Repeated exposure to heterologous hepatitis C viruses associates with enhanced neutralizing antibody breadth and potency

A prophylactic hepatitis C virus (HCV) vaccine that elicits neutralizing antibodies could be key to HCV eradication. However, the genetic and antigenic properties of HCV envelope (E1E2) proteins capable of inducing anti-HCV broadly neutralizing antibodies (bNAbs) in humans have not been defined. Here, we investigated the development of bNAbs in longitudinal plasma of HCV-infected persons with persistent infection or spontaneous clearance of multiple reinfections. By measuring plasma antibody neutralization of a heterologous virus panel, we found that the breadth and potency of the antibody response increased upon exposure to multiple genetically distinct infections and with longer duration of viremia. Greater genetic divergence between infecting strains was not associated with enhanced neutralizing breadth. Rather, repeated exposure to antigenically related, antibody-sensitive E1E2s was associated with potent bNAb induction. These data reveal that a prime-boost vaccine strategy with genetically distinct, antibody-sensitive viruses is a promising approach to inducing potent bNAbs in humans.     

Protective role of IL‐1β against post‐arthroplasty Staphylococcus aureus infection

MyD88 is an adapter molecule that is used by both IL‐1R and TLR family members to initiate downstream signaling and promote immune responses. Given that IL‐1β is induced after Staphylococcus aureus infections and TLR2 is activated by S. aureus lipopeptides, we hypothesized that IL‐1β and TLR2 contribute to MyD88‐dependent protective immune responses against post‐arthroplasty S. aureus infections. To test this hypothesis, we used a mouse model of a post‐arthroplasty S. aureus infection to compare the bacterial burden, biofilm formation and neutrophil recruitment in IL‐1β‐deficient, TLR2‐deficient and wild‐type (wt) mice. By using in vivo bioluminescence imaging, we found that the bacterial burden in IL‐1β‐deficient mice was 26‐fold higher at 1 day after infection and remained 3‐ to 10‐fold greater than wt mice through day 42. In contrast, the bacterial burden in TLR2‐deficient mice did not differ from wt mice. In addition, implants harvested from IL‐1β‐deficient mice had more biofilm formation and 14‐fold higher adherent bacteria compared with those from wt mice. Finally, IL‐1β‐deficient mice had ～50% decreased neutrophil recruitment to the infected postoperative joints than wt mice. Taken together, these findings suggest a mechanism by which IL‐1β induces neutrophil recruitment to help control the bacterial burden and the ensuing biofilm formation in a post‐surgical joint. © 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29: 1621–1626, 2011     

Disappointing short-term results with the DePuy ASR XL metal-on-metal total hip arthroplasty

Outcomes of ultralarge-diameter femoral heads used in metal-on-metal (MOM) total hip arthroplasty (THA) are relatively unknown. This study reports on early failures of the ASR XL (Depuy, Warsaw, Ind) and assesses whether a correlation with cup positioning exists. A retrospective review of 70 consecutive MOM THAs with ultralarge-diameter femoral head and monoblock acetabular component was conducted. Minimum follow-up was 24 months. Of 70 THAs, 12 (17.1%) required revision within 3 years for pain (7), loosening (3), and squeaking (2). Three additional THAs noted squeaking, 2 noted grinding, and 3 additional hips had persistent pain. In total, 20 (28.6%) of 70 demonstrated implant dysfunction. Acetabular components for all symptomatic hips were in acceptable range of cup abduction and anteversion. The failures noted with this design do not correlate to cup placement. The high rate of implant dysfunction at early follow-up suggests serious concerns with the concept of MOM THA with an ultralarge-diameter femoral head paired with a monoblock acetabular cup.     

Impact of renal disease on elective shoulder arthroplasty outcomes for glenohumeral osteoarthritis

