Food environment index and preterm birth rate in the counties of the United States.

OBJECTIVES: To determine the relationship between Food Environment Index (FEI) and Preterm Birth (PTB) rate at the county level of the United States of America (USA) (primary), while evaluating the interaction of multiple factors within a framework of sociodemographic, maternal health, maternal behavioral, and environmental factors. METHODS: This is a population-based retrospective cohort ecological study from 2015-2018. The study compares the characteristics of the population of the counties of the USA. All counties with complete data on their PTB rate and the independent variables were included in the study. Independent variables with greater than 20% missing data were excluded from the study. Purposive sampling technique was applied. A total of 2983/3142 counties were included in the study. RESULTS: The median PTB rate of all counties was 9.90%. The highest PTB rate (23.3%) was in Tallapoosa County, Alabama and the lowest (3.4%) in San Juan County, Washington State. After adjusting for variables, PTB rate had a significant association with FEI (coefficient of correlation - 0.36, p < 0.01, 95% CI - 0.19 to - 0.04). Increase in the rate of unemployment, African American race, adult smoking, obesity, uninsured rate, sexually transmitted diseases (STD), high school education and air pollution was associated with an increase in PTB rate, while an increase in FEI and alcohol abuse rates was associated with a decrease in PTB rate. CONCLUSIONS: FEI can predict the PTB rate in USA counties after adjusting for sociodemographic, health, behavioral and environmental factors. Future studies are needed to confirm these associations and consider them when making policies to reduce PTBs.

Highly efficient CRISPR-Cas9-mediated editing identifies novel mechanosensitive microRNA-140 targets in primary human articular chondrocytes.

OBJECTIVE: MicroRNA 140 (miR-140) is a chondrocyte-specific endogenous gene regulator implicated in osteoarthritis (OA). As mechanical injury is a primary aetiological factor in OA, we investigated miR-140-dependent mechanosensitive gene regulation using a novel CRISPR-Cas9 methodology in primary human chondrocytes. METHOD: Primary (passage 1/2) human OA chondrocytes were isolated from arthroplasty samples (six donors) and transfected with ribonuclear protein complexes or plasmids using single guide RNAs (sgRNAs) targeting miR-140, in combination with Cas9 endonuclease. Combinations of sgRNAs and single/double transfections were tested. Gene editing was measured by T7 endonuclease 1 (T7E1) assay. miRNA levels were confirmed by qPCR in chondrocytes and in wild type murine femoral head cartilage after acute injury. Predicted close match off-targets were examined. Mechanosensitive miR-140 target validation was assessed in 42 injury-associated genes using TaqMan Microfluidic cards in targeted and donor-matched control chondrocytes. Identified targets were examined in RNAseq data from costal chondrocytes from miR-140-/- mice. RESULTS: High efficiency gene editing of miR-140 (90-98%) was obtained when two sgRNAs were combined with double RNP-mediated CRISPR-Cas9 transfection. miR-140 levels fell rapidly after femoral cartilage injury. Of the top eight miR-140 gene targets identified (P < 0.01), we validated three previously identified ones (septin 2, bone morphogenetic protein 2 and fibroblast growth factor 2). Novel targets included Agrin, a newly recognised pro-regenerative cartilage agent, and proteins associated with retinoic acid signalling and the primary cilium. CONCLUSION: We describe a highly efficient CRISPR-Cas9-mediated strategy for gene editing in primary human chondrocytes and identify several novel mechanosensitive miR-140 targets of disease relevance.

Osteoarthritis year in review: genetics, genomics, epigenetics.

OBJECTIVE: In this review, we have highlighted the advances over the past year in genetics, genomics and epigenetics in the field of osteoarthritis (OA). METHODS: A literature search of PubMed was performed using the criteria: "osteoarthritis" and one of the following terms "genetic(s), genomic(s), epigenetic(s), polymorphism, noncoding ribonucleic acid (RNA), microRNA, long noncoding RNA, lncRNA, circular RNA, RNA sequencing (RNA-seq), single cell sequencing, transcriptomics, or deoxyribonucleic acid (DNA) methylation between April 01, 2020 and April 30, 2021. RESULTS: In total we identified 765 unique publications, which eventually reduced to 380 of relevance to the field as judged by two assessors. Many of these studies included multiple search terms. We summarised advances relating to genetics, functional genetics, genomics and epigenetics, focusing on our personal key papers during the year. CONCLUSIONS: This year few studies have identified new genetic variants contributing to OA susceptibility, but a focus has been on refining risk loci or their functional validation. The use of new technologies together with investigating the cross-talk between multiple tissue types, greater sample sizes and/or better patient classification (OA subtypes) will continue to increase our knowledge of disease mechanisms and progress towards understanding and treating OA.

