Narcolepsy and the Dissociation of REM Sleep and Cataplexy through Ambient Temperature Manipulation

Narcolepsy is characterized by increased REM sleep propensity and cataplexy. Although narcolepsy is caused by the selective loss or dysfunction of hypocretin (Hcrt) neurons within the lateral hypothalamus (LH), mechanisms underlying REM sleep propensity and cataplexy remain to be elucidated. We have recently shown that wild type (WT) mice increase REM sleep expression when exposed to thermoneutral ambient temperature (Ta) warming during the light (inactive) phase. We hypothesized that the loss of Hcrt may lead to exaggerated responses with respect to increased REM sleep and cataplexy during Ta warming. To test this hypothesis, Hcrt-KO mice were implanted for chronic sleep recordings and housed in a temperature-controlled cabinet. Sleep-wake expression and both spontaneous cataplexy and food-elicited cataplexy were evaluated at constant Ta and during a Ta manipulation protocol. Here we show several unexpected findings. First, Hcrt-KO mice show opposite circadian patterns with respect to REM sleep responsiveness to thermoneutral Ta warming compared to WT mice. As previously demonstrated, WT mice increased REM sleep when Ta warming is presented during the inactive (light) phase, whereas Hcrt-KO showed a significant decrease in REM sleep expression. In contrast, Hcrt-KO mice increased REM sleep expression upon exposure to Ta warming when presented during the active (dark) phase, a circadian time when WT mice showed no significant changes in REM sleep as a function of Ta. Second, we found that REM sleep and cataplexy can be dissociated through Ta manipulation. Specifically, although Ta warming significantly increased REM sleep expression in Hcrt-KO mice during the active phase, cataplexy bout number and total cataplexy duration significantly decreased. In contrast, cataplexy expression was favoured during Ta cooling when REM sleep expression significantly decreased. Finally, video actigraphy and sleep-wake recordings in Hcrt-KO mice demonstrated that Ta manipulation did not significantly alter waking motor activity patterns or waking or NREM sleep durations. These data suggest that neural circuits gating REM sleep and cataplexy expression can be dissociated with Ta manipulation.

Systematic analysis of C. elegans embryo behavior reveals a stereotyped developmental progression and a rhythmic pattern of behavioral quiescence

Systematic analysis of rich behavioral recordings is being used to uncover how circuits encode complex behaviors. Here we apply the approach to embryos. What are the first embryonic behaviors and how do they evolve as early neurodevelopment ensues? To address these questions, we present a systematic description of behavioral maturation for Caenorhabditis elegans embryos. Posture libraries were derived from a genetically encoded motion capture suit imaged with light-sheet microscopy and annotated using custom semi-automated tracking software (Multiple Hypothesis Hypergraph Tracking; MHHT). Analysis of cell trajectories, postures, and behavioral motifs revealed a stereotyped developmental progression. Early movement is dominated by flipping between dorsal and ventral coiling, which gradually slows into a period of reduced motility. Late-stage embryos exhibit sinusoidal waves of dorsoventral bends, prolonged bouts of directed motion, and a rhythmic pattern of pausing, which we designate slow wave twitch (SWT). Synaptic transmission is required for late-stage motion but not for early flipping or the intervening inactive phase. A high-throughput behavioral assay and calcium imaging revealed that SWT is elicited by the rhythmic activity of a quiescence-promoting neuron (RIS). Similar periodic quiescent states are seen prenatally in divergent animals and may play an important role in promoting normal developmental outcomes.

Care of Women with Chronic Inflammatory Bowel Disease (Chronic IBD) During Pregnancy

The incidence of chronic inflammatory bowel disease (chronic IBD) in persons of reproductive age is high. Chronic IBD does not typically lead to impaired fertility. Nevertheless, the percentage of women suffering from chronic IBD who have children is lower than that of the general population, due to self-imposed childlessness. Providing women with open, unbiased information and, if necessary, helping them to overcome baseless fears should therefore be an essential part of preconception counseling. With the exception of methotrexate, most standard drugs can and should be continued during pregnancy. If the pregnancy occurs during an inactive phase of disease, the rate of complications in pregnancy should, in principle, not be higher than normal. Nevertheless, pregnant women with chronic IBD are classed as high-risk pregnancies. Organ screening in accordance with DEGUM II criteria should be carried out in every case, and women must be monitored for the potential development of placental insufficiency. Any flare-ups which occur during pregnancy should be treated in full. Vaginal delivery can be considered if there is no perianal manifestation of disease; however, the individual risk must be carefully weighed up.

Deconvoluting the Impacts of the Active Material Skeleton and the Inactive Phase Morphology on the Performance of Lithium Ion Battery Electrodes

In order to extract the most capacity out of Li-ion battery (LIB) active materials, the optimization of the electrodes architectures at the mesoscale is essential. This work focuses on the morphology of the inactive phase (carbon additives and binder) through a 3-D modeling approach based on stochastic generation with realistic LiNi1/3Mn1/3Co1/3O2 particle size distributions. It was found that having the inactive phase as a film spread on the active material results in poorer performance in part due to the loss of active surface area when compared to an agglomerates morphology.

