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The skull roof, or calvaria, is comprised of interlocking plates of bones that encase the brain. Separating these bones are fibrous sutures that permit growth. Currently, we do not understand the instructions for directional growth of the calvaria, a process which is error-prone and can lead to skeletal deficiencies or premature suture fusion (craniosynostosis, CS). Here, we identify graded expression of fibronectin (FN1) in the mouse embryonic cranial mesenchyme (CM) that precedes the apical expansion of calvaria. Conditional deletion of Fn1 or Wasl leads to diminished frontal bone expansion by altering cell shape and focal actin enrichment, respectively, suggesting defective migration of calvarial progenitors. Interestingly, Fn1 mutants have premature fusion of coronal sutures. Consistently, syndromic forms of CS in humans exhibit dysregulated FN1 expression, and we also find FN1 expression altered in a mouse CS model of Apert syndrome. These data support a model of FN1 as a directional substrate for calvarial osteoblast migration that may be a common mechanism underlying many cranial disorders of disparate genetic etiologies.
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Fibronectinas , Nascimento Prematuro , Crânio , Animais , Feminino , Humanos , Camundongos , Sinais (Psicologia) , Modelos Animais de Doenças , Fibronectinas/metabolismo , Osteoblastos , Crânio/citologia , Crânio/crescimento & desenvolvimento , Crânio/metabolismo , SuturasRESUMO
AIMS/HYPOTHESIS: Diabetes mellitus is associated with impaired insulin secretion, often aggravated by oversecretion of glucagon. Therapeutic interventions should ideally correct both defects. Glucagon-like peptide 1 (GLP-1) has this capability but exactly how it exerts its glucagonostatic effect remains obscure. Following its release GLP-1 is rapidly degraded from GLP-1(7-36) to GLP-1(9-36). We hypothesised that the metabolite GLP-1(9-36) (previously believed to be biologically inactive) exerts a direct inhibitory effect on glucagon secretion and that this mechanism becomes impaired in diabetes. METHODS: We used a combination of glucagon secretion measurements in mouse and human islets (including islets from donors with type 2 diabetes), total internal reflection fluorescence microscopy imaging of secretory granule dynamics, recordings of cytoplasmic Ca2+ and measurements of protein kinase A activity, immunocytochemistry, in vivo physiology and GTP-binding protein dissociation studies to explore how GLP-1 exerts its inhibitory effect on glucagon secretion and the role of the metabolite GLP-1(9-36). RESULTS: GLP-1(7-36) inhibited glucagon secretion in isolated islets with an IC50 of 2.5 pmol/l. The effect was particularly strong at low glucose concentrations. The degradation product GLP-1(9-36) shared this capacity. GLP-1(9-36) retained its glucagonostatic effects after genetic/pharmacological inactivation of the GLP-1 receptor. GLP-1(9-36) also potently inhibited glucagon secretion evoked by ß-adrenergic stimulation, amino acids and membrane depolarisation. In islet alpha cells, GLP-1(9-36) led to inhibition of Ca2+ entry via voltage-gated Ca2+ channels sensitive to ω-agatoxin, with consequential pertussis-toxin-sensitive depletion of the docked pool of secretory granules, effects that were prevented by the glucagon receptor antagonists REMD2.59 and L-168049. The capacity of GLP-1(9-36) to inhibit glucagon secretion and reduce the number of docked granules was lost in alpha cells from human donors with type 2 diabetes. In vivo, high exogenous concentrations of GLP-1(9-36) (>100 pmol/l) resulted in a small (30%) lowering of circulating glucagon during insulin-induced hypoglycaemia. This effect was abolished by REMD2.59, which promptly increased circulating glucagon by >225% (adjusted for the change in plasma glucose) without affecting pancreatic glucagon content. CONCLUSIONS/INTERPRETATION: We conclude that the GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of glucagon secretion. We propose that the increase in circulating glucagon observed following genetic/pharmacological inactivation of glucagon signalling in mice and in people with type 2 diabetes reflects the removal of GLP-1(9-36)'s glucagonostatic action.
