Pathophysiology of Migraine: A Disorder of Sensory Processing.

Plaguing humans for more than two millennia, manifest on every continent studied, and with more than one billion patients having an attack in any year, migraine stands as the sixth most common cause of disability on the planet. The pathophysiology of migraine has emerged from a historical consideration of the "humors" through mid-20th century distraction of the now defunct Vascular Theory to a clear place as a neurological disorder. It could be said there are three questions: why, how, and when? Why: migraine is largely accepted to be an inherited tendency for the brain to lose control of its inputs. How: the now classical trigeminal durovascular afferent pathway has been explored in laboratory and clinic; interrogated with immunohistochemistry to functional brain imaging to offer a roadmap of the attack. When: migraine attacks emerge due to a disorder of brain sensory processing that itself likely cycles, influenced by genetics and the environment. In the first, premonitory, phase that precedes headache, brain stem and diencephalic systems modulating afferent signals, light-photophobia or sound-phonophobia, begin to dysfunction and eventually to evolve to the pain phase and with time the resolution or postdromal phase. Understanding the biology of migraine through careful bench-based research has led to major classes of therapeutics being identified: triptans, serotonin 5-HT1B/1D receptor agonists; gepants, calcitonin gene-related peptide (CGRP) receptor antagonists; ditans, 5-HT1F receptor agonists, CGRP mechanisms monoclonal antibodies; and glurants, mGlu5 modulators; with the promise of more to come. Investment in understanding migraine has been very successful and leaves us at a new dawn, able to transform its impact on a global scale, as well as understand fundamental aspects of human biology.

The Role of Lung Ultrasound in Systemic Sclerosis: A Systematic Review.

BACKGROUND: In systemic sclerosis (SSc), high-resolution computed tomography (HRCT) of the chest is the standard criterion for the diagnosis of interstitial lung disease (ILD). However, recent evidence suggests that lung ultrasound (LUS) can also detect ILD, without radiation exposure. Thus, our goal was to perform a systematic review, aiming to clarify the role of LUS in the detection of ILD in SSc. METHODS: A systematic review was carried out in PubMed and EMBASE (PROSPERO register number CRD42022293132), to identify studies that compared LUS with HRCT in the detection of ILD in patients with SSc. Risk of bias was assessed with the QUADAS-2 () tool. RESULTS: Three hundred seventy-five publications were identified. After screening, 13 were included in the final analysis. No study presented high risk of bias. Lung ultrasound protocol was highly heterogeneous between authors, specifically concerning transducer, intercostal spaces evaluated, exclusion criteria, and definition of positive LUS. Most authors evaluated the presence of B-lines as a surrogate of ILD, with only 4 focusing on pleural changes. A positive correlation between LUS findings and ILD detected by HRCT was reported. Results also revealed high sensitivity (74.3%-100%) but variable specificity (16%-99%). Positive predictive value varied between 16% and 95.1%, and negative predictive value between 51.7% and 100%. CONCLUSION: Lung ultrasound is sensitive in the detection of ILD, but specificity must be optimized. The value of pleural evaluation also requires further investigation. Moreover, a consensus is needed to define a uniform LUS protocol to implement in future investigations.

Pharmacological modulation of ventral tegmental area neurons elicits changes in trigeminovascular sensory processing and is accompanied by glycemic changes: Implications for migraine.

