Vaccine value profile for Klebsiella pneumoniae.

Klebsiella pneumoniae causes community- and healthcare-associated infections in children and adults. Globally in 2019, an estimated 1.27 million (95% Uncertainty Interval [UI]: 0.91-1.71) and 4.95 million (95% UI: 3.62-6.57) deaths were attributed to and associated with bacterial antimicrobial resistance (AMR), respectively. K. pneumoniae was the second leading pathogen in deaths attributed to AMR resistant bacteria. Furthermore, the rise of antimicrobial resistance in both community- and hospital-acquired infections is a concern for neonates and infants who are at high risk for invasive bacterial disease. There is a limited antibiotic pipeline for new antibiotics to treat multidrug resistant infections, and vaccines targeted against K. pneumoniae are considered to be of priority by the World Health Organization. Vaccination of pregnant women against K. pneumoniae could reduce the risk of invasive K.pneumoniae disease in their young offspring. In addition, vulnerable children, adolescents and adult populations at risk of K. pneumoniae disease with underlying diseases such as immunosuppression from underlying hematologic malignancy, chemotherapy, patients undergoing abdominal and/or urinary surgical procedures, or prolonged intensive care management are also potential target groups for a K. pneumoniae vaccine. A 'Vaccine Value Profile' (VVP) for K.pneumoniae, which contemplates vaccination of pregnant women to protect their babies from birth through to at least three months of age and other high-risk populations, provides a high-level, holistic assessment of the available information to inform the potential public health, economic and societal value of a pipeline of K. pneumoniae vaccines and other preventatives and therapeutics. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public-private partnerships, and multi-lateral organizations, and in collaboration with stakeholders from the WHO. All contributors have extensive expertise on various elements of the K.pneumoniae VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

Effect of screw insertion angle and speed on the incidence of transcortical fracture development in a canine tibial diaphyseal model.

OBJECTIVE: To assess the incidence of transcortical fracture (TCF) development based on screw insertion angle and screw insertion speed. STUDY DESIGN: Cadaveric experimental study. SAMPLE POPULATION: Sixty-six canine tibiae. METHODS: Sixty-six cadaveric tibiae were randomly assigned to one of six groups that varied based on screw insertion angle relative to the pilot hole (0, 5, or 10°) and screw insertion speed (650 or 1350 revolutions per minute [rpm]). Each tibia was mounted in a custom jig. Locking self-tapping screws (3.5 mm) were inserted at varying speeds and insertion angles, based on group assignment. Orthogonal radiographs were evaluated for TCFs. Fisher's exact tests with a Bonferroni correction were performed to evaluate differences in the frequency of TCF between groups. RESULTS: In Group A (0°/650 rpm: control), a 0% TCF rate was observed (n = 0/80). Group B (5°/650 rpm) had a 3.75% TCF rate (n = 3/80). Group C (10°/650 rpm) had a 12.5% TCF rate (n = 10/80). Group D (10°/hand insertion) had a 3.75% TCF rate (n = 3/80). Group E (10°/1350 rpm) had a 17.5% TCF rate (n = 14/80). Group F (0°/1350 rpm) had a 0% TCF rate (n = 0/80). Groups C and E had the highest TCF rates with a difference in TCF rates observed between the control group and Group C (p = .001) and between the control group and Group E (p < .001). CONCLUSION: Increased screw insertion angle and insertion speed appear to be predisposing factors for TCF development in cadaveric bone. CLINICAL SIGNIFICANCE: Ensuring screw insertion is coaxial with the pilot hole and using slower screw insertion speeds may help reduce the risk of TCF development.

Hit 'em Where It Hurts: Gram-Negative Bacterial Lipopolysaccharide as a Vaccine Target.

