Myonuclear alterations associated with exercise are independent of age in humans.

Age-related decline in skeletal muscle structure and function can be mitigated by regular exercise. However, the precise mechanisms that govern this are not fully understood. The nucleus plays an active role in translating forces into biochemical signals (mechanotransduction), with the nuclear lamina protein lamin A regulating nuclear shape, nuclear mechanics and ultimately gene expression. Defective lamin A expression causes muscle pathologies and premature ageing syndromes, but the roles of nuclear structure and function in physiological ageing and in exercise adaptations remain obscure. Here, we isolated single muscle fibres and carried out detailed morphological and functional analyses on myonuclei from young and older exercise-trained individuals. Strikingly, myonuclei from trained individuals were more spherical, less deformable, and contained a thicker nuclear lamina than those from untrained individuals. Complementary to this, exercise resulted in increased levels of lamin A and increased myonuclear stiffness in mice. We conclude that exercise is associated with myonuclear remodelling, independently of age, which may contribute to the preservative effects of exercise on muscle function throughout the lifespan. KEY POINTS: The nucleus plays an active role in translating forces into biochemical signals. Myonuclear aberrations in a group of muscular dystrophies called laminopathies suggest that the shape and mechanical properties of myonuclei are important for maintaining muscle function. Here, striking differences are presented in myonuclear shape and mechanics associated with exercise, in both young and old humans. Myonuclei from trained individuals were more spherical, less deformable and contained a thicker nuclear lamina than untrained individuals. It is concluded that exercise is associated with age-independent myonuclear remodelling, which may help to maintain muscle function throughout the lifespan.

'Modern' distal femoral locking plates allow safe, early weight-bearing with a high rate of union and low rate of failure: five-year experience from a United Kingdom major trauma centre.

AIMS: Fractures of the distal femur can be challenging to manage and are on the increase in the elderly osteoporotic population. Management with casting or bracing can unacceptably limit a patient's ability to bear weight, but historically, operative fixation has been associated with a high rate of re-operation. In this study, we describe the outcomes of fixation using modern implants within a strategy of early return to function. PATIENTS AND METHODS: All patients treated at our centre with lateral distal femoral locking plates (LDFLP) between 2009 and 2014 were identified. Fracture classification and operative information including weight-bearing status, rates of union, re-operation, failure of implants and mortality rate, were recorded. RESULTS: A total of 127 fractures were identified in 122 patients. The mean age was 72.8 years (16 to 101) and 92 of the patients (75%) were female. A consultant performed the operation in 85 of the cases, (67%) with the remainder performed under direct consultant supervision. In total 107 patients (84%) were allowed to bear full weight immediately. The rate of clinical and radiological union was 81/85 (95%) and only four fractures of 127 (3%) fractures required re-operation for failure of surgery. The 30-day, three- and 12-month mortality rates were 6 (5%), 17 (15%) and 25 (22%), respectively. CONCLUSION: Our study suggests an exponential increase in the incidence of a fracture of the distal femur with age, analogous to the population suffering from a proximal femoral fracture. Allowing immediate unrestricted weight-bearing after LDFLP fixation in these elderly patients was not associated with failure of fixation. There was a high rate of union and low rate of re-operation. Cite this article: Bone Joint J 2017;99-B:951-7.

Systematic review of aspirin for thromboprophylaxis in modern elective total hip and knee arthroplasty.

AIMS: There is uncertainty regarding the optimal means of thromboprophylaxis following total hip and knee arthroplasty (THA, TKA). This systematic review presents the evidence for acetylsalicylic acid (aspirin) as a thromboprophylactic agent in THA and TKA and compares it with other chemoprophylactic agents. MATERIALS AND METHODS: A search of literature published between 2004 and 2014 was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 13 studies were eligible for inclusion. RESULTS: Evidence from one good quality randomised controlled trial (RCT) showed no difference in rates of venous thrombo-embolism (VTE) in patients given aspirin or low molecular weight heparin (LMWH) following TKA. There was insufficient evidence from trials with moderate to severe risk of bias being present to suggest aspirin is more or less effective than LMWH, warfarin or dabigatran for the prevention of VTE in TKA or THA. Compared with aspirin, rates of asymptomatic deep vein thrombosis (DVT) in TKA may be reduced with rivaroxaban but insufficient evidence exists to demonstrate an effect on incidence of symptomatic DVT. Compared with aspirin there is evidence of more wound complications following THA and TKA with dabigatran and in TKA with rivaroxaban. Some studies highlighted concerns over bleeding complications and efficacy of aspirin. CONCLUSION: The results suggest aspirin may be considered a suitable alternative to other thromboprophylactic agents following THA and TKA. Further investigation is required to fully evaluate the safety and efficacy of aspirin. Cite this article: Bone Joint J 2016;98-B:1056-61.

