The Clinical Spectrum of Adrenoleukodystrophy at a Portuguese Tertiary Hospital: Case Series and Review of Literature.

Adrenoleukodystrophy, a rare genetic disease associated with the X chromosome (X-ALD - X-linked adrenoleukodystrophy), predominantly affects males and stems from mutations in the ABCD1 gene, responsible for transporting very long chain fatty acids (VLCFA) into peroxisomes. It leads to adrenal insufficiency (AI) and axonal demyelination. In males, the phenotype varies from isolated adrenocortical insufficiency and progressive myelopathy to cerebral adrenoleukodystrophy (CALD). The aim of this case series is to characterize patients with different clinical presentations of X-ALD with follow-up at a tertiary Portuguese hospital. All four patients were males, and the median age at the diagnosis was 5 years. Three patients were diagnosed through family screening, with the oldest already displaying hyperpigmentation. Two distinct forms were identified: adolescent CALD (25%) and isolated primary adrenal insufficiency (75%). Analytical studies revealed elevated plasma VLCFA levels in all cases, and genetic analysis demonstrated two different mutations in the ABCD1 gene. This disorder requires early diagnosis for improved prognosis. Screening male children with primary AIfor X-ALD using a VLCFA panel should be considered, particularly after ruling out the most common causes or when learning difficulties are evident. Genetic confirmation of the diagnosis is essential, enabling genetic counseling, family planning, and preimplantation genetic diagnosis.

Glucocorticoid receptor-dependent therapeutic efficacy of tauroursodeoxycholic acid in preclinical models of spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the ataxin-3 (ATXN3) gene. No effective treatment is available for this disorder, other than symptom-directed approaches. Bile acids have shown therapeutic efficacy in neurodegenerative disease models. Here, we pinpointed tauroursodeoxycholic acid (TUDCA) as an efficient therapeutic, improving the motor and neuropathological phenotype of SCA3 nematode and mouse models. Surprisingly, transcriptomic and functional in vivo data showed that TUDCA acts in neuronal tissue through the glucocorticoid receptor (GR), but independently of its canonical receptor, the farnesoid X receptor (FXR). TUDCA was predicted to bind to the GR, in a similar fashion to corticosteroid molecules. GR levels were decreased in disease-affected brain regions, likely due to increased protein degradation as a consequence of ATXN3 dysfunction being restored by TUDCA treatment. Analysis of a SCA3 clinical cohort showed intriguing correlations between the peripheral expression of GR and the predicted age at disease onset in presymptomatic subjects and FKBP5 expression with disease progression, suggesting this pathway as a potential source of biomarkers for future study. We have established a novel in vivo mechanism for the neuroprotective effects of TUDCA in SCA3 and propose this readily available drug for clinical trials in SCA3 patients.

Effects of Time-Restricted Eating on Aerobic Capacity, Body Composition, and Markers of Metabolic Health in Healthy Male Recreational Runners: A Randomized Crossover Trial.

BACKGROUND: Optimal nutrition is highly valuable for athletes aiming at maintaining or improving body composition and sports performance. When combined with structured exercise, time-restricted energy intake may represent an effective nonpharmacological approach to achieving these results. OBJECTIVE: The aim of this study was to investigate the effects of 4 weeks of time-restricted eating (TRE) vs 4 weeks of habitual diet on aerobic capacity, body composition, and metabolic health in 18- to 30-year-old men accustomed to endurance running. DESIGN: This trial used a randomized-crossover study design. Participants completed graded exercise tests, body composition scans, and fasting blood samples before and after each intervention condition. PARTICIPANTS/SETTING: Sixteen male physical education students were recruited and enrolled in the study from the Faculty of Human Kinetics-University of Lisbon in September 2020, in Lisbon, Portugal. One participant was excluded after 1 week because of a lack of adherence to the study protocol. Therefore, 15 participants completed the study and were involved in the final analysis. INTERVENTION: During the TRE condition, participants consumed two to three meals within an 8-hour eating window (between 1:00 and 9:00 pm). Only water, tea, and coffee (without caloric additives) were permitted to be consumed in the remaining 16 hours per 24-hour period. During the non-TRE condition, participants consumed their habitual diet without any timing restrictions. The order of the TRE intervention and the habitual diet condition was randomized and counterbalanced, and participants served as their own controls. The participants followed a structured training routine during each dietary condition. MAIN OUTCOME MEASURES: Body composition variables, indices of running aerobic capacity, and markers of metabolic health were assessed. STATISTICAL ANALYSES PERFORMED: One-way repeated-measures analysis of variance and covariance were performed to analyze differences between conditions and time with each intervention. RESULTS: Neither condition elicited observed changes in total body mass, fat mass, or fat-free mass between time points. Moreover, no significant changes were observed for markers of metabolic health. Significant improvements were obtained with both conditions for the first ventilatory threshold, maximum oxygen uptake (VO2max), and velocity at VO2max (P < 0.05). CONCLUSIONS: Four weeks of endurance running and TRE, compared with 4 weeks of endurance running and a habitual diet, in healthy trained 18- to 30-year-old male recreational runners did not result in observed differences in total body mass, fat mass, or fat-free mass. In addition, TRE did not offer any additional benefit for improving submaximal or peak exercise capacity in this population.

