Risks of restrictive red blood cell transfusion strategies in patients with cardiovascular disease (CVD): a meta-analysis.

AIM: To evaluate the risks of restrictive red blood cell transfusion strategies (haemoglobin 7-8 g dL-1 ) in patients with and without known cardiovascular disease (CVD). BACKGROUND: Recent guidelines recommend restrictive strategies for CVD patients hospitalised for non-CVD indications, patients without known CVD and patients hospitalised for CVD corrective procedures. METHODS/MATERIALS: Database searches were conducted through December 2017 for randomised clinical trials that enrolled patients with and without known CVD, hospitalised either for CVD-corrective procedures or non-cardiac indications, comparing effects of liberal with restrictive strategies on major adverse coronary events (MACE) and death. RESULTS: In CVD patients not undergoing cardiac interventions, a liberal strategy decreased (P = 0·01) the relative risk (95% CI) (RR) of MACE [0·50 (0·29-0·86)] (I2  = 0%). Among patients without known CVD, the incidence of MACE was lower (1·7 vs 3·9%), and the effect of a liberal strategy on MACE [0·79, (0·39-1·58)] was smaller and non-significant but not different from CVD patients (P = 0·30). Combining all CVD and non-CVD patients, a liberal strategy decreased MACE [0·59, (0·39-0·91); P = 0·02]. Conversely, among studies reporting mortality, a liberal strategy decreased mortality in CVD patients (11·7% vs·13·3%) but increased mortality (19·2% vs 18·0%) in patients without known CVD [interaction P = 0·05; ratio of RR 0·73, (0·53-1·00)]. A liberal strategy also did not benefit patients undergoing cardiac surgery; data were insufficient for percutaneous cardiac procedures. CONCLUSIONS: In patients hospitalised for non-cardiac indications, liberal transfusion strategies are associated with a decreased risk of MACE in both those with and without known CVD. However, this only provides a survival benefit to CVD patients not admitted for CVD-corrective procedures.

Genetic population structure in an equatorial sparrow: roles for culture and geography.

Female preference for local cultural traits has been proposed as a barrier to breeding among animal populations. As such, several studies have found correlations between male bird song dialects and population genetics over relatively large distances. To investigate whether female choice for local dialects could act as a barrier to breeding between nearby and contiguous populations, we tested whether variation in male song dialects explains genetic structure among eight populations of rufous-collared sparrows (Zonotrichia capensis) in Ecuador. Our study sites lay along a transect, and adjacent study sites were separated by approximately 25 km, an order of magnitude less than previously examined for this and most other species. This transect crossed an Andean ridge and through the Quijos River Valley, both of which may be barriers to gene flow. Using a variance partitioning approach, we show that song dialect is important in explaining population genetics, independent of the geographic variables: distance, the river valley and the Andean Ridge. This result is consistent with the hypothesis that song acts as a barrier to breeding among populations in close proximity. In addition, songs of contiguous populations differed by the same degree or more than between two populations previously shown to exhibit female preference for local dialect, suggesting that birds from these populations would also breed preferentially with locals. As expected, all geographic variables (distance, the river valley and the Andean Ridge) also predicted population genetic structure. Our results have important implications for the understanding whether, and at what spatial scale, culture can affect population divergence.

Persistence of Pseudomonas aeruginosa in a pulmonary nodule with late relapse.

Lung nodules are common diagnostic challenges in hematopoietic stem cell transplantation and solid organ transplantation. Pseudomonas aeruginosa is a known cause of lung abscess in these patients, but its ability to persist for months in a quiescent lung nodule and later cause recurrent infection is not well known or documented. A patient with a history of acute pre-B-cell lymphoblastic leukemia had enlargement and cavitation of a small right upper lobe pulmonary nodule 10 months after allogeneic hematopoietic stem cell transplantation. The nodule was the remnant of a presumed P. aeruginosa septic embolus that occurred 2.5 months after transplantation. With antibiotic treatment, the nodule had shrunk in size to <1 cm and remained stable. Transthoracic needle aspiration grew P. aeruginosa indistinguishable by molecular typing from isolates obtained 7.5 months earlier from blood and bronchoalveolar lavage fluid. Sub-centimeter pulmonary nodules attributable to previously treated P. aeruginosa may harbor viable organisms and lead to recrudescent infection.

