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Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2 (SPG2) are X-linked developmental defects of myelin formation affecting the central nervous system (CNS). They differ clinically in the onset and severity of the motor disability but both are allelic to the proteolipid protein gene (PLP), which encodes the principal protein components of CNS myelin, PLP and its spliced isoform, DM20. We investigated 52 PMD and 28 SPG families without large PLP duplications or deletions by genomic PCR amplification and sequencing of the PLP gene. We identified 29 and 4 abnormalities respectively. Patients with PLP mutations presented a large range of disease severity, with a continuum between severe forms of PMD, without motor development, to pure forms of SPG. Clinical severity was found to be correlated with the nature of the mutation, suggesting a distinct strategy for detection of PLP point mutations between severe PMD, mild PMD and SPG. Single amino-acid changes in highly conserved regions of the DM20 protein caused the most severe forms of PMD. Substitutions of less conserved amino acids, truncations, absence of the protein and PLP-specific mutations caused the milder forms of PMD and SPG. Therefore, the interactions and stability of the mutated proteins has a major effect on the severity of PLP-related diseases.

BackgroundHereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurodegenerative disorders characterised by progressive spasticity and weakness in the lower limbs. Mutations in PLP1 on the X chromosome cause spastic paraplegia type 2 (SPG2) or the allelic Pelizaeus–Merzbacher Disease (PMD). The PLP1 protein is a major myelin protein involved in stabilisation and maintenance of the myelin sheath. The function of the protein has been studied in the rumpshaker mouse, which is a model of SPG2/PMD.ObjectiveTo characterise the phenotype of patients with the ‘rumpshaker mutation.’PatientsA family with HSP caused by the ‘rumpshaker mutation.’ResultsThe patients showed nystagmus during infancy and had early onset of HSP. They had normal cognition, and cerebral MRI showed relatively unspecific white matter abnormalities on T2 sequences without clear progression. Urinary urgency was reported among the female carriers. MRS of both patients showed increased myo-inositol in the white matter, while decreased N-acetylaspartate was found exclusively in the oldest patient. All evoked potential examinations were compatible with severe central demyelination, while no signs of peripheral demyelination or axonal degeneration were found. 18F-FDG-PET scans were normal.ConclusionThe phenotypes of the patients reported here are the mildest described to be caused by the rumpshaker mutation and represent the mildest form among the spectrum of PLP1 related disorders. No definite symptoms in the female carriers could be ascribed to the mutation. These data suggest the pathology to be an underlying dysmyelinating disorder in combination with a central axonal degeneration.

To attempt resolving this issue accurately, it was necessary to anchor our experimental approaches in the observations and pioneering work of our predecessors, notably Alphonse Laveran, Louis Parrot, Edmond and Étienne Sergent. The latter, among other things, had identified as natural hosts of leishmaniasis, rodent populations with which hematophagous telmophagous sand fly populations cohabited closely.When human populations emerged in these natural ecosystems, after the sedentarization of more or less important disturbances would have led to a transition of sand fly hematophagy, from zoophilia, to zoo-anthropophilia and anthropophilia.The creation of infrastructures that allow the breeding and integration into experimental groups of both holobiont sand flies and holobiont laboratory rodents (rats, mice, hamsters, etc.) remains crucial. With such infrastructures, it becomes possible to grasp and characterize the multilateral dynamic processes - mostly clinically silent - that account for the biogenesis of tissue and/or cellular niches protecting populations of developmental morphotypes, including those ensuring host-to-host transmission, albeit in small numbers.

Pseudomonas aeruginosa is a gram-negative pathogenic bacterium with a high adaptive potential that allows proliferation in a broad range of hosts or niches. It is also the causative agent of both acute and chronic biofilm-related infections in humans. Three cup gene clusters (cupA-C), involved in the assembly of cell surface fimbriae, have been shown to be involved in biofilm formation by the P. aeruginosa strains PAO1 or PAK. In PA14 isolates, a fourth cluster, named cupD, was identified within a pathogenicity island, PAPI-I, and may contribute to the higher virulence of this strain. Expression of the cupA genes is controlled by the HNS-like protein MvaT, whereas the cupB and cupC genes are under the control of the RocS1A1R two-component system. In this study, we show that cupD gene expression is positively controlled by the response regulator RcsB. As a consequence, CupD fimbriae are assembled on the cell surface, which results in a number of phenotypes such as a small colony morphotype, increased biofilm formation and decreased motility. These behaviors are compatible with the sessile bacterial lifestyle. The balance between planktonic and sessile lifestyles is known to be linked to the intracellular levels of c-di-GMP with high levels favoring biofilm formation. We showed that the EAL domain-containing PvrR response regulator counteracts the activity of RcsB on cupD gene expression. The action of PvrR is likely to involve c-di-GMP degradation through phosphodiesterase activity, confirming the key role of this second messenger in the balance between bacterial lifestyles. The regulatory network between RcsB and PvrR remains to be elucidated, but it stands as a potential model system to study how the equilibrium between the two lifestyles could be influenced by therapeutic agents that favor the planktonic lifestyle. This would render the pathogen accessible for the immune system or conventional antibiotic treatment.