BACKGROUND: Imaging migraine premonitory studies show increased midbrain activation consistent with the ventral tegmental area, an area involved in pain modulation and hedonic feeding. We investigated ventral tegmental area pharmacological modulation effects on trigeminovascular processing and consequent glycemic levels, which could be involved in appetite changes in susceptible migraine patients. METHODS: Serotonin and pituitary adenylate cyclase-activating polypeptide receptors immunohistochemistry was performed in ventral tegmental area parabrachial pigmented nucleus of male Sprague Dawley rats. In vivo trigeminocervical complex neuronal responses to dura mater nociceptive electrical stimulation, and facial mechanical stimulation of the ophthalmic dermatome were recorded. Changes in trigeminocervical complex responses following ventral tegmental area parabrachial pigmented nucleus microinjection of glutamate, bicuculline, naratriptan, pituitary adenylate cyclase-activating polypeptide-38 and quinpirole were measured, and blood glucose levels assessed pre- and post-microinjection. RESULTS: Glutamatergic stimulation of ventral tegmental area parabrachial pigmented nucleus neurons reduced nociceptive and spontaneous trigeminocervical complex neuronal firing. Naratriptan, pituitary adenylate cyclase-activating polypeptide-38 and quinpirole inhibited trigeminovascular spontaneous activity, and trigeminocervical complex neuronal responses to dural-evoked electrical and mechanical noxious stimulation. Trigeminovascular sensory processing through modulation of the ventral tegmental area parabrachial pigmented nucleus resulted in reduced circulating glucose levels. CONCLUSION: Pharmacological modulation of ventral tegmental area parabrachial pigmented nucleus neurons elicits changes in trigeminovascular sensory processing. The interplay between ventral tegmental area parabrachial pigmented nucleus activity and the sensory processing by the trigeminovascular system may be relevant to understand associated sensory and homeostatic symptoms in susceptible migraine patients.

Clinical practice guidelines and recommendations for the management of patients with systemic lupus erythematosus: a critical comparison.

OBJECTIVE: SLE has a great clinical heterogeneity and low prevalence, thus making the development of recommendations or clinical practice guidelines (CPG) based on high-quality evidence difficult. In the last few years, several CPG appeared addressing the management of the disease. The aim of this review is to critically compare the recommendations made in the most recent CPG and to analyse and compare their methodological quality. METHODS: The Appraisal of Guidelines for Research and Evaluation (AGREE) II tool was used to compare the methodological quality of each of the CPG. RESULTS: Most CPG agreed in the general management and first-line treatment recommendations where there is higher quality evidence and disagreed in refractory disease treatment where there is lack of quality evidence. Also, the CPG are agreed in whether a patient should be treated regarding the most severe clinical manifestation or taking into account the treatment that best serves all clinical manifestations. The majority of the appraised CPG scored high-quality ratings, especially for scope and purpose and clarity of presentation, while they were of less quality when assessing applicability of each CPG. CONCLUSION: CPG should aid, but not replace, the health professional's clinical judgment in daily clinical patient management.

Comparative effects of traditional Chinese and Western migraine medicines in an animal model of nociceptive trigeminovascular activation.

Background Migraine is a highly prevalent and disabling disorder of the brain with limited therapeutic options, particularly for preventive treatment. There is a need to identify novel targets and test their potential efficacy in relevant preclinical migraine models. Traditional Chinese medicines have been used for millennia and may offer avenues for exploration. Methods We evaluated two traditional Chinese medicines, gastrodin and ligustrazine, and compared them to two Western approaches with propranolol and levetiracetam, one effective and one ineffective, in an established in vivo rodent model of nociceptive durovascular trigeminal activation. Results Intravenous gastrodin (30 and 100 mg/kg) significantly inhibited nociceptive dural-evoked neuronal firing in the trigeminocervical complex. Ligustrazine (10 mg/kg) and propranolol (3 mg/kg) also significantly inhibited dural-evoked trigeminocervical complex responses, although the timing of responses of ligustrazine does not match its pharmacokinetic profile. Levetiracetam had no effects on trigeminovascular responses. Conclusion Our data suggest gastrodin has potential as an anti-migraine treatment, whereas ligustrazine seems less promising. Interestingly, in line with clinical trial data, propranolol was effective and levetiracetam not. Exploration of the mechanisms and modelling effects of Chinese traditional therapies offers novel route for drug discovery in migraine.

Predicting prognosis in patients with advanced cancer: A prospective study.

