Ventricular interaction and external constraint account for decreased stroke work during volume loading in CHF.

The slope of the stroke work (SW)-pulmonary capillary wedge pressure (PCWP) relation may be negative in congestive heart failure (CHF), implying decreased contractility based on the premise that PCWP is simply related to left ventricular (LV) end-diastolic volume. We hypothesized that the negative slope is explained by decreased transmural LV end-diastolic pressure (LVEDP), despite the increased LVEDP, and that contractility remains unchanged. Rapid pacing produced CHF in six dogs. Hemodynamic and dimension changes were then measured under anesthesia during volume manipulation. Volume loading increased pericardial pressure and LVEDP but decreased transmural LVEDP and SW. Right ventricular diameter increased and septum-to-LV free wall diameter decreased. Although the slopes of the SW-LVEDP relations were negative, the SW-transmural LVEDP relations remained positive, indicating unchanged contractility. Similarly, the SW-segment length relations suggested unchanged contractility. Pressure surrounding the LV must be subtracted from LVEDP to calculate transmural LVEDP accurately. When this was done in this model, the apparent decrease in contractility was no longer evident. Despite the increased LVEDP during volume loading, transmural LVEDP and therefore SW decreased and contractility remained unchanged.

1,4-Disubstituted imidazoles are potential antibacterial agents functioning as inhibitors of enoyl acyl carrier protein reductase (FabI).

1,4-Disubstituted imidazole inhibitors of Staphylococcus aureus and Escherichia coli enoyl acyl carrier protein reductase (FabI) have been identified. Crystal structure data shows the inhibitor 1 bound in the enzyme active site of E. coli FabI.

Inhibitors of bacterial enoyl acyl carrier protein reductase (FabI): 2,9-disubstituted 1,2,3,4-tetrahydropyrido[3,4-b]indoles as potential antibacterial agents.

An SAR study of a screening lead has led to the identification of 2,9-disubstituted 1,2,3,4-tetrahydropyrido[3,4-b]indoles as inhibitors of Staphylococcus aureus enoyl acyl carrier protein reductase (FabI).

Characterization of the MFalpha pheromone of the human fungal pathogen cryptococcus neoformans.

Cryptococcus neoformans is an important human pathogenic fungus with a defined sexual cycle and well-developed molecular and genetic approaches. C. neoformans is predominantly haploid and has two mating types, MATa and MATalpha. Mating is known to be regulated by nutritional limitation and thought also to be regulated by pheromones. Previously, a portion of the MATalpha locus was cloned, and a presumptive pheromone gene, MFalpha1, was identified by its ability to induce conjugation tube-like filaments when introduced by transformation into MATa cells. Here, the ability of the MFalpha1 gene to induce these morphological changes in MATa cells was used as a phenotypic assay to perform a structure-function analysis of the gene. We show that the MFalpha1 open reading frame is required for the morphological response of MATa cells. We also find that the cysteine residue of the C-terminal CAAX motif is required for activity of the MFalpha1 pheromone. In addition, we use a reporter system to measure the expression levels of the MFalpha1 pheromone gene and find that two signals, nutrient starvation and the presence of factors secreted by mating partner cells, impinge on this promoter and regulate MFalpha1 expression. We identify a second pheromone gene, MFalpha2, and show phenotypically that this gene is also expressed. Finally, we have synthesized the MFalpha1 pheromone and show that only the predicted mature modified form of the alpha-factor peptide triggers morphological responses in MATa cells.

Improving child welfare performance through supervisory use of client outcome data.

Despite their benefits, there is little evidence that outcome data are being widely used by program managers or field level supervisors. Three interdependent factors that facilitate the use of outcome data are well-constructed reports, and organizational culture that supports learning and outcome achievement, and managerial skills in interpreting data and taking relevant action. This article describes an outcome reporting package and training oriented toward frontline supervisors to help them use outcome data, shape a learning culture, interpret data, and take focused action toward improving outcomes for children and families.

Effects of positive intrathoracic pressure on pulmonary and systemic hemodynamics.

