Hypoxia determines survival outcomes of bacterial infection through HIF-1alpha dependent re-programming of leukocyte metabolism.

Hypoxia and bacterial infection frequently co-exist, in both acute and chronic clinical settings, and typically result in adverse clinical outcomes. To ameliorate this morbidity, we investigated the interaction between hypoxia and the host response. In the context of acute hypoxia, both S. aureus and S. pneumoniae infections rapidly induced progressive neutrophil mediated morbidity and mortality, with associated hypothermia and cardiovascular compromise. Preconditioning animals through longer exposures to hypoxia, prior to infection, prevented these pathophysiological responses and profoundly dampened the transcriptome of circulating leukocytes. Specifically, perturbation of HIF pathway and glycolysis genes by hypoxic preconditioning was associated with reduced leukocyte glucose utilisation, resulting in systemic rescue from a global negative energy state and myocardial protection. Thus we demonstrate that hypoxia preconditions the innate immune response and determines survival outcomes following bacterial infection through suppression of HIF-1α and neutrophil metabolism. The therapeutic implications of this work are that in the context of systemic or tissue hypoxia therapies that target the host response could improve infection associated morbidity and mortality.

Determination of maternal pedigree and ewe-lamb spatial relationships by application of Bluetooth technology in extensive farming systems.

The objectives of this study were to validate the application of Bluetooth technology to determine maternal pedigree and to determine ewe-lamb spatial relationships in extensive farming systems. A total of 35 first-cross Merino ewes (Merino × Border Leicester and East Friesian) and 23 of their lambs aged 1 to 3 wk were fitted with activity monitors equipped with Bluetooth (BT) technology (ActiGraph wGT3X-BT) by means of halters and collars, respectively. The BT devices on lambs were programmed to receive wireless signals once every minute from nearby BT units on ewes, which were programmed as beacons sending BT signals 4 times every second. Ewes and lambs fitted with sensors were dispatched into the paddocks, and after 10 d, the sensor units were retrieved and the BT signals received by lambs were downloaded using the ActiGraph software. The maternal pedigree of the lambs was determined as the ewe from which the lamb received the most BT signals. The distance between the lamb receiving the signal and the ewe sending the signal was estimated from the strength of BT signal received. The pedigree determined by BT was compared with the pedigree determined by DNA profiling and verification. The results showed that the accuracy of maternal pedigree determined by BT signals reached 100% within the first 15 min of returning animals to pasture of ewes and lambs fitted with sensors. Maternal signals (counts/d) received by 1-, 2-, and 3-wk-old lambs were 617 ± 102, 603 ± 54, and 498 ± 36, respectively, and the corresponding nonmaternal signals received were 140 ± 27, 106 ± 30, and 155 ± 39, respectively. Maternal signals received during the dark period were significantly higher than the maternal signals received during the light period ( < 0.05). Maternal signals received during the light period by 3-wk-old lambs were significantly lower when compared with those received by 1- and 2-wk-old lambs. Over 90% of the BT signals received from within 2 m of the lamb were from its mother. The maternal BT signals expressed as a portion of total BT signals decreased with increasing distance from the lamb. The results show that BT wireless networking is a fast and reliable method for the determination of maternal pedigree of lambs in extensive farming systems. In addition, wireless BT technology is also useful in determining mother-offspring spatial relationships.

Alveolar macrophages in pulmonary host defence the unrecognized role of apoptosis as a mechanism of intracellular bacterial killing.

Alveolar macrophages play an essential role in clearing bacteria from the lower airway, as the resident phagocyte alveolar macrophages must both phagocytose and kill bacteria, and if unable to do this completely must co-ordinate an inflammatory response. The decision to escalate the inflammatory response represents the transition between subclinical infection and the development of pneumonia. Alveolar macrophages are well equipped to phagocytose bacteria and have a large phagolysosomal capacity in which ingested bacteria are killed. The rate-limiting step in control of extracellular bacteria, such as Streptococcus pneumoniae, is the capacity of alveolar macrophages to kill ingested bacteria. Therefore, alveolar macrophages complement canonical microbicidal strategies with an additional level of apoptosis-associated killing to help kill ingested bacteria.

Circulating nitrite anions are a directly acting vasodilator and are donors for nitric oxide.

