Multiligament stifle injury, a multicenter retrospective study in 26 dogs.

OBJECTIVES: To describe multiligament stifle injury in dogs and report complications and long-term outcomes. METHODS: Medical records of dogs surgically treated for multiligament stifle injury were reviewed from six veterinary hospitals. Long-term follow-up was collected from referring veterinarians. RESULTS: Twenty-six client-owned dogs and 26 stifles were included. Road traffic accidents and limb entrapment were the most common causes of injury. Cranial cruciate and lateral collateral ligament rupture was the most common combination of injury (10 cases). The caudal cruciate ligament was damaged in 12/23 cases but was surgically addressed in only 2 cases. Cranial cruciate ligament rupture was present in all cases and was managed using TPLO (6 cases), extracapsular suture (15 cases) and TTA (2 cases). Postoperative immobilisation with a transarticular external skeletal fixator was used in 4/26 cases. Intraoperative complications were reported in 2/23 cases, short-term complications in 17/25 cases, of which eight were major, and long-term complications in 7/18, of which two were major. Patella luxation was seen in one case and is a previously unreported complication. The overall outcome was excellent in 9/24 cases, good in 5/24 cases, fair in 7/24 cases and poor in 3/24 cases. Follow-up time ranged from 1.5 months to 9 years with the median (IQR) of 9.5 (4.0 to 28.5) months. CONCLUSIONS: Multiligament stifle injury in dogs is associated with a high rate of major complications. The overall outcome was good to excellent in just over half of the dogs.

Analysis of feline humeral fracture morphology and a comparison of fracture repair stabilisation methods: 101 cases (2009-2020).

OBJECTIVES: The aims of this study were to describe the type, presentation and prognostic factors of feline humeral fractures over a 10-year period and to compare three stabilisation systems for feline humeral diaphyseal fractures. METHODS: In total, 101 cats with humeral fractures presenting to seven UK referral centres between 2009 and 2020 were reviewed. Data collected included signalment, weight at the time of surgery, fracture aetiology, preoperative presentation, fixation method, surgical details, perioperative management and follow-up examinations. Of these cases, 57 cats with humeral diaphyseal fractures stabilised using three different fixation methods were compared, with outcome parameters including the time to radiographic healing, time to function and complication rate. RESULTS: The majority of the fractures were diaphyseal (71%), with only 10% condylar. Of the known causes of fracture, road traffic accidents (RTAs) were the most common. Neutered males were over-represented in having a fracture caused by an RTA (P = 0.001) and diaphyseal fractures were significantly more likely to result from an RTA (P = 0.01). Body weight had a positive correlation (r = 0.398) with time to radiographic healing and time to acceptable function (r = 0.315), and was significant (P = 0.014 and P = 0.037, respectively). Of the 57 humeral diaphyseal fractures; 16 (28%) were stabilised using a plate-rod construct, 31 (54%) using external skeletal fixation and 10 (18%) using bone plating and screws only. Open diaphyseal fractures were associated with more minor complications (P = 0.048). There was a significant difference between fixation groups in terms of overall complication rate between groups (P = 0.012). There was no significant difference between fixation groups in time to radiographic union (P = 0.145) or time to acceptable function (P = 0.306). CONCLUSIONS AND RELEVANCE: All three fixation systems were successful in healing a wide variety of humeral diaphyseal fractures. There was a significantly higher overall complication rate with external skeletal fixators compared with bone plating; however, the clinical impact of these is likely low.

Traumatic stifle injury in 72 cats: a multicentre retrospective study.

OBJECTIVES: The aim of the study was to describe traumatic stifle injury in cats and report complications and long-term outcome. METHODS: The medical records from seven veterinary hospitals of cats treated for traumatic stifle injury were reviewed. Long-term follow-up data were collected from referring veterinarians and using the Feline Musculoskeletal Pain Index, collected from owners. RESULTS: Seventy-two cats were included in the study. The most common combination of ligament injury involved both cruciate ligaments and the lateral collateral ligament (25.4%). Medial meniscal injury was more common (66.2%) than lateral meniscal injury (59.4%). A temporary transarticular pin was used intraoperatively to aid reduction in 23/73 (31.5%) surgeries. Postoperative immobilisation was applied in 41/72 (56.9%) cats with a mean duration of 4.8 weeks. Short-term complications occurred in 40/64 (62.5%) cats. Long-term complications occurred in seven (17.5%) cats. Overall outcome was excellent in 25/61 (41%) cats, good in 13/61 (21.3%) cats, fair in 11/61 (18%) cats and poor in 12/61 (19.7%) cats. Mean length of follow-up was 29.6 months (range 0.5-204). A significantly poorer outcome was observed in cats with medial meniscal injury and those undergoing revision surgery. Use of a transarticular pin when left in situ for postoperative immobilisation was associated with a poorer outcome (P = 0.043) and a higher risk of complications (P = 0.018). Postoperative immobilisation was not related to outcome. CONCLUSIONS AND RELEVANCE: Traumatic stifle injury in cats can lead to rupture of multiple ligaments causing significant instability of the joint. Surgical treatment is associated with a high rate of short-term complications, although long-term outcome may still be good to excellent in the majority of cats (62.3%). In cats where follow-up was available, postoperative immobilisation had no positive effect on outcome and may not be required. Leaving a transarticular pin for postoperative immobilisation is not recommended as it was significantly associated with a poorer outcome and a higher complication rate.

