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Biomedical subjects

H P Redmond

Publications and source records attributed to H P Redmond.

At least 19 recordsLinked to original sources
PubMed2007

Mobilization of endothelial precursor cells: systemic vascular response to musculoskeletal trauma.

Postnatal vasculogenesis, the process by which vascular committed bone marrow stem cells or endothelial precursor cells (EPC) migrate, differentiate, and incorporate into the nacent endothelium contributing to physiological and pathological neovascularization, has stimulated much interest. Its contribution to tumor nonvascularization, wound healing, and revascularization associated with skeletal and cardiac muscles ischaemia is established. We evaluated the mobilization of EPCs in response to musculoskeletal trauma. Blood from patients (n = 15) following AO type 42a1 closed diaphyseal tibial fractures was analyzed for CD34 and AC133 cell surface marker expression. Immunomagnetically enriched CD34+ mononuclear cell (MNC(CD34+)) populations were cultured and examined for phenotypic and functional vascular endothelial differentiation. Circulating MNC(CD34+) levels increased sevenfold by day 3 postinjury. Circulating MNC(AC133+) increased 2.5-fold. Enriched MNC(CD34+) populations from day 3 samples in culture exhibited cell cluster formation with sprouting spindles. These cells bound UEA-1 and incorporated fluorescent DiI-Ac-LDL intracellularily. Our findings suggest a systemic provascular response is initiated in response to musculoskeletal trauma. Its therapeutic manipulation may have implications for the potential enhancement of fracture healing.

Adult↗
PubMed2006

Laparoscopic surgery protects against the oncologic adverse effects of open surgery by attenuating endothelial progenitor cell mobilization.

BACKGROUND: Endothelial progenitor cells (EPCs) derived from bone marrow incorporate into foci of neovascularization to propagate tumor growth. These cells are mobilized in response to surgical injury. Laparoscopic surgery may protect against the oncologic adverse effects of open surgical tumor excision, and this may be related to attenuated mobilization of EPCs. METHODS: For this study, 132 C57BL/6 mice were randomized to standardized laparotomy, laparoscopy, or control groups. The animals were killed at 6, 24, 48, and 72 h. Femur bone marrow and peripheral blood were harvested. Bone marrow EPCs were detected by flow cytometric dual staining for the stem cell antigen-1/cKit phenotype. Circulating EPCs were characterized in blood by vascular endothelial growth factor receptor 2 positive/macrophage activating complement-1 negative staining. Separately, 12 C57/bl6 mice bearing 3LL Lewis lung tumors 12 days after laparotomy or laparoscopy had their tumors excised and examined for endothelial cell expression (marker P1H12). RESULTS: Laparoscopy decreased circulating EPCs and bone-marrow EPC levels, as compared with laparotomy, at all time points. Bone marrow EPC levels were 2.95% +/- 0.32% after laparotomy, as compared with 0.65 +/- 0.21 in the laparoscopy group (p < 0.05). The circulating EPC level in the laparotomy group was 35.2% +/- 6% of cells, as compared with 3.1% +/- 0.2% in the laparoscopy group (p < 0.05). In homogenized tumors, the percentage of P1H12 expression among laparoscopy-treated animals was 22.1% +/- 4.2%, as compared with 39% +/- 8% in the laparotomy group (p < 0.05). CONCLUSION: Laparoscopy decreased EPC levels in both bone marrow and circulation, resulting in decreased tumor endothelial cell burden. This may represent a novel mechanism by which laparoscopy protects against the oncologic adverse effects of open surgical tumor excision.

Animals↗
PubMed2006

Exploitation of the Toll-like receptor system in cancer: a doubled-edged sword?

The toll-like receptor (TLR) system constitutes a pylogenetically ancient, evolutionary conserved, archetypal pattern recognition system, which underpins pathogen recognition by and activation of the immune system. Toll-like receptor agonists have long been used as immunoadjuvants in anti cancer immunotherapy. However, TLRs are increasingly implicated in human disease pathogenesis and an expanding body of both clinical and experimental evidence suggests that the neoplastic process may subvert TLR signalling pathways to advance cancer progression. Recent discoveries in the TLR system open a multitude of potential therapeutic avenues. Extrapolation of such TLR system manipulations to a clinical oncological setting demands care to prevent potentially deleterious activation of TLR-mediated survival pathways. Thus, the TLR system is a double-edge sword, which needs to be carefully wielded in the setting of neoplastic disease.