The Frank-Starling Law accounts for many changes in cardiac performance previously attributed to changes in contractility in that changes in contractility might have been incorrectly inferred from changing ventricular function curves (i.e. systolic performance plotted against filling pressure) if diastolic compliance also changed. To apply the Frank-Starling Law in the presence of changing diastolic compliance, it is necessary to measure end-diastolic volume directly or to calculate end-diastolic transmural pressure, which requires that pericardial pressure be known. Under most normal circumstances, increased intrathoracic pressure (and other interventions, such as vasodilators or lower-body negative pressure, that decrease central blood volume) decreases the transmural end-diastolic pressures of both ventricles, their end-diastolic volumes and stroke work. However, when ventricular interaction is significant, the effects of these interventions might be quite different; this may be important in patients with heart-failure. Although these interventions decrease RV transmural pressure, they may increase LV transmural pressure, end-diastolic volume, and thus stroke work by the Frank-Starling mechanism.

Restrictive left ventricular filling patterns are predictive of diastolic ventricular interaction in chronic heart failure.

OBJECTIVES: The purpose of this study was to determine whether restrictive left ventricular (LV) filling patterns are associated with diastolic ventricular interaction in patients with chronic heart failure. BACKGROUND: We recently demonstrated a diastolic ventricular interaction in approximately 50% of a series of patients with chronic heart failure, as evidenced by paradoxic increases in LV end-diastolic volume despite reductions in right ventricular end-diastolic volume during volume unloading achieved by lower body negative pressure (LBNP). We reasoned that such an interaction would impede LV filling in mid and late diastole, but would be minimal in early diastole, resulting in a restrictive LV filling pattern. METHODS: Transmitral flow was assessed using pulsed wave Doppler echocardiography in 30 patients with chronic heart failure and an LV ejection fraction < or = 35%. Peak early (E) and atrial (A) filling velocities and E wave deceleration time were measured. Left ventricular end-diastolic volume was measured using radionuclide ventriculography before and during -30-mm Hg LBNP. RESULTS: Nine of the 11 patients with and 2 of the 16 patients without restrictive LV filling patterns (E/A > 2 or E/A 1 to 2 and E wave deceleration time < or = 140 ms) increased LV end-diastolic volume during LBNP (p = 0.001). The change in LV end-diastolic volume during LBNP was correlated with the baseline A wave velocity (r = -0.52, p = 0.005) and E/A ratio (r = 0.50, p = 0.01). CONCLUSIONS: Restrictive LV filling patterns are associated with diastolic ventricular interaction in patients with chronic heart failure. Volume unloading in the setting of diastolic ventricular interaction allows for increased LV filling. Identifying patients with chronic heart failure and restrictive filling patterns may therefore indicate a group likely to benefit from additional vasodilator therapy.

Diastolic ventricular interaction in chronic heart failure: relation to heart rate variability and neurohumoral status.

It is likely that abnormal baroreflex control mechanisms are at least partially responsible for autonomic dysfunction in chronic heart failure. We recently demonstrated that diastolic ventricular interaction is associated with impaired baroreflex control of vascular resistance in heart failure. We reasoned that by constraining left ventricular filling, such interaction would decrease baroreflex activity and, thereby, increase sympathetic and decrease parasympathetic outflow. We hypothesized, therefore, that diastolic ventricular interaction in chronic heart failure patients would be associated with autonomic dysfunction. We used radionuclide ventriculography to measure changes in left and right ventricular end-diastolic volumes during acute volume unloading achieved by -30 mm Hg lower-body negative pressure in 30 patients with chronic heart failure. An increase in left ventricular volume in association with a reduction in right ventricular volume indicates diastolic ventricular interaction (a larger increase indicating a greater degree of interaction). We also measured heart rate variability (n = 23) and resting venous plasma norepinephrine (n = 24), epinephrine (n = 24), and atrial natriuretic peptide (ANP) (n = 14). During lower-body negative pressure, while right ventricular volume decreased in all patients (P < 0.001), left ventricular end-diastolic volume increased (from 152 +/- 25 to 157 +/- 36 ml/m2, P = 0.01). The change in left ventricular volume was positively correlated with resting plasma norepinephrine (P < 0.01) and ANP (P < 0.005), and negatively correlated with the standard deviation of normal to normal R-R intervals (P < 0.005), the root-mean-square of differences between successive normal to normal R-R intervals (P < 0.05), total power (P < 0.01), low-frequency power (P < 0.01), and high-frequency power (P < 0.05). Diastolic ventricular interaction in patients with chronic heart failure is associated with sympathetic nervous system activation evidenced by increased plasma norepinephrine and reduced heart rate variability.

