Sickle cell--betao thalassemia variant with high hemoglobin F and mild clinical course

A 70 year old Black woman had chronic hemolytic anemia without recurrent painful crises. Hemoglobin pattern by electrophoresis was hemoglobin S (69 to 71 per cent), hemoglobin A2 (4.6 per cent) and hemoglobin F (24 to 27 per cent). No hemoglobin A was detected, and the hemoglobin F was distributed heterogeneously in the red cells. Reticulocyte alpha/nonalpha globin chain synthetic ratios were 1.44 to 1.62. Thus, the patient had a high hemoglobin F variant of S-beta zero (betao) thalassemia which has not been described previously. Her clinical course has been mild in comparison with S-betao thalassemia patients who do not have extremely elevated hemoglobin F levels.     

Myelodysplastic syndrome

Myelodysplastic syndrome continues to present a formidable clinical challenge. Despite considerable effort, no therapy apart from allogeneic bone marrow transplantation has been shown to prolong survival. Lack of effective therapy for myelodysplastic syndrome is of further concern given recent reports on the high incidence of myelodysplastic syndrome in patients undergoing intensive chemotherapy and radiation therapy for other malignancies. However, significant strides have been made in the past year toward understanding the molecular pathogenesis of some forms of myelodysplastic syndrome, as well as developing new approaches for therapy of myelodysplastic syndrome. This review highlights recent advances in the molecular genetics of myelodysplastic syndrome, including clonality analysis and identification of genes that are causally implicated in the pathogenesis of myelodysplastic syndrome; results from recent clinical trials for therapy of myelodysplastic syndrome using growth factors, chemotherapy or both; and recent literature on therapy-related myelodysplastic syndrome in intensively treated patients.     

Clinical study of GM-CSF in patients with aplastic anemia and myelodysplastic syndrome. (CSF39-300 Study Group)

We administered granulocyte-macrophage colony stimulating factor (GM-CSF) to patients with aplastic anemia and myelodysplastic syndrome (MDS), as a phase III trial. The GM-CSF was given by 3 hrs intravenous drip infusion daily for at least fourteen days. Twenty-five patients with aplastic anemia and nineteen patients with MDS were evaluable for efficacy. Peripheral blood granulocyte counts, especially neutrophil counts and eosinophil counts, increased markedly by the administration of GM-CSF in each disease. Fifteen patients with MDS and nineteen patients with aplastic anemia responded to the GM-CSF. Dose-related increase of granulocytes were seen in patients with MDS, but no relation was seen in patients with aplastic anemia. Adverse effects were observed in some patients and flu-like syndrome including fever, general fatigue and anorexia were seen most commonly but were transient. Our results showed that GM-CSF is a potent stimulator of hematopoiesis in patients with aplastic anemia and MDS.     

Purification of cytochrome b5 from pig testis microsomes by isoelectric focusing in an immobiline pH gradient

To evaluate the diagnostic value of thrombopoietin (TPO, c-mpl ligand) measurements, and clarify the regulatory mechanisms of TPO in normal and in thrombocytopenic conditions, the plasma TPO concentration was determined in normal individuals (n = 20), umbilical cord blood (n = 40), chronic idiopathic thrombocytopenic purpura (ITP; n = 16), in severe aplastic anaemia (SAA; n = 3), chemotherapy-induced bone marrow hypoplasia (n = 10), myelodysplastic syndrome (MDS; n = 11), and sequentially during peripheral blood progenitor cell transplantation (n = 7). A commercially available ELISA and EDTA-plasma samples were used for the analysis. The plasma TPO concentration in the normals and umbilical cord blood were 52 +/- 12 pg/ml and 66 +/- 12 pg/ml, respectively. The corresponding values in patients with SAA and chemotherapy-induced bone marrow hypoplasia were 1514 +/- 336 pg/ml and 1950 +/- 1684 pg/ml, respectively, and the TPO concentration, measured sequentially after myeloablative chemotherapy and peripheral blood progenitor cell transplantation, was inversely related to the platelet count. In contrast, the plasma TPO recorded in patients with ITP (64 +/- 20 pg/ml) and MDS (68 +/- 23 pg/ml) were only slightly higher than normal levels. In conclusion, TPO levels were significantly elevated in patients in which bone marrow megakaryocytes and platelets in circulation were markedly reduced, whereas TPO levels were normal in ITP patients, and only slightly increased in the MDS patients. These latter patients displayed a preserved number of megakaryocytes in bone marrow biopsies. Our data support the suggestion that megakaryocyte mass affects the plasma TPO concentration. In thrombocytopenic patients a substantially increased plasma TPO implies deficient megakaryocyte numbers. However, TPO measurements do not distinguish between ITP and thrombocytopenia due to dysmegakaryopoiesis, as seen in MDS patients.     

