-F-2'-dUrd was cytotoxic (ED50 = 2.5 mcg/mL) to L-1210 cells in culture; the other two analogues were less cytotoxic. C-5-F-2'-dUrd was inactive--or, at best, borderline active--in tests against P-388 leukemia in vivo.

Protein binding and stereoselectivity of nonsteroidal anti-inflammatory drugs.

Stereoselective binding of nonsteroidal anti-inflammatory drugs (NSAIDs) can be studied using various techniques. Thus the results obtained by different investigators may be poorly consistent and even contradictory. NSAIDs are bound stereoselectively to serum albumin to different degrees depending on the drug investigated (ibuprofen, indoprofen, carprofen, etodolac, ketoprofen and flurbiprofen). For other drugs, both enantiomers are bound to a similar extent (pirprofen, fenoprofen). This stereoselectivity could vary with experimental conditions, in particular with protein concentration (ketoprofen, etodolac), leading to individual differences. Finally, the stereoselectivity of protein binding and of pharmacokinetics can be compared: differences in binding between enantiomers can explain their differences in pharmacokinetics, once metabolic properties such as inversion have been taken into account.

Stereoselective binding of the glucuronide of ketoprofen enantiomers to human serum albumin.

Since acyl glucuronides are known to undergo deconjugation, especially in the presence of human serum albumin (HSA), only a few reports have described their reversible binding to plasma proteins. The aim of this study was to investigate the reversible binding of R and S ketoprofen glucuronides to HSA by a rapid technique, such as ultraviolet circular dichroism. Binding of R ketoprofen glucuronide only induced an extrinsic Cotton effect at 340 nm. Scatchard plot analysis revealed that R ketoprofen and its glucuronide are bound to one site of albumin with an association constant of 28.1 x 10(4) and 6.1 x 10(4) M-1, respectively. Modification of one tyrosine residue by diisopropylfluorophosphate prevented the access of ligands to sites I and II of albumin, and also fully inhibited the binding of R ketoprofen and that of its conjugate. Displacement experiments with specific probes of albumin binding sites suggested that R ketoprofen and the glucuronide are bound to site II rather than site I. However, R ketoprofen was not displaced by its conjugate. S ketoprofen glucuronide is also bound to HSA, since it decreased the binding of the antipode conjugate. However, the binding of this metabolite to albumin did not induce an extrinsic Cotton effect large enough to determine the binding constants. D-Glucuronic acid did not bind to sites I or II of albumin. This moiety is likely responsible for the lower affinity of HSA for the R ketoprofen glucuronide when compared to that for R ketoprofen, due to the hydrophilicity and/or the bulkiness of this group.

RT-PCR-ELOSA tests on pooled sample units for the detection of virus Y in potato tubers.

A highly sensitive RT-PCR protocol able to detect potato virus Y (PVY) in pooled sample units (tubers) was developed. PVY-specific primers selected in the coat protein gene were found to amplify a 359 bp fragment from diluted crude extract of infected tubers. For the detection of the amplification products, a colorimetric detection procedure in microtiter plates was established. The amplicons are hybridized between a covalently linked capture probe and a specific biotinylated detection probe ELOSA tests. This detection method detects at least 50 pg of virus per reaction for the four cultivars tested. The RT-PCR-ELOSA assay was adapted to pooled units in order to increase the sample size while reducing the number of tests.

Fatal overdosage with cisplatin.

This paper presents a case of fatal overdosage due to an accidental massive administration (750 mg instead of 170 mg) of cisplatin, an anticancer agent, to a 63-year-old patient suffering from lymphoma. Platinum was measured in various postmortem samples by means of inductively coupled plasma mass spectrometry. Heart and peripheral blood concentrations of platinum were 1515 and 1253 micro g/L, respectively. Concentrations in urine and bile were 1038 and 501 micro g/L, respectively. Renal dialysis was started immediately after the end of cisplatin perfusion, when the mistake was noticed, but the patient deceased at day 16, presenting renal and hepatic insufficiency, ototoxicity, and pancytopenia.

