Protection from septic shock by neutralization of macrophage migration inhibitory factor.

Identification of new therapeutic targets for the management of septic shock remains imperative as all investigational therapies, including anti-tumor necrosis factor (TNF) and anti-interleukin (IL)-1 agents, have uniformly failed to lower the mortality of critically ill patients with severe sepsis. We report here that macrophage migration inhibitory factor (MIF) is a critical mediator of septic shock. High concentrations of MIF were detected in the peritoneal exudate fluid and in the systemic circulation of mice with bacterial peritonitis. Experiments performed in TNFalpha knockout mice allowed a direct evaluation of the part played by MIF in sepsis in the absence of this pivotal cytokine of inflammation. Anti-MIF antibody protected TNFalpha knockout from lethal peritonitis induced by cecal ligation and puncture (CLP), providing evidence of an intrinsic contribution of MIF to the pathogenesis of sepsis. Anti-MIF antibody also protected normal mice from lethal peritonitis induced by both CLP and Escherichia coli, even when treatment was started up to 8 hours after CLP. Conversely, co-injection of recombinant MIF and E. coli markedly increased the lethality of peritonitis. Finally, high concentrations of MIF were detected in the plasma of patients with severe sepsis or septic shock. These studies define a critical part for MIF in the pathogenesis of septic shock and identify a new target for therapeutic intervention.

Auscultation of the heart: a trial of classroom teaching versus computer-based independent learning.

Declining skills in auscultation of the heart prompted an evaluation of teaching methods for medical students. A comparison of classroom teaching and computer-aided independent learning of auscultation was carried out with two groups of approximately 20 second-year medical students. Both groups used approximately 20 recorded normal and abnormal heart sounds and murmurs, chosen to illustrate learning issues. For the classroom group a cardiologist presented each case through multiple stethophones and led the discussion. The individual study group used a new CD-ROM collection of cases and recordings in quiz format, with a hypertext link to a comprehensive text on auscultation and additional recordings. Students were tested with 16 multiple choice and 5 open questions on eight selected recordings, and evaluated the teaching by questionnaire. The classroom-taught students scored higher on open questions than the CD-ROM-taught group, but in general performance by both groups was satisfactory and equivalent. Students of both groups repeatedly had difficulty classifying regurgitant and ejection murmurs and identifying characteristics of the second heart sound. Both CD-ROM and classroom teaching methods were highly rated by students but most students preferred a combination.

Trends in the prevalence of congenital heart disease: comprehensive observations over a 24-year period in a defined region of Canada.

OBJECTIVE: To determine the prevalence of congenital heart disease (CHD) in the three Maritime provinces, and to study prevalence differences among provinces and defined regions within these provinces. DESIGN: Each province was divided by counties into regions. All cases of CHD who were born alive in the study area between 1966 and 1989 were entered in a registry. Prevalences were analyzed for each province and for selected regions per year, per 1000 live births, and by diagnosis made by one year of age and by the 16th birthday. Comparison was then made with prevalences of a group who had severe lesions. INTERVENTIONS: Excepting a small number of CHD cases who were diagnosed by autopsy only, diagnosis was made by pediatric cardiologists using appropriate procedures, including cardiac ultrasound and cardiac catheterization. SETTING: The only tertiary care centre for children's heart disease in the provinces of Nova Scotia, New Brunswick and Prince Edward Island, areas of relative geographic isolation (combined population of 1.75 million people). MAIN RESULTS: A statistically significant positive linear trend occurred in these provinces during the study. The recorded prevalence of CHD in New Brunswick was significantly lower. Pooled prevalences by the first and 16th birthdays (8.0 and 12.5 per 1000 live births, respectively) of two regions of highest prevalence for 1980-86 were significantly higher (P < 0.05) than the pooled prevalence rate of all the remaining regions. Prevalence rates of a group with severe lesions were stable for 1976-86 in all regions. CONCLUSIONS: Differences in prevalence of CHD among provinces and regions were related to ascertainment levels. Prevalence of CHD with diagnosis by the first and 16th birthdays were approximately 8.0 and 12.5 per 1000 live births, respectively. The prevalence rate of a severe lesion group was a stable measure.

