Evaluation of different coatings of the tibial tray in uncemented total knee arthroplasty. A randomized controlled trial with 5 years follow-up with RSA and DEXA

BackgroundRegenerex® is a porous titanium construct with a 3D interconnecting pore structure and biomechanical characteristics close to that of normal trabecular bone. This study aimed to compare the Regenerex (VR) to the non-interconnecting pore structure Porous Plasma Spray (VP) on tibial implants for total knee arthroplasty (TKA) at 5 years.MethodsWe enrolled and randomized 61 patients (mean age = 63(49–71) years, Female/Male = 35/26) who were planned for an uncemented Vanguard TKA (Biomet, Warsaw, Indiana, USA) to receive either a VR or a VP coated tibial component (31/29). We performed radiostereometric analysis (RSA) and Dual Energy X-ray Absorptiometry (DEXA) postoperatively, and at three, six, 12, 24 and 60 months with measurements of migration. In total 55 patients attended the 5-year follow-up.ResultsOne patient died and four were reoperated during the 60-months period; none due to aseptic loosening. All reoperations were in the VR-group. The mean (range) 60-months MTPM was 1.4 mm (0.5–3.7) for the VP-group and 1.8 mm (0.4–4.9) for the VR-group (p = 0.8). The 24 to 60-months mean (range) MTPM was −0.3 mm (−5 to 1.24) in the VP-group and 0.2 mm (−0.4 to 3.5) in the VR-group (p = 0.8).ConclusionWe did not find any statistically significant differences between the VP- and VR-group and both groups show recognizable migration. We will continue to follow the groups for years to come.     

HLA-E*01:01 + HLA-E*01:01 genotype confers less susceptibility to COVID-19, while HLA-E*01:03 + HLA-E*01:03 genotype is associated with more severe disease

BackgroundHLA-E interaction with inhibitory receptor, NKG2A attenuates NK-mediated cytotoxicity. NKG2A overexpression by SARS-CoV-2 exhausts NK cells function, whereas virus-induced down-regulation of MHC-Ia reduces its derived-leader sequence peptide levels required for proper binding of HLA-E to NKG2A. This leads HLA-E to become more complex with viral antigens and delivers them to CD8⁺ T cells, which facilitates cytolysis of infected cells. Now, the fact that alleles of HLA-E have different levels of expression and affinity for MHC Ia-derived peptide raises the question of whether HLA-E polymorphisms affect susceptibility to COVID-19 or its severity.Methods104 COVID-19 convalescent plasma donors with/without history of hospitalization and 18 blood donors with asymptomatic COVID-19, all were positive for anti-SARS-CoV-2 IgG antibody as well as a group of healthy control including 68 blood donors with negative antibody were subjected to HLA-E genotyping. As a privilege, individuals hadn’t been vaccinated against COVID-19 and therefore naturally exposed to the SARS-CoV-2.ResultsThe absence of HLA-E*01:03 allele significantly decreases the odds of susceptibility to SARS-CoV-2 infection [p = 0.044; OR (95 %CI) = 0.530 (0.286 – 0.983)], suggesting that HLA-E*01:01 + HLA-E*01:01 genotype favors more protection against SARS-CoV-2 infection. HLA-E*01:03 + HLA-E*01:03 genotype was also significantly associated with more severe COVID-19 [p = 0.020; 2.606 (1.163 – 5.844)ConclusionHere, our observation about lower susceptibility of HLA-E*01:01 + HLA-E*01:01 genotype to COVID-19 could be clinical evidence in support of some previous studies suggesting that the lower affinity of HLA-E*01:01 to peptides derived from the leader sequence of MHC class Ia may instead shift its binding to virus-derived peptides, which then facilitates target recognition by restricted conventional CD8⁺ T cells and leads to efficient cytolysis. On the other hand, according to other studies, less reactivity of HLA-E*01:01 with NKG2A abrogates NK cells or T cells inhibition, which may also lead to a greater cytotoxicity against SARS-CoV-2 infected cells compared to HLA-E*01:03. Taken together given HLA-E polymorphisms, the data presented here may be useful in identifying more vulnerable individuals to COVID-19 for better care and management. Especially since along with other risk factors in patients, having HLA-E*01:03 + HLA-E*01:03 genotype may also be associated with the possibility of severe cases of the disease.     

