Genomewide profiling of copy‐number alteration in monoclonal gammopathy of undetermined significance

Monoclonal gammopathy of undetermined significance (MGUS) is a benign condition with an approximate 1% annual risk of symptomatic plasma cell disorder development, mostly to multiple myeloma (MM). We performed genomewide screening of copy‐number alterations (CNAs) in 90 MGUS and 33 MM patients using high‐density DNA microarrays. We identified CNAs in a smaller proportion of MGUS (65.6%) than in MM (100.0%, P = 1.31 × 10^?5) and showed median number of CNAs is lower in MGUS (3, range 0–22) than in MM (13, range 4–38, P = 1.82 × 10^?10). In the MGUS cohort, the most frequent losses were located at 1p (5.6%), 6q (6.7%), 13q (30.0%), 14q (14.4%), 16q (8.9%), 21q (5.6%), and gains at 1q (23.3%), 2p (6.7%), 6p (13.3%), and Xq (7.8%). Hyperdiploidy was detected in 38.9% of MGUS cases, and the most frequent whole chromosome gains were 3 (25.6%), 5 (23.3%), 9 (37.8%), 15 (23.3%), and 19 (32.2%). We also identified CNAs such as 1p, 6q, 8p, 12p, 13q, 16q losses, 1q gain and hypodiploidy, which are potentially associated with an adverse prognosis in MGUS. In summary, we showed that MGUS is similar to MM in that it is a genetically heterogeneous disorder, but overall cytogenetic instability is lower than in MM, which confirms that genetic abnormalities play important role in monoclonal gammopathies.     

A Hodgkin cell-specific antigen is expressed on a subset of auto- and alloactivated T (helper) lymphoblasts

A Hodgkin cell-specific antigen detected by the monoclonal antibody Ki- 1 was found on T helper lymphocytes after activation by autologous and allogeneic stimulator cells. About 50% of lymphoblasts generated by auto- and alloactivation reacted with the antibody. In contrast, only less than 6% of lymphoblasts stimulated with Con-A, phytohemagglutinin (PHA), or protein A, and none of lymphoblasts activated by oxidative mitogenesis, expressed this antigen. Among several permanent cell lines tested, the K562, MOLT-4, HL-60, and EBV transformed B lymphoblastoid cells reacted with the Ki-1 antibody. The results may indicate possible relationships between the autoreactive subset of T lymphocytes and the pathogenesis of Hodgkin's disease.     

Preoperative pulmonary assessment of the older adult

Postoperative pulmonary complications in the elderly are common and are a significant source of morbidity, mortality, and prolonged length of stay. Risk factors differ from the well-known risk factors for cardiac complications and can be divided into patient- and procedure-related factors. Patient-related factors include COPD, recent cigarette use, poor general health status as defined by Goldman or ASA class, dependent functional status, and laboratory parameters including abnormal chest radiograph, renal insufficiency, and low serum albumin. Age is a minor risk factor when adjusted for comorbidities and confers approximately a two-fold increase in risk. Elderly patients who are otherwise acceptable surgical candidates should not be denied surgery based solely on age and concern for postoperative pulmonary complications. The surgical site is the single most important predictor of pulmonary complications. High-risk surgeries include thoracic, upper abdominal, aortic, neurosurgery, and peripheral vascular. Other procedure-related risk factors include surgery lasting longer than 3 hours, the use of general anesthesia, pancuronium use, and emergency surgery. Clinicians should not recommend routine preoperative spirometry before high-risk surgery because it is no more accurate in predicting risk than clinical evaluation. Patients who might benefit from preoperative spirometry include those who have unexplained dyspnea or exercise intolerance and those who have COPD or asthma in whom uncertainty exists as to the status of airflow obstruction when compared with baseline. After identifying patients at risk for postoperative pulmonary complications, clinicians can recommend strategies to reduce risk throughout the operative period. In addition to minimizing or avoiding the above risk factors, optimization of COPD or asthma, deep breathing exercises, incentive spirometry, and epidural local anesthetics reduce the risk of postoperative pulmonary complications in elderly surgical patients.     

