Drug absorption may be delayed after stroke: results of the paracetamol absorption test.

BACKGROUND: Autonomic changes are frequent after stroke but it is not known whether gastric emptying is altered. We have investigated this using the paracetamol absorption test. METHODS: 12 acute stroke patients and 13 healthy controls of similar age received 1 g oral paracetamol tablets. We studied all patients within 24 h of the stroke and 5 days later. Standard pharmacokinetic measurements were derived from the plasma paracetamol-time curve. RESULTS: In acute stroke patients, mean plasma T(max) was delayed compared with that in controls (96.3 vs 46.2 min, P=0.015). The C(max) of paracetamol was also lower (16.1 vs 23.9 mg l(-1), P=0.028). The area under the curve of paracetamol did not differ significantly in acute stroke patients and controls. CONCLUSIONS: Gastric emptying appears to be delayed in acute stroke patients, and this may result in delayed pharmacological action of orally administered drugs.

Donor IFN-gamma receptors are critical for acute CD4(+) T cell-mediated cardiac allograft rejection.

Recent studies using mouse models demonstrate that CD4(+) T cells are sufficient to mediate acute cardiac allograft rejection in the absence of CD8(+) T cells and B cells. However, the mechanistic basis of CD4-mediated rejection is unclear. One potential mechanism of CD4-mediated rejection is via elaboration of proinflammatory cytokines such as IFN-gamma. To determine whether IFN-gamma is a critical cytokine in CD4-mediated acute cardiac allograft rejection, we studied whether the expression of IFN-gamma receptors on the donor heart was required for CD4-mediated rejection. To investigate this possibility, purified CD4(+) T cells were transferred into immune-deficient mice bearing heterotopic cardiac allografts from IFN-gamma receptor-deficient (GRKO) donors. While CD4(+) T cells triggered acute rejection of wild-type heart allografts, they failed to trigger rejection of GRKO heart allografts. The impairment in CD4-mediated rejection of GRKO hearts appeared to primarily involve the efferent phase of the immune response. This conclusion was based on the findings that GRKO stimulator cells provoked normal CD4 proliferation in vitro and that intentional in vivo challenge of CD4 cells with wild-type donor APC or the adoptive transfer of in vitro primed CD4 T cells failed to provoke acute rejection of GRKO allografts. In contrast, unseparated lymph node cells acutely rejected both GRKO and wild-type hearts with similar time courses, illustrating the existence of both IFN-gamma-dependent and IFN-gamma-independent mechanisms of acute allograft rejection.

CD4 T cell-mediated cardiac allograft rejection requires donor but not host MHC class II.

Numerous studies indicate that CD4 T cells are required for acute cardiac allograft rejection. However, the precise role for CD4 T cells in this response has remained ambiguous owing to the multipotential properties of this T-cell subpopulation. In the current study, we demonstrate the capacity of CD4 T cells to serve as direct effector cells of cardiac allograft rejection. We show that CD4 T cells are both necessary and sufficient for acute graft rejection, as indicated by adoptive transfer experiments in immune-deficient SCID and rag1(-/-) recipients. We have analyzed the contribution of direct (donor MHC class II restricted) and indirect (host MHC class II restricted) antigen recognition in CD4-mediated rejection. Acute CD4 T cell-mediated rejection required MHC class II expression by the allograft, indicating the importance of direct graft recognition. In contrast, reciprocal experiments indicate that CD4 T cells can acutely reject allogeneic cardiac allografts established in rag1(-/-) hosts that were also MHC class II deficient. This latter result indicates that indirect presentation of donor antigens by host MHC class II is not required for acute CD4-mediated rejection. Taken together, these results indicate that CD4 T cells can serve as effector cells for primary acute cardiac allograft rejection, predominantly via direct donor antigen recognition and independent of indirect reactivity.

Cardiac angiosarcoma: an unusual presentation with cutaneous metastases.

Angiosarcoma is the most common primary malignant neoplasm of the heart. The incidence of metastatic disease is 66% to 89%; however, initial presentation with metastatic disease is rare. We report the case of a patient who presented initially with soft tissue and cutaneous metastases in the absence of cardiac symptoms.

Diagnosis of clinically unsuspected gallbladder rupture by peritoneal fluid cytology. A case report.

