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Patients with intracerebral hemorrhage (ICH) are at increased risk for major ischemic cardiovascular and cerebrovascular events. However, the use of preventative antithrombotic therapy can increase the risk of ICH recurrence and worsen ICH-related outcomes. Colchicine, an anti-inflammatory agent, has the potential to mitigate inflammation-related atherothrombosis and reduce the risk of ischemic vascular events. Here we investigated the safety and efficacy of colchicine when used both before and acutely after ICH. We predicted that daily colchicine administration would not impact our safety measures but would reduce brain injury and improve functional outcomes associated with inflammation reduction. To test this, 0.05 mg/kg colchicine was given orally once daily to rats either before or after they were given a collagenase-induced striatal ICH. We assessed neurological impairments, intra-parenchymal bleeding, Perls positive cells, and brain injury to gauge the therapeutic impact of colchicine on brain injury. Colchicine did not significantly affect bleeding (average = 40.7 μL) at 48 hrs, lesion volume (average = 24.5 mm3) at 14 days, or functional outcome (median neurological deficit scale score at 2 days post-ICH = 4, i.e., modest deficits) from 1–14 days after ICH. Colchicine reduced the volume of Perls positive cells in the perihematomal zone, indicating a reduction in inflammation. Safety measures (body weight, food consumption, water consumption, hydration, body temperature, activity, and pain) were not affected by colchicine. Although colchicine did not confer neuroprotection or functional benefit, it was able to reduce perihematomal inflammation after ICH without increasing bleeding. Thus, our findings suggest that colchicine treatment is safe, unlikely to worsen bleeding, and is unlikely but may reduce secondary injury after an ICH if initiated early post ICH to reduce the risk of ischemic vascular events. These results are informative for the ongoing CoVasc-ICH phase II randomized trial (NCT05159219).

Intracerebral hemorrhage (ICH) is a devastating insult with few effective treatments. Edema and raised intracranial pressure contribute to poor outcome after ICH. Glibenclamide blocks the sulfonylurea 1 transient receptor potential melastatin 4 (Sur1-Trpm4) channel implicated in edema formation. While glibenclamide has been found to improve outcome and reduce mortality in animal models of severe ischemic stroke, in ICH the effects are less clear. In our previous study, we found no benefit after a moderate-sized bleed, while others have reported benefit. Here we tested the hypothesis that glibenclamide may only be effective in severe ICH, where edema is an important contributor to outcome. Glibenclamide (10 μg/kg loading dose, 200 ng/h continuous infusion) was administered 2 hours post-ICH induced by collagenase injection into the striatum of adult rats. A survival period of 24 hours was maintained for experiments 1-3, and 72 hours for experiment 4. Glibenclamide did not affect hematoma volume (~81 μL) or other safety endpoints (e.g., glucose levels), suggesting the drug is safe. However, glibenclamide did not lessen striatal edema (~83% brain water content), ionic dyshomeostasis (Na+, K+), or functional impairment (e.g., neurological deficits (median = 10 out of 14), etc.) at 24 hours. It also did not affect edema at 72 h (~86% brain water content), or overall mortality rates (25% and 29.4% overall in vehicle vs. glibenclamide-treated severe strokes). Furthermore, glibenclamide appears to worsen cytotoxic edema in the peri-hematoma region (cell bodies were 46% larger at 24 h, p = 0.0017), but no effect on cell volume or density was noted elsewhere. Overall, these findings refute our hypothesis, as glibenclamide produced no favorable effects following severe ICH.

Most genome-wide association (GWA) studies have focused on populations of European ancestry with limited assessment of the influence of the sequence variants on populations of other ethnicities. To determine whether markers that we have recently shown to associate with Bone Mineral Density (BMD) in Europeans also associate with BMD in East-Asians we analysed 50 markers from 23 genomic loci in samples from Korea (n = 1,397) and two Chinese Hong Kong sample sets (n = 3,869 and n = 785). Through this effort we identified fourteen loci that associated with BMD in East-Asian samples using a false discovery rate (FDR) of 0.05; 1p36 (ZBTB40, P = 4.3×10(-9)), 1p31 (GPR177, P = 0.00012), 3p22 (CTNNB1, P = 0.00013), 4q22 (MEPE, P = 0.0026), 5q14 (MEF2C, P = 1.3×10(-5)), 6q25 (ESR1, P = 0.0011), 7p14 (STARD3NL, P = 0.00025), 7q21 (FLJ42280, P = 0.00017), 8q24 (TNFRSF11B, P = 3.4×10(-5)), 11p15 (SOX6, P = 0.00033), 11q13 (LRP5, P = 0.0033), 13q14 (TNFSF11, P = 7.5×10(-5)), 16q24 (FOXL1, P = 0.0010) and 17q21 (SOST, P = 0.015). Our study marks an early effort towards the challenge of cataloguing bone density variants shared by many ethnicities by testing BMD variants that have been established in Europeans, in East-Asians.