Management of severe stifle trauma: 2. Periarticular fractures.

PRACTICAL RELEVANCE: Periarticular stifle fractures are uncommon but challenging injuries to treat. There may be concurrent damage to the ligaments and stabilising structures of the stifle joint itself, which should also be evaluated (see Part 1 of this article series). Improved knowledge of the fixation options and biomechanical challenges of these injuries will aid clinical decision-making and effective repair. CLINICAL CHALLENGES: Due to their nature, periarticular fractures may have small juxta-articular fragments, which require additional thought to address during stabilisation. In juvenile animals, these fractures typically involve the physis and often can be managed with cross pin fixation. In adult cats, locking fixation, specialised plates or external skeletal fixators can be utilised to address the juxta-articular fragments. Readers should also be aware of patellar fracture and dental anomaly syndrome (PADS), where cats develop insufficiency fractures affecting the patella and proximal tibia. A careful oral examination should be performed in affected patients, as these cats may have persistent deciduous teeth. Close attention should be paid to preoperative radiographs for evidence of chronicity of the injury including sclerosis of the patella, remodelling and blunting of the fracture lines. AIMS: The aims of the article are to review the current literature surrounding periarticular fractures of the stifle joint and to summarise the diagnosis, treatment, outcome and complications of each fracture type. As well as discussing general fracture fixation and biomechanical principles applicable to both dogs and cats, information is provided on specific issues facing cats, such as PADS. EVIDENCE BASE: Published data is limited, with reports including only a small number of cats. The information and recommendations in this article have therefore been drawn from a combination of the available literature and the authors' clinical experience.

Management of severe stifle trauma: 1. Stifle luxation.

PRACTICAL RELEVANCE: Traumatic stifle joint luxation is an uncommon but severe injury. There is usually rupture of several stabilising structures of the joint including the cruciate ligaments, collateral ligaments, joint capsule and menisci. Successful management of this condition requires good anatomical knowledge and repair or replacement of all damaged structures to achieve adequate joint reduction and stability. Better understanding of the treatment options available will aid clinical decision-making. CLINICAL CHALLENGES: Due to the significant joint instability associated with these injuries, surgical repair is challenging. The use of a temporary transarticular pin to hold the stifle joint in anatomic reduction greatly aids ligament repair or replacement. Postoperative joint immobilisation has traditionally been recommended to protect the primary repair and aid periarticular fibrosis, but prolonged immobilisation can have deleterious long-term effects on the joint. Thus recommendations for the duration of postoperative immobilisation vary between 2 and 6 weeks. Also, due to their independent, outdoor lifestyle, affected cats may have been involved in a significant trauma with important concurrent injuries that need to be addressed prior to the orthopaedic repair. EVIDENCE BASE: Published data is limited, with reports including only a small number of cats. The information and recommendations in this article have therefore been drawn from the available literature, the authors' experience and preliminary data from an ongoing multicentre retrospective study (unpublished). AIMS: The aims of this article are to give the reader as thorough a summary as possible of the diagnosis, treatment, outcome and complications of traumatic stifle luxation.

Nanoscale Coatings for Ultralow Dose BMP-2-Driven Regeneration of Critical-Sized Bone Defects.

While new biomaterials for regenerative therapies are being reported in the literature, clinical translation is slow. Some existing regenerative approaches rely on high doses of growth factors, such as bone morphogenetic protein-2 (BMP-2) in bone regeneration, which can cause serious side effects. An ultralow-dose growth factor technology is described yielding high bioactivity based on a simple polymer, poly(ethyl acrylate) (PEA), and mechanisms to drive stem cell differentiation and bone regeneration in a critical-sized murine defect model with translation to a clinical veterinary setting are reported. This material-based technology triggers spontaneous fibronectin organization and stimulates growth factor signalling, enabling synergistic integrin and BMP-2 receptor activation in mesenchymal stem cells. To translate this technology, plasma-polymerized PEA is used on 2D and 3D substrates to enhance cell signalling in vitro, showing the complete healing of a critical-sized bone injury in mice in vivo. Efficacy is demonstrated in a Münsterländer dog with a nonhealing humerus fracture, establishing the clinical translation of advanced ultralow-dose growth factor treatment.

