Are there differences between patients with unifocal nummular headache and those who progress to bifocal nummular headache? A retrospective observational study.

OBJECTIVES: This retrospective observational cohort study aimed to compare clinical characteristics and treatment responses in patients exclusively experiencing unifocal nummular headache (NH) with those who develop the bifocal variant. METHODS: A retrospective study was conducted on patients diagnosed with NH who attended a neurology (headache) outpatient clinic between January 2018 and December 2022. The cohort was divided into two groups: Group 1, exclusive unifocal NH; and Group 2, those developing a secondary focal area of pain, i.e., bifocal NH. Data were collected on demographic characteristics, clinical features, other headache comorbidities, and treatment-related information. RESULTS: A total of 23 patients were included in this study: 12 were categorized as unifocal NH (Group 1) and 11 as bifocal NH (Group 2). There were no differences between the two groups in terms of demographic characteristics, clinical features, or treatment response. Nonetheless, patients with bifocal NH exhibited spontaneous remission rates in the first pain area when compared to the unifocal NH group, with statistically significant differences (36% vs. 0%, p = 0.020). CONCLUSION: In our sample, patients with bifocal NH demonstrated spontaneous remission rates in the initial pain area, a phenomenon not observed in patients with unifocal NH. It is worth noting the limited sample size in the present study, highlighting the need for larger cohorts to validate and further explore our findings.

The Role of Neurohospitalism in a Specialized Cardiovascular Hospital.

INTRODUCTION: Cardiology and cardiothoracic surgery are among the specialties that most commonly require neurology inpatient consultations. We aimed to study the neurology referrals by the cardiovascular-specialized hospital included in our tertiary hospital center. METHODS: Retrospective study of consecutive patients referred for neurology inpatient consultation between January 1, 2020, and December 31, 2022. We analyzed referrals, patients' characteristics, and the approach taken. A detailed subanalysis was performed for patients diagnosed with acute ischemic stroke (AIS). RESULTS: 143 patients were observed (mean age 67.3 years, 46 [32.2%] females). Most frequent referral reasons were suspected AIS deficits (39.2%), altered mental status (19.6%), suspected seizures (13.3%), and neuroprognostication (11.9%). Mean referral-to-consult time was 2.7 days, and 117 (81.8%) consults were in-person. Additional investigation, treatment changes, and outpatient clinic referral were proposed, respectively, in 79.7%, 60.1%, and 19.6% of patients. Most common diagnoses were AIS (45.5%), hypoxic-ischemic encephalopathy (18.9%), and delirium (7.0%). Regarding patients with AIS (n = 62), most common stroke causes were post-cardiac procedure (44.6%), infective endocarditis (18.5%), aortic dissection (10.8%), acute myocardial infarction (10.8%), and anticoagulant withdrawal in patients with atrial fibrillation (6.2%). Thirty-four AIS patients were diagnosed less than 24 h since last seen well, of which four (6.2%) were treated (three with thrombolysis and one with mechanical thrombectomy). CONCLUSION: AIS is the most common reason for referral in our cardiovascular hospital. Our results highlight the importance of the availability of a neurologist/neurohospitalist with stroke expertise for consultation of inpatients admitted in a specialized cardiovascular hospital.

Impact of white-matter mask selection on DTI histogram-based metrics as potential biomarkers in cerebral small vessel disease.

