Treatment of humoral rejection after heart transplantation

BACKGROUND: Until a few years ago, the incidence of humoral rejection after heart transplantation was underestimated. These episodes were frequently very aggressive and often fatal, because the maintenance and emergency immunosuppression available at the time only inadequately covered the humoral branch of the immune response. In spite of individual case reports, the effects of blood purification procedures or cyclophosphamide in this situation can only be insufficiently estimated. METHODS: To evaluate this therapy concept, 20 dog-lymphocyte-antigen-matched dogs underwent heterotopic neck-heart transplantation. Fourteen dogs underwent transplantation after having been previously sensitized through multiple skin transplantations, 6 dogs were not sensitized (control). The animals received an induction with 3x 250 mg prednisolone, as well as triple immunosuppression (cyclosporine, azathioprine, and cortisone). Biopsy (light microscopy, immunofluorescence), intramyocardial voltage, electric myocardial impedance (>200 kHz, <10 kHz), and echocardiographic (left ventricular wall thickness, diastolic relaxation velocity) examinations were performed daily to monitor rejection. Rejection therapy was continued for 3 days according to the following regimen: apheresis, cortisone boluses (CB), and cyclophosphamide in group A1 (n = 4), apheresis and CB without cyclophosphamide in group A2 (n = 4), and CB only in group C (n = 6). The subsequent course under triple immunosuppression was then observed. RESULTS: In the sensitized animals the onset of severe humoral rejection on the fifth day deteriorated cardiac function down to 75% (70% to 80%) of the initial values. In groups A1 and A2, apheresis resulted in recovery to near-control values (89% to 94%) within two hours, and indeed to complete recovery (97% to 101%) after the second apheresis, that is, within 1 day. In group C recovery was delayed (2 days) and incomplete (84% to 91 %). After therapy was discontinued, rejection-related functional deterioration recurred immediately in group C, and from 2 to 3 days after apheresis, regardless of whether cyclophosphamide therapy was performed (group A1) or not (group A2). In the control group all animals showed a rejection-free posttransplantation course. CONCLUSIONS: By diluting inflammatory mediators, apheresis leads to a rapid improvement in cardiac function during severe humoral rejection after head transplantation. Neither apheresis nor cyclophosphamide therapy are able to have an immediate positive influence on the activation of the immune cascade and to prevent an ongoing rejection.     

Diastolic dysfunction coincides with early mild transplant rejection: in situ measurements in a heterotopic rat heart transplant model

BACKGROUND: Diastolic dysfunction seen in early clinical transplant rejection has been difficult to demonstrate in experimental rodent models because of the inability to make sensitive in situ measurements of systolic and diastolic functions. We have developed a heterotopic heart transplant model with Fisher 344 and ACI rats (without immunosuppression), where in situ measurements of diastolic and systolic functions were made sequentially (daily) by use of an implanted left ventricular balloon. METHODS: Syngeneic and allogeneic heterotopic heart transplants were performed. In situ function was determined by varying balloon volume to measure the developed pressure, the rates of pressure rise (+dp/dt) and pressure fall (-dp/dt), diastolic pressure-volume relationship, and the time constant of diastolic relaxation (tau). These results were compared with function measurements in transplanted hearts that were excised and perfused in a Langendorff mode (ex vivo) during the same posttransplantation period. RESULTS: Histologic examination revealed that at day 3 after transplantation, allografts showed mild lymphocytic infiltration indicative of mild or early rejection, and by day 5, there was severe rejection with myocyte necrosis. By day 3, the slope of the diastolic pressure-volume relationship (ie, left ventricular stiffness) was significantly higher in allografts as compared with isografts (436 +/- 96 vs 177 +/- 26 mm Hg/mL, p < .05). Similarly, tau was significantly longer in allografts by day 3 after transplantation. Developed pressure and +dp/dt became significantly lower in allografts beginning on day 6. Function measurements made in the isolated perfused ex vivo hearts yielded the same results at day 3 after transplantation as the in situ group of hearts. CONCLUSION: Using a chronically implanted left ventricular balloon, we have developed a heterotopic heart transplant model where sensitive measurements of systolic and diastolic functions can be made. With this preparation, the early changes in the diastolic dysfunction seen clinically can be reproducibly detected. Thus this model may be useful to study mechanisms and interventions during early transplant rejection.     

Progression of chronic renal insufficiency in chronic rejection: the role of chronic transplantation glomerulopathy

The authors studied variations in the pulsatility index of the uterine arteries in postmenopausal women who had received hormone replacement treatment (HRT) for at least one year and compared them to those in a control group not receiving HRT. The results showed a significant variation in this index with the tendency to assume lower values compared to the control group, thus resulting in increased uterine vascularization, almost resembling that observed during the child-bearing period. This drop in the pulsatility index should probably be considered the anatomo-functional in patients not receiving HRT.     

