The current international consensus criteria can lead to under and over-diagnosis of primary progressive aphasia variants.

In the field of primary progressive aphasia (PPA), the most recent international consensus criteria of 2011 for diagnosis and variant classification have been shown not to capture accurately the whole range of PPA patients. Up to 30-40% of PPA patients appear not to satisfy the criteria of the three 'classical' PPA variants (non-fluent/agrammatic, logopenic, semantic) and are labelled either 'mixed PPA' or 'unclassifiable PPA'. Based on the PPA literature since 2011, this article discusses why patients might be under-diagnosed with respect to the three PPA variants, thus leading to the default concept of 'mixed/unclassifiable PPA' and, conversely, why the non-fluent/agrammatic variant appears to be over-diagnosed. It analyses and attempts to show how to resolve these issues, and it accordingly proposes clinical criteria, which are more inclusive to diminish the proportion of so-called mixed/unclassifiable PPA diagnoses and to reduce the proportion of questionable non-fluent/agrammatic diagnoses, which frequently correspond to progressive speech apraxia, rather than to aphasia.

[Toward a preventive management Alzheimer's disease]. / Pour une prise en charge préventive de la maladie d'Alzheimer.

Dementias, and Alzheimer's disease (AD) in particular, will increasingly become a public health issue. However, three major data may change the severity of these pathologies: in young adults, simple measures of healthy lifestyle (control of vascular risk factors, physical activity and cognitive stimulation), have an impact on a future cognitive decline; the same lifestyle interventions may delay the start of the disease for elderly people potentially at-risk; finally, and for the first time, a monoclonal antibody directed against amyloid lesions has just shown a significant effect on the progression of AD in patients at an early stage of the disease. According to these results, we will have to reconsider the strategy for managing minor or severe cognitive disorders and particularly AD. Nowadays, patients start the care process too late. The solution is to act earlier, even preventively. It is necessary to improve a care offer adapted to this new situation in order to impact on the disease as soon as possible, even before the onset of symptoms, based on: 1) predictive algorithms aimed at establishing whose cognitively unimpaired individuals may further develop the disease; these algorithms will be based on demographic, family, cognitive, genomic and biological data, such as in the "Santé Cerveau" project developed in partnership with the Health Regional Agency (ARS) and the general practitioners; 2)and on some expert centers which must become "dementia prevention clinics" to test prevention measures, initiate and validate multi-domain therapeutic education programs; to disclose about the risk in response to the request of worried patients; and to propose early pharmacological treatments if these individuals are on the way to declare AD in the coming months, taking into account competition between risks. This will allow to prepare to make use of new pharmacological treatments that might be discovered.

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

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.

Bay11-7082 inhibits the disintegration of the lymphendothelial barrier triggered by MCF-7 breast cancer spheroids; the role of ICAM-1 and adhesion.

BACKGROUND: Many cancers spread through lymphatic routes, and mechanistic insights of tumour intravasation into the lymphatic vasculature and targets for intervention are limited. The major emphasis of research focuses currently on the molecular biology of tumour cells, while still little is known regarding the contribution of lymphatics. METHODS: Breast cancer cell spheroids attached to lymphendothelial cell (LEC) monolayers were used to investigate the process of intravasation by measuring the areas of 'circular chemorepellent-induced defects' (CCID), which can be considered as entry gates for bulky tumour intravasation. Aspects of tumour cell intravasation were furthermore studied by adhesion assay, and siRNA-mediated knockdown of intracellular adhesion molecule-1 (ICAM-1). Replacing cancer spheroids with the CCID-triggering compound 12(S)-hydroxyeicosatetraenoic acid (HETE) facilitated western blot analyses of Bay11-7082- and baicalein-treated LECs. RESULTS: Binding of LECs to MCF-7 spheroids, which is a prerequisite for CCID formation, was mediated by ICAM-1 expression, and this depended on NF-κB and correlated with the expression of the prometastatic factor S100A4. Simultaneous inhibition of NF-κB with Bay11-7082 and of arachidonate lipoxygenase (ALOX)-15 with baicalein prevented CCID formation additively. CONCLUSION: Two mechanisms contribute to CCID formation: ALOX15 via the generation of 12(S)-HETE by MCF-7 cells, which induces directional migration of LECs, and ICAM-1 in LECs under control of NF-κB, which facilitates adhesion of MCF-7 cells to LECs.