Gamma chain heterogeneity: determination of Hb F composition by perfusion chromatography

The Ggamma:Agamma ratio is around 70:30 at the time of birth and usually 40:60 in the trace amounts of Hb F found in the adult. Changes in this ratio are observed in several hemoglobin disorders providing insights on the genetics and molecular pathophysiology of these diseases. Several techniques have been proposed to measure the Ggamma:Agamma ratio. We here describe perfusion chromatography which is now in routine use in one of our laboratories. The method involves a high velocity flow of the mobile phase through a porous reversed phase chromatographic stationary bed and allows us to determine this parameter one order of magnitude faster than with conventional high performance liquid chromatography.     

Sonographic appearance of ovaries and gonadotropin secretions as prognostic tools of spontaneous puberty in girls with Turner's syndrome

We evaluated the possibility of anticipating spontaneous puberty in peripubertal Turner girls, in order to plan substitutive estrogen treatment. In the 24 patients studied, spontaneous puberty was seen in 4/11 girls with 45 XO karyotype, 5/5 with mosaicisms, 1 out of 2 with structural aberrations of the X chromosome and 0 out of 6 with Xq isochromosomes. When considering sonographic findings, the 6 girls with normal ovaries and 4/9 of those with intermediate ovarian appearance showed spontaneous puberty; the remaining 5 with intermediate ovaries and 9 with streak gonads did not undergo spontaneous puberty. Gonadotropin secretion was normal in girls with normal ovaries, moderately elevated in patients with intermediate ovarian appearance, and very high in those with streak gonads. The prognostic value of sonography and gonadotropins is particularly important in girls with intermediate ovaries. Therefore these evaluations should be performed at peripubertal age in patients with Turner's syndrome to elucidate the degree of ovarian insufficiency.     

Report of two cases presenting with myelodysplastic syndrome during treatment of recurrent breast cancer

Two women with recurrent breast cancer presenting with myelodysplastic syndrome (refractory anemia) during chemotherapy were reported. At diagnosis of myelodysplastic syndrome, white blood cell count, hemoglobin and platelet count were 3,300/mm3, 4600/mm3, 5.5 g/dl, 6.3 g/dl, 1.1 x 10(4)/mm3 and 6.8 x 10(4)/mm3, respectively, in case 1 and 2. Bone marrow taps showed hypercellular marrows with dysplastic changes of erythrocytes, granulocytes and megakaryocytes in both cases. Before the occurrence of the myelodysplastic syndrome, both patients received various cytotoxic agents (mitomycin C: 77 mg, 108 mg; cyclophosphamide: 34,400 mg, 40,000 mg; doxorubicin: 340 mg, 460 mg; methotrexate: 410 mg, 700 mg; and vincristine: 9.5 mg, 14 mg, in case 1 and 2, respectively). One patient died 2 months after the onset of the myelodysplastic syndrome, and the other died 3 months after due to progression of metastatic breast cancer. Risk-benefits analysis of chemotherapy, especially adjuvant chemotherapy, should be performed in cases of breast cancer.     