BACKGROUND: Rupture of the biliary system resulting in bile ascites may occur spontaneously or as a complication of inflammatory disease, biliary tract manipulation or trauma. Leakage of bile into the peritoneal cavity can cause severe chemical peritonitis, requiring rapid surgical intervention. CASE: A 64-year-old male status post total laryngectomy for squamous cell carcinoma developed abdominal pain and ascites. Diagnostic paracentesis was performed, and bile pigment was noted on cytologic examination, raising the possibility of biliary rupture. This was confirmed radiographically, and the patient underwent exploratory laparotomy, where a ruptured gallbladder was found and cholecystectomy performed. CONCLUSION: Recognition of bile pigment on cytologic examination of ascitic fluid followed by measurement of ascitic fluid bilirubin levels can alert clinicians to the presence of clinically unsuspected bile peritonitis in patients with rupture of the biliary system.

Changes in gene expression in the intact human heart. Downregulation of alpha-myosin heavy chain in hypertrophied, failing ventricular myocardium.

Using quantitative RT-PCR in RNA from right ventricular (RV) endomyocardial biopsies from intact nonfailing hearts, and subjects with moderate RV failure from primary pulmonary hypertension (PPH) or idiopathic dilated cardiomyopathy (IDC), we measured expression of genes involved in regulation of contractility or hypertrophy. Gene expression was also assessed in LV (left ventricular) and RV free wall and RV endomyocardium of hearts from end-stage IDC subjects undergoing heart transplantation or from nonfailing donors. In intact failing hearts, downregulation of beta1-receptor mRNA and protein, upregulation of atrial natriuretic peptide mRNA expression, and increased myocyte diameter indicated similar degrees of failure and hypertrophy in the IDC and PPH phenotypes. The only molecular phenotypic difference between PPH and IDC RVs was upregulation of beta2-receptor gene expression in PPH but not IDC. The major new findings were that (a) both nonfailing intact and explanted human ventricular myocardium expressed substantial amounts of alpha-myosin heavy chain mRNA (alpha-MHC, 23-34% of total), and (b) in heart failure alpha-MHC was downregulated (by 67-84%) and beta-MHC gene expression was upregulated. We conclude that at the mRNA level nonfailing human heart expresses substantial alpha-MHC. In myocardial failure this alteration in gene expression of MHC isoforms, if translated into protein expression, would decrease myosin ATPase enzyme velocity and slow speed of contraction.

Detection of Epstein-Barr virus in cardiac biopsies of heart transplant patients with lymphoproliferative disorders.

We investigated whether in situ hybridization for EBV RNA on routine cardiac biopsies could be used as a predictive test for the development of posttransplant lymphoproliferative disorder (PTLD) in cardiac transplant recipients. We examined the sensitivity of the test by determining the frequency of EBV-positive cells in cardiac biopsy specimens from patients with a known history of PTLD. Biopsy specimens obtained during routine monitoring for rejection before or shortly after the diagnosis of PTLD from 10 pediatric heart transplant patients were examined. Four of 74 specimens (5.4%) demonstrated EBV-positive lymphocytes in the cardiac biopsy rejection infiltrates. The four positive specimens were obtained from 3 different patients, all before the diagnosis of PTLD. Given the low number of cardiac biopsy specimens with EBV-positive lymphocytes, as well as the low incidence of PTLD in cardiac transplant patients, we conclude that a routine screening of all cardiac biopsy specimens using in situ hybridization for EBV with the intention of predicting PTLD is not warranted. However, in situ hybridization for EBV might be used in selected cases, such as those in which the transplant patient does not respond to immunosuppressive therapy for rejection. In these patients, the presence of EBV-positive lymphocytes in biopsy specimens initially interpreted as showing rejection might instead raise the suspicion of incipient PTLD.

Giant cell myocarditis.

BACKGROUND: Giant cell myocarditis is a rare and frequently fatal disorder of unknown origin that is defined histopathologically as diffuse myocardial necrosis with multinucleated giant cells in the absence of sarcoidlike granulomata. The clinical and pathologic features of lymphocytic myocarditis have been described in several recent publications, but the features of idiopathic giant cell myocarditis have not been adequately addressed. METHODS AND RESULTS: We describe five patients with idiopathic giant cell myocarditis who were seen at Stanford University over the past 10 years. In each case the onset was subacute congestive heart failure. After diagnosis each patient received immunosuppressive therapy and was evaluated for heart transplantation. Progressive heart failure and ventricular arrhythmias developed in all. Three died rapidly, two of progressive heart failure and one of sudden cause. Two patients underwent orthotopic heart transplantation and are currently alive, one with disease recurrence. Pathologic studies, including endomyocardial biopsy and evaluation of postmortem or explanted material at transplantation were reviewed. The pathologic studies provided additional support that the giant cells derive from a monocytic/histiocytic lineage. Segmental wall motion abnormalities suggest giant cell myocarditis can be a focal, as well as diffuse process at certain stages of its course. This experience is compared with published cases and implications for diagnosis and treatment are discussed. CONCLUSIONS: In view of the uniformly fatal nature of the disease, heart transplantation should be a serious consideration, and the patients evaluated once the diagnosis is established. Triple-drug immunosuppressive therapy should be considered at the time of diagnosis.

