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1.
Nat Commun ; 15(1): 3059, 2024 Apr 18.
Article in English | MEDLINE | ID: mdl-38637500

ABSTRACT

The 2023 monkeypox (mpox) epidemic was caused by a subclade IIb descendant of a monkeypox virus (MPXV) lineage traced back to Nigeria in 1971. Person-to-person transmission appears higher than for clade I or subclade IIa MPXV, possibly caused by genomic changes in subclade IIb MPXV. Key genomic changes could occur in the genome's low-complexity regions (LCRs), which are challenging to sequence and are often dismissed as uninformative. Here, using a combination of highly sensitive techniques, we determine a high-quality MPXV genome sequence of a representative of the current epidemic with LCRs resolved at unprecedented accuracy. This reveals significant variation in short tandem repeats within LCRs. We demonstrate that LCR entropy in the MPXV genome is significantly higher than that of single-nucleotide polymorphisms (SNPs) and that LCRs are not randomly distributed. In silico analyses indicate that expression, translation, stability, or function of MPXV orthologous poxvirus genes (OPGs), including OPG153, OPG204, and OPG208, could be affected in a manner consistent with the established "genomic accordion" evolutionary strategies of orthopoxviruses. We posit that genomic studies focusing on phenotypic MPXV differences should consider LCR variability.


Subject(s)
Mpox (monkeypox) , Orthopoxvirus , Poxviridae , Humans , Monkeypox virus/genetics , Genomics , Mpox (monkeypox)/genetics
2.
Circ Res ; 2024 Apr 19.
Article in English | MEDLINE | ID: mdl-38639088

ABSTRACT

BACKGROUND: Nearly half of adults have hypertension, a major risk factor for cardiovascular disease. Mitochondrial hyperacetylation is linked to hypertension, but the role of acetylation of specific proteins is not clear. We hypothesized that acetylation of mitochondrial CypD (cyclophilin D) at K166 contributes to endothelial dysfunction and hypertension. METHODS: To test this hypothesis, we studied CypD acetylation in patients with essential hypertension, defined a pathogenic role of CypD acetylation in deacetylation mimetic CypD-K166R mutant mice and endothelial-specific GCN5L1 (general control of amino acid synthesis 5 like 1)-deficient mice using an Ang II (angiotensin II) model of hypertension. RESULTS: Arterioles from hypertensive patients had 280% higher CypD acetylation coupled with reduced Sirt3 (sirtuin 3) and increased GCN5L1 levels. GCN5L1 regulates mitochondrial protein acetylation and promotes CypD acetylation, which is counteracted by mitochondrial deacetylase Sirt3. In human aortic endothelial cells, GCN5L1 depletion prevents superoxide overproduction. Deacetylation mimetic CypD-K166R mice were protected from vascular oxidative stress, endothelial dysfunction, and Ang II-induced hypertension. Ang II-induced hypertension increased mitochondrial GCN5L1 and reduced Sirt3 levels resulting in a 250% increase in GCN5L1/Sirt3 ratio promoting CypD acetylation. Treatment with mitochondria-targeted scavenger of cytotoxic isolevuglandins normalized GCN5L1/Sirt3 ratio, reduced CypD acetylation, and attenuated hypertension. The role of mitochondrial acetyltransferase GCN5L1 in the endothelial function was tested in endothelial-specific GCN5L1 knockout mice. Depletion of endothelial GCN5L1 prevented Ang II-induced mitochondrial oxidative stress, reduced the maladaptive switch of vascular metabolism to glycolysis, prevented inactivation of endothelial nitric oxide, preserved endothelial-dependent relaxation, and attenuated hypertension. CONCLUSIONS: These data support the pathogenic role of CypD acetylation in endothelial dysfunction and hypertension. We suggest that targeting cytotoxic mitochondrial isolevuglandins and GCN5L1 reduces CypD acetylation, which may be beneficial in cardiovascular disease.

