[The anamnesis in antiquity; medical questions by Rufus Ephesius (1st to 2nd century AD)]. / De anamnese in de oudheid; de Geneeskundige vragen van Rufus Ephesius (Ie-2e eeuw n.Chr.).

Only one treatise devoted to medical history taking (anamnesis) has come down to us from antiquity: Medical questions by Rufus Ephesius (from about 80 to about 150 AD). The work was rediscovered, published and translated from Greek into French by Daremberg and Ruelle in the 19th century. The word 'anamnesis' for history taking only came into use halfway through the 19th century in German-speaking countries and in the Netherlands. The term was not used in this sense by physicians in antiquity. In contrast to several authors of the Corpus Hippocraticum (5th to 1st century BC), Rufus attached great importance to the interview with the patient and in particular to questions concerning the patient's lifestyle prior to the illness. In this respect, his opinions are remarkably close to modern views.

[The 'Anemia in the midwife practice' standard issued by the Royal Dutch Organisation of Midwives: a risk of not recognizing iron deficiency and hemoglobinopathy]. / De standaard 'Anemie in de eerstelijns verloskundige praktijk' van de Koninklijke Nederlandse Organisatie van Verloskundigen (KNOV): risico voor het niet onderkennen van ijzergebrek en hemoglobinopathie.

The standard entitled 'Anaemia in the midwife practice' issued by the Royal Dutch Organisation of Midwives presumes that the only reason for iron therapy in pregnancy is the prevention of adverse pregnancy outcome due to a low haemoglobin level. Pregnant women are screened for iron deficiency anaemia by means of sequential testing of haemoglobin and mean corpuscular volume (MCV). As a result only 10% of pregnant women will receive iron supplements. This practice will lead to a deterioration in the already low iron status of Dutch premenopausal women. As the haemoglobin reference values are lower than hitherto used, only severely anaemic women will be detected. Due to the low diagnostic accuracy of the MCV test the subsequent selection will be an arbitrary one. The standard sets the cut-off values for haemoglobin in black women at an even lower level, which will reduce the number of haemoglobinopathies detected in the immigrant population. The non-carriers in this group will run an increased risk of adverse pregnancy outcome if these cut-off values are used. We are strongly in favour of the measurement of haemoglobin, erythrocyte indices and ferritin in early pregnancy. In this way, iron deficiency, iron deficiency anaemia, anaemia due to other causes and haemoglobinopathies, the latter highly underestimated in the standard, can be detected.

RBC antibody persistence.

BACKGROUND: A person exposed to foreign blood group antigens may produce antibodies. The persistence of antibodies varies among people and among antibodies. A study was performed to investigate the persistence of clinically significant RBC alloantibodies over a period of 20 years. STUDY DESIGN AND METHODS: A retrospective examination was performed of all records of RBC antibodies in the transfusion laboratory computer database from 1978 through 1997. Records of patients who underwent at least one antibody investigation after an antibody had been detected were studied. The study included all antibodies against the Rh, K, Fy, Jk, and MNs blood group systems. An antibody was regarded as not persistent if, after previous detection, the screening or panel studies became negative for the antibody under study. Anti-D due to RhIg administration was excluded. RESULTS: An analysis was performed of 480 records consisting of 593 antibodies that fulfilled the criteria. Median antibody follow-up was 10 months (range, 1-240). In 137 patients, 153 (26%) antibodies became undetectable over the course of time. After initial negative screening investigations, 310 antibodies were formed. The antibodies that were still detectable had a median follow-up of 7 months (range, 1-193). A patient's age, sex, and antibody specificity were of no influence on the length of time that antibodies were detectable. Antibodies detected with a more sensitive screening technique were less persistent (p = 0.0002). For 28 patients, detection of antibodies was highly irregular. CONCLUSIONS: About 25 percent of all antibodies became undetectable over the course of time. The antibody screening technique used, rather than the antibody specificity, affected these results. To prevent delayed hemolytic transfusion reactions, precise antibody documentation is of great importance.