Forearm vasoconstriction during dynamic leg exercise in patients with chronic heart failure.

Previous studies assessing vascular responses in nonexercising beds during exercise in patients with chronic heart failure (CHF) have yielded varying results. We proposed that the clinical and hemodynamic severity of heart failure may explain some of the variation. We reasoned that diastolic ventricular interaction (DVI), by limiting the ability of such patients to increase left ventricular (LV) volume and stroke volume during exercise, would attenuate baroreflex activation, resulting in increased sympathetic activation and hence exaggerated vasoconstriction. We hypothesized therefore that vasoconstriction in nonexercising beds would be exaggerated in patients with symptomatic and hemodynamically severe heart failure, particularly if associated with DVI. We measured forearm vascular resistance (FVR) during semierect cycle exercise in 22 CHF patients and 23 control subjects. DVI was assessed by measuring changes in ventricular volumes (radionuclide ventriculography) during volume unloading (-30 mm Hg lower-body negative pressure) in the heart failure patients and was inferred when LV end-diastolic volume paradoxically increased. Patients with symptoms of heart failure developed larger increases in FVR during exercise than did asymptomatic patients. There were significant correlations between the change in FVR during peak exercise and the resting mean pulmonary arterial pressure and pulmonary vascular resistance. CHF patients with DVI developed exaggerated increases in FVR (median [25th to 75th percentile]) compared with the remaining patients during low-workload exercise (138 [66 to 171] vs 6.4 [-4.3 to 28] units, P = 0.002) and during peak exercise (160 [90 to 384] vs 61 [-7.4 to 75] units, P < 0.02). Vasoconstriction in nonexercising beds is exaggerated in CHF patients with clinically and hemodynamically severe heart failure, particularly if associated with DVI. This may explain some of the reported variation in the degree of sympathetic activation that occurs during exercise in CHF patients.

Diastolic ventricular interaction in chronic heart failure.

BACKGROUND: Diastolic ventricular interaction describes a situation in which the volume of one ventricle is directly influenced by the volume of the other ventricle. Such interaction is normally negligible, but it is accentuated in circumstances associated with pulmonary hypertension and volume overload. When this interaction occurs, acute volume unloading results in a reduction in right ventricular end-diastolic volume, as expected, but left ventricular end-diastolic volume paradoxically increases. Since chronic heart failure is a volume-overloaded state associated with pulmonary hypertension, we hypothesised that this interaction may be clinically important in patients with heart failure. METHODS: A radionuclide technique incorporating cardiac scintigraphy was used to measure the effect of acute volume unloading, achieved by 30 mm Hg lower-body suction, on right and left ventricular end-diastolic volumes in 21 patients with chronic heart failure and 12 healthy individuals (controls). FINDINGS: In nine heart-failure patients, there was a paradoxical increase in left ventricular end-diastolic volume in association with an expected decrease in right ventricular end-diastolic volume during lower-body suction. This response was not seen in the control group. The mean change in left ventricular end-diastolic volume differed significantly between the heart-failure patients and controls (6 [SD 19] vs -19 [12] mL, p = 0.0003). However, the change in right ventricular end-diastolic volume was similar in the two groups (-18 [11] vs -20 [8]%. p = 0.70). Patients who increased left ventricular end-diastolic volume during lower-body suction had higher resting pulmonary arterial and pulmonary capillary wedge pressures than the remaining heart-failure patients. INTERPRETATION: The response of nine patients in our study suggests diastolic ventricular interaction, which we believe could be common in patients with chronic heart failure. This finding is relevant to their management, since it emphasises the importance of venodilator therapy. The relation between stroke volume and left ventricular end-diastolic volume, by the Frank-Starting law of the heart, may explain why some patients with chronic heart failure paradoxically increase stroke volume when pulmonary capillary wedge pressure is lowered with vasodilators.

