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1.
Arthroscopy ; 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38901678

RESUMO

The Shoulder Instability-Return to Sports After Injury (SIRSI) scale is a useful psychological readiness tool to determine whether athletes are prepared to return to sport. Although questions remain on the optimal timing of survey administration based on the type of procedure (i.e., arthroscopic Bankart repair vs Latarjet procedure) and external factors contributing to psychological readiness, its current use begs the question of what other applications may be appropriate. The SIRSI scale has recently been able to effectively predict patient-reported and clinical outcomes, such as postoperative instability recurrence. However, it also may have added value as a serial screening tool for determining a safe return to preinjury activity rather than just serving as a harbinger of further negative outcomes after shoulder stabilization. Increasingly, we must recognize the fundamental limitations in our current rehabilitation pathways and sometimes myopic, 1-dimensional return-to-play criteria (e.g., range of motion or isokinetic testing) in facilitating a safe return to competition. We must transition to a more regimented, criteria-based return-to-play battery that incorporates optimized psychological readiness. As such, the SIRSI scale, like its anterior cruciate ligament counterpart, could become the standard of care in determining confidence in returning to sport and ultimately serve as a benchmark of surgical success.

2.
Arthroscopy ; 40(7): 2083-2095, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38151167

RESUMO

PURPOSE: To systematically review the literature and report the outcomes of various surgical treatments for reverse Hill-Sachs lesions (RHSL) in the setting of posterior shoulder instability. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. All studies assessing outcomes of surgical treatment of RHSL from inception to January 2023 were identified in PubMed, Embase, and Cochrane Library. Inclusion criteria consisted of studies reporting outcomes, minimum mean 1-year follow-up, and minimum Level IV evidence. Outcomes were assessed using Forest plots with random effects models using R software. RESULTS: A total of 29 studies consisting of 291 patients were included with a mean age of 42 years (range 16-88 years), 87% male gender, and mean follow-up of 4.5 years. The mean size of impacted or affected cartilage was 35%, and time from injury to surgery was mean 15 weeks. Nearly all studies were Level IV evidence, and quality of studies was low. Random effect models were performed, and data are presented as range. A low incidence of instability was noted for all surgical techniques with good patient-reported outcome measures. Most studies reported outcomes of the modified McLaughlin procedure (13 studies, 126 patients) with overall Constant-Murley Score of 65 to 92. Trends were seen towards better Constant-Murley Score and external rotation with a shorter delay between injury, and when arthroscopic and joint preserving treatments were performed. CONCLUSIONS: This systematic review showed low rates of instability recurrence, reproducible range of motion, and favorable patient-reported outcome measures were reported following all treatments for RHSLs with posterior instability. There was a significant association between better outcomes and a shorter delay between injury and surgery. The level of evidence is limited, given the small and retrospective studies which can be explained by the rarity of these injuries. LEVEL OF EVIDENCE: Level IV; systematic review of Level III and IV studies.


Assuntos
Instabilidade Articular , Medidas de Resultados Relatados pelo Paciente , Recidiva , Humanos , Instabilidade Articular/cirurgia , Idoso , Adulto , Adolescente , Pessoa de Meia-Idade , Masculino , Feminino , Adulto Jovem , Idoso de 80 Anos ou mais , Luxação do Ombro/cirurgia , Artroscopia/métodos , Articulação do Ombro/cirurgia , Resultado do Tratamento
3.
J Biol Chem ; 298(5): 101925, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35413287

RESUMO

Conditional proteolytic degradation is an irreversible and highly regulated process that fulfills crucial regulatory functions in all organisms. As proteolytic targets tend to be critical metabolic or regulatory proteins, substrates are targeted for degradation only under appropriate conditions through the recognition of an amino acid sequence referred to as a "degron". DEAD-box RNA helicases mediate all aspects of RNA metabolism, contributing to cellular fitness. However, the mechanism by which abiotic-stress modulation of protein stability regulates bacterial helicase abundance has not been extensively characterized. Here, we provide in vivo evidence that proteolytic degradation of the cyanobacterial DEAD-box RNA helicase CrhR is conditional, being initiated by a temperature upshift from 20 to 30 °C in the model cyanobacterium, Synechocystis sp. PCC 6803. We show degradation requires a unique, highly conserved, inherently bipartite degron located in the C-terminal extension found only in CrhR-related RNA helicases in the phylum Cyanobacteria. However, although necessary, the degron is not sufficient for proteolysis, as disruption of RNA helicase activity and/or translation inhibits degradation. These results suggest a positive feedback mechanism involving a role for CrhR in expression of a crucial factor required for degradation. Furthermore, AlphaFold structural prediction indicated the C-terminal extension is a homodimerization domain with homology to other bacterial RNA helicases, and mass photometry data confirmed that CrhR exists as a dimer in solution at 22 °C. These structural data suggest a model wherein the CrhR degron is occluded at the dimerization interface but could be exposed if dimerization was disrupted by nonpermissive conditions.


