Pseudo-eye-of-the-tiger sign in cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS).

The well-known eye-of-the-tiger sign features bilateral and symmetrical changes in the globus pallidus, with a central area of high signal and peripheral low signal on T2-weighted MRI. Although formally considered pathognomonic of pantothenate kinase-associated neurodegeneration (PKAN), there are other neurodegenerative or genetic diseases showing similar findings. Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late-onset ataxia, that was recently associated with biallelic AAGGG repeat expansion in the RFC1 gene. Although its predominant MRI finding is cerebellar atrophy, there may be other less common associated findings. Our aim is to present two cases of CANVAS with associated (pseudo-)eye-of-the-tiger sign, highlighting the possibility of yet another differential diagnosis for this imaging sign.

Correlation between neuroimaging, neurological phenotype, and functional outcomes in Wilson's disease.

INTRODUCTION: Wilson's disease (WD) is associated with a variety of movement disorders and progressive neurological dysfunction. The aim of this study was to correlate baseline brain magnetic resonance imaging (MRI) features with clinical phenotype and long-term outcomes in chronically treated WD patients. METHODS: Patients were retrospectively selected from an institutional database. Two experienced neuroradiologists reviewed baseline brain MRI. Functional assessment was performed using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) scale, and disease severity was classified using the Global Assessment Scale for Wilson's Disease (GASWD). RESULTS: Of 27 patients selected, 14 were female (51.9%), with a mean (standard deviation [SD]) age at onset of 19.5 (7.1) years. Neurological symptoms developed in 22 patients (81.5%), with hyperkinetic symptoms being the most common (70.4%). Baseline brain MRI showed abnormal findings in 18 cases (66.7%), including T2 hyperintensities in 59.3% and atrophy in 29.6%. After a mean (SD) follow-up of 20.9 (11.0) years, WD patients had a mean score of 19.2 (10.2) on WHODAS 2.0 and 6.4 (5.7) on GASWD. The presence of hyperkinetic symptoms correlated with putaminal T2 hyperintensities (p = 0.003), putaminal T2 hypointensities (p = 0.009), and mesencephalic T2 hyperintensities (p = 0.009). Increased functional disability was associated with brain atrophy (p = 0.007), diffusion abnormalities (p = 0.013), and burden of T2 hyperintensities (p = 0.002). A stepwise regression model identified atrophy as a predictor of increased WHODAS 2.0 (p = 0.023) and GASWD (p = 0.007) scores. CONCLUSIONS: Atrophy and, to a lesser extent, deep T2 hyperintensity are associated with functional disability and disease severity in long-term follow-up of WD patients.

Brain imaging findings in Liberfarb syndrome: hypomyelination and optic nerve and cerebellar atrophy.

Liberfarb syndrome is an extremely rare mitochondrial multisystem disorder, recently described and characterized by early-onset retinal degeneration and sensorineural hearing loss, spondyloepimetaphyseal dysplasia, joint laxity, short stature, microcephaly, developmental delay and intellectual disability, but clinical variability has been observed. We report a case that presented to the hospital with a flare-up of the disease. We describe the brain magnetic resonance imaging findings, which are still not well characterized, to raise awareness of this diagnosis.

Olfactory Cleft Length: A Possible Risk Factor for Persistent Post-COVID-19 Olfactory Dysfunction.

INTRODUCTION: To date, little is known about predisposing factors for persistent COVID-19-induced olfactory dysfunction (pCIOD). The objective was to determine whether olfactory cleft (OC) measurements associate with pCIOD risk. MATERIAL AND METHODS: Three subgroups were recruited: group A included patients with pCIOD, group B included patients without olfactory dysfunction following SARS-CoV-2 infection (ntCIOD), and group C consisted in controls without past history of SARS-CoV-2 infection (noCOVID-19). Olfactory perception threshold (OPT) and visual analog scale for olfactory impairment (VAS-olf) were obtained. OC measurements were obtained through computed tomography scans. Results were subsequently compared. RESULTS: A total of 55 patients with a mean age of 39 ± 10 years were included. OPT was significantly lower in pCIOD patients (group A: 4.2 ± 2.1 vs. group B: 12.3 ± 1.8 and group C: 12.2 ± 1.5, p < 0.001). VAS-olf was significantly higher in pCIOD (group A: 6 ± 2.6 vs. group B: 1.7 ± 1.6 and group C: 1.6 ± 1.5, p < 0.001). OC length was significantly higher in group A (42.8 ± 4.6) compared to group B (39.7 ± 3.4, p = 0.047) and C (39.8 ± 4, p = 0.037). The odd of pCIOD occurring after COVID-19 infection increased by 21% (95% CI [0.981, 1.495]) for a one unit (mm) increase in OC length. The odd of pCIOD occurring was 6.9 times higher when OC length >40 mm. CONCLUSION: Longer OC may be a predisposing factor for pCIOD. This study is expected to encourage further research on OC morphology and its impact on olfactory disorders.