Activities of beta-lactams against Acinetobacter genospecies as determined by agar dilution and E-test MIC methods.

The agar dilution MIC method was used to test activities of ticarcillin, ticarcillin-clavulanate, amoxicillin, amoxicillin-clavulanate, ampicillin, ampicillin-sulbactam, piperacillin, piperacillin-tazobactam, inhibitors alone, ceftazidime, and imipenem against 237 Acinetobacter genospecies. A total of 93.2% of strains were beta-lactamase positive by the chromogenic cephalosporin method. Overall, ampicillin-sulbactam was the most active combination against all strains (MIC at which 50% of the isolates are inhibited [MIC50] and MIC90, 4.0 and 32.0 microg/ml; 86.9% susceptible at < or = 16 microg/ml), followed by ticarcillin-clavulanate (16.0 and 128.0 microg/ml; 85.7% susceptible at < or = 64 microg/ml), piperacillin-tazobactam (16.0 and 128.0 microg/ml; 84.8% susceptible at < or = 64 microg/ml), and amoxicillin-clavulanate (16.0 and 64.0 microg/ml; 54.4% susceptible at < or =16 microg/ml). Ceftazidime and imipenem yielded MIC50s and MIC90s of 8.0 and 64.0 microg/ml (ceftazidime) and 0.5 and 1.0 microg/ml (imipenem), respectively; 71.3% of strains were susceptible to ceftazidime at < or = 16 microg/ml, and 99.2% were susceptible to imipenem at < or = 8 microg/ml. Sulbactam was the most active beta-lactamase inhibitor alone (MIC50 and MIC90, 2.0 and 16.0 microg/ml); clavulanate and tazobactam were less active (16.0 and 32.0 microg/ml for both compounds). Enhancement of beta-lactams by beta-lactamase inhibitors was not always seen in beta-lactamase-positive strains, and activity of combinations such as ampicillin-sulbactam was due to the inhibitor alone. Acinetobacter baumannii was the most resistant genospecies. By contrast, Acinetobacter haemolyticus, Acinetobacter calcoaceticus, Acinetobacter johnsonii, Acinetobacter junii, Acinetobacter radioresistens, and other non-Acinetobacter baumannii strains were more susceptible to all compounds tested. E-test MICs were within 1 dilution of agar dilution MICs in 38.4 to 89.6% of cases and within 2 dilutions in 61.6 to 98.6% of cases.

Diastolic ventricular interaction: a possible mechanism for abnormal vascular responses during volume unloading in heart failure.

