ABSTRACT
The peptide antibiotic albicidin is a DNA topoisomerase inhibitor with low-nanomolar bactericidal activity towards fluoroquinolone-resistant Gram-negative pathogens. However, its mode of action is poorly understood. We determined a 2.6 Å resolution cryoelectron microscopy structure of a ternary complex between Escherichia coli topoisomerase DNA gyrase, a 217 bp double-stranded DNA fragment and albicidin. Albicidin employs a dual binding mechanism where one end of the molecule obstructs the crucial gyrase dimer interface, while the other intercalates between the fragments of cleaved DNA substrate. Thus, albicidin efficiently locks DNA gyrase, preventing it from religating DNA and completing its catalytic cycle. Two additional structures of this trapped state were determined using synthetic albicidin analogues that demonstrate improved solubility, and activity against a range of gyrase variants and E. coli topoisomerase IV. The extraordinary promiscuity of the DNA-intercalating region of albicidins and their excellent performance against fluoroquinolone-resistant bacteria holds great promise for the development of last-resort antibiotics.
ABSTRACT
The cAMP-dependent aquaporin-2 (AQP2) redistribution from intracellular vesicles into the plasma membrane of renal collecting duct principal cells induces water reabsorption and fine-tunes body water homeostasis. However, the mechanisms controlling the localization of AQP2 are not understood in detail. Using immortalized mouse medullary collecting duct (MCD4) and primary rat inner medullary collecting duct (IMCD) cells as model systems, we here discovered a key regulatory role of Aurora kinase A (AURKA) in the control of AQP2. The AURKA-selective inhibitor Aurora-A inhibitor I and novel derivatives as well as a structurally different inhibitor, Alisertib, prevented the cAMP-induced redistribution of AQP2. Aurora-A inhibitor I led to a depolymerization of actin stress fibers, which serve as tracks for the translocation of AQP2-bearing vesicles to the plasma membrane. The phosphorylation of cofilin-1 (CFL1) inactivates the actin-depolymerizing function of CFL1. Aurora-A inhibitor I decreased the CFL1 phosphorylation, accounting for the removal of the actin stress fibers and the inhibition of the redistribution of AQP2. Surprisingly, Alisertib caused an increase in actin stress fibers and did not affect CFL1 phosphorylation, indicating that AURKA exerts its control over AQP2 through different mechanisms. An involvement of AURKA and CFL1 in the control of the localization of AQP2 was hitherto unknown.
Subject(s)
Aquaporin 2/metabolism , Aurora Kinase A/metabolism , Kidney Tubules, Collecting/metabolism , Actins/metabolism , Animals , Aurora Kinase A/antagonists & inhibitors , Aurora Kinase A/genetics , Cell Proliferation , Cell Survival/drug effects , Cyclic AMP/metabolism , Gene Silencing , Immunohistochemistry , Kidney Tubules, Collecting/cytology , Kidney Tubules, Collecting/drug effects , Male , Molecular Structure , Phosphorylation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Transport/drug effects , RatsABSTRACT
The worrisome development and spread of multidrug-resistant bacteria demands new antibacterial agents with strong bioactivities particularly against Gram-negative bacteria. Albicidins were recently structurally characterized as highly active antibacterial natural products from the bacterium Xanthomonas albilineans. Albicidin, which effectively targets the bacterial DNA-gyrase, is a lipophilic hexapeptide mostly consisting of para amino benzoic acid units and only one α-amino acid. In this study, we report on the design and synthesis of new albicidins, containing N-atoms on each of the 5 different phenyl rings. We systematically introduced N-atoms into the aromatic backbone to monitor intramolecular H-bonds and for one derivative correlated them with a significant enhancement of the antibacterial activity and activity spectrum, particularly also towards Gram-positive bacteria. In parallel we conducted DFT calculations to find the most stable conformation of each derivative. A drastic angle-change was observed for the lead compound and shows a preferred planarity through H-bonding with the introduced N-atom at the D-fragment of albicidin. Finally, we went to the next level and conducted the first in vivo experiments with an albicidin analogue. Our lead compound was evaluated in two different mouse experiments: In the first we show a promising PK profile and the absence of toxicity and in the second very good efficiency and reduction of the bacterial titre in an E. coli infection model with FQ-resistant clinically relevant strains. These results qualify albicidins as active antibacterial substances with the potential to be developed as a drug for treatment of infections caused by Gram-negative and Gram-positive bacteria.