Repeatability of quantitative sensory testing in healthy cats in a clinical setting with comparison to cats with osteoarthritis.

Objectives The aim of this study was to evaluate the repeatability of quantitative sensory tests (QSTs) in a group of healthy untrained cats (n = 14) and to compare the results with those from cats with osteoarthritis (n = 7). Methods Peak vertical force (PVF) and vertical impulse were measured on a pressure plate system. Thermal sensitivity was assessed using a temperature-controlled plate at 7°C and 40°C. Individual paw lifts and overall duration of paw lifts were counted and measured for each limb. Paw withdrawal thresholds were measured using manual and electronic von Frey monofilaments (MVF and EVF, respectively) applied to the metacarpal or metatarsal pads. All measurements were repeated twice to assess repeatability of the tests. Results In healthy cats all tests were moderately repeatable. When compared with cats with osteoarthritis the PVF was significantly higher in healthy hindlimbs in repeat 1 but not in repeat 2. Cats with osteoarthritis of the forelimbs showed a decrease in the frequency of paw lifts on the 7°C plate compared with cats with healthy forelimbs, and the duration of paw lifts was significantly less than healthy forelimbs in the first repeat but not in the second repeat. Osteoarthritic limbs had significantly lower paw withdrawal thresholds with both MVF and EVF than healthy limbs. Conclusions and relevance QSTs are moderately repeatable in untrained cats. Kinetic gait analysis did not permit differentiation between healthy limbs and those with osteoarthritis, but thermal sensitivity testing (cold) does. Sensory threshold testing can differentiate osteoarthritic and healthy limbs, and may be useful in the diagnosis and monitoring of this condition in cats in the clinical setting.

Evaluation of osteotomy accuracy and rotational and angular alignment for cranial closing wedge ostectomy performed with and without alignment aids.

OBJECTIVE: To (1) investigate the use of K-wires as alignment aids for cranial closing wedge ostectomy (CCWO) and (2) evaluate their effect on osteotomy accuracy and angular/rotational alignment. STUDY DESIGN: Cadaveric study. ANIMALS: Cadaveric pelvic limbs (n = 20). METHODS: CCWO was performed with and without alignment aids on 20 cadaveric pelvic limbs. CT scans were performed pre- and post-operatively to evaluate tibial torsion and valgus/varus deformity. Digital photographs of the ostectomized bone wedges were used to assess divergence of the 2 osteotomies, and the area of the medial and lateral aspects measured to assess osteotomy angulation within the dorsal plane. RESULTS: Osteotomy divergence angle, the difference between the area of the medial and lateral aspects of the ostectomized wedges, and the difference between the pre- and post-operative angles of valgus/varus deformity were all significantly smaller for the alignment aid group. The difference in pre- and post-operative tibial torsion was not significantly different between groups. CONCLUSIONS: K-wires can be used successfully as alignment aids during CCWO and help to create a significantly more orthogonal osteotomy. This allows a significant reduction in the difference between the preoperative and postoperative angles of valgus or varus, which may reduce the risk of developing a clinically important iatrogenically introduced valgus/varus deformity postoperatively.

A retrospective analysis of urethral rupture in 63 cats.

The aim of this study was to investigate the short- and long-term morbidity and mortality associated with urethral rupture in cats. Medical records were reviewed from four veterinary hospitals. Diagnosis was made from retrograde urethrography or direct visualisation during surgery. Location of rupture was categorised as pre-, intra- or post-pelvic. Follow-up data were collected from referring veterinarians. Sixty-three cats were included in the study of which, males predominated (88.9%). Trauma was the most common cause (n = 35; 55.6%) with the remainder due to iatrogenic injury. Forty-eight cats (88.9%) were treated surgically and six (11.1%) managed conservatively. Significant differences between cats suffering traumatic versus iatrogenic injury included the presence of musculoskeletal injuries (P <0.001); the location of rupture (P <0.001); the degree of rupture (P <0.001); definitive management (P <0.001) and short-term complications (P = 0.026). Short-term complications were significantly associated with the following: musculoskeletal injuries (P = 0.012); uroabdomen/uroretroperitoneum (P = 0.004); azotaemia (P = 0.021); postoperative urinary diversion (P = 0.036) and >1 surgery performed (P = 0.006). Forty-seven cats (74.6%) survived to discharge. Prognostic factors associated with survival to discharge included the presence of musculoskeletal injuries (P = 0.017); cause of rupture (P = 0.017); location of rupture (P = 0.039) and definitive management (P = 0.020). Twenty-four cats (57.1%) suffered short-term complications and 10 (27.0%) suffered long-term complications. Of those cats surviving to discharge 30 (71.4%) had a good outcome. Median follow-up was 16 months. Outcome was significantly associated with cause of rupture (P = 0.04); short-term complications (P = 0.03) and long-term complications (P <0.001). In conclusion, a significantly greater proportion of cats with iatrogenic injuries survived to discharge and had a good outcome compared with those that suffered trauma.

