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1.
J Foot Ankle Surg ; 60(1): 11-16, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33214101

RESUMO

The goal of this study was to compare immediate weightbearing (IWB) and traditional weightbearing (TWB) postoperative protocols in unstable ankle fractures, as this has not been compared in prior works. We hypothesize that an immediate weightbearing protocol after ankle fracture fixation will lead to an earlier return to work. An ankle fracture registry was reviewed for operatively treated unstable bimalleolar and trimalleolar ankle fractures at an ambulatory surgery center and followed up at associated outpatient clinics. All fracture cases reviewed occurred from 2009 to 2015. Immediate weightbearing patients were placed into a controlled ankle motion (CAM) boot and allowed to fully bear weight the day of surgery. Traditional weightbearing patients were placed into a CAM boot with 6 weeks of non-weightbearing. Demographics, fixation technique, and injury characteristics were surveyed. Physical job demand was stratified for 69 patients meeting the inclusion criteria (34 IWB and 35 TWB). The main outcome of this study was measured as the time to return to work. Subgroup analysis of patients with nonsedentary jobs demonstrated a significantly earlier return to work for the IWB group (5.7 versus 10.0 weeks, p = .04). Multivariate regression analysis identified a statistically significant 2.25-week (p = .05) earlier return to work for the IWB group after adjustment for occupational physical demand, demographics, fracture characteristics, and participation in a light work period before full work return. In patients with nonsedentary jobs, an IWB protocol after operative management of bimalleolar and trimalleolar ankle fractures resulted in an earlier return to work compared with traditional protocols.


Assuntos
Fraturas do Tornozelo , Fraturas do Tornozelo/diagnóstico por imagem , Fraturas do Tornozelo/cirurgia , Fixação Interna de Fraturas , Humanos , Ocupações , Retorno ao Trabalho , Resultado do Tratamento , Suporte de Carga
2.
J Am Chem Soc ; 140(40): 12808-12818, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30200760

RESUMO

The large family of mononuclear molybdenum and tungsten enzymes all possess the special ligand molybdopterin (MPT), which consists of a metal-binding dithiolene chelate covalently bound to a pyranopterin group. MPT pyran cyclization/scission processes have been proposed to modulate the reactivity of the metal center during catalysis. We have designed several small-molecule models for the Mo-MPT cofactor that allow detailed investigation into how pyran cyclization modulates electronic communication between the dithiolene and pterin moieties and how this cyclization alters the electronic environment of the molybdenum catalytic site. Using a combination of cyclic voltammetry, vibrational spectroscopy (FT-IR and rR), electronic absorption spectroscopy, and X-ray absorption spectroscopy, distinct changes in the Mo≡O stretching frequency, Mo(V/IV) reduction potential, and electronic structure across the pterin-dithiolene ligand are observed as a function of pyran ring closure. The results are significant, for they reveal that a dihydropyranopterin is electronically coupled into the Mo-dithiolene group due to a coplanar conformation of the pterin and dithiolene units, providing a mechanism for the electron-deficient pterin to modulate the Mo environment. A spectroscopic signature identified for the dihydropyranopterin-dithiolene ligand on Mo is a strong dithiolene → pterin charge transfer transition. In the absence of a pyran group bridge between pterin and dithiolene, the pterin rotates out of plane, largely decoupling the system. The results support a hypothesis that pyran cyclization/scission processes in MPT may function as a molecular switch to electronically couple and decouple the pterin and dithiolene to adjust the redox properties in certain pyranopterin molybdenum enzymes.


Assuntos
Coenzimas/química , Metaloproteínas/química , Pteridinas/química , Pterinas/química , Piranos/química , Cristalografia por Raios X , Ciclização , Modelos Moleculares , Conformação Molecular , Cofatores de Molibdênio , Oxirredução , Espectroscopia de Infravermelho com Transformada de Fourier , Tolueno/análogos & derivados , Tolueno/química
3.
J Hand Surg Am ; 41(12): e485-e489, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28029392

RESUMO

This case presents surgical treatment of a unique form of syndactyly: an isolated fenestrated, complex, crisscross syndactyly of the right middle and ring fingers. A 2-year-old boy presented with the ring finger lying dorsal and the middle finger lying volar, with the middle phalanges syndactylized. A surgical release was performed with a subsequent z-plasty, 2 years later, for scar elongation. At the age of 4, he has essentially full function of his hand with minimal limitations. This case demonstrates that 2 digits that were syndactylized in a coronal plane (ring finger dorsal and middle finger volar) can be successfully surgically separated.