ABSTRACT
Albicidin is a potent antibacterial oligoaromatic peptide that is susceptible to the protease AlbD, a resistance factor. This potentially restricts the use of albicidin as a drug. To overcome this obstacle, we synthesized and evaluated six analogues with isosteric replacement of the key amide link. Protease stability was established while maintaining the antibacterial activity, including three analogues with up to eight times higher activity compared with the natural albicidin.
Subject(s)
Amides/chemistry , Bacterial Proteins/chemistry , Protease Inhibitors/pharmacology , Anti-Bacterial Agents/chemistry , Bacterial Proteins/metabolism , Drug Resistance, Bacterial/drug effects , Molecular Structure , Organic Chemicals/chemical synthesis , Organic Chemicals/chemistry , Organic Chemicals/pharmacology , Protease Inhibitors/chemistry , Xanthomonas/chemistryABSTRACT
The natural product albicidin is a highly potent inhibitor of bacterial DNA gyrase. Its outstanding activity, particularly against Gram-negative pathogens, qualifies it as a promising lead structure in the search for new antibacterial drugs. However, as we show here, the N-terminal cinnamoyl moiety of albicidin is susceptible to photochemical E/Z isomerization. Moreover, the newly formed Z isomer exhibits significantly reduced antibacterial activity, which hampers the development and biological evaluation of albicidin and potent derivatives thereof. Hence, we synthesized 13 different variants of albicidin in which the vulnerable para-coumaric acid moiety was replaced; this yielded photostable analogues. Biological activity assays revealed that diaryl alkyne analogues exhibited virtually undiminished antibacterial efficacy. This promising scaffold will therefore serve as a blueprint for the design of a potent albicidin-based drug.
Subject(s)
Alkynes , Xanthomonas , Acrylamides , Anti-Bacterial Agents/pharmacology , Microbial Sensitivity Tests , Organic Chemicals , Structure-Activity RelationshipABSTRACT
In failing hearts, Na+/Ca2+ exchanger (NCX) overactivity contributes to Ca2+ depletion, leading to contractile dysfunction. Inhibition of NCX is expected to normalize Ca2+ mishandling, to limit afterdepolarization-related arrhythmias, and to improve cardiac function in heart failure (HF). SAR340835/SAR296968 is a selective NCX inhibitor for all NCX isoforms across species, including human, with no effect on the native voltage-dependent calcium and sodium currents in vitro. Additionally, it showed in vitro and in vivo antiarrhythmic properties in several models of early and delayed afterdepolarization-related arrhythmias. Its effect on cardiac function was studied under intravenous infusion at 250,750 or 1500 µg/kg per hour in dogs, which were either normal or submitted to chronic ventricular pacing at 240 bpm (HF dogs). HF dogs were infused with the reference inotrope dobutamine (10 µg/kg per minute, i.v.). In normal dogs, NCX inhibitor increased cardiac contractility (dP/dtmax) and stroke volume (SV) and tended to reduce heart rate (HR). In HF dogs, NCX inhibitor significantly and dose-dependently increased SV from the first dose (+28.5%, +48.8%, and +62% at 250, 750, and 1500 µg/kg per hour, respectively) while significantly increasing dP/dtmax only at 1500 (+33%). Furthermore, NCX inhibitor significantly restored sympathovagal balance and spontaneous baroreflex sensitivity (BRS) from the first dose and reduced HR at the highest dose. In HF dogs, dobutamine significantly increased dP/dtmax and SV (+68.8%) but did not change HR, sympathovagal balance, or BRS. Overall, SAR340835, a selective potent NCX inhibitor, displayed a unique therapeutic profile, combining antiarrhythmic properties, capacity to restore systolic function, sympathovagal balance, and BRS in HF dogs. NCX inhibitors may offer new therapeutic options for acute HF treatment. SIGNIFICANCE STATEMENT: HF is facing growing health and economic burden. Moreover, patients hospitalized for acute heart failure are at high risk of decompensation recurrence, and no current acute decompensated HF therapy definitively improved outcomes. A new potent, Na+/Ca2+ exchanger inhibitor SAR340835 with antiarrhythmic properties improved systolic function of failing hearts without creating hypotension, while reducing heart rate and restoring sympathovagal balance. SAR340835 may offer a unique and attractive pharmacological profile for patients with acute heart failure as compared with current inotrope, such as dobutamine.