BACKGROUND: Baroreflex dysfunction is common in chronic heart failure and contributes to the associated sympathoexcitation. Baroreceptor activity normally decreases during volume unloading, causing an increase in sympathetic outflow and resulting in forearm vasoconstriction. Some heart failure patients develop attenuated vasoconstriction or paradoxical vasodilation. The mechanism for this is unknown. We have recently demonstrated diastolic ventricular interaction in some patients with chronic heart failure as evidenced by increases in left ventricular (LV) end-diastolic volume in association with decreases in right ventricular (RV) volume during volume unloading. We reasoned that such an increase in LV volume, by increasing LV mechanoreceptor activity, would decrease sympathetic outflow and could therefore explain the abnormal vascular responses seen in such patients. METHODS AND RESULTS: We assessed changes in forearm vascular resistance (FVR) during application of -20 and -30 mm Hg lower-body negative pressure (LBNP) in 24 patients with chronic heart failure and 16 control subjects. Changes in LV and RV end-diastolic volumes were assessed during -30 mm Hg LBNP in all heart failure patients. Diastolic ventricular interaction was demonstrated in 12 patients as evidenced by increases in LV end-diastolic volume in association with decreases in RV end-diastolic volume during LBNP. Changes in FVR during LBNP (-20 and -30 mm Hg) were markedly attenuated in these 12 patients (-1.6+/-11.2 and -0.9+/-12.5 U) compared with both the remaining patients (11.9+/-10.0 and 17.0+/-12.3 U) and the control subjects (16.5+/-9.5 and 23.1+/-13.9 U) (P<.01 for both comparisons at each level of LBNP). FVR decreased in 5 of these 12 patients during -30 mm Hg LBNP, a response seen in none of the remaining patients (P=.01). CONCLUSIONS: Diastolic ventricular interaction in patients with chronic heart failure is associated with attenuated forearm vasoconstriction or paradoxical vasodilation during LBNP. This may explain the apparent derangement in baroreflex control of sympathetic outflow during acute volume unloading in heart failure.

Interruption of the gpxA gene increases the sensitivity of Neisseria meningitidis to paraquat.

Antioxidant enzymes are thought to be important for the survival of pathogenic Neisseria species. We have further characterized the glutathione peroxidase homolog gene (gpxA), which we recently isolated from Neisseria meningitidis FAM20 (T.D.E. Moore and P.F. Sparling, Infect. Immun. 63:1603-1607, 1995). GpxA was found to be produced constitutively in vivo. An isogenic, omega insertion mutant in the gpxA gene was constructed and characterized. The gpxA insertion mutant was much more sensitive to the oxidative stress caused by paraquat and slightly more sensitive to hydrogen peroxide. This is the first demonstration of a phenotype arising from a mutation of a glutathione peroxidase homolog gene in a prokaryotic organism. Protection of the cell by GpxA from the effects of oxidative stress caused by aerobic metabolism may contribute to the ability of Neisseria meningitidis to cause disease in the human host.

Demonstration of late cardiotoxicity following bone marrow transplantation by assessment of exercise diastolic filling characteristics.

We evaluated the role of rest and exercise left ventricular diastolic filling parameters as a marker of cardiotoxicity in 25 consecutive patients 1 year following BMT. Ten age- and sex-matched subjects served as controls. Patients were evaluated in toto and in three sub-groups according to chemotherapy. Left ventricular ejection fraction (EF), peak filling rate (PFR) and time to peak filling (TTPF) were assessed at rest and at peak exercise. EF and PFR were similar at rest and at peak exercise in patients and controls. TTPF was significantly prolonged at rest in patients compared to controls (200 +/- 65 vs 131 +/- 26 ms, P = 0.003) and at peak exercise was markedly longer in patients (142 +/- 40 vs 54 +/- 19 ms, P < 0.001). Sub-group analysis demonstrated abnormal resting TTPF in those patients who had received either combination anthracycline and CY or anthracycline and melphalan, while those patients who received CY alone had normal resting TTPF. However, exercise TTPF was abnormally prolonged in all patient groups. While all controls demonstrated a normal decrease in TTPF during exercise, four of the 25 patients had a paradoxical increase in TTPF during exercise. Exercise diastolic function may provide evidence of cardiotoxicity in long-term survivors of BMT.

Stability of amoxicillin-clavulanate in BACTEC medium determined by high-performance liquid chromatography and bioassay.

The stabilities of amoxicillin (16 micrograms/ml) and clavulanate (8 micrograms/ml), alone and in combination in BACTEC medium (Middlebrook 7H12B medium), were determined by high-performance liquid chromatography (HPLC) and bioassay. By HPLC, the half-life of amoxicillin (trihydrate and sodium) in combination with clavulanate in nonradiolabelled 7H12B medium was 6.7 days, whereas the half-life of clavulanate in combination with amoxicillin was 2.0 days. By bioassay, the half-lives of amoxicillin trihydrate and clavulanate in radiolabelled 7H12B medium were comparable (7 and 2 days, respectively) to those determined by HPLC. When clavulanate was tested alone, the half-life was determined to be 1.88 days by HPLC and 1.87 days by bioassay. The relatively short half-life of clavulanate can be adjusted by a procedure of "topping up," or adding one-half the concentration of clavulanate every second day, in order to allow accurate amoxicillin-clavulanate MIC testing with the BACTEC mycobacterial susceptibility system.

