In-vivo assessment of T cell kinetics in individuals at risk for type 1 diabetes.

We previously assessed the kinetics of T cell turnover in vivo by labeling cells with 2 H-H2 O over 42 days in individuals with type 1 diabetes (T1D) and demonstrated an increased turnover of CD4 memory T cells. We have now tested T cell turnover in individuals at risk for T1D using a 3-4-day labeling protocol with 2 H-glucose. We studied 30 relatives with T1D with and without autoantibodies, and 10 healthy controls. Peripheral blood mononuclear cells (PBMC) were flow-sorted into T cell subsets of interest; 2 H-DNA enrichment was measured by mass spectrometry and in-vivo turnover was calculated as maximum fractional enrichment of deuterated adenosine (Fmax ). Among CD4+ cells, Fmax was highest in regulatory T cells (Treg ), followed by effector and central memory T cells and lowest in naive cells. Similarly, CD8+ central and effector memory T cells had a higher turnover than CD8+ terminally differentiated effector memory T cells (TEMRA) and CD8+ -naive T cells. Relatives as a group showed significantly increased Treg turnover by Fmax compared to controls (1·733 ± 0·6784% versus 1·062 ± 0·3787%, P = 0·004), suggesting pre-existing immune dysfunction within families with T1D. However, there was no significant difference in Fmax between groups according to autoantibody or glucose tolerance status. Repeat testing in 20 subjects 1 year later demonstrated relatively higher within-subject compared to between-subject variability for the measurement of Fmax in various T cell subsets. The short labeling protocol with 2 H-glucose should be applied in the context of a clinical trial in which the therapy is expected to have large effects on T cell turnover.

Allergen-specific IgE as a biomarker of exposure plus sensitization in inner-city adolescents with asthma.

BACKGROUND: Relationships among allergen-specific IgE levels, allergen exposure and asthma severity are poorly understood since sensitization has previously been evaluated as a dichotomous, rather than continuous characteristic. METHODS: Five hundred and forty-six inner-city adolescents enrolled in the Asthma Control Evaluation study underwent exhaled nitric oxide (FE(NO)) measurement, lung function testing, and completion of a questionnaire. Allergen-specific IgE levels and blood eosinophils were quantified. Dust samples were collected from the participants' bedrooms for quantification of allergen concentrations. Participants were followed for 12 months and clinical outcomes were tracked. RESULTS: Among sensitized participants, allergen-specific IgE levels were correlated with the corresponding settled dust allergen levels for cockroach, dust mite, and mouse (r = 0.38, 0.34, 0.19, respectively; P < 0.0001 for cockroach and dust mite and P = 0.03 for mouse), but not cat (r = -0.02, P = 0.71). Higher cockroach-, mite-, mouse-, and cat-specific IgE levels were associated with higher FE(NO) concentrations, poorer lung function, and higher blood eosinophils. Higher cat, dust mite, and mouse allergen-specific IgE levels were also associated with an increasing risk of exacerbations or hospitalization. CONCLUSIONS: Allergen-specific IgE levels were correlated with allergen exposure among sensitized participants, except for cat. Allergen-specific IgE levels were also associated with more severe asthma across a range of clinical and biologic markers. Adjusting for exposure did not provide additional predictive value, suggesting that higher allergen-specific IgE levels may be indicative of both higher exposure and a greater degree of sensitization, which in turn may result in greater asthma severity.

Increased Tolerance to Less Extensively Heat-Denatured (Baked) Milk Products in Milk-Allergic Children.

BACKGROUND: Most milk-allergic children tolerate baked milk. OBJECTIVE: To investigate the effect of more frequent versus less frequent introduction of higher doses of more allergenic (less heat-denatured) forms of milk (MAFM) on progression to tolerance. METHODS: Milk-allergic children were challenged with increasing doses of MAFM; baked foods were incorporated into the diet; challenges were repeated at 6- or 12-month intervals over 36 months. RESULTS: A total of 136 children (70% males) were enrolled in the active group (median age, 7 years). At baseline, 41 (30%) reacted to muffin, 31 (23%) to pizza, 11 (8%) to rice pudding, 43 (32%) to non-baked milk; and 10 (7%) tolerated non-baked milk. Children who tolerated baked milk but reacted to non-baked liquid milk were randomized to MAFM challenges every 6 months (n = 41) or 12 months (n = 44). At month 36, 61% children in the 6-month and 73% in the 12-month escalation groups tolerated MAFM. Overall, 41 (48%) children who ingested baked-milk diet became tolerant to non-baked milk; no difference was seen between 6- and 12- month escalations. Among children who reacted to muffin at baseline and continued avoidance, 20% developed tolerance to baked milk and 0% tolerated non-baked milk. None of the 34 children who qualified for inclusion but chose not to take part in the active study became tolerant to any form of milk by history. CONCLUSIONS: Majority of children tolerated baked milk at baseline. Baked-milk diets were associated with progressive immunomodulation. Most children who incorporated baked milk into their diet progressed to tolerating MAFM, but there was no advantage to more frequent attempts to escalate to MAFM, per intention-to-treat analysis.

