Cognition, mood and fatigue in patients in the early stage of multiple sclerosis.

QUESTION UNDER STUDY: Cognitive impairment occurs during multiple sclerosis (MS) and contributes to the burden of the disease, but its effect in the initial phase of MS still needs to be better understood. METHODS: We prospectively studied 127 early MS patients presenting with a clinically isolated syndrome (CIS) or definite MS, a mean disease duration of 2.6 years, and with minor disability (mean Expanded Disability Status Scale score 1.8). Patients were tested for long-term memory, executive functions, attention, fatigue, mood disorders, functional handicap and quality of life (QoL). Twenty-one CIS patients were excluded from study as the diagnosis of MS could not be confirmed. RESULTS: Over the 106 MS patients analysed, 31 (29.3%) were cognitively impaired (23.6% for memory, 10.4% for attention and 5.7% for executive functions). Cognitive deficits were already present in CIS patients in whom the diagnosis was not yet confirmed (20%). Impaired cognition was associated with anxiety (p = 0.05), depression(p = 0.004), fatigue (p = 0.03), handicap (p <0.001) and a lower QoL (p <0.001). After adjustment for QoL, handicap, depression, anxiety and fatigue were no longer associated with the presence of cognitive deficits. CONCLUSIONS: In this well-defined early MS group one third of the patients already exhibited cognitive deficits, which were usually apparent in an effortful learning situation and were generally mild. Mood disorders, fatigue, handicap and decreased QoL were all associated with the occurrence of cognitive deficits. QoL itself appeared to take all the other factors into account. Our results confirm the existence of an interplay between cognitive, affective and functional changes and fatigue in early MS.

The unfolded protein response: integrating stress signals through the stress sensor IRE1α.

Stress induced by accumulation of unfolded proteins at the endoplasmic reticulum (ER) is a classic feature of secretory cells and is observed in many tissues in human diseases including cancer, diabetes, obesity, and neurodegeneration. Cellular adaptation to ER stress is achieved by the activation of the unfolded protein response (UPR), an integrated signal transduction pathway that transmits information about the protein folding status at the ER to the nucleus and cytosol to restore ER homeostasis. Inositol-requiring transmembrane kinase/endonuclease-1 (IRE1α), the most conserved UPR stress sensor, functions as an endoribonuclease that processes the mRNA of the transcription factor X-box binding protein-1 (XBP1). IRE1α signaling is a highly regulated process, controlled by the formation of a dynamic scaffold onto which many regulatory components assemble, here referred to as the UPRosome. Here we provide an overview of the signaling and regulatory mechanisms underlying IRE1α function and discuss the emerging role of the UPR in adaptation to protein folding stress in specialized secretory cells and in pathological conditions associated with alterations in ER homeostasis.

Resting-state temporal synchronization networks emerge from connectivity topology and heterogeneity.

Spatial patterns of coherent activity across different brain areas have been identified during the resting-state fluctuations of the brain. However, recent studies indicate that resting-state activity is not stationary, but shows complex temporal dynamics. We were interested in the spatiotemporal dynamics of the phase interactions among resting-state fMRI BOLD signals from human subjects. We found that the global phase synchrony of the BOLD signals evolves on a characteristic ultra-slow (<0.01Hz) time scale, and that its temporal variations reflect the transient formation and dissolution of multiple communities of synchronized brain regions. Synchronized communities reoccurred intermittently in time and across scanning sessions. We found that the synchronization communities relate to previously defined functional networks known to be engaged in sensory-motor or cognitive function, called resting-state networks (RSNs), including the default mode network, the somato-motor network, the visual network, the auditory network, the cognitive control networks, the self-referential network, and combinations of these and other RSNs. We studied the mechanism originating the observed spatiotemporal synchronization dynamics by using a network model of phase oscillators connected through the brain's anatomical connectivity estimated using diffusion imaging human data. The model consistently approximates the temporal and spatial synchronization patterns of the empirical data, and reveals that multiple clusters that transiently synchronize and desynchronize emerge from the complex topology of anatomical connections, provided that oscillators are heterogeneous.

