Plasma Levels of Neuron/Glia-Derived Apoptotic Bodies, an In Vivo Biomarker of Apoptosis, Predicts Infarct Growth and Functional Outcome in Patients with Ischemic Stroke.

Evidence demonstrating the involvement of apoptosis in the death of the potentially salvageable area (penumbra zone) in patients during stroke remains limited. Our aim was to investigate whether apoptotic processes occur in penumbral brain tissue by analyzing circulating neuron- and glia-derived apoptotic bodies (CNS-ApBs), which are vesicles released into the bloodstream during the late stage of apoptosis. We have also assessed the clinical utility of plasma neuronal and glial apoptotic bodies in predicting early neurological evolution and functional outcome. The study included a total of 71 patients with acute hemispheric ischemic stroke (73 ± 10 years; 30 women). Blood samples were collected from these patients immediately upon arrival at the hospital (within 9 h) and at 24 and 72 h after symptom onset. Subsequently, isolation, quantification, and phenotypic characterization of CNS-ApBs during the first 72 h post-stroke were performed using centrifugation and flow cytometry techniques. We found a correlation between infarct growth and final infarct size with the amount of plasma CNS-ApBs detected in the first 72 h after stroke. In addition, patients with neurological worsening (progressive ischemic stroke) had higher plasma levels of CNS-ApBs at 24 h after symptom onset than those with a stable or improving course. Circulating CNS-ApB concentration was further associated with patients' functional prognosis. In conclusion, apoptosis may play an important role in the growth of the cerebral infarct area and plasma CNS-ApB quantification could be used as a predictive marker of penumbra death, neurological deterioration, and functional outcome in patients with ischemic stroke.

Expression patterns of Mal genes and association with differential maltose and maltotriose transport rate of two Saccharomyces pastorianus yeasts.

Beer brewing is a well-known process that still faces great challenges, such as the total consumption of sugars present in the fermentation media. Lager-style beer, a major worldwide beer type, is elaborated by Saccharomyces pastorianus (Sp) yeast, which must ferment high maltotriose content worts, but its consumption represents a notable problem, especially among Sp strains belonging to group I. Factors, such as fermentation conditions, presence of maltotriose transporters, transporter copy number variation, and genetic regulation variations contribute to this issue. We assess the factors affecting fermentation in two Sp yeast strains: SpIB1, with limited maltotriose uptake, and SpIB2, known for efficient maltotriose transport. Here, SpIB2 transported significantly more maltose (28%) and maltotriose (32%) compared with SpIB1. Furthermore, SpIB2 expressed all MAL transporters (ScMALx1, SeMALx1, ScAGT1, SeAGT1, MTT1, and MPHx) on the first day of fermentation, whereas SpIB1 only exhibited ScMalx1, ScAGT1, and MPH2/3 genes. Some SpIB2 transporters had polymorphic transmembrane domains (TMD) resembling MTT1, accompanied by higher expression of these transporters and its positive regulator genes, such as MAL63. These findings suggest that, in addition to the factors mentioned above, positive regulators of Mal transporters contribute significantly to phenotypic diversity in maltose and maltotriose consumption among the studied lager yeast strains.IMPORTANCEBeer, the third most popular beverage globally with a 90% market share in the alcoholic beverage industry, relies on Saccharomyces pastorianus (Sp) strains for lager beer production. These strains exhibit phenotypic diversity in maltotriose consumption, a crucial process for the acceptable organoleptic profile in lager beer. This diversity ranges from Sp group II strains with a notable maltotriose-consuming ability to Sp group I strains with limited capacity. Our study highlights that differential gene expression of maltose and maltotriose transporters and its upstream trans-elements, such as MAL gene-positive regulators, adds complexity to this variation. This insight can contribute to a more comprehensive analysis needed to the development of controlled and efficient biotechnological processes in the beer brewing industry.

Endovascular treatment in Danon disease: a case report.

BACKGROUND: Danon disease is a lysosomal storage disorder with X-linked inheritance. The classic triad is severe hypertrophic cardiomyopathy, myopathy, and intellectual disability, with different phenotypes between both genders. Ischemic stroke is an uncommon complication, mostly cardioembolic, related to intraventricular thrombus or atrial fibrillation, among others. CASE REPORT: We report the case of a 14-year-old Caucasian male patient with Danon disease who suffered from an acute ischemic stroke due to occlusion in the M1 segment of the middle cerebral artery. He underwent mechanical thrombectomy, resulting in successful revascularization with satisfactory clinical outcome. We objectified the intraventricular thrombus in the absence of arrhythmic events. CONCLUSION: To our knowledge, we report the first case of ischemic stroke related to Danon disease treated with endovascular treatment.

