Immunohistochemical quantification of inflammatory cells in endomyocardial biopsy fragments after heart transplantation: a new potential method to improve the diagnosis of rejection after heart transplantation.

Inconsistencies in cardiac rejection grading systems corroborate the concept that the evaluation of inflammatory intensity and myocyte damage seems to be subjective. We studied in 36 patients the potential role of the immunohistochemical (IHC) counting of inflammatory cells in endomyocardial biopsy (EMB) as an objective tool, testing the hypothesis of correlation between the International Society for Heart and Lung Transplantation 2004 rejection and IHC counting of inflammatory cells. We observed a progressive increment in CD68+ cells/mm(2) (P = .000) and CD3+ cells/mm(2) (P = .000) with higher rejection grade. A strong correlation between the grade of cellular rejection and both CD68+ cells/mm(2) and CD3+ cells/mm(2) was obtained (P = .000). One patient with CD3+ and CD68+ cells/mm(2) above the upper limit of the 95% confidence interval for cells/mm(2) found in rejection grade 1R evolved to rejection grade 2R without treatment. In patients with 2R that did not respond to treatment the values of CD68+ or CD3+ cells were higher than the overall median values for rejection grade 2R. For diagnosis of rejection needing treatment, the CD68+ and CD3+ cells/mm(2) areas under the receiver operating characteristic curves were 0.956 and 0.934, respectively. IHC counting of mononuclear inflammatory infiltrate in EMB seems to have additive potential role in evaluation of EMB for the diagnosis and prognosis of rejection episodes.

Recovery of renal function in heart transplantation patients after conversion from a calcineurin inhibitor-based therapy to sirolimus.

BACKGROUND: Renal failure is the most important comorbidity in patients with heart transplantation, it is associated with increased mortality. The major cause of renal dysfunction is the toxic effects of calcineurin inhibitors (CNI). Sirolimus, a proliferation signal inhibitor, is an imunossupressant recently introduced in cardiac transplantation. Its nonnephrotoxic properties make it an attractive immunosuppressive agent for patients with renal dysfunction. In this study, we evaluated the improvement in renal function after switching the CNI to sirolimus among patients with new-onset kidney dysfunction after heart transplantation. METHODS: The study included orthotopic cardiac transplant (OHT) patients who required discontinuation of CNI due to worsening renal function (creatinine clearance < 50 mL/min). We excluded subjects who had another indication for initiation of sirolimus, that is, rejection, malignancy, or allograft vasculopathy. The patients were followed for 6 months. The creatinine clearance (CrCl) was estimated according to the Cockcroft-Gault equation using the baseline weight and the serum creatinine at the time of introduction of sirolimus and 6 months there after. Nine patients were included, 7 (78%) were males and the overall mean age was 60.1 +/- 12.3 years and time since transplantation 8.7 +/- 6.1 years. The allograft was beyond 1 year in all patients. There was a significant improvement in the serum creatinine (2.98 +/- 0.9 to 1.69 +/- 0.5 mg/dL, P = .01) and CrCl (24.9 +/- 6.5 to 45.7 +/- 17.2 mL/min, P = .005) at 6 months follow-up. CONCLUSION: The replacement of CNI by sirolimus for imunosuppressive therapy for patients with renal failure after OHT was associated with a significant improvement in renal function after 6 months.

Prophylactic donor tricuspid annuloplasty in orthotopic bicaval heart transplantation.