Assuntos
RNA Helicases DEAD-box , Synechocystis , RNA Helicases DEAD-box/metabolismo , Proteólise , RNA Bacteriano/metabolismo , Synechocystis/enzimologia , Synechocystis/genética
4.
Appl Environ Microbiol ; 89(4): e0001523, 2023 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-36920190

RESUMO

Compartmentalization of macromolecules into discrete non-lipid-bound bodies by liquid-liquid phase separation (LLPS) is a well-characterized regulatory mechanism frequently associated with the cellular stress response in eukaryotes. In contrast, the formation and importance of similar complexes is just becoming evident in bacteria. Here, we identify LLPS as the mechanism by which the DEAD-box RNA helicase, cyanobacterial RNA helicase redox (CrhR), compartmentalizes into dynamic membraneless organelles in a temporal and spatial manner in response to abiotic stress in the cyanobacterium Synechocystis sp. strain PCC 6803. Stress conditions induced CrhR to form a single crescent localized exterior to the thylakoid membrane, indicating that this region is a crucial domain in the cyanobacterial stress response. These crescents rapidly dissipate upon alleviation of the stress conditions. Furthermore, CrhR aggregation was mediated by LLPS in an RNA-dependent reaction. We propose that dynamic CrhR condensation performs crucial roles in RNA metabolism, enabling rapid adaptation of the photosynthetic apparatus to environmental stresses. These results expand our understanding of the role that functional compartmentalization of RNA helicases and thus RNA processing in membraneless organelles by LLPS-mediated protein condensation performs in the bacterial response to environmental stress. IMPORTANCE Oxygen-evolving photosynthetic cyanobacteria evolved ~3 billion years ago, performing fundamental roles in the biogeochemical evolution of the early Earth and continue to perform fundamental roles in nutrient cycling and primary productivity today. The phylum consists of diverse species that flourish in heterogeneous environments. A prime driver for survival is the ability to alter photosynthetic performance in response to the shifting environmental conditions these organisms continuously encounter. This study demonstrated that diverse abiotic stresses elicit dramatic changes in localization and structural organization of the RNA helicase CrhR associated with the photosynthetic thylakoid membrane. These dynamic changes, mediated by a liquid-liquid phase separation (LLPS)-mediated mechanism, reveal a novel mechanism by which cyanobacteria can compartmentalize the activity of ribonucleoprotein complexes in membraneless organelles. The results have significant consequences for understanding bacterial adaptation and survival in response to changing environmental conditions.


Assuntos
Synechocystis , Synechocystis/genética , Synechocystis/metabolismo , Condensados Biomoleculares , Oxirredução , RNA Helicases DEAD-box/metabolismo , RNA/metabolismo , Organelas/metabolismo
5.
Proc Natl Acad Sci U S A ; 113(31): 8813-8, 2016 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-27432973

RESUMO

A highly conserved DNA uptake system allows many bacteria to actively import and integrate exogenous DNA. This process, called natural transformation, represents a major mechanism of horizontal gene transfer (HGT) involved in the acquisition of virulence and antibiotic resistance determinants. Despite evidence of HGT and the high level of conservation of the genes coding the DNA uptake system, most bacterial species appear non-transformable under laboratory conditions. In naturally transformable species, the DNA uptake system is only expressed when bacteria enter a physiological state called competence, which develops under specific conditions. Here, we investigated the mechanism that controls expression of the DNA uptake system in the human pathogen Legionella pneumophila We found that a repressor of this system displays a conserved ProQ/FinO domain and interacts with a newly characterized trans-acting sRNA, RocR. Together, they target mRNAs of the genes coding the DNA uptake system to control natural transformation. This RNA-based silencing represents a previously unknown regulatory means to control this major mechanism of HGT. Importantly, these findings also show that chromosome-encoded ProQ/FinO domain-containing proteins can assist trans-acting sRNAs and that this class of RNA chaperones could play key roles in post-transcriptional gene regulation throughout bacterial species.