Features Of The Clinical And Laboratory Course Of Tuberculosis Lymphadenopathy In Patients Without And With HIV Infection

Tuberculous lymphadenopathy without HIV infection, in comparison with those with HIV infection, was characterized by a more favorable clinical course, limited lesion and, especially important, limited caseous-necrotic changes. Analysis of the histological picture of the removed lymph nodes in patients with HIV-i made it possible to distinguish three activities of tuberculous lymphadenopathy: an inactive phase (with a predominance of a productive cellular reaction) - in 3 patients (5.3%), an active (with a predominantly productive-necrotic tissue reaction) - in 11 patients (19.3%), the phase of progression of the pathological process (mainly necrotic lesions, suppuration and formation of fistulas) - in 43 patients (75.4%). It was found that the inactive phase is 5.5 times more common in patients without HIV than in patients with HIV (29.3% and 5.3%, respectively, P˂0.001), while the active phase and the progression phase was 1.5 and 1.3 times more frequent in patients with HIV than in patients without HIV (19.3% and 13.1, respectively, P˃0.5; 75.4% and 57, 6%, respectively, P˂0.02).

Abstract MP21: Circadian Cycle Exaggerates Sympathoexcitatory Responses To Activation Of Chemosensitive Renal Sensory Nerves

Renal sensory nerves contribute to hypertension and renal dysfunction in chronic kidney disease. Selective chemokines (e.g., bradykinin or capsaicin) activate renal sensory nerves and produce reflexive efferent sympathetic nerve activity (SNA) and arterial blood pressure (ABP) responses. SNA, ABP, and renal function exhibit circadian patterns; yet the impact of circadian cycle on chemosensitive responses is unknown. We hypothesized that SNA and hemodynamic responses would be greater during the active phrase or nighttime versus the inactive phase or daytime. In Inactin anesthetized rats, simultaneous renal and splanchnic SNA and ABP were measured during intrarenal arterial infusion of capsaicin or bradykinin (0.1 μM - 30.0 μM; 50 μl over 15 s) at nighttime (N; 20:00-04:00; n= 12M, 10F) versus daytime (D; 09:00-16:00; n= 8M, 8F). Baseline mean ABP was significantly elevated during nighttime (N: 104±2 mmHg; D: 97±2 mmHg, p=0.04). Intrarenal capsaicin infusion produced concentration-dependent increases in renal and splanchnic SNA. Renal SNA increased more at nighttime versus daytime at 10 μM (N: 723±136 vs D: 409±79 %; p=0.03) and 30 μM (N: 826±181 vs D: 509±80 %; p=0.03). Similarly, splanchnic SNA was greater during nighttime versus daytime at 10 μM (N: 501±117 vs D: 204±53 %, p=0.03) and 30 μM (N: 537±101 vs D: 295±68 %; p=0.03). However, ABP responses were similar between nighttime versus daytime (30uM: 7±1 vs 6±1 mmHg, respectively). Intrarenal infusion of bradykinin produced concentration-dependent increases in renal and splanchnic SNA. Renal SNA increased more at nighttime versus daytime at 10 μM (N: 1773±216 vs D: 1249±112 %; p=0.01) and 30 μM (N: 2605±263 vs D: 1783±163 %; p=0.001). Similarly, splanchnic SNA was exaggerated at nighttime versus daytime at 0.1 μM (N: 163±65 vs D: 0±0 %; p=0.02), 1.0 μM (N: 566±114 vs D: 184±52 %; p=0.005), 10 μM (N: 1110±193 vs D: 583±87 %; p=0.006) and 30 μM (N: 2008±193 vs D: 1044±162 %; p<0.001). ABP response were similar between nighttime versus daytime at 30 μM (10±2 vs 6±1 mmHg, respectively). Circadian cycle exaggerates sympathoexcitatory responses produced by chemosensitive renal sensory nerve activation.

CGRP induces migraine-like symptoms in mice during both the active and inactive phases

Background Circadian patterns of migraine attacks have been reported by patients but remain understudied. In animal models, circadian phases are generally not taken into consideration. In particular, rodents are nocturnal animals, yet they are most often tested during their inactive phase during the day. This study aims to test the validity of CGRP-induced behavioral changes in mice by comparing responses during the active and inactive phases. Methods Male and female mice of the outbred CD1 strain were administered vehicle (PBS) or CGRP (0.1 mg/kg, i.p.) to induce migraine-like symptoms. Animals were tested for activity (homecage movement and voluntary wheel running), light aversive behavior, and spontaneous pain at different times of the day and night. Results Peripheral administration of CGRP decreased the activity of mice during the first hour after administration, induced light aversive behavior, and spontaneous pain during that same period of time. Both phenotypes were observed no matter what time of the day or night they were assessed. Conclusions A decrease in wheel activity is an additional clinically relevant phenotype observed in this model, which is reminiscent of the reduction in normal physical activity observed in migraine patients. The ability of peripheral CGRP to induce migraine-like symptoms in mice is independent of the phase of the circadian cycle. Therefore, preclinical assessment of migraine-like phenotypes can likely be done during the more convenient inactive phase of mice.

