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Pediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient's tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Pediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and treatments development in advanced pediatric malignancies., (© 2023. Springer Nature Limited.)

Providing sufficient energy for autonomous systems at the nanoscale is one of the major challenges of the Internet of Nano Things (IoNT). Existing battery technologies and conventional integrated circuits cannot be used in such small dimensions. Even if they are small enough to be used at the nano level, they still cannot be used in medical applications due to biocompatibility issues. M13 is a very promising virus with piezoelectric properties, which has attracted much interest in the scientific community as a bioenergy harvester. However, M13 studies presented so far in the literature are designed only for macroscale systems. In this paper, we simulate two designs of a bio-inspired nanogenerator based on the properties of M13 for nanosystems. We derive the stiffness matrix of M13, its dielectric and piezoelectric matrices and its density. We verify our calculated values by comparing our simulations with the results of experimental studies presented in the literature. We also evaluate the system's performance in terms of frequency response and loading characteristics. The results presented in this study show that a single M13 is a very promising nano-generator that can be used for medical applications.

In this paper, we propose a bio-inspired receiver, which detects the electrons transmitted through a nanowire, then, it converts the detected information to blue light using bioluminescence. We simulate the construction of the nanowire, present its electrical characteristics and calculate its maximum capacity for a better design of the receiver. The designed receiver contains two parts; a part that detects the transmitted electrons, which we model by using an equivalent circuit, and a part that converts the detected electrons to blue light. We derive the analytical expressions of the components of the equivalent circuit and give an approximation of their values. We calculate the probability of photons emission for each electrical pulse detected. We also determine the optimal threshold for Integrate Sample and Dump (ISD) receiver. We calculate the error probability of bits detection and present analytical and simulation results to evaluate the performance of the designed receiver. The results of this study show that the designed receiver can accurately detect the electrons sent through a conductive nanowire. Thus providing, to the best of our knowledge, the first technical solution that leads towards integrated wired electrical and optical nanonetworks.

Primary renal marginal zone B lymphoma is extremely rare. The renal involvement by the lymphoma is most often a manifestation of a disseminated disease. We report the case of a 53-year-old patient who presented lower back pain and kidney failure. The renal biopsy showed a marginal zone B lymphoma type MALT and the PET scan showed bilateral renal involvement. A treatment based on rituximab combined with chemotherapy (cyclophosphamide, prednisone and oncovin) was started with good outcome.

Methylmalonic aciduria (MMA) is an inborn error of metabolism with multiple monogenic causes and a poorly understood pathogenesis, leading to the absence of effective causal treatments. Here we employ multi-layered omics profiling combined with biochemical and clinical features of individuals with MMA to reveal a molecular diagnosis for 177 out of 210 (84%) cases, the majority (148) of whom display pathogenic variants in methylmalonyl-CoA mutase (MMUT). Stratification of these data layers by disease severity shows dysregulation of the tricarboxylic acid cycle and its replenishment (anaplerosis) by glutamine. The relevance of these disturbances is evidenced by multi-organ metabolomics of a hemizygous Mmut mouse model as well as through identification of physical interactions between MMUT and glutamine anaplerotic enzymes. Using stable-isotope tracing, we find that treatment with dimethyl-oxoglutarate restores deficient tricarboxylic acid cycling. Our work highlights glutamine anaplerosis as a potential therapeutic intervention point in MMA., (© 2023. The Author(s).)

Cancer cells reprogram their metabolism to support growth and invasion. While previous work has highlighted how single altered reactions and pathways can drive tumorigenesis, it remains unclear how individual changes propagate at the network level and eventually determine global metabolic activity. To characterize the metabolic lifestyle of cancer cells across pathways and genotypes, we profiled the intracellular metabolome of 180 pan-cancer cell lines grown in identical conditions. For each cell line, we estimated activity for 49 pathways spanning the entirety of the metabolic network. Upon clustering, we discovered a convergence into only two major metabolic types. These were functionally confirmed by 13 C-flux analysis, lipidomics, and analysis of sensitivity to perturbations. They revealed that the major differences in cancers are associated with lipid, TCA cycle, and carbohydrate metabolism. Thorough integration of these types with multiomics highlighted little association with genetic alterations but a strong association with markers of epithelial-mesenchymal transition. Our analysis indicates that in absence of variations imposed by the microenvironment, cancer cells adopt distinct metabolic programs which serve as vulnerabilities for therapy., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: In 2018, the World Health Organization (WHO) launched the Global Initiative for Childhood Cancer (GICC). The goal is to achieve a global survival rate of at least 60% for all children with cancer by 2030. Morocco was designated as a pilot country for this initiative., Procedure: This retrospective study included a cohort of children aged 0-15 years, with one of the six indexed cancers (acute lymphoblastic leukemia [ALL], Burkitt lymphoma [BL], Hodgkin lymphoma, retinoblastoma [RB], Wilms tumor or nephroblastoma, low-grade glioma), diagnosed between January 1, 2017 and December 31, 2019 at the six Moroccan Pediatric Hematology and Oncology units. Patients were followed-up until August 31, 2020. The Kaplan-Meier method was used to estimate survival rates, the log-rank test for comparing survival curves, and the Cox model for identifying prognostic factors., Results: Data on 878 patients were included in the study. The most frequently reported cancer type was ALL (n = 383, 43.6%), followed by Wilms tumor (n = 139, 15.8%) and BL (n = 133, 15%). Most patients were less than 5 years of age (n = 446, 50.9%) and the male/female ratio was 1.46. The 1, 2, and 3-year overall survival rates were 80.1%, 73.6%, and 68.2%, respectively. In a multivariable Cox regression model, care center, cancer type, age group, and distance to the care center were statistically significantly associated to survival. Patients aged 10 years and older and patients living more than 100 km from the care center were more likely to die (respectively, HR = 1.39, p = .045 and HR = 1.44, p = .010)., Conclusion: The reported results represent the baseline for measuring the impact of GICC implementation in Morocco., (© 2022 Wiley Periodicals LLC.)

