Chris Johnston

The open abdomen and temporary abdominal closure systems - historical evolution and systematic review

Aim  Several techniques for temporary abdominal closure have been developed. We systematically review the literature on temporary abdominal closure to ascertain whether the method can be tailored to the indication.

Fracture healing in HIV-positive populations

Highly active anti-retroviral therapy has transformed HIV into a chronic disease with a long-term asymptomatic phase. As a result, emphasis is shifting to other effects of the virus, aside from immunosuppression and mortality. We have reviewed the current evidence for an association between HIV infection and poor fracture healing. The increased prevalence of osteoporosis and fragility fractures in HIV patients is well recognised. The suggestion that this may be purely as a result of highly active anti-retroviral therapy has been largely rejected. Apart from directly impeding cellular function in bone remodelling, HIV infection is known to cause derangement in the levels of those cytokines involved in fracture healing (particularly tumour necrosis factor-alpha) and appears to impair the blood supply of bone. Many other factors complicate this issue, including a reduced body mass index, suboptimal nutrition, the effects of anti-retroviral drugs and the avoidance of operative intervention because of high rates of wound infection. However, there are sound molecular and biochemical hypotheses for a direct relationship between HIV infection and impaired fracture healing, and the rewards for further knowledge in this area are extensive in terms of optimised fracture management, reduced patient morbidity and educated resource allocation. Further investigation in this area is overdue.

Indications for Thrombolysis in Deep Venous Thrombosis

OBJECTIVES Deep venous thromboses (DVTs) are a significant cause of morbidity and mortality in the general and inpatient population. Current anticoagulation therapy is efficient in reducing thrombus propagation but does not contribute to clot lysis or prevention of post-thrombotic limb syndrome. Catheter directed thrombolysis (CDT) is an alternative method for treating DVTs but there is no consensus regarding indications for its use. DATA SOURCES PubMed and Cochrane library were searched for all articles on deep vein thrombosis and thrombolysis. REVIEW METHOD Articles presenting data on DVT thrombolysis, DVT anticoagulation, mechanical thrombectomy, venous stenting and May-Thurners syndrome were considered for inclusion in the review. RESULTS CDT reduced clot burden, DVT recurrence and may prevent the formation of post-thrombotic syndrome. Indications for its use include younger individuals with a long life expectancy and few co-morbidities, limb-threatening thromboses and proximal ilio-femoral DVTs. There is a marked lack of randomised controlled trials comparing CDT-related mortality and long term outcomes compared to anticoagulation alone. The effectiveness of combined pharmaco-mechanic thrombectomy, although promising, need to be further investigated, as is the role of caval filters in preventing DVT-associated pulmonary emboli. CONCLUSIONS These results suggest that the outcome of CDT in DVT management are encouraging in selected patient cohorts, but further evidence is required to establish longer term benefits and cost-effectiveness.

Cultivation of Heligmosomoides Polygyrus: An Immunomodulatory Nematode Parasite and its Secreted Products

Heligmosomoides polygyrus (formerly known as Nematospiroides dubius, and also referred to by some as H. bakeri) is a gastrointestinal helminth that employs multiple immunomodulatory mechanisms to establish chronic infection in mice and closely resembles prevalent human helminth infections. H. polygyrus has been studied extensively in the field of helminth-derived immune regulation and has been found to potently suppress experimental models of allergy and autoimmunity (both with active infection and isolated secreted products). The protocol described in this paper outlines management of the H. polygyrus life cycle for consistent production of L3 larvae, recovery of adult parasites, and collection of their excretory-secretory products (HES).

TGF-β in tolerance, development and regulation of immunity

Graphical abstract

Helminths and immunological tolerance

Current immunosuppression regimens for solid-organ transplantation have shown disappointing efficacy in the prevention of chronic allograft rejection and carry unacceptable risks including toxicity, neoplasia, and life-threatening infection. Achievement of immunological tolerance (long-term antigen unresponsiveness in an immunocompetent host) presents the exciting prospect of freedom from immunosuppression for transplant recipients. It is now 60 years since the first demonstration of immunological tolerance in animal models of transplantation, but translation into routine clinical practice remains elusive. Helminth parasites may provide novel strategies toward achieving this goal. Helminths are remarkably successful parasites: they currently infect more than one quarter of the world’s population. It is now well established that the parasites’ success is the result of active immunomodulation of their hosts’ immune response. Although this primarily secures ongoing survival of the parasites, helminth-induced immunomodulation can also have a number of benefits for the host. Significant reductions in the prevalence of allergy and autoimmune conditions among helminth-infected populations are well recognized and there is now a significant body of evidence to suggest that harmful immune responses to alloantigens may be abrogated as well. Here, we review all existing studies of helminth infection and transplantation, explore the mechanisms involved, and discuss possible avenues for future translation to clinical practice.