Assuntos
Dedos/anormalidades , Sindactilia/cirurgia , Pré-Escolar , Dedos/diagnóstico por imagem , Dedos/cirurgia , Humanos , Masculino , Procedimentos Ortopédicos/métodos , Radiografia , Sindactilia/diagnóstico por imagem
4.
Inorg Chem ; 54(17): 8214-22, 2015 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-25942001

RESUMO

The conserved pterin dithiolene ligand that coordinates molybdenum (Mo) in the cofactor (Moco) of mononuclear Mo enzymes can exist in both a tricyclic pyranopterin dithiolene form and as a bicyclic pterin-dithiolene form as observed in protein crystal structures of several bacterial molybdoenzymes. Interconversion between the tricyclic and bicyclic forms via pyran scission and cyclization has been hypothesized to play a role in the catalytic mechanism of Moco. Therefore, understanding the interconversion between the tricyclic and bicyclic forms, a type of ring-chain tautomerism, is an important aspect of study to understand its role in catalysis. In this study, equilibrium constants (K(eq)) as well as enthalpy, entropy, and free energy values are obtained for pyran ring tautomerism exhibited by two Moco model complexes, namely, (Et4N)[Tp*Mo(O)(S2BMOPP)] (1) and (Et4N)[Tp*Mo(O)(S2PEOPP)] (2), as a solvent-dependent equilibrium process. Keq values obtained from (1)H NMR data in seven deuterated solvents show a correlation between solvent polarity and tautomer form, where solvents with higher polarity parameters favor the pyran form.


Assuntos
Coenzimas/química , Molibdênio/química , Compostos Organometálicos/química , Pterinas/química , Solventes/química , Ciclização , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química , Teoria Quântica , Termodinâmica
5.
PLoS Genet ; 8(5): e1002667, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22589731

RESUMO

The pairing of homologous chromosomes is a fundamental feature of the meiotic cell. In addition, a number of species exhibit homolog pairing in nonmeiotic, somatic cells as well, with evidence for its impact on both gene regulation and double-strand break (DSB) repair. An extreme example of somatic pairing can be observed in Drosophila melanogaster, where homologous chromosomes remain aligned throughout most of development. However, our understanding of the mechanism of somatic homolog pairing remains unclear, as only a few genes have been implicated in this process. In this study, we introduce a novel high-throughput fluorescent in situ hybridization (FISH) technology that enabled us to conduct a genome-wide RNAi screen for factors involved in the robust somatic pairing observed in Drosophila. We identified both candidate "pairing promoting genes" and candidate "anti-pairing genes," providing evidence that pairing is a dynamic process that can be both enhanced and antagonized. Many of the genes found to be important for promoting pairing are highly enriched for functions associated with mitotic cell division, suggesting a genetic framework for a long-standing link between chromosome dynamics during mitosis and nuclear organization during interphase. In contrast, several of the candidate anti-pairing genes have known interphase functions associated with S-phase progression, DNA replication, and chromatin compaction, including several components of the condensin II complex. In combination with a variety of secondary assays, these results provide insights into the mechanism and dynamics of somatic pairing.


Assuntos
Pareamento Cromossômico/genética , Proteínas de Drosophila , Drosophila melanogaster , Heterocromatina/genética , Meiose , Interferência de RNA , Ciclossomo-Complexo Promotor de Anáfase , Aneuploidia , Animais , Técnicas de Cultura de Células , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Quebras de DNA de Cadeia Dupla , Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/classificação , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Hibridização in Situ Fluorescente , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Mitose , Recombinação Genética , Complexos Ubiquitina-Proteína Ligase/genética , Coesinas
6.
Proc Natl Acad Sci U S A ; 109(52): 21301-6, 2012 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-23236188

