1. J Clin Endocrinol Metab. 2010 Jul 21. [Epub ahead of print]
Systematic Analysis of G Protein-Coupled Receptor Gene Expression in
Adrenocorticotropin-Independent Macronodular Adrenocortical Hyperplasia
Identifies Novel Targets for Pharmacological Control of Adrenal Cushing's
Syndrome.
Assie G, Louiset E, Sturm N, René-Corail F, Groussin L, Bertherat J, Thomas M,
Lefebvre H, Feige JJ, Clauser E, Chabre O, Cherradi N.
Université Paris Descartes (G.A., L.G., J.B., E.C.), Institut National de la
Santé et de la Recherche Médicale Unité 567 (G.A., F.R.-C., L.G., J.B., E.C.),
Institut Cochin, Centre National de la Recherche Scientifique (Unité Mixte de
Recherche 8104), and Assistance Publique Hôpitaux de Paris (G.A., L.G., J.B.),
Hôpital Cochin, Department of Endocrinology, Reference Center for Rare Adrenal
Diseases, 75014 Paris, France; Institut National de la Santé et de la Recherche
Médicale Unité 982/Equipe d'Accueil (E.L., H.L.), Différenciation et
Communication Neuronale and Neuroendocrine Laboratory, University of Rouen, 76821
Mont Saint Aignan, France; Laboratoire de Pathologie Cellulaire (N.S.) and
Department of Endocrinologie (O.C.), Centre Hospitalier Universitaire Albert
Michallon, 38043 Grenoble, France; Université Joseph Fourier (N.S., M.T.,
J.-J.F., N.C.), 38041 Grenoble, France; Institut National de la Santé et de la
Recherche Médicale, Unité 878 (M.T., J.-J.F., O.C., N.C.) and Commissariat à
l'Energie Atomique (M.T., J.-J.F., O.C., N.C.), Institut de Recherches en
Technoloqies et Sciences pour le Vivant/Laboratoire d'Angiogenése et
Physiopathologie Vasculaire, 38054 Grenoble, France; and Department of
Endocrinology (H.L.), Rouen University Hospital, Institute for Biomedial
Research, University of Rouen, 76031 Rouen, France.
Context: Stimulation of cortisol secretion through abnormally expressed G
protein-coupled receptors (GPCRs) is a frequent feature of ACTH-independent
macronodular adrenal hyperplasia (AIMAH). This has opened a pharmacological
strategy that targets GPCRs for the treatment of Cushing's syndrome in AIMAH.
However, only few drugs are available for the presently described GPCRs.
Objective: The objective of the study was to identify new GPCR targets for the
pharmacological treatment of adrenal Cushing's syndrome. Design and Patients: We
designed a cDNA chip containing 865 nucleotidic sequences of GPCRs. mRNAs were
extracted from three normal adrenals, 18 AIMAHs, four adrenals from Cushing's
disease patients, and 13 cortisol-secreting adenomas. A set of GPCR mRNAs that
showed significantly higher or lower expression in AIMAH than in normal adrenal
were studied by quantitative RT-PCR analysis. Analysis of protein expression and
function were performed on selected GPCRs. Setting: The study was conducted at a
tertiary care center and basic research laboratories. Results: The ACTH MC2
receptor showed a low expression in 15 of 18 AIMAHs samples, whereas several
previously undescribed GPCR genes were found highly expressed in a subset of
AIMAH, such as the receptors for motilin (MLNR; three of 18 AIMAHs) and
gamma-aminobutyric acid (GABBR1; five of 18 AIMAHs), and the alpha2A adrenergic
receptor (ADRA2A; 13 of 18 AIMAHs), on which we focused our attention. Western
blot and immunochemistry analyses showed expression of ADRA2A protein in AIMAH
but not in normal adrenal cortex. The ADRA2A agonist clonidine enhanced both
basal and stimulated cortisol production. Clonidine-induced increase in basal
cortisol levels was blocked by the ADRA2A antagonist yohimbine. Conclusion:
ADRA2A is a potential target for pharmacological treatment of Cushing's syndrome
linked to AIMAH.