In vitro inhibition of breast cancer spheroid-induced lymphendothelial defects resembling intravasation into the lymphatic vasculature by acetohexamide, isoxsuprine, nifedipin and proadifen.

BACKGROUND: As metastasis is the prime cause of death from malignancies, there is vibrant interest to discover options for the management of the different mechanistic steps of tumour spreading. Some approved pharmaceuticals exhibit activities against diseases they have not been developed for. In order to discover such activities that might attenuate lymph node metastasis, we investigated 225 drugs, which are approved by the US Food and Drug Administration. METHODS: A three-dimensional cell co-culture assay was utilised measuring tumour cell-induced disintegrations of the lymphendothelial wall through which tumour emboli can intravasate as a limiting step in lymph node metastasis of ductal breast cancer. The disintegrated areas in the lymphendothelial cell (LEC) monolayers were induced by 12(S)-HETE, which is secreted by MCF-7 tumour cell spheroids, and are called 'circular chemorepellent induced defects' (CCIDs). The putative mechanisms by which active drugs prevented the formation of entry gates were investigated by western blotting, NF-κB activity assay and by the determination of 12(S)-HETE synthesis. RESULTS: Acetohexamide, nifedipin, isoxsuprine and proadifen dose dependently inhibited the formation of CCIDs in LEC monolayers and inhibited markers of epithelial-to-mesenchymal-transition and migration. The migration of LECs is a prerequisite of CCID formation, and these drugs either repressed paxillin levels or the activities of myosin light chain 2, or myosin-binding subunit of myosin phosphatase. Isoxsuprine inhibited all three migration markers, and isoxsuprine and acetohexamide suppressed the synthesis of 12(S)-HETE, whereas proadifen and nifedipin inhibited NF-κB activation. Both the signalling pathways independently cause CCID formation. CONCLUSION: The targeting of different mechanisms was most likely the reason for synergistic effects of different drug combinations on the inhibition of CCID formation. Furthermore, the treatment with drug combinations allowed also a several-fold reduction in drug concentrations. These results encourage further screening of approved drugs and their in vivo testing.

Aphasia(s) in Alzheimer.

Language disorders of degenerative origin are frequently tied to Alzheimer disease (AD) the different variants of which can result in primary and secondary aphasia syndromes. More specifically, Alzheimer pathology can primarily erode frontal, temporal or parietal language cortices resulting in three genuine AD language variants which account for about 30% of primary degenerative aphasias. Likewise, it can spread from non-language to language cortices leading to secondary language disorders like in typical amnesic AD and in several atypical AD variants. This paper reviews the whole set of AD variants by characterising their impact on the neural language system and on linguistic functioning. It also provides cues for diagnostic strategies which are essential for linguistic, syndromic and nosological patient classification, for adequate clinical follow-up and for guiding language rehabilitation. Such diagnostic approaches, founded on detailed linguistic phenotyping while integrating anatomical and neuropathological findings, also represent a crucial issue for future drug trials targeting the physio-pathological processes in degenerative aphasias.

NF-κB mediates the 12(S)-HETE-induced endothelial to mesenchymal transition of lymphendothelial cells during the intravasation of breast carcinoma cells.