ECG predictors of T wave oversensing in subcutaneous implantable cardioverter defibrillators.

BACKGROUND: T wave oversensing (TWOS) is the commonest cause of inappropriate shocks in subcutaneous implantable cardioverter defibrillators (S-ICDs). We hypothesise that predictors of TWOS can be derived from surface ECG parameters. METHODS: In a cohort of SICD recipients in two UK centres, all patients who had TWOS (study group) were compared to all those who had not (control group). The pre-implant screen was scanned and the R wave, T wave amplitudes, QRS interval, time to peak T wave, QT interval and R:T ratio was measured using digital callipers. Logistic regression was performed to identify ECG predictors of TWOS. RESULTS: One hundred one patients were studied. Six (5.9%) had TWOS. The mean age of the population was 58.6±18years and the median follow-up was 19.5months. By univariate analysis, the predictors of TWOS are QRS duration (140.7±28.7 vs. 105.9±24.6, P=0.007), time to peak T wave (corrected for heart rate, pTc) (403.9±22.6 vs. 347.8±41.4, P=0.006), QTc interval (500.4±41.2 vs. 446.8±49.7, P=0.021), and R:T ratio (3.5±1.1 vs. 9.5±13.2, P=0.034). By multivariate analysis, time to pTc is the most predictive of TWOS. A time to pTc of 390ms cut-off point provided a sensitivity 38.5%, a specificity of 98.9%, a positive predictive value for TWOS of 83.3%, and a negative predictive value of 91.6% (AUC=0.687). CONCLUSION: In this study, time to pTc is the most powerful ECG predictor of TWOS.

Atrial fibrillation and hypertrophic cardiomyopathy: who to anticoagulate?

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiac conditions. Atrial fibrillation (AF) has been demonstrated to be the most frequent arrhythmia encountered in HCM patients. Research focusing on AF and embolic stroke in HCM patients has been sparse and the sample size of most studies is small. The prognostic significance of AF in HCM patients is still not well known. The aim of this article is to provide further understanding of the anti-coagulation requirement of HCM patients with AF.

Implantable cardioverter defibrillators in octogenarians: clinical outcomes from a single center.

AIMS: Limited data exist on outcomes in very elderly ICD recipients. We describe outcomes in new ICD and Cardiac Resynchronisation Therapy with Defibrillator (CRT-D) implants in octogenarians at our institution. METHODS: Patients aged 80 years and above who underwent de novo ICD or CRT-D implantation from January 2006 to July 2012 were identified. Clinical data were collected from the procedural record, medical and ICD notes. Baseline characteristics were compared using independent sample t test for continuous variables and Fisher's exact test for categorical variables. Kaplan-Meier curves were constructed. RESULTS: Ten per cent of all new ICD/CRT-D implants were aged 80 years and over. Median age was 83.0 years. Median follow-up was 29 months. Death occurred in 17 (34%). Median time to death was 23 months. Three deaths (6%) occurred within 12 months of ICD implantation. Appropriate therapy (ATP or shock) occurred in 19 (38%). Inappropriate therapy occurred in 6 (12%). Rates of appropriate shocks and inappropriate therapy (shocks and ATP) and significant valvular incompetence were higher amongst deceased patients (P=0.03 OR 5.9 95% CI 1.3-27) and (P=0.02 OR 12 95% CI 1.3-112). Univariate analysis identified diuretic use (P=0.008 95% C.I. 0.05 to 0.63) and appropriate shock (P= 0.025 95% C.I. 1.25 to 26.3) as predictors of mortality. CONCLUSION: Octogenarians make up a small but increasing number of ICD recipients. This study highlights high survival rates at one year with acceptable rates of appropriate and inappropriate device therapy. Ongoing debate regarding the appropriateness of ICD in very elderly patients is warranted.

