EEG neurofeedback research: A fertile ground for psychiatry?

The clinical efficacy of neurofeedback is still a matter of debate. This paper analyzes the factors that should be taken into account in a transdisciplinary approach to evaluate the use of EEG NFB as a therapeutic tool in psychiatry. Neurofeedback is a neurocognitive therapy based on human-computer interaction that enables subjects to train voluntarily and modify functional biomarkers that are related to a defined mental disorder. We investigate three kinds of factors related to this definition of neurofeedback. We focus this article on EEG NFB. The first part of the paper investigates neurophysiological factors underlying the brain mechanisms driving NFB training and learning to modify a functional biomarker voluntarily. Two kinds of neuroplasticity involved in neurofeedback are analyzed: Hebbian neuroplasticity, i.e. long-term modification of neural membrane excitability and/or synaptic potentiation, and homeostatic neuroplasticity, i.e. homeostasis attempts to stabilize network activity. The second part investigates psychophysiological factors related to the targeted biomarker. It is demonstrated that neurofeedback involves clearly defining which kind of relationship between EEG biomarkers and clinical dimensions (symptoms or cognitive processes) is to be targeted. A nomenclature of accurate EEG biomarkers is proposed in the form of a short EEG encyclopedia (EEGcopia). The third part investigates human-computer interaction factors for optimizing NFB training and learning during the closed loop interaction. A model is proposed to summarize the different features that should be controlled to optimize learning. The need for accurate and reliable metrics of training and learning in line with human-computer interaction is also emphasized, including targeted biomarkers and neuroplasticity. All these factors related to neurofeedback show that it can be considered as a fertile ground for innovative research in psychiatry.

Intellectual ability in the duchenne muscular dystrophy and dystrophin gene mutation location.

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy during childhood. Mutations in dystrophin (DMD) gene are also recognized as a cause of cognitive impairment. We aimed to determine the association between intelligence level and mutation location in DMD genes in Serbian patients with DMD. Forty-one male patients with DMD, aged 3 to 16 years, were recruited at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia. All patients had defined DMD gene deletions or duplications [multiplex ligation-dependent probe amplification (MLPA), polymerase chain reaction (PCR)] and cognitive status assessment (Wechsler Intelligence Scale for Children, Brunet-Lezine scale, Vineland-Doll scale). In 37 patients with an estimated full scale intelligence quotient (FSIQ), six (16.22%) had borderline intelligence (70

Epidemiology of Charcot-Marie-Tooth disease in the population of Belgrade, Serbia.

BACKGROUND: The aim of this study was to determine prevalence and 15-year survival in Charcot-Marie-Tooth disease (CMT). METHODS: The study covers the period from 1 January 1988 to 31 December 2007 in the territory of Belgrade. Data on a number of CMT-affected persons and their basic demographic characteristics as well as data on the disease were collected from medical records. Data on the course and outcome of the disease were obtained through direct contact with patients, their families and their physicians. RESULTS: We registered 161 patients with CMT in the population of Belgrade. The most frequent type was CMT1. The crude prevalence of CMT disease in the Belgrade population on 31 December 2007 was 9.7/100,000 for all subtypes, 7.1/100,000 for CMT1, and 2.3/100,000 for CMT2. Gender-specific prevalence was 11.2/100,000 for males and 8.3/100,000 for females. The highest age-specific prevalence was registered in the oldest age group (75+ years; 19.1/100,000), and the lowest one in patients aged 5-14 years (5.0/100,000). The cumulative probability of 15-year survival for CMT patients in Belgrade was 85.6 ± 7.8% (44.9 ± 31.8% for males and 98.2 ± 1.8% for females). CONCLUSIONS: The prevalence of CMT found in Belgrade is similar to the prevalence registered in Southern European countries.

Postmastectomy radiotherapy in intermediate risk stage I-II breast cancer patients.

