Hematopoietic growth factors and transfusion medicine

Some children with severe motor disorders have unintelligible speech, and may be recommended augmentative communication systems, such as a symbol chart or a voice output aid. The paper reports the outcome after 15-18 months for 35 children of recommendations for augmentative communication. Using structured questionnaires, parents were asked whether equipment was provided as recommended. Their perception of success in children's use of augmentative aids was recorded and related to potentially influential factors. Twenty-five symbol systems, 10 speech output devices and 11 switches were received; 18 symbol systems were used for communication and 10 were used frequently. Seven speech output devices were used for communication but only two were reported to be used frequently. Factors leading to more successful outcomes include early receipt of the aid, perceived adequate local training in the use of the aid, and children aged 6 years or more at initial assessment. The findings also suggest that referring professionals will need to be better informed about the nature and limitations of augmentative communication aids, and that improved local professional input and careful interagency planning and co-ordination are required to achieve optimal outcome.     

The use of hematopoietic growth factors in treating HIV infection

Human immunodeficiency virus infection causes multilineage hematopoietic defects. Defects in the production and function of CD4+ helper cells have been the focus of the majority of HIV research, but anemia, neutropenia, and thrombocytopenia are significant clinical problems as well. Bone marrow suppression is the dose-limiting toxicity for a number of antiviral and prophylactic medications. Hematopoietic growth factors such as granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor are used to optimize the delivery of antiretroviral and prophylactic therapy. Because of the expense involved, the most appropriate use of these hematopoietic growth factors remains a subject of intense investigation. This review focuses on recent experimental results.     

Standardization of the CFU-GM assay using hematopoietic growth factors

BACKGROUND: The recently discovered LRP protein has been shown to be involved in drug resistance and possibly in detoxification processes. MATERIALS AND METHODS: To study the relation between LRP expression and exposure to cigarette smoke, LRP immunoreactivity was evaluated in 39 paraffin embedded normal lung tissues derived from patients operated on for pneumothorax, and related to amount of pack years smoked. We also studied the LRP protein expression in 36 non-small-cell lung cancer (NSCLC) samples and related the expression to patient characteristics and survival. Furthermore 17 lung tumor samples (10 NSCLC and 7 SCLC) derived from patients treated with chemotherapy were analysed in order to investigate the relation between LRP or MRP expression and the patient's response to chemotherapy. RESULTS: In the normal lung tissues, LRP intensity levels were not correlated to the amount of pack years smoked, although a trend was seen for higher LRP intensity levels in patients who smoked more than 10 pack years. LRP expression was significantly higher in NSCLC samples than in SCLC samples, and all SCLC samples displayed very low LRP expression. Within NSCLC, squamous cell and adenocarcinomas had higher LRP expression than large cell undifferentiated and mixed tumors. In NSCLC patients LRP expression was not a prognostic factor for survival. At initial analysis LRP expression levels did not predict for the response to chemotherapy. Only 3 out of 17 patients expressed MRP, and all SCLC samples were MRP negative. CONCLUSIONS: Striking different expression levels were seen between NSCLC and SCLC for both LRP and MRP. In a preliminary analysis LRP expression was not predictive for response to chemotherapy in lung cancer patients. In pneumothorax patients LRP levels were not correlated with the amount of pack years smoked.     

Mathematical calculations in transfusion medicine

This article provides simple mathematical formulas for approximating values such as blood volume, red cell mass, and plasma volume. Additionally, other useful formulas and examples are given to estimate increments in hemoglobin, platelets, and factor VIII levels following the transfusion of blood components.     

Lack of effect of hematopoietic growth factors on human breast epithelial cell growth in serum-free primary culture

A number of recombinant cytokines believed to regulate normal hematopoiesis are now being used in cancer treatment protocols to reduce the myelosuppressive toxicity of intensive chemoradiotherapy regimens. It is widely assumed that such cytokines are relatively specific for hematopoietic cells, although some cell lines derived from a variety of non-hematopoietic human tumors can respond to some of these factors. However, relatively little is known about their ability to stimulate (or inhibit) the proliferation of freshly isolated normal or malignant non-hematopoietic cells. We have used a serum-free culture medium that selectively supports the growth of human breast epithelial cells (HBEC) obtained directly from normal or malignant tissue samples to evaluate potential stimulatory or inhibitory effects of eight cytokines: granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, Steel factor, interleukin-2, interleukin-3, interleukin-6, transforming growth factor-beta and macrophage inflammatory protein-1 alpha, on these cells cultured both in the presence of epidermal growth factor, a potent stimulator of HBEC growth, and in its absence. HBEC growth was assessed after 7 and 14 days using the tetrazolium-dye reduction assay. Potential effects on the well studied MCF-7 breast cancer cell line, cultured under the same conditions, were also investigated. None of the cytokines (which were tested over a wide range of concentrations) had any modulating effect on the growth of normal or malignant HBEC under the conditions used with the exception of transforming growth factor-beta, which was consistently and significantly inhibitory.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of growth factors in mesangial cell ion channel regulation