Cancer 3D Models for Metallodrug Preclinical Testing.

Despite being standard tools in research, the application of cellular and animal models in drug development is hindered by several limitations, such as limited translational significance, animal ethics, and inter-species physiological differences. In this regard, 3D cellular models can be presented as a step forward in biomedical research, allowing for mimicking tissue complexity more accurately than traditional 2D models, while also contributing to reducing the use of animal models. In cancer research, 3D models have the potential to replicate the tumor microenvironment, which is a key modulator of cancer cell behavior and drug response. These features make cancer 3D models prime tools for the preclinical study of anti-tumoral drugs, especially considering that there is still a need to develop effective anti-cancer drugs with high selectivity, minimal toxicity, and reduced side effects. Metallodrugs, especially transition-metal-based complexes, have been extensively studied for their therapeutic potential in cancer therapy due to their distinctive properties; however, despite the benefits of 3D models, their application in metallodrug testing is currently limited. Thus, this article reviews some of the most common types of 3D models in cancer research, as well as the application of 3D models in metallodrug preclinical studies.

Risk factors for lumbosacral radiculoplexus neuropathy.

INTRODUCTION/AIMS: Recently, our group found an association between diabetes mellitus (DM) and lumbosacral radiculoplexus neuropathy (LRPN) in Olmsted County, Minnesota; we found a higher risk (odds ratio [OR], 7.91) for developing LRPN in diabetic compared with nondiabetic patients. However, the influence of other comorbidities and anthropomorphic variables was not studied. METHODS: Demographic and clinical data from 59 LRPN patients and 177 age/sex-matched controls were extracted using the Rochester LRPN epidemiological study. Differences between groups were compared by chi-square/Fisher exact test or Wilcoxon rank-sum test. Uni- and multivariate logistic regression analysis were performed. RESULTS: Factors predictive of LRPN on univariate analysis were DM (OR, 7.91; 95% confidence interval [CI], 4.11-15.21), dementia (OR, 6.36; 95% CI, 1.13-35.67), stroke (OR, 3.81; 95% CI, 1.32-11.01), dyslipidemia (OR, 2.844; 95% CI, 1.53-5.27), comorbid autoimmune disorders (OR, 2.72; 95% CI, 1.07-6.93), hypertension (OR, 2.25; 95% CI, 1.2-4.13), obesity (OR, 2.05; 95% CI, 1.11-3.8), body mass index (BMI) (OR, 1.1; 95% CI, 1.04-1.15), and weight (OR, 1.02; 95% CI, 1.009-1.037). On multivariate logistic regression analysis only DM (OR, 8.03; 95% CI, 3.86-16.7), comorbid autoimmune disorders (OR, 4.58; 95% CI, 1.45-14.7), stroke (OR, 4.13; 95% CI, 1.2-14.25), and BMI (OR, 1.07; 95% CI, 1.01-1.13) were risk factors for LRPN. DISCUSSION: DM is the strongest risk factor for the development of LRPN, followed by comorbid autoimmune disorders, stroke, and higher BMI. Altered metabolism and immune dysfunction seem to be the most influential factors in the development of LRPN.

Excited state deactivation mechanisms in Shikonin rationalized from its naphthoquinone parent structures.

