Mast cell degranulation is essential for anastomotic healing in well perfused and poorly perfused rat colon.

BACKGROUND: Mast cell degranulation is an important step in early wound healing in the skin however the role of the mast cell in anastomotic healing is less clear. The aim of this study was to investigate the importance of mast cell degranulation in anastomotic healing and to assess whether a promoter of mast cell degranulation could increase anastomotic healing in poorly perfused bowel. METHODS: Fifty Wistar rats were divided into five groups: control, normally perfused bowel with mast cell stabilisation, normally perfused bowel with mast cell degranulation, hypoperfused bowel, and hypoperfused bowel with mast cell degranulation. A colo-colonic anastomosis was formed in each animal. Four d later, following sacrifice, the strength of the anastomosis was assessed in each animal. RESULTS: Mast cell stabilisation reduced anastomotic healing in normally perfused bowel (P < 0.001). Hypoperfused bowel resulted in reduced anastomotic strength (P < 0.001) however the addition of a mast cell degranulating agent increased healing in hypoperfused bowel to levels comparable with control. CONCLUSIONS: Mast cell degranulation is essential for early anastomotic healing. Healing is reduced in hypoperfused bowel but the administration of a mast cell degranulation agent can compensate for the adverse effects of a poor blood supply on anastomotic healing.

Understanding the inflammatory response to cardiac surgery.

The systemic inflammatory response to cardiac surgery is common, and resultant impairment of multiple organ function is generally mild or subclinical due to physiological reserve within organ systems. Unfortunately, the changing profile of patients referred for surgery suggests that the systemic inflammatory response may prominently influence surgical outcome in the future. Older, co-morbid patients with more limited physiological reserve are being referred for complex lengthy procedures, and paediatric surgery has witnessed a shift to earlier complex primary correction or palliation involving long cardiopulmonary bypass times or a period of suboptimal organ perfusion using circulatory arrest or low flow cardiopulmonary bypass. Unique to cardiac surgery is the predictability of the inflammatory response, but prophylactic therapies have not translated into clinical benefit, which the preconditioning phenomenon may address.

The role of endothelial dysfunction in the pathogenesis of impaired diabetic wound healing: a novel therapeutic target?

The global burden of diabetes is attributed to its multiple associated complications including impaired wound healing which can ultimately result in amputation. Peripheral vascular disease, infection, neuropathy and abnormal local cellular and cytokine activity are some of the traditionally cited pathological instigators of defective diabetic wound repair. Despite intensive research and subsequent advances in diabetic wound care technology a single treatment with measurable clinical impact has yet to be determined. The phenomenon of endothelial dysfunction as seen in atherosclerosis and recently identified as a characteristic of diabetic vasculature may contribute to impaired cutaneous healing in this group. Indicators of endothelial dysfunction have been demonstrated in diabetic wounds by a number of investigators. Successful results are being obtained with modifiers of endothelial function in the management of cardiovascular disease. We hypothesise that endothelial dysfunction plays a substantial contributory role in the pathogenesis of wound healing impairment of diabetes and holds potential as a target for therapeutic intervention.

Topical diphenylhydantoin sodium can improve healing in a diabetic incisional animal wound model.

OBJECTIVE: Anecdotally, topical application of diphenylhydantoin sodium (DpH) (phenytoin) has been shown to aid wound healing. We previously reported improved healing following topical infiltration of DpH in a healthy animal wound model. This study evaluates its effect on an incisional wound model in diabetic animals. METHOD: Twenty-five male Sprague-Dawley rats were rendered diabetic by a single intraperitoneal injection of streptozotocin. Two caudal and two cephalad wounds were made on the dorsal surface. A polyvinyl alcohol sponge was placed in a subcutaneous pocket created proximal to both cephalad wounds. Each wound was either treated topically with 10mg DpH in a 200microl carrier or an equal volume of the saline vehicle (control) on the day of wounding and days 3 and 6 post-incision. The animals were sacrificed on day 10. The breaking strength of fresh and fixed wounds was determined by tensiometry, and the hydroxyproline content was determined spectrophotometrically. RESULTS: There was a significant overall increase in both fresh (24%) and fixed (18%) wound-breaking strength of the DpH-treated wounds when compared with the controls (p<0.05). This was associated with an increase in collagen synthesis as indicated by the increased hydroxyproline content in the DpH-infiltrated sponges when compared with the controls. CONCLUSION: Our data suggest that topical DpH improves healing in a diabetic wound model. Topical administration of DpH has the potential to accelerate diabetic wound healing and should be evaluated in human diabetic wounds.

