Multinodular goiter and parotid carcinoma : a new case of Cowden's disease

Cowden's Disease is an autosomal dominant genodermatosis associated with abnormalities of the breast, thyroid gland, gastrointestinal tract. We describe a 23-year-old girl who was diagnosed with this disease when she consulted for evaluation of a multinodular goiter. Further investigations revealed breast lesions, gastric polyposis and parotid cancer. Recognizing Cowden's disease is important for prompt screening for malignancies. Skin lesions are markers of precancerous development.     

Mechanisms underlying lipopolysaccharide-induced kinin B1 receptor up-regulation in the pig iris sphincter in vitro

Kinin B1 receptors are known to be highly induced after inflammatory stimuli in several biological systems. We report that incubation of pig iris sphincter with lipopolysaccharide from Escherichia coli caused a marked and time-related up-regulation of B1, accompanied by a reduction of B2 receptor-mediated contractile responses. The up-regulation of B1 receptors by lipopolysaccharide stimulation was decreased by the inhibitors of protein synthesis, cycloheximide and actinomycin D, and by dexamethasone and the nuclear factor-kappaB (NF-kappaB) inhibitor pyrrolidinedithiocarbamate (PDTC). In addition, lipopolysaccharide-induced up-regulation of B1 receptors in the pig iris sphincter was significantly reduced by the p38 inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) and to a lesser extent by the extracellular signal-regulated kinases 1 and 2 (ERK1/2) blocker 2'-amino-3'-methoxyflavone (PD98059). Molecular biology experiments demonstrated that in vitro incubation with lipopolysaccharide resulted in a time-dependent and remarkable activation of NF-kappaB and of p38 and ERK1/2 mitogen-activated protein (MAP) kinases, in pig iris sphincter preparations. While attempting to verify how MAP kinases are part of the B1 receptor-activated signaling transduction pathways, we observed that PD98059 was able to markedly reduce the contraction induced by B1 receptor activation in lipopolysaccharide-pretreated pig iris sphincter muscle but that this response was only partially decreased by SB203580. Our results extend the previous evidence on the mechanisms underlying the B1 receptor upregulation processes and demonstrate for the first time how this takes place in an ocular tissue, the pig iris sphincter. It is therefore possible to define B1 receptors as therapeutic targets for the treatment of infectious and inflammatory alterations of the eye.     

Curiethérapie à haute dose dans le cancer du col utérin : utilisation de l’applicateur en anneau

Purpose

To evaluate the local control and the tolerance of cervical high-dose-rate (HDR) brachytherapy using an applicator ring.

Patients and methods

This is a retrospective study of 105 patients treated in the radiotherapy department for cervical cancer and who received brachytherapy in HDR with an applicator ring in addition to external-beam radiation therapy (EBRT) at the National Institute of Oncology (INO) in Rabat between January 2007 and October 2012.

Results

The mean age of our population was 51.7 ± 12.7 years old; According to the International Federation of Gynecology and Obstetrics (FIGO) 52.4% of patients were stage II, 28.6% stage I, and 19% stage III. Dosimetry was in 2D for 83 patients (78.2%) and 3D for 22 patients (22.8%). For 2D dosimetry, the mean dose to point A was 7.66 ± 0.46 Gy, the mean dose to the bladder point was 4.5 ± 1.5 Gy, and the average dose at the rectum point was 2.7 ± 1.4 Gy. The biological equivalent doses (BED) averages were 91.8 ± 23.2 Gy for the bladder and 68 ± 16 Gy for the rectum (including the dose received by the EBRT with α/β = 3 for organs at risk (OAR). In 3D dosimetry the BED averages for the volume 2 cm³ were 5.8 ± 0.5 Gy for the bladder and 3.5 ± 0.7 Gy for the rectum, with an equivalent 2 Gy dose (EQD2) average of 86 ± 6 Gy for the bladder and 65 ± 7 Gy for the rectum. The mean dose to CTV high risk (D₉₀) was 86.44 ± 3.45 Gy. After a median follow-up of 23 months, the evolution was marked by three local recurrences, two lymph node recurrences and one lung metastases; the rate of recurrence-free survival in our population was 83.7%. Side effects found in our patients were as follows: radiation cystitis in 16 cases (69% grade 1 and 31% grade 2) and radiation proctitis in 8 cases 56% of our patients presented vaginal narrowing (synechiae, atresia). No statistically significant correlation was found between the occurrence of complications and the type of dosimetry (2D or 3D).

