Supramolecular ferric porphyrins and a cyclodextrin dimer as antidotes for cyanide poisoning.

OBJECTIVES: This study aimed to evaluate the antidotal effect of a newly developed supramolecular complex, ferric porphyrins and a cyclodextrin dimer (Fe(III)PIm3CD), that possess a higher binding constant and quicker binding rate to cyanide ions than those of hydroxocobalamin (OHCbl) in the presence of serum protein. METHODS: First, in vitro cytochrome activity and cell viability were evaluated in murine fibroblast cells cultured with various doses of Fe(III)PIm3CD and potassium cyanide (KCN). Next, BALB/c mice were pretreated with intravenous OHCbl (0.23 mmol/kg), Fe(III)PIm3CD (0.23 mmol/kg), or saline and then received KCN (lethal dose 100% (LD100): 0.23 mmol/kg) through a stomach tube. Finally, as a resuscitation model, KCN-induced apnea was treated with a bolus injection of an equimolar dose of antidotes followed by a slow infusion of the same reagent. RESULTS: Fe(III)PIm3CD showed dose-dependent antidotal effects in vitro. Pretreatment with Fe(III) PIm3CD prevented KCN-induced apnea significantly better than OHCbl. Resuscitation with Fe(III)PIm3CD resulted in an earlier resumption of respiration than that seen with OHCbl. However, 24-h survival was similar among the treatments (Fe(III)PIm3CD, nine of nine mice; OHCbl, eight of nine mice). CONCLUSION: Fe(III)PIm3CD exerted significant antidotal effects on cyanide toxicity in vitro and in vivo, with a potency equal in the mortality of cyanide-poisoned mice or superior in the respiratory status during an acute phase to those of OHCbl.

Partial left ventriculectomy: the 2nd International Registry Report 2000.

BACKGROUND: Partial left ventriculectomy (PLV) has been performed without standardized inclusion or exclusion criteria. METHODS: An international registry of PLV was expanded, updated, and refined to include 287 nonischemic cases voluntarily reported from 48 hospitals in 11 countries. RESULTS: Gender, age, ventricular dimension, etiology, ethnology, myocardial mass, operative variation, presence or absence of mitral regurgitation, and transplant indication had no effects on event-free survival, which was defined as absence of death or ventricular failure that required a ventricular assist device or listing for transplantation. Preoperative patient conditions, such as duration of symptoms (> 9 vs < 3 years; p = 0.001), New York Heart Association (NYHA) class (Class IV vs < Class IV; p = 0.002), depressed contractility (fractional shortening [FS] < 5% vs > 12%; p = 0.001), and refractory decompensation that required emergency procedure (p < 0.001) were associated with reduced event-free survival. Five or more cases in each hospital led to significantly better outcomes than the initial four cases. Rescue procedures for 14 patients nonsignificantly improved patient survival (2-year survival 52%) over event-free survival (2-year survival 48%; p = 0.49), with improved NYHA class among survivors (3.6 to 1.8; p < 0.001). Outcome was better in 1999 than in all series before 1999 (p = 0.02) most likely due to patient selection, which was refined to avoid known risk factors such as reduced proportion of patients in NYHA Class IV, FS < 5%, and hospitals with experience in 10 or less cases. A combination of these risk factors could have stratified 17 high-risk patients with 0% 1-year survival and 26 low-risk patients with 75% 2-year event-free survival. CONCLUSION: Avoidance of risk factors appears to improve survival and might help stratify high- or low-risk patients. Although less symptomatic patients with preserved contractility had better results after PLV, change of indication requires prospective randomized comparison with medical therapies or other approaches.

Improved left ventricular contraction and energetics in a patient with Chagas' disease undergoing partial left ventriculectomy.

A 43-year-old patient with heart failure, precluded from heart transplantation or dynamic cardiomyoplasty because of Chagas' disease cardiomyopathy, mitral regurgitation, and ventricular mural thrombi, underwent mitral valvuloplasty and partial left ventriculectomy (PLV) between the papillary muscles. Intraoperative pressure-volume relationship analyses suggested improvement in left ventricular contraction, energetics, isovolumic relaxation, and mitral valve competency. These improvements allowed prompt, short-term recovery despite unchanged myocardial pathology, which suggests that a surgical approach can alter anatomic-geometric factors and achieve clinical improvement in a dilated failing ventricle.