Subject(s)
Heart Failure/drug therapy , Membrane Transport Modulators/therapeutic use , Sodium-Calcium Exchanger/antagonists & inhibitors , Vagus Nerve/drug effects , Animals , Baroreflex , Dogs , Heart/drug effects , Heart Rate , Membrane Transport Modulators/administration & dosage , Membrane Transport Modulators/pharmacology , Myocardial Contraction , Myocardium/metabolism , SwineABSTRACT
Albicidin is a recently described natural product that strongly inhibits bacterial DNA gyrase. The pronounced activity, particularly against Gram-negative bacteria, turns it into a promising lead structure for an antibacterial drug. Hence, structure-activity relationship studies are key for the in-depth understanding of structural features/moieties affecting gyrase inhibition, antibacterial activity and overcoming resistance. The 27â newly synthesized albicidins give profound insights into possibilities for variations of the C-terminus. Furthermore, in the present study, a novel derivative has been identified as overcoming resistance posed by the Klebsiella-protease AlbD. Structural modifications include, for example, azahistidine replacing the previous instable cyanoalanine as the central amino acid, as well as a triazole amide bond isostere between building blocksâ D and E.
ABSTRACT
PURPOSE: The purpose of this study was to examine the medium-term outcomes of patients undergoing proximal interphalangeal (PIP) joint arthroplasty using a pyrocarbon implant. METHODS: The study comprised an analysis of 170 PIP joint pyrocarbon arthroplasties in 99 patients with a minimum 2-year clinical follow-up. Diagnoses included inflammatory arthritis (n = 49), posttraumatic arthritis (n = 29), and osteoarthritis (n = 92). Univariate logistic regression and Kaplan-Meier survival analyses were performed. RESULTS: At an average follow-up of 6 years (range, 2-14 years), 58 reoperations (34%) were required, including 36 (21%) involving implant revision surgery. The majority of revisions were performed for either dislocations (n = 16) or pain and stiffness (n = 14). The 5- and 10-year survival-free of revision surgery rates were 79% and 77%, respectively. The risk for revision surgery was higher in patients with posttraumatic arthritis. There were 15 intraoperative complications involving a fracture and 26 postoperative complications, including 21 dislocations. In unrevised implants, patients had significant improvements in their preoperative to postoperative pain levels, with no change in their PIP joint total arc of motion. At a mean radiographic follow-up of 5.4 years, there were 28% with grade 3+ loosening and 36% with progressive implant instability. Implant loosening or progressive instability was not associated with worse pain or PIP joint total arc of motion. CONCLUSIONS: Approximately 1 in 5 PIP joint arthroplasties with a pyrocarbon implant will require revision surgery by 5 years, and 1 in 3 will undergo more than 1 operation. Furthermore, 1 in 4 PIP joint arthroplasties will have grade 3+ radiographic loosening and 1 in 3 will have progressive loosening or subsidence by 5 years. These results are particularly concerning in young patients and those with posttraumatic arthritis. Overall, in patients that do not require revision surgery, pain relief was improved and motion maintained. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.
