Distorted-wave impulse approximation calculations of proton polarization following pi + absorption in nuclei

Within the Cooperative Study of Sickle Cell Disease, 694 infants with confirmed sickle cell disease were enrolled at less than 6 months of age. Information about the nature and frequency of complications was collected prospectively over a 10-year period. Painful crises and acute chest syndrome were the most common sickle cell-related events in homozygous sickle cell anemia (SS), hemoglobin SC disease (SC), and S beta thalassemia patients (overall incidence in SS patients of 32.4 and 24.5 cases per 100 person-years, respectively). Bacteremia occurred most frequently in SS children under 4 years of age and in SC patients less than 2 years of age. The mortality rate was low in this cohort compared with that found in previous reports. Twenty children, all with Hb SS, died (1.1 deaths per 100 person-years among SS patients). Infection, most commonly with Streptococcus pneumoniae and Hemophilus influenzae, caused 11 deaths. Two children died of splenic sequestration, 1 of cerebrovascular accident, and 6 of unclear causes. Two patients underwent cholecystectomies, and 17 underwent splenectomies after one or more splenic sequestration crises. The experience of this cohort should reflect closely the true clinical course of those children with Hb SS and Hb SC disease who are observed in sickle cell centers in the United States.     

Reversible splenic hypofunction in hypertransfused children with homozygous sickle cell disease

Functional hyposplenism, as documented by technetium 99 metastable sulfur colloid spleen scan and increased pocked erythrocyte count (also known as a pit count), is well described in children under 2 years of age with homozygous sickle cell anemia. We evaluated the clinical course and splenic function of 16 patients with sickle cell anemia (ages 3 to 20 years) on a hypertransfusion program for more than 6 months following a cerebrovascular accident. Patients were followed with simultaneous spleen scan and pitted erythrocyte count using direct interference contrast microscopy. Pit counts were taken prior to each transfusion and hemoglobin S level maintained at less than 20%. With the exception of two patients, splenic function was recovered only in those patients who were younger than 10 years of age at the time transfusion was initiated. There were no serious bacterial infections or other complications of sickle cell anemia documented in the hypertransfused group. Based on our results and the literature review, we conclude that some patients with sickle cell anemia receiving intensive hypertransfusion therapy for a cerebrovascular accident recover a normal splenic phagocytic function. Age and level at which the hemoglobin S is maintained are important factors in reestablishing splenic phagocytic function.     

Mortality of children with sickle cell disease in a pediatric department in Central Africa

BACKGROUND: Sickle cell disease is a serious public health problem in Gabon with a relatively high mortality rate. PATIENTS AND METHODS: Charts of 23 children (nine boys, 14 girls) who died of complications from sickle cell anemia in the department of pediatrics of Owendo Pediatric Hospital (Libreville, Gabon), from January 1, 1990 through December 31, 1992, were analysed retrospectively. RESULTS: Approximately two-thirds of the children (60.9%) were under 5 years of age. The great majority of patients were from low socio-economic standard families. Of 319 deaths observed during the study period, 23 were due to sickle cell disease-associated complications, for an overall mortality rate of 7.2% and a related mortality of 3.6%. Commonest causes of deaths were severe anemia (11 cases, i.e., 47.8%), which affected predominantly the younger patients between 6 months and 5 years (eight cases), infections (30.4%) and blood transfusion complications (21.7%). CONCLUSION: To decrease these mortality rates, appropriate health supervision and well-designed preventive strategies are needed.     

Acute splenic sequestration together with aplastic crisis caused by human parvovirus B19 in patients with sickle cell disease

Three children with homozygous sickle cell disease, 22 months and 8 and 10 years of age, had clinical and hematologic manifestations of aplastic and splenic sequestration crisis simultaneously. They had an acute drop in hemoglobin level (16, 20, and 45 gm/L), reticulocytopenia (0.1%, 0.6%, and 0.3%), and sudden splenic enlargement. Evidence of recent parvovirus infection was demonstrated.     