RESUMO

A host of observations demonstrating the relationship between nuclear architecture and processes such as gene expression have led to a number of new technologies for interrogating chromosome positioning. Whereas some of these technologies reconstruct intermolecular interactions, others have enhanced our ability to visualize chromosomes in situ. Here, we describe an oligonucleotide- and PCR-based strategy for fluorescence in situ hybridization (FISH) and a bioinformatic platform that enables this technology to be extended to any organism whose genome has been sequenced. The oligonucleotide probes are renewable, highly efficient, and able to robustly label chromosomes in cell culture, fixed tissues, and metaphase spreads. Our method gives researchers precise control over the sequences they target and allows for single and multicolor imaging of regions ranging from tens of kilobases to megabases with the same basic protocol. We anticipate this technology will lead to an enhanced ability to visualize interphase and metaphase chromosomes.


Assuntos
Coloração Cromossômica/métodos , Genoma/genética , Hibridização in Situ Fluorescente/métodos , Sondas de Oligonucleotídeos/metabolismo , Animais , Caenorhabditis elegans/genética , Núcleo Celular/metabolismo , Cromossomos/genética , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Feminino , Biblioteca Gênica , Humanos , Interfase/genética , Metáfase/genética , Camundongos , Ovário/citologia , Ovário/metabolismo , Coloração e Rotulagem
7.
bioRxiv ; 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38659801

RESUMO

Analyzing scored sleep is a fundamental prerequisite to understanding how sleep changes between health and disease. Classically, this is accomplished by manually calculating various measures (e.g., percent of non-rapid eye movement sleep) from a collection of scored sleep files. This process can be tedious and error prone especially when studies include a large number of animals or involve long recording sessions. To address this issue, we present SleepInvestigatoR, a versatile tool that can quickly organize and analyze multiple scored sleep files into a single output. The function is written in the open-source statistical language R and has a total of 25 parameters that can be set to match a wide variety of experimenter needs. SleepInvestigatoR delivers a total of 22 unique measures of sleep, including all measures commonly reported in the rodent literature. A simple plotting function is also provided to quickly graph and visualize the scored data. All code is designed to be implemented with little formal coding knowledge and step-by-step instructions are provided on the corresponding GitHub page. Overall, SleepInvestigatoR provides the sleep researcher a critical tool to increase efficiency, interpretation, and reproducibility in analyzing scored rodent sleep.

8.
Pharmacol Biochem Behav ; 240: 173791, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38761993

RESUMO

Fentanyl has become the leading driver of opioid overdoses in the United States. Cessation of opioid use represents a challenge as the experience of withdrawal drives subsequent relapse. One of the most prominent withdrawal symptoms that can contribute to opioid craving and vulnerability to relapse is sleep disruption. The endocannabinoid agonist, 2-Arachidonoylglycerol (2-AG), may promote sleep and reduce withdrawal severity; however, the effects of 2-AG on sleep disruption during opioid withdrawal have yet to be assessed. Here, we investigated the effects of 2-AG administration on sleep-wake behavior and diurnal activity in mice during withdrawal from fentanyl. Sleep-wake activity measured via actigraphy was continuously recorded before and after chronic fentanyl administration in both male and female C57BL/6J mice. Immediately following cessation of fentanyl administration, 2-AG was administered intraperitoneally to investigate the impact of endocannabinoid agonism on opioid-induced sleep disruption. We found that female mice maintained higher activity levels in response to chronic fentanyl than male mice. Furthermore, fentanyl administration increased wake and decreased sleep during the light period and inversely increased sleep and decreased wake in the dark period in both sexes. 2-AG treatment increased arousal and decreased sleep in both sexes during first 24-h of withdrawal. On withdrawal day 2, only females showed increased wakefulness with no changes in males, but by withdrawal day 3 male mice displayed decreased rapid-eye movement sleep during the dark period with no changes in female mice. Overall, repeated administration of fentanyl altered sleep and diurnal activity and administration of the endocannabinoid agonist, 2-AG, had sex-specific effects on fentanyl-induced sleep and diurnal changes.