Fetal hemoglobin levels in sudden infant death syndrome

OBJECTIVE: The aim of this study was to determine and compare fetal hemoglobin levels from infants dying of the sudden infant death syndrome (SIDS) with aged-matched control infants dying of other causes. Similar previous studies have reported both elevated and normal levels of fetal hemoglobin in whole blood samples from infants dying of SIDS. DESIGN: Triton-acid-urea gel electrophoresis and densitometry were used to determine fetal hemoglobin levels in postmortem whole blood samples from infants dying of SIDS and from appropriately age-matched control infants. Whole blood samples were analyzed blindly and matched for postgestational age. Infant ages at death ranged from birth to less than 1 year. MAIN OUTCOME MEASURES: Fetal hemoglobin in whole blood from infants dying of SIDS and control infants. RESULTS: During the period of postnatal development most associated with SIDS cases (2 to 6 months after birth), fetal hemoglobin levels were found to be significantly elevated in postmortem whole blood samples from SIDS infants compared with gestational age-matched control infants dying of causes other than SIDS. CONCLUSION: We conclude that levels of fetal hemoglobin are elevated in postmortem whole blood of SIDS infants compared with controls. Furthermore, the apparent conflict in the literature regarding fetal hemoglobin levels in SIDS infants and controls is most likely due to variability in the control data of some studies.     

Long-term survival (10 years or more) in 30 patients with primary amyloidosis

The median survival in primary systemic (AL) amyloidosis is less than 18 months. No published series of patients with AL amyloidosis have reported survival of more than 10 years. The records of all Mayo Clinic patients with a diagnosis of AL amyloidosis between January 1, 1966 and March 1, 1987 were reviewed. Patients with secondary amyloidosis, familial amyloidosis, senile systemic amyloidosis, and localized amyloidosis were excluded. During the 21 years of the study, 841 patients with AL amyloidosis were seen. Of these, 29 were excluded because the diagnosis was made at autopsy, and 2 others were excluded because no follow-up data were available. Actuarial survival for the 810 patients was 51% at 1 year, 16% at 5 years, and 4.7% at 10 years. Thirty patients survived for 10 years or more after the histologic diagnosis of AL amyloidosis; all received alkylating-agent therapy. In 14 patients, the monoclonal protein disappeared from the serum or urine. Of 10 patients with nephrotic syndrome, 4 had an objective response. Congestive heart failure, older age, creatinine value of 2 mg/dL or more, bone marrow plasma cell value of 20% or more, platelet count of 500 x 10(9)/L or less, and the presence of peripheral neuropathy were underrepresented in the 10-year survivors and are unfavorable prognostic features. Five percent of patients with AL amyloidosis survived for 10 years or more.     

One-stage curative treatment of neoplastic colonic obstruction: long-term results, comparison with elective surgery and therapeutic implications

Over a period of ten years (1980-1989) 528 patients with colon cancer were treated at one institution. One hundred seventy nine (33.9%) were obstructed (O) and underwent emergency surgery, while 349 received elective (E) treatment; of these 363 had one-stage curative treatment. Operative mortality was 10.3% (O) and 3.5% (E) respectively (p < .0.5). Three hundred forty three patients survived surgery and entered follow-up: 96 were O (M:F, 54:42) and 247 E (M:F, 119:128, p = N.S.). Their mean age was 69.5 and 64.4 (p < .001), respectively. Dukes' stage and histological grading were evenly distributed within the two groups, but sites of the primary were not (p < .001). During the follow-up local recurrence occurred in 40 patients (13 O, 27 E, p = N.S.) and metastatic disease in 78 (28 O, 50 E, p < .05, Life Table Analysis) including liver recurrence in 17 O and 30 E (p = .063). Five year crude survival (51%) was significantly worse in obstructed patients. Multivariate analysis showed that Dukes' stage and obstruction were the only prognostic factors of recurrent disease, while survival was affected by the same variables and age over 70. When recurrent disease was introduced in the model survival depended on Dukes' stage, site of the primary and age over 70 and the variable obstruction disappeared as prognostic factor. Right sided tumours showed a better and those at the splenic flexure a worse prognosis. Despite one-stage curative treatment obstruction carries a significantly higher risk of developing metastatic disease, suggesting that obstruction enhances cancer cell dissemination. These patients might benefit from per-operative intra-portal and post-operative systemic adjuvant chemotherapy.     