Nephrotic syndrome in Nigerian children with homozygous sickle cell disease

Two hundred and seventy two children with the nephrotic syndrome were seen and followed up at the Paediatric Renal Unit of the University of Nigeria Teaching Hospital, Enugu over 12 1/2 year period, between June 1983 and December 1995. Of these, there were nine (3.3%) children with homozygous sickle cell disease (SS). This latter group had a mean age of 9.6 +/- 3.2 years, male to female ratio of 1:2 and serum cholesterol of 3.13 +/- 1.48 mmol/l at the time of diagnosis. The mortality rate was 55.6% in these sicklers, death occurring within one and a half to five years of diagnosis. Causes of death were attributable to sickle cell disease in 60%, renal diseases in 20%, and other causes in 20%. Renal biopsy in two of the sicklers showed membrano-proliferative glomerulonephritis (MPGN) and focal glomerulosclerosis (FGS) respectively. Homozygous sickle cell disease does seem to predispose to the development of the nephrotic syndrome and those that do develop nephrotic syndrome exhibit some special characteristics, when compared to non-sicklers with nephrotic syndrome. These include older age of onset of the nephrotic syndrome, reverse sex ratios, lower serum cholesterol, higher mortality rate and sickle cell complications rather than chronic renal failure as the major cause of death.     

Circulating activated endothelial cells in sickle cell anemia

BACKGROUND: The vascular wall participates in the pathogenesis of sickle cell disease. To determine whether the endothelium is activated in this disease, we studied the number, origin, and surface phenotype of circulating endothelial cells in patients with sickle cell anemia. METHODS: We used immunohistochemical examination of buffy-coat smears to enumerate circulating endothelial cells, and we evaluated the surface phenotype by applying preparations of circulating endothelial cells. An immunofluorescence microscopy panel of antibodies was used, including a specific anti-endothelial-cell antibody, P1H12. RESULTS: Mean (+/-SD) numbers of circulating endothelial cells in normal blood donors, patients with sickle cell trait, and patients with hemolytic anemias not due to hemoglobin S were 2.6+/-1.6, 3.0+/-2.6, and 2.0+/-0.8 per milliliter of whole blood, respectively. Patients with sickle cell anemia who presented with acute painful episodes had 22.8+/-18.2 circulating endothelial cells per milliliter of blood (P<0.001 for the comparison with normal donors), and patients with no such events within one month before or after blood sampling had 13.2+/-11.8 circulating endothelial cells per milliliter of blood (P=0.002 for the comparison with normal donors and P=0.019 for the comparison with patients with acute events). Serial observations of three patients showed a tendency toward higher levels of circulating endothelial cells at the onset of acute painful crises. The average viability of circulating endothelial cells was 66+/-30 percent. In patients with sickle cell anemia, regardless of clinical status, the circulating endothelial cells were predominantly microvascular in origin (CD36-positive), and most of the cells expressed four markers of endothelial-cell activation: intercellular adhesion molecule 1, vascular-cell adhesion molecule 1, E-selectin, and P-selectin. CONCLUSIONS: Our studies suggest that the vascular endothelium is activated in patients with sickle cell anemia, regardless of the patients' clinical status. Adhesion proteins on activated endothelial cells may have a role in the vascular pathology of sickle cell disease.     

Renal length in sickle cell disease: observations from a cohort study

Renal length has been measured by ultrasound in 237 subjects with homozygous sickle cell (SS) disease, 147 with sickle cell-hemoglobin C (SC) disease, and in 78 age-matched controls with a normal hemoglobin (AA) genotype. As expected, renal length increased with age in all genotypes but mean length was significantly greater in SS disease compared with SC disease (mean difference 4.3 mm after adjustment for height) and significantly greater in both genotypes than in AA controls (SS/AA difference 9.2 mm, SC/AA difference 5.0 mm after adjustment for height). Examination of relationships between renal length and some hematological indices (hemoglobin, fetal hemoglobin, reticulocyte counts, alpha thalassemia status) in SS or SC disease showed only a significant negative correlation with hemoglobin and positive correlation with reticulocyte count in SS disease. Further analysis suggested that the stronger relationship was between renal length and high reticulocyte count. The mechanism of renal enlargement is unknown although glomerular hypertrophy and increased renal blood volume are likely contributors.     

Knockout-transgenic mouse model of sickle cell disease

When transgenic mice that expressed human sickle hemoglobin were mated with mice having knockout mutations of the mouse alpha- and beta-globin genes, animals were produced that synthesized only human hemoglobin in adult red blood cells. Similar to many human patients with sickle cell disease, the mice developed a severe hemolytic anemia and extensive organ pathology. Numerous sickled erythrocytes were observed in peripheral blood. Although chronically anemic, most animals survived for 2 to 9 months and were fertile. Drug and genetic therapies can now be tested in this mouse model of sickle cell disease.     

