•GABA levels are decreased in medial frontal brain areas of schizophrenia patients.•Glutamate levels are lower in medial and lateral frontal areas in chronic patients.•Working memory performance is ...associated with frontal GABA and Glu.•Prediction errors are associated Glu and medial frontal GABA.•Processing speed correlates with medial frontal GABA levels.
A large proportion of patients with schizophrenia exhibit deficits in cognitive control functions including working memory, processing speed and inhibitory control, which have been associated with frontal brain areas. In this systematic review, we investigated differences between chronic schizophrenia patients, first-episode (FEP) patients and healthy control groups in the neurometabolite levels of GABA, glutamate, glutamine and Glx in frontal brain areas. Additionally, we reviewed correlations between cognitive control functions or negative symptoms and these neurometabolite levels. Several studies reported decreased GABA or glutamate concentrations in frontal lobe areas, particularly in chronic schizophrenia patients, while the results were mixed for FEP patients. Working memory performance and prediction errors have been associated with frontal GABA and glutamate levels, and processing speed with frontomedial GABA levels in chronic patients. The relationship between metabolites and negative symptom severity was somewhat inconsistent. Future studies should take the participants' age, medication status or responsivity, disease stage and precise anatomical location of the voxel into account when comparing neurometabolite levels between schizophrenia patients and healthy controls.
Abstract Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is now a well-recognized and potentially severe complication of HSCT that carries a high risk of ...death. In those who survive, TA-TMA may be associated with long-term morbidity and chronic organ injury. Recently, there have been new insights into the incidence, pathophysiology, and management of TA-TMA. Specifically, TA-TMA can manifest as a multi-system disease occurring after various triggers of small vessel endothelial injury, leading to subsequent tissue damage in different organs. While the kidney is most commonly affected, TA-TMA involving organs such as the lung, bowel, heart, and brain is now known to have specific clinical presentations. We now review the most up-to-date research on TA-TMA, focusing on the pathogenesis of endothelial injury, the diagnosis of TA-TMA affecting the kidney and other organs, and new clinical approaches to the management of this complication after HSCT.
What is known and objective
The C5 inhibitor eculizumab is the standard of care for treatment of atypical haemolytic uraemic syndrome (aHUS). Ravulizumab, a next‐generation C5 inhibitor, was ...engineered to have a longer terminal half‐life than eculizumab. We describe practical benefits of the advanced ravulizumab 100 mg/mL formulation.
Comment
Use of ravulizumab results in fewer maintenance infusions per year (25%–50%) compared with eculizumab. Maintenance infusion time of ravulizumab 100 mg/mL is 2–4 times shorter than ravulizumab 10 mg/mL in all weight cohorts and approximately half that of eculizumab for patients weighing <40 kg. Ravulizumab 100 mg/mL requires fewer vials annually than eculizumab in most weight cohorts.
What is new and conclusion
With ravulizumab 100 mg/mL, patients and caregivers experience fewer infusions per year and decreased annual infusion times, improving infusion experience. Infusion centres can expect corresponding decreases in resource utilization.
Ravulizumab, a next‐generation C5 inhibitor, was engineered to have a longer terminal half‐life than eculizumab. With ravulizumab 100 mg/mL, patients and caregivers experience fewer infusions per year and decreased annual infusion times, improving infusion experience. Infusion centres can expect corresponding decreases in resource utilisation.
Hematopoietic stem cell transplant (HSCT)-associated thrombotic microangiopathy (TMA) is a complication that occurs in 25% to 35% of HSCT recipients and shares histomorphologic similarities with ...hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). The hallmark of all thrombotic microangiopathies is vascular endothelial cell injury of various origins, resulting in microangiopathic hemolytic anemia, platelet consumption, fibrin deposition in the microcirculation, and tissue damage. Although significant advances have been made in understanding the pathogenesis of other thrombotic microangiopathies, post-HSCT TMA remains poorly understood. We report an analysis of the complement alternative pathway, which has recently been linked to the pathogenesis of both the Shiga toxin mediated and the atypical forms of HUS, with a focus on genetic variations in the complement Factor H (CFH) gene cluster and CFH autoantibodies in six children with post-HSCT TMA. We identified a high prevalence of deletions in CFH-related genes 3 and 1 (delCFHR3-CFHR1) and CFH autoantibodies in these patients with HSCT-TMA. Conversely, CFH autoantibodies were not detected in 18 children undergoing HSCT who did not develop TMA. Our observations suggest that complement alternative pathway dysregulation may be involved in the pathogenesis of post-HSCT TMA. These findings shed light on a novel mechanism of endothelial injury in transplant-TMA and may therefore guide the development of targeted treatment interventions.
•Genetic variations in the alternative pathway of complement may be associated with thrombotic microangiopathy in children receiving HSCT.•These findings may guide the development of novel treatment interventions for this poorly understood transplant complication.