Subject(s)
Arthroplasty, Replacement, Finger , Finger Joint/surgery , Joint Prosthesis , Adult , Age Factors , Aged , Aged, 80 and over , Arthritis/surgery , Carbon , Female , Finger Joint/diagnostic imaging , Follow-Up Studies , Hand Strength , Humans , Intraoperative Complications , Male , Middle Aged , Postoperative Complications , Radiography , Range of Motion, Articular , Reoperation/statistics & numerical data , Retrospective Studies , Risk Factors , Young AdultABSTRACT
Natural products represent an important source of potential novel antimicrobial drug leads. Low production by microorganisms in cell culture often delays the structural elucidation or even prevents a timely discovery. Starting from the anti-Gram-negative antibacterial compound albicidin produced by Xanthomonas albilineans, we describe a bioactivity-guided approach combined with non-targeted tandem mass spectrometry and spectral (molecular) networking for the discovery of novel antimicrobial compounds. We report eight new natural albicidin derivatives, four of which bear a ß-methoxy cyanoalanine or ß-methoxy asparagine as the central α-amino acid. We present the total synthesis of these albicidins, which facilitated the unambiguous determination of the (2 S,3 R)-stereoconfiguration which is complemented by the assessment of the stereochemistry on antibacterial activity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Biological Products/chemical synthesis , Biological Products/chemistry , Chromatography, High Pressure Liquid , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Organic Chemicals/chemical synthesis , Organic Chemicals/chemistry , Stereoisomerism , Structure-Activity Relationship , Tandem Mass Spectrometry , Xanthomonas/chemistry , Xanthomonas/metabolismABSTRACT
The design, synthesis, and structure-activity relationship of 1-phenoxy-2-aminoindanes as inhibitors of the Na+/H+ exchanger type 3 (NHE3) are described based on a hit from high-throughput screening (HTS). The chemical optimization resulted in the discovery of potent, selective, and orally bioavailable NHE3 inhibitors with 13d as best compound, showing high in vitro permeability and lacking CYP2D6 inhibition as main optimization parameters. Aligning 1-phenoxy-2-aminoindanes onto the X-ray structure of 13d then provided 3D-QSAR models for NHE3 inhibition capturing guidelines for optimization. These models showed good correlation coefficients and allowed for activity estimation. In silico ADMET models for Caco-2 permeability and CYP2D6 inhibition were also successfully applied for this series. Moreover, docking into the CYP2D6 X-ray structure provided a reliable alignment for 3D-QSAR models. Finally 13d, renamed as SAR197, was characterized in vitro and by in vivo pharmacokinetic (PK) and pharmacological studies to unveil its potential for reduction of obstructive sleep apneas.
Subject(s)
Indans/chemistry , Indans/pharmacology , Sodium-Hydrogen Exchangers/antagonists & inhibitors , Administration, Oral , Animals , Caco-2 Cells , Crystallography, X-Ray , Cytochrome P-450 CYP2D6/metabolism , Cytochrome P-450 CYP2D6 Inhibitors/administration & dosage , Cytochrome P-450 CYP2D6 Inhibitors/chemistry , Cytochrome P-450 CYP2D6 Inhibitors/pharmacokinetics , Cytochrome P-450 CYP2D6 Inhibitors/pharmacology , Drug Design , Drug Discovery , Humans , Indans/administration & dosage , Indans/pharmacokinetics , Models, Molecular , Quantitative Structure-Activity Relationship , Rats, Sprague-Dawley , Sodium-Hydrogen Exchanger 3 , Sodium-Hydrogen Exchangers/chemistry , Sodium-Hydrogen Exchangers/metabolism , SwineABSTRACT
The peptide antibiotic albicidin, which is synthesized by the plant pathogenic bacterium, Xanthomonas albilineans, represents the most prominent member of a new class of antibacterial gyrase inhibitors. It shows remarkable antibacterial activities against Gram-positive and Gram-negative microorganisms. Its unique structure potentially represents a new lead structure for the development of an antibacterial drug. Here we report the synthesis of 14 albicidin derivatives with structural variations at the N-terminus, primarily investigating the effects of variation of cinnamoyl, phenylpropanoyl, and benzoyl residues. Gyrase inhibition in vitro and determination of minimal inhibitory concentrations were assessed in parallel. Activities in a nanomolar range and the importance of N-acylation were demonstrated.
