Left ventricular systolic and diastolic dysfunction after infusion of tumor necrosis factor-alpha in conscious dogs.

We used a load-insensitive index of systolic left ventricular (LV) function and an analysis of diastolic pressure-dimension relationships to test the hypothesis that recombinant human (rh) tumor necrosis factor-alpha (TNF alpha) impairs LV function in dogs. Animals were studied 7-10 d after aseptic implantation of instrumentation to monitor cardiac output, external anterior-posterior LV diameter, and LV and pleural pressures. Data were analyzed from seven dogs that received active rhTNF alpha (100 micrograms/kg over 60 min) and from five dogs that received heat-inactivated rhTNF alpha. At 24 h after infusion of active rhTNF alpha, the slope of the LV end-diastolic dimension-stroke work relationship decreased significantly, indicating a decrement in LV systolic contractility. Simultaneously, LV unstressed dimension increased significantly, suggesting diastolic myocardial creep. The end-diastolic relationship between LV transmural pressure and normalized LV dimension (strain) was markedly displaced to the left, suggesting increased diastolic elastic stiffness. Despite these changes in LV performance, cardiac index was maintained by tachycardia. The abnormalities in LV function were resolved by 72 h. We conclude that rhTNF alpha reversibly impairs LV systolic and diastolic function in unanesthetized dogs. Because dysfunction occurs greater than 6 h after the infusion of rhTNF alpha and persists for 24-48 h, the mechanism underlying this phenomenon may involve secondary mediators or a change in myocardial gene expression.

The distribution of neurotrophin receptor TrkC-like immunoreactive fibers and varicosities in the rhesus monkey brain.

The distribution of immunoreactivity for the neurotrophin receptor tyrosine kinase TrkC was examined in the brain of the adult rhesus monkey. TrkC-like immunoreactivity was widespread and consisted primarily of varicose fibers. The most dense populations of fibers were in the basal forebrain (in the cholinergic cell groups Ch1, Ch2 and Ch4), in the raphé complex throughout its rostrocaudal extent, and in the locus coeruleus. Other fibers were present in the thalamus, hypothalamus, central gray matter of the midbrain, dorsal midline of the brainstem and the cerebral cortex. The only neuronal cell bodies with consistent labeling were located in the lateral hypothalamus. Purkinje cells in the cerebellum showed variable labeling. Specific labeling of varicosities and cell bodies was abolished by omission of the primary antiserum or by preabsorption with the TrkC peptide antigen. We conclude that TrkC-like immunoreactivity can be detected in a wide variety of subcortical locations in the adult rhesus monkey. Labeling was particularly prominent in the vicinity of the major cholinergic, serotonergic and adrenergic nuclei, known from other studies to be vulnerable in the ageing brain. This suggests that the ligand for TrkC, neurotrophin-3, may persist as a survival factor for critical neurons into adulthood.

Load-insensitive assessment of myocardial performance after tumor necrosis factor-alpha in dogs.

Tumor necrosis factor-alpha (TNF alpha) has been implicated as an endogenous mediator of the cardiovascular manifestations of sepsis and septic shock. We studied the acute effects of a single dose (50 or 200 micrograms/kg) of intravenous recombinant human TNF alpha (rhTNF alpha) on myocardial function in halothane-anesthetized dogs. Regional cardiac dimensions were measured by using sonomicrometry. Intracavitary left ventricular, ascending aortic, and pulmonary artery pressures were measured by use of micromanometers. Cardiac index was determined by means of thermodilution. Myocardial performance was analyzed by assessing changes in the slope of the left ventricular end-diastolic length-stroke work relationship obtained by performing transient vena caval occlusions. Animals were resuscitated by means of normal saline solutions to maintain baseline regional end-diastolic length. Over a 3-hour period of observation, rhTNF alpha decreased systemic vascular resistance index, but the cytokine did not compromise intrinsic myocardial performance. The circulatory response to rhTNF alpha was a hyperdynamic state characterized by tachycardia, augmented cardiac index, and increased intrinsic myocardial contractility (leftward shift of the left ventricular end-diastolic length-stroke work relationship). In addition, rhTNF alpha caused systemic acidosis and increased plasma levels of prostacyclin metabolite (6-keto-prostaglandin F1 alpha). After the dose of rhTNF alpha large volumes of fluid were required to maintain baseline end-diastolic length. We conclude that in the acute setting, rhTNF alpha elicits abnormalities in peripheral vascular tone that are not accompanied by depression of myocardial function.

