Branched Chain Amino Acids are associated with Metabolic Complications in Liver Transplant Recipients

BACKGROUND: Obesity, dyslipidemia and type 2 diabetes (T2D) contribute substantially to increased cardiovascular morbidity and mortality in patients after orthotopic liver transplantation (OLTx). Elevated plasma branched chain amino acids (BCAA) are linked to metabolic disturbances and cardiovascular disease (CVD) risk profiles in several non-OLTx populations. METHODS: Cross-sectional analysis of liver transplant recipients from TransplantLines, a single-center biobank and cohort study. BCAA plasma levels were measured by means of nuclear-magnetic resonance spectroscopy. CVD and cardiometabolic factors were collected by using data from electronic patient records. Associations were determined between BCAA plasma levels and T2D, Metabolic Syndrome (MetS), CVD as well as mTOR inhibition in liver transplant recipients. RESULTS: 336 Patients were divided into sex-stratified tertiles of total BCAA. MetS (P<0.001) and T2D (P=0.002) were significantly more frequent in subjects in the highest BCAA tertile. In logistic regression analyses, the multivariable adjusted odds ratio (OR) per 1 standard deviation increase in BCAA was 1.68 (95%CI: 1.18-2.20, P=0.003) for MetS and 1.60 (95%CI: 1.14-2.23, P=0.006) for T2D. Use of Sirolimus (mTOR inhibitor) was significantly associated with higher BCAA plasma levels, independent of age, sex, time after OLTx, MetS and other immunosuppressive medication (adjusted P=0.002). CONCLUSION: Elevated BCAA plasma levels are associated with T2D, MetS and use of Sirolimus in liver transplant recipients. BCAA plasma levels may represent a valuable biomarker for cardiometabolic complications after OLTx

Scientific Reports / Surgical and Functional Outcome after Endoprosthetic Reconstruction in Patients with Osteosarcoma of the Humerus

Endoprosthetic reconstruction (EPR) is the most widely used reconstruction technique after humeral osteosarcoma (OSA). Complications are common and function is often compromised due to the premise of wide resection. In the current study we evaluated (1) the risk of complications after resection and EPR; (2) the functional outcome and how it is influenced by the preservation/resection of deltoid muscle (DM), rotator cuff (RC), axillary nerve or the type of resection (intra-/extraarticular) and (3) if the preservation/resection of DM, RC, axillary nerve or the type of resection has a negative influence on the oncological outcome. We retrospectively evaluated data of 49 patients with humeral OSA. All patients underwent resection and EPR. Complication-free survival according to the ISOLS classification was estimated by a competing risk model. Functional outcome was evaluated by range of motion (ROM) in abduction and the MSTS score. Eleven patients (22%) had at least one complication. The estimated cumulative incidence for the first complication was 18% at one year, 23% at five years, and 28% at ten years, respectively. Soft tissue failure was the most common complication. ROM and MSTS scores were significantly higher in patients where DM and RC (p=0.043/p=0.046) and axillary nerve (p=0.014/p=0.021) could be preserved. Preservation of these structures had no negative influence on the surgical margins. In conclusion, EPR is a good treatment method with an acceptable complication rate. Preservation of the abductor mechanism, when possible in the setting of obtaining negative margins, provides superior functional outcome.(VLID)472614