Incidence of myocarditis in peripartum cardiomyopathy.

Peripartum cardiomyopathy (PC), an uncommon cause of peripartum heart failure, is defined as a cardiomyopathy presenting in the last trimester of pregnancy or the first 6 months postpartum, without evidence of preexisting cardiovascular disease. The etiology of PC and idiopathic dilated cardiomyopathy (IDC) remains uncertain. Several reports have addressed possible differences in clinical presentation and prognosis between these groups. A relatively high incidence of myocarditis has been recently reported in patients with PC, raising the possibility that this may represent a distinct difference between this condition and IDC. A retrospective review of endomyocardial biopsy specimens from 34 patients fulfilling the criteria for a diagnosis of PC was therefore performed to further evaluate this finding. Results indicate a lower incidence of myocarditis (8.8%, 3 of 34) than that reported in other studies. This incidence was comparable to that found in an age- and sex-matched control population undergoing transplantation for IDC (9.1%, 2 of 22). Factors that may influence the diverse range in the reported incidence of myocarditis are discussed.

Acute rejection: significance of elapsed time after transplantation.

In July 1990 the new standardized grading scheme for the International Society for Heart and Lung Transplantation was established. One of the purposes of "splitting" the grades was to learn the significance and outcome of the various grades proposed. Between January 1990 and November 1992, 263 grade 1A, 19 grade 1B, and 100 grade 2 "new" rejection episodes were identified at our institution. These episodes occurred in 86 adult recipients who underwent transplantation between January 1990 and August 1992 and 98 recipients who underwent transplantation before January 1990, in whom the episodes occurred more than 1 year from the date of transplantation. The outcome of the episode was determined on subsequent endomyocardial biopsy samples to be resolution or "progression" to a higher grade. The percentage of focal mild (grade 1A) rejection episodes progressing to a moderate (grade 3A) rejection in the first 6 months after transplantation was 24.4% (20 of 82) compared with a progression rate of 5.1% (3 of 59) and 2% (3 of 149) in episodes occurring beyond 6 months and 1 year after transplantation, respectively (p < 0.005). Of the focal moderate (grade 2) rejection episodes receiving no augmentation of immunosuppression, 35.7% (5 of 14) occurring within the initial 6 months and 7.3% (3 of 41) of all such episodes diagnosed beyond 1 year after transplantation progressed to a moderate rejection. A similar trend was seen in the focal moderate rejection episodes that received augmentation of immunosuppression: 26.3% (5 of 19) of episodes occurring within 6 months and 0 of 15 of all episodes occurring beyond 1 year after transplantation progressed to a moderate rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Follicular large-cell lymphoma: intermediate or low grade?

PURPOSE: To evaluate the benefit of anthracycline-based chemotherapy, identify prognostic factors, and determine the value of the International Prognostic Factors Index for patients with follicular large-cell (FLC) lymphoma. PATIENTS AND METHODS: This retrospective study includes 96 patients with FLC lymphoma treated at Stanford University Medical Center between 1969 and 1991. Fifty-five patients received doxorubicin plus cyclophosphamide-containing chemotherapy regimens, 21 patients received other chemotherapy regimens, 15 patients received radiotherapy only, and five patients received no initial therapy. Thirty-four patients had stage I or II disease and 62 patients had stage III or IV disease. RESULTS: With a median follow-up duration of 5.2 years (range, 1 to 18), the actuarial 5- and 10-year overall survival rates were 75% and 54%, with actuarial 5- and 10-year freedom from progression (FFP) rates of 53% and 42%, respectively. Patients treated with chemotherapy regimens that contained both doxorubicin and cyclophosphamide had a superior actuarial 10-year FFP rate (55% v 25%, P = .06) and overall survival rate (65% v 42%, P = .04) compared with patients treated with other chemotherapy regimens. Only one patient treated with doxorubicin plus cyclophosphamide relapsed after 3 years. In the multivariate analysis, discordant lymphoma and treatment with chemotherapy regimens not containing both cyclophosphamide and doxorubicin predicted for worse FFP and overall survival rates. In addition, poor performance status and increasing areas of diffuse histology predicted for a worse survival, while anemia and male sex predicted for a worse FFP. The age-specific International Index was useful in predicting outcome; however, few patients with FLC lymphoma had high-risk features. CONCLUSION: The plateau in FFP implies that patients with FLC lymphoma enjoy sustained remissions after standard anthracycline-based chemotherapy. FLC lymphoma should continue to be approached as an intermediate-grade lymphoma with curative intent.