Ultrasonographic study of the orbit as an early diagnostic tool in Vogt Koyanagi Harada disease (VKH): A case report.

In recent years, ultrasound has demonstrated its usefulness in the approach to vascular structures and other tissues such as the orbit, facilitating the early diagnosis of various diseases without having to rely on other more invasive or less available tests. In Vogt Koyanagi Harada syndrome, characterised by bilateral acute uveitis, ocular ultrasound is a clear example of the usefulness of ultrasonography in early diagnosis, facilitating the initiation of specific treatment to change the ominous natural history of this disease. This case shows the usefulness of the echography to make the differential diagnosis with other diseases that clinical onset could be similar than VKH, but with a different diagnostic and therapeutic approach.

Increased vertebral canal diameter measured by ultrasonography as a sign of vasculitis in patients with giant cell arteritis.

Introduction: The diagnosis of giant cell arteritis (GCA) by ultrasonography including large vessels, apart from the temporal artery increases the sensibility of the study and informs about the risk of specific complications. However, there is less information about the study of these arteries, whose affection carries higher proportion of severe complications. Objectives: To describe and analyze the value of the diameter of the cervical vertebral canal of the vertebral artery (VA) as a sign of vertebral vasculitis (VV) related to GCA and estimate the risk of stroke complications. Materials and methods: Observational study of a population that includes patients with GCA with and without VA vasculitis as well as healthy subjects. We evaluated whether there were differences in VA diameter in the groups and, if so, we estimated the diagnostic capacity of the variable that best defines VA diameter using a ROC curve. Cut-off points with their associated reliability chosen thereafter. Results: There were 347 subjects included:107 with GCA of whom 37 had vertebral vasculitis, 240 healthy controls. In patients with GCA and VV, the VA diameter was increased (No GCA 3.4 mm, GCA without VV 3.6 mm, GCA with VV 5.2 mm p < 0.01). According to the ROC curves, the variable defining vertebral diameter with best diagnostic accuracy is the sum of both sides (area under the curve of 0.98). With a cut-off point of 8.45 mm, the reliability values are: sensitivity 94.1%, specificity 94.5%, PPV 82.1% and NPV 98.4%. With a cut-off point of 9.95 mm, the sensitivity is 52.9% and the specificity is 100%. Likewise, VA diameter is independently associated with the presence of stroke in the vertebrobasilar territory (OR 1.6, range 1.2-2.2). Conclusion: The VA diameter, measured as the sum of both sides, is an objectively measurable sign with very high reliability for detect vertebral vasculitis in patients with GCA. It is proposed here as a novel echographic sign, which can aid the detection of the involvement of an artery where the complications are especially serious.

Beneficial Effects of Daily Consumption of Garlic and Onion Extract Concentrate on Infectious Respiratory Diseases in Elderly Resident Volunteers.

Aging is a biological process with high susceptibility to several infections. This risk increases in older patients in residential care facilities (RCF). Thus, there is a clear demand for developing preventive interventions with new therapeutic compounds that combine efficacy and safety. This could be the case of compounds derived from plants of the genus Allium spp. The purpose of this study was to evaluate the impact of a combination of a garlic and onion extract concentrate standardized in organosulfur compounds derived from propiin on the incidence of respiratory tract infections in elderly patients of RCF. Sixty-five volunteers were selected at random to receive a placebo or a single daily dose of the extract for thirty-six weeks. Different clinical visits were performed to evaluate the main respiratory diseases with an infectious origin, as well as the associated symptoms and their duration. The extract showed a clinical safety profile and significantly reduced the incidence of respiratory infections. Moreover, the treatment decreased the number and duration of the associated symptoms compared with the placebo group. For the first time, we demonstrated the protective effect of Alliaceae extract in respiratory infectious diseases in elderly healthy volunteers, which could be used prophylactically against the most common infectious respiratory diseases.

The Prebiotic Effects of an Extract with Antioxidant Properties from Morus alba L. Contribute to Ameliorate High-Fat Diet-Induced Obesity in Mice.