Infections with antimicrobial-resistant (AMR) bacteria pose an increasing threat to the ability to perform surgical procedures, organ transplantation, and treat cancer among many other medical conditions. There are few new antimicrobials in the development pipeline. Vaccines against AMR Gram-negative bacteria may reduce the use of antimicrobials and prevent bacterial transmission. This review traces the origins of lipopolysaccharide (LPS)-based vaccines against Gram-negative bacteria, the role of O polysaccharides and LPS core regions as potential vaccine targets, the development of new vaccine technologies, and their application to vaccines in current development.

The effect of two platelet-rich plasma aspiration techniques on plasma cellular concentrations using a double syringe gravitational centrifugation system.

OBJECTIVE: To identify which aspiration technique increased plasma platelet concentration and which technique minimized plasma leukocyte and erythrocyte concentrations using a gravitational double-syringe platelet rich plasma (PRP) system. STUDY DESIGN: Controlled laboratory study. ANIMALS: Thirty adult dogs. METHODS: Whole blood was collected into two autologous conditioned plasma (ACP) syringes and an ethylenediaminetetraacetic acid (EDTA tube) (control samples). The ACP syringes were centrifuged for 5 min at 1500 rpm. The proximal 2 mL of plasma from one ACP syringe was deposited in an EDTA tube (preflash samples). Plasma from the second ACP syringe was withdrawn until the buffy coat was pierced, producing a "flash" of red blood cells, agitated and deposited into an EDTA tube (flash samples). Complete blood counts were performed. RESULTS: Mean plasma platelet concentrations of the control, preflash, and flash samples were 2.4 × 105 /dL, 3.3 × 105 /dL and 4.1 × 105 /dL, respectively. The mean platelet concentration of the flash samples was 7.9 × 104 /dL higher than the preflash samples (p = .005). The mean platelet concentration was lower in the control samples than the preflash (p = .002) and flash (p < .0001) samples. The median plasma leukocyte concentration of the preflash samples (0/dL) was lower than in the flash samples (2.4 × 103 /dL) (p = .001). The median plasma hematocrit value of the preflash samples (0%) was lower than in the flash samples (1.0%) (p = .002). CONCLUSION: The flash method is not necessary to produce a PRP sample. CLINICAL SIGNIFICANCE: Both methods produced PRP. However, clinicians should avoid aspirating the buffy coat when processing PRP for therapies where leukocytes and erythrocytes are contraindicated.

The effect of grip location on Kirschner wire bend characteristics: An in vitro study.

OBJECTIVE: To determine the effect of Kirschner wire (K-wire) grip location on bend angle, bend radius, and torque when performing a Z-bend technique. STUDY DESIGN: Experimental study. SAMPLE POPULATION: Ten samples at each of five grip locations for each of three K-wire diameters. METHODS: K-wires of three diameters (0.9, 1.1, 1.6 mm) were drilled into PVC pipe, and a Jacob's chuck was used to bend the wires at five periodic grip locations (distance from the bone model). Torque, bend angle, and bend radius were determined for each sample. Outcome variables were statistically analyzed by grip location to determine significant relationships. RESULTS: A grip location of 2.0 cm in the 0.9 mm K-wire group minimized bend angle (mean ± SD: 75.92° ± 0.81) and bend radius (2.89 mm ± 0.08). A grip location of 3.0 cm in the 1.1 mm K-wire group minimized bend angle (72.88° ± 0.98) and bend radius (2.47 mm ± 0.20). A grip location of 3.0 cm minimized bend angle (74.38° ± 1.93) and bend radius (2.71 mm ± 0.27) in the 1.6 mm K-wire group. Torque at these grip locations for the 0.9, 1.1, and 1.6 mm K-wires was 6.50 N-m ± 0.0, 11.00 N-m ± 0.0, and 19.05 N-m ± 0.16, respectively. CONCLUSION: Bend angle and bend radius can be minimized by bending K-wires at specific grip locations, though torque is not minimized at these locations. Clinical significance These findings provide an evidence-based recommendation of where surgeons should grip K-wires when bending them.

Evaluation of the clinical value of routine radiographic examination during convalescence for tibial plateau-leveling osteotomy.

