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.

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.

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.

Acoustical and physical dynamics of the diatonic harmonica.

The harmonica is arguably the most widely played instrument in the world, yet there is a surprising paucity of published studies of its acoustics or physical dynamics. The typical diatonic harmonica and the physical forces involved in its natural function are described, and simple observations of the harp's functions are reported. The speaking of the reeds, naturally, when producing a bend, and when speaking as an overblow or overdraw is discussed and investigated by simple stopping of the reeds, by videostroboscopic analysis, and by recording vibration of the reeds with displacement gauges. The reeds of the ten hole harmonica can be made to vibrate at varying frequencies depending on the size and shape of the player's vocal tract. Three different modes of speaking from each hole and its pair of reeds are revealed and studied: first, naturally in a closing mode, either blown or drawn; second, as a bend, either blown or drawn, with pitch in the interval between the two notes in the hole; and third, as an overblow or overdraw in an opening mode with a pitch outside the interval between the two natural notes of the hole. This dynamic interaction allows the player to speak with the instrument perhaps as with no other.

Transplantation of the heart: reminiscences of the past and inklings of the future.

I recall the origins of cardiac surgery and the evolution of cardiac transplantation. Although the results of transplantation have been greatly improved during the past two decades, newer concepts and research offer the hope of an even greater future.

The need for accurate risk-adjusted measures of outcome in surgery. Lessons learned through coronary artery bypass.

OBJECTIVE: The authors review the Pennsylvania Health Care Cost Containment Council reports on coronary artery surgery and compare this reporting structure to others, including the Society for Thoracic Surgeons database, currently used by their own program. The authors review the growing likelihood of a need for outcome measures for all of the surgical subspecialties. SUMMARY AND BACKGROUND DATA: Pressure from consumers and insurers will require surgical specialties to be graded by objective outcome measures. Practitioners must be prepared and become involved in the process. METHODS: The authors reviewed the data, which grades all of Pennsylvania's hospitals at which coronary artery bypass is performed. Apparently, the major risk factors commonly employed in most other risk adjustment schemes for cardiac surgery have been deleted, and the practitioners might be judged unfairly. The Pennsylvania system appears to be insurance driven to reward low-cost providers who operate on patients with the lowest risk. RESULTS: Review of data suggests that the Pennsylvania Health Care Cost Containment Council's annual publication, A Consumer's Guide for Coronary Artery Bypass Surgery, misrepresents fair risk adjustment in favor of lower-risk patients, thereby encouraging better score cards for those institutions with patients who are less ill. Data regarding charges for the procedure have not been risk adjusted or related to a regional economic index. CONCLUSIONS: Surgeons must prepare to better understand relevant models that evaluate outcome. Cardiothoracic surgery is one of the first specialties to feel the pressures of mandated evaluations, and the lessons learned in Pennsylvania should be applicable to other states and their practitioners.

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.

Clinical experience with the Medtronic-Hall valve prosthesis.

Medtronic-Hall valves were implanted during 204 procedures performed between 1982 and 1988. Mean population age was 54.4 years; 96% of patients were in New York Heart Association functional class III or greater. Emergency operations constituted 16% of the procedures. Rheumatic heart disease was the single most common indication for valve replacement. In 18% of patients, operation was performed to replace a previous prosthetic valve. The mean follow-up was 3.2 years. Overall operative mortality was 10.3%, the highest mortality being for double-valve replacements (24%). Valve-related mortality, by position, was 5.3% for aortic valves, 6.0% for mitral valves, and 4.0% for multiple-valve replacements. Actuarial 5-year freedom from events were: survival, 68%; thromboembolism, 90%; prosthetic valve endocarditis, 98%; paravalvular leak, 95%; and reoperation, 92%. Complications with the highest mortality were thromboembolism (36%) and endocarditis (33%). The complication rates in this series are high but the patients were more severely ill than in other reports, and operative survivors experienced a considerable improvement in New York Heart Association functional class.

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.

Equitable allocation of extrarenal organs: with special reference to the liver.

A national plan is proposed for the equitable allocation of extrarenal organs, with particular reference to the liver. The principles of the plan include preferential use of the organs in the local and regional area of procurement, with national listing of the organs left over after the original cut. At each of the local, regional, and national levels, the allocation is based on total points awarded for medical urgency, time waiting, blood group conformity, and physical location of both donor and recipient. The plan, which should be applicable as well for allocation of hearts, is compatible with international sharing with nearby countries such as Canada.

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.

Cardiac transplantation: improved quality of survival with a modified immunosuppressive protocol.

The effects on renal function on two different immunosuppressive protocols were evaluated retrospectively in two subsequent groups of heart transplant recipients. In group I, cyclosporine was given before the procedure at a loading dose of 17.5 mg/kg and then continued after the procedure to keep a whole blood level about 1000 ng/ml. In group II, cyclosporine was started only after the procedure at a lower dosage and was complemented by azathioprine, which was used for the first postoperative week. Group II showed a better perioperative renal function as determined by serum blood urea nitrogen and serum creatinine levels. Group II also showed a significant decrease of chronic nephrotoxicity secondary to long-term therapy with cyclosporine. Despite this improvement in late renal function, group II still shows a slow rise in serum creatinine. We think that even these lower dosages of cyclosporine can cause chronic nephrotoxicity and that further modification of the immunosuppressive regimen is required to completely abolish this toxic side effect.

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.

Development of coronary artery disease in cardiac transplant patients receiving immunosuppressive therapy with cyclosporine and prednisone.

Coronary artery disease (CAD) has been shown in previous uncontrolled studies to be a limiting factor to long-term survival in patients undergoing cardiac transplantation and who were taking conventional immunosuppressive agents. To study the development of CAD after cardiac transplantation in patients taking the newer immunosuppressive agent cyclosporine, we prospectively performed yearly coronary arteriography on all eligible transplantation patients (first year, 57 patients; second year, 30 patients; third year, 14 patients). The prevalence of CAD by life table analysis was 18% at 1 year, 27% at 2 years, and 44% at 3 years. The occurrence of two or more major rejection episodes was associated (p less than .005) with the development of CAD. In two patients who died of CAD, coronary artery histology revealed subintimal inflammatory cellular infiltration in some lesions. These data demonstrate that the prevalence of CAD rises progressively over time and immunologic factors may be important in its development.