Disease Progression↗
PubMed2006

Cancer surgery: risks and opportunities.

In the recent past, several papers have pointed to the possibility that tumour removal generates a permissive environment in which tumour growth is potentiated. This phenomenon has been coined "perioperative tumour growth" and whilst it represents a departure in terms of our attitude to the surgical process, this concept was first hinted at by Paget(1) himself. Despite this, the time interval immediately before and after cancer surgery (i.e. the perioperative period) remains an underutilised interval during which chemotherapeutic regimens are rarely implemented. Herein, we present a summarised review of the literature that supports the concept that tumour removal may potentiate the growth of residual neoplastic disease. We also outline current knowledge regarding underlying mechanisms and in this manner highlight potential therapeutic entry points. Finally, we emphasise the urgent need for trials of agents that could protect patients against the harmful host-tumour interactions that may occur during the perioperative period.

Humans↗
PubMed2006

Rapid intraoperative parathyroid hormone assay--more than just a comfort measure.

BACKGROUND: Minimally invasive radio-guided parathyroidectomy (MIRP) has been embraced as an acceptable therapeutic approach to primary hyperparathyroidism. Preoperative sestamibi scanning has facilitated this technique. Here we evaluate the addition of a rapid intraoperative parathyroid hormone (iPTH) assay for patients undergoing MIRP. METHODS: A series of 51 patients underwent sestamibi localization of parathyroid glands followed by MIRP for primary hyperparathyroidism. Using peripheral venous samples, iPTH levels were measured prior to gland excision, as well as post-excision at 5, 10, and 15 minutes, taking a 50% reduction in iPTH level as indicative of complete excision. Next, changes in serum iPTH were compared with preoperative and postoperative changes in serum calcium, as well as levels of intraoperative ex-vivo radiation counts taken by hand-held gamma probe. RESULTS: In this series, a drop of greater than 50% in iPTH levels was observed in 94% of patients (n=48). Moreover, a significant drop in iPTH occurred within 10 minutes of excision in the majority (n=42) of cases (P<0.004). Changes in iPTH were comparable with the therapeutic reduction in calcium levels, as well as with the change in intraoperative ex-vivo gamma counts. CONCLUSIONS: This study demonstrates that the addition of an iPTH assay to MIRP provides a quick and reliable intraoperative diagnostic modality in confirming correct adenoma removal. Moreover, it precludes the requirement of frozen section.

Adult↗
PubMed2006

The immunological consequences of injury.

Immediate and early trauma death rates are determined by "first hits" such as hypoxia, hypotension and organ injury, while late mortality correlates closely with "second hits" such as infection. An imbalance between the early systemic inflammatory response (SIRS), and the later compensatory counter-inflammatory response (CARS), is considered to be responsible for much post-traumatic morbidity and mortality. From a clinical perspective, this remains a significant healthcare problem, which has stimulated decades of experimental and clinical research aimed at understanding the functional effects of injury on the immune system. This review describes the impact of injury on the innate and adaptive immune systems. Though it is worth noting that the features of the immune response to injury overlap in many areas with immune dysregulation in sepsis, we attempt here to elucidate the mechanism by which injury predisposes to infection rather than to describe the alterations in host immunity consequent to established sepsis.

Antibody Formation↗
PubMed2006

Sentinel lymph node biopsy: is it possible to reduce false negative rates by excluding patients with nodular melanoma?

OBJECTIVE: The aim of this study was to review the outcome of sentinel lymph node biopsy (SLNB) in patients with melanoma and to delineate whether patients with nodular melanoma are more likely to develop nodal recurrence despite negative SLNB. METHODS: Consecutive patients with cutaneous melanoma undergoing SLNB were identified from a departmental database between 1997 and 2005. Factors including demographic data, site, histological subtype, depth and outcome were examined. RESULTS: Of 131 patients, 103 were node negative and eligible for study. The median age was 53 (16-82) years with 46 patients being male (45%) and 57 female (55%). Primary melanoma sites included lower limb (49; 48%), upper limb (29; 28%), head (12; 11%), trunk (7; 7%) and back (6; 6%). The median Breslow thickness was 2mm. Superficial spreading accounted for 43% of melanoma with nodular accounting for 42%. Median follow-up was 40 (3-90) months. Of 20 relapses, seven recurred in the same nodal basin, three were satellite recurrences, one recurred with both satellite and nodal lesions simultaneously, and nine experienced haematogenous spread. Of the eight patients who developed recurrence in the same nodal basin, four were of nodular histological subtype (p=NS). All of the three patients with satellite lesions had nodular melanoma histologically (p=0.02). When nodal and satellite recurrences were combined, eight of 11 were histologically nodular (p=0.01). CONCLUSIONS: This study indicates that lymphatic recurrence occurs more often in SLNB negative patients with nodular melanoma. Further evaluation of the inclusion criteria for sentinel node biopsy is warranted.