Ghrelin level as a biomarker for knee osteoarthritis severity and appearance in HIV + patients

BackgroundKnee Osteoarthritis (KOA) is a multifactorial disease with several mechanisms to promote articular cartilage damage. New molecules, such as ghrelin, have been recently reported to participate in the pathogenesis and progression of KOA. In HIV + patients, arthralgias are the most frequent musculoskeletal manifestations, mainly affecting joints such as the knee. Also, it has been reported that HIV + patients have a reduction of ghrelin even with treatment compared to HIV- patients. However, there is no report in the literature evaluating ghrelin and KOA in the HIV + population. We aimed to evaluate whether serum ghrelin levels can function as a biomarker for OA in HIV + patients.MethodsWe recruited 40 patients, 20 HIV+, and 20 HIV- controls, and grouped as follows: HIV+/KOA+; HIV+/KOA-; HIV-/KOA+; HIV-/KOA-. Clinical features were obtained during clinical visits. Peripheral blood samples were acquired to measure serum ghrelin levels.ResultsThe HIV+/KOA + group significantly reduced serum ghrelin levels when compared with the other groups. Comparing the ghrelin levels with the patients’ nadir of CD4⁺ T-cells count, we identified a statistically significant negative correlation in the KOA- group (r = −0.80, P < 0.007). An ROC curve analysis, for the accuracy of ghrelin levels to identified HIV+/KOA + from HIV+/KOA- patients, found an area under the curve of 0.83 (95 % CI 0.65–0.10; P = 0.017), with a cut-off < 4026 pg/mL serum ghrelin levels, with a sensitivity of 0.62 (95 % CI 0.32–0.86), and a specificity of 0.10 (95 % CI 0.59–0.10).ConclusionThis study shows the potential use of ghrelin levels as a biomarker for KOA in the high-risk HIV population that should be further analyzed.     

Human leukocyte antigen association with azathioprine-induced drug hypersensitivity reactions in patients with anti-neutrophil cytoplasmic antibody associated vasculitis

Azathioprine (AZA) drug hypersensitivity reaction (DHR) is an uncommon yet potentially lethal condition that often goes unrecognised in patients with anti-Neutrophil Cytoplasmic Antibody (ANCA) associated vasculitis (AAV). We conducted a retrospective review of AAV patients on AZA maintenance therapy (N = 35). Participants were categorised into those who had experienced AZA-DHR (N = 15) and those who were AZA-tolerant (N = 20). Human leukocyte antigen (HLA) typing was performed in both groups. The primary endpoint was identification of a HLA gene association with AZA-DHR in the context of AAV. HLA-C*06:02, was solely expressed in AZA-DHR patients (33.3 %), whilst no patient who tolerated AZA carried this allele (0.0 %). This yielded a positive predictive value of 100 % for HLA-C*06:02 in predicting AZA-DHR in AAV patients, negative predictive value of 66.7 %, sensitivity of 33.3 % and specificity of 100 %. HLA-C*06:02 may predict the development of AZA-DHR in patients with AAV and inform safer therapeutic choice.     

Antigen-independent IL-17A production by bystander-activated CD4+IL-1R1+ cells in patients with multiple sclerosis

Multiple sclerosis (MS) is a demyelinating disease caused by auto-antigen recognizing CD4⁺ T cells. However, IL-17A-producing CD4⁺ T cells that are bystander-activated by IL-1β and IL-23, and T cell receptors independently, could contribute to experimental autoimmune encephalomyelitis. Here, we studied the differences in the frequency and function of bystander-activated CD4⁺ T cells in patients with MS. A significantly higher frequency of CD4 + IL-1Rl + T cells was found in memory than in naïve CD4⁺ T cells and in Th17/Th17.1 than in Th1/Th2 subtypes in both MS and healthy controls (HC). Following IL-1β and IL-23 stimulation, IL-1Rl expression was markedly increased in both memory and Th17/Th17.1 cells, and their IL-17A-production was increased after bystander-activation, which was significantly higher in MS compared with HC. Our study suggests a potential role of IL-17A-producing bystander-activated CD4⁺IL-1Rl⁺ T cells in MS.     