OBJECTIVE: Histogram-based metrics extracted from diffusion-tensor imaging (DTI) have been suggested as potential biomarkers for cerebral small vessel disease (SVD), but methods and results have varied across studies. This work aims to assess the impact of mask selection for extracting histogram-based metrics of fractional anisotropy (FA) and mean diffusivity (MD) on their sensitivity as SVD biomarkers. METHODS: DTI data were collected from 17 SVD patients and 12 healthy controls. FA and MD maps were estimated; from these, histograms were computed on two whole-brain white-matter masks: normal-appearing white-matter (NAWM) and mean FA tract skeleton (TBSS). Histogram-based metrics (median, peak height, peak width, peak value) were extracted from the FA and MD maps. These were compared between groups and correlated with the patients' cognitive scores (executive function and processing speed). RESULTS: White-matter mask selection significantly impacted FA and MD histogram metrics. In particular, significant interactions were found between Mask and Group for FA peak height (p = 0.027), MD Median (p = 0.035) and MD peak width (p = 0.047); indicating that the mask used affected their ability to discriminate between groups. In fact, MD peak width showed a significant 8.8% increase in patients when using TBSS (p = 0.037), but not when using NAWM (p = 0.69). Moreover, the mask may have an effect on the correlations with cognitive measures. Nevertheless, MD peak width (TBSS: r = - 0.75, NAWM: r = - 0.71) and MD peak height (TBSS: r = 0.65, NAWM: r = 0.62) remained significantly correlated with executive function, regardless of the mask. CONCLUSION: The impact of the processing methodology, in particular the choice of white-matter mask, highlights the need for standardized MRI data-processing pipelines.

Altered bone microarchitecture in a type 1 diabetes mouse model Ins2Akita.

Type 1 diabetes mellitus (T1DM) has been associated to several cartilage and bone alterations including growth retardation, increased fracture risk, and bone loss. To determine the effect of long term diabetes on bone we used adult and aging Ins2 Akita mice that developed T1DM around 3-4 weeks after birth. Both Ins2 Akita and wild-type (WT) mice were analyzed at 4, 6, and 12 months to assess bone parameters such as femur length, growth plate thickness and number of mature and preapoptotic chondrocytes. In addition, bone microarchitecture of the cortical and trabecular regions was measured by microcomputed tomography and gene expression of Adamst-5, Col2, Igf1, Runx2, Acp5, and Oc was quantified by quantitative real-time polymerase chain reaction. Ins2 Akita mice showed a decreased longitudinal growth of the femur that was related to decreased growth plate thickness, lower number of chondrocytes and to a higher number of preapoptotic cells. These changes were associated with higher expression of Adamst-5, suggesting higher cartilage degradation, and with low expression levels of Igf1 and Col2 that reflect the decreased growth ability of diabetic mice. Ins2 Akita bone morphology was characterized by low cortical bone area (Ct.Ar) but higher trabecular bone volume (BV/TV) and expression analysis showed a downregulation of bone markers Acp5, Oc, and Runx2. Serum levels of insulin and leptin were found to be reduced at all-time points Ins2 Akita . We suggest that Ins2 Akita mice bone phenotype is caused by lower bone formation and even lower bone resorption due to insulin deficiency and to a possible relation with low leptin signaling.

Intravenous Thrombolysis for Acute Ischemic Stroke After Recent Myocardial Infarction: Case Series and Systematic Review.

Background and Purpose- The safety of IV r-tPA (intravenous tissue-type plasminogen activator) for acute ischemic stroke (AIS) treatment after recent myocardial infarction (MI) is still a matter of debate. We studied the safety of delivering IV r-tPA to AIS patients with a MI within the preceding 3 months. Methods- Retrospective review of consecutive AIS admitted to 2 tertiary university hospitals' and systematic literature review for AIS patients with history of MI in the previous 3 months. Patients were divided into 2 groups: treated or not treated with standard IV r-tPA dose for AIS. Cardiac complications (cardiac rupture/tamponade, intracardiac thrombus embolization, or life-threatening arrhythmias) were compared between groups and assessed by type of MI (non-ST-segment-elevation myocardial infarction [STEMI], or STEMI) and time elapsed between vascular events. Results- One hundred and two patients were included; 46 (45.1%) were derived from literature review. Median age (interquartile range) was 64 (53-75) years old, and 69 (67.6%) were men. Forty-seven (46.1%) received IV r-tPA. In the treated group, 25 (53.2%) and 23 (48.9%) patients had, respectively, concurrent AIS and MI and STEMI, in comparison with 12 (21.8%; P=0.002) and 36 (65.5%; P=0.110) patients in the nontreated. Four (8.5%) IV r-tPA-treated patients died from confirmed or presumed cardiac rupture/ tamponade, all with a STEMI in the week preceding stroke. This complication occurred in 1 (1.8%) patients in the nontreated group (P=0.178). There were no differences in thrombus embolization (1 [2.1%) versus 2 [3.6]; P=1.000) and life-threatening arrhythmias (3 [6.4%) versus 7 [12.7]; P=0.335). No non-STEMI patients receiving IV r-tPA had cardiac complications. Conclusions- In patients with AIS and recent or concurrent MI, MI type and the time elapsed between the 2 events should be taken into consideration when deciding to deliver IV r-tPA. Although recent non-STEMI or concurrent events seem safe, STEMI in the week preceding stroke should prompt caution. The low number of events and publication bias may have influenced our conclusions.

Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins.

BACKGROUND: Mutations in pre-mRNA splicing factor PRPF31 can lead to retinitis pigmentosa (RP). Although the exact disease mechanism remains unknown, it has been hypothesized that haploinsufficiency might be involved in the pathophysiology of the disease. METHODS: In this study, we have analyzed a mouse model containing the p.A216P mutation in Prpf31 gene. RESULTS: We found that mutant Prpf31 protein produces cytoplasmic aggregates in the retinal pigment epithelium and decreasing the protein levels of this splicing factor in the nucleus. Additionally, normal protein was recruited in insoluble aggregates when the mutant protein was overexpressed in vitro. In response to protein aggregation, Hspa4l is overexpressed. This member of the HSP70 family of chaperones might contribute to the correct folding and solubilization of the mutant protein, allowing its translocation to the nucleus. CONCLUSIONS: Our data suggests that a mechanism haploinsufficiency and dominant-negative is involved in retinal degeneration due to mutations in PRPF31. HSP70 over-expression might be a new therapeutic target for the treatment of retinal degeneration due to PRPF31 mutations.

Portuguese Observational Study of Ischaemic Stroke in Patients Medicated with Non-Vitamin K Antagonist Oral Anticoagulants.

INTRODUCTION: Clinical trials and subsequent meta-analyses showed advantages of non-vitamin K antagonists oral anticoagulants (NOACs) over vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation. The impact of preadmission anticoagulation in acute ischaemic stroke (AIS) has not been established. OBJECTIVE: To compare functional outcome of patients with AIS with preadmission NOACs vs. VKAs. METHODS: A retrospective analysis was conducted on consecutive AIS patients under oral anticoagulation (VKAs or NOACs) admitted in 4 Portuguese hospitals within a period of 30 months. Two primary outcomes were defined and compared between VKA and NOAC groups: symptomatic intracerebral hemorrhage transformation (sICH) and modified Rankin Scale (mRS) at 3 months. RESULTS: Four hundred sixty-nine patients were included, of whom 332 (70.8%) were treated with VKA and 137 (29.2%) with NOAC. Patients' median age was 78.0 and 234 (49.9%) were male. NOAC-treated patients had a higher median CHA2DS2-VASc score than those under VKA (5.0 vs. 4.0, p = 0.023). The two primary outcomes showed no statistical differences between the VKAs' group and the NOACs' group (sICH: 5.4 vs. 5.4% [p = 0.911]; mRS at 3 months: 3.0 vs. 3.0 [p = 0.646], respectively). CONCLUSION: Preadmission anticoagulation with NOACs in AIS has a functional impact similar to that of VKAs.

Prediabetes Is Associated with Unfavorable Outcome in Young Adult Patients with Ischemic Stroke.