Primary cilia of renal epithelial cells express several members of the transient receptor potential (TRP) class of cation-conducting channel, including TRPC1, TRPM3, TRPM4, TRPP2, and TRPV4. Some ...cases of autosomal dominant polycystic kidney disease (ADPKD) are caused by defects in TRPP2 (also called polycystin-2, PC2, or PKD2). A large-conductance, TRPP2-dependent channel in renal cilia has been well described, but it is not known whether this channel includes any other protein subunits. To study this question, we investigated the pharmacology of the TRPP2-dependent channel through electrical recordings from the cilia of mIMCD-3 cells, a murine cell line of renal epithelial origin. The pharmacology was found to match that of TRPM3 channels. The ciliary TRPP2-dependent channel is known to be activated by depolarization and by increasing cytoplasmic Ca2+. This activation was greatly enhanced by external pregnenolone sulfate, an agonist of TRPM3 channels. Pregnenolone sulfate did not change the single-channel current-voltage relation. The channels were effectively blocked by isosakuranetin, a specific inhibitor of TRPM3 channels. Both pregnenolone sulfate and isosakuranetin were effective at concentrations as low as 1 μM. Knocking out TRPM3 by CRISPR/Cas9 genome editing eliminated the ciliary channel. Thus the channel is both TRPM3-dependent and TRPP2-dependent, suggesting that it may include both types of subunit. Knocking out TRPM3 did not change the level of TRPP2 protein in the cilia, so it is unlikely that the absence of functional ciliary channels results from a failure of trafficking.
Sometime between 1703 and 1705, a Chowan headman wrote to North Carolina's Executive Council. The “humble pitison of John hiter Engon” reminded the council, whose seat stood on the banks of a river ...and in a precinct that bore the name of his people, and in a land he was pledged to defend, that “he is not a strangr nor a foriner but in his one Netev ples.” Though officially tributaries to the English, the Chowans were active players in colonial politics, often using written petitions to express their political ideas and to shape colonial policy. This article shows the versatility of the political strategies used by Indigenous leaders, many of whom were as comfortable in colonial council chambers as they were in their own councils, and places the Chowans' petitions in the context of regional patterns of petitioning by Natives. The Chowans' experience also reveals that issues of consent, tribute, and justice—themes more common to Latin American history—were of paramount importance in Anglo-Indian relations. Indeed, like other Indians facing forms of colonial rule throughout the hemisphere, the Chowans used the law to retain autonomy and elicit colonial protection while avoiding complete domination.
Ravulizumab, a long-acting complement C5 inhibitor engineered from eculizumab, allows extending maintenance dosing from every 2–3 weeks to every 4–8 weeks depending on bodyweight. Here, we evaluated ...the efficacy and safety of ravulizumab in complement inhibitor-naïve children (under 18 years) with atypical hemolytic uremic syndrome. In this phase III, single-arm trial, ravulizumab was administered every eight weeks in patients 20 kg and over, and four weeks in patients under 20 kg. The primary endpoint was a complete thrombotic microangiopathy response (normalization of platelet count and lactate dehydrogenase, and a 25% or more improvement in serum creatinine) through 26 weeks. Secondary endpoints included change in hematologic parameters and kidney function. 18 patients with a median age of 5.2 years were evaluated. At baseline, symptoms of atypical hemolytic uremic syndrome outside the kidney were present in 72.2% of patients and 38.9% had been in intensive care. Baseline estimated glomerular filtration rate was 22 mL/min/1.73 m2. By week 26, 77.8% of patients achieved a complete thrombotic microangiopathy response; 94.4%, 88.9% and 83.3% of patients achieved platelet normalization, lactate dehydrogenase normalization and a 25% or more improvement in serum creatinine, respectively. By week 50, 94.4% patients had achieved a complete thrombotic microangiopathy response. Median improvement in platelet count was 246 and 213 x109/L through week 26 and week 50, respectively. The median increase above baseline in estimated glomerular filtration rate was 80 and 94 mL/min/1.73m2 through week 26 and week 50, respectively. No unexpected adverse events, deaths, or meningococcal infections occurred. Thus, ravulizumab rapidly improved hematologic and kidney parameters with no unexpected safety concerns in complement inhibitor-naïve children with atypical hemolytic uremic syndrome.
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Abstract
Objective
After two stimulus pairs with a common stimulus are presented, healthy adults readily derive multiple indirect associations between each stimulus without explicit training. Factors ...related to this ability to derive new associations are relatively unstudied. We investigated the effects of sex and episodic memory performance on response times (RT) for different stimulus types (letters versus symbols) during trained and derived relational responding.
Method
Ninety-four cognitively healthy young adults were administered a relational responding (RR) task and the Hopkins Verbal Learning Test–Revised (HVLT-R) remotely via videoconferencing. In the RR task, two associations were directly trained in a single learning trial (A → B; A → C). Four other associations can be derived (B → A; C → A; B → C; C → B). Moderated multiple regressions examined main and interaction effects of sex and HVLT-R performance on correct RTs for trained and derived relations between letters and symbols, separately.
Results
Higher HVLT-R immediate and delayed recall scores were associated with faster RTs for all derived, but not trained, relations in the letter (p = 0.001–0.022) and symbol (p = 0.006–0.043) conditions. There was no main effect of sex, but significant sex by HVLT-R interactions were observed for several derived relations in the symbol (p = 0.032–0.044) and letter conditions (p = 0.035). Only males showed a significant RR-HVLT-R association.
Conclusions
After a single presentation of two stimulus pairs, participants learned the two trained associations and independently derived four new, untrained stimulus relations. Better HVLT-R performance predicted faster RT uniquely for derived relations between letters/symbols. This relationship was more robust in males. Future research should evaluate the effectiveness of RR-based interventions for memory rehabilitation.
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