BACKGROUND: The intravasation of breast cancer into the lymphendothelium is an early step of metastasis. Little is known about the mechanisms of bulky cancer invasion into lymph ducts. METHODS: To particularly address this issue, we developed a 3-dimensional co-culture model involving MCF-7 breast cancer cell spheroids and telomerase-immortalised human lymphendothelial cell (LEC) monolayers, which resembles intravasation in vivo and correlated the malignant phenotype with specific protein expression of LECs. RESULTS: We show that tumour spheroids generate 'circular chemorepellent-induced defects' (CCID) in LEC monolayers through retraction of LECs, which was induced by 12(S)-hydroxyeicosatetraenoic acid (HETE) secreted by MCF-7 spheroids. This 12(S)-HETE-regulated retraction of LECs during intravasation particularly allowed us to investigate the key regulators involved in the motility and plasticity of LECs. In all, 12(S)-HETE induced pro-metastatic protein expression patterns and showed NF-κB-dependent up-regulation of the mesenchymal marker protein S100A4 and of transcriptional repressor ZEB1 concomittant with down-regulation of the endothelial adherence junction component VE-cadherin. This was in accordance with ∼50% attenuation of CCID formation by treatment of cells with 10 µM Bay11-7082. Notably, 12(S)-HETE-induced VE-cadherin repression was regulated by either NF-κB or by ZEB1 since ZEB1 siRNA knockdown abrogated not only 12(S)-HETE-mediated VE-cadherin repression but inhibited VE-cadherin expression in general. INTERPRETATION: These data suggest an endothelial to mesenchymal transition-like process of LECs, which induces single cell motility during endothelial transmigration of breast carcinoma cells. In conclusion, this study demonstrates that the 12(S)-HETE-induced intravasation of MCF-7 spheroids through LECs require an NF-κB-dependent process of LECs triggering the disintegration of cell-cell contacts, migration, and the generation of CCID.

Microarchitecture is severely compromised but motor protein function is preserved in dystrophic mdx skeletal muscle.

Progressive force loss in Duchenne muscular dystrophy is characterized by degeneration/regeneration cycles and fibrosis. Disease progression may involve structural remodeling of muscle tissue. An effect on molecular motorprotein function may also be possible. We used second harmonic generation imaging to reveal vastly altered subcellular sarcomere microarchitecture in intact single dystrophic mdx muscle cells (approximately 1 year old). Myofibril tilting, twisting, and local axis deviations explain at least up to 20% of force drop during unsynchronized contractile activation as judged from cosine angle sums of myofibril orientations within mdx fibers. In contrast, in vitro motility assays showed unaltered sliding velocities of single mdx fiber myosin extracts. Closer quantification of the microarchitecture revealed that dystrophic fibers had significantly more Y-shaped sarcomere irregularities ("verniers") than wild-type fibers (approximately 130/1000 microm(3) vs. approximately 36/1000 microm(3)). In transgenic mini-dystrophin-expressing fibers, ultrastructure was restored (approximately 38/1000 microm(3) counts). We suggest that in aged dystrophic toe muscle, progressive force loss is reflected by a vastly deranged micromorphology that prevents a coordinated and aligned contraction. Second harmonic generation imaging may soon be available in routine clinical diagnostics, and in this work we provide valuable imaging tools to track and quantify ultrastructural worsening in Duchenne muscular dystrophy, and to judge the beneficial effects of possible drug or gene therapies.

The role of ultrafast magnon generation in the magnetization dynamics of rare-earth metals.

Ultrafast demagnetization of rare-earth metals is distinct from that of 3d ferromagnets, as rare-earth magnetism is dominated by localized 4f electrons that cannot be directly excited by an optical laser pulse. Their demagnetization must involve excitation of magnons, driven either through exchange coupling between the 5d6s-itinerant and 4f-localized electrons or by coupling of 4f spins to lattice excitations. Here, we disentangle the ultrafast dynamics of 5d6s and 4f magnetic moments in terbium metal by time-resolved photoemission spectroscopy. We show that the demagnetization time of the Tb 4f magnetic moments of 400 fs is set by 4f spin-lattice coupling. This is experimentally evidenced by a comparison to ferromagnetic gadolinium and supported by orbital-resolved spin dynamics simulations. Our findings establish coupling of the 4f spins to the lattice via the orbital momentum as an essential mechanism driving magnetization dynamics via ultrafast magnon generation in technically relevant materials with strong magnetic anisotropy.

Collective oscillations of an imbalanced Fermi gas: axial compression modes and polaron effective mass.

We investigate the low-lying compression modes of a unitary Fermi gas with imbalanced spin populations. For low polarization, the strong coupling between the two spin components leads to a hydrodynamic behavior of the cloud. For large population imbalance we observe a decoupling of the oscillations of the two spin components, giving access to the effective mass of the Fermi polaron, a quasiparticle composed of an impurity dressed by particle-hole pair excitations in a surrounding Fermi sea. We find m*/m = 1.17(10), in agreement with the most recent theoretical predictions.