3.
Medicina (Kaunas) ; 60(3)2024 Feb 27.
Article in English | MEDLINE | ID: mdl-38541128

ABSTRACT

Background and Objectives: Addressing deep carious lesions poses significant challenges in daily dental practice due to the inherent complexity of their treatment. Traditionally, complete removal of carious tissues has been the norm, potentially leading to pulp tissue exposure and subsequent pulpitis. In contemporary dentistry, there is a growing preference for minimally invasive techniques, such as selective removal, offering a more conservative approach with enhanced predictability and success rates. Materials and Methods: Our study commenced with a comprehensive systematic review. After that, we performed a meta-analysis focused exclusively on randomized controlled trials involving permanent dentition. Our investigation incorporated seven selected articles, which scrutinized success rates and the incidence of pulp exposure in minimally invasive techniques (MIT) versus conventional techniques (CT). Statistical analysis employed U Mann-Whitney and Wilcoxon tests to interpret the results. Results: Although the difference did not reach statistical significance, MIT demonstrated marginally superior success rates compared to CT. Furthermore, MIT exhibited a lower percentage of pulp exposure when contrasted with CT. However, due to the limited sample size, statistical significance for this difference could not be established. Conclusions: Minimally invasive techniques for caries removal emerge as a conservative and promising approach to safeguard pulp tissues in comparison to conventional techniques. The need for additional randomized controlled trials is emphasized to unequivocally establish the superior success rates of these procedures over their conventional counterparts.


Subject(s)
Dental Caries , Dentition, Permanent , Humans , Dental Caries Susceptibility , Dental Care , Sample Size , Dental Caries/surgery
4.
Appetite ; 197: 107308, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38508419

ABSTRACT

Alcohol consumption continues to be prevalent and is on the rise in many countries, posing a grave risk for the health and wellbeing of millions and creating a strain on health services worldwide. A hopeful trend has emerged, however, as consumers' growing preference for healthier, sustainable lifestyles has led traditional alcoholic brands to innovate, launching reduced or non-alcoholic (NoLo) options. This aligns with the SDGs and is reflected in NoLo spirits representing four of Spain's top ten disruptive innovations of 2022. This paper uses a mixed methodology in a qualitative-quantitative sequential approach to gain insight into this phenomenon. The study involved 13 in-depth interviews with HoReCa (an acronym for Hotels, Restaurants, and Caterings) professionals and four focus groups among consumers. Second, behavioral reasoning theory (BRT) was used in a quantitative study aiming to explore motivations for and against consuming NoLo spirits. Data from a survey of 620 participants was conducted and analyzed using SEM-PLS to measure the antecedents of consumer's behavioral intention towards NoLo spirits and to gauge the potential for marketing opportunities. The research reveals that the purchase intention of NoLo spirits is strongly related to health consciousness, while enjoying the effects of alcohol for fun and entertainment, and the social pressure to drink hinders its consumption. In addition, it was found that "reasons for" are more substantial than "reasons against" the consumption of those beverages, differing significantly by age group. Results offer implications for theory and practice, including recommendations for practitioners and regulators willing to improve sustainability in the industry. Further, this paper helps augment the innovation adoption literature by using BRT in the paradoxical context of consumers' increasing alcohol abuse despite their professed attempts to adopt healthier lifestyles.


Subject(s)
Alcohol Drinking , Alcoholism , Humans , Beverages , Marketing , Consumer Behavior
5.
Sci Total Environ ; 919: 170860, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38346655

ABSTRACT

Grazing livestock derive most of their mineral requirements from foraging. The presence of toxic elements in soils has become a significant concern for food safety and ecosystem services. Understanding the mineral content profiles in soil and forage is crucial for assessing animal health, predicting potential transfers of minerals or heavy metals into the food-chain, and assessing threats to the environment and human health. In this study, Na, Mg, P, K, Ca, Mn, Fe, Co, Cu, Zn, Se, As, Cd, Hg, and Pb were measured to determine the mineral status of three different pasture-based farming systems (with grazing sheep livestock) in a Spanish region of significant economic importance. A risk assessment evaluation of animal, environmental, and human health was performed on soil, forage, feed, serum, milk, and wool. Notably, traces of Pb, and As were identified in pastures in all farms. Our calculation of pollution indices revealed moderate levels of contamination by various elements, including Co, Cu, Zn, Se, As, Cd, Hg, and Pb. The two farms with more intense agrosystem practices showed a significant potential ecological risk, characterized by high soil levels of Hg and Cd. Animals from these farms also had high concentrations of these metals in wool. Although the target Hazard Quotient derived from milk consumption suggests that dairy products from this area are safe for consumption for adults, only milk from a dehesa farm (mix of woodland and pastureland) was free of potential health concerns related to Pb exposure. Our assessment of mineral profiles reveals a cohesive relationship between soil quality and derived animal products, particularly of the Merino sheep breeding and farming system. The results reveal the importance of adopting and reinforcing strategies to preserve dehesas as a sustainable and environmentally friendly agrosystem in the western Mediterranean region.


