The NLRP3 Inflammasome: Relevance in Solid Organ Transplantation.

The NOD, LRR, and pyrin domain-containing 3 (NLRP3) protein has been established as a central component of the inflammasome and regulates the inflammatory response to a myriad of environmental, microbial, and endogenous danger stimuli. Assembly of the NLRP3 inflammasome results in the cleavage and activation of caspase-1, in turn causing release of the pro-inflammatory interleukins 1-beta and 18. This activation response, while crucial to coordinated innate immune defense, can be aberrantly activated by the likes of cell-free DNA, and cause significant autoimmune pathology. Complications of autoimmunity induced by aberrant NLRP3 inflammasome activation have a great degree of mechanistic crossover with alloimmune injury in solid organ transplant, and stratagems to neutralize NLRP3 inflammasome activation may prove beneficial in solid organ transplant management. This article reviews NLRP3 inflammasome biology and the pathology associated with its hyperactivation, as well as the connections between NLRP3 inflammasome activation and allograft homeostasis.

Pubic lice: an endangered species?

UNLABELLED: The incidence of pubic lice infestations is estimated to be between 1.3% and 4.6%, with an average incidence of 2% worldwide. It is also estimated that 70% to 80% of adults now remove pubic hair in part or entirety, using a variety of methods. It is hypothesized that the destruction of this pubic hair habitat may account for the falling incidence of pubic lice and may possibly lead to its eradication or atypical presentation. AIM: To report the changing incidence of pubic lice infestation from our unit over the last 10 years and assess its association, if any, with pubic hair removal of any kind. METHODS: Assessment of medical records and questionnaires were used to identify the incidence of hair removal and pubic lice infestation over a 10-year period. Data were anonymized and analyzed to identify any correlation. RESULTS: A significant and strong correlation between the falling incidence of pubic lice infections and increase in pubic hair removal was observed, with a Pearson correlation r value of 0.9686 (95% confidence intervals, 0.88-0.992). The P value is less than 0.0001. CONCLUSIONS: The increased incidence of hair removal may lead to atypical patterns of pubic lice infestations or its complete eradication as the natural habitat of this parasite is destroyed.

Validation of a gene expression signature to measure immune quiescence in kidney transplant recipients in the CLIA setting.

Aim: Allograft rejection remains a major cause of graft failure in kidney transplantation. Here the authors report the validation of a non-invasive molecular diagnostic assay, AlloMap Kidney, using peripheral blood. Methods: The AlloMap Kidney test is a gene expression profile utilizing the RNA-seq platform to measure immune quiescence in kidney transplant patients. Results/Conclusions: Analytical validation showed robust performance characteristics with an accuracy correlation coefficient of 0.997 and a precision coefficient of variation of 0.049 across testing. Clinical validation from the prospective, multi-center studies of 235 samples (66 rejection and 169 quiescence specimens) demonstrated the sensitivity of 70% and specificity of 66% for allograft rejection, while the negative predictive value was 95% to discriminate rejection from quiescence at 10% prevalence of rejection.

Endotoxemia in pediatric critical illness--a pilot study.

INTRODUCTION: The aim was to investigate the prevalence of endotoxemia in children admitted to pediatric intensive care unit (PICU), and its association with disease severity and outcome. METHODS: We conducted a prospective, observational cohort study of children admitted to PICU at St. Mary's Hospital, London over a 6-month period. One hundred consecutive patients were recruited. Demographic and clinical data were collected. Severity of illness was assessed by the pediatric index of mortality 2 (PIM2) score. The pediatric logistic organ dysfunction (PELOD) score was performed daily for the first 4 days. Patients were categorized according to primary reason for PICU admission. Blood samples were taken within 24 hours of admission and endotoxemia was measured using the endotoxin activity assay (EAA). Patients were stratified according to EAA level (high, EAA > 0.4, low, EAA < 0.4) and categorized as septic, post-surgical, respiratory or other. Data were analyzed using appropriate non-parametric tests. RESULTS: EAA level was significantly lower in PICU controls versus other PICU admissions (P = 0.01). Fifty-five children had endotoxemia on admission. Forty-one (75%) of these were eventually diagnosed with an infectious cause of admission. Nine children without infection had elevated EAA on admission. An infectious cause of admission was significantly associated with endotoxemia (P < 0.005). Of 15 children with gram-negative infection, only 9 (60%) had endotoxemia on admission. Endotoxemia on admission was not associated with shock or death. However, there was a tendency for increased PELOD score and length of stay in endotoxemic children. CONCLUSIONS: Endotoxemia is common in children admitted to intensive care. Understanding the implications of endotoxemia and potential anti-endotoxin strategies may have the potential to reduce severity of illness and length of PICU stay in critically ill children.