Orthotopic nonauxiliary homotransplantation of part of the liver in dogs.

An experimental study was carried out investigating the feasibility of using only a portion of a donor liver in orthotopic, nonauxiliary transplantation, establishing a canine model. After being totally hepatectomized, 20 immunosuppressed adult beagles received a 60% donor liver graft, derived from tissue-typed identical littermates. Preservation time was 5 hr. In control experiments, 10 beagles, only half of them immunosuppressed, underwent an operation involving complete liver mobilization, vascular exclusion, cooling of the liver in situ, and a 40% partial hepatectomy with biliary anastomosis. The surgical procedure, including the method of cooling and preservation, is described in detail. Survival rate amounted to 90% for the control group and 50% for the transplanted group, while all surviving dogs were sacrificed 24 wk postoperatively. At sacrifice, the liver weight amounted to the weight of the total native liver at operation. Body weight profiles reflect good general condition of the surviving dogs. No major differences were noted between the immunosuppressed and the nonimmunosuppressed control dogs. No complications were related to the fact that only a partial liver was grafted or left in situ.

Hemorrhoidectomy: Hospital Leopold Bellan procedure.

The authors describe their hemorrhoidectomy technique, a modification of Milligan-Morgan. It differs by the association of a posterior anoplasty (with internal sphincterotomy in the case of a fissure or sphincter hypertonia) and of a sub-mucocutaneous dissection of the security bridges. They report on their experience with 410 operations carried out during the year 1985. Immediate complications are mainly hemorrhage (2.68%) and urinary problems (9%). Average cicatrization time is about six weeks. At one year, there were no relapses nor fissures. A moderate stenosis was observed in 1.45% of the cases, and a hypocontinence to flatus in 2.3%. Use of a CO2 laser does not result in any modification of these results.

[Value of velocimetric and echotomographic examination in monitoring central catheterizations]. / Intérêt de l'examen vélocimétrique et échotomographique dans la surveillance des cathétérismes centraux.

Thrombosis around a centrally-implanted catheter is a complication of this method of venous approach. Usually asymptomatic, it is normally detected by phlebography, histopathology or computed angiotomography. Thirty-five patients with catheters in internal jugular vein composed of silicone (13 cases) or polyurethane (22 cases) were followed up by velocimetric and echotomographic examinations before introduction and one and three weeks after introduction of a catheter, these exploratory procedures possessing the advantage of being rapid, repetable and non-invasive. Three thrombosis were diagnosed using this method, including two without clinical signs, one on a silicone and two a polyurethane catheter. This represents 8.6% of total population, comparable with results of phlebography and histopathology reported in the litterature. The echotomographic appearance of the fibrinoplatelet sleeve left by the catheter after its removal is also described. Combined velocimetric and echotomographic examination is an investigational method which is non-invasive, reliable, rapid and repeatable for evaluation of appearance, localization, extension and also follow up of thrombosis.

[Monitoring therapeutic arteriovenous fistulas in chronic hemodialysis patients. Value of the continuous Doppler test combined with real-time echotomography]. / Surveillance des fistules artério-veineuses thérapeutiques chez des hémodialysés chroniques. Intérêt de l'examen au Doppler continu couplé à l'examen échotomographique en temps réel.

Continuous doppler investigation of functioning of therapeutic arteriovenous fistula is a well-established routine. The availability for the last few years of high frequency (10 mg/Hz) real-time ultrasound has enabled visualization of superficial arteries and veins. Total afferent and efferent branches of these therapeutic fistulae can be visualized. Examination should therefore include continuous doppler recordings combined with real-time ultrasound of both transverse and sagittal sections of the different arteries and veins participating in the fistula. The indication for examination is clinical in cases with low or high output or during the immediate postoperative period to detect early thrombosis.

[Stereoselective protein binding of non-steroidal anti-inflammatory agents. Pharmacological implications]. / Fixation protéque stéréosélective des anti-inflammatoires non stéroïdiens. Implications pharmacologiques.