PURPOSE: To evaluate the correlation of postmastectomy radiotherapy (PMRT) with local relapse rate, disease-free survival (DFS) and overall survival (OS) in a group of breast cancer (BC) patients at intermediate risk for locoregional relapse (stage I-II with either 1-3 positive axillary nodes, or node-negative grade III BC) treated with radical mastectomy. PATIENTS AND METHODS: We evaluated 482 stage I-II BC patients, with either node-negative grade 3 tumors or with 1-3 positive nodes irrespective of tumor grade, treated with radical mastectomy at our Institute from 1986 to 1994. After mastectomy they received either adjuvant CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy (N=172), or adjuvant endocrine therapy (N=310). Postoperative radiotherapy (RT group) to the regional lymph nodes with tumor dose (TD) 48 Gy in 22 fractions was delivered to 199 patients. RESULTS: After a median follow-up of 79.5 months, no difference in relapse rate between the two groups was seen (30.6% in the RT group vs. 36.7% in the no RT group; x(2), p=0.1). Local recurrence rate occurring alone or with distant metastases was 4.52% in the RT group vs. 7.77% in the no RT group (x(2), p=0.1). However, local recurrence rate alone was significantly higher in the RT group compared to the no RT group (2.01 vs. 6.01%, x(2), p=0.041). In premenopausal patients local relapses occurred in 3.2% of patients with postoperative RT and in 8.2% in patients without RT (Fisher's exact test, p=0.48). Non significant difference was registered in postmenopausal patients with (4.76%) or without RT (6.58%). Ten-year DFS and OS were 53.5% and 68.7% in the RT group vs. 52.9% and 75.2% in the no RT group (non significant difference). CONCLUSION: Our results did not show that PMRT significantly influences the incidence of disease relapse, DFS and OS in stage I-II BC patients with intermediate risk for disease relapse. However, it seems that PMRT might influence the occurrence of locoregional recurrence in these patients.

Survival and mortality of myotonic dystrophy type 1 (Steinert's disease) in the population of Belgrade.

The purpose of this investigation was to determine survival and mortality in patients with myotonic dystrophy type 1 (DM1) in the Belgrade population within the period from 1983 to 2002. Data of a number of diagnosed DM1 patients with their demographic, clinical and genetic characteristics were gathered from hospital records in all neurologic institutions in Belgrade for the period 1983-2002. Death certificates were reviewed to determine the cause of death. Survival analysis by life table method and Cox proportional hazard model was performed. Within the observed period, in the population of Belgrade, 15 fatal outcomes among 101 patients with DM1 were registered. Average DM1 mortality rate was 0.5/1,000,000 (95% CI 0.3-0.8), and standardized mortality ratio (SMR) was 5.3. A significant inverse correlation was found between age at onset of DM1 and CTG repeats (P=0.023). The cumulative probability of 15-year survival for DM1 patients in Belgrade was 49+/-5% (48+/-2% for males and 50+/-7% for females). Younger age at onset was a significant unfavorable prognostic factor (hazard ratio=4.2; P=0.012).

Haplotype analysis of the DM1 locus in the Serbian population.

OBJECTIVES: Analysis of the CTG-repeat number and three biallelic markers, Alu(+/-), HinfI(+/-), and TaqI(+/-), in the DMPK gene in healthy and myotonic dystrophy type 1 (DM1) Serbian individuals. Also, the consideration of haplotypes in the light of the proposed models of CTG-repeat evolution and origin of the DM1 mutation. MATERIALS AND METHODS: Markers were analyzed by PCR and haplotypes were obtained on 203 unrelated normal chromosomes and 24 unrelated DM1 chromosomes. RESULTS: A strong linkage disequilibrium was detected between the three biallelic markers alone (P <0.0001) and between distinct CTG-repeat size classes and reconstructed haplotypes. Greater than 98% of normal chromosomes contain (+++) and (- - -) haplotypes. The (+++) haplotype is the most common, while the (CTG)(9-17) are the most frequent alleles. We found a complete association of (+++) haplotype with (CTG)(> or =18) and mutated alleles. CONCLUSIONS: (CTG)(9-17)/(+++) haplotype is the ancestral haplotype and DM1 mutation occurred on (CTG)(18-35)/+++ chromosome.

Lack of clinical utility of folate levels in the evaluation of macrocytosis or anemia.

PURPOSE: Folate levels are routinely ordered in the evaluation of macrocytosis with or without frank anemia, yet the value of these tests is questionable. We evaluated the clinical utility of folate testing in routine clinical practice. SUBJECTS AND METHODS: We conducted a retrospective review of all serum and erythrocyte folate assays performed over a one-year period at three hospitals. We determined the frequency of low values, then reviewed the medical records of all patients with low values to determine whether low folate levels changed clinician behavior. We also performed a cost analysis to determine the cost of testing per case in which behavior changed. RESULTS: Only 2.3% of the 2,998 folate levels obtained during the study period were low. The low levels were noted in the record in 53% of cases, and folic acid was prescribed or continued at discharge in only 24%. The cost analysis showed that nearly $10,000 was spent in folate testing per patient in which behavior changed. CONCLUSIONS: Folate values were rarely low in the population tested, and low values infrequently led to a change in clinician behavior. Given the limited clinical value of folate tests, we propose that, in cases of macrocytosis with or without anemia, to minimize cost and prevent missed cases of true folate deficiency, empirical supplementation with folic acid should be used in place of testing for deficiency.