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Diabetes Mellitus Tipo 2 , Hipoglicemia , Ilhotas Pancreáticas , Fragmentos de Peptídeos , Humanos , Glucagon/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Ilhotas Pancreáticas/metabolismo , Hipoglicemia/metabolismo , Insulina/metabolismoRESUMO
Glial fibrillary acidic protein (GFAP) is a promising biomarker for brain and spinal cord disorders. Recent studies have highlighted the differences in the reliability of GFAP measurements in different biological matrices. The reason for these discrepancies is poorly understood as our knowledge of the protein's 3-dimensional conformation, proteoforms, and aggregation remains limited. Here, we investigate the structural properties of GFAP under different conditions. For this, we characterized recombinant GFAP proteins from various suppliers and applied hydrogen-deuterium exchange mass spectrometry (HDX-MS) to provide a snapshot of the conformational dynamics of GFAP in artificial cerebrospinal fluid (aCSF) compared to the phosphate buffer. Our findings indicate that recombinant GFAP exists in various conformational species. Furthermore, we show that GFAP dimers remained intact under denaturing conditions. HDX-MS experiments show an overall decrease in H-bonding and an increase in solvent accessibility of GFAP in aCSF compared to the phosphate buffer, with clear indications of mixed EX2 and EX1 kinetics. To understand possible structural interface regions and the evolutionary conservation profiles, we combined HDX-MS results with the predicted GFAP-dimer structure by AlphaFold-Multimer. We found that deprotected regions with high structural flexibility in aCSF overlap with predicted conserved dimeric 1B and 2B domain interfaces. Structural property predictions combined with the HDX data show an overall deprotection and signatures of aggregation in aCSF. We anticipate that the outcomes of this research will contribute to a deeper understanding of the structural flexibility of GFAP and ultimately shed light on its behavior in different biological matrices.
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Medição da Troca de Deutério , Proteína Glial Fibrilar Ácida , Fosfatos , Humanos , Medição da Troca de Deutério/métodos , Proteína Glial Fibrilar Ácida/química , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/fisiologia , Conformação Proteica , Reprodutibilidade dos Testes , Proteínas RecombinantesRESUMO
Ecological and evolutionary transitions offer an excellent opportunity to examine the molecular basis of adaptation. Fishes of the order Beloniformes include needlefishes, flyingfishes, halfbeaks, and allies, and comprise over 200 species occupying a wide array of habitats-from the marine epipelagic zone to tropical rainforest rivers. These fishes also exhibit a diversity of diets, including piscivory, herbivory, and zooplanktivory. We investigated how diet and habitat affected the molecular evolution of cone opsins, which play a key role in bright light and colour vision and are tightly linked to ecology and life history. We analyzed a targeted-capture dataset to reconstruct the evolutionary history of beloniforms and assemble cone opsin sequences. We implemented codon-based clade models of evolution to examine how molecular evolution was affected by habitat and diet. We found high levels of positive selection in medium- and long-wavelength beloniform opsins, with piscivores showing increased positive selection in medium-wavelength opsins and zooplanktivores showing increased positive selection in long-wavelength opsins. In contrast, short-wavelength opsins showed purifying selection. While marine/freshwater habitat transitions have an effect on opsin molecular evolution, we found that diet plays a more important role. Our study suggests that evolutionary transitions along ecological axes produce complex adaptive interactions that affect patterns of selection on genes that underlie vision.
