Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized ...behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD.
Background and purpose
Humanized monoclonal antibody galcanezumab, which binds to calcitonin‐gene‐related peptide, has shown efficacy for episodic and chronic migraine prevention. These analyses ...evaluated galcanezumab response for migraine headache prevention in patients who previously failed onabotulinumtoxinA (‘nonresponse’ or ‘inadequate response’ or safety reasons).
Methods
Post hoc analyses included data from three double‐blind, placebo‐controlled, phase 3 episodic or chronic migraine studies; 2886 patients randomly received 120 or 240 mg galcanezumab or placebo. During double‐blind periods the study drug was administered subcutaneously once a month for 6 months in EVOLVE‐1 and ‐2 and for 3 months in REGAIN. The 120 mg groups received a 240 mg loading dose at month 1. Pooled analyses included 129 patients who failed onabotulinumtoxinA. Using mixed effect model repeat measurements, the least squares mean change from baseline in the number of migraine headache days (MHDs) was calculated for the first 3 months of treatment.
Results
For pooled analyses, significant decreases from baseline in the number of MHDs were observed for 120 mg (−3.91) and 240 mg (−5.27) galcanezumab overall versus placebo (−0.88) across 3‐month time points for patients who failed onabotulinumtoxinA. Corresponding data for patients with chronic migraine showed significant decreases: 120 mg (−3.18) and 240 mg (−4.26) galcanezumab versus placebo (0.16). Significant reductions in the number of MHDs per month with acute medication use included 120 mg galcanezumab (−4.35) and 240 mg galcanezumab (−4.55) versus placebo (−0.83). Estimates of ≥50% response during months 1–3 were 9.4% for placebo, 41.3% for 120 mg galcanezumab and 47.5% for 240 mg galcanezumab.
Conclusion
Galcanezumab is an option for prevention of migraine in patients who have previously failed onabotulinumtoxinA preventive therapy.
In high-yielding dairy cows, the rapidly increasing milk production after parturition can result in a negative nutrient balance, since feed intake is insufficient to cover the needs for lactation. ...Mobilizing body reserves, mainly adipose tissue (AT), might affect steroid metabolism. We hypothesized, that cows differing in the extent of periparturient lipomobilization, will have divergent steroid profiles measured in serum and subcutaneous (sc)AT by a targeted metabolomics approach and steroidogenic enzyme profiles in scAT and liver. Fifteen weeks antepartum, 38 multiparous Holstein cows were allocated to a high (HBCS) or normal body condition (NBCS) group fed differently until week 7 antepartum to either increase (HBCS BCS: 3.8 ± 0.1 and BFT: 2.0 ± 0.1 cm; mean ± SEM) or maintain BCS (NBCS BCS: 3.0 ± 0.1 and BFT: 0.9 ± 0.1 cm). Blood samples, liver, and scAT biopsies were collected at week -7, 1, 3, and 12 relative to parturition. Greater serum concentrations of progesterone, androsterone, and aldosterone in HBCS compared to NBCS cows after parturition, might be attributed to the increased mobilization of AT. Greater glucocorticoid concentrations in scAT after parturition in NBCS cows might either influence local lipogenesis by differentiation of preadipocytes into mature adipocytes and/or inflammatory response.
Excessive mobilization of body reserves during the transition from pregnancy to lactation imposes a risk for metabolic diseases on dairy cows. We aimed to establish an experimental model for high v. ...normal mobilization and herein characterized performance, metabolic and endocrine changes from 7 weeks antepartum (a.p.) to 12 weeks postpartum (p.p.). Fifteen weeks a.p., 38 pregnant multiparous Holstein cows were allocated to two groups that were fed differently to reach either high or normal body condition scores (HBCS: 7.2 NEL MJ/kg dry matter (DM); NBCS: 6.8 NEL MJ/kg DM) at dry-off. Allocation was also based on differences in body condition score (BCS) in the previous and the ongoing lactation that was further promoted by feeding to reach the targeted BCS and back fat thickness (BFT) at dry-off (HBCS: >3.75 and >1.4 cm; NBCS: <3.5 and <1.2 cm). Thereafter, both groups were fed identical diets. Blood samples were drawn weekly from 7 weeks a.p. to 12 weeks p.p. to assess the serum concentrations of metabolites and hormones. The HBCS cows had greater BCS, BFT and BW than the NBCS cows throughout the study and lost more than twice as much BFT during the first 7 weeks p.p. compared with NCBS. Milk yield and composition were not different between groups, except that lactose concentrations were greater in NBSC than in HBCS. Feed intake was also greater in NBCS, and NBCS also reached a positive energy balance earlier than HBCS. The greater reduction in body mass in HBCS was accompanied by greater concentrations of non-esterified fatty acids, and β-hydroxybutyrate in serum after calving than in NBCS, indicating increased lipomobilization and ketogenesis. The mean concentrations of insulin across all time-points were greater in HBCS than in NBCS. In both groups, insulin and IGF-1 concentrations were lower p.p than in a.p. Greater free thyroxine (fT4) concentrations and a lower free 3-3′-5-triiodothyronine (fT3)/fT4 ratio were observed in HBCS than in NBCS a.p., whereas p.p. fT3/fT4 ratio followed a reverse pattern. The variables indicative for oxidative status had characteristic time courses; group differences were limited to greater plasma ferric reducing ability values in NBSC. The results demonstrate that the combination of pre-selection according to BCS and differential feeding before dry-off to promote the difference was successful in obtaining cows that differ in the intensity of mobilizing body reserves. The HBCS cows were metabolically challenged due to intense mobilization of body fat, associated with reduced early lactation dry matter intake and compromised antioxidative capacity.