Subject(s)
Mercury , Metals, Heavy , Soil Pollutants , Animals , Sheep , Humans , Soil , Farms , Livestock , Cadmium , Ecosystem , Lead , Agriculture , Minerals , Metals, Heavy/analysis , Sheep, Domestic , Soil Pollutants/analysis , Environmental Monitoring , Risk Assessment
6.
Med. clín (Ed. impr.) ; 162(4): 182-189, Feb. 2024. ilus, graf
Article in Spanish | IBECS | ID: ibc-230575

ABSTRACT

La hidradenitis supurativa (HS) es una enfermedad inflamatoria crónica y recurrente derivada de la unidad pilosebácea, que afecta aproximadamente al 1% de la población general. Se caracteriza clínicamente por nódulos inflamatorios, abscesos y túneles en las áreas intertriginosas del cuerpo, especialmente en las regiones axilar, inguinal y anogenital. La etiopatogenia de la HS no está totalmente aclarada, aunque se considera que es multifactorial, y resultado de una compleja interacción entre factores genéticos, hormonales, ambientales e inmunológicos. En este sentido, determinadas citocinas proinflamatorias como el factor de necrosis tumoral-alfa (TNF-α), la interleucina (IL)-1β y la IL-17, entre otras, parecen desempeñar un papel fundamental en la patogénesis de la enfermedad. Actualmente, la HS es considerada una enfermedad inflamatoria sistémica asociada con numerosas comorbilidades, incluyendo enfermedades cardiovasculares, inmunomediadas y trastornos endocrino-metabolicos. El tratamiento de la HS debe realizarse con un enfoque individualizado y orientado al paciente, considerando modalidades de tratamiento médico y quirúrgico.(AU)


Hidradenitis suppurativa (HS) is a chronic and debilitating inflammatory disease derived from the pilosebaceous unit, that affects approximately 1% of the general population. Clinically, it is characterized by inflammatory nodules, abscesses, and tunnels in the intertriginous areas of the body, especially in the axillary, inguinal, and anogenital regions. The etiopathogenesis of HS is not completely understood, although it is considered to be multifactorial, and the result of a complex interaction between genetic, hormonal, environmental, and immunological factors. In this sense, several proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-L-1β, and IL-17, among others, appear to play a crucial role in the pathogenesis of the disease. Currently, HS is recognized as a systemic disease associated with numerous comorbidities, including cardiovascular, immune-mediated, and endocrine-metabolic diseases. The treatment of HS must be carried out with an individualized and patient-oriented approach, considering medical and surgical treatment modalities.(AU)


Subject(s)
Humans , Male , Comorbidity , Inflammation , Hidradenitis Suppurativa/diagnostic imaging , Hidradenitis Suppurativa/etiology , Hidradenitis Suppurativa/epidemiology , Clinical Medicine , Hidradenitis Suppurativa/drug therapy , Microbiota
7.
Sensors (Basel) ; 24(2)2024 Jan 16.
Article in English | MEDLINE | ID: mdl-38257659

ABSTRACT

Low back pain (LBP) is a significant global health challenge due to its high prevalence, and chronicity and recurrence rates, with projections suggesting an increase in the next years due to population growth and aging. The chronic and recurrent nature of LBP, responsible for a significant percentage of years lived with disability, underscores the need for effective management strategies, including self-management strategies advocated by current guidelines, to empower patients and potentially improve healthcare efficiency and clinical outcomes. Therefore, the aim of this study was to analyze the added value of face-to-face visits in patients with chronic LBP undergoing a self-management program based on therapeutic exercises on pain intensity, disability, quality of life and treatment adherence and satisfaction. A randomized clinical trial was conducted, allocating 49 patients into a experimental group with a mobile health (mHealth) app usage and face-to-face sessions and 49 patients into an active control group without face-to-face sessions. Pain intensity, disability and quality of life were assessed at baseline, 4 weeks postintervention and 12 weeks postintervention. Patients' satisfaction and adherence were assessed at the end of the study. The multivariate general model revealed no statistically significant time × group interaction for any outcome (p > 0.0068) but mental quality of life (p = 0.006). Within-group differences revealed significant improvements for all the clinical indicators (all, p < 0.001). Patients allocated to the experimental group reported greater satisfaction and adherence (both, p < 0.001) compared to the control group. The use of mHealth apps such as Healthy Back® as part of digital health initiatives may serve as a beneficial approach to enhance the management of LBP.


