Respiratory syncytial virus-associated infections in adult recipients of solid organ transplants

OBJECTIVES: To define discrete developmental levels of understanding of the ways in which normal children and adolescents link autonomy and will to moral obligation and to study the correlation between this progression and previously identified stages of conscience conceptualization. METHOD: One hundred thirty-two normal volunteers between the ages of 5 and 17 years were individually interviewed using the moral volition section of the semistructured Stilwell Conscience Interview. Analysis of the interviews resulted in five levels of understanding of moral self-evaluation and volitionally chosen behavior. RESULTS: Analyses of variance and covariance showed that the five levels of moral volition had significant correlation with five conceptualization stages, with stage criteria showing a stronger correlation than age. Self-identified tasks of oughtness were hierarchically defined beginning with those defining a morality of restraint followed by moralities of mastery/sufficiency, virtuous striving, idealization, and individual responsibility. Perception of increased independence of self in interaction with conscience was noteworthy at stages 4 and 5. CONCLUSIONS: Moral volition is the domain of conscience functioning that defines understanding of moral self-evaluation and volitionally chosen actions; five levels of understanding can be demonstrated in normal children between the ages of 5 and 17 years.     

Outcomes of 50 leukemia patients who received bone marrow transplants from unrelated donors]

In this study, we examined the ability of tumour necrosis factor-alpha (TNF) to stimulate the mitogen-activated protein (MAP) kinase homologues p42/44 MAP kinase, c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase and its effect upon DNA synthesis in primary cultures of bovine aortic endothelial cells (BAECs). TNF strongly stimulated p38 MAP kinase and JNK activity in both a time- and concentration-dependent manner. By contrast, TNF was a very poor activator of p42/44 MAP kinase relative to the known activator of p42/44 MAP kinase in endothelial cells, adenosine triphosphate (ATP). TNF-stimulated activation of p38 MAP kinase, and MAPKAP kinase-2, a known downstream target of p38 MAP kinase, was strongly inhibited by pre-incubation with the p38 MAP kinase inhibitor SB203580, whereas the minor activation of p42/44 MAP kinase was abolished by pre-incubation of the cell with the novel MAP kinase kinase 1 inhibitor PD098059. Addition of TNF resulted in a 50-60% decrease in DNA synthesis in BAECs. Pre-incubation with PD098059 or co-incubation with ATP failed to modify the inhibitory effect of TNF upon DNA synthesis. SB203580 reduced basal DNA synthesis by approximately 50%; however, if failed to modify the inhibition mediated by TNF. These results indicate that TNF strongly activates both p38 MAP kinase, JNK and, to a minor extent, p42/p44 MAP kinase. It is likely that only one of these kinases, JNK, plays a role in the regulation of DNA synthesis in these cells.     

Trauma management in solid organ transplant recipients

The recognition that cell death in the myocardium is not only necrotic in nature but is also mediated by activation of the suicide program of myocytes has raised several questions concerning the magnitude of this phenomenon, and whether these two distinct forms of cell death are disease-dependent or coexist in the pathologic heart. Additionally, the times required for the completion of apoptotic and necrotic myocyte cell death are unknown, making the analysis of their respective rates in the myocardium impossible at present. The documentation that mechanical forces in vitro, mimicking diastolic Laplace overloading in vivo, can transmit a death signal to myocytes suggests that programmed cell death may be triggered in the stressed myocardium independently from the etiology of the overload. Because increasing pressure or volume loads, or both, in the failing heart induce myocyte hypertrophy and proliferation, a challenging question is whether the induction of genes regulating these cellular growth processes may activate programmed cell death as well. Finally, the identification of the mechanisms responsible for the translation of a diffuse environmental condition into a death signal in a limited number of cells scattered across the ventricular wall is a major challenge of future research.     