Excess cost of emergency department visits for nonurgent care.

After examining data for patients with selected conditions and statistically adjusting for patient, diagnosis, and treatment characteristics, this Data Watch finds that charges for emergency department visits were two to three times more than charges for visits in other settings. Large differences persist when conditions are examined individually and when total episode charges are examined. Based on our findings, a rough estimate of nationwide excess charges is $5-$7 billion for 1993.

Sodium bicarbonate versus Carbicarb in canine myocardial hypercarbic acidosis.

The objective of this study was to compare the in vivo effects of sodium bicarbonate (NaHCO3) and Carbicarb infusion on regional contractile performance and acid-base status in the setting of hypercarbic acidosis. Animals (N = 9) were anesthetized and paralyzed using sodium pentothal, halothane, and pancuronium bromide, and mechanically ventilated with an air-O2 mixture so that arterial PO2 was > or = 300 mm Hg. Following beta-adrenergic blockade, alveolar ventilation was gradually reduced over a 50-minute period to increase arterial PCO2 to 60 to 80 mm Hg. Each of the following solutions was then infused in consecutive order directly into the left anterior descending artery coronary artery for 15 minutes: (1) 8.4% NaHCO3 at 2 mL/min; (2) 5% sodium chloride at 2 mL/min, equivalent to NaHCO3 in osmolality; (3) 6.3% Carbicarb at 0.5 mL/min, equivalent to NaHCO3 in buffer capacity; and (4) 6.3% Carbicarb at 2 mL/min, equivalent to NaHCO3 in volume. Regional stroke work analog (ultrasonic dimension transducers), interstitial myocardial pH (Khuri electrode), coronary blood flow (doppler flow probe), and hemodynamic/metabolic variables (heart rate, blood pressure, arterial and coronary venous blood gases) were measured at 1, 5, 10, and 15 minutes during each infusion and 10 minutes after the infusion was discontinued, ie, at 25 minutes. Animals were allowed to recover for 45 minutes between interventions. Values at each time point were compared with baseline for statistical significance. Small reductions in interstitial myocardial pH (P < .05) and stroke work (P > .05) were observed within 1 minute of NaHCO3 administration. Both parameters increased significantly from baseline levels thereafter, ie, interstitial myocardial pH at 5 minutes and stroke work at 15 minutes. Infusion of Carbicarb invariably was associated with an increase (P < .05) in interstitial myocardial pH. Stroke work increased (P < .05) during low-dose Carbicarb administration, but infusion of the higher dose was accompanied by a biphasic response, ie, an increase (P < .05) from 0 to 5 minutes, followed by a gradual decrease that achieved statistical significance 10 minutes after termination of the infusion. End-diastolic length was inversely proportional to changes in stroke work, and coronary blood flow varied directly with changes in coronary venous Pco2. Myocardial O2 consumption decreased (P < .05) during Carbicarb infusion, but changes during NaHCO3 did not reach statistical significance. Our findings lend support to the hypothesis that intramyocardial pH determines myocardial function independent of CO2 production by buffer therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Designing special test instruments for preventive maintenance.

Periodic performance testing of biomedical equipment can be made considerably more efficient by careful design of test procedures and by fabrication of special test instruments which are designed for those procedures. The design philosophy behind such procedures and instruments and its applicability to a wide variety of biomedical devices is discussed. As a practical example, an ECG machine/patient monitor test system is described and construction details are given.

Effect of antenatal betamethasone administration on placental vascular resistance.

BACKGROUND: High placental vascular resistance is an important cause of fetal growth restriction and subsequent perinatal mortality. Identification of affected pregnancies allows appropriate fetal surveillance and delivery, but there are no known therapeutic strategies to decrease resistance and improve blood flow. However, placental corticotropin-releasing hormone (CRH) is thought to be a potent fetoplacental vasodilator, and exogenous corticosteroids can increase placental CRH secretion. Therefore, we examined whether corticosteroids could improve fetoplacental blood flow in pregnancies with increased vascular resistance. METHODS: A retrospective review of umbilical-artery flow-velocity waveforms (FVWs) before and after betamethasone administration was undertaken in pregnancies with increased placental vascular resistance, as shown by umbilical-artery absent end-diastolic flow (AEDF). FVWs were obtained by pulsed-wave doppler ultrasonography. We studied all 28 pregnancies monitored at the maternal-fetal medicine unit of a university teaching hospital since 1995. FINDINGS: The median duration of gestation at presentation with AEDF was 27 weeks (range 23-33). In 19 (68% [95% CI 49-86]) pregnancies, umbilical-artery diastolic flow returned within 24 h after betamethasone administration, consistent with decreased resistance. The median duration of this effect was 3 days (range 2-7). There were no differences in duration of gestation at diagnosis or delivery, or in birthweight between fetuses showing a return of flow after betamethasone and those not showing a return of flow. INTERPRETATION: In pregnancies with umbilical-artery AEDF, betamethasone treatment is associated with decreased placental vascular resistance, possibly induced via increased placental CRH secretion. This study does not provide insights into whether this effect would be beneficial or harmful to the fetus.