BACKGROUND: Prediabetes has been associated with unfavorable short-term outcome in patients with ischemic stroke (IS). However, its effect in the subset of young adult patients has not been fully assessed. Our aim was to study the association between prediabetes and 3-month outcome in young adult patients with IS. METHODS: This is a retrospective analysis of consecutive patients aged 18-55 years with a clinical diagnosis of acute IS between January 2010 and December 2016. According to their glucose profile, patients were divided in 3 groups: normal glucose metabolism, prediabetes, and diabetes. The outcome at 3 months was assessed by the modified Rankin Scale (mRS) and dichotomized as good (mRS score ≤2) and poor (mRS score >2) outcomes. RESULTS: A total of 247 patients were included, the median age was 49 years (interquartile range 42-53), and 144 (58.3%) were men. Prediabetes was diagnosed in 79 patients (32.0%) and diabetes was diagnosed in 45 patients (18.2%). Prediabetic (adjusted odds ratio [OR] 2.4, 95% confidence interval [CI] 1.1-5.1, P = .031) and diabetic (adjusted OR 2.8, 95% CI 1.3-6.1, P = .020) patients had a worse prognosis at 3 months. A statistical significant shift in the distribution of the mRS score at 3 months was found in prediabetic (adjusted OR 2.5, 95% CI .3-1.5, P = .002) and diabetic (adjusted OR 3.74, 95% CI .5-2.2, P = .002) patients. CONCLUSION: In young adults with IS, prediabetes and diabetes increase the risk of unfavorable outcome at 3 months.

Herbal Supplements Association with Reversible Cerebral Vasoconstriction Syndrome: A Case Report.

BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) is a clinico-radiologic syndrome characterized by thunderclap headache and reversible multifocal arterial constrictions that resolves within 3 months. RCVS can be either spontaneous or related to a trigger; vasoactive drugs including over-the-counter medicine are common culprits. Nevertheless, there are sparse data on the association of herbal supplements in the genesis of unexplained RCVS. METHODS: We describe a case of RCVS with a temporal association with the consumption of a diet pill composed of green tea, L-carnitine, and conjugated linoleic acid. We reviewed the literature describing RCVS cases associated with consumption of herbal supplements or plants. RESULTS: A 50-year-old black woman presented at the emergency room with a thunderclap headache less than 1 week after beginning a new herbal supplement with weight loss purpose. Angiographic study revealed multiple arterial constriction of virtually all intracranial territories that were reversed 28 days later. The patient was discharged with minimal symptoms. From our review, we identified 5 previous reports of herbal product-related triggers. CONCLUSIONS: Different factors can trigger RCVS. Besides our case, at least 5 other nutraceutical products were described to be associated with the disorders, 3 of them in patients without any other clear cause. Clinicians should be aware of the possible role of herbal supplements in RCVS, and their use should be systematically assessed in large RCVS cohorts to clarify this association.

GLUT1 activity contributes to the impairment of PEDF secretion by the RPE.

PURPOSE: In this study, we aimed to understand whether glucose transporter 1 (GLUT1) activity affects the secretion capacity of antiangiogenic factor pigment epithelium-derived factor (PEDF) by the RPE cells, thus explaining the reduction in PEDF levels observed in patients with diabetic retinopathy (DR). METHODS: Analysis of GLUT1 expression, localization, and function was performed in vitro in RPE cells (D407) cultured with different glucose concentrations, corresponding to non-diabetic (5 mM of glucose) and diabetic (25 mM of glucose) conditions, further subjected to normoxia or hypoxia. The expression of PEDF was also evaluated in the secretome of the cells cultured in these conditions. Analysis of GLUT1 and PEDF expression was also performed in vivo in the RPE of Ins2(Akita) diabetic mice and age-matched wild-type (WT) controls. RESULTS: We observed an increase in GLUT1 under hypoxia in a glucose-dependent manner, which we found to be directly associated with the translocation and stabilization of GLUT1 in the cell membrane. This stabilization led to an increase in glucose uptake by RPE cells. This increase was followed by a decrease in PEDF expression in RPE cells cultured in conditions that simulated DR. Compared with non-diabetic WT mice, the RPE of Ins2(Akita) mice showed increased GLUT1 overexpression with a concomitant decrease in PEDF expression. CONCLUSIONS: Collectively, our data show that expression of GLUT1 is stimulated by hyperglycemia and low oxygen supply, and this overexpression was associated with increased activity of GLUT1 in the cell membrane that contributes to the impairment of the RPE secretory function of PEDF.