Obesity is a global health issue, in which modifications in gut microbiota composition have a key role. Different therapeutic strategies are being developed in combination with diet and exercise, including the use of plant extracts, such as those obtained from Morus alba L. leaves. Recent studies have revealed their anti-inflammatory and antioxidant properties. The aim of the present work was to evaluate whether the beneficial effects of M. alba L. leaf extract in high-fat diet-induced obesity in mice is correlated with its impact on gut microbiota. The extract reduced body weight gain and attenuated lipid accumulation, as well as increased glucose sensitivity. These effects were associated with an amelioration of the obesity-associated inflammatory status, most probably due to the described antioxidant properties of the extract. Moreover, M. alba L. leaf extract mitigated gut dysbiosis, which was evidenced by the restoration of the Firmicutes/Bacteroidota ratio and the decrease in plasma lipopolysaccharide (LPS) levels. Specifically, the extract administration reduced Alistipes and increased Faecalibaculum abundance, these effects being correlated with the beneficial effects exerted by the extract on the obesity-associated inflammation. In conclusion, anti-obesogenic effects of M. alba L. leaf extract may be mediated through the amelioration of gut dysbiosis.

Directed Evolution of Aerotolerance in Sulfide-Dependent Thiazole Synthases.

Sulfide-dependent THI4 thiazole synthases could potentially be used to replace plant cysteine-dependent suicide THI4s, whose high protein turnover rates make thiamin synthesis exceptionally energy-expensive. However, sulfide-dependent THI4s are anaerobic or microoxic enzymes and hence unadapted to the aerobic conditions in plants; they are also slow enzymes (kcat < 1 h-1). To improve aerotolerance and activity, we applied continuous directed evolution under aerobic conditions in the yeast OrthoRep system to two sulfide-dependent bacterial THI4s. Seven beneficial single mutations were identified, of which five lie in the active-site cleft predicted by structural modeling and two recapitulate features of naturally aerotolerant THI4s. That single mutations gave substantial improvements suggests that further advance under selection will be possible by stacking mutations. This proof-of-concept study established that the performance of sulfide-dependent THI4s in aerobic conditions is evolvable and, more generally, that yeast OrthoRep provides a plant-like bridge to adapt nonplant enzymes to work better in plants.

Gut Microbiota Composition Can Predict Colonization by Multidrug-Resistant Bacteria in SARS-CoV-2 Patients in Intensive Care Unit: A Pilot Study.

The SARS-CoV-2 infection has increased the number of patients entering Intensive Care Unit (ICU) facilities and antibiotic treatments. Concurrently, the multi-drug resistant bacteria (MDRB) colonization index has risen. Considering that most of these bacteria are derived from gut microbiota, the study of its composition is essential. Additionally, SARS-CoV-2 infection may promote gut dysbiosis, suggesting an effect on microbiota composition. This pilot study aims to determine bacteria biomarkers to predict MDRB colonization risk in SARS-CoV-2 patients in ICUs. Seventeen adult patients with an ICU stay >48 h and who tested positive for SARS-CoV-2 infection were enrolled in this study. Patients were assigned to two groups according to routine MDRB colonization surveillance: non-colonized and colonized. Stool samples were collected when entering ICUs, and microbiota composition was determined through Next Generation Sequencing techniques. Gut microbiota from colonized patients presented significantly lower bacterial diversity compared with non-colonized patients (p < 0.05). Microbiota in colonized subjects showed higher abundance of Anaerococcus, Dialister and Peptoniphilus, while higher levels of Enterococcus, Ochrobactrum and Staphylococcus were found in non-colonized ones. Moreover, LEfSe analysis suggests an initial detection of Dialister propionicifaciens as a biomarker of MDRB colonization risk. This pilot study shows that gut microbiota profile can become a predictor biomarker for MDRB colonization in SARS-CoV-2 patients.

Symptoms timeline and outcomes in amyotrophic lateral sclerosis using artificial intelligence.

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative motor neuron disease. Although an early diagnosis is crucial to provide adequate care and improve survival, patients with ALS experience a significant diagnostic delay. This study aimed to use real-world data to describe the clinical profile and timing between symptom onset, diagnosis, and relevant outcomes in ALS. Retrospective and multicenter study in 5 representative hospitals and Primary Care services in the SESCAM Healthcare Network (Castilla-La Mancha, Spain). Using Natural Language Processing (NLP), the clinical information in electronic health records of all patients with ALS was extracted between January 2014 and December 2018. From a source population of all individuals attended in the participating hospitals, 250 ALS patients were identified (61.6% male, mean age 64.7 years). Of these, 64% had spinal and 36% bulbar ALS. For most defining symptoms, including dyspnea, dysarthria, dysphagia and fasciculations, the overall diagnostic delay from symptom onset was 11 (6-18) months. Prior to diagnosis, only 38.8% of patients had visited the neurologist. In a median post-diagnosis follow-up of 25 months, 52% underwent gastrostomy, 64% non-invasive ventilation, 16.4% tracheostomy, and 87.6% riluzole treatment; these were more commonly reported (all Ps < 0.05) and showed greater probability of occurrence (all Ps < 0.03) in bulbar ALS. Our results highlight the diagnostic delay in ALS and revealed differences in the clinical characteristics and occurrence of major disease-specific events across ALS subtypes. NLP holds great promise for its application in the wider context of rare neurological diseases.

