Elevated serum levels of macrophage migration inhibitory factor and stem cell growth factor β in patients with idiopathic and systemic sclerosis associated pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) can be idiopathic or secondary to autoimmune diseases, and it represents one of the most threatening complications of systemic sclerosis (SSc). Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with proinflammatory functions that appears to be involved in the pathogenesis of hypoxia-induced PH. In SSc patients, high serum levels of MIF have been associated with the development of ulcers and PAH. Stem cell growth factor β (SCGF β) is a human growth factor that, together with MIF, is involved in the pathogenesis of chronic spinal cord injury. The aim of our study was to measure serum levels of MIF in patients with idiopathic and SSc-associated PAH. We enrolled 13 patients with idiopathic PAH and 15 with SSc-associated PAH. We also selected 14 SSc patients without PAH and 12 normal healthy controls, matched for sex and age. PAH was confirmed by right hearth catheterism (mPAP>25 mmHg). MIF and SCGF β levels were measured by ELISA. We found significantly higher circulating levels of MIF and of SCGF β in patients with idiopathic PAH (P=0.03 and P=0.004) and with PAH secondary to SSc (P=0.018 and P=0.023) compared to SSc patients without PAH. Higher levels of MIF were found in those patients with an higher New York Heart Association (NYHA) class (P=0.03). We can hypothesize that MIF and SCGF β are able to play a role in PAH, both idiopathic or secondary, and in the future they may be evaluated as useful biomarkers and prognostic factors for this serious vascular disease

BDNF-TrkB signaling in striatopallidal neurons controls inhibition of locomotor behaviour

The physiology of brain-derived neurotrophic factor signaling in enkephalinergic striatopallidal neurons is poorly understood. Changes in cortical Bdnf expression levels, and/or impairment in brain-derived neurotrophic factor anterograde transport induced by mutant huntingtin (mHdh) are believed to cause striatopallidal neuron vulnerability in early-stage Huntington’s disease. Although several studies have confirmed a link between altered cortical brain-derived neurotrophic factor signaling and striatal vulnerability, it is not known whether the effects are mediated via the brain-derived neurotrophic factor receptor TrkB, and whether they are direct or indirect. Using a novel genetic mouse model, here, we show that selective removal of brain-derived neurotrophic factor–TrkB signaling from enkephalinergic striatal targets unexpectedly leads to spontaneous and drug-induced hyperlocomotion. This is associated with dopamine D2 receptor-dependent increased striatal protein kinase C and MAP kinase activation, resulting in altered intrinsic activation of striatal enkephalinergic neurons. Therefore, brain-derived neurotrophic factor/TrkB signaling in striatopallidal neurons controls inhibition of locomotor behavior by modulating neuronal activity in response to excitatory input through the protein kinase C/MAP kinase pathway

Transient developmental imbalance of cortical interneuron subtypes presages long-term changes in behavior

Cortical GABAergic interneurons are generated in large numbers in the ganglionic eminences and migrate into the cerebral cortex during embryogenesis. At early postnatal stages, during neuronal circuit maturation, autonomous and activity-dependent mechanisms operate within the cortex to adjust cell numbers by eliminating naturally occurring neuron excess. Here, we show that when cortical interneurons are generated in aberrantly high numbers—due to a defect in precursor cell proliferation during embryogenesis—extra parvalbumin interneurons persist in the postnatal mouse cortex during critical periods of cortical network maturation. Even though cell numbers are subsequently normalized, behavioral abnormalities remain in adulthood. This suggests that timely clearance of excess cortical interneurons is critical for correct functional maturation of circuits that drive adult behavior

Derangement of Ras-Guanine Nucleotide-Releasing Factor 1 (Ras-GRF1) and Extracellular Signal-Regulated Kinase (ERK) Dependent Striatal Plasticity in L-DOPA-Induced Dyskinesia

BACKGROUND: Bidirectional long-term plasticity at the corticostriatal synapse has been proposed as a central cellular mechanism governing dopamine-mediated behavioral adaptations in the basal ganglia system. Balanced activity of medium spiny neurons (MSNs) in the direct and the indirect pathways is essential for normal striatal function. This balance is disrupted in Parkinson's disease and in L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), a common motor complication of current pharmacotherapy of Parkinson's disease. METHODS: Electrophysiological recordings were performed in mouse cortico-striatal slice preparation. Synaptic plasticity, such as long-term potentiation (LTP) and depotentiation, was investigated. Specific pharmacological inhibitors or genetic manipulations were used to modulate the Ras-extracellular signal-regulated kinase (Ras-ERK) pathway, a signal transduction cascade implicated in behavioral plasticity, and synaptic activity in different subpopulations of striatal neurons was measured. RESULTS: We found that the Ras-ERK pathway, is not only essential for long-term potentiation induced with a high frequency stimulation protocol (HFS-LTP) in the dorsal striatum, but also for its reversal, synaptic depotentiation. Ablation of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a neuronal activator of Ras proteins, causes a specific loss of HFS-LTP in the medium spiny neurons in the direct pathway without affecting LTP in the indirect pathway. Analysis of LTP in animals with unilateral 6-hydroxydopamine lesions (6-OHDA) rendered dyskinetic with chronic L-DOPA treatment reveals a complex, Ras-GRF1 and pathway-independent, apparently stochastic involvement of ERK. CONCLUSIONS: These data not only demonstrate a central role for Ras-ERK signaling in striatal LTP, depotentiation, and LTP restored after L-DOPA treatment but also disclose multifaceted synaptic adaptations occurring in response to dopaminergic denervation and pulsatile administration of L-DOPA

