Particularités du variant logopénique au sein des aphasies progressives primaires [Specificities of the logopenic variant of primary progressive aphasia].

The logopenic variant of primary progressive aphasia is a syndrome with neuropsychological and linguistic specificities, including phonological loop impairment for which diagnosis is currently mainly based on the exclusion of the two other variants, semantic and nonfluent/agrammatic primary progressive aphasia. The syndrome may be underdiagnosed due (1) to mild language difficulties during the early stages of the disease or (2) to being mistaken for mild cognitive impairment or Alzheimer's disease when the evaluation of episodic memory is based on verbal material and (3) finally, it is not uncommon that the disorders are attributed to psychiatric co-morbidities such as, for example, anxiety. Moreover, compared to other variants of primary progressive aphasia, brain abnormalities are different. The left temporoparietal junction is initially affected. Neuropathology and biomarkers (cerebrospinal fluid, molecular amyloid nuclear imaging) frequently reveal Alzheimer's disease. Consequently this variant of primary progressive aphasia does not fall under the traditional concept of frontotemporal lobar degeneration. These distinctive features highlight the utility of correct diagnosis, classification, and use of biomarkers to show the neuropathological processes underlying logopenic primary progressive aphasia. The logopenic variant of primary progressive aphasia is a specific form of Alzheimer's disease frequently presenting a rapid decline; specific linguistic therapies are needed. Further investigation of this syndrome is needed to refine screening, improve diagnostic criteria and better understand the epidemiology and the biological mechanisms involved.

Insertion of a malE B-Galactosidase fusion protein into the envelope of Escherichia coli disrupts biogenesis of outer membrane proteins and processing of inner membrane proteins

The synthesis of a membrane-bound MalE ,B-galactosidase hybrid protein, when induced by growth of Escherichia coli on maltose, leads to inhibition of cell division and eventually a reduced rate of mass increase. In addition, the relative rate of synthesis of outer membrane proteins, but not that of inner membrane proteins, was reduced by about 50%o. Kinetic experiments demonstrated that this reduction coincided with the period of maximum synthesis of the hybrid protein (and another maltose-inducible protein, LamB). The accumulation of this abnormal protein in the envelope therefore appeared specifically to inhibit the synthesis, the assembly of outer membrane proteins, or both, indicating that the hybrid protein blocks some export site or causes the sequestration of some limiting factor(s) involved in the export process. Since the MalE protein is normally located in the periplasm, the results also suggest that the synthesis of periplasmic and outer membrane proteins may involve some steps in common. The reduced rate of synthesis of outer membrane proteins was also accompanied by the accumulation in the envelope of at least one outer membrane protein and at least two inner membrane proteins as higher-molecular-weight forms, indicating that processing (removal of the N-terminal signal sequence) was also disrupted by the presence of the hybrid protein. These results may indicate that the assembly of these membrane proteins is blocked at a relatively late step rather than at the level of primary recognition of some site by the signal sequence. In addition, the results suggest that some step common to the biogenesis of quite different kinds of envelope protein is blocked by the presence of the hybrid protein.

A functional variant in the Stearoyl-CoA desaturase gene promoter enhances fatty acid desaturation in pork

There is growing public concern about reducing saturated fat intake. Stearoyl-CoA desaturase (SCD) is the lipogenic enzyme responsible for the biosynthesis of oleic acid (18:1) by desaturating stearic acid (18:0). Here we describe a total of 18 mutations in the promoter and 3′ non-coding region of the pig SCD gene and provide evidence that allele T at AY487830:g.2228T>C in the promoter region enhances fat desaturation (the ratio 18:1/18:0 in muscle increases from 3.78 to 4.43 in opposite homozygotes) without affecting fat content (18:0+18:1, intramuscular fat content, and backfat thickness). No mutations that could affect the functionality of the protein were found in the coding region. First, we proved in a purebred Duroc line that the C-T-A haplotype of the 3 single nucleotide polymorphisms (SNPs) (g.2108C>T; g.2228T>C; g.2281A>G) of the promoter region was additively associated to enhanced 18:1/18:0 both in muscle and subcutaneous fat, but not in liver. We show that this association was consistent over a 10-year period of overlapping generations and, in line with these results, that the C-T-A haplotype displayed greater SCD mRNA expression in muscle. The effect of this haplotype was validated both internally, by comparing opposite homozygote siblings, and externally, by using experimental Duroc-based crossbreds. Second, the g.2281A>G and the g.2108C>T SNPs were excluded as causative mutations using new and previously published data, restricting the causality to g.2228T>C SNP, the last source of genetic variation within the haplotype. This mutation is positioned in the core sequence of several putative transcription factor binding sites, so that there are several plausible mechanisms by which allele T enhances 18:1/18:0 and, consequently, the proportion of monounsaturated to saturated fat.