Is the 31 CAG repeat allele of the spinocerebellar ataxia 1 (SCA1) gene locus non-specifically associated with trinucleotide expansion diseases?

A number of human hereditary neuromuscular and neurodegenerative disorders are caused by the expansion of trinucleotide repeats within certain genes. The molecular mechanisms that underlie these expansions are not yet known. We have analyzed six trinucleotide repeat-containing loci [spinocerebellar ataxias (SCA1, SCA3, SCA8), dentatorubral-pallidoluysian atrophy (DRPLA), Huntington chorea (HD) and fragile X syndrome (FRAXA)] in myotonic dystrophy type 1 (DM1) patients (n = 52). As controls, we analyzed two groups of subjects: healthy control subjects (n =133), and a group of patients with non-triplet neuromuscular diseases (n = 68) caused by point mutations, deletions or duplications (spinal muscular atrophy, Charcot-Marie-Tooth disease, type 1A, hereditary neuropathy with liability to pressure palsies, and Duchenne and Becker muscular dystrophy). Allele frequency distributions for all tested loci were similar in these three groups with the exception of the SCA1 locus. In DM1 patients, the SCA1 allele with 31 CAG repeats account for 40.4% of all chromosomes tested, which is significantly higher than in two other groups (11.3% in healthy controls and 6.6% in the group of non-triplet diseased patients; P < 0.001, Fisher's exact test). This is consistent with our previous findings in HD patients. The absence of this association in non-triplet diseases as well as in healthy controls could indicate a possible role of this SCA1 allele with 31 repeats in triplet diseases. Here we discuss a possible role of the SCA1 region in pathological trinucleotide repeat expansions.

[Radiotherapy of locally advanced breast carcinoma in elderly female patients]. / Radioterapija lokalno odmaklog karcinoma dojke kod bolesnica starije zivotne dobi.

INTRODUCTION: Breast cancer is the most frequent cancer in elderly patients (over 65 years). The recent data indicate that in women aged over 72 years the incidence of breast cancer is twice greater than in women aged 45 years. As more and more women are getting older, the total incidence of breast cancer can be expected to increase. The treatment of these patients is complicated by many other diseases including cardiovascular and pulmonary disorders associated with aging, and because chemotherapy and radical surgery are often contraindicated. MATERIAL AND METHODS: In an one year period in the Institute of Oncology and Radiology of Serbia a group of 53 elderly (65 years and more) patients with locally advanced breast cancer were treated. Twenty four patients (group A) were treated with hypofractionated (concentrated) radiotherapy. The irradiation was delivered to the breast with TD24-26 Gy with two tangentional portals and 19 Gy to regional lymphatics with anterior fields owner 8 fractions, breast and lymphatics alternatively. The same treatment plan was repeated after 28 days (split course). Co60 was used. Twenty nine patients (group B) were treated with conventional fractionated radiotherapy. Irradiation was delivered to the breast with 51 Gy tumour dose in 16 fractions and to the lymphatics with 45 Gy in 15 fractions. Breast and lymphatics were irradiated alternatively, during 31 working days. After 51 Gy the whole breast was boosted with 20 Gy tumour dose and axilla with TD 12 Gy. The concentrated radiotherapy is, in fact, an alternative for radical--conventional or protracted radiotherapy according to the so-called hypofractionated split course technique. Both techniques have very similar TDF factors. The aim of such a plan is the achievement of adequate tumour dose adapted to the age of patients (the patients should be treated in a smaller number of fractions). All patients were aged 65 years or were older. The median age in group A was 72 years and in group B 68 years. Also in all patients breast cancer was locally advanced (stadium III). In group A median follow-up was 29.79 months and in group B 23.62 months. RESULTS: All patients had acute skin reactions. In group A (irradiated with concentrated technique) 91.7% of patients had erythema, 8.3% dry desquamation, but moist desquamation was not observed. In group B (irradiated with conventional technique) 27.6% of patients had erythema, 55.2% dry desquamation and 17.2% moist desquamation. Delayed radiation changes manifested as fibrosis of the breast and region of axilla were noted in 29.24% of patients in group A and 13.8% in group B. The relapse in group A was 41.7% with median relapse free interval of 13.9 months and in group B 48.2% with relapse free interval of 15.6 months. There was no significant statistical difference between the two groups according to standard statistical methods (chi 2 = 0.96; DF = 3; p > 0.05). After approximately 30 months of follow-up, 50% of patients in group A are alive without signs of disease; 16.7% are alive with disease, and 16.7% are dead due to primary disease. In group B 24.1% of patients are alive without signs of disease; 24.1% are alive with disease; and 20.7% are dead due to primary disease. There was no significant statistical difference between the two groups (chi 2 = 4.09; DF = 4; p > 0.05). The overall survival rate in group A was 67% after 4 years and 53% in group B. Relapse free survival was 53% in group A after 4 years and 36% in group B. In conclusion, according to our study there was no statistically significant difference in local control between conventional and hypofractionated radiotherapy in the treatment in elderly patients. The main advantage of concentrated schedule is shortening of duration of irradiation, but the main disadvantage is a high incidence of fibrosis which makes difficult the evaluation of local control. Consensus about treatment of breast cancer in elderly women has not yet been clearly established. Our data suggest that hypofractionated schedule is an effective, suitable and comfortable therapeutic approach in the management of breast cancer in elderly women.