AB0724 CANDIDATE PREDICTIVE BIOMARKERS OF POOR TREATMENT RESPONSE IN OLIGOARTICULAR ONSET JUVENILE ARTHRITIS TO EARLY STEROID INJECTIONS

Background:Intra-articular corticosteroid injections are the first-line antirheumatic drugs of oligoarticular onset juvenile arthritis. Despite significant advances in treatment (anti-TNF, block IL6) this choice of pediatric chronic joint disease still remains relevant. Pediatric rheumatologists and to this day there are no consensus on the best modality for treatment.Objectives:The aim of this study was to search of biomarkers ineffective of early intra-articular steroid injections of oligoarticular onset juvenile arthritis.Methods:Clinical, imaging, laboratory data (blood and synovial fluid), and effect of early isolated intra-articular injections (is-IAI) of triamcinolone acetonide 92 children (89% girls) aged median (IQR) 4,2 (1,6 – 7,6) years with oligoarticular onset juvenile arthritis without extra-articular manifestations (oligo-JA) were collected retrospectively and analyzed. All children were met ILAR criteria. Triamcinolone acetonide (TA) was administered intra-articular at a dose of 20-40 mg with an injection interval of 3-6-12 months which was depended on the activity of the disease. All children were divided into two groups: active / inactive arthritis based on the effectiveness of local corticosteroid treatment. The average follow-up was 48 [38; 62] months.Results:32 children (35%; all girls) were achieved remission oligo-JA after is-IAI of TA with mean of 2 [1,75; 2] injection per joint (inactive arthritis > 24 months). The mean interval between two consecutive is-IAI was 7 [5,25; 10] months. Other children did not achieve inactive oligo-JA after is-IAI of TA with mean of 3 [2; 4] injection per joint. The mean interval between first two consecutive injection was 5,5 [4,25; 7] months and other injections - 2 [2; 3] months. All children who did not achieve remission oligo-JA for is-IAI were treated by DMARDs. Statistical analyses were performed to determine the relationships between clinical, instrumental, laboratory signs and efficacy is-IAI of TA. Measures included the number of swollen or tender joints [active joint counts]; biological inflammatory markers [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum and synovial fluid level of interleukin 6 (IL6) and tumor necrosis factor alfa (TNF-α)]; autoimmunity [titer of antinuclear factor (ANF)] and physicians’ assessment of JIA disease activity [clinical Juvenile Arthritis Disease Activity Score including maximal 10 joints (cJADAS10)]. Efficacy is-IAI of TA was no associated significantly with number of active joint of onset oligo-JA, cJADAS10, serum level of CRP mg/ml, ESR mm/h, IL6 pg/ml and TNF-α pg/ml, titer of ANF. The mean inflamed synovial fluid of IL6 levels 2208 [710; 4564] / 3234 [1265; 16902] pg/ml and TNF-α levels 3,3 [2,5; 3,8] / 1,1 [0,6; 3,7] pg/ml at onset of inactive and active oligo-JA were not significantly differ. The analysis revealed a correlation between a short phase of beneficial effect after is-IAI of TA and risk of activity disease (with an inactive phase of arthritis less than 3 months, the risk activity was OR = 2.09, p <0.001; with an inactive phase less than 2 months - OR = 8.9, p <0.001).Conclusion:TA is an effective and safe treatment in children with oligo-JA. Research was revealed that about a third of children with oligo-JA achieved inactive arthritis of average after two intra-articular injections of TA (all girls). There are no biomarkers for prediction of poor treatment response in oligo-JA to early steroid injections. But a short phase of beneficial effect after is-IAI of TA may be sign of risk activity disease. In addition boys with oligoarticular onset juvenile arthritis may be considered like potentially ineffective for local steroid therapy.References:[1]Kozhevnikov A.N., Pozdeeva N.A., Konev M.A., Maricheva O.N., Afonichev K.A., Novik G.A. X-ray diagnosis of juvenile chronic oligoarthritis. Bulletin of Siberian Medicine. 2017; 16 (3): 224–234 DOI:10.20538/1682-0363-2017-3-224–234.Disclosure of Interests:None declared

Distinct Western North Pacific Tropical Cyclogenesis During Inactive Intraseasonal Phase of August 1996 and 2014

While intraseasonal oscillation was in the inactive phase over the western North Pacific (WNP) during August of 1996 and 2014, no tropical cyclone (TC) genesis occurred in August of 2014, whereas 9 TCs (average 5.7 TCs) formed in August of 1996 with 5 TCs in the northeastern part (the largest number since 1979) and 4 TCs in the southwestern part. The present analysis reveals an obvious southwest-northeast-oriented lower-level wave train over the WNP associated with anomalous convection around the Maritime Continent in August 1996. This wave train induced anomalous cyclone and enhanced convection over the northeastern WNP, which provided a favorable background for TC genesis. Over the southwestern WNP, although monthly mean anomalies were unfavorable, the intraseasonal variation contributed to positive vorticity anomalies at the time and location of TC genesis. In contrast, both monthly anomalies and daily variations of environment factors were hostile to TC genesis during August 2014.