Cooperative and redundant signaling of leukotriene B4 and leukotriene D4 in human monocytes.

BACKGROUND: Leukotriene B(4) (LTB(4)) and cysteinyl leukotrienes (cysLTs) are important immune mediators, often found concomitantly at sites of inflammation. Although some of the leukotriene-mediated actions are distinctive (e.g., bronchial constriction for cysLTs), many activities such as leukocyte recruitment to tissues and amplification of inflammatory responses are shared by both classes of leukotrienes. OBJECTIVE: We used human monocytes to characterize leukotriene-specific signaling, gene expression signatures, and functions and to identify interactions between LTB(4)- and cysLTs-induced pathways. METHODS: Responsiveness to leukotrienes was assessed using oligonucleotide microarrays, real-time PCR, calcium mobilization, kinase activation, and chemotaxis assays. RESULTS: Human monocytes were found to express mRNA for high- and low-affinity LTB(4) receptors, BLT(1) and BLT(2), but signal predominantly through BLT(1) in response to LTB(4) stimulation as shown using selective agonists, inhibitors, and gene knock down experiments. LTB(4) acting through BLT(1) coupled to G-protein α inhibitory subunit activated calcium signaling, p44/42 mitogen-activated protein kinase, gene expression, and chemotaxis. Twenty-seven genes, including immediate early genes (IEG), transcription factors, cytokines, and membrane receptors were significantly up-regulated by LTB(4). LTB(4) and LTD(4) had similar effects on signaling, gene expression, and chemotaxis indicating redundant cell activation pathways but costimulation with both lipid mediators was additive for many monocyte functions. CONCLUSION: Leukotriene B(4) and LTD(4) display both redundant and cooperative effects on intracellular signaling, gene expression, and chemotaxis in human monocytes. These findings suggest that therapies targeting either leukotriene alone may be less effective than approaches directed at both.

Acute G-CSF therapy is not protective during lethal E. coli sepsis.

We investigated whether decreases in circulating polymorphonuclear neutrophils (PMN) during lethal Escherichia coli (E. coli) sepsis in canines are related to insufficient host granulocyte colony-stimulating factor (G-CSF). Two-year-old purpose-bred beagles had intraperitoneal E. coli-infected or -noninfected fibrin clots surgically placed. By 10 to 12 h following clot, both infected survivors and nonsurvivors had marked increases (P = 0.001) in serum G-CSF levels (mean peak G-CSF ng/ml +/- SE, 1,931 +/- 364 and 2,779 +/- 681, respectively) compared with noninfected controls (134 +/- 79), which decreased at 24 to 48 h. Despite increases in G-CSF, infected clot placement caused delayed (P = 0.06) increases in PMN (mean +/- SE change from baseline in cells x 10(3)/mm(3) at 24 and 48 h) in survivors (+3.9 +/- 3.9 and +13.8 +/- 3.6) compared with noninfected controls (+13.1 +/- 2.8 and +9.1 +/- 2.5). Furthermore, infected nonsurvivors had decreases in PMN (-1.4 +/- 1.0 and -1.1 +/- 2.3, P = 0.006 compared with the other groups). We next investigated whether administration of G-CSF immediately after clot placement and continued for 96 h to produce more rapid and prolonged high levels of G-CSF after infection would alter PMN levels. Although G-CSF caused large increases in PMN compared with control protein from 2 to 48 h following clot in noninfected controls, it caused much smaller increases in infected survivors and decreases in infected nonsurvivors (P = 0.03 for the ordered effect of G-CSF comparing the three groups). Thus insufficient host G-CSF is unlikely the cause of decreased circulating PMN in this canine model of sepsis. Other factors associated with sepsis either alone or in combination with G-CSF itself may reduce increases or cause decreases in circulating PMN.

Signaling by eNOS through a superoxide-dependent p42/44 mitogen-activated protein kinase pathway.