Shikonin, a naphthoquinone dye, is a molecule of colour of natural origin, whose peculiar properties have not yet been fully rationalized. Its core structure consists of a di-hydroxy-naphthoquinone with an additional non-aromatic hydroxy group. From a comprehensive study involving fast spectroscopic techniques (fs-TA and fs-UC) and TDDFT electronic structure calculations on shikonin (Shk) and its derivatives 5-hydroxy-1,4-naphthoquinone (5HNQ), 5,8-diacetoxy-1,4-naphthoquinone (DiAc), 5,8-dihidroxy-1,4-naphthoquinone (DHNQ) and acetylshikonin, AcShk, it is shown that intramolecular excited state proton transfer (ESIPT) is present and is determinant in the deactivation of the hydroxy containing molecules. This is mirrored by the dominance of the internal conversion deactivation channel. In Shk, the non-aromatic hydroxy group determines the preferred conformer in both the ground- and excited-state, as reflected in the doubling of the fluorescence quantum yield value of this molecule relative to DHNQ. From fs-UC, a kinetic isotopic effect of 1.7 was obtained for DHNQ.

Smoldering lesions in MS: if you like it then you should put a rim on it.

PURPOSE: In multiple sclerosis (MS), chronic active/smoldering white matter lesions presenting with hypointense rims on susceptibility-weighted imaging (SWI) of the brain have been recognized as an important radiological feature. The aim of this work was to study the prevalence of paramagnetic rim lesions (RLs) in MS patients in a clinical setting and to assess differences in demographic and clinical variables regarding the presence of RLs. METHODS: All 3 T brain magnetic resonance (MR) studies performed in MS patients between July 2020 and January 2021 were reviewed. In all patients, RLs were assessed on three-dimensional (3D) SWI images and the T2 FLAIR lesion load volume was assessed. Demographic, laboratory (oligoclonal bands in CSF), and clinical data, including functional status with Expanded Disability Status Scale (EDSS), were retrieved from the clinical files. RESULTS: Of the 192 patients, 113 (59%) presented with at least 1 RL. In the RL-positive group, the mean RL count was 4.81 ranging from 1 to 37. There was no significant difference in the number of RLs between the different types of MS (p = 0.858). Regarding the presence of RLs, there were no significant differences based on gender (p = 0.083), disease duration (p = 0.520), treatment regime (p = 0.326), EDSS score (p = 0.103), and the associated T2 FLAIR lesion load volume. CONCLUSION: SWI RLs were frequently detected in our cohort regardless of the MS type, T2 FLAIR lesion load volume, demographic features, disease duration, or clinical score. Our results suggest that RLs are not associated with more severe forms of the disease. Today, RLs can be seen on 3 T 3D SWI, although this is not a clinical standard sequence yet. Therefore, it should be considered an additional helpful MR sequence in the diagnostic workup of MS, although more studies are warranted to establish the role of RLs as prognostic markers.

ICU and Hospital Outcomes in Patients with Hepatopulmonary Syndrome Undergoing Liver Transplantation.

PURPOSE: There are limited data regarding hospital and intensive care unit (ICU) outcomes in patients with hepatopulmonary syndrome (HPS) following liver transplantation (LT). METHODS: Data were retrospectively collected from consecutive HPS adult patients who underwent LT and were immediately admitted to the ICU at three transplant centers with shared management protocols, from 2002 to 2018. Demographic, clinical, surgical, laboratory, and outcome data were extracted. RESULTS: We identified 137 patients (74 male, 54%), with a median age at LT of 58 years (IQR: 52-63). One hundred and 31 (95.6%) patients were admitted to the ICU on invasive mechanical ventilation (MV). The median time on invasive MV in the ICU was 12 hours (IQR: 5-28) and 97 patients (74%) were extubated within 24 hours of ICU admission. The median highest positive end expiratory pressure and fraction of inspired oxygen (FiO2) were 7 (IQR: 5-8) and 0.6 (IQR: 0.5-0.7), respectively. 7 patients (5%) developed severe post-transplant hypoxemia. Of all patients, 42 (30.4%) required vasopressors and the median ICU and hospital length of stay (LOS) were 3 (IQR: 1-5) and 10 (IQR: 7-20) days, respectively. The in-hospital mortality rate was 3.6% (5/137). HPS severity was not associated with hospital mortality. CONCLUSION: Most HPS patients have short durations of MV, ICU, and hospital LOS post-LT. HPS severity does not impact hospital mortality.

