CELL TO CELL INTERACTION IN THE IMMUNE RESPONSE : II. THE SOURCE OF HEMOLYSIN-FORMING CELLS IN IRRADIATED MICE GIVEN BONE MARROW AND THYMUS OR THORACIC DUCT LYMPHOCYTES

The number of discrete hemolytic foci and of hemolysin-forming cells arising in the spleens of heavily irradiated mice given sheep erythrocytes and either syngeneic thymus or bone marrow was not significantly greater than that detected in controls given antigen alone. Thoracic duct cells injected with sheep erythrocytes significantly increased the number of hemolytic foci and 10 million cells gave rise to over 1000 hemolysin-forming cells per spleen. A synergistic effect was observed when syngeneic thoracic duct cells were mixed with syngeneic marrow cells: the number of hemolysin-forming cells produced in this case was far greater than could be accounted for by summating the activities of either cell population given alone. The number of hemolytic foci produced by the mixed population was not however greater than that produced by an equivalent number of thoracic duct cells given without bone marrow. Thymus cells given together with syngeneic bone marrow enabled irradiated mice to produce hemolysin-forming cells but were much less effective than the same number of thoracic duct cells. Likewise syngeneic thymus cells were not as effective as thoracic duct cells in enabling thymectomized irradiated bone marrow-protected hosts to produce hemolysin-forming cells in response to sheep erythrocytes. Irradiated recipients of semiallogeneic thoracic duct cells produced hemolysin-forming cells of donor-type as shown by the use of anti-H2 sera. The identity of the hemolysin-forming cells in the spleens of irradiated mice receiving a mixed inoculum of semiallogeneic thoracic duct cells and syngeneic marrow was not determined because no synergistic effect was obtained in these recipients in contrast to the results in the syngeneic situation. Thymectomized irradiated mice protected with bone marrow for a period of 2 wk and injected with semiallogeneic thoracic duct cells together with sheep erythrocytes did however produce a far greater number of hemolysin-forming cells than irradiated mice receiving the same number of thoracic duct cells without bone marrow. Anti-H2 sera revealed that the antibody-forming cells arising in the spleens of these thymectomized irradiated hosts were derived, not from the injected thoracic duct cells, but from bone marrow. It is concluded that thoracic duct lymph contains a mixture of cell types: some are hemolysin-forming cell precursors and others are antigen-reactive cells which can interact with antigen and initiate the differentiation of hemolysin-forming cell precursors to antibody-forming cells. Bone marrow contains only precursors of hemolysin-forming cells and thymus contains only antigen-reactive cells but in a proportion that is far less than in thoracic duct lymph.     

Nebulised heparin: a new approach to the treatment of acute lung injury?

The administration of heparin by nebulisation has been proposed for the 'local' treatment of pulmonary coagulation disturbances in acute lung injury (ALI). Alveolar and lung micro-vascular fibrin accumulation and breakdown inhibition indeed play a central role in the development and clinical course of this disease. Preclinical studies provide some evidence of the beneficial effects of heparin inhalation in several animal models of ALI. Clinical investigations are sparse, and trials such as the one presented by Dixon and colleagues in a recent issue of Critical Care are welcome as they provide insight into the possible clinical use of nebulised heparin in this situation. This phase 1 trial involved 16 patients with early ALI, and showed the feasibility of the approach. In addition, non-significant changes in respiratory functions and systemic anticoagulant effects were documented with the four doses tested. The study of Dixon and colleagues adds to data that helps pave the way towards a possible clinical use of heparin by nebulisation in ALI. It remains to be clarified in which clinical situations, at what time points and with which dosages the best chances exist for a beneficial effect on the prognosis of these patients.     

Central venous-to-arterial carbon dioxide difference: an additional target for goal-directed therapy in septic shock?