Partial left ventriculectomy: history, current status, and future role.

Whereas discouraging clinical results and lack of scientific evidence decreased the initial interest in partial left ventriculectomy (PLV), factors contributing to success and failure have now been identified by clinical observations, theoretical analyses, and data from an international registry, which are herein reviewed to outline the current status and future role of this procedure as a treatment of heart failure.

Perioperative hemodynamics in patients undergoing partial left ventriculectomy.

OBJECTIVES: Effects of partial left ventriculectomy (PLV) were studied by analyzing perioperative hemodynamics with measurements of left ventricular (LV) pressure-volume (PV) relationships and thermodilution catheter measurements in the pulmonary artery. METHODS: Between July and October 1996, 43 consecutive patients underwent PLV with and without mitral valvuloplasty with a thermodilution catheter and PV loop analysis immediately before and after surgery. Patients were 52+/-13 years and 67+/-13 kg, with reduced functional capacity (New York Heart Association 3.3+/-0.3) due to cardiomyopathy (24), ischemic disease (13), valvular disease (3), and Chagas' disease (3). RESULTS: PLV required cardiopulmonary bypass for 44+/-24 minutes, with the heart arrested in 10 patients for 26+/-22 minutes for coronary artery bypass grafting (8), aortic valve replacement (2), and autotransplantation (2). Two patients failed to come off bypass, six died in the hospital and 35 (35 [81.4%] of 43) were discharged. Changes in PV loops included decreased end-diastolic and end-systolic volume, resulting in no change in stroke volume. Pulmonary artery wedge pressure decreased despite elevated end-diastolic pressure. Ejection fraction, end-systolic elastance (E-max), afterload recruitable stroke work, and volume intercepts all improved and resulted in similar stroke work with less energy expenditure (less PV area), thus improving myocardial energetic efficiency. CONCLUSION: Results suggest that PLV improves systolic function but decreases diastolic compliance, which results in reduced net ventricular function immediately after surgery. Thus, immediate hemodynamic improvements appeared to derive from reduced severity in mitral regurgitation and perioperative load manipulation. Improved myocardial energetics may ameliorate LV function and improve the course of underlying myocardial disease.

Histopathology of resected myocardium and outcome of partial left ventriculectomy.

BACKGROUND: Since preoperative hemodynamics are not proven to be a predictor of effects of partial left ventriculectomy (PLV), myocardial histopathology may be better correlated with effects and outcome of PLV. METHODS: Myocyte size (micron) in the excised myocardium was measured in 338 patients undergoing PLV. Endocardial fibrosis, interstitial fibrosis, and inflammatory cell infiltration were enumerated as none = 0, mild = 1, moderate = 2, and severe = 3. These histopathologic observations were correlated with patients' postoperative survival. RESULTS: Reduced survival was seen in patients with advanced (> or = moderate) interstitial fibrosis in all patients (n = 338, p = 0.064) and in the subgroup with nonischemic etiology (n = 229, p = 0.0039). Although correlation between endocardial and interstitial fibrosis was significant (r = 0.55, p < 0.01), endocardial fibrosis failed to correlate with postoperative survival. While Chagas' disease was associated with severe inflammation and poor survival, the presence of inflammatory cell infiltration had no effect on survival in all patients combined (p = 0.943). Although most patients (n = 266, 79%) had myocyte diameter over 30 micron, those with less hypertrophy (< 30 micron, n = 70, 21%) had a tendency toward increased survival (p = 0.067) regardless of underlying etiology. CONCLUSION: Interstitial fibrosis may be an important factor in stratification of patients for repair (PLV) or replacement (transplantation). PLV may be more beneficial in patients with less hypertrophy, before develqpment of interstitial fibrosis. Endomyocardial biopsy might not predict the extent or variation in degree of interstitial fibrosis, which may be better evaluated by other metabolic or perfusion studies that measure overall myocardial histopathology and viability.

Two-week, but not 1-week, hypoxic exposure enhances nitric oxide-mediated basal tone regulation in rat resistance pulmonary arteries.

We measured internal diameter (ID) changes in resistance and conduit pulmonary arteries of 1- and 2-week hypoxic rats and normoxic control rats in response to nitric oxide synthase (NOS) inhibitors in vivo. At 2 weeks of hypoxic exposure, the ID reduction as a result of NOS inhibition was enhanced within the resistance arteries, but not at 1 week of hypoxia.