Interpretation of the three-dimensional structure of living nuclei by specimen tilt

Functional human globin messenger RNA was isolated from reticulocytes of two patients with homozygous beta 0-thalassemia, three patients with sickle cell beta 0-thalassemia, and one patient doubly heterozygous for beta 0-thalassemia and hemoglobin Lepore. When incubated in the Krebs type II mouse ascites tumor-cell-free system, messenger RNA from these patients actively directed the synthesis of human beta s and/or alpha- and gamma-globin chains but failed to stimulate the synthesis of any beta A-chains, even though nonthalassemic human globin mRNA preparations consistently stimulated two to four times as much beta A- or beta S-globin chain synthesis as alpha-chain synthesis when incubated in the same system under the same conditions. These results strongly suggest that functional beta A-chain-specific globin mRNA is absent in beta 0-thalassemia.     

Routine erythrocyte measurements in diagnosis of iron-deficiency anemia and thalassemia minor

A study was made of the routine electronic measurements of erythrocyte size and hemoglobin concentration in blood samples from 122 patients with decreased transferrin saturation and 66 patients with elevated levels of hemoglobin A2 or F. The medical histories of these patients were reviewed to identify 52 cases of uncomplicated iron-deficiency anemia and 39 cases of uncomplicated thalassemia minor. Four decision functions were compared for separating these two disorders. The functions evaluated were: D.F'. = MCV--[5 X Hb]-RBC; ratio MCV/RBC; ratio MCH/RBC, and RBC. The rules performed better in the uncomplicated cases than in the routine laboratory defined cases. Only minor differences in the performances of the various decision functions were observed. None was sufficiently accurate for final diagnosis, but they should have value in screening patients and in determining which additional test should be considered.     

Enhanced fetal hemoglobin production by phenylacetate and 4-phenylbutyrate in erythroid precursors derived from normal donors and patients with sickle cell anemia and beta-thalassemia

In both sickle cell (SS) anemia and beta-thalassemia (beta-thal), an increase in fetal hemoglobin (HbF) ameliorates the clinical symptoms of the underlying disease. Several pharmacologic agents have been used to elevate HbF levels in adults; however, concerns regarding adverse effects of the prevailing drugs raise an urgent need for other agents capable of stimulating HbF production. We show here that sodium phenylacetate (NaPA) and its precursor, sodium 4-phenylbutyrate (NaPB), can enhance HbF production in cultured erythroid progenitor derived from normal donors and patients with SS anemia or beta-thal, when used at pharmacologic concentrations. Treatment resulted in (1) reduced cell proliferation, (2) elevated hemoglobin (Hb) content per cell (mean cellular Hb [MCH]), and (3) an increased proportion of HbF produced, associated with elevated levels of gamma-globin mRNA. Moreover, the active phenyl-fatty acids, with NaPA as a prototype, potentiated HbF induction by other drugs of clinical interest, including hydroxyurea (HU), sodium butyrate, and 5-azacytidine (5AzaC). Efficacy could be further enhanced by introducing chlorine substituents at the phenyl ring to increase drug lipophilicity. Our findings indicate that NaPA and NaPB, both already proven safe and effective in treatment of children with urea cycle disorders, might benefit also patients with severe hemoglobinopathies. The two-phase liquid culture procedure used in this study should prove valuable in further studies exploring the mechanisms of HbF induction by these agents, and might provide an assay to predict patient response in the clinical setting.     