Multiple roles of mouse Numb in tuning developmental cell fates.

BACKGROUND: Notch signaling regulates multiple differentiation processes and cell fate decisions during both invertebrate and vertebrate development. Numb encodes an intracellular protein that was shown in Drosophila to antagonize Notch signaling at binary cell fate decisions of certain cell lineages. Although overexpression experiments suggested that Numb might also antagonize some Notch activity in vertebrates, the developmental processes in which Numb is involved remained elusive. RESULTS: We generated mice with a homozygous inactivation of Numb. These mice died before embryonic day E11.5, probably because of defects in angiogenic remodeling and placental dysfunction. Mutant embryos had an open anterior neural tube and impaired neuronal differentiation within the developing cranial central nervous system (CNS). In the developing spinal cord, the number of differentiated motoneurons was reduced. Within the peripheral nervous system (PNS), ganglia of cranial sensory neurons were formed. Trunk neural crest cells migrated and differentiated into sympathetic neurons. In contrast, a selective differentiation anomaly was observed in dorsal root ganglia, where neural crest--derived progenitor cells had migrated normally to form ganglionic structures, but failed to differentiate into sensory neurons. CONCLUSIONS: Mouse Numb is involved in multiple developmental processes and required for cell fate tuning in a variety of lineages. In the nervous system, Numb is required for the generation of a large subset of neuronal lineages. The restricted requirement of Numb during neural development in the mouse suggests that in some neuronal lineages, Notch signaling may be regulated independently of Numb.

Phylogenomics of C(4) photosynthesis in sedges (Cyperaceae): multiple appearances and genetic convergence.

C(4) photosynthesis is an adaptive trait conferring an advantage in warm and open habitats. It originated multiple times and is currently reported in 18 plant families. It has been recently shown that phosphoenolpyruvate carboxylase (PEPC), a key enzyme of the C(4) pathway, evolved through numerous independent but convergent genetic changes in grasses (Poaceae). To compare the genetics of multiple C(4) origins on a broader scale, we reconstructed the evolutionary history of the C(4) pathway in sedges (Cyperaceae), the second most species-rich C(4) family. A sedge phylogeny based on two plastome genes (rbcL and ndhF) has previously identified six fully C(4) clades. Here, a relaxed molecular clock was used to calibrate this tree and showed that the first C(4) acquisition occurred in this family between 19.6 and 10.1 Ma. According to analyses of PEPC-encoding genes (ppc), at least five distinct C(4) origins are present in sedges. Two C(4) Eleocharis species, which were unrelated in the plastid phylogeny, acquired their C(4)-specific PEPC genes from a single source, probably through reticulate evolution or a horizontal transfer event. Acquisitions of C(4) PEPC in sedges have been driven by positive selection on at least 16 codons (3.5% of the studied gene segment). These sites underwent parallel genetic changes across the five sedge C(4) origins. Five of these sites underwent identical changes also in grass and eudicot C(4) lineages, indicating that genetic convergence is most important within families but that identical genetic changes occurred even among distantly related taxa. These lines of evidence give new insights into the constraints that govern molecular evolution.

Rapid transgene expression in multiple precursor cell types of adult rat subventricular zone mediated by adeno-associated type 1 vectors.

Abstract The adult rat brain subventricular zone (SVZ) contains proliferative precursors that migrate to the olfactory bulb (OB) and differentiate into mature neurons. Recruitment of precursors constitutes a potential avenue for brain repair. We have investigated the kinetics and cellular specificity of transgene expression mediated by AAV2/1 vectors (i.e., adeno-associated virus type 2 pseudotyped with AAV1 capsid) in the SVZ. Self-complementary (sc) and single-stranded (ss) AAV2/1 vectors mediated efficient GFP expression, respectively, at 17 and 24 hr postinjection. Transgene expression was efficient in all the rapidly proliferating cells types, that is, Mash1(+) precursors (30% of the GFP(+) cells), Dlx2(+) neuronal progenitors (55%), Olig2(+) oligodendrocyte progenitors (35%), and doublecortin-positive (Dcx(+)) migrating cells (40%), but not in the slowly proliferating glial fibrillary acidic protein-positive (GFAP(+)) neural stem cell pool (5%). Because cell cycle arrest by wild-type and recombinant AAV has been described in primary cultures, we examined SVZ proliferative activity after vector injection. Indeed, cell proliferation was reduced immediately after vector injection but was normal after 1 month. In contrast, migration and differentiation of GFP(+) precursors were unaltered. Indeed, the proportion of Dcx(+) cells was similar in the injected and contralateral hemispheres. Furthermore, 1 month after vector injection into the SVZ, GFP(+) cells, found, as expected, in the OB granular cell layer, were mature GABAergic neurons. In conclusion, the rapid and efficient transgene expression in SVZ neural precursors mediated by scAAV2/1 vectors underlines their potential usefulness for brain repair via recruitment of immature cells. The observed transient precursor proliferation inhibition, not affecting their migration and differentiation, will likely not compromise this strategy.