BACKGROUND: Prognosis is one of the most challenging questions with which physicians are confronted. Accuracy in the prediction of survival is necessary for clinical, ethical, and organizational reasons. AIM: Evaluate young doctors' clinical prediction of survival and the aids they could get: expert opinion, Palliative Prognostic score, and Palliative Prognostic Index. DESIGN: Prospective, observational study. SETTING/PARTICIPANTS: Advanced cancer patients under observation of an inhospital palliative care team, from April to July 2014. A total of 38 patients were included, mostly male (65.8%), average age 68.5 years. Average survival time was 24 days. Follow-up concluded with death or after 90 days. RESULTS: Young doctors' clinical prediction of survival was adequate at 10.5%, with 55.3% severe errors in an optimistic direction. Palliative care experts were more adequate (23.7%) and made less severe errors (42.1%). Palliative Prognostic score and Palliative Prognostic Index were even more adequate (47% and 55%, respectively) and made even less severe errors (0% and 11%, respectively). The best correlation with observed survival was achieved when palliative care experts used palliative prognostic score ( rs = -0.629; p < 0.01). CONCLUSION: Young doctors' clinical prediction of survival is often inadequate. Palliative Prognostic score, which includes clinical prediction of survival, calculated by palliative care experts had the best performance. Our results support the recommendation of using clinical prediction of survival together with prognostic scores.

Neuroendocrine signaling modulates specific neural networks relevant to migraine.

Migraine is a disabling brain disorder involving abnormal trigeminovascular activation and sensitization. Fasting or skipping meals is considered a migraine trigger and altered fasting glucose and insulin levels have been observed in migraineurs. Therefore peptides involved in appetite and glucose regulation including insulin, glucagon and leptin could potentially influence migraine neurobiology. We aimed to determine the effect of insulin (10U·kg-1), glucagon (100µg·200µl-1) and leptin (0.3, 1 and 3mg·kg-1) signaling on trigeminovascular nociceptive processing at the level of the trigeminocervical-complex and hypothalamus. Male rats were anesthetized and prepared for craniovascular stimulation. In vivo electrophysiology was used to determine changes in trigeminocervical neuronal responses to dural electrical stimulation, and phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) immunohistochemistry to determine trigeminocervical and hypothalamic neural activity; both in response to intravenous administration of insulin, glucagon, leptin or vehicle control in combination with blood glucose analysis. Blood glucose levels were significantly decreased by insulin (p<0.001) and leptin (p<0.01) whereas glucagon had the opposite effect (p<0.001). Dural-evoked neuronal firing in the trigeminocervical-complex was significantly inhibited by insulin (p<0.001), glucagon (p<0.05) and leptin (p<0.01). Trigeminocervical-complex pERK1/2 cell expression was significantly decreased by insulin and leptin (both p<0.001), and increased by glucagon (p<0.001), when compared to vehicle control. However, only leptin affected pERK1/2 expression in the hypothalamus, significantly decreasing pERK1/2 immunoreactive cell expression in the arcuate nucleus (p<0.05). These findings demonstrate that insulin, glucagon and leptin can alter the transmission of trigeminal nociceptive inputs. A potential neurobiological link between migraine and impaired metabolic homeostasis may occur through disturbed glucose regulation and a transient hypothalamic dysfunction.

Different evolutionary histories of two cation/proton exchanger gene families in plants.

BACKGROUND: Gene duplication events have been proposed to be involved in the adaptation of plants to stress conditions; precisely how is unclear. To address this question, we studied the evolution of two families of antiporters. Cation/proton exchangers are important for normal cell function and in plants, Na+,K+/H+ antiporters have also been implicated in salt tolerance. Two well-known plant cation/proton antiporters are NHX1 and SOS1, which perform Na+ and K+ compartmentalization into the vacuole and Na+ efflux from the cell, respectively. However, our knowledge about the evolution of NHX and SOS1 stress responsive gene families is still limited. RESULTS: In this study we performed a comprehensive molecular evolutionary analysis of the NHX and SOS1 families. Using available sequences from a total of 33 plant species, we estimated gene family phylogenies and gene duplication histories, as well as examined heterogeneous selection pressure on amino acid sites. Our results show that, while the NHX family expanded and specialized, the SOS1 family remained a low copy gene family that appears to have undergone neofunctionalization during its evolutionary history. Additionally, we found that both families are under purifying selection although SOS1 is less constrained. CONCLUSIONS: We propose that the different evolution histories are related with the proteins' function and localization, and that the NHX and SOS1 families are examples of two different evolutionary paths through which duplication events may result in adaptive evolution of stress tolerance.

Side-effects of analgesic kyotorphin derivatives: advantages over clinical opioid drugs.