Alloimmunization after blood transfusion in patients with hematologic and oncologic diseases.

BACKGROUND: Because of intensive marrow depression and improved survival, patients with hematologic and oncologic malignancies are dependent on transfusion for a longer period. It has been advocated that these patients should receive blood that is matched for blood group antigens other than ABO and D. A retrospective study was performed on the rate of alloimmunization against red cell antigens in 564 patients with malignant hematologic diseases over a period of 10 years. STUDY DESIGN AND METHODS: Records of transfusion and immunohematologic studies of all patients (n = 1066) with malignant myeloproliferative and lymphoproliferative diseases diagnosed between 1987 and 1996 at one hospital were collected from the hospital computer blood bank files. Transfusions were correlated with antibody formation. Factors affecting this correlation were analyzed. RESULTS: Seventy-one antibodies were found in 51 patients. The overall immunization rate was 9.0 percent. Fifty percent of antibodies were formed after 13 units had been transfused. Once a patient had formed an antibody, the probability of additional antibodies increased 3.3-fold. Anti-c, anti-E, and anti-K composed the majority of antibodies found. Four patients formed Rh system antibodies after incompatible platelet transfusions. Patients who underwent intensive chemotherapy formed antibodies at a much lower rate than other patients. More than 40 percent of antibodies became undetectable after the first detection. No difficulty was encountered in finding compatible blood for these patients. CONCLUSIONS: Antibody formation in hematologic malignancies is comparable to that in other diseases requiring multiple blood transfusions. Extensive antigen matching before transfusion of patients with hematologic and oncologic malignancies is not necessary and leads to increased costs.

A case of non-beta-globin gene linked beta thalassaemia in a Dutch family with two additional alpha-gene defects: the common -alpha3.7 deletion and the rare IVS1-116 (A-->G) acceptor splice site mutation.

We describe a family with beta thalassaemia, apparently not linked to the beta-globin gene cluster, in combination with alpha thalassaemia. The propositus, an adult Dutch Caucasian male, and his son presented with microcytic hypochromic parameters. Their lysates displayed the normal adult pattern on electrophoresis. The HbA2 concentration, which is usually increased in beta thalassaemia, was normal. The in vitro biosynthetic rate of the globin chains was strongly unbalanced even in the presence of a coexisting alpha-thalassaemia defect. Routine analysis of the beta genes, including the promoter region, was performed repeatedly by polymerase chain reaction (PCR), denaturing gradient gel electrophoresis (DGCE) and direct sequencing. No molecular abnormalities were detected. Large beta deletions were excluded by haplotype determination, using seven polymorphic markers distributed over an area of 50 kb, from 1 kb 5' of the epsilon gene to 4 kb 3' of the beta gene. The haplotype analysis of the beta-gene cluster revealed that the unaffected daughter had received the same beta haplotype as her beta-thalassaemic brother from their beta-thalassaemic father. These data suggest that the beta-gene cluster shared by father and son was not directly associated with a reduced beta-globin chain expression. In order to exclude the remote possibility of a beta-locus-control region (LCR) rearrangement in the paternal haplotype of the daughter, the sequence of the HS2 element was examined in the nuclear family. We compared the haematological and clinical data of this family with the data reported in the limited number of similar cases. We discuss the possibility that the mutation of a trans-acting erythroid factor(s), not linked to the beta-genes cluster, may impair the beta-gene expression of both alleles.

Vitamin supplementation reduces blood homocysteine levels: a controlled trial in patients with venous thrombosis and healthy volunteers.