OBJECTIVE: To determine how frequently routine follow-up radiographic findings would result in a change to the postoperative plan following tibial plateau-leveling osteotomy (TPLO) in dogs. STUDY DESIGN: Retrospective study SAMPLE POPULATION: Short-term group: 100 cases; intermediate-term group: 50 cases. METHODS: Medical records of 100 consecutive cases meeting the inclusion criteria were reviewed (the short-term group). The cases had no owner-perceived issues and underwent routinely prescribed radiographic follow up between 40 and 60 postoperative days after TPLO performed by one experienced surgeon. Complications identified on physical examination (PE) and radiographic examination (RE) were recorded, along with any changes to the postoperative plan. Medical records of 50 consecutive cases that had short-term and intermediate-term (≥180 days) REs and PEs were reviewed similarly (intermediate-term group). RESULTS: Fifty-one cases in the short-term group had no complications on PE or RE. Forty-nine dogs were diagnosed with minor complications (patellar ligament desmitis, patella or fibula fracture, gait abnormalities): 42 on RE only; 6 on PE and RE; 1 on PE only. Exercise restriction was extended for 2 weeks in 2 cases with radiographic patellar ligament desmitis. Two cases in the intermediate-term group had minor complications at intermediate-term RE. No new PE or RE complications developed between short-term and intermediate-term evaluations. CONCLUSION: At routine rechecks of dogs with no owner-perceived issues after TPLO, 49% had minor complications but only 2% were deemed significant enough to alter patient management. The likelihood of new radiographic complications developing after short-term evaluation is low. CLINICAL SIGNIFICANCE: Routine radiographic recheck examinations rarely altered the postoperative plan in TPLO cases with unremarkable clinical recoveries.

A Nonlethal Murine Flame Burn Model Leads to a Transient Reduction in Host Defenses and Enhanced Susceptibility to Lethal Pseudomonas aeruginosa Infection.

Of the 486,000 burn injuries that required medical treatment in the United States in 2016, 40,000 people were hospitalized, with >3,000 fatalities. After burn injury, humans are at increased risk of sepsis and mortality from infections caused by Pseudomonas aeruginosa, an opportunistic pathogen. We hypothesize that systemic events were initiated from the burn that increased the host's susceptibility to P. aeruginosa. A nonlethal 10% total body surface area (TBSA), full-thickness flame burn was performed in CD-1 mice without and with subsequent P. aeruginosa (strain M2) infection. The 50% lethal dose for subcutaneous infection with P. aeruginosa M2 at the burn site immediately after the burn decreased by 6 log, with mortality occurring between 18 and 26 h, compared with P. aeruginosa-infected mice without burn injury. Bacteria in distal organs were detected by 18 h, concurrent with the onset of clinical symptoms. Serum proinflammatory cytokines (interleukin-6 [IL-6], IL-1ß, gamma interferon, and tumor necrosis factor alpha) and the anti-inflammatory cytokine IL-10 were first detected at 12 h postburn with infection and continued to increase until death. Directly after burn alone, serum levels of HMGB1, a danger-associated molecular pattern and TLR4 agonist, transiently increased to 50 ng/ml before returning to 20 ng/ml. Burn with P. aeruginosa infection increased serum HMGB1 concentrations >10-fold (250 ng/ml) at the time of death. This HMGB1-rich serum stimulated TLR4-mediated NF-κB activation in a TLR4 reporter cell line. Treatment of infected burned mice with P5779, a peptide inhibitor of HMGB1, increased the mean survival from 23 to 42 h (P < 0.0001). We conclude that the high level of serum HMGB1, which preceded the increase in proinflammatory cytokines, is associated with postburn mortality.

Evaluation of the risk of patella fracture as the result of decreasing tibial plateau angle following tibial plateau leveling osteotomy.