The adverse side-effects associated with opioid administration restrain their use as analgesic drugs and call for new solutions to treat pain. Two kyotorphin derivatives, kyotorphin-amide (KTP-NH2) and ibuprofen-KTP-NH2 (IbKTP-NH2) are promising alternatives to opioids: they trigger analgesia via an indirect opioid mechanism and are highly effective in several pain models following systemic delivery. In vivo side-effects of KTP-NH2 and IbKTP-NH2 are, however, unknown and were evaluated in the present study using male adult Wistar rats. For comparison purposes, morphine and tramadol, two clinically relevant opioids, were also studied. Results showed that KTP-derivatives do not cause constipation after systemic administration, in contrast to morphine. Also, no alterations were observed in blood pressure or in food and water intake, which were only affected by tramadol. A reduction in micturition was detected after KTP-NH2 or tramadol administrations. A moderate locomotion decline was detected after IbKTP-NH2-treatment. The side-effect profile of KTP-NH2 and IbKTP-NH2 support the existence of opioid-based mechanisms in their analgesic actions. The conjugation of a strong analgesic activity with the absence of the major side-effects associated to opioids highlights the potential of both KTP-NH2 and IbKTP-NH2 as advantageous alternatives over current opioids.

Osteolysis in Systemic Sclerosis: A Scoping Review.

OBJECTIVE: To perform a scoping review focusing on osteolysis in systemic sclerosis (SSc). METHODS: This review was performed in line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) recommendations. RESULTS: From a total of 351 results, 29 articles were included for the final analysis. The publications included proved to be heterogeneous regarding the population and inclusion criteria. The lack of a standardized method of detection of osteolysis further enhanced these inequalities. Most studies reported location/prevalence of osteolysis and associations with other manifestations, with only a minority focusing on topics like predictors of osteolysis and its prognostic value. None of the authors addressed treatment approach. The most frequently analyzed and prevalent location was acro-osteolysis (AO). Diffuse cutaneous subtype and anti-topoisomerase I antibody correlated positively with AO. Disease duration, calcinosis, and digital ischemia were the features more frequently associated with AO, but only the last 2 predicted AO. Ultrasound showed high sensitivity for detection of AO. CONCLUSION: Despite the effect that osteolysis has on patients with SSc, there is a significant lack of studies on this area. Notably, there are no studies that we know of focused on treatment. Also, there is a lack of longitudinal studies that would allow a reliable assessment of its prognostic value and predictors.

Use of homologous platelet gel to manage refractory diabetic lower extremity ulcers: additional experience at a tertiary hospital.

BACKGROUND: DLEUs are a major cause of morbidity. Appropriate treatment is essential, and newer methods to achieve ulcer healing have been described, including application of PG. OBJECTIVE: This study evaluated the effectiveness and safety of homologous PG in patients with chronic noninfected DLEU refractory to standard treatment as well as possible correlations between patient comorbidities and response to treatment. MATERIALS AND METHODS: Data from patients with chronic refractory DLEU managed with homologous PG between January 2014 and October 2022 were evaluated (comorbidities, wound characteristics, number and time of treatment, outcome). Outcome was classified as complete response (complete ulcer healing with reepithelialization), partial response (≥50% reduction in area and/or improvement of pain), or absence of response. The chi-square test was used to compare groups, with alpha level set at less than .05. RESULTS: A total of 81 patients (63 male, 18 female; median age, 65 years; median HbA1c, 7.6%; median ulcer area, 2.9 cm2) were proposed for PG application. A total of 62 patients had 3 or more comorbidities. Outcome was evaluated in 69 patients, with response observed in 49% (complete, 32%; partial, 17%). Worse outcomes occurred in patients with polyneuropathy (chi-square statistic: 4.183; P = .041). CONCLUSION: Homologous PG is a safe and possibly effective therapeutic alternative for DLEU that is unresponsive to standard therapies.

Mitral annular disjunction: Beyond mitral valve prolapse.

