Divergent role of Mitochondrial Amidoxime Reducing Component 1 (MARC1) in human and mouse.

Recent human genome-wide association studies have identified common missense variants in MARC1, p.Ala165Thr and p.Met187Lys, associated with lower hepatic fat, reduction in liver enzymes and protection from most causes of cirrhosis. Using an exome-wide association study we recapitulated earlier MARC1 p.Ala165Thr and p.Met187Lys findings in 540,000 individuals from five ancestry groups. We also discovered novel rare putative loss of function variants in MARC1 with a phenotype similar to MARC1 p.Ala165Thr/p.Met187Lys variants. In vitro studies of recombinant human MARC1 protein revealed Ala165Thr substitution causes protein instability and aberrant localization in hepatic cells, suggesting MARC1 inhibition or deletion may lead to hepatoprotection. Following this hypothesis, we generated Marc1 knockout mice and evaluated the effect of Marc1 deletion on liver phenotype. Unexpectedly, our study found that whole-body Marc1 deficiency in mouse is not protective against hepatic triglyceride accumulation, liver inflammation or fibrosis. In attempts to explain the lack of the observed phenotype, we discovered that Marc1 plays only a minor role in mouse liver while its paralogue Marc2 is the main Marc family enzyme in mice. Our findings highlight the major difference in MARC1 physiological function between human and mouse.

Activin E-ACVR1C cross talk controls energy storage via suppression of adipose lipolysis in mice.

Body fat distribution is a heritable risk factor for cardiovascular and metabolic disease. In humans, rare Inhibin beta E (INHBE, activin E) loss-of-function variants are associated with a lower waist-to-hip ratio and protection from type 2 diabetes. Hepatic fatty acid sensing promotes INHBE expression during fasting and in obese individuals, yet it is unclear how the hepatokine activin E governs body shape and energy metabolism. Here, we uncover activin E as a regulator of adipose energy storage. By suppressing ß-agonist-induced lipolysis, activin E promotes fat accumulation and adipocyte hypertrophy and contributes to adipose dysfunction in mice. Mechanistically, we demonstrate that activin E elicits its effect on adipose tissue through ACVR1C, activating SMAD2/3 signaling and suppressing PPARG target genes. Conversely, loss of activin E or ACVR1C in mice increases fat utilization, lowers adiposity, and drives PPARG-regulated gene signatures indicative of healthy adipose function. Our studies identify activin E-ACVR1C as a metabolic rheostat promoting liver-adipose cross talk to restrain excessive fat breakdown and preserve fat mass during prolonged fasting, a mechanism that is maladaptive in obese individuals.

Systematic review of topical interventions for the management of odour in patients with chronic or malignant fungating wounds.

Chronic wounds adversely affect the quality of life of individuals and odour is a well-recognised associated factor. Odour can affect sleep, well-being, social interactions, diet and potentially wound healing. This systematic review aims to examine the effectiveness of topical interventions in the management of odour associated with chronic and malignant fungating wounds. A systematic review guided by PRISMA recommendations of randomised controlled trials where odour intensity/odour is the primary outcome was undertaken. Inclusion criteria were adults (18 years and over) with chronic venous, arterial, diabetic or pressure ulcers or with malignant fungating wounds where odour has been managed through topical application of pharmacological/non-pharmacological agents. Searches were conducted in CENTRAL, CINAHL, EMBASE, MEDLINE, Scopus, and Web of Science. Eligibility screening, risk of bias assessment and data extraction was completed by authors working independently. Searches retrieved 171 titles and abstracts (157 post de-duplication). Thirteen studies were retained for full text review of which five (n = 137 individuals) examining the following treatments remained: metronidazole (n = 4), silver (n = 1). Meta-analysis was not possible but individual studies suggest improved outcomes (i.e., reduced odour) using metronidazole. Treatment options to manage wound odour are limited and hampered by lack of clinical trials, small sample sizes, and absence of standardised outcomes and consistent measurement. Whereas metronidazole and silver may have a role in controlling wound odour, robust and well-designed interventions with rigorous procedures and standardised odour outcomes are necessary to evaluate their contribution.