Subject(s)
Low Back Pain , Mobile Applications , Humans , Low Back Pain/therapy , Quality of Life , Aging , Digital Health
8.
Environ Toxicol Pharmacol ; 105: 104330, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38042261

ABSTRACT

Evidence suggests that acaricide residues, such as tau-fluvalinate and coumaphos, are very prevalent in honey bee colonies worldwide. However, the endpoints and effects of chronic oral exposure to these compounds remain poorly understood. In this study, we calculated LC50 and LDD50 endpoints for coumaphos and tau-fluvalinate, and then evaluated in vivo and in vitro effects on honey bees using different biomarkers. The LDD50 values for coumaphos were 0.539, and for tau-fluvalinate, they were 12.742 in the spring trial and 8.844 in the autumn trial. Chronic exposure to tau-fluvalinate and coumaphos resulted in significant changes in key biomarkers, indicating potential neurotoxicity, xenobiotic biotransformation, and oxidative stress. The Integrated Biomarker Response was stronger for coumaphos than for tau-fluvalinate, supporting their relative lethality. This study highlights the chronic toxicity of these acaricides and presents the first LDD50 values for tau-fluvalinate and coumaphos in honey bees, providing insights into the risks faced by colonies.


Subject(s)
Acaricides , Pyrethrins , Bees , Animals , Coumaphos/toxicity , Acaricides/toxicity , Pyrethrins/toxicity , Nitriles/toxicity
9.
Med Clin (Barc) ; 162(4): 182-189, 2024 02 23.
Article in English, Spanish | MEDLINE | ID: mdl-37968174

ABSTRACT

Hidradenitis suppurativa (HS) is a chronic and debilitating inflammatory disease derived from the pilosebaceous unit, that affects approximately 1% of the general population. Clinically, it is characterized by inflammatory nodules, abscesses, and tunnels in the intertriginous areas of the body, especially in the axillary, inguinal, and anogenital regions. The etiopathogenesis of HS is not completely understood, although it is considered to be multifactorial, and the result of a complex interaction between genetic, hormonal, environmental, and immunological factors. In this sense, several proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-L-1ß, and IL-17, among others, appear to play a crucial role in the pathogenesis of the disease. Currently, HS is recognized as a systemic disease associated with numerous comorbidities, including cardiovascular, immune-mediated, and endocrine-metabolic diseases. The treatment of HS must be carried out with an individualized and patient-oriented approach, considering medical and surgical treatment modalities.


Subject(s)
Hidradenitis Suppurativa , Humans , Hidradenitis Suppurativa/diagnosis , Hidradenitis Suppurativa/etiology , Hidradenitis Suppurativa/therapy , Skin , Tumor Necrosis Factor-alpha , Interleukin-17
11.
Rehabilitación (Madr., Ed. impr.) ; 57(4): [100781], Oct-Dic, 2023. ilus, tab
Article in Spanish | IBECS | ID: ibc-228353

ABSTRACT

Desde 2020 se ha vivido una situación sin precedentes, experimentando un confinamiento total de la población debido al SARS-CoV-2, que ha afectado al tratamiento de distintas patologías, como la enfermedad pulmonar obstructiva crónica (EPOC). Por ello, se implementaron programas de telerrehabilitación para continuar los tratamientos. Se realizó una búsqueda bibliográfica entre octubre y noviembre de 2020, cuyo objetivo fue analizar y actualizar la eficacia de la telerrehabilitación en pacientes con EPOC, y 8 artículos cumplieron los criterios de selección. La telerrehabilitación pulmonar reflejó mejoras en la calidad de vida y estado físico, y disminuyó las hospitalizaciones y exacerbaciones. Asimismo, los pacientes mostraron un grado elevado de satisfacción y adherencia. La telerrehabilitación pulmonar obtiene resultados similares a la rehabilitación pulmonar, pudiendo utilizarla en pacientes con dificultad de desplazamiento a su centro sanitario o en confinamiento. No obstante, se debe investigar qué programa de telerrehabilitación es el ideal.(AU)


