Diamond-Like Carbon: A Surface for Extreme, High-Wear Environments.

In this study, we present an in-depth characterization of a diamond-like carbon (DLC) film, using a range of techniques to understand the structure and chemistry of the film both in the interior and particularly at the DLC/air surface and DLC/liquid interface. The DLC film is found to be a combination of sp2 and sp3 carbon, with significant oxygen present at the surface. The oxygen seems to be present as OH groups, making the DLC somewhat hydrophilic. Quartz-Crystal Microbalance (QCM) isotherms and complementary neutron reflectivity data indicate significant adsorption of a model additive, bis(2-ethylhexyl) sulfosuccinate sodium salt (AOT) surfactant, onto the DLC from water solutions and indicate the adsorbed film is a bilayer. This initial study of the structure and composition of a model surfactant is intended to give a clearer insight into how DLC and additives function as antiwear systems.

Perioperative mortality in bariatric surgery: meta-analysis.

BACKGROUND: Bariatric surgery is an established treatment for severe obesity; however, fewer than 1 per cent of eligible patients undergo surgery. The perceived risk of surgery may contribute to the low uptake. The aim of this study was to determine perioperative mortality associated with bariatric surgery, comparing different operation types and data sources. METHODS: A literature search of Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials was conducted to identify studies published between 1 January 2014 and 31 July 2020. Inclusion criteria were studies of at least 1000 patients reporting short-term mortality after bariatric surgery. Data were collected on RCTs. Meta-analysis was performed to establish overall mortality rates across different study types. The primary outcome measure was perioperative mortality. Different operation types were compared, along with study type, in subgroup analyses. The study was registered at PROSPERO (2019: CRD 42019131632). RESULTS: Some 4356 articles were identified and 58 met the inclusion criteria. Data were available on over 3.6 million patients. There were 4707 deaths. Pooled analysis showed an overall mortality rate of 0.08 (95 per cent c.i. 0.06 to 0.10; 95 per cent prediction interval 0 to 0.21) per cent. In subgroup analysis, there was no statistically significant difference between overall, 30-day, 90-day or in-hospital mortality (P = 0.29). There was no significant difference in reported mortality for RCTs, large studies, national databases or registries (P = 0.60). The pooled mortality rates by procedure type in ascending order were: 0.03 per cent for gastric band, 0.05 per cent for sleeve gastrectomy, 0.09 per cent for one-anastomosis gastric bypass, 0.09 per cent for Roux-en-Y gastric bypass, and 0.41 per cent for duodenal switch (P < 0.001 between operations). CONCLUSION: Bariatric surgery is safe, with low reported perioperative mortality rates.

Weight loss surgery helps patients with severe obesity. This study looked at the risk of dying after weight loss surgery in over 3.6 million patients. The risk was less than 1 in 1000 (0.08 per cent). The risk was lowest for gastric band and sleeve gastrectomy, then for gastric bypasses and highest for the duodenal switch operation. This shows that weight loss surgery is safe, with a low risk of dying similar to that of other common operations.

Mixing Natural and Synthetic Surfactants: Co-Adsorption of Triterpenoid Saponins and Sodium Dodecyl Sulfate at the Air-Water Interface.

Saponins are highly surface active glycosides, derived from a wide range of plant species. Their ability to produce stable foams and emulsions has stimulated their applications in beverages, foods, and cosmetics. To explore a wider range of potential applications, their surface mixing properties with conventional surfactants have been investigated. The competitive adsorption of the triterpenoid saponin escin with an anionic surfactant sodium dodecyl sulfate, SDS, at the air-water interface has been studied by neutron reflectivity, NR, and surface tension. The NR measurements, at concentrations above the mixed critical micelle concentration, demonstrate the impact of the relative surface activities of the two components. The surface mixing is highly nonideal and can be described quantitatively by the pseudophase approximation with the inclusion of the quadratic and cubic terms in the excess free energy of mixing. Hence, the surface mixing is highly asymmetrical and reflects both the electrostatic and steric contributions to the intermolecular interactions. The relative importance of the steric contribution is reinforced by the observation that the micelle mixing is even more nonideal than the surface mixing. The mixing properties result in the surface adsorption being largely dominated by the SDS over the composition and concentration range explored. The results and their interpretation provide an important insight into the wider potential for mixing saponins with more conventional surfactants.