Our single channel work has characterized two ion channels capable of depolarizing mesangial cells and activating classic, voltage-activated Ca2+ channels in response to growth-stimulatory peptides (such as Ang II, ET and insulin): (1) Ca(2+)-dependent, 4 pS Cl- channel promoting Cl- efflux; and (2) Ca(2+)-dependent, 27 pS nonselective cation channels promoting cation influx. We have also characterized a third channel which provides an alternative, receptor-operated pathway for Ca2+ entry in response to the growth factor, PDGF: (3) Ca(2+)-permeable, 1 pS cation channel. Consistent with our model of mesangial cell signal transduction (Fig. 1), these three mesangial cell ion channels are activated by binding of growth factors to membrane receptors (Fig. 8). Defective channel regulation, such as occurs in early diabetes mellitus, would promote mesangial cell relaxation and pathogenic glomerular hyperfiltration. Glomerular hyperfiltration and hypertension have been proposed to be major pathogenic factors in renal disease progression [4, 29, 38, 39]. Compensatory renal growth factor responses initially provide adaptive changes in glomerular hemodynamics after loss of functional renal mass. However, chronic stimulation of these mesangial cell ion channels by renal growth factors would promote sustained extracellular Ca2+ entry, resulting in mesangial cell contraction and growth, and progressive decreases in Kf and GFR. Eventually, this process leads to irreversible renal damage due to the development of glomerulosclerosis and interstitial fibrosis.     

Blood groups and transfusion medicine in Taiwan

There are significant differences in the frequencies of various blood group antigens between Taiwanese and Caucasians, and also in the frequencies of the corresponding alloantibodies. The most interesting discoveries concerning Taiwanese are: 1) The most common ABO subgroups are the B3 phenotype, followed by the Ael phenotype. 2) The secretory H-deficient para-Bombay phenotype (OHm), which results from mutations in five different h genes, is not uncommon. 3) The Le(a+b+) phenotype has a frequency of about 25% and the Le(a+b-) phenotype is absent except in a few of the indigenous groups. 4) Anti-'Mi(a)' is the most common clinically significant alloantibody causing intravascular hemolytic transfusion reactions and hemolytic disease of the newborn. 5) The incidence of the corresponding MiIII blood group phenotype varies among the different ethnic groups, ranging from 0% among descendants of mainland Chinese from north of the Yangste to 88.4% among the Ami tribe. 6) There is an almost complete absence of Di(a) and St(a) antigens among the indigenous populations, in contrast to incidences of greater than 2% among the Chinese ethnic groups. 7) Nearly all (99.67%) Taiwanese are positive for the Rh(D) antigen. Among those with Rh(D) negative phenotype, about 30% have a very weak Rh(D) positive phenotype (Del phenotype). Since the corresponding anti-D antibody is also rarely encountered, routine D typing is not necessary. 8) Some rare blood group phenotypes found in Taiwanese are the i phenotype associated with congenital cataract, DVI phenotype, Dc- phenotype, Jk(a-b-) phenotype, and Lu(a-b-) phenotype.     

Role of fibroblast growth factors and their receptors in mouse primordial germ cell growth

Primordial germ cells (PGCs) are the embryonic progenitors of mature germ cells. During their proliferative stage, murine PGCs may be transiently cultured on mitotically inactive feeder layers. This culture system has permitted identification of several growth factors active toward PGCs. We and others have previously identified basic fibroblast growth factor (bFGF) as a powerful mitogen in this system. Here we characterize some of the functions of bFGF in PGC culture. Our data demonstrate that fibroblast growth factor (FGF) receptors I and II are present in the developing gonad and are consistent with expression of these receptors by PGCs. Moreover, PGCs can bind radiolabeled bFGF in vitro, demonstrating that the factor can act directly on these cells. While mitotic PGCs of either sex are shown to bind radiolabeled bFGF, oogonia that are undergoing meiotic arrest exhibit reduced bFGF binding, indicating potential developmental regulation of an FGF receptor.     