C-reactive protein in the monitoring of acute rejection after heart transplantation

OBJECTIVE: To measure short duration sounds (L(PEAK)) in the neonatal intensive care unit and describe their intensity, incidence, and periodicity in relationship to activities within the unit. STUDY DESIGN: We measured 1-minute L(PEAK) at four locations within the intensive care unit, accumulating 48 hours of data for each weekday. RESULTS: Thirty-one percent of the L(PEAK) exceeded 90 dB. For further analysis, the data were transformed to the proportion exceeding 90 dB. These values varied significantly with day, week, location, and time of day. During physician rounds, there was a 16% relative increase in L(PEAK). CONCLUSION: These data demonstrate the intensity, incidence, and periodicity of short duration sounds in the intensive care nursery. Short duration sounds are known to affect the infant's physiological and behavioral states and should be addressed in future recommendations for sound control and reduction strategies.     

Evidence that recipient CD8+ T cell depletion does not alter development of chronic vascular rejection in a rat heart allograft model

Progressive chronic vascular rejection is a central feature of indefinitely surviving WF.1L LEW/Gut (RT1(1)) heart grafts transplanted to LEW (RT1(1)) recipients in unmodified donor-recipient combinations. At 70 days posttransplantation, large vessels of the grafts are characterized by the presence of vasculitis, vasculitis with associated variable myointimal thickening, and occlusive myointimal thickening with minimal or absent concomitant vasculitis. To assess the potential role of CD8+ T cells as critical effectors of chronic vascular rejection in this model, LEW recipients of WF.1L heart grafts were effectively depleted of CD8+ T cells as a result of prior thymectomy and anti-CD8 (MRC OX8) monoclonal antibody administration prior to transplantation. WF.1L heart grafts transplanted to LEW recipients that had undergone prior sham thymectomy and MRC OX8 administration, or thymectomy and administration of antibody-free culture supernatant, provided appropriate controls. At 70 days posttransplantation, large vessels of WF.1L heart grafts in all 3 transplantation groups showed similar morphologic features, which were comparable to those observed in heart grafts of long-surviving unmodified donor-recipient pairs. This study has shown that profound selective depression of recipient CD8+ T cells does not alter the characteristic features of chronic vascular rejection in this rat cardiac model, and provides evidence that CD8+ T cells play no critical role in the initiation or development of progressive vascular damage in this setting.     

Factors contributing to the incidence of dark cutting beef

The 1995 National Beef Quality Audit reported that dark cutting beef (dark cutters) cost $6.08 per animal harvested in the United States. Feedlot data were obtained over a 3-yr period from nine commercial feedyards (15,439 pens of cattle; 2,672,223 total cattle). Feedyard, sex, implant treatment, days from final implant to harvest, maximum and minimum daily temperatures, and temperature fluctuations from 2 d before harvest to the day of harvest all contributed (P < .05) to the incidence of dark cutters. Heifers yielded a higher (P < .05) percentage of dark cutters per pen and, when reimplanted a second time with an estrogenic implant, produced greater (P < .05) mean percentages of dark cutters per pen than heifers reimplanted with either androgens or combination (androgen and estrogen) growth promotants. Furthermore, heifers produced higher (P < .05) mean percentages of dark cutters per pen than steers during periods of hot (> 35 degrees C) weather 2 to 1 d before harvest. Steers, when treated with a combination (androgen and estrogen) implant when entering the feedyard and as a reimplant, produced higher (P < .05) mean percentages of dark cutters per pen when compared to other moderate growth-promoting implant strategies. When producers opted to implant steers with estrogenic growth promotants, either as the cattle entered the feedlot or as a final reimplant before harvest, the occurrence of dark cutters was reduced from 9.2 per thousand cattle shipped to 2.0 and .5 per thousand cattle shipped, respectively. Producers that reimplanted heifers before harvest with products that were not primarily estrogenic reduced the occurrence of dark cutters from 10.4/1,000 cattle shipped to 5.2/1,000 cattle shipped when androgen-based growth promotants were used and to 3.5/1,000 cattle shipped when combination (androgen and estrogen) implants were administered. In addition to implant selection, those producers that held cattle on-feed over 100 d past reimplantation reduced the incidence of dark cutters per pen by an average of 38% among heifers and 69% among steers. By reducing the occurrence of dark cutters, there is an opportunity for beef producers to realize large economic savings.     