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Opsinas dos Cones , Animais , Opsinas dos Cones/genética , Filogenia , Opsinas/genética , Peixes/genética , Evolução MolecularRESUMO
BACKGROUND: Consistent patterns of reduced cortical thickness have been identified in early Alzheimer's disease (AD). However, the pathological factors that influence rates of cortical thinning within these AD signature regions remain unclear. METHODS: Participants were from the Insight 46 substudy of the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort), a prospective longitudinal cohort study. Linear regression was used to examine associations of baseline cerebral ß-amyloid (Aß) deposition, measured using florbetapir positron emission tomography, and baseline white matter hyperintensity volume (WMHV) on MRI, a marker of cerebral small vessel disease, with subsequent longitudinal changes in AD signature cortical thickness quantified from baseline and repeat MRI (mean [SD] interval 2.4 [0.2] years). RESULTS: In a population-based sample of 337 cognitively normal older white adults (mean [SD] age at baseline 70.5 [0.6] years; 48.1% female), higher global WMHV at baseline related to faster subsequent rates of cortical thinning in both AD signature regions (~0.15%/year faster per 10 mL additional WMHV), whereas baseline Aß status did not. Among Aß positive participants (n=56), there was some evidence that greater global Aß standardised uptake value ratio at baseline related to faster cortical thinning in the AD signature Mayo region, but this did not reach statistical significance (p=0.08). CONCLUSIONS: Cortical thinning within AD signature regions may develop via cerebrovascular pathways. Perhaps reflecting the age of the cohort and relatively low prevalence of Aß-positivity, robust Aß-related differences were not detected. Longitudinal follow-up incorporating additional biomarkers will allow assessment of how these relationships evolve closer to expected dementia onset.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Afinamento Cortical Cerebral , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Substância Branca , Humanos , Feminino , Masculino , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Estudos Longitudinais , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Afinamento Cortical Cerebral/diagnóstico por imagem , Afinamento Cortical Cerebral/patologia , Estudos Prospectivos , Etilenoglicóis , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Córtex Cerebral/metabolismo , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/patologia , Compostos de AnilinaRESUMO
The Society for Craniofacial Genetics and Developmental Biology (SCGDB) held its 46th Annual Meeting at Cincinnati Children's Hospital Medical Center in Cincinnati, Ohio on October 10th-12th, 2023. On the first day of the meeting, Drs. Sally Moody and Justin Cotney were each honored with the SCGDB Distinguished Scientist Awards for their exceptional contributions to the field of craniofacial biology. The following two days of the meeting featured five sessions that highlighted new discoveries in signaling and genomic mechanisms regulating craniofacial development, human genetics, translational and regenerative approaches, and clinical management of craniofacial differences. Interactive workshops on spatial transcriptomics and scientific communication, as well as a poster session facilitated meaningful interactions among the 122 attendees representing diverse career stages and research backgrounds in developmental biology and genetics, strengthened the SCGDB community.
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Anormalidades Craniofaciais , Biologia do Desenvolvimento , Humanos , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologiaRESUMO
BACKGROUND: There is little international data on morbidity and mortality of surgery for perforated peptic ulcer (PPU). This study aimed to understand the global 30-day morbidity and mortality of patients undergoing surgery for PPU and to identify variables associated with these. METHOD: We performed an international study of adults (≥ 18 years) who underwent surgery for PPU from 1st January 2022 to 30th June 2022. Patients who were treated conservatively or had an underlying gastric cancer were excluded. Patients were divided into subgroups according to age (≤ 50 and > 50 years) and time from onset of symptoms to hospital presentation (≤ 24 and > 24 h). Univariate and Multivariate analyses were carried out to identify factors associated with higher 30-day morbidity and mortality. RESULTS: 1874 patients from 159 centres across 52 countries were included. 78.3% (n = 1467) of the patients were males and the median (IQR) age was 49 years (25). Thirty-day morbidity and mortality were 48.5% (n = 910) and 9.3% (n = 174) respectively. Median (IQR) hospital stay was 7 (5) days. Open surgery was performed in 80% (n = 1505) of the cohort. Age > 50 years [(OR = 1.7, 95% CI 1.4-2), (OR = 4.7, 95% CI 3.1-7.6)], female gender [(OR = 1.8, 95% CI 1.4-2.3), (OR = 1.9, 95% CI 1.3-2.9)], shock on admission [(OR = 2.1, 95% CI 1.7-2.7), (OR = 4.8, 95% CI 3.2-7.1)], and acute kidney injury [(OR = 2.5, 95% CI 1.9-3.2), (OR = 3.9), 95% CI 2.7-5.6)] were associated with both 30-day morbidity and mortality. Delayed presentation was associated with 30-day morbidity [OR = 1.3, 95% CI 1.1-1.6], but not mortality. CONCLUSIONS: This study showed that surgery for PPU was associated with high 30-day morbidity and mortality rate. Age, female gender, and signs of shock at presentation were associated with both 30-day morbidity and mortality.