Branched-chain amino acids (BCAA) are major components of milk protein and important precursors for nonessential AA. Thus, the BCAA transport and break-down play a key role in the metabolic ...adaptation to the high nutrient demands in lactation. However, in monogastrics, increased BCAA levels have been linked with obesity and certain metabolic disorders such as impaired insulin sensitivity. Our objective was to study the effect of over-conditioning at calving on plasma BCAA levels as well as the tissue abundance of the most relevant BCAA transporters and degrading enzymes in dairy cows during late pregnancy and early lactation. Thirty-eight Holstein cows were allocated 15 wk antepartum to either a normal- (NBCS) or over-conditioned (HBCS) group, receiving 6.8 or 7.2 MJ of NEL/kg of DM, respectively, during late lactation to reach the targeted differences in body condition score (BCS) and back fat thickness (BFT; NBCS: BCS <3.5, BFT <1.2 cm; HBCS: BCS >3.75, BFT >1.4 cm) until dry-off. During the dry period and next lactation, cows were fed the same diets, whereby differences in BCS and BFT were maintained: prepartum means were 3.16 ± 0.06 and 1.03 ± 0.07 cm (NBCS) vs. 3.77 ± 0.08 and 1.89 ± 0.11 cm (HBCS), postpartum means were 2.89 ± 0.06 and 0.81 ± 0.05 cm (NBCS) vs. 3.30 ± 0.06 and 1.38 ± 0.08 cm (HBCS). Blood and biopsies from liver, semitendinosus muscle, and subcutaneous adipose tissue (scAT) were sampled at d 49 antepartum, 3, 21, and 84 postpartum. Free BCAA were analyzed and the mRNA abundance of solute carrier family 1 member 5 (SLC1A5), SLC7A5, and SLC38A2 as well as branched-chain aminotransferase 2 (BCAT2), branched-chain α-keto acid dehydrogenase E1α (BCKDHA), and branched-chain α-keto acid dehydrogenase E1β (BCKDHB) as well as the protein abundance of BCKDHA were assessed. Concentrations of all BCAA changed with time, most markedly in HBCS cows, with a nadir around calving. Apart from Ile, neither individual nor total BCAA differed between groups. The HBCS group had greater BCKDHA mRNA as well as higher prepartum BCKDHA protein abundance in scAT than NBCS cows, pointing to a greater oxidative capacity for the irreversible degradation of BCAA transamination products in scAT of over-conditioned cows. Prepartum hepatic BCKDHA protein abundance was lower in HBCS than in NBCS cows. In both groups, SLC1A5, SLC7A5, and BCAT2 mRNA were most abundant in scAT, whereas SLC38A2 was higher in scAT and muscle compared with liver, and BCKDHA and BCKDHB mRNA were greatest in liver and muscle, respectively. Our results indicate that scAT may be a major site of BCAA uptake and initial catabolism, with the former, however, being independent of BCS and time relative to calving in dairy cows.
We simulate and elucidate the self-channeling of high-power 10 μm infrared pulses in atomic gases. The major new result is that the peak intensity can remain remarkably stable over many Rayleigh ...ranges. This arises from the balance between the self-focusing, diffraction, and defocusing caused by the excitation induced dephasing due to many-body Coulomb effects that enhance the low-intensity plasma densities. This new paradigm removes the Rayleigh range limit for sources in the 8-12 μm atmospheric transmission window and enables transport of individual multi-TW pulses over multiple kilometer ranges.
Redox-active small molecules, used traditionally in redox flow batteries (RFBs), are susceptible to crossover and require expensive ion exchange membranes (IEMs) to achieve long lifetimes. ...Redox-active polymer (RAP) solutions show promise as candidate electrolytes to mitigate crossover through size-exclusion, enabling the use of porous separators instead of IEMs. Here, poly(vinylbenzyl ethyl viologen) is studied as a surrogate RAP for RFBs. For oxidized RAPs, ionic conductivity varies weakly between 1.6 and 2.1 S m−1 for RAP concentrations of 0.13–1.27 mol kg−1 (monomeric repeat unit per kg solvent) and 0.32 mol kg−1 LiBF4 with a minor increase upon reduction. In contrast, viscosity varies between 1.8 and 184.0 mPa s over the same concentration range with weakly shear-thinning rheology independent of oxidation state. Techno-economic analysis is used to quantify reactor cost as a function of electrolyte transport properties for RAP concentrations of 0.13–1.27 mol kg−1, assuming a hypothetical 3V cell and facile kinetics. Among these concentrations, reactor cost is minimized over a current density range of 600–1000 A m−2 with minimum reactor cost between $11–17 per kWh, and pumping pressures below 10 kPa. The predicted low reactor cost of RAP RFBs is enabled by sustained ionic mobility in spite of the high viscosity of concentrated RAP solutions.
