Cellular and Enzymatic Determinants Impacting the Exolytic Action of an Anti-Staphylococcal Enzybiotic.

Bacteriophage endolysins are bacteriolytic enzymes that have been explored as potential weapons to fight antibiotic-resistant bacteria. Despite several studies support the application of endolysins as enzybiotics, detailed knowledge on cellular and enzymatic factors affecting their lytic activity is still missing. The bacterial membrane proton motive force (PMF) and certain cell wall glycopolymers of Gram-positive bacteria have been implicated in some tolerance to endolysins. Here, we studied how the anti-staphylococcal endolysin Lys11, a modular enzyme with two catalytic domains (peptidase and amidase) and a cell binding domain (CBD11), responded to changes in the chemical and/or electric gradients of the PMF (ΔpH and Δψ, respectively). We show that simultaneous dissipation of both gradients enhances endolysin binding to cells and lytic activity. The collapse of ΔpH is preponderant in the stimulation of Lys11 lytic action, while the dissipation of Δψ is mainly associated with higher endolysin binding. Interestingly, this binding depends on the amidase domain. The peptidase domain is responsible for most of the Lys11 bacteriolytic activity. Wall teichoic acids (WTAs) are confirmed as major determinants of endolysin tolerance, in part by severely hindering CBD11 binding activity. In conclusion, the PMF and WTA interfere differently with the endolysin functional domains, affecting both the binding and catalytic efficiencies.

A role for Mitochondrial Rho GTPase 1 (MIRO1) in motility and membrane dynamics of peroxisomes.

Peroxisomes are dynamic organelles which fulfil essential roles in lipid and ROS metabolism. Peroxisome movement and positioning allows interaction with other organelles and is crucial for their cellular function. In mammalian cells, such movement is microtubule-dependent and mediated by kinesin and dynein motors. The mechanisms of motor recruitment to peroxisomes are largely unknown, as well as the role this plays in peroxisome membrane dynamics and proliferation. Here, using a combination of microscopy, live-cell imaging analysis and mathematical modelling, we identify a role for Mitochondrial Rho GTPase 1 (MIRO1) as an adaptor for microtubule-dependent peroxisome motility in mammalian cells. We show that MIRO1 is targeted to peroxisomes and alters their distribution and motility. Using a peroxisome-targeted MIRO1 fusion protein, we demonstrate that MIRO1-mediated pulling forces contribute to peroxisome membrane elongation and proliferation in cellular models of peroxisome disease. Our findings reveal a molecular mechanism for establishing peroxisome-motor protein associations in mammalian cells and provide new insights into peroxisome membrane dynamics in health and disease.

The Use of Video-Head Impulse Test in Different Head Positions in Vertical Nystagmus and Ataxia Associated with Probable Thiamine Deficiency.

Upward and downward bias of eye movement signals in the semicircular canals (SCC)- and/or otolith-related central pathways have been proposed to explain the occurrence of vertical nystagmus (downbeat nystagmus [DBN] and upbeat nystagmus [UBN]) and its frequent modulation with head position. Video-head impulse test (VHIT), usually performed in upright position, is a recent development for measuring SCC function. We performed longitudinal nystagmus and VHIT assessments in different head positions in a patient with probable thiamine deficiency, in order to explore a possible relationship between the positional behavior of vertical nystagmus and SCC function. Initially, UBN in upright position changed to DBN in prone position and remained relatively unchanged in supine position. This was associated with both anterior and posterior SCC hyperactive responses in upright position, and a relative enhancement of the anterior SCC responses in prone position and the posterior SCC responses in supine position. Over 1 year, in prone position, change from UBN to DBN and the enhancement of anterior SCC responses remained, while in supine position, UBN either decreased or changed to DBN, when compared to upright position. This was associated with a relative enhancement of the anterior SCC responses in supine position, albeit inconsistently, and the presence of posterior SCC hypoactive responses in all positions, including prone. While not contradicting a primary otolithic dysfunction in the genesis of UBN change to DBN with head position, we provide evidence for positional modulation of SCC function in thiamine deficiency and a possible relationship with nystagmus positional behavior.

Telomere shortening and aortic plaque progression in Apoliprotein E knockout mice after pulmonary exposure to candle light combustion particles.

