Arthroscopic surgery of the hip is a well-established technique with numerous recognized indications. Despite the well-accepted nature of this procedure, there have been no outcomes studies with ...extended followup. We investigated the response to hip arthroscopy in a consecutive series of patients with 10 years followup. Since 1993, all patients undergoing hip arthroscopy have been assessed prospectively with a modified Harris hip score preoperatively and then postoperatively at 3, 12, 24, 60, and 120 months. A cohort of 50 patients (52 hips) was identified who had achieved 10-year followup and represent the substance of this study. There was 100% followup. The average age of the patients was 38 years (range, 14–84 years), with 27 males and 23 females. The median improvement was 25 points (preoperative, 56 points; postoperative, 81 points). Fourteen patients were converted to THA and two died. Four patients underwent repeat arthroscopy. There were two complications in one patient. The presence of arthritis at the time of the index procedure was an indicator of poor prognosis. This study substantiates the long-term effectiveness of arthroscopy in the hip as treatment for various disorders, including labral pathology, chondral damage, synovitis, and loose bodies. Arthritis is an indicator of poor long-term outcomes with these reported methods.
Level of Evidence:
Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
Type 1 diabetes (T1D) develops when insulin-secreting β-cells, found in the pancreatic islets of Langerhans, are destroyed by infiltrating T cells. How human T cells recognize β-cell-derived antigens ...remains unclear. Genetic studies have shown that HLA and insulin alleles are the most strongly associated with risk of T1D. These long-standing observations implicate CD4(+) T-cell responses against (pro)insulin in the pathogenesis of T1D. To dissect the autoimmune T-cell response against human β-cells, we isolated and characterized 53 CD4(+) T-cell clones from within the residual pancreatic islets of a deceased organ donor who had T1D. These 53 clones expressed 47 unique clonotypes, 8 of which encoded proinsulin-specific T-cell receptors. On an individual clone basis, 14 of 53 CD4(+) T-cell clones (26%) recognized 6 distinct but overlapping epitopes in the C-peptide of proinsulin. These clones recognized C-peptide epitopes presented by HLA-DQ8 and, notably, HLA-DQ8 transdimers that form in HLA-DQ2/-DQ8 heterozygous individuals. Responses to these epitopes were detected in the peripheral blood mononuclear cells of some people with recent-onset T1D but not in HLA-matched control subjects. Hence, proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4(+) T cells are strongly implicated in the autoimmune pathogenesis of human T1D.
Magnetic resonance imaging (MRI) has detected changes in pancreas volume and other characteristics in type 1 and type 2 diabetes. However, differences in MRI technology and approaches across ...locations currently limit the incorporation of pancreas imaging into multisite trials. The purpose of this study was to develop a standardized MRI protocol for pancreas imaging and to define the reproducibility of these measurements. Calibrated phantoms with known MRI properties were imaged at five sites with differing MRI hardware and software to develop a harmonized MRI imaging protocol. Subsequently, five healthy volunteers underwent MRI at four sites using the harmonized protocol to assess pancreas size, shape, apparent diffusion coefficient (ADC), longitudinal relaxation time (T1), magnetization transfer ratio (MTR), and pancreas and hepatic fat fraction. Following harmonization, pancreas size, surface area to volume ratio, diffusion, and longitudinal relaxation time were reproducible, with coefficients of variation less than 10%. In contrast, non-standardized image processing led to greater variation in MRI measurements. By using a standardized MRI image acquisition and processing protocol, quantitative MRI of the pancreas performed at multiple locations can be incorporated into clinical trials comparing pancreas imaging measures and metabolic state in individuals with type 1 or type 2 diabetes.
A direct association of islet-autoreactive T cells with β cell destruction in human pancreatic islets from type 1 diabetes (T1D) patients has never been demonstrated, and little is known about ...disease progression after diagnosis. Frozen pancreas samples were obtained from 45 cadaveric T1D donors with disease durations ranging from 1 wk to >50 yr, 14 nondiabetic controls, 5 nondiabetics with islet autoantibodies, 2 cases of gestational diabetes, and 6 T2D patients. Sections were systematically analyzed for the presence of insulin-sufficient β cells, CD8(+) insulitic lesions, and HLA class I hyperexpression. Finally, consecutive sections from HLA-A2-expressing individuals were probed for CD8 T cell reactivity against six defined islet autoantigens associated with T1D by in situ tetramer staining. Both single and multiple CD8 T cell autoreactivities were detected within individual islets in a subset of patients up to 8 yr after clinical diagnosis. Pathological features such as HLA class I hyperexpression and insulitis were specific for T1D and persisted in a small portion of the patients with longstanding disease. Insulitic lesions consistently presented in a multifocal pattern with varying degrees of infiltration and β cell loss across affected organs. Our observations provide the first direct proof for islet autoreactivity within human islets and underscore the heterogeneous and chronic disease course.
