Risk factors for complications and in-hospital mortality: An analysis of 19,834 open pelvic ring fractures.

BACKGROUND: Open pelvic fractures are rare injuries, associated with high patient morbidity and mortality. Few studies have investigated the impact of patient demographics, comorbidities, and injury related factors on complication and mortality rates. The purpose of this study was to: (1) identify the overall incidence of complications and mortality after open pelvic fractures, (2) compare patient factors between those who did and did not develop complications, (3) identify perioperative independent risk factors for complications and mortality. METHODS: A query was performed for patients with open pelvic fractures between 2007 and 2017 using the American College of Surgeons National Trauma Data Bank. Patient and injury specific variables were collected and complications were identified using International Classification of Disease Ninth and Tenth edition Codes. Patient demographic and perioperative data was compared using Fisher's exact test and chi-square test for categorical variables, and Welch's t-test for continuous variables. Using pooled data from multiple imputations, logistic regressions were used to calculate odds ratios and confidence intervals of independent risk factors for complications. RESULTS: A total of 19,834 open pelvic fracture cases were identified, with 9622 patients (48.5%) developing at least one complication. Patients who developed complications were older (35.0 vs 38.1 years), and had higher Injury Severity Scores (17.7 vs 26.5), lower Glasgow Coma Scores (14.2 vs 11.7), and a larger proportion presenting with hypotension (21% vs 6.9%). After pooled regression involving 19 factors, these were the strongest independent predictors of inpatient complication and mortality. CONCLUSION: We report a mortality rate of 14%, with an inclusive complication rate of 48.5%. Evaluating risk factors for morbidity and mortality for this devastating orthopaedic injury provides knowledge of an inherently sparse population. LEVEL OF EVIDENCE: Level II, Retrospective study.

Incidental Ultrastructural Findings in the Sural Nerve and Dorsal Root Ganglion of Aged Control Sprague Dawley Rats in a Nonclinical Carcinogenicity Study.

Xenobiotic-induced peripheral nerve damage is a growing concern. Identifying relative risks that a new drug may cause peripheral nerve injury over long periods of administration is gathering importance in the evaluation of animal models. Separating out age-related changes in peripheral nerves of rats caused by compression injury from drug-induced effects has been difficult. Biopsy of the sural nerve is utilized in humans for investigations of peripheral neuropathy, because it is largely removed from the effects of nerve compression. This study used transmission electron microscopy to identify incidental findings in the sural nerves and dorsal root ganglia of aged control rats over time. The goal was to establish a baseline understanding of the range of possible changes that could be noted in controls compared to rats treated with any new investigative drug. In this evaluation, most sural nerve fibers from aged control rats had few ultrastructural abnormalities of pathologic significance. However, glycogenosomes, polyglucosan bodies, swollen mitochondria, autolysosomes, split myelin, Schwann cell processes, and endoneural macrophages with phagocytosed debris (considered an indication of ongoing degenerative changes) were occasionally noted.

Simulating clamp placement across the trans-syndesmotic angle of the ankle to minimize malreduction: A radiological study.

BACKGROUND: Ankle fractures associated with syndesmotic injury have a poorer prognosis than those without such an injury. Anatomic reduction of the distal tibiofibular joint restores joint congruency and minimizes contact pressures, yet operative fixation of syndesmotic ankle injuries is frequently complicated by malreduction of the syndesmosis. Current methods of assessing reduction have been shown to be inadequate. As such, additional methods to judge the accuracy of syndesmotic reduction are required. QUESTIONS/PURPOSES: The purposes of our study were (1) to determine the anatomic axis of the syndesmosis, or the trans-syndesmotic angle (TSA), and (2) to describe the intraoperative fluoroscopic appearance of syndesmotic clamp reduction oriented along the anatomic syndesmotic angle. METHODS: Computed tomography (CT) scans of 45 uninjured adult ankles were analyzed to measure the TSA, defined as the angle between the plane of a lateral ankle radiograph and a line drawn perpendicular to the fibular incisura. Three-dimensional reconstructions of CT scans were then used to demonstrate clamp placement collinear with the TSA as would be seen on an intraoperative lateral ankle radiograph. RESULTS: The average TSA measured 21±5° anterior to the plane of a lateral radiograph. When a simulated reduction clamp tine was placed on the fibular ridge and the clamp oriented along the TSA, the medial tine, as seen on a lateral radiograph, was within the anterior one-third of the tibia 93% of the time. It was, on average, 23±7% of the distance from the anterior to the posterior tibial cortex, with tine placement occurring in this range in 73% of ankles. The medial tine rested 53±17% of the distance between the anterior cortices of the tibia and fibula, with 71% of tines placed in this range. CONCLUSIONS: Reduction clamp placement oriented along the TSA has a predictable appearance on lateral ankle imaging and can guide clamp positioning during syndesmotic reduction. With one tine placed on the fibular ridge, placing the medial clamp tine in the anterior third of the tibia, or halfway between the anterior cortices of the tibia and fibula is the most accurate position for reduction in line with the TSA. LEVEL OF EVIDENCE: 2 (Retrospective diagnostic).