Particles from burning candles contribute to the overall indoor exposure to particulate matter (PM). However, little is known about the effects of indoor sources of particles on cardiovascular disease endpoints. This study investigated the effect of pulmonary exposure to particles from combustion of candles and progression of atherosclerosis. Telomere shortening was assessed in tissues due to its relationship to risk of cardiovascular diseases. The particles were collected from burning candles and used for toxicological studies in cultured endothelial cells and apolipoprotein E (ApoE) knockout mice. Three hours exposure to particles increased the production of reactive oxygen species in endothelial cells, whereas there was no effect on cytotoxicity. Intratracheal instillation of particles (0.5 or 5 mg/kg) once a week for 5 weeks in ApoE-/- mice was associated with an accelerated progression of atherosclerosis in aorta and telomere shortening in the lung and spleen, whereas there was no effect on inflammation in the lungs (i.e. cell numbers), cell damage (i.e. lactate dehydrogenase) and lung barrier damage (i.e. protein concentration) as measured in bronchoalveolar lavage fluid. The results indicate that particles from burning candles are hazardous and this indoor emission source is an important contribution to the health risk of exposure to PM.

Ferulic acid supresses Th2 immune response and prevents remodeling in ovalbumin-induced pulmonary allergy associated with inhibition of epithelial-derived cytokines.

Asthma is characterized by intermittent airway obstruction and chronic inflammation, orchestrated primarily by Th2 cytokines. There is a strong rationale for developing new asthma therapies, since current treatment protocols present side effects and may not be effective in cases of difficult-to-control asthma. The purpose of this study was to evaluate the effect of ferulic acid, a phenolic acid commonly present in plants, in the ovalbumin-induced pulmonary allergy murine model. METHODS: BALB/c mice were sensitized and challenged with ovalbumin, and treatments were provided by gavage. Six groups of mice (n = 6) were studied, labeled as: control, pulmonary allergy, dexamethasone, and 3 receiving ferulic acid (at 25, 50, and 100 mg/kg). Lung tissue, bronchoalveolar lavage fluid and serum were collected for analysis. RESULTS: Ferulic acid treatment inhibited an established allergic Th2-response by decreasing the key features of pulmonary allergy, including lung and airway inflammation, eosinophil infiltration, mucus production and serum levels of OVA-specific IgE. These results were associated with lower levels of CCL20, CCL11 and CCL5 chemokines and IL-4, IL-5, IL-13, TSLP, IL-25 and IL-33 cytokines in lung tissue homogenate. CONCLUSIONS: In this study it was demonstrated for the first time that ferulic acid treatment is able to suppress one of the main features of the airway remodeling, indicated by reduction of mucus production, besides the Th2 pathogenic response on ovalbumin-induced pulmonary allergy. Taken together, results shows that the immunopathological mechanism underlying these effects is linked to a reduction of the epithelial-derived chemokines and cytokines, suggesting that ferulic acid may be useful as a potential therapeutic agent for asthma.

Cerebrovascular Dissemination in Time and Space as a Predictor of Cardioembolism.

BACKGROUND: Cardioembolism has tendency to recur and cause lesions in distinct cerebrovascular territories. Using the imaging characteristics of cerebral lesions to determine dissemination in time and space (DTS) is a concept already used in other neurologic conditions; however, it has never been applied as a diagnostic tool in ischemic stroke etiology. AIM: This study aimed to assess DTS as a diagnostic marker of cardioembolism. METHODS: We enrolled consecutive patients with acute ischemic stroke of various etiologies admitted in a cerebrovascular disease nursery from a university hospital in a retrospective cohort study. We excluded patients with coexisting etiologies, incomplete study, or without an acute vascular lesion on computed tomography scan. Lacunar infarctions were not considered. Cerebrovascular territory was divided into right anterior, left anterior, and posterior. Localization of the acute vascular lesion(s), existence of previous vascular lesions, and their respective areas were analyzed. The presence of dissemination in time, space, or DTS was determined. RESULTS: We included 661 patients (mean age: 74.05 years (SD: 13.01)). Cardioembolism was the etiology with most DTS (30.47% of cardioembolic strokes); DT occurred more frequently within the atherosclerotic subtype (9.88%); DS was more prevalent within the arterial dissection group (3.33%). There was a statistically significant difference in stroke etiology between patients with DTS and patients without dissemination (P < .001). DTS had 81.67% specificity, 30.47% sensitivity, 66.67% positive predictive value, and 49.40% negative predictive value for the identification of cardioembolism. CONCLUSION: DTS is a specific diagnostic predictor of cardioembolic stroke and may be helpful in guiding etiologic investigation.