Searching for a Paradigm Shift in Auger-Electron Cancer Therapy with Tumor-Specific Radiopeptides Targeting the Mitochondria and/or the Cell Nucleus.

Although 99mTc is not an ideal Auger electron (AE) emitter for Targeted Radionuclide Therapy (TRT) due to its relatively low Auger electron yield, it can be considered a readily available "model" radionuclide useful to validate the design of new classes of AE-emitting radioconjugates. With this in mind, we performed a detailed study of the radiobiological effects and mechanisms of cell death induced by the dual-targeted radioconjugates 99mTc-TPP-BBN and 99mTc-AO-BBN (TPP = triphenylphosphonium; AO = acridine orange; BBN = bombesin derivative) in human prostate cancer PC3 cells. 99mTc-TPP-BBN and 99mTc-AO-BBN caused a remarkably high reduction of the survival of PC3 cells when compared with the single-targeted congener 99mTc-BBN, leading to an augmented formation of γH2AX foci and micronuclei. 99mTc-TPP-BBN also caused a reduction of the mtDNA copy number, although it enhanced the ATP production by PC3 cells. These differences can be attributed to the augmented uptake of 99mTc-TPP-BBN in the mitochondria and enhanced uptake of 99mTc-AO-BBN in the nucleus, allowing the irradiation of these radiosensitive organelles with the short path-length AEs emitted by 99mTc. In particular, the results obtained for 99mTc-TPP-BBN reinforce the relevance of targeting the mitochondria to promote stronger radiobiological effects by AE-emitting radioconjugates.

Radiolabeled Gold Nanoseeds Decorated with Substance P Peptides: Synthesis, Characterization and In Vitro Evaluation in Glioblastoma Cellular Models.

Despite some progress, the overall survival of patients with glioblastoma (GBM) remains extremely poor. In this context, there is a pressing need to develop innovative therapy strategies for GBM, namely those based on nanomedicine approaches. Towards this goal, we have focused on nanoparticles (AuNP-SP and AuNP-SPTyr8) with a small gold core (ca. 4 nm), carrying DOTA chelators and substance P (SP) peptides. These new SP-containing AuNPs were characterized by a variety of analytical techniques, including TEM and DLS measurements and UV-vis and CD spectroscopy, which proved their high in vitro stability and poor tendency to interact with plasma proteins. Their labeling with diagnostic and therapeutic radionuclides was efficiently performed by DOTA complexation with the trivalent radiometals 67Ga and 177Lu or by electrophilic radioiodination with 125I of the tyrosyl residue in AuNP-SPTyr8. Cellular studies of the resulting radiolabeled AuNPs in NKR1-positive GBM cells (U87, T98G and U373) have shown that the presence of the SP peptides has a crucial and positive impact on their internalization by the tumor cells. Consistently, 177Lu-AuNP-SPTyr8 showed more pronounced radiobiological effects in U373 cells when compared with the non-targeted congener 177Lu-AuNP-TDOTA, as assessed by cell viability and clonogenic assays and corroborated by Monte Carlo microdosimetry simulations.

A look beyond dietary (poly)phenols: The low molecular weight phenolic metabolites and their concentrations in human circulation.

A large number of epidemiological studies have shown that consumption of fruits, vegetables, and beverages rich in (poly)phenols promote numerous health benefits from cardiovascular to neurological diseases. Evidence on (poly)phenols has been applied mainly to flavonoids, yet the role of phenolic acids has been largely overlooked. Such phenolics present in food combine with those resulting from gut microbiota catabolism of flavonoids and chlorogenic acids and those produced by endogenous pathways, resulting in large concentrations of low molecular weight phenolic metabolites in human circulation. Independently of the origin, in human intervention studies using diets rich in (poly)phenols, a total of 137 low molecular weight phenolic metabolites have been detected and quantified in human circulation with largely unknown biological function. In this review, we will pinpoint two main aspects of the low molecular weight phenolic metabolites: (i) the microbiota responsible for their generation, and (ii) the analysis (quali- and quantitative) in human circulation and their respective pharmacokinetics. In doing so, we aim to drive scientific advances regarding the ubiquitous roles of low molecular weight phenolic metabolites using physiologically relevant concentrations and under (patho)physiologically relevant conditions in humans.