The Stroke Chronometer-A New Strategy to Reduce Door-to-Needle Time.

BACKGROUND AND OBJECTIVE: In acute stroke patients' treatment, time is of utmost importance. Significant efforts must be made to reduce door-to-needle time (DNT), taking into account its effect on treatment efficacy and patients' prognosis. The objective of this study is to assess the effect of implementing a countdown timer in the acute stroke emergency room, on door-to-computed tomography time (DCTT) and DNT. METHODS: Implementation of protocol that postulates the activation of a countdown timer every time an acute stroke patient is admitted. DCTT and DNT in patients submitted to thrombolysis were compared before and after the implementation of the chronometer. Multivariate analysis of DNT and DCTT was conducted adjusted to age, sex, National Institutes of Health Stroke Scale at admission, time from stroke onset to admission, and anterior circulation. RESULTS: Of the 76 patients treated with thrombolysis in 2015 in our hospital, 71 had stroke code activation by the emergency medical services or at hospital admission. Protocol was initiated on July 1, with 41 patients (58%) included in the second semester. The Stroke Chronometer implementation resulted in a reduction of the mean DCTT from 27.1 to 18.4 minutes (P = .004; 95% CI 2.56-12.45) and of the mean DNT from 52.7 to 39.2 minutes (P = .016; 95% CI 2.49-23.18), respectively, first and second semesters. CONCLUSION: The Stroke Chronometer strategy has revealed to be an effective method to reduce DCTT and DNT.

Orolingual angiodema associated with alteplase treatment of acute stroke: a reappraisal.

BACKGROUND: Orolingual angioedema has been increasingly recognized as a potentially life-threatening complication associated with alteplase treatment of stroke. Concomitant treatment with an angiotension converting enzyme inhibitor (ACEi) and localization of infarction in the territory of middle cerebral artery seem to be associated with a higher risk of this complication. METHODS: We report the cases of orolingual angioedema among the patients undergoing alteplase treatment in our Stroke Unit. Additionally, we reviewed the literature to evaluate the pathophysiology, clinical characteristics, and treatment options. RESULTS: In our Stroke Unit, among 236 patients given alteplase for acute stroke, 8 patients (3.4%) developed angioedema. The clinical picture varied from localized labial edema to extensive lingual edema with respiratory distress but in all cases it gradually resolved with symptomatic treatment. Seven patients had a hemispheric stroke (4 with lateralized angioedema, contralateral to the ischemic lesion), whereas the other 1 patient had a right superior cerebellar artery stroke (with lateralized angioedema, ipsilateral to the ischemic lesion). The National Institutes of Health Stroke Scale score at admission ranged from 6 to 24 (median 12.5). Five patients were taking an ACEi. Our results are similar to previously published data. In the literature, it appears that orolingual angioedema occurs in .2-5.1% of all stroke patients receiving Alteplase treatment. CONCLUSIONS: Orolingual angioedema is a potential complication of which treating physicians in stroke units need to be aware, even in those cases without history of ACEi treatment and without infarction in the territory of the middle cerebral artery. All patients who receive alteplase treatment should be monitored carefully.

Human Stem Cells for Cardiac Disease Modeling and Preclinical and Clinical Applications-Are We on the Road to Success?

Cardiovascular diseases (CVDs) are pointed out by the World Health Organization (WHO) as the leading cause of death, contributing to a significant and growing global health and economic burden. Despite advancements in clinical approaches, there is a critical need for innovative cardiovascular treatments to improve patient outcomes. Therapies based on adult stem cells (ASCs) and embryonic stem cells (ESCs) have emerged as promising strategies to regenerate damaged cardiac tissue and restore cardiac function. Moreover, the generation of human induced pluripotent stem cells (iPSCs) from somatic cells has opened new avenues for disease modeling, drug discovery, and regenerative medicine applications, with fewer ethical concerns than those associated with ESCs. Herein, we provide a state-of-the-art review on the application of human pluripotent stem cells in CVD research and clinics. We describe the types and sources of stem cells that have been tested in preclinical and clinical trials for the treatment of CVDs as well as the applications of pluripotent stem-cell-derived in vitro systems to mimic disease phenotypes. How human stem-cell-based in vitro systems can overcome the limitations of current toxicological studies is also discussed. Finally, the current state of clinical trials involving stem-cell-based approaches to treat CVDs are presented, and the strengths and weaknesses are critically discussed to assess whether researchers and clinicians are getting closer to success.