Assuntos
Regulação Bacteriana da Expressão Gênica , Transferência Genética Horizontal , Legionella pneumophila/genética , RNA Bacteriano/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , DNA Bacteriano/genética , Perfilação da Expressão Gênica/métodos , Humanos , Legionella pneumophila/metabolismo , Doença dos Legionários/microbiologia , Modelos Genéticos , Regulon/genética , Transformação Bacteriana
6.
Am Heart J ; 204: 102-108, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30092411

RESUMO

BACKGROUND: Ethnicity, along with a variety of genetic and environmental factors, is thought to influence the efficacy of antihypertensive therapies. Current UK guidelines use a "black versus white" approach; in doing so, they ignore the United Kingdom's largest ethnic minority: Asians from South Asia. STUDY DESIGN: The primary purpose of the AIM-HY INFORM trial is to identify potential differences in response to antihypertensive drugs used as mono- or dual therapy on the basis of self-defined ethnicity. A multicenter, prospective, open-label, randomized study with 2 parallel, independent trial arms (mono- and dual therapy), AIM-HY INFORM plans to enroll a total of 1,320 patients from across the United Kingdom. Those receiving monotherapy (n = 660) will enter a 3-treatment (amlodipine 10 mg od; lisinopril 20 mg od; chlorthalidone 25 mg od), 3-period crossover, lasting 24 weeks, whereas those receiving dual therapy (n = 660) will enter a 4-treatment (amlodipine 5 mg od and lisinopril 20 mg od; amlodipine 5 mg od and chlorthalidone 25 mg od; lisinopril 20 mg od and chlorthalidone 25 mg od; amiloride 10 mg od and chlorthalidone 25 mg od), 4-period crossover, lasting 32 weeks. Equal numbers of 3 ethnic groups (white, black/black British, and Asian/Asian British) will ultimately be recruited to each of the trial arms (ie, 220 participants per ethnic group per arm). Seated, automated, unattended, office, systolic blood pressure measured 8 weeks after each treatment period begins will serve as the primary outcome measure. CONCLUSION: AIM-HY INFORM is a prospective, open-label, randomized trial which aims to evaluate first- and second-line antihypertensive therapies for multiethnic populations.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/etnologia , Adolescente , Adulto , Idoso , Anlodipino/uso terapêutico , Povo Asiático , População Negra , Clortalidona/uso terapêutico , Estudos Cross-Over , Esquema de Medicação , Quimioterapia Combinada , Hemodinâmica , Humanos , Hipertensão/fisiopatologia , Lisinopril/uso terapêutico , Pessoa de Meia-Idade , Estudos Prospectivos , Reino Unido , População Branca , Adulto Jovem
7.
Br J Clin Pharmacol ; 84(12): 2914-2922, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30194849

RESUMO

AIMS: Although high blood pressure (BP) is common in acute stroke and associated with poor outcome, the Efficacy of Nitric Oxide in Stroke (ENOS) trial showed no beneficial effect of antihypertensive treatment in this situation. Antihypertensive agents have accentuated effects in dehydrated patients. We assessed the impact of dehydration on haemodynamics, the effects of antihypertensive treatment, and prognosis in the ENOS trial. METHODS: ENOS randomized 4011 patients with acute stroke and raised systolic BP to a glyceryl trinitrate (GTN) patch or no GTN patch, and to continue or to stop existing antihypertensive treatment within 48 h of onset. The primary outcome was functional outcome (modified Rankin Scale, mRS) at day 90. Blood markers of dehydration at baseline were collected at two sites (n = 310) and their relationship with haemodynamics and outcome was assessed. RESULTS: There were no significant associations between dehydration markers and fall in blood pressure from baseline to day 1, and no significant interaction with allocated treatment. Overall, increasing urea was associated with an unfavourable shift in mRS [odds ratio 3.43, 95% confidence interval (CI) 1.42, 8.32; P = 0.006] and increased risk of death at day 90 (hazard ratio 4.55, 95% CI 1.51, 13.66; P = 0.007). CONCLUSIONS: Blood pressure-lowering treatment was safe in dehydrated patients, with no precipitous changes in BP, thus supporting its use in acute stroke prior to blood markers of dehydration becoming available. Increased baseline urea was associated with poor prognosis after stroke.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Acidente Vascular Cerebral/fisiopatologia , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nitroglicerina/uso terapêutico , Prognóstico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/mortalidade
8.
Curr Hypertens Rep ; 20(4): 31, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29637415

RESUMO

PURPOSE OF REVIEW: Hypertension affects more than 30% of the world's adult population and thiazide (and thiazide-like) diuretics are amongst the most widely used, effective, and least costly treatments available, with all-cause mortality benefits equivalent to angiotensin-converting enzyme inhibitors or calcium channel antagonists. A minority of patients develop thiazide-induced hyponatremia (TIH) and this is largely unpredictable at the point of thiazide prescription. In some cases, TIH can cause debilitating symptoms and require hospital admission. Although TIH affects only a minority of patients exposed to thiazides, the high prevalence of hypertension leads to TIH being the most common cause of drug-induced hyponatremia requiring hospital admission in the UK. This review examines current clinical and scientific understanding of TIH. Consideration is given to demographic associations, limitations of current electrolyte monitoring regimens, clinical presentation, the phenotype evident on routine clinical blood and urine tests as well as more extensive analyses of blood and urine in research settings, recent genetic associations with TIH, and thoughts on management of the condition. RECENT FINDINGS: Recent genetic and phenotyping analysis has suggested that prostaglandin E2 pathways in the collecting duct may have a role in the development of TIH in a subgroup of patients. Greater understanding of the molecular pathophysiology of TIH raises the prospect of pre-prescription TIH risk profiling and may offer novel insights into how TIH may be avoided, prevented and treated. The rising prevalence of hypertension and the widespread use of thiazides mean that further understanding of TIH will continue to be a pressing issue for patients, physicians, and scientists alike for the foreseeable future.