Practice patterns in flexor tendon repair.

BACKGROUND: There is a considerable volume of literature describing new and supposedly superior methods of flexor tendon repair. AIM: The purpose of this study was to assess the flexor tendon techniques currently used in the Republic of Ireland. METHODS: A postal survey was conducted of all consultant plastic surgeons and consultant orthopaedic surgeons who were members of the Irish Hand Surgery Society. RESULTS: The response rate was 90% (27/30). A simple running peripheral suture was used by 73% (P = 0.03) and the Kessler was the core suture of choice for 68% (P = 0.06). A significant number of respondents use non-absorbable suture materials for core (P = 0.0028) and peripheral suture (P < 0.0001). Seventy-seven percent sutured the flexor sheath where possible (P = 0.009). CONCLUSIONS: Notwithstanding the proposed advantages of newer techniques, it is evident from this study that the two-stranded Kessler core and simple running peripheral suture remains the most popular flexor tendon repair, with sheath closure preferred by the majority of respondents.

The evolution of trauma services at Beaumont Hospital.

OBJECTIVE: To review and examine the epidemiology, severity and management of trauma admissions at the national neurosurgical teaching hospital. METHODS: An extensive audit of volume, type and severity of injury and the management requirements of the trauma population admitted to the hospital. RESULTS: The vast majority of severely injured patients were referred from outside the catchment area of the hospital with only 26% being admitted directly through the Emergency Department. As a consequence, 73% of patients arrived out of normal working hours, which posed problems in providing skilled trauma specialists. CONCLUSIONS: The management of patients with serious injury is complex. The large proportion of patients with critical injuries, some of whom were paediatric, highlighted the need for 24 h cover by senior trauma personnel and the provision of radiology and operating facilities to meet their needs. The inclusion of indicators of alterations in innate or adaptive immune responses may improve the predictive power of severity of injury scores.

Matrix metalloproteinases 2 and 9 in human atherosclerotic and non-atherosclerotic cerebral aneurysms.

Matrix metalloproteinases 2 and 9 (MMP 2 and -9) have been implicated in the pathogenesis of atherosclerosis and aneurysm formation. The goal of the study was to establish the role of these metalloproteinases in both human atherosclerotic and non-atherosclerotic cerebral aneurysms. Eleven cerebral aneurysms (four atherosclerotic, seven non-atherosclerotic) were immunohistochemically stained for MMP 2 and -9. As controls, atherosclerotic and normal Circle of Willis arteries were similarly immunostained. All specimens were retrieved at autopsy and were paraffin-embedded. In order to evaluate the real MMP 2 and -9 activities, gelatin zymography was also performed in only two available specimens of non-atherosclerotic intracranial aneurysms, because of the relative unavailability of fresh intracranial aneurysm tissue (i.e. reluctance to excise the aneurysm fundus at surgery). Our data establish that MMP 2 and -9 were expressed minimally or not at all in normal Circle of Willis arteries but were strongly expressed in medial smooth muscle cells of atherosclerotic Circle of Willis arteries. In the aneurysm group, both MMP 2 and -9 were strongly expressed in the atherosclerotic aneurysms, but MMP 2 alone was detected in the non-atherosclerotic aneurysms. Zymography revealed a weak enzyme activity correlating to MMP 9 standard recombinant protein. MMP 2 activity was not demonstrated in either specimen. This study shows that the expression of MMP 2 and -9 is associated with atherosclerosis, be it in aneurysmal or non-aneurysmal cerebral vessels but MMP 2 appears to be specifically expressed in aneurysms devoid of atherosclerosis perhaps suggesting a pathogenic role for MMP 2 in the alteration of the extracellular matrix of cerebral arteries during aneurysm formation.