Tumor-primed human natural killer cells lyse NK-resistant tumor targets: evidence of a two-stage process in resting NK cell activation.

NK cells are defined as those cells that lyse tumor cells without priming. In this study, we show that the preincubation of resting human NK cells with the leukemia cell CTV-1 primes NK cells to lyse NK-resistant cell lines, primary leukemias, and solid tumors even when HLA-matched, allogeneic or autologous. The primed NK cells remained nonresponsive to HLA-C matched and mismatched normal mononuclear cells from multiple donors. CD69, a known NK trigger receptor, was shown to be the predominant trigger on the tumor-primed NK cells because lysis was blocked with the rCD69 protein. The lack of lytic activity against normal hemopoietic cells implied that the ligand for CD69 is tumor restricted, and this was confirmed by experiments using fluorochrome labeled rCD69. It has been recently shown that resting NK cells require prior stimulation with IL-2 before triggering by all known NK-triggering ligands. In this study, we show that a tumor cell can provide the NK priming signal independently of IL-2. These data provide evidence for two NK evasion strategies for tumor cells, namely the prevention of priming (type1 evasion) and failure to trigger (type 2 evasion). Most NK-resistant cell lines are type 1 and fail to prime resting NK cells but are lysed by IL-2-primed NK cells. In contrast, CTV-1 cells prime resting NK cells but fail to trigger (type 2), and coincubation with CTV-1 primes for triggering by type 1 NK-resistant tumor cells. These tumor-activated NK cells lyse a broad spectrum of tumor cells with a degree of specificity never previously reported.

Ligation of CD8alpha on human natural killer cells prevents activation-induced apoptosis and enhances cytolytic activity.

It has been previously shown that the subset of human natural killer (NK) cells which express CD8 in a homodimeric alpha/alpha form are more cytotoxic than their CD8- counterparts but the mechanisms behind this differential cytolytic activity remained unknown. Target cell lysis by CD8- NK cells is associated with high levels of effector cell apoptosis, which is in contrast to the significantly lower levels found in the CD8alpha+ cells after lysis of the same targets. We report that cross-linking of the CD8alpha chains on NK cells induces rapid rises in intracellular Ca2+ and increased expression of CD69 at the cell surface by initiating the influx of extracellular Ca2+ ions. We demonstrate that secretion of cytolytic enzymes initiates NK-cell apoptosis from which CD8alpha+ NK cells are protected by an influx of exogenous calcium following ligation of CD8 on the NK-cell surface. This ligation is through interaction with fellow NK cells in the cell conjugate and can occur when the target cells lack major histocompatibility complex (MHC) Class I expression. Protection from apoptosis is blocked by preincubation of the NK cells with anti-MHC Class I antibody. Thus, in contrast to the CD8- subset, CD8alpha+ NK cells are capable of sequential lysis of multiple target cells.

Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs.

We studied the actions of geldanamycin (GA) and herbimycin A (HMA), inhibitors of the chaperone proteins Hsp90 and GRP94, on B chronic lymphocytic leukemia (CLL) cells in vitro. Both drugs induced apoptosis of the majority of CLL isolates studied. Whereas exposure to 4-hour pulses of 30 to 100 nM GA killed normal B lymphocytes and CLL cells with similar dose responses, T lymphocytes from healthy donors as well as those present in the CLL isolates were relatively resistant. GA, but not HMA, showed a modest cytoprotective effect toward CD34+ hematopoietic progenitors from normal bone marrow. The ability of bone marrow progenitors to form hematopoietic colonies was unaffected by pulse exposures to GA. Both GA and HMA synergized with chlorambucil and fludarabine in killing a subset of CLL isolates. GA- and HMA-induced apoptosis was preceded by the up-regulation of the stress-responsive chaperones Hsp70 and BiP. Both ansamycins also resulted in down-regulation of Akt protein kinase, a modulator of cell survival. The relative resistance of T lymphocytes and of CD34+ bone marrow progenitors to GA coupled with its ability to induce apoptosis following brief exposures and to synergize with cytotoxic drugs warrant further investigation of ansamycins as potential therapeutic agents in CLL.