Data from: Oncological and surgical outcome after treatment of pelvic sarcomas

Background and Objectives. Treatment of pelvic tumors remains challenging due to complex anatomy, poor oncological outcome and high complication rates. We sought to investigate the long-term oncological and surgical outcome of these patients. Methods. Between 1980 and 2012, 147 patients underwent surgical treatment for pelvic sarcoma. Histological diagnosis was Chondrosarcoma in 54, Ewing's Sarcoma/PNET in 37, Osterosarcoma in 32 and others in 24 patients. Statistical analysis for the evaluation of oncological and surgical outcome was performed by applying Cox proportional hazards regression and Fine-Gray regression models for competing risk (CR) endpoints. Results. The estimated overall survival (OS) to death was 80%, 45% and 37% at 1, 5 and 10 years, respectively. Univariate analyses revealed a statistically significant unadjusted influence of age age (p=0.038; HR=1.01), margin (p=0.043; HR=0.51) and grade (p=0.001; HR=2.27) on OS. Considering the multivariable model, grade (p=0.005; HR=3.04) and tumor volume (p=0.014; HR=1.18) presented themselves as independent prognostic factors on OS. CR analysis showed a cumulative incidence for major complication of 31% at 5 years. Endoprosthetic reconstruction had a higher risk for experiencing a major complication (p<0.0001) and infection (p=0.001). Conclusions. Pelvic resections are still associated with a high incidence of complications. Patients with pelvic reconstruction and high volume tumors are especially at risk. Consequently, a cautious decision-making process is necessary when indicating pelvic reconstruction, although a restrictive approach to pelvic reconstruction is not necessarily reasonable when the other option is major amputation

Muscle Fibre Architecture of Thoracic and Lumbar Longissimus Dorsi Muscle in the Horse

As the longissimus dorsi muscle is the largest muscle in the equine back, it has great influence on the stability of the spine and facilitates proper locomotion. The longissimus muscle provides support to the saddle and rider and thereby influences performance in the horse. Muscular dysfunction has been associated with back disorders and decline of performance. In general, muscle function is determined by its specific intramuscular architecture. However, only limited three-dimensional metrical data are available for the inner organisation of the equine longissimus dorsi muscle. Therefore, we aimed at investigating the inner architecure of the equine longissimus. The thoracic and lumbar longissimus muscles of five formalin-fixed cadaveric horse backs of different ages and body types were dissected layerwise from cranial to caudal. Three-dimensional coordinates along individual muscle fibre bundles were recorded using a digitisation tool (MicroScribe®), to capture their origin, insertion and general orientation. Together with skeletal data from computed tomography (CT) scans, 3D models were created using imaging software (Amira). For further analysis, the muscle was divided into functional compartments during preparation and morphometric parameters, such as the muscle fascicle length, pennation angles to the sagittal and horizontal planes, muscle volume and the physiological cross-sectional area (PCSA), were determined. Fascicle length showed the highest values in the thoracic region and decreased from cranial to caudal, with the cranial lumbar compartment showing about 75% of cranial fascicle length, while in most caudal compartments, fascicle length was less than 50% of the fascicle length in thoracic compartments. The pennation angles to the horizontal plane show that there are differences between compartments. In most cranial compartments, fascicles almost run parallel to the horizontal plane (mean angle 0°), while in the caudal compartment, the angles increase up to a mean angle of 38°. Pennation angles to the sagittal plane varied not only between compartments but also within compartments. While in the thoracic compartments, the fascicles run nearly parallel to the spine, in the caudal compartments, the mean angles range from 0–22°. The muscle volume ranged from 1350 cm3 to 4700 cm3 depending on body size. The PCSA ranged from 219 cm2 to 700 cm2 depending on the muscle volume and mean fascicle length. In addition to predictable individual differences in size parameters, there are obvious systemic differences within the muscle architecture along the longissimus muscle which may affect its contraction behaviour. The obtained muscle data lay the anatomical basis for a specific biomechanical model of the longissimus muscle, to simulate muscle function under varying conditions and in comparison to other species

Data from: Outcome after reconstruction of the proximal tibia – complications and competing risk analysis