Co-immunotherapy with interleukin-2 and taurolidine for progressive metastatic melanoma.

BACKGROUND: Recombinant interleukin-2(rIL-2) therapy in metastatic melanoma is limited by toxicities, particularly vascular leak syndrome(VLS). Taurolidine potentiates the anti-neoplastic effects of IL-2 while reducing its associated endothelial cell dysfunction in experimental settings. We hypothesized that co-administration of rIL-2 with taurolidine could enhance tolerability without weakening effectiveness. METHODS: Eleven patients with progressive metastatic melanoma received high-dose rIL-2 with co-infusion of taurolidine. Patients were monitored for the development of toxicities and evidence of response. RESULTS: Ten patients tolerated twenty-nine courses of high-dose rIL-2 without dose-reduction. Most toxicities were low-grade. No patient developed VLS. Seven patients died from disease progression. Two had complete clinical and radiological responses to treatment. Two patients remain alive despite evidence of disease progression a mean of 17.5 months after diagnosing metastatic disease. CONCLUSION: Co-administration of taurolidine with high-dose rIL-2 in stage IV melanoma patients appears to greatly enhance the tolerability of this regime without diminishing its therapeutic value.

Taurine and vitamin C modify monocyte and endothelial dysfunction in young smokers.

BACKGROUND: Endothelial dysfunction initiated by monocyte-endothelial interactions has previously been observed in many vasculopathies, including chronic cigarette smoking. Taurine, a semiessential amino acid, and vitamin C, a naturally occurring antioxidant, have previously been shown to have endothelial protective effects when exposed to proinflammatory insults. Therefore, we hypothesized that taurine and vitamin C would restore endothelial function in young smokers by modifying monocyte-endothelial interactions. METHODS AND RESULTS: Endothelial-dependent vasodilatation was assessed in vivo using duplex ultrasonography, and monocyte-endothelial interactions were assessed in vitro using endothelial cell culture (human umbilical vein endothelial cells [HUVECs]) with monocyte-conditioned medium (MCM). Endothelial-dependent vasodilatation was significantly impaired in young smokers compared with nonsmokers. Pretreatment of young smokers for 5 days with 2 g/d vitamin C and, more significantly, with 1.5 g/d taurine attenuated this response. MCM taken from smokers impaired the release of nitric oxide and increased the levels of endothelin-1 release from HUVECs. When HUVECs were cultured with MCM from smokers who had been treated with taurine, the levels of nitric oxide and endothelin-1 returned toward control levels. This was attributed to an upregulation in endothelial nitric oxide synthase expression. CONCLUSIONS: These observations suggest that taurine supplementation has a beneficial impact on macrovascular endothelial function, and an investigation of its effect on altered endothelial function in dyslipidemic states is warranted.

The role of hereditary hemochromatosis in aseptic loosening following primary total hip arthroplasty.

Hereditary hemochromatosis (HH) results in increased iron absorption and subsequent deposition in tissue. This condition occurs predominantly in individuals of Northern European and Celtic origin with Ireland having one of the highest allele frequencies in the world. This study examines the hypothesis that homozygosity for either the C282Y or H63D mutations in the HFE gene may be associated with aseptic loosening following total hip arthroplasty (THA). Two groups of individuals were screened for the C282Y and H63D mutations associated with HH. Group 1 were individuals who had undergone primary hip arthroplasty and group 2 were individuals who had undergone revision hip arthroplasty for aseptic loosening. Exclusion criteria included rheumatoid or other inflammatory arthropathies and revision due to causes other than aseptic loosening. Significantly more patients in the revision THA group were homozygous for the C282Y genotype (P = 0.014). Aseptic loosening occurred earlier in these patients (P = 0.009), in particular in the patients who had clinical signs of hemochromatosis. No association was seen with the H63D mutation and revision THA. The incidence of HH in the group of primary THA patients was no higher than the background incidence. Patients who require primary THA and who are homozygous for the C282Y mutation have an increased risk of developing aseptic loosening, leading to revision THA. Moreover C282Y homozygosity appears to be associated with earlier aseptic loosening than in individuals without the C282Y mutation.