Breeding hybrids with maximum heterosis requires efficient cross-pollination and an improved male sterility system. Renewed efforts have been made to dissect the phenotypic variation and genetic basis of hybrid floral traits, although the potential of tailoring the appropriate flower design on seed setting is less known. To this end, elite wheat genotypes were crossed using a chemical hybridizing agent at different doses. A total of 23 hybrids were developed from a partial diallel design; and planted in an alpha lattice design with their parents at two locations in Morocco, for two years, to evaluate for yield components, heterosis and combining abilities. The 13.5 L ha -1 dose induced a maximum level of sterility (95%) and seed set showed large phenotypic variation and high heritability. In parallel, seed set showed tight correlation with pollen mass (0.97), visual anther extrusion (0.94) and pollen shedding (0.91) ( p < 0.001), allowing direct selection of the associated traits. Using the combined data, mid-parent heterosis ranges were -7.64-14.55% for biomass (BM), -8.34-12.51% for thousand kernel weight (TKW) and -5.29-26.65% for grain yield (YLD); while best-parent heterosis showed ranges of -11.18-7.20%, -11.35-11.26% and -8.27-24.04% for BM, TKW and YLD, respectively. The magnitude of general combining ability (GCA) variance was greater than the specific combining ability (SCA) variance suggesting a greater additive gene action for BM, TKW and YLD. The favorable GCA estimates showed a simple method to predict additive effects contributing to high heterosis and thus could be an effective approach for the selection of promising parents in early generations.

Inflammatory bowel disease (IBD) is a lifelong inflammatory disorder with relapsing-remission cycles, which is currently diagnosed by clinical symptoms and signs, along with laboratory and imaging findings. However, such clinical findings are not parallel to the disease activity of IBD and are difficult to use in treatment monitoring. Therefore, non-invasive quantitative imaging tools are required for the multiple follow-up exams of IBD patients in order to monitor the disease activity and determine treatment regimens. In this study, we evaluated a dual P- and E-selectin-targeted microbubble (MB Selectin ) in an interleukin-2 receptor α deficient (IL-2Rα -/- ) spontaneous chronic IBD mouse model for assessing long-term anti-inflammatory effects with ultrasound molecular imaging (USMI). We used IL-2Rα -/- (male and female on a C57BL/6 genetic background; n = 39) and C57BL/6 wild-type (negative control; n = 6) mice for the study. USMI of the proximal, middle, and distal colon was performed with MB Selectin using a small animal scanner (Vevo 2100) up to six times in each IL-2Rα -/- mouse between 6-30 weeks of age. USMI signals were compared between IL-2Rα -/- vs. wild-type mice, and sexes in three colonic locations. Imaged colon segments were analyzed ex vivo for inflammatory changes on H&E-stained sections and for selectin expression by immunofluorescence staining. We successfully detected spontaneous chronic colitis in IL-2Rα -/- mice between 6-30 weeks (onset at 6-14 weeks) compared to wild-type mice. Both male and female IL-2Rα -/- mice were equally ( p = 0.996) affected with the disease, and there was no significant ( p > 0.05) difference in USMI signals of colitis between the proximal, middle, and distal colon. We observed the fluctuating USMI signals in IL-2Rα -/- mice between 6-30 weeks, which might suggest a resemblance of the remission-flare pattern of human IBD. The ex vivo H&E and immunostaining further confirmed the inflammatory changes, and the high expression of P- and E-selectin in the colon. The results of this study highlight the IL-2Rα -/- mice as a chronic colitis model and are suitable for the long-term assessment of treatment response using a dual P- and E-selectin-targeted USMI.

We characterized the size of the premarket safety population for 278 small-molecule new molecular entities (NMEs) and 61 new therapeutic biologics (NTBs) approved by the US Food and Drug Administration (FDA) between October 1, 2002, and December 31, 2014, evaluating the relationship of premarket safety population size to regulatory characteristics and postmarket safety outcomes. The median size of the safety population was 1,044, and was lower for NTBs than NMEs (median: 920 vs. 1,138, P = 0.04), orphan products than nonorphan products (393 vs. 1,606, P < 0.001), and for products with fast-track designation (617 vs. 1,455, P < 0.001), priority review (630 vs. 1,735, P < 0.001), and accelerated approval (475 vs. 1,164, P < 0.001), than products without that designation. The median number of postmarket safety label updates and issues added to the label were higher with larger premarket exposure among nonorphan products, but not among orphan products. Products with accelerated approval using a surrogate end point had a higher median number of safety issues added to the label than those with full approval, but this did not vary with the size of the safety population; fast-track and priority review were not associated with the number of safety issues added to the label. A smaller safety population size was associated with a longer time to first safety outcome for nonorphan products but not orphan products. For orphan and nonorphan products combined, smaller premarket safety population size is not associated with the number or timing of postmarket safety outcomes, regardless of expedited program participation., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

Hybrid wheat breeding is one of the most promising technologies for further sustainable yield increases. However, the cleistogamous nature of wheat displays a major bottleneck for a successful hybrid breeding program. Thus, an optimized breeding strategy by developing appropriate parental lines with favorable floral trait combinations is the best way to enhance the outcrossing ability. This study, therefore, aimed to dissect the genetic basis of various floral traits using genome-wide association study (GWAS) and to assess the potential of genome-wide prediction (GP) for anther extrusion (AE), visual anther extrusion (VAE), pollen mass (PM), pollen shedding (PSH), pollen viability (PV), anther length (AL), openness of the flower (OPF), duration of floret opening (DFO) and stigma length. To this end, we employed 196 ICARDA spring bread wheat lines evaluated for three years and genotyped with 10,477 polymorphic SNP. In total, 70 significant markers were identified associated to the various assessed traits at FDR ≤ 0.05 contributing a minor to large proportion of the phenotypic variance (8-26.9%), affecting the traits either positively or negatively. GWAS revealed multi-marker-based associations among AE, VAE, PM, OPF and DFO, most likely linked markers, suggesting a potential genomic region controlling the genetic association of these complex traits. Of these markers, Kukri&#95;rep&#95;c103359&#95;233 and wsnp&#95;Ex&#95;rep&#95;c107911&#95;91350930 deserve particular attention. The consistently significant markers with large effect could be useful for marker-assisted selection. Genomic selection revealed medium to high prediction accuracy ranging between 52% and 92% for the assessed traits with the least and maximum value observed for stigma length and visual anther extrusion, respectively. This indicates the feasibility to implement genomic selection to predict the performance of hybrid floral traits with high reliability.

We examined the relationship of regulatory and review characteristics to postmarketing safety-related regulatory actions for 61 new therapeutic biologics (NTBs) approved between October 1, 2002 and December 31, 2014. We also compared NTBs with small-molecule new molecular entities (NMEs) on these measures. Postmarketing safety-related regulatory actions were defined as a safety-related withdrawal or a safety-related update to a safety section of the label through June 30, 2018. Four NTBs were withdrawn, two for safety reasons. At least one safety-related update was added to the labels of 54 (88.5%) NTBs. Label updates occurred throughout the follow-up period. Time to the first safety-related regulatory action was shorter for NTBs approved under accelerated approval. The occurrence of safety events was more likely to occur with NTBs than with NMEs. This may be explained in part by the higher proportion of NTBs in the anatomical therapeutic chemical classification categories with higher frequency of safety-related updates. NTBs also had shorter time to safety events than NMEs. These findings underscore the importance of continued development of the life cycle safety surveillance system for both drugs and biologics with consideration for product type and its characteristics, including pharmacologic action., (Published 2020. This article is a US Government work and is in the public domain in the USA.)