Subject(s)
Anti-Bacterial Agents/pharmacology , Xanthomonas/drug effects , Acylation , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Organic Chemicals/chemical synthesis , Organic Chemicals/chemistry , Organic Chemicals/pharmacology , Structure-Activity Relationship , Xanthomonas/chemistryABSTRACT
To investigate the pharmacophore regions of the antibiotic albicidin, derivatives with variations on the central amino acid were synthesized. Charged as well as uncharged residues were chosen to explore the influence of charge, chirality, and steric bulk. The bioactivity of the newly synthesized derivatives was determined by a microdilution technique to obtain minimum inhibitory concentrations (MIC) values. The compounds were also tested in a cell-free system to obtain information about their ability to inhibit their primary target, DNA gyrase. It was then shown that derivatives with uncharged side chains retain antibacterial activity, whereas incorporation of charged amino acid residues decreases the antibacterial activity dramatically, possibly due to restricted cell penetration of these derivatives. From the newly synthesized derivatives, the threonine derivative shows the most promising results in both tests. The information will help to develop the features of albicidin toward more drug-like structures.
Subject(s)
Alanine/analogs & derivatives , Alanine/chemistry , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Bacillus subtilis/drug effects , DNA Gyrase/metabolism , Escherichia coli/drug effects , Micrococcus luteus/drug effects , Organic Chemicals/chemical synthesis , Organic Chemicals/pharmacology , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacology , XanthomonasABSTRACT
While digital methods have a firm position in dentistry, a total digital workflow for multi-unit layered restorations has yet to be fully realized. Many clinicians are using a CAD/CAM workflow of some kind, but there is still a significant gap to be filled for completing the digital workflow. This article describes how practitioners can transition into the full digital workflow, showing the use of digital processes for anterior cosmetic cases. The pros and cons of "going fully digital" in an effort to increase efficiency while maintaining high-level quality with regards to fit and ceramics layering will be discussed.
Subject(s)
Computer-Aided Design , Dental Prosthesis Design , Esthetics, Dental , Workflow , Dental Porcelain , Humans , Software , Technology, Dental , User-Computer InterfaceABSTRACT
This review summarizes the treatment and resulting outcomes for total talar dislocation. The PubMed database was searched for articles about humans with total talar dislocation published in the English language in the last twenty years. The following data were entered into a Microsoft Excel spreadsheet: type of dislocation, nature of associated fractures (if any), type of reduction/fixation utilized, immobilization, weight-bearing status, outcome, complications and average follow-up time. Thirty-nine articles reporting a total of 86 cases of total talar dislocation are included in this review. Seventy-three of these were open injuries and 13 closed. Forty-three cases had an associated foot or ankle fracture, 32 of those cases specifically having a fracture of the talus. The talus was preserved in the initial management of 74 cases, whereas the remaining 12 cases were managed by primary talectomy. The mean duration of follow-up was 32 months. Twenty-two cases required a secondary arthrodesis or another additional procedure. A good outcome was achieved in 35% of cases, a fair outcome in 37% and a poor outcome in 27%. The complication of avascular necrosis (AVN) occurred in 22 cases and 14 subjects developed clinically significant osteoarthritis. Generally, the outcome of current treatments associated with total talar dislocation is not ideal, only 1/3 of cases achieving good outcomes. So far, preservation of the talus is the best treatment option. AVN is still a relatively common complication even in the absence of fracture or postoperative infection.
Subject(s)
Ankle Injuries/therapy , Ankle Joint , Joint Dislocations/therapy , Orthopedic Procedures/methods , Talus/injuries , Ankle Fractures/complications , Ankle Fractures/therapy , Ankle Injuries/complications , Ankle Joint/surgery , Humans , Joint Dislocations/complications , Talus/surgeryABSTRACT
Liners and bases are a class of dental materials that provide added protection for the health and well-being of a tooth being restored. They help prevent postoperative sensitivity resulting from an incomplete dentinal seal. Some practitioners use them, while others choose not to. In this case report, a resin-modified glass-ionomer (RMGI) liner was utilized in deep restorations on premolars that had old, existing amalgam restorations and were experiencing microleakage and sensitivity problems. The materials and technique used allowed for conservative treatment while delivering an esthetic and functionally pleasing result.