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Úlcera Péptica Perfurada , Humanos , Úlcera Péptica Perfurada/cirurgia , Úlcera Péptica Perfurada/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/etiologia , Tempo de Internação/estatística & dados numéricos , Saúde Global , Fatores de RiscoRESUMO
BACKGROUND: There are concerns that airway management in patients with suspected or confirmed cervical spine injury may exacerbate an existing neurological deficit, cause a new spinal cord injury or be hazardous due to precautions to avoid neurological injury. However, there are no evidence-based guidelines for practicing clinicians to support safe and effective airway management in this setting. METHODS: An expert multidisciplinary, multi-society working party conducted a systematic review of contemporary literature (January 2012-June 2022), followed by a three-round Delphi process to produce guidelines to improve airway management for patients with suspected or confirmed cervical spine injury. RESULTS: We included 67 articles in the systematic review, and successfully agreed 23 recommendations. Evidence supporting recommendations was generally modest, and only one moderate and two strong recommendations were made. Overall, recommendations highlight key principles and techniques for pre-oxygenation and facemask ventilation; supraglottic airway device use; tracheal intubation; adjuncts during tracheal intubation; cricoid force and external laryngeal manipulation; emergency front-of-neck airway access; awake tracheal intubation; and cervical spine immobilisation. We also signpost to recommendations on pre-hospital care, military settings and principles in human factors. CONCLUSIONS: It is hoped that the pragmatic approach to airway management made within these guidelines will improve the safety and efficacy of airway management in adult patients with suspected or confirmed cervical spine injury.
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Manuseio das Vias Aéreas , Vértebras Cervicais , Serviços Médicos de Emergência , Traumatismos da Coluna Vertebral , Humanos , Manuseio das Vias Aéreas/métodos , Manuseio das Vias Aéreas/normas , Vértebras Cervicais/lesões , Traumatismos da Coluna Vertebral/terapia , Serviços Médicos de Emergência/métodos , Serviços Médicos de Emergência/normas , Sociedades Médicas , Intubação Intratraqueal/métodos , Técnica DelphiRESUMO
Heterotopic ossification is the inappropriate formation of bone in soft tissues of the body. It can manifest spontaneously in rare genetic conditions or as a response to injury, known as acquired heterotopic ossification. There are several experimental models for studying acquired heterotopic ossification from different sources of damage. However, their tenuous mechanistic relevance to the human condition, invasive and laborious nature and/or lack of amenability to chemical and genetic screens, limit their utility. To address these limitations, we developed a simple zebrafish injury model that manifests heterotopic ossification with high penetrance in response to clinically emulating injuries, as observed in human myositis ossificans traumatica. Using this model, we defined the transcriptional response to trauma, identifying differentially regulated genes. Mutant analyses revealed that an increase in the activity of the potassium channel Kcnk5b potentiates injury response, whereas loss of function of the interleukin 11 receptor paralogue (Il11ra) resulted in a drastically reduced ossification response. Based on these findings, we postulate that enhanced ionic signalling, specifically through Kcnk5b, regulates the intensity of the skeletogenic injury response, which, in part, requires immune response regulated by Il11ra.