Cochlear implant outcomes in patients with Meniere's disease: a large case series

OBJECTIVE: To perform a matched cohort study to assess whether patients with Meniere's Disease (MD) require more intensive auditory rehabilitation following cochlear implantation (CI) and identify factors that may affect outcomes in patients with MD. METHODS: A retrospective case review was performed. MD and control patients were matched for age, biological sex, implant manufacturer and electrode design. Outcomes measured were speech scores, number of visits to audiology department following switch-on, and post-operative active MD. RESULTS: Forty consecutive implanted MD patients were identified between May 1993 and May 2019. Patients with active MD following CI required significantly more visits to the audiology department compared to controls (P < 0.01) and patients who had inactive MD post-operatively (P < 0.01). However, in MD patients, active MD was less likely following CI (P = 0.03). In patients who continued to experience active MD post-operatively, further medical and surgical ablative intervention was required to control ongoing Meniere's attacks. CONCLUSION: We present the largest case series of performance outcomes in CI patients with MD. Although speech outcomes in MD patients are comparable to controls, patients with active MD pre-operatively are more likely to experience variation in CI performance requiring a prolonged period of auditory rehabilitation compared to inactive preoperative MD

CD4 T lymphocyte autophagy is upregulated in the salivary glands of primary Sjögren’s syndrome patients and correlates with focus score and disease activity

Background: Primary Sjögren’s syndrome (pSS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands and peripheral lymphocyte perturbation. In the current study, we aimed to investigate the possible pathogenic implication of autophagy in T lymphocytes in patients with pSS. Methods: Thirty consecutive pSS patients were recruited together with 20 patients affected by sicca syndrome a nd/or chronic sialoadenitis and 30 healthy controls. Disease activity and damage were evaluated according to SS disease activity index, EULAR SS disease activity index, and SS disease damage index. T lymphocytes were analyzed for the expression of autophagy-specific markers by biochemical, molecular, and histological assays in peripheral blood and labial gland biopsies. Serum interleukin (IL)-23 and IL-21 levels were quantified by enzyme-linked immunosorbent assay. Results: Our study provides evidence for the first time that autophagy is upregulated in CD4+ T lymphocyte salivary glands from pSS patients. Furthermore, a statistically significant correlation was detected between lymphocyte autophagy levels, disease activity, and damage indexes. We also found a positive correlation between autophagy enhancement and the increased salivary gland expression of IL-21 and IL-23, providing a further link between innate and adaptive immune responses in pSS. Conclusions: These findings suggest that CD4+ T lymphocyte autophagy could play a key role in pSS pathogenesis. Additionally, our data highlight the potential exploitation of T cell autophagy as a biomarker of disease activity and provide new ground to verify the therapeutic implications of autophagy as an innovative drug target in pSS

Mechanisms underlying the impairment of hippocampal long-term potentiation and memory in experimental Parkinson&apos;s disease

Although patients with Parkinson's disease show impairments in cognitive performance even at the early stage of the disease, the synaptic mechanisms underlying cognitive impairment in this pathology are unknown. Hippocampal long-term potentiation represents the major experimental model for the synaptic changes underlying learning and memory and is controlled by endogenous dopamine. We found that hippocampal long-term potentiation is altered in both a neurotoxic and transgenic model of Parkinson's disease and this plastic alteration is associated with an impaired dopaminergic transmission and a decrease of NR2A/NR2B subunit ratio in synaptic N-methyl-d-aspartic acid receptors. Deficits in hippocampal-dependent learning were also found in hemiparkinsonian and mutant animals. Interestingly, the dopamine precursor l-DOPA was able to restore hippocampal synaptic potentiation via D1/D5 receptors and to ameliorate the cognitive deficit in parkinsonian animals suggesting that dopamine-dependent impairment of hippocampal long-term potentiation may contribute to cognitive deficits in patients with Parkinson's disease