Brain abscess in solid organ transplant recipients receiving cyclosporine-based immunosuppression

There is currently a stark therapeutic void in the treatment of evolving stroke. Although P-selectin is rapidly expressed by hypoxic endothelial cells in vitro, the functional significance of P-selectin expression in stroke remains unexplored. In order to identify the pathophysiological consequences of P-selectin expression and to identify P-selectin blockade as a potential new approach for the treatment of stroke, experiments were performed using a murine model of focal cerebral ischemia and reperfusion. Early P-selectin expression in the postischemic cerebral cortex was demonstrated by the specific accumulation of radiolabeled anti-murine P-selectin IgG, with the increased P-selectin expression localized to the ipsilateral cerebral microvascular endothelial cells by immunohistochemistry. In experiments designed to test the functional significance of increased P-selectin expression in stroke, neutrophil accumulation in the ischemic cortex of mice expressing the P-selectin gene (PS +/+) was demonstrated to be significantly greater than that in homozygous P-selectin-null mice (PS -/-). Reduced neutrophil influx was accompanied by greater postischemic cerebral reflow (measured by laser Doppler) in the PS -/- mice. In addition, PS -/- mice demonstrated smaller infarct volumes (5-fold reduction, P<.05) and improved survival compared with PS +/+ mice (88% versus 44%, P<.05). Functional blockade of P-selectin in PS +/+ mice using a monoclonal antibody directed against murine P-selectin also improved early reflow and stroke outcome compared with control mice, with reduced cerebral infarction volumes noted even when the blocking antibody was administered after occlusion of the middle cerebral artery. These data are the first to demonstrate a pathophysiological role for P-selectin in stroke and suggest that P-selectin blockade may represent a new therapeutic target in the treatment of stroke.     

Early cyclosporine taper in high-risk sibling allogeneic bone marrow transplants

Graft-versus-tumour reactions as a form of adoptive immunotherapy may help prevent the recurrence of haematological malignancy following allogeneic BMT. We hypothesised that such reactions may be maximised by shortening the duration of post-transplant immunosuppression by a rapid taper of cyclosporine (CYA). CYA dose was tapered between days 30 and 60 in patients at high risk of relapse, provided there was no evidence of prior significant acute GVHD. Twenty-six of 58 high-risk patients eligible at the time of transplant were subsequently tapered. Seven (27%) developed grade III/IV acute GVHD after completion of the taper, which was fatal in one patient. Chronic GVHD was observed in most patients, although with minimal overall impact on performance status. The overall probability of survival at 2 years was 43%. This non-randomised experience indicates that a rapid taper of CYA is tolerable and may provide an alternative to immunotherapy with donor leukocyte infusion in the high-risk allograft setting.     

Cells capable of bone production engraft from whole bone marrow transplants in nonablated mice

Allogeneic and autologous marrow transplants are routinely used to correct a wide variety of diseases. In addition, autologous marrow transplants potentially provide opportune means of delivering genes in transfected, engrafting stem cells. However, relatively little is known about the mechanisms of engraftment in transplant recipients, especially in the nonablated setting and with regard to cells not of hemopoietic origin. In particular, this includes stromal cells and progenitors of the osteoblastic lineage. We have demonstrated for the first time that a whole bone marrow transplant contains cells that engraft and become competent osteoblasts capable of producing bone matrix. This was done at the individual cell level in situ, with significant numbers of donor cells being detected by fluorescence in situ hybridization in whole femoral sections. Engrafted cells were functionally active as osteoblasts producing bone before being encapsulated within the bone lacunae and terminally differentiating into osteocytes. Transplanted cells were also detected as flattened bone lining cells on the periosteal bone surface.     

Relation between urinary cytology abnormalities and cyclosporine A therapy in bone marrow transplant recipients

The aim of the study was to determine the relationship, if any, between abnormalities in urinary cytology and the administration of cyclosporine A in bone marrow transplant recipients. Specific attention was given to the presence of tubular cells with round inclusions (TCRI). Two bone marrow transplant recipient groups were studied: one with allogeneic bone marrow transplantation (BMT) (20 patients) who were treated with cyclosporine A, and the other with autologous BMT (12 patients) who did not receive cyclosporine A. Urinary cytology showed TCRI in 41.66% of the patients after autologous BMT and in 80% of the patients after allogeneic BMT. In the group of patients treated with allogeneic BMT, the occurrence of TCRI was associated with a high incidence of glycosuria and was followed by an increase in the blood level of cyclosporine A, an increase in the serum creatinine concentration and a decrease in the creatinine clearance. These results demonstrated that TCRI, although related to, were not found to be exclusively specific to the administration of cyclosporine A.     