Differential regulation by hematopoietic growth factors of apoptosis and mitosis in acute myeloblastic leukemia cells

We evaluated the effects of various hematopoietic growth factors (HGFs) on the prevention of apoptosis in blasts from 19 patients with acute myeloblastic leukemia (AML) by assessing DNA ladder formation. After incubation without HGF, apoptosis was noted in all but two patients. HGFs prevented, did not affect, or enhanced apoptosis in 39 (60%), 14 (22%), or 12 (18%) of 65 suspension cultures, respectively. HGFs that prevented apoptosis also stimulated and/or synergized blast colony formation in 35 of 39 corresponding methylcellulose cultures. HGFs that alone stimulated colony formation also prevented apoptosis in all but two of 28 corresponding suspension cultures. In contrast, HGFs that did not prevent apoptosis also failed to stimulate growth in 17 of 26 corresponding methylcellulose cultures. HGFs that enhanced apoptosis alone never stimulated colony formation. After incubation, we noted enhanced c-fos and cjun genes as well as induction of p21 protein. An appropriate dose of HGF elevated c-fos, reduced c-jun and p21, induced G1/S transition, and inhibited apoptosis. In two patients, apoptosis was not induced after incubation. Cells not treated with HGF expressed no c-fos, c-jun, or c-myc, and remained in G0/G1. Taken together, our results support the conclusion that not only c-fos, cjun, and c-myc, but also p53 and p21 are required for blast apoptosis. HGF differentially prevents apoptosis and induces mitosis, and both events seem to be integral to the self-renewal of AML clonogenic cells.     

Current status of clinical indications for hematopoietic growth factors after chemo-/radiotherapy in gynecology

With the identification and recombinant production of the hematopoietic growth factors, these cytokines have been evaluated in the treatment of primary bone marrow failure states and following myelosuppressive chemotherapy or radiotherapy. An increasing number of clinical trials with hematopoietic factors have been performed in patients with haematological and oncological diseases. Granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin and, in phase I/II trials, thrombopoietin (TPO) are available for the clinical use. Most studies have been performed with G-CSF and GM-CSF, their beneficial effects are proven regarding acceleration of hematopoietic recovery following chemotherapy. This results in a marked reduction of infectious risks and a shortening of drug- and radiation-induced myelosuppression. CSFs are most important in mobilizing peripheral blood progenitor cells (PBPC) and have allowed high-dose therapy combined with stem cell support in gynecological malignancies, e.g. ovarian carcinoma and breast cancer. However, evidence based, clinical practical guidelines for the use of hematopoietic growth factors in gynecological malignancies are not for all circumstances available.     

Role of the insulin-like growth factors and their binding proteins in lactation

Insulin-like growth factor (IGF)-I is thought to mediate a portion of the effects of bST on lactation in dairy cows. Serum concentrations of IGF-I are increased in lactating cows that were treated with bST, and IGF-I receptors are present in bovine mammary tissue. In addition, close arterial infusion of IGF-I into the mammary gland of goats increases milk yield. Little evidence exists to support a direct galactopoietic effect of IGF-I in ruminants. However, IGF-I is a potent mitogen for mammary epithelial cells and may also influence the inhibition of apoptosis of this cell type. The IGF are found in association with a family of individual binding proteins. The high affinity of the IGF for these proteins relative to the IGF receptor allows them to modulate IGF-I bioactivity in the mammary gland at the cellular level. Mammary epithelial cells synthesize multiple forms of IGF binding proteins, and one of these, IGF binding protein-3, is specifically regulated by the IGF. Stimulation of DNA synthesis by IGF-I is enhanced in bovine mammary epithelial cells that overexpress the IGF binding protein-3. These data indicate that IGF-I can stimulate the synthesis of an IGF binding protein, which enhances its own mitogenic activity. However, whether this mechanism is operative in the lactating mammary gland in vivo is unknown. Given the complexity of the interactions between the IGF and their binding proteins, more information is needed before the role of these growth factors in regulating growth, differentiation, and apoptosis of mammary epithelial cells is delineated.     

Current good manufacturing practices for transfusion medicine

Transfusion medicine is most tightly controlled in the US by CGMPs that are written as regulations, guidances, and quality management documents. Because the US regulatory scheme requires that each unit of human blood donated for transfusion (and other purposes) be documented from the moment of donor registration until the last component of that donation is finally disposed of, there is precious little that remains solely within the discretion of the treating physician who orders transfusions for her or his patients. An additional complication for transfusion medicine specialists is that the search for the requirements must extend to all possible areas of information, including the possibly unexpected source within the private sector.