Opposite effects of CCK(B) agonists in grooming behaviour in rats: further evidence for two CCK(B) subsites

1. The hypothesis of the existence of two CCK(B) receptor subsites, CCK(B1) and CCK(B2) corresponding probably to different coupling states of CCK(B) receptors, was studied by measuring grooming behaviour in rats. 2. The B1 receptor agonist, BC197 (300 μg kg(−1), i.p.) produced a 45–50% decrease in grooming activity, which was prevented by both the CCK(B) receptor antagonists CI-988 (20 μg kg(−1) i.p.) and L-365,260 (200 μg kg(−1), i.p.). 3. In contrast, 3, 10 and 30 μg kg(−1), i.p., of the potent B2 receptor agonist, BC264, enhanced grooming (150–190%). This effect was prevented by previous injection of 75 μg kg(−1) of L-365,260 while higher doses (200 μg kg(−1), i.p.) produced only a partial antagonism. Moreover, CI-988 (20 μg kg(−1), i.p.), showed an opposite effect in potentiating the responses induced by BC264. However, 200 μg kg(−1) of CI-988 tended to suppress the increase of grooming induced by BC264. 4. The effects of BC264 were prevented by the D(1) receptor (SCH 23390) and D(2) receptor (sulpiride) antagonists, while those of BC197 were only antagonized by sulpiride, emphasizing the existence of a link between peptidergic (CCK) and dopaminergic systems. 5. This study brings additional evidence for the existence of the two CCK(B) receptor subsites and suggests that particular attention should be focused on the selectivity of CCK(B) receptor agonists, notably to explain the fact that some compounds such as Boc-CCK4 induce anxiogenic-like effects while others, including BC264, are devoid of these effects

Recanalization Treatments for Pediatric Acute Ischemic Stroke in France

International audienceImportance: There is to date limited evidence that revascularization strategies are associated with improved functional outcome in children with acute ischemic stroke (AIS).Objectives To report clinical outcomes and provide estimates of revascularization strategy safety and efficacy profiles of intravenous thrombolysis (IVT) and/or endovascular treatment (EVT) in children with AIS.Design, Setting, and Participants The KidClot multicenter nationwide cohort study retrospectively collected data of children (neonates excluded) with AIS and recanalization treatment between January 1, 2015, and May 31, 2018. Data analysis was performed from January 1, 2015, to May 31, 2019.Exposure: IVT and/or EVT.Main Outcomes and Measures Primary outcome was day 90 favorable outcome (modified Rankin Scale [mRs] 0-2, with 0 indicating no symptoms and 6 indicating death). Secondary end points included 1-year favorable outcome (mRs, 0-2), mortality, and symptomatic intracerebral hemorrhage. Other measures included the Pediatric National Institutes of Health Stroke Scale (pedNIHSS), with pedNIHSS 0 indicating no symptoms, 1 to 4 corresponding to a minor stroke, 5 to 15 corresponding to a mild stroke, greater than 15 to 20: severe stroke, and the adult Alberta Stroke Program Early CT Score (ASPECTS), which provides segmental assessment of the vascular territory, with 1 point deducted from the initial score of 10 for every region involved (from 10 [no lesion] to 0 [maximum lesions]).Results: Overall, 68 children were included in 30 centers (IVT [n = 44]; EVT [n = 40]; 44 boys [64.7%]; median [IQR] age, 11 [4-16] years; anterior circulation involvement, 57 [83.8%]). Median (IQR) pedNIHSS score at admission was 13 (7-19), higher in the EVT group at 16 (IQR, 10-20) vs 9 (6-17) in the IVT only group (P < .01). Median time from stroke onset to imaging was higher in the EVT group at 3 hours and 7 minutes (IQR, 2 hours and 3 minutes to 6 hours and 24 minutes) vs 2 hours and 39 minutes (IQR, 1 hour and 51 minutes to 4 hours and 13 minutes) (P = .04). Median admission ASPECTS score was 8 (IQR, 6-9). The main stroke etiologies were cardioembolic (21 [30.9%]) and focal cerebral arteriopathy (17 [25.0%]). Median (IQR) time from stroke onset to IVT was 3 hours and 30 minutes (IQR, 2 hours and 33 minutes to 4 hours and 28 minutes). In the EVT group, the rate of postprocedure successful reperfusion (≥modified Treatment in Cerebral Infarction 2b) was 80.0% (32 of 40). Persistent proximal arterial stenosis was more frequent in focal cerebral arteriopathy (P < .01). Death occurred in 3 patients (4.4%). Median pedNIHSS reduction at 24 hours was 4 (IQR, 0-9) points. Intracerebral hemorrhage occurred in 4 patients and symptomatic intracerebral hemorrhage occurred in 1 patient, all in the EVT group. The median mRS was 2 (IQR, 0-3) at day 90 and 1 (IQR, 0-2) at 1 year, which was not significantly different between EVT and IVT only groups, although different in initial severity.Conclusions and Relevance: The findings of this cohort study suggest that use of EVT and/or IVT is safe in children with AIS

