The role of the adrenalectomy in the management of pheochromocytoma: the experience of a Portuguese referral center.

PURPOSE: Pheochromocytoma is a rare neuroendocrine tumor. Despite the low incidence, these tumors are of indisputable importance. This study aimed to analyze the management of pheochromocytoma in a referral center, with an emphasis on the minimally invasive adrenalectomy, which is the preferred therapeutic approach. METHODS: A retrospective analysis was performed on a cohort of patients diagnosed with pheochromocytoma who underwent adrenalectomy between January 2013 and December 2022. Clinical data including demographics, timelines, symptomatology, comorbidities, biochemical markers, genetic testing, surgical details, and follow-up outcomes, were collected and analyzed. RESULTS: The cohort included 44 patients, predominantly women (52.27%), with a median age of 53.39 years (range 13-83). Most of patients exhibited paroxysmal symptoms suggesting catecholamine excess. Documented hypertension was the most frequent (86.36%), along with glucose anomalies (40.01%) and anxiety disorder (31.82%). Genetic testing was performed in 36 (81.81%) patients and 14 (38.88%) revealed a positive result, predominantly RET pathogenic variant. Laparoscopic surgery was performed in 34 (79.07%) patients, showing significantly shorter operative time (2.5 h vs. 4.25 h, t-test p < 0,001) and fewer complications (23.53% vs 77.78%, p = 0.008). Postoperative complications occurred in 36.36% of the patients, mostly mild (grade I, 56.25%), with no mortality. SDHB pathogenic variant correlated with both recurrent and metastatic disease (p = 0.006). One-year follow-up reported 9.09% recurrence and 6.82% metastasis. CONCLUSIONS: Adrenalectomy demonstrated a high safety and effectiveness. This study exhibited a higher rate of genetic testing referral than other studies. Despite past advances, there is still a need for further studies to establish protocols and evaluate new techniques.

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

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

Climate and urbanization drive changes in the habitat suitability of Schistosoma mansoni competent snails in Brazil.

Schistosomiasis is a neglected tropical disease caused by Schistosoma parasites. Schistosoma are obligate parasites of freshwater Biomphalaria and Bulinus snails, thus controlling snail populations is critical to reducing transmission risk. As snails are sensitive to environmental conditions, we expect their distribution is significantly impacted by global change. Here, we used machine learning, remote sensing, and 30 years of snail occurrence records to map the historical and current distribution of forward-transmitting Biomphalaria hosts throughout Brazil. We identified key features influencing the distribution of suitable habitat and determined how Biomphalaria habitat has changed with climate and urbanization over the last three decades. Our models show that climate change has driven broad shifts in snail host range, whereas expansion of urban and peri-urban areas has driven localized increases in habitat suitability. Elucidating change in Biomphalaria distribution-while accounting for non-linearities that are difficult to detect from local case studies-can help inform schistosomiasis control strategies.

Seventy years of pheochromocytomas and paragangliomas in Argentina. The FRENAR database.

Pheochromocytomas and paragangliomas (PPGL) are neuroendocrine tumors characterized by the excessive production of catecholamines. This study aims to describe the clinical characteristics of PPGL cases in Argentina over recent decades. A multicenter retrospective cross-sectional analysis was carried out using a database comprising both pediatric and adult patients with confirmed PPGL diagnoses based on pathological reports. A cohort of 486 patients with PPGL was recruited. Women represent 58.4% of the patients, with a mean age of 38.3 years old at the time of diagnosis and 15.2% of the patients were under the age of 18. Hypertension, as well as classic signs and symptoms, were present in 80.9% of the patients. The adrenal incidentaloma, as a mode of presentation, increased in the last two decades rising from 3.9% (1953-2000) to 21.8% (2001-2022), p<0.001. Most tumors were located within the adrenal glands, accounting 83.0% of the cases, with bilateral occurrences noted in 20.0%. The median tumor size was 4.8cm. Local recurrence and metastases were observed in 10.9% and 12.2%. Out of 412 patients, 87.0% exhibited urinary excretion elevation of catecholamines and/or their metabolites. Furthermore, 148 patients, representing 30.4% of the study population, displayed a distinct genetic profile indicative of hereditary syndromes. The distribution of hereditary syndromes revealed that MEN2, VHL, and PGL4 constituted the most prevalent syndromes. This population-based study, spanning seven decades, offers valuable insights into the demographic and clinical characteristics of PPGL patients in Argentina.