Adding Insult on Injury: Immunogenic Role for Donor-derived Cell-free DNA?

Donor-derived cell-free DNA (dd-cfDNA) in the blood circulation is an early marker of injury in solid organ transplantation. Here, we review recent evidence that indicates that dd-cfDNA may itself be a trigger of inflammation, thereby adding insult on injury. Early unresolving molecular allograft injury measured via changes in dd-cfDNA may be an early warning sign and may therefore enable stratification of patients who are at risk of subsequent allograft injury. Considering dd-cfDNA as a continuous and clinically significant biomarker opens up the potential for new management strategies, therapeutics, and ways to quantify interventions by considering the immunological potential of dd-cfDNA.

Preserving and perfusing the allograft pancreas: Past, present, and future.

The concept of organ preservation by perfusion dates back to the mid-19th century. Innovations since then have included temperature regulation, perfusion fluid composition and various pumping systems. Advances made in liver, heart and kidney machine preservation are now contributing to increased graft utilisation, assessment of graft viability and potentially improved graft survival. Pancreas transplantation has not benefitted to the same extent from the application of perfusion technology, although the need is just as great. This overview reviews current pancreas specific preservation techniques. We explore concepts, which include static cold storage, use of preservation solutions, the 'two-layer method', and machine perfusion. We also discuss ideas for future development. Narrative review of literature from inception to December 2017 using OVID interfaces searching EMBASE, Google Scholar, and MEDLINE databases. All studies relevant to pancreas perfusion and preservation were examined for clinical relevance with no exclusion criteria. Conference papers and presentations were also reviewed and included where appropriate. The application of recent advances in understanding in ischaemia-reperfusion as well as technical developments in machine preservation Ischaemia-reperfusion have the potential to improve organ utilisation, viability and outcome.

Urological Nephrectomies for Benign Disease: A Possible Missed Resource in Organ Donation.

OBJECTIVES: The deficit of organs for renal transplant is a global issue. The United Kingdom Hospital Episode Statistics indicates there that were 8168 nephrectomies undertaken in 2014. Furthermore, according to the British Association of Urological Surgeons 2014 nephrectomy report, 71.8% of patients undergoing a nephrectomy had creatinine levels of less than 120 IU/L and roughly 20% had the procedure for benign and functional causes. MATERIALS AND METHODS: We report a prospective case series from March 2014 to March 2016 involving 6 patients showing 3 successful transplants performed following 3 native nephrectomies. RESULTS: All recipients had normal creatinine levels with good function at 12 months, and all nephrectomy patients, in addition to maintaining normal renal function, had definitive resolution of symptoms. The main limitation of this series was the small sample size. CONCLUSIONS: There is no doubt that all should be done to save native organ function, and all salvage procedures and psychological testing must be robust before considering this route. However, within the group that proceeds to nephrectomy, some cases may have the potential to generate a new pool of donor organs suitable for transplant, helping to tackle the organ deficit in renal transplantation.

Helminths in organ transplantation.