Partial left ventriculectomy. The First Japanese Registry Report 1999.

OBJECTIVE: Partial left ventriculectomy has been performed without standardized inclusion/exclusion criteria. A registry has been established to accumulate experience with this procedure to identify indications, risks and benefits. METHODS: In response to a mailed inquiry, 90 cases were voluntarily registered from 28 Japanese institutions. RESULTS: Males (n = 67, 74.4%) predominated, and 29 (32.2%) patients were over 60 years old. The underlying cardiac pathologies included dilated cardiomyopathy (n = 75, 83.3%), valvular disease (n = 8, 8.9%), the dilated phase of hypertrophic cardiomyopathy (n = 4, 4.5%), and others (n = 3, 3.3%). Gender, age, etiology, papillary muscle excision and absent transplant indication did not significantly affect survival. Poorer preoperative condition, reduced contraction and decompensation necessitating emergency operation were each associated with a significantly higher risk. Hospitals performing less than 5 cases had poorer results than more experienced institutions (p = .0019), which showed a tendency towards improved survival in the second half of their experience (p = .096). Hospital mortality (n = 29, 32.6%) and late death (n = 10, 11.2%) were mainly from ventricular failure with few sudden deaths over a period of 63.6 patient years follow-up. Late mortality was equally distributed in the first year and leveled off with significantly improved cardiac functional class in survivors. CONCLUSION: Partial left ventriculectomy was associated with better survival in less symptomatic patients with better contractile reserve undergoing an elective operation preserving the papillary muscles. Avoidance of identified risk factors may allow better patient selection and improved survival in the current environment where rescue transplantation is not readily available. Long-term follow-up is warranted with more registry data.

Myocardial revascularization of the beating heart in high-risk patients.

OBJECTIVE: Myocardial revascularization without cardiopulmonary bypass (CPB) has been proposed as an alternative technique in patients at high risk for conventional coronary artery bypass grafting (CABG). The purpose of this article is to evaluate the potential benefit of such an approach. METHODS: We retrospectively evaluated the perioperative results of off-pump CABG (OPCAB) performed from January 1995 to December 1999. Patients were divided into three groups on the basis of their preoperative risk factors: age greater than 80 years, reoperative CABG, and left ventricular ejection fraction percentage (LVEF%) less than 40%. The three subgroups were compared with patients operated on-CPB (ONCAB) during the same period of time. A total of 172 octogenarians had ONCAB versus 97 OPCAB, 307 reoperations were ONCAB versus 274 OPCAB, and 514 patients with LVEF% less than 40% were operated ONCAB versus 220 OPCAB. RESULTS: Preoperative comorbidities were homogeneously distributed in the OPCAB and ONCAB groups. More extensive coronary artery disease was found in the ONCAB groups. A trend for a lower number of perioperative complications was reported in the OPCAB groups. Freedom from overall complications was significantly higher (p < 0.005) in the OPCAB group. Actual mortality rates in the OPCAB and ONCAB groups were comparable (p = NS). CONCLUSIONS: CABG can be performed safely without CPB in patients with a high preoperative risk profile. Freedom from perioperative complications is markedly higher when the OPCAB approach is utilized.

Partial left ventriculectomy for patients with ischemic cardiomyopathy.