Over the last two decades, liquid perfluorocarbon nanodroplets (PFC-NDs), also known as Phase Change Contrast Agents (PCCAs), that are capable of vaporizing into gaseous echogenic microbubbles via an external stimulus, have gained much attention for diagnostic and therapeutic applications. In the present work, a microfluidic platform is evaluated for the preparation of various size-controlled nanodroplets. Here, two major lines of investigations were carried out. The first was to define the microfluidic device settings for the preparation of nanodroplets depending on the nature of the encapsulating shell such as lipids, fluorinated surfactants and PLGA biopolymers as well as the liquid perfluorocarbon core (perfluoropentane, perfluorohexane). Specifically, the effect of the microfluidic system parameters, such as total flow rate and flow rate ratio on PFC-NDs attributes including size and uniformity was assessed. Secondly, a custom-made set-up, based on echogenicity signals from produced bubbles, was designed and successfully applied to determine the Acoustic Droplet Vaporization (ADV) threshold of PFC-NDs. Finally, the influence of various formulation parameters on the vaporization outcome was investigated depending on the PFC type and the encapsulating shell composition (soft versus hard shells). This study indicates the usefulness of this novel formulation platform enabling the rapid design and optimization of narrowly dispersed nanodroplets at a reliable yield and ultimately accelerate nanomedicines development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: In low- and middle-income countries, therapeutic options for advanced, refractory, or relapsing malignancies are limited due to local constraints such as cost of drugs, distance from oncology centers, and lack of availability of new anticancer drugs. Metronomics, which combines metronomic chemotherapy (MC) and drug repositioning, allows for the provision of new therapeutic options for patients in this setting., Aim of the Study: To evaluate the activity and toxicity of a metronomic regimen in Moroccan pediatric patients with refractory or relapsing malignancies., Patients and Methods: From July 2014 to January 2018, patients with refractory/relapsing solid tumors treated in five pediatric oncology centers were consecutively enrolled. The metronomic regimen consisted of 28-day cycles with daily oral administration of cyclophosphamide (30 mg/m 2 ) from days 1 to 21, together with oral etoposide (25 mg/m 2 ) from days 1 to 21 followed by break of one week and daily valproic acid (20 mg/kg) from days 1 to 28., Results: Ninety-eight children (median age, 8 years) were included. Underlying malignancies were neuroblastoma (24 patients), Ewing sarcoma (18), osteosarcoma (14), rhabdomyosarcoma (14), and miscellaneous tumors (28). A total of 557 cycles were given (median: 6; range, 1-18 cycles). One-year progression-free survival of our patients was 19%, and one-year overall survival was 22%. Complete response was obtained in three cases (3%), partial response in 11 cases (11%), and tumor stabilization for more than six months in 28 cases (28%)., Conclusion: This three-drug metronomic combination was well tolerated and associated with tumor response and disease stabilization in 42 patients even for a long period., (© 2020 Wiley Periodicals LLC.)

Introduction: The treatment of chronic myeloid leukemia (CML) has been revolutionized by the advent of tyrosine kinase inhibitors. The results of the IRIS trial demonstrated the efficacy and long-term safety profile of Imatinib. The objective of our work is to report the results at 15 years of treatment of CML in chronic phase with Imatinib in Morocco., Patients and Methods: Retrospective study realized at the hematology unit of CHU d'Ibn-Rochd in Casablanca, from January 2003 to September 2018, including all CML patients in the chronic phase at diagnosis, were treated with Imatinib for a minimum duration of 6 months., Results: In total, 318 patients were collected, the median age was 41.5 years, the sex ratio M/F was 0.7, the Sokal score was high in 56% of cases. The complete hematological response at 3 months was 92%, the complete cytogenetic response at 12 months and the cumulative response were obtained in 43% (29/67) and 55% (153/279) of the cases respectively, the molecular response was evaluated in 125 patients witch 85% were on major molecular response. On a median follow-up of 44 months, the OS and EFS at 10 years were 86% and 59%, respectively., Discussion: Our profile is characterized by a young age of the patients, the female predominance and a high Sokal score. The rate of complete cytogenetic response remains lower compared to what is described, however the survival rates as well as the tolerance were similar to those of the literature., (Copyright © 2020 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Microbubble ultrasound contrast agents have now been in use for several decades and their safety and efficacy in a wide range of diagnostic applications have been well established. Recent progress in imaging technology is facilitating exciting developments in techniques such as molecular, 3-D and super resolution imaging and new agents are now being developed to meet their specific requirements. In parallel, there have been significant advances in the therapeutic applications of microbubbles, with recent clinical trials demonstrating drug delivery across the blood-brain barrier and into solid tumours. New agents are similarly being tailored toward these applications, including nanoscale microbubble precursors offering superior circulation times and tissue penetration. The development of novel agents does, however, present several challenges, particularly regarding the regulatory framework. This article reviews the developments in agents for diagnostic, therapeutic and "theranostic" applications; novel manufacturing techniques; and the opportunities and challenges for their commercial and clinical translation., Competing Interests: Declaration of Competing Interest TB and SC are full time employees of Bracco Suisse. The other authors are hold full time academic positions and have the following company affiliations: ES is a founder and non-executive director of SonoTarg Ltd.; MB is a founder and chief scientific officer of Respirogen Inc., (Copyright © 2020 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Forward genetic screens with genome-wide CRISPR libraries are powerful tools for resolving cellular circuits and signaling pathways. Applying this technology to organoids, however, has been hampered by technical limitations. Here we report improved accuracy and robustness for pooled-library CRISPR screens by capturing sgRNA integrations in single organoids, substantially reducing required cell numbers for genome-scale screening. We applied our approach to wild-type and APC mutant human intestinal organoids to identify genes involved in resistance to TGF-β-mediated growth restriction, a key process during colorectal cancer progression, and validated hits including multiple subunits of the tumor-suppressive SWI/SNF chromatin remodeling complex. Mutations within these genes require concurrent inactivation of APC to promote TGF-β resistance and attenuate TGF-β target gene transcription. Our approach can be applied to a variety of assays and organoid types to facilitate biological discovery in primary 3D tissue models., Competing Interests: Declaration of Interests H.C. is an inventor on applications/patents related to organoid technology. The other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Inter-Symbol Interference (ISI) is one of the challenges of bio-inspired diffusion-based molecular communication. The degradation of the remaining molecules from a previous transmission is the solution that biological systems use to mitigate this ISI. While most prior work has proposed the use of enzymes to catalyze the molecules degradation, enzymes also degrade the molecules carrying the information, which drastically decreases the signal strength. In this paper, we propose the use of photolysis reactions, which use the light to instantly transform the emitted molecules so they no longer be recognized after their detection. The light will be emitted in an optimal time, allowing the receiver to detect as many molecules as possible, which increases both the signal strength and ISI mitigation. A lower bound expression on the expectation of the observed molecules number at the receiver is derived. Bit error probability expression is also formulated, and both expressions are validated with simulation results, which show a visible enhancement when using photolysis reactions. The performance of the proposed method is evaluated using Interference-to-Total-Received molecules metric (ITR) and the derived bit error probability.