Tissue factor expression by endothelial cells in sickle cell anemia

The role of the vascular endothelium in activation of the coagulation system, a fundamental homeostatic mechanism of mammalian biology, is uncertain because there is little evidence indicating that endothelial cells in vivo express tissue factor (TF), the system's triggering mechanism. As a surrogate for vessel wall endothelium, we examined circulating endothelial cells (CEC) from normals and patients with sickle cell anemia, a disease associated with activation of coagulation. We find that sickle CEC abnormally express TF antigen (expressed as percent CEC that are TF-positive), with 66+/-13% positive in sickle patients in steady-state, 83+/-19% positive in sickle patients presenting with acute vasoocclusive episodes, and only 10+/-13% positive in normal controls. Repeated samplings confirmed this impression that TF expression is greater when sickle patients develop acute vasoocclusive episodes. Sickle CEC are also positive for TF mRNA, with excellent concurrence between antigen and mRNA expression. The TF expressed on the antigen-positive CEC is functional, as demonstrated by a binding assay for Factor VIIa and a chromogenic assay sensitive to generation of Factor Xa. By establishing that endothelial cells in vivo can express TF, these data imply that the vast endothelial surface area does provide an important pathophysiologic trigger for coagulation activation.     

Managing diabetes: current strategies

BACKGROUND: Diabetes is a significant cause for morbidity and mortality in developed countries. Current diabetes treatment goals involve more than normalizing glucose levels and preventing the acute effects of high or low glucose levels. RESULTS: People with diabetes are hospitalized 1.5 to 3 times more often than people who do not have diabetes, have 2 to 4 times greater risk of atherosclerotic disease, and have the highest incidence of adult blindness, chronic renal failure, and nontraumatic amputations. CONCLUSION: The challenge that faces clinicians who care for people with diabetes is to prevent--or at least attenuate--the effects of the chronic complications of this disease.     

Season and migration alters the corticosterone response to capture and handling in an Arctic migrant, the white-crowned sparrow (Zonotrichia leucophrys gambelii)

PURPOSE: Blood pressure in individuals who have sickle cell disease has been reported to be lower than published normal values. We determine whether and to what degree this is true, using data obtained as part of a large natural history study. PATIENTS AND METHODS: Blood pressure was measured annually for 3,317 subjects with sickle cell disease who were 2 years old or older. Values obtained were compared with those reported by the National Health and Nutrition Examination Survey I and II (NHANES I and II). They were further analyzed with respect to age, sex, height, weight, hematologic diagnosis, blood urea nitrogen and creatinine, stroke, and death. RESULTS: Blood pressure was significantly lower in subjects with sickle cell anemia than published norms for age, race, and sex, a difference that increased with age. It correlated with body mass index, hemoglobin, measures of renal function and age, but the strength of the correlation varied among age and sex subgroups. The risk for occlusive stroke increased with systolic but not diastolic pressure. Mortality was related to elevated blood pressure in males (P < 0.05) and to a lesser extent in females (P = 0.10). In subjects with hemoglobin SC disease, blood pressure also deviated from normal but to a lesser degree. CONCLUSION: Blood pressure is generally lower than normal in individuals with sickle cell anemia. Those with high values relative to this population had an increased risk of stroke and death. Blood pressure should be monitored but values obtained must be assessed relative to the lower values expected for patients with this disease. Those with blood pressure values above 140/90 mm Hg should be evaluated and considered for treatment.     

Intrasplenic masses of "preserved" functioning splenic tissue in sickle cell disease: correlation of imaging findings (CT, ultrasound, MRI, and nuclear scintigraphy)

PURPOSE: We studied six patients with sickle cell disease (SSD), five homozygous for sickle cell anemia and one with sickle beta-thalassemia, in whom rounded intrasplenic masses proved to be preserved functioning splenic tissue. MATERIALS AND METHODS: Available images including computed tomography, ultrasonography, bone scans (Tc-99m MDP), liver spleen scans (Tc-99m sulfur colloid), and MRI were evaluated. RESULTS: The masses were low density on CT (in an otherwise calcified spleen), hypoechoic relative to the echogenic spleen on US, and had the imaging characteristics of normal spleen on MRI. They failed to accumulate Tc-99m MDP but did demonstrate uptake of Tc-99m sulfur colloid. CONCLUSION: In a patient with SSD and intrasplenic masses, proper correlation of multiple imaging modalities will establish the diagnosis of functioning splenic tissue and avoid mistaken diagnosis of splenic abscess or infarction.     