The profile of patients with venous leg ulcers: A systematic review and global perspective.

BACKGROUND: A holistic profile that includes demographic, medical history and wound characteristics of individuals with venous leg ulceration is lacking. Lack of such a profile negatively impacts the ability to develop interventions to improve patient outcomes. OBJECTIVES: To describe the profile of the patient population with venous leg ulceration from published observational (non-interventional) studies and to identify gaps in the knowledge base for future research in this area. METHODS: A systematic review of observational studies that included more than 50 patients, from any world region, of any age and in any care setting. RESULTS: twenty studies, involving 3395 patients, from all world regions met our criteria. Demographic characteristics were well reported and showed a female to male ratio of 1.2:1, average age of 47-65 years, high levels of co-morbidities including hypertension (53-71%) and diabetes (16-20%), and only one study reporting ethnicity. When reported, approximately 4-30% had high levels of depression. The average wound size was 18.6-43.39 cm2; mean wound duration was 13.8-65.5 months, mean number of recurrences was four. No study reported on demographic factors plus medical history plus wound characteristics together. CONCLUSION: a comprehensive, holistic profile of the population with VLU is lacking. There is a critical need for more comprehensive profiling to enable the development of targeted interventions to improve outcomes.

Angiopoietin-like protein 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance.

Angiopoietin-like protein (ANGPTL)3 regulates plasma lipids by inhibiting LPL and endothelial lipase (EL). ANGPTL3 inactivation lowers LDL-C independently of the classical LDLR-mediated pathway and represents a promising therapeutic approach for individuals with homozygous familial hypercholesterolemia due to LDLR mutations. Yet, how ANGPTL3 regulates LDL-C levels is unknown. Here, we demonstrate in hyperlipidemic humans and mice that ANGPTL3 controls VLDL catabolism upstream of LDL. Using kinetic, lipidomic, and biophysical studies, we show that ANGPTL3 inhibition reduces VLDL-lipid content and size, generating remnant particles that are efficiently removed from the circulation. This suggests that ANGPTL3 inhibition lowers LDL-C by limiting LDL particle production. Mechanistically, we discovered that EL is a key mediator of ANGPTL3's novel pathway. Our experiments revealed that, although dispensable in the presence of LDLR, EL-mediated processing of VLDL becomes critical for LDLR-independent particle clearance. In the absence of EL and LDLR, ANGPTL3 inhibition perturbed VLDL catabolism, promoted accumulation of atypical remnants, and failed to reduce LDL-C. Taken together, we uncover ANGPTL3 at the helm of a novel EL-dependent pathway that lowers LDL-C in the absence of LDLR.

ANGPTL8 requires ANGPTL3 to inhibit lipoprotein lipase and plasma triglyceride clearance.

Angiopoietin-like (ANGPTL)3 and ANGPTL8 are secreted proteins and inhibitors of LPL-mediated plasma triglyceride (TG) clearance. It is unclear how these two ANGPTL proteins interact to regulate LPL activity. ANGPTL3 inhibits LPL activity and increases serum TG independent of ANGPTL8. These effects are reversed with an ANGPTL3 blocking antibody. Here, we show that ANGPTL8, although it possesses a functional inhibitory motif, is inactive by itself and requires ANGPTL3 expression to inhibit LPL and increase plasma TG. Using a mutated form of ANGPTL3 that lacks LPL inhibitory activity, we demonstrate that ANGPTL3 activity is not required for its ability to activate ANGPTL8. Moreover, coexpression of ANGPTL3 and ANGPTL8 leads to a far more efficacious increase in TG in mice than ANGPTL3 alone, suggesting the major inhibitory activity of this complex derives from ANGPTL8. An antibody to the C terminus of ANGPTL8 reversed LPL inhibition by ANGPTL8 in the presence of ANGPTL3. The antibody did not disrupt the ANGPTL8:ANGPTL3 complex, but came in close proximity to the LPL inhibitory motif in the N terminus of ANGPTL8. Collectively, these data show that ANGPTL8 has a functional LPL inhibitory motif, but only inhibits LPL and increases plasma TG levels in mice in the presence of ANGPTL3.