PMID: 20660048 [PubMed - as supplied by publisher]
2. J Alzheimers Dis. 2010 Jul 15. [Epub ahead of print]
Frontotemporal Dementia Phenotype Associated with MAPT Gene Duplication.
Rovelet-Lecrux A, Hannequin D, Guillin O, Legallic S, Jurici S, Wallon D,
Frebourg T, Campion D.
Inserm U614, University of Medicine, Rouen, France.
Microduplications at 17q21.31 have recently been reported in children with mental
retardation, autism spectrum disorders and/or dysmorphic features, as well as in
a single schizophrenic patient. This rearrangement encompasses the microtubule
associated protein tau (MAPT) gene, mutations of which are a major cause of
frontotemporal lobar degeneration (FTLD). However, no 17q21.31 microduplication
has been so far identified in this condition. We screened chromosomal
rearrangements in FTLD patients using quantitative multiplex PCR of short
fluorescent fragments and high resolution array CGH. We found a 439-kb
microduplication at the 17q21.31 locus encompassing the MAPT, IMP5, CRHR1, and
STH genes in the index case of a family in which three patients have developed a
FTLD phenotype associated with marked memory impairment. None of these patients
had mental retardation or dysmorphic features. Since no pathological examination
was available, we are not certain that this case corresponds to a FTLD with
neuronal and glial tau inclusions (FTLD-tau), and we cannot exclude that any
other gene included in the rearrangement might be responsible for the
neurodegenerative process. However, the clinical phenotype of the three patients
is functionally consistent with the regional pattern of lesions previously
reported in mice overexpressing human tau.
PMID: 20634582 [PubMed - as supplied by publisher]
3. Fertil Steril. 2010 Jul 14. [Epub ahead of print]
Has B-Lynch suture hidden long-term effects?
Sentilhes L, Descamps P, Marpeau L.
Department of Obstetrics and Gynecology, Rouen University Hospital, Rouen,
France.
PMID: 20633876 [PubMed - as supplied by publisher]
4. Presse Med. 2010 Jul 6. [Epub ahead of print]
[Influence of age on characteristics of cutaneous vasculitis: A series of 132
patients.]
[Article in French]
Marie I, Mikolajcz S, Benichou J, Grassi V, Levesque H.
CHU de Rouen, Département de médecine interne, 76031 Rouen cedex, France.
OBJECTIVES: Age onset of cutaneous vasculitis may influence clinical
manifestations and outcome of this condition. However, to date, no authors have
analyzed characteristics of cutaneous vasculitis, especially causes, in elderly
patients (>/=65years). METHODS: The aims of this retrospective study were to
compare clinical and biochemical characteristics as well as causes of cutaneous
vasculitis between elderly patients (n=58) and younger subjects (n=74). RESULTS:
Median time onset between first clinical symptoms and diagnosis of cutaneous
vasculitis was similar between elderly and younger (15 vs 10days; P=0.39).
Clinical characteristics did not differ between the 2 groups. The following
biochemical parameters were more frequently found in elderly patients: higher
median levels of erythrocyte sedimentation rate (44 vs 28mm/h; P=0.006), urea (8
vs 5mmol/L; P<0.0001), creatininemia (92 vs 74mumol/L; P=0.004), and lower values
of serum protein (P=0.023). The more common causes of cutaneous vasculitis in
elderly patients were as follows: infections (n=24), drugs (n=12), systemic
vasculitides (n=8) and cancer (n=8); only cancer-associated cutaneous vasculitis
was more frequently observed in elderly patients (P=0.02). CONCLUSION: Our study
suggests that age onset of cutaneous vasculitis may influence causes of cutaneous
vasculitis, as cancer were more common in elderly patients. Moreover, infectious
manifestations were different in elderly patients (urinary and pulmonary
infections) compared to younger patients (otorhinolaryngeal infections). In
essence, our data underline that the search for cancer should be performed in
elderly patients exhibiting cutaneous vasculitis. Copyright © 2010 Elsevier
Masson SAS. All rights reserved.