OBJECTIVE: To evaluate the effect of postoperative tibial plateau angle (TPA) following tibial plateau leveling osteotomy (TPLO) on the risk of patella fracture during the convalescent period. STUDY DESIGN: Retrospective study. SAMPLE POPULATION: Fracture group: 20 stifles; reference group: 65 stifles. METHODS: Medical records were reviewed for stifles with patellar fractures after a TPLO procedure (fracture group) and stifles with >180 days radiographic examination with no complications following TPLO (reference group). Stifle radiographs were masked to group and final TPA (fTPA) was measured, at the time of fracture diagnosis (fracture group) and at last follow-up (reference group), using PACS software. TPAs in the fracture and reference groups were compared using the Wilcoxon rank-sum test. Statistical significance was set at .05. RESULTS: Patellar fractures were diagnosed at a median of 69 days (range 31-189) after surgery. The median duration of follow-up time for the reference group was 471 days (range 180-1868). Median fTPA for the fracture group was 1.4° (range [-10.3]-7.1). Median fTPA for the reference group was 4.1° (range [-3.9]-14.1). The odds of patellar fractures increased by 21.7% (95% CI: 8.6%-35.6%) for every 1° decrease in fTPA. CONCLUSION: The risk of patella fractures increased as TPAs after TPLOs decreased. CLINICAL SIGNIFICANCE: Care should be taken to avoid excessive rotation during TPLO to decrease the likelihood of postoperative patellar fractures.

Outcomes Associated With Osteochondral Allograft Transplantation in Dogs.

The purpose of this study was to retrospectively characterize outcomes and complications associated with osteochondral allograft transplantation for treating chondral and osteochondral lesions in a group of client-owned dogs with naturally-occurring disease. Records were reviewed for information on signalment, treated joint, underlying pathology (e.g., osteochondritis dissecans; OCD), and type, size, and number of grafts used. Complications were classified as "trivial" if no treatment was provided, "non-surgical" if non-surgical treatment were needed, "minor surgical" if a minor surgical procedure such as pin removal were needed but the graft survived and function was acceptable, or "major" if the graft failed and revision surgery were needed. Outcomes were classified as unacceptable, acceptable, or full function. Thirty-five joints in 33 dogs were treated including nine stifles with lateral femoral condyle (LFC) OCD and 10 stifles with medial femoral condyle (MFC) OCD treated with osteochondral cylinders or "plugs." There were 16 "complex" procedures of the shoulder, elbow, hip, stifle, and tarsus using custom-cut grafts. In total there were eight trivial complications, one non-surgical complication, two minor surgical complications, and five major complications for a total of 16/35 cases with complications. Accordingly, there were five cases with unacceptable outcomes, all of whom had major complications while the other 30 cases had successful outcomes. Of the 30 cases with successful outcomes, 15 had full function and 15 had acceptable function. Based on these subjective outcome assessments, it appears osteochondral allograft transplantation is a viable treatment option in dogs with focal or complex cartilage defects. However, no conclusions can be made regarding the inferiority or superiority of allograft transplantation in comparison to other treatment options based upon these data.

The effect of extracorporeal shockwave on liposomal bupivacaine in a tibial plateau leveling osteotomy model.