Expedited transfer to a cardiac arrest centre for non-ST-elevation out-of-hospital cardiac arrest (ARREST): a UK prospective, multicentre, parallel, randomised clinical trial

Background: The International Liaison Committee on Resuscitation has called for a randomised trial of delivery to a cardiac arrest centre. We aimed to assess whether expedited delivery to a cardiac arrest centre compared with current standard of care following resuscitated cardiac arrest reduces deaths. Methods: ARREST is a prospective, parallel, multicentre, open-label, randomised superiority trial. Patients (aged ≥18 years) with return of spontaneous circulation following out-of-hospital cardiac arrest without ST elevation were randomly assigned (1:1) at the scene of their cardiac arrest by London Ambulance Service staff using a secure online randomisation system to expedited delivery to the cardiac catheter laboratory at one of seven cardiac arrest centres or standard of care with delivery to the geographically closest emergency department at one of 32 hospitals in London, UK. Masking of the ambulance staff who delivered the interventions and those reporting treatment outcomes in hospital was not possible. The primary outcome was all-cause mortality at 30 days, analysed in the intention-to-treat (ITT) population excluding those with unknown mortality status. Safety outcomes were analysed in the ITT population. The trial was prospectively registered with the International Standard Randomised Controlled Trials Registry, 96585404. Findings: Between Jan 15, 2018, and Dec 1, 2022, 862 patients were enrolled, of whom 431 (50%) were randomly assigned to a cardiac arrest centre and 431 (50%) to standard care. 20 participants withdrew from the cardiac arrest centre group and 19 from the standard care group, due to lack of consent or unknown mortality status, leaving 411 participants in the cardiac arrest centre group and 412 in the standard care group for the primary analysis. Of 822 participants for whom data were available, 560 (68%) were male and 262 (32%) were female. The primary endpoint of 30-day mortality occurred in 258 (63%) of 411 participants in the cardiac arrest centre group and in 258 (63%) of 412 in the standard care group (unadjusted risk ratio for survival 1·00, 95% CI 0·90–1·11; p=0·96). Eight (2%) of 414 patients in the cardiac arrest centre group and three (1%) of 413 in the standard care group had serious adverse events, none of which were deemed related to the trial intervention. Interpretation: In adult patients without ST elevation, transfer to a cardiac arrest centre following resuscitated cardiac arrest in the community did not reduce deaths. Funding: British Heart Foundation

POS0850 NAILFOLD CAPILLARY DILATIONS IN RAYNAUD'S PHENOMENON: QUANTIFYING A PREDICTIVE THRESHOLD FOR THE 'SCLERODERMA PATTERN'

Background:Non-specific abnormalities could be detected by nailfold videocapillaroscopy (NVC) in subject with primary Raynaud's Phenomenon (RP) several years before the clinical onset of connective tissue diseases (CTD)s [1]. Previous findings from our group proved that ≤30 μm capillary dilations in RP patients have a negative predictive value for developing the 'scleroderma pattern' during follow-up [2].Objectives:To investigate the role of NVC >30 μm capillary dilations as positive predictive factors of the 'scleroderma pattern' in RP patients later developing systemic sclerosis (SSc)-related RP.Methods:A 10-year retrospective NVC-based investigation evaluated the dataset of sequential NVCs of 18 RP patients later developing SSc (cases) and 19 sex- and age-matched RP patients later developing other CTDs (controls). Both cases and controls had ≥1 NVC performed before the 'scleroderma pattern'/CTD diagnosis (basal NVC) showing >30 μm dilated capillaries. Each NVC was qualitatively and semi-quantitatively assessed, recording number of total capillaries, number and average/site-specific diameters (arterial, apical, venous) of >30 μm dilated capillaries [3]. Statistical analysis was performed to stratify the risk of developing the 'scleroderma pattern'.Results:Significant differences of capillary diameters were observed between cases and controls both at basal NVC and during follow-up (p30 μm dilated capillaries in basal NVC was the strongest predictor of 'scleroderma pattern' in a median 3-year time, with a 27% cut-off (PPV 0.79, 95%CI 0.54,0.94; p40 μm (p25 µm (p<0.05) and average diameter ≥35 µm (p<0.005). Conversely, CTDs patients showed a stable NVC 'non-scleroderma pattern' over a median 10-year time.Conclusion:This is the first study to show that NVC-detected homogeneous and progressive capillary loop dilations in RP patients significantly contribute to predict the 'scleroderma pattern' evolution within a median 3-year time, possibly providing a "very early" window of opportunity in SSc pre-clinical stages.References:[1]Cutolo M et al. Expert Rev Clin Immunol. 2019;15(7):753–64. [2] Trombetta AC et al. J Rheumatol 2016;43:599–606. [3] Smith et al. Autoimmun Rev 2020; 19(3):102458.Disclosure of Interests:None declare