Enteric helminth-induced type I interferon signaling protects against pulmonary virus infection through interaction with the microbiota

Background: Helminth parasites have been reported to have beneficial immunomodulatory effects in patients with allergic and autoimmune conditions and detrimental consequences in patients with tuberculosis and some viral infections. Their role in coinfection with respiratory viruses is not clear. Objective: Here we investigated the effects of strictly enteric helminth infection with Heligmosomoides polygyrus on respiratory syncytial virus (RSV) infection in a mouse model. Methods: A murine helminth/RSV coinfection model was developed. Mice were infected by means of oral gavage with 200 stage 3 H polygyrus larvae. Ten days later, mice were infected intranasally with either RSV or UV‐inactivated RSV. Results: H polygyrus–infected mice showed significantly less disease and pulmonary inflammation after RSV infection associated with reduced viral load. Adaptive immune responses, including TH2 responses, were not essential because protection against RSV was maintained in Rag1−/− and Il4r&agr;−/− mice. Importantly, H polygyrus infection upregulated expression of type I interferons and interferon‐stimulated genes in both the duodenum and lung, and its protective effects were lost in both Ifnar1−/− and germ‐free mice, revealing essential roles for type I interferon signaling and microbiota in H polygyrus–induced protection against RSV. Conclusion: These data demonstrate that a strictly enteric helminth infection can have remote protective antiviral effects in the lung through induction of a microbiota‐dependent type I interferon response. Graphical abstract Figure. No Caption available.

A structurally distinct TGF-β mimic from an intestinal helminth parasite potently induces regulatory T cells

Helminth parasites defy immune exclusion through sophisticated evasion mechanisms, including activation of host immunosuppressive regulatory T (Treg) cells. The mouse parasite Heligmosomoides polygyrus can expand the host Treg population by secreting products that activate TGF-β signalling, but the identity of the active molecule is unknown. Here we identify an H. polygyrus TGF-β mimic (Hp-TGM) that replicates the biological and functional properties of TGF-β, including binding to mammalian TGF-β receptors and inducing mouse and human Foxp3+ Treg cells. Hp-TGM has no homology with mammalian TGF-β or other members of the TGF-β family, but is a member of the complement control protein superfamily. Thus, our data indicate that through convergent evolution, the parasite has acquired a protein with cytokine-like function that is able to exploit an endogenous pathway of immunoregulation in the host.Heligmosomoides polygyrus can activate mammalian TGF-β signalling pathways, but how it does so is not known. Here the authors identify and isolate a H. polygyrus TFG-β mimic that can bind both mammalian TGF-β receptor subunits, activate Smad signalling and generate inducible regulatory T cells.

A role for helminth parasites in achieving immunological tolerance in transplantation

BACKGROUND Helminths infect more than a quarter of the worlds population. Their success as parasites is the result of active immunomodulation of the host immune response, which can have benefits for the host, particularly in suppressing harmful allergic and autoimmune responses. Accordingly, we tested the hypothesis that helminth infection reduces the immune response to allograft transplantation. METHODS C57BL/6 mice were implanted with a subcutaneous minipump that delivered a continuous infusion of secreted products from the model mouse intestinal parasite, Heligmosomoides polygyrus (equivalent to 7 μg of protein per day). Simultaneously, fully allogeneic skin grafts from BALB/c donors were performed. 7 days later, lymphocytes were isolated from allograft draining lymph nodes and analysed by flow cytometry. FINDINGS Flow cytometric analysis showed a 41·7% increase in the mean percentage of CD4+CD25+Foxp3+ regulatory T cells (of total CD4 cells) from a baseline of 8·1% (95% CI 7·4-8·8) in untreated mice to 11·5% (8·8-14·2) in the treatment group (p=0·0085). Treatment with parasite products also increased mean expression of the regulatory cell surface receptor PD1 by 62·2% in the effector CD4 T-cell population from a baseline of 7·7% (5·7-9·6) to 12·5% (7·5-17·4) (p=0·03). INTERPRETATION The results show that helminth-derived products can powerfully induce regulatory immunological mechanisms in the presence of a fully allogeneic transplant. Identification of the specific mechanisms involved in suppression of allograft rejection by helminth parasites could lead towards development of safe and effective novel therapeutic strategies. FUNDING Wellcome Trust.

DEMONSTRATION OF THE ANTHELMINTIC POTENCY OF MARIMASTAT IN THE HELIGMOSOMOIDES POLYGYRUS RODENT MODEL

ABSTRACT In the course of a structure-based drug discovery program the known anticancer candidate marimastat was uncovered as a potent inhibitor of an enzyme in nematode cuticle biogenesis. It was shown to kill Caenorhabditis elegans, and the sheep parasites Haemonchus contortus and Teladorsagia circumcinta via an entirely novel nematode-specific pathway, specifically by inhibiting cuticle-remodeling enzymes that the parasites require for the developmentally essential molting process. This discovery prompted an investigation of the compounds effect on Heligmosomoides polygyrus parasites in a mouse model of helminth infection. Mice were administered the drug via oral gavage daily from day of infection for a period of 2 wk. A second group received the drug via intra-peritoneal implantation of an osmotic minipump for 4 wk. Control groups were administered identical volumes of water by oral gavage in both cases. Counts of H. polygyrus fecal egg and larval load showed that marimastat effected a consistent and significant reduction in egg laying, and a consistent but minor reduction in adult worm load when administered every day, starting on the first day of infection. However, the drug failed to have any significant effect on egg counts or worm burdens when administered to mice with established infections. Therefore, marimastat does not appear to show promise as an anthelmintic in gastrointestinal nematode infections, although other metalloproteases such as batimastat may prove more effective.