OBJECTIVE: To determine the effect of extracorporeal shock wave (ESWT) on liposomal bupivacaine in a tibial-plateau-leveling osteotomy model. STUDY DESIGN: In vitro study. SAMPLE POPULATION: Ten samples per group. METHODS: In addition to a control group (sham treatment), five treatment groups were defined as A, energy (E) 3 (0.22 mJ/mm2 ), 360 pulses per minute (p/m); B, E6 (0.29 mJ/mm2 ), 360 p/m; C, E8 (0.39 mJ/mm2 ), 360 p/m; D, E6, 480 p/m; E, E8 480 p/m. Two-milliliter aliquots of liposomal bupivacaine were placed in a gelatin chamber and treated with 1000 pulses according to group. All samples remained in the chamber for 170 seconds to reflect the longest treatment group. Free bupivacaine concentrations were determined after treatment with high-performance liquid chromatography. RESULTS: The median free bupivacaine concentration was reported as control, 1.90 mg/mL; A, 2.10 mg/mL; B, 2.03 mg/mL; C, 2.94 mg/mL; D, 2.71 mg/mL; E, 4.35 mg/mL. Groups C (P = .027), D (P = .034), and E (P = .002) were different from the control group. Groups C (P = .0025) and D (P = .0025) were different from group E. Additional intertreatment group differences were found. CONCLUSION: Extracorporeal shock wave therapy caused a dose-dependent release of bupivacaine; however, there was no significant release of bupivacaine from liposomes when ESWT was applied at currently recommended therapeutic settings in this model. CLINICAL SIGNIFICANCE: This in vitro study provides evidence that concurrent electrohydraulic ESWT and liposomal bupivacaine is likely safe at currently recommended settings, however, higher energy and pulse frequency settings should be avoided.

Use of an amikacin-infused collagen sponge concurrent with implant removal for treatment of tibial plateau leveling osteotomy surgical site infection in 31 cases.

OBJECTIVE: To report the use and long-term outcome of dogs with surgical site infection (SSI) after tibial plateau leveling osteotomy (TPO), treated with an amikacin-infused collagen sponge and implant removal. STUDY DESIGN: Retrospective study. ANIMALS: Thirty-one client-owned dogs. METHODS: Medical records were reviewed for dogs with SSI after a TPLO that were treated with surgical implant removal and concurrent implantation of an amikacin-infused collagen sponge. Relevant clinical and surgical data were recorded. The TPLO implants were routinely removed; the surgical site was swabbed for culture. The sponge was aseptically infused with amikacin prior to implantation. Postprocedure examinations consisted of visual inspection of the incision by the surgeon and lameness scoring. RESULTS: Thirty-one dogs met all inclusion criteria. Median follow-up time was 687 days. Short-term examination after implant removal and sponge implantation revealed uneventful incisional healing in 24 dogs. Six (19.4%) dogs exhibited inflamed incision sites a median of 4 days (range, 3-9) postoperatively that resolved without additional treatment. One (3.2%) dog required empirical antibiotic treatment 7 days postoperatively but was lost to long-term follow-up. Long-term follow-up examination revealed no clinical evidence of SSI recurrence and no lameness in the remaining 30 cases. CONCLUSION: Surgical implant removal and implantation of an absorbable collagen sponge infused with amikacin alone was an effective treatment for postoperative TPLO SSI. CLINICAL SIGNIFICANCE: This procedure had a 96.8% long-term resolution of SSI. It should be considered as a treatment option for TPLO SSI.

The Fyn kinase inhibitor, AZD0530, suppresses mouse alcohol self-administration and seeking.

Fyn is a member of the Src family of protein tyrosine kinases (PTKs) that plays an important role not only in normal synaptic functions but also in brain pathologies including alcohol use disorder. We previously reported that repeated cycles of binge drinking and withdrawal activate Fyn in the dorsomedial striatum (DMS) of rodents, and that Fyn signaling in the DMS contributes to rat alcohol intake and relapse. Here, we used AZD0530, a CNS penetrable inhibitor of Src PTKs developed for the treatment of Alzheimer disease and cancer and tested its efficacy to suppress alcohol-dependent molecular and behavioral effects. We show that systemic administration of AZD0530 prevents alcohol-induced Fyn activation and GluN2B phosphorylation in the DMS of mice. We further report that a single dose of AZD0530 reduces alcohol operant self-administration and promotes extinction of alcohol self-administration without altering basal and dopamine D1 receptor-dependent locomotion. Together, our findings suggest that AZD0530, through its inhibitory actions on Fyn kinase, dampens alcohol seeking and drinking.

Neuraminidase 1-mediated desialylation of the mucin 1 ectodomain releases a decoy receptor that protects against Pseudomonas aeruginosa lung infection.