Changes in human immunodeficiency virus type 1 virus load during mobilization and harvesting of hemopoietic progenitor cells. Adult AIDS Clinical Trials Group 285 Study Team.

Genetic modification of hemopoietic progenitor cells ex vivo, followed by the infusion of the genetically modified cells into the human immunodeficiency virus-1 (HIV-1) infected donor, has been proposed as a treatment for HIV-1 infection. The current study was undertaken to evaluate the effect of hemopoietic stem cell mobilization and harvesting on HIV-1 replication in persons with HIV-1 infection. Eighteen HIV-1-infected persons received recombinant granulocyte colony-stimulating factor (G-CSF; Filgrastim) 10 microg/kg per day, for 7 days. On days 4 and 5, peripheral blood mononuclear cells were harvested by leukapheresis. The CD4+ lymphocyte count at entry was >500/microL for 6 subjects, 200 to 500/microL for 6 subjects, and <200/microL for 6 subjects. For 9 of 18 subjects, plasma HIV-1 RNA levels increased 4- to 100-fold (>0.6 log(10)) above baseline between days 4 and 7 and returned to baseline by day 27. Significant increases of plasma HIV-1 RNA levels occurred in 5 subjects despite 3-drug antiretroviral therapy. Changes in CD4+ and CD34+ cells during mobilization and harvesting were similar in all subjects whether they had or did not have increased plasma HIV-1 RNA levels. Thus, mobilization and harvesting of bone marrow progenitor cells from persons infected with HIV-1 induced a transient increase in viral replication in some patients but was not associated with adverse effects. (Blood. 2000;95: 48-55)

Reduced mobilization of CD34+ stem cells in advanced human immunodeficiency virus type 1 disease.

Granulocyte colony-stimulating factor (r-met Hu G-CSF; filgrastim; 10 microgram/kg/day for 7 days) was used to mobilize CD34+stem cells into the peripheral blood of human immunodeficiency virus type 1 (HIV-1)-infected individuals and a group of HIV-1-uninfected donors as a measure of immunologic reserve in HIV-1-infected people. G-CSF mobilized CD34+ cells of HIV-1-infected individuals with cell counts >500 CD4+ cells/mm3, as well as in HIV-1-uninfected donors. In contrast, CD34 cell mobilization was significantly blunted in HIV-1-infected individuals with cell counts <500 CD4+ cells/mm3 (<200 cell days vs. >650 cell days, P<.0005, compared with the >500 CD4+ cell cohort). At least 1.75x10(7) CD34 cells were harvested by leukapheresis from patients in each study cohort. CD34+ cell viability and the ability to differentiate precursor cells into myeloid and erythroid progenitor cells were not affected by HIV-1 infection.

HIV type 1 RNA expression in bone marrows of patients with a spectrum of disease.