Ultrasound-Guided Resection of High-Grade Gliomas: A Single-Arm Meta-Analysis.

BACKGROUND: High-grade gliomas (HGGs) present a challenge in neuro-oncology, often necessitating surgical resection for optimal management. Ultrasound holds promise in achieving better gross total resection (GTR) and improving outcomes. This meta-analysis systematically evaluates literature providing robust evidence on the use of intraoperative ultrasonography (iUSG) in HGG resection. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines a comprehensive search was made across PubMed, Embase, Cochrane, and Web of Science utilized terms related to iUSG for HGG resection. The meta-analysis examined randomized trials and observational cohort studies on iUSG-guided HGG resection. GTR, subtotal resection, and postresection complications were assessed. Statistical analysis, employing R software for a single proportion analysis with confidence intervals of 95%, I2 statistics for heterogeneity, and the instrumental variables method with restricted maximum likelihood for a random effects model. RESULTS: A total of 178 patients were included in our study. The GTR overall rate in patients with iUSG-guided resection was found to be 64% (95% confidence interval: 46%-81%). Two-dimensional ultrasound remains dominant at 80% against other options of ultrasound. Complications were reported at a 15% rate (95% confidence interval: 7%-23%). CONCLUSIONS: Our study provided robust data on the utilization of iUSG-guided resection regarding the attainment of GTR and the complications related to resection. However, challenges such as outcome heterogeneity and limited complication reporting highlight the need for further research to optimize iUSG in HGG treatment. Long-term follow-up studies on patient survival and postsurgery quality of life will complement existing literature, guiding clinical practices in managing HGG.

Mitotic bookmarking by transcription factors: be aware of redundancy.

A recent report by Chervova, Molliex, et al. shows redundant functions for the transcription factors (TFs) ESRRB and NR5A2 as mitotic bookmarkers in mouse embryonic stem (ES) cells. These occupy some of their target sites in mitotic chromatin, ensuring their robust reactivation after cell division, including markers and regulators of pluripotency.

Climate and urbanization drive changes in the habitat suitability of Schistosoma mansoni competent snails in Brazil.

Schistosomiasis is a neglected tropical disease caused by Schistosoma parasites. Schistosoma are obligate parasites of freshwater Biomphalaria snails, so controlling snail populations is critical to reducing transmission risk. As snails are sensitive to environmental conditions, we expect their distribution is significantly impacted by global change. Here, we leveraged machine learning, remote sensing, and 30 years of snail occurrence records to map the historical and current distribution of competent Biomphalaria throughout Brazil. We identified key features influencing the distribution of suitable habitat and determined how Biomphalaria habitat has changed with climate and urbanization over the last three decades. Our models show that climate change has driven broad shifts in snail host range, whereas expansion of urban and peri-urban areas has driven localized increases in habitat suitability. Elucidating change in Biomphalaria distribution - while accounting for non-linearities that are difficult to detect from local case studies - can help inform schistosomiasis control strategies.

Multi-beam, WDM-based photonic beamformer with spectrum reuse.

This manuscript presents a wavelength-division multiplexing (WDM)-based photonic beamformer for an RF phased array antenna transmitter, capable of simultaneously generating multiple beams using the same optical spectrum. In the proposed architecture, for each RF beam, a WDM signal comprising the modulated RF sidebands undergoes complex-valued filtering, while another WDM signal with the same channels, but carrying only optical carriers, goes through an optical frequency-shifting stage. The proposed architecture allows the same WDM channels to be reused for multiple RF beams. The detection of the frequency-shifted optical carrier and the filtered RF sideband of each WDM channel at the photodetector produces a frequency-converted, correctly weighted signal to be fed to each antenna element. The features described herein are analytically derived, numerically simulated, and experimentally demonstrated. Results showcase two independent beams being transmitted in different directions.

Mechanistic insights into glycoside 3-oxidases involved in C-glycoside metabolism in soil microorganisms.

