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Biomedical subjects

F D Moore

Publications and source records attributed to F D Moore.

At least 19 recordsLinked to original sources

Ischaemia-reperfusion is an event triggered by immune complexes and complement.

BACKGROUND: Reperfusion injury is a common clinical problem that lacks effective therapy. Two decades of research implicating oxygen free radicals and neutrophils has not led to a single successful clinical trial. METHODS: The aim was to review new clinical and preclinical data pertaining to the alleviation of reperfusion injury. A review of the literature was undertaken by searching the MEDLINE database for the period 1966-2003 without language restrictions. RESULTS AND CONCLUSION: Evidence now points to complement and immune complexes as critical players in mediating reperfusion injury. Ischaemia is postulated to induce a phenotypical cellular change through the surface expression of a neoantigen. Preformed circulating natural IgM antibodies are then trapped and complement is activated. Final events leading to reperfusion injury include formation of the membrane attack complex and mast cell degranulation.

Antigen-Antibody Complex↗

Recombinant soluble P-selectin glycoprotein ligand 1 moderates local and remote injuries following experimental lower-torso ischaemia.

BACKGROUND: A central role for the polymorphonuclear leucocyte (PMN) in skeletal muscle ischaemia-reperfusion has been demonstrated by the observation that PMN depletion reduced local and remote pulmonary vascular permeability. This study investigated the role of recombinant soluble P-selectin glycoprotein ligand-immunoglobulin fusion protein (rPSGL-Ig), a P- and E-selectin antagonist, in moderating injury. METHODS: Mice underwent 2 h of hindlimb ischaemia and 3 h of reperfusion. Muscle and lung vascular permeability index (PI) was assessed by extravasation of (125)I-radiolabelled albumin. Lung myelo peroxidase (MPO) activity was also measured. RESULTS: In mice treated with rPSGL-Ig 1 mg/kg before reperfusion (n = 12) muscle PI was reduced by 40 per cent, whereas it was moderated by 20 per cent in animals treated 30 min after reperfusion (n = 15). Lung PI in mice treated with rPSGL-Ig before (n = 12) and 30 min after (n = 15) reperfusion was reduced by over 99 and 98 per cent respectively. Lung MPO activity in mice treated with rPSGL-Ig before (n = 10) and 30 min after (n = 12) reperfusion was reduced by 68 and 58 per cent respectively. Treatment with rPSGL-Ig 1 h after reperfusion, or with m20ek.Fc 1 mg/kg (n = 9; negative control for rPSGL-Ig which is inactive for selectin binding) before reperfusion failed significantly to moderate local or remote organ injury. CONCLUSION: Selectin blockade moderated local skeletal muscle and remote lung injury following hindlimb ischaemia--reperfusion. Significantly, delayed antiselectin therapy also decreased injury.

Animals↗

Necrotizing pancreatitis: contemporary analysis of 99 consecutive cases.

OBJECTIVE: To analyze the impact of a conservative strategy of management in patients with necrotizing pancreatitis, reserving intervention for patients with documented infection or the late complications of organized necrosis. SUMMARY BACKGROUND DATA: The role of surgery in patients with sterile pancreatic necrosis remains controversial. Although a conservative approach is being increasingly used, few studies have evaluated this strategy when applied to the entire spectrum of patients with necrotizing pancreatitis. METHODS: The authors reviewed 1,110 consecutive patients with acute pancreatitis managed at Brigham and Women's Hospital between January 1, 1995, and January 1, 2000, focusing on those with pancreatic necrosis documented by contrast-enhanced computed tomography. Fine-needle aspiration, the presence of extraintestinal gas on computed tomography, or both were used to identify infection. RESULTS: There were 99 (9%) patients with necrotizing pancreatitis treated, with an overall death rate of 14%. In three patients with underlying medical problems, the decision was made initially not to intervene. Of the other 62 patients without documented infection, all but 3 were managed conservatively; this group's death rate was 11%. Of these seven deaths, all were related to multiorgan failure. Five patients in this group eventually required surgery for organized necrosis, with no deaths. Of the 34 patients with infected necrosis, 31 underwent surgery and 3 underwent percutaneous drainage. Only four (12%) of these patients died, all of multiorgan failure. Of the total 11 patients who died, few if any would have been candidates for earlier surgical intervention. CONCLUSIONS: These results suggest that conservative strategies can be applied successfully to manage most patients with necrotizing pancreatitis, although some will eventually require surgery for symptomatic organized necrosis. Few if any patients seem likely to benefit from a more aggressive strategy.

Adult↗

Neutrophils, not complement, mediate the mortality of experimental hemorrhagic pancreatitis.