RANKL expression, function, and therapeutic targeting in multiple myeloma and chronic lymphocytic leukemia.

Bone destruction is a prominent feature of multiple myeloma, but conflicting data exist on the expression and pathophysiologic involvement of the bone remodeling ligand RANKL in this disease and the potential therapeutic benefits of its targeted inhibition. Here, we show that RANKL is expressed by primary multiple myeloma and chronic lymphocytic leukemia (CLL) cells, whereas release of soluble RANKL was observed exclusively with multiple myeloma cells and was strongly influenced by posttranscriptional/posttranslational regulation. Signaling via RANKL into multiple myeloma and CLL cells induced release of cytokines involved in disease pathophysiology. Both the effects of RANKL on osteoclastogenesis and cytokine production by malignant cells could be blocked by disruption of RANK-RANKL interaction with denosumab. As we aimed to combine neutralization of RANKL with induction of antibody-dependent cellular cytotoxicity of natural killer (NK) cells against RANKL-expressing malignant cells and as denosumab does not stimulate NK reactivity, we generated RANK-Fc fusion proteins with modified Fc moieties. The latter displayed similar capacity compared with denosumab to neutralize the effects of RANKL on osteoclastogenesis in vitro, but also potently stimulated NK cell reactivity against primary RANKL-expressing malignant B cells, which was dependent on their engineered affinity to CD16. Our findings introduce Fc-optimized RANK-Ig fusion proteins as attractive tools to neutralize the detrimental function of RANKL while at the same time potently stimulating NK cell antitumor immunity.

MP2RAGE Multiple Sclerosis Magnetic Resonance Imaging at 3 T.

OBJECTIVES: Lesion detection and characterization in multiple sclerosis (MS) are an essential part of its clinical diagnosis and an important research field. In this pilot study, we applied the recently introduced two inversion-contrast magnetization-prepared rapid gradient echo sequence (MP2RAGE) to patients with early-stage MS.¦MATERIALS AND METHODS: The MP2RAGE is a 3-dimensional (3D) magnetization-prepared rapid gradient echo derivative providing homogeneous T1 weighting and simultaneous T1 mapping. The MP2RAGE performance was compared with that of 2 clinical routine sequences (2D fluid-attenuated inversion recovery [FLAIR] and 3D magnetization-prepared rapid gradient echo [MP-RAGE]) and 2 state-of-the art clinical research sequences (the 3D FLAIR-SPACE [sampling perfection with application-optimized contrasts by using different flip-angle evolutions], a fluid-attenuated variable flip-angle fast spin echo technique, and the 3D double-inversion recovery SPACE). A cohort of 10 early-stage female MS patients (age, 31.6 ± 4.7 years; disease duration, 3.8 ± 1.9 years; median expanded disability status scale score, 1.75) and 10 age- and gender-matched controls were enrolled after approval of the local institutional review board was obtained. Multiple sclerosis lesions were identified and assigned to brain locations and tissue types by two experienced physicians in all 5 contrasts. Subsequently, lesions were manually delineated for comparison and statistical analysis of lesion count, volume and quantitative measures.¦RESULTS AND CONCLUSIONS: The results show that the 3D T1-weighted high-resolution MP2RAGE contrast provides a sensitive means for MS lesion assessment. The additional quantitative T1 relaxation time maps obtained with the MP2RAGE provide further potential diagnostic and prognostic information that could help (a) to better discriminate lesion subtypes and (b) to stage and predict the activity and the evolution of MS. Results also indicate that the T2-weighted double-inversion recovery and FLAIR-SPACE contrasts are attractive complements to the MP2RAGE for lesion detection.