Central nervous system infections in heart and heart-lung transplant recipients.

Infections, a major cause of morbidity and mortality in immunosuppressed heart and heart-lung transplant recipients, frequently involve the central nervous system and can produce devastating neurologic sequelae. Between 1980 and 1987, a total of 363 heart transplant and 54 heart-lung transplant recipients at the University of Pittsburgh sustained 13 intracranial infections two to 143 weeks after transplantation. Computed tomography demonstrated well-defined Nocardia and Aspergillus abscesses in four patients. Cerebrospinal fluid was normal in all cases studied, including in those patients in whom culture confirmed meningitis. Computed tomography-guided stereotactic surgery was used to diagnose and aspirate two nocardial brain abscesses. The prognosis for patients with central nervous system infections was related to their overall condition at the time of diagnosis. Both patients with nocardial abscesses and one patient with Listeria leptomeningitis survived, but all ten other patients died because of extensive multisystem infectious complications.

Long-term follow-up after aortic valvuloplasty and defect closure in ventricular septal defect with aortic regurgitation.

The clinical course was studied in 25 patients with ventricular septal defect (VSD) and aortic regurgitation (AR) who had undergone aortic valvuloplasty and VSD closure. Twelve patients had a doubly committed subarterial VSD and 13 had a perimembranous type of VSD. Preoperatively, progressive hemodynamic disturbance after the onset of AR occurred in 11 patients (44%). The follow-up period extended from 6 months to 23 years (mean 10 years). Four patients required prosthetic valve replacement after valvuloplasty. One of these had had initial improvement of the AR but required valve replacement 20 years later; the condition of the other 3 did not improve initially and their valves were replaced 1 month to 8.5 years later. Four other patients had no initial improvement as a result of valvular reconstructive surgery, but the AR did not progress and remained hemodynamically well tolerated. Hence, the overall success rate of the valvuloplasty, defined as improving or preventing progressive AR, was 21 of 25 (84%). Since initial and long-term improvement in aortic valve function can be expected in most patients after valvuloplasty and closure of the VSD, early surgical intervention is recommended in patients with a VSD and AR.

Absent right superior vena cava with persistent left superior vena cava: implications and management.

Seven cases of absent right superior vena cava with persistent left superior vena cava and normal situs were diagnosed at Children's Hospital of Pittsburgh. All patients had associated cardiac defects. In two cases the diagnosis was made at autopsy, the first in 1957 and in a 26 day old infant with multiple cogenital defects and the second in 1965 in a 22 day old infant who had pulmonary atresia with ventricular septal defect and patent ductus arteriosus. Since 1966 absent right superior vena cava has been diagnosed at cardiac catheterization in five children. Three of these children have had surgery, two for subaortic stenosis and one for an atrial septal defect. One has an insignificant atrial septal defect and the fifth has a ventricular septal defect. The electrocardiogram of four reveals s short P-R interval and a leftward frontal plane axis of the P wave, suggesting a low atrial focus. None has had any significant conduction problem. All five children are living and well, the oldest has survived 13 years postoperatively. Certain precautions are necessary should corrective cardiac surgery or transvenous pacemaker insertion be necessary.

Powerful but limited immunosuppression for cardiac transplantation with cyclosporins and low-dose steroid.

