Epstein-Barr virus lymphoproliferation after bone marrow transplantation

We review 15 cases of secondary B-cell lymphoproliferative disorders that occurred among 2,475 patients who received allogeneic bone marrow transplants (BMTs) at the Fred Hutchinson Cancer Research Center (Seattle) between 1969 and 1987. The histopathologic findings in 14 of the 15 patients spanned a wide spectrum of lymphoproliferative lesions. One patient had features characteristic of angioimmunoblastic lymphadenopathy. Epstein-Barr virus (EBV) genomic sequences were identified by Southern blot analysis in each of the 13 patients evaluated. Ten of the 12 lesions evaluated originated in donor cells. In two patients, who had mixed chimerism after transplantation, the lesions originated in host cells. The combined evidence from immunoglobulin light chain staining and the analysis of immunoglobulin heavy chain gene rearrangement indicated that the lesions in most patients represented polyclonal proliferations that gave rise to clonal subpopulations. The results indicate an overall actuarial incidence of 0.6% for this complication in BMT recipients. Anti-CD3 monoclonal antibody (MoAb) treatment of acute graft-v-host disease (GVHD) and T cell depletion of the donor marrow were statistically significant risk factors, and GVHD appeared to play a contributing role, particularly in the setting of human leukocyte antigen (HLA) disparity. Two patients had no identifiable risk factors. Prophylaxis or treatment with acyclovir had no detectable effect in the patients; all but two died with uncontrolled lymphoproliferation.     

A Hypertransfused Mouse Assay for Thrombopoietic Factors

A method was developed for the quantitative separation of platelets from CF1mouse whole blood. This made it possibleto determine the platelet incorporation of³⁵S-sulfate without the necessity of doingplatelet counts. Daily hypertransfusions ofthe mice to three to four times normalplatelet levels for 4-5 days significantlyreduced platelet uptake of radiosulfate toan average of about 40% of the nontransfused controls. Mice rendered thrombocytopenic 48 hr earlier by antiplateletserum, had 2-day ³⁵S uptakes over 2 1/2times the controls and 6 times the hypertransfused animals. The administration of atotal of 2 ml of serum, given twice daily for3 days from a thrombocytopenic patientwith Hodgkin's disease caused a highlysignificant 103% rise in radiosulfate incorporation when compared with saline in thehypertransfused mouse. Normal humanserum from a healthy donor caused a smalland insignificant rise. The serum from a patient with Hodgkin's disease caused ahighly significant 63% rise in ³⁵S incorporation when compared to the normal serum.

Submitted on June 19, 1972 Revised on March 10, 1973 Accepted on March 10, 1973     

Effect of hepatic dysfunction on oral cyclosporin pharmacokinetics in marrow transplant patients

The effect of hepatic dysfunction, defined as abnormal serum bilirubin level, on oral cyclosporin (CSP) pharmacokinetics was examined in 28 marrow transplant patients who received CSP for prophylaxis of graft-v- host disease. Serum CSP concentrations were measured by radioimmunoassay. Forty-one concentration-time courses were studied, divided among patients with no (less than 1.2 mg/dL), mild (1.2 to 2.0 mg/dL), and moderate (2.0 to 5.0 mg/dL) hepatic dysfunction. CSP elimination, as determined by elimination rate constant and clearance, was delayed in patients with moderate hepatic dysfunction compared to those with no hepatic dysfunction (P less than .05). The volume of distribution, lag time for absorption, maximum serum concentration, and time at which the maximum concentration was achieved was not affected by hepatic function. These data indicate that patients with moderate hepatic dysfunction have delayed CSP or CSP metabolite elimination and may be at higher risk for developing CSP-related toxicity.     