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Ossificação Heterotópica , Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Peixe-Zebra/genética , Ossificação Heterotópica/genética , Ossificação Heterotópica/patologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Regulação da Expressão Gênica , Envelhecimento/genética , Envelhecimento/patologia , Ferimentos e Lesões/complicações , Ferimentos e Lesões/genética , Ferimentos e Lesões/patologia , Modelos Animais de Doenças , Mutação/genéticaRESUMO
Central nervous system histoplasmosis is a serious complication of a common endemic mycosis, but it is rare in immunocompetent hosts. SARS-CoV-2 has introduced significant challenges into the healthcare setting with overlapping clinical presentations that may delay the diagnosis of alternative conditions. Additionally, it may lead to immune dysregulation and increase the risk for secondary infections, including invasive fungal diseases. Limited reports have described disseminated histoplasmosis in adults associated with COVID-19, but none have described central nervous system infection or complications in pediatric patients. We report a case of disseminated histoplasmosis involving the central nervous system in a previously healthy 13-year-old male with SARS-CoV-2 infection. An extensive immunological evaluation did not identify an underlying immunodeficiency. We highlight the potential of COVID-19 immune dys-regulation to contribute to the development or progression of invasive fungal disease. [Pediatr Ann. 2024;53(8):e305-e309.].
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COVID-19 , Infecções Fúngicas do Sistema Nervoso Central , Histoplasmose , Humanos , Adolescente , Histoplasmose/diagnóstico , Histoplasmose/tratamento farmacológico , Histoplasmose/complicações , Masculino , COVID-19/complicações , COVID-19/diagnóstico , Infecções Fúngicas do Sistema Nervoso Central/diagnóstico , Antifúngicos/uso terapêutico , SARS-CoV-2RESUMO
G protein-coupled receptors (GPCRs) bind to different G protein α-subtypes with varying degrees of selectivity. The mechanism by which GPCRs achieve this selectivity is still unclear. Using 13C methyl methionine and 19F NMR, we investigate the agonist-bound active state of ß1AR and its ternary complexes with different G proteins in solution. We find the receptor in the ternary complexes adopts very similar conformations. In contrast, the full agonist-bound receptor active state assumes a conformation differing from previously characterised activation intermediates or from ß1AR in ternary complexes. Assessing the kinetics of binding for the agonist-bound receptor with different G proteins, we find the increased affinity of ß1AR for Gs results from its much faster association with the receptor. Consequently, we suggest a kinetic-driven selectivity gate between canonical and secondary coupling which arises from differential favourability of G protein binding to the agonist-bound receptor active state.
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Proteínas de Ligação ao GTP , Receptores Acoplados a Proteínas G , Receptores Acoplados a Proteínas G/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Ligação ProteicaRESUMO
Global health reciprocal innovation (GHRI) is a recent and more formalised approach to conducting research that recognises and develops innovations (eg, medicines, devices, methodologies) from low- and middle-income countries (LMICs). At present, studies using GHRI most commonly adapt innovations from LMICs for use in high-income countries (HICs), although some develop innovations in LMICs and HICs. In this paper, we propose that GHRI implicitly makes two ethical commitments: (1) to promote health innovations from LMICs, especially in HICs, and (2) to conduct studies on health innovations from LMICs in equitable partnerships between investigators in LMICs and HICs. We argue that these commitments take a significant step towards a more equal global health research enterprise while helping to ensure that populations and investigators in LMICs receive equitable benefits from studies using GHRI. However, studies using GHRI can raise potential ethical concerns and face legal and regulatory barriers. We propose ethical, legal and regulatory considerations to help address these concerns and barriers. We hope our recommendations will allow GHRI to move the global health research enterprise forward into an era where all people are treated equally as knowers and learners, while populations in both LMICs and HICs benefit equitably from studies using GHRI.