Pseudomonas aeruginosa (Pa) expresses an adhesin, flagellin, that engages the mucin 1 (MUC1) ectodomain (ED) expressed on airway epithelia, increasing association of MUC1-ED with neuraminidase 1 (NEU1) and MUC1-ED desialylation. The MUC1-ED desialylation unmasks both cryptic binding sites for Pa and a protease recognition site, permitting its proteolytic release as a hyperadhesive decoy receptor for Pa. We found here that intranasal administration of Pa strain K (PAK) to BALB/c mice increases MUC1-ED shedding into the bronchoalveolar compartment. MUC1-ED levels increased as early as 12 h, peaked at 24-48 h with a 7.8-fold increase, and decreased by 72 h. The a-type flagellin-expressing PAK strain and the b-type flagellin-expressing PAO1 strain stimulated comparable levels of MUC1-ED shedding. A flagellin-deficient PAK mutant provoked dramatically reduced MUC1-ED shedding compared with the WT strain, and purified flagellin recapitulated the WT effect. In lung tissues, Pa increased association of NEU1 and protective protein/cathepsin A with MUC1-ED in reciprocal co-immunoprecipitation assays and stimulated MUC1-ED desialylation. NEU1-selective sialidase inhibition protected against Pa-induced MUC1-ED desialylation and shedding. In Pa-challenged mice, MUC1-ED-enriched bronchoalveolar lavage fluid (BALF) inhibited flagellin binding and Pa adhesion to human airway epithelia by up to 44% and flagellin-driven motility by >30%. Finally, Pa co-administration with recombinant human MUC1-ED dramatically diminished lung and BALF bacterial burden, proinflammatory cytokine levels, and pulmonary leukostasis and increased 5-day survival from 0% to 75%. We conclude that Pa flagellin provokes NEU1-mediated airway shedding of MUC1-ED, which functions as a decoy receptor protecting against lethal Pa lung infection.

Novel inhibitors of As(III) S-adenosylmethionine methyltransferase (AS3MT) identified by virtual screening.

Due to increased interest in As(III) S-adenosylmethionine methyltransferase (AS3MT), a search for chemical probes that can help elucidate function was initiated. A homology model was built based on related enzymes, and virtual screening produced 426 potential hits. Evaluation of these compounds in a functional enzymatic assay revealed several modest inhibitors including an O-substituted 2-amino-3-cyano indole scaffold. Two iterations of near neighbor searches revealed compound 5 as a potent inhibitor of AS3MT with good selectivity over representative methyltransferases DOT1L and NSD2 as well as a representative set of diverse receptors. Compound 5 should prove to be a useful tool to investigate the role of AS3MT and a potential starting point for further optimization.

Developmental seizures and mortality result from reducing GABAA receptor α2-subunit interaction with collybistin.

Fast inhibitory synaptic transmission is mediated by γ-aminobutyric acid type A receptors (GABAARs) that are enriched at functionally diverse synapses via mechanisms that remain unclear. Using isothermal titration calorimetry and complementary methods we demonstrate an exclusive low micromolar binding of collybistin to the α2-subunit of GABAARs. To explore the biological relevance of collybistin-α2-subunit selectivity, we generate mice with a mutation in the α2-subunit-collybistin binding region (Gabra2-1). The mutation results in loss of a distinct subset of inhibitory synapses and decreased amplitude of inhibitory synaptic currents. Gabra2-1 mice have a striking phenotype characterized by increased susceptibility to seizures and early mortality. Surviving Gabra2-1 mice show anxiety and elevations in electroencephalogram δ power, which are ameliorated by treatment with the α2/α3-selective positive modulator, AZD7325. Taken together, our results demonstrate an α2-subunit selective binding of collybistin, which plays a key role in patterned brain activity, particularly during development.

Effect of hypobaria and hyperoxia during sepsis on survival and energy metabolism.