Background and Objectives: The proximal tibia (pT) is a common site for bone tumors. Improvements in imaging, chemotherapy and surgical technique made limb salvage surgery the treatment of choice. Yet, reconstructions of the pT have been associated with less favorable outcome compared to other parts of the extremities. The aim of this study was to evaluate the outcome of patients with a modular endoprosthetic reconstruction of the pT. Methods: Eighty-one consecutive patients with an average age of 29 years underwent endoprosthetic reconstruction of the pT. Postoperative complications were categorized according to the ISOLS classification, and revision-free survival until first complication (any Type 1–5), soft tissue failure (Type 1), aseptic loosening (Type 2), structural failure (Type 3), infection (Type 4), and local tumor progression (Type 5) was estimated by using a Fine-Gray model for competing risk analyses for univariate and multivariable regression with Firth’s bias correction. Results: A total of 45 patients (56%) had at least one complication. Cumulative incidence for complication Types 1 to 5 at 5 years with death and amputation as competing events revealed a risk of 41% for the first complication, 14% for Type 1, 16% for Type 2, 11% for Type 3, 17% for Type 4, and 1% for Type 5. Conclusion: Despite inclusion of amputation and death as strong competing events, pT replacements are still associated with a high risk of postoperative failures. The results suggest that infection and soft tissue failures (Type 1 and 5) seem to depend from each other. Sufficient soft tissue reconstruction and closure allow better function and reduce the risk of infection as the most prominent complication. The use of a rotating hinge design has significantly reduced structural failures over time

Martorell hypertensive ischemic leg ulcer must not be confounded with pyoderma gangrenosum: Management is totally different

Introduction: Martorell hypertensive ischemic leg ulcer (HYTILU) and pyoderma gangrenosum share a violaceous, rapidly progressive necrotic wound border and excruciating pain as essential clinical features. Clinicians unaware of Martorell HYTILU readily misdiagnose pyoderma gangrenosum or necrotic vasculitis. This can be detrimental since disease management is totally different. Material and methods: This review includes two patient series with Martorell hypertensive ischemic leg ulcer (HYTILU), 31 patients from the University Hospital of Zurich and 64 patients from a randomized controlled trial in France. The analysis of confounding Martorell HYTILU and histological study is based on the Zurich data and the analysis of therapeutic issues is based on the French and Zurich data. Results: Fifty-two percent (16/31 patients) were referred with an erroneous diagnosis of pyoderma gangrenosum, and another 19% (6/31 patients) with an erroneous diagnosis of necrotizing vasculitis. The hallmark of Martorell HYTILU are the location at the laterodorsal leg or Achilles tendon (in the present series 100%) in a patient with usually long-standing and controlled hypertension (95–100%), often accompanied by diabetes (40–60%). Histology of a several centimeter long, 4–6 mm narrow, and deep (to fascia) performed spindle-shape skin and ulcer biopsy shows a skin infarction with sclerotic subcutaneous arterioles. Arteriolosclerosis is defined by thick vessel walls at the cost of a narrow lumen, and in approximately 70% of histologic sections part of the arterioles show a striking medial calcification. The narrow lumen may be occluded by acute or organized thrombosis. In the French multicenter serie, at 8 weeks only 10% (3/31 patients) healed by conservative means, and this could not be improved with the use of topical application of platelet-derived growth factor-BB (becaplermin) (18% healing, 5/28 patients, no significant difference). In the Zurich series, 84% of patients (26/31) had wound surgery (necrosectomy, split skin graft) to heal the ulcer and 10% (3/31) died from wound infection and sepsis, amongst two under immunosuppression received for misdiagnosed pyoderma gangrenosum. Conclusions: Martorell HYTILU can easily be confounded with pyoderma gangrenosum or necrotizing vasculitis. Physicians involved in wound treatment should be sensitized to the typical clinical setting: a progressive and extremely painful skin infarction at the laterodorsal leg in a hypertensive and often diabetic subject. Diagnosis is confirmed histologically on a long-enough, narrow, but deep spindle-shape skin and ulcer biopsy, showing a highly characteristic form of stenotic and occlusive subcutaneous arteriolosclerosis. Management is essentially based on wound surgery. Conservative means are almost uneffective. Immunosuppression must be avoided, and antibiotic treatment introduced as required