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Países em Desenvolvimento , Saúde Global , Humanos , Pesquisa Biomédica/ética , Pesquisa Biomédica/legislação & jurisprudência , Difusão de Inovações , Cooperação InternacionalRESUMO
BACKGROUND: Although elective procedures have life-changing potential, all surgeries come with an inherent risk of reoperation. There is a gap in knowledge investigating the risk of reoperation across orthopaedics. We aimed to identify the elective orthopaedic procedures with the highest rate of unplanned reoperation and the reasons for these procedures having such high reoperation rates. METHODS: Patients in the NSQIP database were identified using CPT and ICD-10 codes. We isolated 612,815 orthopaedics procedures from 2018 to 2020 and identified the 10 CPT codes with the greatest rate of unplanned return to the operating room. For each index procedure, we identified the ICD-10 codes for the reoperation procedure and categorized them into infection, mechanical failure, fracture, wound disruption, hematoma or seroma, nerve pathology, other, and unspecified. RESULTS: Below knee amputation (BKA) (CPT 27880) had the highest reoperation rate of 6.92% (37 of 535 patients). Posterior-approach thoracic (5.86%) or cervical (4.14%) arthrodesis and cervical laminectomy (3.85%), revision total hip arthroplasty (5.23%), conversion to total hip arthroplasty (4.33%), and revision shoulder arthroplasty (4.22%) were among the remaining highest reoperation rates. The overall leading causes of reoperation were infection (30.1%), mechanical failure (21.1%), and hematoma or seroma (9.4%) for the 10 procedures with the highest reoperation rates. CONCLUSIONS: This study successfully identified the elective orthopaedic procedures with the highest 30-day return to OR rates. These include BKA, posterior thoracic and cervical spinal arthrodesis, revision hip arthroplasty, revision total shoulder arthroplasty, and cervical laminectomy. With this data, we can identify areas across orthopaedics in which revising protocols may improve patient outcomes and limit the burden of reoperations on patients and the healthcare system. Future studies should focus on the long-term physical and financial impact that these reoperations may have on patients and hospital systems. LEVEL OF CLINICAL EVIDENCE: IV.
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Procedimentos Cirúrgicos Eletivos , Salas Cirúrgicas , Procedimentos Ortopédicos , Reoperação , Humanos , Reoperação/estatística & dados numéricos , Procedimentos Ortopédicos/métodos , Procedimentos Ortopédicos/estatística & dados numéricos , Feminino , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Masculino , Pessoa de Meia-Idade , Medição de Risco , Bases de Dados Factuais , IdosoRESUMO
Recent adaptive radiations provide evolutionary case studies, which provide the context to parse the relationship between genomic variation and the origins of distinct phenotypes. Sympatric radiations of the charr complex (genus Salvelinus) present a trove for phylogenetics as charrs have repeatedly diversified into multiple morphs with distinct feeding specializations. However, species flocks normally comprise only two to three lineages. Dolly Varden charr inhabiting Lake Kronotske represent the most extensive radiation described for the charr genus, containing at least seven lineages, each with defining morphological and ecological traits. Here, we perform the first genome-wide analysis of this species flock to parse the foundations of adaptive change. Our data support distinct, reproductively isolated lineages with little evidence of hybridization. We also find that specific selection on thyroid signaling and craniofacial genes forms a genomic basis for the radiation. Thyroid hormone is further implicated in subsequent lineage partitioning events. These results delineate a clear genetic basis for the diversification of specialized lineages, and highlight the role of developmental mechanisms in shaping the forms generated during adaptive radiation.
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BACKGROUND: Individuals with PPP2R5D-related neurodevelopmental disorder have an atypical gait pattern characterized by ataxia and incoordination. Structured, quantitative assessments are needed to further understand the impact of these impairments on function. RESEARCH QUESTION: How do gait parameters and ambulatory function of individuals with PPP2R5D-related neurodevelopmental disorder compare to age and sex matched healthy norms? METHODS: Twenty-six individuals with PPP2R5D pathogenic genetic variants participated in this observational, single visit study. Participants completed at least one of the following gait assessments: quantitative gait analysis at three different speeds (preferred pace walking (PPW), fast paced walking (FPW) and running, six-minute walk test (6MWT), 10-meter walk run (10MWR), and timed up and go (TUG). Descriptive statistics were used to summarize gait variables. Percent of predicted values were calculated using published norms. Paired t-tests and regression analyses were used to compare gait variables. RESULTS: The median age of the participants was 8 years (range 4-27) and eighteen (69.2 %) were female. Individuals with PPP2R5D-related neurodevelopmental disorder walked slower and with a wider base of support than predicted for their age and sex. Stride velocity ranged from 48.9 % to 70.1 % and stride distance from 58.5 % to 81.9 % of predicted during PPW. Percent of predicted distance walked on the 6MWT ranged from 30.6 % to 71.1 % representing varied walking impairment. Increases in stride distance, not cadence, were associated with changes in stride velocity in FPW (R2 = 0.675, p =< 0.001) and running conditions (R2 = 0.918, p =< 0.001). SIGNIFICANCE: We quantitatively assessed the abnormal gait in individuals with PPP2R5D-related neurodevelopmental disorder. These impairments may affect ability to adapt to environmental changes and participation in daily life. Rehabilitative interventions targeting gait speed and balance may improve function and safety for individuals with PPP2R5D-related neurodevelopmental disorder.