Interferon-Alpha Decreases Cancer Stem Cell Properties and Modulates Exosomes in Malignant Melanoma.

Malignant melanoma (MM) can spread to other organs and is resistant in part due to the presence of cancer stem cell subpopulations (CSCs). While a controversial high dose of interferon-alpha (IFN-α) has been used to treat non-metastatic high-risk melanoma, it comes with undesirable side effects. In this study, we evaluated the effect of low and high doses of IFN-α on CSCs by analyzing ALDH activity, side population and specific surface markers in established and patient-derived primary cell lines. We also assessed the clonogenicity, migration and tumor initiation capacities of IFN-α treated CSCs. Additionally, we investigated genomic modulations related to stemness properties using microRNA sequencing and microarrays. The effect of IFN-α on CSCs-derived exosomes was also analyzed using NanoSight and liquid chromatography (LC-HRMS)-based metabolomic analysis, among others. Our results showed that even low doses of IFN-α reduced CSC formation and stemness properties, and led to a significant decrease in the ability to form tumors in mice xenotransplants. IFN-α also modulated the expression of genes and microRNAs involved in several cancer processes and metabolomics of released exosomes. Our work suggests the utility of low doses of interferon, combined with the analysis of metabolic biomarkers, as a potential clinical approach against the aggressiveness of CSCs in melanoma.

Nationwide Access to Endovascular Treatment for Acute Ischemic Stroke in Portugal.

INTRODUCTION: Since the publication of endovascular treatment trials and European Stroke Guidelines, Portugal has re-organized stroke healthcare. The nine centers performing endovascular treatment are not equally distributed within the country, which may lead to differential access to endovascular treatment. Our main aim was to perform a descriptive analysis of the main treatment metrics regarding endovascular treatment in mainland Portugal and its administrative districts. MATERIAL AND METHODS: A retrospective national multicentric cohort study was conducted, including all ischemic stroke patients treated with endovascular treatment in mainland Portugal over two years (July 2015 to June 2017). All endovascular treatment centers contributed to an anonymized database. Demographic, stroke-related and procedure-related variables were collected. Crude endovascular treatment rates were calculated per 100 000 inhabitants for mainland Portugal, and each district and endovascular treatment standardized ratios (indirect age-sex standardization) were also calculated. Patient time metrics were computed as the median time between stroke onset, first-door, and puncture. RESULTS: A total of 1625 endovascular treatment procedures were registered. The endovascular treatment rate was 8.27/100 000 inhabitants/year. We found regional heterogeneity in endovascular treatment rates (1.58 to 16.53/100 000/year), with higher rates in districts closer to endovascular treatment centers. When analyzed by district, the median time from stroke onset to puncture ranged from 212 to 432 minutes, reflecting regional heterogeneity. DISCUSSION: Overall endovascular treatment rates and procedural times in Portugal are comparable to other international registries. We found geographic heterogeneity, with lower endovascular treatment rates and longer onset-to-puncture time in southern and inner regions. CONCLUSION: The overall national rate of EVT in the first two years after the organization of EVT-capable centers is one of the highest among European countries, however, significant regional disparities were documented. Moreover, stroke-onset-to-first-door times and in-hospital procedural times in the EVT centers were comparable to those reported in the randomized controlled trials performed in high-volume tertiary hospitals.