Changes in fetoplacental vessel flow velocity waveforms following maternal administration of betamethasone.

OBJECTIVE: To determine the timing of the onset of the umbilical artery flow velocity waveform changes following maternal administration of betamethasone in pregnancies complicated by umbilical artery absent end-diastolic flow, and to explore whether these changes are associated with flow velocity waveform changes in other fetoplacental vessels. SUBJECTS AND METHODS: This was a prospective study of 12 women with pregnancies complicated by umbilical artery absent end-diastolic flow. Flow velocity waveforms were recorded from the umbilical artery, fetal middle cerebral artery, renal artery, aorta and ductus venosus, before and after maternal betamethasone administration, using real-time pulsed wave Doppler. RESULTS: In all 12 pregnancies, the administration of maternal betamethasone was followed by the return of end-diastolic flow within 24 h. End-diastolic flow was first observed at 4 h and was present in all women studied at 8 h. In addition, there was a statistically significant decrease in the pulsatility index in the fetal aorta at 8 h and the middle cerebral artery at 24 h. No change was observed in the ductus venosus or the renal artery flow velocity waveforms. CONCLUSION: The findings suggest that, in pregnancies complicated by absent end-diastolic flow in the umbilical artery, maternally administered betamethasone induces a return in umbilical artery end-diastolic flow as early as 4 h, along with widespread vasodilatation throughout the fetoplacental vasculature.

Ice nucleation temperature of individual leaves in relation to population sizes of ice nucleation active bacteria and frost injury.

Ice nucleation temperatures of individual leaves were determined by a tube nucleation test. With this assay, a direct quantitative relationship was obtained between the temperatures at which ice nucleation occurred on individual oat (Avena sativa L.) leaves and the population sizes of ice nucleation active (INA) bacteria present on those leaves. In the absence of INA bacteria, nucleation of supercooled growth-chamber grown oat leaves did not occur until temperatures were below approximately -5 degrees C. Both nucleation temperature and population size of INA bacteria were determined on the same individual, field-grown oat leaves. Leaves with higher ice nucleation temperatures harbored larger populations of INA bacteria than did leaves with lower nucleation temperatures. Log(10) mean populations of INA bacteria per leaf were 5.14 and 3.51 for leaves with nucleation temperatures of -2.5 degrees C and -3.0 degrees C, respectively. Nucleation frequencies (the ratio of ice nuclei to viable cells) of INA bacteria on leaves were lognormally distributed. Strains from two very different collections of Pseudomonas syringae and one of Erwinia herbicola were cultured on nutrient glycerol agar and tested for nucleation frequency at -5 degrees C. Nucleation frequencies of these bacterial strains were also lognormally distributed within each of the three sets. The tube nucleation test was used to determine the frequency with which individual leaves in an oat canopy harbored large populations of INA bacteria throughout the growing season. This test also predicted relative frost hazard to tomato (Lycopersicon esculentum Mill) plants.

Raindrop Momentum Triggers Growth of Leaf-Associated Populations of Pseudomonas syringae on Field-Grown Snap Bean Plants.

Observational and microclimate modification experiments were conducted under field conditions to determine the role of the physical environment in effecting large increases in phyllosphere population sizes of Pseudomonas syringae pv. syringae, the causal agent of bacterial brown spot disease of snap bean (Phaseolus vulgaris L.). Comparisons of daily changes in population sizes of P. syringae on three plantings of snap bean cultivar Cascade and one of cultivar Eagle with weather conditions indicated a strong association of rainfalls with periods of 1 to 3 days in duration during which increases in bacterial population sizes were greater than 10-fold and up to 1,000-fold. The effects of rain on populations of P. syringae were explored further by modifying the microclimate of bean plants in the field with polyethylene shelters to shield plants from rain and fine-mesh inert screens to modify the momentum of raindrops. After each of three separate intense rains, the greater-than-10-fold increases in population sizes of P. syringae observed on plants exposed to the rains did not occur on plants in the shelters or under the screens. The screens decreased the velocity and, thus, the momentum of raindrops but not the volume or quality of rainwater that fell on plants under the screens. Thus, the absence of increases in population sizes of P. syringae on plants under the screens suggests that raindrop momentum plays a role in the growth-triggering effect of intense rains on populations of P. syringae on bean plants under field conditions.