Objective : Acute mouse models of inflammatory bowel disease (IBD) fail to mirror the chronic nature of IBD in patients. We sought to develop a chronic mouse IBD model for assessing long-term anti-inflammatory effects with ultrasound molecular imaging (USMI) by using dual P- and E-selectin targeted microbubbles (MB Selectin ). Materials and Methods : Interleukin 10 deficient (IL-10 -/- on a C57BL/6 genetic background; n=55) and FVB (n=16) mice were used. In IL-10 -/- mice, various experimental regimens including piroxicam, 2,4,6-trinitrobenzenesulfonic acid (TNBS) or dextran sulfate sodium (DSS), respectively were used for promoting colitis; colitis was induced with DSS in FVB mice. Using clinical and small animal ultrasound scanners, evolution of inflammation in proximal, middle and distal colon, was monitored with USMI by using MB Selectin at multiple time points. Imaged colon segments were analyzed ex vivo for inflammatory changes on H&E staining and for P-selectin expression on immunofluorescence staining. Results : Sustained colitis was not detected with USMI in IL-10 -/- or FVB mice with various experimental regimens. USMI signals either gradually decreased after the colitis enhancing/inducing drug/agents were discontinued, or the mortality rate of mice was high. Inflammation was observed on H&E staining in IL-10 -/- mice with piroxicam promotion, while stable overexpression of P-selectin was not found on immunofluorescence staining in the same mice. Conclusion : Sustained colitis in IL-10 -/- mice induced with piroxicam, TNBS or DSS, and in FVB mice induced with DSS, was not detected with USMI using MB Selectin , and this was verified by immunofluorescence staining for inflammation marker P-selectin. Thus, these models may not be appropriate for long-term monitoring of chronic colitis and subsequent treatment response with dual-selectin targeted USMI., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Aim: The goals of this paper are: to report the incidence of AML in elderly, to describe cytogenetic characteristics of this population, to observe rare and novel cytogenetic abnormalities and lastly, to compare our finding with that previously reported in the literature., Methods: We conducted a retrospective analysis of 283 patients with acute myeloid leukaemia (AML) treated in our unit, we will report the incidence of AML in elderly, describe cytogenetic characteristics of this population, observe rare and novel cytogenetic abnormalities and compare our finding with that previously reported in the literature., Results: Among the 283 patients, 157 (54.4%) patients performed the karyotype, the cytogenetic analysis failed in 17 cases (11%). Prognostic group distribution was found to be favorable in 8 patients (6%) with 6 cases of t (8; 21) and 2 cases of inv (16), intermediate group in 94 patients (67%), including 58 cases (41,5%) with a normal karyotype, and an unfavorable group in 38 patients (27%) including complex karyotype (15%), -5 or del 5q (3%), -7 or del 7q (3.5%), t (9; 22) (2%). Some rare anomalies were observed., Conclusion: However, the occurrence of a complex karyotype was more frequent than younger patients. In our unit, elderly benefit from supportive care, our study shows that it is a heterogeneous group and our treatment approach have to change especially for the patient from favourable risk group who can benefit from intensive chemotherapy. We have to improve our diagnosis with including molecular genetics that provides a documented substrate for a thoughtfully considered treatment plan.

Purpose To evaluate whether dual-selectin-targeted US molecular imaging allows longitudinal monitoring of anti-inflammatory treatment effects in an acute terminal ileitis model in swine. Materials and Methods The Institutional Animal Care and Use Committee approved all animal studies. Fourteen swine with chemically induced acute terminal ileitis (day 0) were randomized into the following groups: (a) an anti-inflammatory treatment group (n = 8; meloxicam, 0.25 mg per kilogram of body weight; prednisone, 0.5 mg/kg) and (b) a control group (n = 6; saline). US molecular imaging was performed with a clinical US machine after intravenous injection of clinically translatable dual P- and E-selectin-targeted microbubbles (5 × 10 8 /kg). Three inflamed bowel segments per swine were imaged at baseline, as well as on days 1, 3, and 6 after treatment initiation. At day 6, bowel segments were analyzed ex vivo for selectin expression levels by using quantitative immunofluorescence. Results After induction of inflammation, US molecular imaging signal increased at day 1 in both animal groups (P < .001). At day 3, signal in the treatment group decreased (P < .001 vs day 1), while signal in control animals did not significantly change (P = .18 vs day 1) and was higher (P = .001) compared with that in the treatment group. At day 6, signal in the treatment group further decreased and remained lower (P = .02) compared with that in the control group. Immunofluorescence confirmed significant (P ≤ .04) downregulation of both P- and E-selectin expression levels in treated versus control bowel segments. Conclusion Dual-selectin-targeted US molecular imaging allows longitudinal monitoring of anti-inflammatory treatment effects in a large-animal model of acute ileitis. This supports further clinical development of this quantitative and radiation-free technique for monitoring inflammatory bowel disease. © RSNA, 2018 Online supplemental material is available for this article.