Enabling recruitment success in bariatric surgical trials: pilot phase of the By-Band-Sleeve study.

BACKGROUND: Randomized controlled trials (RCTs) involving surgical procedures are challenging for recruitment and infrequent in the specialty of bariatrics. The pilot phase of the By-Band-Sleeve study (gastric bypass versus gastric band versus sleeve gastrectomy) provided the opportunity for an investigation of recruitment using a qualitative research integrated in trials (QuinteT) recruitment intervention (QRI). PATIENTS/METHODS: The QRI investigated recruitment in two centers in the pilot phase comparing bypass and banding, through the analysis of 12 in-depth staff interviews, 84 audio recordings of patient consultations, 19 non-participant observations of consultations and patient screening data. QRI findings were developed into a plan of action and fed back to centers to improve information provision and recruitment organization. RESULTS: Recruitment proved to be extremely difficult with only two patients recruited during the first 2 months. The pivotal issue in Center A was that an effective and established clinical service could not easily adapt to the needs of the RCT. There was little scope to present RCT details or ensure efficient eligibility assessment, and recruiters struggled to convey equipoise. Following presentation of QRI findings, recruitment in Center A increased from 9% in the first 2 months (2/22) to 40% (26/65) in the 4 months thereafter. Center B, commencing recruitment 3 months after Center A, learnt from the emerging issues in Center A and set up a special clinic for trial recruitment. The trial successfully completed pilot recruitment and progressed to the main phase across 11 centers. CONCLUSIONS: The QRI identified key issues that enabled the integration of the trial into the clinical setting. This contributed to successful recruitment in the By-Band-Sleeve trial-currently the largest in bariatric practice-and offers opportunities to optimize recruitment in other trials in bariatrics.

Adaptation of the By-Band randomized clinical trial to By-Band-Sleeve to include a new intervention and maintain relevance of the study to practice.

BACKGROUND: Recruitment into surgical RCTs can be threatened if new interventions available outside the trial compete with those being evaluated. Adapting the trial to include the new intervention may overcome this issue, yet this is not often done in surgery. This paper describes the challenges, rationale and methods for adapting an RCT to include a new intervention. METHODS: The By-Band study was designed in the UK in 2009-2010 to compare the effectiveness of laparoscopic adjustable gastric band and Roux-en-Y gastric bypass for severe obesity. It contained a pilot phase to establish whether recruitment was possible, and the grant proposal specified that an adaptation to include sleeve gastrectomy would be considered if practice changed and recruitment was successful. Information on changing obesity surgery practice, updated evidence and expert opinion about trial design were used to inform the adaptation. RESULTS: The pilot phase recruited over 13 months in 2013-2014 and randomized 80 patients (79 anticipated). During this time, major changes in obesity practice in the UK were observed, with gastric band reducing from 32·6 to 15·8 per cent and sleeve gastrectomy increasing from 9·0 to 28·1 per cent. The evidence base had not changed markedly. The British Obesity and Metabolic Surgery Society and study oversight committees supported an adaptation to include sleeve gastrectomy, and a proposal to do so was approved by the funder. CONCLUSION: Adaptation of a two-group surgical RCT can allow evaluation of a third procedure and maintain relevance of the RCT to practice. It also optimizes the use of existing trial infrastructure to answer an additional important research question. Registration number: ISRCTN00786323 (http://www.isrctn.com/).

Comparative Adsorption of Saturated and Unsaturated Fatty Acids at the Iron Oxide/Oil Interface.

A detailed comparison of the adsorption behavior of long straight chain saturated and unsaturated fatty acids at the iron oxide/oil interface has been considered using a combination of surface study techniques. Both depletion isotherms and polarized neutron reflectometry (PNR) show that the extent of adsorption decreases as the number of double bonds in the alkyl chains increases. Sum frequency generation spectroscopic measurements demonstrate that there is also an increase in chain disorder within the adsorbed layer as the unsaturation increases. However, for the unsaturated analogues, a decrease in peak intensity is seen for the double bond peak upon heating, which is thought to arise from isomerization in the surface-bound layer. The PNR study of oleic acid adsorption indicates chemisorbed monolayer adsorption, with a further diffuse reversible adsorbed layer formed at higher concentrations.

Effect of the definition of type II diabetes remission in the evaluation of bariatric surgery for metabolic disorders.