Mitral annular disjunction (MAD) is an easily identifiable entity on transthoracic echocardiography, but is still poorly recognized or ignored. It is often associated with mitral valve prolapse and is itself a risk marker for ventricular arrhythmias and sudden cardiac death, but the management and risk stratification of these patients is not systematized. Two clinical cases of MAD associated with mitral valve prolapse and ventricular arrhythmias are presented. The first case is of a patient with a history of surgical intervention on the mitral valve due to Barlow's disease. He presented to the emergency department with sustained monomorphic ventricular tachycardia requiring emergent electrical cardioversion. MAD with transmural fibrosis at the level of the inferolateral wall was documented. The second report is of a young woman with palpitations and frequent premature ventricular contractions on Holter with documentation of valvular prolapse and MAD, and focuses on the risk stratification approach. The present article offers a review of the literature regarding the arrhythmic risk of MAD and mitral valve prolapse, as well as a review of risk stratification in these patients.

The prognostic role of right ventricular dysfunction in patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) primarily affects the left ventricle (LV) sparing the right ventricle (RV) in vast majority of cases. However, several studies employing CMR have revealed that myocardial hypertrophy may also involve the RV. To assess RV size and function in a large prospectively cohort of HCM patients and to evaluate whether these parameters in association with other MR findings can predict cardiac events. Two participating centers prospectively included patients with known or suspected HCM between 2011 and 2017. CMR studies were performed with three different scanners. Outcome measures were a composite of ventricular arrhythmias, hospitalization for HF and cardiac death. Of 607 consecutive patients with known or suspected HCM, 315 had complete follow-up information (mean 65 ± 20 months). Among them, 115 patients developed major cardiac events (MACE) during follow-up. At CMR evaluation, patients with events had higher left atrium (LA) diameter (41.5 ± 8 mm vs. 37.17 ± 7.6 mm, p < 0.0001), LV mass (156.7 vs. 144 g, p = 0.005) and myocardial LGE (4.3% vs. 1.9%, p = 0.001). Similarly, patients with events had lower RV stroke volume index (42.7 vs. 47.0, p = 0.0003) and higher prevalence of both RV hypertrophy (16.4% vs. 4.7%, p = 0.0005) and reduced RV ejection fraction (12.2% vs. 4.4%, p = 0.006). In the multivariate analysis, LA diameter and RV stroke volume index were the strongest predictors of events (p < 0.001 and p = 0.0006, respectively). Anatomic and functional RV anomalies detected and characterized with CMR may have may have a major role in predicting the prognosis of HCM patients.

Effectiveness of biosimilar infliximab CT-P13 compared to originator infliximab in biological-naïve patients with rheumatoid arthritis and axial spondyloarthritis: data from the Portuguese Register.

OBJECTIVES: To compare the effectiveness of the infliximab biosimilar CT-P13 with originator infliximab over 24 months of follow-up in biological-naïve patients with rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA). METHODS: Biological-naïve patients from the Rheumatic Diseases Portuguese Register (Reuma.pt), with a clinical diagnosis of RA or axSpA, who were starting either the infliximab biosimilar CT-P13 or the originator infliximab after 2014 (date of market entry of CT-P13 in Portugal), were included. Patients on biosimilar and originator were compared regarding different response outcomes at 3 and 6 months, adjusting for age, sex and baseline C-reactive protein (CRP). The main outcome was the change in DAS28-erytrocyte sedimentation rate (ESR) for RA and the ASDAS-CRP for axSpA. Additionally, the effect of infliximab biosimilar vs originator on different response outcomes over 24 months of follow-up was tested with longitudinal generalized estimating equations (GEE) models. RESULTS: In total, 140 patients were included, 66 (47%) of which with RA. The distribution of patients starting the infliximab biosimilar and the originator was the same between the two diseases (approximately 60% and 40%, respectively). From the 66 patients with RA, 82% were females, mean age was 56 years (SD 11) and mean DAS28-ESR 4.9 (1.3) at baseline. As for the patients with axSpA, 53% were males, mean age was 46 years (13) and mean ASDAS-CRP 3.7 (0.9) at baseline. There were no differences in efficacy between RA patients treated with the infliximab biosimilar and the originator, either at 3 months (∆DAS28-ESR: -0.6 (95% CI -1.3; 0.1) vs -1.2 (-2.0; -0.4)), or at 6 months (∆DAS28-ESR: -0.7 (-1.5; 0.0) vs -1.5 (-2.4; -0.7)). This was also true for patients with axSpA (∆ASDAS-CRP at 3 months: -1.6 (-2.0; -1.1) vs -1.4 (-1.8; -0.9) and at 6 months: -1.5 (-2.0; -1.1) vs -1.1 (-1.5; -0.7)). Results were similar with the longitudinal models over 24 months. CONCLUSION: There are no differences in effectiveness between the infliximab biosimilar CT-P13 and the infliximab originator in the treatment of biological-naïve patients with active RA and axSpA in clinical practice.