Thrombomodulin: tumour biology and prognostic implications.

BACKGROUND: Thrombomodulin (TM) is an endothelial receptor that exerts anti-coagulant, anti-fibrinolytic, and anti-inflammatory activity by inhibiting thrombin and cellular adhesion. There is growing evidence that TM plays a role in tumour behaviour. METHODS: The electronic literature (1966-2004) was reviewed with a specific focus on tumour biology. RESULTS: TM is expressed on both the endothelium and tumour cells in several cancers. Loss of expression denotes a more malignant profile with poorer prognosis. Loss of TM is mediated by hypoxia, endotoxin, and various cytokines, while up-regulation can be achieved by pharmacological manipulation (e.g. pentoxyfylline and statins). CONCLUSION: Originally described as an endothelial anticoagulant, TM plays a key role in tumour biology and prognostics, and provides a potential therapeutic target in impeding cancer spread.

Role of endotoxin in mononuclear phagocyte-mediated inflammatory responses.

Lipopolysaccharide (LPS), which is derived from the cell wall of gram-negative and some gram-positive bacteria, plays a major role is the pathogenesis of septic shock. Initiation of these responses depends on LPS interaction with a number of immune cells, not least the mononuclear phagocyte (MP). Mononuclear phagocytes bind the LPS/lipopolysaccharide-binding protein complex through the CD14 receptor and thus mediate the release of a wide range of inflammatory mediators. Release of these mediators is teleologically beneficial but under certain circumstances may be detrimental, resulting in the systemic inflammatory response syndrome. The development of this syndrome is not clearly understood but appears, in part, to be dependent on the ability of the host to respond to these mediators. This review evaluates the mechanisms of LPS-MP interaction and the therapeutic strategies aimed at inhibiting this interaction.

Taurolidine, an antilipopolysaccharide agent, has immunoregulatory properties that are mediated by the amino acid taurine.

Taurolidine has bactericidal and antilipopolysaccharide properties. It is broken down into the amino acid taurine, which has been shown to modulate intracellular calcium activity, a critical component in the priming and activation of macrophages and polymorphonuclear leukocytes. We hypothesized that taurolidine may function to enhance immune activity in these cells. The aim of this study was to investigate the immunological effects of taurolidine and correlate findings with survival after a septic challenge in a murine model. Study 1: CD-1 mice underwent cecal ligation and puncture, were randomized to receive taurolidine (200 mg/kg body weight/i.p.) or saline control, and studied for end point survival. Study 2: CD-1 mice were randomized to receive taurolidine (200 mg/kg body weight/i.p.) or saline control. Peritoneal macrophages (PM luminal diameters) were assessed for O2-, NO, tumor necrosis factor-alpha (TNF-alpha), CD11b, phagocytosis, and PMN influx. O2-, TNF-alpha, CD11b expression, and phagocytosis were significantly increased in the taurolidine group. Study 3: PM luminal diameters were cultured in vitro +/- 0.5 mg/ml taurolidine and PM luminal diameter antimicrobial function assessed (O2-, NO, TNF-alpha, and phagocytosis). O2-, TNF-alpha, and phagocytosis were significantly increased, whereas NO was reduced. Study 4: PM luminal diameters were also cultured with taurine (0.5 mg/ml). Similar increase in O2-, TNF-alpha, and phagocytosis were identified. Intracellular PM luminal diameter [Ca2+] was also assessed and increases in free, unbound intracellular [Ca2+] occurred after taurine culture. Thus, in addition to its bactericidal and antilipopolysaccharide activity, taurolidine primes PM luminal diameters for enhanced antimicrobial activity and these effects appear mediated by the amino acid taurine.

Mechanisms involved in sodium arsenite-induced apoptosis of human neutrophils.