Susceptibilities of nontuberculosis mycobacterial species to amoxicillin-clavulanic acid alone and in combination with antimycobacterial agents.

Neither amoxicillin nor clavulanic acid used alone was active at the highest level tested, i.e., 256.0 micrograms/ml, in vitro against 24 isolates of Mycobacterium fortuitum, Mycobacterium kansasii, and Mycobacterium marinum. However, the MIC of an amoxicillin-clavulanic acid combination of 2:1 was < or = 8.0/4.0 micrograms/ml for 50 percent of the isolates tested, with all isolates being inhibited in the range of 4.0/2.0 to 32.0/16.0 micrograms/ml, respectively. Titration of amoxicillin-clavulanic acid with a fixed 2-micrograms/ml concentration of ethambutol resulted in synergistic activity against 3 of 9 isolates of M. fortuitum, 10 of 10 isolates of M. kansasii, and 5 of 5 isolates of M. marinum. This observation was confirmed in a checkerboard analysis in which fractional inhibitory concentrations were < or = 0.5 for 20 of the 24 isolates. Synergistic activity was observed against the other four isolates in one of two trials. On the other hand, titration of amoxicillin-clavulanic acid in the presence of either one or two fixed concentrations of isoniazid, rifampin, cycloserine, tetracycline, or amikacin failed to result in synergism.

The first 18 months of mental health reform in Kansas.

OBJECTIVE: The effects of the first 18 months of implementation of the Kansas Mental Health Reform Act were evaluated. The act designated community mental health centers as gatekeepers for admission to mental health services, created screening and diversion services for state hospital admission, allocated state hospital bed days to each center, and reallocated funds from hospitals to communities. METHODS: Data from the catchment area in which reform was implemented in the 18-month study period, January 1991 to June 1992, were compared with data for that area before reform, and with data for the two state hospital catchment areas in which reform was not yet implemented. RESULTS: In the catchment area in which reform was implemented, state hospitalization decreased by about 29 percent, and state mental health funds allocated to the area's mental health centers almost doubled. Service utilization by patients discharged from the state hospital was higher than in the other two catchment areas, and most indicators of living status and vocational or educational involvement reflected improvement. CONCLUSIONS: The first 18 months of implementation suggest that state-level systems change can decrease state hospitalization and improve the utilization of community services while improving the quality of life for people with severe and persistent mental illness.

Isolation and identification of a glutathione peroxidase homolog gene, gpxA, present in Neisseria meningitidis but absent in Neisseria gonorrhoeae.

Antioxidant enzymes are thought to be important for the survival of pathogenic Neisseria species. We isolated a glutathione peroxidase-related gene (gpxA) from Neisseria meningitidis FAM20. The N. meningitidis glutathione peroxidase homolog was 49 to 57% identical to seven other glutathione peroxidase family members over a 49-amino-acid region which is conserved among various species. The gpxA sequence was present in all 7 meningococcal strains tested but absent in 10 gonococcal strains and 6 nonpathogenic neisserial strains as determined by Southern hybridization. The homology of gpxA to mammalian glutathione peroxidases and the presence of this gene specifically in the meningococcus suggest that it is important in the cellular metabolism or defense processes particular to this pathogen.

Endotoxin levels in adult liver donors.

This study was undertaken to determine the levels of endotoxin in a group of adult donors whose livers were procured for transplantation. In the group of 25 adults, endotoxin levels were found to be significantly elevated in the systemic venous blood when compared to control levels. Portal venous endotoxin levels were also elevated following hepatic hilar dissection and after cannulation of the portal vein prior to removing the donor liver.