Objective  To test the hypothesis that, in resuscitated septic shock patients, central venous-to-arterial carbon dioxide difference [P(cv-a)CO₂] may serve as a global index of tissue perfusion when the central venous oxygen saturation (ScvO₂) goal value has already been reached. Design  Prospective observational study. Setting  A 22-bed intensive care unit (ICU). Patients  After early resuscitation in the emergency unit, 50 consecutive septic shock patients with ScvO₂ > 70% were included immediately after their admission into the ICU (T0). Patients were separated in Low P(cv-a)CO₂ group (Low gap; n = 26) and High P(cv-a)CO₂ group (High gap; n = 24) according to a threshold of 6 mmHg at T0. Measurements  Measurements were performed every 6 h over 12 h (T0, T6, T12). Results  At T0, there was a significant difference between Low gap patients and High gap patients for cardiac index (CI) (4.3 ± 1.6 vs. 2.7 ± 0.8 l/min/m2, P < 0.0001) but not for ScvO₂ values (78 ± 5 vs. 75 ± 5%, P = 0.07). From T0 to T12, the clearance of lactate was significantly larger for the Low gap group than for the High gap group (P < 0.05) as well as the decrease of SOFA score at T24 (P < 0.01). At T0, T6 and T12, CI and P(cv-a)CO₂ values were inversely correlated (P < 0.0001). Conclusion  In ICU-resuscitated patients, targeting only ScvO₂ may not be sufficient to guide therapy. When the 70% ScvO₂ goal-value is reached, the presence of a P(cv-a)CO₂ larger than 6 mmHg might be a useful tool to identify patients who still remain inadequately resuscitated. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

The impact of poison control centers on poisoning-related visits to EDs--United States, 2003

Purpose

This study analyzes the association between center usage rates and the rates of nonadmitted visits to emergency departments (EDs) for poisoning.

Basic Procedures

With a log-normal regression model, we analyzed the association between the number of human exposure calls per hospitalized poisoning patient and the number of nonhospitalized ED visits. The data were from 14 states at county level.

Main Findings

A 1% higher poison control center (PCC) human exposure call rate for unintentional poisoning is associated, but not necessarily causally, with a 0.18% lower ED visit rate (P < .0001). If the observed association is causative, 15.5 PCC human poison exposure calls prevent one nonadmitted ED visit, yielding a $205 net cost saving and a benefit-cost ratio of 1.4. The savings ignore any reduction in hospital admissions.

Principal Conclusions

Increased PCC exposure calls appear to be associated with reduced ED use for unintentional poisoning and appear to reduce net medical spending.     

Predicting maternal and behavioral measures of infant pain: the relative contribution of maternal factors

The Sociocommunication Model of Infant Pain [Craig KD, Pillai Riddell R. Social influences, culture and ethnicity. In: Finley GA, McGrath PJ, editors. Pediatric pain: biological and social context, Seattle: IASP Press; 2003.] theorizes that maternal variables influence the pained infant and that the pained infant reciprocally influences maternal responses to the infant. The current analysis examines the relative predictive utility of maternal behavioral and psychosocial variables for both maternal judgments of her infant's pain and behavioral measures of infant pain, after infant factors have been controlled. A convenience sample of 75 mother-infant dyads was videotaped during a routine immunization in a pediatrician's office. Mothers were interviewed on the telephone, within two weeks, to complete a series of questionnaires. Infants were between the ages of 5 and 20 months. Infant pain was measured directly after the immunization using subjective maternal judgments. In addition, both maternal soothing behaviors and infant pain behaviors post-immunization were measured using objective coding systems. During the telephone interview, mothers were asked to recall infant pain levels for the day after the immunization and were also assessed for level of acculturative stress, perceived social support, general relationship style, feelings towards her infant and endorsed psychopathology. Regression analyses suggested that the role of maternal behavioral and psychosocial variables was highly dependent on the infant pain measure being predicted. These results imply that given the dependence of infants on their primary caregivers, quite often mothers, it is important to understand the dynamic influence of infants' behavior on maternal judgments of infants' pain and maternal psychosocial variables on infants' expression of pain.     

Biventricular adaptation to volume overload in mice with aortic regurgitation

Background

Pulmonary regurgitation is a common and clinically important residual lesion after repair of tetralogy of Fallot. Cardiovascular magnetic resonance (CMR) phase contrast velocity mapping is widely used for measurement of pulmonary regurgitant fraction. Breath-hold acquisitions, usually acquired during held expiration, are more convenient than the non-breath-hold approach, but we hypothesized that breath-holding might affect the amount of pulmonary regurgitation.

Methods

Forty-three adult patients with a previous repair of tetralogy of Fallot and residual pulmonary regurgitation were investigated with CMR. In each, pulmonary regurgitant fraction was measured from velocity maps transecting the pulmonary trunk, acquired during held expiration, held inspiration, by non-breath-hold acquisition, and also from the difference of right and left ventricular stroke volume measurements.

Results

Pulmonary regurgitant fraction was lower when measured by velocity mapping in held expiration compared with held inspiration, non-breath-hold or stroke volume difference (30.8 vs. 37.0, 35.6, 35.4%, p = 0.00017, 0.0035, 0.026). The regurgitant volume was lower in held expiration than in held inspiration (41.9 vs. 48.3, p = 0.0018). Pulmonary forward flow volume was larger during held expiration than during non-breath-hold (132 vs. 124 ml, p = 0.0024).