Apoptosis is a distinct mechanism by which eukaryotic cells die. Factors governing the induction of polymorphonuclear leukocyte (PMN) apoptosis should be important in understanding resolution of acute inflammation. The mechanisms for induction of PMN apoptosis remain uncertain; however, oxidative stress has been suggested. The aims of this study were to determine whether reactive oxygen intermediates play a role in PMN apoptosis and to investigate inhibition of this process by selective use of antioxidants. PMN were isolated from 10 healthy volunteers. PMN (1 x 10(6) PMN/mL) were cultured in 40, 80, and 160 microM of arsenite for 2, 6, 12, 18, and 24 h. Apoptosis was assessed qualitatively by morphology and gel electrophoresis and quantitatively by CD16 receptor expression and propidium iodide DNA staining. There was a significant (P < 0.05) increase in the rate of apoptosis on incubation with arsenite (80 and 160 microM). To investigate the mechanism of this process, intracellular respiratory burst activity was measured following arsenite culture. We found that arsenite-induced PMN apoptosis correlated with an increase in intracellular respiratory burst. To further investigate the role of oxidative injury in inducing apoptosis, the antioxidants catalase, dimethyl sulfoxide (DMSO), glutathione (GSH), N-acetylcysteine (NAC), and taurine were investigated and we demonstrated that GSH, NAC, and taurine were significantly protective against arsenite-induced apoptosis. However, catalase and DMSO failed to induce protection. This study demonstrates that arsenite induces PMN apoptosis through an oxygen-dependent mechanism that can be prevented through selective antioxidants.

Anaplastic (undifferentiated) thyroid cancer: improved insight and therapeutic strategy into a highly aggressive disease.

BACKGROUND: This review article discusses the clinical and diagnostic implications of anaplastic thyroid cancer, recognizing the aggressive nature of the disease and extensive disease progression upon diagnosis. Standard treatment strategies (surgical, chemotherapy, radiation) are discussed, comparing adjuvant and neo-adjuvant regimens and the emergence of tumour resistance with expression of multidrug resistance pumps. We question the pathological evolution of anaplasia as a 'de novo' disease or a post malignant transformation or dedifferentiation and the therapeutic implications of p53 mutation. Future treatment options are reviewed with an emphasis on specific molecular targets responsible for the neoplastic phenotype. METHOD: An electronic search on Medline and Pubmed was performed under 'anaplastic thyroid carcinoma', 'anaplastic thyroid carcinogenesis', 'anaplastic thyroid carcinoma treatment reviews'. Relevant papers were systematically reviewed from 1965 to present.

Fractured penis: a clinical misnomer!

BACKGROUND: A 'fracture' of the penis refers to a tear in the deep layer of the tunica albuginea (Buck's fascia) and may be associated with a urethral injury. AIM: To describe a classical case of a 'fractured' penis and discuss the management options. METHOD: A case report of a 30-year-old man presented with a 'fractured' penis and who underwent surgical intervention. CONCLUSION: This rare occurrence represents a urological emergency and necessitates imaging and repair of the cavernosal defect in order to prevent poor functional outcome.

Twitter expands the reach and engagement of a national scientific meeting: the Irish Society of Urology.

BACKGROUND: Social media is the interaction among people in which they create, share or exchange information and ideas in virtual communities and web-based networks. This year, the Irish Society of Urology (ISU) expanded its involvement in social media with a preregistered Twitter hashtag (#ISU14) for the annual meeting. AIM: The aim of this study was to highlight the use of Twitter at an annual national meeting held in 2014. METHODS: The Symplur healthcare analytics website was used to prospectively examine traffic related to the 2014 ISU Annual Meeting. This feature was used to generate statistics for the number of impressions, unique tweets (excluding retweets) and distinct contributors who used the indexing hashtag #ISU14. Individual tweets were assessed using the conference hashtag on the Twitter website. RESULTS: The total number of attendees at the conference was 119, and 99 individuals participated in Twitter using the conference hashtag (#ISU14). 31 % of attendees participated in tweeting at the conference. Over the course of the conference, a total of 798 unique tweets were generated, creating over 665,000 impressions in cyberspace. 590 (73.9 %) tweets were generated from attendees at the conference, while 26.1 % of tweets were from virtual followers. 702 (87.9 %) tweets were from urologists and 439 (55 %) tweets were of scientific nature. Tweet activity peaked during the guest lectures on both days. CONCLUSION: Twitter use at the ISU has been shown to facilitate interaction between delegates and allows users to follow as well as participate from afar.