OBJECTIVE: The objective of this study was to evaluate the effects of prophylactic heart donor tricuspid annuloplasty to improve the degree of valvar regurgitation and the hemodynamic performance after orthotopic heart transplantation using bicaval anastomosis. METHODS: From March 1985 to December 2005, of the 368 patients undergoing orthotopic heart transplantation, 20 patients were selected because they survived more than 6 months. They were divided into 2 groups: group I-10 patients underwent prophylactic heart donor tricuspid annuloplasty by the De Vega technique; group II-10 patients did not receive a graft with this procedure. Their presurgical clinical characteristics were the same. In the postsurgical period, tricuspid regurgitation degree evaluated by transthoracic Doppler echocardiography was qualified from 0 to 3: 0 = absent; 1 = mild; 2 = moderate; and 3 = severe. Myocardial performance was evaluated by the ventricular ejection fraction and by an invasive hemodynamic study, performed during routine endomyocardial biopsies. RESULTS: At a follow-up of 14.6 +/- 4.3 months (6 and 16 months), group I showed no mortality, whereas group II had 10% (P > .05). However, it was not related to the annuloplasty. The mean degree of tricuspid regurgitation in group I was 0.4 +/- 0.6; in group II, 1.6 +/- 0.8 (P < .05). There was a significant difference between the 2 groups in the right atrium pressure, which was higher in group II. CONCLUSIONS: Prophylactic tricuspid annuloplasty in the heart donor significantly reduced the degree of valvular regurgitation after heart transplantation using a bicaval anastomosis without significantly interfering with the hemodynamic performance of the allograft.

Later evolution after cardiac transplantation in Chagas' disease.

OBJECTIVE: This research reported the accumulated experience with cardiac transplantation in Chagas' disease, emphasizing reactivation, immunosuppression, and mortality. METHODS: Fifty-nine patients undergoing cardiac transplantation had Chagas' disease with classically accepted recipient selection criteria. In this series, 84.7% of the patients were functional class IV; 36.0% used vasopressor support; and 13.5% mechanical circulatory assistance. One patient received a heart and kidney transplantation. RESULTS: After the initial experience the doses of immunosuppressants were significantly reduced with improvement in outcomes. The diagnosis of the reactivation of disease was documented by the identification of parasite in the myocardium, or on subcutaneous or serological exams. Reactivation of disease was significantly reduced by decreasing the immunosuppression. Immediate mortality occurred in 10 cases: three infections, two allograft dysfunction, two rejections, and two sudden deaths. Subsequent mortality happened in 14 patients: four by lymphoma, three by infection, two by Kaposi's sarcoma two by rejection, two by constrictive pericarditis, and one by reactivation of disease in the brain. CONCLUSIONS: There's no correlation between the disease and pre- or postoperative prophylaxis. The early diagnosis and specific treatment of reactivation did not leave functional sequelae in the myocardium. Reduction in immunosuppression significantly reduced reactivation of disease and neoplasms. The combined transplantation can be realized safely with more care about the immunosuppressants.

Relapses, recurrences, valve replacements, and mortality during the long-term follow-up after infective endocarditis.

BACKGROUND: Late prognosis after infective endocarditis has not been systematically studied in large series of patients with different underlying heart conditions in recent years. METHODS: We studied an inception cohort study of 420 patients discharged after treatment of endocarditis from a university tertiary care hospital. The patients were aged 34.2+/-17.2 years (mean +/- SD), ranging from 2 months to 83 years; 270 (64.3%) were men and 150 (35.7%) were women. Mean follow-up was 6.1+/-4.3 years for survivors and 3.7+/-3.7 years for the patients who died during the follow-up. We studied the frequency and risk factors for relapses and recurrences of endocarditis, cardiac valve replacements, and deaths during the follow-up. Statistical analysis was performed through comparison of groups, of event-free survival, and risk ratios. RESULTS: Relapses were observed in 14 (3.3%) patients. There was one recurrence of endocarditis in 48 (11.4%) patients, two (0.5%) in 2 patients, three in 1 patient (0.2%), and five (0.2%) in 1 patient. Valve replacement was performed in 83 (19.7%) patients. Ninety-eight (12.3%) patients died. Risk factors for recurrent endocarditis were increasing age (risk ratio 1.02) and male sex (risk ratio 1.61). Risk factors for valve replacement were recurrent endocarditis (risk ratio 1.62) and prosthetic valve endocarditis (risk ratio 1.61). Risk factors for death were increasing age (risk ratio 1.03) and recurrent endocarditis (risk ratio 2.06). CONCLUSIONS: The long-term event-free survival for patients who survived their first episode of endocarditis was low. Recurrent endocarditis, prosthetic valve endocarditis, and increasing age contributed to the high rate of events during the follow-up.

Distribution of neuronal receptors for nerve growth factor in the rat.

