Human cytomegalovirus increases constitutive production of interleukin- 6 and leukemia inhibitory factor by bone marrow stromal cells

Human cytomegalovirus (CMV) infection is often associated with myelosuppression and acute inflammatory reaction in immunocompromised patients. We have previously documented that CMV exposure of bone marrow (BM) stromal cells reduces the capacity of these cells to support hematopoiesis because of a decreased production of colony- stimulating factors. This study examines the potential role of CMV on constitutive and lipopolysaccharide (LPS)-stimulated production of cytokines involved in inflammatory reaction, interleukin-6 (IL-6) and leukemia inhibitory factor (LIF) by BM stromal cells. The release of IL- 6 was already detectable 2 hours post CMV-infection (2.5-fold increase in production) and the cumulative production of IL-6 after 5 days of infection was 23 +/- 1.2 ng/mL (ninefold increase in production). CMV was also able to induce a time-dependent production of LIF that was maximal 8 hours after CMV infection (2.5-fold increase in production). Concomitantly, there was no detectable release of granulocyte colony- stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) by CMV-infected stromal cells. The similar IL-6 and LIF production in the presence of polymyxin B ruled out the possibility that this increase could be caused by contamination of the viral stock by endotoxin. In addition, ultraviolet-inactivated virus behaved similarly to live virus and caused the release of IL-6 and LIF. However, heat-inactivated CMV was unable to induce IL-6 and LIF secretion by BM stromal cells. The production of IL-6 and LIF was also evaluated after stimulation by LPS. After 5 days of CMV exposure, the LPS-stimulated production of IL-6 and LIF was significantly lower than uninfected controls. This LPS-induced release of cytokine production was found to be dependent of viral replication. The experiments have shown that CMV is a potent inducer of IL-6 and LIF with differential effect on constitutive and LPS- stimulated cytokine production by stromal cells; we suggest that CMV induction of IL-6 and LIF during the first hours of infection could play a role in CMV-induced inflammatory reaction. Moreover, our results show that human CMV can disturb the balanced cytokine network involved in the regulation of hematopoiesis.     

Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicenter study

A phase III prospective randomized multicenter study was performed to determine whether quinine could improve the response rate of poor-risk acute leukemias (ALs) to standard chemotherapy including a multidrug resistance (MDR)-related cytotoxic agent. The rationale of the study was based on the negative prognostic value of MDR phenotype in ALs and the ability of quinine to reverse this phenotype both in vitro and ex vivo. Three hundred fifteen patients (median age, 49 years; range, 16 to 65) with relapsed (n = 108) or refractory (n = 32) acute myeloblastic leukemia (AML), relapsed (n = 27) or refractory (n = 9) acute lymphoblastic leukemia (ALL), secondary AL (n = 22) or blastic transformation of myelodysplastic syndrome ([MDS] n = 74) or myeloproliferative syndrome ([MPS] n = 43) were randomly assigned to receive mitoxantrone ([MXN] 12 mg/m2/d, days 2 to 5) and cytarabine ([Ara-C] 1 g/m2/12 h, days 1 to 5) alone or in combination with quinine (30 mg/kg/d, days 1 to 5; continuous intravenous infusion beginning 24 hours before MXN infusion). Side effects of quinine were observed in 56 of 161 quinine-treated patients and disappeared in all but four cases after one or two 20% dose decreases. Sera from quinine-treated patients showed increased MXN uptake in an MDR-positive cell line compared with matched sera obtained before quinine infusion. Quinine induced a significant increase in the incidence of nausea, vomiting, mucositis, and cardiac toxicity. A complete response (CR) was observed in 85 of 161 patients (52.8%) from the quinine-treated group versus 70 of 154 patients (45.5%) in the control group (P = .19). The most important differences between quinine and control group CR rates were observed in patients with refractory AMLs and blastic transformation of MDS and MPS. The CR rate was higher in P-glycoprotein-positive cases, although the difference was not significant. Failure of the regimen due to blastic persistence or blast number increase was higher in the control group (61 of 154 patients) than in the quinine group (45 of 161, P = .04). Early death was observed in eight cases (four in each arm) and death in aplasia in 27 cases (20 in quinine group v seven in control group, P = .01). The significant increase of toxicity in the quinine arm could have masked the clinical benefit of MDR reversion in poor- risk ALs.     