Severe forms of periodontitis can often result in pathological tooth migration. In such cases, orthodontic realignment is an indispensable complement to periodontal management. However, in some cases involving very advanced periodontal destruction, the question arises as to the limits of conservative treatment. Are the results of orthodontic periodontic treatment stable over time? All orthodontic treatment must be preceded by reduction of the inflammation. This paper uses clinical cases to illustrate each step to be followed in the periodontal therapeutic process in order to achieve successful orthodontic-periodontal treatment from etiologic therapy to surgical decontamination and long-term periodontal follow-up., (Copyright © 2018 CEO. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: The goal of this study is to assess functional and aesthetic results of anterior lamellar resection with lid margin splitting of the upper lid in the treatment of cicatricial trachomatous entropion., Patients and Methods: Descriptive cross-sectional study of a series of 26 consecutive patients treated between January 2014 and December 2015. All patients were operated for cicatricial trachomatous entropion in our tertiary center using the technique of the anterior lamellar resection with lid margin splitting of the upper eyelid. All patients were followed for 6 to 12 months after surgery. The anatomical, functional and aesthetic results were evaluated six months after surgery. They were considered good if there was no recurrence of the entropion, no lashes in contact with the cornea and no associated eyelid complications., Results: The mean age of the patients was 68.5±10 years with a male predominance (sex ratio=1.8). The average initial corrected visual acuity was 0.65±0.35 LogMAR, ranging from counting fingers at 1m to 6/10. Involvement was bilateral in 34.6% of cases. Correction of the cicatricial entropion was achieved in 24 patients (92.3% of cases) and full correction of misdirected lashes without any contact with the ocular surface was obtained in 23 patients (88.4% of cases). The lid margin was regular in 88.4% of cases. A significant improvement of the tear film and corneal surface was observed in 84.6% of patients. During the follow-up period, no cases of recurrent entropion were reported., Discussion: Among the various surgical techniques, anterior lamellar resection with lid margin splitting is one that most respects the anatomy of the upper eyelid and allows precise intraoperative control of eyelid rotation and eversion of the misdirected lashes. Therefore, it reduces significantly the risk of recurrence and significantly enhances the aesthetic results of surgery., Conclusion: Anterior lamellar resection with lid margin splitting of the upper eyelid is a simple and effective technique that significantly improves the aesthetic result of cicatricial trachomatous entropion., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Purpose: To evaluate the aesthetic and functional results of the Köllner-Hughes tarsoconjonctival flap technique for large defects of over three-quarter of the lower eyelid., Patients and Methods: A retrospective descriptive study of a series of 15 patients treated between January 2013 and December 2015. We included all patients who underwent reconstructive surgery for a tumor involving more than three-quarter of the lower eyelid and sparing the canthi. Reconstruction of the lower eyelid defect was performed using Köllner-Hughes technique., Results: The mean age of our patients was 65.7±8 years. The sex ratio was 1.5 with male predominance. All patients had well-differentiated basal cell carcinoma of the lower eyelid. The average size of the eyelid defect induced by the surgery was 18±4mm. Release of the tarsoconjonctival flap was performed after a period of 8 to 10 weeks after the reconstructive surgery. After a mean follow-up of 12±6 months, the aesthetic and functional results were satisfactory in 86.7% of cases especially in terms of eyelid closure and protection of the ocular surface. Complications included erythema of the newly formed free edge in 26.7% of cases, keratinization and hypertrophy of the free edge in 20% of cases, the deformation of the upper free edge with an associated entropion in 20% of cases and lower eyelid retraction in 6.67% of cases. Ocular surface disease such assuperficial punctate keratitis or dry eye was found in 13.4% of cases., Discussion: Several authors have chosen the Köllner-Hughes technique to treat increasingly wide eyelid defects with very satisfactory results. Eyelid reconstruction with the Köllner and Hughes technique is a very attractive procedure because it offers several advantages. It is a quick and easy technique that covers wide defects over three-quarter of the lower eyelid well with very satisfactory cosmetic results and without significantly increasing morbidity at the donor site. In combination with additional procedures, this technique can totally reconstruct the lower eyelid. Despite all its benefits, the Köllner-Hughes tarsoconjonctival flap has some minor drawbacks, such as the need for two surgeries spaced a few weeks apart to open the palpebral fissure; therefore it is contraindicated for one-eyed patients and children because of the risk of amblyopia., Conclusion: The tarsoconjonctival flap as initially described by Köllner and Hughes was indicated in the reconstruction of moderate and medium-sized defects of the lower eyelid. In our practice, we can extend the indications of this technique to much larger defects than three-quarter of the lower eyelid, while ensuring satisfactory aesthetic results and minimal complications., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

A xenogeneic collagen matrix recently has been suggested as an alternative to connective tissue graft for the treatment of gingival recession. The matrix avoids the second surgical site, and as a consequence could decrease surgical morbidity. This new matrix was used in various clinical situations and compared to connective tissue graft (CTG) in a split-mouth design case series. A total of 17 recessions were treated with a coronally advanced flap, 9 with CTG, and 8 with the matrix. Mean recession reduction was 2.00 mm with the CTG and 2.00 mm with the matrix. No significant statistical differences between the techniques were observed in this case report.

Introduction: The prevalence of pseudoexfoliation syndrome is estimated at 8 % of all cataracts operated within our institution. The goal of our study was to describe the frequency of intraoperative and postoperative complications and long-term anatomical and functional results of phacoemulsification in pseudoexfoliation syndrome., Patients and Methods: A retrospective observational study of a series including 103 patients (107 eyes) with cataract associated with pseudoexfoliation syndrome admitted between January 2010 and September 2014. All patients underwent phacoemulsification., Results: The average age of our patients was 72.5±6 years. The average initial corrected visual acuity was 0.52±0.14LogMAR. The cataract was grade C3N3 in 58 % of cases. The pseudoexfoliation syndrome was bilateral in 69 % of cases. Pupillary dilatation was≤6mm in 54 % of cases. Among intraoperative complications, zonular dialysis was found in 1.8 % of cases. Posterior capsular rupture and vitreous loss was noted at 5.4 % of patients. The incidence of secondary cataract was 31.7 % at 12 months. The mean postoperative best corrected visual acuity was 0.13±0.15 LogMAR., Discussion: The small pupil associated with high grade of the cataracts in our series explains the slightly higher frequency of intraoperative zonular dialysis. Cataract surgery by phacoemulsification allows for a statistically significant improvement in visual acuity (P<0.001). The incidence of secondary cataract, the main postoperative complication, is higher in our series compared to data in the literature., Conclusion: Pseudoexfoliation syndrome is common in our country. Functional results of phacoemulsification are very satisfactory, and secondary cataract is the main complication. A meticulous search for pseudoexfoliation is mandatory during the initial examination in order to reduce intraoperative complications. Careful removal of the cortex and systematic polishing of the lens capsule should limit the incidence of secondary cataracts., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: Previous studies have reported that up to 75 % of milk allergic subjects tolerate heated milk products. However, the food used for heated milk challenge is often prepared in a non-standardized manner by the parents at home, which may prove inconvenient and even sometimes raise concerns with regards to test validity. Instant skim milk powder is made by a food process that involves heating skim milk to up to 250 °C (390 °F) for up to 30 min which ought to be sufficient to denature thermo-labile proteins., Objective: To appraise the use of instant skim milk for the purpose of heated milk food challenge., Methods: We reviewed all oral food challenges to instant skim milk powder performed at Sainte-Justine University Hospital Center in Montreal, Canada between November 2008 and January 2013 (cumulative dose of 4 g proteins)., Results: During the study period, 39 children underwent an open food challenge to instant skim milk powder. Thirty patients (76.9 %) passed the challenge without clinical reaction, of which 26 successfully introduced heated milk products at home. The remaining four children reported intermittent mild reactions to specific forms of heated milk goods while they tolerated others. Subjects' clinical and paraclinical characteristics were comparable to previous cohorts evaluating baked milk challenge, which reported similar rates of heated milk positive challenges, ranging from 17 to 28 %., Conclusion: Challenge with instant skim milk powder could be a safe, convenient and easily standardizable alternative to home baked food for heated milk challenge. Further controlled studies are needed before this can be implemented to practice.

