The nature and combination of subunits used in epitope-based Schistosoma japonicum vaccine formulations affect their efficacy

<p>Abstract</p> <p>Background</p> <p>Schistosomiasis remains a major public health problem in endemic countries and is caused by infections with any one of three primary schistosome species. Although there are no vaccines available to date, this strategy appears feasible since natural immunity develops in individuals suffering from repeated infection during a lifetime. Since vaccinations resulting in both Th1- and Th2-type responses have been shown to contribute to protective immunity, a vaccine formulation with the capacity for stimulating multiple arms of the immune response will likely be the most effective. Previously we developed partially protective, single Th- and B cell-epitope-based peptide-DNA dual vaccines (PDDV) (T3-PDDV and B3-PDDV, respectively) capable of eliciting immune responses against the <it>Schistosoma japonicum </it>22.6 kDa tegument antigen (Sj22.6) and a 62 kDa fragment of myosin (Sj62), respectively.</p> <p>Results</p> <p>In this study, we developed PDDV cocktails containing multiple epitopes of <it>S. japonicum </it>from Sj22.6, Sj62 and Sj97 antigens by predicting cytotoxic, helper, and B-cell epitopes, and evaluated vaccine potential <it>in vivo</it>. Results showed that mice immunized with a single-epitope PDDV elicited either Tc, Th, or B cell responses, respectively, and mice immunized with either the T3- or B3- single-epitope PDDV formulation were partially protected against infection. However, mice immunized with a multicomponent (3 PDDV components) formulation elicited variable immune responses that were less immunoprotective than single-epitope PDDV formulations.</p> <p>Conclusions</p> <p>Our data show that combining these different antigens did not result in a more effective vaccine formulation when compared to each component administered individually, and further suggest that immune interference resulting from immunizations with antigenically distinct vaccine targets may be an important consideration in the development of multicomponent vaccine preparations.</p

Horrifying Basal Cell Carcinoma Presenting as Progressive Pyoderma Gangrenosum: Case Report

Introduction: Skin ulcers can be challenging to diagnose and manage, particularly with comorbid autoimmune and gastrointestinal diseases. Occam’s razor encourages the simplest explanation to guide care, but reconsideration must occur when intervention proves futile. Case Presentation: We report the case of a 70-year-old male, with a 17-year history of expanding pretibial skin ulcer, presumed by prior care providers to be pyoderma gangrenosum related to Crohn’s disease. A surgical biopsy performed upon presentation to our institution revealed basal cell carcinoma of the skin, invasive to the proximal tibia with associated deep infection, prompting transfemoral amputation. Conclusion: This report is written as a reminder to reconsider a diagnosis and consider seeking additional expertise when a patient’s condition progressively worsens despite intervention. Earlier diagnosis likely would have facilitated therapeutic limb salvage care

Dynamics of Th17 Cells and Their Role in Schistosoma japonicum Infection in C57BL/6 Mice

Th17 immune cells secrete the IL-17 cytokine and contribute to host defenses against certain infections. Recent studies linked IL-17 with the severity of liver inflammation and suggested that Th17 cells contribute to the pathology in schistosomiasis, a serious disease caused by parasitic worms such as Schistosoma japonicum widespread in vertebrates including humans. However, the role of Th17 cells in protection against S. japonicum infection is still unclear. For the first time, we describe here the changes in Th17 cell levels during S. japonicum infection and suggest that the schistosome egg antigens are primarily responsible for stimulating the generation of host Th17 cells after S. japonicum infection. We further show that the level of Th17 cells in the host is determined by a combination of factors, namely exposure to complex parasitic antigens that either induce or suppress their generation. We also suggest that lowering IL-17 levels may favor the host's protective responses against S. japonicum infection. Our findings help to better understand the relationship between the host and parasite in terms of immune protection and pathology in schistosomiasis and may contribute to the future development of vaccination and therapeutic strategies

Bone density changes after five or more years of unilateral lower extremity osseointegration: Observational cohort study