Assuntos
Diuréticos/efeitos adversos , Hipertensão/tratamento farmacológico , Hiponatremia/induzido quimicamente , Hiponatremia/genética , Tiazidas/efeitos adversos , Diuréticos/uso terapêutico , Humanos , Hipertensão/dietoterapia , Hipertensão/fisiopatologia , Hiponatremia/diagnóstico , Hiponatremia/terapia , Tiazidas/uso terapêutico
9.
Lancet Oncol ; 17(2): 224-233, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26703894

RESUMO

BACKGROUND: Hyperbaric oxygen has been used as a therapy for patients experiencing chronic intestinal syndromes after pelvic radiotherapy for decades, yet the evidence to support the use of this therapy is based almost exclusively on non-randomised studies. We aimed to provide conclusive results for the clinical benefits of hyperbaric oxygen in patients with chronic bowel dysfunction after radiotherapy for pelvic malignancies. METHODS: HOT2 was a double-blind, sham-controlled, phase 3 randomised study of patients (≥18 years) with chronic gastrointestinal symptoms for 12 months or more after radiotherapy and which persisted despite at least 3 months of optimal medical therapy and no evidence of cancer recurrence. Participants were stratified by participating hyperbaric centre and randomly assigned (2:1) by a computer-generated list (block size nine or 12) to receive treatment with hyperbaric oxygen therapy or sham. Participants in the active treatment group breathed 100% oxygen at 2·4 atmospheres of absolute pressure (ATA) and the control group breathed 21% oxygen at 1·3 ATA; both treatment groups received 90-min air pressure exposures once daily for 5 days per week for a total of 8 weeks (total of 40 exposures). Staff at the participating hyperbaric medicine facilities knew the allocated treatment, but patients, clinicians, nurse practitioners, and other health-care professionals associated with patients' care were masked to treatment allocation. Primary endpoints were changes in the bowel component of the modified Inflammatory Bowel Disease Questionnaire (IBDQ) score and the IBDQ rectal bleeding score 12 months after start of treatment relative to baseline. The primary outcome was analysed in a modified intention-to-treat population, excluding patients who did not provide IBDQ scores within a predetermined time-frame. All patients have completed 12 months of follow-up and the final analysis is complete. The trial is registered with the ISRCTN registry, number ISRCTN86894066. FINDINGS: Between Aug 14, 2009, and Oct 23, 2012, 84 participants were randomly assigned: 55 to hyperbaric oxygen and 29 to sham control. 75 (89%) participants received 40 pressure exposures, all participants returned the IBDQ at baseline, 75 (89%) participants returned the IBDQ at 2 weeks post-treatment, and 79 (94%) participants returned the IBDQ at 12 months post-start of treatment. Patients were excluded from analyses of co-primary endpoints if they had missing IBDQ scores for intestinal function or rectal bleeding at baseline or at 12 months. In an analysis of 46 participants in the active treatment group and 23 participants in the control group, we found no significant differences in the change of IBDQ bowel component score (median change from baseline to 12 months of 4 (IQR -3 to 11) in the treatment group vs 4 (-6 to 9) in the sham group; Mann-Whitney U score 0·67, p=0·50). In an analysis of 29 participants in the active treatment group and 11 participants in the sham group with rectal bleeding at baseline, we also found no significant differences in the change of IBDQ rectal bleeding score (median change from baseline to 12 months of 3 [1 to 3] in the treatment group vs 1 [1 to 2] in the sham group; U score 1·69, p=0·092). Common adverse events in both groups were eye refractive changes (three [11%] of 28 patients in the control group vs 16 [30%] of 53 patients in the treatment group), increased fatigue (three [11%] vs two [4%]), and ear pain (six [21%] vs 15 [28%]). Eight serious adverse events were reported in eight patients: two were reported in two patients in the control group (tonsillitis requiring surgery [grade 3]; recurrent cancer of the vulva [grade 4]) and six serious adverse events were reported in six patients in the treatment group (malignant spinal cord compression requiring surgery [grade 3]; malignant paraortic lymph node involvement requiring surgery [grade 3]; recurrence of vomiting and dehydration [grade 3]; diarrhoea and fever associated with Campylobacter infection [grade 3]; recurrence of abdominal pain, bloating, diarrhoea, and urinary tract infection [grade 3]; aneurysm [grade 4]), none of which were deemed treatment-related. INTERPRETATION: We found no evidence that patients with radiation-induced chronic gastrointestinal symptoms, including those patients with rectal bleeding, benefit from hyperbaric oxygen therapy. These findings contrast with evidence used to justify current practices, and more level 1 evidence is urgently needed. FUNDING: Cancer Research UK and National Health Service (NHS) funding to the National Institute of Health Research Biomedical Research Centre at The Royal Marsden and the Institute of Cancer Research.