Hepatitis C virus NS3-4A inhibits the peroxisomal MAVS-dependent antiviral signalling response.

Hepatitis C virus (HCV) is the cause of one of the most prevalent viral infections worldwide. Upon infection, the HCV genome activates the RIG-I-MAVS signalling pathway leading to the production of direct antiviral effectors which prevent important steps in viral propagation. MAVS localizes at peroxisomes and mitochondria and coordinate the activation of an effective antiviral response: peroxisomal MAVS is responsible for a rapid but short-termed antiviral response, while the mitochondrial MAVS is associated with the activation of a stable response with delayed kinetics. The HCV NS3-4A protease was shown to specifically cleave the mitochondrial MAVS, inhibiting the downstream response. In this study, we have analysed whether HCV NS3-4A is also able to cleave the peroxisomal MAVS and whether this would have any effect on the cellular antiviral response. We show that NS3-4A is indeed able to specifically cleave this protein and release it into the cytosol, a mechanism that seems to occur at a similar kinetic rate as the cleavage of the mitochondrial MAVS. Under these conditions, RIG-I-like receptor (RLR) signalling from peroxisomes is blocked and antiviral gene expression is inhibited. Our results also show that NS3-4A is able to localize at peroxisomes in the absence of MAVS. However, mutation studies have shown that this localization pattern is preferred in the presence of a fully cleavable MAVS. These findings present evidence of a viral evasion strategy that disrupts RLR signalling on peroxisomes and provide an excellent example of how a single viral evasion strategy can block innate immune signalling from different organelles.

Atherosclerosis and vasomotor dysfunction in arteries of animals after exposure to combustion-derived particulate matter or nanomaterials.

Exposure to particulate matter (PM) from traffic vehicles is hazardous to the vascular system, leading to clinical manifestations and mortality due to ischemic heart disease. By analogy, nanomaterials may also be associated with the same outcomes. Here, the effects of exposure to PM from ambient air, diesel exhaust and certain nanomaterials on atherosclerosis and vasomotor function in animals have been assessed. The majority of studies have used pulmonary exposure by inhalation or instillation, although there are some studies on non-pulmonary routes such as the gastrointestinal tract. Airway exposure to air pollution particles and nanomaterials is associated with similar effects on atherosclerosis progression, augmented vasoconstriction and blunted vasorelaxation responses in arteries, whereas exposure to diesel exhaust is associated with lower responses. At present, there is no convincing evidence of dose-dependent effects across studies. Oxidative stress and inflammation have been observed in the arterial wall of PM-exposed animals with vasomotor dysfunction or plaque progression. From the data, it is evident that pulmonary and systemic inflammation does not seem to be necessary for these vascular effects to occur. Furthermore, there is inconsistent evidence with regard to altered plasma lipid profile and systemic inflammation as a key step in vasomotor dysfunction and progression of atherosclerosis in PM-exposed animals. In summary, the results show that certain nanomaterials, including TiO2, carbon black and carbon nanotubes, have similar hazards to the vascular system as combustion-derived PM.

Bullous hemorrhagic dermatosis induced by enoxaparin.

The bullous hemorrhagic dermatosis induced by enoxaparin is a rare adverse reaction, which may be under-reported given its favorable evolution. We report a 71-year-old man who developed hemorrhagic bullae at sites distant from subcutaneous enoxaparin injections. It is important that clinicians be aware of the different adverse reactions of these widely used drugs.

Sporadic Carney complex without PRKAR1A mutation in a young patient with ischemic stroke.

We describe a 29-year-old male, with a previous history of testicular tumor, who presented with a posterior circulation ischemic stroke associated to an atrial myxoma. Dermatologic observation disclosed spotty skin and mucosal pigmentation (lentigines), and a cutaneous myxoma was histopathologically confirmed. Although there was no family history of any of the Carney complex (CNC) features and no mutations in the PRKAR1A gene were found, these findings lead to the diagnosis of CNC. We emphasize the importance of recognizing this entity in young patients with stroke.

Different locations but common associations in subcortical hypodensities of presumed vascular origin: cross-sectional study on clinical and neurosonologic correlates.