ANGPTL8 Blockade With a Monoclonal Antibody Promotes Triglyceride Clearance, Energy Expenditure, and Weight Loss in Mice.

Angiopoietin-like protein (ANGPTL)8 is a negative regulator of lipoprotein lipase-mediated plasma triglyceride (TG) clearance. In this study, we describe a fully human monoclonal antibody (REGN3776) that binds monkey and human ANGPTL8 with high affinity. Inhibition of ANGPTL8 with REGN3776 in humanized ANGPTL8 mice decreased plasma TGs and increased lipoprotein lipase activity. Additionally, REGN3776 reduced body weight and fat content. The reduction in body weight was secondary to increased energy expenditure. Finally, single administration of REGN3776 normalized plasma TGs in dyslipidemic cynomolgus monkeys. In conclusion, we show that blockade of ANGPTL8 with monoclonal antibody strongly reduced plasma TGs in mice and monkeys. These data suggest that inhibition of ANGPTL8 may provide a new therapeutic avenue for the treatment of dyslipidemia with beneficial effects on body weight.

ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys.

Angiopoietin-like protein 3 (ANGPTL3) is a circulating protein synthesized exclusively in the liver that inhibits LPL and endothelial lipase (EL), enzymes that hydrolyze TGs and phospholipids in plasma lipoproteins. Here we describe the development and testing of a fully human monoclonal antibody (REGN1500) that binds ANGPTL3 with high affinity. REGN1500 reversed ANGPTL3-induced inhibition of LPL activity in vitro. Intravenous administration of REGN1500 to normolipidemic C57Bl/6 mice increased LPL activity and decreased plasma TG levels by ≥50%. Chronic administration of REGN1500 to dyslipidemic C57Bl/6 mice for 8 weeks reduced circulating plasma levels of TG, LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C) without any changes in liver, adipose, or heart TG contents. Studies in EL knockout mice revealed that REGN1500 reduced serum HDL-C through an EL-dependent mechanism. Finally, administration of a single dose of REGN1500 to dyslipidemic cynomolgus monkeys caused a rapid and pronounced decrease in plasma TG, nonHDL-C, and HDL-C. REGN1500 normalized plasma TG levels even in monkeys with a baseline plasma TG greater than 400 mg/dl. Collectively, these data demonstrate that neutralization of ANGPTL3 using REGN1500 reduces plasma lipids in dyslipidemic mice and monkeys, and thus provides a potential therapeutic agent for treatment of patients with hyperlipidemia.

Management of abductor mechanism deficiency following total hip replacement.

Deficiency of the abductor mechanism is a well-recognised cause of pain and limping after total hip replacement (THR). This can be found incidentally at the time of surgery, or it may arise as a result of damage to the superior gluteal nerve intra-operatively, or after surgery owing to mechanical failure of the abductor muscle repair or its detachment from the greater trochanter. The incidence of abductor failure has been reported as high as 20% in some studies. The management of this condition remains a dilemma for the treating surgeon. We review the current state of knowledge concerning post-THR abductor deficiency, including the aetiology, diagnosis and management, and the outcomes of surgery for this condition.

Medium-term follow-up series using a modular distal fixation prosthesis to address proximal femoral bone deficiency in revision total hip arthroplasty. A 5- to 9-year follow-up study.