BACKGROUND: The American Diabetes Association recently defined remission of type II diabetes as a return to normal measures of glucose metabolism (haemoglobin (Hb) A1c below 6 per cent, fasting glucose less than 5·6 mmol/l) at least 1 year after bariatric surgery without hypoglycaemic medication. A previously used common definition was: being off diabetes medication with normal fasting blood glucose level or HbA1c below 6 per cent. This study evaluated the proportion of patients achieving complete remission of type II diabetes following bariatric surgery according to these definitions. METHODS: This was a retrospective review of data collected prospectively in three bariatric centres on patients undergoing gastric bypass, sleeve gastrectomy and gastric banding. RESULTS: Some 1006 patients underwent surgery, of whom 209 had type II diabetes. Median follow-up was 23 (range 12-75) months. HbA1c was reduced after operation in all three surgical groups (P < 0·001). A total of 72 (34·4 per cent) of 209 patients had complete remission of diabetes, according to the new definition; the remission rates were 40·6 per cent (65 of 160) after gastric bypass, 26 per cent (5 of 19) after sleeve gastrectomy and 7 per cent (2 of 30) after gastric banding (P < 0·001 between groups). The remission rate for gastric bypass was significantly lower with the new definition than with the previously used definition (40·6 versus 57·5 per cent; P = 0·003). CONCLUSION: Expectations of patients and clinicians may have to be adjusted as regards remission of type II diabetes after bariatric surgery. Focusing on improved glycaemic control rather than remission may better reflect the benefit of this type of surgery and facilitate improved glycaemic control after surgery.

Two cases of non-parasitic splenic cysts and spleen-preserving therapy.

We review two different presentations of non-parasitic splenic cysts, both of which are post-traumatic in aetiology. The first case was of slower onset and was managed electively. The second case was of acute onset and was managed as an emergency. Non-parasitic splenic cysts are uncommon and the optimal management strategy for them is not well defined. Historically, treatment has been with open splenectomy; however, infection rates following this surgery have been high, making it an unattractive management option. Both cases were managed successfully with laparoscopic fenestration with no recurrence at subsequent follow-up.

Adsorption and self-assembly properties of the plant based biosurfactant, Glycyrrhizic acid.

There is an increased interest in the use of natural surfactant as replacements for synthetic surfactants due to their biosustainable and biocompatible properties. A category of natural surfactants which are attracting much current interest is the triterpenoid saponins; surface active components found extensively in a wide range of plant species. A wide range of different saponin structures exist, depending upon the plant species they are extracted from; but regardless of the variation in structural details they are all highly surface active glycosides. Greater exploitation and application requires a characterisation and understanding of their basic adsorption and self-assembly properties. HYPOTHESIS: Glycyrrhizic acid, extracted from Licorice root, is a monodesmosidic triterpenoid saponin. It is widely used in cosmetic and pharmaceutical applications due to its anti-inflammatory properties, and is an ingredient in foods as a sweetener additive. It has an additional attraction due to its gel forming properties at relatively low concentrations. Although it has attracted much recent attention, many of its basic surface active characteristics, adsorption and self-assembly, remain relatively unexplored. How the structure of the Glycyrrhizic acid saponin affects its surface active properties and the impact of gelation on these properties are important considerations, and to investigate these are the focus of the study. EXPERIMENTS: In this paper the adsorption properties at the air-water interface and the self-assembly in solution have been investigated using by neutron reflectivity and small angle neutron scattering; in non-gelling and gelling conditions. FINDINGS: The adsorption isotherm is determined in water and in the presence of gelling additives, and compared with the adsorption behaviour of other saponins. Gelation has minimal impact on the adsorption; apart from producing a rougher surface with a surface texture on a macroscopic length scale. Globular micelles are formed in aqueous solution with modest anisotropy, and are compared with the structure of other saponin micelles. The addition of gelling agents results in only minimal micelle growth, and the solutions remain isotropic under applied shear flow.

Surfactant/biosurfactant mixing: Adsorption of saponin/nonionic surfactant mixtures at the air-water interface.