C-glycosides are natural products with important biological activities but are recalcitrant to degradation. Glycoside 3-oxidases (G3Oxs) are recently identified bacterial flavo-oxidases from the glucose-methanol-coline (GMC) superfamily that catalyze the oxidation of C-glycosides with the concomitant reduction of O2 to H2O2. This oxidation is followed by C-C acid/base-assisted bond cleavage in two-step C-deglycosylation pathways. Soil and gut microorganisms have different oxidative enzymes, but the details of their catalytic mechanisms are largely unknown. Here, we report that PsG3Ox oxidizes at 50,000-fold higher specificity (kcat/Km) the glucose moiety of mangiferin to 3-keto-mangiferin than free D-glucose to 2-keto-glucose. Analysis of PsG3Ox X-ray crystal structures and PsG3Ox in complex with glucose and mangiferin, combined with mutagenesis and molecular dynamics simulations, reveal distinctive features in the topology surrounding the active site that favor catalytically competent conformational states suitable for recognition, stabilization, and oxidation of the glucose moiety of mangiferin. Furthermore, their distinction to pyranose 2-oxidases (P2Oxs) involved in wood decay and recycling is discussed from an evolutionary, structural, and functional viewpoint.

Age- and caste-independent piRNAs in the germline and miRNA profiles linked to caste and fecundity in the ant Temnothorax rugatulus.

Social insects are models for studies of phenotypic plasticity. Ant queens and workers vary in fecundity and lifespan, which are enhanced and extended in queens. Yet, the regulatory mechanisms underlying this variation are not well understood. Ant queens live and reproduce for years, so that they need to protect their germline from transposable element (TE) activity, which may be redundant in short-lived, often sterile workers. We analysed the expression of two protective classes of small RNAs, microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs), in various tissues, castes and age classes of the ant Temnothorax rugatulus. In queens, piRNAs were highly abundant in ovaries with TEs being their clear targets, with reduced but still detectable piRNA-specific ping-pong signatures in thorax and brains. piRNA pathway activity varied little with age in queens. Moreover, the reduced ovaries of workers also exhibited similar piRNA activity and this not only in young, fertile workers, but also in older foragers with regressed ovaries. Therefore, these ants protect their germline through piRNA activity, regardless of ovarian development, age or caste, even in sterile workers often considered the soma of the superorganism. Our tissue-specific miRNA analysis detected the expression of 304 miRNAs, of which 105 were expressed in all tissues, 10 enriched in the brain, three in the thorax, whereas 83 were ovarian-specific. We identified ovarian miRNAs whose expression was related to caste, fecundity and age, and which likely regulate group-specific gene expression. sRNA shifts in young- to middle-aged queens were minor, suggesting delayed senescence in this reproductive caste.

Home-based telerehabilitation for community-dwelling persons with stroke during the COVID-19 pandemic: A pilot study.

OBJECTIVES: To determine the feasibility and safety of use of asynchronous telerehabilitation for community-dwelling persons with stroke in the Philippines during the COVID-19 (SARS-CoV-2) pandemic, and to evaluate the change in participants' telerehabilitation perceptions, physical activity, and well-being after a 2-week home-based telerehabilitation programme using a common social media application. DESIGN: Pilot study. PARTICIPANTS: Nineteen ambulatory, non-aphasic adult members of a national university hospital stroke support group in the Philippines. METHODS: Pre-participation screening was performed using the Physical Activity Readiness Questionnaire. The participants were medically cleared prior to study enrollment. They then engaged in telerehabilitation by watching original easy-to-follow home exercise videos prepared and posted by the study authors on a private group page on Facebook™ every other day for 2 weeks. Descriptive statistics was performed. RESULTS: All 19 participants (mean age: 54.9 years) completed the programme with no significant adverse events. The majority of subjects improved their telerehabilitation perceptions (based on the Telepractice Questionnaire), physical activity levels (based on the Simple Physical Activity Questionnaire), and perceived well-being (based on the Happiness Scale). CONCLUSION: Asynchronous telerehabilitation using a common low-cost social media application is feasible and safe for community-dwelling persons with chronic stroke in a lower-middle-income country.

Brain perfusion imaging by multi-delay arterial spin labeling: Impact of modeling dispersion and interaction with denoising strategies and pathology.