Real-time visualization of PH domain-dependent translocation of phospholipase C-delta1 in renal epithelial cells (MDCK): response to hypo-osmotic stress

BACKGROUND: The aim of this study was to compare the prognostic efficacy of cardiac troponin T (cTnT) and I (cTnI) in patients with clinical unstable angina. METHODS: We studied 74 patients with chest pain at rest, electrocardiographic evidence of myocardial ischemia, and normal (<6.7 ng/mL) values of creatine kinase-MB. cTnT was measured with a commercial assay (cutoff level 0.1 ng/mL) and cTnI with a preliminary research application (cutoff level 3.1 ng/mL). All patients had blood drawn at baseline and 8 hours thereafter. The prospectively defined end point was the proportion of patients identified by each assay as having myocardial damage. RESULTS: cTnT and cTnI were elevated in the same percentage of patients (18 of 74; 24%). Overall, 23 patients had elevations of 1 or both markers. In 13 there were elevations of both. Ten patients had elevations of only one (5 for each marker). In 51 patients, no elevations were present. Death or nonfatal myocardial infarction was more frequent in patients with elevated cTnI (27.7% vs 5.3%; P =.02) than those with normal values. The prognostic influence of cTnT was less (17% vs 8.5%; P =.2). However, the difference between the 2 markers when compared directly was not statistically significant (27.7% vs 17%; P = NS). CONCLUSIONS: These data indicate that both markers identify myocardial damage in equal numbers of patients with clinical unstable angina. Patients with elevations had a worse short-term outcome. The significance of the minor differences in prognostic value will require additional studies.     

Atypical presentation of preeclampsia in high-order multifetal gestations

OBJECTIVE: To describe our experience with preeclampsia in high-order multifetal gestations. METHODS: Records for all triplet and quadruplet pregnancies delivered after 24 weeks' gestation from January 1988 through June 1994 were reviewed. All patients were treated with bed rest from 20 weeks' gestation onward and received corticosteroids weekly beginning at 24 weeks. Tocolytics were used as needed. RESULTS: Twenty-one triplet and eight quadruplet pregnancies were studied. The mean gestational age at delivery was 32.3 and 27.9 weeks, and mean birth weights were 1547 and 1028 g, respectively. Seventeen of 29 patients developed preeclampsia, 14 of the 21 triplet mothers and three of the eight quadruplet mothers. Among 16 patients who were delivered for preeclampsia, only eight had blood pressure (BP) elevation before delivery, whereas ten had epigastric pain, visual disturbances and/or headache; nine had elevated liver enzyme levels; and seven had low platelet counts. Only three patients had proteinuria, and only six had edema. Five women developed the syndrome of hemolysis, elevated liver enzymes, and low platelets postpartum, all of whom had normal BP before delivery. Two patients developed preeclampsia after delivery. A total of 95 infants were delivered, all by cesarean, of whom 93 (98%) survived. CONCLUSION: Preeclampsia is common in high-order multifetal gestations and often presents in an atypical manner. Hypertension is not always the presenting sign, and symptoms consistent with severe preeclampsia and abnormal laboratory values predominate.     

Clinical implications of chromosomal abnormalities in 401 patients with myelodysplastic syndromes: a multicentric study in Japan

It is well known that cytogenetic analysis in patients with myelodysplastic syndrome (MDS) provides information useful in determining their prognosis. Based on the chromosomal results obtained from 401 MDS patients by a multicentric study in Japan, we studied correlations between chromosomal findings and prognosis or leukemic transformation in MDS patients. Patients with complex aberrations (cytogenetic abnormalities at more than three chromosomes), of any subtype, had a poor prognosis; for example, > 60% of patients with refractory anemia (RA) showing complex aberrations died within one year, but only 11% of them developed leukemia. In patients with RA with ringed sideroblasts (RARS), > 70% of those with complex aberrations evolved into the leukemic phase and survived for less than one year, suggesting a biologic heterogeneity in RARS patients. By contrast, about 5% of patients with RA or RARS exhibiting chromosomal findings other than -7/7q-, +8, two aberrations, and complex aberrations, developed leukemia and had a favorable prognosis. Therefore, the presence of chromosome abnormalities alone in patients with RA or RARS is not a factor in predicting leukemic transformation or poor prognosis. In patients with refractory anemia with an excess of blasts (RAEB), the presence of chromosome aberrations at MDS diagnosis affected the occurrence of leukemic transformation (24% versus 43%), however, no particular difference was noted in patients with RAEB in transformation with regard to whether they had chromosome changes or not, and about 60% of them evolved into leukemia. The poor prognosis related to complex aberrations was consistently noted in all MDS subtypes or age-matched groups, indicating that this cytogenetic anomaly is an independent risk factor for a poor prognosis in MDS patients. The duration between MDS diagnosis and development of the leukemic phase and that between the latter and death were significantly shorter in patients with complex aberrations than those without this change. Although the clinical significance of certain chromosomal abnormalities differs among subtypes of MDS, a new scoring system for predicting prognosis by cytogenetic changes, in combination with hematologic parameters, was proposed.     