HIV-1-infected individuals at various stages of disease harbor virus in their lymphoid organs, which serve as reservoirs of viral replication throughout the course of infection. Hematologic abnormalities are extremely common in HIV-1-infected individuals and occur at all stages of disease. To determine if the bone marrow is a reservoir of HIV-1 in vivo and if active HIV-1 RNA expression in that site is related to hematologic disease in infected individuals, we examined HIV-1 RNA expression in bone marrow biopsies from 37 patients with a broad spectrum of hematologic and HIV-1-related disease. To detect HIV-1 RNA expression, we performed in situ hybridization. Double-label in situ hybridization-immunohistochemistry was used for precise identification of the type of cell expressing viral RNA. Six of 37 (16%) patients demonstrated HIV-1 RNA expression in the bone marrow. Double-label analysis performed on two marrows localized HIV-1 RNA to cells of the macrophage lineage. Active HIV-1 expression correlated with advanced HIV-1-related disease and CD4 cell depletion rather than a specific hematologic or clinical diagnosis. These data suggest that although the bone marrow does not serve as a reservoir of viral expression throughout the course of infection as do the lymphoid organs, HIV-1-expressing cells are present in the bone marrow during late stages of disease. These data also suggest that hematologic abnormalities in the majority of infected individuals may result from indirect effects of HIV-1 such as cytokine dysregulation rather than HIV-1 expression in the bone marrow itself.

The BCR-ABL oncogene requires both kinase activity and src-homology 2 domain to induce cytokine secretion.

Expression of either the BCR-ABL or the v-abl oncogene in the factor-dependent murine myeloid cell line FDCP-1 results in growth factor independence. Studies with temperature-sensitive mutants of v-abl show that this growth factor independence is oncogene dependent. Likewise, cells expressing a kinase inactive mutant of BCR-ABL did not grow in the absence of interleukin-3 (IL-3). Conditioned media from cells expressing either v-abl or BCR-ABL contained growth factor(s) capable of stimulating the proliferation of uninfected FDCP-1 cells. Based on enzyme-linked immunosorbent assay studies and antibody neutralization studies, the major growth factor present in these conditioned media is IL-3. Because of the importance of SH2 domains in regulating substrate interactions, we examined the ability of SH2 deletion mutants in BCR-ABL to induce growth factor independence. Cells expressing a mutant of BCR-ABL lacking the SH2 domain were growth factor independent; however, they did not secrete growth factors. This finding suggests that while IL-3 produced by cells infected with BCR-ABL may contribute to autocrine or paracrine growth factor independence, expression of an activated tyrosine kinase alone may be able to induce growth factor independence. Furthermore, the secretion of cytokines maybe correlated with a specific region of the BCR-ABL oncogene, suggesting that activation (phosphorylation) of specific substrates may be critical for transcriptional activation of cytokine genes.

Over-expression of c-src or v-src in bone marrow stromal cells stimulates hematopoiesis in long-term bone marrow culture.

The S17 murine stromal cell line was infected with retroviral vectors encoding the v-src and c-src oncogenes and cells expressing high levels of either pp60v-src or pp60c-src were isolated. Long-term bone marrow cultures (LTBMCs) established with these different stromal cell lines showed that progenitor cells proliferated to a greater extent in cultures with stromal cells that over-expressed either c-src or v-src. An increase in the number of granulocytes, monocytes, and colony-forming units granulocyte-macrophage (CFU-GM) in the nonadherent cell population of LTBMCs prepared with S17/v-src or S17/c-src stromal cells was observed. Conditioned media from the S17/v-src and S17/src stromal cell lines stimulated the formation of CFU-GM in the absence of additional hematopoietic cell growth factors. Conditioned media from S17/v-src and S17/c-src stimulated proliferation of the granulocyte-macrophage colony-stimulating factor (GM-CSF)-responsive cell line FDCP-1 and this stimulation was inhibited by neutralizing antisera to murine GM-CSF. An increase in the concentration of GM-CSF was confirmed by enzyme-linked immunosorbent assay. No secretion of interleukin-1 alpha (IL-1 alpha) or tumor necrosis factor-alpha was detected by any of the stromal cell lines. There was no increase in the secretion of either CSF-1 or IL-6 by either S17/v-src or S17/c-src. The addition of 1 micrograms/mL monoclonal anti-GM-CSF antibody to LTBMCs caused a decrease in the number of nonadherent cells in cultures established with each of the different stromal cell lines. Northern blot analysis showed no difference in the level of GM-CSF RNA among the different stromal cell lines. These studies suggest that the increased proliferation of hematopoietic progenitor cells in LTBMCs with S17/v-src or S17/c-src cells may result from a posttranscriptional event that elevates production of GM-CSF by the S17/c-src and S17/v-src stromal cells.