Cyclosporin and low-dose prednisone provide powerful but limited immunosuppression for orthotopic cardiac transplantation. Optimal long-term survival was possible only with rescue therapy using rabbit antithymocyte globulin (RATG) when myocyte necrosis could not be reversed with pulse steroid therapy. The continued absence of rejection following rescue therapy with RATG in six of the last 19 patients is responsible for the improved 79% cumulative survival rate at 9 months compared to the 61% cumulative survival rate at 1 year for the initial 23 patients. The difference is that among the latter group, seven patients had persistent histologic rejection with focal myocyte necrosis which was not reversed with pulse therapy of steroids (hydrocortisone) or an increased dose of maintenance prednisone (30 to 40 mg/day). Three of these seven died of acute rejection within 3 months and four died between 8 and 13 months. Consequently, the cumulative survival rate of these 23 patients at 2 years was 41%. The projected 2 year cumulative survival rate of the 19 patients should not decrease greatly, as new episodes of rejection have not occurred beyond 3 months in either group.

Role of the antibody to vascular endothelial cells in hyperacute rejection in patients undergoing cardiac transplantation.

Traditionally, the human lymphocyte antigens have been considered to be the major barrier to successful transplantation, and lymphocytes have been used as the target cell in evaluating histocompatibility. The presence in the serum of recipients of preformed antibodies, cytotoxic to donors lymphocytes, is associated with a high probability of hyperacute rejection. We identified 11 patients in whom, despite a compatible direct lymphocytotoxic cross-match, acute failure of the cardiac homograft was associated with histologic and immunologic findings consistent with hyperacute rejection. Direct immunofluorescence and immunohistochemical staining showed the presence of antibodies on the surface of vascular endothelial cells in each of these 11 patients. The serum of these recipients was found to contain antibodies against a panel of endothelial cells. In contrast, cytotoxic antibodies to vascular endothelial cells were not present in a control group of 18 heart transplant recipients who did not experience hyperacute rejection. Thus the presence of antibodies against vascular endothelial cells seems to be related to hyperacute rejection of the cardiac allograft.

Arteriovenous ECMO for neonatal respiratory support. A study in perigestational lambs.

A study was undertaken to investigate the applicability of the arteriovenous mode of perfusion for partial support of neonatal respiration. Perigestational lambs, delivered by cesarean section, served as the animal model of respiratory distress. Arteriovenous flow was accomplished between a single umbilical artery and vein. A microchannel membrane oxygenator was used to provide partial respiratory support to the newborn lambs. Total systemic flow, pulmonary blood flow, and pulmonary vascular resistance were assessed at various rates of arteriovenous perfusion and correlated with systemic oxygenation. A reduction in right-to-left shunting of blood and pulmonary vascular resistance occurred as arterial oxygenation rose from conditions of hypoxemia to PaO2 values higher than 50 torr. Myocardial performance was not impaired at rates of arteriovenous perfusion below 30 percent of the total systemic flow, as evidenced by normal electrocardiographic tracings, pulmonary capillary wedge pressures, and central venous pressures. Arteriovenous extracorporeal membrane oxgenation (ECMO) may be particularly suitable for use in infants with hypoxia and high pulmonary vascular resistance.

Targeted blood levels of cyclosporin for cardiac transplantation.

Forty-nine patients have undergone cardiac transplantation since July, 1982, and have been treated with maintenance cyclosporin and low-dose prednisone, 15 to 20 mg. Cyclosporin dose has been targeted to a whole-blood level of 1,000 ng/ml as measured by radioimmune assay. The actuarial survival rate in this group of patients has been 79% at 12 months and 71% at 21 months. Histologic rejection has occurred at all blood levels of cyclosporin, as has significant nephrotoxicity. The hepatic toxicity encountered has been more a clinical nuisance than significant problem. The administered dose of cyclosporin required to reach a target of 1,000 ng/ml has varied between 2 and 30 mg/kg/day. The average perioperative and late serum creatinine levels were 1.2 and 1.49 mg/dl and occurred with cyclosporin levels of 1,078 and 1,068 ng/ml, respectively. Late cyclosporin toxicity has persisted despite reduction in the dose of cyclosporin below the targeted 1,000 ng/ml. Some method of blood level monitoring is necessary in patients receiving cyclosporin immune suppression to assure adequacy of the administered dose. The 1,000 ng/ml target has provided adequate immune suppression. Significant nephrotoxicity has not correlated with the blood level measured.

Double-outlet right ventricle with tunnel from left ventricle to aorta.

The successful surgical correction of an unusual form of double-outlet right ventricle (DORV) in a 4-year-old boy is described. A long tunnel-like structure was present between the left ventricle and the aorta and also communicated with the right ventricle. hemodynamic and angiographic evaluation demonstrated restrictive communications between the tunnel, the aorta, and each of the ventricles. A pathological concept explaining the anatomic abnormality seen in this patient is discussed.

