Rheologic predictors of the severity of the painful sickle cell crisis

Deformable sickle erythrocytes have been reported by Mohandas and Evans to be more adherent to vascular endothelium than rigid irreversibly sickled cells (ISC). To define the clinical implications of this finding we have determined genetic, hematological, clinical, and rheological characteristics of sickle erythrocytes obtained from 65 patients with sickle cell anemia and fetal hemoglobin (Hb F) levels less than 15%. The alpha-globin gene number had a significant effect on the hematological parameters, the percentage of dense cells, ISC number, and HB A2 levels. The presence or absence of alpha thalassemia, however, had no effect on the frequency and severity of the sickle cell painful crisis (r = 0.06, P greater than .05). RBC deformability, determined by an ektacytometer, showed great heterogeneity among patients with three or four alpha-globin genes. Linear regression analyses of the data showed significant positive correlation of the frequency and severity of the painful crisis with RBC deformability (r = 0.49, P less than .001), and negative correlations with the percentage of dense cells (r = -0.37, P = .002), and the percentage of ISC (r = -0.46, P less than .001). We propose that the more deformable the sickle RBC are, the greater their adherence to vascular endothelium, and the more they cause vaso-occlusive crises, RBC deformability and the percentage of dense cells (or ISC) seem to have a predictive value of the frequency and severity of painful crises in sickle cell anemia.     

Sustained, retransplantable, multilineage engraftment of highly purified adult human bone marrow stem cells in vivo

Data from many laboratory and clinical investigations indicate that CD34+ cells comprise approximately 1% of human bone marrow (BM) mononuclear cells, including the progenitor cells of all the lymphohematopoietic lineages and lymphohematopoietic stem cells (stem cells). Because stem cells are an important but rare cell type in the CD34+ cell population, investigators have subdivided the CD34+ cell population to further enrich stem cells. The CD34+/CD38- cell subset comprises less than 10% of human CD34+ adult BM cells (equivalent to < 0.1% of marrow mononuclear cells), lacks lineage (lin) antigens, contains cells with in vitro replating capacity, and is predicted to be highly enriched for stem cells. The present investigation tested whether the CD34+/CD38- subset of adult human marrow generates human hematopoiesis after transfer to preimmune fetal sheep. CD34+/ CD38- cells purified from marrow using immunomagnetic microspheres or fluorescence-activated cell sorting generated easily detectable, long- term, multilineage human hematopoiesis in the human-fetal sheep in vivo model. In contrast, transfer of CD34+/CD38+ cells to preimmune fetal sheep generated only short-term human hematopoiesis, possibly suggesting that the CD34+/CD38+ cell population contains relatively early multipotent hematopoletic progenitor cells, but not stem cells. This work extends the prior in vitro evidence that the earliest cells in fetal and adult human marrow lack CD38 expression. In summary, the CD34+/ CD38- cell population has a high capacity for long-term multilineage hematopoietic engraftment, suggesting the presence of stem cells in this minor adult human marrow cell subset.     

Temporary cardiac pacing using a new, steerable, balloon-tipped pacing catheter

A new balloon-tipped, flow-directed, steerable pacing catheter for unipolar temporary ventricular pacing is presented. It was successfully and uneventfully tested in 25 patients with acute myocardial infarction in the coronary care unit. The main advantage of the new catheter is the ease with which a stable contact may be achieved between the pacing electrode and the endocardium.     

Bereavement-related depression in the older adult population: A distinct disorder?

Background

Bereavement is a phenomenon that shares many symptoms with depression, and that a great number of older adults experience following the loss of a close relative. The objectives of the present study were to (1) determine whether the symptoms of depression reported by bereaved individuals differ from those with non-bereavement minor/major depression (NBRD), (2) assess whether BRD is as persistent during a one year follow-up as compared to NBRD, and (3) identify factors and consequences associated with BRD.

Methods

The data used for this study came from the Longitudinal Study ESA (Study Health of Elders), conducted between 2005 and 2008, using a representative sample (n=2811) of community-dwelling older adults, aged 65 and over. To test our hypothesis, an exploratory latent class analysis and multivariate logistic regression were used.

Results

BRD prevalence among older adults suffering from depression was 39%. BRD individuals report all symptoms of depression, but in lower probabilities, and BRD is as persistent as MDD over 12 months, suggesting that it does not differ from NBRD. The principal factors associated with BRD were widowhood and lower level of education. Individuals with BRD are less likely to consult medical services and be dispensed an antidepressant, compared to NBRD.

Limitations

We have to be cautious when generalizing our findings to individuals with major depression alone, since our results included both minor and major depressions in the same group.

Conclusion

No evidence was found that BRD differed from non BRD in terms of depressive symptoms and persistence. The bereavement exclusion criterion in the DSM-IV should be reconsidered.     

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.     

Recurrence of aplastic anemia following cyclophosphamide and syngeneic bone marrow transplantation: evidence for two mechanisms of graft failure

Two patients with aplastic anemia were treated with high-dose cyclophosphamide and marrow transplantation from their normal, genetically identical twin. Both patients rapidly recovered normal marrow function, but marrow failure recurred 13 and 18 months later. Because donor and host pairs were identical twins, these cases of graft failure could not have resulted from the usual cause of graft failure, ie, immunological reactivity of host cells against unshared minor histocompatibility antigens of the donor. These results imply that there are at least two mechanisms responsible for graft failure after marrow transplantation for severe aplastic anemia.     

