Factors in intestinal lymph after shock increase neutrophil adhesion molecule expression and pulmonary leukosequestration

BACKGROUND: Because the ischemic gut may produce factors that initiate systemic inflammation, we tested the hypothesis that factors released from the gut into the mesenteric lymphatics increase neutrophil (PMN) adhesion molecule expression after trauma and shock. METHODS: At 1 and 4 hours after hemorrhagic shock (30 mm Hg x 90 minutes) plus trauma (laparotomy) (T/HS) or sham-shock (T/SS), with or without mesenteric lymph duct ligation, PMN CD11b and CD18 expression was assessed in male rats. In additional rats, mesenteric lymph samples were tested for their ability to increase PMN CD11b expression in vitro. Lastly, at 4 hours after T/SS or T/HS with or without lymph duct ligation, pulmonary PMN sequestration was measured. RESULTS: Compared with T/SS rats, T/HS was associated with up-regulation of PMN CD11b and CD18 expression, which was largely prevented by ligation of the mesenteric lymph duct (p < 0.01). Lymph duct ligation also prevented T/HS-induced pulmonary leukocyte sequestration (p < 0.01). In addition, mesenteric lymph from rats subjected to T/HS but not T/SS increased CD11b expression (p < 0.01). CONCLUSION: Factors produced or released by the postischemic intestine and carried in the mesenteric lymph appear responsible for PMN activation and pulmonary PMN sequestration after an episode of T/HS.     

Inosine exerts a broad range of antiinflammatory effects in a murine model of acute lung injury

OBJECTIVE: To investigate the effects of inosine on the acute lung inflammation induced by lipopolysaccharide (LPS) in vivo and on the activation and cytotoxicity elicited by proinflammatory cytokines on human lung epithelial (A549) cells in vitro. SUMMARY BACKGROUND DATA: Inosine is an endogenous purine recently shown to exert immunomodulatory and antiinflammatory effects. METHODS: Mice challenged with intratracheal LPS (50 microg) were treated after 1, 6, and 12 hours with inosine (200 mg/kg intraperitoneal) or vehicle. After 24 hours, bronchoalveolar lavage fluid was obtained to measure proinflammatory (tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-1beta, IL-6), and antiinflammatory (IL-10, IL-4) cytokines, chemokines (MIP-1alpha and MIP-2), myeloperoxidase activity and total cell counts, nitric oxide production, and proteins. Lung histology and immunohistochemical detection of 3-nitrotyrosine, a marker of nitrosative stress, were performed in inflated-fixed lungs. In vitro, cell viability and production of the chemokine IL-8 were evaluated in A549 cells stimulated with a mixture of cytokines in the presence or absence of inosine. RESULTS: Inosine downregulated the LPS-induced expression of TNF-alpha, IL-1beta, IL-6 and MIP-2 and tended to reduce MIP-1alpha, whereas it enhanced the production of IL-4. Total leukocyte counts, myeloperoxidase, nitric oxide production, and proteins were all significantly decreased by inosine. The purine also improved lung morphology and suppressed 3-nitrotyrosine staining in the lungs after LPS. Inosine attenuated the cytotoxicity and the expression of IL-8 induced by proinflammatory cytokines in A549 cells. CONCLUSIONS: Inosine largely suppressed LPS-induced lung inflammation in vivo and reduced the toxicity of cytokines in lung cells in vitro. These data support the proposal that inosine might represent a useful adjunct in the therapy of acute respiratory distress syndrome.     

Isolated traumatic brain injury: age is an independent predictor of mortality and early outcome

BACKGROUND: Geriatric trauma patients have a worse outcome than the young with comparable injuries. The contribution of traumatic brain injury (TBI) to this increased mortality is unknown and has been confounded by the presence of other injuries. The purpose of this study was to investigate the role of age in the mortality and early outcome from isolated TBI. METHODS: This was a retrospective analysis of all adult patients with isolated TBI (Abbreviated Injury Scale score > or = 3) admitted during a 5-year period to two Level I trauma centers. Mortality, Glasgow Outcome Scale score at discharge, therapy, and complications were compared for elderly (age > or = 65 years) and younger patients. RESULTS: Of 694 patients, 22% were defined as elderly. The mortality for the elderly group was twice that of their younger counterparts (30% vs. 14%, p < 0.001), even for those with mild to moderate TBI (Glasgow Coma Scale score of 9-15). Thirteen percent of elderly survivors had a poor functional outcome (Glasgow Outcome Scale score of 2 or 3) at hospital discharge versus 5% in the young group (p < 0.01). Independent factors associated with a high mortality were age and Glasgow Coma Scale score. CONCLUSION: The mortality from TBI is higher in the geriatric population at all levels of head injury. In addition, functional outcome at hospital discharge is worse. Although some of this increased mortality may be explained by complications or type of head injury, age itself is an independent predictor for mortality in TBI.     