PMID: 20615657 [PubMed - as supplied by publisher]
5. Joint Bone Spine. 2010 Jul 5. [Epub ahead of print]
Anakinra efficacy in a Caucasian patient with renal AA amyloidosis secondary to
cryopyrin-associated periodic syndrome.
Aït-Abdesselam T, Lequerré T, Legallicier B, François A, Le Loët X, Vittecoq O.
Department of Rheumatology, Rouen University Hospital, Inserm U905, Institute of
Biomedical Research, 76031 Rouen cedex, France.
PMID: 20609610 [PubMed - as supplied by publisher]
6. Br J Psychiatry. 2010 Jul;197(1):28-35.
Morbid risk for schizophrenia in first-degree relatives of people with
frontotemporal dementia.
Schoder D, Hannequin D, Martinaud O, Opolczynski G, Guyant-Maréchal L, Le Ber I,
Campion D.
INSERM U614, University of Medicine, Rouen, and Department of Research, Rouvray
Psychiatric Hospital, Sotteville-les-Rouen, France.
BACKGROUND: Familial co-occurrence of frontotemporal dementia and schizophrenia
has never been investigated. AIMS: To test the hypothesis that frontotemporal
dementia and schizophrenia might have a common aetiology in some families in
which both syndromes coexist (mixed families). METHOD: The morbid risk for
schizophrenia, calculated in first-degree relatives of 100 frontotemporal
dementia probands, was compared with that calculated in first-degree relatives of
100 Alzheimer's disease probands. In mixed families, sequencing analysis of known
frontotemporal dementia genes and detailed phenotype characterisation of
individuals with frontotemporal dementia and schizophrenia were performed.
RESULTS: The morbid risk for schizophrenia was significantly higher in relatives
of frontotemporal dementia probands (1.35, s.e. = 0.45) than in relatives of
Alzheimer's disease probands (0.32, s.e. = 0.22). Ten mixed families were
characterised. In three of them a frontotemporal dementia causal mutation was
identified that was present in individuals with schizophrenia. Several specific
clinical features were noted in people with schizophrenia and frontotemporal
dementia in mixed families. CONCLUSIONS: Co-occurrence of schizophrenia and
frontotemporal dementia could indicate, in some families, a common aetiology for
both conditions.
PMID: 20592430 [PubMed - in process]
7. Gynecol Obstet Fertil. 2010 Jul-Aug;38(7-8):490-5. Epub 2010 Jun 25.
[Surgical treatment of tubo-ovarian abscess occurring in deep endometriosis]
[Article in French]
Mokdad C, Rozsnayi F, Delaunay F, Gregorczyk V, Auber M, Puscasiu L, Marpeau L,
Roman H.
Clinique gynécologique et obstétricale, CHU Charles-Nicolle, Rouen, France.
Tubo-ovarian abscesses are likely to occur in women suffering from deep
endometriosis. The aim of surgical management of tubo-ovarian abscesses is the
laparoscopic drainage, while deep endometriosis resection should be delayed.
Laparoscopic procedure carried out in emergency does not attempt at the excision
of deep endometriotic lesions, and must avoid the choice of the laparoconversion,
in order to avoid further changes in the pelvic anatomy rendering more difficult
a curative surgery. We report six cases of patients presenting tubo-ovarian
abscesses arising on deep endometriosis, and we discuss the choice of the 2-step
surgical management. In four cases, deep endometriosis resection has been
performed by laparoscopic route few months after the drainage of abscess and
provided macroscopically complete excision of the disease. Copyright 2010
Elsevier Masson SAS. All rights reserved.