Novel Horizons in Postbiotics: Lactobacillaceae Extracellular Vesicles and Their Applications in Health and Disease.

Lactobacillus probiotics contained in dietary supplements or functional foods are well-known for their beneficial properties exerted on host health and diverse pathological situations. Their capacity to improve inflammatory bowel disease (IBD) and regulate the immune system is especially remarkable. Although bacteria-host interactions have been thought to occur directly, the key role that extracellular vesicles (EVs) derived from probiotics play on this point is being unveiled. EVs are lipid bilayer-enclosed particles that carry a wide range of cargo compounds and act in different signalling pathways. Notably, these EVs have been recently proposed as a safe alternative to the utilisation of live bacteria since they can avoid the possible risks that probiotics may entail in vulnerable cases such as immunocompromised patients. Therefore, this review aims to give an updated overview of the existing knowledge about EVs from different Lactobacillus strains, their mechanisms and effects in host health and different pathological conditions. All of the information collected suggests that EVs could be considered as potential tools for the development of future novel therapeutic approaches.

Case report: Endovascular embolization of a cerebral pseudoaneurysm caused by SARS-CoV2 infection.

Background: Severe COVID-19 has been shown to produce convulsions, encephalitis, Guillain-Barré syndrome, or cerebrovascular disease. However, only 4 case reports described subarachnoid or brain hemorrhage caused by ruptured cerebral aneurysms or pseudoaneurysms in patients with COVID-19. Cerebral pseudoaneurysms represent <1% of all intracranial aneurysms and have been related to radiation therapy, vasculitis, rupture of true saccular aneurysms, arteriovenous malformations, and infections by bacteria and viruses, such as Epstein-Bar and Herpes virus. Case presentation: A 28-year-old Caucasian woman, with no medical history of interest and completely vaccinated against SARS-CoV-2, was admitted to Neurology due to progressive tetraparesis with areflexia, a cough, and a fever of 38°C. SARS-CoV2 PCR was positive while lumbar puncture, blood tests, and electromyogram showed criteria for Guillain-Barré syndrome. Despite the treatment, the patient developed dyspnea and tetraplegia requiring invasive mechanical ventilation. There was motor neurological improvement but a decreased level of consciousness was observed on day 13. A brain CT scan demonstrated an acute haematoma and cerebral arteriography showed a 4-mm pseudoaneurysm located in a branch of the left middle cerebral artery. Given the high risk of rebleeding, endovascular treatment was decided upon. Therefore, complete embolization of the pseudoaneurysm was carried out by using the synthetic glue N-butyl-cyanocrylate. Two days later, the patient was clinically and neurologically recovered and was discharged. Lastly, a new angiography showed no evidence of the pseudoaneurysm 3-weeks later. Conclusions: We report, for the first time, a patient suffering a severe immune reaction caused by SARS-CoV2 infection and developing a cerebral pseudoaneurysm treated with endovascular embolization without complications.

Genotype-phenotype correlations in valosin-containing protein disease: a retrospective muticentre study.

BACKGROUND: Valosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Paget's disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype-phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype-phenotype correlations. METHODS: Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene. RESULTS: Two hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC <70% and being a full-time wheelchair user were associated with death. CONCLUSION: This study expands the knowledge on the phenotypic presentation, natural history, genotype-phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease.

Metrics of progression and prognosis in untreated adults with thymidine kinase 2 deficiency: An observational study.