Operative Versus Conservative Management of Displaced Tibial Shaft Fracture in Adolescents.

BACKGROUND: Displaced tibial shaft fractures are common in adolescent patients, yet there is no standardized management strategy. We compared surgical fixation and closed reduction and casting (CRC) of these fractures to assess treatment outcomes and determine predictors of failure. METHODS: We retrospectively reviewed all patients aged 12 to 18 who presented with a displaced tibial shaft fracture that required reduction over an 8-year period. Exclusion criteria included open fractures and lack of follow-up to radiographic union or to 6 months from the index procedure. Fractures were initially treated based on surgeon preference either with CRC or with immediate intramedullary nailing. Seventy-four patients met inclusion criteria: 57 were initially managed with CRC and 17 with operative fixation. Radiographic healing was defined as bridging of 3 cortices and adequacy of final alignment was defined as <5 degrees of angular deformity in both planes and <1.0 cm of shortening. Outcomes were analyzed both on intent-to-treat principles and by definitive treatment method. RESULTS: Although all fractures in both groups achieved bony healing, 23 of the 57 patients who underwent CRC failed closed treatment and ultimately required surgery (40.3%). Multivariate analysis of patient and fracture characteristics revealed fracture displacement of >20% (odds ratio=7.8, P<0.05) and the presence of a fibula fracture (odds ratio=5.06, P=0.05) as predictors of closed treatment failure. Patients ultimately managed with intramedullary nailing trended toward increased adequacy of final alignment (92.5% vs. 72.4%, P=0.10) but required longer hospitalization (5.4 vs. 1.9 d, P<0.001) and had a higher incidence of anterior knee pain (20% vs. 0%, P<0.01). There was no significant difference between groups with respect to time to healing. CONCLUSIONS: Treatment outcomes between initial operative fixation and closed reduction of displaced tibia fractures in adolescents are similar, but patients must be counseled about the high failure rates with CRC. Predictors of CRC failure include initial fracture displacement and the presence of a fibula fracture-these variables should be considered when selecting a treatment method. LEVEL OF EVIDENCE: Level III-Therapeutic study.

Popliteal artery pseudoaneurysm: an unusual complication of tibial traction.

Traction pins are an essential tool in the orthopedic surgeon's armamentarium. Historically a definitive treatment for some fractures, they are mainly used as a temporizing measure today. Despite their frequent use and relative simplicity, traction pins can have complications, many of which can be subtle and easily overlooked. Here we report on an unusual complication that was difficult to diagnose but caused significant morbidity before being diagnosed and treated. Pseudoaneurysms can cause a range of symptoms and usually present as a painful, tender, pulsatile mass, but in this instance the popliteal artery pseudoaneurysm presented as chronic, painful lower extremity swelling. With diagnosis and treatment, the patient's symptoms resolved. We discuss the complications associated with traction-pin placement.

Dynamic Locked Plating of Distal Femur Fractures.