Risk factors for pulmonary tuberculosis in bone marrow transplant recipients

Little is known about the profile of infection with Mycobacterium tuberculosis in bone marrow transplant (BMT) recipients. Of five BMT series with a total of more than 5,000 patients, only 10 cases of M. tuberculosis infection were described, with an overall incidence of 0.19%. We have conducted a prospective evaluation of 183 consecutive BMT recipients, and 10 patients were found to develop pulmonary tuberculosis post-BMT, yielding an incidence of 5.5%. We described the clinical features of these 10 patients, and analyzed the risk factors for development of tuberculosis using age- and sex-matched case control subjects who did not develop the disease. The median age of the 10 patients who developed tuberculosis was 29 yr (range, 17 to 40 yr). The median time for onset of symptoms was 150 d (range, 23 to 550 d), mainly presenting with fever and cough, with infiltrates on chest radiograph. Respiratory tract specimens, mostly sputum, yielded positive smears for acid-fast bacilli in three and positive M. tuberculosis culture in eight, whereas lung tissue histology was the first diagnostic test in two patients. Treatment with standard antituberculosis drugs for a longer duration was highly effective, with no excessive side effects. Risk factors identified for development of tuberculosis included allogeneic BMT (p < 0.05, relative risk [RR] = 23.7), total body irradiation (p < 0. 05, RR = 4.9), and chronic graft-versus-host disease (GVHD) (p < 0. 05, RR = 3.6). It is postulated that chronic GVHD predisposed to development of tuberculosis mainly via disruption of host reconstitution of immune defenses against M. tuberculosis.     

A conceptual model of adaptation to illness and quality of life for cancer patients treated with bone marrow transplants

OBJECTIVES: Our goal was to determine the risk of cancer after hospitalization for endometriosis. STUDY DESIGN: Records of 20,686 women hospitalized with endometriosis during the period 1969 to 1983, as identified through the nationwide Swedish Inpatient Register, were linked against the National Swedish Cancer Registry through 1989 to identify all subsequent diagnoses of cancer. The study subjects were followed up for a mean of 11.4 years, with the cohort contributing 216,851 woman years of follow-up. Standardized incidence ratios were computed by the use of age- and period-specific incidence rates derived from the Swedish population. Because of the high proportion of subjects with gynecologic operations (55.6%), evaluation of the risk of gynecologic cancers involved truncation of person years at the time of any such operation. RESULTS: The overall cancer risk was 1.2 (95% confidence interval 1.1 to 1.3). Significant excesses were observed for breast cancer (standardized incidence ratio = 1.3, 95% confidence interval 1.1 to 1.4), ovarian cancer (1.9, 1.3 to 2.8), and hematopoietic malignancies (1.4, 1.0 to 1.8); this latter excess was largely driven by an excess risk of non-Hodgkin's lymphoma (1.8, 1.2 to 2.6). The risk of ovarian cancer was particularly elevated among subjects with a long-standing history of ovarian endometriosis (4.2, 2.0 to 7.7). Cervical cancer risk was slightly reduced (0.7, 0.4 to 1.3) whereas no association was observed for cancer of the endometrium (1.1, 0.6 to 1.9). CONCLUSIONS: These findings suggest that further attention be given to the risk of breast, ovarian and hematopoietic cancers among women with endometriosis and to exploring possible hormonal and immunologic reasons for the excess risks.     

Outcomes following mechanical ventilation in children undergoing bone marrow transplantation

Between 1976 and 1992, 869 patients <19 years of age underwent BMT at the University of Minnesota for a variety of malignant and non-malignant disorders. One hundred and ninety-six required mechanical ventilation (MV) at some time from the start of pre-BMT cyto reduction through the first year following BMT. Reasons for MV included respiratory compromise, upper airway management and non-pulmonary indications for respiratory support. In multivariate models, underlying diagnosis, receipt of HLA-mismatched marrow and the presence of acute graft-versus-host disease (aGVHD) were independent predictors of the need for MV. Indication for MV, underlying diagnosis, and presence of aGVHD were independent predictors of successful extubation. Overall survival at 2 years was 14% among MV patients and 52% among non-MV patients. While the need for MV during BMT reduces the overall likelihood of survival, 40% of children who required MV were successfully extubated; 35% of these extubated patients were long-term survivors. This outcome is better than that reported for adult BMT patients requiring respiratory support, who show survival of <5% at 6 months following BMT. Our data suggest extrapolation of outcome data from adult to pediatric patients is not appropriate and aggressive care of pediatric patients requiring respiratory support is not futile.     

