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Background: Shoulder replacement is a reliable treatment for the relief of pain and improvement of function in patients with glenohumeral arthritis, rotator cuff arthropathy, osteonecrosis and fracture. Limited data is available comparing revision rates for the different types of shoulder replacement when used in younger patients. This study aims to compare the survivorship of hemi resurfacing, stemmed hemiarthroplasty, total shoulder arthroplasty and reverse total shoulder arthroplasty in younger patients using data from a large national arthroplasty registry. Methods: Data from the Australian Orthopaedic Association National Joint Replacement Registry was obtained for the period 16 April 2004-31 December 2018. The study population included all shoulder arthroplasty patients aged <65â years. These were stratified into two groups: <55â years and 55-64â years. A total of 8742 primary shoulder arthroplasty procedures were analysed (1936 procedures in the <55â years and 6806 in the 55-64â years age group). Results: In the <55â years age group, there was no difference in revision rate for total shoulder arthroplasty versus reverse total shoulder arthroplasty at any time point. Reverse total shoulder arthroplasty had a lower revision rate after six months when compared to hemi resurfacing (HRA) (p = 0.031). Also, reverse total shoulder arthroplasty had a higher early rate of revision in the first 12â months compared to hemiarthroplasty (p = 0.018). However, from 2 years reverse total shoulder arthroplasty had a lower revision rate overall (p = 0.029).In the 55-64â years patient age group, reverse total shoulder arthroplasty had a lower earlier revision rate. This was statistically significant compared to hemi resurfacing (HRA) (p = 0.028), hemiarthroplasty (p = 0.049) and total shoulder arthroplasty (p < 0.001). Conclusion: This study demonstrated that for patients aged <55â years there was no significant difference in the rate of revision when total shoulder arthroplasty and reverse total shoulder arthroplasty were compared. reverse total shoulder arthroplasty had a lower rate of revision when compared to hemi resurfacing and hemiarthroplasty after 2 years. reverse total shoulder arthroplasty had the lowest comparative revision rate in patients aged 55-64â years overall.
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The Trillat procedure has been described for the management of shoulder instability in younger patients but also for shoulder instability in older patients with irreparable rotator cuff tears. We describe an all-arthroscopic technique using screw fixation. This technique allows for safe dissection, clearance and osteotomy of the coracoid, and direct visualization during screw tensioning and fixation to minimize the risk of subscapularis impingement. We outline our stepwise approach to medialize and distalize the coracoid process using arthroscopic screw fixation and present pearls to avoid fracture through the superior bone bridge.
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In continuum bone remodelling, bone is considered as continuous matter on the macroscale. Motivated by i) the underlying trabecular microstructure of bone resulting in size-dependence and ii) the non-local characteristics of osteocyte mechanosensing, a novel phenomenological approach based on a micromorphic formulation is proposed. Via illustrative benchmark examples, i.e. elementary unit cube, rod-shaped bone samples, and a 3D-femur sample, the novel approach is compared to the established local formulation, and the influence of the characteristic size of the microcontinuum and the coupling between macro- and microscale deformation is analysed. Taken together, the interaction between continuum points at the macroscale and their neighbourhood is effectively captured by the micromorphic formulation thus influencing the resulting distribution of nominal bone density at the macroscale.