OBJECTIVES: Nonunion after locked bridge plating of comminuted distal femur fractures is not uncommon. "Dynamic" locked plating may create an improved mechanical environment, thereby achieving higher union rates than standard locked plating constructs. SETTING: Academic Level 1 Trauma Center. PATIENTS/PARTICIPANTS: Twenty-eight patients with comminuted supracondylar femur fractures treated with either dynamic or standard locked plating. INTERVENTION: Dynamic plating was achieved using an overdrilling technique of the near cortex to allow for a 0.5-mm "halo" around the screw shaft at the near cortex. Standard locked plating was done based on manufacturer's suggested technique. The patients treated with dynamic plating were matched 1:1 with those treated with standard locked plating based on OTA classification and working length. MAIN OUTCOME MEASUREMENTS: Three blinded observers made callus measurements on 6-week radiographs using a 4-point ordinal scale. The results were analyzed using a 2-tailed t test and 2-way intraclass correlations. RESULTS: The dynamic plating group had significantly greater callus (2.0; SD, 0.7) compared with the control group (1.3: SD, 0.8, P = 0.048) with substantial agreement amongst observers in both consistency (0.724) and absolute score (0.734). With dynamic plating group, 1 patient failed to unite, versus three in the control group (P = 0.59). The dynamic group had a mean change in coronal plane alignment of 0.5 degrees (SD, 2.6) compared with 0.6 (SD, 3.0) for the control group (P = 0.9) without fixation failure in either group. CONCLUSIONS: Overdrilling the near cortex in metaphyseal bridge plating can be adapted to standard implants to create a dynamic construct and increase axial motion. This technique seems to be safe and leads to increased callus formation, which may decrease nonunion rates seen with standard locked plating. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Triple monoamine uptake inhibitors demonstrate a pharmacologic association between excessive drinking and impulsivity in high-alcohol-preferring (HAP) mice.

Approximately 30% of current drinkers in the United States drink excessively, and are referred to as problem/hazardous drinkers. These individuals, who may not meet criteria for alcohol abuse or dependence, comprise binge, heavy drinkers, or both. Given their high prevalence, interventions that reduce the risk of binge and heavy drinking have important public health implications. Impulsivity has been repeatedly associated with excessive drinking in the clinical literature. As impulsivity is correlated with, and may play a critical role in, the initiation and maintenance of excessive drinking, this behavior may be an important target for therapeutic intervention. Hence, a better understanding of pharmacological treatments capable of attenuating excessive drinking and impulsivity may markedly improve clinical outcomes. The high-alcohol-preferring (HAP) mice represent a strong rodent model to study the relationship between impulsivity and excessive alcohol drinking, as recent evidence indicates they consume high levels of alcohol throughout their active cycle and are innately impulsive. Using this model, the present study demonstrates that the triple monoamine uptake inhibitors (TUIs) amitifadine and DOV 102, 677 effectively attenuate binge drinking, heavy drinking assessed via a 24-hour free-choice assay, and impulsivity measured by the delay discounting procedure. In contrast, 3-PBC, a GABA-A α1 preferring ligand with mixed agonist-antagonist properties, attenuates excessive drinking without affecting impulsivity. These findings suggest that in HAP mice, monoamine pathways may predominate as a common mechanism underlying impulsivity and excessive drinking, while the GABAergic system may be more salient in regulating excessive drinking. We further propose that TUIs such as amitifadine and DOV 102, 677 may be used to treat the co-occurrence of impulsivity and excessive drinking.

Is primary total elbow arthroplasty safe for the treatment of open intra-articular distal humerus fractures?

OBJECTIVES: Total elbow arthroplasty (TEA) is a viable treatment for elderly patients with distal humerus fracture who frequently present with low-grade open fractures. This purpose of this study was to evaluate the results of a protocol of serial irrigations and debridements (I&Ds) followed by primary TEA for the treatment of open intra-articular distal humerus fractures. METHODS: Seven patients (mean 74 years; range 56-86 years) with open (two Grade I and five Grade 2) distal humerus fractures (OTA 13C) who were treated between 2001 and 2007 with a standard staged protocol that included TEA were studied. Baseline Disabilities of the Arm, Shoulder and Hand (DASH) scores were obtained during the initial hospitalization, and the 6- and 12-month follow-up visits. Elbow range of motion (ROM) measurements were obtained at each follow-up visit. RESULTS: Follow-up averaged 43 (range 4-138) months. There were no wound complications and no deep infections. Complications included one case of heterotopic ossification with joint contracture, one olecranon fracture unrelated to the TEA, and two loose humeral stems. The average final ROM was from 21° (range 5-30°) to 113° flexion (range 90-130°). DASH scores averaged 25 at pre-injury baseline and 48 at the most recent follow-up visits. CONCLUSIONS: TEA has become a mainstream option for the treatment of distal humerus fractures which are on occasion open. There is hesitation in using arthroplasty in an open fracture setting due to a potential increased infection risk. The absence of any infectious complications and satisfactory functional outcomes observed in the current series indicates that TEA is a viable treatment modality for complex open fractures of the distal humerus.