Background In addition to headache, migraine patients often experience sensory hypersensitivity to external stimuli. While photophobia and phonophobia are part of the diagnostic criteria of migraine, many patients also exhibit cutaneous allodynia and osmophobia. However, the presence and intensity of these four hypersensitivities are rarely assessed systematically and simultaneously due to the lack of a simple and rapid self-report questionnaire. Methods We have identified existing questionnaires for allodynia, photophobia and phonophobia and selected one of each, that were translated in French and validated (according to COSMIN’s recommendations). We also proposed a 2-item questionnaire (presence and intensity) for each of these 3 hypersensitivities plus osmophobia, resulting in the 8-item Migraine Hypersensitivity Questionnaire (MHQ-8) exploring these four hypersensitivities. In addition, the headache impact test (HIT-6), the migraine disability assessment (MIDAS) and the hospital anxiety and depression scale (HADS) were also answered. The survey was conducted in Pain and Neurology departments during specialised consultations for headaches. Content validity, structural validity, internal consistency, transcultural validity, reliability, criterion validity, construct validity and responsiveness were tested. Confirmatory factor analysis (CFA) was used to test the dimensionality of the questionnaires. Results The study sample consisted in N  = 329 patients with a mean age of 43.7 ± 13.2 and a mean number of 10.2 ± 7.0 migraine days per month; 84% of them were women and 27% had chronic migraine. Overall, 312 to 327 questionnaires were usable for the hypersensitivity questionnaires. The reliability of the MHQ-8 was good to excellent with a Cronbach’s alpha of α = 0.88 (photophobia), α = 0.89 (phonophobia), α = 0.91 (allodynia), α = 0.95 (osmophobia), and α = 0.85 for the whole questionnaire. The intraclass correlation coefficient assessing test-retest reliability was 0.83, 0.77, 0.87, and 0.90, respectively; it was 0.88 for the whole questionnaire. The factor analysis on the MHQ-8 items showed excellent exploratory results, and the indicators of the CFA showed good performances with CFI and TLI at 0.999, RMSEA at 0.054 and SRMR at 0.021. Conclusions The MHQ-8 developed in this study is valid and reliable. It serves as a new diagnostic tool for the four sensory hypersensitivities that can occur during migraine attacks and may be useful in both clinical research and daily practice.

Elucidating and characterizing the dynamic biological processes that account for the sustainability of Leishmania populationsTo attempt resolving this issue accurately, it was necessary to anchor our experimental approaches in the observations and pioneering work of our predecessors, notably Alphonse Laveran, Louis Parrot, Edmond and Étienne Sergent. The latter, among other things, had identified as natural hosts of leishmaniasis, rodent populations with which hematophagous telmophagous sand fly populations cohabited closely.When human populations emerged in these natural ecosystems, after the sedentarization of Homo sapiens, more or less important disturbances would have led to a transition of sand fly hematophagy, from zoophilia, to zoo-anthropophilia and anthropophilia.The creation of infrastructures that allow the breeding and integration into experimental groups of both holobiont sand flies and holobiont laboratory rodents (rats, mice, hamsters, etc.) remains crucial. With such infrastructures, it becomes possible to grasp and characterize the multilateral dynamic processes – mostly clinically silent – that account for the biogenesis of tissue and/or cellular niches protecting populations of Leishmania developmental morphotypes, including those ensuring host-to-host transmission, albeit in small numbers.Décrypter et caractériser les processus biologiques dynamiques qui rendent compte de la pérennité des populations de LeishmaniaPour tenter de répondre le plus rigoureusement possible à cette question, il importait d’ancrer nos approches expérimentales aux observations et aux travaux pionniers de nos prédécesseurs, parmi lesquels Alphonse Laveran, Louis Parrot, Edmond et Étienne Sergent. Ces derniers, entre autres, avaient identifié comme populations naturellement hôtes de leishmanies, des rongeurs avec lesquels cohabitaient intimement des populations de phlébotomes hématophages telmophages.Quand ont émergé les peuples d’humains au sein de tels écosystèmes naturels, à la sédentarisation d’Homo sapiens, des perturbations d’amplitude variable se seraient traduites par une transition de l’hématophagie de ces phlébotomes, de la zoophilie à la zoo-anthropophilie et à l’anthropophilie.La création d’infrastructures où élever et intégrer dans des groupes expérimentaux, d’une part des phlébotomes holobiontes et, d’autre part des rongeurs de laboratoire holobiontes (rats, souris, hamsters, etc.) reste essentielle. Grâce à de telles infrastructures, il devient possible de saisir et caractériser les processus dynamiques multilatéraux – le plus souvent cliniquement silencieux – rendant compte de la biogenèse des niches tissulaires et/ou cellulaires protégeant des populations de morphotypes de Leishmania en développement, y compris ceux assurant la transmission d’hôte à hôte, bien qu’ils soient en petit nombre.