Myasthenia gravis after allogeneic bone marrow transplantation. A case report and a review of the literature

PURPOSE: The treatment of infant acute lymphoblastic leukemia (ALL) continues to be a significant challenge for pediatric oncologists due to the high incidence of early relapses. Salvage regimens used to date have met limited success. We describe two cases of relapsed infant ALL who have achieved long-term survival with an intensive antimetabolite-based salvage regimen. PATIENTS AND METHODS: Two consecutive infants with relapsed ALL presented at our institution and were treated with an antimetabolite-based regimen. Both cases exhibited clinical and biological phenotypes previously associated with infantile ALL. RESULTS: Both patients have achieved prolonged and sustained remissions 48 and 30 months EFS respectively following therapy with intensive antimetabolite-based salvage regimen. CONCLUSIONS: An intensive multiagent antimetabolite based salvage regimen resulted in prolonged EFS in two cases of relapsed infant ALL. Dose intensification was achieved by administering repeated cycles of the same treatment schema using high dose chemotherapy throughout therapy. These infants were spared prophylactic cranial irradiation without a negative impact on outcome. The use of L-asparaginase, timed after high-dose Cytarabine (ARA-C) throughout therapy, might have contributed to their cure.     

Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings

PURPOSE: To compare outcomes of bone marrow transplants for leukemia from HLA-identical siblings, haploidentical HLA-mismatched relatives, and HLA-matched and mismatched unrelated donors. PATIENTS: A total of 2,055 recipients of allogeneic bone marrow transplants for chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) were entered onto the study. Transplants were performed between 1985 and 1991 and reported to the International Bone Marrow Transplant Registry (IBMTR). Donors were HLA-identical siblings (n = 1,224); haploidentical relatives mismatched for one (n = 238) or two (n = 102) HLA-A, -B, or -DR antigens; or unrelated persons who were HLA-matched (n = 383) or mismatched for one HLA-A, -B, or -DR antigen (n = 108). HLA typing was performed using serologic techniques. RESULTS: Transplant-related mortality was significantly higher after alternative donor transplants than after HLA-identical sibling transplants. Among patients with early leukemia (CML in chronic phase or acute leukemia in first remission), 3-year transplant-related mortality (+/-SE) was 21% +/- 2% after HLA-identical sibling transplants and greater than 50% after all types of alternative donor transplants studied. Among patients with early leukemia, relative risks of treatment failure (inverse of leukemia-free survival), using HLA-identical sibling transplants as the reference group, were 2.43 (P < .0001) with 1-HLA-antigen-mismatched related donors, 3.79 (P < .0001) with 2-HLA-antigen-mismatched related donors, 2.11 (P < .0001) with HLA-matched unrelated donors, and 3.33 (P < .0001) with 1-HLA-antigen-mismatched unrelated donors. For patients with more advanced leukemia, differences in treatment failure were less striking: 1-HLA-antigen-mismatched relatives, 1.22 (P = not significant [NS]); 2-HLA-antigen-mismatched relatives, 1.81 (P < .0001); HLA-matched unrelated donors, 1.39 (P = .002); and 1-HLA-antigen-mismatched unrelated donors, 1.63 (P = .002). CONCLUSION: Although transplants from alternative donors are effective in some patients with leukemia, treatment failure is higher than after HLA-identical sibling transplants. Outcome depends on leukemia state, donor-recipient relationship, and degree of HLA matching. In early leukemia, alternative donor transplants have a more than twofold increased risk of treatment failure compared with HLA-identical sibling transplants. This difference is less in advanced leukemia.     

Human herpesvirus-6 and human herpesvirus-7 infections in bone marrow transplant recipients

Tricalcium phosphate (TCP) was combined with amylopectin to form a deliverable carrier paste for recombinant human transforming growth factor beta 1 (rhTGF-beta 1) intended for bone repair applications. Approximately 80% of rhTGF-beta 1 was released from the carrier within 24 h following in vitro incubation in serum. Full biological activity was maintained, suggesting the growth factor was stable in this formulation before and after in vitro release. In vivo efficacy also was assessed, in comparison to a sham control group and a placebo-treated group, using a rabbit unilateral segmental defect model (1 cm). Radiographs of defect sites taken at scheduled intervals and the mechanical testing of treated limbs at 56 days demonstrated a higher incidence of radiographic bone union, in concert with a stronger torque strength, in the rhTGF-beta 1-treated group compared to the placebo group. The short duration of the study and the fact that the model used was not a critical defect may account for the lack of superiority of the rhTGF-beta 1-treated group over the healing of the sham control. The in vivo pharmacokinetics of the growth factor evaluated in the same rabbit model suggested that rhTGF-beta 1 persisted intact at the defect site for more than 21 days. Gamma imaging and radioactivity recovery at defects administered to [131I]- and [125I]-labeled rhTGF-beta 1, respectively, estimated the half-life of rhTGF-beta 1 eliminated from the applied site to be 4-6 days. The present report substantiates the potential of rhTGF-beta 1 and its carrier for treatment of bone defects.     