Foreign accents have been shown to have considerable impact on how language is processed [1]. However, the impact of a foreign accent on semantic processing is not well understood. Conflicting results have been reported by previous event-related potential (ERP) studies investigating the impact of foreign-accentedness on the N400 effect elicited by semantic violations. Furthermore, these studies have only examined a subset of the four characteristics of the N400 (i.e. onset latency, latency, amplitude, and scalp distribution), and have been conducted in linguistic environments where foreign-accented speech is relatively uncommon. The current study therefore compared the N400 effect elicited by semantic violations in native Australian English vs. Mandarin-accented English, in a context where foreign-accented speech is common. Factors which may be responsible for individual variability in N400 amplitude were also investigated. The results showed no differences between the N400s elicited by native and foreign-accented speech in any of the four aforementioned characteristics. However, the analysis of individual variability revealed an effect of familiarity with foreign-accented speech on the amplitude of N400 effects for semantic violations. An effect of working memory capacity on N400 amplitude was also found. These findings highlight the relevance of the ambient linguistic environment for studies of speech processing, and demonstrate the interacting influences of both speaker- and listener-related factors on semantic processing., Competing Interests: The authors have declared that no competing interests exist.

This study investigated a theoretically challenging dissociation between good production and poor perception of tones among neurologically unimpaired native speakers of Cantonese. The dissociation is referred to as the near-merger phenomenon in sociolinguistic studies of sound change. In a passive oddball paradigm, lexical and nonlexical syllables of the T1/T6 and T4/T6 contrasts were presented to elicit the mismatch negativity (MMN) and P3a from two groups of participants, those who could produce and distinguish all tones in the language (Control) and those who could produce all tones but specifically failed to distinguish between T4 and T6 in perception (Dissociation). The presence of MMN to T1/T6 and null response to T4/T6 of lexical syllables in the dissociation group confirmed the near-merger phenomenon. The observation that the control participants exhibited a statistically reliable MMN to lexical syllables of T1/T6, weaker responses to nonlexical syllables of T1/T6 and lexical syllables of T4/T6, and finally null response to nonlexical syllables of T4/T6, suggests the involvement of top-down processing in speech perception. Furthermore, the stronger P3a response of the control group, compared with the dissociation group in the same experimental conditions, may be taken to indicate higher cognitive capability in attention switching, auditory attention or memory in the control participants. This cognitive difference, together with our speculation that constant top-down predictions without complete bottom-up analysis of acoustic signals in speech recognition may reduce one's sensitivity to small acoustic contrasts, account for the occurrence of dissociation in some individuals but not others.

TRPV4 is a mechanically activated Ca(2+)-passing channel implicated in the sensing of forces, including those acting on bones. To date, 33 mutations are known to affect human bone development to different extents. The spectrum of these skeletal dysplasias (SD) ranges from dominantly inherited mild brachylomia (BO) to neonatal lethal forms of metatropic dysplasia (MD). Complexities of the results from fluorescence and electrophysiological studies have led to questions on whether channel activity is a good predictor of disease severity. Here we report on a systematic examination of 14 TRPV4 mutant alleles covering the entire SD spectrum. Expressed in Xenopus oocyte and without any stimulation, the wild-type channel had a ~1% open probability (Po) while those of most of the lethal MD channels approached 100%. All mutant channels had higher basal open probabilities, which limited their further increase by agonist or hypotonicity. The magnitude of this limitation revealed a clear correlation between the degree of over-activity (the molecular phenotype) and the severity of the disease over the entire spectrum (the biological phenotype). Thus, while other factors are at play, our results are consistent with the increased TRPV4 basal activity being a critical determinant of the severity of skeletal dysplasia. We discuss how the channel over-activity may lead to the "gain-of-function" phenotype and speculate that the function of wild-type TRPV4 may be secondary in normal bone development but crucial in an acute process such as fracture repair in the adult.