A meta-analysis of cortical inhibition and excitability using transcranial magnetic stimulation in psychiatric disorders

ObjectiveTo evaluate transcranial magnetic stimulation (TMS) measures of inhibition and excitation in obsessive–compulsive disorder (OCD), major depressive disorder (MDD) and schizophrenia (SCZ).MethodsParadigms included: short-interval cortical inhibition (SICI), cortical silent period (CSP), resting motor threshold, intracortical facilitation, and motor evoked potential amplitude. A literature search was performed using PubMed, Ovid Medline, Embase Psychiatry and PsycINFO 1990 through April 2012.ResultsA significant Hedge’s g was found for decreased SICI (g = 0.572, 95% confidence interval [0.179, 0.966], p = 0.004), enhanced intracortical facilitation (g = 0.446, 95% confidence interval [0.042, 0.849], p = 0.030) and decreased CSP (g = ?0.466, 95% confidence interval [?0.881, ?0.052], p = 0.027) within the OCD population. For MDD, significant effect sizes were demonstrated for decreased SICI (g = 0.641, 95% confidence interval [0.384, 0.898], p = 0.000) and shortened CSP (g = ?1.232, 95% confidence interval [?1.530, ?0.933], p = 0.000). In SCZ, a significant Hedge’s g was shown for decreased SICI (g = 0.476, 95% confidence interval [0.331, 0.620], p = 0.000).ConclusionInhibitory deficits are a ubiquitous finding across OCD, MDD, SCZ and enhancement of intracortical facilitation is specific to OCD.SignificanceProvides a clear platform from which diagnostic procedures can be developed.     

Effect of bilateral median nerve excision on sciatic functional index in rat: an applicable animal model for autologous nerve grafting

Autologous nerve graft is still the treatment of choice in peripheral nerve injury when end-to-end nerve repair is not possible. The sciatic nerve is the most widely used nerve in rat experimental studies. To assess the possibility of using the rat median nerve as a delayed animal autologous nerve graft model in nerve regeneration studies, the effect of median nerve excision on the sciatic functional index (SFI) was evaluated. Thirty rats were distributed into three equal groups: in the sciatic and median nerve excision (SMNE) group, 10 mm of the right sciatic nerve was excised and 5 mm of both median nerves were excised a week later; in the median nerve excision (MNE) group, 5 mm of both median nerves were excised (both sciatic nerves remained intact); in the control group, no intervention was performed. SFI was calculated before and after each intervention. There was no significant difference between mean SFI values calculated before and after median nerve excision in SMNE (-86.8 versus -88.4, P = 0.61) and MNE groups (-3.9 versus -3.3, P = 0.93). Therefore, it may be suggested that median nerve excision does not affect SFI measurements in intact and/or completely injured sciatic nerve, which may propose the median nerve as an autologous donor nerve graft model in rats.     

Use of E mu-PIM-1 transgenic mice short-term in vivo carcinogenicity testing: lymphoma induction by benzo[a]pyrene, but not by TPA

E mu-pim-1 transgenic mice are predisposed to develop lymphomas. Due to their low spontaneous tumour incidence and their increased sensitivity towards the lymphomagen ethylnitrosourea these mice may present an interesting model for short-term carcinogenicity testing. Here, we report on the further exploration of this transgenic mouse model with two additional carcinogens known to have, among others, the lymphohaematopoietic system as target, i.e. benzo[a]pyrene (B[a]P) and 12-O-tetradecanoylphorbol-13-acetate (TPA). B[a]P, given three times a week (by gavage) for 13 weeks at 4.3, 13 or 39 mg/kg body weight, resulted in a dose-related increase in lymphomas up to a 90% incidence in E(mu)-pim-1 mice during the observation period of 40 weeks. B[a]P also induced tumours of the forestomach within this observation period, though at a lower incidence and apparently equally effective in wildtype and transgenic mice. TPA, on the other hand, was unable to induce lymphomas (or tumours in any other organ) in either transgenic or wildtype animals within the observation period of 44 weeks, when applied dermally at the maximum tolerated dose of 3 microg/mouse, twice a week for 35 weeks. Molecular analysis showed that B[a]P-induced lymphomas in transgenic mice were of T-cell origin, 80% of which had elevated levels of c-myc expression. None of the lymphomas had increased N-myc expression and mutation analysis of the ras-gene family revealed a K-ras mutation in only one out of eight tumours investigated. Also, none of the lymphomas showed aberrant expression of p53 as determined by immunohistochemistry. It is concluded that the E mu-pim-1 mouse model will not be very suitable for short-term carcinogenicity testing in general: only genotoxic chemicals that have the lymphohaematopoietic system as target for carcinogenesis in wild- type mice, appear to be efficiently identified.      