Molecular epidemiology of norovirus variants detected in children under five years of age in Hyderabad,India

PurposeNoroviruses are common viral agents in acute diarrhea in all age groups worldwide. Norovirus has been classified into 10 genogroups, GI to GX with over 48 genotypes among them the GII.4 genotype has evolved over time with a clear pattern of periodic variant replacement. Immunity is strain or genotype specific with little or no protection conferred across genogroups. The present study was aimed to determine the epidemiology, prevalent genotypes of norovirus in children below five years of age in the Hyderabad region, India.MethodsThe stool samples and clinical data were collected from 458 children below 5 years of age comprising of cases with acute gastroenteritis (n ?= ?366) and a control group (n ?= ?92) admitted to the pediatric ward. All the samples were tested for Norovirus by ELISA and RT-PCR. Sequencing was done for predominant strains.Results10.3% (n ?= ?38) of cases and 3.2% (n ?= ?3) of the control group were found to be Norovirus positive. Predominant genotypes were GII-82.5% followed by GI-12.5%.ConclusionSequencing and Phylogenetic analyses of 20 GII.4 strains was done. All of the isolates are clustered away from published the GII.4 variants thus suggesting the appearance of a new variant.     

Phenotypic analysis of monocytes and CD4+ T cells in hepatitis E patients with or without pregnancy

High mortality in pregnant women is a characteristic of hepatitis E virus (HEV) infection. Role of monocytes/T cells in HEV infection during pregnancy is still unclear. We compared CD14⁺monocytes and CD4⁺T cells by flow-cytometry in hepatitis-E patients including 13 pregnant (Antenatal care, ANC), 25 non-ANC patients and respective controls (12 and 20). Non-ANC-patients showed significantly higher frequency of monocytes with increased expression of CD80, CD86 and HLA-DR than control individuals (p < 0.001).Healthy pregnancy was associated with increased frequency of monocytes with higher CD80 expression and lower levels of HLA-DR (p < 0.05) compared to non-ANC controls. ANC-patients exhibited elevated levels of monocytes (p < 0.01) with higher expression of CD80 (p < 0.001) and reduced levels of HLA-DR and CD86 (p < 0.05) when compared with non-ANC patients. TLR2 and TLR4 surface expression on monocytes was higher in non-ANC-patients (p < 0.00) and lower in the ANC-patients (p < 0.01). Healthy-ANCs exhibited lower TLR4 expression on monocytes (p < 0.05). HEV infection did not change the frequency of CD4⁺ and CD4⁺CD28⁺T cells in patients’ group (p > 0.05). Compared to respective controls, CD137⁺ and CD152⁺CD4⁺T cells were higher (p < 0.05) in both patients' categories. Higher levels of CD152⁺CD4⁺T cells (p < 0.001) was noted in healthy pregnant women. Among patients' groups, the CD4⁺T cells and their subpopulation were not different (p > 0.05).We found higher and reduced levels of circulating inflammatory cytokines (IL12, TNFα, IL6 and IL8; miliplex-assay) in non-ANC and ANC-patients respectively. In conclusion, on contrary to the classical activation of CD14⁺monocytes in the non-ANC-patients, impaired response was evident in the ANC-patients while the CD4⁺T cell populations were similar in the patient groups.     

Prevalence and risk factors for endogenous fungal endophthalmitis in adult patients with candidemia at a tertiary care hospital in the Republic of Korea over 13 years

BackgroundEndogenous fungal endophthalmitis (EFE) is a critical complication of candidemia. We conducted a study to investigate the prevalence and risk factors for EFE.MethodsAdult candidemia patients ≥ 19 years who underwent an ophthalmological examination at a tertiary care hospital in the Republic of Korea from 2006 to 2018 were enrolled.ResultsThere was a total of 152 adult candidemia patients analyzed. EFE was found in 29 patients (19.1%). Patients were categorized into two groups (Non-endophthalmitis [NE] and endophthalmitis [E]). Between the two groups, there was no significant difference in terms of age, sex, and underlying comorbidities. However, there were more Candida albicans candidemia, abnormal alanine aminotransferase (ALT) at the time of candidemia diagnosis, receipt of antifungal treatment ≥ 48 hours after onset of candidemia symptoms and blood culture sample (AOCS), and candidemia clearance ≥ 5 days after initiation of antifungal treatment (AIAT) in the E group. A predictive model for the E was created, which had an area of 0.811 under the receiver operating characteristics curve. In a multivariate logistic regression analysis, C. albicans candidemia, ALT at the time of candidemia diagnosis, receipt of antifungal treatment ≥ 48 hours AOCS, and candidemia clearance ≥ 5 days AIAT were significantly associated with EFE.ConclusionEFE occurred in 19% of adult patients with candidemia. Adult candidemia patients with C. albicans candidemia, abnormal ALT, receipt of antifungal treatment ≥ 48 hours AOCS, and candidemia clearance ≥ 5 days AIAT need to be closely monitored for the possibility of EFE.     