Sickle cell anemia results from a single amino acid substitution in the gene encoding the β-globin subunit. Polymerization of deoxygenated sickle hemoglobin leads to decreased deformability of red blood cells. Hashimoto's thyroiditis is a common thyroid disease now recognized as an auto-immune thyroid disorder, it is usually thought to be haemolytic autoimmune anemia. We report the case of a 32 years old women admitted for chest pain and haemolysis anemia in which Hashimoto's thyroiditis and sickle cell anemia were found. In our observation the patient is a young woman whose examination did not show signs of goitre but the analysis of thyroid function tests performed before an auto-immune hemolytic anemia (confirmed by a high level of unconjugated bilirubin and a Coombs test positive for IgG) has found thyroid stimulating hormone (TSH) and positive thyroid antibody at rates in excess of 4.5 times their normal value. In the same period, as the hemolytic anemia, and before the atypical chest pain and anguish they generated in the patient, the search for hemoglobinopathies was made despite the absence of a family history of haematological disease or painful attacks in childhood. Patient electrophoresis's led to research similar cases in the family. The mother was the first to be analyzed with ultimately diagnosed with sickle cell trait have previously been ignored. This case would be a form with few symptoms because the patient does not describe painful crises in childhood or adolescence.

Background: We previously estimated that the annual rate of accidental exposure to peanut in 1411 children with peanut allergy, followed for 2227 patient-years, was 11.9% (95% CI, 10.6, 13.5). This cohort has increased to 1941 children, contributing 4589 patient-years, and we determined the annual incidence of accidental exposure, described the severity, management, location, and identified associated factors., Findings: Children with physician-confirmed peanut allergy were recruited from Canadian allergy clinics and allergy advocacy organizations from 2004 to May 2014. Parents completed questionnaires regarding accidental exposure to peanut over the preceding year. Five hundred and sixty-seven accidental exposures occurred in 429 children over 4589 patient-years, yielding an annual incidence rate of 12.4% (95% CI, 11.4, 13.4). Of 377 accidental exposures that were moderate or severe, only 109 (28.9%) sought medical attention and of these 109, only 40 (36.7%) received epinephrine. Of the 181 moderate/severe accidental exposures treated outside a health care facility, only 11.6% received epinephrine. Thirty-seven percent of accidental exposures occurred at home. In multivariate analyses, longer disease duration, recruitment through an allergy advocacy association, and having other food allergies decreased the likelihood of accidental exposures. Age ≥ 13 years at study entry and living with a single parent increased the risk., Conclusion: Despite increased awareness, accidental exposures continue to occur, mainly at home, and most are managed inappropriately by both health care professionals and caregivers. Consequently, more education is required on the importance of strict allergen avoidance and the need for prompt and correct management of anaphylaxis.

The objective of this study was to tailor a drug release profile through the adjustment of some key processing parameters involved in melt-extrusion: die temperature, shear rate, die length and drug particle size. Two experimental designs were selected, namely a 2-level full factorial design to examine the effects and significance of the processing factors, and a central composite design of the surface responses to find the best set of factor levels to obtain given specifications of drug release. Extrudates of poly(ethylene-co-vinyl acetate) and phenylpropanolamine hydrochloride were prepared using a ram extruder. Drug release profiles from the matrix systems were fitted using a power law, for which a new mathematical expression of a burst release was provided. The burst release and exponent were selected as the responses. The processing factors had a drastic influence on the drug release. Within the domain that was investigated, the burst release and the exponent varied from 6 to 54% and 0.1 to 0.4, respectively, resulting in a time requires for 50% drug release extending from hours to weeks. These results demonstrated the possibilities of modulating the release profile by means of the processing parameters rather than through the classical approach of altering the formulation., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In the frame of our molecular imaging activities, a PEGylated lipopeptide has been developed as a specific ligand for the human vascular endothelial growth factor receptor 2, which is considered as one of the important molecular marker of angiogenesis. In this study, the potential of affinity capillary electrophoresis (ACE) is evaluated to measure the interactions of an active PEGylated lipopeptide, its hydrolysis product and its precursor consisting of a peptide structure with different micelles including Brij-35, Tween-20, and pegylated phospholipids. Given the amphiphilic structure of the PEGylated lipopeptide, a MEKC method allowing the simultaneous separation of the compounds of interest was set up, using low percentages of acetonitrile. Analytes were resolved using a BGE consisting of 100 mM borate buffer pH 9.0, 1 mM Brij, and 25% acetonitrile. Optimized conditions were then used to perform ACE experiments. The affinity constants of the analytes with the micelles were calculated on the basis of their mobility decrease when surfactant concentration increased in the electrolyte. The use of different linearization models to estimate affinity constants was discussed and comparison of different surfactants was reported. PEGylated lipopeptide interacted more strongly with pegylated phospholipid micelles than with Brij-35 or Tween-20. Moreover, it is likely that the chemical structure of the compounds, and particularly the lipidic part of the molecules, significantly affects the interaction with micelles. In conclusion, the ACE method can be readily applied to investigate interactions of our targeting lipopeptides with various micelles currently used for the preparation of pharmaceutical vehicles., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: HAI cause considerable morbidity and mortality and are associated with prolonged hospital stay and increased health care costs. To describe the incidence of HAI in paediatric cancer patients as the first step towards improving infection control policies., Methods: A prospective surveillance study was performed in the Casablanca university hospital paediatric haematology/oncology unit over an 8-month period from January to August 2011. Data including extrinsic risk factors associated with HAI were recorded., Results: The incidence of HAI was 28 per 1000 patient-days. The median age was 9.6 years and the most frequent diagnosis was acute myeloid leukaemia (32%). Neutropenia at diagnosis was significantly correlated with the risk of HAI. 55.7% of HAls were nosocomial fever of unknown origin. Gram-negative bacteria were the main pathogens (60%), gram-positive cocci were responsible for 26% of HAI and Candida for 14% of HAI. The length of hospital stay for patients with and without infection were 16.5 and 5 days, respectively (P < 0.001). Six of the 11 deaths were related to HAI., Conclusion: These findings suggest the need to evaluate infection control measures in order to reduce morbidity and mortality in paediatric haematology/oncology units.