Janus kinase (JAK) inhibitors, including baricitinib, block cytokine signaling and are effective disease-modifying treatments for several autoimmune diseases. Whether baricitinib preserves β-cell ...function in type 1 diabetes is unclear.
In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned patients with type 1 diabetes diagnosed during the previous 100 days to receive baricitinib (4 mg once per day) or matched placebo orally for 48 weeks. The primary outcome was the mean C-peptide level, determined from the area under the concentration-time curve, during a 2-hour mixed-meal tolerance test at week 48. Secondary outcomes included the change from baseline in the glycated hemoglobin level, the daily insulin dose, and measures of glycemic control assessed with the use of continuous glucose monitoring.
A total of 91 patients received baricitinib (60 patients) or placebo (31 patients). The median of the mixed-meal-stimulated mean C-peptide level at week 48 was 0.65 nmol per liter per minute (interquartile range, 0.31 to 0.82) in the baricitinib group and 0.43 nmol per liter per minute (interquartile range, 0.13 to 0.63) in the placebo group (P = 0.001). The mean daily insulin dose at 48 weeks was 0.41 U per kilogram of body weight per day (95% confidence interval CI, 0.35 to 0.48) in the baricitinib group and 0.52 U per kilogram per day (95% CI, 0.44 to 0.60) in the placebo group. The levels of glycated hemoglobin were similar in the two trial groups. However, the mean coefficient of variation of the glucose level at 48 weeks, as measured by continuous glucose monitoring, was 29.6% (95% CI, 27.8 to 31.3) in the baricitinib group and 33.8% (95% CI, 31.5 to 36.2) in the placebo group. The frequency and severity of adverse events were similar in the two trial groups, and no serious adverse events were attributed to baricitinib or placebo.
In patients with type 1 diabetes of recent onset, daily treatment with baricitinib over 48 weeks appeared to preserve β-cell function as estimated by the mixed-meal-stimulated mean C-peptide level. (Funded by JDRF International and others; BANDIT Australian New Zealand Clinical Trials Registry number, ACTRN12620000239965.).
Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells in pancreatic islets are progressively destroyed. Clinical trials of immunotherapies in recently diagnosed T1D ...patients have only transiently and partially impacted the disease course, suggesting that other approaches are required. Our previous studies have demonstrated that heparan sulfate (HS), a glycosaminoglycan conventionally expressed in extracellular matrix, is present at high levels inside normal mouse beta cells. Intracellular HS was shown to be critical for beta cell survival and protection from oxidative damage. T1D development in Non-Obese Diabetic (NOD) mice correlated with loss of islet HS and was prevented by inhibiting HS degradation by the endoglycosidase, heparanase. In this study we investigated the distribution of HS and heparan sulfate proteoglycan (HSPG) core proteins in normal human islets, a role for HS in human beta cell viability and the clinical relevance of intra-islet HS and HSPG levels, compared to insulin, in human T1D. In normal human islets, HS (identified by 10E4 mAb) co-localized with insulin but not glucagon and correlated with the HSPG core proteins for collagen type XVIII (Col18) and syndecan-1 (Sdc1). Insulin-positive islets of T1D pancreases showed significant loss of HS, Col18 and Sdc1 and heparanase was strongly expressed by islet-infiltrating leukocytes. Human beta cells cultured with HS mimetics showed significantly improved survival and protection against hydrogen peroxide-induced death, suggesting that loss of HS could contribute to beta cell death in T1D. We conclude that HS depletion in beta cells, possibly due to heparanase produced by insulitis leukocytes, may function as an important mechanism in the pathogenesis of human T1D. Our findings raise the possibility that intervention therapy with dual activity HS replacers/heparanase inhibitors could help to protect the residual beta cell mass in patients recently diagnosed with T1D.