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BACKGROUND: The treatment of shoulder osteoarthritis in the young patient remains challenging. The higher functional demands and higher expectations of the young patient cohort are often coupled with increased failure and revision rates. Consequently, shoulder surgeons are faced with a unique challenge with implant selection. The aim of this study was to compare the survivorship and reasons for revision of 5 classes of shoulder arthroplasty in patients aged <55 years with a primary diagnosis of osteoarthritis by use of data from a large national arthroplasty registry. METHODS: The study population included all primary shoulder arthroplasty procedures undertaken for osteoarthritis in patients aged <55 years and reported to the registry between September 1999 and December 2021. Procedures were grouped into the following classes: total shoulder arthroplasty (TSA), hemiarthroplasty resurfacing (HRA), hemiarthroplasty stemmed metallic head (HSMH), hemiarthroplasty stemmed pyrocarbon head (HSPH), and reverse total shoulder arthroplasty (RTSA). The outcome measure was the cumulative percent revision, which was defined using Kaplan-Meier estimates of survivorship to describe the time to the first revision. Hazard ratios (HRs) were calculated from Cox proportional hazards models, adjusting for age and sex, to compare revision rates among groups. RESULTS: There were 1564 shoulder arthroplasty procedures in patients aged <55 years, of which 361 (23.1%) were HRA, 70 (4.5%) were HSMH, 159 (10.2%) were HSPH, 714 (45.7%) were TSA, and 260 (16.6%) were RTSA. HRA had a higher rate of revision than RTSA after 1 year (HRA = 2.51 (95% CI 1.30, 4.83), P = .005), with no difference prior to that time. In addition, HSMH had a higher rate of revision than RTSA for the entire period (HR, 2.69 [95% confidence interval, 1.28-5.63], P = .008). There was no significant difference in the rate of revision for HSPH and TSA when they were compared with RTSA. Glenoid erosion was the most common cause of revision for HRA (28.6% of revisions) and HSMH (50%). Instability/dislocation was the leading cause of revision for RTSA (41.7%) and HSPH (28.6%), and for TSA, the majority of revisions were for either instability/dislocation (20.6%) or loosening (18.6%). CONCLUSION: These results should be interpreted within the context of the lack of availability of long-term data on RTSA and HSPH stems. RTSA outperforms all implants regarding revision rates at mid-term follow-up. The high early dislocation rate associated with RTSA, as well as the lack of revision options available to address this, indicates that careful selection of patients and a greater appreciation of anatomic risk factors are needed in the future.
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Artroplastia do Ombro , Artroplastia de Substituição , Luxações Articulares , Ortopedia , Osteoartrite , Articulação do Ombro , Humanos , Artroplastia do Ombro/efeitos adversos , Articulação do Ombro/cirurgia , Sobrevivência , Resultado do Tratamento , Estudos Retrospectivos , Austrália , Reoperação , Luxações Articulares/cirurgia , Sistema de RegistrosRESUMO
BACKGROUND: The most common complication with reverse shoulder arthroplasty Grammont based design with a 155° neck shaft angle (NSA) is scapular notching. Scapular notching has been associated with reduced clinical outcomes. Reducing the humeral NSA from 155° has been shown to reduce the incidence of scapular notching however it is unknown whether there is a difference in scapular notching between a 145° and 135° NSA. The purpose of this study was to evaluate the effect of decreasing the NSA on scapular notching rate and postoperative range of motion comparing 145° and 135° NSA stems at minimum 2 yr of follow-up. METHODS: Consecutive patients undergoing primary reverse shoulder arthroplasty with a NSA of either 145° or 135° between January 2014 and February 2019 were retrospectively reviewed. Patients were included if they were over the age of 18, had minimum clinical follow-up of 24 mo with true postoperative anteroposterior radiographic view. RESULTS: One hundred and three patients were included for the final analysis: 73 with a 145° NSA and 30 with a 135° NSA stem. The mean age and mean follow-up were respectively 70.9 yr (range, 52.0-89.0) and 32.1 mo. The overall incidence of scapular notching was 46.6 %. There was a statistically significant difference in scapular notching between the 145° (53.4%) and 135° (30%) NSA groups (P = .028). There was no difference in terms of postoperative Constant-Murley Score (mean, 66.1 vs. 68.2; P = .395), Subjective Shoulder Value (mean, 76.5 vs. 83.1%, P = .167), forward flexion (mean, 140° vs. 142°, P = .704), abduction (mean, 123.2° vs. 121.5°, P = .771), external rotation with the arm at the side (mean, 34.1° vs. 37.3°, P = .341) and internal rotation (mean, 5.3 vs. 5.4 pts P = .336) between the 2 groups. CONCLUSION: This is the first study to compare the effect of a 145° vs. 135° NSA on scapular notching rates. The key finding of this study is that scapular notching rate was significantly reduced from 53% to 30% in 135° NSA compared to 145° NSA, after at least 24 mo of follow-up. Our data also show that glenoid lateralization and inferiorization has an influence on scapular notching. We are unable to state that the reduced scapular notching rate was due to a reduction in NSA alone. Despite a lower rate of scapular notching, the 135° NSA group has not shown any significant better clinical and functional outcomes.