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Transtornos do Neurodesenvolvimento , Proteína Fosfatase 2 , Humanos , Feminino , Masculino , Criança , Adolescente , Transtornos do Neurodesenvolvimento/fisiopatologia , Pré-Escolar , Adulto Jovem , Adulto , Teste de Caminhada , Análise da Marcha , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Neurológicos da Marcha/etiologia , Marcha/fisiologia , Caminhada/fisiologiaRESUMO
Purpose: To synthesize existing literature regarding the indications and outcomes of femoral rotational osteotomies (FDO) for femoroacetabular impingement (FAI) due to. Methods: Medline, Cochrane, and Embase were searched using keywords "femoroacetabular impingement", "rotational osteotomy" and others to identify FAI patients undergoing FDO. Double-screened studies were reviewed by blinded authors according to inclusion criteria. Data from full texts was extracted including study type, number of patients, sex, mean age, surgical indication, type of dysplasia, associated pathology, surgical technique, follow-up, and pre-op/post-op evaluations of the following: impingement test, femoral version (FV), 'other angles measured', outcome scores, range of motion (ROM). Results: 7 studies including 91 patients (97 FDO surgeries), 73 females (80 %) with mean age of 28.3 years, and follow-up mean of 2.44 ± 2.83 years. Pain or impingement was the most common clinical indication, while others included aberrant FV and ROM measurements for both anteverted and retroverted femurs. There were reports of FDO being performed with concomitant procedures addressing other pathology. Various outcome scores and ROM measurements showed postoperative improvement after FDO. Complication data was sparse, preventing aggregation. The rate of unplanned reoperation was 40 % (where reported), with 'hardware removal' being the most common. Conclusions: FDO is effective in treating FAI due to increased FV, improving clinical symptoms, and potentially delaying articular degeneration. Hardware removal surgery remains an inherent risk in undergoing FDO. Further work is needed to discover indications warranting FDO as a primary treatment versus hip arthroscopy. Level of evidence: This review contains 4 studies with Level IV evidence and 3 studies with Level III evidence.
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BACKGROUND: Protein phosphatase 2 regulatory subunit B' Delta (PPP2R5D)-related neurodevelopmental disorder is a rare genetic condition caused by pathogenic variants in the PPP2R5D gene. Clinical signs include hypotonia, gross motor delay, intellectual disability (ID), epilepsy, speech delays, and abnormal gait among other impairments. As this disorder was recognized within the last decade, there are only 103 people published diagnoses to date. A thorough understanding of the motor manifestations of this disorder has not yet been established. Knowledge of the natural history of PPP2R5D related neurodevelopmental disorder will lead to improved standard of care treatments as well as serve as a baseline foundation for future clinical trials. Appropriate outcome measures are necessary for use in clinical trials to uniformly measure function and monitor potential for change. The aim of this study was to validate the gross motor function measure (GMFM) in children and adults with PPP2R5D-related neurodevelopmental disorder in order to better characterize the disorder. RESULTS: Thirty-eight individuals with PPP2R5D pathogenic variants, median age 8.0 years (range 1-27) were evaluated. Gross motor, upper limb and ambulatory function were assessed using the GMFM-66, six-minute walk test (6MWT), 10-meter walk run (10MWR), timed up and go (TUG), and revised upper limb module (RULM). The pediatric disability inventory computer adapted test (PEDI-CAT) captured caregiver reported assessment. Median GMFM-66 score was 60.6 (SD = 17.3, range 21.1-96.0). There were strong associations between the GMFM-66 and related mobility measures, 10MWR (rs = -0.733; p < 0.001), TUG (rs= -0.747; p = 0.003), 6MWT (r = 0.633; p = 0.006), RULM (r = 0.763; p < 0.001), PEDICAT-mobility (r = 0.855; p < 0.001), and daily activities (r = 0.822; p < 0.001) domains. CONCLUSIONS: The GMFM is a valid measure for characterizing motor function in individuals with PPP2R5D related neurodevelopmental disorder. The GMFM-66 had strong associations with the RULM and timed function tests which characterized gross motor, upper limb and ambulatory function demonstrating concurrent validity. The GMFM-66 was also able to differentiate between functional levels in PPP2R5D related neurodevelopmental disorder demonstrating discriminant validity. Future studies should examine its sensitivity to change over time, ability to identify sub-phenotypes, and suitability as an outcome measure in future clinical trials in individuals with PPP2R5D variants.