BackgroundRenal disease including chronic renal disease and end-stage renal disease has been associated with the development of primary glenohumeral osteoarthritis. However, little is known about how renal disease affects outcomes after shoulder arthroplasty. Thus, the purpose of this study was to evaluate the impact of renal disease on outcomes of shoulder arthroplasty for glenohumeral osteoarthritis.MethodsThis was a retrospective review using the Nationwide Readmissions Database. Using International Classification of Diseases, 9th Revision, codes, patients who underwent shoulder arthroplasty (including total shoulder arthroplasty and reverse total shoulder arthroplasty) for primary glenohumeral osteoarthritis were identified. These patients were divided into 3 groups: no renal disease, predialysis chronic renal disease (including stages 1-5), and end-stage renal disease. Primary outcomes of interest included the risk of complications during index hospitalization as well as within 90 days of index surgery. Secondary outcomes included index hospitalization length of stay, cost, and discharge location.ResultsFrom 2010 to 2014, a total of 29,336 patients underwent shoulder arthroplasty for glenohumeral osteoarthritis. Of these 29,336, 27,928 (95.2%) patients had no renal disease, 1355 (4.6%) had predialysis chronic renal disease, and 53 (0.2%) patients had end-stage renal disease. Compared with patients with no renal disease, both predialysis chronic renal disease and end-stage renal disease patients had an increased risk of receiving blood transfusions (odds ratio [OR] = 2.04, P < .0001, and 5.37, P = .04, respectively) and experiencing any postoperative complication during the index hospitalization (OR = 2.31, P < .0001, and 3.94, P = .003, respectively). Specifically, predialysis chronic renal disease patients were at an increased risk for cardiac (OR = 1.96, P < .0001) and respiratory (OR = 1.55, P < .0001) complications as well as acute renal failure (OR = 14.70, P < .0001) postoperatively. End-stage renal disease patients were at an increased risk for cardiac (OR = 3.87, P = .003) complications as well as acute renal failure (OR = 10.35, P = .002) postoperatively. Within 90 days, end-stage renal disease patients had an increased risk of hospital readmission (OR = 8.01, P < .0001), dislocation (OR = 8.70, P = .039), and surgical site infection (OR = 19.06, P = .001). Finally, compared with patients with no renal disease, predialysis chronic renal disease and end-stage renal disease patients both had increased hospital length of stay and cost; predialysis chronic renal disease patients had an increased risk of discharge to a skilled nursing facility (OR = 1.39, P = .039).Discussion and ConclusionThis retrospective cohort study demonstrates that even predialysis chronic renal disease patients have worse outcomes compared with patients with no renal disease after shoulder arthroplasty for glenohumeral osteoarthritis. These findings serve to highlight the importance of close perioperative monitoring to prevent complications in a potentially overlooked patient population.     

A rare case of solitary colonic fibromatosis mimicking a cystic tumour

Mesenteric fibromatosis or intrabdominal desmoid tumour is a rare proliferative disease that frequently involves the gastrointestinal tract. These tumours account for less than 3% of all tumours among soft tissue neoplasms. Most such lesions are large (10cm or more in diameter) at the time of the excision. Although grossly well-circumscribed, they lesions typically infiltrate the surrounding soft tissues including the bowel wall. The case described here concerns a 62-year-old woman with a partly cystic mesenteric fibromatosis incorporating the large bowel wall, which degenerated into an abscess. A right colectomy was undertaken, and the sample was sent for histological examination. Based on the morphological and immunohistochemical findings, a diagnosis of abdominal fibromatosis was established. The surgical margins were free of disease, and the examined lymph nodes showed cortical hyperplasia and histiocytosis of the lymph sinuses. The patient recovered from surgery with no complications; her fever subsided, and she was discharged from hospital 12 days later. Surgery is the primary therapy for extra-abdominal and intra-abdominal desmoid tumours. Considering the unique biology of desmoid tumours, conservative treatment strategies merit further investigation in both unresectable primary disease and resectable disease. The optimal criteria for choosing surgical or non-surgical treatment still need further evaluation with randomized controlled studies.     

Ontogeny of intrinsic innervation in the human kidney

We aimed to define, for the first time, the ontogeny of intrarenal innervation and to assess the distribution and nature of parenchymal nerves in the human fetal kidney. Our material consisted of routinely-processed renal tissue sections from 17 human fetuses, six of 20–24 gestational weeks (gw) and 11 of 25–40 gw, and three adults. We used immunohistochemistry with antibodies to the pan-neural markers neuron-specific enolase (NSE), neurofilaments (NF), PGP9.5, S100, and the adrenergic marker tyrosine hydroxylase (TH). NSE-, NF-, S100-, and PGP9.5-positive nerves, associated with arterial and venous vasculature, were identified in the renal cortex from 20 gw onwards, and their density appeared to increase with gestation, reaching adult levels at 28 gw. Most of the intrarenal nerves were TH-positive. Nerve fibers extended from the corticomedullary region to the outer cortex, reaching the renal capsule in the 3rd trimester. In detail, NSE-, NF-, S100-, PGP9.5-, and TH-immunoreactive fibers were observed in close apposition to the renal artery and its branches, occasionally reaching the afferent and efferent arteriole (3rd trimester). Nerve fibers were detected in close apposition to the juxtaglomerular apparatus in the 2nd and 3rd trimesters. In the renal medulla, NSE-, PGP9.5-, S100-, and TH-positive nerve fibers were detected close to tubular cells as early as 20 gw. However, their density gradually decreased during the 3rd trimester, and they were not observed in the medulla of the adult kidney. In conclusion, the human fetal kidney appears richly innervated during the 2nd and 3rd trimesters. There is a progressive increase in the density of parenchymal nerve fibers towards term from the corticomedullary region to the cortex. Most intrarenal nerves are adrenergic and have a predominant perivascular distribution, implying that renal innervation plays an important functional role during intrauterine life.     