BACKGROUND: Partial left ventriculectomy (PLV) has been performed in patients with dilated cardiomyopathy (DCM), but improved myocardial energetics may make PLV useful also for ischemic cardiomyopathy (ICM) unamenable to conventional treatment. METHODS: Of 262 patients undergoing PLV, 94 patients with ICM as the underlying pathology were analyzed and compared with 168 patients with DCM. RESULTS: ICM patients were older (57.3 years vs 50.9 years, p = 0.0001) and heavier (69.7 kg vs 65.9 kg, p = 0.039) than those with DCM, but ventricular end-diastolic and end-systolic dimensions were similar with comparably depressed fractional shortening (16% vs 15%, p = 0.294) and equally severe functional limitation [New York Heart Association (NYHA) Class 3.7 vs 3.6, p = 0.734]. A majority of patients in both groups underwent lateral PLV (76% vs 74%, p = 0.883) with myocardium excised between papillary muscles and simultaneous mitral valvuloplasty (41% vs 74%, p < 0.0001). Because ICM patients required coronary artery bypass grafting (CABG) more frequently (79% vs 0.6%, p < 0.0001), operation was more extensive in terms of bypass time (74 minutes vs 47 minutes, p < 0.0001), percentage requiring cardiac arrest (43% vs 19%, p < 0.0001), and arrest duration (34 minutes vs 28 minutes, p = 0.280), but all had similar resection and postoperative ventricular dimensions. Nonetheless, ICM patients required shorter intensive care unit (ICU) time (4.4 days vs 5.9 days, p = 0.048) and similar postoperative hospital stays, resulting in similar hospital survival rates (69% vs 71%, p = 0.778) and functional capacity in long-term follow-up. CONCLUSIONS: Results suggest that PLV can be performed in patients with ICM with comparable risks and benefits as in DCM. Relative efficacy of CABG and mitral repair as compared to volume reduction remains to be studied.

Mitral regurgitation after partial left ventriculectomy as the cause of ventricular redilatation.

BACKGROUND: It remains unclear whether ventricular redilatation after partial left ventriculectomy (PLV) is due to underlying pathology or to continued volume overload amenable to surgery. METHODS: Among patients undergoing PLV, 32 had Doppler echocardiography preoperatively, immediately after surgery (< 1 week), early after surgery (1-3 months), and late after surgery (8-14 months). Patients were divided into groups with mitral regurgitation (MR; MR+, n = 16) and without postoperative MR (MR-, n = 16) and were compared for ventricular size, performance, and survival. RESULTS: After initial surgical reduction, left ventricular dimension on average gradually increased back to the preoperative level in subgroups of patients with valvular disease and cardiomyopathy and in all patients combined. Most patients showed drastically reduced left ventricular dimension early after PLV. In MR+ patients, dimension increased back to the preoperative level within 3 months after surgery, whereas the MR- group maintained reduced dimension throughout the first year in all patients combined and in a subgroup of patients with cardiomyopathy. Occurrence of significant MR after PLV appeared to be related to severity of fibrosis in excised myocardium but not to severity of preexisting MR, etiology, or performance of mitral valvuloplasty. CONCLUSIONS: Early postoperative MR, residual or new, appeared to play an important role in dictating early hemodynamics and late outcome in patients undergoing PLV. Results suggest an aggressive simultaneous approach to abolish MR. Causative role of myocardial fibrosis remains unclear and needs further study.

Transventricular mitral annuloplasty in a patient undergoing partial left ventriculectomy.

A 70-year-old male patient with heart failure resulting from dilated cardiomyopathy underwent a partial left ventriculectomy between the papillary muscles and a newly devised transventricular mitral annuloplasty. Intraoperative transesophageal Doppler echocardiography revealed reduced ventricular dimensions and corrected mitral insufficiency with unchanged ventricular filling patterns, allowing prompt recovery despite unchanged myocardial pathology.

Perioperative ventricular arrhythmias in patients undergoing partial left ventriculectomy.

BACKGROUND: Although incidence of ventricular arrhythmias after partial left ventriculectomy (PLV) has been reported, there are no studies comparing incidence before and after PLV. Although operative scars may give rise to arrhythmias, improved energetic efficiency after PLV may decrease their incidence. METHODS: Pre- and postoperative ventricular arrhythmias were monitored by Holter ECG and analyzed in 17 patients undergoing PLV in Curitiba, Brazil. RESULTS: Although total 24-hour heart beat (THB) increased significantly (p = 0.018), ventricular premature contractions (VPCs) decreased markedly (p = 0.036), excluding one patient dying in low cardiac output (LOS) who had terminal arrhythmias increased multifold. In the remaining 16 patients, VPC pairs were also reduced significantly on the average (p = 0.038). In contrast, ventricular tachycardia (VT; more than three consecutive VPCs) disappeared in five patients, decreased in two patients, and newly occurred in four patients, with five patients showing no change; one of them developed a prolonged VT, successfully reversed by external cardioversion. CONCLUSIONS: Despite notable significant increase in THB immediately after PLV, PVC and PVC pairs were significantly decreased in contrast to VT, which disappeared in some patients and newly occurred in other patients, remaining constant on the average. Sustained VT occurring in a patient with all other arrhythmias suppressed may suggest a unique electrophysiological substrate, may justify prophylactic use of amiodarone or an implantable cardioverter-defibrillator, and may underscore the importance of further and extended studies.