The direct cost of low birth weight.

Medical and technological advances in the care of infants with low birth weight (less than 2,500 grams, or 5 pounds, 8 ounces) and very low birth weight (less than 1,500 grams, or 3 pounds, 5 ounces) have substantially increased the survival rate for these infants and have led to concerns about the demands their care places upon their families and society. The dollar cost of the resources used disproportionately to care for low birth weight children is one measure of the burden of low birth weight. Using analyses of national survey data for 1988 for children ages 0 to 15, this article presents estimates of the direct incremental costs of low birth weight--costs of the resources used to care for low birth weight infants above and beyond those used for infants of normal birth weight. In 1988, health care, education, and child care for the 3.5 to 4 million children ages 0 to 15 born low birth weight between $5.5 and $6 billion more than they would have if those children had been born normal birth weight. Low birth weight accounts for 10% of all health care costs for children, and the incremental direct costs of low birth cost weight are of similar magnitude to those of unintentional injuries among children and in 1988 were substantially greater than the direct costs of AIDS among Americans of all ages in that year.

Contribution of the Regulatory Gene lemA to Field Fitness of Pseudomonas syringae pv. syringae.

In Pseudomonas syringae pv. syringae, lemA is required for brown spot lesion formation on snap bean and for production of syringomycin and extracellular proteases (E. M. Hrabak and D. K. Willis, J. Bacteriol. 174: 3011-3022, 1992; E. M. Hrabak and D. K. Willis, Mol. Plant-Microbe Interact. 6:368-375, 1993; D. K. Willis, E. M. Hrabak, J. J. Rich, T. M. Barta, S. E. Lindow, and N. J. Panopoulos, Mol. Plant-Microbe Interact. 3:149-156, 1990). The lemA mutant NPS3136 (lemA1::Tn5) was previously found to be indistinguishable from its pathogenic parent B728a in its ability to grow when infiltrated into bean leaves of plants maintained under controlled environmental conditions (Willis et al., Mol. Plant-Microbe Interact. 3:149-156, 1990). We compared population sizes of NPS3136 and B728aN (a Nal(supr) clone of wild-type B728a) in two field experiments to determine the effect of inactivation of lemA on the fitness of P. syringae pv. syringae. In one experiment, the bacterial strains were spray inoculated onto the foliage of 25-day-old bean plants. In the other, seeds were inoculated at the time of planting. In both experiments, the strains were inoculated individually and coinoculated in a 1:1 ratio. NPS3136 and B728aN achieved similar large population sizes on germinating seeds. However, in association with leaves, population sizes of NPS3136 were diminished relative to those of B728aN in both experiments. Thus, lemA contributed significantly to the fitness of P. syringae pv. syringae in association with bean leaves but not on germinating seeds under field conditions. When NPS3136 was coinoculated with B728aN, the mutant behaved as it did when inoculated alone. However, population sizes of B728aN in the coinoculation treatment were much lower than those when it was inoculated alone. Inactivation of the lemA gene appeared to have rendered the mutant suppressive to B728aN.

Correction of intramyocardial hypercarbic acidosis with sodium bicarbonate.