Visual signs and symptoms in patients with the visual variant of Alzheimer disease.

BACKGROUND: Prominent visual symptoms can present in the visual variant of Alzheimer's disease (VVAD). Ophthalmologists have a significant role to play in the early diagnosis of VVAD. METHODS: We retrospectively reviewed the files of ten consecutive patients diagnosed with VVAD. All patients had a full neuro-ophthalmologic examination, a formal neurological and neuro-psychological testing, and cerebral MRI to confirm diagnosis. In addition, functional neuroimaging was obtained in seven patients. RESULTS: The common primary symptom at presentation with all patients was difficulty with near vision (reading difficulty n = 8, "visual blur" in near vision n = 2), and difficulty writing (n = 3). Following assessment, impaired reading and writing skills were evident in 9/10 and 8/10 patients respectively. Median distance visual acuity was 20/25 and at near the median visual acuity was J6. Partial homonymous visual field defect was detected in 80 % (8/10) of the patients. Color vision was impaired in all patients when tested with Ishihara pseudoisochromatic plates, but simple color naming was normal in 8/9 tested patients. Simultanagnosia was present in 8/10 patients. Vision dysfunction corresponded with cerebral MRI findings where parieto-occipital cortical atrophy was observed in all patients. PET scan (5 patients) or SPECT (2 patients) revealed parieto-occipital dysfunction (hypometabolism or hypoperfusion) in all 7 tested patients CONCLUSIONS: Visual difficulties are prominent in VVAD. Dyslexia, incomplete homonymous hemianopia, preserved color identification with abnormal color vision on Ishihara, and simultanagnosia were all symptoms observed frequently in this patient series. Ophthalmologists should be aware of the possibility of neurodegenerative disorders such as VVAD in patients with unexplained visual complaints, in particular reading difficulties.

Theory of mind impairment in patients with behavioural variant fronto-temporal dementia (bv-FTD) increases caregiver burden.

BACKGROUND: Theory of mind (ToM), the capacity to infer the intention, beliefs and emotional states of others, is frequently impaired in behavioural variant fronto-temporal dementia patients (bv-FTDp); however, its impact on caregiver burden is unexplored. SETTING: National Institute of Neurological Disorders and Stroke, National Institutes of Health. SUBJECTS: bv-FTDp (n = 28), a subgroup of their caregivers (n = 20) and healthy controls (n = 32). METHODS: we applied a faux-pas (FP) task as a ToM measure in bv-FTDp and healthy controls and the Zarit Burden Interview as a measure of burden in patients' caregivers. Patients underwent structural MRI; we used voxel-based morphometry to examine relationships between regional atrophy and ToM impairment and caregiver burden. RESULTS: FP task performance was impaired in bv-FTDp and negatively associated with caregiver burden. Atrophy was found in areas involved in ToM. Caregiver burden increased with greater atrophy in left lateral premotor cortex, a region associated in animal models with the presence of mirror neurons, possibly involved in empathy. CONCLUSION: ToM impairment in bv-FTDp is associated with increased caregiver burden.

A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance.

UNLABELLED: Patients carrying very rare loss-of-function mutations in interleukin-1 receptor-associated kinase 4 (IRAK4), a critical signaling mediator in Toll-like receptor signaling, are severely immunodeficient, highlighting the paramount role of IRAK kinases in innate immunity. We discovered a comparatively frequent coding variant of the enigmatic human IRAK2, L392V (rs3844283), which is found homozygously in ∼15% of Caucasians, to be associated with a reduced ability to induce interferon-alpha in primary human plasmacytoid dendritic cells in response to hepatitis C virus (HCV). Cytokine production in response to purified Toll-like receptor agonists was also impaired. Additionally, rs3844283 was epidemiologically associated with a chronic course of HCV infection in two independent HCV cohorts and emerged as an independent predictor of chronic HCV disease. Mechanistically, IRAK2 L392V showed intact binding to, but impaired ubiquitination of, tumor necrosis factor receptor-associated factor 6, a vital step in signal transduction. CONCLUSION: Our study highlights IRAK2 and its genetic variants as critical factors and potentially novel biomarkers for human antiviral innate immunity. (Hepatology 2015;62:1375-1387).

An outcome and cost analysis of anal fistula plug insertion vs endorectal advancement flap for complex anal fistulae.