Medical treatment of Marfan syndrome: a time for change.

It is accepted practice to prescribe beta-blockers in order to retard aortic dilatation and prevent aortic dissection and rupture in patients with Marfan syndrome. A critical review of the published pharmacological studies shows this practice to be based on limited evidence. The data from small clinical and experimental studies with surrogate end points suggest greater potential benefit from alternative drug regimens, and a recent experimental study showed that losartan may interrupt the mechanism of disease as well as deal with its functional consequences. It is now essential to perform large, collaborative, randomised controlled trials with clinical end points of new treatments in Marfan syndrome.

Evaluation of common vaginal tunic ligation during field castration in draught colts.

The objective of this study was to determine if ligation of the common vaginal tunic could prevent or reduce the incidence of omental herniation and eventration in draught colts undergoing routine field castration. It was found that common vaginal tunic ligation, while not completely preventing omental herniation and evisceration, significantly reduced the incidence of these complications and should be considered in those males deemed at increased risk of significant post castration complications.

Photochemical internalisation of chemotherapy potentiates killing of multidrug-resistant breast and bladder cancer cells.

Multidrug resistance (MDR) is the major confounding factor in adjuvant solid tumour chemotherapy. Increasing intracellular amounts of chemotherapeutics to circumvent MDR may be achieved by a novel delivery method, photochemical internalisation (PCI). PCI consists of the co-administration of drug and photosensitiser; upon light activation the latter induces intracellular release of organelle-bound drug. We investigated whether co-administration of hypericin (photosensitiser) with mitoxantrone (MTZ, chemotherapeutic) plus illumination potentiates cytotoxicity in MDR cancer cells. We mapped the extent of intracellular co-localisation of drug/photosensitiser. We determined whether PCI altered drug-excreting efflux pump P-glycoprotein (Pgp) expression or function in MDR cells. Bladder and breast cancer cells and their Pgp-overexpressing MDR subclones (MGHU1, MGHU1/R, MCF-7, MCF-7/R) were given hypericin/MTZ combinations, with/without blue-light illumination. Pilot experiments determined appropriate sublethal doses for each. Viability was determined by the 3-[4,5-dimethylthiazolyl]-2,5-diphenyltetrazolium bromide assay. Intracellular localisation was mapped by confocal microscopy. Pgp expression was detected by immunofluorescence and Pgp function investigated by Rhodamine123 efflux on confocal microscopy. MTZ alone (0.1-0.2 microg ml(-1)) killed up to 89% of drug-sensitive cells; MDR cells exhibited less cytotoxicity (6-28%). Hypericin (0.1-0.2 microM) effects were similar for all cells; light illumination caused none or minimal toxicity. In combination, MTZ /hypericin plus illumination, potentiated MDR cell killing, vs hypericin or MTZ alone. (MGHU1/R: 38.65 and 36.63% increase, P<0.05; MCF-7/R: 80.2 and 46.1% increase, P<0.001). Illumination of combined MTZ/hypericin increased killing by 28.15% (P<0.05 MGHU1/R) compared to dark controls. Intracytoplasmic vesicular co-localisation of MTZ/hypericin was evident before illumination and at serial times post-illumination. MTZ was always found in sensitive cell nuclei, but not in dark resistant cell nuclei. In illuminated resistant cells there was some mobilisation of MTZ into the nucleus. Pgp expression remained unchanged, regardless of drug exposure. Pgp efflux was blocked by the Pgp inhibitor verapamil (positive control) but not impeded by hypericin. The increased killing of MDR cancer cells demonstrated is consistent with PCI. PCI is a promising technique for enhancing treatment efficacy.

Surgical repair of femoral fractures in New World camelids: five cases (1996-2003).