Circulating angiogenic biomolecules at rest and in response to upper-limb exercise in individuals with spinal cord injury

Objective

Individuals with spinal cord injury (SCI) show structural and functional vascular maladaptations and muscle loss in their lower limbs. Angiogenic biomolecules play important roles in physiological and pathological angiogenesis, and are implicated in the maintenance of muscle mass. This study examined the responses of angiogenic molecules during upper-limb aerobic exercise in patients with SCI and in able-bodied (AB) individuals.

Methods

Eight SCI patients with thoracic lesions (T₆–T₁₂, ASIA A) and eight AB individuals performed an arm-cranking exercise for 30 minutes at 60% of their VO_2max. Plasma concentrations of vascular endothelial growth factor (VEGF-A₁₆₅), VEGF receptor 1 (sVEGFr-1), VEGF receptor 2 (sVEGFr-2), metalloproteinase 2 (MMP-2), and endostatin were measured at rest, after exercise, and at 1.5 and 3.0 hours during recovery.

Results

The two-way analysis of variance showed non-significant main effects of “group” and significant main effects of “time/exercise” for all angiogenic biomolecules examined (P < 0.01–0.001). The arm-cranking exercise significantly increased plasma concentrations of VEGF, sVEGFr-1, sVEGFr-2, MMP-2, and endostatin in both groups (P < 0.001–0.01). The magnitude of the increase was similar in both patients with SCI and AB individuals, as shown by the non-significant group × time interaction for all angiogenic parameters.

Conclusions

Upper-limb exercise (arm-cranking for 30 minutes at 60% of VO_2max) is a sufficient stimulus to trigger a coordinated circulating angiogenic response in patients with SCI. The response of angiogenic molecules to upper-limb aerobic exercise in SCI appears relatively similar to that observed in AB individuals.     

Endoscopic sphincterotomy in patients with "acalculus" cholangitis associated with juxtapapillary diverticula

BACKGROUND/AIMS: The aim of this study was to investigate patients who underwent endoscopic sphincterotomy for "acalculus" cholangitis associated with juxtapapillary diverticula. METHODOLOGY: In a retrospective study we analyzed 87 patients who underwent endoscopic sphincterotomy for cholangitis; the cholangitis considered "acalculus", when outlining the extra- and intrahepatic bile ducts, we could not observe any intraluminal defect or stricture, and during the clearing of the bile ducts with the balloon, after endoscopic sphincterotomy, there was no evidence of stones, fragments of stones or sludge. Patients who had undergone previous endoscopic sphincterotomy, or who had additional pancreatobiliary diseases were excluded from this study. There were 11 patients with "acalculus" cholangitis associated with juxtapapillary diverticula, and sufficient clinical data available for this study. RESULTS: Nine patients presented pain, fever, and jaundice. In two patients diagnosis was established via the test of abnormal liver biochemistry. Seven patients had positive blood cultures and three of them developed confusion and hypotension. Endoscopic sphincterotomy succeeded in all cases; no evidence of stones, fragments of stones or sludge was recorded during the clearing of bile ducts, after endoscopic sphincterotomy, with the balloon. Five patients presented mild post-endoscopic sphincterotomy complications successfully treated. In the follow-up period, from 4 months to 7 years after endoscopic sphincterotomy, none of the patients developed symptoms of cholangitis. CONCLUSIONS: We recommend endoscopic sphincterotomy in patients with "acalculus" cholangitis associated with juxtapapillary diverticula, despite the absence of obvious obstruction, and the possible morbidity which is inherent with an invasive procedure like endoscopic sphincterotomy.     

The effects of recombinant-DNA-derived interferons on the growth of myeloid progenitor cells

Interferons (IFNs) have been shown to have significant effects on hematopoietic cell growth. Previous studies defining these effects have utilized mouse and human alpha-, beta-, and gamma-IFN isolated from supernatants of stimulated cells. Despite purification, the possible presence of other lymphokines and soluble factors remains a concern. In this study, the effects of gene-cloned alpha- and gamma-IFN on colony- forming units of granulocyte/macrophage (CFU-GM) progenitors cultured from the peripheral blood of normal volunteers were examined. In addition, blast cell colonies from one patient with acute myelogenous leukemia (AML) were studied. The growth of normal CFU-GM and AML blast cell colonies was inhibited in a dose-dependent manner by gamma- and alpha-IFN. gamma-IFN was ten to 100 times more potent than alpha-IFN in that this species of IFN reduced colony formation by greater than 50% at concentrations of less than 15 antiviral U/mL. The effects of gamma- IFN were neutralized by a monoclonal antibody specific for gamma-IFN. These in vitro studies indicate that human gamma-IFN may be an important modulator of myelopoiesis. Although these data indicate a possible efficacy of gamma-IFN in the treatment of AML, the in vitro results should be considered for their in vivo significance.