Follow-up after patch aortoplasty for coarctation of aorta.

BACKGROUND: Patch aortoplasty (PA) for coarctation of aorta (COA) can lead to aneurysm formation at the repair site. X-ray, echocardiogram and computed tomography are unreliable for diagnosis of this complication. OBJECTIVE: To evaluate prospectively patients with PA for COA by magnetic resonance imaging (MRI) to detect presence of aneurysm at the repair site. DESIGN: All patients who underwent PA at the authors' institution were identified. MRI was performed in transverse and long axis oblique views on all patients except those who had, or were going to have, aortic angiography for other reasons. Details of the surgical procedure were obtained from the hospital records. RESULTS: Of the 18 patients studied, 15 had MRI and three had aortic angiography. Age at PA ranged from one week to 13.3 years (mean 6.3 years). The interval from PA to MRI or angiography was 9.5 years (range four to 12.5). No aneurysm was detected in any patient. Recoarctation was diagnosed in two patients not previously suspected but discovered on MRI. At PA the intimal shelf causing coarctation was either not excised or only minimally trimmed in 14 of 15 instances. CONCLUSIONS: The incidence of late aneurysm formation following PA for COA is low in the authors' patients, possibly due to minimal intimal damage at repair, although these patients should be followed longer. MRI was useful for assessment of aneurysm and restenosis.

The natural course of supravalvar aortic stenosis and peripheral pulmonary artery stenosis in Williams's syndrome.

The haemodynamic findings from two serial cardiac catheterisations in ten patients with Williams's syndrome were reviewed. The median ages at study were one and nine years. Raised mean (SD) left ventricular peak systolic pressures associated with supravalvar aortic stenosis increased significantly with time from 121 (25) mm Hg to 153 (29) mm Hg. The peak systolic pressure drop between the left ventricle and aorta (measured in seven patients) increased significantly from 25 (25) mm Hg to 50 (35) mm Hg. Raised right ventricular peak systolic pressure associated with peripheral pulmonary artery stenosis (in eight patients) decreased significantly with time from 52 (26) mm Hg to 28 (6) mm Hg. Supravalvar aortic stenosis in Williams's syndrome seems to progress rapidly, and careful monitoring is indicated. There is a strong likelihood that peripheral pulmonary artery stenosis in Williams's syndrome will improve spontaneously with time.

Infantile hypertrophic cardiomyopathy with QT prolongation.

A neonate presented with neonatal myocardial dysfunction and long QT interval with subsequent appearance of hypertrophic cardiomyopathy at one week of age. Maternal glucose metabolism was normal. By 15 months of age the hypertrophy had largely resolved but the long QT persisted. The possible relationship between these conditions is discussed.

Echocardiography by telephone--evaluation of pediatric heart disease at a distance.

A 24-hour telephone transmission service was established for pediatric echocardiography between a general hospital and a children's hospital 500 km distant. Studies were transmitted in real time for interpretation and diagnosis by a pediatric cardiologist. In the first 9 months of operation, studies were transmitted for 18 children with a median age of 5 months. Image and sound quality was excellent. Complete segmental diagnosis was made in 16 patients, and further study was needed in 2 others. In 8 of the 18 patients a new diagnosis was provided, and in 10 patients diagnosis was confirmed. Congenital heart disease was found in 12 patients, other heart disease in 2 and a normal heart in 4. The population included 2 fetuses whose echocardiograms showed hypoplastic left heart and intracardiac tumor. In 4 patients transport was avoided. This is the first report of echocardiographic transmission by telephone, which was shown to be clearly feasible, cost-effective and diagnostic. It provides emergency access to specialist expertise, and may avoid hazardous and expensive transport of ill children.

Williams syndrome: a neuropsychological profile.