Although it has been hypothesized that exogenously administered bicarbonate can exacerbate intramyocardial acidosis and compromise contractile function, this phenomenon has not been demonstrated in an intact model in which intramyocardial pH (pH(int)), regional venous pCO2, and regional contractile function have been simultaneously monitored. In 20 anesthetized dogs, we studied the effects of intracoronary infusions of sodium bicarbonate NaHCO3 30 mEg over 15 min, on regional pH(int), (glass electrode) and regional stroke work (SW, sonomicrometry) before and after creating systemic hypercarbic acidosis by hypoventilation. During NaHCO3 administration, regional coronary venous pCO2 increased rapidly during the first minute (eucapnea; 34 +/- 7 to 55 +/- 18 mm Hg; hypercapnea: 70 +/- 15 to 98 +/- 23 mm Hg, P < 0.05 for both increases). Regional venous pH rose from 7.36 +/- .04 to 7.55 +/- .06 (P < 0.05) after the first minute of NaHCO3 infusion during eucapnea and from 7.09 +/- .09 to 7.22 +/- .09 (P < 0.05) during hypercapnea. During the first minute of NaHCO3 infusion, pH(int) declined minimally. However, during the remaining 14 min of each infusion, pH(int) increased significantly (eucapnea: 7.19 +/- 0.10 to 7.43 +/- 0.12; hypercapnea: 6.86 +/- 0.14 to 7.02 +/- 0.15, P < 0.05 for both changes). Regional SW decreased significantly during the first minute of infusion, both during eucapnea (23,400 +/- 7,400 to 18,000 +/- 6,300 ergs/cm2, P < 0.05) and hypercapnea (27,000 +/- 9,100 to 25,000 +/- 10,000 ergs/cm2, P < 0.05). The first minute of contractile dysfunction was followed by recovery and ultimately supranormal contractile function during the remainder of each bicarbonate infusion. To test the hypothesis that transient intracellular acidosis during bicarbonate infusions was underestimated by measurements of pH(int), measurements of intracellular pH using the pH-sensitive dye, BCECF, were performed in isolated guinea pig papillary muscles incubated in vitro. These measurements confirmed the presence of transient intracellular acidosis during bicarbonate infusion. In conclusion, (1) the intracoronary administration of sodium bicarbonate causes a transient depression in myocardial contractile function that is related to transient intracellular acidosis; and (2) despite exacerbating hypercarbia, sodium bicarbonate ultimately neutralizes intracellular acid and augments myocardial contractile function.

Economic implications of neonatal intensive care unit collaborative quality improvement.

OBJECTIVE: To make measurable improvements in the quality and cost of neonatal intensive care using a multidisciplinary collaborative quality improvement model. DESIGN: Interventional study. Data on treatment costs were collected for infants with birth weight 501 to 1500 g for the period of January 1, 1994 to December 31, 1997. Data on resources expended by hospitals to conduct this project were collected in a survey for the period January 1, 1995 to December 31, 1996. SETTING: Ten self-selected neonatal intensive care units (NICUs) received the intervention. They formed 2 subgroups (6 NICUs working on infection, 4 NICUs working on chronic lung disease). Nine other NICUs served as a contemporaneous comparison group. PATIENTS: Infants with birth weight 501 to 1500 g born at or admitted within 28 days of birth between 1994 and 1997 to the 6 study NICUs in the infection group (N = 2993) and the 9 comparison NICUs (N = 2203); infants with birth weight 501 to 1000 g at the 4 study NICUs in the chronic lung disease group (N = 663) and the 9 comparison NICUs (N = 1007). INTERVENTIONS: NICUs formed multidisciplinary teams which worked together to undertake a collaborative quality improvement effort between January 1995 and December 1996. They received instruction in quality improvement, reviewed performance data, identified common improvement goals, and implemented "potentially better practices" developed through analysis of the processes of care, literature review, and site visits. MAIN OUTCOME MEASURES: Treatment cost per infant is the primary economic outcome measure. In addition, the resources spent by hospitals in undertaking the collaborative quality improvement effort were determined. RESULTS: Between 1994 and 1996, the median treatment cost per infant with birth weight 501 to 1500 g at the 6 project NICUs in the infection group decreased from $57 606 to $46 674 (a statistical decline); at the 4 chronic lung disease hospitals, for infants with birth weights 501 to 1000 g, it decreased from $85 959 to $77 250. Treatment costs at hospitals in the control group rose over the same period. There was heterogeneity in the effects among the NICUs in both project groups. Cost savings were maintained in the year following the intervention. On average, hospitals spent $68 206 in resources to undertake the collaborative quality improvement effort between 1995 and 1996. Two thirds of these costs were incurred in the first year, with the remaining third in the second year. The average savings per hospital in patient care costs for very low birth weight infants in the infection group was $2.3 million in the post-intervention year (1996). There was considerable heterogeneity in the cost savings across hospitals associated with participation in the collaborative quality improvement project. CONCLUSION: Cost savings may be achieved as a result of collaborative quality improvement efforts and when they occur, they appear to be sustainable, at least in the short run. In high-cost patient populations, such as infants with very low birth weights, cost savings can quickly offset institutional expenditures for quality improvement efforts.