TimiRGeN: R/Bioconductor package for time series microRNA-mRNA integration and analysis.

MOTIVATION: The analysis of longitudinal datasets and construction of gene regulatory networks (GRNs) provide a valuable means to disentangle the complexity of microRNA (miRNA)-mRNA interactions. However, there are no computational tools that can integrate, conduct functional analysis and generate detailed networks from longitudinal miRNA-mRNA datasets. RESULTS: We present TimiRGeN, an R package that uses time point-based differential expression results to identify miRNA-mRNA interactions influencing signaling pathways of interest. miRNA-mRNA interactions can be visualized in R or exported to PathVisio or Cytoscape. The output can be used for hypothesis generation and directing in vitro or further in silico work such as GRN construction. AVAILABILITY AND IMPLEMENTATION: TimiRGeN is available for download on Bioconductor (https://bioconductor.org/packages/TimiRGeN) and requires R v4.0.2 or newer and BiocManager v3.12 or newer. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Identification of long non-coding RNAs expressed in knee and hip osteoarthritic cartilage.

OBJECTIVE: Long intergenic non-coding RNAs (lincRNAs) are emerging as key regulators in gene expression; however, little is known about the lincRNA expression changes that occur in osteoarthritis (OA). Here we aimed to define a transcriptome of lncRNAs in OA cartilage, specifically comparing the lincRNA transcriptome of knee and hip cartilage. METHOD: RNA-seq was performed on nucleic acid extracted from hip cartilage from patients undergoing joint replacement surgery because of either OA (n = 10) or because of a neck of femur fracture (NOF; n = 6). After transcript alignment, counts were performed using Salmon and differential expression for ENSEMBL lincRNAs determined using DESeq2. Hip RNA-seq lincRNA expression was compared to a knee dataset (ArrayExpress; E-MTAB-4304). ChIP-seq data from ENCODE was used to determine whether lincRNAs were associated with promoters (plncRNA) or unidirectional enhancer-like regulatory elements (elncRNAs). RESULTS: Our analysis of the hip transcriptome identified 1692 expressed Transcripts Per Million (TPM ≥1) Ensembl lincRNAs, of which 198 were significantly (FDR ≤0.05) differentially expressed in OA vs normal (NOF) cartilage. Similar analysis of knee cartilage transcriptome identified 648 Emsembl lincRNAs with 93 significantly (FDR ≤0.05) differentially expressed in intact vs damaged cartilage. In total, 1834 lincRNAs were expressed in both hip and knee cartilage, with a highly significant correlation in expression between the two cartilages. CONCLUSION: This is the first study to use RNA-seq to map and compare the lincRNA transcriptomes of hip and knee cartilage. We propose that lincRNAs expressed selectively in cartilage, or showing differential expression in OA, will play a role in cartilage homoeostasis.

Nonrestorative Treatments for Caries: Systematic Review and Network Meta-analysis.

