Magnitude of the inflammatory response to cardiopulmonary bypass and its relation to adverse clinical outcomes

INTRODUCTION: Cardiopulmonary bypass (CPB) induces an inflammatory response believed to contribute to postoperative morbidity. We hypothesized that the magnitude of the inflammatory response following CPB would be associated with adverse clinical outcomes. METHODS: Twenty-nine patients had plasma TNF, IL-6, IL-8, elastase, histamine, complement C5a, and complement C3a measured by ELISA before, during, and after cardiac operations employing CPB. Inflammatory mediator levels were analyzed with respect to outcomes. RESULTS: Mediator levels peaked at 4 h post-CPB and either returned to baseline or substantially decreased by 24 h. Patients with peak mediator levels above the median for the group as a whole were classified as 'hyper-responders'; those with levels below the median were classified as 'normal responders'. While IL-8, C3a, and IL-6 levels were independently associated with adverse outcomes, TNF, histamine, and C5a levels were not. Elastase levels trended towards adverse outcomes. IL-8 'hyper-responders' experienced significantly greater postoperative weight gain and had higher IL-8 levels at 24 h (p<0.05), with trends towards renal impairment and protracted supplemental oxygen requirements. C3a 'hyper-responders' strongly trended towards increased bleeding, delayed extubation, greater postoperative weight gain, and decreased levels of independent functioning at discharge (p < or = 0.10). IL-6 'hyper-responders' experienced significantly more postoperative bleeding, delayed extubation, and higher IL-6 levels at 24 h compared to 'normal responders' (p < 0.05). They strongly trended towards greater postoperative weight gain and decreased levels of independent functioning at discharge (p < or = 0.10). CONCLUSIONS: Patients who have an exaggerated inflammatory response to CPB tend to bleed more, require more respiratory support, demonstrate greater capillary leak via weight gain, and display a decline in independent functioning relative to normal responders. Thus, it appears that the magnitude of the inflammatory response to CPB adversely influences clinical outcomes.     

fMRI activation in the human frontal eye field is correlated with saccadic reaction time

Variation in response latency to identical sensory stimuli has been attributed to variation in neural activity mediating preparatory set. Here we report evidence for a relationship between saccadic reaction time (SRT) and set-related brain activity measured with event-related functional magnetic resonance imaging. We measured hemodynamic activation time-courses during a preparatory "gap" period, during which no visual stimulus was present and no saccades were made. The subjects merely anticipated appearance of the target. Saccade direction and latency were recorded during scanning, and trials were sorted according to SRT. Both the frontal (FEF) and supplementary eye fields showed pre-target preparatory activity, but only in the FEF was this activity correlated with SRT. Activation in the intraparietal sulcus did not show any preparatory activity. These data provide evidence that the human FEF plays a central role in saccade initiation; pre-target activity in this region predicts both the type of eye movement (whether the subject will look toward or away from the target) and when a future saccade will occur.     

Steroids to reduce the impact on delirium (STRIDE): a double-blind,randomised, placebo-controlled feasibility trial of pre-operative dexamethasone in people with hip fracture

Neuro-inflammation may be important in the pathogenesis of postoperative delirium following hip fracture surgery. Studies have suggested a potential role for steroids in reducing postoperative delirium; however, the potential efficacy and safety of pre-operative high-dose dexamethasone in this specific population is largely unknown. Conducting such a study could be challenging, considering the multidisciplinary team involvement and the emergency nature of the surgery. The aim of this study was to assess feasibility and effectiveness of dexamethasone given as early as possible following hospital admission for hip fracture, to inform whether a full-scale trial is warranted. This single-centre, randomised, double-blind, placebo-controlled study randomly allocated 79 participants undergoing hip fracture surgery to dexamethasone 20 mg or placebo pre-operatively. Eligibility and recruitment rates, timing of the intervention and adverse events were recorded. Incidence and severity of postoperative delirium were assessed using the 4AT delirium screening tool and the Memorial Delirium Assessment Scale. Postoperative pain, length of stay and mortality were also assessed. The eligibility rate for inclusion was 178/527 (34%), and 57/178 (32%) of eligible patients presented to hospital when no researcher was available (e.g. after-hours, weekends, public holidays). Recruitment was limited mainly by ethical limitations (not including patients with impaired cognition) and lack of weekend staffing. Median (IQR [range]) time from emergency department admission to drug administration was 13.3 (5.9–17.6 [1.8–139.6]) hours. There was a significant difference in delirium severity scores, favouring the dexamethasone group: median (IQR [range]) 5 (3–6 [3–7]) vs. 9 (6–13 [5–14]) in the placebo group, with the probability of superiority effect size being 0.89, p = 0.010. Delirium incidence did not differ between groups: 6/40 (15%) in the dexamethasone group vs. 9/39 (23%) in the placebo group, relative risk (95%CI) 0.65 (0.22–1.65), p = 0.360). A larger randomised controlled trial is feasible and ideally this should include people with existing cognitive impairment, seven days-a-week cover and a multicentre design.     