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Artroplastia do Ombro , Articulação do Ombro , Prótese de Ombro , Humanos , Adulto , Pessoa de Meia-Idade , Artroplastia do Ombro/efeitos adversos , Articulação do Ombro/diagnóstico por imagem , Articulação do Ombro/cirurgia , Seguimentos , Estudos Retrospectivos , Ombro/cirurgia , Amplitude de Movimento Articular , Resultado do TratamentoRESUMO
Monkeypox, a member of the Orthopoxvirus genu, has been the center of global attention since it has been declared a public health emergency by the World Health Organization. Typically, it is a self-limiting disease; however, it can occasionally have severe presentations in patients with underlying conditions, such as HIV, malignancy, and transplantation. In this article, we will present a case of an immunocompetent patient with a severe presentation of monkeypox. The patient presented with facial pustules with superimposed bacterial infection; furthermore, he had painful vesicles in oral and nasal mucosa and the penis. Dermatologic conditions such as atopic dermatitis has been associated with severe monkeypox. While our patient does not have a history of atopic dermatitis, he does report contact dermatitis as well as a history of skin infections. Researchers have hypothesized that disruption of the skin barrier allows for proliferation of the monkeypox virus; therefore, it is important to take a thorough history of the patient's skin conditions. Lastly, we described the use of Tecovirimat in our patient. Although it is impossible to demonstrate the efficacy of this medication without a randomized clinical trial, our patient seemed to have a faster improvement of the lesions after initiating this antiviral.
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There is growing evidence that individual bacteria sense and respond to changes in mechanical loading. However, the subtle responses of multispecies biofilms to dynamic fluid shear stress are not well documented because experiments often fail to disentangle any beneficial effects of shear stress from those delivered by convective transport of vital nutrients. We observed the development of biofilms with lognormally distributed microcolony sizes in drinking water on the walls of flow channels underflow regimes of increasing complexity. First, where regular vortices induced oscillating wall shear and simultaneously enhanced mass transport, which produced the thickest most extensive biofilms. Second, where unsteady uniform flow imposed an oscillating wall shear, with no enhanced transport, and where the biomass and coverage were only 20% smaller. Finally, for uniform steady flows with constant wall shear where the extent, thickness, and density of the biofilms were on average 60% smaller. Thus, the dynamics of shear stress played a significant role in promoting biofilm development, over and above its magnitude or mass transfer effects, and therefore, mechanosensing may prevail in complex multispecies biofilms which could open up new ways of controlling biofilm structure.
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Biofilmes , Água Potável , Bactérias , Estresse MecânicoRESUMO
Serotonin 2A receptors (5-HT2ARs) mediate the hallucinogenic effects of psychedelic drugs and are a key target of the leading class of medications used to treat psychotic disorders. These findings suggest that dysfunction of 5-HT2ARs may contribute to the symptoms of schizophrenia, a mental illness characterized by perceptual and cognitive disturbances. Indeed, numerous studies have found that 5-HT2ARs are reduced in the brains of individuals with schizophrenia. However, the mechanisms that regulate 5-HT2AR expression remain poorly understood. Here, we show that a physiologic environmental stimulus, sleep deprivation, significantly upregulates 5-HT2AR levels in the mouse frontal cortex in as little as 6-8 h (for mRNA and protein, respectively). This induction requires the activity-dependent immediate early gene transcription factor early growth response 3 (Egr3) as it does not occur in Egr3 deficient (-/-) mice. Using chromatin immunoprecipitation, we show that EGR3 protein binds to the promoter of Htr2a, the gene that encodes the 5-HT2AR, in the frontal cortex in vivo, and drives expression of in vitro reporter constructs via two EGR3 binding sites in the Htr2a promoter. These results suggest that EGR3 directly regulates Htr2a expression, and 5-HT2AR levels, in the frontal cortex in response to physiologic stimuli. Analysis of publicly available post-mortem gene expression data revealed that both EGR3 and HTR2A mRNA are reduced in the prefrontal cortex of schizophrenia patients compared to controls. Together these findings suggest a mechanism by which environmental stimuli alter levels of a brain receptor that may mediate the symptoms, and treatment, of mental illness.