Spermiogenesis deficiency in mice lacking the Trf2 gene.

The discovery of TATA-binding protein-related factors (TRFs) has suggested alternative mechanisms for gene-specific transcriptional regulation and raised interest in their biological functions. In contrast to recent observations of an embryonic lethal phenotype for TRF2 inactivation in Caenorhabditis elegans and Xenopus laevis, we found that Trf2-deficient mice are viable. However, Trf2-/- mice are sterile because of a severe defect in spermiogenesis. Postmeiotic round spermatids advance at most to step 7 of differentiation but fail to progress to the elongated form, and gene-specific transcription deficiencies were identified. We speculate that mammals may have evolved more specialized TRF2 functions in the testis that involve transcriptional regulation of genes essential for spermiogenesis.

[Iliac ureteral fistulas. Diagnosis and management of an increasing problem]. / Ureteroiliakale Fisteln. Diagnostik und Management eines zunehmenden Problems.

Iliac-ureteral fistulas (IUF) are a rare but potential life threatening event and an important cause of gross hematuria. We report on three cases of IUF. In all cases, prior chronic ureteral stenting, extended pelvic surgery or pelvic irradiation had been performed. Diagnosis was confirmed with angiography in one case, in the others a CT scan revealed the IUF. Treatment included surgical exploration with local reconstruction, extra-anatomical bypass and nephrectomy with arterial patch repair. The increasing incidence of IUF is a consequence of an increasing number of advanced and extended pelvic operations, radiation therapy and long-term ureteral stenting. Diagnosis should be made by provocative angiography or CT. Treatment options vary depending on the site and morphology of the local situation, but morbidity and mortality is still high due to delayed adequate diagnosis and treatment. A conclusive algorithm should be followed for the successful management of IUF.

TRM6/61 connects PKCα with translational control through tRNAi(Met) stabilization: impact on tumorigenesis.

Accumulating evidence suggests that changes of the protein synthesis machinery alter translation of specific mRNAs and participate in malignant transformation. Here we show that protein kinase C α (PKCα) interacts with TRM61, the catalytic subunit of the TRM6/61 tRNA methyltransferase. The TRM6/61 complex is known to methylate the adenosine 58 of the initiator methionine tRNA (tRNAi(Met)), a nuclear post-transcriptional modification associated with the stabilization of this crucial component of the translation-initiation process. Depletion of TRM6/61 reduced proliferation and increased death of C6 glioma cells, effects that can be partially rescued by overexpression of tRNAi(Met). In contrast, elevated TRM6/61 expression regulated the translation of a subset of mRNAs encoding proteins involved in the tumorigenic process and increased the ability of C6 cells to form colonies in soft agar or spheres when grown in suspension. In TRM6/61/tRNAi(Met)-overexpressing cells, PKCα overexpression decreased tRNAi(Met) expression and both colony- and sphere-forming potentials. A concomitant increase in TRM6/TRM61 mRNA and tRNAi(Met) expression with decreased expression of PKCα mRNA was detected in highly aggressive glioblastoma multiforme as compared with Grade II/III glioblastomas, highlighting the clinical relevance of our findings. Altogether, we suggest that PKCα tightly controls TRM6/61 activity to prevent translation deregulation that would favor neoplastic development.

hTFIIIB-beta stably binds to pol II promoters and recruits RNA polymerase III in a hTFIIIC1 dependent way.