Management of bilateral ductus arteriosus in complex cyanotic heart disease.

Bilateral ductus arteriosus (BDA) usually is associated with complex cyanotic heart disease. Since pulmonary valve atresia often is part of the complex, hypoxia may necessitate emergency cardiac catheterization and surgery for these critically ill newborn infants. Optimum management depends on accurate delineation of the intracardiac and great vessel anatomy. Since the ductus arteriosus has a tendency to close spontaneously, the true anatomy of the fourth to sixth aortic arch connections should be determined on the first catheterization. An over-all plan for future care by the medical-surgical team should have been made at the time of the initial surgical procedure. The case histories of four newborn infants with BDA associated with cyanotic heart diseases are reported. The anatomy and basic embryology of the fourth to sixth arch system is reviewed and recommendations for long-term management are given.

The third manpower study of thoracic surgery: 1980 report of the Ad Hoc Committee on Manpower of The American Association for Thoracic Surgery and The Society of Thoracic Surgeons.

An ad hoc committee was appointed by The Society of Thoracic Surgeons (STS) in 1977 in order to determine the available manpower and workload of thoracic surgeons in 1976. This committee conducted a survey of the professional activities and geographic location of all known surgeons certified by the American Board of Thoracic Surgery (ABTS) at that time. A summary of this study indicated the available and projected thoracic surgery manpower. The report also determined the present and projected health care needs of the population of the United States through 1993. Because thoracic surgery needs to continue to meet the health care needs of the United States in an appropriate yet economical fashion, the STS and The American Association for Thoracic Surgery (AATS) undertook a joint review to determine again the available manpower and its workload in calendar year 1980. In addition, this study compared its findings with the 1976 report in order to detect changes in the workload and need for thoracic surgical services. A questionnaire was mailed to 3,584 certified thoracic surgeons. There were 2,675 responses. The material was sent to the Academic Computer Services at George Washington University Medical Center for tabulation and data processing. This report summarizes the results of this survey. It also compares these data with those obtained in the 1976 study and, based on this information, attempts to project the thoracic surgery manpower needs in the next decade by using several hypothetical models.

Pulmonary valvulotomy alone for pulmonary stenosis: results in children with and without muscular infundibular hypertrophy.

Pulmonary valvulotomy for valvular pulmonic stenosis has been performed in 78 children at the Children's Hospital of Pittsburgh. Although 27 patients had muscular hypertrophy of the infundibulum, a muscle resection was employed in only one child. Examinations 2 to 18 years after operation have not demonstrated electrocardiographic (ECG) or clinical evidence of persistent right ventricular hypertension, indicating resolution of the muscular outflow tract narrowing. Systolic right ventricular pressure averaged 30 mm Hg in 10 patients at postoperative catheterization: Six of these patients had peak right ventricular pressures greater than 100 mm Hg immediately after valvulotomy. The diameter of the infundibulum in systole was compared to valve ring diameter and expressed as a ratio (I/V). This correlated with the preoperative and intraoperative right ventricular pressures, but did not identify patients who might fail to resolve secondary muscular hypertrophy. A murmur of pulmonary regurgitation was present in 70% of the patients after operation, but was without clinical significance. In the absence of fixed infundibular obstruction or excessive right ventricular hypertension above 200 mm Hg, resection of infundibular hypertrophy is not recommended.

Systemic-pulmonary artery anastomoses in infancy.

Over the last 10 years, 142 systemic-pulmonary artery anastomoses were performed in 134 infants under 1 year of age. These included shunts from the subclavian artery (46 per cent), ascending aorta (41 per cent), descending aorta (9 per cent), and superior vena cava (1 per cent) to the pulmonary artery. Ninety-six (72 per cent) of the infants were less than 4 months of age at the time of the initial procedure, and one half were less than 1 month old. When groups of patients were compared according to diagnosis and age at the time of operation, the immediate and long-term results of the subclavian-pulmonary artery (Blalock-Taussig) anastomosis were better than the results with the other procedures. In view of the ease of closure of this anastomosis at the time of corrective surgery, as well as the recent further improvement of vascular surgical techniques, the Blalock-Taussig shunt is the procedure of choice in most infants requiring a systemic-pulmonary artery anastomosis, even during the early months of life.

Discrete subvalvular aortic stenosis. An evaluation of operative therapy.