Adolescent↗
PubMed2006

Treatment of sepsis: current status of clinical immunotherapy.

While antibiotics address the root cause of sepsis--that of pathogen infection--they fail to provide an adequate cure for the condition. Currently, 30% to 50% of septic patients die, and this figure is likely to increase in line with the proliferation of multi-drug resistant bacteria. With an increased understanding of the immune response, it has been proposed that modulation of this defence mechanism offers the best hope of cure. Many entry-points in the immune system have been identified and targeted therapies have been developed,but why are these not in routine clinical practice? This review examines the latest evidence for the use of immuno-modulating drugs, obtained from human clinical trials. We discuss cytokine-based therapies, steroids and anti-coagulants. Finally, consideration is given as to why successful therapies in the laboratory, and in vivo models, do not automatically translate into clinical benefit

Animals↗
PubMed2005

Regulatory T-cells and autoimmunity.

Approximately 20% of the population is affected by autoimmune or inflammatory diseases mediated by an abnormal immune response. A characteristic feature of autoimmune disease is the selective targeting of a single cell type, organ or tissue by certain populations of autoreactive T-cells. Examples of such diseases include rheumatoid arthritis, insulin-dependent diabetes mellitus, and systemic lupus erythematosus (SLE), all of which are characterized by chronic inflammation, tissue destruction and target organ malfunction. Although strong evidence links most autoimmune diseases to specific genes, considerable controversy prevails regarding the role of regulatory T-cell populations in the disease process. These cells are now also believed to play a key role in mediating transplantation tolerance and inhibiting the induction of tumor immunity. Though the concept of therapeutic immune regulation aimed at treating autoimmune pathology has been validated in many animal models, the development of strategies for the treatment of human autoimmune disorders remains in its infancy. The main obstacles to this include the conflicting findings of different model systems, as well as the contrasting functions of regulatory T-cells and cytokines involved in the development of such disorders. This review examines the role of regulatory T-cells in the pathogenesis of autoimmunity and describes the therapeutic potential of these cells for the prevention of immune-mediated pathologies in the future. Although much remains to be learned about such pathologies, a clearer understanding of the mechanisms by which regulatory T-cells function will undoubtedly lead to exciting new possibilities for immunotherapeutics.

Animals↗
PubMed2005

Activated protein C attenuates acute ischaemia reperfusion injury in skeletal muscle.

Activated protein C (APC) is an endogenous anti-coagulant with anti-inflammatory properties. The purpose of the present study was to evaluate the effects of activated protein C in the setting of skeletal muscle ischaemia reperfusion injury (IRI). IRI was induced in rats by applying rubber bands above the levels of the greater trochanters bilaterally for a period of 2h followed by 12h reperfusion. Treatment groups received either equal volumes of normal saline or activated protein C prior to tourniquet release. Following 12h reperfusion, muscle function was assessed electrophysiologically by electrical field stimulation. The animals were then sacrificed and skeletal muscle harvested for evaluation. Activated protein C significantly attenuated skeletal muscle reperfusion injury as shown by reduced myeloperoxidase content, wet to dry ratio and electrical properties of skeletal muscle. Further in vitro work was carried out on neutrophils isolated from healthy volunteers to determine the direct effect of APC on neutrophil function. The effects of APC on TNF-alpha stimulated neutrophils were examined by measuring CD18 expression as well as reactive oxygen species generation. The in vitro work demonstrated a reduction in CD18 expression and reactive oxygen species generation. We conclude that activated protein C may have a protective role in the setting of skeletal muscle ischaemia reperfusion injury and that this is in part mediated by a direct inhibitory effect on neutrophil activation.

Acute Disease↗
PubMed2005

Intravenous antioxidant modulation of end-organ damage in L-arginine-induced experimental acute pancreatitis.