Five New World camelids were admitted to the Western College of Veterinary Medicine between 1996 and 2003 for evaluation of femoral fractures. There were three alpacas and two llamas. Four of the animals were female and three were less than 3 months of age. Fracture configurations consisted of distal physeal fractures (three), a comminuted diaphyseal/metaphyseal fracture, and a transverse diaphyseal fracture. Fractures were diagnosed with a combination of physical examination and radiographs in all cases. All five fractures were repaired with internal fixation and three animals were discharged from the hospital with fractures that healed. One cria underwent successful internal fixation but died from pulmonary oedema during recovery from anaesthesia. Postoperative complications were rare and limited to inadequate fracture stability in one alpaca and prolonged recovery to weight bearing in another. One llama with a comminuted metaphyseal fracture, repaired with a 4.5 mm dynamic compression plate, subsequently had catastrophic failure of the bone 17 days after surgery. Overall the clients were pleased with the outcome of discharged animals. Although femoral fractures are considered rare, they pose a unique opportunity for the large animal veterinarian to successfully achieve fracture union with the aid of internal fixation.

Routine castration in 568 draught colts: incidence of evisceration and omental herniation.

REASONS FOR PERFORMING STUDY: Castration is one of the most common routine surgical procedures performed in the horse, from which a number of potential complications can arise. We undertook a prospective evaluation of short-term complications associated with castration of draught colts over a 3-year period (1998-2000). OBJECTIVES: To compare castration complications in a large number of draught foals with previously published literature. METHODS: Five hundred and sixty-eight draught colts, age 4 or 5 months, were castrated in field conditions. Foals were observed for complications for 24 h post operatively. RESULTS: There was no significant difference in complication rates between open and closed surgical techniques. Inguinal/scrotal hernia rate was 4.6% (26/568) prior to surgery, and evisceration of the small intestine occurred in 4.8% (27/568). Foals observed to eviscerate underwent immediate surgical correction with an overall survival rate of 72.2% (13/18). Omental herniation was seen in 2.8% (16/568) of colts. CONCLUSIONS: This study showed no difference between the closed and open techniques of castration and the rate of omental herniation or evisceration. The evisceration rate in combination with the omental and presurgical herniation rates approached 12.2%, which is high enough to warrant further examination. POTENTIAL RELEVANCE: Future investigation should help to assess predisposing factors for evisceration. Regardless of the technique employed, herniation appears to pose a significant risk to draught foals undergoing castration.

An in vitro biomechanical comparison of two interlocking-nail systems for fixation of ostectomized equine third metacarpal bones.

OBJECTIVE: To compare the mechanical properties of 2 interlocking-nail systems for fixation of ostectomized equine third metacarpi (MC3): (1) a standard interlocking nail with 2 parallel screws proximal and distal to a 1-cm ostectomy; and (2) a modified interlocking nail with 2 screws proximal and distal to a 1-cm ostectomy with the screws offset by 30 degrees. ANIMAL OR SAMPLE POPULATION: Twelve pairs of adult equine forelimbs intact from the midradius distally. METHODS: Twelve pairs of equine MC3 were divided into 2 test groups (6 pairs each): torsion and caudocranial 4-point bending. Standard interlocking nails (6-hole, 13-mm diameter, 230-mm length) were placed in 1 randomly selected bone from each pair. Modified interlocking nails (6-hole, 13-mm, 230-mm length, screw holes offset by 30 degrees) were placed in the contralateral bone from each pair. All bones had 1-cm mid-diaphyseal ostectomies. Six construct pairs were tested in caudocranial 4-point bending to determine stiffness and failure properties. The remaining 6 construct pairs were tested in torsion to determine torsional stiffness and yield load. Mean values for each fixation method were compared using a paired t test within each group. Significance was set at P <.05. RESULTS: Mean (+/-SEM) values for the MC3-standard interlocking-nail composite and the MC3-modified interlocking-nail composite, respectively, in 4-point bending were: composite rigidity, 3,119 +/- 334.5 Nm/rad (newton. meter/radian) and 3,185 +/- 401.2 Nm/rad; yield bending moment, 205.0 +/- 18.46 Nm and 186.7 +/- 6.17 Nm; and failure bending moment, 366.4 +/- 21.82 Nm and 378.1 +/- 20.41 Nm. There were no significant differences in the biomechanical values for bending between the 2 fixation methods. In torsion, mean (+/-SEM) values for the MC3-standard interlocking-nail composite and the MC3-modified interlocking-nail composite were: composite rigidity, 135.5 +/- 7.128 Nm/rad and 112.5 +/- 7.432 Nm/rad; gap stiffness, 207.6 +/- 10.57 Nm/rad and 181.7 +/- 12.89 Nm/rad; and yield load, 123.3 +/- 2.563 Nm and 107.5 +/- 8.353 Nm, respectively. Composite rigidity and gap stiffness for standard interlocking-nail fixations were significantly higher than the modified interlocking-nail fixation technique in torsion. Yield load had a tendency to be higher for the standard interlocking-nail fixation (P =.15). CONCLUSIONS: No significant differences in biomechanical properties were identified between a standard interlocking nail and one with the screw holes offset by 30 degrees in caudocranial 4-point bending. The standard interlocking nail was superior to the modified interlocking nail in torsional gap stiffness and composite rigidity. The torsional yield load also tended to be higher for the standard interlocking nail. CLINICAL RELEVANCE: The standard interlocking nail with parallel screw holes is superior to a modified interlocking nail with the screw holes offset by 30 degrees in ostectomized equine MC3 bones in vitro when tested in torsion.