Expression of endothelial nitric oxide synthase (eNOS) in transfected U-937 cells upregulates phorbol 12-myristate 13-acetate (PMA)-induced tumor necrosis factor-alpha (TNF-alpha) production through a superoxide (O(2)(-))-dependent mechanism. Because mitogen-activated protein kinases (MAPK) have been shown to participate in both reactive oxygen species signaling and TNF-alpha regulation, their possible role in eNOS-derived O(2)(-) signal transduction was examined. A redox-cycling agent, phenazine methosulfate, was found to both upregulate TNF-alpha (5.8 +/- 1.0 fold; P = 0.01) and increase the phosphorylation state of p42/44 MAPK (3.1 +/- 0.2 fold; P = 0.01) in PMA-differentiated U-937 cells. Although S-nitroso-N-acetylpenicillamine, a nitric oxide (NO) donor, also increased TNF-alpha production, NO exposure led to phosphorylation of p38 MAPK, not p42/44 MAPK. Upregulation of TNF-alpha production by eNOS transfection was associated with increases in activated p42/44 MAPK (P = 0.001), whereas levels of phosphorylated p38 MAPK were unaffected. Furthermore, cotransfection with Cu/Zn superoxide dismutase, which blocks TNF-alpha upregulation by eNOS, also abolished the effects on p42/44 MAPK. Expression of Gln(361)eNOS, a mutant that produces O(2)(-) but not NO, still resulted in p42/44 MAPK phosphorylation. In contrast, two NADPH binding site deletion mutants of eNOS that lack oxidase activity had no effect on p42/44 MAPK. Finally, PD-98059, a p42/44 MAPK pathway inhibitor, blocked TNF-alpha upregulation by eNOS (P = 0.02). Thus O(2)(-) produced by eNOS increases TNF-alpha production via a mechanism that involves p42/44 MAPK activation.

Questionnaire test-retest reliability: outcome measure of a vocational rehabilitation programme.

In a clinical follow-up case series study, the test-retest reliability of an outcome measure questionnaire was tested. The study group consisted of 48 patients who had taken part in a vocational rehabilitation programme. Test-retest reliability of a questionnaire was evaluated with the reliability index two years after entering the programme. It was found that the test-retest reliability of demographic data was rather good, although the questions concerning basic and occupational training showed instability over time. The answers concerning general health symptoms, mental working capacity and perceived changes in life during the past 12 months showed particularly high variability. The respondents' opinions on their general outlook of life seemed rather stable. Opinions about the perceived benefits from the intervention were marginally stable. The respondents' opinions about the benefits perceived from the physicians' work were more stable than the opinions about the perceived help from the other members of the rehabilitative team. It was concluded that an outcome analysis questionnaire is a useful tool to document the respondents' general and present perception of life and their present health situation as well as the rehabilitation process. The further development of generally applicable outcome measures for health promotion programmes will require unified, long-term efforts.

Superoxide production and reactive oxygen species signaling by endothelial nitric-oxide synthase.

Reactive oxygen species can function as intracellular messengers, but linking these signaling events with specific enzymes has been difficult. Purified endothelial nitric-oxide synthase (eNOS) can generate superoxide (O(2)) under special conditions but is only known to participate in cell signaling through NO. Here we show that eNOS regulates tumor necrosis factor alpha (TNFalpha) through a mechanism dependent on the production of O(2) and completely independent of NO. Expression of eNOS in transfected U937 cells increased phorbol 12-myristate 13-acetate-induced TNFalpha promoter activity and TNFalpha production. N(omega)-Methyl-l-arginine, an inhibitor of eNOS that blocks NO production but not its NADPH oxidase activity, did not prevent TNFalpha up-regulation. Likewise, Gln(361)eNOS, a competent NADPH oxidase that lacks NOS activity, retained the ability to increase TNFalpha. Similar to the effect of eNOS, a O(2) donor dose-dependently increased TNFalpha production in differentiated U937 cells. In contrast, cotransfection of superoxide dismutase with eNOS prevented TNFalpha up-regulation, as did partial deletion of the eNOS NADPH binding site, a mutation associated with loss of O(2) production. Thus, eNOS may straddle a bifurcating pathway that can lead to the formation of either NO or O(2), interrelated but often opposing free radical messengers. This arrangement has possible implications for atherosclerosis and septic shock where endothelial dysfunction results from imbalances in NO and O(2) production.