Embolic stroke and misidentification candida species endocarditis: Case presentation and literature review.

Fungal endocarditis is a rare but serious form of infective endocarditis associated with high morbidity and mortality. Among fungal pathogens, Candida species are the most frequently isolated and commonly found in individuals with predisposing factors, such as prosthetic heart valves. The clinical presentation of endocarditis is highly variable and nonspecific, often including symptoms and signs of embolization. In this paper, we present a case of fungal prosthetic valve endocarditis in which the initial presentation was an acute ischemic stroke. The initial misidentification of Candida famata was attributed to limitations in the presumptive methodology used through selective chromogenic culture identification. However, the surgical specimen underwent mass spectrometry, leading to the correct identification of Candida guilliermondii instead of Candida famata. Furthermore, we conducted a non-systematic narrative review of the literature on Candida endocarditis. Our findings underscore the importance of considering fungal endocarditis in the differential diagnosis of patients with possible extracardiac complications, particularly those with a history of heart valve replacement. Early diagnosis and a comprehensive treatment strategy tailored by species identification and antifungal susceptibility testing are crucial in improving patient outcomes.

Fibroblast growth factor signaling in axons: from development to disease.

The fibroblast growth factor (FGF) family regulates various and important aspects of nervous system development, ranging from the well-established roles in neuronal patterning to more recent and exciting functions in axonal growth and synaptogenesis. In addition, FGFs play a critical role in axonal regeneration, particularly after spinal cord injury, confirming their versatile nature in the nervous system. Due to their widespread involvement in neural development, the FGF system also underlies several human neurological disorders. While particular attention has been given to FGFs in a whole-cell context, their effects at the axonal level are in most cases undervalued. Here we discuss the endeavor of the FGF system in axons, we delve into this neuronal subcompartment to provide an original view of this multipurpose family of growth factors in nervous system (dys)function. Video Abstract.

Spatial -omics technologies: the new enterprise in 3D breast cancer models.

The fields of tissue bioengineering, -omics, and spatial biology are advancing rapidly, each offering the opportunity for a paradigm shift in breast cancer research. However, to date, collaboration between these fields has not reached its full potential. In this review, we describe the most recently generated 3D breast cancer models regarding the biomaterials and technological platforms employed. Additionally, their biological evaluation is reported, highlighting their advantages and limitations. Specifically, we focus on the most up-to-date -omics and spatial biology techniques, which can generate a deeper understanding of the biological relevance of bioengineered 3D breast cancer in vitro models, thus paving the way towards truly clinically relevant microphysiological systems, improved drug development success rates, and personalised medicine approaches.

Genetic Ablation of Inositol 1,4,5-Trisphosphate Receptor Type 2 (IP3R2) Fails to Modify Disease Progression in a Mouse Model of Spinocerebellar Ataxia Type 3.

Spinocerebellar ataxia type 3 (SCA3) is a rare neurodegenerative disease caused by an abnormal polyglutamine expansion within the ataxin-3 protein (ATXN3). This leads to neurodegeneration of specific brain and spinal cord regions, resulting in a progressive loss of motor function. Despite neuronal death, non-neuronal cells, including astrocytes, are also involved in SCA3 pathogenesis. Astrogliosis is a common pathological feature in SCA3 patients and animal models of the disease. However, the contribution of astrocytes to SCA3 is not clearly defined. Inositol 1,4,5-trisphosphate receptor type 2 (IP3R2) is the predominant IP3R in mediating astrocyte somatic calcium signals, and genetically ablation of IP3R2 has been widely used to study astrocyte function. Here, we aimed to investigate the relevance of IP3R2 in the onset and progression of SCA3. For this, we tested whether IP3R2 depletion and the consecutive suppression of global astrocytic calcium signalling would lead to marked changes in the behavioral phenotype of a SCA3 mouse model, the CMVMJD135 transgenic line. This was achieved by crossing IP3R2 null mice with the CMVMJD135 mouse model and performing a longitudinal behavioral characterization of these mice using well-established motor-related function tests. Our results demonstrate that IP3R2 deletion in astrocytes does not modify SCA3 progression.