Diltiazem disposition and metabolism in recipients of renal transplants

Owing to increasing evidence showing the importance of lipid peroxidation in oxidative stress in vivo, the role and evaluation of antioxidants have received much attention. Ginkgo biloba extract (GBE), well-known as an efficient drug against diseases induced by free radicals, has been suggested to exert its effect by antioxidant action. A method was established to determine the activity of GBE as a hydrogen donor by stoichiometric and kinetic studies, and GBE was compared with several other antioxidants such as alpha-tocopherol, propyl gallate, and two kinds of flavonoids which are found in GBE, quercetin, and kaempferol. It was found that there were 6.62 x 10(19) active hydrogens in 1 g of GBE. Stoichiometric studies showed that one molecule of alpha-tocopherol reacted with one molecule of galvinoxyl radical. For quercetin, kaempferol and propyl gallate, the experimental stoichiometric numbers were 4.0, 1.9, and 3.1, respectively. The rates of reaction of antioxidants with galvinoxyl in ethanol were determined spectrophotometrically, using a stopped-flow technique. The second-order rate constant, k2, obtained at 25 degrees C was 0.13 (g/L)(-1)s(-1) for GBE and 5.9 x 10(3), 2.1 x 10(3), 1.2 x 10(4), and 2.4 x 10(3) M(-1)s(-1) for quercetin, kaempferol, propyl gallate, and alpha-tocopherol, respectively. The second-order rate constant, k2', on the molar basis of active hydroxyl groups in the tested substances obtained at 25 degrees C decreased in the order of propyl gallate > alpha-tocopherol > quercetin > GBE approximately kaempferol. This is the first study on GBE as an antioxidant which reports both stoichiometric and kinetic results.     

Antithrombin-III for the treatment of chemotherapy-induced organ dysfunction following bone marrow transplantation

A hypercoaguable state has been shown to follow high-dose chemotherapy for bone marrow transplantation (BMT). Deficiency of the natural anticoagulants, antithrombin III (AT-III), protein C and protein S correlate with organ dysfunction following BMT. We treated 10 patients with severe post-BMT organ dysfunction with AT-III concentrate. Indications for treatment included AT-III anticoagulant level less than 88% and life-threatening single or multiorgan dysfunction. All patients were loaded with 50 units/kg AT-III every 8 h for three doses followed by 50 units/kg/day each day for 3-12 days. Clinical improvement was seen within 1-5 days of start of therapy in all patients. Patients with veno-occlusive disease (VOD) showed a decrease in platelet consumption in nine of nine patients, resolution of hepatic tenderness in six of eight patients, and reduction of severe ascites and weight gain in four of five patients. The probability of death due to VOD and life-threatening organ dysfunction was significantly less in the AT-III-treated group when compared to a historical control group receiving the same preparative regimen (P = 0.047 and P = 0.034, respectively). Significant improvements in organ dysfunction following AT-III treatment in this small study supports a causal relationship between AT-III deficiency and post-BMT chemotherapy-induced organ dysfunction.     

Quantitation of hepatitis G virus RNA in allogeneic bone marrow transplant recipients. Stem Cell Transplantation Team

In thermolysin, tryptophan 115 seems to be at the S2 subsite. Trp-115 was replaced with tyrosine, phenylalanine, leucine, and valine during site-directed mutagenesis in order to evaluate the role of Trp-115 in the proteolytic activity of thermolysin. The mutant enzymes with Tyr-115 or Phe-115 had as much proteolytic activity as the wild-type enzyme, but the other two mutant enzymes had no activity. We found earlier that the substitution of Trp-115 with alanine, glutamic acid, lysine, and glutamine causes the enzyme to lose all activity, so an aromatic amino acid at position 115 seems to be essential for thermolysin.