Lambert-Eaton myaesthenic syndrome: a possible association with Hodgkin's lymphoma

Lambert-Eaton myasthenic syndrome is a presynaptic neuromuscular junction disorder typically associated with small cell lung carcinoma. The characterstic electrophysiological abnormality is a low amplitude compound muscle action potential that shows a marked increment after maximal voluntary contraction or brief tetanic nerve stimulation. We describe a patient who had LEMS in association with Hodgkin's disease. A 61 year old woman presented with proximal muscle weakness 6 years following successful treatment of Hodgkin's disease. Her symptoms responded well to treatment with diaminopyridine. 9 additional patients have been described with LEMS in association with lymphoproliferative diseases. A systemic malignancy is usually found within 2 years of LEMS diagnosis but may present later. LEMS should be considered in patients with Hodgkin's disease presenting with muscle weakness.     

The presence of an extensive intraductal component following a limited excision correlates with prominent residual disease in the remainder of the breast

Previous studies of patients with infiltrating ductal breast cancer treated with conservative surgery (ie, limited excision) and radiotherapy have indicated that the presence of an extensive intraductal component (EIC) in the excision specimen is highly associated with subsequent breast recurrence. The reason for this association is not clear, but possible explanations include the presence of more extensive disease in the breast or increased radiation resistance among tumors with an EIC (EIC+) compared with those without (EIC-) tumors. To investigate this association further, we related the presence or absence of an EIC in the primary tumors of 214 women who underwent mastectomy to the likelihood of finding additional foci of cancer in their mastectomy specimens using a correlated pathologic-radiologic mapping technique. Primary tumors that were EIC+ were significantly more likely to have carcinoma in the remainder of the breast than those which were EIC--(74% v 42%; P = .00001). This difference was primarily due to the presence of residual intraductal carcinoma. Seventy-one percent of EIC+ patients had residual intraductal carcinoma compared with 28% of EIC-patients (P less than .00001). In particular, 44% of EIC+ patients had "prominent" residual intraductal carcinoma compared with 3% of EIC-patients (P less than .00001). We conclude that patients whose tumors contain an EIC more frequently have a large subclinical tumor burden in the remainder of the breast compared with patients whose tumors do not contain an EIC. This observation may explain the association between EIC and subsequent breast recurrence when patients are treated with a limited excision before radiotherapy.     

Early breast cancer: predictors of breast recurrence for patients treated with conservative surgery and radiation therapy

The identification of factors associated with breast recurrence following conservative surgery (CS) and radiation therapy (RT) is of potential use in refining patient selection criteria and treatment technique. In an attempt to define such factors we examined the relationship between various clinical, pathologic and treatment characteristics and the likelihood of breast recurrence in 783 patients with clinical stage I or II breast cancer treated between July 1968 and December 1982. Treatment consisted of complete gross excision of the primary tumor and RT to a total dose of at least 60 Gy to the primary site. During this period, pre-treatment mammograms and detailed histologic assessment of the margins of resection were not routinely performed. Median follow-up for surviving patients was 80 months. Thirteen patients (1.6%) were lost to follow-up. Ninety-one patients (12%) have developed a breast recurrence, corresponding to 5- and 10-year actuarial rates of 10 and 18%, respectively. The major feature associated with breast recurrence was the presence of an "extensive intraductal component" (EIC+). An EIC+ tumor was seen in 28% of evaluable cases with infiltrating ductal carcinoma and accounted for 60% of breast recurrences. Forty-three of 166 patients (26%) with EIC+ tumors developed a breast recurrence compared with 29 of 418 patients (7%) without an EIC (EIC-) (p = 0.0001). The 5-year actuarial rates of breast relapse were 24 and 6%, respectively (p = 0.0001). Very young age (defined as 34 years of age or younger) was also a significant factor associated with the risk of breast recurrence. Very young patients comprised 8% of the patient population and accounted for 16% of breast recurrences. Fifteen of 61 very young patients (25%) developed a breast recurrence compared with 76 of 722 older patients (11%) (p = 0.001). The corresponding 5-year actuarial rates of breast recurrence were 21 and 9% (p = 0.005). None of the other clinical or pathological factors examined by univariate analysis were significantly correlated with recurrence in the breast. A multivariate model of site of first failure (polychotomous logistic regression) also showed that EIC+ tumors and very young age were the main factors associated with a high relative risk of breast recurrence. We conclude that EIC+ tumors and very young age are associated with a high risk of breast recurrence for patients treated with limited excision prior to RT.     