Acute myocardial infarction: prognosis after recovery

A prognostic index for 2-year survival after recovery from acute myocardial infarction was constructed from variables obtained during its course. One hundred ten of 143 patients survived 2 years, and 27 of 33 patients died of cardiac-related causes. Univariate analysis showed that 12 variables were significantly different between the surviving and nonsurviving groups. Discriminant analysis indicated five variables with meaningful predictive value to be included in a prognostic index: admission systolic blood pressure; highest blood urea nitrogen level in the cardiac care unit: atrial arrhythmias in the cardiac care unit; angina pectoris for more than 3 months or a previous myocardial infarction; and more than one ventricular ectopic beat per hour recorded on a dynamic electrocardiogram during the 17th to 24th hospital day. The prognostic index emphasizes the importance of extensive myocardial impairment and provides a means for identifying patients at risk of early mortality.     

Lyme disease in Italy, 1983-1996

The behaviour of canine malignant lymphomas is difficult to predict on the basis of histomorphology alone, but the majority of such tumours are "high-grade" by most classifications. The aim of this study was to examine the prognostic significance of argyrophilic nucleolar organizer region (AgNOR) counts and of proliferating cell nuclear antigen (PCNA)-positive cell counts in canine malignant lymphomas; and to relate the results to the histological grade (Kiel classification) and to the survival time of treated and untreated dogs. Low- and high-grade malignant lymphomas differed significantly in having mean AgNOR counts of 3.3 and 5.7 respectively. Untreated dogs with a mean AgNOR count higher than 5.5 did not survive more than 85 days; the median survival time for this group was 38.5 days. Untreated dogs with a mean AgNOR count lower than 4.0 survived at least 82 days and one dog more than 300 days; the median survival time for this group was 154 days. Treated dogs with a mean AgNOR count higher than 5.5 did not survive more than 126 days; the median survival time for this group was 73.5 days. Treated dogs with a mean AgNOR count lower than 4.0 had a median survival time of 205.5 days and one dog survived 367 days. The mean AgNOR count would seem to be a valuable prognostic marker for canine malignant lymphomas, but PCNA counts had no prognostic significance in relation to the median survival time in treated or untreated dogs.     

Training of new coworkers in the intensive care unit as a means for quality assurance

Among patients with bone marrow failure, differentiating acquired aplastic anemia (AA) from hypocellular refractory anemia (hypo RA) can be a difficult and challenging task. Morphological, cytochemical, immunocytochemical, and cytogenetic studies may provide tools for discriminating between both entities. In addition, differences in the pattern of proliferation and apoptosis of bone marrow cells in AA and in the myelodysplastic syndrome have been reported. Because of the correlation between p53 and apoptosis, we examined the overexpression of p53 on bone marrow biopsies in RA and AA. Our study included 14 patients with hypo RA, 14 patients with hypercellular (hyper) RA, ten patients with classic acquired AA, and 37 hematologically normal individuals. p53 was overexpressed in eight (57%) hypo RA patients and 11 (79%) hyper RA patients. All normal individuals and patients with AA showed no overexpression of p53 in their marrow. These results were statistically significant:p < 0.01 (AA vs hypo RA), p<0.001 (AA vs hyper RA), while the difference between hypo RA and hyper RA was not statistically significant. We conclude that p53 overexpression in bone marrow biopsies is a valuable tool for studying bone marrow failure and may provide additional information to help differentiate hypo RA from acquired AA.