Primary pericardial synovial sarcoma is extremely rare, with few published cases in the literature. We report the case of an adolescent aged 13 years with primary pericardial synovial sarcoma discovered during tamponade, confirmed by molecular biology, and for whom treatment combined radiosurgery and adjuvant chemotherapy. The particularity of the case we are reporting stems from the young age of our patient (13 years) as well as the duration of remission, which is quite long (21 months) prior to a superior mediastinal relapse compared to cases reported in the literature. < Learning objective: Synovial sarcoma is difficult to diagnose and has a poor prognosis. Here, a 13-year-old diagnosed with primary pericardial synovial sarcoma was treated with combined radiosurgery and adjuvant chemotherapy leading to continuous remission for 21 months. This regimen could be used to successfully manage future patients. Molecular biology is useful in the diagnosis of synovial sarcoma through the identification of t(X;18) translocation in atypical locations as in the present case.>.

Prompt epinephrine administration is crucial in managing anaphylaxis, but epinephrine auto-injectors (EAIs) are underutilized by patients and their families. Children with peanut allergy were recruited from the Allergy Clinics at the Montreal Children's Hospital, food allergy advocacy organizations and organizations providing products to allergic individuals. Parents of children who had been prescribed an EAI were queried on whether they were fearful of using it and on factors that may contribute to fear. A majority of parents (672/1209 = 56%) expressed fear regarding the use of the EAI. Parents attributed the fear to hurting the child, using the EAI incorrectly or a bad outcome. Parents whose child had longer disease duration or a severe reaction and parents who were satisfied with the EAI training or found it easy to use were less likely to be afraid. Families may benefit from simulation training and more education on the recognition and management of anaphylaxis., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Overall survival from leukemia is less in low and middle-income countries than in high-income countries. Our purpose was to describe the incidence, clinical features, and mortality of febrile illness with or without documented infection in children and young adults treated for AML and ALL in two centers in Rabat and Casablanca during 2011., Methods: This retrospective cohort study included patients <30 years of age who were newly diagnosed with AML and ALL in 2011 in Casablanca and Rabat. Each patient's chart was evaluated for patient demographics, febrile episodes, chemotherapy regimen, and clinical or microbiological evidence of infection, neutropenia, antibiotics, and mortality., Results: One hundred sixty-six evaluable patients had 228 inpatient febrile episodes. The median number of febrile episodes in AML was three per patient, and for ALL, one per patient. Clinically identified infections mainly included pneumonitis and mucositis. Coagulase negative staphylococcus was the most commonly isolated bacterium, followed by gram-negative bacteria. Fifty-three percent of febrile episodes were classified as fever of undetermined origin. Broad-spectrum antibiotics were routinely used, with the addition of antifungals in 62 episodes and vancomycin in 83 episodes. The rate of deaths per febrile illness was 11.3% (16/141) in patients with AML, and 9.2% (8/87) in patients with ALL., Conclusion: The higher rate of infectious deaths in leukemia compared to that reported in high-income countries, suggests that improvements in infection care and prevention, including consistent access to rapid hospitalization, diagnostics and antibiotics; and standardizing quality of patient care are necessary to improve as well as survival in patients with leukemia in Morocco., (Copyright © 2013 Wiley Periodicals, Inc.)

MYCN protooncogene status was assessed for the first time in Morocco in peripheral neuroblastic tumors, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Correlations with age at diagnosis, stage, mitosis-karyorrhexis index, differentiation, and Shimada histology were evaluated. Thirty-six formalin-fixed, paraffin-embedded peripheral neuroblastic tumor tissue specimens collected between 2007 and 2010 from the Pathology Department were assessed for MYCN amplification using fluorescence in situ hybridization. MYCN amplification was found in 27.8% of cases. An association of MYCN amplification with unfavorable Shimada grading, higher mitosis-karyorrhexis index, and undifferentiated morphologic phenotype was found. We found no correlation with older age, advanced stage, or the presence of metastasis. Our results suggested that the presence of MYCN amplification is a strong biological indicator of a poor outcome and aggressive disease in neuroblastoma and nodular ganglioneuroblastoma.

Due to their high specificity and efficiency, antibodies are ideal ligands for target-specific ultrasound contrast agents. The present study focuses on the chemical stability of antibodies during functionalisation with sulfosuccinimidyl-pyridyldithiopropionamidohexanoate (SPDP), a heterobifunctional linker, which exposes free thiol groups upon treatment with a reducing agent. Thiolated antibodies can then react with thiol-reactive group, such as maleimide present on the microbubble surface to form stable covalent complexes. The immunoglobulin structure relies on several intra- and inter-chain disulfide bridges which might be affected by reducing agents. A capillary electrophoresis-sodium dodecyl sulfate (CE-SDS) method with UV detection was applied to address the effect of the functionalisation process on the structural integrity of the antibodies and revealed that antibody disulfide bonds are prone to reduction as function of the reducing agents. Depending on the coupling conditions, various IgG fragments were identified reflecting different combinations between the light and heavy chains. Furthermore, two commonly used reducing agents, namely triscarboxyethylphosphine (TCEP) and 1,4-dithiothreitol (DTT) were compared under various preparation conditions. Results showed that reduction conditions based on DTT as a reducing agent under acidic pH were more appropriate to preserve intra- and inter-disulfide bridges of SPDP-modified antibodies.

The transition of a targeted ultrasound contrast agent from animal imaging to testing in clinical studies requires considerable chemical development. The nature of the construct changes from an agent that is chemically attached to microbubbles to one where the targeting group is coupled to a phospholipid, for direct incorporation to the bubble surface. We provide an efficient method to attach a heterodimeric peptide to a pegylated phospholipid and show that the resulting construct retains nanomolar affinity for its target, vascular endothelial growth factor receptor 2 (VEGFR2), for both the human (kinase insert domain-containing receptor - KDR) and the mouse (fetal liver kinase 1 - Flk-1) receptors. The purified phospholipid-PEG-peptide isolated from TFA-based eluents is not stable with respect to hydrolysis of the fatty ester moieties. This leads to the time-dependent formation of the lysophospholipid and the phosphoglycerylamide derived from the degradation of the product. Purification of the product using neutral eluent systems provides a stable product. Methods to prepare the lysophospholipid (hydrolysis product) are also included. Biacore binding data demonstrated the retention of binding of the lipopeptide to the KDR receptor. The phospholipid-PEG2000-peptide is smoothly incorporated into gas-filled microbubbles and provides imaging of angiogenesis in a rat tumor model.