Non steroidal anti-inflammatory drugs (NSAIDs) contain a chiral carbon alpha to carboxyl function. Except for naproxen, chiral NSAIDs are marketed for clinical use as racemate, ie an equimolar mixture of the two enantiomers R(-) and S(+). However, in vitro studies have shown that the anti-inflammatory activity exists almost solely in the S form. The unbound fraction is able to diffuse into tissues and to reach sites of action. It represents also the pharmacological active form. Stereoselective protein binding studies carried out at various concentrations of NSAIDs and albumin are used to evaluate the free fraction of the active enantiomer. Two optical isomers do not interact in the same manner with proteins and this binding stereoselectivity depends on NSAID and experimental conditions. Thus, it seems difficult to predict the in vivo free concentration of each enantiomer and protein binding experiments should be achieved taking into account the physiopathological parameters which influence this biological process. This enantioselectivity is determinant for the pharmacokinetic properties and could be responsible of the parameters variation obtained for each enantiomer. It could explain the variability in response to NSAIDs too. In fact, the anti-inflammatory effect is directly function of the free concentration of the S isomer. To correlate the NSAID dose with its activity, it should be better to determine this free fraction in the site of action, in particular in the synovial fluid. But the clinical response, as for example the antalgic effect, remains very far from the pharmacological activity, ie the cyclooxygenase inhibition.

[Intramural abscesses of the rectum]. / Les abcés intramuraux de rectum.

Intramural abscesses of the rectum developed in the complex longitudinal layer may be isolated or associated with a transphincteric fistula. They may be acute or subacute and are diagnosed by intrarectal palpation. The only treatment is surgical: the abscess is opened into the rectal cavity, except in case of association with suprasphincteric fistula, when it must be drained through the skin. Postoperative complications are minor ones and relapses are rare (1.75% of cases).

Simultaneous determination of seven azole antifungal drugs in serum by ultra-high pressure liquid chromatography and diode array detection.

Azole antifungals are a group of fungistatic agents that can be administered orally or parenterally. The determination of the concentrations of these antifungals (miconazole, fluconazole, ketoconazole, posaconazole, voriconazole, itraconazole, and its major active metabolite, hydroxy-itraconazole) in serum can be useful to adapt the doses to pharmacological ranges because of large variability in the absorption and metabolism of the drugs, multiple drug interactions, but also potential resistance or toxicity. A method was developed and validated for the simultaneous determination of these drugs in serum utilizing ultra-high pressure liquid chromatography and diode array detection (UHPLC-DAD). After a simple and rapid liquid-liquid extraction, the pre-treated sample was analysed on an UHPLC-DAD system (Waters Corporation(®)). The chromatographic separation was carried out on an Acquity BEH C18 column (Waters Corporation) with a gradient mode of mobile phase composed of acetonitrile and aqueous ammonium bicarbonate 10·0 M pH10. The flow rate was 0·4 ml/min and the injection volume was 5 µl. The identification wavelength varied according to the drug from 210 to 260 nm. The method was validated by the total error method approach by using an analytical validation software (e•noval V3·0 Arlenda(®)). The seven azole antifungals were identified by retention time and specific UV spectra, over a 13-minute run time. All calibration curves showed good linearity (r(2)>0·99) in ranges considered clinically adequate. The assay was linear from 0·05 to 10 mg/l for voriconazole, posaconazole, itraconazole, hydroxy-itraconazole, and ketoconazole, from 0·3 to 10 mg/l for fluconazole, and from 0·1 to 10 mg/l for miconazole. The bias and imprecision values for intra- and inter-assays were lower than 10% and than 15%, respectively. In conclusion, a simple, sensitive, and selective UHPLC-DAD method was developed and validated to determine seven azole antifungal drugs in human serum. This method is applicable to patient samples, and can be applied successfully to clinical applications and therapeutic drug monitoring.