Seven children with Williams syndrome were seen for neuropsychological assessment. Their performances were compared with those obtained from a clinical control group matched for age, sex, and Peabody Picture Vocabulary Test Standard Score. The results support the view that children with Williams syndrome suffer from a severe impairment in visual-motor integration. No child in the Experimental Group outperformed his/her matched control on either subtest assessing visual-motor integration skills, while no significant differences were noted between the groups on tests for simple motor skills (e.g., finger oscillation). Significant differences were also found on the subtests of the Wide Range Achievement Test. No significant differences between the groups were noted on tests for general language skills. The remedial educational, and neuropsychological implications of these findings are discussed.

Stenosis of individual pulmonary veins: radiologic findings.

Congenital stenosis of individual pulmonary veins is uncommon. Of the 49 cases reported, four were seen at the IWK Hospital for Children and are reported here. Plain radiographs show a shift of the heart toward the side of major involvement, Kerley B lines, fluid in the fissures, and interstitial edema of the affected lobes. These findings, while subtle, should nevertheless suggest stenosis. Technetium-99m macro-aggregate lung perfusion scans show absence of or diminished perfusion of the affected lobes. The diagnosis can usually be confirmed with angiography. Congenital stenosis of individual pulmonary veins should be considered in children with repeated pulmonary infections, dyspnea, failure to thrive, hemoptysis, or unexplained pulmonary hypertension.

Balloon catheter dilatation of coarctation of the aorta in young infants.

In four young infants with symptomatic coarctation of the aorta the narrow aortic segment was dilated with a balloon angioplasty catheter. Three of the infants also had appreciable heart defects and one infant had undergone surgery before and had had one previous dilatation. Dilatation was well tolerated and good femoral pulses appeared in all cases, but these disappeared over one to seven days. Despite this, two patients showed some symptomatic improvement over four months. One patient died after perforation of the aorta by an angiographic catheter after dilatation. Relieving coarctation in young infants by catheter dilatation appears incomplete, but it may give symptomatic improvement. Further trial of the procedure will determine whether patients who have undergone surgery and those who have not may benefit. Careful attention to technique and avoidance of manipulations after dilatation are essential if complications are to be avoided.

Polytetrafluoroethylene shunts in congenital heart disease.

Over a 2-year period the authors inserted 22 systemic to pulmonary artery shunts using a polytetrafluoroethylene (PTFE) graft in 19 children. A modified Blalock-Taussig shunt was established in 18 instances and an aorta to pulmonary artery shunt in 3: one patient had an aorta to right ventricle infundibulum shunt. Three children had obstructed grafts and in two others the grafts became stenosed; on of the latter group had successful removal of thrombus. The remaining grafts functioned well. Three other patients are presented. In two an interrupted aortic arch was repaired using a PTFE graft; one of these patients died at later closure of an aortopulmonary window, the other did well following repair of a ventricular septal defect and aortic valvotomy. The third child had a right ventricle to pulmonary artery shunt established for tetralogy of Fallot with pulmonary atresia; this resulted in some growth of the pulmonary arteries. The modified Blalock-Taussig shunt, using a PTFE graft, can be inserted without opening the pericardium, normal flow through the subclavian artery is not interrupted, the PTFE is easy to handle and the shunt can be inserted and taken down more easily than traditional shunts. For these reasons, the authors believe that this procedure, using PTFE, has an important role to play in the surgical management of children with congenital heart disease.

Acute pharmacologic testing of incessant supraventricular tachycardia in a child.

A 3 1/2-year-old child with incessant supraventricular tachycardia was investigated with intravenous vago-mimetic drugs, which had unexpected beneficial results. These observations suggested selection of digitalis as the antiarrhythmic drug, which would not otherwise have been chosen. The potential advantages of non-invasive, acute autonomic modulation for optimal drug selection in children with arrhythmias are illustrated by this case.

The spectrum of cardiac rate and rhythm in normal newborns.