Shopping for health information.

In this time of ongoing health care changes, consumers need to become better informed to actively participate in their health care decisions. As a result, hospital libraries are being challenged to address this need. Scottsdale Healthcare's Health Sciences Libraries have responded to this challenge by establishing a Health Information Center at the premiere shopping mall in the area. Implementing a Health Information Center at a mall is a unique way to bring medical information to the community. The purpose of this paper is to describe the planning process, the implementation, and the future vision of the Health Information Center at Scottsdale Fashion Square.

A Sp1 binding site of the tumor necrosis factor alpha promoter functions as a nitric oxide response element.

Regulation of gene transcription is an incompletely understood function of nitric oxide (NO). Human leukocytes produce increased amounts of tumor necrosis factor alpha (TNF-alpha) in response to NO. This effect is associated with decreases in intracellular cAMP, suggesting that NO might regulate gene transcription through promoter sequences sensitive to cAMP such as cAMP response elements (CRE) and Sp1 binding sites. Here we report that a Sp1 binding site in the TNF-alpha promoter conveys NO responsiveness. Human U937 cells were differentiated for TNF-alpha production with phorbol 12-myristate 13-acetate. NO donors and H89, an inhibitor of cAMP-dependent protein kinase increased, while dibutyryl cAMP (Bt(2)cAMP) decreased TNF-alpha promoter activity. Deletion or mutation of the proximal Sp1 site, but not the CRE site, abolished the activating effects of NO donors and H89. Further, NO- and H89-mediated increases in TNF-alpha promoter activity were associated with decreased Sp1 binding. The insertion of Sp1 sites into a minimal cytomegalovirus promoter conferred NO responsiveness, an effect blocked by Bt(2)cAMP. Mutation of these inserted Sp1 sites prevented this heterologous promoter from responding to NO, H89 and Bt(2)cAMP. These results identify the Sp1 binding site as a promoter motif that allows NO to control gene transcription.

[Psycho-neurogenic factors as a cause of life-threatening arrhythmias]. / Psycho-neurogene Faktoren bei der Genese lebensbedrohlicher Arrhythmien.

Tachyarrhytmias often occur during increased emotional arousal or mental excitation. The implantable cardioverter defibrillator (ICD) allows the exact documentation of arrhythmic episodes and their time of onset. Therefore, the type of arrhythmia can be differentiated as well as the circumstances surrounding the event. These features allow the assessment of possible psychic arrhythmogenic factors in the natural environment. We analyzed the ICD-protocols of three male patients (in ages between 60 and 68), whose devices had successfully terminated a ventricular tachycardia and compared the onset of the episodes with the patients' detailed descriptions of the corresponding life situations. The analysis of the circumstances at the time of arrhythmia-onset revealed a relationship between the occurrence of life-threatening arrhythmias in natural environment and emotional stress. The stressors could be defined as situations of increased vulnerability leading to sympathetic excitation. The induction of tachyarrhythmia was promoted in case 1 by acute psychic distress (public speaking), by the increasing panic-attack-like vicious circle of the cognitive anticipation of an unfavorable outcome (case 2), and an adverse anger reaction superimposed on persistent feelings of help- and hopelessness (case 3). These findings are in line with several experimental and epidemiological studies providing evidence for a relationship between psychic arousal and the induction of tachyarrhythmias. The knowledge of emotional and mental factors that function as a trigger for arrhythmias may lead to new therapeutic approaches in the prevention of sudden cardiac death.

ICAM-1 and CD11b inhibition worsen outcome in rats with E. coli pneumonia.