Since 2020 we have lived an exceptional situation that made us experience a complete lockdown due to SARS-CoV-2, what affected the treatments of different pathologies, such as the chronic obstructive pulmonary disease (COPD). Because of those reasons, it has arisen the idea of implementing the tele-rehabilitation program as a treatment of these pathologies. The search was done between the months of October and November 2020, with the aim of analyzing and updating the efficacy of the tele-rehabilitation in patients who have COPD, finding eight articles which met the inclusion criteria. The pulmonary tele-rehabilitation is able to improve the quality of life and physical state, and decreasing the number of hospitalizations and exacerbations. Furthermore, patients showed a great level of satisfaction and adherence to this treatment program. The pulmonary tele-rehabilitation can achieve similar results as of pulmonary rehabilitation. For this reason, people who have difficulties to go to their outpatients clinic or even in a lockdown can use it. However, it is necessary to investigate which tele-rehabilitation program is better.(AU)


Subject(s)
Humans , Male , Female , Telerehabilitation , Pulmonary Disease, Chronic Obstructive/rehabilitation , Physical Therapy Modalities , /rehabilitation , Quality of Life
12.
Biomedicines ; 11(12)2023 Nov 29.
Article in English | MEDLINE | ID: mdl-38137395

ABSTRACT

This narrative review explores the complex relationship between aerobic exercise (AE) and neuropathic pain (NP), particularly focusing on peripheral neuropathies of mechanical origin. Pain, a multifaceted phenomenon, significantly impacts functionality and distress. The International Association for the Study of Pain's definition highlights pain's biopsychosocial nature, emphasizing the importance of patient articulation. Neuropathic pain, arising from various underlying processes, presents unique challenges in diagnosis and treatment. Our methodology involved a comprehensive literature search in the PubMed and SCOPUS databases, focusing on studies relating AE to NP, specifically in peripheral neuropathies caused by mechanical forces. The search yielded 28 articles and 1 book, primarily animal model studies, providing insights into the efficacy of AE in NP management. Results from animal models demonstrate that AE, particularly in forms like no-incline treadmill and swimming, effectively reduces mechanical allodynia and thermal hypersensitivity associated with NP. AE influences neurophysiological mechanisms underlying NP, modulating neurotrophins, cytokines, and glial cell activity. These findings suggest AE's potential in attenuating neurophysiological alterations in NP. However, human model studies are scarce, limiting the direct extrapolation of these findings to human neuropathic conditions. The few available studies indicate AE's potential benefits in peripheral NP, but a lack of specificity in these studies necessitates further research. In conclusion, while animal models show promising results regarding AE's role in mitigating NP symptoms and influencing underlying neurophysiological mechanisms, more human-centric research is required. This review underscores the need for targeted clinical trials to fully understand and harness AE's therapeutic potential in human neuropathic pain, especially of mechanical origin.

14.
Environ Sci Pollut Res Int ; 30(56): 118855-118870, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37922086

ABSTRACT

In recent years, there have been increasing ecological and global concerns associated to Potentially Toxic Elements (PTEs). Thus, the relevance of wild mammals as biomonitors has been globally recognised. In the present study, Cd, Pb, Hg, Zn and As concentrations were quantified in European hedgehog and badger inhabiting SW Europe, and cumulative trends in relation to age and sex were evaluated. Liver and kidney samples were collected, mineralised and PTE content was determined by ICP-MS. Zn was the most abundant element quantified in both organs (239 and 89.8 mg kg-1 for hedgehogs and 179 and 164 mg kg-1 dw for badgers). In hedgehogs, very high Hg concentration were quantified (4.35 and 15.5 mg kg-1 dw in liver and kidney), and Cd was the most abundant for badgers (4.70 and 7.61 mg kg-1 dw in liver and kidney). Positive correlations were observed for the concentrations of PTE in the organs of both species. Age-dependence increased only Cd concentration, with levels in adult kidneys being significantly higher. In this study, European hedgehog and badger were used as biomonitors for the determination of PTEs to provide current reference values in relatively non-polluted areas of SW Europe, and to enhance the use of these species for future ecotoxicological studies.