AIM: The study aimed to compare the rate of success and cost of anal fistula plug (AFP) insertion and endorectal advancement flap (ERAF) for anal fistula. METHOD: Patients receiving an AFP or ERAF for a complex single fistula tract, defined as involving more than a third of the longitudinal length of of the anal sphincter, were registered in a prospective database. A regression analysis was performed of factors predicting recurrence and contributing to cost. RESULTS: Seventy-one patients (AFP 31, ERAF 40) were analysed. Twelve (39%) recurrences occurred in the AFP and 17 (43%) in the ERAF group (P = 1.00). The median length of stay was 1.23 and 2.0 days (P < 0.001), respectively, and the mean cost of treatment was euro5439 ± euro2629 and euro7957 ± euro5905 (P = 0.021), respectively. On multivariable analysis, postoperative complications, underlying inflammatory bowel disease and fistula recurring after previous treatment were independent predictors of de novo recurrence. It also showed that length of hospital stay ≤ 1 day to be the most significant independent contributor to lower cost (P = 0.023). CONCLUSION: Anal fistula plug and ERAF were equally effective in treating fistula-in-ano, but AFP has a mean cost saving of euro2518 per procedure compared with ERAF. The higher cost for ERAF is due to a longer median length of stay.

Molecular mechanism of a green-shifted, pH-dependent red fluorescent protein mKate variant.

Fluorescent proteins that can switch between distinct colors have contributed significantly to modern biomedical imaging technologies and molecular cell biology. Here we report the identification and biochemical analysis of a green-shifted red fluorescent protein variant GmKate, produced by the introduction of two mutations into mKate. Although the mutations decrease the overall brightness of the protein, GmKate is subject to pH-dependent, reversible green-to-red color conversion. At physiological pH, GmKate absorbs blue light (445 nm) and emits green fluorescence (525 nm). At pH above 9.0, GmKate absorbs 598 nm light and emits 646 nm, far-red fluorescence, similar to its sequence homolog mNeptune. Based on optical spectra and crystal structures of GmKate in its green and red states, the reversible color transition is attributed to the different protonation states of the cis-chromophore, an interpretation that was confirmed by quantum chemical calculations. Crystal structures reveal potential hydrogen bond networks around the chromophore that may facilitate the protonation switch, and indicate a molecular basis for the unusual bathochromic shift observed at high pH. This study provides mechanistic insights into the color tuning of mKate variants, which may aid the development of green-to-red color-convertible fluorescent sensors, and suggests GmKate as a prototype of genetically encoded pH sensors for biological studies.

Are patients with non-invasive papillary thyroid carcinoma, follicular variant (niFV-PTC) and minimally invasive follicular thyroid carcinoma with capsular invasion only (miFTC-CIO) overtreated?An institutional experience

Background. Recently several meetings and position papers advocate a change in terminology regarding thyroid neoplasms with indolent behavior, proposing the term "tumor" instead of "carcinoma". This change concerns non-invasive papillary thyroid carcinoma, follicular variant (niFV-PTC) and minimally invasive follicular thyroid carcinoma with capsular invasion only (miFTC-CIO). The aim of our study was to evaluate the impact of considering niFV-PTC and miFTC-CIO as lesions of low malignant potential, and to see how this change would influence patient management at our institution. Methods. A 32 months retrospective review of all well differentiated thyroid carcinomas (WDTC) (papillary and follicular carcinomas) diagnosed at our institution was performed, excluding tumors of uncertain malignant potential as well as poorly differentiated and anaplastic carcinomas. We retrieved cases of niFV-PTC and miFTC-CIO, reviewed histological slides to confirm diagnosis and recorded patient treatment. Results. A total of 9 (7.3%) niFV-PTC (4 males and 5 females, aged between 30 and 68 years, mean: 50.8 years old) and 2 (1.6%) cases of miFTC-CIO (2 females, 31 and 51 years old) were identified out of 122 WDTC diagnosed in the study period. The initial treatment consisted in 5 lobectomies and 6 total thyroidectomies (3 because of a compressive goiter, 2 because of a fine-needle aspiration diagnosis of suspicious for papillary thyroid carcinoma and 1 because of a fine-needle aspiration diagnosis of papillary carcinoma). The treatment following the histological diagnosis consisted in 4 thyroidectomy completions among patients who underwent simple lobectomy (4/5, 80%) and 9/11 (82%) radioablations with I131. Conclusions. The incidence of niFV-PTC is low at our institution, probably because we apply strict diagnostic criteria for this lesion. Simple lobectomy with negative margins is the treatment of choice in cases diagnosed as niFV-PTC and miFTC-CIO, due to the indolent course of these neoplasms. All cases with thyroidectomy completions and radioablations could have been avoided. As a consequence, the change of such terminology heavily impacts the malignancy risk evaluated cytologically as well as patients' management.