Abnormal function of the bone marrow microenvironment in chronic myelogenous leukemia: role of malignant stromal macrophages

The bone marrow microenvironment supports and regulates the proliferation and differentiation of hematopoietic cells. Dysregulated hematopoiesis in chronic myelogenous leukemia (CML) is caused, at least in part, by abnormalities in CML hematopoietic progenitors leading to altered interactions with the marrow microenvironment. The role of the microenvironment itself in CML has not been well characterized. We examined the capacity of CML stroma to support the growth of long-term culture-initiating cells (LTC-IC) obtained from normal and CML marrow. The growth of normal LTC-IC on CML stroma was significantly reduced compared with normal stroma. This did not appear to be related to abnormal production of soluble factors by CML stroma because normal LTC- IC grew equally well in Transwells above CML stroma as in Transwells above normal stroma. In addition, CML and normal stromal supernatants contained similar quantities of both growth-stimulatory (granulocyte colony-stimulating factor (CSF), interleukin-6, stem cell factor, granulocyte-macrophage CSF, and interleukin-1 beta) and growth- inhibitory cytokines (transforming growth factor-beta, macrophage inflammatory protein-1 alpha, and tumor necrosis factor-alpha). The relative proportion of different cell types in CML and normal stroma was similar. However, polymerase chain reaction and fluorescence in situ hybridization studies showed the presence of bcr-abl-positivo cells in CML stroma, which were CD14+ stromal macrophages. To assess the effect of these malignant macrophages on stromal function, CML and normal stromal cells were separated by fluorescence-activated cell sorting into stromal mesenchymal cell (CD14-) and macrophage (CD14+) populations. CML and normal CD14- cells supported the growth of normal LTC-IC equally well. However, the addition of CML macrophages to normal or CML CD14- mesenchymal cells resulted in impaired progenitor support. This finding indicates that the abnormal function of CML bone marrow stroma is related to the presence of malignant macrophages. In contrast to normal LTC-IC, the growth of CML LTC-IC on allogeneic CML stromal layers was not impaired and was significantly better than that of normal LTC-IC cocultured with the same CML stromal layers. These studies demonstrate that, in addition to abnormalities in CML progenitors themselves, abnormalities in the CML marrow microenvironment related to the presence of malignant stromal macrophages may contribute to the selective expansion of leukemic progenitors and suppression of normal hematopoiesis in CML.     

Management of tandem occlusions in patients who receive rtPA

Journal of Thrombosis and Thrombolysis - Tandem occlusions exist in 17–32% of large vessel occlusion (LVO) strokes. A significant concern is bleeding when carotid stenting is performed in...     

Nucleoli in cells of the granulopoietic proliferating compartment in patients suffering from the refractory anemia of the myelodysplastic syndrome

Granulocytic precursors of the granulopoietic proliferating compartment (GPC) were investigated in patients suffering from refractory anemia (RA) of myelodysplastic syndrome (MDS) to provide an information on the number of nucleoli and incidence of main nucleolar types in these cells stained with the simple cytochemical procedure for the demonstration of RNA. The results demonstrated that the incidence of main nucleolar types in all stages of the granulopoietic proliferating compartment in RA patients of MDS generally did not differ in comparison with that of control patients without a disturbed granulopoiesis. In contrast, the number of nucleoli expressed by the values of the nucleolar coefficient in all stages of GPC in RA patients was significantly smaller than in control persons. In addition, the values of the nucleolar coefficient of myeloblasts in patients with RA of MDS were close to those in patients with acute myeloid leukemias.     