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Proteína 3 de Resposta de Crescimento Precoce , Receptor 5-HT2A de Serotonina , Privação do Sono , Animais , Proteína 3 de Resposta de Crescimento Precoce/metabolismo , Lobo Frontal , Genes Precoces , Camundongos , RNA Mensageiro , Receptor 5-HT2A de Serotonina/genética , Serotonina , Privação do Sono/genéticaRESUMO
BACKGROUND: The optimal surgical management of glenohumeral osteoarthritis in young patients remains an unsolved problem. Humeral resurfacing hemiarthroplasty and stemmed hemiarthroplasty using metallic heads are 2 surgical options that avoid the complications of loosening or wear of the glenoid component seen in total shoulder arthroplasty. Despite the potential benefits, improvement in survivorship has not been demonstrated from joint registry studies or other studies at mid-term follow-up. This is predominantly because of glenoid erosion and pain that occur when the metal resurfaced head articulates with the native glenoid. The use of pyrolytic carbon (pyrocarbon) as a resurfacing material has been proposed as an alternative bearing surface thought to reduce glenoid erosion owing to a marked reduction in wear rates in vitro. This study aimed to compare the survivorship of shoulder hemi-resurfacing using pyrocarbon with shoulder hemi-resurfacing and stemmed hemiarthroplasty using metallic heads. METHODS: Data from the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) were analyzed for all patients aged <55 years who had undergone a primary shoulder replacement for osteoarthritis from April 16, 2004, to December 31, 2019. The outcomes of shoulder procedures using pyrocarbon hemi-resurfacing were compared with procedures using metal hemi-resurfacing and metal stemmed hemiarthroplasty. The reasons for revision in each arthroplasty class were analyzed. The analyses were undertaken using Kaplan-Meier estimates of survivorship and hazard ratios (HRs) from Cox proportional hazards models. RESULTS: We analyzed 393 primary shoulder procedures, of which 163 were pyrocarbon hemi-resurfacing procedures, 163 were metal hemi-resurfacing procedures, and 67 were metal stemmed hemiarthroplasties.The cumulative percentage of revision at 6 years was 8.9% for pyrocarbon hemi-resurfacing, 17.1% for metal hemi-resurfacing, and 17.5% for metal stemmed hemiarthroplasty. Pyrocarbon hemi-resurfacing prostheses had a statistically lower revision rate than other hemi-resurfacing prostheses (HR, 0.41; 95% confidence interval, 0.18-0.93; P = .032). Pain, prosthesis fracture, and infection were the key reasons for revision. No pyrocarbon hemi-resurfacing cases were revised for glenoid erosion. In male patients, pyrocarbon humeral resurfacing had a lower cumulative percentage of revision compared with metal stemmed hemiarthroplasty (HR, 0.32; 95% confidence interval, 0.11-0.93; P = .037). CONCLUSION: Pyrocarbon humeral resurfacing arthroplasty had statistically lower revision rates at mid-term follow-up in patients aged <55 years compared with other hemi-resurfacing procedures.
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Carbono , Hemiartroplastia , Metais , Ortopedia , Osteoartrite , Articulação do Ombro , Adulto , Austrália , Seguimentos , Hemiartroplastia/instrumentação , Humanos , Úmero/cirurgia , Masculino , Pessoa de Meia-Idade , Ortopedia/métodos , Osteoartrite/cirurgia , Sistema de Registros , Reoperação/estatística & dados numéricos , Articulação do Ombro/cirurgia , Resultado do TratamentoRESUMO
OBJECTIVE: Racket and paddle sports are popular worldwide. Although there are several epidemiologic studies on tennis, there are limited epidemiologic studies on injuries in badminton, squash, racquetball, table tennis, pickleball and other racket and paddle sports. We aimed to analyze acute racket and paddle sports injuries that presented to emergency departments. DESIGN: Descriptive epidemiologic study; level of evidence 3. SETTING: United States emergency departments (USEDs). METHODS: Data from National Electronic Injury Surveillance System (NEISS) were queried to characterize racket and paddle sports-related (RPSR) injuries that presented to USEDs over a 10-year period. RESULTS: From 2007 to 2016, there were 7,723 cases of racket and paddle sports-related (RPSR) injuries that presented to USEDs. This data provides a weighted estimate of 301,038 RPSR injuries in USEDs over the 10-year study period. The majority (60.3) of these injuries were in men. Men had a higher percentage of injuries of most body parts except the lower arm, wrist, and ankle. The mean age at the time of injury was 37 years. The highest percentage of sprains, strains, and lower extremity injuries occurred in athletes between ages 18-40 years. Between sports, table tennis had highest percentage of skin and internal organ injuries while badminton had the highest percentage of sprains, strains, fractures, and dislocations. CONCLUSION: This study is the largest nationally representative study of RPSR injuries to date. RPSR injuries are varied in their presentation based on age, sex, body location, and type of injury. CLINICAL RELEVANCE: This study determined common RPSR injuries presenting to USEDs, their patterns, and severity over a 10-year period. Researchers and clinicians can begin to use this data for future research studies and may consider this early data in management decisions.