Cam-type femoroacetabular impingement is a recognized cause of intraarticular pathology and secondary osteoarthritis in young adults. Arthroscopy is reportedly useful to treat selected hip ...abnormalities and has been proposed as a method of correcting underlying impingement. We report the outcomes of arthroscopic management of cam-type femoroacetabular impingement. We prospectively assessed all 200 patients (207 hips) who underwent arthroscopic correction of cam impingement from December 2003 to October 2007, using a modified Harris hip score. The minimum followup was 12 months (mean, 16 months; range, 12–24 months); no patients were lost to followup. The average age was 33 years with 138 men and 62 women. One hundred and fifty-eight patients (163 hips) underwent correction of cam impingement (femoroplasty) alone while 42 patients (44 hips) underwent concomitant correction of pincer impingement. The average increase in Harris hip score was 20 points; 0.5% converted to THA. We had a 1.5% complication rate. The short-term outcomes of arthroscopic treatment of cam-type femoroacetabular impingement are comparable to published reports for open methods with the advantage of a less invasive approach.
Level of Evidence:
Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
Purpose We report the results of arthroscopic management of femoroacetabular impingement with 2-year follow-up. Methods All patients undergoing hip arthroscopy were prospectively assessed with the ...modified Harris Hip Score. Arthroscopic correction of femoroacetabular impingement was first performed in 2003. The cohort of this study consists of the first 100 consecutive cases that had achieved 2-year follow-up. Results There was 100% follow-up at 2 years. The mean age was 34 years (range, 13 to 76 years), with 67 male and 33 female patients. There were 63 cam, 18 pincer, and 19 combined lesions. Acetabular articular damage was found in 97 cases, femoral damage was present in 23, and there were 92 labral tears. The median improvement was 21.5 points, with 79 good and excellent results. No patient required revision to total hip arthroplasty, but 6 patients underwent a subsequent arthroscopic procedure. There were 3 complications including a transient neurapraxia of the pudendal nerve and a transient neurapraxia of the lateral femoral cutaneous nerve, which resolved uneventfully, and 1 mild case of heterotopic ossification. Conclusions We report favorable outcomes for the arthroscopic management of femoroacetabular impingement in our early experience in the first 100 consecutive cases. The high incidence of significant articular damage observed at the time of arthroscopic intervention is concerning. Level of Evidence Level IV, therapeutic case series.
Genome-wide association studies have identified
as an important non-MHC gene for autoimmunity. Single nucleotide polymorphisms that reduce
expression have been linked with the development of various ...autoimmune disorders, including type 1 diabetes. The tyrosine phosphatase PTPN2 attenuates T-cell receptor and cytokine signaling in T cells to maintain peripheral tolerance, but the extent to which PTPN2 deficiency in T cells might influence type 1 diabetes onset remains unclear. NOD mice develop spontaneous autoimmune type 1 diabetes similar to that seen in humans. In this study, T-cell PTPN2 deficiency in NOD mice markedly accelerated the onset and increased the incidence of type 1 diabetes as well as that of other disorders, including colitis and Sjögren syndrome. Although PTPN2 deficiency in CD8
T cells alone was able to drive the destruction of pancreatic β-cells and the onset of diabetes, T-cell-specific PTPN2 deficiency was also accompanied by increased CD4
T-helper type 1 differentiation and T-follicular-helper cell polarization and increased the abundance of B cells in pancreatic islets as seen in human type 1 diabetes. These findings causally link PTPN2 deficiency in T cells with the development of type 1 diabetes and associated autoimmune comorbidities.
Purpose To report the results of hip arthroscopy among high-level baseball players as recorded by outcome scores and return to baseball. Methods All patients undergoing hip arthroscopy were ...prospectively assessed with the modified Harris Hip Score. On review of all procedures performed over a 12-year period, 44 hips were identified among 41 intercollegiate or professional baseball players who had achieved 2-year follow-up. Results Among the 41 players, follow-up averaged 45 months (range, 24 to 120 months), with a mean age of 23 years (range, 18 to 34 years). There were 23 collegiate (1 bilateral) and 18 professional (2 bilateral) baseball players, including 10 Major League Baseball players. Of the 8 Major League Baseball pitchers, 6 (75%) also underwent ulnar collateral ligament elbow surgery. Improvement in the modified Harris Hip Score averaged 13 points (from 81 points preoperatively to 94 points postoperatively); a paired-samples t test determined that this mean improvement of 13 points was statistically significant ( P < .001). Players returned to baseball after 42 of 44 procedures (95%) at a mean of 4.3 months (range, 3 to 8 months), with 90% regaining the ability to participate at their previous level of competition. There were no complications. Three players (1 bilateral) underwent repeat arthroscopy. Conclusions This study supports the idea that arthroscopic treatment for a variety of hip pathologies in high-level baseball players provides a successful return to sport and improvement in functional outcome scores. Level of Evidence Level IV, therapeutic case series.
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