Chemoactivation of the neutrophil (PMN) via the complement system has been observed in many inflammatory conditions and is thought to play a pathogenic role in acute pancreatitis. This study examined the effects of PMN depletion in experimental hemorrhagic pancreatitis and tested the role played by complement. Severe pancreatitis was induced by a choline-deficient, 0.5% ethionine-supplemented diet in female Institute of Cancer Research (ICR) mice weighing 11-13 g. Neutropenia was induced by an antibody injection. Total complement depletion was achieved by tail vein injections of cobra venom factor (CVF). Serum amylase levels and local pancreatic injury were not significantly modulated by either PMN or complement depletion at 72 hours. Systemic and remote organ injury, assessed by the formation of ascites, hematocrit, and serum alanine aminotransferase levels, was significantly reduced in neutropenic mice but failed to be moderated by complement depletion. In addition, liver and lung myeloperoxidase activity was independent of complement depletion. At 5 days, mortality was zero in PMN-depleted mice. There was no improvement in survival in the CVF-treated group. Neutrophils are important in the systemic injury and mortality of severe pancreatitis. PMN chemoactivation involves mechanisms other than complement.

Acute Disease↗

Mast cells mediate complement activation after acid aspiration.

A significant role for the alternative complement pathway in acid aspiration has been demonstrated by the observation that C3 but not C4 genetic knockout mice are protected from permeability edema. Using mast cell-deficient mice (W/Wv), we tested the hypothesis that mast cells mediate complement activation after acid aspiration. Tracheostomy tubes were placed in anesthetized mice and 2 mL/kg 0.1 N HCL was instilled in the trachea. After 4 h, extravasation of 125I-albumin was used to calculate lung vascular permeability. The serum alternative complement pathway hemolytic activity was examined, and lung immunohistochemistry was performed. Lung permeability in W/Wv mice was 62% less than that of mast cell sufficient (+/+) animals and similar to +/+ mice treated with the chymase inhibitor chymostatin (65% decrease). Treatment of +/+ mice with D-PRO2,D-TRP(7,9)-Substance P, an antagonist to the neuropeptide substance P, reduced injury by 66%. Serum complement hemolytic activity was intact in injured w/wv mice and +/+ animals treated with chymostatin or dpdt-sp, but was decreased to 65% in the injured untreated +/+ group. Alveolar C3 deposition was intense in injured untreated +/+ mice but absent in the other groups. We interpret these data to indicate that mast cells mediate complement activation, via chymase degranulation, after acid aspiration. This mast cell activity likely is regulated by the release of substance P.

Animals↗

Moderation of skeletal muscle reperfusion injury by a sLe(x)-glycosylated complement inhibitory protein.

The role of the sialyl Lewis(x) (sLe(x))-decorated version of soluble complement receptor type 1 (sCR1) in moderating skeletal muscle reperfusion injury, by antagonizing neutrophil endothelial selectin interaction and complement activation, is examined. Mice underwent 2 h of hindlimb ischemia and 3 h of reperfusion. Permeability index (PI) was assessed by extravasation of 125I-labeled albumin. Neutrophil depletion and complement inhibition with sCR1 reduced permeability by 72% (PI 0.81 +/- 0.10) compared with a 42% decrease (PI 1.53 +/- 0.08) observed in neutropenic mice, indicating that part of the complement-mediated injury is neutrophil independent. sCR1sLe(x) treatment reduced PI by 70% (PI 0.86 +/- 0.06), an additional 20% decrease compared with sCR1 treatment (PI 1.32 +/- 0.08). Treatment with sCR1sLe(x) 0.5 and 1 h after reperfusion reduced permeability by 63% (PI 0.09 +/- 0.07) and 52% (PI 1.24 +/- 0.09), respectively, compared with the respective decreases of 41% (PI 1.41 +/- 0.10) and 32% (PI 1.61 +/- 0.07) after sCR1 treatment. Muscle immunohistochemistry stained for sCR1 only on the vascular endothelium of sCR1sLe(x)-treated mice. In conclusion, sCR1sLe(x) is more effective than sCR1 in moderating skeletal muscle reperfusion injury.

Animals↗

Sialyl Lewis(x) hybridized complement receptor type 1 moderates acid aspiration injury.