We investigated whether inhibiting an endothelial adhesion molecule [intracellular adhesion molecule 1 (ICAM-1)] would alter outcome and lung injury in a similar fashion to inhibition of a leukocyte adhesion molecule (integrin CD11b) in a rat model of gram-negative pneumonia. Inhibition of ICAM-1 with monoclonal antibody (MAb) 1A29 (1 mg/kg sc or 0.2 or 2 mg/kg iv, q 12 h x 3) or of CD11b with MAb 1B6 (1 mg/kg sc, q 12 h x 3) were compared against similarly administered placebo proteins in rats challenged with intrabronchial Escherichia coli. After challenge, all animals were treated with antibiotics. ICAM-1 MAb (6 mg/kg, iv, total dose) increased mortality vs. control (P = 0.03). CD11b MAb (3 mg/kg, sc, total dose) did not significantly (P = 0.16) increase mortality rates, but this was not in a range of probability to exclude a harmful effect. All other doses of MAb had no significant effect on survival rates. ICAM-1 and CD11b MAbs had significantly different effects on the time course of lung injury, circulating white cells and lymphocytes, and lung lavage white cells and neutrophils (P = 0.04-0.003). CD11b MAb decreased, whereas ICAM-1 MAb increased these measures compared with control from 6 to 12 h after E. coli. However, from 144 to 168 h after E. coli both MAbs increased these measures compared with control rats but to a greater level with CD11b MAb. Thus both ICAM-1 and CD11b appear to be necessary for survival during E. coli pneumonia. Although these adhesion molecules may participate differently in early lung injury, with CD11b increasing and ICAM-1 decreasing inflammation and injury, both are important for the resolution of later injury. During gram-negative pneumonia the protective roles of ICAM-1 and CD11b may make their therapeutic inhibition difficult.

Long-acting psychotraumatic properties of a cardiac arrest experience.

OBJECTIVE: Progress in resuscitation medicine allows an increasing proportion of patients to survive an out-of-hospital cardiac arrest. However, little is known about long-term adaptation to the vital breakdown. The present study assessed the long-term prevalence and severity of emotional disability of cardiac arrest survivors and ascertained whether survivors suffer from recurrent and intrusive recollections of the cardiac arrest. METHOD: Follow-up analysis was performed on all cardiac arrest survivors discharged from the hospital over a 5-year interval (1990-1994) in a defined inner city and suburban area. From 118 initially hospitalized cardiac arrest survivors, 45 patients were discharged alive from the hospital. After a mean follow-up period of 39 months (range = 22-64), 25 patients exhibited sufficient cerebral performance for psychodiagnostic assessment; 21 patients were assessed. RESULTS: Despite an impaired ability to concentrate, cardiac arrest survivors had levels of psychological adjustment at follow-up that were similar to those of 35 cardiac patients whose clinical course was not complicated by cardiac arrest. However, the diagnosis of psychotraumatic symptoms in cardiac arrest survivors led to a sharp separation between favorable and nonfavorable outcome in affective regulation and level of functioning. Of the cardiac arrest patients, those with high scores of intrusion and avoidance (N = 8) reported an enduring sense of demoralization with significantly more somatic complaints, depression, anxiety, lack of confidence in the future, and narrowing of social activities than those with low scores (N = 11). Long-acting sedation at illness onset significantly predicted a favorable outcome. CONCLUSIONS: This study provides the first empirical evidence that the application of the posttraumatic stress disorder paradigm in the long-term evaluation of cardiac arrest survivors significantly contributes to defining a patient population at high risk for serious emotional disability.

Down-regulation of nitric oxide production by ibuprofen in human volunteers.

Ibuprofen has been shown in vitro to modulate production of nitric oxide (NO), a mediator of sepsis-induced hypotension. We sought to determine whether ibuprofen alters NO production and, thereby, vascular tone, in normal and endotoxin-challenged volunteers. Techniques for detecting NO were validated in 17 subjects infused with sodium nitroprusside, a NO donor. Then, endotoxin (4 ng/kg) or saline (vehicle alone) was administered in a single-blinded, crossover design to 12 other subjects randomized to receive either ibuprofen (2400 mg p.o.) or a placebo. Endotoxin decreased mean arterial pressure (MAP; P =.002) and increased alveolar NO flow rates (P =.04) and urinary excretion of nitrite and nitrate (P =.07). In both endotoxemic and normal subjects, ibuprofen blunted the small fall in MAP associated with bed rest (P =.005) and decreased alveolar NO flow rates (P =.03) and urinary excretion of nitrite and nitrate (P =.02). However, ibuprofen had no effect on the decrease in MAP caused by endotoxin, although it blocked NO production to the point of disrupting the normal relationship between increases in exhaled NO flow rate and decreases in MAP (P =.002). These are the first in vivo data to demonstrate that ibuprofen down-regulates NO in humans. Ibuprofen impaired the NO response to bed rest, producing a small rise in blood pressure. Although ibuprofen also interfered with the ability of endotoxin to induce NO production, it had no effect on the fall in blood pressure, suggesting that the hemodynamic response to endotoxin is not completely dependent on NO under these conditions.