Assessment of calcinosis in Portuguese patients with systemic sclerosis - a multicenter study.

INTRODUCTION/OBJECTIVES: The study aims to define the clinical and subclinical calcinosis prevalence, the sensitivity of radiographed site and clinical method for its diagnosis, and the phenotype of Portuguese systemic sclerosis (SSc) patients with calcinosis. METHOD: A cross-sectional multicenter study was conducted with SSc patients fulfilling Leroy/Medsger 2001 or ACR/EULAR 2013 classification criteria, registered in the Reuma.pt. Calcinosis was assessed through clinical examination and radiographs of hands, elbows, knees, and feet. Independent parametric or non-parametric tests, multivariate logistic regression, and sensitivity calculation of radiographed site and clinical method for calcinosis detection were performed. RESULTS: We included 226 patients. Clinical calcinosis was described in 63 (28.1%) and radiological calcinosis in 91 (40.3%) patients, of which 37 (40.7%) were subclinical. The most sensitive location to detect calcinosis was the hand (74.7%). Sensitivity of the clinical method was 58.2%. Calcinosis patients were more often female (p = 0.008) and older (p < 0.001) and had more frequently longer disease duration (p < 0.001), limited SSc (p = 0.017), telangiectasia (p = 0.039), digital ulcers (p = 0.001), esophageal (p < 0.001) and intestinal (p = 0.003) involvements, osteoporosis (p = 0.028), and late capillaroscopic pattern (p < 0.001). In multivariate analysis, digital ulcers (OR 2.63, 95% CI 1.02-6.78, p = 0.045) predicted overall calcinosis, esophageal involvement (OR 3.52, 95% CI 1.28-9.67, p = 0.015) and osteoporosis (OR 4.1, 95% CI 1.2-14.2, p = 0.027) predicted hand calcinosis, and late capillaroscopic pattern (OR 7.6, 95% CI 1.7-34.9, p = 0.009) predicted knee calcinosis. Anti-nuclear antibody positivity was associated with less knee calcinosis (OR 0.021, 95% CI 0.001-0477, p = 0.015). CONCLUSIONS: Subclinical calcinosis high prevalence suggests that calcinosis is underdiagnosed and radiographic screening might be relevant. Multifactorial pathogenesis may explain calcinosis predictors' variability. Key Points • Prevalence of subclinical calcinosis in SSc patients is substantial. • Hand radiographs are more sensitive to detect calcinosis than other locations or clinical method. • Digital ulcers were associated with overall calcinosis, esophageal involvement and osteoporosis were associated with hand calcinosis, and late sclerodermic pattern in nailfold capillaroscopy was associated with knee calcinosis. • Anti-nuclear antibody positivity may be a protective factor for knee calcinosis.

Left ventricular noncompaction associated with a pathogenic mutation in the MYH7 gene: Known mutation, different phenotype.

Left ventricular noncompaction (LVNC) is a genetically heterogeneous cardiomyopathy, with familial and sporadic forms, but genetic testing only identifies a pathogenic mutation in a minority of cases. The main complications are heart failure, embolism and dysrhythmias. Herein we report a familial case of LVNC associated with a mutation in the MYH7 gene and review the literature regarding controversies in LVNC. A 50-year-old woman was referred to the cardiology clinic for palpitations. She underwent echocardiography and cardiac magnetic resonance imaging that revealed mild left ventricular systolic dysfunction and LVNC criteria. She had several episodes of non-sustained ventricular tachycardia and received an implantable cardioverter-defibrillator (ICD). Genetic testing revealed the c.1003G>C (p.Ala335Pro) mutation in the MYH7 gene. Familial screening showed clear genotype-phenotype cosegregation, which provided strong evidence for the pathogenic role of this mutation. To the best of our knowledge, this is the first report of LVNC associated with the p.Ala335Pro mutation in the MYH7 gene. This mutation has been described in hypertrophic cardiomyopathy, suggesting that the same pathogenic sarcomere mutation may be associated with different cardiomyopathies. This case also highlights the current difficulties regarding decisions on ICD implantation for primary prevention of sudden cardiac death in LVNC.