Inflammatory level under different p53 mutation status and the regulation role of curcumin in tumor microenvironment

The inflammation is tightly associated with tumor development, promoting or inhibiting tumorigenesis. And mutant p53 is speculated to promote inflammation and tumorigenesis. The tumor associated macrophages are usually educated to present the anti-inflammatory profile to tune down antitumor immunity. However, the impact of p53 mutants on macrophages is not clear. Here, we compared the basal inflammatory level and macrophage profiles in tumor cells and tumor samples with different p53 mutations. Data revealed that a lower inflammatory level was maintained in immune organs and tumor cells with p53 point mutations than those with p53 null mutation. Using the tumor cell-derived conditional media to culture macrophages, we found that the media from cells with p53 mutations, especially the point mutations, could decrease M1 markers and inhibit phagocytosis, suggesting the p53 mutation promoted M2 profile polarization.To target the p53 mutation induced M2 macrophage polarization, we applied low-concentration curcumin to the tumor cells with different p53 mutations. The data showed that curcumin could inhibit STAT3 signal and decrease PPARγ and CSF1 in tumor cells and tumor samples. In vitro, the co-culture assays showed that the curcumin treatment shifted p53 mutation educated macrophages back towards M1 profile. In vivo, the curcumin-treated MEFs showed obvious tumor inhibition, and the tumor samples displayed inhibited M2 markers. Results suggested that curcumin could inhibit p53 mutation educated macrophage induction and suppress M2-promoted tumorigenesis.Our study illustrated the inflammatory level under different p53 status and the inflammatory regulated role of curcumin in tumor environment. This study might provide a potential method in tumor personalized treatment aiming immune therapy in different p53 status.     

Insufficient lateral joint laxity after bicruciate-retaining total knee arthroplasty potentially influences kinematics during flexion: A biomechanical cadaveric study

BackgroundSoft tissue balancing in bicruciate-retaining (BCR) total knee arthroplasty (TKA) is a challenge that must be overcome to achieve excellent clinical outcomes. However, the optimal degree of joint laxity has yet to be clarified. This cadaveric study sought to examine joint laxity after BCR TKA using a navigation system.MethodsKnee joint laxity was quantified using an image-free navigation system in 8 intact fresh frozen cadavers under three conditions: the native knee, BCR TKA knee, and BCR TKA knee after anterior cruciate ligament resection. Rotational kinematics in the BCR TKA knee during flexion were compared according to whether joint laxity was increased or decreased.ResultsKnee joint laxity after BCR TKA under varus-valgus movement, anterior translation, and internal-external rotation loadings was similar to that of the native knee. However, lateral joint laxity was decreased during flexion in some cases. BCR TKA-treated knees with decreased lateral joint laxity at 90° of flexion demonstrated more limited tibial internal rotation in deep flexion than the native knee (p < 0.05). The loss of internal rotation in deep flexion was partly recovered by using a lateral insert with a posterior slope of +3°.ConclusionsRestoring optimal joint laxity was not always straightforward in BCR TKA if the 4 ligaments were preserved. Lateral joint laxity was potentially decreased in BCR TKA and may result in kinematic conflict during flexion. Surgeons should be aware of the need to achieve sufficient lateral joint laxity in this type of BCR TKA.     