Saponins are naturally occurring biosurfactants present in a wide range of plant species. They are highly surface active glycosides, and are used to stabilise foams and emulsions in foods, beverages and cosmetics. They have great potential for an even wider range of applications, especially when mixed with different synthetic surfactants. Understanding those mixing properties are key to the exploitation of saponins in that wider range of potential applications. The surface adsorption properties of the saponin, escin, with two conventional nonionic surfactants, polyethylene glycol surfactants, have been studied at the air-water interface using neutron reflectivity, NR, and surface tension, ST. Although the saponin and polyethylene glycol, CnEOm, surfactants are both nonionic the disparity in the relative surface activities and packing constraints result in non-ideal mixing. Comparison with the predictions of the pseudo phase approximation requires the inclusion of the quadratic, cubic and quartic terms in the expansion of the excess free energy of mixing to explain the variations in the surface composition. For escin/pentaethylene glycol monododecyl ether, C12EO5, the interaction is attractive and close to ideal. For escin/octaethylene glycol monododecyl ether, C12EO8, it is repulsive and close to the criteria for demixing. The differences in mixing behaviour are attributed to greater packing constraints imposed by the larger ethylene oxide headgroup of the C12EO8 compared to C12EO5.

Commissioning guidance for weight assessment and management in adults and children with severe complex obesity.

The challenge of managing the epidemic of patients with severe and complex obesity disease in secondary care is largely unmet. In England, the National Institute of Health and Care Excellence and the National Health Service England have published guidance on the provision of specialist (non-surgical) weight management services. We have undertaken a systematic review of 'what evidence exists for what should happen in/commissioning of: primary or secondary care weight assessment and management clinics in patients needing specialist care for severe and complex obesity?' using an accredited methodology to produce a model for organization of multidisciplinary team clinics that could be developed in every healthcare system, as an update to a previous review. Additions to the previous guidance were multidisciplinary team pathways for children/adolescent patients and their transition to adult care, anaesthetic assessment and recommendations for ongoing shared care with general practitioners, as a chronic disease management pathway.

Recommendations on the most suitable quality-of-life measurement instruments for bariatric and body contouring surgery: a systematic review.

OBJECTIVE: The objective of this study is to systematically assess the quality of existing patient-reported outcome measures developed and/or validated for Quality of Life measurement in bariatric surgery (BS) and body contouring surgery (BCS). METHODS: We conducted a systematic literature search in PubMed, EMBASE, PsycINFO, CINAHL, Cochrane Database Systematic Reviews and CENTRAL identifying studies on measurement properties of BS and BCS Quality of Life instruments. For all eligible studies, we evaluated the methodological quality of the studies by using the COnsensus-based Standards for the selection of health Measurement INstruments checklist and the quality of the measurement instruments by applying quality criteria. Four degrees of recommendation were assigned to validated instruments (A-D). RESULTS: Out of 4,354 articles, a total of 26 articles describing 24 instruments were included. No instrument met all requirements (category A). Seven instruments have the potential to be recommended depending on further validation studies (category B). Of these seven, the BODY-Q has the strongest evidence for content validity in BS and BCS. Two instruments had poor quality in at least one required quality criterion (category C). Fifteen instruments were minimally validated (category D). CONCLUSION: The BODY-Q, developed for BS and BCS, possessed the strongest evidence for quality of measurement properties and has the potential to be recommended in future clinical trials.

Mortality related to primary bariatric surgery in England.

BACKGROUND: Bariatric surgery is an accepted treatment option for severe obesity. Previous analysis of the independently collected Hospital Episode Statistics (HES) data for outcomes after bariatric surgery demonstrated a 30-day postoperative mortality rate of 0·3 per cent in the English National Health Service (NHS). However, there have been no published mortality data for bariatric procedures performed since 2008. This study aimed to assess mortality related to bariatric surgery in England from 2009. METHODS: HES data were used to identify all patients who had primary bariatric surgery from 2009 to 2016. Clinical codes were used selectively to identify all primary bariatric procedures but exclude revision or conversion procedures and operations for malignant or other benign disease. The primary outcome measures were HES in-hospital and Office for National Statistics (ONS) 30-day mortality after discharge. RESULTS: A total of 41 241 primary bariatric procedures were carried out in the NHS between 2009 and 2016, with 29 in-hospital deaths (0·07 per cent). The 30-day mortality rate after discharge was 0·08 per cent (32 of 41 241). Both the in-hospital and 30-day mortality rates after discharge demonstrated a downward trend over the study period. CONCLUSION: Overall in-hospital and 30-day mortality rates remain very low after primary bariatric surgery. An increased uptake of bariatric surgery within the English NHS has been safe.