HLA-B7-Restricted EBV-Specific CD8+ T Cells Are Dysregulated in Multiple Sclerosis.

It was hypothesized that the EBV-specific CD8(+) T cell response may be dysregulated in multiple sclerosis (MS) patients, possibly leading to a suboptimal control of this virus. To examine the CD8(+) T cell response in greater detail, we analyzed the HLA-A2-, HLA-B7-, and HLA-B8-restricted EBV- and CMV-specific CD8(+) T cell responses in a high number of MS patients and control subjects using tetramers. Content in cytolytic granules, as well as cytotoxic activity, of EBV- and CMV-specific CD8(+) T cells was assessed. We found that MS patients had a lower or a higher prevalence of HLA-A2 and HLA-B7, respectively. Using HLA class I tetramers in HLA-B7(+) MS patients, there was a higher prevalence of MS patients with HLA-B*0702/EBV(RPP)-specific CD8(+) T cells ex vivo. However, the magnitude of the HLA-B*0702/EBV(RPP)-specific and HLA-B*0702/CMV(TPR)-specific CD8(+) T cell response (i.e., the percentage of tetramer(+) CD8(+) T cells in a study subject harboring CD8(+) T cells specific for the given epitope) was lower in MS patients. No differences were found using other tetramers. After stimulation with the HLA-B*0702/EBV(RPP) peptide, the production of IL-2, perforin, and granzyme B and the cytotoxicity of HLA-B*0702/EBV(RPP)-specific CD8(+) T cells were decreased. Altogether, our findings suggest that the HLA-B*0702-restricted viral (in particular the EBV one)-specific CD8(+) T cell response is dysregulated in MS patients. This observation is particularly interesting knowing that the HLA-B7 allele is more frequently expressed in MS patients and considering that EBV is associated with MS.

Effect of bicarbonate and lactate buffer on glucose and lactate metabolism during hemodiafiltration in patients with multiple organ failure.

OBJECTIVE: To compare the effects of sodium bicarbonate and lactate for continuous veno-venous hemodiafiltration (CVVHDF) in critically ill patients. DESIGN AND SETTINGS: Prospective crossed-over controlled trial in the surgical and medical ICUs of a university hospital. PATIENTS: Eight patients with multiple organ dysfunction syndrome (MODS) requiring CVVHDF. INTERVENTION: Each patient received the two buffers in a randomized sequence over two consecutive days. MEASUREMENTS AND RESULTS: The following variables were determined: acid-base parameters, lactate production and utilization ((13)C lactate infusion), glucose turnover (6,6(2)H(2)-glucose), gas exchange (indirect calorimetry). No side effect was observed during lactate administration. Baseline arterial acid-base variables were equal with the two buffers. Arterial lactate (2.9 versus 1.5 mmol/l), glycemia (+18%) and glucose turnover (+23%) were higher in the lactate period. Bicarbonate and glucose losses in CVVHDF were substantial, but not lactate elimination. Infusing (13)C lactate increased plasma lactate levels equally with the two buffers. Lactate clearance (7.8+/-0.8 vs 7.5+/-0.8 ml/kg per min in the bicarbonate and lactate periods) and endogenous production rates (14.0+/-2.6 vs 13.6+/-2.6 mmol/kg per min) were similar. (13)C lactate was used as a metabolic substrate, as shown by (13)CO(2) excretion. Glycemia and metabolic rate increased significantly and similarly during the two periods during lactate infusion. CONCLUSION: Lactate was rapidly cleared from the blood of critically ill patients without acute liver failure requiring CVVHDF, being transformed into glucose or oxidized. Lactate did not exert undesirable effects, except moderate hyperglycemia, and achieved comparable effects on acid-base balance to bicarbonate.