With transplantation becoming an increasingly routine form of treatment for diverse populations, and with international travel becoming ever more accessible and affordable, the danger of transplantation-mediated helminth infections, exacerbated by coincident immunosuppression, must be considered. In this Review, we attempt to catalogue all clinically-relevant helminthiases that have been reported to coincide with transplantation, whether by transplantation-mediated transmission, reactivation of latent infections in an immunosuppressed context, or possible de-novo infection during the immunosuppressed peritransplant period. Helminthiasis has been reported in cases of kidney, liver, bowel, pancreas, heart, lung, and stem-cell transplant, and blood transfusion. For each helminthiasis, known risk factors, symptoms, and suggested options for screening and treatment are given. We conclude that helminths are a small but important and potentially severe source of disease after transplantation, and, with options for diagnosis and treatment, these pathogens warrant greater consideration during organ implantation. The achievement of immunological tolerance using helminth-derived products is also an exciting future prospect.

Advances in pancreas transplantation.

The potential to reverse diabetes has to be balanced against the morbidity of long-term immunosuppression associated with transplantation. For a patient with renal failure, the treatment of choice is often a simultaneous transplant of the pancreas and kidney or pancreas after kidney. For a patient with glycaemic instability, choices between a solid organ or islet transplant have to be weighed against benefits and risks of remaining on insulin. Results of simultaneous transplant of the pancreas and kidney transplantation are comparable to other solid-organ transplants, and there is evidence of improved quality of life and life expectancy. There is some evidence of benefit with respect to the progression of secondary diabetic complications in patients with functioning transplants for several years.

Pancreas Transplantation: Past, Present, Future.

Diabetes is the pandemic disease of the modern era, with 10% of these patients having type 1 diabetes mellitus. Despite the prevalence, morbidities, and associated financial burden, treatment options have not changed since the introduction of injectable insulin. To date, over 40,000 pancreas transplants have been performed globally. It remains the only known method for restoring glycemic control and thus curing type 1 diabetes mellitus. The aim of this review is to bring pancreatic transplantation out of the specialist realm, informing practitioners about this important procedure, so that they feel better equipped to refer suitable patients for transplantation and manage, counsel, and support when encountering them within their own specialty. This study was a narrative review conducted in October 2015, with OVID interface searching EMBASE and MEDLINE databases, using Timeframe: Inception to October 2015. Articles were assessed for clinical relevance and most up-to-date content, with articles written in English as the only inclusion criterion. Other sources used included conference proceedings/presentations and unpublished data from our institution (Oxford Transplant Centre). Pancreatic transplantation is growing and has quickly become the gold standard of care for patients with type 1 diabetes mellitus and renal failure. Significant improvements in quality of life and life expectancy make pancreatic transplant a viable and economically feasible intervention. It remains the most effective method of establishing and maintaining euglycemia, halting and potentially reversing complications associated with diabetes.

The association of noise and surgical-site infection in day-case hernia repairs.

INTRODUCTION: Surgical-site infections (SSIs) are associated with an increased duration of hospital stay, poorer quality of life, and an marked increase in cost to the hospital. Lapses in compliance with aseptic principles are a substantial risk factor for SSI, which may be attributable to distractions such as noise during the operation. The aims of this study were to assess whether noise levels in the operating room are associated with the development of SSI and to elucidate the extent to which these levels affect the financial burden of surgery. METHODS: Prospective data collection from elective, day-case male patients undergoing elective hernia repairs was undertaken. Patients were included if they were fit and at low risk for SSI. Sound levels during procedures was measured via a decibel meter and correlated with the incidence of SSI. Data analysis was performed with IBM SPSS (IBM, Armonk, NY). RESULTS: Noise levels were substantially greater in patients with SSI from time point of 50 minutes onwards, which correlated to when wound closure was occurring. Additional hospital costs for these patients were £243 per patient based on the National Health Service 2013 reference costing. CONCLUSION: Decreasing ambient noise levels in the operating room may aid in reducing the incidence of SSIs, particularly during closure, and decrease the associated financial costs of this complication.

Effect of tyrosine kinase inhibitors on wound healing and tissue repair: implications for surgery in cancer patients.