The goal of nonrestorative or non- and microinvasive caries treatment (fluoride- and nonfluoride-based interventions) is to manage the caries disease process at a lesion level and minimize the loss of sound tooth structure. The purpose of this systematic review and network meta-analysis was to summarize the available evidence on nonrestorative treatments for the outcomes of 1) arrest or reversal of noncavitated and cavitated carious lesions on primary and permanent teeth and 2) adverse events. We included parallel and split-mouth randomized controlled trials where patients were followed for any length of time. Studies were identified with MEDLINE and Embase via Ovid, Cochrane CENTRAL, and Cochrane Database of Systematic Reviews. Pairs of reviewers independently conducted the selection of studies, data extraction, risk-of-bias assessments, and assessment of the certainty in the evidence with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Data were synthesized with a random effects model and a frequentist approach. Forty-four trials (48 reports) were eligible, which included 7,378 participants and assessed the effect of 22 interventions in arresting or reversing noncavitated or cavitated carious lesions. Four network meta-analyses suggested that sealants + 5% sodium fluoride (NaF) varnish, resin infiltration + 5% NaF varnish, and 5,000-ppm F (1.1% NaF) toothpaste or gel were the most effective for arresting or reversing noncavitated occlusal, approximal, and noncavitated and cavitated root carious lesions on primary and/or permanent teeth, respectively (low- to moderate-certainty evidence). Study-level data indicated that 5% NaF varnish was the most effective for arresting or reversing noncavitated facial/lingual carious lesions (low certainty) and that 38% silver diamine fluoride solution applied biannually was the most effective for arresting advanced cavitated carious lesions on any coronal surface (moderate to high certainty). Preventing the onset of caries is the ultimate goal of a caries management plan. However, if the disease is present, there is a variety of effective interventions to treat carious lesions nonrestoratively.

The Birmingham Interlocking Pelvic Osteotomy for acetabular dysplasia: 13- to 21-year survival outcomes.

AIMS: The aim of this study was to evaluate the long-term clinical and radiographic outcomes of the Birmingham Interlocking Pelvic Osteotomy (BIPO). PATIENTS AND METHODS: In this prospective study, we report the mid- to long-term clinical outcomes of the first 100 consecutive patients (116 hips; 88 in women, 28 in men) undergoing BIPO, reflecting the surgeon's learning curve. Failure was defined as conversion to hip arthroplasty. The mean age at operation was 31 years (7 to 57). Three patients (three hips) were lost to follow-up. RESULTS: Survivorship was 76% at ten years and 57% at a mean of 17 years. Younger patients (< 20 years) had the best survivorship (20 hips at risk; 90% at 17 years; 95% confidence interval 65 to 97). Post-operative complications occurred after 12 operations (10.4%) over the duration of the study. Increasing patient age and hip arthritis grade were primary determinants of surgical failure. CONCLUSION: BIPO provides good to excellent survivorship in appropriately selected patients, with a relatively low rate of complications. Our results are comparable with other established methods of periacetabular osteotomy (PAO), such as the Bernese PAO, even during the surgeon's initial learning curve. Cite this article: Bone Joint J 2017;99-B:724-31.

Functional orientation of the acetabular component in ceramic-on-ceramic total hip arthroplasty and its relevance to squeaking.

AIMS: Long-term clinical outcomes for ceramic-on-ceramic (CoC) bearings are encouraging. However, there is a risk of squeaking. Guidelines for the orientation of the acetabular component are defined from static imaging, but the position of the pelvis and thus the acetabular component during activities associated with edge-loading are likely to be very different from those measured when the patient is supine. We assessed the functional orientation of the acetabular component. PATIENTS AND METHODS: A total of 18 patients with reproducible squeaking in their CoC hips during deep flexion were investigated with a control group of 36 non-squeaking CoC hips. The two groups were matched for the type of implant, the orientation of the acetabular component when supine, the size of the femoral head, ligament laxity, maximum hip flexion and body mass index. RESULTS: The mean functional anteversion of the acetabular component at the point when patients initiated rising from a seated position was significantly less in the squeaking group than in the control group, 8.1° (-10.5° to 36.0°) and 21.1° (-1.9° to 38.4°) respectively (p = 0.002). CONCLUSION: The functional orientation of the acetabular component during activities associated with posterior edge-loading are different from those measured when supine due to patient-specific pelvic kinematics. Individuals with a large anterior pelvic tilt during deep flexion might be more susceptible to posterior edge-loading and squeaking as a consequence of a significant decrease in the functional anteversion of the acetabular component. Cite this article: Bone Joint J 2016;98-B:910-16.

Repeated large-scale retreat and advance of Totten Glacier indicated by inland bed erosion.