Thermotolerance attenuates ischemia-reperfusion induced renal injury and increased expression of ICAM-1.

Thermotolerance describes the process in which hyperthermia induces a transient resistance of the stressed cells to subsequent episodes of oxidative stress. The aims of this study were first, to assess the effect of ischemia-reperfusion (IR) injury on renal function and the expression of the ICAM-1 receptor and MHC antigens, and second, to evaluate the protective effects of thermotolerance on IR induced renal injury and its potential for decreasing allograft rejection, by decreasing alloantigen expression. Sprague-Dawley rats were randomized into three groups: control, IR, and hyperthermia + IR (HIR) (n=8 per group). Thermotolerance was induced 18 hr prior to IR by increasing the core body temperature to 41 degrees C+/-0.5 degrees C for 15 min. After left uninephrectomy, IR was induced by clamping the right renal pedicle for 45 min, followed by 2 hr reperfusion. Myeloperoxidase (MPO) activity was used as an indicator of renal neutrophil influx. Kidney edema was assessed using the weight difference between left and right kidneys. Renal function was evaluated by measuring serum creatinine and urea 2 hr following clamp removal. Immunocytochemistry was used to measure expression of ICAM-1 and MHC antigen. Renal function was significantly impaired by IR with serum creatinine and urea levels of 131.5+/-5.01 microM and 11.2+/-0.71 mM, respectively, compared with controls of 67.9+/-5.11 microM and 8.1+/-0.36 mM, P<0.005 in both cases. Renal function was preserved in the HIR group, serum creatinine (84.8+/-8.58 microM) and urea (9.0+/-0.52 mM) were comparable to that of controls. Renal endothelium was activated in the IR group compared with controls, with increased ICAM-1, and tubular epithelium showed increased class II MHC expression. This up-regulation was prevented by prior induction of thermotolerance. Endothelial permeability was increased in the IR group with MPO activity of 0.8+/-0.08 units/g tissue--twice that of control levels P<0.05--and a marked increase in organ edema. Thermotolerance preserved endothelial barrier function. Thermotolerance may prevent IR injury by preventing endothelium activation and has the potential to modify allograft rejection by decreasing expression of ICAM-1, an important T cell receptor, and class II MHC.

Bacterial ingestion, tumor necrosis factor-alpha, and heat induce programmed cell death in activated neutrophils.

Resolution of acute inflammation requires the removal of sequestered neutrophils (PMN) from the inflammatory site by apoptosis and ingestion by tissue macrophages; however, sequestered PMN are prevented from undergoing programmed cell death by some of the mediators of the acute inflammatory process, including lipopolysaccharide (LPS), granulocyte-macrophage colony-stimulating factor, and interleukin 2. This delay in apoptosis could lead to necrosis resulting in tissue damage. Tumor necrosis factor-alpha (TNF-alpha), Escherichia coli ingestion resulting in a respiratory burst, and heat have been shown to induce PMN apoptosis. The effects of TNF-alpha, E. coli ingestion, and heat shock on the one hand and LPS on the other, on PMN apoptosis are unknown. The aim of this study was to determine if TNF-alpha, E. coli ingestion, and heat shock, which have been shown to induce PMN apoptosis, could override the delay in apoptosis associated with LPS. PMN (10(6)) isolated from 10 healthy volunteers were cultured in either medium alone or PMN cultured with LPS (10 ng/mL/1 h). PMN activation was assessed subsequently by phagocytosis of E. coli and CD11b expression. PMN were then further studied under four culture conditions: medium alone, TNF-alpha (100 U/mL), E. coli (1:25, PMN:E. coli), and heat shock (42 degrees C for 45 min). Apoptosis was assessed over time by propidium iodide staining of DNA and Fc gamma RIII receptor expression. The results demonstrate, for the first time, that the mechanisms by which LPS delays PMN apoptosis are overridden by the mechanisms by which TNF-alpha, E. coli ingestion, and heat shock induce programmed cell death. Factors regulating PMN apoptosis have an important role to play in the resolution of acute inflammation. Identification of these factors and their interaction have important implications for the development of therapeutic strategies aimed at modulating the acute inflammatory response.