Quercus suber Roots Activate Antioxidant and Membrane Protective Processes in Response to High Salinity.

Cork oak (Quercus suber) is a species native to Mediterranean areas and its adaptation to the increasingly prevalent abiotic stresses, such as soil salinization, remain unknown. In sequence with recent studies on salt stress response in the leaf, it is fundamental to uncover the plasticity of roots directly exposed to high salinity to better understand how Q. suber copes with salt stress. In the present study we aimed to unveil the antioxidants and key-genes involved in the stress-responses (early vs. later responses) of Q. suber roots exposed to high salinity. Two-month-old Q. suber plants were watered with 300 mM NaCl solution and enzymatic and non-enzymatic antioxidants, lipid peroxidation and the relative expression of genes related to stress response were analysed 8 h and 6 days after salt treatment. After an 8 h of exposure, roots activated the expression of QsLTI30 and QsFAD7 genes involved in stress membrane protection, and QsRAV1 and QsCZF1 genes involved in tolerance and adaptation. As a result of the continued salinity stress (6 days), lipid peroxidation increased, which was associated with an upregulation of QsLTI30 gene. Moreover, other protective mechanisms were activated, such as the upregulation of genes related to antioxidant status, QsCSD1 and QsAPX2, and the increase of the antioxidant enzyme activities of superoxide dismutase, catalase, and ascorbate peroxidase, concomitantly with total antioxidant activity and phenols. These data suggest a response dependent on the time of salinity exposure, leading Q. suber roots to adopt protective complementary strategies to deal with salt stress.

Population structure in Quercus suber L. revealed by nuclear microsatellite markers.

Quercus suber L. is a sclerophyllous tree species native to the western Mediterranean, a region that is considered highly vulnerable to increased temperatures and severe dry conditions due to environmental changes. Understanding the population structure and demographics of Q. suber is essential in order to anticipate whether populations at greater risk and the species as a whole have the genetic background and reproductive dynamics to enable rapid adaptation. The genetic diversity of Q. suber has been subject to different studies using both chloroplast and nuclear data, but population structure patterns remain unclear. Here, we perform genetic analyses on Q. suber using 13 nuclear microsatellite markers, and analysed 17 distinct locations across the entire range of the species. Structure analyses revealed that Q. suber may contain three major genetic clusters that likely result from isolation in refugia combined with posterior admixture and putative introgression from other Quercus species. Our results show a more complex structure scenario than previously inferred for Q. suber using nuclear markers and suggest that different southern populations contain high levels of genetic variation that may contribute to the resilience of Q. suber in a context of environmental change and adaptive pressure.

Linear scleroderma en coup de sabre - a different clinical presentation.

Localized scleroderma (LoS) is a rare condition featuring skin and underlying tissue sclerosis not usually compromising other systems. A subtype of LoS including lesions in the head is further classified as linear scleroderma en coup de sabre (LSeCS). Neurological involvement in LSeCS can reach up to 4% and may include seizures. Cutaneous lesions usually emerge before neurologic symptoms and these oftentimes manifest with intracranial abnormalities. We describe a case of an 11-year-old boy with an onset of self-limited unexplained seizures at 20-months of life. During the first year of follow-up, a midline frontoparietal lesion with alopecia and hypopigmentation was noted and a referral to dermatology and pediatric rheumatology consultation was made. A diagnosis of LEsCS was made. A 10-year follow-up of this patient is presented with favorable outcome. LSeCS is a rare form of LoS most frequently diagnosed in children and adolescents. A meticulous examination of these patients should be performed with particular attention to the face and scalp. The mainstay therapeutical approach is based on methotrexate and corticosteroids. Neurologic abnormalities associated with skin lesions on the head should should raise clinical suspicion of LSeCS.