Long-Term Neurophysiological Adaptations to Strength Training: A Systematic Review With Cross-Sectional Studies.

ABSTRACT: Santos, PDG, Vaz, JR, Correia, J, Neto, T, and Pezarat-Correia, P. Long-term neurophysiological adaptations to strength training: a systematic review with cross-sectional studies. J Strength Cond Res 37(10): 2091-2105, 2023-Neuromuscular adaptations to strength training are an extensively studied topic in sports sciences. However, there is scarce information about how neural mechanisms during force production differ between trained and untrained individuals. The purpose of this systematic review is to better understand the differences between highly trained and untrained individuals to establish the long-term neural adaptations to strength training. Three databases were used for the article search (PubMed, Web of Science, and Scopus). Studies were included if they compared groups of resistance-trained with untrained people, aged 18-40 year, and acquired electromyography (EMG) signals during strength tasks. Twenty articles met the eligibility criteria. Generally, strength-trained individuals produced greater maximal voluntary activation, while reducing muscle activity in submaximal tasks, which may affect the acute response to strength training. These individuals also presented lower co-contraction of the antagonist muscles, although it depends on the specific training background. Global intermuscular coordination may be another important mechanism of adaptation in response to long-term strength training; however, further research is necessary to understand how it develops over time. Although these results should be carefully interpreted because of the great disparity of analyzed variables and methods of EMG processing, chronic neural adaptations seem to be decisive to greater force production. It is crucial to know the timings at which these adaptations stagnate and need to be stimulated with advanced training methods. Thus, training programs should be adapted to training status because the same stimulus in different training stages will lead to different responses.

Mn-Based Methacrylated Gellan Gum Hydrogels for MRI-Guided Cell Delivery and Imaging.

This work aims to engineer a new stable injectable Mn-based methacrylated gellan gum (Mn/GG-MA) hydrogel for real-time monitored cell delivery into the central nervous system. To enable the hydrogel visualization under Magnetic Resonance Imaging (MRI), GG-MA solutions were supplemented with paramagnetic Mn2+ ions before its ionic crosslink with artificial cerebrospinal fluid (aCSF). The resulting formulations were stable, detectable by T1-weighted MRI scans and also injectable. Cell-laden hydrogels were prepared using the Mn/GG-MA formulations, extruded into aCSF for crosslink, and after 7 days of culture, the encapsulated human adipose-derived stem cells remained viable, as assessed by Live/Dead assay. In vivo tests, using double mutant MBPshi/shi/rag2 immunocompromised mice, showed that the injection of Mn/GG-MA solutions resulted in a continuous and traceable hydrogel, visible on MRI scans. Summing up, the developed formulations are suitable for both non-invasive cell delivery techniques and image-guided neurointerventions, paving the way for new therapeutic procedures.

Repairing Annulus Fibrosus Fissures Using Methacrylated Gellan Gum Combined with Novel Silk.

Intervertebral disc (IVD) herniation often causes severe pain and is frequently associated with the degeneration of the IVD. As the IVD degenerates, more fissures with increasing size appear within the outer region of the IVD, the annulus fibrosus (AF), favoring the initiation and progression of IVD herniation. For this reason, we propose an AF repair approach based on methacrylated gellan gum (GG-MA) and silk fibroin. Therefore, coccygeal bovine IVDs were injured using a biopsy puncher (⌀ 2 mm) and then repaired with 2% GG-MA as a filler material and sealed with an embroidered silk yarn fabric. Then, the IVDs were cultured for 14 days either without any load, static loading, or complex dynamic loading. After 14 days of culture, no significant differences were found between the damaged and repaired IVDs, except for a significant decrease in the IVDs' relative height under dynamic loading. Based on our findings combined with the current literature that focuses on ex vivo AF repair approaches, we conclude that it is likely that the repair approach did not fail but rather insufficient harm was done to the IVD.

How does the polymer architecture and position of cationic charges affect cell viability?