Climate variations cause ice sheets to retreat and advance, raising or lowering sea level by metres to decametres. The basic relationship is unambiguous, but the timing, magnitude and sources of sea-level change remain unclear; in particular, the contribution of the East Antarctic Ice Sheet (EAIS) is ill defined, restricting our appreciation of potential future change. Several lines of evidence suggest possible collapse of the Totten Glacier into interior basins during past warm periods, most notably the Pliocene epoch, causing several metres of sea-level rise. However, the structure and long-term evolution of the ice sheet in this region have been understood insufficiently to constrain past ice-sheet extents. Here we show that deep ice-sheet erosion-enough to expose basement rocks-has occurred in two regions: the head of the Totten Glacier, within 150 kilometres of today's grounding line; and deep within the Sabrina Subglacial Basin, 350-550 kilometres from this grounding line. Our results, based on ICECAP aerogeophysical data, demarcate the marginal zones of two distinct quasi-stable EAIS configurations, corresponding to the 'modern-scale' ice sheet (with a marginal zone near the present ice-sheet margin) and the retreated ice sheet (with the marginal zone located far inland). The transitional region of 200-250 kilometres in width is less eroded, suggesting shorter-lived exposure to eroding conditions during repeated retreat-advance events, which are probably driven by ocean-forced instabilities. Representative ice-sheet models indicate that the global sea-level increase resulting from retreat in this sector can be up to 0.9 metres in the modern-scale configuration, and exceeds 2 metres in the retreated configuration.

The distribution of basal water between Antarctic subglacial lakes from radar sounding.

Antarctica's subglacial lakes have two end member geophysical expressions: as hydraulically flat, radar reflective regions highlighted in ice surface topography and radar sounding profiles ('definite lakes'), and as localized sites of elevation change identified from repeat elevation observations ('active lakes') that are often found in fast flowing ice streams or enhanced ice flow tributaries. While 'definite lakes' can be identified readily by high bed reflectivity in radar sounding, the identification and characterization of less distinct subglacial lakes and water systems with radar sounding are complicated by variable radio-wave attenuation in the overlying ice. When relying on repeat elevation observations, the relatively short times series and biased distribution of elevation observations, along with the episodic nature of 'active lake' outflow and replenishment, limit our understanding of how water flows under the ice sheet. Using recently developed methods for quantifying the radar scattering behaviour of the basal interface of the ice, we can avoid the problem of attenuation, and observe the plumbing of the subglacial landscape. In West Antarctica's Ross Sea Embayment, we confirm that extensive distributed water systems underlie these ice streams. Distributed water sheets are upstream in the onset regions of fast flow, while canal systems underly downstream regions of fast flow. In East Antarctica, we use specularity analysis to recover substantial hydraulic connectivity extending beyond previous knowledge, connecting the lakes already delineated by traditional radar sounding or surface elevation transients.

Detecting new microRNAs in human osteoarthritic chondrocytes identifies miR-3085 as a human, chondrocyte-selective, microRNA.

OBJECTIVE: To use deep sequencing to identify novel microRNAs (miRNAs) in human osteoarthritic cartilage which have a functional role in chondrocyte phenotype or function. DESIGN: A small RNA library was prepared from human osteoarthritic primary chondrocytes using in-house adaptors and analysed by Illumina sequencing. Novel candidate miRNAs were validated by northern blot and qRT-PCR. Expression was measured in cartilage models. Targets of novel candidates were identified by microarray and computational analysis, validated using 3'-UTR-luciferase reporter plasmids. Protein levels were assessed by western blot and functional analysis by cell adhesion. RESULTS: We identified 990 known miRNAs and 1621 potential novel miRNAs in human osteoarthritic chondrocytes, 60 of the latter were expressed in all samples assayed. MicroRNA-140-3p was the most highly expressed microRNA in osteoarthritic cartilage. Sixteen novel candidate miRNAs were analysed further, of which six remained after northern blot analysis. Three novel miRNAs were regulated across models of chondrogenesis, chondrocyte differentiation or cartilage injury. One sequence (novel #11), annotated in rodents as microRNA-3085-3p, was preferentially expressed in cartilage, dependent on chondrocyte differentiation and, in man, is located in an intron of the cartilage-expressed gene CRTAC-1. This microRNA was shown to target the ITGA5 gene directly (which encodes integrin alpha5) and inhibited adhesion to fibronectin (dependent on alpha5beta1 integrin). CONCLUSION: Deep sequencing has uncovered many potential microRNA candidates expressed in human cartilage. At least three of these show potential functional interest in cartilage homeostasis and osteoarthritis (OA). Particularly, novel #11 (microRNA-3085-3p) which has been identified for the first time in man.