BACKGROUND: Subcortical hypodensities of presumed vascular etiology (SHPVO) are a clinical, radiological and neuropathological syndrome with a still largely unexplained pathophysiology. Parallel to the clinical heterogeneity, there is also recognised cerebral topographical diversity with undetermined etiological implications. Our aim is to assess clinical and neurosonological predictors of SHPVO according to their location. METHODS: Cross sectional analysis of consecutive patients that underwent neurosonologic evaluation and head CT within one month, during a one year period. We excluded patients with absent temporal sonographic window, any pathology with a possible confounding effect on cerebral arterial pulsatility, atrial fibrillation and other etiologies of white matter diseases. The mean pulsatility index (PI) of both middle cerebral arteries was measured in the middle third of the M1 segment; intima media thickness was evaluated in the far wall of both common carotid arteries. SHPVO were rated by analysis of head CT in deep white matter (DWMH), periventricular white matter (PVWMH) and basal ganglia (BGH). We conducted a multivariate ordinal logistic regression model including all clinical, demographic and ultrasonographic characteristics to determine independent associations with SHPVO. RESULTS: We included 439 patients, mean age 63.47 (SD: 14.94) years, 294 (67.0%) male. The independent predictors of SHPVO were age (OR = 1.067, 95% CI: 1.047-1.088, p < 0.001 for DWMH; OR = 1.068, 95% CI: 1.049-1.088, p < 0.001 for PVWMH; OR = 1.05, 95% CI: 1.03-1.071, p < 0.001 for BGH), hypertension (OR = 1.909, 95% CI: 1.222-2.981, p = 0.004 for DWMH; OR = 1.907, 95% CI: 1.238-2.938, p = 0.003 for PVWMH; OR = 1.775, 95% CI: 1.109-2.843, p = 0.017 for BGH) and PI (OR = 17.994, 95% CI: 6.875-47.1, p < 0.001 for DWMH; OR = 5.739, 95%CI: 2.288-14.397, p < 0.001 for PVWMH; OR = 11.844, 95% CI: 4.486-31.268, p < 0.001 for BGH) for all locations of SHPVO. CONCLUSIONS: Age, hypertension and intracranial pulsatility are the main independent predictors of SHPVO across different topographic involvement and irrespective of extracranial atherosclerotic involvement.

Recurrence in intracranial atherosclerotic disease: a stenosis-based analysis.

BACKGROUND: Intracranial atherosclerotic disease is a common cause of stroke; its incidence and prevalence vary widely by ethnicity. The aim of our study was to analyze the recurrence rate of cerebrovascular events in patients with symptomatic and asymptomatic intracranial stenosis (IS). METHODS: We conducted a historical cohort study including all patients admitted in our hospital for stroke or transient ischemic attack (TIA) during 2011 and 2012 with information on intracranial circulation (ultrasonography and/or computed tomography angiography). We identified patients with symptomatic and asymptomatic IS and studied the recurrence of cerebrovascular events (TIA or ischemic stroke within the territory of the stenosis) for a minimum follow-up period of 6 months after the diagnosis of IS. For the recurrence rate estimation, patients with other potentially embolic diseases (in cervical arteries or heart) were excluded. We calculated the rate of recurrence of cerebrovascular events and performed Kaplan-Meier survival curves for symptomatic and asymptomatic IS. RESULTS: We investigated 1302 patients, mean age was 72.41 years (standard deviation 12.75). We identified 218 IS in 158 patients, 77 were symptomatic and 141 were asymptomatic. The recurrence rate of cerebrovascular events was 12.32 per 100 patient-years, with a mean time to recurrence of 1.73 months for symptomatic intracranial stenosis (SIS) and .88 per 100 patient-years for asymptomatic IS (P < .001). CONCLUSIONS: These results indicate a high risk of early recurrence of stroke in the territory of a SIS, highlighting the importance of its early diagnosis and aggressive treatment.

Dating violence and nursing student well-being.