Introdução: A aprovação do tratamento endovascular para o acidente vascular cerebral isquémico obrigou à reorganização dos cuidados de saúde em Portugal. Os nove centros que realizam tratamento endovascular não estão distribuídos equitativamente pelo território, o que poderá causar acesso diferencial a tratamento. O principal objetivo deste estudo é realizar uma análise descritiva da frequência e métricas temporais do tratamento endovascular em Portugal continental e seus distritos. Material e Métodos: Estudo de coorte nacional multicêntrico, incluindo todos os doentes com acidente vascular cerebral isquémico submetidos a tratamento endovascular em Portugal continental durante um período de dois anos (julho 2015 a junho 2017). Foram colhidos dados demográficos, relacionados com o acidente vascular cerebral e variáveis do procedimento. Taxas de tratamento endovascular brutas e ajustadas (ajuste indireto a idade e sexo) foram calculadas por 100 000 habitantes/ano para Portugal continental e cada distrito. Métricas de procedimento como tempo entre instalação, primeira porta e punção foram também analisadas. Resultados: Foram registados 1625 tratamentos endovasculares, indicando uma taxa bruta nacional de tratamento endovascular de 8,27/100 000 habitantes/ano. As taxas de tratamento endovascular entre distritos variaram entre 1,58 e 16,53/100 000/ano, com taxas mais elevadas nos distritos próximos a hospitais com tratamento endovascular. O tempo entre sintomas e punção femural entre distritos variou entre 212 e 432 minutos. Discussão: A análise nacional a taxas de tratamento endovascular e tempos de atuação é comparável a outros registos internacionais. Verificaram-se heterogeneidades geográficas, com taxas de tratamento endovascular menores e maior tempo para tratamento nos distritos do sul e interior. Conclusão: Portugal continental apresenta uma taxa nacional de tratamento endovascular elevada, apresentando, contudo, assimetrias regionais no acesso. As métricas temporais foram comparáveis com as observadas nos ensaios clínicos piloto.

Generation and cardiac differentiation of a human induced pluripotent stem cell line UALGi002-A from a female patient with Left-Ventricular Noncompaction Cardiomyopathy.

Left Ventricular Noncompaction Cardiomyopathy (LVNC) is characterized by abnormal number and prominence of trabeculations of the left ventricle of the heart. Although LVNC has been associated with mutations in several genes encoding for transcriptional regulators, ion channels, sarcomeric and mitochondrial proteins, approximately 60% of LVNC patients do not present these genetic alterations. Here, we describe an induced pluripotent stem cell (hiPSC) line (UALGi002-A) originated from a LVNC female patient (LVNC-hiPSC) who does not present any previously known mutations associated to LVNC. The LVNC-hiPSC exhibited full pluripotency and differentiation potential and retained a normal karyotype after reprogramming. Moreover, the LVNC-hiPSC differentiated into contracting cardiomyocytes. This cellular model will be useful to study the molecular, genetic and functional aspects of LVNC in vitro.

Generation of a human induced pluripotent stem cell line (UALGi001-A) from a patient with Left-Ventricular Noncompaction Cardiomyopathy.

Left Ventricular Noncompaction Cardiomyopathy (LVNC) is characterized by excessive trabeculation of the left ventricle. To date, mutations in more than 40 genes have been associated with LVNC, however the exact mechanisms underlying the disease remain unknown. Here, we describe an induced pluripotent stem cell (iPSC) line (UALGi001-A) from a LVNC patient (LVNC-iPSC) that does not present mutations in the genes most commonly associated with the disease (van Waning et al., 2019). The LVNC-iPSC exhibited full pluripotency and differentiation potential, and retained a normal karyotype after reprogramming. This in vitro cellular model will be useful to study the molecular, genetic and functional aspects of LVNC.

Human-derived NLS enhance the gene transfer efficiency of chitosan.