Identification of the pathogenic pathways in osteoarthritic hip cartilage: commonality and discord between hip and knee OA.

OBJECTIVE: To define for the first time the transcriptomes of normal and end-stage osteoarthritis (OA) hip cartilage. MATERIALS AND METHODS: RNA was isolated from cartilage within 2h of joint replacement surgery. Gene expression was analyzed using Agilent GeneSpring GX 11 following hybridization to Illumina Human HT-12 V3 microarrays. Real-time reverse-transcription polymerase chain reaction (RT-PCR) was used to validate the expression of six genes identified by microarray as differentially expressed. Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) were used to investigate enriched functions or canonical pathways amongst differentially expressed genes respectively. RESULTS: In total we identified 998 differentially expressed genes (fold change ≥ ±1.5, P-value ≤ 0.01) between neck of femur fracture (NOF) (n = 10) and OA hip (n = 9) patient cartilage. These differentially expressed genes were enriched within 71 canonical pathways. A comparison between a comparable knee dataset(20) only identified 229 genes similarly differentially expressed although remarkably 34 canonical pathways overlapped between experiments. CONCLUSIONS: This study is the first to report a comprehensive gene expression analysis of human hip OA cartilage compared to control (NOF) cartilage at the whole-genome level. Our differential gene expression dataset shows excellent correlation with similar defined studies using comparable tissue but reveals discord between hip and knee OA at the individual gene status but with commonality with regards the molecular pathways involved.

Injectable biomaterials for adipose tissue engineering.

Adipose tissue engineering has recently gained significant attention from materials scientists as a result of the exponential growth of soft tissue filler procedures being performed within the clinic. While several injectable materials are currently being marketed for filling subcutaneous voids, they often face limited longevity due to rapid resorption. Their inability to encourage natural adipose formation or ingrowth necessitates repeated injections for a prolonged effect and thus classifies them as temporary fillers. As a result, a significant need for injectable materials that not only act as fillers but also promote in vivo adipogenesis is beginning to be realized. This paper will discuss the advantages and disadvantages of commercially available soft tissue fillers. It will then summarize the current state of research using injectable synthetic materials, biopolymers and extracellular matrix-derived materials for adipose tissue engineering. Furthermore, the successful attributes observed across each of these materials will be outlined along with a discussion of the current difficulties and future directions for adipose tissue engineering.

Birmingham hip resurfacing at a mean of ten years: results from an independent centre.

We report the findings of an independent review of 230 consecutive Birmingham hip resurfacings (BHRs) in 213 patients (230 hips) at a mean follow-up of 10.4 years (9.6 to 11.7). A total of 11 hips underwent revision; six patients (six hips) died from unrelated causes; and 13 patients (16 hips) were lost to follow-up. The survival rate for the whole cohort was 94.5% (95% confidence interval (CI) 90.1 to 96.9). The survival rate in women was 89.1% (95% CI 79.2 to 94.4) and in men was 97.5% (95% CI 92.4 to 99.2). Women were 1.4 times more likely to suffer failure than men. For each millimetre increase in component size there was a 19% lower chance of a failure. The mean Oxford hip score was 45.0 (median 47.0, 28 to 48); mean University of California, Los Angeles activity score was 7.4 (median 8.0, 3 to 9); mean patient satisfaction score was 1.4 (median 1.0, 0 to 9). A total of eight hips had lysis in the femoral neck and two hips had acetabular lysis. One hip had progressive radiological changes around the peg of the femoral component. There was no evidence of progressive neck narrowing between five and ten years. Our results confirm that BHR provides good functional outcome and durability for men, at a mean follow-up of ten years. We are now reluctant to undertake hip resurfacing in women with this implant.

Epigenetic mechanisms in cartilage and osteoarthritis: DNA methylation, histone modifications and microRNAs.

Osteoarthritis (OA) is a complex multifactorial disease with a strong genetic component. Several studies have suggested or identified epigenetic events that may play a role in OA progression and the gene expression changes observed in diseased cartilage. The aim of this review is to inform about current research in epigenetics and epigenetics in OA. Epigenetic mechanisms include DNA methylation, histone modifications, and microRNAs. Collectively, these enable the cell to respond quickly to environmental changes and can be inherited during cell division. However, aberrant epigenetic modifications are associated with a number of pathological conditions, including OA. Advancements in epigenetic research suggests that global analysis of such modifications in OA are now possible, however, with the exception of microRNAs, it will be a significant challenge to demonstrate how such events impact on the disease.