Sustaining and improving working capacity--programme description and two years follow-up.

In 1991 the Social Insurance Institution Rehabilitation Act introduced a working capacity sustaining and improving training programme (TYK). The goal of this programme is to sustain the physio-psycho-social competences of older workers and employees by creating a chain of in-house rehabilitation phases and training phases at the workplace. We describe the programme in its early state of implementation. Two years after entering the programme 17 patients were working, six were on sick leave, three were out of work, 16 were on pension, and six patients could not be retrieved.

Increasing doses of pentoxifylline as a continuous infusion in canine septic shock.

We investigated effects of pentoxifylline during septic shock. Two-year-old (10-12 kg), purpose-bred beagles were infected i.p. with Escherichia coli 0111:B4 (1.2-1.5 x 10(9) colony-forming units per kilogram b.wt.) in a fibrin clot and then immediately treated with one of five doses of pentoxifylline (0.5-20 mg. kg-1. h-1 i.v.) as a 36-h continuous infusion or placebo. All animals received antibiotics and fluid resuscitation. Pentoxifylline levels increased in a dose-dependent manner during (p =.001) and were undetectable 12 h after stopping the infusion. During infusion of pentoxifylline at all doses, there were increases (p =.003), and once the infusion was stopped, there were decreases (p =.049) in endotoxin levels compared with controls. After clot implantation, at all pentoxifylline doses there was a significant increase in tumor necrosis factor levels, compared with controls (p =.025). The relative risk of death was significantly increased with pentoxifylline therapy in a dose-dependent fashion (20 >/= 10 >/= 5.0 >/= 1.0 >/= 0.5 mg. kg-1, p =.008). One hypothesis consistent with these data is that high pentoxifylline levels slowed endotoxin clearance, resulting in high levels of endotoxemia and increased proinflammatory mediator release and death. Pentoxifylline, used as a long-term continuous infusion as is commonly done clinically, can be harmful during Gram-negative septic shock.

Interleukin-8 priming of human neutrophils is not associated with persistently altered calcium fluxes but is additive with lipopolysaccharide.

Interleukin-8 (IL-8) priming was studied in neutrophils to examine its dependency on altered calcium fluxes and for similarity to lipopolysaccharide (LPS). IL-8 caused a rapid rise in [Ca2+]i that returned to baseline values by 20 min. Peak [Ca2+]i transients in response to N-formyl-methionyl-leucyl-phenylalanine (fMLP) were unaltered in IL-8-primed compared with unprimed cells. In comparison to LPS and tumor necrosis factor (TNF), IL-8 was a much weaker priming agent as measured by either O2- or H2O2 production. Despite their large disparity in potency, IL-8 and LPS printing were additive using fMLP, a receptor-dependent stimulator, and synergistic using the post-receptor, protein kinase C activator, phorbol 12-myristate 13-acetate (PMA) to trigger the respiratory burst. In contrast, IL-8 and TNF priming were synergistic for fMLP (P = 0.05), but completely nonadditive when PMA was used as the neutrophil stimulant (P = 0.05 for subadditivity). Thus, lasting alterations in [Ca2+]i are not a necessary characteristic of IL-8-primed cells. IL-8 and LPS appear to prime by non-overlapping pathways, whereas IL-8 and TNF appear to share mechanisms distal to protein kinase C activation. IL-8 and LPS may independently contribute to neutrophil-mediated host defense or injury by priming through distinct pathways.