Inhaled nitric oxide (NO) is a pulmonary vasodilator, but also acts systemically, causing negative cardiac inotropic effects and a fall in systemic vascular resistance. Circulating metabolites of NO are presumed to be responsible. We questioned the role of nitrite anions and the manner in which they might contribute to these effects. Nitrite and nitrate anions coexist in blood, while circulating levels of dissolved NO are very low. Nitrate anions are not biologically active, but nitrite anions may have a biological role through the release of NO. In vitro, at 37 degrees C and in aerated Krebs bicarbonate solution, the steady-state concentration of dissolved NO was proportional to the concentration of NO in the gas. Nanomolar concentrations of dissolved NO coexisted with micromolar concentrations of nitrite anions. The idea of an equilibrium between the two in solution was also supported by the observed release of NO from nitrite anions in the absence of gas. With rings of precontracted pig pulmonary arteries (prostaglandin F(2alpha); 10 micromol/l), the steady-state concentration of dissolved NO causing 50% relaxation (EC(50)) was 0.84+/-0.25 nmol/l, corresponding to a gaseous concentration of 2.2 p.p.m. The EC(50) of nitrite was 4.5+/-0.7 micromol/l, a concentration normally found in plasma. The estimated concentration of dissolved NO derived from this nitrite was 4.5 pmol/l, some 100 times lower than would be needed to cause relaxation. The rate of exhalation of NO was increased and pulmonary vascular resistance was reduced by the addition of nitrite solution to the perfusate of isolated perfused and ventilated pig lungs, but only when millimolar concentrations were achieved. Thus circulating nitrite anions are a direct vasodilator, only being a carrier of effective amounts of "free" NO at higher than physiological concentrations.

The acute effects of dexfenfluramine on human and porcine pulmonary vascular tone and resistance.

STUDY OBJECTIVES: Treatment with anorectics has become an important aspect of care for the severely obese. One such anorectic, the phenylethylamine dexfenfluramine (dFen), has been associated with the development of pulmonary hypertension. It works by reducing the neuronal uptake of 5-hydroxytryptamine (5-HT; serotonin) through inhibition of the 5-HT transporter. In this study we investigated whether dFen has a direct vasoconstrictor action on human and porcine pulmonary vasculature. DESIGN: For the human study, tissue was obtained from patients who had undergone lung and heart-lung transplantation. The effect of dFen was studied in seven isolated colloid perfused human lungs and in rings of human pulmonary artery (PA) dissected from the lungs of a further 19 patients. For the porcine study, regional pulmonary vascular resistances (PVRs) were measured in isolated perfused porcine lungs. Vasoconstriction was assessed following dFen alone and in combination with hypoxia, cyclo-oxygenase blockade (indomethacin, 10(-5) mol/L), or nitric oxide synthase (NOS) blockade (N(G)-nitro-L-arginine, 10(-5) mol/L). RESULTS: In the human study, 5-HT and dFen caused only limited increases in tension of isolated rings of PA. The concentration of dFen, 10(-4) mol/L, that was needed to increase tension was higher than that found normally in treated patients where peak levels are 3. 3 x 10(-7) mol/L. Other vasoconstrictors such as prostaglandin F(2)alpha, 10(-5) mol/L, and the thromboxane analog U46619, 10(-6) mol/L, produced far greater increases in tension. Ketanserin, 10(-4) mol/L, attenuated the constrictor response to 5-HT but had no effect on the constrictor response to dFen. Removal of the endothelium did not influence the response to dFen. In the isolated ventilated and perfused lungs, dFen caused an increase in PVR again only at a comparatively high concentration, 10(-4) mol/L. In the porcine study, dFen, 10(-4) mol/L, did not increase any PVR during normoxia or following NOS blockade. Small insignificant increases in PVR occurred during hypoxia and after cyclo-oxygenase blockade. CONCLUSION: These results do not support the view that dFen would act as a direct vasoconstrictor when given in the usual doses. However, delayed elimination of dFen could raise tissue concentrations to high levels and give rise to vasoconstriction and pulmonary hypertension.

Q-wave versus non-Q wave myocardial infarction: a meaningless distinction.