Pattern recognition receptor expression is not impaired in patients with chronic mucocutanous candidiasis with or without autoimmune polyendocrinopathy candidiasis ectodermal dystrophy.

Patients with chronic mucocutaneous candidiasis (CMC) have an unknown primary immune defect and are unable to clear infections with the yeast Candida. CMC includes patients with AIRE gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, suggesting that defective expression of pattern recognition receptors (PRRs) may underlie disease pathogenesis. In 29 patients with CMC (13 with APECED) and controls, we assessed dendritic cell (DC) subsets and monocyte Toll-like receptor (TLR) expression in blood. We generated and stimulated monocyte-derived (mo)DCs with Candida albicans, TLR-2/6 ligand and lipopolysaccharide and assessed PRR mRNA expression by polymerase chain reaction [TLR-1-10, Dectin-1 and -2, spleen tyrosine kinase (Syk) and caspase recruitment domain (CARD) 9] in immature and mature moDCs. We demonstrate for the first time that CMC patients, with or without APECED, have normal blood levels of plasmocytoid and myeloid DCs and monocyte TLR-2/TLR-6 expression. We showed that in immature moDCs, expression levels of all PRRs involved in anti-Candida responses (TLR-1, -2, -4, -6, Dectin-1, Syk, CARD9) were comparable to controls, implying that defects in PRR expression are not responsible for the increased susceptibility to Candida infections seen in CMC patients. However, as opposed to healthy controls, both groups of CMC patients failed to down-regulate PRR mRNA expression in response to Candida, consistent with defective DC maturation, as we reported recently. Thus, impaired DC maturation and consequent altered regulation of PRR signalling pathways rather than defects in PRR expression may be responsible for inadequate Candida handling in CMC patients.

Differential Toll-like receptor-dependent collagenase expression in chondrocytes.

OBJECTIVES: To characterise the catabolic response of osteoarthritic chondrocytes to Toll-like receptor (TLR) ligands. METHODS: Induction of the collagenases, matrix metalloproteinase (MMP)1 and MMP13, by TLR ligands was assessed in chondrocytes by real-time reverse transcriptase (RT)-PCR. TLR signalling pathway activation and their involvement in collagenase induction were confirmed by immunoblotting and use of pathway inhibitors and siRNA. TLR expression was compared in the femoral head cartilage of normal controls and patients with osteoarthritis (OA) by real-time RT-PCR. RESULTS: Ligands for TLR6/2 and TLR3 showed the greatest upregulation of MMP1 and MMP13 respectively, although all TLR ligands upregulated these MMPs. MMP1 and MMP13 induction by TLR3 and TLR1/2 or TLR6/2 ligands were dependent on Trif and MyD88, respectively. These inductions were dependent upon the nuclear factor (NF)kappaB pathway, but were differentially inhibited by various mitogen-activated protein kinase inhibitors, with MMP13 induction most reliant on the extracellular signal-regulated kinase pathway. In addition, ligands for TLR1/2 and TLR6/2, but not TLR3, induced significant collagenolysis in a cartilage resorption assay. Finally, TLR2 was significantly downregulated and TLR3 upregulated in OA, compared to normal, cartilage. CONCLUSIONS: Activation of chondrocyte TLRs leads to differential collagenase gene activation. Treatment of chondrocytes with TLR1/2 or TLR6/2 ligands resulted in collagen resorption. The modulated expression of chondrocyte TLR2 and TLR3 in OA cartilage, compared to normal, may reflect a response to repair cartilage or prevent further extracellular matrix destruction. These data suggest modulation of TLR-mediated signalling as a potential therapeutic strategy for the treatment of OA.

IL-21 modulates CD4+ CD25+ regulatory T-cell homeostasis in experimental autoimmune encephalomyelitis.