BACKGROUND: Injured warfighters air evacuated to tertiary medical care facilities are subjected to many stresses that may promote the development of sepsis. In this study, we tested the hypothesis that exposure to "in-flight" hypobaria and/or hyperoxia within 24 hours after onset of intra-abdominal infection in rats accelerates the development and/or severity of sepsis and neurologic injury in survivors. METHODS: Sprague-Dawley rats underwent cecal ligation/puncture (CLP) or sham procedures. Twenty-four hours later, rats were then placed in hypobaric chambers for 6 hours and assigned to normobaric conditions and maintained at either 21% or 100% O2, or under hypobaric conditions (pressure equivalent to an altitude of 8,000 ft) but maintained under either 28% or 100% O2. Two days after CLP or sham, blood samples were obtained for cytokine levels, and mitochondria were isolated from the brain and heart of a subset of animals for analysis of mitochondrial oxygen consumption. Animals were also evaluated for neuromotor impairment before and 15 days postsurgery. RESULTS: Among the 70 rats studied, 16.7% of CLP but none of the sham-treated rats died. All of the CLP but none of the sham rats had evidence of peritonitis at 2 days. Twenty percent (6 of 30) CLP rats undergoing hypobaria versus 12.5% (3 of 24) of CLP rats exposed to normobaria died (p = 0.715) while 12% (3 of 25) of CLP rats exposed to hyperoxia versus 20.7% (6 of 29) of CLP rats exposed to normoxia died (p = 0.48). The ratio of mitochondrial ATP-generating O2 consumption to resting respiration was higher in the CLP plus hypobaria under 100% compared with shams. The only difference in H2O2 production was observed in mitochondria from CLP rats exposed to hyperoxia under normobaric conditions. Composite neurologic scores obtained 15 days postinjury were lower than those at baseline for shams. CONCLUSION: We conclude that neither "in-flight" hyperoxia nor hypobaria exacerbate sepsis or neurologic injury.

SURGICAL MANAGEMENT OF APPENDICULAR LONG-BONE FRACTURES IN FREE-RANGING FLORIDA PANTHERS ( PUMA CONCOLOR CORYI): SIX CASES (2000-2014).

The clinical outcomes of six free-ranging Florida panthers ( Puma concolor coryi) that underwent surgical stabilization of appendicular long-bone fractures (three femoral fractures, one tibial and one tibial and fibular fracture and two radial and ulnar fractures) were evaluated. These panthers presented to the University of Florida from 2000-2014. Estimated age of the panthers ranged from 0.5 to 4.5 yr, and weights ranged from 22 to 65 kg. Causes of injuries were vehicular collision ( n = 4) and capture related ( n = 2). All panthers underwent open reduction and fracture stabilization. Fixation failure necessitated three subsequent surgeries in one panther. Five panthers survived the immediate postoperative period, and all of these panthers' fractures obtained radiographic union (range, 8-36 [mean, 22] wk). The five surviving panthers underwent convalescence for 7-14 mo at White Oak Conservation Center before being released back into the wild; however, one panther was killed when hit by a car 3 days after release. The remaining four panthers were tracked for up to 106 mo in the wild and successfully integrated back into the native population. Surgical stabilization of appendicular long-bone fractures in free-ranging Florida panthers can be successful, but must take into account the stress that a large, undomesticated felid will place on the stabilized limb during convalescence as well as the difficulties involved in rehabilitating a wild panther in captivity.

Metabotropic Glutamate Receptors 2 and 3 as Targets for Treating Nicotine Addiction.