Subject(s)
Dental Caries/therapy , Dental Restoration, Permanent/instrumentation , Dentin Sensitivity/prevention & control , Glass Ionomer Cements , Acid Etching, Dental , Bicuspid , Dental Leakage/prevention & control , Dental Marginal Adaptation , Esthetics, Dental , Female , Humans , Middle Aged , RetreatmentABSTRACT
BACKGROUND: Precise correlations between medial malleolar fracture geometry and fracture mechanism have not been thoroughly described. This study sought to determine the prevalence of different medial malleolar fracture types and to elucidate the association between fracture geometry and fracture mechanism. METHODS: The records of 112 medial malleolar ankle fractures were reviewed. For each fracture, the direction of the fracture line in the medial malleolus (transverse, oblique, vertical, or comminuted), the Lauge-Hansen classification, and the presence or absence of syndesmotic injury was recorded. Bivariate correlation analysis was performed to determine if correlations existed. RESULTS: Transverse fractures were the most prevalent type of medial malleolar fracture [n=64 (57%)], and they correlated with supination-external rotation injuries. These were followed by oblique fractures [29 (26)], which correlated with pronation-external rotation injuries [29 (26)], and vertical fractures [7 (6)], which correlated with supination-adduction injuries [9 (8)]. Comminuted fractures [12 (11)] and pronation-abduction injuries [22 (20)] did not correlate with any other categories. Syndesmotic injuries were correlated with transverse fractures, bimalleolar fractures, and pronation-external rotation injuries. CONCLUSION: Medial malleolar fractures can be divided into four fracture types: transverse fractures, which correlated with supination-external rotation injuries; oblique fractures, which correlated with pronation-external rotation injuries; vertical fractures, which correlated with supination-adduction injuries; and comminuted fractures, which did not correlate with a particular type of injury. Syndesmotic injury was positively correlated with transverse fractures of the medial malleolus, bimalleolar fractures, and pronation-external rotation injuries. These findings suggest that medial malleolar fracture geometry can provide valuable information for the clinician when classifying and managing ankle fractures.
Subject(s)
Tibial Fractures/classification , Tibial Fractures/etiology , Adolescent , Adult , Aged , Aged, 80 and over , Ankle Injuries/etiology , Female , Fractures, Comminuted/etiology , Humans , Male , Middle Aged , Pronation , Rotation , Supination , Young AdultABSTRACT
BACKGROUND: Evaluation of operative techniques used for medial malleolar fractures by classifying fracture geometry has not been well documented. METHODS: One hundred eleven patients with medial malleolar fractures (transverse n = 63, oblique n = 29, vertical n = 7, comminuted n = 12) were included in this study. Seventy-two patients had complicating comorbidities. All patients were treated with buttress plate, lag screw, tension band, or K-wire fixation. Treatment outcomes were evaluated on the basis of radiological outcome (union, malunion, delayed union, or nonunion), need for operative revision, presence of postoperative complications, and AOFAS Ankle-Hindfoot score. RESULTS: For transverse fractures, tension band fixation showed the highest rate of union (79%), highest average AOFAS score (86), lowest revision rate (5%), and lowest complication rate (16%). For oblique fractures, lag screws showed the highest rate of union (71%), highest average AOFAS score (80), lowest revision rate (19%), and lowest complication rate (33%) of the commonly used fixation techniques. For vertical fractures, buttress plating was used in every case but 1, achieving union (whether normal or delayed) in all cases with an average AOFAS score of 84, no revisions, and a 17% complication rate. Comminuted fractures had relatively poor outcomes regardless of fixation method. CONCLUSIONS: The results of this study suggest that both tension bands and lag screws result in similar rates of union for transverse fractures of the medial malleolus, but that tension band constructs are associated with less need for revision surgery and fewer complications. In addition, our data demonstrate that oblique fractures were most effectively treated with lag screws and that vertical fractures attained superior outcomes with buttress plating. LEVEL OF EVIDENCE: Level III, retrospective comparative series.