Context: Rehabilitation following lower extremity amputation presents multiple challenges, many related to the traditional prosthesis (TP) socket. Without skeletal loading, bone density also rapidly decreases. Transcutaneous osseointegration for amputees (TOFA) surgically implants a metal prosthesis attachment directly into the residual bone, facilitating direct skeletal loading. Quality of life and mobility are consistently reported to be significantly superior with TOFA than TP. Objective: To investigate how femoral neck bone mineral density (BMD, g/cm2) changes for unilateral transfemoral and transtibial amputees at least five years following single-stage press-fit osseointegration. Methods: Registry review was performed of five transfemoral and four transtibial unilateral amputees who had dual x-ray absorptiometry (DXA) performed preoperatively and after at least five years. The average BMD was compared using Student's t-test (significance p < .05). First, all nine Amputated versus Intact limbs. Second, the five patients with local disuse osteoporosis (ipsilateral femoral neck T-score < −2.5) versus the four whose T-score was greater than −2.5. Results: The average Amputated Limb BMD was significantly less than the Intact Limb, both Before Osseointegration (0.658 ± 0.150 vs 0.929 ± 0.089, p < .001) and After Osseointegration (0.720 ± 0.096 vs 0.853 ± 0.116, p = .018). The Intact Limb BMD decreased significantly during the study period (0.929 ± 0.089 to 0.853 ± 0.116, p = .020), while the Amputated Limb BMD increased a not statistically significant amount (0.658 ± 0.150 to 0.720 ± 0.096, p = .347). By coincidence, all transfemoral amputees had local disuse osteoporosis (BMD 0.545 ± 0.066), and all transtibial patients did not (BMD 0.800 ± 0.081, p = .003). The local disuse osteoporosis cohort eventually had a greater average BMD (not statistically significant) than the cohort without local disuse osteoporosis (0.739 ± 0.100 vs 0.697 ± 0.101, p = .556). Conclusions: Single-stage press-fit TOFA may facilitate significant BMD improvement to unilateral lower extremity amputees with local disuse osteoporosis

Lengthening the Lower Extremities of Children with Ollier’s and Maffucci’s Enchondromatosis Using Implantable Lengthening Nails

There are multiple forms of enchondromatosis with Ollier’s and Maffucci’s being the most prevalent types. Limb length discrepancy is a common problem in patients with Ollier’s and Maffucci’s enchondromatosis. There are multiple reports about lengthening bones in patients with enchondromatosis using external fixators. However, there are no case series regarding the use of implantable lengthening technology. The purpose of this paper is to describe our experience with implantable nail lengthening in patients with enchondromatosis. A retrospective chart and radiographic review of patients with enchondromatosis who underwent implantable nail limb lengthening was performed. Seven patients with 14 bony segments were reviewed. A total of 11/14 lengthenings were completed without difficulty. There were no issues in terms of fixation location in patients with Ollier’s disease. One patient with Maffucci’s syndrome experienced migration of the nail during two lengthenings due to a combination of intralesional fixation and preconsolidation. One patient with Ollier’s disease developed a knee extension contracture requiring manipulation under anesthesia. No other complications were recorded. The use of implantable nail lengthening to resolve limb length discrepancies in patients with Ollier’s disease appears to be safe and effective

Current challenges and future prospects of osseointegration limb reconstruction for amputees

Although osseointegration has proven successful at improving the physical deficits that traditional prostheses leave unfulfilled, future innovation should be systematically guided rather than randomly explored. Therefore, this article attempts to summarise, in a systematic manner, the challenges and prospects of osseointegration limb reconstruction for amputees from an implant design and manufacturing point of view, to provide a template for the development of the next generation of osseointegration implants. A scoping literature review was conducted, and key papers were identified and summarised. To combat osseointegration-related infection, advances such as smart implant coatings, mechanical inactivation of bacteria, biofilm eradication, implant monitoring technologies and nanotechnology were evaluated. Regarding production and biomaterials, the potential of 3D printing to balance supply and demand to achieve cost-effectiveness and sustainability were investigated. Considering the evolution of designs and the goal to provide a sensate limb, the prospects of smart implants, biofeedback and myoelectric pattern recognition were also explored. Osseointegration appears to follow a trajectory like that of total joint arthroplasty, which gained widespread clinical acceptance and adoption over the last 50 years. In our opinion, the future of amputee rehabilitation is bright, and we are optimistic osseointegration will continue to progress and advance as new technologies emerge

