Vaccination against T-cell epitopes of native ApoB100 reduces vascular inflammation and disease in a humanized mouse model of atherosclerosis.

BACKGROUND AND OBJECTIVES: The T-cell response to low-density lipoprotein (LDL) in the vessel wall plays a critical role in atherosclerotic plaque formation and stability. In this study, we used a new translational approach to investigate epitopes from human apolipoprotein B100 (ApoB100), the protein component of LDL, which triggers T-cell activation. We also evaluated the potential of two selected native ApoB100 epitopes to modulate atherosclerosis in human ApoB100-transgenic Ldlr-/- (HuBL) mice. METHODS AND RESULTS: HuBL mice were immunized with human atherosclerotic plaque homogenate to boost cellular autoimmune response to tissue-derived ApoB100 epitopes. In vitro challenge of splenocytes from immunized mice with a library of overlapping native peptides covering human ApoB100 revealed several sequences eliciting T-cell proliferation. Of these sequences, peptide (P) 265 and P295 were predicted to bind several human leucocyte antigen (HLA) haplotypes and induced high levels of interferon (IFN)-γ. Vaccination of HuBL mice with these peptides mounted a strong adaptive immune response to native ApoB100, including high levels of epitope-specific plasma IgGs. Interestingly, P265 and P295 vaccines significantly decreased plaque size, reduced macrophage infiltration and increased IgG1 deposition in the plaques. Purified IgGs from vaccinated mice displayed anti-inflammatory properties against macrophages in vitro, reducing their response to LPS in a dose-dependent manner. CONCLUSION: We identified two specific epitopes from human native ApoB100 that trigger T-cell activation and protect HuBL mice against atherosclerosis when used in a vaccine. Our data suggest that vaccination-induced protective mechanisms may be mediated at least in part through specific antibody responses to LDL that inhibit macrophage activation.

Stem cell-mediated natural tissue engineering.

Recently, we demonstrated that a fully differentiated tissue developed on a ventricular septal occluder that had been implanted due to infarct-related septum rupture. We suggested that this tissue originated from circulating stem cells. The aim of the present study was to evaluate this hypothesis and to investigate the physiological differentiation and transdifferentiation potential of circulating stem cells. We developed an animal model in which a freely floating membrane was inserted into each the left ventricle and the descending aorta. Membranes were removed after pre-specified intervals of 3 days, and 2, 6 and 12 weeks; the newly developed tissue was evaluated using quantitative RT-PCR, immunohistochemistry and in situ hybridization. The contribution of stem cells was directly evaluated in another group of animals that were by treated with granulocyte macrophage colony-stimulating factor (GM-CSF) early after implantation. We demonstrated the time-dependent generation of a fully differentiated tissue composed of fibroblasts, myofibroblasts, smooth muscle cells, endothelial cells and new blood vessels. Cells differentiated into early cardiomyocytes on membranes implanted in the left ventricles but not on those implanted in the aortas. Stem cell mobilization with GM-CSF led to more rapid tissue growth and differentiation. The GM-CSF effect on cell proliferation outlasted the treat ment period by several weeks. Circulating stem cells contributed to the development of a fully differentiated tissue on membranes placed within the left ventricle or descending aorta under physiological conditions. Early cardiomyocyte generation was identified only on membranes positioned within the left ventricle.

Reduced opioid requirements following unicompartmental knee arthroplasty compared with total knee arthroplasty.