Assuntos
Ácidos Araquidônicos , Ritmo Circadiano , Endocanabinoides , Fentanila , Glicerídeos , Camundongos Endogâmicos C57BL , Sono , Síndrome de Abstinência a Substâncias , Animais , Feminino , Masculino , Camundongos , Ácidos Araquidônicos/farmacologia , Glicerídeos/farmacologia , Fentanila/farmacologia , Fentanila/administração & dosagem , Ritmo Circadiano/efeitos dos fármacos , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Analgésicos Opioides/administração & dosagem
9.
bioRxiv ; 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-39026736

RESUMO

Purpose: Fentanyl, a highly potent synthetic opioid, is a major contributor to the ongoing opioid epidemic. During adulthood, fentanyl is known to induce pronounced sleep and circadian disturbances during use and withdrawal. Children exposed to opioids in utero are likely to develop neonatal opioid withdrawal syndrome, and display sleep disturbances after birth. However, it is currently unknown how neonatal opioid withdrawal from fentanyl impacts sleep and circadian rhythms in mice later in life. Methods: To model neonatal opioid withdrawal syndrome, mice were treated with fentanyl from postnatal days 1 through 14, analogous to the third trimester of human gestation. After weaning, fentanyl and saline treated mice underwent non-invasive sleep and circadian rhythm monitoring during adolescence postnatal days 23 through 30. Results: Neonatal fentanyl exposure led to reduced duration of wake and a decrease in the number of bouts of non-rapid eye movement sleep. Further, neonatally exposed mice displayed an increase in the average duration of rapid eye movement sleep bouts, reflecting an overall increase in the percent time spent in rapid eye movement sleep across days. Conclusions: Neonatal fentanyl exposure leads to altered sleep-wake states during adolescence in mice.

10.
Foot Ankle Int ; 34(2): 159-66, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23413053

RESUMO

BACKGROUND: Successful correction of hindfoot alignment in adult acquired flatfoot deformity (AAFD) is likely influenced by the degree of medializing calcaneal osteotomy (MCO) performed, but it is not known if other reconstruction procedures significantly contribute as well. The purpose of this study was to evaluate the correlation between common preoperative and postoperative variables and hindfoot alignment. METHODS: Thirty patients with stage II AAFD undergoing flatfoot reconstruction were followed prospectively. Preoperative and postoperative radiographs were reviewed to assess for correction in hindfoot alignment as measured by the change in hindfoot moment arm. Nineteen variables were analyzed, including age, gender, height, weight, body mass index (BMI), medial cuneiform-fifth metatarsal height, anteroposterior (AP) talonavicular coverage, AP talus-first metatarsal, lateral talus-first metatarsal and calcaneal pitch angles as well as intraoperative use of the MCO, lateral column lengthening (LCL), Cotton osteotomy, first tarsometatarsal fusion, flexor digitorum longus transfer, spring ligament reconstruction, and gastrocnemius recession or Achilles lengthening. Mean age was 57.3 years (range, 22-77). Final radiographs were obtained at a mean of 47 weeks (range, 25-78) postoperatively. RESULTS: Seven variables were found to significantly affect hindfoot moment arm. These were gender (P < .05), the amount of MCO performed (P < .001), LCL (P < .01), first tarsometatarsal fusion (P < .01), spring ligament reconstruction (P < .01), medial cuneiform-fifth metatarsal height (P < .001), and calcaneal pitch angle (P < .05). Multivariate regression analysis revealed that MCO was the only significant predictor of hindfoot moment arm. The final regression model for MCO showed a good fit (R(2) = .93, P < .001). CONCLUSION: Correction of hindfoot valgus alignment obtained in flatfoot reconstruction is primarily determined by the MCO procedure and can be modeled linearly. We believe that the hindfoot alignment view can serve as a valuable preoperative measurement to help surgeons adjust the proper amount of correction intraoperatively. LEVEL OF EVIDENCE: Level IV, prospective case series.