Hyperhomocysteinemia is a risk factor for atherosclerosis and thrombosis and is inversely related to plasma folate and vitamin B12 levels. We assessed the effects of vitamin supplementation on plasma homocysteine levels in 89 patients with a history of recurrent venous thrombosis and 227 healthy volunteers. Patients and hyperhomocysteinemic (homocysteine level >16 micromol/L) volunteers were randomized to placebo or high-dose multivitamin supplements containing 5 mg folic acid, 0.4 mg hydroxycobalamin, and 50 mg pyridoxine. A subgroup of volunteers without hyperhomocysteinemia was also randomized into three additional regimens of 5 mg folic acid, 0.5 mg folic acid, or 0.4 mg hydroxycobalamin. Before and after the intervention period, blood samples were taken for measurements of homocysteine, folate, cobalamin, and pyridoxal-5'-phosphate levels. Supplementation with high-dose multivitamin preparations normalized plasma homocysteine levels (< or = 16 micromol/L) in 26 of 30 individuals compared with 7 of 30 in the placebo group. Also in normohomocysteinemic subjects, multivitamin supplementation strongly reduced homocysteine levels (median reduction, 30%; range, -22% to 55%). In this subgroup the effect of folic acid alone was similar to that of multivitamin: median reduction, 26%; range, -2% to 52% for 5 mg folic acid and 25%; range, -54% to 40% for 0.5 mg folic acid. Cobalamin supplementation had only a slight effect on homocysteine lowering (median reduction, 10%; range, -21% to 41%). Our study shows that combined vitamin supplementation reduces homocysteine levels effectively in patients with venous thrombosis and in healthy volunteers, either with or without hyperhomocysteinemia. Even supplementation with 0.5 mg of folic acid led to a substantial reduction of blood homocysteine levels.

Intensive postremission chemotherapy without maintenance therapy in adults with acute lymphoblastic leukemia. Dutch Hemato-Oncology Research Group.

PURPOSE: To investigate the value of intensive consolidation chemotherapy not followed by maintenance therapy in adult acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: A multicenter phase II trial was conducted in 130 adult patients with ALL between 16 and 60 years of age. After standard induction therapy, postinduction chemotherapy was given: three courses of high-dose cytarabine (2,000 mg/m2 every 12 hours for four doses) in combination with amsacrine (course one), mitoxantrone (course two), and etoposide (course three). CNS prophylaxis consisted of 10 injections of intrathecal methotrexate (IT MTX). Patients younger than 50 years with an HLA-identical sibling were eligible to receive allogeneic bone marrow transplantation (BMT). RESULTS: Ninety-five patients (73%) achieved complete remission (CR); 82% were younger than 50 years and 41% were older than 50 years. Seventeen patients (13%) were resistant to chemotherapy, and 18 (14%) died during induction treatment. Only age and performance status were significantly associated with response (P<.001 and .03, respectively). Death during consolidation occurred in four patients. The estimated 5-year overall survival (OS) was 22% for the entire group and 26% for patients younger than 35 years. Disease-free survival (DFS) at 5 years was 28% +/- 6 for patients younger than 35 years, 25% +/- 9 for patients between 35 and 50 years, and 0% for patients older than 50 years. Increasing age (P<.01) and expression of CD34 (P<.01) were adverse factors. Only three patients (3%) developed an isolated CNS relapse. CONCLUSION: Intensive consolidation including high-dose cytarabine not followed by maintenance therapy provides an outcome for adult patients with ALL that may be worse or even inferior compared with studies using long-term maintenance therapy. High-dose cytarabine in combination with IT MTX was effective for CNS prophylaxis.

Prospective randomized placebo-controlled study of granulocyte-macrophage colony-stimulating factor without stem-cell transplantation after high-dose melphalan in patients with multiple myeloma.