IL-10-producing memory B regulatory cells as a novel target for HLA-G to prolong human kidney allograft survival

Despite the growing interest in the role of regulatory B cells (Bregs) in autoimmunity, their distinct role and function in kidney transplant outcomes remain elusive. Here, we retrospectively analyzed the proportion of Bregs, transitional Bregs (tBregs) and memory Bregs (mBregs) and their capacity to produce IL-10 in non-rejected (NR) versus rejected (RJ) kidney transplant recipients. In the NR group, we observed a significant increase in the proportion of mBregs (CD19⁺CD24^hiCD27⁺) but no difference in tBregs (CD19⁺CD24^hiCD38⁺), as compared to the RJ group. We also observed a significant increase in IL-10-producing mBregs (CD19⁺CD24^hiCD27⁺IL-10⁺) in the NR group. As our group and others have previously reported a potential role of the human leukocyte antigen G (HLA-G) in human renal allograft survival, notably through IL-10, we then investigated possible crosstalk between HLA-G and IL-10⁺ mBregs. Our ex vivo data suggest a role of HLA-G in enhancing IL-10⁺ mBreg expansion upon stimulation, which further decreased CD3⁺ T cell proliferation capability. Using RNA-sequencing (RNA-seq), we identified potential key signaling pathways involved in HLA-G-driven IL-10⁺ mBreg expansion, such as the MAPK, TNF and chemokine signaling pathways. Together, our study highlights a novel HLA-G-mediated IL-10-producing mBreg pathway that may serve as a therapeutic target to improve kidney allograft survival.     

Aberrant expression of inhibitory receptors on B cells in patients with Graves’ disease

The pathophysiological mechanism underlying Graves’ disease (GD) remains incompletely understood. Inhibitory receptors on B cells are critical for humoral immunity, which plays a key role in GD pathogenesis. This study aimed to investigate B cell subsets distribution and inhibitory receptor expression on these subsets in GD patients. Peripheral blood was drawn from 41 healthy controls and 46 GD patients (21 patients with moderate GD, 25 patients with severe GD). B cell subset distribution and CD22, CD32b and CD72 expression on B cells were analyzed by flow cytometry. Serum cytokines were examined by enzyme-linked immunosorbent assay (ELISA). Compared with healthy controls, the naïve B cell percentage was increased, while the preswitched memory and conventional memory B cell percentages were decreased. The inhibitory receptors expression, especially CD32b, on B cell subsets was significantly decreased in patients with GD. In addition, the inhibitory receptors expression on B cell subsets from severe GD patients exhibited a decreasing trend compared with those from moderate GD patients. These results suggest that abnormal B cell subset distribution occurs in GD. Impaired inhibitory receptors, in particular CD32b, play a crucial role in GD pathogenesis and might be a therapeutic target to rebuild self-immune tolerance in GD.     

Interrogation of selected genes influencing serum LDL-Cholesterol levels in patients with well characterized NAFLD

BackgroundThe clinical significance of rare mutations in LDL metabolism genes on nonalcoholic fatty liver disease (NAFLD) severity is not well understood.ObjectiveTo examine the significance of mutations in LDL metabolism genes including apolipoprotein B (APOB), proprotein convertase subtilisin kexin 9 (PCSK9) and LDL receptor (LDLR) in patients with NAFLD.MethodsPatients with biopsy-confirmed NAFLD from the NASH Clinical Research Network studies were stratified into 3 groups of LDL-C (≤50 mg/dL, 130–150 mg/dL, ≥ 190 mg/dL) and then 120 (40 per group) were randomly selected from the strata. We examined the presence of mutations on LDL genes and analyzed its association with selected NAFLD-related features. Multivariable analyses were adjusted for age, race, gender and use of statins.ResultsAmong 40 patients with LDL-C ≤ 50 mg/dL, 7 (18%) patients had heterozygous variants in APOB and 2 had heterozygous variants in PCSK9 (5%). We also found heterozygous mutations in 3 (8%) patients with LDL-C ≥ 190 mg/dL; 2 and 1 located in LDLR and APOE genes, respectively. Compared to wild-type controls with LDL-C ≤ 50, APOB carriers displayed higher levels of alanine aminotransferase (85.86 ± 35.14 U/L vs 45.61 ± 20.84 U/L, Adj. P = 0.002) and steatosis >66% (57% vs 24%, Adj. P = 0.050). These associations remained statistically significant after excluding statin users. Other histological features of NAFLD severity were not different between wild-type controls and APOB mutation carriers.ConclusionMutations in the APOB gene are common among NAFLD patients with very low LDL-C and may be associated with increased aminotransferase levels and steatosis severity.     