Arthrodesis of the equine proximal interphalangeal joint: a biomechanical comparison of three 4.5-mm and two 5.5-mm cortical screws.

OBJECTIVE: To compare the biomechanical characteristics and mode of failure of 2 parallel-screw techniques for proximal interphalangeal joint arthrodesis in horses. STUDY DESIGN: Randomized block design, blocking for horse (1-5), method of screw fixation (three 4.5-mm vs two 5.5-mm), side (left limb vs right limb), and end (front limb vs hind limb). Constructs were loaded to failure in 3-point bending in a dorsal-to-palmar (plantar) direction. SAMPLE POPULATION: Twenty limbs (10 limb pairs) from 5 equine cadavers. METHODS: A combined aiming device was used to facilitate consistent screw placement. Three parallel 4.5-mm cortical screws were placed in lag fashion in 1 limb of a pair, and 2 parallel 5.5-mm cortical screws were placed in lag fashion in the contralateral limb. Arthrodesis constructs were tested in 3-point bending in a dorsal-to-palmar (plantar) direction using a materials-testing machine. Loading rate was 19 mm/s. Maximal bending moment at failure and composite stiffness were obtained from bending moment-angular deformation curves. Data were analyzed using ANOVA and chi(2) analysis. RESULTS: There were no significant differences in bending moment (P >.05, power = 0.8 @ delta = 19%) or composite stiffness (P >.05, power = 0.8 @ delta = 19%) between the 2 fixation techniques. Higher maximal bending moment was found in front limbs than hind limbs, and front limbs with two 5.5-mm screws than hind limbs with two 5.5-mm screws. In all cases, constructs completely failed. A greater number of 4.5-mm cortical screws failed than 5.5-mm cortical screws. CONCLUSIONS-In pastern arthrodesis constructs loaded in 3-point bending, end (front limb vs hind limb) affected maximal bending moment at failure of constructs. There was no significant effect of horse, treatment, or side on maximal bending moment or stiffness. Two 5.5-mm cortical screws should provide a surgically simpler pastern arthrodesis than three 4.5-mm cortical screws while maintaining similar biomechanical characteristics. CLINICAL RELEVANCE: Three 4.5-mm screws or two 5.5-mm screws will provide similar biomechanical characteristics in bending when performing equine pastern arthrodesis.

Dorsally recumbent male equine urogenital endoscopic surgery.

Possibly no other development has revolutionized general surgery more dramatically than laparoscopic surgery in human patients. The development of instrumentation suitable for use in horses has allowed the veterinary surgeon to begin to introduce minimally invasive procedures. Clearly, in people, one of the greatest benefits is reduced patient morbidity and earlier return to function. The author's experience with laparoscopic procedures in the horse would tend to reinforce those observations. The most significant obstacle to widespread acceptance of minimally invasive surgery in the horse is possibly the veterinarian's reluctance to expend the funds necessary to purchase the necessary equipment as well as a hesitancy to abandon time-honored approaches to common surgical conditions. As a profession, veterinarians have been criticized for undervaluing their own services. Clearly, these new minimally invasive procedures can be successfully marketed if the advantages of the approaches in terms of patient well-being are impressed on the client.