Subject(s)
Mercury , Metalloids , Mustelidae , Animals , Hedgehogs , Cadmium , Metals , Europe
15.
Macromolecules ; 56(18): 7286-7299, 2023 Sep 26.
Article in English | MEDLINE | ID: mdl-37781211

ABSTRACT

Cationic polymers are widely used materials in diverse biotechnologies. Subtle variations in these polymers' properties can change them from exceptional delivery agents to toxic inflammatory hazards. Conventional screening strategies optimize for function in a specific application rather than observing how underlying polymer-cell interactions emerge from polymers' properties. An alternative approach is to map basic underlying responses, such as immunogenicity or toxicity, as a function of basic physicochemical parameters to inform the design of materials for a breadth of applications. To demonstrate the potential of this approach, we synthesized 107 polymers varied in charge, hydrophobicity, and molecular weight. We then screened this library for cytotoxic behavior and immunogenic responses to map how these physicochemical properties inform polymer-cell interactions. We identify three compositional regions of interest and use confocal microscopy to uncover the mechanisms behind the observed responses. Finally, immunogenic activity is confirmed in vivo. Highly cationic polymers disrupted the cellular plasma membrane to induce a toxic phenotype, while high molecular weight, hydrophobic polymers were uptaken by active transport to induce NLRP3 inflammasome activation, an immunogenic phenotype. Tertiary amine- and triethylene glycol-containing polymers did not invoke immunogenic or toxic responses. The framework described herein allows for the systematic characterization of new cationic materials with different physicochemical properties for applications ranging from drug and gene delivery to antimicrobial coatings and tissue scaffolds.

16.
Eur J Pharm Sci ; 191: 106618, 2023 Dec 01.
Article in English | MEDLINE | ID: mdl-37866674

ABSTRACT

This work proposes the development of a thermosensitive local drug release system based on Polaxamer 407, also known as Pluronic® F-127 (PF-127), Gellan Gum (GG) and the inclusion complex Sulfobutylated-ß-cyclodextrin (CD) with Farnesol (FOH). Rheological properties of the hydrogels and their degradation were studied. According to the rheological results, a solution of 20% w/v of PF-127 forms a strong gel with a gelling temperature of about 25 °C (storage modulus of 15,000 Pa). The addition of the GG increased the storage modulus (optimal concentration of 0.5 % w/v) twofold without modifying the gelling temperature. Moreover, including 0.5% w/v of GG also increased 6 times the degradation time of the hydrogel. Regarding the inclusion complex, the addition of free CD decreased the viscosity and the gel strength since polymer chains were included in CD cavity without affecting the gelling temperature. Contrarily, the inclusion complex CD-FOH did not significantly modify any property of the formulation because the FOH was hosted in the CD. Furthermore, a mathematical model was developed to adjust the degradation time. This model highlights that the addition of the GG decreases the number of released chains from the polymeric network (which coincides with an increase in the storage modulus) and that the free CD reduces the degradation rate, protecting the polymeric chains. Finally, FOH release was quantified with a specific device, that was designed and printed for this type of system, observing a sustainable drug release (similar to FOH aqueous solubility, 8 µM) dependent on polymer degradation.


Subject(s)
Hydrogels , beta-Cyclodextrins , Farnesol , Drug Delivery Systems , Polysaccharides, Bacterial , Poloxamer
17.
Int J Mol Sci ; 24(20)2023 Oct 23.
Article in English | MEDLINE | ID: mdl-37895147

ABSTRACT

Histiocytoses encompass a group of exceptionally rare disorders characterized by the abnormal infiltration of tissues by histocytes. Among these, Erdheim-Chester disease (ECD) stands out as a multisystem histiocytosis that typically affects bones and various other tissues. Historically, the treatment of ECD has been challenging. However, recent breakthroughs in our understanding, particularly the discovery of somatic mutations in the RAS-MAPK pathway, have opened new opportunities for targeted therapy in a significant subset of patients with ECD and other histiocytoses. In this report, we present the case of a patient with ECD harboring a previously unidentified microduplication in the NRAS gene in a small fraction of skin cells. This discovery played a pivotal role in tailoring an effective therapeutic approach involving kinase inhibitors downstream of NRAS. This case underscores the crucial role of deep sequencing of tissue samples in ECD, enabling the delivery of personalized targeted therapy to patients.