PMID: 20579921 [PubMed - in process]
8. Gynecol Obstet Fertil. 2010 Jul-Aug;38(7-8):447-54. Epub 2010 Jun 25.
[Predictive value of uterine artery velocity waveforms in monitoring of
pregnancies with high obstetrical risk antiphospholipid syndrome: the Rouen
experience]
[Article in French]
Seror J, Verspyck E, Borg JY, Berkane N, Marpeau L.
Clinique gynécologique et obstétricale, CHU de Rouen, Rouen cedex, France.
jeremy.seror@tnn.aphp.fr
OBJECTIVES: Anti-phospholipid syndrome (APLS) and obstetrical complications have
been associated for years. The purpose of this study was to define a high
obstetrical risk subpopulation of APLS and search predictive criteria of
complications likely to improve monitoring of pregnancy. PATIENTS AND METHODS: We
conducted a retrospective study at the CHU of Rouen between 1998 and January
2008. Pregnancies were included for patients with APLS according to the criteria
of Sydney without repeated miscarriages item. RESULTS: The study involved 20
pregnancies from eight patients. Fourteen pregnancies gave birth to living
children or 70 %, 28.6 % were complicated with pre-eclampsia, 50 % of haemolysis
elevated liver enzymes low platelets (HELLP) syndrome associated with a 28.6 %
stunting and 42 % of premature birth. Patients received treatment involving
aspirin and heparin. The obstetrical prognosis was significantly poorer in the
subgroup with APLS notch bilateral persistent middle of the term of birth of 35.5
versus 28 weeks of gestation, and median birth weight of 950 g versus 2780 g
(p<0.05). DISCUSSION AND CONCLUSION: Patients were selected according to the more
specific criteria of APLS (thrombosis and fetal loss) and a history of severe
obstetrical complications. In some series, these complications play a major role;
in others, they are unsignificant. Rate, in this study, is high (47 %) and the
presence of bilateral notch seems to be an excellent predictive marker of
vascular complications in this population. Copyright 2010 Elsevier Masson SAS.
All rights reserved.
PMID: 20579918 [PubMed - in process]
9. J Nucl Med. 2010 Jul;51(7):1044-8. Epub 2010 Jun 16.
Leukocyte SPECT/CT for detecting infection of left-ventricular-assist devices:
preliminary results.
Litzler PY, Manrique A, Etienne M, Salles A, Edet-Sanson A, Vera P, Bessou JP,
Hitzel A.
Department of Thoracic and Cardiovascular Surgery, Rouen University Hospital,
Rouen, France.
We report our experience with using integrated molecular and anatomic hybrid
imaging to assess infection in patients who have a left-ventricular-assist device
(LVAD). METHODS: Thirteen (99m)Tc-exametazime-leukocyte planar and SPECT/CT scans
were obtained for 8 consecutive patients who had an implanted LVAD. SPECT/CT was
used to assess suspected device-related infections (n = 8) and to evaluate the
efficiency of current antibiotic therapy (n = 5). RESULTS: Device-related
infection was seen on 8 of the 13 scans. SPECT/CT was positive for infection in
all 8 patients, whereas planar scans were positive in 6 of 8. SPECT/CT provided
relevant information on the extent of infection and its exact location in all
patients. Additional distant infectious foci were demonstrated in 3 of 13
patients. CONCLUSION: SPECT/CT led to an accurate diagnosis of LVAD-related
infection, revealing both anatomic location and extent. This noninvasive approach
could lead to improved therapeutic strategies.
PMID: 20554736 [PubMed - indexed for MEDLINE]
10. Arch Pediatr. 2010 Jul;17(7):1042-6. Epub 2010 Jun 9.
[Administration of a single winter oral dose of 200,000 IU of vitamin D3 in
adolescents in Normandy: evaluation of the safety and vitamin D status obtained]
[Article in French]
Mallet E, Philippe F, Castanet M, Basuyau JP.