Is the timing of implant placement and loading influencing esthetic outcomes in single-tooth implants?-A systematic review.

OBJECTIVES: To address the following question: "Is the timing of implant placement and/or loading influencing the esthetic outcomes of implant-supported single crowns?" MATERIAL AND METHODS: A literature screening was performed in four electronic databases until June 2020. Randomized controlled clinical trials with a minimum of 10 patients and 1 year of follow-up and reporting on dimensional changes of the peri-implant mucosa (midfacial recession, papilla level) and esthetic indexes were included. Cochrane Risk of Bias Tool was used, and comparable trials were subjected to meta-analyses. RESULTS: Out of 8549 articles, 72 full-text articles were assessed for eligibility and 18 were included. Nine trials evaluated the timing of implant placement, and nine trials evaluated the timing of loading. The included trials comparing immediate implant placement to delayed implant placement evaluating the midfacial recession reported heterogeneous findings. No differences were found at 1 and 2-years, when comparing midfacial recession and papilla level between immediate and early implant placement. In immediate and delayed implant placement, when comparing conventional and immediate loading, the midfacial mucosal margin change was not statistically significant at the 1-year follow-up. When evaluating the timing of implant placement and/or loading the included trials found no differences in the Pink Esthetic score, White Esthetic score, and Papilla Index between groups. CONCLUSIONS: Both immediate and early implant placement protocols presented stable treatment results in terms of esthetic outcomes at the 1-, 2-, and 10-years follow-up. Loading protocols did not seem to influence esthetic outcomes in short- and medium-term follow-ups.

Spasmodic cough preceding CANVAS phenotype in a family with biallelic repeat expansions in RFC1.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late-onset, multisystem ataxia that remained only clinically defined, until recently, when the discovery of biallelic repeat expansion in the RFC1 gene allowed the genetic link. We describe the first Portuguese familial CANVAS harboring the pathogenic RFC1 expansion. Detail clinical features and course of four affected members are provided. Phenotype characterizations are important as the novel RFC1 mutation is expected to be a major cause of idiopathic late-onset ataxia.

Clearance and persistence of SARS-CoV-2 RNA in patients with COVID-19.

Patients with coronavirus disease-2019 may be discharged based on clinical resolution of symptoms, and evidence for viral RNA clearance from the upper respiratory tract. Understanding the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral clearance profile is crucial to establish a re-testing plan on discharge and ending isolation of patients. We aimed to evaluate the number of days that a patient needed to achieve undetectable levels of SARS-CoV-2 in upper respiratory tract specimens (nasopharyngeal swab and/or an oropharyngeal swab). The clearance and persistence of viral RNA was evaluated in two groups of positive patients: those who achieved two negative reverse transcription-polymerase chain reaction (RT-PCR) tests and those who kept testing positive. Patients were organized thereafter in two subgroups, mild illness patients discharged home and inpatients who had moderate to severe illness. Results from RT-PCR tests were then correlated with results from the evaluation of the immune response. The study evidenced that most patients tested positive for more than 2 weeks and that persistence of viral RNA is not necessarily associated with severe disease but may result from a weaker immune response instead.

Pulmonary Arteriovenous Malformations in Non-hereditary Hemorrhagic Telangiectasia Patients: An 18-Year Retrospective Study.