Pet in the therapy room: An attachment perspective on Animal-Assisted Therapy

John Bowlby's (1973 Bowlby, J. 1973. Attachment and loss: Vol. 2. Separation: Anxiety and anger, New York, NY: Basic Books. [Crossref] , [Google Scholar], 1980 Bowlby, J. 1980. Attachment and loss: Vol. 3. Sadness and depression, New York, NY: Basic Books.  [Google Scholar], 1982 Bowlby, J. 1982. Attachment and loss: Vol. 1. Attachment, New York, NY: Basic Books. Original work published 1969 [Google Scholar]) attachment theory is one of the most influential theories in personality and developmental psychology and provides insights into adjustment and psychopathology across the lifespan. The theory is also helpful in defining the target of change in psychotherapy, understanding the processes by which change occurs, and conceptualizing cases and planning treatment (Daniel, 2006 Daniel, S. I.F. 2006. Adult attachment patterns and individual psychotherapy: A review. Clinical Psychology Review, 26: 968–984. [Crossref], [PubMed], [Web of Science ®] , [Google Scholar]; Obegi & Berant, 2008 Obegi, J. H. and Berant, E. 2008. Attachment theory and research in clinical work with adults, New York, NY: Guilford Press.  [Google Scholar]; Sable, 2004 Sable, P. 2004. Attachment, ethology, and adult psychotherapy. Attachment & Human Development, 6: 3–19. [Taylor & Francis Online], [Web of Science ®] , [Google Scholar]; Wallin, 2007 Wallin, D. J. 2007. Attachment in psychotherapy, New York, NY: Guilford Publications.  [Google Scholar]). Here, we propose a model of Animal-Assisted Therapy (AAT) based on attachment theory and on the unique characteristics of human–pet relationships. The model includes clients' unmet attachment needs, individual differences in attachment insecurity, coping, and responsiveness to therapy. It also suggests ways to foster the development of more adaptive patterns of attachment and healthier modes of relating to others.     

Cardiovascular responses to family visits in coronary care unit patients.

Changes in four cardiovascular indicators: systolic blood pressure, diastolic blood pressure, heart rate, and premature ventricular contractions, were studied as responses to family visits and a 10-minute interview with the investigator in 24 patients in a coronary care unit. By use of a repeated-measures design, data were compared by multivariate analysis of variance. No significant differences were found between the group mean systolic and diastolic blood pressure, heart rate, and rate of premature ventricular contractions during family visits and interviews. The lowest systolic and diastolic blood pressure values were significantly lower during the visit than during the interview, suggesting that the visit had a calming effect on patients. Although the highest heart rate was significantly higher during the visit than during the interview, the difference was clinically inconsequential. The wide variance in premature ventricular contraction values suggests individual variation in responses, but no significant differences were found between visits and interviews. Although family visits were no more physiologically stressful than a comparative social interaction, select subsamples of patients with cardiac disease should be studied for more specific reaction patterns.     

Atrial septal defect: attenuation of respiratory variation in systolic and diastolic time intervals

The effects of pathologic states on right and left ventricular function have been studied extensively. However, there have been few studies on the interrelations between right and left ventricular function in normal human subjects and in patients with disease. Respiratory effects on ventricular interrelations reflected by diastolic time, right or left ventricular systolic time and ventricular performance (pre-ejection period/ejection time ratio) were studied in 12 normal subjects and 15 patients with a normal pressure-large shunt atrial septal defect. Simultaneous pulmonary artery (intracardiac manometer recordings) and left ventricular external recordings were performed in both groups. Left ventricular diastolic time increased with inspiration in the normal subjects and decreased in the patients with atrial septal defect (12.6 +/- 2.39 [1 SE] versus -13.4 +/- 3.48 ms, p less than 0.001). Left ventricular systolic time and ejection time decreased with inspiration in the normal group and remained unchanged in the patient group (-7.6 +/- 0.95 versus -0.9 +/- 0.77 ms, p less than 0.001 and -10.4 +/- 1.09 versus -1.7 +/- 0.80 ms, p less than 0.001, respectively). Left ventricular pre-ejection period/ejection time ratio increased with inspiration in the normal subjects and remained unchanged in the patients with atrial septal defect (0.03 +/- 0.008 versus 0 +/- 0.01, p less than 0.01). Right ventricular diastolic time decreased with inspiration in normal and patient groups (-8.8 +/- 1.6 versus -17 +/- 3.87 ms).(ABSTRACT TRUNCATED AT 250 WORDS)     

Liver-derived fetal hematopoietic stem cells selectively and preferentially home to the fetal bone marrow