AIMS: Unicompartmental knee arthroplasty (UKA) provides improved early functional outcomes and less postoperative morbidity and pain compared with total knee arthroplasty (TKA). Opioid prescribing has increased in the last two decades, and recently states in the USA have developed online Prescription Drug Monitoring Programs to prevent overprescribing of controlled substances. This study evaluates differences in opioid requirements between patients undergoing TKA and UKA. PATIENTS AND METHODS: We retrospectively reviewed 676 consecutive TKAs and 241 UKAs. Opioid prescriptions in morphine milligram equivalents (MMEs), sedatives, benzodiazepines, and stimulants were collected from State Controlled Substance Monitoring websites six months before and nine months after the initial procedures. Bivariate and multivariate analysis were performed for patients who had a second prescription and continued use. RESULTS: Patients undergoing UKA had a second opioid prescription filled 50.2% of the time, compared with 60.5% for TKA (p = 0.006). After controlling for potential confounders, patients undergoing UKA were still less likely to require a second prescription than those undergoing TKA (adjusted odds ratio (OR) 0.58, 95% confidence interval (CI) 0.42 to 0.81; p = 0.001). Continued opioid use requiring more than five prescriptions occurred in 13.7% of those undergoing TKA and 5.8% for those undergoing UKA (p = 0.001), and was also reduced in UKA patients compared with TKA patients (adjusted OR 0.33, 95% CI 0.16 to 0.67; p = 0.022) in multivariate analysis. The continued use of opioids after six months was 11.8% in those undergoing TKA and 8.3% in those undergoing UKA (p = 0.149). The multivariate models for second prescriptions, continued use with more than five, and continued use beyond six months yielded concordance scores of 0.70, 0.86, and 0.83, respectively. CONCLUSION: Compared with TKA, patients undergoing UKA are less likely to require a second opioid prescription and use significantly fewer opioid prescriptions. Thus, orthopaedic surgeons should adjust their patterns of prescription and educate patients about the reduced expected analgesic requirements after UKA compared with TKA. Cite this article: Bone Joint J 2019;101-B(7 Supple C):22-27.

Transfemoral amputation following total knee arthroplasty: mortality and functional outcomes.

AIMS: The aim of this study was to characterize the factors leading to transfemoral amputation after total knee arthroplasty (TKA), as well as the rates of mortality and functional independence after this procedure in these patients. PATIENTS AND METHODS: This was a multicentre retrospective review with a prospective telephone survey for the assessment of function. All patients with a TKA who subsequently required transfemoral amputation between January 2001 and December 2015 were included. Demographic information, medical comorbidities, and postoperative mortality data were collected. A 19-item survey was used for the assessment of function in surviving patients. RESULTS: A total of 111 patients were included. Their mean age was 61.0 years (42.0 to 88.0) at the time of TKA, with a subsequent mean of 3.7 operations (0 to 15) over a mean period of 6.1 years (0.05 to 30.1) before amputation. The indication for amputation was chronic infection in 97 patients (87.4%). The rate of five-year survival was 51.7%, and advanced age (p = 0.001) and renal failure (p = 0.045) were associated with an increased risk of mortality. Of the 62 surviving patients, 34 completed the survey; 32 (94.1%) owned a prosthesis but only 19 (55.9%) used it; 19 (55.9%) primarily used a wheelchair for mobility; 27 (79.5%) had phantom pain; and 16 (47.1%) required chronic pain medication. Only 18 patients (52.9%) were satisfied with the quality of life. CONCLUSION: Patients with complications after TKA, in whom transfemoral amputation is considered, should be made aware of the high rate of mortality and the poor functional outcome in the survivors. Alternative forms of treatment including arthrodesis of the knee should be investigated.

[Punctate cytology of benign and malignant changes in the thyroid gland (author's transl)]. / Punktatzytologie benigner und maligner Schilddrüsen-veränderungen

80 thyroid gland aspirates obtained post-operatively were compared with 69 clinically punctured cases. The results suggest that the vast majority of cytological misdiagnoses are caused by a faulty withdrawal technique. As a contribution to the differential diagnosis of "follicular neoplasia" an attempt was made to introduce the diameter of the nucelus obtained morphometrically as a parameter of malignancy. In aspirates of highly differentiated follicular carcinomas a significantly higher percentage of thyrocytes with larger nuclear diameters are found than in benign nodular changes in the thyroid gland.