PURPOSE: Pulmonary arteriovenous malformations (PAVMs) are most commonly associated with hereditary hemorrhagic telangiectasia (HHT). Patients with PAVMs can present with serious complications including stroke, transient ischemic attack (TIA), and brain abscess. PAVMs are rare in non-HHT patients and little is known about this patient population. The aim of this retrospective study is to better understand clinical presentation and outcomes of PAVMs occurring exclusively in non-HHT patients. METHODS: Non-HHT patients with PAVMs at the Mayo Clinic-Rochester between 01/01/2000 and 12/31/2018 were reviewed. Patients with Curacao score > 1 were excluded. Demographics, imaging characteristics, neurological complications, and follow-up imaging were analyzed. RESULTS: Seventy-seven patients with PAVMs were identified. The mean age at diagnosis was 48.2 ± 18.3 years with female preponderance (59.7%). The majority of PAVMs had lower lobe predominance (66.7%) and were simple and single in 75.3% and 89.6% of cases, respectively. Most patients were asymptomatic (46.8%) with dyspnea being the most common symptom (28.6%). Neurologic complications occurred in 19.5% of patients. The majority of PAVMs were idiopathic (61%). Thirty patients (39%) had one or more possible risk factors including previous thoracic surgery (23.4%), congenital heart disease (19.5%), and chest trauma (10.4%). Embolization was performed in 37 (48.1%) patients and only 4 (5.2%) underwent surgical resection. CONCLUSIONS: Non-HHT PAVMs occur more commonly in females, are most commonly simple and single, and have lower lobe predominance and a high rate of neurologic complications. Potential predisposing risk factors were identified in about 40% of the cases. Clinicians should be aware of the risk of PAVM development in patients with history of chest trauma, congenital heart disease, lung infection/abscess, and thoracic surgery.

In Vitro and Ex Vivo Models - The Tumor Microenvironment in a Flask.

Experimental tumor modeling has long supported the discovery of fundamental mechanisms of tumorigenesis and tumor progression, as well as provided platforms for the development of novel therapies. Still, the attrition rates observed today in clinical translation could be, in part, mitigated by more accurate recapitulation of environmental cues in research and preclinical models. The increasing understanding of the decisive role that tumor microenvironmental cues play in the outcome of drug response urges its integration in preclinical tumor models. In this chapter we review recent developments concerning in vitro and ex vivo approaches.

Spider mites escape bacterial infection by avoiding contaminated food.

To fight infection, arthropods rely on the deployment of an innate immune response but also upon physical/chemical barriers and avoidance behaviours. However, most studies focus on immunity, with other defensive mechanisms being relatively overlooked. We have previously shown that the spider mite Tetranychus urticae does not mount an induced immune response towards systemic bacterial infections, entailing very high mortality rates. Therefore, we hypothesized that other defence mechanisms may be operating to minimize infection risk. Here, we test (a) if spider mites are also highly susceptible to other infection routes-spraying and feeding-and (b) if they display avoidance behaviours towards infected food. Individuals sprayed with or fed on Escherichia coli or Pseudomonas putida survived less than the control, pointing to a deficient capacity of the gut epithelium, and possibly of the cuticle, to contain bacteria. Additionally, we found that spider mites prefer uninfected food to food contaminated with bacteria, a choice that probably does not rely on olfactory cues. Our results suggest that spider mites may rely mostly on avoidance behaviours to minimize bacterial infection and highlight the multi-layered nature of immune strategies present in arthropods.

Social safeness and disordered eating: Exploring underlying mechanisms of body appreciation and inflexible eating.

Feelings of social safeness and connectedness have been associated with adaptive emotion regulation processes and well-being indicators. Further, literature has demonstrated that interpersonal experiences play an important role in the etiology and maintenance of body and eating psychopathology. However, the study of the role of social variables and emotion regulation processes in the engagement in inflexible eating rules and eating psychopathology is still in its early stages. The current study aims to fill some gaps within the literature and explore the mediator role of body appreciation and inflexible eating rules in the link between social safeness and disordered eating. Participants were 253 women, aged between 18 and 50 years old, who completed a series of online self-report measures. Results from the tested path analysis model showed that social safeness holds a significant effect on eating psychopathology, through the mechanisms of body appreciation and inflexible eating rules. Also, results suggested that women who present higher levels of social safeness tend to present a more positive and respectful attitude towards their body and decreased adoption of inflexible eating rules, which seem to explain lower levels of disordered eating behaviours. These findings seem to present empirical support for the development of intervention programs that promote a positive, affectionate and healthy relationship with one's body image, in order to prevent the inflexible adherence to eating rules and disordered eating behaviours.