Effects of dietary fish oil on fatty acids and eicosanoids in metastasizing human breast cancer cells

We examined the relationships between the suppressive effects of dietary fish oil on growth and metastasis of MDA-MB-435 human breast cancer cells in female nude mice and the primary tumor phospholipid fatty acid concentrations, phospholipase A2 activity, and eicosanoid levels. Mice (n = 120) were fed a 23% (wt/wt) corn oil (CO) linoleic acid (LA)-rich diet for seven days before and after 10(6) tumor cells were injected into a mammary fat pad, and then the mice receive one of three isocaloric diets containing 23% total fat but different proportions of CO and menhaden oil (MO) (18% CO-5% MO, 11.5% CO-11.5% MO, 5% CO-18% MO) or a 23% fat diet containing 18% deodorized fish oil supplemented with tocopherol and tert-butylhydroquinone antioxidants (FAO). Primary tumor growth rate was significantly greater in mice fed the 18% CO diet than in the three diets containing higher levels of fish oil (all p < 0.05). The 18% MO diet, but not the 11.5% MO or the 18% FAO diet, suppressed the development of lung metastases compared with the 18% CO diet. Increasing the proportion of MO relative to CO in the diets produced corresponding increases in the primary tumor phospholipid eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) concentrations and reductions in LA and arachidonic acid. There was a significant positive correlation between the LA concentration in these tumors and the extent of lung metastasis (r = 0.504). Tumor phospholipase A2 activity was unaffected by dietary MO intake. Prostaglandin E2 concentration was inversely correlated with phospholipid EPA (r = -0.484) and DHA (r = -0.439), but there was no relationship with lung metastasis. Tumor leukotriene B4 and 5-hydroxyeicosatetraenoic acid levels were not reduced by dietary MO. The 18% FAO- and the 18% MO-fed mice showed similar relationships for the phospholipid fatty acids and prostaglandin E2, despite the lack of effect on metastasis. The strong correlation between phospholipid LA levels and metastasis and the lack of an association with tumor eicosanoids suggest that the 18% MO diet inhibited metastasis because dietary LA was replaced by other fatty acids.     

Lack of microsatellite instability in human prostate-cancer

DNA replication errors are especially frequent in repetitive DNA sequences, including microsatellites. Thus, microsatellites are sensitive indicators of the genetic instability observed in many types of human cancers, particularly colorectal cancer. We tested prostate carcinomas for the presence of microsatellite alleles not present in normal tissue from the same individuals. Analysis of 7 microsatellites in each of 30 patients revealed instability at only one microsatellite in one tumor. This level of microsatellite instability, considerably lower than that reported previously, may reflect differences in patient pools. We discuss the implications of the genetic stability of prostate cancers relative to other cancers.     

CD18-mediated neutrophil recruitment contributes to the pathogenesis of reperfused but not nonreperfused stroke

BACKGROUND AND PURPOSE: Neutrophil (PMN) recruitment mediated by increased expression of intercellular adhesion molecule-1 expression (ICAM-1, CD54) in the cerebral microvasculature contributes to the pathogenesis of tissue injury in stroke. However, studies using blocking antibodies against the common beta2-integrin subunit on the PMN, the counterligand for ICAM-1 (CD18), have demonstrated equivocal efficacy. The current study tested the hypothesis that mice deficient in CD18 would be protected in the setting of reperfused but not nonreperfused stroke. METHODS: Two groups of mice were studied, those whose PMNs could express CD18 (CD18 +/+) and those mice hypomorphic for the CD-18 gene (CD18 -/-). PMNs obtained from CD18 -/- or CD18 +/+ mice were fluorescently labeled and tested for binding to murine brain endothelial monolayers. Using a murine model of focal cerebral ischemia in which an occluding suture placed in the middle cerebral artery (MCA) is removed after 45 minutes (transient ischemia, reperfused stroke) or left in place (permanent ischemia, nonreperfused stroke), cerebral infarct volumes (% ipsilateral hemisphere by TTC staining), cerebral blood flow (CBF, % contralateral hemisphere by laser-Doppler flowmetry), and survival (%) were examined 24 hours after the initial ischemic event. Adoptive transfer studies used 111In-labeled PMNs (from either CD18 +/+ or CD18 -/- mice) to examine the relative accumulation of PMNs in the ischemic region. RESULTS: PMNs obtained from CD18 -/- mice exhibit reduced adhesivity (compared with CD18 +/+ PMNs) for both quiescent and cytokine-activated endothelial monolayers. CD18 -/- mice (n=14) subjected to transient focal cerebral ischemia demonstrated a 53% decrease in infarct volumes versus CD18 +/+ mice (n=26, P<0.05), improved penumbral CBF at 24 hours (1.8-fold, P=0.02), and a 3.7-fold decrease in mortality (P=0.02). However, when CD18 -/- mice (n=12) were subjected to permanent focal cerebral ischemia, no differences were noted in infarct volume, mortality, or CBF versus similarly treated CD18 +/+ mice (n=10). There was a greater accumulation of CD18 +/+ PMNs in the ischemic zone of CD18 +/+ animals than CD18 -/- animals subjected to reperfused stroke (82% increase, P=0.02), although there was no difference between groups when subjected to permanent MCA occlusion. CONCLUSIONS: Deficiency for the CD18 gene confers cerebral protection in a murine model of reperfused stroke, but this benefit does not extend to CD18-deficient animals subjected to permanent MCA occlusion. These data suggest that anti-PMN strategies should be targeted to reperfused stroke and may perhaps be used in conjunction with thrombolytic therapy that establishes reperfusion.