Polymer chemistry, composition and molar mass are factors that are known to affect cytotoxicity, however the influence of polymer architecture has not been investigated systematically. In this study the influence of the position of the cationic charges along the polymer chain on cytotoxicity was investigated while keeping constant the other polymer characteristics. Specifically, copolymers of various architectures, based on a cationic pH responsive monomer, 2-(dimethylamino)ethyl methacrylate (DMAEMA) and a non-ionic hydrophilic monomer, oligo(ethylene glycol)methyl ether methacrylate (OEGMA) were engineered and their toxicity towards a panel of cell lines investigated. Of the seven different polymer architectures examined, the block-like structures were less cytotoxic than statistical or gradient/tapered architectures. These findings will assist in developing future vectors for nucleic acid delivery.

StressMatic: A Novel Automated System to Induce Depressive- and Anxiety-like Phenotype in Rats.

Major depressive disorder (MDD) is a multidimensional psychiatric disorder that is estimated to affect around 350 million people worldwide. Generating valid and effective animal models of depression is critical and has been challenging for neuroscience researchers. For preclinical studies, models based on stress exposure, such as unpredictable chronic mild stress (uCMS), are amongst the most reliable and used, despite presenting concerns related to the standardization of protocols and time consumption for operators. To overcome these issues, we developed an automated system to expose rodents to a standard uCMS protocol. Here, we compared manual (uCMS) and automated (auCMS) stress-exposure protocols. The data shows that the impact of the uCMS exposure by both methods was similar in terms of behavioral (cognition, mood, and anxiety) and physiological (cell proliferation and endocrine variations) measurements. Given the advantages of time and standardization, this automated method represents a step forward in this field of preclinical research.

The Predictive Value of Glasgow-Blatchford Score: The Experience of an Emergency Department.

INTRODUCTION: Upper gastrointestinal bleeding (UGB) is a common emergency and a major cause of morbidity and mortality worldwide. An early and accurate assessment at admission is essential to estimate the severity of each case, assisting in the management of patients. The Glasgow-Blatchford score (GBS) is currently recommended for risk stratification of UGB in the emergency department (ED), helping triage patients to in-hospital vs. ambulatory management. The aim of this study was to test the validity of the GBS in an ED. METHODS: Patients who presented to the ED with a diagnosis of UGB between 2017 and 2018 were retrospectively analyzed. RESULTS: The mean GBS value of the 149 patients included in the study was 10.3. Of the patients, 4.3% had values ≤1 and 8.7% had values ≤3. The sensitivity and negative predictive value for intervention needs (98.9% and 91.7%) and complications in 30 days (100% and 100%) remained high with a threshold ≤3. In the receiver operating characteristic curves, GBS presented an area under the curve of 0.883 and 0.625, regarding the need for intervention and complications in 30 days, respectively. CONCLUSIONS: In our population, the threshold ≤2, and eventually ≤3, allows the identification of twice as many low-risk patients, manageable as outpatients, without significant increases in intervention needs or complications in 30 days.

Effect of Time-Restricted Eating and Resistance Training on High-Speed Strength and Body Composition.

This study examined the effects of four weeks of resistance training combined with time-restricted eating (TRE) vs. habitual diet on fat and fat-free mass as well as maximum and explosive force production in healthy, trained participants (18 males, aged 23.7 ± 2.6 years). The order of dieting was randomized and counterbalanced, and the participants served as their own controls. TRE involved an 8-h eating window and non-TRE involved a habitual meal pattern. Participants completed performance strength tests and body composition scans at baseline and post-intervention. The participants followed a structured training routine during each dietary intervention (four sets of maximum repetitions at 85% 1RM in five dynamic exercises, three times/week). Both interventions elicited deceases in fat mass (p < 0.05) but not in fat-free mass. After training (controlling for baseline values as covariates), non-TRE was compatible with better lower body jump performance than TRE (p < 0.05). Conversely, training with TRE elicited higher values in terms of peak force and dynamic strength index at the level of the upper body (p < 0.05). Thus, it can be concluded that there were no differences in fat mass and fat-free mass changes between interventions in already trained young males. Additionally, while the combination of TRE and resistance training might be beneficial for individuals focusing on developing high-speed strength performance at the upper body level, this is not applicable to those focusing on training the lower body.

Modified triangular osteosynthesis in the treatment of bilateral sacroiliac joint dislocation.

Bilateral sacroiliac joint dislocation is a rare injury associated with rotational and vertical instability of the pelvic ring. The ideal strategy for the reduction and fixation of this injury is poorly described in the current literature. Triangular osteosynthesis provides multiplanar stability to the posterior pelvic ring allowing early weight bearing. We present the case of a young female with a bilateral sacroiliac joint dislocation who underwent a modified bilateral triangular osteosynthesis, using S1 pedicle screws to improve the reduction of the sacroiliac joint.