Conclusion

Pulmonary regurgitant fraction was significantly lower in held expiration compared with held inspiration, free breathing and stroke volume difference. Altered airway pressure could be a contributory factor. This information is relevant if breath-hold acquisition is to be substituted for non-breath-hold in the investigation of patients with a view to re-intervention.     

Bench-to-bedside review: The inflammation-perpetuating pattern-recognition receptor RAGE as a therapeutic target in sepsis

Sepsis still represents an important clinical and economic challenge for intensive care units. Severe complications like multi-organ failure with high mortality and the lack of specific diagnostic tools continue to hamper the development of improved therapies for sepsis. Fundamental questions regarding the cellular pathogenesis of experimental and clinical sepsis remain unresolved. According to experimental data, inhibiting macrophage migration inhibitory factor, high-mobility group box protein 1 (HMGB1), and complement factor C5a and inhibiting the TREM-1 (triggering receptor expressed on myeloid cells 1) signaling pathway and apoptosis represent promising new therapeutic options. In addition, we have demonstrated that blocking the signal transduction pathway of receptor of advanced glycation endproducts (RAGE), a new inflammation-perpetuating receptor and a member of the immunglobulin superfamily, increases survival in experimental sepsis. The activation of RAGE by advanced glycation end-products, S100, and HMGB1 initiates nuclear factor kappa B and mitogen-activated protein kinase pathways. Importantly, the survival rate of RAGE knockout mice was more than fourfold that of wild-type mice in a septic shock model of cecal ligation and puncture (CLP). Additionally, the application of soluble RAGE, an extracellular decoy for RAGE ligands, improves survival in mice after CLP, suggesting that RAGE is a central player in perpetuating the innate immune response. Understanding the basic signal transduction events triggered by this multi-ligand receptor may offer new diagnostic and therapeutic options in patients with sepsis.     

Volume-targeted modes of modern neonatal ventilators: how stable is the delivered tidal volume?

Objective Volume-targeted modes are designed to deliver a constant tidal volume (V_t) at lowest possible pressure independently of changes in compliance, resistance, and leak of the respiratory system. We examined whether these volume-targeted modes respond rapidly enough to sudden changes in respiratory mechanics (e.g., selective intubation, surfactant administration, endotracheal tube kinking, de-kinking, obstruction), resulting in insufficient or excessive V_t delivery. Design and setting Bench study of six neonatal ventilators in the volume-targeted mode simulating preterm and full-term infant settings on a test lung. Measurements and results Breath-to-breath expiratory V_t were measured after rapid compliance, resistance, and leak changes. Under our test settings all ventilators showed important volume overshooting following rapid increase in compliance or decrease in resistance. Between one and 16 inflations were required to return to the set V_t. Some ventilators delivered inaccurate V_t under steady state condition while others showed considerable breath-to-breath V_t variability. Conclusions We observed inaccurate V_t delivery under specific conditions as well as immediate and sometimes prolonged volume overshooting after a rapid respiratory system compliance increase or resistance decrease in volume-targeted modes of modern neonatal ventilators. Similar discrepancies between the set V_t and the delivered inflations can be harmful in clinical situations, especially in newborns. Their clinical relevance needs to be clarified with safety studies in the neonatal population and we encourage manufacturers to further improve the ventilators algorithms. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

Electrophysiologic latency to the external obliques of the laryngeal cough expiration reflex in humans

OBJECTIVE: The purpose of this study was to trigger the laryngeal cough expiration reflex using inhaled tartaric acid aerosol and to record the latency between the time of initiation of the laryngeal cough expiration reflex component of the laryngeal cough reflex and the onset of electromyographically recorded responses in the external abdominal oblique in humans. DESIGN: Five male subjects were tested in the seated position, and four latencies were recorded for each subject. The latencies were recorded from laryngeal stimulation to an electromyogram in the muscle belly of the left external abdominal oblique. The time line was activated by a microswitch attached to a breath-activated nebulizer. Data were analyzed using SPSS for mean latency and standard deviation. RESULTS: The mean (standard deviation) latency to the external abdominal oblique muscle was 17.6 +/- 10.6 msec. No adverse events to inhalation were reported. CONCLUSION: SIn humans, nebulized tartaric acid stimulates primarily rapid adapting receptors in the supraglottic larynx rather than C-fiber receptors. This receptor location in humans evolved neurologically to protect the airway during speech and swallowing, making the laryngeal cough expiration reflex an inseparable component of the laryngeal cough reflex, thus making it clinically significant when assessing airway protection.