Magnetic resonance arthrography in children with developmental hip dysplasia.

Conventional and gadolinium enhanced magnetic resonance arthrograms were done on 14 hips in 10 children ages 7 to 24 months. The contralateral normal hips in those with unilateral disease were studied with unenhanced magnetic resonance imaging for comparison. By conventional arthrography, there were no well visualized structures. Visualized structures seen as filling defects were the labrum, ligamentum teres, and transverse acetabular ligament. By magnetic resonance arthrography, well visualized structures were the labrum, ligamentum teres, transverse acetabular ligament, and pulvinar. By unenhanced magnetic resonance imaging, well visualized structures were the labrum, ligamentum teres, and transverse acetabular ligament. The difference in visualization by magnetic resonance arthrography versus conventional arthrography was statistically significant with respect to all five structures: labrum, ligamentum teres, transverse acetabular ligament, pulvinar, and psoas tendon. The difference in visualization by magnetic resonance arthrography versus unenhanced magnetic resonance imaging was statistically significant with respect to the labrum and pulvinar. Magnetic resonance arthrography is indicated for assessing complete concentric reduction when it does not appear to be achieved by conventional arthrography, for confirming closed reduction immediately after manipulation, and potentially for preoperative planning for an open reduction.

Segmental differences in vasodilatation due to basal NO release in in vivo cat pulmonary vessels.

This study was conducted to examine segmental differences in vasodilatation caused by the basal release of nitric oxide (NO) in the serially connected pulmonary vessels and to estimate the relative contributions of endothelial and neuronal NO synthase (NOS), and inducible NOS to the vasodilatation. Using an X-ray TV system on in vivo cat lungs, we measured internal diameter (ID) changes in resistance (100-400 microm ID), small conduit (600-1000 microm) and large conduit (1200-1700 microm) arteries, and veins of the same size. Non-selective NOS inhibitors, L-NAME (30-50 mg/kg i.v.) and L-NMMA (40-60 mg/kg i.v.), decreased the ID of all vessels studied, although their D-isomers had no effect. The decrease was larger in conduit arteries than in resistance arteries, with maximum response of small conduit arteries (25 +/- 2%), while venous segments displayed relatively uniform response (10-12%). L-Arginine completely abolished the ID decrease but hexamethonium bromide and phentolamine had no effect. Selective inhibitors of inducible NOS, L-canavanine (100 mg/kg i.v.) and S-methylisothiourea (10 mg/kg i.v.) did not affect any of the vessels. The data suggest that basal release of NO chiefly derived from endothelial NOS serves to dilate cat pulmonary arteries and veins, particularly small conduit arteries.

Neurological function after deep hypothermic circulatory arrest in the rat.

BACKGROUND: Integrated neurological function, behavior, and somatic recovery were studied in 35 rats undergoing 5 to 80 minutes of hypothermic circulatory arrest (HCA). METHODS AND RESULTS: A closed extracorporeal circulation system (ECC) consisting of a miniature oxygenator and heat exchanger, primed with 6 mL of asanguinous solution, was connected to a closed-chest rat with cannulae in the right atrium for venous drainage (ID = 1.7 mm) and in the ascending aorta for arterial return (ID = 1.0 mm). The rat was surface- and core-cooled until rectal temperature reached 18 degrees C, when ECC was stopped and cardioplegic solution delivered. After 5, 10, 20, 40 (each n = 5), and 80 minutes (n = 15) of HCA, the rat was reperfused, weaned from ECC, and followed with behavioral scoring, passive avoidance tasks, and cardiopulmonary exercise testing until euthanized for morphological study. Every rat resumed weight gain in the first week after HCA and regained preoperative exercise capacity by the fourth week. Only rats undergoing 80 minutes of HCA showed behavioral abnormalities such as stereotypy and incomplete righting reflex, which eventually disappeared in the fourth week. Learning ability was preserved in all except for rats after 80 min of HCA, who failed to acquire new memory to avoid electric stimuli (n = 10) up to 3 months after HCA, when pyramidal cells were partly replaced by astroglia in the cerebral cortex and CA1 sector of hippocampus. Nonetheless, old memory established before HCA was preserved even after 80 minutes of HCA and allowed rats (n = 5) to avoid electric stimuli. CONCLUSIONS: Homogeneity of animals, miniature ECC system, and an established testing system allowed evaluation of rats after HCA, which disclosed learning disability (functional disorder) and pyramidal cell loss (organic defect) after 80 minutes of HCA despite recovery of somatic function, behavior, and growth.