BACKGROUND: Oxidative stress mediates acinar injury in experimental acute pancreatitis (AP) and antioxidants are depleted in human AP. This study tests the hypothesis that exogenous antioxidant supplementation ameliorates experimental AP. METHODS: Male Sprague-Dawley rats were randomly allocated to 1 of 4 groups (n = 5/group) and sacrificed at 72 h. AP was induced by 250 mg per 100 g body weight of 20% L-arginine hydrochloride in 0.15 mol/l sodium chloride. Group allocations were: group 1 (control) no intervention; group 2 AP; group 3 early multiple antioxidant (MAOX) intervention comprising 15 microg/kg selenium, 30 microg/kg ascorbate and 300 mg/kg N-acetylcysteine given at 6 and 30 h and group 4 the MAOX combination above given at 24 and 48 h. Endpoints were: serum amylase, antioxidant levels, bronchoalveolar lavage (BAL) protein and lung myeloperoxidase (MPO) activity and histological assessment of pancreatic injury. RESULTS: L-arginine induced AP characterised by oedema, neutrophil infiltration, acinar cell degranulation and elevated serum amylase. Early MAOX reduced pulmonary MPO and BAL protein and reduced acinar swelling, degranulation and pancreatic parenchymal infiltration by inflammatory cells. These features were absent when intervention was delayed. CONCLUSION: In this model, early but not late antioxidant intervention ameliorates pancreatic and pulmonary injury.

Acetylcysteine↗
PubMed2005

Provider volume and outcomes for oncological procedures.

BACKGROUND: Oncological procedures may have better outcomes if performed by high-volume providers. METHODS: A review of the English language literature incorporating searches of the Medline, Embase and Cochrane collaboration databases was performed. Studies were included if they involved a patient cohort from 1984 onwards, were community or population based, and assessed health outcome as a dependent variable and volume as an independent variable. The studies were also scored quantifiably to assess generalizability with respect to any observed volume-outcome relationship and analysed according to organ system; numbers needed to treat were estimated where possible. RESULTS: Sixty-eight relevant studies were identified and a total of 41 were included, of which 13 were based on clinical data. All showed either an inverse relationship, of variable magnitude, between provider volume and mortality, or no volume-outcome effect. All but two clinical reports revealed a statistically significant positive relationship between volume and outcome; none demonstrated the opposite. CONCLUSION: High-volume providers have a significantly better outcome for complex cancer surgery, specifically for pancreatectomy, oesphagectomy, gastrectomy and rectal resection.

Health Facility Size↗
PubMed2005

The impact of bone marrow micrometastases on metastatic disease-free survival in patients with colorectal carcinoma.

AIMS: The biological relevance of bone marrow micrometastases (BMM) in colorectal cancer remains unknown. Here, we investigate their nature by examining the impact of the presence of BMM on metastatic disease-free survival in a cohort of patients with this disease. METHODS: Sixty-three consecutive patients undergoing surgery for colorectal cancer of any stage were studied after approval of the study protocol by the local ethics committee and with full individual informed consent. All had bilateral iliac crest bone marrow aspirates prior to operation. Aspirates were then examined for the presence of aberrant cytokeratin-18-positive cells by a blinded observer using both flow cytometric and APAAP immunohistochemical techniques. RESULTS: Mean follow-up after surgery was 4.6 years (range 1.9-6.9) for those without hepatic metastases at diagnosis. Seven of 34 patients with Dukes' stage A or B developed metastatic disease after a mean interval of 4.7 years (range 3.8-6.8). However, only 2 of these patients demonstrated BMM at the time of surgery. Nine of 15 patients with Dukes' C carcinoma at the time of surgery subsequently developed metastases after a mean interval of 4.4 years (range 1.9-6.9). Again, only two of these patients had BMM detectable initially. In only three of the 14 patients known to have metastases at the time of operation (i.e. Dukes''D' disease) were BMM found. CONCLUSION: The presence of BMM as detected by this methodology was not predictive of tumour recurrence or metastasis. This study does not support the consideration of adjuvant therapy based on the presence of BMM at a single pre-operative time point in patients with colorectal cancer.

Adult↗
PubMed2005

A characterization of anaerobic colonization and associated mucosal adaptations in the undiseased ileal pouch.