BACKGROUND: Violence in dating relationships involves dimensions such as physical, psychological and sexual abuse, requiring strategies for prevention and early intervention. OBJECTIVE: To identify the socio-demographic variables that influence violence in dating relationships; to identify whether having been a victim and/or witnessing violence in childhood has significant effect on violence in dating relationships; to verify the correlation between violence in dating relationships and psychological well-being. MATERIAL AND METHOD: Quantitative non-experimental, cross-sectional, descriptive correlational study. Data collection conducted by a socio-demographic characterisation questionnaire; Dating Relationship Victimization Practices and Behaviours Scale and Demonstration of Psychological Well-Being Measurement Scale. The non-probabilistic, convenience sample consisted of 203 students from the Health School of Viseu. RESULTS: Mostly female students gender; Mean age of 18.85 years, minimum of 18 and maximum of 34; Gender and having been a victim or witness of violence against children and sexual violence are variables that seem to intervene in dating violence and psychological well-being. Age has an influence on psychological well-being. Stalking violence and psychological violence were more prevalent in the study sample. It was found that the presence of any type of violence is associated with a decrease in student psychological well-being. CONCLUSION: By analysing the results we can infer the need to include this topic in education/training, active methodologies and effective participation of all stakeholders in the process, with a view to promoting and developing relationship and affective skills.

Differential Dominance of Ecological Processes Shapes the Longhorn Beetle Community in Tropical Rainforests and Temperate Forests of Southwest China.

(1) Background: Understanding the relationship between community assembly and species coexistence is key to understanding ecosystem diversity. Despite the importance of wood-boring longhorn beetles (Cerambycidae) in forests, factors affecting their population dynamics, species richness, and ecological interactions remain underexplored. (2) Methods: We surveyed cerambycid beetles and plants within five plots each across three transects in tropical rainforests and temperate forests of Yunnan, China, known for its rich biodiversity and varied elevation gradients. We explored a range of analytical tools, including α-diversity comparisons, distance-decay relationships, redundancy analysis, ß-dissimilarity metrics, and various neutral community model analyses. (3) Results: The results revealed a stark contrast between the two forest types: the tropical rainforests hosted 212 Cerambycidae and 135 tree species, whereas the temperate forests had only 16 Cerambycidae and 18 tree species. This disparity was attributed to differences in environmental heterogeneity and dispersal limitations. In temperate forests, pronounced environmental variability leads to steeper distance-decay relationships and reduced α-diversity of Cerambycidae, implying stronger dispersal constraints and weaker plant-beetle associations. Conversely, the more homogenous tropical rainforests exhibited stochastic processes that enhanced Cerambycidae diversity and plant-beetle interactions. (4) Conclusions: Our findings underscore that environmental heterogeneity, dispersal limitations, and host-specificity are pivotal in shaping biodiversity patterns in Cerambycidae, with significant variations across climatic zones.

Rubber plantations are impermeable to an avian understory specialist in Sri Lanka.

BACKGROUND: Understanding how landscape characteristics affect animal movement is essential for conservation in human-dominated habitats. A fundamental question is how monoculture agroforests, including rubber and tea plantations, affect wildlife and its movement. Experimental translocations represent an important technique to assess animals' habitat selection while moving through agricultural matrices, especially when complemented with observations of birds' natural movements, and with "control" translocations, in which birds are moved within their natural habitat such as forest. Yet, experimental translocations have been little used for birds outside the Western Hemisphere. METHODS: We conducted experimental translocations and home-range measurements on an understory forest specialist, Brown-capped Babbler (BCBA, Pellorneum fuscocapillus), and a forest generalist, Tickell's Blue Flycatcher (TBFL, Cyornis tickelliae). These species were studied in three rubber plantations, which also included some open areas mostly planted with tea, and in three forest reserves of Sri Lanka. RESULTS: Four of the five BCBAs translocated within disturbed habitats (rubber plantations) could not return to their capture locations. However, all four individuals within undisturbed habitats (forest reserves) successfully returned to their point of origin within 10.5 daytime hours. In contrast, all TBFLs returned to their capture locations in both disturbed (n = 7) and undisturbed habitats (n = 3) within 11.3 daytime hours. A Cox-proportional survival model demonstrated that the percentage of rubber cover decreased return time, similar to the effect of open-area cover. The home range surveys (n = 13 for BCBA, n = 10 for TBFL) revealed that very little of the birds' natural home-ranges was covered by rubber (0.2% for BCBA, 13.1% for TBFL at 50% Kernel Density Estimates KDE). Home range size for BCBA was approximately half the size in disturbed habitats compared to undisturbed ones, although there was no significant difference between habitats for TBFL. CONCLUSIONS: We conclude that rubber plantations can be impermeable to understory habitat specialist birds, and even generalist species may avoid them long-term. Our findings highlight the potential utility of strips of native vegetation, particularly those featuring understory layers, as corridors to facilitate the movement of forest specialists in landscapes dominated by rubber plantations and other types of disturbed habitats.