Preclinical optimization of MDM2 antagonist scheduling for cancer treatment by using a model-based approach.

PURPOSE: Antitumor clinical activity has been demonstrated for the MDM2 antagonist RG7112, but patient tolerability for the necessary daily dosing was poor. Here, utilizing RG7388, a second-generation nutlin with superior selectivity and potency, we determine the feasibility of intermittent dosing to guide the selection of initial phase I scheduling regimens. EXPERIMENTAL DESIGN: A pharmacokinetic-pharmacodynamic (PKPD) model was developed on the basis of preclinical data to determine alternative dosing schedule requirements for optimal RG7388-induced antitumor activity. This PKPD model was used to investigate the pharmacokinetics of RG7388 linked to the time-course of the antitumor effect in an osteosarcoma xenograft model in mice. These data were used to prospectively predict intermittent and continuous dosing regimens, resulting in tumor stasis in the same model system. RESULTS: RG7388-induced apoptosis was delayed relative to drug exposure with continuous treatment not required. In initial efficacy testing, daily dosing at 30 mg/kg and twice a week dosing at 50 mg/kg of RG7388 were statistically equivalent in our tumor model. In addition, weekly dosing of 50 mg/kg was equivalent to 10 mg/kg given daily. The implementation of modeling and simulation on these data suggested several possible intermittent clinical dosing schedules. Further preclinical analyses confirmed these schedules as viable options. CONCLUSION: Besides chronic administration, antitumor activity can be achieved with intermittent schedules of RG7388, as predicted through modeling and simulation. These alternative regimens may potentially ameliorate tolerability issues seen with chronic administration of RG7112, while providing clinical benefit. Thus, both weekly (qw) and daily for five days (5 d on/23 off, qd) schedules were selected for RG7388 clinical testing.

Little evidence of a role for the α1GABAA subunit-containing receptor in a rhesus monkey model of alcohol drinking.

BACKGROUND: Alcohol potentiates GABAergic neurotransmission via action at the GABAA receptor. α1 subunit-containing GABAA receptors have been implicated as mediators, in part, of the behavioral and abuse-related effects of alcohol in rodents. METHODS: We systematically investigated the effects of 1 α1-preferring benzodiazepine agonist, zolpidem, and 2 antagonists, ß-carboline-3-carboxylate-tert-butyl ester (ßCCT) and 3-propoxy-ß-carboline hydrochloride (3-PBC), on oral self-administration of alcohol (2% w/v) or sucrose solution and observable behavior in rhesus macaques. We compared these effects to those of the nonselective benzodiazepine agonist triazolam, antagonist flumazenil, and inverse agonist ß-carboline carboxylate (ßCCE). RESULTS: Alcohol and sucrose solutions maintained reliable baseline drinking behavior across the study. The α1-preferring compounds did not affect intake, number of sipper extensions, or blood alcohol levels (BALs) at any of the doses tested. Zolpidem, ßCCT, and 3-PBC increased latency to first sipper extension in animals self-administering alcohol, but not sucrose, solution. Triazolam exerted biphasic effects on alcohol-drinking behavior, increasing intake at low doses but decreasing BAL and increasing latency at higher doses. At doses higher than those effective in alcohol-drinking animals, triazolam increased sucrose intake and latency. Flumazenil nonsystematically increased number of extensions for alcohol but decreased BAL, with no effects on sucrose drinking. ßCCE decreased sipper extensions for alcohol and increased latency for first sucrose sipper extension, but full dose-effect relationships could not be determined due to seizures at higher doses. CONCLUSIONS: Alcohol-drinking animals appeared more sensitive to the effects of GABAergic compounds on drinking behavior. However, these results do not support a strong contribution of α1GABAA receptors to the reinforcing effects of alcohol in primates.

What happens to serum metal ion levels after a metal-on-metal bearing is removed?