This historical cohort study evaluated clinical characteristics of progression and prognosis in adults with thymidine kinase 2 deficiency (TK2d). Records were available for 17 untreated adults with TK2d (mean age of onset, 32 years), including longitudinal data from 6 patients (mean follow-up duration, 26.5 months). Pearson's correlation assessed associations between standard motor and respiratory assessments, clinical characteristics, and laboratory values. Longitudinal data were assessed by linear regression mixed models. Respiratory involvement progressed at an annual rate of 8.16% decrement in forced vital capacity (FVC). Most patients under noninvasive ventilation (NIV) remained ambulant (12/14, 86%), reduced FVC was not associated with concomitant decline in 6-minute walk test (6MWT), and 6MWT results were not correlated with FVC. Disease severity, assessed by age at NIV onset, correlated most strongly at diagnosis with: creatinine levels (r = 0.8036; P = 0.0009), followed by FVC (r = 0.7265; P = 0.0033), mtDNA levels in muscle (r = 0.7933; P = 0.0188), and age at disease onset (r = 0.7128; P = 0.0042). This population of adults with TK2d demonstrates rapid deterioration of respiratory muscles, which progresses independently of motor impairment. The results support FVC at diagnosis, mtDNA levels in muscle, and age at disease onset as prognostic indicators. Creatinine levels may also be potentially prognostic, as previously reported in other neuromuscular disorders.

Identification of potential target genes in Homo sapiens, by miRNA of Triticum aestivum: A cross kingdom computational approach.

Plant-derived miRNAs can be found in the human body after dietary intake, and they can affect post-transcriptional gene regulation in human. It is important to identify targets to determine the possible effects in human genes by using computational approach. In this study, 787 possible mRNAs human targets were predicted by 84 miRNAs of wheat. A total of 14 miRNAs were identified with individual binding to 33 mRNAs associated with schizophrenia, epilepsy, neurodevelopmental disorders, and various cancers, located in the 3'UTR of the mRNA. A functional enrichment was carried out, where the results showed associations to pathways such as dopaminergic synapse (hsa04728), and signaling pathways, significantly associated with the target genes. The prediction of target mRNAs in humans by wheat miRNAs, offer candidates that could facilitate the search and verification, which could be of relevance for future projects and therefor contribute in the therapeutic treatment of various human diseases.

Contribution of Orbital Ultrasound to the Diagnosis of Central Retinal Artery Occlusion.

We aimed to evaluate the diagnostic value of orbital ultrasound in the etiologic diagnosis of central retinal artery occlusion (CRAO). For this purpose, patients with CRAO evaluated at our center between 2011 and 2021 were reviewed. Demographic variables, vascular risk factors and ultrasound findings were collected. An orbital duplex was performed in all cases and complemented with other diagnostic explorations. We attended 36 cases of CRAO. In all patients, orbital ultrasound confirmed the diagnosis of CRAO: in 75% emboli material (spot sign) was observed in CRA and in 25% flow alteration in CRA without visible embolus. The positive spot sign (PSS) group differed from patients with negative spot sign (NSS) in terms of etiology: 8 PSS cases (29.6%) had a major cardioembolic cause, 4 (14.8%) a large vessel atheromatous disease, 15 (55.6%) an undetermined cause. Some 21 (77.8%) PSS patients had some minor cardioembolic cause, mainly calcifications of the left valves. In the NSS group, 2 (22%) were diagnosed with giant cell arteritis (GCA). In CRAO, the ultrasound spot sign could be a guide for the detection of embolic sources. Its absence makes it necessary to consider more strongly the possibility of arteritis. Furthermore, our findings suggest a key role of calcium embolism in PSS patients.

Muscle MRI characteristic pattern for late-onset TK2 deficiency diagnosis.

BACKGROUND AND OBJECTIVE: TK2 deficiency (TK2d) is a rare mitochondrial disorder that manifests predominantly as a progressive myopathy with a broad spectrum of severity and age of onset. The rate of progression is variable, and the prognosis is poor due to early and severe respiratory involvement. Early and accurate diagnosis is particularly important since a specific treatment is under development. This study aims to evaluate the diagnostic value of lower limb muscle MRI in adult patients with TK2d. METHODS: We studied a cohort of 45 genetically confirmed patients with mitochondrial myopathy (16 with mutations in TK2, 9 with mutations in other nuclear genes involved in mitochondrial DNA [mtDNA] synthesis or maintenance, 10 with single mtDNA deletions, and 10 with point mtDNA mutations) to analyze the imaging pattern of fat replacement in lower limb muscles. We compared the identified pattern in patients with TK2d with the MRI pattern of other non-mitochondrial genetic myopathies that share similar clinical characteristics. RESULTS: We found a consistent lower limb muscle MRI pattern in patients with TK2d characterized by involvement of the gluteus maximus, gastrocnemius medialis, and sartorius muscles. The identified pattern in TK2 patients differs from the known radiological involvement of other resembling muscle dystrophies that share clinical features. CONCLUSIONS: By analyzing the largest cohort of muscle MRI from patients with mitochondrial myopathies studied to date, we identified a characteristic and specific radiological pattern of muscle involvement in patients with TK2d that could be useful to speed up its diagnosis.