Small-molecule tyrosine kinase inhibitors (TKIs) represent a major advance in the treatment of certain forms of cancer. Unexpectedly, however, their use is associated with serious toxic effects on many vital organs and functions. Some of these effects, such as venous thromboembolism, haemorrhage, gastric perforation and a potential for impaired tissue healing, have direct implications for the safety of surgery in cancer patients. A number of currently approved TKIs are suspected or have been reported to impair wound healing but, understandably, there have been no formal pre- or post-approval clinical trials to evaluate the extent of the risk. Consequently, drug labels typically recommend discontinuation of the TKI concerned prior to elective surgery. In patients with gastric perforation, permanent discontinuation is advised. These recommendations, which are based on a precautionary principle, raise a dilemma, especially in patients with TKI-responsive tumours. This review focuses on the labelled potential of these novel antineoplastic agents to impair tissue repair and wound healing, and the evidence concerning the likely mechanisms involved. At present, because of the lack of formal clinical data, there are no evidence-based guidelines on the management of surgery in patients treated with TKIs. There is a need for a central registry of clinical outcomes following emergency surgery in cancer patients receiving TKIs and TKI-naïve matched controls. Analysis of outcomes data from such registries will assist in formulating guidelines on the management of elective surgery in TKI-treated patients. If TKIs are shown to significantly impair wound healing, patients receiving TKI therapy will require special monitoring and a collaborative approach between oncologists and surgeons for individualized reappraisal of the risk/benefit of the TKI treatment.

Osteogenesis imperfecta and congenital diaphragmatic hernia.

Osteogenesis imperfecta and congenital diaphragmatic hernia are both conditions that can occur due to genetic mutation. We present the first case to be reported of a child with both osteogenesis imperfecta and congenital diaphragmatic hernias, showing that the incidence of this presentation may be more than chance.

Facial cutaneous metastasis of colorectal adenocarcinoma.

Facial cutaneous metastasis from carcinoma is a rare and late clinical finding that is associated with disseminated disease and a poor prognosis. Skin metastases predominantly originate from primary tumours of the lung and melanoma. Skin metastases from colon tumours occur in only 4-6.5% of cases of metastatic colorectal cancer. They are most often located on the abdominal skin. We present an unusual case in which a primary colorectal adenocarcinoma metastasised to the face. This cutaneous lesion occurred 4 years after diagnosis of the primary tumour. This case highlights the importance of prompt investigation of new or evolving skin lesions in patients with a history of malignancy. Early detection and initiation of treatment may prevent development of widespread skin metastases and extend life expectancy.

Doctor, I have a sore throat.

Lemierre's syndrome is a rare yet potentially fatal cause of sore throat. Recently published literature suggests an increase in the incidence of this 'forgotten disease', highlighting Lemierre's syndrome as a clinically important differential diagnosis of sore throat. We present a case report of an 85-year-old man who developed a sore throat, which illustrates the re-emergence of Lemierre's syndrome. Reducing the morbidity and mortality from this disease requires a high index of clinical suspicion to ensure prompt diagnosis and initiation of appropriate multidisciplinary management.

Blind drunk.

Purtscher's retinopathy is a haemorrhagic and vaso-occlusive retinal vasculopathy, caused by microembolisation occluding retinal and choroidal arterioles. This leads to retinal haemorrhages and ischaemia. The usual cause is severe trauma. 1 However, a variety of conditions including acute pancreatitis, childbirth, long bone fracture, chest trauma and systemic inflammatory vasculitides may cause similar retinal presentations. 1-4 This highlights Purtscher's retinopathy as a clinically important differential diagnosis of visual loss. We present a case report of a 43-year-old man who was diagnosed with acute pancreatitis. While in hospital he developed sudden onset unilateral loss of vision. This case highlights the need to ensure prompt diagnosis and initiation of appropriate multidisciplinary management.

A lumpy appendix.

A De Garengeot hernia is a rare and interesting presentation of a groin lump, with the diagnosis usually only being identified during surgery. It still presents clinicians with diagnostic and therapeutic challenges, owing to the lack of signs associated with sepsis and so an important case to highlight. We present a case report of a 90-year-old woman who developed a De Garengeot hernia as part of her presentation of bowel obstruction illustrating the importance of careful examination and to ensure prompt diagnosis and initiation of appropriate multidisciplinary management.