Département de pédiatrie médicale, CIC INSERM 204, CHU Charles-Nicolle, 1 rue de
Germont, Rouen cedex, France.
Adolescence, a period of growth and acquisition of bone mass, requires adequate
calcium and vitamin D intake. This study was designed to assess the impact of a
single loading dose of 200,000 IU of vitamin D(3) on the winter vitamin D status
of healthy adolescents. Vitamin D status was assessed by 25-OH-D levels before, 3
weeks, and 3 months after this single dose, and safety was assessed by serum
calcium and PTH and urinary calcium excretion in random samples from 27, 23, and
17 healthy adolescents derived from the same institution. The 25-OH-D peak value
2 weeks after the vitamin D supplement of 71-129 nmol/l (mean, 96 nmol/l), and a
residual level at 3 months of 29-83 nmol/l (mean, 57 nmol/l) serum calcium and
urinary calcium excretion expressed by the calcium/creatinine ratio were normal
and stable at 2 weeks and 3 months, remaining less than 0.5 for the
calcium/creatinine ratio. This simple measure, ensuring good compliance during
adolescence, ensures optimal winter vitamin D status with no signs of overload.
Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.
PMID: 20542672 [PubMed - in process]
11. Nephrol Dial Transplant. 2010 Jul;25(7):2376-8. Epub 2010 Apr 20.
Acute renal failure and Fanconi syndrome due to deferasirox.
Grangé S, Bertrand DM, Guerrot D, Eas F, Godin M.
Nephrology Department, Rouen University Hospital, 1 Avenue de Germont, 76031
Rouen Cedex, Rouen, France. stevengrange@gmail.com
Deferasirox is the first oral iron chelator and, as such, is widely used for the
treatment of chronic iron overload. However, recent data from large studies
confirmed the renal toxicity of deferasirox. We report a case of Fanconi syndrome
associated with acute renal failure in a patient receiving deferasirox. In
particular, new insights regarding the pathophysiology of the renal disease due
to this treatment are discussed. This case highlights the importance of a careful
monitoring of kidney function, markers of proximal tubulopathy and ferritinaemia
in patients receiving deferasirox.
PMID: 20466673 [PubMed - in process]
12. Brain Res. 2010 Jul 23;1345:182-9. Epub 2010 May 10.
Filamin-A and Myosin VI colocalize with fibrillary Tau protein in Alzheimer's
disease and FTDP-17 brains.
Feuillette S, Deramecourt V, Laquerriere A, Duyckaerts C, Delisle MB, Maurage CA,
Blum D, Buée L, Frébourg T, Campion D, Lecourtois M.
Inserm U614, Institute for Biomedical Research, Faculty of Medicine, University
of Rouen, Rouen, France.
Tauopathies, including Alzheimer's disease (AD), fronto-temporal dementia with
parkinsonism linked to chromosome 17 (FTDP-17), Pick's disease and progressive
supranuclear palsy, are neurodegenerative disorders neuropathologically
characterized by the presence of intraneuronal fibrillary inclusions composed of
abnormally phosphorylated-Tau. Tau protein is a neuronal microtubule-associated
protein (MAP) involved in microtubules polymerization and stabilization. So far,
the molecular mechanisms underlying Tau-mediated cellular toxicity remain
elusive. To address the determinants of Tau neurotoxicity, we previously
performed a misexpression screening in a Drosophila tauopathy model to identify
genetic modifiers of the human Tau-induced neurodegeneration. We identified
several components of the actin network as modifiers of Tau V337M-induced
neurodegeneration, i.e. Filamin-A, Myosin VI, Paxillin and Transgelin-3. The aim
of this study was to assess whether these genetic interactions were associated
with a colocalization of the proteins (i) in the brains of patients with Tau
pathologies, and (ii) in the brain of transgenic mice overexpressing human mutant
Tau. We found that Filamin-A and Myosin VI indeed colocalize with fibrillary Tau
protein in AD and FTDP-17 and in Thy-Tau22 transgenic mice. Copyright 2010
Elsevier B.V. All rights reserved.