Membrane-associated sickle hemoglobin: a major determinant of sickle erythrocyte rigidity

Micropipette aspiration tests on single erythrocytes have previously shown that the static rigidity (membrane shear modulus) of oxygenated sickle cells increased with increasing hemoglobin concentration, whereas the rigidity of normal cells was independent of hemoglobin concentration. Moreover, it was observed that after mechanical extension, sickle cells exhibited persistent deformation more frequently and to a greater extent than normal cells. To ascertain if differences in association of normal and sickle hemoglobin with the membrane could account for these observations, we measured rheologic properties of normal membranes reconstituted with sickle hemoglobin and sickle membranes reconstituted with normal hemoglobin. The static rigidity of normal ghosts reloaded with sickle hemoglobin was higher than those of either normal ghosts reloaded with normal hemoglobin or native normal cells. On the other hand, the increased rigidity of native sickle cells decreased to near-normal values following reconstitution with normal hemoglobin. Furthermore, we observed that normal ghosts reconstituted with sickle hemoglobin exhibited persistent bumps after mechanical extension, but no bumps formed on normal ghosts reconstituted with normal hemoglobin. Moreover residual bumps were not produced on sickle cells reloaded with normal hemoglobin. Since mechanical characteristics peculiar to sickle cells could be induced in normal cells by incorporation of sickle hemoglobin, and since normal characteristics could be restored to sickle cells by incorporation of normal hemoglobin, we suggest that the interaction of sickle hemoglobin with the cell membrane is responsible for augmented static rigidity of oxygenated sickle erythrocytes.     

Deferred consent in a minimal-risk study involving critically ill subarachnoid hemorrhage patients

INTRODUCTION:

Alterations from first-party and surrogate decision-maker consent can enhance the feasibility of research involving critically ill patients.

OBJECTIVE:

To describe the use of a deferred-consent model to enable participation of critically ill patients in a minimal-risk biomarker study.

METHODS:

A prospective observational study was conducted in which serum biomarker samples were collected three times daily over the first 14 days following aneurysmal subarachnoid hemorrhage. Sample collection was initiated on intensive care unit admission and consent was obtained when research personnel could approach the patient or the patient’s surrogate decision maker.

RESULTS:

Twenty-seven patients were eligible for the study, of whom only five were capable of providing informed consent. Full consent was obtained for 21 (78%) patients through self- (n=4) and surrogate (n=17) consent. Partial consent or refusal (only permitting the collection of blood samples as a part of routine care or use of data) occurred in three patients. Among the 22 consents sought from surrogates, three (11%) refused participation. The refusals included the sickest patients in the cohort. Once consent was provided, no patient or surrogate withdrew consent before study completion.

DISCUSSION:

Use of a deferred consent model enabled participation of critically ill patients in a minimal-risk biomarker study with no withdrawals.

CONCLUSIONS:

Further research and enhanced awareness of the potential utility of hybrid models, including deferred consent in addition to patient or surrogate consent, in the conduct of low-risk and minimally interventional time-sensitive studies of critically ill patients are required.     

Do medical procedures in the arm increase the risk of lymphoedema after axillary surgery? A review

Lymphoedema of the arm is a potentially serious consequence of any axillary procedure performed during the management of breast cancer. In an attempt to reduce its incidence and severity, patients are instructed to avoid venepunctures and blood pressure measurements on the treated arm. These precautions are not possible in some patients and attempts to adhere to them can cause discomfort, anxiety and stress for both patients and their health‐care workers. The strength with which these recommendations are made is in contrast to the level of evidence underpinning them. This paper reviews this evidence regarding the safety, or lack thereof, of blood pressure monitoring and intravenous puncture in women who have had axillary surgery. With this evidence generally being anecdotal in nature, there appears to be no rigorous evidence‐based support for the risk‐reduction behaviours of avoiding blood pressure monitoring and venepuncture in the affected arm in the prevention of lymphoedema after axillary procedure. A clinical trial was proposed to investigate whether such avoidance measures were valuable, but failed during its inception. There remains a need for research from prospective trials on this controversial topic to determine the most appropriate patient recommendations that should be provided after axillary procedure regarding the risks for development of lymphoedema.     

Oral pretreatment with recombinant human lactoferrin limits trauma-hemorrhagic shock–induced gut injury and the biological activity of mesenteric lymph

Background

Lactoferrin (LF) is a pleiotropic glycoprotein that is found in bodily secretions and is postulated to enhance the gastrointestinal barrier and promote mucosal immunity. Thus, the ability of talactoferrin, an oral recombinant form of human LF, to limit gut injury and the production of biologically active gut-derived products was tested using a rat model of trauma–hemorrhagic shock (T/HS).

Methods

Male rats were orally dosed with vehicle or talactoferrin (1000 mg/kg, every day) for 5 d before being subjected to T/HS or trauma–sham shock (T/SS). Subsequently, rats were subjected to a laparotomy (trauma) and hemorrhagic shock (mean arterial pressure, 30–35 mm Hg × 90 min) or to T/SS, followed by resuscitation with their shed blood. Before inducing shock, the mesenteric lymphatic duct was catheterized for collection of mesenteric lymph. Four hours after the end of the shock or sham-shock period, rats were sacrificed, a segment of the distal ileum was collected for morphologic analysis, and lymph samples were processed and frozen. Subsequently, lymph samples were tested in several pharmacodynamic assays, including endothelial cell permeability, neutrophil respiratory burst activity, and red blood cell (RBC) deformability. Total white blood cell counts in lymph samples were also quantified.

Results

Pretreatment with talactoferrin reduced the incidence of T/HS-induced morphologic injury of ileum to T/SS levels. Post-T/HS lymph from vehicle-treated rats increased endothelial monolayer permeability and neutrophil priming for an augmented respiratory burst, and induced loss of RBC deformability, compared with T/SS groups. Talactoferrin pretreatment significantly reduced the biological activity of T/HS lymph on respiratory burst activity and RBC deformability, but had no effect on the lymph cell count or endothelial cell permeability.

Conclusions

These results provide a proof of principle that prophylactic dosing of oral talactoferrin can potentially protect the gut in a T/HS model and limit the production of biologically active factors in rat gastrointestinal tissue subjected to ischemia-reperfusion–type injuries.