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Paralisia Cerebral , Deficiência Intelectual , Criança , Humanos , Lactente , Pré-Escolar , Adolescente , Adulto Jovem , Adulto , Paralisia Cerebral/diagnóstico , Marcha , Avaliação de Resultados em Cuidados de Saúde , Destreza Motora , Proteína Fosfatase 2/genéticaRESUMO
The transition from fins to limbs has been a rich source of discussion for more than a century. One open and important issue is understanding how the mechanisms that pattern digits arose during vertebrate evolution. In this context, the analysis of Hox gene expression and functions to infer evolutionary scenarios has been a productive approach to explain the changes in organ formation, particularly in limbs. In tetrapods, the transcription of Hoxd genes in developing digits depends on a well-characterized set of enhancers forming a large regulatory landscape1,2. This control system has a syntenic counterpart in zebrafish, even though they lack bona fide digits, suggestive of deep homology3 between distal fin and limb developmental mechanisms. We tested the global function of this landscape to assess ancestry and source of limb and fin variation. In contrast to results in mice, we show here that the deletion of the homologous control region in zebrafish has a limited effect on the transcription of hoxd genes during fin development. However, it fully abrogates hoxd expression within the developing cloaca, an ancestral structure related to the mammalian urogenital sinus. We show that similar to the limb, Hoxd gene function in the urogenital sinus of the mouse also depends on enhancers located in this same genomic domain. Thus, we conclude that the current regulation underlying Hoxd gene expression in distal limbs was co-opted in tetrapods from a preexisting cloacal program. The orthologous chromatin domain in fishes may illustrate a rudimentary or partial step in this evolutionary co-option.
RESUMO
Antagonism of the human adenosine A3 receptor (hA3R) has potential therapeutic application. Alchemical relative binding free energy calculations of K18 and K32 suggested that the combination of a 3-(2,6-dichlorophenyl)-isoxazolyl group with 2-pyridinyl at the ends of a carbonyloxycarboximidamide group should improve hA3R affinity. Of the 25 new analogues synthesized, 37 and 74 showed improved hA3R affinity compared to K18 (and K32). This was further improved through the addition of a bromine group to the 2-pyridinyl at the 5-position, generating compound 39. Alchemical relative binding free energy calculations, mutagenesis studies and MD simulations supported the compounds' binding pattern while suggesting that the bromine of 39 inserts deep into the hA3R orthosteric pocket, so highlighting the importance of rigidification of the carbonyloxycarboximidamide moiety. MD simulations highlighted the importance of rigidification of the carbonyloxycarboximidamide, while suggesting that the bromine of 39 inserts deep into the hA3R orthosteric pocket, which was supported through mutagenesis studies 39 also selectively antagonized endogenously expressed hA3R in nonsmall cell lung carcinoma cells, while pharmacokinetic studies indicated low toxicity enabling in vivo evaluation. We therefore suggest that 39 has potential for further development as a high-affinity hA3R antagonist.