The homeostasis of CD4+ CD25+ regulatory T cells (Tregs) depends on the cytokine interleukin (IL)-2. As IL-21 shares sequence homology with IL-2 and the IL-21 receptors contain a gamma-chain common to IL-2, we hypothesized that IL-21 could also affect the homeostasis of Tregs. We tested this hypothesis in experimental autoimmune encephalomyelitis (EAE), an animal model of relapsing-remitting human multiple sclerosis. We show that blockade of IL-21 in SJL/J mice before and after the induction of EAE enhances the influx of inflammatory cells into the central nervous system (CNS). The blockade of IL-21 leads to proliferation of proteolipid peptide (PLP(139-151))-autoreactive CD4+ T cells, which are capable to cause severe EAE in adoptively transferred recipient mice. Conversely, Tregs from mice where IL-21 was blocked, lose their capacity to prevent EAE induced PLP(139-151)-reactive T cells. Notably, direct effects of IL-21 on Tregs are confirmed by studies of blockade of IL-21 in mice expressing a green fluorescent protein 'knocked' into a Foxp3 allele, in which a reduction of the number of Tregs and a downregulation of their frequency and expression of Foxp3 are observed. These data suggest a role of the IL-21/IL-21R axis in the homeostasis of Tregs in CNS autoimmunity.

The results of primary Birmingham hip resurfacings at a mean of five years. An independent prospective review of the first 230 hips.

We report an independent prospective review of the first 230 Birmingham hip resurfacings in 212 patients at a mean follow-up of five years (4 to 6). Two patients, one with a loose acetabular component and the other with suspected avascular necrosis of the femoral head, underwent revision. There were two deaths from unrelated causes and one patient was lost to follow-up. The survivorship with the worst-case scenario was 97.8% (95% confidence interval 95.8 to 99.5). The mean Harris hip score improved significantly (paired t-test, p < 0.05) from 62.54 (8 to 92) pre-operatively to 97.7 (61 to 100) at a mean of three years (2.1 to 4.3), then deteriorated slightly to a mean of 95.2 (47 to 100) at a mean of five years. The mean flexion improved from 91.5 degrees (25 degrees to 140 degrees) to 110.4 degrees (80 degrees to 145 degrees) at a mean of three years with no further improvement at five years (111.2 degrees; 70 degrees to 160 degrees). On radiological review at five years, one patient had a progressive lucent line around the acetabular component and six had progressive lucent lines around the femoral component. A total of 18 femoral components (8%) had migrated into varus and those with lucent lines present migrated a mean of 3.8 degrees (1.02 degrees to 6.54 degrees) more than the rest. Superolateral notching of the femoral neck and reactive sclerosis at the tip of the peg of the femoral component were associated with the presence of lucent lines (chi-squared test, p < 0.05), but not with migration of the femoral component, and are of unknown significance. Our results with the Birmingham hip resurfacing continue to be satisfactory at a mean follow-up of five years.

Treatment of BXSB-Yaa mice with IL-21R-Fc fusion protein minimally attenuates systemic lupus erythematosus.

Interleukin-21 (IL-21) is a pleiotropic cytokine whose function is only now being unraveled. Abundant evidence indicates that activated CD4 T cells are the primary, if not the only, source of IL-21. While it is clear that IL-21 is actively transcribed by naïve activated T cells, recent studies have shown that IL-21 potentially promotes a developmental shift of naïve T cells toward the Th2 phenotype. BXSB-Yaa mice develop an autoimmune syndrome similar to systemic lupus erythematosus (SLE), affecting males earlier than females on account of the presence of the Yaa (Y-linked autoimmune acceleration) locus. Previous results indicate the elevation of IL-21 expression by BXSB-Yaa mice at an age when the early characteristics of autoimmune processes first become evident. We set out to determine whether IL-21 was necessary for disease progression in BXSB-Yaa mice. Mice were treated for 24 weeks with soluble IL-21R-Fc in order to therapeutically neutralize the IL-21 present. The results overall suggest a biphasic effect of IL-21, negatively influencing survival early on and positively influencing survival at later stages. We propose that IL-21 exerts a pleiotropic effect in which it promotes the protective effects of CD8+ suppressor cells in the early disease phase and then promotes the humoral components of SLE in the later disease stages. This experiment provides preliminary evidence for a role of IL-21 in modulating the severity of SLE in BXSB-Yaa mice.