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Traumatismos em Atletas , Esportes com Raquete , Entorses e Distensões , Tênis , Adolescente , Adulto , Traumatismos em Atletas/epidemiologia , Serviço Hospitalar de Emergência , Humanos , Masculino , Entorses e Distensões/epidemiologia , Tênis/lesões , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Stress fractures of the upper limb affect athletes from a wide range of sports. Athletes involved in throwing sports are particularly susceptible along with athletes from sports involving high repetitive and compressive loads such as gymnastics. Diagnosis can be made from clinical history, examination and radiography in some cases however MRI imaging is often required for definitive diagnosis. The mainstay of management is rest and activity modification however advanced pathology often requires surgical management for successful resolution and return to play. In the elbow, the bones susceptible to excessive stress in sport are the distal humerus, the olecranon process of the ulna, the coronoid process of the ulna, the sublime tubercle and the radial head. In immature patients, medial epicondyle apophysis is the most common location. The article presents a narrative review of the literature.
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Traumatismos em Atletas/diagnóstico por imagem , Lesões no Cotovelo , Articulação do Cotovelo/diagnóstico por imagem , Fraturas Ósseas/diagnóstico por imagem , Fraturas de Estresse/diagnóstico por imagem , Traumatismos em Atletas/terapia , Fraturas Ósseas/terapia , Fraturas de Estresse/terapia , HumanosRESUMO
In young patients, irreparable subscapularis tears can be managed by latissimus dorsi (LD) transfer on the lesser tuberosity. We provide a technical guide for isolated LD anterior transfer. The surgical procedure begins with glenohumeral exploration and release of the remaining subscapularis. Then, we dissect the LD tendon below the subscapularis. At the upper and inferior borders, we dissect the LD from the teres major, protecting the radial nerve anteriorly and inferiorly. Next, we detach the LD. Inferiorly, we cut the aponeurotic expansion for the triceps. A Foley catheter is used as a shuttle relay, anterior to the axillary nerve and medial and posterior to the radial nerve. We continue with an open dissection of the LD, posterior to the axillary fossa, to release the LD from the skin and tip of the scapula. The LD is transferred on the lesser tuberosity after retrieved by the Foley catheter, with care taken not to twist the tendon. It is fixed with 2 lateral anchors and 1 medial anchor. A shoulder brace is worn for 6 weeks. Physiotherapy begins thereafter.
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The lower trapezius tendon (LTT) transfer has been described for the management of irreparable posterosuperior rotator cuff tears. Here we describe our technique of an arthroscopic-assisted LTT transfer using an Achilles tendon-bone allograft. This technique allows for augmentation of the tendon transfer using an Achilles tendon allograft while also keeping the calcaneal bone insertion, which allows for added bony fixation into the humerus and also minimizing the risk of the "killer turn" phenomenon at the aperture of fixation.
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Rationale: Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants worldwide. Although T-helper type 2 (Th2) cell pathology is implicated in severe disease, the mechanisms underlying the development of immunopathology are incompletely understood.Objectives: We aimed to identify local immune responses associated with severe RSV in infants. Our hypothesis was that disease severity would correlate with enhanced Th2 cellular responses.Methods: Nasal aspirates were collected from infants hospitalized with severe (admitted to the pediatric ICU) or moderate (maintained in the general ward) RSV disease at 5 to 9 days after enrollment. The immune response was investigated by evaluating T-lymphocyte cellularity, cytokine concentration, and viral load.Measurements and Main Results: Patients with severe disease had increased proportions of CD8 (cluster of differentiation 8)-positive T cells expressing IL-4 (Tc2) and reduced proportions of CD8+ T cells expressing IFNγ (Tc1). Nasal aspirates from patients with severe disease had reduced concentrations of IL-17. Patients with greater frequencies of Tc1, CD8+ T cells expressing IL-17 (Tc17), and CD4+ T cells expressing IL-17 (Th17) had shorter durations of hospitalization.Conclusions: Severe RSV disease was associated with distinct T-cell profiles. Tc1, Tc17, and Th17 were associated with shorter hospital stay and may play a protective role, whereas Tc2 cells may play a previously underappreciated role in pathology.