Author Correction 2024: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials(Nature Communications, (2021), 12, (1), 10.1038/s41467-021-22446-z)

Correction to: Nature Communicationshttps://doi.org/10.1038/s41467-021-22446-z, published online 15 April 2021 The original version of this article contained an error in Table 1, which misidentified the trial included in the meta-analysis registered as NCT04323527 as CloroCOVID19II instead of CloroCOVID19III. The NCT04323527 registration includes the trials CloroCOVID19I and CloroCOVID19III. CloroCOVID19I was not included in the meta-analysis. In addition, the original version of the Methods section inadvertently omitted details of which formulations of hydroxychloroquine or chloroquine the reported dosages refer to. The following information has been included in the legend for Table 1 and in the corrected methods section: “In all trials that used hydroxychloroquine, dosages refer to hydroxychloroquine sulfate. In trials that used chloroquine, the dosages for ARCHAIC, ChiCTR2000030054 and ChiCTR2000031204 refer to chloroquine phosphate, while those for CloroCOVID19II and CloroCOVID19III refer to chloroquine base. The American Journal of Tropical Medicine and Hygiene has issued a retraction note (1) for one of the trials (2) that had been included in the calculations of our meta-analysis. Exclusion of the data from this trial changes neither the results nor inferences of the meta-analysis. For hydroxychloroquine, the original odds ratio for mortality was 1.11 (95% CI: 1.02–1.20; I 2 = 0%; 26 trials; 10,012 patients) and excluding the retracted trial the odds ratio for mortality would remain 1.11 (95% CI: 1.02–1.20, I 2 = 0%; 25 trials; 9818 patients). Retraction Notice. The American Journal of Tropical Medicine and Hygiene 107, 728-728, https://doi.org/10.4269/ajtmh.1073ret (2022). Abd-Elsalam, S. et al. RETRACTED: Hydroxychloroquine in the Treatment of COVID-19: A Multicenter Randomized Controlled Study. Am J Trop Med Hyg 103, 1635-1639, https://doi.org/10.4269/ajtmh.20-0873 (2020). The errors in Table 1 and in the Methods section have been corrected in both the PDF and HTML versions of the Article

Engineering of human-induced pluripotent stem cells for precise disease modeling

Stem cell technologies and gene editing techniques are two of the most promising recent developments in biomedicine. The ability to reprogram common human cells into induced pluripotent stem cells (hiPSCs) and turn them into the cells of interest has already become a powerful research tool, thus providing a unique platform for disease studies. In combination with the use of designer nucleases approach to repair or to introduce disease-causing mutations, both are valuable in developing personalized disease models. This chapter provides an overview on designer nucleases-based gene editing in hiPSCs, describing the principles of CRISPR/Cas systems along with consecutive methodological steps such as nucleases selection, isolation, and genotyping of modified hiPSC clones with emphasis on the crucial role of isogenic cell lines in disease modeling. Moreover, the production of rare or complex genotypes in patient cell lines requires efficient and streamlined gene editing technologies. However, precise genome editing applications rely on infrequent homology-directed repair (HDR), with the abundant nonhomologous end joining (NHEJ) formed indels presenting a barrier to achieving high rates of precise sequence modification. The methods presented here are supported by theoretical framework to allow for the incorporation of inevitable improvements to achieve either higher rates of gene editing by promotion of HDR over NHEJ or application of different CRISPR/Cas platforms for robust and multiplex gene editing, toward decoding of neurodevelopmental as well as for modeling of late onset disorders by fast-forwarding the biological clock. Due to easy in theory but laborious and inefficient in practice, the precise and efficient genome editing in hiPSCs could be only achieved by the proper combination of the described methods in the process. This eventually would lead to generation of wide range of disease models for decoding of sporadic, polygenic, undiagnosed, and rare disorders using the adequate experimental design following appropriate gene editing toolbox selection