Assuntos
Calcâneo/cirurgia , Pé Chato/cirurgia , Osteotomia/métodos , Adulto , Idoso , Calcâneo/diagnóstico por imagem , Feminino , Pé Chato/classificação , Pé Chato/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Radiografia , Adulto Jovem
11.
bioRxiv ; 2023 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-38187736

RESUMO

Fentanyl has become the leading driver of opioid overdoses. Cessation of opioid use represents a challenge as the experience of withdrawal drives subsequent relapse. One of the most prominent withdrawal symptoms that can contribute to opioid craving and vulnerability to relapse is sleep disruption. The endocannabinoid agonist, 2-Arachidonoylglycerol (2-AG), may promote sleep and reduce withdrawal severity; however, the effects of 2-AG on sleep disruption during opioid withdrawal have yet to be assessed. Here, we investigate the effects of 2-AG administration on sleep-wake behavior and diurnal activity in mice during withdrawal from fentanyl. Sleep-wake activity was continuously recorded before and after chronic fentanyl administration in both male and female C57BL/6J mice. Immediately following cessation of fentanyl administration, 2-AG was administered intraperitoneally to investigate the impact of endocannabinoid agonism on opioid-induced sleep disruption. Female mice maintained higher activity levels in response to chronic fentanyl than male mice. Furthermore, fentanyl increased wake and decreased sleep during the light period and inversely increased sleep and decreased wake in the dark period in both sexes. 2-AG treatment increased arousal and decreased sleep in both sexes during first 24 hrs of withdrawal. On withdrawal day 2, only female showed increased wakefulness with no changes in males, but by withdrawal day 3 male mice displayed decreased rapid-eye movement sleep during the dark period with no changes in female mice. Overall, repeated administration of fentanyl altered sleep and diurnal activity and administration of the endocannabinoid agonist, 2-AG, had sex-specific effects on fentanyl-induced sleep and diurnal changes.

12.
J Inorg Biochem ; 249: 112388, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37837940

RESUMO

Eight [Ru(bpy)2L]2+ and three [Ru(phen)2L]2+complexes (where bpy = 2,2'-bipyridine and phen = 1,10-phenanthroline are ancillary ligands, and L = a polypyridyl experimental ligand) were investigated for their G-quadruplex binding abilities. Fluorescence resonance energy transfer melting assays were used to screen these complexes for their ability to selectively stabilize human telomeric DNA variant, Tel22. The best G-quadruplex stabilizers were further characterized for their binding properties (binding constant and stoichiometry) using UV-vis, fluorescence spectroscopy, and mass spectrometry. The ligands' ability to alter the structure of Tel22 was determined via circular dichroism and PAGE studies. We identified me2allox as the experimental ligand capable of conferring excellent stabilizing ability and good selectivity to polypyridyl Ru(II) complexes. Replacing bpy by phen did not significantly impact interactions with Tel22, suggesting that binding involves mostly the experimental ligand. However, using a particular ancillary ligand can help fine-tune G-quadruplex-binding properties of Ru(II) complexes. Finally, the fluorescence "light switch" behavior of all Ru(II) complexes in the presence of Tel22 G-quadruplex was explored. All Ru(II) complexes displayed "light switch" properties, especially [Ru(bpy)2(diamino)]2+, [Ru(bpy)2(dppz)]2+, and [Ru(bpy)2(aap)]2+. Current work sheds light on how Ru(II) polypyridyl complexes interact with human telomeric DNA with possible application in cancer therapy or G-quadruplex sensing.


Assuntos
Quadruplex G , Rutênio , Humanos , Rutênio/química , Ligantes , DNA/química , Transferência Ressonante de Energia de Fluorescência
13.
J Am Chem Soc ; 134(48): 19584-7, 2012 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-23157708

RESUMO

The syntheses and X-ray structures of two molybdenum pyranopterin dithiolene complexes in biologically relevant Mo(4+) and Mo(5+) states are reported. Crystallography reveals that these complexes possess a pyran ring formed through a spontaneous cyclization reaction of a dithiolene side-chain hydroxyl group at a C═N bond of the pterin. NMR data on the Mo(4+) complex suggest that a reversible pyran ring cyclization occurs in solution. These results provide experimental evidence that the pyranopterin dithiolene ligand in molybdenum and tungsten enzymes could participate in catalysis through dynamic processes modulated by the protein.