Tobacco smoking, driven by the addictive properties of nicotine, continues to be a worldwide health problem. Based on the well-established role of glutamatergic neurotransmission in drug addiction, novel medication development strategies seek to halt nicotine consumption and prevent relapse to tobacco smoking by modulating glutamate transmission. The presynaptic inhibitory metabotropic glutamate receptors 2 and 3 (mGluR2/3) are key autoreceptors on glutamatergic terminals that maintain glutamate homeostasis. Accumulating evidence suggests the critical role of mGluR2/3 in different aspects of nicotine addiction, including acquisition and maintenance of nicotine taking, nicotine withdrawal, and persistent nicotine seeking even after prolonged abstinence. The involvement of mGluR2/3 in other neuropsychiatric conditions, such as anxiety, depression, schizophrenia, Alzheimer's disease, Parkinson's disease, and pain, provides convincing evidence suggesting that mGluR2/3 may provide an effective therapeutic approach for comorbidity of smoking and these conditions. This focused review article highlights that mGluR2/3 provide a promising target in the search for smoking cessation medication with novel mechanisms of actions that differ from those of currently U.S. Food and Drug Administration-approved pharmacotherapies.

Modified cranial closing wedge osteotomy for treatment of cranial cruciate ligament insufficiency in dogs with excessive tibial plateau angles: Technique and complications in 19 cases.

OBJECTIVE: To describe short-term outcomes of a modified cranial closing wedge osteotomy (CCWO) for treatment of dogs with cranial cruciate ligament disease and excessive tibial plateau angle (eTPA). STUDY DESIGN: Retrospective clinical study. ANIMALS: 18 client-owned dogs (19 stifles) with cranial cruciate ligament disease and eTPA (>34°). METHODS: A modified CCWO was performed with Kirschner wires as osteotomy alignment aids. A juxta-articular neutral wedge osteotomy equal in angle to the preoperative TPA was performed. Fixation was achieved with a tibial plateau leveling osteotomy (TPLO) plate and tension band wire apparatus (89%) or a TPLO plate (11%). Preoperative and postoperative, and recheck TPA, cranial tibial long axis shift, and major and minor complications were recorded. RESULTS: The mean preoperative TPA (49.5° ± 6.7°) was reduced postoperatively (8.3° ± 4.8°). Four of 19 joints (21%) developed 2 major and 3 minor complications during the intraoperative and follow-up period (577 day mean in-hospital recheck). Two cases were diagnosed with surgical site infections requiring implant removal for resolution. Fixation failure or implant complications were not observed in any dog during the limited radiographic follow-up period. All dogs were sound or recovering as expected, with 15/19 dogs (79%) showing complete radiographic osteotomy healing at their final in-hospital follow-up examination. CONCLUSION: Modified CCWO should be considered for the treatment of cranial cruciate ligament disease in dogs with eTPA. In this case series, the described technique was associated with uneventful osteotomy healing without implant failures in all dogs, although radiographic follow-up was limited in some cases.

Closed reduction and fluoroscopic-assisted percutaneous pinning of 42 physeal fractures in 37 dogs and 4 cats.

OBJECTIVE: To report complications and clinical outcome of dogs and cats that underwent fluoroscopic-assisted percutaneous pinning (FAPP) of physeal fractures. STUDY DESIGN: Retrospective study. ANIMALS: Client-owned dogs (n = 37) and cats (n = 4). MATERIALS AND METHODS: Records (August 2007-August 2014) of physeal fractures treated with FAPP in 3 hospitals were evaluated. Data collected included signalment, fracture characteristics (etiology, location, duration, Salter-Harris classification, preoperative and postoperative displacement), surgical information (implant size, surgical duration), and outcome assessment information (functional outcome, radiographic outcome, and complications). RESULTS: The majority of animals (92%) were classified as full functional outcome. No significant predictors of functional outcome were identified. The overall complication rate was 15% (n = 6). Elective pin removal rate was 41% (n = 17). Goniometry and limb circumference measurements of the affected and contralateral limbs were not significantly different in dogs for which measurements were obtained. Seventeen of 18 animals (16 dogs, 2 cats) measured had bone length changes on follow-up radiographs. CONCLUSION: FAPP is associated with an excellent functional outcome in a narrow selection of fracture configurations, specifically those with minimal displacement and for which anatomical alignment can be achieved with closed reduction.