Assuntos
Gastroenteropatias/terapia , Oxigenoterapia Hiperbárica , Neoplasias Pélvicas/radioterapia , Lesões por Radiação/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Método Duplo-Cego , Feminino , Gastroenteropatias/etiologia , Gastroenteropatias/fisiopatologia , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/terapia , Humanos , Oxigenoterapia Hiperbárica/efeitos adversos , Masculino , Pessoa de Meia-Idade , Lesões por Radiação/etiologia , Radioterapia/efeitos adversos , Reto , Inquéritos e Questionários , Avaliação de Sintomas
11.
Nucleic Acids Res ; 42(8): 5234-44, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24520115

RESUMO

While functional mature microRNAs (miRNAs) are small ∼22 base oligonucleotides that target specific mRNAs, miRNAs are initially expressed as long transcripts (pri-miRNAs) that undergo sequential processing to yield the mature miRNAs. We have previously reported that the pri-miR-17∼92 cluster adopts a compact globular folded structure that internalizes a 3' core domain resulting in reduced miRNA maturation and subsequent mRNA targeting. Using a site-specific photo-cross-linker we have identified a tertiary contact within the 3' core domain of the pri-miRNA between a non-miRNA stem-loop and the pre-miR-19b hairpin. This tertiary contact is involved in the formation of the compact globular fold of the cluster while its disruption enhances miR-92a expression and mRNA targeting. We propose that this tertiary contact serves as a molecular scaffold to restrict expression of the proposed antiangiogenic miR-92a, allowing for the overall pro-angiogenic effect of miR-17∼92 expression.


Assuntos
MicroRNAs/química , MicroRNAs/metabolismo , RNA Mensageiro/metabolismo , Adenosina/análise , Pareamento de Bases , Células HEK293 , Células HeLa , Humanos , Conformação de Ácido Nucleico , Dobramento de RNA , Precursores de RNA/química , RNA Longo não Codificante , Sequências Repetitivas de Ácido Nucleico , Ribonuclease III/metabolismo
12.
Br J Clin Pharmacol ; 79(4): 566-77, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25139696

RESUMO

AIMS: Hyponatraemia is one of the major adverse effects of thiazide and thiazide-like diuretics and the leading cause of drug-induced hyponatraemia requiring hospital admission. We sought to review and analyze all published cases of this important condition. METHODS: Ovid Medline, Embase, Web of Science and PubMed electronic databases were searched to identify all relevant articles published before October 2013. A proportions meta-analysis was undertaken. RESULTS: One hundred and two articles were identified of which 49 were single patient case reports. Meta-analysis showed that mean age was 75 (95% CI 73, 77) years, 79% were women (95% CI 74, 82) and mean body mass index was 25 (95% CI 20, 30) kg m(-2) . Presentation with thiazide-induced hyponatraemia occurred a mean of 19 (95% CI 8, 30) days after starting treatment, with mean trough serum sodium concentration of 116 (95% CI 113, 120) mm and serum potassium of 3.3 (95% CI 3.0, 3.5) mm. Mean urinary sodium concentration was 64 mm (95% CI 47, 81). The most frequently reported drugs were hydrochlorothiazide, indapamide and bendroflumethiazide. CONCLUSIONS: Patients with thiazide-induced hyponatraemia were characterized by advanced age, female gender, inappropriate saliuresis and mild hypokalaemia. Low BMI was not found to be a significant risk factor, despite previous suggestions. The time from thiazide initiation to presentation with hyponatraemia suggests that the recommended practice of performing a single investigation of serum biochemistry 7-14 days after thiazide initiation may be insufficient or suboptimal. Further larger and more systematic studies of thiazide-induced hyponatraemia are required.