The potentially enhanced anti-inflammatory effects of the sialyl Lewis(x) (sLe(x))-decorated version of soluble complement receptor type 1 (sCR1) in moderating acid aspiration injury are examined. HCl was instilled in tracheostomy tubes placed in mice, and extravasation of (125)I-labeled albumin in bronchoalveolar lavage (BAL) fluid was used to calculate the vascular permeability index (PI). Neutrophil counts in BAL fluid and immunohistochemistry were performed. PI was moderated by 82% after treatment with sCR1sLe(x) compared with 54% in sCR1-untreated mice (P < 0.05). Respective reductions in PI in mice treated 0.5 and 1 h after acid aspiration with sCR1sLe(x) of 70 and 57% were greater than the decreases in PI of 45 and 38% observed in respective sCR1-treated groups (P < 0.05). BAL fluid neutrophil counts in sCR1sLe(x)-treated mice were significantly less than those in sCR1-treated animals, which were similar to those in untreated mice. Immunohistochemistry stained for sCR1 only on the pulmonary vascular endothelium of sCR1sLe(x)- but not sCR1-treated mice. In conclusion, sCR1sLe(x) moderates permeability by antagonizing complement activation and neutrophil adhesion. Delayed complement and neutrophil antagonism significantly reduces injury.

Animals↗

Somatic mitochondrial DNA (mtDNA) mutations in papillary thyroid carcinomas and differential mtDNA sequence variants in cases with thyroid tumours.

Somatic mutations in mtDNA have recently been identified in colorectal tumours. Studies of oncocytic tumours have led to hypotheses which propose that defects in oxidative phosphorylation may result in a compensatory increase in mitochondrial replication and/or gene expression. Mutational analysis of mtDNA in thyroid neoplasia, which is characterised by increased numbers of mitochondria and is also one of the most common sites of oncocytic tumours. has been limited to date. Using the recently developed technique of two-dimensional gene scanning, we have successfully examined 21 cases of thyroid tumours, six cases of non-neoplastic thyroid pathology, 30 population controls, nine foetal thyroid tissues and nine foetal tissues of non-thyroid origin, either kidney or liver. We have identified three different somatic mutations (23%) in papillary thyroid carcinomas. In addition, we have found significant differential distributions of mtDNA sequence variants between thyroid carcinomas and controls. Interestingly, these variants appear to be more frequent in the genes which encode complex I of the mitochondrial electron transport chain compared to normal population controls. These findings suggest first, that somatic mtDNA mutations may be involved in thyroid tumorigenesis and second, that the accumulation of certain non-somatic variants may be related to tumour progression in the thyroid.

Adenoma↗

Ethical problems special to surgery: surgical teaching, surgical innovation, and the surgeon in managed care.

This article will concern itself with 3 ethical challenges that are special to the role of the surgeon in our society. First is the teaching of surgery. This might be called "performing an operation for the first time (for the individual surgeon)." Second is surgical innovation. This might be termed "performing a new operation for the first time ever." The third ethical challenge is the role of the surgeon in managed care. This might be stated as "Can we trust corporations to provide all-risk coverage and freedom in clinical decisions?"

Diffusion of Innovation↗

Endothelial selectin blockade attenuates lung permeability of experimental acid aspiration.

BACKGROUND: A central role for the polymorphonuclear leukocyte (PMN) in experimental acid aspiration has been demonstrated by the observation that PMN depletion reduced pulmonary vascular permeability. This study investigates the role of recombinant soluble P-selectin glycoprotein ligand-immunoglobulin fusion protein (rPSGL-Ig), a P- and E-selectin antagonist in moderating acid aspiration lung injury. METHODS: Tracheostomy tubes were placed in male C57BL/6 mice and 0.1 N HCl was instilled into the trachea at 2 mL/kg after intravenous injection of (125)I-albumin. After 4 hours the lung vascular permeability index (PI) and PMN accumulation in the bronchoalveolar lavage fluid were assessed. RESULTS: PI in neutropenic mice was 63% reduced compared with the untreated group and similar to the PI of mice treated with 1 mg/kg rPSGL-Ig before acid aspiration. PMN count of 19 +/- 5 in the bronchoalveolar lavage fluid in rPSGL-Ig treated mice was significantly less than the untreated group PMN count of 586 +/- 72. The respective PI in mice treated with rPSGL-Ig (1/2) hour and 1 hour after acid aspiration was 45% and 39% reduced compared with the untreated group. CONCLUSIONS: Endothelial selectin blockade is as effective as PMN depletion in moderating acid aspiration induced lung permeability. Delayed antiselectin therapy can decrease lung injury.

Animals↗

Neutrophil mediated remote organ injury after lower torso ischemia and reperfusion is selectin and complement dependent.