Background PTEN hamartoma tumour syndrome (PHTS) encompasses several clinical syndromes with germline mutations in the PTEN tumour suppressor gene, including Cowden syndrome which is characterised by an increased risk of breast and thyroid cancers. Because PHTS is rare, data regarding cancer risks and genotype–phenotype correlations are limited. The objective of this study was to better define cancer risks in this syndrome with respect to the type and location of PTEN mutations. Methods 154 PHTS individuals with a deleterious germline PTEN mutation were recruited from the activity of the Institut Bergonié genetic laboratory. Detailed phenotypic information was obtained for 146 of them. Age and sex adjusted standardised incidence ratio (SIR) calculations, cumulative cancer risk estimations, and genotype–phenotype analyses were performed. Results Elevated SIRs were found mainly for female breast cancer (39.1, 95% CI 24.8 to 58.6), thyroid cancer in women (43.2, 95% CI 19.7 to 82.1) and in men (199.5, 95% CI 106.39 to 342.03), melanoma in women (28.3, 95% CI 7.6 to 35.4) and in men (39.4, 95% CI 10.6 to 100.9), and endometrial cancer (48.7, 95% CI 9.8 to 142.3). Cumulative cancer risks at age 70 were 85% (95% CI 70% to 95%) for any cancer, 77% (95% CI 59% to 91%) for female breast cancer, and 38% (95% CI 25% to 56%) for thyroid cancer. The risk of cancer was two times greater in women with PHTS than in men with PHTS (p<0.05). Conclusions This study shows a considerably high cumulative risk of cancer for patients with PHTS, mainly in women without clear genotype–phenotype correlation for this cancer risk. New recommendations for the management of PHTS patients are proposed.

Gastric cancer’s (GC) bad prognosis is usually associated with metastatic spread. Invasive cancer stem cells (CSC) are considered to be the seed of GC metastasis and not all CSCs are able to initiate metastasis. Targeting these aggressive metastasis-initiating CSC (MIC) is thus vital. Leukaemia inhibitory factor (LIF) is hereby used to target Hippo pathway oncogenic members, found to be induced in GC and associated with CSC features. LIF-treated GC cell lines, patient-derived xenograft (PDX) cells and/or CSC tumourspheres underwent transcriptomics, laser microdissection-associated proteomics, 2D and 3D invasion assays and in vivo xenograft in mice blood circulation. LIFR expression was analysed on tissue microarrays from GC patients and in silico from public databases. LIF-treated cells, especially CSC, presented decreased epithelial to mesenchymal transition (EMT) phenotype and invasion capacity in vitro, and lower metastasis initiation ability in vivo. These effects involved both the Hippo and Jak/Stat pathways. Finally, GC’s high LIFR expression was associated with better clinical outcomes in patients. LIF treatment could thus represent a targeted anti-CSC strategy to fight against metastatic GC, and LIFR detection in primary tumours could constitute a potential new prognosis marker in this disease.

After loading with live Leishmania (L) amazonensis amastigotes, mouse myeloid dendritic leucocytes/DLs are known to undergo reprogramming of their immune functions. In the study reported here, we investigated whether the presence of live L. amazonensis amastigotes in mouse bone marrow-derived DLs is able to trigger re-programming of DL lipid, and particularly neutral lipid metabolism. Affymetrix-based transcriptional profiles were determined in C57BL/6 and DBA/2 mouse bone marrow-derived DLs that had been sorted from cultures exposed or not to live L. amazonensis amastigotes. This showed that live amastigote-hosting DLs exhibited a coordinated increase in: (i) long-chain fatty acids (LCFA) and cholesterol uptake/transport, (ii) LCFA and cholesterol (re)-esterification to triacyl-sn-glycerol (TAG) and cholesteryl esters (CE), respectively. As these neutral lipids are known to make up the lipid body (LB) core, oleic acid was added to DL cultures and LB accumulation was compared in live amastigote-hosting versus amastigote-free DLs by epi-fluorescence and transmission electron microscopy. This showed that LBs were both significantly larger and more numerous in live amastigote-hosting mouse dendritic leucocytes. Moreover, many of the larger LB showed intimate contact with the membrane of the parasitophorous vacuoles hosting the live L. amazonensis amastigotes. As leucocyte LBs are known to be more than simple neutral lipid repositories, we set about addressing two related questions. Could LBs provide lipids to live amastigotes hosted within the DL parasitophorous vacuole and also deliver? Could LBs impact either directly or indirectly on the persistence of L. amazonensis amastigotes in rodent skin?