Nuclear import is considered as one of the major limitations for non-viral gene delivery systems and the incorporation of nuclear localization signals (NLS) that mediate nuclear intake can be used as a strategy to enhance internalization of exogenous DNA. In this work, human-derived endogenous NLS peptides based on insulin growth factor binding proteins (IGFBP), namely IGFBP-3 and IGFBP-5, were tested for their ability to improve nuclear translocation of genetic material by non-viral vectors. Several strategies were tested to determine their effect on chitosan mediated transfection efficiency: co-administration with polyplexes, co-complexation at the time of polyplex formation, and covalent ligation to chitosan. Our results show that co-complexation and covalent ligation of the NLS peptide derived from IGFBP-3 to chitosan polyplexes yields a 2-fold increase in transfection efficiency, which was not observed for NLS peptide derived from IGFBP-5. These results indicate that the integration of IGFBP-NLS-3 peptides into polyplexes has potential as a strategy to enhance the efficiency of non-viral vectors.

Mutations of the GLA gene in young patients with stroke: the PORTYSTROKE study--screening genetic conditions in Portuguese young stroke patients.

BACKGROUND AND PURPOSE: Fabry disease is an X-linked monogenic disorder caused by mutations in the GLA gene. Recent data suggest that stroke in young adults may be associated with Fabry disease. We aimed to ascertain the prevalence of this disorder among young adult patients with stroke in Portugal by GLA genotyping. METHODS: During 1 year, all patients aged 18 to 55 years with first-ever stroke, who were admitted into any of 12 neurology hospital departments in Portugal, were prospectively enrolled (n=625). Ischemic stroke was classified according to Trial of Org 10172 in Acute Stroke Treatment criteria. Alpha-galactosidase activity was further assayed in all patients with GLA mutations. RESULTS: Four hundred ninety-three patients (mean age, 45.4 years; 61% male) underwent genetic analyses: 364 with ischemic stroke, 89 with intracerebral hemorrhage, 26 with subarachnoid hemorrhage, and 14 with cerebral venous thrombosis. Twelve patients had missense GLA mutations: 9 with ischemic stroke (p.R118C: n=4; p.D313Y: n=5), including 5 patients with an identified cause of stroke (cardiac embolism: n=2; small vessel disease: n=2; other cause: n=1), 2 with intracerebral hemorrhage (p.R118C: n=1; p.D313Y: n=1), and one with cerebral venous thrombosis (p.R118C: n=1). Leukocyte alpha-galactosidase activity was subnormal in the hemizygous males and subnormal or low-normal in the heterozygous females. Estimated prevalence of missense GLA mutations was 2.4% (95% CI, 1.3% to 4.1%). CONCLUSIONS: Despite a low diagnostic yield, screening for GLA mutations should probably be considered in different types of stroke. Restricting investigation to patients with cryptogenic stroke may underestimate the true prevalence of Fabry disease in young patients with stroke.

CITED2 and the modulation of the hypoxic response in cancer.

CITED2 (CBP/p300-interacting transactivator with Glu/Asp-rich C-terminal domain, 2) is a ubiquitously expressed protein exhibiting a high affinity for the CH1 domain of the transcriptional co-activators CBP/p300, for which it competes with hypoxia-inducible factors (HIFs). CITED2 is particularly efficient in the inhibition of HIF-1α-dependent transcription in different contexts, ranging from organ development and metabolic homeostasis to tissue regeneration and immunity, being also potentially involved in various other physiological processes. In addition, CITED2 plays an important role in inhibiting HIF in some diseases, including kidney and heart diseases and type 2-diabetes. In the particular case of cancer, CITED2 either functions by promoting or suppressing cancer development depending on the context and type of tumors. For instance, CITED2 overexpression promotes breast and prostate cancers, as well as acute myeloid leukemia, while its expression is downregulated to sustain colorectal cancer and hepatocellular carcinoma. In addition, the role of CITED2 in the maintenance of cancer stem cells reveals its potential as a target in non-small cell lung carcinoma and acute myeloid leukemia, for example. But besides the wide body of evidence linking both CITED2 and HIF signaling to carcinogenesis, little data is available regarding CITED2 role as a negative regulator of HIF-1α specifically in cancer. Therefore, comprehensive studies exploring further the interactions of these two important mediators in cancer-specific models are sorely needed and this can potentially lead to the development of novel targeted therapies.