BACKGROUND: Lower torso ischemia and reperfusion leads to remote organ leukosequestration and injury. We now examine the intermediary role of selectins and complement in mediating lung and liver injury after hindlimb ischemia. METHODS: Mice underwent a 2-hour bilateral tourniquet hind-limb ischemia followed by 3 hours of reperfusion. RESULTS: Neutrophil depletion significantly decreased lung vascular permeability index (PI), measured by the extravasation of 125I-albumin, and liver injury as assessed by serum alanine aminotransferse levels. Lung PI and serum alanine aminotransferse levels were also reduced in mice treated with recombinant soluble P-selectin glycoprotein ligand-immunoglobulin fusion protein. Complement inhibition with soluble complement receptor type 1 decreased lung PI and serum alanine aminotransferse levels. C5-deficient mice exhibited a similar decrease in lung PI and liver injury. Lung and liver injury were restored in C5-deficient mice reconstituted with wild-type serum. CONCLUSION: Remote organ injury after lower torso reperfusion is selectin and complement dependent.

Alanine Transaminase↗

Soluble P-selectin moderates complement dependent injury.

P-selectin is an adhesion molecule expressed on activated endothelial and platelet membranes containing 9 short consensus repeats (SCRs) similar to the composition of complement regulatory proteins. In our murine model of intestinal ischemia and reperfusion where local injury is mediated by the classical complement pathway we hypothesized the SCRs would moderate the complement response. Confirmatory data were sought following hindlimb ischemia and reperfusion where injury is both complement- and neutrophil-mediated. Mice deficient in P-selectin (P-/-) were found to have similar intestinal and hindlimb permeability compared to normal wild types mice (P+/+). When reconstituted with P+/+ platelets, but not P-/- platelets, P-/- mice subjected to intestinal ischemia had a significant 29% decrease in permeability (P < 0.05) and after hindlimb ischemia the decrease was 33% (P<0.05). Reperfusion after intestinal ischemia led to a 76% fall in CH50 in P-/- compared to sham animals (P < 0.05) indicating complement activation and consumption, but only a 36% fall in animals reconstituted with P+/+ platelets (P < 0.05). Full-length, soluble P-selectin (sPsel) derived from processed platelets, but not the truncated version of sPsel has been shown to adhere to a heat labile fraction of serum and sensitized red blood cells thereby reducing Clq adherence to the sensitized red cell. From these data we conclude that sPsel moderates complement activation by competing with C1q binding to antibody, thereby limiting activation of the classical pathway that mediates murine reperfusion injury.

Animals↗

Soluble P-selectin moderates complement-dependent reperfusion injury of ischemic skeletal muscle.

P-selectin is an adhesion molecule expressed on activated endothelial and platelet surfaces. The function of the short consensus repeats (SCRs) of P-selectin, homologous with the SCRs of complement regulatory proteins is largely unknown. In a model of murine hindlimb ischemia where local reperfusion injury is partly mediated by IgM natural antibody and classical complement pathway activation, we hypothesized that human soluble P-selectin (sP-sel) would moderate the complement component of the inflammatory response. Infusion of sP-sel supernatant or purified (p) sP-sel prepared from activated human platelets, reduced ischemic muscle vascular permeability by 48% and 43%, respectively, following reperfusion. Hindlimb immunohistochemistry demonstrated negligible C3 staining colocalized with IgM in these groups compared with intense staining in the untreated injured mice. In vitro studies of mouse serum complement hemolytic activity showed that psP-sel inhibited the classical but not alternative complement pathway. Flow cytometry demonstrated that psP-sel inhibited C1q adherence to sensitized red blood cells. From these data we conclude that sP-sel moderates skeletal muscle reperfusion injury by inhibition of the classical complement pathway.

Animals↗

John Collins Warren and his act of conscience: a brief narrative of the trial and triumph of a great surgeon.

On examination of the correspondence among the principals involved, as well as the original patent application being prepared by Morton, it has become possible to reconstruct some of the remarkable details attending the first use of ether anesthesia at the Massachusetts General Hos pital in the autumn of 1846. At the time that Warren invited Morton to demonstrate the use of his "ethereal vapor" for anesthesia in a minor operation on Oct. 16, 1846, the exact chemical composition of the agent used was being held secret by Morton; Warren was clearly disturbed by this unethical use of a secret "nostrum." When the time arrived 3 weeks later for its possible use for a serious "capital" operation, Warren employed a simple stratagem of public confrontation to discover from Morton the true nature of the substance to be used. On being informed that it was pure unadulterated sulfuric ether, not some mysterious new discovery labeled "Letheon," Warren gave approval for its first use in a "capital" operation (low thigh amputation) on Nov. 7, 1846. Despite this revelation to the immediate participants, a veil of secrecy continued to surround the substance for many months, an anomalous situation evidently traceable to Morton's desire for personal reward from the discovery. It was this matter of secrecy, rather than priority for its discovery, that surrounded the early use of ether anesthesia with controversy and recrimination both in this country and abroad.

Anesthesia, Inhalation↗