We reviewed a series of 39 patients (40 cases) receiving the Link MP stem in revision hip arthroplasty. Average follow-up was 68 months (range 60-115 months). Proximal femoral defects were classified using the Endo-Klinik and Paprosky classifications. Indications included: osteolysis 13 cases; septic loosening 8 cases; periprosthetic fractures 18 cases; metastatic bone disease 1 case. We found 92.5% overall survival rate, average Harris Hip Score past two years of 67 and average Oxford Hip Score past five years of 43. We found no implant failure or loosening. Complications included: 4 deep infections (2 revised to excision arthroplasty), 5 dislocations (1 revision of the proximal modular segment for impingement). We concluded that revision was successful in cases of peri-prosthetic fractures, septic and aseptic loosening. We advocate use of cerclage wires to prevent peri-operative fractures and use of proximal modular segments with CCD angle of 126 to avoid dislocation.

An evaluation of the safety and efficacy of simultaneous bilateral total knee arthroplasty.

This study directly compared the clinical and radiographic results and patient satisfaction of a group of simultaneous, bilateral total knee arthroplasties (92) with a year of surgery matched unilateral total knee arthroplasties (92). Death within 1 month of surgery occurred in 1 bilateral patient and no unilateral patients. Significant cardiorespiratory complications were recorded in 6 bilateral patients and 2 unilateral patients. Patients with pre-existing cardiorespiratory conditions were particularly at risk. Analysis revealed a 98% 7-year survivorship for unilateral procedures and 97% for bilateral. In this study, 95% of bilateral patients stated they would choose the same option again.

An audit on the blood transfusion requirements for revision hip arthroplasty.

The hospital transfusion committee of Swindon and Marlborough NHS Trust had formulated a maximum surgical blood ordering schedule (MSBOS) which included the standard practice of 6 units of blood for revision hip arthroplasty. A retrospective audit of 73 patients who underwent revision hip arthroplasty over a year was undertaken to identify current practice and to ensure that the standard was adequate for patient safety. Information regarding the number of units requested, number of units transfused, pre-operative haemoglobin (Hb), lowest postoperative Hb and number of additional units of blood requested within 3 days postoperatively, was collected from patients' case-notes. Of the 73 patients, 80.3% received less than 6 units, 12.2% received 6 units and 7.5% received more than 6 units. Based on pre-operative Hb, blood usage was analysed. Of cross-matched units, 92.3% were used when pre-operative Hb was < 12 g/dl, 64.4% were used when Hb was between 12.1-13.0 g/dl, 54.3% were used when the Hb was between 13.1-14.0 g/dl, 38.9% were used when Hb was between 14.1-15.0 g/dl and 39.7% used with pre-operative Hb of > 15.0 g/dl. Of the total, 14 patients had a postoperative Hb of < 9 g/dl for whom additional units of blood were ordered and given to achieve a Hb of between 10.1-14.2 g/dl prior to discharge. This audit suggests that in patients with pre-operative Hb of 13 g/dl or more, the cross-match could be 4 units instead of 6 units for revisions.

A retrieval study of capital hip prostheses with titanium alloy femoral stems.

We have examined 26 retrieved, failed titanium-alloy femoral stems. The clinical details, radiological appearances and the histology of the surrounding soft tissues in each patient were also investigated. The stems were predominantly of the flanged design and had a characteristic pattern of wear. A review of the radiographs showed a series of changes, progressive with time. The first was lateral debonding with subsidence of the stem. This was followed by calcar resorption and fragmentation or fracture of the cement. Finally, osteolysis was seen, starting with a radiolucency at the cement-bone interface and progressing to endosteal cavitation. Three histological appearances were noted: granulomatous, necrobiotic and necrotic. We suggest that an unknown factor, possibly related to the design of the stem, caused it to move early. After this, micromovement at the cement-stem interface led to the generation of particulate debris and fracture of the cement. A soft-tissue reaction to the debris resulted in osteolysis and failure of fixation of the prostheses.

The use of cold compression dressings after total knee replacement: a randomized controlled trial.