PURPOSE: To evaluate the impact of granulocyte-macrophage colony-stimulating factor (GM-CSF) or placebo on the durations of intravenous (IV) antibiotic use, hospitalization, neutropenia, and fever, as well as remission rates, after high-dose melphalan (HDM) without stem-cell transplantation (SCT) in patients with multiple myeloma (MM). PATIENTS AND METHODS: One hundred two patients with high-risk MM were randomized 2:1 in a prospective multicenter trial to receive 5 microg/kg/d GM-CSF (69 patients) or placebo (33 patients) starting the day after 140 mg/m2 IV melphalan for up to 21 days. RESULTS: GM-CSF significantly reduced neutropenia after HDM (median, 23.5 v 29 days; P = .0468), with a trend to reduce the duration of hospitalization (median, 32 v 38 days; P = .0841). Nevertheless, GM-CSF did not significantly reduce infectious toxicity as regards the number of days with fever (median, 5 v 3; P = .359), the number of days with IV antibiotics (median, 22 v 27; P = .14), or early deaths, with an 11.5% treatment-related mortality rate in the GM-CSF group (eight of 69 v two of 32 patients in the placebo group; P = .686). There was no difference in response rates between the two groups of patients. CONCLUSION: GM-CSF after HDM without SCT is feasible and significantly shortens neutropenia with a trend toward reduction of hospitalization duration, but does not significantly reduce the morbidity and mortality of such therapy. Thus, when intensive therapy is indicated, given that the mortality of HDM followed by SCT reported in the literature is less than 5% and patients are discharged at approximately day 15, despite the risk of contamination by clonogenic malignant cells, SCT appears to be preferable to GM-CSF after HDM.

An IVS1-116 (A-->G) acceptor splice site mutation in the alpha 2 globin gene causing alpha + thalassaemia in two Dutch families.

We report the characterization of an alpha +(-)thalassaemia determinant due to a transition A-->G of the acceptor splice consensus site sequence (IVS1-116) of the first intron of the alpha 2-globin gene. The mutation, found in two apparently unrelated Dutch Caucasian families, was detected by DGGE analysis followed by direct sequencing. Haplotype analysis suggests a common origin of the mutation in both families. The disruption of the acceptor splice site consensus sequence interferes with the correct splicing and leads to the retention of the first intron in the abnormally spliced mRNA. The alpha +(-)thalassaemia phenotype observed in the carriers is caused by the absence of functional mRNA which cannot be replaced by the abnormally spliced mRNA. The low amounts of abnormal mRNA found in reticulocytes is, most probably, due to the post-transcriptional instability which follows the presence of a termination codon in the retained intronic sequence. This situation is often associated with a decreased mRNA stability as observed for several nonsense mutations of the beta-globin gene.

[Radioactive phosphorus (32P); an old but not bad treatment for polycythemia vera]. / Radioactief fosfor (32P); een oude, maar geen slechte behandeling voor polycythaemia vera.

OBJECTIVE: To determine if there is a place for radiophosphorus (32P) in the treatment of polycythaemia vera (PV) and essential thrombocytosis (ET). DESIGN: Retrospective. SETTING: Leyenburg Hospital, The Hague, the Netherlands. METHOD: Data on 144 patients with the diagnoses 'PV' or 'ET' from 1965 to 1994 were collected. Available data were insufficient in 19 of these. Regarding 125 patients, 80 with PV and 45 with ET, the survival and the frequency of acute leukaemia with various forms of treatment (32P, busulfan or combination of several treatment modalities) were studied. Moreover, in the PV group the duration of survival was compared with the expected duration of survival in a comparable group of the population. RESULTS: Of the 80 PV patients, five developed acute leukaemia: two in the 32P group (5%), two in the busulfan group (12%) and one in the group given combination therapy (4%). Of the 26 patients of the ET group treated with busulfan, one developed acute leukaemia (4%). The survival in the PV group was 4 years shorter than the expected duration of survival in a comparable group of the population. CONCLUSION: Since 32P is efficacious and causes little inconvenience, it should be the drug of first choice in the treatment of PV in the elderly.

Unrelated bone marrow transplantation as a rescue procedure following inadvertent loss of an autologous bone marrow graft.