PURPOSE: Arterial spin labeling (ASL) acquisitions at multiple post-labeling delays may provide more accurate quantification of cerebral blood flow (CBF), by fitting appropriate kinetic models and simultaneously estimating relevant parameters such as the arterial transit time (ATT) and arterial cerebral blood volume (aCBV). We evaluate the effects of denoising strategies on model fitting and parameter estimation when accounting for the dispersion of the label bolus through the vasculature in cerebrovascular disease. METHODS: We analyzed multi-delay ASL data from 17 cerebral small vessel disease patients (50 ± 9 y) and 13 healthy controls (52 ± 8 y), by fitting an extended kinetic model with or without bolus dispersion. We considered two denoising strategies: removal of structured noise sources by independent component analysis (ICA) of the control-label image timeseries; and averaging the repetitions of the control-label images prior to model fitting. RESULTS: Modeling bolus dispersion improved estimation precision and impacted parameter values, but these effects strongly depended on whether repetitions were averaged before model fitting. In general, repetition averaging improved model fitting but adversely affected parameter values, particularly CBF and aCBV near arterial locations in patients. This suggests that using all repetitions allows better noise estimation at the earlier delays. In contrast, ICA denoising improved model fitting and estimation precision while leaving parameter values unaffected. CONCLUSION: Our results support the use of ICA denoising to improve model fitting to multi-delay ASL and suggest that using all control-label repetitions improves the estimation of macrovascular signal contributions and hence perfusion quantification near arterial locations. This is important when modeling flow dispersion in cerebrovascular pathology.

Machine learning-aided LiDAR range estimation.

Automotive light detection and ranging (LiDAR) requires accurate and computationally efficient range estimation methods. At present, such efficiency is achieved at the cost of curtailing the dynamic range of a LiDAR receiver. In this Letter, we propose using decision tree ensemble machine learning models to overcome such a trade-off. Simple and yet powerful models are developed and proven capable of performing accurate measurements across a 45-dB dynamic range.

BDNF/TrkB signaling endosomes in axons coordinate CREB/mTOR activation and protein synthesis in the cell body to induce dendritic growth in cortical neurons.

Brain-derived neurotrophic factor (BDNF) and its receptors tropomyosin kinase receptor B (TrkB) and the p75 neurotrophin receptor (p75) are the primary regulators of dendritic growth in the CNS. After being bound by BDNF, TrkB and p75 are endocytosed into endosomes and continue signaling within the cell soma, dendrites, and axons. We studied the functional role of BDNF axonal signaling in cortical neurons derived from different transgenic mice using compartmentalized cultures in microfluidic devices. We found that axonal BDNF increased dendritic growth from the neuronal cell body in a cAMP response element-binding protein (CREB)-dependent manner. These effects were dependent on axonal TrkB but not p75 activity. Dynein-dependent BDNF-TrkB-containing endosome transport was required for long-distance induction of dendritic growth. Axonal signaling endosomes increased CREB and mTOR kinase activity in the cell body, and this increase in the activity of both proteins was required for general protein translation and the expression of Arc, a plasticity-associated gene, indicating a role for BDNF-TrkB axonal signaling endosomes in coordinating the transcription and translation of genes whose products contribute to learning and memory regulation.

Nonlinearity measurement undergoing dispersion and loss.

Accurate knowledge of the nonlinear coefficient is extremely important to make reliable predictions about optical pulses propagating along waveguides. Nevertheless, determining this parameter when dispersion and loss are as important as nonlinear effects brings both theoretical and experimental challenges that have not yet been solved. A general method for measuring the nonlinear coefficient of waveguides under these demanding conditions is here derived and demonstrated experimentally in a kilometer-long standard silica fiber pumped close to 2 µm.

Nematode gene annotation by machine-learning-assisted proteotranscriptomics enables proteome-wide evolutionary analysis.

Nematodes encompass more than 24,000 described species, which were discovered in almost every ecological habitat, and make up >80% of metazoan taxonomic diversity in soils. The last common ancestor of nematodes is believed to date back to ∼650-750 million years, generating a large and phylogenetically diverse group to be explored. However, for most species high-quality gene annotations are incomprehensive or missing. Combining short-read RNA sequencing with mass spectrometry-based proteomics and machine-learning quality control in an approach called proteotranscriptomics, we improve gene annotations for nine genome-sequenced nematode species and provide new gene annotations for three additional species without genome assemblies. Emphasizing the sensitivity of our methodology, we provide evidence for two hitherto undescribed genes in the model organism Caenorhabditis elegans Extensive phylogenetic systems analysis using this comprehensive proteome annotation provides new insights into evolutionary processes of this metazoan group.

Trial of Deferiprone in Parkinson's Disease.

BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).

Denaturing for Nanoarchitectonics: Local and Periodic UV-Laser Photodeactivation of Protein Biolayers to Create Functional Patterns for Biosensing.