How reorganizing a general medicine clinic affected residents' and patients' satisfaction.

The authors examined how satisfied patients and residents were before and after the restructuring of the general medicine clinic at a large urban teaching hospital in 1985; the change to a longitudinal care clinic was made to provide greater continuity of care, more consistent access of residents to attending physicians, and a more structured educational curriculum. Questionnaires to assess satisfaction were administered three weeks before and ten months after the change to all 80 of the second- and third-year residents. A convenience sample of 310 patients seen during a two-week period before the change and another such sample of 267 patients seen during a two-week period ten months after the change comprised the patients who completed a patients' satisfaction questionnaire. The residents were significantly more satisfied with the quality of care, functioning, and educational value of the new longitudinal care clinic. Their average overall rating of satisfaction (on a scale where 1 = completely dissatisfied and 5 = completely satisfied) increased from 2.3 to 3.7 (p less than .001). Unexpectedly, the patients were "very satisfied" with both clinic models and their overall ratings changed little (4.5 before, 4.4 after). In addition, the patients' and residents' before-and-after perceptions of the quality of care delivered in the clinic differed substantially. These findings show that the longitudinal care clinic significantly enhanced the satisfaction of the residents but not of the patients. Furthermore, the data suggest that results from standardized patients' satisfaction surveys may not accurately assess the quality of care being delivered.

[Infections of the breast]. / Infekcija dojke.

The authors present their experiences of 45 female patients under the treatment of an acute purulent mastitis in five years period. From 45 treated female patients 8 (17.7%) were treated clinically, and 37 (82.2%) in the outpatient department. At the age to 35 years old, there were 87% of female patients from which 79.2% who bore the first child, and 21.7% of those who bore more than one child. From an acute lactic mastitis were treated 39 (86.6%) from which 2 (4.4%) were young girls, and 4 (8.8%) patients with already finished period of reproduction. Right-side localization of the pathological process was in 22 (48.8%) cases, left-side in 19 (42.2%) cases, and both-sides in 4 (8.8%) cases. In 15 (33.3%) female patients we have followed an immunological status. It is characteristic an immunological disbalance in acute phase. Following the immunological status, it can be useful for estimating and prognosis in treatment. In literature, there are quotation details of purulent diseases, among which breast infection takes a considerable place from 1.6 to 18%, and the death-rate is described in high percentage from 9.6 to 1.7%. Our attitude in the treatment of breast infection, especially when purulent process is present, as first we have to evacuate the suppuration, then to make good breast drainage, and separately to infiltrate the tissue because there are small abscesses in it, which bring to dissemination of pus within the breast. According to all mentioned above, we also give an antibiotic therapy.

Erythropoietin induces rapid increases in intracellular free calcium in human bone marrow cells.

Elevation of intracellular free calcium (Ca++) is an early activation event that occurs as a result of ligand binding in several human cell systems. In this report, erythropoietin, the major hormone governing erythroid differentiation, was found to elicit an increase in Ca++ in human bone marrow mononuclear cells. Two chelators of intracellular calcium, quin 2 and the more specific and sensitive analogue, fura-2, were used to characterize the response evoked by both recombinant and native hormone. Erythropoietin caused a rapid, dose-dependent rise (within seconds) in Ca++ in bone marrow mononuclear cells, which could be prevented by preincubation of hormone with a rabbit erythropoietin antiserum. The erythropoietin response did not occur in purified populations of T- or B-lymphocytes. These studies suggested that increased Ca++ on erythropoietin binding may be an early transmembrane signal in hormone action.

Aluminum inhibits erythropoiesis in vitro.

Anemia has been associated with aluminum intoxication in patients on chronic dialysis and in animals. In studies presented here, in vitro human erythroid culture was used to delineate the effects of aluminum on normal hematopoiesis. Aluminum by itself in routine culture, even at very high levels (1,035 ng/ml), did not significantly affect erythroid colony growth. The addition of human transferrin to the culture, however, resulted in a marked dose-dependent inhibition of erythroid, but not myeloid colony growth. At all doses, CFU-E progenitors showed greater inhibition than burst-forming units (BFU-E). Aluminum inhibition was not overcome by increasing the dose of erythropoietin or adding additional burst-promoting activity to the culture. Inhibition by aluminum was directly related to the number of binding sites on transferrin in the culture, and was not observed in the presence of fully iron-saturated transferrin.