Personalized volumetric assessment of lower body muscles in patients with knee injuries: A descriptive case series

BackgroundPatients with knee joint pathology present with variable muscular responses across the muscles of the lower limb and pelvis. Conventional approaches to characterizing muscle function are limited to gross strength assessments that may overlook subtle changes both in the thigh, hip and shank musculature.PurposeTo describe individualized patterns of lower extremity muscle volumes in patients with knee pathologies.MethodsThis was a retrospective case series performed in a University medical center. Nine patients diagnosed with meniscus tear recommended to undergo meniscectomy volunteered. Participants underwent 3.0 Tesla magnetic resonance imaging (MRI) of the lower extremities. Thirty-five MRI-derived muscle volumes were compared between limbs and expressed as percentage asymmetry. For additional context, z-scores were also calculated for mass- and height-normalized muscles and pre-determined muscle groupings relative to a normative database.ResultsThere were no consistent patterns observed when considering between-limb asymmetries among all patients. The ankle musculature (dorsiflexors, plantar flexors, and invertors) was the only muscle group to be consistently smaller than normal for all patients, with the psoas major and flexor hallucis longus being the only individual muscles. The severity or chronicity of injury and presence of surgical intervention did not appear to have a clear effect on muscle volumes.ConclusionPatients with a history of meniscal pathology demonstrate inconsistent patterns of lower extremity muscle volumes about the hip, knee, and ankle between limbs and in comparison to uninjured individuals. These data support the need for individualized assessment and intervention in this population.     

Epitopes,paratopes, and other topes 30 years on: Understanding what we are talking about

The question of which protein antigens, such as HLA class I or class II molecules, will bind, and how well, to a given antibody is often assumed to depend exclusively on the details of protein surface structure. These structures are usually based on static models resulting from X-ray crystallography. While these notions are useful, the ultimate causal factors determining how well a given antigen binds a given antibody are based in thermodynamics and can include atomic mobility and the time-varying conformations of proteins. In this article, fundamental biophysical principles of antibody-antigen interaction are discussed, concepts critical for a deeper understanding of the pertinent molecular phenomena are highlighted, and common misunderstandings are identified and debunked.     

“Geographical distribution of risk genotypes in pediatric patients with celiac disease in Spain”

Celiac disease is strongly associated with HLA DQ, specifically with haplotypes.DRB1*03-DQA1*05:01/DQB1*02:01 (DQ2.5), DRB1*07-DQA1*02:01/DQB1*02:02 (DQ2.2), DRB1*11-DQA1*05:05/DQB1*03:01 (DQ7.5), and DRB1*04-DQA1*03:01/DQB1*03:02 (DQ8). The distribution of these risk haplotypes in patients with celiac disease is different in the geographical areas investigated. A high frequency of DRB1*07- DQA1*02:01/DQB1*02:02 (DQ2.2) and DRB1*11-DQA1*05:05/DQB1*03:01 (DQ7.5), has been described in Southern Europe.We analyzed 2102 confirmed CD cases with information on both DQB1* alelles and their distribution by geographical area in Spain. According to the presence of this haplotype in one or two chromosomes, the genotype is classified in: DQ2 homozygous, DQ2 heterozygous (cis or trans), DQ8 homozygous, DQ8/DQ2.5, DQ 2.2 homozygous and genotype known as “half DQ2”.Two different patterns of risks related to CD were identified. In the Basque Country and Navarre, the Mediterranean Area (Aragon, Catalonia, Valencia, Balearic Islands, and Murcia), the South of Spain (Andalucía and Extremadura), and the Canary Islands, higher frequency of DQ2.5 trans, and more than 80% of DQ2.5/DQ2.2 homozygosis were described. The Cantabrian Coast (Cantabria, Asturias, and Galicia) and Central Areas (Castilla-León and Castilla-La Mancha) showed a higher percentage of DQ2.5/DQ2.5 homozygosis and a lower DQ2.5 in trans frequency, as in Northern Europe. Madrid has an intermediate model between the two described above. 17 cases (0.8%) did not carry any CD risk haplotypes.