In the course of ontogeny, the homing site for the hematopoietic stem cells (HSC) moves with certain predictability from the yolk sac to the liver/spleen and then to the marrow. The pattern of this migration has thus far been established mostly on a morphologic basis. To delineate further the course of this migration and to gain insight into its possible mechanism, we used in utero transplantation of allogeneic or xenogeneic HSC in preimmune sheep fetuses. Sex chromosome, type of hemoglobin, and species-specific surface markers were used to follow the path of transplanted cells in the fetus. Before the development of the bone marrow, transplanted HSC (liver- or marrow-derived) homed exclusively to the liver/spleen. With the development of marrow, around day 60 of gestation (term, 145 days), homing occurred also in the nascent marrow and by day 80 transplanted cells homed exclusively to the marrow. This suggests that there may be a hierarchy in homing sites, with those of the marrow having higher affinity than those of liver/spleen. Interestingly, despite a change in homing that was followed by the expansion of the marrow compartment of HSC (ie, HSC proliferation), these cells did not participate actively in blood cell formation during most of the prenatal period. Liver remained the major hematopoietic organ throughout the gestation. It was only during the perinatal period that this organ assumed the function of hematopoiesis from the liver. This lack of expression of HSC in fetal marrow can possibly be attributable to the immaturity of marrow stroma required for differentiation and maturation of progenitors and the orderly egress of mature cells into the blood stream. The availability of this model allows us to begin studies in the molecular mechanism of stem cell homing in vivo during ontogeny.     

Autologous bone marrow transplantation for acute myeloid leukemia using busulfan plus etoposide as a preparative regimen

We have studied the use of a new preparative regimen for the treatment of patients in remission of acute myeloid leukemia (AML) with autologous bone marrow transplantation. Chemotherapy consisted of busulfan 1 mg/kg every 6 hours for 4 days (total dose, 16 mg/kg) on days -7 through -4 followed by an intravenous infusion over 6 to 10 hours of etoposide 60 mg/kg on day -3. Autologous bone marrow, treated in vitro with 100 micrograms/mL of 4-hydroperoxycyclophosphamide, was infused on day 0. We have treated 58 patients up to the age of 60 years, 32 in first remission, 21 in second or third remission, and 5 with primary refractory AML unresponsive to high-dose Ara-C, but achieving remission with aggressive salvage regimens. Of the first remission patients, there has been 1 treatment related death and 5 relapses. With median follow-up of 22 months, the actuarial relapse rate is 22% +/- 9% and disease-free survival is 76% +/- 9% at 3 years. Patients with favorable French-American-British (FAB) subtypes (M3 or M4 EO) did especially well, with no relapses seen in 15 patients observed for a median of 30 months. Actuarial relapse rate at 3 years was 48% for first remission patients with less favorable FAB subtypes. Of patients in second or third remission, there were 5 treatment related deaths and 4 relapses. With median follow-up of 22 months, the actuarial relapse rate is 25% +/- 11% and disease-free survival is 56% +/- 11% at 3 years. Four of five primary refractory patients died during treatment and 1 remains in remission with short follow-up. These preliminary data are very encouraging and, if confirmed, support the use of autologous purged bone marrow transplantation using aggressive preparative regimens as one approach to improve the outcome of adults with AML.     

Individual cell-by-cell quantitation of lymphocyte surface membrane Ig in normal and CLL lymphocyte and during ontogeny of mouse B lymphocytes by immunoperoxidase assay

A new quantitative immunoperoxidase method is presented for determining absolute amounts of peroxidase and, consequently, surface antigen densities of individual cells in B lymphocytes from normal individuals, from subjects with CLL and prolymphocytic leukemia, and during ontogeny of B lympocytes in the mouse. The following results were observed: (1) The density of B antigenic sites were lower on CLL than on normal B lymphocytes. (2) The B antigens density of leukemic lymphocytes varied less from cell to cell, forming a homogeneous peak on histograms. (3) In a very rare case of CLL, the antigen density was measured at the time of initial diagnosis (22,500 sites or 647 U) and during the development of a blastic crisis (135,000 sites or 2576 U). The cell by cell distribution changed from a homogeneous peak with a low number of antigenic sites per cell to a heterogeneous peak with a high number of antigenic sites per cell. (4) In prolymphocytic leukemia, the density of B antigenic sites was greater than on normal B lymphocytes and much more heterogeneous than on CLL lymphocytes. (5) During ontogeny of B lymphocytes in the mouse, maturation is associated with the appearance of a population of cells of intermediate to high Smig density. The finding of a decrease in, and altered distribution of, surface markers in CLL is compared with these ontologic findings in the mouse, and the concept that a monoclonal B lymphocyte in CLL may be arrested at a particular stage in its differentiation is discussed.