Afferent reinnervation after lung transplantation in the rat.

Denervation at lung transplantation results in loss of cough reflex and attenuated local defense mechanisms, accounting for increased incidence and severity of infection after lung transplantation. We studied the presence or absence of spontaneous afferent reinnervation in rats at various intervals after orthotopic left pulmonary isografting (n = 52). Normal rats (n = 21) and rats undergoing left hilar stripping (n = 14) served as control subjects. Afferent reinnervation was tested physiologically by reflex bradycardia in response to intravenous infusion of capsaicin (30 microg/kg), an extract of paprika stimulating pulmonary C-fibers. Injection of capsaicin was repeated before and after right pulmonary artery occlusion to divert all pulmonary blood flow to the left lung or isograft. Whereas rats early after surgical denervation lost the reflex after right pulmonary artery occlusion, rats examined 8 months or longer after surgery showed potent reflex bradycardia in response to capsaicin, as did the control rats. Immunohistochemical staining for sensory neuron-specific substances, such as calcitonin gene-related peptide and substance P, were identified only in the right native lung and left pulmonary isografts 2 months or longer after transplantation. Fluorogold was found only in the ipsilateral nodose ganglion after left lung intrapleural injection of the neuron-specific tracer in rats 8 months or longer after denervation. These experiments provide physiological, morphologic, and neurologic evidence suggesting that afferent lung innervation, abolished early after transplantation, is spontaneously reestablished and functioning in the ipsilateral vagus nerve by 8 months after pulmonary isografting in the rat.

Delayed diagnosis of a glenohumeral joint dislocation in a child with developmental delay.

Glenohumeral joint dislocations rarely occur in children. Those that have been reported have all been reduced in a closed fashion. With the exception of one, there have not been any comorbidities in the children that would have led to a delay in diagnosis. To the best of our knowledge, we report the first case of a child with a delayed diagnosis of an anterior dislocation of the glenohumeral joint that required an open reduction. In a child with other medical problems, especially developmental delay, who may have difficulty expressing his symptoms, early detection and intervention are crucial and may obviate the need for open reduction of the dislocated and painful glenohumeral joint.

Partial left ventriculectomy in patients with dialated failing ventricle.

BACKGROUND: While partial left ventriculectomy (PLV) improves left ventricular energetic efficiency, concomitant reduction in mitral regurgitation may improve ventricular function. METHODS: Two hundred ninety-five patients undergoing lateral ventricular wall excision between the papillary muscles (lateral PLV) and 101 patients with an additional excision of papillary muscles and mitral valve replacement (extended PLV) were compared with 65 patients undergoing excision of anterior wall or ventricular aneurysm (anterior PLV). RESULTS: All patients had reduced functional capacity, New York Heart Association (NYHA) Class III to IV (3.62+/-0.49). Etiologies were cardiomyopathy (37.3%), coronary artery disease (32.3%), valvular disease (19.7%), Chagas' disease (7.8%), and others (2.8%). Patients undergoing lateral and extended PLV had cardiomyopathy as the primary cause of heart failure, while a majority of anterior PLV patients had ischemic disease. Associated procedures included mitral valvuloplasty or replacement (lateral PLV 67%, extended PLV 100%, anterior PLV 40%) and tricuspid annuloplasty (67%, 76%, 28%, respectively.) In each group after surgery, end-systolic dimension decreased more than end-diastolic dimension despite reduced mitral regurgitation. Although extended PLV resulted in greater volume reduction and less mitral regurgitation, these patients had delayed recovery and poor survival. Patients with valvular disease had the most advanced myocardial hypertrophy with the best survival, while those with Chagas' disease had more severe myocarditis, interstitial fibrosis, and the poorest survival. CONCLUSION: Lateral PLV improved hemodynamics and functional capacity as much as aneurysmectomy by reducing ventricular volume and mitral regurgitation. Inclusion and exclusion criteria have to be sought to make PLV safer and more effective.