The whole subject can thus be summed up in two statements. 1. Every appropriately designed study comparing first Q and NQMI's has found no difference in post-MI course of the two categories and no foundation for the common notion that the NQMI is a uniquely "unstable" entity, to be classed with unstable angina in terms of prognosis and management. Nine such studies have been published. On the other hand, all studies alleging the "unstable" character of the NQMI have been invalidated by major flaws, chief among them the comparison of undifferentiated mixtures of first and subsequent infarcts with widely differing mortality and morbidity. This confusion is further compounded by the fact that subsequent infarcts generate Qwaves less than half as often as first infarcts. 2. All current studies indicate that there is no benefit to an invasive as compared with a conservative protocol for management of NQMI. Since the characterization of an infarct as "non-Q' conveys no therapeutic implications, the classification becomes irrelevant and should be discarded. Two quotations sum the whole matter succinctly. Moss (63) commented that "The Q-wave versus non-Q-wave categorization does not provide sufficient sensitivity, specificity, or predictive accuracy about the subsequent clinical course of patients with a first myocardial infarction to use it as reliable data in the clinical decision-making process." Surawicz (64) put the matter even more concisely: ". . . a non-Qwave MI is not a unique entity: rather it is a smaller and less extensive MI." In a word, the magnitude of a myocardial infarction should be judged on anatomical and functional considerations rather than on the designation of Qwave versus non-Qwave infarction.

Value of leads V7-V9 in diagnosing posterior wall acute myocardial infarction and other causes of tall R waves in V1-V2.

Left posterolateral chest leads (V7, V8, V9) helped distinguish the multiple causes of tall R waves in V1 and/or V2, diagnosed true posterior myocardial infarction when standard leads did not, and identified the presence or absence of posterior injury in patients with inferior infarction.

The role of nitric oxide in respiratory disease.

Nitric oxide (NO) is found in both the upper and lower airways of man. In the lower airways it is found at concentrations less than 3 ppb, and in the upper airways at about 400 ppb. The NO found in the upper airways is thought to play a role in maintaining the sterility of the paranasal sinuses. NO is also produced by the endothelium of the pulmonary vasculature. Endothelium-derived NO is a potent vasodilator involved in maintaining low pulmonary tone. Impaired endothelial NO production is thought to be involved in some types of pulmonary hypertension. When inhaled, NO acts as a selective pulmonary vasodilator which is used to treat respiratory diseases. One area in which NO has proven to be particularly effective is in the treatment of persistent pulmonary hypertension of the newborn. Inhaled NO therapy can be used in the treatment of adult respiratory distress syndrome, primary pulmonary hypertension and chronic obstructive pulmonary disease.

The use of ratings of perceived exertion for regulating exercise levels in rowing ergometry.

The purpose of this study was to examine the validity of the use of ratings of perceived exertion (RPE) to estimate and regulate exercise intensity during rowing ergometry. Nine competitive male rowers [mean age 28.6 years, (SD 6.3)] completed two rowing trials on an ergometer. The first trial (estimation) consisted of an incremental protocol designed to elicit a range of work outputs (WO) and heart rates (HR). The subjects indicated their perception of effort using a 15-point scale at each intensity level. In the second trial (production), 7-14 days later, the subjects were asked to produce exercise intensities corresponding to five levels of RPE: 15, 11, 17, 13, and 19. Data analysis revealed high Pearson correlation coefficients between HR and RPE (r = 0.95, P < 0.01) and WO and RPE (r = 0.96, P < 0.01) during the estimation trial. In addition, significant correlations (P < 0.01) were obtained between the estimation and production trials for HR (r = 0.82) and WO (r = 0.84). Posthoc analysis of variance revealed that the observed differences in mean HR were not significant (P > 0.05) at three of the five intensity levels (RPE 15, 17 and 19), but were at the two lowest RPE levels (11 and 13). Significant mean differences in WO were seen at all but RPE 17. These data support the validity of the RPE scale as a measure of physiological strain among competitive male rowers, and offer support for its use as a method of regulating the intensity of rowing ergometry, especially at higher levels.

Ventricular tachycardia, diagnosis and misdiagnosis: a case report.

We report a patient who, despite significant cardiac disease and inappropriate therapy, endured continuous undiagnosed ventricular tachycardia (VT) for 5 days without hemodynamic deterioration. The two main reasons for the frequently missed diagnosis of VT are (1) the mistaken belief that VT cannot be well tolerated, and (2) ignorance of the many helpful electrocardiographic clues. Six precepts for avoiding misdiagnosis are enunciated.

