Experimental myocardial infarction: XI. Circulatory effects of hypoxia in intact conscious dogs with coronary occlussion

This study was designed to detect possible deleterious effects of systemic hypoxia upon the ischemic canine heart. Myocardial infarction was produced in intact conscious dogs by occluding either the left anterior descending or the circumflex coronary artery, using a balloon cuff implanted around the vessel. Periods of 12, 8 and 6 percent oxygen breathing were imposed on the animals before and after acute myocardial infarction. Cardiac output, systemic arterial and pulmonary arterial pressures and the maximal rate of rise of left ventricular pressure (dP/dt) increased with hypoxia produced by breathing of 6 percent oxygen both before and after coronary occlusion. Left ventricular end-diastolic pressure did not increase during hypoxia after myocardial infarction. Thus, despite the presence of ischemic heart failure (sinus tachycardia, increased left ventricular end-diastolic pressure), the response to hypoxia was quantitatively similar to the response observed before coronary occlusion. Hypoxia after coronary occlusion did not further depress overall left ventricular function.     

Continuous negative extrathoracic pressure versus positive end-expiratory pressure in piglets after saline lung lavage

Recent reports have suggested that substituting continuous negative extrathoracic pressure (CNEP) for positive end-expiratory pressure (PEEP) may result in clinical benefits to infants with pulmonary disease. Other studies have suggested potential hemodynamic advantages. We compared the effects of CNEP and PEEP in 13 mechanically ventilated newborn piglets after acute lung injury induced by saline lavage. The piglets were instrumented, salinelavaged, and exposed to 15 minute periods of incremental CNEP (–3, –6, –9, –12 cmH₂O) (n = 7) or PEEP (3, 6, 9, 12 cmH₂O) (n = 6). We measured and/or calculated dynamic lung compliance (C_Ldyn), lung resistance (R_L), end-expiratory lung volume (EELV), blood gases, cardiac output (CO), heart rate (HR), transmural vascular pressures, and pulmonary and systemic vascular resistance. Pulmonary function abnormalities after saline lavage included decreased P_ao2, C_Ldyn, EELV, and increased P_aco₂ and R_L (P < 0.05). Except for decreased CO, lung inflation with both CNEP and PEEP resulted in large increases in P_aO₂ without major pulmonary or hemodynamic effects. Other than differences in EELV at 3, 6, and 9 cmH₂O distending pressure, there were no differences in pulmonary function or hemodynamics between sequences of incremental CNEP and PEEP. We conclude that CNEP and PEEP are physiologically equivalent in this model of acute lung injury. Pediatr Pulmonol. 1994; 17:161–168. © 1994 Wiley-Liss, Inc.     

Preservation of pulmonary function in the ventilated neonatal piglet with normal lungs

Little attention has been focused on the progressive pulmonary deterioration which occurs in mechanically ventilated infants with normal or mildly abnormal lungs. We hypothesized that lung function would deteriorate over a 24-hr period in anesthetized neonatal piglets with normal lungs mechanically ventilated at 2 cm H₂O PEEP (2PEEP group). We further hypothesized that an intermittent lung inflation procedure consisting of 15 out of 60 min of increasing lung distention (4,8,12 cm H₂O PEEP), with the remaining 45 min at 2 cm H₂O PEEP (Inflation group) would prevent this deterioration in lung function, similar to piglets mechanically ventilated continuously at 6 cm H₂O PEEP (6PEEP). Results indicate that 2PEEP piglets experienced progressive deterioration in lung function, including dynamic lung compliance (-42%) and lung resistance (+55%). In contrast, Inflation piglets and GPEEP piglets had no deterioration in lung function. Hemodynamics were similar between groups, although they were the most stable in the 6PEEP group. Histopathological changes were not significantly different. We conclude that (1) prolonged mechanical ventilation at 2 cm H₂O PEEP in neonatal piglets resulted in progressive deterioration in pulmonary function, (2) intermittent lung inflation or continuous 6 cm H₂O PEEP prevented deterioration, and (3) functional changes occurred without changes in histopathology. Lung inflation strategies other than PEEP can be used to prevent deterioration in lung function which accompanies prolonged mechanical ventilation in anesthetized nonspontaneously breathing piglets with normal lungs. © 1995 Wiley-Liss, Inc.     

Effect of propranolol on the QT intervals of normal individuals during exercise: a new method for studying interventions.