A mild form of SLC29A3 disorder: a frameshift deletion leads to the paradoxical translation of an otherwise noncoding mRNA splice variant

We investigated two siblings with granulomatous histiocytosis prominent in the nasal area, mimicking rhinoscleroma and Rosai-Dorfman syndrome. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous frameshift deletion in SLC29A3, which encodes human equilibrative nucleoside transporter-3 (hENT3). Germline mutations in SLC29A3 have been reported in rare patients with a wide range of overlapping clinical features and inherited disorders including H syndrome, pigmented hypertrichosis with insulin-dependent diabetes, and Faisalabad histiocytosis. With the exception of insulin-dependent diabetes and mild finger and toe contractures in one sibling, the two patients with nasal granulomatous histiocytosis studied here displayed none of the many SLC29A3-associated phenotypes. This mild clinical phenotype probably results from a remarkable genetic mechanism. The SLC29A3 frameshift deletion prevents the expression of the normally coding transcripts. It instead leads to the translation, expression, and function of an otherwise noncoding, out-of-frame mRNA splice variant lacking exon 3 that is eliminated by nonsense-mediated mRNA decay (NMD) in healthy individuals. The mutated isoform differs from the wild-type hENT3 by the modification of 20 residues in exon 2 and the removal of another 28 amino acids in exon 3, which include the second transmembrane domain. As a result, this new isoform displays some functional activity. This mechanism probably accounts for the narrow and mild clinical phenotype of the patients. This study highlights the"rescue" role played by a normally noncoding mRNA splice variant of SLC29A3, uncovering a new mechanism by which frameshift mutations can be hypomorphic.

A chromosomal insertion toolbox for promoter probing, mutant complementation and pathogenicity studies in Ralstonia solanacearum

We describe here the construction of a delivery system for stable and directed insertion of gene constructs in a permissive chromosomal site of the bacterial wilt pathogen Ralstonia solanacearum. The system consists of a collection of suicide vectors the Ralstonia chromosome (pRC) series that carry an integration element flanked by transcription terminators and two sequences of homology to the chromosome of strain GMI1000, where the integration element is inserted through a double recombination event. Unique restriction enzyme sites and a GATEWAY cassette enable cloning of any promoter::gene combination in the integration element. Variants endowed with different selectable antibiotic resistance genes and promoter::gene combinations are described. We show that the system can be readily used in GMI1000 and adapted to other R. solanacearum strains using an accessory plasmid. We prove that the pRC system can be employed to complement a deletion mutation with a single copy of the native gene, and to measure transcription of selected promoters in monocopy both in vitro and in planta. Finally, the system has been used to purify and study secretion type III effectors. These novel genetic tools will be particularly useful for the construction of recombinant bacteria that maintain inserted genes or reporter fusions in competitive situations (i.e., during plant infection).

Impact of reclassifying noninvasive follicular variant of papillary thyroid carcinoma on the risk of malignancy in The Bethesda System for Reporting Thyroid Cytopathology.

BACKGROUND: Recent discussions have focused on redefining noninvasive follicular variant of papillary thyroid carcinoma (NI-FVPTC) as a neoplasm rather than a carcinoma. This study assesses the potential impact of such a reclassification on the implied risk of malignancy (ROM) for the diagnostic categories of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). METHODS: The study consisted of consecutive fine-needle aspiration biopsy (FNAB) cases collected between January 1, 2013 and June 30, 2014 from 5 academic institutions. Demographic information, cytology diagnoses, and surgical pathology follow-up were recorded. The ROM was calculated with and without NI-FVPTC and was presented as a range: all cases (ie, overall risk of malignancy [OROM]) versus those with surgical follow-up only. RESULTS: The FNAB cohort consisted of 6943 thyroid nodules representing 5179 women and 1409 men with an average age of 54 years (range, 9-94 years). The combined average ROM and OROM for the diagnostic categories of TBSRTC were as follows: nondiagnostic, 4.4% to 25.3%; benign, 0.9% to 9.3%; atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 12.1% to 31.2%; follicular neoplasm (FN), 21.8% to 33.2%; suspicious for malignancy (SM), 62.1% to 82.6%; and malignant, 75.9% to 99.1%. The impact of reclassifying NI-FVPTC on the ROM and OROM was most pronounced and statistically significant in the 3 indeterminate categories: the AUS/FLUS category had a decrease of 5.2% to 13.6%, the FN category had a decrease of 9.9% to 15.1%, and the SM category had a decrease of 17.6% to 23.4% (P < .05), whereas the benign and malignant categories had decreases of 0.3% to 3.5% and 2.5% to 3.3%, respectfully. The trend of the effect on the ROM and OROM was similar for all 5 institutions. CONCLUSIONS: The results from this multi-institutional cohort indicate that the reclassification of NI-FVPTC will have a significant impact on the ROM for the 3 indeterminate categories of TBSRTC. Cancer Cytopathol 2016;124:181-187. © 2015 American Cancer Society.