Factors contributing to the reduction of stuttering during singing

This study was conducted to determine if the reduction of stuttering typically observed during singing is associated with altered vocalization or the familiarity of the melody and lyrics of the song sung by the stutterer, or both. Subjects were eight adult male stutterers. Prior to testing, each of these individuals demonstrated that he knew the melody and lyrics of a well-known song from memory. Subsequently, subjects were asked to read these lyrics aloud and then sing them. Next, subjects had to read aloud and then sing a set of unfamiliar lyrics to the conventional melody of the same song. The stutterers' reading and singing performances were audiotaped. The dependent measures of utterance duration and stuttering frequency were extracted from the tapes. Results showed that subjects' utterance durations were significantly longer during singing than reading. The main effects of singing and familiarity were both associated with significant reductions in stuttering frequency. The greatest decrement in stuttering occurred in the condition where subjects sang the familiar melody and lyrics. These findings were interpreted to mean that changes in vocalization cannot account for all of the decrease in stuttering that occurs during singing. During song, the familiarity of the melody and lyrics being produced may also affect stuttering frequency.     

Daily noninvasive rejection monitoring improves long-term survival in pediatric heart transplantation

BACKGROUND: Acute rejection episodes and transplant vasculopathy (TVP) account for most of the late deaths after heart transplantation in both adults and children. Accumulating evidence indicates that fatal acute rejection and TVP are related to unrecognized and untreated early and ongoing acute rejection. Day-by-day surveillance of the heart and prompt treatment of any rejection may yield improved long-term survival. METHODS: In almost all patients having transplantation at our institution (978 patients since 1986), the intramyocardial electrogram (IMEG) was recorded routinely every day through a telemetry pacemaker and transmitted to our center by telephone modem. Earlier studies showed a substantial voltage drop in the IMEG QRS complex is highly indicative of acute rejection, including humoral rejection. In this study, we reviewed the data from 69 pediatric patients up to 16 years old for the incidence of acute rejection, TVP, and long-term outcome. Diagnostic endomyocardial biopsies were performed in only 10 patients, and recent coronary angiograms from 29 children were reviewed. RESULTS: In 50 children discharged after heart transplantation, IMEG surveillance data for a mean of 2.9 years indicated 72 acute rejection episodes. During follow-up of 1 month to 10.5 years (mean follow-up, 4.4 years), 2 patients died late of causes unrelated to either rejection or TVP. Another patient died of rejection during unrecognized underimmunosuppression nearly 8 years after transplantation and nearly 31/2 years after discontinuing IMEG recordings. Two patients without IMEG recording died of acute rejection or late TVP. In 1 patient, moderate TVP was seen on an angiogram after 41/2 years (incidence, 2.0%; 5-year incidence, 5.6%). CONCLUSIONS: Daily recording of the IMEG can reliably detect early stages of acute rejection episodes, and immediate rejection treatment seems to keep the incidence of TVP low. The IMEG appears better than all the other rejection monitoring protocols currently in use.     

Factors contributing to the presentation of diabetic foot ulcers

We have undertaken a prospective study of the presentation of all 669 ulcers seen in a specialist multidisciplinary foot clinic between 1 January 1993 and 1 August 1996, with particular reference to the factors which precipitated ulceration as well as to any delays in referral. Nearly two-thirds (61.3%) of all lesions were first detected by the patient or a relative, and the remainder by a healthcare professional. The median (range) time which elapsed between ulcer onset and first professional review was 4 (0-247) days, and the median time between first review and first referral to the specialist clinic was 15 (0-608) days. Significant delays were judged to have occurred in 39 instances. The most common precipitant of ulceration was rubbing from footwear, which was responsible for 138 (20.6%). Fifty-eight (8.7%) were the result of immobilization from other illness, and a further 24 were the consequence of surgery. Overall, professional factors contributed to the development or deterioration of 106 lesions (15.8% total). These results should form the basis of strategies designed to minimize the onset of ulceration in those known to be at risk: educational strategies need to be directed at professionals as much as at patients.     

Results of transplantation for acute and chronic hepatic allograft rejection

B-chronic lymphocytic leukemia (CLL) is characterized by an accumulation of long-lived, resting B cells expressing the Bcl-2 protein. However, less than 10% of the CLL patients shows bcl-2 gene rearrangement in blood cells, using traditional Southern blotting analysis. In the present study, rearrangement of the bcl-2 gene in CLL cells was studied by pulsed-field gel electrophoresis (PFGE). With this method, large DNA fragments (> 50-10,000 kb) could be analyzed. Blood CLL cells from 9 of 9 patients and 2 of 2 CLL cell lines showed rearranged bcl-2 gene. In comparison, healthy blood B cells and lymphoblastoid cell lines (LCLs) established from normal peripheral blood lymphocytes of the patients showed only germ line configuration. Thus, the possibility of restriction fragment length polymorphisms (RFLPs) in this gene could be excluded. The primary cell involved in CLL might be a progenitor B cell that has accidentally rearranged the bcl-2 gene. As a consequence, such cells express stable amount of Bcl-2 protein and do not enter apoptosis. During prolonged survival, such cells may acquire secondary changes including chromosomal translocations and mutations.     