Assuntos
Coenzimas/química , Metaloproteínas/química , Modelos Moleculares , Molibdênio/química , Compostos Organometálicos/química , Pteridinas/química , Pterinas/química , Cristalografia por Raios X , Ciclização , Ligantes , Cofatores de Molibdênio , Compostos Organometálicos/síntese química , Compostos Organometálicos/classificação
14.
Inorg Chem ; 51(23): 12669-81, 2012 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-23167624

RESUMO

The synthesis, characterization, binding to calf thymus DNA, and plasmid DNA photocleavage studies of two ruthenium(II) pteridinylphenanthroline complexes are reported where the new pteridinylphenantholine ligands in these complexes are additions to a larger family designed to resemble DNA bases. [Ru(bpy)(2)(L-keto)](PF(6))(2)1 is synthesized from ligand substitution of Ru(bpy)(2)Cl(2) by 4-keto-pteridino[6,7-f]phenanthroline (L-keto). Increasing the reaction temperature during synthesis of 1 causes a ring scission of the L-keto ligand within the pyrimidine ring yielding a second Ru complex, [Ru(bpy)(2)(L-aap)](PF(6))(2)2 where L-aap is 2-amino-3-amidopyrazino[5,6-f]phenanthroline. The ring cleavage reaction is accompanied by the loss of one carbon in the pyrimidine ring. Complexes 1 and 2 are characterized by (1)H NMR, UV/visible absorption and FT-IR spectroscopies and by cyclic voltammetry, and these results are presented in comparison to the previously reported related complexes [Ru(bpy)(2)(L-allox)](PF(6))(2), [Ru(bpy)(2)(L-amino)](PF(6))(2), and [Ru(bpy)(2)(dppz)](PF(6))(2). In addition, 2 has been structurally characterized by X-ray diffraction. Both 1 and 2 are good intercalators of calf thymus DNA as determined by viscometry and binding constants obtained from absorption titrations. Only the ring-cleaved complex 2 exhibits a high degree of pBR322 plasmid photocleavage in contrast to the other pteridinyl-phenanthroline complexes, which exhibit no plasmid DNA photocleavage. Complex 1, however, decomposes in buffer forming the photocleaver 2, demonstrating that sample age and reactivity can affect observed photocleavage. Complex 2 appears to photocleave DNA through a singlet oxygen mechanism.


Assuntos
DNA/química , Compostos Organometálicos/química , Pteridinas/química , Piridinas/química , Rutênio/química , Animais , Bovinos , Clivagem do DNA , Ligantes , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química , Processos Fotoquímicos , Plasmídeos
15.
Front Integr Neurosci ; 16: 899637, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757099

RESUMO

Opioid use disorder (OUD) and deaths from drug overdoses have reached unprecedented levels. Given the enormous impact of the opioid crisis on public health, a more thorough, in-depth understanding of the consequences of opioids on the brain is required to develop novel interventions and pharmacological therapeutics. In the brain, the effects of opioids are far reaching, from genes to cells, synapses, circuits, and ultimately behavior. Accumulating evidence implicates a primary role for the extracellular matrix (ECM) in opioid-induced plasticity of synapses and circuits, and the development of dependence and addiction to opioids. As a network of proteins and polysaccharides, including cell adhesion molecules, proteases, and perineuronal nets, the ECM is intimately involved in both the formation and structural support of synapses. In the human brain, recent findings support an association between altered ECM signaling and OUD, particularly within the cortical and striatal circuits involved in cognition, reward, and craving. Furthermore, the ECM signaling proteins, including matrix metalloproteinases and proteoglycans, are directly involved in opioid seeking, craving, and relapse behaviors in rodent opioid models. Both the impact of opioids on the ECM and the role of ECM signaling proteins in opioid use disorder, may, in part, depend on biological sex. Here, we highlight the current evidence supporting sex-specific roles for ECM signaling proteins in the brain and their associations with OUD. We emphasize knowledge gaps and future directions to further investigate the potential of the ECM as a therapeutic target for the treatment of OUD.