Outcome reporting in bariatric surgery: an in-depth analysis to inform the development of a core outcome set, the BARIACT Study.

Outcome reporting in bariatric surgery needs a core outcome set (COS), an agreed minimum set of outcomes reported in all studies of a particular condition. The aim of this study was to summarize outcome reporting in bariatric surgery to inform the development of a COS. Outcomes reported in randomized controlled trials (RCTs) and large non-randomized studies identified by a systematic review were listed verbatim and categorized into domains, scrutinizing the frequency of outcome reporting and uniformity of definitions. Ninety studies (39 RCTs) identified 1,088 separate outcomes, grouped into nine domains with most (n = 920, 85%) reported only once. The largest outcome domain was 'surgical complications', and overall, 42% of outcomes corresponded to a theme of 'adverse events'. Only a quarter of outcomes were defined, and where provided definitions, which were often contradictory. Percentage of excess weight loss was the main study outcome in 49 studies, but nearly 40% of weight loss outcomes were heterogeneous, thus not comparable. Outcomes of diverse bariatric operations focus largely on adverse events. Reporting is inconsistent and ill-defined, limiting interpretation and comparison of published studies. Thus, we propose and are developing a COS for the surgical treatment of severe and complex obesity.

The evolution of transsphenoidal pituitary microsurgery.

Serious interest in pituitary disease started 100 years ago when acromegaly was described (1886, Marie). Transcranial pituitary operations soon followed (1889, Horsley). Transnasal operations (1907, Schloffer) were complicated by cerebrospinal fluid leakage and meningitis. Improvements led to definitive transseptal (1910, Cushing and Hirsch) and transethmoidal (1911, Chiari) decompressing surgery for tumors. The mortality rate fell below 10%, and relief, mainly from local effects, often followed, sometimes for many years. By 1930 Cushing and most U.S. surgeons used a transcranial approach because suprasellar lesions were inaccessible from below, but several European surgeons continued to use transsphenoidal operations when appropriate (Hirsch, Dott, and Nager). By 1950 antibiotics had reduced infection, and cortisone soon rendered total hypophysectomy by all routes safe for tumorous and normal glands. Microsurgical transethmosphenoidal hypophysectomy was introduced by ear, nose, and throat surgeons (1957 or 1958, Gisselsson, Riskaer, Bateman, MacBeth, and James). Neurosurgeons introduced intraoperative radiofluoroscopy (1957, Guiot), air encephalography, televised fluoroscopy, microsurgical transseptal hypophysectomy, and selective anterior hypophysectomy (1965, Hardy). Microadenomectomy for lesions invisible radiologically was introduced in 1968 (Hardy). The operative death rate is now negligible. Computerized tomographic scanning helps locate tumors, but increasingly surgeons now regard endocrinologic diagnosis alone as justification for operation. Early outcome is excellent, especially in experienced hands, and particularly for noninvasive tumors, but later results are forthcoming.

Survival and causes of death after adrenalectomy for Cushing's disease.

A consecutive series of 79 patients with Cushing's disease, treated by bilateral adrenalectomy (subtotal, total initially, or total finally) between 1953 and 1980, were studied to determine the survival and mortality rates and causes of death as long as 28 years after surgery. There were three early postoperative deaths, the last in 1974, caused by coma of unknown cause, severe diarrhea, and pulmonary embolism, respectively. The actuarial survival rates at intervals of 1, 2, 3, 5, 10, 15, and 20 years after surgery were approximately 87%, 83%, 82%, 79%, 72%, 68%, and 62%, respectively. These are significantly less than the rates for the general population (p less than 0.001). There were no differences between the sexes or between the types of operation (p greater than 0.05). The commonest causes of death were cardiac or vascular lesions (11 patients) and the local effects of pituitary tumors (four patients). These long-term results of an established method of treatment provide a standard by which other, especially newer, methods may be compared.

Neutrophil adhesion receptor CD18 mediates remote but not localized acid aspiration injury.