CTLA-4 ablation and interleukin-12 driven differentiation synergistically augment cardiac pathogenicity of cytotoxic T lymphocytes

CD8+ cytotoxic T lymphocytes contribute to viral and autoimmune myocarditis and cardiac allograft rejection. The role of cytotoxic T-lymphocyte-associated antigen (CTLA)-4 as a negative regulator of CD4+ T cells is well defined, yet CTLA-4 regulation of CD8+ T cells is less clear. We studied CTLA-4 regulation of cytotoxic T lymphocytes in a transgenic model of CD8+ T-cell-mediated myocarditis. We generated CTLA-4(-/-) Rag 2(-/-) OT-1 mice, the CD8+ T cells of which express an ovalbumin (OVA) peptide-specific, class I major histocompatibility complex-restricted T-cell receptor. CTLA-4(-/-Tc12) OT-1 effectors, differentiated with interleukin-12 present, are hyperproliferative in vitro, compared with CTLA-4(+/+)Tc12 OT-1 controls. Transfer of low doses of CTLA-4(-/-Tc12) OT-1 cells to cMy-mOVA mice, which express OVA on cardiac myocytes, causes severe myocarditis, with 99% mortality, compared with no mortality after transfer of low doses of CTLA-4(+/+)Tc12 OT-1 cells. High doses of CTLA-4(+/+)Tc12 cells cause lethal myocarditis in cMy-mOVA mice, but high doses of CTLA-4(+/+)Tc0 CTL, generated without interleukin-12, are hypoproliferative within the cardiac-draining lymph node and do not significantly infiltrate the heart. In contrast, CTLA-4(-/-Tc0) cytotoxic T lymphocytes do proliferate in the cardiac-draining lymph node and diffusely infiltrate the heart. Nonetheless, high doses of CTLA-4(-/-Tc0) cells cause only limited tissue damage, and the disease is not lethal. These data show that CTLA-4 regulates myocarditic CD8+ T cell responses and that CTLA-4 deficiency partly overcomes a differentiation block that exists when na?ve CD8+ T cells are stimulated without interleukin-12. Therefore, targeting CTLA-4 solely or in conjunction with interleukin-12 could influence effector CD8+ T cell responses in therapeutically beneficial ways.     

Role of substance P in the regulation of glucose metabolism via insulin signaling-associated pathways

Substance P (SP), encoded by the tachykinin 1 (Tac1) gene, is the most potent tachykinin ligand for the high-affinity neurokinin-1 receptor (NK-1R). We previously reported that NK-1R-deficient mice show less weight gain and reduced circulating levels of leptin and insulin in response to a high-fat diet (HFD) and demonstrated the presence of functional NK-1R in isolated human preadipocytes. Here we assessed the effects of SP on weight gain in response to HFD and determined glucose metabolism in Tac1-deficient (Tac1(-/-)) mice. The effect of SP on the expression of molecules that may predispose to reduced glucose uptake was also determined in isolated human mesenteric, omental, and sc preadipocytes. We show that although weight accumulation in response to HFD was similar between Tac1(-/-) mice and wild-type littermates, Tac1(-/-) mice demonstrated lower glucose and leptin and increased adiponectin blood levels and showed improved responses to insulin challenge after HFD. SP stimulated phosphorylation of c-Jun N-terminal kinase, protein kinase C, mammalian target of rapamycin, and inhibitory serine insulin receptor substrate-1 phosphorylation in human preadipocytes in vitro. Preincubation of human mesenteric preadipocytes with the protein kinase C pseudosubstrate inhibitor reduced insulin receptor substrate 1 phosphorylation in response to SP. Lastly, SP also induced insulin receptor substrate-1 phosphorylation in mature human sc adipocytes. Our results demonstrate an important role for SP in adipose tissue responses and obesity-associated pathologies. These novel SP effects on molecules that enhance insulin resistance at the adipocyte level may reflect an important role for this peptide in the pathophysiology of type 2 diabetes.