INTRODUCTION: The resolution of pouchitis with metronidazole points to an anaerobic aetiology. Pouchitis is mainly seen in patients with ulcerative colitis pouches (UCP). We have recently found that sulphate reducing bacteria (SRB), a species of strict anaerobe, colonize UCP exclusively. Herein, we aimed to correlate levels of different bacterial species (including SRB) with mucosal inflammation and morphology. METHODS: Following ethical approval, fresh faecal samples and mucosal biopsies were taken from 9 patients with UCP and 5 patients with familial adenomatous polyposis pouches (FAPP). For the purposes of comparison, faecal samples and mucosal biopsies were also taken from the stomas of 7 of the 9 patients with UC (UCS). Colonization by four types of strict anaerobes (SRB, Clostridium perfringens, Bifidobacteria and Bacteroides) as well as by three types of facultative anaerobes (Enterococci, Coliforms and Lactobacilli) was evaluated. Inflammatory scores and mucosal morphology were assessed histologically in a blinded fashion by a pathologist. RESULTS: In general, strict anaerobes predominated over facultative in the UCP (P = 0.041). SRB were present in UCP exclusively. Even after exclusion of SRB from total bacterial counts, strict anaerobes still predominated. In the UCS, facultative anaerobes predominated. Strict and facultative anaerobes were present at similar levels in the FAPP. Enterococci were present at significantly reduced levels in the UCP when compared with the UCS (P = 0.031). When levels of SRB and other anaerobic species were individually correlated with mucosal inflammation and morphology, no trends were observed. CONCLUSION: We have previously identified that SRB exclusively colonize UCP. In addition we have now identified a novel increase in the strict/facultative anaerobic ratio within the UCP compared to UCS. These stark differences in bacterial colonization, however, appear to have limited impact on mucosal inflammation or morphology.

Adenomatous Polyposis Coli↗
PubMed2005

Continuous crossover femoropopliteal bypass in a 68-year-old gentleman with rest pain.

Patients who have had multiple previous attempts at limb salvaging surgery frequently go on to have an amputation. This, however, results both in psychological perturbation for the patient and high rehabilitation costs for the community. Successful limb salvage surgery therefore has an important role in vascular surgery. We describe the management of a patient with critical limb ischemia that had previously undergone multiple limb salvage procedures and whose limb was saved by the use of a continuous femoropopliteal crossover bypass graft. The patient, who may have been deemed by some as a candidate for amputation, has full use of his limb 6 months after surgery with ankle brachial pressure index readings of 0.6. Continuous femoropopliteal crossover bypass grafting is a poorly described surgical technique that may be appropriate in a subgroup of patients and may allow salvage of a limb that otherwise may have been deemed fit for amputation.

Aged↗
PubMed2004

Perioperative topical nitrate and sphincter function in patients undergoing transanal stapled anastomosis: a randomized, placebo-controlled, double-blinded trial.

PURPOSE: The use of transanal stapling devices may impair continence because of digital dilatation and/or instrumentation. This study assessed the effect of pharmacological dilatation of the sphincter prior to stapler insertion. METHODS: A randomized, placebo-controlled, double-blinded study of 60 patients undergoing transanal stapled anastomosis was undertaken. Consenting patients were randomly assigned to receive a single intraoperative dose of topical 0.2 percent nitroglycerin (glyceryl trinitrate) ointment or nitroglycerin-free placebo. All patients were assessed preoperatively and postoperatively by clinical methods (Wexner incontinence scores and examination), anorectal manometry by a station pull-through technique, and endoanal ultrasonography. RESULTS: Intraoperative mean (+/-SEM) resting pressures (mmHg) were significantly reduced by nitroglycerin compared with prenitroglycerin levels (9.9 +/- 0.9 vs. 50.5 +/- 2.7; P = 0.002) or controls (56.0 +/- 3.2; P = 0.001). Twenty-one of the 28 controls (75 percent) but only 4 of the 32 patients in the nitroglycerin group (12.5 percent) required digital dilatation to insert the stapling instrument ( P = 0.003). Squeeze pressures were unaltered by the intervention but mean resting pressures were higher in the nitroglycerin group postoperatively (52.9 +/- 3.2 - 31.6 +/- 1.3 = 21.3 mmHg; 95 percent confidence interval, 14-27). Incontinence scores were lower in the nitroglycerin group at the 3-month (1.1 +/- 0.2 vs. 4.6 +/- 0.3; P = 0.003) and 12-month (0.9 +/- 0.1 vs. 4.4 +/- 0.3; P = 0.002) clinic visits. CONCLUSION: Preoperative nitroglycerin dilatation protects sphincter function in patients undergoing transanal stapled anastomoses.

Administration, Topical↗