This prospective, controlled study compared cold compressive dressings with wool and crepe in the postoperative management of patients undergoing total knee replacement (TKR). Forty TKR patients were assessed for blood loss, pain, swelling, and range of motion. Patients in the cold compression group had less blood loss through suction drainage (982 mL versus 768 mL). A higher proportion of patients in the treatment group did not require blood transfusion postoperatively. Mean opiate requirements were lower in the cold compression group (0.57 versus 0.71 mg/kg/48 hours). The cold compression device appeared to reduce blood loss and pain following TKR.

Autophor cementless total hip arthroplasty for osteoarthrosis secondary to congenital hip dysplasia.

The authors present a consecutive series of 38 arthroplasties for osteoarthrosis secondary to hip dysplasia. All arthroplasties were performed by a single surgeon using Mittelmeier II (Autophor, Osteo AG, Selzach, Switzerland) ceramic cementless components. Crowe grades of subluxation were 60% grade I, 16% grade II, 12% grade III, and 12% grade IV. In all cases, the acetabular component was seated in the true acetabulum. The mean follow-up period was 75 months (range, 40-122 months). By the time of review, six hips (16%) had required revision for aseptic loosening, mainly of the femoral component. Good or excellent results were achieved in only 63% of the patients. In the group of surviving arthroplasties, the median Charnley hip scores before surgery were: pain, 2; movement, 3; and walking, 3. After surgery, the scores were: pain, 5; movement, 5; and walking, 6. All improvements were significant. The mean postoperative Harris hip score was 84. Poor scores were associated with contralateral hip disease (2 cases) and spina bifida (2 cases), significantly affecting function. The Autophor prosthesis can produce satisfactory results in some of these young patients with hip dysplasia. However, femoral loosening is a major problem and because of this, the authors have since changed to a newer stem design.

Failure of the sliding hip screw in the treatment of femoral neck fractures: 'left-handed surgeons for left-sided hips'.

The pre-operative radiographs of 265 patients consecutively treated with sliding hip screws were reviewed. In 244 cases the fixation was for a basicervical or intertrochanteric fracture. The post-operative radiographs of these 244 patients were examined for technical failure of the device. Of the 15 failures analysed, one had occurred where insufficient sliding length had been available to the screw within the barrel, and one was due to jamming of the screw within the barrel. Of the remaining 13 fixations, 12 had occurred where the screw had been poorly positioned within the femoral head, and one device had failed for no obvious reason. Malpositioning of the failures occurred significantly more frequently on the left than on the right, in a Unit where all the surgeons were right-handed. We conclude that the majority of technical failures of the sliding hip screw occur because of poor positioning of the screw. This occurs more commonly on the left side when the surgeon is right-handed.

Audit of a bone bank.

The results are reported of an audit of allografts collected in the first 18 months of the Leicester Bone Bank. We retrieved 161 femoral heads at primary arthroplasty of which 103 were implanted into 59 patients. There were deep infections in two recipients and wound infections in five. In two of these cases, culture of the femoral head at implantation was positive but the organisms grown were not those which caused the clinical infection. We retrieved 22 large allografts from six cadavers. Four of these were contaminated at retrieval and required irradiation for sterilisation. There has been one clinical infection in the nine large allografts implanted so far. We recommend that all bone banks undertake prospective audit to ensure that high standards are maintained and wastage minimised.

Bilateral knee replacements: simultaneous or staged?

Approximately one-third of primary knee replacements are performed on patients with bilateral symptomatic disease. This retrospective study compared the complication rate, functional outcome and cost implications of performing bilateral total knee replacements under a single anaesthetic or as staged procedures with a control group of unilateral cases. There was no significant difference in the complications or outcome. There was a significant reduction in the mean hospital admission time of 7 days per knee replacement (P < 0.001, Student's t test) by performing bilateral knee replacements for osteoarthritis under the same anaesthetic. However, a survey of practising knee surgeons in three health regions in the United Kingdom shows that only 24% would regularly perform bilateral knee replacements under one anaesthetic.