CNF1 Improves Astrocytic Ability to Support Neuronal Growth and Differentiation In vitro

Modulation of cerebral Rho GTPases activity in mice brain by intracerebral administration of Cytotoxic Necrotizing Factor 1 (CNF1) leads to enhanced neurotransmission and synaptic plasticity and improves learning and memory. To gain more insight into the interactions between CNF1 and neuronal cells, we used primary neuronal and astrocytic cultures from rat embryonic brain to study CNF1 effects on neuronal differentiation, focusing on dendritic tree growth and synapse formation, which are strictly modulated by Rho GTPases. CNF1 profoundly remodeled the cytoskeleton of hippocampal and cortical neurons, which showed philopodia-like, actin-positive projections, thickened and poorly branched dendrites, and a decrease in synapse number. CNF1 removal, however, restored dendritic tree development and synapse formation, suggesting that the toxin can reversibly block neuronal differentiation. On differentiated neurons, CNF1 had a similar effacing effect on synapses. Therefore, a direct interaction with CNF1 is apparently deleterious for neurons. Since astrocytes play a pivotal role in neuronal differentiation and synaptic regulation, we wondered if the beneficial in vivo effect could be mediated by astrocytes. Primary astrocytes from embryonic cortex were treated with CNF1 for 48 hours and used as a substrate for growing hippocampal neurons. Such neurons showed an increased development of neurites, in respect to age-matched controls, with a wider dendritic tree and a richer content in synapses. In CNF1-exposed astrocytes, the production of interleukin 1β, known to reduce dendrite development and complexity in neuronal cultures, was decreased. These results demonstrate that astrocytes, under the influence of CNF1, increase their supporting activity on neuronal growth and differentiation, possibly related to the diminished levels of interleukin 1β. These observations suggest that the enhanced synaptic plasticity and improved learning and memory described in CNF1-injected mice are probably mediated by astrocytes

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Cow's milk consumption increases iodine status in women of childbearing age in a randomized controlled trial

Background: Recent evidence has highlighted the prevalence of mild-to-moderate iodine deficiency in women of childbearing age and pregnant women, with important public health ramifications owing to the role of iodine, required for thyroid hormone production, in neurodevelopment. Cow’s milk contributes the greatest amount to iodine intakes in several countries. Objective: The objective of this study was to investigate the effect of increased cow’s milk consumption on iodine status, thyroid hormone concentrations and selenium status. Methods: A 12 week, randomized-controlled trial was conducted in 78 low-moderate milk consuming (<250ml/d) healthy women (18-45 years). The intervention group were asked to consume 3L of semi49 skimmed milk per week, while the control group continued their usual milk consumption (baseline median (IQR): 140 (40-240) mL/d). At baseline, week 6 and week 12 participants provided a spot51 urine sample [urinary iodine concentration (UIC); creatinine] and a fasting blood sample [thyroid hormone concentrations; serum total selenium; selenoprotein P]. This study was registered at ClinicalTrials.gov Study (Ref: NCT02767167). Results: At baseline, the median (IQR) UIC of all participants was 78.5 (39.1-126.1)μg/L. Changes in the median UIC from baseline to week 6 (35.4 vs. 0.6 μg/L; P=0.014) and week 12 (51.6 vs. -3.8 μg/L; P=0.045) were significantly greater in the intervention group compared with the control group. However, despite being higher within the intervention group at weeks 6 and 12, the change in the iodine:creatinine ratio from baseline was not significantly different between groups at either week 6 (P=0.637) or 12 (P=0.178). There were no significant differences in thyroid hormone concentrations or selenium status between groups at any time point. Conclusions: The present study has demonstrated that the consumption of additional cow’s milk can significantly increase UIC in women of childbearing age. These results suggest that cow’s milk is a potentially important dietary source of iodine in this population group

Enhancement of learning and memory after activation of cerebral Rho GTPases

The mechanism whereby the morphology and connectivity of the dendritic tree is regulated depends on an actin dynamics that, in turn, is controlled by Rho GTPases, a family of small GTP-binding proteins encompassing Rho, Rac, and Cdc42 subfamilies. Cytotoxic necrotizing factor 1 (CNF1), a protein toxin from Escherichia coli, constitutively activates Rho GTPases, thus leading to remodeling of the actin cytoskeleton in intact cells. Here, we show that the modulation of cerebral RhoA and Rac1 activity induced by CNF1 in mice leads to (i) rearrangement of cerebral actin cytoskeleton, (ii) enhanced neurotransmission and synaptic plasticity, and (iii) improved learning and memory in various behavioral tasks. The effects persist for weeks and are not observed in mice treated with a recombinant CNF1, in which the enzymatic activity was abolished by substituting serine to cysteine at position 866. The results suggest that learning ability can be improved through pharmacological manipulation of neural connectivity

Presentation and outcomes of paediatric craniopharyngioma in the west of Scotland: a 25 year experience

Purpose: Craniopharyngiomas can be aggressive leading to significant complications and morbidity. It is not clear whether there are any predictive factors for incidence or outcomes. Our aim was therefore to record the incidence, presentation, characteristics and progression of paediatric craniopharyngiomas in the West of Scotland. Method: Retrospective case note review for children diagnosed with paediatric craniopharyngiomas at the Royal Hospital for Children Glasgow, from 1995 to 2021 was conducted. All analyses were conducted using GraphPad Prism 9.4.0. Results: Of 21 patients diagnosed with craniopharyngiomas, the most common presenting symptoms were headaches (17/21, 81%); visual impairment (13/21, 62%); vomiting (9/21, 43%) and growth failure (7/21, 33%). Seventeen (81%) patients underwent hydrocephalus and/or resection surgery within 3 months of diagnosis, usually within the first 2 weeks (13/21, 62%). Subtotal resection surgeries were performed in 71% of patients, and median time between subsequent resection surgeries for tumour recurrence was 4 years (0,11). BMI SDS increased at 5 year follow-up (p = 0.021) with 43% being obese (BMI &gt; + 2SD). More patients acquired hypopituitarism post-operatively (14/16, 88%) compared to pre-operatively (4/15, 27%). A greater incidence of craniopharyngiomas were reported in more affluent areas (10/21, 48%) (SIMD score 8–10) compared to more deprived areas (6/10, 29%) (SIMD score 1–3). Five patients (24%) died with a median time between diagnosis and death of 9 years (6,13). Conclusion: Over 25 years the management of craniopharyngioma has changed substantially. Co-morbidities such as obesity are difficult to manage post-operatively and mortality risk can be up to 25% according to our cohort

Hybrid Reconnaissance Mission to the 30 October 2020 Aegean Sea Earthquake and Tsunami (Izmir, Turkey & Samos, Greece): Description of Data Collection Methods and Damage

On 30 October 2020, an earthquake of Mw 6.9 hit the Aegean coasts of Turkey and Greece. The epicentre was some 14 km northeast of Avlakia on Samos Island, and 25 km southwest of Seferihisar, Turkey, triggering also a tsunami. The event has been followed by &amp;gt;4,000 aftershocks up to Mw 5.2 The Earthquake Engineering Field Investigation Team (EEFIT) has immediately gathered a team to conduct a hybrid reconnaissance study, bringing together remote and field investigation techniques. The mission took place between 16 November and 17 December, inclusive of three sets of field study carried out by the field crews for building damage assessment in the affected areas in Turkey and Greece under the coordination of the remote team. The mission also aimed to assess the viability of alternative data sources for an appraisal of the future viability of hybrid missions. This paper summarises the mission setup and findings, and discusses the benefits of and difficulties encountered during this hybrid reconnaissance activity.</jats:p