PLOS ONE / Oncological and surgical outcome after treatment of pelvic sarcomas

Background and objectives Treatment of pelvic tumors remains challenging due to complex anatomy, poor oncological outcome and high complication rates. We sought to investigate the long-term oncological and surgical outcome of these patients. Methods Between 1980 and 2012, 147 patients underwent surgical treatment for pelvic sarcoma. Histological diagnosis was Chondrosarcoma in 54, Ewings Sarcoma/PNET in 37, Osterosarcoma in 32 and others in 24 patients. Statistical analysis for the evaluation of oncological and surgical outcome was performed by applying Cox proportional hazards regression and Fine-Gray regression models for competing risk (CR) endpoints. Results The estimated overall survival (OS) to death was 80%, 45% and 37% at 1, 5 and 10 years, respectively. Univariate analyses revealed a statistically significant unadjusted influence of age age (p = 0.038; HR = 1.01), margin (p = 0.043; HR = 0.51) and grade (p = 0.001; HR = 2.27) on OS. Considering the multivariable model, grade (p = 0.005; HR = 3.04) and tumor volume (p = 0.014; HR = 1.18) presented themselves as independent prognostic factors on OS. CR analysis showed a cumulative incidence for major complication of 31% at 5 years. Endoprosthetic reconstruction had a higher risk for experiencing a major complication (p<0.0001) and infection (p = 0.001). Conclusions Pelvic resections are still associated with a high incidence of complications. Patients with pelvic reconstruction and high volume tumors are especially at risk. Consequently, a cautious decision-making process is necessary when indicating pelvic reconstruction, although a restrictive approach to pelvic reconstruction is not necessarily reasonable when the other option is major amputation.(VLID)486947

The influence of antibiotic-loaded cement spacers on the risk of reinfection after septic two-stage hip revision surgery

Purpose The aim of this study was the evaluation of possible outcome differences of patients undergoing two-stage hip exchange with antibiotic-loaded spacers, compared to patients without an interim spacer implantation. Methods We evaluated 46 patients undergoing two-stage hip revision surgery. Twenty-five patients received an interim ALS. Additional to a KaplanMeier survival analysis, a competing risk analysis was performed to estimate the cumulative incidence function for re-revisions due to infection accounting for death as a competing event. Results Nine patients (seven non-ALS vs. two ALS) had to undergo re-revision surgery due to reinfection of the hip joint. The non-ALS group showed a risk of re-revision of 19% (95% CI 538%) at 12 and 24 months and 30% (95% CI 1251%) at 36 months. The group with ALS implantation displayed a 0% risk of re-revision surgery in the first 36 months. The Gray test revealed a significant difference in the cumulative incidence between both observed groups (p = 0.026). Conclusion Our findings suggest that ALS implantation significantly reduces the risk of reinfection after two-stage hip revision surgery.(VLID)357000

Fragment screening using biolayer interferometry reveals ligands targeting the SHP-motif binding site of the AAA+ ATPase p97

Biosensor techniques have become increasingly important for fragment-based drug discovery during the last years. The AAA+ ATPase p97 is an essential protein with key roles in protein homeostasis and a possible target for cancer chemotherapy. Currently available p97 inhibitors address its ATPase activity and globally impair p97-mediated processes. In contrast, inhibition of cofactor binding to the N-domain by a protein-protein-interaction inhibitor would enable the selective targeting of specific p97 functions. Here, we describe a biolayer interferometry-based fragment screen targeting the N-domain of p97 and demonstrate that a region known as SHP-motif binding site can be targeted with small molecules. Guided by molecular dynamics simulations, the binding sites of selected screening hits were postulated and experimentally validated using protein- and ligand-based NMR techniques, as well as X-ray crystallography, ultimately resulting in the first structure of a small molecule in complex with the N-domain of p97. The identified fragments provide insights into how this region could be targeted and present first chemical starting points for the development of a protein-protein interaction inhibitor preventing the binding of selected cofactors to p97