To survey the distribution of neuronal receptors for NGF, sections of the rat brain, spinal cord, and peripheral ganglia were incubated in vitro with radioiodinated NGF and examined by autoradiography. NGF binds selectively with high affinity to most sympathetic neurons and many primary sensory neurons together with their intraspinal or intramedullary axons. In autoradiographs of the brain, labeled neuronal perikarya are seen in the basal forebrain, the caudate-putamen, the medulla oblongata, the ventral cochlear nucleus, and the dorsal nucleus of the lateral lemniscus. The distribution of neurons binding NGF resembles the distribution of cholinergic neurons in the forebrain, but these 2 systems overlap very little in the brain stem. In extracts of the brain or spinal cord enriched for plasma membranes, avid binding sites are regionally manifest with properties similar to those of fetal peripheral neurons. The localization of neurons expressing the high-affinity receptor for NGF defies simple correlation with neurotransmitter function or embryogenesis.

Peripheral injury enhances central regeneration of primary sensory neurones.

The success of peripheral and fetal neural tissue in promoting outgrowth of axons from the adult mammalian central nervous system has tended to focus attention on local interactions between extending axons and their environment. The contribution to axon regeneration of biochemical and morphological changes in injured neurones is more difficult to evaluate. We report here that long spinal axons of primary sensory neurones are 100 times more likely to regenerate into peripheral nerve grafts if their peripheral axons are also cut. Regenerative behaviour at the axon tip seems to be strongly influenced by inducible events in the nerve cell.

Transplantation of embryonic spinal and cerebral tissue to sciatic nerves of adult rats.

Neurons and glia in spinal or cerebral tissue removed from young rat embryos survived for months after subperineurial implantation in the sciatic nerve of isogenous rats. With HRP tracing, axons from a few grafted neurons were demonstrated to grow distally into host nerves.

Regeneration of long spinal axons in the rat.

To investigate regeneration of long spinal axons, the right lateral column of the rat spinal cord was cut at high cervical, low cervical, midthoracic or lumbar level, and one end of an autologous sciatic nerve segment was grafted to the spinal cord at the site of incision. Three to six months after operation, the origin of axons in the grafts was traced retrogradely with horseradish peroxidase injected into the grafts and, in some cases, anterogradely with radioautography of tritiated amino acids injected into the brainstem. Axons from each of the major lateral spinal tracts arising in the brainstem as well as axons ascending from the lower spinal cord succeeded in growing into low cervical grafts. However, long descending axons rarely regenerated after midthoracic or lumbar injury; axons ascending from lumbar segments of the spinal cord usually failed to enter high cervical grafts. Differences in axonal regrowth at the four segmental levels were not simply attributable to dwindling of axonal number in fibre tracts. Axonal regeneration from Clarke's column or the red nucleus was observed only with lesions causing atrophy of many neurons. There was no obvious example of a fibre tract in the lateral spinal columns from which axons failed to regenerate nor from which axons regenerated exceptionally well. Under the conditions of these experiments, the distance from cell body to injury appeared to be an important determinant of axonal regeneration.

Regeneration and retrograde degeneration of axons in the rat optic nerve.

The retinal stump of the rat optic nerve was examined histologically 1-64 weeks after intracranial section of the nerve with or without grafting of autologous peripheral nerve segments. Single unmyelinated axons and bundles of unmyelinated axons appeared in cut optic nerves and were most abundant 2-4 weeks after section. With light and electron microscope radioautography after injection of tritiated amino acids into the globe, it was confirmed that many unmyelinated fibres arose from the optic nerve rather than from nearby peripheral nerves and it was estimated that some axons regenerated as far as 0.5 mm. At or near the end of retinofugal axons, structures resembling growth cones were seen at 2 weeks and vesicle-containing swellings similar to synapses were found at 1-2 months. Outgrowth from optic nerve axons was not obviously enhanced by peripheral nerve grafts although a few retinofugal axons became ensheathed by Schwann cells. Retrograde axonal degeneration was rapid in both cut and grafted optic nerves, the number of nerve fibres near the globe falling to less than 10% of normal after 4 weeks. A few myelinated and unmyelinated fibres were still present 64 weeks after nerve transection. In conclusion, some cut axons in the rat optic nerve display a transient regenerative response before undergoing retrograde degeneration.