Serum cobalt (Co) and chromium (Cr) levels are commonly used to screen for excessive wear of metal-on-metal hip replacements. However, it is unknown how rapidly these should decline after revision. 25 patients with average Co and Cr ion levels of 56.3 µg/L and 20.5 µg/L were followed with serial ion level testing post-revision. Over the first 6 weeks post-revision, the rate of decline for Co and Cr was approximately 2% per day and this slowed to approximately 1% decline per day over the ensuing 6 weeks. This translated to a decline of approximately 80% from the starting value after 6 weeks and a decline of approximately 90% after 12 weeks post-revision. The rate of decline for both Co and Cr was significantly faster during the first 6 weeks (P<0.001). In patients with ultra-high Cr levels>20 µg/L, the rate of Cr decline is less predictable and may be protracted leading to persistent elevation above 5 µg/L for one year or more post-revision in some cases.

Insights into functional pharmacology of α1 GABA(A) receptors: how much does partial activation at the benzodiazepine site matter?

RATIONALE: Synthesis of ligands inactive or with low activity at α1 GABA(A) receptors has become the key concept for development of novel, more tolerable benzodiazepine (BZ)-like drugs. WYS8, a remarkably (105 times) α1-subtype selective partial positive modulator, may serve as a pharmacological tool for refining the role of α1 GABA(A) receptors in mediation of BZs' effects. OBJECTIVES: Here, the effects of WYS8 on GABA-induced currents and on diazepam-induced potentiation of recombinant BZ-sensitive GABA(A) receptors were studied in more detail. In addition, the behavioral profile of WYS8 (0.2, 1, and 10 mg/kg i.p.), on its own and in combination with diazepam, was tested in the spontaneous locomotor activity, elevated plus maze, grip strength, rotarod, and pentylenetetrazole tests. RESULTS: WYS8, applied at an in vivo attainable concentration of 100 nM, reduced the stimulation of GABA currents by 1 µM diazepam by 57 % at α1ß3γ2, but not at α2ß3γ2, α3ß3γ2, or α5ß3γ2 GABA(A) receptors. The administration of WYS8 alone induced negligible behavioral consequences. When combined with diazepam, WYS8 caused a reduction in sedation, muscle relaxation, and anticonvulsant activity, as compared with this BZ alone, whereas ataxia was preserved, and the anxiolytic effect of 2 mg/kg diazepam was unmasked. CONCLUSIONS: Hence, a partial instead of full activation at α1 GABA(A) receptors did not necessarily result in the attenuation of the effects assumed to be mediated by activation of these receptors, or in the full preservation of the effects mediated by activation of other GABA(A) receptors. Thus, the role of α1 GABA(A) receptors appears more complex than that proposed by genetic studies.

MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models.

MDM2 negatively regulates p53 stability and many human tumors overproduce MDM2 as a mechanism to restrict p53 function. Thus, inhibitors of p53-MDM2 binding that can reactivate p53 in cancer cells may offer an effective approach for cancer therapy. RG7112 is a potent and selective member of the nutlin family of MDM2 antagonists currently in phase I clinical studies. RG7112 binds MDM2 with high affinity (K(D) ~ 11 nmol/L), blocking its interactions with p53 in vitro. A crystal structure of the RG7112-MDM2 complex revealed that the small molecule binds in the p53 pocket of MDM2, mimicking the interactions of critical p53 amino acid residues. Treatment of cancer cells expressing wild-type p53 with RG7112 activated the p53 pathway, leading to cell-cycle arrest and apoptosis. RG7112 showed potent antitumor activity against a panel of solid tumor cell lines. However, its apoptotic activity varied widely with the best response observed in osteosarcoma cells with MDM2 gene amplification. Interestingly, inhibition of caspase activity did not change the kinetics of p53-induced cell death. Oral administration of RG7112 to human xenograft-bearing mice at nontoxic concentrations caused dose-dependent changes in proliferation/apoptosis biomarkers as well as tumor inhibition and regression. Notably, RG7112 was highly synergistic with androgen deprivation in LNCaP xenograft tumors. Our findings offer a preclinical proof-of-concept that RG7112 is effective in treatment of solid tumors expressing wild-type p53.