Assuntos
Hiponatremia/induzido quimicamente , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Fatores Etários , Monitoramento de Medicamentos , Feminino , Humanos , Hiponatremia/epidemiologia , Hiponatremia/urina , Masculino , Fatores Sexuais
13.
Clin Sci (Lond) ; 126(10): 721-6, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24266877

RESUMO

The study of families with rare inherited forms of hypo- and hyper-tension has been one of the most successful strategies to probe the molecular pathophysiology of blood pressure control and has revealed dysregulation of distal nephron Na+ reabsorption to be a common mechanism. FHHt (familial hyperkalaemic hypertension; also known as Gordon's syndrome) is a salt-dependent form of hypertension caused by mutations in the regulators of the thiazide-sensitive Na+-Cl- co-transporter NCC [also known as SLC12A3 (solute carrier family 12 member 3)] and is effectively treated by thiazide diuretics and/or dietary salt restriction. Variation in at least four genes can cause FHHt, including WNK1 [With No lysine (=K) 1] and WNK4, KLHL3 (kelch-like family member 3), and CUL3 (cullin 3). In the present study we have identified novel disease-causing variants in CUL3 and KLHL3 segregating in 63% of the pedigrees with previously unexplained FHHt, confirming the importance of these recently described FHHt genes. We have demonstrated conclusively, in two unrelated affected individuals, that rare intronic variants in CUL3 cause the skipping of exon 9 as has been proposed previously. KLHL3 variants all occur in kelch-repeat domains and so probably disrupt WNK complex binding. We have found no evidence of any plausible disease-causing variants within SLC4A8 (an alternative thiazide-sensitive sodium transporter) in this population. The results of the present study support the existing evidence that the CUL3 and KLHL3 gene products are physiologically important regulators of thiazide-sensitive distal nephron NaCl reabsorption, and hence potentially interesting novel anti-hypertensive drug targets. As a third of our non-WNK FHHt families do not have plausible CUL3 or KLHL3 variants, there are probably additional, as yet undiscovered, regulators of the thiazide-sensitive pathways.


Assuntos
Proteínas de Transporte/genética , Proteínas Culina/genética , Predisposição Genética para Doença , Mutação/genética , Pseudo-Hipoaldosteronismo/genética , Proteínas Adaptadoras de Transdução de Sinal , Processamento Alternativo/genética , Segregação de Cromossomos/genética , Análise Mutacional de DNA , Éxons/genética , Família , Feminino , Humanos , Masculino , Proteínas dos Microfilamentos , Linhagem , Fenótipo
14.
Ann Jt ; 9: 16, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38694813

RESUMO

Background and Objective: Anterior shoulder dislocations can result in acute glenoid rim fractures that compromise the bony stability of the glenohumeral joint. Adequate fixation of these fractures is required to restore stability, decrease shoulder pain, and facilitate return to activity. The double-row suture bridge is a relatively novel fixation technique, first described in 2009, that accomplishes internal fixation with sufficient stability using an all-arthroscopic technique to restore the glenoid footprint. A 40-year-old female with recurrent anterior shoulder instability in the setting of seizure disorder was found to have a bony Bankart lesion of 25% to 30% with a concomitant superior labral tear. The patient was treated with a double-row bony Bankart bridge and labral repair. At six months follow-up, she has progressed to a full recovery with no recurrence. Methods: A search was conducted in May 2023 in PubMed, EMBASE, and CINAHL with the search terms bony Bankart, bone Bankart, osseous Bankart, acute, bridge, suture bridge, double row. Key Content and Findings: Double-row suture bridge repairs result in improvement in shoulder function as determined by ASES (93.5), QuickDASH (4.5), SANE (95.9), and SF-12 (55.6). The overall recurrence rate of anterior instability after a bony Bankart bridge repair is 8%. When examining the return to prior level of function, 81.4% of patients were able to do so with only 7.9% of patients reporting significant modifications to their activity level. In mid-term results, double row suture bridge demonstrates similar outcomes to other all-arthroscopic fixation methods of bony Bankart injuries. Importantly, bony Bankart bridge remains a viable option for critical glenoid lesions over the 20% cutoff used in other all arthroscopic techniques. Biomechanically, the double-row suture bridge offers distinct benefits over its single-row counterpart including increased compression, reduced displacement, and reduced step-off. Conclusions: Although there is limited data, the studies discussed and the demonstrative case show the potential benefit of all-arthroscopic double-row suture bridge fixation including increased compression, decreased displacement, and a lower complication rate in patients with large bony Bankart lesions traditionally requiring bony augmentation. However, more robust studies are necessary to determine the long-term success of the double-row suture bridge.

15.
J Hum Hypertens ; 38(1): 8-18, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37964158

RESUMO

Alongside the lack of homogeneity among international guidelines and consensus documents on primary hyperaldosteronism, the National UK guidelines on hypertension do not provide extensive recommendations regarding the diagnosis and management of this condition. Local guidelines vary from area to area, and this is reflected in the current clinical practice in the UK. In an attempt to provide support to the clinicians involved in the screening of subjects with hypertension and clinical management of suspected cases of primary hyperaldosteronism the following document has been prepared on the behalf of the BIHS Guidelines and Information Service Standing Committee. Through remote video conferences, the authors of this document reviewed an initial draft which was then circulated among the BIHS Executive members for feedback. A survey among members of the BIHS was carried out in 2022 to assess screening strategies and clinical management of primary hyperaldosteronism in the different regions of the UK. Feedback and results of the survey were then discussed and incorporated in the final document which was approved by the panel after consensus was achieved considering critical review of existing literature and expert opinions. Grading of recommendations was not performed in light of the limited available data from properly designed randomized controlled trials.