We report a 27-year-old male patient with acute myeloid leukaemia who was successfully treated with an unrelated bone marrow graft within 7 days following the loss of his autologous bone marrow graft. Several factors were found to be essential in order to locate an HLA-ABDR (DRB1)DQ(DQB1) identical, sex-matched, CMV-negative and ABO compatible donor within a week. These included a common HLA phenotype of the patient, the presence of an experienced donor registry in close proximity to a blood bank associated with an HLA laboratory, a large donor file with fully HLA-ABDR typed donors and the almost exclusive use of blood bank donors as potential bone marrow donors. The possibility of further streamlining the logistics of finding a suitable unrelated bone marrow donor is discussed.

Clinical significance of bcl2 and p53 protein expression in diffuse large B-cell lymphoma: a population-based study.

PURPOSE: We studied the prognostic significance of bcl2 and p53 protein expression in relation to clinical and pathologic characteristics in patients with diffuse large B-cell lymphoma (LCL). PATIENTS AND METHODS: Three hundred seventy-two patients with LCL were retrieved from a population-based registry for non-Hodgkin's lymphoma (NHL). bcl2 and p53 protein expression was studied on paraffin-embedded tumor tissue by immunohistochemistry in relation to clinical factors. Response to therapy and survival were analyzed in 165 patients who were uniformly staged and treated and for whom all prognostic data were available according to the International Prognostic Index (IPI). RESULTS: Forty-five percent of tumors showed strong expression of the bcl2 protein (bcl2++), with a higher frequency in patients with primary nodal involvement. Disease-free survival (DFS) was significantly better in bcl2-negative/intermediate (bcl2-/+) cases as compared with bcl2++ cases (P = .0011). At 5 years, bcl2-/+ patients showed a DFS rate of 74%, in contrast to bcl2++ patients with a DFS rate of 41% (P = .002). Bcl2 was the strongest independent prognostic value in a multivariate analysis, with a relative risk (RR) of 3.0 in comparison to p53 expression and the clinical factors of the IPI. Overall survival (OS) was not significantly influenced by bcl2 protein expression. p53 protein expression was found in 13% of cases, with a higher frequency in patients with extensive disease. p53 expression did not influence the chance to achieve complete remission (CR) and survival. CONCLUSION: bcl2 protein is frequently expressed in LCL and is a strong independent prognostic factor for DFS. p53 expression is related with high tumor burden, but is not an independent risk factor for CR and survival.

[Agranulocytosis caused by clozapine: the importance of leukocyte monitoring and efficacy of hematopoietic growth factors]. / Agranulocytose door clozapine: het belang van leukocytencontrole en het nut van bloedgroeifactoren.

In four patients, a woman aged 85 and three men aged 33, 42 and 70 years, clozapine-induced agranulocytosis was diagnosed. In three patients the white cell counts were not performed as they should have been. Two patients were treated for their agranulocytosis with granulocyte colony-stimulating factor (G-CSF; filgrastim). Two patients were not treated. The literature concerning clozapine-induced agranulocytosis and its treatment with growth factors consists of only a few case reports. Therefore a definite conclusion about the efficacy of the treatment for this particular indication is not yet possible.

Is hyperhomocysteinaemia a risk factor for recurrent venous thrombosis?

Several studies have shown a relation between hyperhomocysteinaemia and arterial vascular disease. We looked at the association between hyperhomocysteinaemia and venous thrombosis which could be clinically important as hyperhomocysteinaemia is easily corrected by vitamin supplementation. We studied 185 patients with a history of recurrent venous thrombosis and 220 controls from the general population. Homocysteine concentrations were measured before and 6 h after oral methionine loading. We defined hyperhomocysteinaemia as the homocysteine concentration above the fasting or the postmethionine value found for the 90th percentile of the controls. Of the 185 patients with recurrent thrombosis, 46 (25%) had fasting homocysteine concentrations above the 90th percentile or the controls (odds ratio is 3.1 [1.8-5.5]). After adjustment for age, sex, and menopausal status the odds ratio was 2.0 (1.5-2.7). Similar results were found for the post-methionine value (unadjusted odds ratio 3.1 [1.7-5.5], adjusted 2.6 [1.9-3.5]). Hyperhomocysteinaemia is a common risk factor for recurrent venous thrombosis and can lead to a two-fold or three-fold increase in risk.

Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-Hodgkin's lymphoma.

BACKGROUND: High-dose chemoradiotherapy combined with autologous bone marrow transplantation can cure patients with disseminated, aggressive non-Hodgkin's lymphoma in whom first-line chemotherapy has failed. In contrast, cure is rare with second-line chemotherapy. It has been suggested that patients with slow responses to the initial phase of first-line chemotherapy are at high risk for relapse. Therefore, such patients are potential candidates for early bone marrow transplantation. METHODS: To investigate whether patients with slow responses, defined as only a partial response after three courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), would benefit from early transplantation, we conducted a prospective, randomized trial. The early application of high-dose chemoradiotherapy and autologous bone marrow transplantation was compared with the continuation of CHOP therapy for another five courses. Patients with complete responses after three courses of CHOP (fast responses) and patients who responded partially but still had tumor-positive marrow continued with another five courses of CHOP. The study end points were the response rate, overall survival, disease-free survival, and event-free survival. RESULTS: Of 286 patients who could be evaluated for the rapidity of their response after three courses of CHOP, 38 percent had fast responses, 47 percent had slow responses, and 15 percent had no response. Among 106 patients with slow responses who had lymphoma-negative marrow, 69 patients (65 percent) were randomized. Seventy-four percent of the CHOP group and 68 percent of the transplantation group had complete remissions (P = 0.54). At four years the rates of overall, disease-free, and event-free survival were 85, 72, and 53 percent, respectively, in the CHOP group and 56, 60, and 41 percent in the transplantation group (P > 0.10). The disease-free survival in both groups did not differ significantly from that of nonrandomized patients with fast responses (54 percent at four years). CONCLUSIONS: The early application of high-dose, marrow-ablative chemoradiotherapy with autologous bone marrow transplantation does not improve the outcome in patients with aggressive non-Hodgkin's lymphoma that responds slowly to first-line CHOP chemotherapy.

Detection of monosomy 7 and trisomy 8 in myeloid neoplasia: a comparison of banding and fluorescence in situ hybridization.

Fluorescence in situ hybridization (FISH) is a powerful tool for detection of numerical and structural chromosomal aberrations. We have compared conventional banding techniques and FISH for the detection of monosomy 7 (-7) and trisomy 8 (+8) in 89 patients with myeloid malignancies. Of these patients, 21 had -7, 30 had +8, four had both, and 34 had no aberrations or aberrations other than -7 or +8 as assessed by banding techniques. Sequential samples were available in 23 patients. Alphoid DNA probes specific for chromosomes no. 7 and 8 were used for FISH. As controls, 10 normal bone marrow (BM) samples were hybridized with the chromosomes no. 7 and 8 probes, and in addition all tumor samples were hybridized with a chromosome no. 1 specific probe. The cut-off value for -7 was 18% one-spot cells, and for +8 was 3% three-spot cells. FISH analysis of 44 samples with -7 or +8, and at least 10 metaphases evaluated, showed that the proportions of aberrant metaphase cells mirrored the interphase clone sizes. Most samples with nonclonal metaphase aberrations, including those with only a few metaphases, had increased numbers of aberrant interphase cells: 20% to 80% for -7, and 3% to 43% for +8. Interphase cytogenetics of the 34 samples without -7 or +8 did not show significant cell populations with -7 or +8. In four patients, -7 or +8 could not be confirmed by FISH due to additional structural aberrations, marker chromosomes, or wrongly interpreted banding results. As FISH will be used more and more in cytogenetic diagnosis, clinical follow-up, and therapy monitoring, it will be necessary to standardize FISH procedures and supplement the Standing Committee on Human Cytogenetic Nomenclature (ISCN) definitions of a clone with criteria specifically for in situ hybridization.