Role of gamma-aminobutyric acid type A (GABAA) receptor subtypes in acute benzodiazepine physical dependence-like effects: evidence from squirrel monkeys responding under a schedule of food presentation.

RATIONALE: Assays of schedule-controlled responding can be used to characterize the pharmacology of benzodiazepines and other GABAA receptor modulators, and are sensitive to changes in drug effects that are related to physical dependence. OBJECTIVE: The present study used this approach to investigate the role of GABAA receptor subtypes in mediating dependence-like effects following benzodiazepine administration. METHODS: Squirrel monkeys (n = 6) were trained on a fixed-ratio schedule of food reinforcement. Initially, the response rate-decreasing effects of chlordiazepoxide (0.1-10 mg/kg; nonselective GABAA receptor agonist), zolpidem (0.032-1.0 mg/kg; α1 subunit-containing GABAA subtype-preferring agonist), and HZ-166 (0.1-10 mg/kg; functionally selective α2 and α3 subunit-containing GABAA receptor agonist) were assessed. Next, acute dependence-like effects following single injections of chlordiazepoxide, zolpidem, and HZ-166 were assessed with flumazenil (0.1-3.2 mg/kg; nonselective GABAA receptor antagonist). Finally, acute dependence-like effects following zolpidem administration were assessed with ßCCt and 3-PBC (0.1-3.2 mg/kg and 0.32-10 mg/kg, respectively; α1 subunit-containing GABAA receptor antagonists). RESULTS: Chlordiazepoxide, zolpidem, and HZ-166 produced dose- and time-dependent decreases in response rates, whereas flumazenil, ßCCT, and 3-PBC were ineffective. After the drug effects waned, flumazenil produced dose-dependent decreases in response rates following administration of 10 mg/kg chlordiazepoxide and 1.0 mg/kg zolpidem, but not following any dose of HZ-166. Further, both ßCCT and 3-PBC produced dose-dependent decreases in response rates when administered after 1.0 mg/kg zolpidem. CONCLUSIONS: These data raise the possibility that α1 subunit-containing GABAA receptors play a major role in physical dependence-related behaviors following a single injection of a benzodiazepine.

Effects of the benzodiazepine GABAA α1-preferring ligand, 3-propoxy-ß-carboline hydrochloride (3-PBC), on alcohol seeking and self-administration in baboons.

RATIONALE: The various α subtypes of GABAA receptors have been strongly implicated in alcohol reinforcement and consumption. OBJECTIVES: The effects of the GABAA α1-preferring ligand, 3-propoxy-ß-carboline hydrochloride (3-PBC), on seeking and self-administration responses were evaluated in two groups of baboons trained under a 3-component chained schedule of reinforcement (CSR). METHODS: Alcohol (4 % w/v; n = 5; alcohol group) or a preferred nonalcoholic beverage (n = 4; control group) was available for self-administration only in component 3 of the CSR. Responses in component 2 provided indices of motivation to drink (seeking). 3-PBC (1.0-30.0 mg/kg) and saline were administered before drinking sessions under both acute and 5-day dosing conditions. RESULTS: Repeated, and not acute, doses of 3-PBC significantly decreased total self-administration responses (p < 0.05), volume consumed (p < 0.05), and gram per kilogram of alcohol (p < 0.05) in the alcohol group. In the control group, 5-day administration of 3-PBC significantly decreased total self-administration responses (p < 0.05) but produced nonsignificant decreases in volume consumed. Within-session pattern of drinking was characterized by a high level of drinking in the first 20 min of the session for both groups, which was significantly (p < 0.05) decreased by all doses of 3-PBC (1.0-18.0 mg/kg) only in the alcohol group. In contrast, the first drinking bout in the control group was only reduced at the highest doses of 3-PBC (10.0 and 18.0 mg/kg). CONCLUSIONS: The results support the involvement of the GABAA α1 subtype receptor in alcohol reinforcement and consumption.

Benzodiazepine-induced spatial learning deficits in rats are regulated by the degree of modulation of α1 GABA(A) receptors.