A comparative immunohistochemical study of uterine smooth muscle neoplasms with emphasis on the epithelioid variant.

We evaluated the immunophenotypes of 22 spindled and 36 epithelioid uterine smooth muscle neoplasms (SMNs) and 16 extrauterine nongastrointestinal spindled smooth-muscle neoplasms for various markers. The epithelioid neoplasms were subdivided into two histological groups designated true and intermediate, the former showing typical epithelioid features and the latter showing epithelioid features that could be explained by cross-sectioning of blunt spindled cells. Desmin, muscle-specific actin, and smooth muscle actin were equally sensitive in detecting muscle differentiation in all these neoplasms. The true epithelioid variants were more frequently keratin positive but less frequently positive for vimentin, CD34 or the muscle markers, compared with their spindled counterparts. The intermediate epithelioid variants more closely resembled the spindled neoplasms in their immunostaining for muscle markers, vimentin, and CD34 but like the true epithelioid variants were relatively frequently positive for keratin. CD34 was positive in 36% of the spindled and 6% of the true epithelioid uterine SMNs, in most cases faintly. Antikeratin AE1 was positive more frequently than CAM5.2, with 18% of the spindled and 35% of the true epithelioid neoplasms being AE1 positive. The immunophenotype of uterine SMNs, including the epithelioid variant, permits their distinction from carcinomas based on their frequent reactivity for muscle markers in spite of their high rate of keratin positivity. They show sufficient overlap in immunoreactivity with endometrial stromal sarcomas to preclude definitive differentiation from them on immunohistochemical features alone.

Long-term outcome after heart transplantation for peripartum cardiomyopathy.

To elucidate the long-term outcome and frequency of complications after heart transplantation for peripartum cardiomyopathy (PPCM), we compared the courses of eight consecutive patients undergoing transplantation for PPCM with those of nine female age-matched control subjects undergoing transplantation for idiopathic dilated cardiomyopathy (IDCM). No significant differences could be found in baseline variables between the two groups with the exception of the number of pregnancies (2.5 +/- 1.5 vs 0, p = 0.0002). Two patients in each group died during the first 6 months after transplantation, and one in each group died later. Actuarial survival rates were 75% +/- 15% and 78% +/- 14% (p = NS) at 1 year and 60% +/- 18% and 78% +/- 14% (p = NS) at 5 years in PPCM and IDCM patients, respectively. Linearized rejection rates during the first 3 months were 1.85 +/- 0.56 and 1.91 +/- 0.49 (p = NS) and during the second 3 months were 0.18 +/- 0.18 and 0.45 +/- 0.26 (p = NS), respectively. Similarly no significant differences in linearized infection rates were found. Among patients surviving more than 6 months after transplantation, after a mean follow-up period of 4.5 +/- 3.1 years for those with PPCM and 7.8 +/- 3.2 years for those with IDCM, 83% and 100%, respectively, were rehabilitated; hemodynamic findings were normal in all patients and the frequency of other transplant-associated complications was similar in both groups. In conclusion, heart transplantation is a valuable option for patients with PPCM and severe congestive heart failure that is unresponsive to conventional treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Graft coronary disease in pediatric heart and combined heart-lung transplant recipients: a study of fifteen cases.

Graft coronary disease (GCD) has emerged as the most important deterrent to long-term survival in adult heart transplant recipients. The incidence, natural history, and pathobiology of GCD is less well understood in the pediatric transplant population. This study evaluated the histopathologic and immunohistochemical features of GCD in the Stanford pediatric heart and heart-lung group. Eighty-eight patients, ages 1 week to 18 years, received heart transplants between 1974 and 1992, and 15 patients, ages 1 month to 18 years received heart-lung transplants between 1981 and 1992 at Stanford University Hospital. There were 50 males and 38 females in the heart transplant group; 39 (11%) had idiopathic cardiomyopathy, 26 (30%) had congenital heart disease, 13 (15%) had viral cardiomyopathy, seven (8%) had familial cardiomyopathy, two (2%) had cardiomyopathy resulting from doxorubicin therapy, and one other case was not further delineated. In the heart-lung transplant group, there were eight males and seven females; pretransplantation diagnoses included nine (60%) with congenital heart disease and Eisenmenger's physiology, three (20%) with primary pulmonary hypertension, and one (7%) each with cystic fibrosis, bronchopulmonary dysplasia, and congenital lymphangiectasia. Fifteen (17%) of the heart transplant recipients and three (20%) of the heart-lung transplant recipients had GCD on angiographic or pathologic examination. Histopathologic samples were available on 14 cases (11 heart transplants and three heart-lung transplants).(ABSTRACT TRUNCATED AT 250 WORDS)