Prehospital actions by health-care providers and physicians.

Extensive worldwide experience and literature exist on the benefits of early intervention in patients with an acute myocardial infarction. To make these benefits available to as much of the population as possible a number of goals have to be accomplished. Patients and bystanders must be taught to recognize the significance of symptoms and call immediately for assistance. Local emergency medical service has to dispatch appropriate personnel and equipment to the scene expeditiously. Transport without unacceptable delays must occur to appropriate facilities along with rapid initiation of treatment. A program to achieve these goals would be expected to substantially reduce morbidity and mortality. Attention is directed to prehospital actions by health-care providers including dispatch of personnel and equipment to the scene, stabilization and treatment in the field, and triage and transport of the patient to the most appropriate medical facility.

Limb leads of the electrocardiogram: sequencing revisited.

The six limb leads are normally presented in a format the logic of which is traditional rather than anatomical and does not allow visual interpolation such as is customary with the six chest leads. The sequence: a VL, I, -aVR, II, aVF, III was suggested years ago, and is used in some European countries, particularly Sweden. It provides a better impression of the extent of the changes of inferior infarction and makes the rather neglected lead aVR much more useful, though reversed in polarity. It also provides a more direct indication of the electrical axis, and simplifies comparisons with the frontal plane vectorcardiogram. Because modern digital electrocardiographs can provide the sequenced format, this seems a good time to review the advantages of adopting it.

Ventricular tachycardia: noninvasive differentiation from supraventricular tachycardia.

The paramount importance of differentiating the wide-QRS tachycardias is stressed, and the alarming frequency of errors made by practicing physicians and cardiovascular nurses is documented. The most common causes of error are outlined, of which the most important is ignorance of diagnostically helpful QRS morphology in the electrocardiogram (EKG). The QRS contours and polarity that are useful in diagnosis are described in detail and illustrated. Finally, certain compromises in electrode placement that may be necessary in the operating room are suggested.

Differential diagnosis of supraventricular and ventricular tachycardia.

Few if any medical decisions are of more urgent importance than the accurate discrimination between ventricular tachycardia and supraventricular tachycardia with ventricular aberration, and probably no common diagnosis is more often missed. Yet the distinction can often be readily made with a knowledge of the several clues here described. These include QRS morphology, polarity and width; and clinical or electrocardiographic evidence of independent atrial activity. Knowledge and application of these serviceable clues should enable the clinician to establish a correct diagnosis in 90% of wide-QRS tachycardias without resorting to invasive studies.

Why are so many critical care nurses unable to recognize ventricular tachycardia in the 12-lead electrocardiogram?

We submitted the 12-lead electrocardiogram of an easily recognized ventricular tachycardia to more than 2500 critical care nurses for diagnosis. Seventy-eight percent of these failed to diagnose ventricular tachycardia, opting for supraventricular tachycardia with ventricular aberration. It was clear that only 0.5% of 2500 experienced nurses knew the three clues available for diagnosing ventricular tachycardia.

Potential benefits of a computer ECG interpretation system for primary care physicians in a community hospital.

One hundred fifteen ECGs from a hospital service were interpreted by 2 primary care physicians and 2 expert electrocardiographers. When their interpretations were compared with one another and with the Marquette MAC II ECG Interpretation Program, there was great variability. Computer ECG interpretations appeared to benefit primary care physicians most by providing a backup opinion. This second opinion was also of use to expert electrocardiographers. Additional long-term benefits that may be derived from computer systems include improvement of physician interpretation ability, reduction in interpretation time, and standardization of electrocardiographic nomenclature and criteria.

Left bundle branch block with right axis deviation: a marker of congestive cardiomyopathy.

Three patients with primary congestive cardiomyopathy (COCM), complete left bundle branch block (LBBB) and right axis deviation in the standard leads are described. Review of 50 additional patients from the literature since 1950 indicates that the uncommon combination of LBBB and RAD is a marker of severe myocardial disease, especially COCM. The mechanism of production of this electrocardiographic pattern appears to be diffuse conduction system involvement in advanced myocardial disease.