Subject(s)
Ankle Fractures/surgery , Ankle Joint/surgery , Fracture Fixation, Internal/methods , Postoperative Complications/etiology , Adult , Aged, 80 and over , Female , Fracture Fixation, Internal/adverse effects , Humans , Male , Middle Aged , Postoperative Complications/epidemiology , Retrospective StudiesABSTRACT
EDUCATIONAL OBJECTIVES As a result of reading this article, physicians should be able to: 1. Understand the etiology, epidemiology, and importance of treatment of isolated subtalar dislocation. 2. Understand the most common management practices when treating isolated subtalar dislocation and identify variations in management that may affect prognosis. 3. Consolidate reported patient outcomes as they pertain to variations in management strategies to explore which practices may provide the best prognosis after treatment of isolated subtalar dislocation. 4. Highlight the importance of further study to determine the best course of management for isolated subtalar dislocation regarding variables in treatment. This study reviews the literature on isolated subtalar dislocation published within the past 5 years. Variation in management existed mostly in the categories of treatment choice, immobilizer type, and period of immobilization, with closed reduction, closed reduction and percutaneous pinning, below-knee casting, less than 4 weeks of immobilization, and 6 weeks of immobilization reporting good results. The good results described after the addition of percutaneous K-wire fixation to the initial treatment method of isolated subtalar dislocation, immobilization via below-knee casting, and shorter periods of immobilization suggest that these practices may be useful for the treatment of this rare injury.
Subject(s)
Immobilization/methods , Joint Dislocations/therapy , Orthopedic Procedures/methods , Subtalar Joint/injuries , HumansABSTRACT
Tetrahymena thermophila are free-living, ciliated eukaryotes. Their behavioral response to stimuli is well characterized and easily observable, since cells swim toward chemoattractants and avoid chemorepellents. Chemoattractant responses involve increased swim speed or a decreased change in swim direction, while chemorepellent signaling involves ciliary reversal, which causes the organism to jerk back and forth, swim in small circles, or spin in an attempt to get away from the repellent. Many food sources, such as proteins, are chemoattractants for these organisms, while a variety of compounds are repellents. Repellents in nature are thought to come from the secretions of predators or from ruptured organisms, which may serve as "danger" signals. Interestingly, several peptides involved in vertebrate pain signaling are chemorepellents in Tetrahymena, including substances P, ACTH, PACAP, VIP, and nociceptin. Here, we characterize the response of Tetrahymena thermophila to three different isoforms of nociceptin. We find that G-protein inhibitors and tyrosine kinase inhibitors do not affect nociceptin avoidance. However, the calcium chelator, EGTA, and the SERCA calcium ATPase inhibitor, thapsigargin, both inhibit nociceptin avoidance, implicating calcium in avoidance. This result is confirmed by electrophysiology studies which show that 50 µM nociceptin-NH2 causes a sustained depolarization of approximately 40 mV, which is eliminated by the addition of extracellular EGTA.
ABSTRACT
INTRODUCTION: Little is known about the setting in which observation services are provided, or how observation patients are managed in settings such as accredited cardiovascular patient care centers. OBJECTIVE: To describe the characteristics of observation services in accredited Cardiovascular Patient Care hospitals, or those seeking accreditation. METHODS: This is a cross-sectional survey of hospitals either accredited by the Society of Cardiovascular Patient Care, or considering accreditation in 2010. The survey was a web-based free service linked to an e-mail sent to Cardiovascular Patient Care coordinators at the respective institutions. The survey included 17 questions which focused on hospital characteristics and observation services, specifically management, settings, staffing, utilization, and performance data. RESULTS: Of the 789 accredited hospitals, 91 hospitals (11.5%) responded to the survey. Responding hospitals had a median of 250 inpatient beds (interquartile range [IQR] 277), 32.5 emergency department (ED) beds or hall spots, with an average annual ED census of 41,660 (IQR 30,149). These hospitals had an average of 8 (IQR 9) observation unit beds whose median length of stay (LOS) was 19 hours (IQR 8.1), with a discharge rate of 89.1% (IQR 15). There was an average of 1 observation bed to 3.8 ED beds. Observation units were most commonly administered by emergency medicine (48.5%), but staffed by a broad spectrum of specialties. Nonemergency medicine units had longer LOSs, which were not significant. Most common conditions were chest pain and abdominal pain. CONCLUSIONS: Accredited chest pain centers have observation units whose LOSs and discharge rates are comparable to prior studies with utilization patterns that may serve as benchmarks for similar hospitals.