A new method was used to study the effect of a single dose of propranolol on the QT intervals during exercise in 11 normal volunteers. They exercised maximally on a bicycle ergometer and repeated the test after taking propranolol (40 mg) by mouth two hours before. Electrocardiograms were continuously recorded on magnetic tape and the cardiac cycle length (RR interval) and the QT interval were measured every five seconds by a computer aided method. The RR-QT data from each test during the exercise phase were analysed by an exponential formula, QT = A - B x exp (-k x RR) and by Bazett's formula, QT = K x square root of (RR). Three reference QT intervals, QTc1, QTc2, and QTc3, estimated at RR = 400, 700, and 1000 ms respectively from the regression curves of both formulas were compared. The exponential formula, which consistently gave a better fit with the data, showed that propranolol had a biphasic action on the QT intervals during exercise. It significantly prolonged the mean (SD) interval at longer cycle lengths (from 287 (27) to 305 (18) ms at RR = 1000 ms and shortened it at shorter cycle lengths (from 198 (14) to 179 (16) ms at RR = 400 ms). In contrast, Bazett's formula did not show any significant effect when the same raw data were used. The exponential formula can be adapted to study other interventions or conditions that affect QT intervals.     

Defective presentation of the CD1d1-restricted natural Va14Ja18 NKT lymphocyte antigen caused by beta-D-glucosylceramide synthase deficiency

Va14Ja18 natural T (NKT) cells play an immunoregulatory role, which is controlled by a self glycolipid(s) presented by CD1d. Although the synthetic antigen alpha-D-galactosylceramide (alpha-D-GalCer) stimulates all Va14Ja18 NKT cells, alpha-anomeric D-glycosylceramides are currently unknown in mammals. We have used beta-D-GalCer-deficient mice and beta-D-glucosylceramide (beta-D-GlcCer)-deficient cells to define the chemical nature of a natural NKT cell antigen. beta-D-GalCer-deficient mice exhibit normal NKT cell development and function, and cells from these animals potently stimulate NKT hybridomas. In striking contrast, the same hybridomas fail to react to CD1d1 expressed by a beta-D-GlcCer-deficient cell line. Importantly, human beta-D-GlcCer synthase cDNA transfer, and hence the biosynthesis of beta-D-GlcCer, restores the recognition of mutant cells expressing CD1d1 by the Va14Ja18 NKT hybridomas. Additionally, suppression of beta-D-GlcCer synthesis inhibits antigen presentation to Va14Ja18 NKT cells. The possibility that beta-D-GlcCer itself is the natural NKT cell antigen was excluded because it was unable to activate NKT hybridomas in a cell-free antigen-presentation assay. These findings suggest that beta-D-GlcCer may play an important role in generating and/or loading a natural Va14Ja18 NKT antigen.     

Impact of Alternative Medical Device Approval Processes on Costs and Health

Background

Medical devices are often introduced prior to randomized‐trial evidence of efficacy and this slows completion of trials. Alternative regulatory approaches include restricting device use outside of trials prior to trial evidence of efficacy (like the drug approval process) or restricting out‐of‐trial use but permitting coverage within trials such as Medicare''s Coverage with Study Participation (CSP).

Methods

We compared the financial impact to manufacturers and insurers of three regulatory alternatives: (1) limited regulation (current approach), (2) CSP, and (3) restrictive regulation (like the current drug approval process). Using data for patent foramen ovale closure devices, we modeled key parameters including recruitment time, probability of device efficacy, market adoption, and device cost/price to calculate profits to manufacturers, costs to insurers, and overall societal impact on health.

Results

For manufacturers, profits were greatest under CSP—driven by faster market adoption of effective devices—followed by restrictive regulation. Societal health benefit in total quality‐adjusted life years was greatest under CSP. Insurers’ expenditures for ineffective devices were greatest with limited regulation. Findings were robust over a reasonable range of probabilities of trial success.

Conclusions

Regulation restricting out‐of‐trial device use and extending limited insurance coverage to clinical trial participants may balance manufacturer and societal interests.     

Evaluation of the impact of computed high <Emphasis Type="Italic">b</Emphasis>-value diffusion-weighted imaging on prostate cancer detection

Purpose

The purpose of this study was to compare high b-value (b = 2000 s/mm²) acquired diffusion-weighted imaging (aDWI) with computed DWI (cDWI) obtained using four diffusion models—mono-exponential (ME), intra-voxel incoherent motion (IVIM), stretched exponential (SE), and diffusional kurtosis (DK)—with respect to lesion visibility, conspicuity, contrast, and ability to predict significant prostate cancer (PCa).