CsA levels in the early posttransplant period--predictive of chronic rejection in liver transplantation?

The increasing success of clinical liver transplantation has brought rejection to the forefront as a cause of morbidity and graft loss. The relationship of immunosuppressive drug doses and levels to acute and chronic rejection remains a matter of debate. The effect of blood CsA levels and drug doses on the incidence of acute and chronic rejection and the impact of acute rejection episodes on the occurrence of chronic rejection were studied in 146 grafts in 132 patients. These patients were transplanted in the 4-year period from June 1989 using CsA-based immunosuppression (CsA, azathioprine, prednisolone). Liver grafts in patients maintained on median CsA levels (whole blood, trough level) of > or = 175 micrograms/L in the first 28 days posttransplant had a significantly lower incidence of chronic rejection (2 out of 49 vs. 22 out of 97; P = 0.002). There was no significant difference in incidence of graft loss due to fatal sepsis (6% vs. 5%) or nephrotoxicity between the high and low CsA level groups. The overall graft loss rate was lower in the higher CsA level group (22% vs. 37%). The total doses of the individual drugs did not correlate with the incidence of acute or chronic rejection. Although the occurrence of acute rejection itself did not determine later chronic rejection, late occurrence (P < 0.00001) and multiple episodes (two or more; P = 0.0002) of acute rejection were significant risk factors for the occurrence of chronic rejection. We conclude that to minimize graft loss to rejection, CsA levels should be maintained at greater than 175 micrograms/L in the early posttransplant period, and late and recurrent episodes of acute rejection should be prevented.     

Routine surveillance endomyocardial biopsy: late rejection after heart transplantation

BACKGROUND: Transplant programs use routine surveillance endomyocardial biopsies (RSEMB), which are performed at preset intervals to diagnose cardiac rejection. This retrospective study determined the incidence of graft rejection detected by RSEMB. METHODS: The records of 95 patients who underwent heart transplantation between 1987 and 1995 were reviewed. Rejection incidence was recorded for 80 patients who survived at least 30 days, with a mean follow-up of 35 months. RESULTS: One thousand five hundred sixteen total biopsies were performed; 1,170 were RSEMB. Four hundred seventy-five total rejection episodes occurred and 269 (56%) were diagnosed by RSEMB. Two distinct patient groups were identified. The majority (70 patients), had a decline in the incidence of rejection and no rejection episodes were identified by RSEMB after 36 months. In contrast, the high rejection group (10 patients) had a significantly higher ongoing rejection rate (p < or = 0.04 to p < or = 0.001) throughout their postoperative course up to 72 months. CONCLUSIONS: The majority of our transplant patients demonstrate a decrease in rejection with time and do not require RSEMB beyond 30 months. We identified a group of patients who exhibited a higher rate of rejection and need continued RSEMB.     

Detection of acute rejection of heart transplantation by Doppler color imaging

Doppler tissue imaging is a new technique of measuring the velocities of myocardial wall motion. In order to assess its value in the diagnosis of acute rejection, the velocities of the interventricular septum and left ventricular posterior wall were measured in systole and early diastole in 34 cardiac transplant patients at the time of their endomyocardial biopsy, using an M mode left parasternal short axis view. During 40 episodes of acute rejection (26 mild and/or moderate, 10 sub-severe and 4 severe), the wall velocities decreased significantly (p < 0.001) both in the interventricular septum and endocardium of the posterior wall. Myocardial velocities were significantly slower in sub-severe or severe rejection than in mild or moderate rejection. The most sensitive criterion was the measurement of posterior wall endocardial velocity in early diastole, a decrease of 10% having a sensitivity of 92% whereas the sensitivity of usual Doppler echocardiographic parameters is only 73%. Acute rejection, even mild cases, can be diagnosed with excellent sensitivity by measuring myocardial velocities by Doppler tissue imaging. This technique has the advantage of being non-invasive, reproducible and reliable in the follow-up of cardiac transplant patients.     

Factors contributing to so-called idiopathic headaches]

The interest in factors that may trigger in some cases idiopathic headache has increased in recent years. This problem has not been discussed in Polish literature up to now. An analysis of precipitating factors in a group of 116 patients: 70 with migraine, 30 with tension type of headache and 16 with cluster headache was conducted. In these groups: 60 patients (87%) with migraine, 24 patients (80%) with tension type headache and 15 patients (94%) with cluster headache confirmed activity of precipitating factors was shown. Stress was the most frequently cited precipitant in all types of idiopathic headaches (migraine-58%; tension type headache-53%; cluster headache-50%). Weather changes were in the second place. Excessive environmental factors, oversleep, some foods were also prominent factors.