It has been shown that under specific conditions, transcription of protein coding genes can be efficiently initiated by RNA polymerase (pol) III in vitro. We examined the formation and composition of such pol III transcription complexes on the duck histone H5 and alphaA-globin promoters and found that the essential step for the formation of pol III transcription complexes on these pol II promoters was the stable binding of transcription factor (TF) IIIB-beta. For this process, the intact TFIIIB-beta complex, consisting of TBP and associated factors (TAFs) was needed and the prior association of pol III assembly factors was not necessary. We demonstrate for the first time that hTFIIIB-beta alone is able to bind to pol II promoter DNA. This resulted in a very stable complex which was resistant to high concentrations of heparin. Although immunodepletion revealed that TBP is essentially required for complex formation, other components of hTFIIIB-beta must also be involved, since TBP itself is unable to form heparin-resistant complexes and does not mediate pol III commitment per se. pol III is recruited to these pol II promoters in a strictly TFIIIC1 dependent way. After binding of TFIIIB-beta, the addition of TFIIIC1 and pol III were sufficient to yield productive pol III transcription complexes, which utilized the correct pol II initiation site. From these findings, we postulate that TFIIIC1 is involved in the recruitment of pol III and may thus form a bridge between TFIIIB-beta and the enzyme. This finding provides the first evidence for functional contacts between TFIIIC1 and pol III, which could be of general importance for the assembly of pol III transcription complexes.

Disparate ultrafast dynamics of itinerant and localized magnetic moments in gadolinium metal.

The Heisenberg-Dirac intra-atomic exchange coupling is responsible for the formation of the atomic spin moment and thus the strongest interaction in magnetism. Therefore, it is generally assumed that intra-atomic exchange leads to a quasi-instantaneous aligning process in the magnetic moment dynamics of spins in separate, on-site atomic orbitals. Following ultrashort optical excitation of gadolinium metal, we concurrently record in photoemission the 4f magnetic linear dichroism and 5d exchange splitting. Their dynamics differ by one order of magnitude, with decay constants of 14 versus 0.8 ps, respectively. Spin dynamics simulations based on an orbital-resolved Heisenberg Hamiltonian combined with first-principles calculations explain the particular dynamics of 5d and 4f spin moments well, and corroborate that the 5d exchange splitting traces closely the 5d spin-moment dynamics. Thus gadolinium shows disparate dynamics of the localized 4f and the itinerant 5d spin moments, demonstrating a breakdown of their intra-atomic exchange alignment on a picosecond timescale.

Increased incorporation of fatty acids into phospholipids of lungs and livers of rabbits under the influence of bromhexine and ambroxol.

The incorporation of lauric acid, palmitic acid and oleic acid into phospholipids of lung and liver has been studied in tissue slices of control rabbits and of rabbits treated with bromhexine or ambroxol in doses of 10 mg/kg. A marked increase (up to 200% of the controls) of palmitic acid incorporation into phosphatidylcholine (lecithin) and phosphatidylethanolamine of the lung was found whereas the incorporation rate of palmitic acid into lecithin and phosphatidylethanolamine of the liver displayed no significant change. The incorporation of lauric acid and oleic acid into lung phospholipids was not accelerated. The observed effects were more marked in short time experiments (analysis 2 h after drug injection) than after treatements for 7 days. It is concluded that the phospholipid synthesis is stimulated by the drugs especially in the lungs. This seems to be of particular interest with respect to the surfactant system of the lung and might have some therapeutic relevance.

Generalized fungal infection in a patient with AIDS appearing as skin papules.

Human immunodeficiency virus infection (HIV) is unique among cutaneous fungal infections caused by defects of the cell-mediated immune system. Infections with Candida albicans occur with increased frequency and severity among HIV-infected individuals. Oral candidiasis is the most common manifestation, superficial cutaneous infections of the dermis are rarely seen. We report a HIV-positive man from Cameroon presenting with generalized cutaneous papules and nodes, oral candidiasis, and soor esophagitis, who was successfully treated with fluconazole monotherapy.

A high-order harmonic generation apparatus for time- and angle-resolved photoelectron spectroscopy.

We present a table top setup for time- and angle-resolved photoelectron spectroscopy to investigate band structure dynamics of correlated materials driven far from equilibrium by femtosecond laser pulse excitation. With the electron-phonon equilibration time being in the order of 1-2 ps it is necessary to achieve sub-picosecond time resolution. Few techniques provide both the necessary time and energy resolution to map non-equilibrium states of the band structure. Laser-driven high-order harmonic generation is such a technique. In our experiment, a grating monochromator delivers tunable photon energies up to 40 eV. A photon energy bandwidth of 150 meV and a pulse duration of 100 fs FWHM allow us to cover the k-space necessary to map valence bands at different kz and detect outer core states.