16.
Front Syst Neurosci ; 16: 1059089, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36532632

RESUMO

Despite the prevalence of opioid misuse, opioids remain the frontline treatment regimen for severe pain. However, opioid safety is hampered by side-effects such as analgesic tolerance, reduced analgesia to neuropathic pain, physical dependence, or reward. These side effects promote development of opioid use disorders and ultimately cause overdose deaths due to opioid-induced respiratory depression. The intertwined nature of signaling via µ-opioid receptors (MOR), the primary target of prescription opioids, with signaling pathways responsible for opioid side-effects presents important challenges. Therefore, a critical objective is to uncouple cellular and molecular mechanisms that selectively modulate analgesia from those that mediate side-effects. One such mechanism could be the transactivation of receptor tyrosine kinases (RTKs) via MOR. Notably, MOR-mediated side-effects can be uncoupled from analgesia signaling via targeting RTK family receptors, highlighting physiological relevance of MOR-RTKs crosstalk. This review focuses on the current state of knowledge surrounding the basic pharmacology of RTKs and bidirectional regulation of MOR signaling, as well as how MOR-RTK signaling may modulate undesirable effects of chronic opioid use, including opioid analgesic tolerance, reduced analgesia to neuropathic pain, physical dependence, and reward. Further research is needed to better understand RTK-MOR transactivation signaling pathways, and to determine if RTKs are a plausible therapeutic target for mitigating opioid side effects.

17.
Foot Ankle Int ; 32(7): 665-73, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21972760

RESUMO

BACKGROUND: One of the major concerns with lateral column lengthening (LCL) in symptomatic flatfoot deformity treatment is the risk of postoperative plantar lateral foot discomfort. We evaluated whether this risk can be minimized by using trial metal wedges. Using our study's evaluation tools, the incidence of postoperative plantar lateral foot discomfort before and after using trial metal wedges was determined. MATERIALS AND METHODS: The incidence of planter lateral foot pain after LCL was retrospectively assessed in 122 consecutive patients (132 feet) after they had undergone flatfoot reconstruction with LCL between 2001 and 2007. To determine if the incidence could be reduced, levels of pain or revision were compared before and after the use of trial metal wedges. The ratio of wedge size to preoperative radiographic calcaneal length was also determined. RESULTS: The overall incidence of plantar lateral discomfort was 11.2%. The incidence of pain or revision was lower after the introduction of trial metal wedges (6.3% compared to 14.7%), but did not reach significance (p = 0.084). There was no significant difference found in the ratio of the size of bone graft wedge to calcaneal length between the two groups (p = 0.805). CONCLUSION: The incidence of plantar lateral foot discomfort overall was 11.2% after LCL. We believe this risk may be reduced using trial metal wedges, properly judging eversion stiffness and carefully assessing the position of the foot intraoperatively.


Assuntos
Pé Chato/fisiopatologia , Pé Chato/cirurgia , Procedimentos Ortopédicos/efeitos adversos , Dor Pós-Operatória/epidemiologia , Dor Pós-Operatória/etiologia , Instrumentos Cirúrgicos , Atividades Cotidianas , Adulto , Idoso , Feminino , Pé Chato/diagnóstico por imagem , Humanos , Incidência , Masculino , Metais , Pessoa de Meia-Idade , Medição da Dor , Dor Pós-Operatória/prevenção & controle , Qualidade de Vida , Radiografia , Reoperação , Estudos Retrospectivos , Estatísticas não Paramétricas
18.
Foot Ankle Int ; 32(3): 225-32, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21477539

RESUMO

BACKGROUND: The surgical indications, timing, and procedure for flexible flatfoot reconstruction in young patients remains controversial. This retrospective study reports the clinical results of reconstruction of flexible, idiopathic, symptomatic flatfoot in adolescent and young adults indicated for surgery by persistent pain and functional limitations. The hypothesis was that the results of these procedures allow patients to return to sports activities with minimal discomfort or pain. MATERIALS AND METHODS: Sixteen consecutive idiopathic flatfeet in ten patients with a mean age of 15.6 years at the time of surgery (range, 10 to 22) were assessed at a final followup visit at average of 5.2 (range, 2 to 10) years. Reconstruction included combined medializing calcaneal osteotomy and lateral column lengthening in all 16 patients. Flexor digitorum longus transfer (nine), medial column stabilization (eight), and gastroncnemius recession (eight) were carried out as needed. The AOFAS, SF-36, and FAOS questionnaires were completed. Sports activity and patient satisfaction were also assessed. Standard preoperative and postoperative radiographic parameters were measured. RESULTS: The mean AOFAS score increased on average from 49.1 to 93.4. Only one patient reported a postoperative restriction in sports. The satisfaction level was excellent in 15 feet and good in one foot. Significant improvement in radiographic parameters was noted for the AP talonavicular coverage angle (p < 0.001) and lateral talar-first metatarsal angle (p < 0.001). CONCLUSION: Flexible flatfoot reconstruction in a cohort of symptomatic adolescent and young adult patients achieved a reduction of pain and improved functional outcome including the ability to participate in sporting activities.