Assuntos
Hiperaldosteronismo , Hipertensão , Humanos , Hipertensão/diagnóstico , Hipertensão/terapia , Consenso , Hiperaldosteronismo/complicações , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/terapia
16.
Arthrosc Sports Med Rehabil ; 6(3): 100911, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-39006786

RESUMO

Purpose: To identify prognostic factors associated with a delayed return-to-sport (RTS) time in amateur athletes who return to full participation after a primary isolated anterior cruciate ligament (ACL) reconstruction. Methods: A retrospective review was performed among athletes who underwent ACL reconstruction between October 2014 and October 2021. Inclusion criteria were any amateur athletes with an ACL reconstruction who had a documented RTS and greater than 1-year follow-up. Nonathletes, those with multiligamentous knee injury, and those missing documented RTS timelines were excluded. RTS was defined as participation in athletics at a level equivalent to or greater than the preinjury level participation. Demographic and prognostic factors, including previous knee surgery, meniscal involvement, level of participation, surgical approach, and graft type, were recorded along with RTS time and analyzed via Poisson regression. Results: In total, 91 athletes, average age 18.8 (± 6.7) years, who underwent ACL reconstruction at a single institution from 2014 to 2021 were identified with an average follow-up time of 4.6 (± 2.5) years (range 1.1, 9.0). Meniscal involvement (1.11; 95% confidence interval [CI] 1.08-1.15, P < .001) and previous knee surgery (1.43; 95% CI 1.29-1.58; P < .001) were related to a delayed RTS. Quadriceps tendon and bone-patellar tendon-bone autografts, as well as allograft, showed a significant association with a longer RTS time when compared with hamstring autograft (1.16, 95% CI 1.13-1.20, P < .001; 1.04, 95% CI 1.01-1.07, P = .020; 1.11, 95% CI 1.03-1.19, P = .004, respectively), as did anteromedial portal drilling, when compared with the outside in approach for femoral drilling (1.19, 95% CI 1.16-1.23, P < .001). Conclusions: Previous knee surgery, anteromedial femoral drilling, quadriceps tendon autograft, and meniscus tear were most associated with a delayed timeline for RTS among young athletes who were able to return. Level of Evidence: Level IV, prognostic case series.

17.
Sports Health ; : 19417381241264502, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-39101547

RESUMO

BACKGROUND: Multiple studies have analyzed pitching kinematics using motion analysis technology, but lower extremity drive leg impulse (DLI) and drive leg slope (DLS) are not as well characterized. The purpose of this study was to investigate associations between DLI and DLS and pitch velocity as well as angular velocity of the pelvis, trunk, and humerus. HYPOTHESIS: Increased DLI and DLS will be correlated positively with pitch velocity and associated with increased angular velocities in the humerus, trunk, and pelvis. STUDY DESIGN: Retrospective case series. LEVEL OF EVIDENCE: Level 4. METHODS: Three-dimensional motion analyses data from 174 pitchers (age, 17.0 ± 1.0 years; height, 1.82 ± 0.07 m; weight, 80.0 ± 11.3 kg) throwing combined 613 fastball pitches were included. Pitchers threw 2 to 5 pitches, and the variables collected between pitches were averaged and recorded. Statistical analysis was performed using linear regressions to determine the association between DLS as well as DLI and pitch velocity and angular velocities of the pelvis, trunk, and humerus. RESULTS: Pitchers with higher DLI were associated with lower pitch velocities (ß = -22.32; 95% CI, -32.75 to -11.88, P < 0.01). There were no significant associations for DLS and velocity (ß = -0.60; 95% CI, -1.48 to 0.29, P = 0.18) or DLS and DLI with rotational velocities except for DLI and trunk kinematics (ß = -0.60; 95% CI, -1.48 to 0.29, P = 0.18). CONCLUSION: In the combined cohort, DLI correlated negatively with pitch velocity, although this relationship does not exist in the subgroup analysis. Higher DLS was found in pitchers with slower pitch velocities in the elite, high school, and youth groups, although not statistically significant. No associations were found with DLS and any angular velocities between any level of play analyzed in this study, suggesting no consistent association regardless of playing level.