Despite significant advances in understanding the role of benzodiazepine (BZ)-sensitive populations of GABAA receptors, containing the α1, α2, α3 or α5 subunit, factual substrates of BZ-induced learning and memory deficits are not yet fully elucidated. It was shown that α1-subunit affinity-selective antagonist ß-CCt almost completely abolished spatial learning deficits induced by diazepam (DZP) in the Morris water maze. We examined a novel, highly (105 fold) α1-subunit selective ligand-WYS8 (0.2, 1 and 10 mg/kg), on its own and in combination with the non-selective agonist DZP (2 mg/kg) or ß-CCt (5 mg/kg) in the water maze in rats. The in vitro efficacy study revealed that WYS8 acts as α1-subtype selective weak partial positive modulator (40% potentiation at 100nM). Measurement of concentrations of WYS8 and DZP in rat serum and brain tissues suggested that they did not substantially cross-influence the respective disposition. In the water maze, DZP impaired spatial learning (acquisition trials) and memory (probe trial). WYS8 caused no effect per se, did not affect the overall influence of DZP on the water-maze performance and was devoid of any activity in this task when combined with ß-CCt. Nonetheless, an additional analysis of the latency to reach the platform and the total distance swam suggested that WYS8 addition attenuated the run-down of the spatial impairment induced by DZP at the end of acquisition trials. These results demonstrate a clear difference in the influence of an α1 subtype-selective antagonist and a partial agonist on the effects of DZP on the water-maze acquisition.

Augmentation of tendon healing with butyric acid-impregnated sutures: biomechanical evaluation in a rabbit model.

BACKGROUND: Butyric acid (BA) has been shown to be angiogenic and to enhance transcriptional activity in tissue. These properties of BA have the potential to augment biological healing of a repaired tendon. PURPOSE: To evaluate this possibility both biomechanically and histologically in an animal tendon repair model. STUDY DESIGN: Controlled laboratory study. METHODS: A rabbit Achilles tendon healing model was used to evaluate the biomechanical strength and histological properties at 6 and 12 weeks after repair. Unilateral tendon defects were created in the middle bundle of the Achilles tendon of each rabbit, which were repaired equivalently with either Ultrabraid BA-impregnated sutures or control Ultrabraid sutures. RESULTS: After 6 weeks, BA-impregnated suture repairs had a significantly increased (P < .0001) Young's modulus and ultimate tensile strength relative to the control suture repairs. At 12 weeks, no statistical difference was observed between these measures. The histological data at 6 weeks demonstrated significantly increased (P < .005) vessel density within 0.25 mm of the repair suture in the BA-impregnated group. There was also an associated 42% increase in the local number of myofibroblasts in the BA samples relative to the controls at this time. By 12 weeks, these differences were not observed. CONCLUSION: Tendons repaired with BA-impregnated sutures demonstrated improved biomechanical properties at 6 weeks relative to control sutures, suggesting a neoangiogenic mechanism of enhanced healing through an increased myofibroblast presence. CLINICAL RELEVANCE: These findings demonstrate that a relatively simple alteration of suture material may augment early tendon healing to create a stronger repair construct during this time.

The role of α1 and α5 subunit-containing GABAA receptors in motor impairment induced by benzodiazepines in rats.

Benzodiazepines negatively affect motor coordination and balance and produce myorelaxation. The aim of the present study was to examine the extent to which populations of γ-aminobutyric acid A (GABAA) receptors containing α1 and α5 subunits contribute to these motor-impairing effects in rats. We used the nonselective agonist diazepam and the α1-selective agonist zolpidem, as well as nonselective, α1-subunit and α5-subunit-selective antagonists flumazenil, ßCCt, and XLi093, respectively. Ataxia and muscle relaxation were assessed by rotarod and grip strength tests performed 20 min after intraperitoneal treatment. Diazepam (2 mg/kg) induced significant ataxia and muscle relaxation, which were completely prevented by pretreatment with flumazenil (10 mg/kg) and ßCCt (20 mg/kg). XLi093 antagonized the myorelaxant, but not the ataxic actions of diazepam. All three doses of zolpidem (1, 2, and 5 mg/kg) produced ataxia, but only the highest dose (5 mg/kg) significantly decreased the grip strength. These effects of zolpidem were reversed by ßCCt at doses of 5 and 10 mg/kg, respectively. The present study demonstrates that α1 GABAA receptors mediate ataxia and indirectly contribute to myorelaxation in rats, whereas α5 GABAA receptors contribute significantly, although not dominantly, to muscle relaxation but not ataxia.