Th2 responses in OVA-sensitized BALB/c mice are down-modulated by Mycobacterium bovis BCG treatment.

OBJECTIVE: This study aimed to determine whether Mycobacterium bovis Bacillus Calmette-Guérin (BCG) treatment can reverse an established allergic airway inflammation in a BALB/c mouse model of ovalbumin (OVA)-induced airway inflammation. METHODS: OVA sensitized BALB/c mice were challenged with aerosolized OVA on days 28 to 30, 34, 41 and 63. Mice were intranasal treated with BCG on days 35 and 42. Twenty-four hours after the last challenge, blood samples were collected to detect anti-OVA immunoglobulin isotypes, and bronchoalveolar lavage (BAL) was harvested for cell count. Additionally, lungs were collected for histological analysis, detection of the eosinophil peroxidase (EPO) activity and measurement of cytokines and CCL11. The expression of CTLA-4, Foxp3 and IL-10 was also determined in lung tissue by flow cytometry. RESULTS: BCG treatment was able to inhibit an established allergic Th2-response, by decreasing the allergen-induced eosinophilic inflammation, EPO activity, levels of CCL11 and IL-4, serum levels of IgE and IgG1. Mycobacteria treatment increased lung levels of IFN-γ, IL-10 and TGF-ß, and expressions of Foxp3 and CTLA-4 in CD4(+)T cells. Additionally, an increased production of IL-10 by CD8(+) T cells was observed, even though no detectable changes in CD4(+)IL-10(+) was noticed. CONCLUSION: BCG treatment inhibits features of allergic airway inflammation and the results suggest that the mechanism underlying the down-regulatory effects of BCG on OVA-induced airway inflammation appear to be associated with the induction of both Th1 and T regulatory immune responses.

Carbon Conductive Paste Smart Textile Strain Sensor for Sports and Rehabilitation.

Due to the growth observed in the wearable market, stretchable strain sensors have been the focus of several studies. However, combining high sensitivity and linearity with low hysteresis presents a difficult challenge.Here, we propose a stretchable strain sensor obtained with off-the-shelf materials by printing a carbon conductive paste into a piece of fabric to be integrated into a smart garment. This process is cheap and easily scalable, allowing its mass production. The sensor developed has a large sensitivity (GF=11.27), high linearity (R2>0.99), very low hysteresis (γH =4.23%) and brings an added value, for example, in sports or rehabilitation monitoring.

Adult-onset leukodystrophy with vanishing white matter: a case series of 19 patients.

BACKGROUND: Leukodystrophy with vanishing white matter (LVWM) is an autosomal recessive disease with typical pediatric-onset caused by mutations in one of the five EIF2B genes. Adult-onset (AO) cases are rare. METHODS: In this observational study, we reviewed clinical and laboratory information of the patients with AO-LVWM assessed at two referral centers in Italy and Portugal from Jan-2007 to Dec-2019. RESULTS: We identified 18 patients (13 females) with AO-LVWM caused by EIF2B5 or EIF2B3 mutations. Age of neurological onset ranged from 16 to 60 years, with follow-ups occurring from 2 to 37 years. Crucial symptoms were cognitive and motor decline. In three patients, stroke-like events were the first manifestation; in another, bladder dysfunction remained the main complaint across decades. Brain MRI showed white matter (WM) rarefaction in all cases, except two. Diffusion-weighted imaging documented focal hyperintensity in the acute stage of stroke-like events. 1H-spectroscopy primarily showed N-acetyl-aspartate reduction; 18fluorodeoxyglucose-PET revealed predominant frontoparietal hypometabolism; evoked potential studies demonstrated normal-to-reduced amplitudes; neuro-ophthalmological assessment showed neuroretinal thinning, and b-wave reduction on full-field electroretinogram. Interestingly, we found an additional patient with LVWM-compatible phenotype and monoallelic variants in two distinct eIF2B genes, EIF2B1 and EIF2B2. CONCLUSIONS: AO-LVWM presents varying clinical manifestations at onset, including stroke-like events. WM rarefaction is the most consistent diagnostic clue even in the latest onset cases. Spectroscopy and electrophysiological features are compatible with axon, rather than myelin, damage. Cerebral glucose metabolic abnormalities and retinal alterations can be present. LVWM might also be caused by a digenic inheritance affecting the eIF2B complex.