Assuntos
Pé Chato/cirurgia , Adolescente , Calcâneo/cirurgia , Criança , Feminino , Pé Chato/diagnóstico por imagem , Seguimentos , Humanos , Masculino , Músculo Esquelético/cirurgia , Procedimentos Ortopédicos , Osteotomia , Satisfação do Paciente , Radiografia , Estudos Retrospectivos , Tendões/cirurgia , Resultado do Tratamento , Adulto Jovem
19.
PLoS One ; 16(11): e0259242, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34727125

RESUMO

INTRODUCTION: Femoral head collapse (FHC) is a rarely reported complication of hip intra-articular corticosteroid injection (IACSI). Upon observing a high rate of FHC after hip IACSI, we sought to (1) describe how we addressed the problem through a systematic evaluation of clinical data and institutional care practices followed by process improvement efforts; and (2) report our results. METHODS: Patients receiving hip IACSI during a 27-month period underwent retrospective review to determine the rate of FHC and to identify associated patient factors or practice shortfalls. Findings led to institution-wide interventions: (1) to improve patient/provider awareness of this association; and (2) to develop/implement practice guidelines. Rates of FHC after hip IACSI and practice patterns among providers before and after intervention were compared. RESULTS: Initial FHC rate after hip IACSI was 20.4%. Patient-related factors included body mass index (p = 0.025), history of cancer therapy (p = 0.012), Vitamin D level (p = 0.030), and multiple injections (p = 0.004). Volume/dose of injectate and post-injection surveillance methods varied widely. Quality improvement (QI) intervention resulted in fewer treatment referrals (from 851 to 436), fewer repeat injections (mean = 1.61 to 1.37; p = 0.0006), and a 5% lower FHC rate (p = 0.1292). Variation in practice patterns persisted, so a systems-based Clinical Pathway was established. DISCUSSION: When a high rate of FHC after hip IACSI was found to be associated with certain patient and practice factors, introduction of education materials and treatment guidelines decreased number of referrals, number of injections per patient, and FHC rate. In the absence of the systems-based Pathway, the type, dose, and volume of injectate and post-procedure follow-up remained variable.


Assuntos
Injeções Intra-Articulares , Cabeça do Fêmur , Humanos , Pessoa de Meia-Idade
20.
Artigo em Inglês | MEDLINE | ID: mdl-34543235

RESUMO

INTRODUCTION: This study sought to determine (1) incident risk, (2) chief report, (3) risk factors, and (4) total cost of unplanned healthcare visits to an emergency and/or urgent care (ED/UC) facility within 30 days of an outpatient orthopaedic procedure. METHODS: This was a retrospective database review of 5,550 outpatient surgical encounters from a large metropolitan healthcare system between 2012 and 2016. Statistical analysis consisted of measuring the ED/UC incident risk, respective to the procedures and anatomical region. Patient-specific risk factors were evaluated through multigroup comparative statistics. RESULTS: Of the 5,550 study patients, 297 (5.4%) presented to an ED/UC within 30 days of their index procedure, with 23 (0.4%) needing to be readmitted. Native English speakers, patients older than 45 years, and nonsmokers had significant reduced relative risk of unplanned ED or UC visit within 30 days of index procedure (P < 0.01). In addition, hand tendon repair/graft had the greatest risk incidence for ED/UC visit (11.0%). Unplanned ED/UC reimbursements totaled $146,357.34, averaging $575.65 per visit. DISCUSSION: This study provides an evaluation of outpatient orthopaedic procedures and their relationship to ED/UC visits. Specifically, this study identifies patient-related and procedural-related attributes that associate with an increased risk for unplanned healthcare utilization.


Assuntos
Procedimentos Ortopédicos , Pacientes Ambulatoriais , Assistência Ambulatorial , Serviço Hospitalar de Emergência , Humanos , Procedimentos Ortopédicos/efeitos adversos , Estudos Retrospectivos
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