18.
Knee ; 48: 257-264, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38788308

RESUMO

PURPOSE: To assess the reimplantation rate and predictors of patients requiring second-staged matrix-induced autologous chondrocyte implantation (MACI) reimplantation after initial first stage cartilage biopsy. METHODS: A retrospective review was performed from 2018 to 2022 among patients who underwent only phase I MACI biopsy procedure (biopsy group) or both phase I with transition to phase II implantation of chondrocytes (implantation group) at a single tertiary center. Demographic, qualitative, and quantitative measurements were recorded, and univariate and multivariate regression analysis was performed to assess predictors of ultimately requiring second stage MACI implantation. RESULTS: A total of 71 patients (51% female, age 27.7 ± 10.6 years (range 12-50)) were included in this study. Eventually, 25 of 71 patients (35.2%) experienced persistence of symptoms after initial MACI biopsy and other concomitant procedures, requiring second-stage implantation. Univariate analysis showed the implantation group compared to the biopsy group had a greater lesion size (5.2 cm2 ± 3.3 vs. 3.3 cm2 ± 1.4, p = 0.024), a higher proportion patients ≥ 26 years of age (76% vs. 43%, p = 0.009), a medial femoral condyle lesion more commonly (33% vs 11%, p = 0.005), were more often female (72% vs. 39%, p = 0.008), and had less often soft tissue repair at time of biopsy (32% vs. 61%, p = 0.020). Backward multivariate logistic regression analysis revealed that size of the lesion (OR 1.43, p = 0.031) and age ≥ 26 years old at time of biopsy (OR 3.55, p = 0.042) were independent predictors of not responding to initial surgery and requiring implantation surgery. CONCLUSION: This study found that 35% of patients undergoing MACI phase I biopsy harvest eventually required autologous implantation. Independent risk factors for progressing to implantation after failed initial surgery were larger defect size and older age. LEVEL OF EVIDENCE: III, Cohort Study.


Assuntos
Cartilagem Articular , Condrócitos , Transplante Autólogo , Humanos , Feminino , Condrócitos/transplante , Masculino , Adulto , Estudos Retrospectivos , Cartilagem Articular/cirurgia , Cartilagem Articular/patologia , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Criança , Biópsia , Coleta de Tecidos e Órgãos/métodos , Reoperação
19.
Arthrosc Tech ; 13(2): 102840, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38435260

RESUMO

Batter's Shoulder is a unique injury that may be associated with recurrent microtrauma followed by acute subluxation of the humeral head on the posterior glenoid edge, leading to posterior labral tears. Early identification of this injury is critical, as it may be treated with conservative nonsurgical treatments prior to labral tear onset. If conservative treatment fails and pain persists, surgical options include arthroscopic fixation to reapproximate the posterior labrum to the glenoid and restore capsular tension. Previous studies have shown the benefit of using knotless suture anchors in arthroscopic shoulder fixation. This technical note demonstrates that Batter's Shoulder is a unique injury associated with posterior labral tears of the shoulder and provides a contemporary method of arthroscopic fixation of a posterior labral tear using retensionable knotless all-suture anchors.

20.
Arthrosc Sports Med Rehabil ; 6(1): 100840, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38187952

RESUMO

Purpose: To characterize clinical and patient-reported outcomes for patients after isolated biceps tenodesis (BT) who underwent either standard or expedited sling immobilization protocols following surgery. Methods: This retrospective cohort study compared patients who were assigned to use a sling for either 4 to 6 weeks (standard) or 0 to 2 weeks (expedited) following an isolated BT. Primary endpoint included rate of re-rupture, surgical revision, loss of fixation, and Popeye deformity. Secondary endpoints included shoulder range of motion (ROM) as well as pre- and postoperative patient-reported outcomes (PROs) of pain and function. Missing data were managed via multiple imputation with chained equations. Complication prevalence 95% confidence intervals were calculated using the Clopper Pearson method and a series of hierarchical mixed effects linear regressions were performed to assess differences between sling interventions in PROs and ROM. Results: The average age of the standard cohort (n = 66) was 49 years (±14 years), and the average age of the expedited cohort (n = 69) was 47 years (±14 years). The expedited and standardized cohorts demonstrated 0.4 and 0.3 complications per 10,000 exposure days, respectively, with no significant difference between groups (1.4 [95% confidence interval 0.2-10.0], P = .727). There was no demonstrated difference in forward flexion, abduction, or external ROM. The expedited group had less improvement in visual analog scale for pain scores that was not clinically significant and there were no differences in PROs of function. Conclusions: No statistically significant difference in the rate of re-rupture, surgical revision, loss of fixation, or Popeye deformity was noted between protocols after isolated BT. Furthermore, there were no clinically significant differences in ROM or PROs identified between protocols after isolated BT. This study suggests that patients who have undergone isolated BT may safely discontinue sling use within 2 weeks after surgery. Level of Evidence: Level III, retrospective comparative study.

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