The nanostructuration of biolayers has become a paradigm for exploiting nanoscopic light-matter phenomena for biosensing, among other biomedical purposes. In this work, we present a photopatterning method to create periodic structures of biomacromolecules based on a local and periodic mild denaturation of protein biolayers mediated by UV-laser irradiation. These nanostructures are constituted by a periodic modulation of the protein activity, so they are free of topographic and compositional changes along the pattern. Herein, we introduce the approach, explore the patterning parameters, characterize the resulting structures, and assess their overall homogeneity. This UV-based patterning principle has proven to be an easy, cost-effective, and fast way to fabricate large areas of homogeneous one-dimensional protein patterns (2 min, 15 × 1.2 mm, relative standard deviation ≃ 16%). This work also investigates the implementation of these protein patterns as transducers for diffractive biosensing. Using a model immunoassay, these patterns have demonstrated negligible signal contributions from non-specific bindings and comparable experimental limits of detection in buffer media and in human serum (53 and 36 ng·mL-1 of unlabeled IgG, respectively).

Efficacy of smartphone-based retinal photography by undergraduate students in screening and early diagnosing diabetic retinopathy.

BACKGROUND: To evaluate the efficacy of retinal photography obtained by undergraduate students using a smartphone-based device in screening and early diagnosing diabetic retinopathy (DR). METHODS: We carried out an open prospective study with ninety-nine diabetic patients (194 eyes), who were submitted to an ophthalmological examination in which undergraduate students registered images of the fundus using a smartphone-based device. At the same occasion, an experienced nurse captured fundus photographs from the same patients using a gold standard tabletop camera system (Canon CR-2 Digital Non-Mydriatic Retinal Camera), with a 45º field of view. Two distinct masked specialists evaluated both forms of imaging according to the presence or absence of sings of DR and its markers of severity. We later compared those reports to assess agreement between the two technologies. RESULTS: Concerning the presence or absence of DR, we found an agreement rate of 84.07% between reports obtained from images of the smartphone-based device and from the regular (tabletop) fundus camera; Kappa: 0.67; Sensitivity: 71.0% (Confidence Interval [CI]: 65.05-78.16%); Specificity: 94.06% (CI: 90.63-97.49%); Accuracy: 84.07%; Positive Predictive Value (PPV): 90.62%; Negative Predictive Value (NPV): 80.51%. As for the classification between proliferative diabetic retinopathy and non-proliferative diabetic retinopathy, we found an agreement of 90.00% between the reports; Kappa: 0.78; Sensitivity: 86.96%; (CI: 79.07-94.85%); Specificity: 91.49% (CI: 84.95-98.03%); Accuracy: 90.00%; PPV: 83.33%; NPV: 93.48%. Regarding the degree of classification of DR, we found an agreement rate of 69.23% between the reports; Kappa: 0.52. As relating to the presence or absence of hard macular exudates, we found an agreement of 84.07% between the reports; Kappa: 0.67; Sensitivity: 71.60% (CI: 65.05-78.16%); Specificity: 94.06% (CI: 90.63-97.49%); Accuracy: 84.07%; PPV: 90.62%; NPV: 80.51%. CONCLUSION: The smartphone-based device showed promising accuracy in the detection of DR (84.07%), making it a potential tool in the screening and early diagnosis of DR.

The Caenorhabditis elegans TDRD5/7-like protein, LOTR-1, interacts with the helicase ZNFX-1 to balance epigenetic signals in the germline.

LOTUS and Tudor domain containing proteins have critical roles in the germline. Proteins that contain these domains, such as Tejas/Tapas in Drosophila, help localize the Vasa helicase to the germ granules and facilitate piRNA-mediated transposon silencing. The homologous proteins in mammals, TDRD5 and TDRD7, are required during spermiogenesis. Until now, proteins containing both LOTUS and Tudor domains in Caenorhabditis elegans have remained elusive. Here we describe LOTR-1 (D1081.7), which derives its name from its LOTUS and Tudor domains. Interestingly, LOTR-1 docks next to P granules to colocalize with the broadly conserved Z-granule helicase, ZNFX-1. The Tudor domain of LOTR-1 is required for its Z-granule retention. Like znfx-1 mutants, lotr-1 mutants lose small RNAs from the 3' ends of WAGO and mutator targets, reminiscent of the loss of piRNAs from the 3' ends of piRNA precursor transcripts in mouse Tdrd5 mutants. Our work shows that LOTR-1 acts with ZNFX-1 to bring small RNA amplifying mechanisms towards the 3' ends of its RNA templates.