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Linfócitos T CD8-Positivos/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Correlação de Dados , Feminino , Humanos , Lactente , Recém-Nascido , Tempo de Internação , Masculino , Índice de Gravidade de DoençaRESUMO
Previous research has indicated that two components of reaching behavior, initiation time and reach curvature, exhibit distinct patterns of trial sequence effects in congruency tasks. The observed patterns have been proposed to reflect two dissociable processes underlying decision behavior, with initiation times capturing the functioning of a threshold adjustment process involving the temporary inhibition of motor output, and reach curvatures reflecting a controlled selection process that supports goal-driven stimulus-response translation. The tasks used in previous studies, however, did not control for a range of associative-priming confounds commonly featured in congruency tasks. Consequently, the extent to which the observed patterns reflected the proposed processes or associative-priming confounds remained unclear. We therefore presented 45 adult participants with a reach-tracking version of the Stroop task that featured both confound-minimized and confound-laden trials. Initiation times revealed main effects of previous and current congruency on both confound-minimized and confound-laden trials, consistent with the claim that initiation times can be used to target the functioning of the threshold adjustment process. Conversely, reach curvatures exhibited a clear sensitivity to associative-priming effects, revealing a congruency sequence effect on confound-laden but not on confound-minimized trials. This finding is consistent with the claim that reach curvatures can be used to target the functioning of the controlled selection process. Thus, by directly evaluating the influence of associative-priming confounds, the present study revealed the strongest evidence to date that decision behavior in tasks involving conflict is fundamentally structured by the functioning of two dissociable processes.
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Aprendizagem por Associação , Cognição , Conflito Psicológico , Tomada de Decisões , Movimento , Adulto , Feminino , Objetivos , Humanos , Inibição Psicológica , Masculino , Motivação , Tempo de Reação , Teste de Stroop , Adulto JovemRESUMO
We recently found that a cyclohexanecarboxamide derived from 4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-ene displayed low nanomolar inhibition of 11ß-HSD1. In continuation of our efforts to discover potent and selective 11ß-HSD1 inhibitors, herein we explored several replacements for the cyclohexane ring. Some derivatives exhibited potent inhibitory activity against human 11ß-HSD1, although with low selectivity over the isoenzyme 11ß-HSD2, and poor microsomal stability.
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11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Técnicas de Química Sintética , Desenho de Fármacos , Ativação Enzimática , Inibidores Enzimáticos/síntese química , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Relação Estrutura-AtividadeRESUMO
The peptide hormone human relaxin-2 (H2-RLX) has emerged as a potential therapy for cardiovascular and fibrotic diseases, but its short in vivo half-life is an obstacle to long-term administration. The discovery of ML290 demonstrated that it is possible to identify small molecule agonists of the cognate G-protein coupled receptor for H2-RLX (relaxin family peptide receptor-1 (RXFP1)). In our efforts to generate a new medicine for liver fibrosis, we sought to identify improved small molecule functional mimetics of H2-RLX with selective, full agonist or positive allosteric modulator activity against RXFP1. First, we confirmed expression of RXFP1 in human diseased liver. We developed a robust cellular cAMP reporter assay of RXFP1 signaling in HEK293 cells transiently expressing RXFP1. A high-throughput screen did not identify further specific agonists or positive allosteric modulators of RXFP1, affirming the low druggability of this receptor. As an alternative approach, we generated novel ML290 analogues and tested their activity in the HEK293-RXFP1 cAMP assay and the human hepatic cell line LX-2. Differences in activity of compounds on cAMP activation compared with changes in expression of fibrotic markers indicate the need to better understand cell- and tissue-specific signaling mechanisms and their disease-relevant phenotypes in order to enable drug discovery.