Conclusion

Using the applicator ring in cervical HDR brachytherapy provides good local control with acceptable complications.     

MLPA and sequence analysis of DPY19L2 reveals point mutations causing globozoospermia

STUDY QUESTION: Do DPY19L2 heterozygous deletions and point mutations account for some cases of globozoospermia? SUMMARY ANSWER: Two DPY19L2 heterozygous deletions and three point mutations were identified, thus further confirming that genetic alterations of the DPY19L2 gene are the main cause of globozoospermia and indicating that DPY19L2 molecular diagnostics should not be stopped in the absence of a homozygous gene deletion. WHAT IS KNOWN ALREADY: Globozoospermia is a rare phenotype of primary male infertility characterized by the production of a majority of round-headed spermatozoa without acrosome. We demonstrated previously that most cases in man were caused by a recurrent homozygous deletion of the totality of the DPY19L2 gene, preventing sperm head elongation and acrosome formation. In mammals, DPY19L2 has three paralogs of yet unknown function and one highly homologous pseudogene showing >95% sequence identity with DPY19L2. Specific amplification and sequencing of DPY19L2 have so far been hampered by the presence of this pseudogene which has greatly complicated specific amplification and sequencing. STUDY DESIGN, SIZE, DURATION: In this cohort study, 34 patients presenting with globozoospermia were recruited during routine infertility treatment in infertility centers in France and Tunisia between January 2008 and December 2011. The molecular variants identified in patients were screened in 200 individuals from the general population to exclude frequent non-pathological polymorphisms. PARTICIPANTS/MATERIALS, SETTING, METHODS: We developed a Multiplex Ligation-dependent Probe Amplification test to detect the presence of heterozygous deletions and identified the conditions to specifically amplify and sequence the 22 exons and intronic boundaries of the DPY19L2 gene. The pathogenicity of the identified mutations and their action on the protein were evaluated in silico. MAIN RESULTS AND THE ROLE OF CHANCE: There were 23 patients who were homozygous for the DPY19L2 deletion (67.6%). Only eight of the eleven non-homozygously deleted patients could be sequenced due to poor DNA quality of three patients. Two patients were compound heterozygous carrying one DPY19L2 deleted allele associated respectively with a nonsense (p.Q342*) and a missense mutation (p.R290H). One patient was homozygous for p.M358K, another missense mutation affecting a highly conserved amino acid. Due to the localization of this mutation and the physicochemical properties of the substituted amino acids, we believe that this variant is likely to disrupt one of the protein transmembrane domains and destabilize the protein. Overall, 84% of the fully analysed patients (n = 31) had a molecular alteration of DPY19L2. There was no clear phenotypic difference between the homozygous deleted individual, patients carrying a point mutation and undiagnosed patients. LIMITATIONS, REASONS FOR CAUTION: Globally poor fertilization rates are observed after intracytoplasmic sperm injection of round spermatozoa. Further work is needed to assess whether DPY19L2 mutated patients present a better or worse prognostic than the non-diagnosed patients. Evaluation of the potential benefit of treatment with a calcium ionophore, described to improve fertilization, should be evaluated in these two groups. WIDER IMPLICATIONS OF THE FINDINGS: In previous work, deletions of DPY19L2 had only been identified in North African patients. Here we have identified DPY19L2 deletions and point mutations in European patients, indicating that globozoospemia caused by a molecular defect of DPY19L2 can be expected in individuals from any ethnic background. STUDY FUNDING/COMPETING INTEREST(S): None of the authors have any competing interest. This work is part of the project 'Identification and Characterization of Genes Involved in Infertility (ICG2I)' funded by the program GENOPAT 2009 from the French Research Agency (ANR).     

Precision of the transpulmonary thermodilution measurements

Introduction  

We wanted to determine the number of cold bolus injections that are necessary for achieving an acceptable level of precision for measuring cardiac index (CI), indexed global end-diastolic volume (GEDVi) and indexed extravascular lung water (EVLWi) by transpulmonary thermodilution.     

Reduction of hospitalizations with diarrhea among children aged 0–5 years in Nouakchott,Mauritania, following the introduction of rotavirus vaccine

Introduction

Rotavirus vaccine was introduced in Mauritania in December 2014. We investigated hospitalizations with diarrhea during pre and post-vaccination periods among children aged 0–5?years in Nouakchott, the capital of Mauritania.