We present the incidence and the immunologic characteristics of acute lymphoblastic leukemia (ALL) subsets in Moroccan children. We studied 279 unselected patients below the age of 18 years with newly diagnosed ALL. Cases were classified according to immunophenotype: 216 (77.42%) precursor B-cell phenotype (pB-cell), mature B-cell in 4 (1.43%), and T-cell in 59 (21.15%) cases. The subclassification using the CD10 antibody revealed 197 cases pB-ALL CD10+ (91.2%) and 9 cases T-ALL CD10+ (19.2%). The age distribution showed a peak in incidence between 3 and 5 years among the pB-cell ALLs subtype. There was a significantly higher frequency of males in the T-ALL subset (M/F ratio: 2.93 : 1) and more females in the T-ALL CD10+ subset when compared with the T-ALL CD10- subset. All tested pB-cell-lineage ALLs expressed CD19, CD79a, and surface CD22, terminal deoxynucleotidyl transferase (TdT) was detectable in 89.9% of cases, and cells in 74.1% of cases express CD34. All tested T-lineage ALL cells have surface CD7 and cytoplasmic CD3 (cCD3) antigens, CD5 was found in 98.2% cases, and 70.5% express TdT. CD1a, surface CD3 (sCD3), and CD4 are detected in more than 80% of cases; this frequency is higher than the 45% generally observed. Myeloid antigens occur more frequently and were expressed in 124 (57.4%) of pB-cell-ALL cases and 20 (33.9%) of T-cell ALL cases. Our results show that the distribution of ALLs in Moroccan children is similar with the general distribution pattern in developed countries except for the high frequency of T-ALL phenotype. The phenotypic profiles of our patients are close to those reported in literature for B-lineage ALLs; for the T-cell ALL subgroup, the blast cells express more CD1a, surface CD3, and CD4 while expressing less TdT. The high frequency of CD1a expression resulted in an excess of the common thymocyte subtype.

Objective: To investigate and explain unexpected fertility in a man with der(22;22)(q10;10q)., Design: Lymphocyte cultures, cytogenetic preparation, microsatellite genotyping analysis, affiliation test using AmpFlSTR Profiler PlusTM PCR amplication., Setting: Research laboratory., Patient(s): Human lymphocyte cells., Intervention(s): Genetic counselling., Main Outcome Measure(s): ISCN (International System for human Cytogenetic Nomenclature). International recommendations and nomenclature of molecular biology., Results: The cytogenetic analysis of the father and his son revealed the presence of a der(22;22)(q10;10q). The mother's karyotype was normal. Molecular study including microsatellite markers of chromosomes 22 and the paternity test confirmed the inheritance of this paternal rearrangement with the lack of the maternal 22 chromosome., Conclusion(s): No paternally imprinted genes with major effects map to chromosome 22, although a later effect on the child's fertility is expected.

Dextromethorphan (DEM) is a widely used probe drug for human cytochrome P450 2D6 isozyme activity assessment by measuring the ratio between DEM and its N-demethylated metabolite dextrorphan (DOR). DOR is excreted in urine mainly conjugated to glucuronic acid. Prior to quantification, DOR must be deconjugated to avoid variability caused by the polymorphic glucuronosyltransferase enzyme. A chemical hydrolysis method was optimized using a chemometric approach. Three factors (acid concentration, hydrolysis time and temperature) were selected and simultaneously varied to study their effect on conjugated DOR hydrolysis. Hydrolysis conditions that maximize DOR release without significant degradation of both DEM and DOR were chosen and results were compared to those obtained by enzymatic method using beta-glucuronidase. An HPLC method with fluorescence detection was developed for the simultaneous quantitation of DEM, DOR and levallorphan, used as an internal standard. Separation was performed on a phenyl analytical column (150 mmx4.6 mm i.d., 5 microm) with a mobile phase consisting of 18% acetonitrile and 50 mM phosphoric acid (pH 3). The overall analytical procedure was validated and showed good performances in terms of selectivity, linearity, sensitivity, precision and accuracy. Finally, this assay was used to determine DEM/DOR molar ratios in fibromyalgia patients for the purpose of determining phenotype status for the CYP2D6.

Willebrand's disease is the most frequent inborn coagulopathy and type 3 is its most severe form. Pregnancy and delivery are critical events in women with Willebrand's disease of type 3. Prophylactic treatment for delivery and early postpartum period is recommended. We report the management of pregnancy and successful delivery of a 32-year-old woman with type 3. Prophylactic treatment with 2000 IU of Willebrand's disease factor (WdF) was given twice a day during the delivery day and the day after, and 1000 IU per day during the next three days. The patient did not show any spontaneous metrorrhagia but anemia. No bleeding was observed in the newborn.

A focused microwave-assisted extraction method was developed for the extraction of diosgenin from fenugreek (Trigonella foenum-graecum) seeds, air-dried and fresh leaves and air-dried roots. Several experimental parameters were studied, including extraction time, microwave power applied and percentage of 2-propanol in the extraction mixture as well as their interactions, in order to optimize the extraction efficiency. The two latter parameters were found to be the most important. Response surface modelling was used to predict the extraction yield of diosgenin in selected matrices. The analysis of diosgenin in crude extracts was carried out by capillary gas chromatography-mass spectrometry (GC-MS).

An efficient, fast and reliable analytical method was developed for the simultaneous evaluation of the activities of five major human drug metabolising cytochrome P450 (1A2, 2C9, 2C19, 2D6 and 3A4) with a cocktail approach including five probe substances, namely caffeine, flurbiprofen, omeprazole, dextromethorphan and midazolam. All substances were administered simultaneously and a single plasma sample was obtained 2h after the administration. Plasma samples were handled by liquid-liquid extraction and analysed by gradient high performance liquid chromatography (HPLC) coupled to UV and fluorescence detectors. The chromatographic separation was achieved using a Discovery semi-micro HS C18 HPLC column (5 microm particle size, 150 mm x 2.1 mm i.d.) protected by a guard column (5 microm particle size, 20 mm x 2.1 mm i.d.) The mobile phase was constituted of a methanol, acetonitrile and 20mM ammonium acetate (pH 4.5) with 0.1% triethylamine mixture and was delivered at a flow rate of 0.3 mL min(-1). All substances were separated simultaneously in a single run lasting less than 22 min. The HPLC method was formally validated and showed good performances in terms of linearity, sensitivity, precision and accuracy. Finally, the method was found suitable for the screening of these compounds in plasma samples.