Methods

Ninety four patients underwent 3 T MRI including acquisition of b = 2000 s/mm² aDWI and low b-value DWI. High b = 2000 s/mm² cDWI was obtained using ME, IVIM, SE, and DK models. All images were scored on quality independently by three radiologists. Lesions were identified on all images and graded for lesion conspicuity. For a subset of lesions for which pathological truth was established, lesion-to-background contrast ratios (LBCRs) were computed and binomial generalized linear mixed model analysis was conducted to compare clinically significant PCa predictive capabilities of all DWI.

Results

For all readers and all models, cDWI demonstrated higher ratings for image quality and lesion conspicuity than aDWI except DK (p < 0.001). The LBCRs of ME, IVIM, and SE were significantly higher than LBCR of aDWI (p < 0.001). Receiver Operating Characteristic curves obtained from binomial generalized linear mixed model analysis demonstrated higher Area Under the Curves for ME, SE, IVIM, and aDWI compared to DK or PSAD alone in predicting significant PCa.

Conclusion

High b-value cDWI using ME, IVIM, and SE diffusion models provide better image quality, lesion conspicuity, and increased LBCR than high b-value aDWI. Using cDWI can potentially provide comparable sensitivity and specificity for detecting significant PCa as high b-value aDWI without increased scan times and image degradation artifacts.

     

Diltiazem as monotherapy for systemic hypertension: a multicenter, randomized, placebo-controlled trial

A multicenter, randomized, placebo-controlled, parallel group study of diltiazem in essential hypertension was carried out in 77 patients (40 diltiazem, 37 placebo) with stable supine diastolic blood pressure (BP) between 95 and 110 mm Hg. Patients were withdrawn from previous antihypertensive therapy for at least 4 weeks, titrated to the optimal dose, and followed for a total of 12 weeks during therapy. A diltiazem dose of 360 mg/day was required in 85% of the patients. Average BP in all positions was significantly (p less than 0.0001) reduced by diltiazem compared with placebo. With diltiazem, average supine BP fell from 156/100 mm Hg at baseline to 141/87 at end titration and 145/90 mm Hg at week 12, whereas average standing BP fell from 152/101 mm Hg to 136/90 and 143/91 mm Hg, respectively, at those times. There was no significant change in heart rate at week 12. Diltiazem tended to be more effective in older patients, but caused no increase in orthostatic BP drop. There were no statistically significant changes in BP in the placebo group. Two patients receiving placebo and 1 patient receiving diltiazem discontinued therapy as a result of adverse effects, and overall, side effects were only slightly more common with diltiazem treatment. Thus, diltiazem was effective and well tolerated single therapy for mild to moderate systemic hypertension and appears to compare favorably to most agents being used.     

The role of ventricular tachycardia ablation in the reduction of implantable defibrillator shocks

Frequent shocks from an implantable defibrillator (ICD) can have adverse cardiac affects and lead to increased pain, anxiety, and a decreased quality of life. Pharmacologic attempts and ICD reprogramming strategies aimed at reducing ICD shocks have modest results, with frequent discontinuation of medicines because of side effects. Ventricular tachycardia (VT) ablation is recommended in the treatment of patients with frequent ICD shocks caused by VT. VT ablation may also be considered in patients with an initial ICD shock and as prophylactic treatment in patients with a history of sustained VT who are undergoing ICD implant.     

Subpopulations of human helper and suppressor T lymphocytes

Mitogen driven differentiation of normal human mononuclear cells is a a well-established model for the study of antibody synthesis in man. In certain rare individuals who are clinically normal, unfractionated mononuclear cells or a mixture of purified B plus T lymphocytes differentiate into immunoglobulin producing cells in response to purified protein derivative of tuberculin (PPD) but not in response to pokeweed mitogen (PWM). To evaluate this observation we have irradiated T cells from such individuals to eliminate naturally occurring suppressor T cell activity and then added the irradiated T cells back to autologous B cells before culture. The B cells then responded to PWM. The original PPD responses of cells from these individuals were now significantly reduced. Although, there was no difference between PWM nonresponders and responders in the number of OKT-8 positive cells, elimination of OKT-8 positive cells in the PWM nonresponders with OKT-8 monoclonal antibody and complement resulted in a significantly increased response to PWM. This study indicates that there are suppressor T cells which specifically inhibit B cell response to PWM without affecting the PPD response. These results also show that the helper T cells involved in the PWM response are radioresistant and those involved in the PPD response are radiosensitive.