The distribution and variation of cardiac rate and rhythm in normal neonates has previously received little attention. This has made clinical assessment of dysrhythmia in newborns difficult. We therefore performed continuous 24-hour electrocardiography in 29 normal newborn subjects (age range, 1 to 6 days; mean, 3.5 days). The ECG tapes were then analysed in detail to define the normal range of cardiac rate, conduction intervals, and rhythm during waking and sleeping periods. Maximum sinus rate (awake) ranged from 150 to 222 beats per minute (mean, 192 +/- 16 [SD]), and minimum rate (awake) from 78 to 140 beats per minute (mean, 107 +/- 15). During sleep, the maximum rate ranged from 125 to 210 (mean, 168 +/- 23) and the minimum from 72 to 120 beats per minute (mean, 92 +/- 11). The maximum variation in rate for any individual during the 24-hour period ranged from 73 to 134 beats per minute (mean, 100 +/- 17). Sinus rhythm predominated with mild irregularity occurring episodically in 24 and moderate irregularity in 4 infants. An isolated atrial premature beat was present in 2 subjects, and an atrioventricular (AV) junctional escape rhythm occurred in one other after a sinus pause of 840 msec. Ventricular premature beats or AV conduction abnormalities were not observed. The corrected QT interval (QTc) ranged from 0.298 to 0.514 sec (mean, 0.390 +/- 0.026). The maximum variation in QTc over 24 hours ranged from 0.052 to 0.160 sec (mean, 0.097 +/- 0.028). We conclude that cardiac rhythm and conduction appear more stable in normal newborns than in older normal subjects and that bradycardia, conduction defects, and ventricular ectopy of the type recently reported in young normal adults seem to be more uncommon in the neonatal period.

Surgical correction of pulmonary atresia with multiple large systemic-pulmonary collaterals.

A young patient in whom the pulmonary blood flow was supplied completely by five systemic-pulmonary collaterals underwent reconstruction of the pulmonary outflow tract by a new technique. This consisted of the insertion of a valve-bearing conduit between the right ventricle and an isolated segment of the descending aorta, which gave rise to three of the collaterals. Although the patient had a hypoplastic pulmonary artery confluence, other factors mitigated against its use as the sole conduit for right ventricular output.

Aortopulmonary window or aortopulmonary communication?

Two patients had a vessel-like aortopulmonary "window" which could be ligated without the institution of cardiopulmonary bypass. While embryologically and functionally these communications are identical to the classic aortopulmonary "window," it is suggested that the term "aortopulmonary communication" is more appropriate.

Anomalous origin of left main cononary artery from anterior sinus of Valsalva with myocardial infarction.

The origin of the left main coronary artery, or its branches, from the right or anterior sinus of Valsalva is a recognized congenital anomaly. The origin of the entire left main coronary artery from a separate ostium in the right sinus of Valsalva and its course to the right and behind the ascending aorta, in a living patient without associated congenital heart disease, has not been described. This anomaly was recognized as the cause of an anterior myocardial infarction in a 12-year-old girl, and it is the subject of this case report.

Double outlet right ventricle (S,D,L) with subaortic ventricular septal defect and pulmonary stenosis. Report of six cases.

The clinical, hemodynamic, angiocardiographic and pathologic findings are presented in an infrequent but surgically correctable type of double outlet right ventricle. This study is based on six cases, one with autopsy confirmation. In all, the viscera and atria were in situs solitus (S). A ventricular d-loop was present (D). There was I-malposition of the great arteries, the aorta being to the left of, and anterior to, the pulmonary artery (L). Hence, this anomaly may conveniently be represented as double outlet right ventricle (S,D,L,). The ventricular septal defect to the ventricular septum. A bilateral conus was present beneath both the aortic and pulmonary valves, preventing any semilunar-atrioventricular fibrous continuity. The subpulmonary conus was poorly expanded, resulting in pulmonary infundibular and valvular (annular) stenosis. The clinical features were those of cyanosis, clubbing and accentuation of the second heart sound in the pulmonary area (related to aortic valve closure). There was a systolic ejection murmur along the upper left sternal border, related to pulmonary outflow tract stenosis. Selective right and left ventricular angiocardiography was diagnostic. Relatively early surgical correction is suggested to minimize the progression of pulmonary infundibular stenosis and to avoid acquired atresia. In this malformation, pulmonary outflow tract reconstruction is more difficult than in tetralogy of Fallot because of the rather posterior location of the pulmonary outflow tract, and because the right coronary artery crosses the stenotic pulmonary outflow tract in front of the pulmonary valve.