Transtibial osseointegration for patients with peripheral vascular disease: A case series of 6 patients with minimum 3-year follow-up

Background: The management of peripheral vascular disease (PVD) can require amputation. Osseointegration surgery is an emerging rehabilitation strategy for amputees. In this study, we report on 6 patients who had PVD requiring transtibial amputation (PVD-TTA) and either simultaneous or subsequent osseointegration (PVD-TTOI). Methods: Six patients (aged 36 to 84 years) with transtibial amputation and preexisting PVD underwent osseointegration between 2014 and 2016 and were followed for 3 to 5 years. Pre- and postoperative clinical and functional outcomes (pain, prosthesis wear time, mobility, walking ability, and quality of life) and adverse events (infection, fracture, implant failure, revision surgery, additional amputation, and death) were prospectively recorded. Results: All patients’ mobility improved following osseointegration. Three patients initially had required the use of a wheelchair, precluding baseline walking tests; the other 3 were classified as K level 1 or 2, with mean baseline Timed Up and Go (TUG) test = 14.0 ± 2.2 s and 6-Minute Walk Test (6MWT) = 262 ± 75 m. At the time of the latest follow-up, all patients were K level 2 or 3; mean TUG = 12.7 ± 7.2 s and 6MWT = 353 ± 148 m. Four patients wore their prosthesis ≥16 hours daily. Three patients had superficial soft-tissue infections. One other patient experienced recurrent infections 2.8 years after osseointegration requiring debridements and transfemoral amputation; the patient died 2 days following surgery from myocardial infarction caused by coronary atherosclerosis. Conclusions: All 6 patients who underwent PVD-TTOI in this case series survived through 2 years. Patients who initially had used a wheelchair achieved and maintained independent, unaided ambulation until PVD-related impairments in the contralateral leg occurred in 1 patient. Patients previously using a traditional socket prosthesis reported improvement in mobility and quality of life. One patient’s death underscores the importance of careful patient selection. However, marked improvement in the other 5 patients suggests cautious optimism that PVD-TTA is not an absolute osseointegration contraindication. Conscientious further investigation seems appropriate. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence

Partial Regulatory T Cell Depletion Prior to Schistosomiasis Vaccination Does Not Enhance the Protection

National Natural Science Foundation of China [30801046]; Anhui Academic and Technical Reserve Candidate Leaders; Anhui University of Science and Technology [2010YB004]CD4(+)CD25(+) regulatory T cells (Tregs) do not only influence self-antigen specific immune responses, but also dampen the protective effect induced by a number of vaccines. The impact of CD4(+)CD25(+) Tregs on vaccines against schistosomiasis, a neglected tropical disease that is a major public health concern, however, has not been examined. In this study, a DNA vaccine encoding a 26 kDa glutathione S-transferase of Schistosoma japonicum (pVAX1-Sj26GST) was constructed and its potential effects were evaluated by depleting CD25(+) cells prior to pVAX1-Sj26GST immunization. This work shows that removal of CD25(+) cells prior to immunization with the pVAX1-Sj26GST schistosomiasis DNA vaccine significantly increases the proliferation of splenocytes and IgG levels. However, CD25(+) cell-depleted mice immunized with pVAX1-Sj26GST show no improved protection against S. japonicum. Furthermore, depletion of CD25(+) cells causes an increase in both proinflammatory cytokines (e. g. IFN-gamma, GM-CSF and IL-4) and an anti-inflammatory cytokine (e. g. IL-10), with CD4(+)CD25(-) T cells being one of the major sources of both IFN-gamma and IL-10. These findings indicate that partial CD25(+) cell depletion fails to enhance the effectiveness of the schistosome vaccine, possibly due to IL-10 production by CD4(+)CD25(-) T cells, or other cell types, after CD25(+) cell depletion during vaccination