Angiocardiographic and operative observations support the validity of classifying the spectrum of congenital subvalvular aortic stenosis into a membrane, fibromuscular collar, and tunnel. Our current operative method is to excise a thin membrane or thick fibrous ridge, and, if a fibromuscular collar or tunnel is identified, to effect a left ventricular myomectomy as described by Morrow for hypertrophic subaortic stenosis. Data from experience with 35 children indicate that this approach is effective and safe. Gradients are substantially reduced and residual obstruction acceptable. Successive clinical evaluations (100 percent of 33 survivors) over an interval of 1 to 13 years (mean of 6) affirm that amelioration of the obstruction endures.

Indications for and results of single, bilateral, and heart-lung transplantation for pulmonary hypertension.

The indications for single, bilateral, and heart-lung transplantation for patients with pulmonary hypertension remain controversial. We retrospectively analyzed the results from 11 single, 22 bilateral, and 24 heart-lung transplant procedures performed between January 1989 and January 1993 on 57 consecutive patients with pulmonary hypertension caused by primary pulmonary hypertension (n = 27) or Eisenmenger's syndrome (n = 30). Candidates with a left ventricular ejection fraction less than 35%, coronary artery disease, or Eisenmenger's syndrome caused by surgically irreparable complex congenital heart disease received heart-lung transplantation. All other candidates received single or bilateral lung transplantation according to donor availability. Although postoperative pulmonary artery pressures decreased in all three allograft groups, those in single lung recipients remained significantly higher than those in bilateral and heart-lung recipients. The cardiac index improved significantly in only the bilateral and heart-lung transplant recipients. A significant ventilation/perfusion mismatch occurred in the single lung recipients as compared with bilateral and heart-lung recipients because of preferential blood flow to the allograft. Graft-related mortality was significantly higher and overall functional recovery as assessed by New York Heart Association functional class was significantly lower at 1 year in the single as compared with bilateral and heart-lung recipients. Thus bilateral lung transplantation may be a more satisfactory option for patients with pulmonary hypertension with simple congenital heart disease, absent coronary arterial disease, and preserved left ventricular function. Other candidates will still require heart-lung transplantation.

Valve replacement in children and adolescents.

Replacement of diseased heart valves has become the treatment of choice in many adults. Valve replacement in older children and adolescents has been done in our institution only when other procedures are ineffective. Over the past 10 years, 24 patients have received 28 artificial valves. Thirteen (54 per cent) had rheumatic heart disease; the remainder had congenital or acquired valvular abnormalities. The Björk-Shiley valve was most commonly used in the aortic position and the Beall prosthesis in the mitral position. Sixteen patients (67 per cent) survived operation and have been followed from 3 to 79 months, averaging 27 months. All are free of cardiac symptoms. Hemarthrosis occurred once in 2 survivors (13 per cent). Eight patients died (33 per cent), 5 immediately postoperatively and 3 within a year after the operation. The mortality rate has declined to 21 percent during the past 3 years. Our experience in the pediatric age group suggests that valve replacement is a serious undertaking with higher mortality rate than in adults. The operation should be reserved for those patients in whom valvuloplasty or valvulotomy is expected to be ineffective.

Traumatic false aneurysm and arteriovenous fistula of the profunda femoris artery: surgical management and review of the literature.

Successful surgical repair of a false aneurysm and an arteriovenous fistula of the deep femoral vessels has been achieved 8 years after the initial injury. A review of the literature disclosed 20 other similar cases from military and civilian practice; ligation of the artery was utilized 14 times with generally poor results when long-term follow-up was available. Most vascular wounds were due to fragments, as was the case in our patient, and involvement of the deep femoral vessels was recognized more frequently in delayed complications than in acute injuries. Ten cases of false aneurysm of the deep femoral artery without arteriovenous fistula have been found to be associated with fracture or orthopedic precedures. Mild intravascular hemolysis was present in our patient and was corrected promptly after operation. Only one other such case was found in the literature. The profunda femoris artery, which was dilated and elongated, resumed a normal caliber in its proximal segment on arteriography performed one year after the operation. Preservation of the deep femoral artery may be of significance for a good clinical result in the treatment of arteriovenous fistulas and is of special interest in view of its potential importance in reconstructive procedures for atherosclerotic occlusive disease. Early diagnosis and treatment of arteriovenous fistulas for the prevention of hemodynamic, systemic, and structural changes in the vessel wall are advocated.