Subject(s)
Erdheim-Chester Disease , Humans , Erdheim-Chester Disease/drug therapy , Erdheim-Chester Disease/genetics , Proto-Oncogene Proteins B-raf/genetics , Mutation , Membrane Proteins/genetics , GTP Phosphohydrolases/genetics
19.
Anesth Analg ; 137(5): 996-1006, 2023 Nov 01.
Article in English | MEDLINE | ID: mdl-37678264

ABSTRACT

BACKGROUND: Renal ischemia and reperfusion (IR) contribute to perioperative acute kidney injury, and oxygen is a key regulator of this process. We hypothesized that oxygen administration during surgery and renal IR would impact postoperative kidney function and injury in mice. METHODS: Mice were anesthetized, intubated, and mechanically ventilated with a fraction of inspired oxygen (F io2 ) 0.10 (hypoxia), 0.21 (normoxia), 0.60 (moderate hyperoxia), or 1.00 (severe hyperoxia) during 67 minutes of renal IR or sham IR surgery. Additional mice were treated before IR or sham IR surgery with 50 mg/kg tempol, a superoxide scavenger. At 24 hours, mice were sacrificed, and blood and kidney collected. We assessed and compared kidney function and injury across groups by measuring blood urea nitrogen (BUN, primary end point), renal histological injury, renal expression of neutrophil gelatinase-associated lipocalin (NGAL), and renal heme oxygenase 1 ( Ho-1 ), peroxisome proliferator-activated receptor gamma coactivator 1-α ( Pgc1-α ), and glutathione peroxidase 4 ( Gpx-4 ) transcripts, to explore potential mechanisms of any effect of oxygen. RESULTS: Hyperoxia and hypoxia during renal IR surgery decreased renal function and increased kidney injury compared to normoxia. Baseline median (interquartile range) BUN was 22.2 mg/dL (18.4-26.0), and 24 hours after IR surgery, BUN was 17.5 mg/dL (95% confidence interval [CI], 1.3-38.4; P = .034) higher in moderate hyperoxia-treated animals, 51.8 mg/dL (95% CI, 24.9-74.8; P < .001) higher in severe hyperoxia-treated animals, and 64.9 mg/dL (95% CI, 41.2-80.3; P < .001) higher in hypoxia-treated animals compared to animals treated with normoxia ( P < .001, overall effect of hyperoxia). Hyperoxia-induced injury, but not hypoxia-induced injury, was attenuated by pretreatment with tempol. Histological injury scores, renal NGAL staining, and renal transcription of Ho-1 and suppression of Pgc1- α followed the same pattern as BUN, in relation to the effects of oxygen treatment. CONCLUSIONS: In this controlled preclinical study of oxygen treatment during renal IR surgery, hyperoxia and hypoxia impaired renal function, increased renal injury, and impacted expression of genes that affect mitochondrial biogenesis and antioxidant response. These results might have implications for patients during surgery when high concentrations of oxygen are frequently administered, especially in cases involving renal IR.

20.
Sci Adv ; 9(31): eadi0482, 2023 08 02.
Article in English | MEDLINE | ID: mdl-37531427

ABSTRACT

Mineralized tissues, such as bones or teeth, are essential structures of all vertebrates. They enable rapid movement, protection, and food processing, in addition to providing physiological functions. Although the development, regeneration, and pathogenesis of teeth and bones have been intensely studied, there is currently no tool to accurately follow the dynamics of growth and healing of these vital tissues in space and time. Here, we present the BEE-ST (Bones and tEEth Spatio-Temporal growth monitoring) approach, which allows precise quantification of development, regeneration, remodeling, and healing in any type of calcified tissue across different species. Using mouse teeth as model the turnover rate of continuously growing incisors was quantified, and role of hard/soft diet on molar root growth was shown. Furthermore, the dynamics of bones and teeth growth in lizards, frogs, birds, and zebrafish was uncovered. This approach represents an effective, highly reproducible, and versatile tool that opens up diverse possibilities in developmental biology, bone and tooth healing, tissue engineering, and disease modeling.


Subject(s)
Tooth , Zebrafish , Mice , Animals , Tooth/physiology , Tooth Root , Bone and Bones , Bone Development
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