Thoracic empyema: a study of 56 patients

Fifty seven children with thoracic empyema (37 boys and 20 girls) aged less than 12 years were seen at the University of Port Harcourt Teaching Hospital between January 1989 and December 1991. Staphylococcus aureus was the most common organism isolated from the pus of these patients (36 (63%) patients). Pseudomonas aeruginosa, the next most common organism, was isolated in 10 (18%) patients. The most common symptoms at presentation were acute illness with fever and cough (51 (89%) patients). All the patients were treated with closed intercostal tube drainage and appropriate antibiotics. Decortication was resorted to in only one patient. There were two deaths and the overall survival rate was 97%.     

Effect of erythropoietic stress on donor hematopoietic cell expression in chimeric rhesus monkeys transplanted in utero.

We have previously reported the successful development of hematopoietic chimerism after the in utero transplantation of fetal hematopoietic stem cells (HSC) in rhesus monkeys (Macaca mulatta). These animals exhibit sustained engraftment without immunosuppression or graft-versus-host disease (GVHD). To assess the functional response of the donor-derived erythropoietic population, we assayed the relative expression of donor and recipient hematopoietic progenitors in chimeric monkeys before and after anemic stress. Anemia in our chimeric animals resulted in increased erythropoietin (EPO) production comparable to controls. This was accompanied by changes in erythroid progenitor profiles, again similar to controls. Chimeric animals demonstrated normal reticulocytosis and reconstituted their hematocrit after hemorrhage at the same rate as controls. The donor-derived erythropoietic population exhibited normal responses to recipient regulatory signals and did not seem to expand at the expense of other hematopoietic lineages. Thus the proportions of engraftment for the myeloid and erythroid precursors in bone marrow and for blood lymphocytes remained stable. Our results demonstrate that the in utero transplantation of fetal HSC results in stable engraftment of donor erythropoietic progenitors, which appear to be fully integrated within the recipient's regulatory system. The abnormalities reported in the postnatal transplantation setting can then be attributed to immunologic reactions requiring conditioning myeloablative regimens. Fetal transplantation bypasses all these factors.     

Inappropriate erythropoietin secretion in polycythemia vera

A patient with classical polycythemia vera (PV) was found to have an inappropriately elevated serum erythropoietin (Ep) level. Investigations did not reveal any lesion or blood abnormality known to be associated with excessive Ep production and erythrocytosis. Sudden withdrawal of blood to reduce the Hb and Hct from 18.5 gm% and 56% to 13.6 gm% and 41.5%, respectively, resulted in an increment of serum Ep to abnormal level. With iron treatment there was a brisk return of Hb and Hct to prebleeding levels which was associated with reduction in the serum Ep. The inverse relationship between the EP and Hb or Hct is inconsistent with the presence of excessive Ep-producing lesion. These results suggested that the threshold for Ep secretion from normal Ep-secreting tissue to Hb and Hct levels is set at an abnormal level. This patient's marrow cells when cultured in vitro in the absence of Ep, unlike other PV patients' (except one) marrow cells, did not grow erythroid colonies. In the presence of Ep, however, the colonies comparable to those formed from normal marrow cultures were obtained. These results suggested that his marrow erythropoietic cells were neither Ep independent nor Ep-hyperresponsive, as has been suggested by some investigators for erythropoiesis in PV. This patient presents phenomena that hitherto have not been reported.