Display omitted
•Ionic conductivity and viscosity of redox-active polymer solutions are measured.•Techno-economic analysis is used to assess reactor cost and pumping pressure.•Predicted reactor cost is well below system-level targets for grid energy storage.•Predicted pumping pressure is within previously reported ranges for flow batteries.
Abstract
Background
Emergency department (ED) visits for nursing home residents lead to higher morbidity and mortality. Therefore, inappropriate visits (for conditions treatable elsewhere) or ...potentially avoidable visits (those avoidable through adequate chronic care management) must be minimized. This study aimed to investigate factors and resource consumption patterns associated with inappropriate and potentially avoidable visits in a Swiss tertiary hospital.
Methods
This is a single-center retrospective chart review in an urban Swiss university hospital ED. A consecutive sample of 1276 visits by nursing home residents (≥ 65 years old), recorded between January 1, 2015 and December 31, 2017 (three calendar years) were included. Case characteristics were extracted from ED electronic documentation. Appropriateness was assessed via a structured Appropriateness Evaluation Protocol; potentially avoidable visits—measured as ambulatory-care sensitive conditions (ACSCs)—were analyzed separately. Inter-group differences concerning ED resource use were tested respectively with chi-square or Wilcoxon rank sum tests. To identify predictors of inappropriate or potentially-avoidable visits, we used multivariable logistic regression analysis.
Results
Six percent of visits were rated as inappropriate: they had lower triage levels (OR 0.55 95%-CI 0.33-0.92,
p=
0.024) and, compared to ambulance calls, they had higher odds of initiation via either patient-initiated walk-in (OR 3.42 95%-CI 1.79-6.55,
p≤
0.001) or GP referrals (OR 2.13 95%-CI 1.16-3.90,
p=
0.015). For inappropriate visits, overall ED resource use was significantly lower (median 568 vs. 1403 tax points,
p≤
0.001). Of all visits included, 29% were due to (often potentially-avoidable) ACSCs. In those cases, compared to ambulance initiation, odds of being potentially-avoidable were considerably lower for walk-in patients (OR 0.46 95%-CI 0.27-0.77,
p=
0.004) but higher for GP referrals (OR 1.40 95%-CI 1.00-1.94,
p=
0.048). Nurse work (93 tax points vs. 64,
p≤
0.001) and laboratory resource use (334 tax points vs. 214,
p≤
0.001) were higher for potentially-avoidable ED visits.
Conclusions
We revealed substantial differences between the investigated groups. While nearly one third of ED visits from nursing homes were potentially avoidable, inappropriate visits were lower in numbers and not resource-intensive. Further research is required to differentiate potentially avoidable visits from inappropriate ones and to determine these findings’ public health implications.
•People's self-assessment gives important insights into multiple sclerosis (MS).•Over 4,500 people with MS participated in this survey on their disease perception.•In RRMS with less disability, ...fatigue and vision impairment were most bothersome.•Over 60% of people with RRMS reported relapse-independent progression.•Symptomatic pharmacological therapy was more prevalent in immunotherapy users.
Assessment of the disease course by people with multiple sclerosis (pwMS) themselves is important for a better understanding of the complex disease, patient counseling and treatment decisions. This may also facilitate identifying the often-unnoticed transition from relapsing-remitting (RRMS) to secondary progressive multiple sclerosis (SPMS).
MS Perspectives was designed to collect data on patients' self-assessment of multiple sclerosis (MS) symptoms, relapse-independent progression, and impact on everyday life.
MS Perspectives is a cross-sectional online survey conducted among adult pwMS in Germany. The questionnaire included 36 items on sociodemographic and clinical characteristics as well as pharmacological and non-pharmacological treatment.
In total, 4555 pwMS completed the survey between December 2021 and February 2022, 69.2% had RRMS, 15.1% had SPMS. Relapse-independent worsening of symptoms was reported by 88.9% of RRMS patients with marked to severe and by 61.8% with no or mild to moderate disability. Problems with walking were most frequently (32.1%) mentioned as most bothersome by RRMS patients with marked to severe disability, fatigue, and cognitive impairment by RRMS patients with no or mild to moderate disability.
MS Perspectives gives an important insight in the self-assessed disease course and impact on daily life in a large-scale cohort of pwMS.
PDF