PMID: 20460118 [PubMed - in process]
13. Autophagy. 2010 Jul 1;6(5). [Epub ahead of print]
Autophagosome maturation is impaired in Fabry disease.
Chévrier M, Brakch N, Lesueur C, Genty D, Ramdani Y, Moll S, Djavaheri-Mergny M,
Brasse-Lagnel C, Laquerrière A, Barbey F, Bekri S.
Laboratoire de Biochimie Médicale, Rouen University Hospital and EA 4309,
University of Rouen, France.
Fabry disease is a lysosomal storage disorder (LSD) caused by a deficiency in
alpha-galactosidase A. The disease is characterized by severe major organ
involvement, but the pathologic mechanisms responsible have not been elucidated.
Disruptions of autophagic processes have been reported for other LSDs, but have
not yet been investigated in Fabry disease. Renal biopsies were obtained from
five adult male Fabry disease patients before and after three years of enzyme
replacement therapy (ERT) with agalsidase alfa. Vacuole accumulation was seen in
renal biopsies from all patients compared with control biopsies. Decreases in the
number of vacuoles were seen after three years of ERT primarily in renal
endothelial cells and mesangial cells. Measurement of the levels of LC3, a
specific autophagy marker, in cultured cells from Fabry patients revealed
increased basal levels compared to cells from non-Fabry subjects and a larger
increase in response to starvation than seen in non-Fabry cells. Starvation in
the presence of protease inhibitors did not result in a significant increase in
LC3 in Fabry cells, whereas a further increase in LC3 was observed in non-Fabry
cells, an observation that is consistent with impaired autophagic flux in Fabry
disease. Overexpression of LC3 mRNA in Fabry fibroblasts compared to control
cells is consistent with an upregulation of autophagy. Furthermore, LC3 and
p62/SQSTM1 (that binds to LC3) staining in renal tissues and in cultured
fibroblasts from Fabry patients supports impairment of autophagic flux. These
findings suggest that Fabry disease is linked to a deregulation of autophagy.
PMID: 20431343 [PubMed - as supplied by publisher]
14. Biochimie. 2010 Jul;92(7):729-35. Epub 2010 Feb 25.
Amino acid regulation of mammalian gene expression in the intestine.
Brasse-Lagnel CG, Lavoinne AM, Husson AS.
Appareil Digestif, Environnement et Nutrition (ADEN EA 4311), IFR n degrees 23,
Université de Rouen, 22 boulevard Gambetta, Rouen cedex, France.
Some amino acids exert a wide range of regulatory effects on gene expression via
the activation of different signalling pathways and transcription factors, and a
number of cis elements were shown to respond to changes in amino acid
concentration. Particular attention has been paid to the effects of glutamine and
arginine, which modulate a number of cell functions through the activation of
various pathways in different tissues. In the intestine, appropriate
concentrations of both arginine and/or glutamine contribute to facilitate cell
proliferation, to limit the inflammatory response and apoptosis, and to modulate
intermediary metabolism through specific transcription factors. Particularly,
besides its role as a major fuel for enterocytes, the regulatory effects of
glutamine have been extensively studied and the molecular mechanisms involved
appear diversified and complex. Indeed, in addition to a major role of NF-kappaB
in its anti-inflammatory action and a stimulatory role of AP-1 in its
growth-promoting action and cell survival, the involvement of some other
transcription factors, such as PPAR-gamma or HSF-1, was shown to maintain
intestinal cell integrity. The signalling pathways leading to the activation of
transcription factors imply several kinases, particularly MAP kinases in the
effect of glutamine and p70 S6 kinase for those of arginine, but in most cases
the precise pathways from the entrance of the aminoacid into the cell to the
activation of gene transcription has remained elusive. Copyright 2010 Elsevier
Masson SAS. All rights reserved.
PMID: 20188788 [PubMed - in process]