A note on nucleoli in granulocytic precursors of the granulopoietic proliferating compartment in patients suffering from the chronic phase of chronic myeloid leukemia treated with two different drugs with different mode of action

The incidence of main nucleolar types in granulocytic precursors was studied in the granulopoietic proliferating compartment (GPC) of patients suffering from chronic phase of the chronic myeloid leukemia (CML) who were treated by the widely used therapy with two different drugs with different mode of action - hydroxyurea (HU) and interferon alpha (IFN-alpha). In comparison with IFN early stages of GPC, i.e. myeloblasts and promyelocytes in patients treated with HU possessed more frequently micronucleoli which are known to reflect the direct as well as indirect inhibition of the nucleolar biosynthetic activities. On the other hand, the incidence of micronucleoli in these cells of a small percentage of patients treated with IFN also reached the average values of these nucleoli which were noted in patients treated with HU.     

A further study on the number of silver stained granules of active nucleolus organizer regions in mitotic Yoshida and Zajdela rat experimental tumor cells

Yoshida ascitic sarcoma and Zajdela ascitic hepatoma were investigated in Norway rats to provide more information on active nucleolus organizer regions (NORs) represented by silver stained granules (SSGs). Diploid Yoshida sarcoma cells were characterized by the presence of 6 (3 doublets) of SSGs in the metaphase and 3 + 3 SSGs in future daughter nuclei in the anaphase or telophase. In contrast Zajdela hepatoma cells (frequently hypoploid) possessed 6 SSGs less frequently in the metaphase and the number of anaphasic or telophasic cells with 3 SSGs in future daughter nuclei was also reduced. The number of SSGs in future nuclei of anaphasic or telophasic Yoshida sarcoma cells was usually the same, i.e. such anaphases or telophases were symetric. In Zajdela hepatoma cells the number of symetric anaphases and telophases was substantially reduced in favor of asymetric anaphases or telophases which contained different number of SSGs in future nuclei.     

The effect of three human recombinant hematopoietic growth factors (granulocyte-macrophage colony-stimulating factor, granulocyte colony- stimulating factor, and interleukin-3) on phagocyte oxidative activity

Hematopoietic growth factors not only modulate blood progenitor cell activity but also alter the function of mature phagocytes. Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; 1 ng/mL for 60 min) did not stimulate luminol-enhanced chemiluminescence of polymorphonuclear leukocytes (PMNs) in suspension but primed PMN for as much as a 15-fold increase in chemiluminescence in response to f-met- leu-phe (fMLP). Mixed mononuclear leukocytes (monocytes [approximately 20%] and lymphocytes [approximately 80%]; MNL) chemiluminescence was very low even after rhGM-CSF priming, but MNLs added to the PMNs (PMN- MNL) resulted in near doubling of rhGM-CSF-primed PMN fMLP-stimulated chemiluminescence. The enhancing factor(s) from MNLs were inherent rather than induced by the GM-CSF, and purified lymphocytes increased GM-CSF-primed PMN chemiluminescence equal to mixed MNLs. We could not detect cell-free "enhancing factor(s)," but cell-to-cell contact further enhanced rhGM-CSF-primed fMLP-stimulated PMN-MNL oxidative activity by 40%. Polyclonal rabbit anti-tumor necrosis factor (TNF) (but not preimmune serum) decreased both fMLP-stimulated rhGM-CSF- primed PMNs and PMN-MNL chemiluminescence, suggesting that TNF on the PMN surface is enhancing GM-CSF-primed chemiluminescence. GM-CSF priming markedly increased PMN superoxide release (sevenfold), but PMN superoxide release was not further enhanced by the presence of MNLs. Recombinant human granulocyte colony-stimulating factor (rhG-CSF) and interleukin-3 (rhIL-3) displayed much smaller effects on pure PMNs and mixed PMN-MNL chemiluminescence and superoxide release than rhGM-CSF. rhGM-CSF primes PMNs for increased oxidative activity more than rhG-CSF and rhIL-3. Maximal oxidative activity was observed when mixed PMN-MNL were primed with GM-CSF in a cell pellet-promoting cell-to-cell contact. This enhanced activity can be attributed, in part, to both inherent enhancing factor(s) on lymphocytes and PMN-associated TNF induced by GM-CSF.