BACKGROUND: Acid aspiration leads to lung polymorphonuclear neutrophil (PMN) sequestration and an associated increase in permeability. Although it is known that the neutrophil adhesion receptor (CD18) plays no role in determining PMN accumulations in the region aspirated, we postulated that this PMN adhesion receptor and its endothelial ligand, intercellular adhesion molecule-1 (ICAM-1), mediate remote neutrophil sequestration. METHODS: Anesthetized rabbits underwent localized aspiration of either 0.1N HCl 0.1 ml/kg (n = 18) or saline solution (n = 18). RESULTS: After 30 minutes leukopenia was noted, 2290 +/- 200 white blood cells/mm3 (p < 0.05). At 3 hours diapedesis occurred in the aspirated segment with accumulations in bronchoalveolar lavage fluid (X10(4)) of 87 +/- 6 PMN/ml versus control of 6 +/- 1 PMN/ml (p < 0.05). Histologic evidence of generalized lung leukosequestration occurred. The wet to dry weight ratio of the nonaspirated lung rose to 5.7 +/- 0.2 versus control of 3.9 +/- 0.1 (p < 0.05). Treatment (n = 18) with the CD18 monoclonal antibody (mAb) (R15.7, 1 mg/kg) had no effect on neutrophil accumulations in the aspirated segment. However, the mAb attenuated the remote inflammatory response: early leukopenia (5790 +/- 400 white blood cells/mm3); lung leukosequestration (24 +/- 4 PMN/10 high-power fields); protein leak in bronchoalveolar lavage fluid (570 +/- 50 micrograms/ml); and edema, wet to dry weight ratio (4.9 +/- 0.1) (all p < 0.05). Treatment with the ICAM-1 mAb (RR1/1, 1 mg/kg) (n = 9) did not reduce neutrophil accumulations in the aspirated segment but limited the remote inflammatory response. CONCLUSIONS: Acid aspiration leads to neutrophil adhesion and edema in regions remote from those aspirated via neutrophil CD18 and endothelial ICAM-1.

Lavage with leukotriene B4 induces lung generation of tumor necrosis factor-alpha that in turn mediates neutrophil diapedesis.

In experimental models of acute respiratory failure, leukotriene (LT) B4 is generated in the lungs, followed by a 2- to 3-hour delay before there is substantial neutrophil (PMN) accumulation and increased permeability. This study tests whether lavage with LTB4 induces tumor necrosis factor (TNF) synthesis by the lungs that in turn mediates PMN diapedesis. Anesthetized rats underwent lavage with 0.1 ml LTB4 (10(-6) mol/L) into a lung segment. This led to localized TNF synthesis measured in bronchoalveolar lavage fluid with peak concentrations of 580 pg/ml after 1 1/2 hours and 120 pg/ml after 3 hours. These values were higher than after lavage with 0.1 ml saline solution: 0.7 and 4.3 pg/ml, respectively (both p < 0.05). There was a delay before PMN accumulated in bronchoalveolar lavage fluid (x 10(4)). After 30 minutes, the numbers were 2.2 PMN/ml, whereas at 4 hours there was a rise to 40 PMN/ml and at 5 hours 60 PMN/ml, higher than after saline lavage (all p < 0.05). Pretreatment of rats by lavage into airways with actinomycin D, 12 ng in 0.1 ml, minimized LTB4-induced TNF synthesis after 1 1/2 and 3 hours (38 and 51 pg/ml), as well as the delayed diapedesis after 4 hours (12 PMN/ml) (all p < 0.05). Similarly, pretreatment of other rats by lavage with TNF-alpha antiserum (rabbit antimurine), but not normal serum, limited LTB4-induced diapedesis (13 PMN/ml) (p < 0.05). Interestingly, administration of the protein synthesis inhibitor actinomycin D by lavage 10 minutes after LTB4 did not prevent TNF generation after 1 1/2 or 3 hours (490 and 440 pg/ml). However, this agent did limit PMN diapedesis after 4 hours (14 PMN/ml) (p < 0.05), an event possibly caused by limiting later synthesis of endothelial adhesion proteins, a thesis consistent with the findings that pretreatment of rats by lavage with actinomycin D was without any effect on N-formyl-methionyl-phenylalanine (10(-8) mol/L)-induced diapedesis. This agent is known to induce PMN migration without need for synthesis of endothelial adhesion proteins. The data indicate that lavage with LTB4 induces local TNF-alpha generation that in turn mediates a delayed PMN diapedesis. This event is likely regulated by endothelial synthesis of adhesion proteins.

Synergism between leukotriene B4 and thromboxane A2 in mediating acid-aspiration injury.

Acid aspiration leads to thromboxane-dependent lung neutrophil sequestration associated with microvascular permeability increase. Leukotriene B4 (LTB4) is postulated to be a cofactor in the thromboxane-induced inflammatory response. This study tests the interaction between LTB4 and thromboxane, focusing on LTB4 induction of thromboxane-dependent lung neutrophil sequestration after acid aspiration. Anesthetized rats underwent tracheostomy and insertion of a cannula in a left lung segment. This was followed by instillation of either 0.1 ml 0.1N hydrochloric acid (n = 18) or 0.1 ml saline in control rats (n = 18). When assayed at 3 hours, acid aspiration led to increased plasma levels of LTB4 and thromboxane B2 (TxB2), higher than control values (p less than 0.05). The rise in plasma LTB4 was correlated (p less than 0.05; r = 0.83) with sequestration of neutrophils in the nonaspirated lung. The entrapment of thromboxane-dependent lung neutrophil was associated with an increase in protein concentration in bronchoalveolar lavage of the aspirated and nonaspirated sides and an increase in lung wet to dry weight ratio. Pretreatment of other rats (n = 18) with the lipoxygenase inhibitor diethylcarbamazine IV prevented an aspiration-induced rise in plasma LTB4 and TxB2. Further, there was an attenuation of lung leukosequestration and protein leak in bronchoalveolar lavage and lung edema (all p less than 0.05). Pretreatment of other rats (n = 12) with the leukotriene receptor antagonist FPL 55712 IV did not prevent the aspiration-induced rise in LTB4 or TxB2, but otherwise was as effective as diethylcarbamazine in preventing injury. Finally, other hydrochloric acid-aspirated rats (n = 8) were pretreated intravenously with the thromboxane synthetase inhibitor OKY 046 or the thromboxane receptor antagonist SQ 29548. Both agents limited the aspiration-induced rise in plasma LTB4 (p less than 0.05). The data indicate that localized acid aspiration induces synthesis of LTB4 and thromboxane A2. Inhibition of either leukotriene or thromboxane will limit PMN adhesion and increased lung permeability.

Oxygen free radicals are required for ischemia-induced leukotriene B4 synthesis and diapedesis.

Hind limb ischemia and reperfusion have been shown to result in high plasma levels of leukotriene B4 (LTB4) and polymorphonuclear neutrophil (PMN) sequestration in the pulmonary microvasculature. This study tests whether LTB4 is derived from PMNs and its role in mediating ischemic plasma-induced diapedesis. Plasma derived from rabbit hind limbs after 3 hours of tourniquet ischemia and 10 minutes of reperfusion (n = 6) showed an increased LTB4 level of 560 pg/ml, higher than sham plasma values of 106 pg/ml (p less than 0.05). Introduction of ischemic plasma in abraded skin chambers placed on the dorsum of normal rabbits (n = 6) led after 3 hours to PMN diapedesis of 1175 PMN/mm3, associated with a further increase in LTB4 levels to 820 pg/ml (both p less than 0.05). In contrast, ischemic plasma derived from neutropenic animals (n = 4; nitrogen mustard, 2 mg/kg; PMNs less than 30/mm3) contained lower levels of LTB4, 160 pg/ml (p less than 0.05). When introduced in skin chambers in normal rabbits (n = 4), this plasma induced accumulations of only 163 PMN/mm3, accompanied by a smaller increase in LTB4 levels in the blister fluid after 3 hours, 397 pg/ml (both p less than 0.05). A correlation was found between LTB4 levels in ischemic plasma and PMN accumulations in blister fluid (r = 0.92; p less than 0.05). Intravenous pretreatment of rabbits (n = 4) used in the blister chamber bioassay with the LT receptor antagonist FPL-55712, 40 micrograms/kg/hr, attenuated diapedesis induced by ischemic and ischemic-neutropenic plasma, 103 and 35 PMN/mm3, respectively (both p less than 0.05). Pretreatment with superoxide dismutase, 1500 units/kg, and catalase, 5000 units/kg, both conjugated to polyethylene glycol (n = 4), prevented ischemic plasma-induced LTB4 synthesis, as well as ischemic plasma-induced diapedesis, 12 PMN/mm3 (p less than 0.05). Finally, pretreatment with allopurinol, 25 mg/kg, was similarly effective in preventing LTB4 synthesis and PMN migration. These data suggest that oxygen free radicals are essential for ischemia-induced PMN synthesis of LTB4 that in turn mediates their diapedesis.