Effect of cholecystokinin-pancreozymin (CCK-PZ) on glycoprotein secretion from mouse gallbladder epithelium: an ultrastructural and cytochemical study

L-Azetidine-2-carboxylic acid, the naturally occurring lower homologue of L-proline, is incorporated into hemoglobin S (sickle hemoglobin) in vitro. Sickle erythrocytes from patients with sickle cell anemia incubated with L-[3H] azetidine-2-carboxylate synthesized radiolabeled hemoglobin which when isolated from cell lysates, co-chromatographed with hemoglobin S on DEAE-cellulose columns. The alpha/beta ratio of azetidine carboxylate incorporation into the globin chains of sickle hemoglobin was 0.94, which is consistent with the presence of four proline residues in each polypeptide chain. Incorporation of azetidine carboxylate into hot trichloroacetic acid-insoluble material in sickle erythrocytes indicated that the homologue was present in the polypeptide backbone of the globin chains of sickle hemoglobin. Amino acid analysis of the hot trichloroacetic acid-insoluble material from sickle erythrocytes which had been incubated with radiolabeled azetidine carboxylate indicated that 75% of the radioactivity could be accounted for as intact homologue while 20% of the radioactivity co-chromatographed with alanine. These results suggest that azetidine carboxylate is incorporated unaltered into hemoglobin S in addition to being metabolized to alanine in sickle erythrocytes prior to incorporation into protein. The kinetics of thermal precipitation of hemoglobin S (oxygen ligand) into which radioactive azetidine carboxylate or radioactive proline had been incorporated in vitro is identical. This observation, together with the behavior of hemoglobin S and the globin chains from hemoglobin S containing azetidine carboxylate during ion-exchange chromatography, indicates that homologue replacement of prolyl residues does not significantly alter the overall charge or stability of the hemoglobin S tetramer. Azetidine carboxylate did not inhibit uptake of radiolabeled proline by sickle erythrocytes suggesting that the homologue does not adversely affect amino acid transport in these cells.     

Erythropoiesis in chronic renal disease

The diminished erythropoiesis in the anemia of chronic renal disease has been attributed to three possible factors: (1) decreased erythropoietin production, (2) inhibition of erythropoietin activity, and (3) decreased bone marrow response to erythropoietin. In this report we isolated and evaluated these parameters in 19 patients with chronic renal disease, nine patients with iron-deficiency anemia, and seven control subjects. The results in patients with chronic renal failure were as follows: (1) erythropoietin enhanced heme synthesis in bone marrow cell cultures by 88 +/- 12 per cent in renal failure, as compared to 65 +/- 7 per cent in the control group; (2) plasma erythropoietin activity did not increase appropriately for the degree of anemia; and (3) erythropoietin inhibitor activity in renal failure was not greater than in a control group. In conclusion, the relative failure of erythropoiesis in chronic renal disease appears to be due primarily to decreased production of erythropoietin and not to diminished marrow response to erythropoietin.     

Acute splenic sequestration in hemoglobin sickle O-Arab disease

A white girl with sickle O-Arab disease (Hb S/O-Arab) had three separate episodes of acute splenic sequestration at 8, 12, and 15 months of age with hemoglobin levels falling to 3.9, 2.8, and 4.2 g/dl, respectively. Functional hyposplenism was suggested by the radionucleotide spleen scan. Following splenectomy her hemoglobin stabilized in the range of 0.7--8.5 g/dl. Life-threatening episodes of splenic sequestration, pneumococcal infections and osteomyelitis may occur in both Hb S/O-Arab and homozygous sickle cell diseases.     

A new technique for laparoscopic splenectomy with massively enlarged spleens

Splenectomy is indicated in several hematological disorders and it can be particularly challenging in children with sickle cell disease, splenomegaly, and recurrent sequestration. Over the last 6 months, we have developed a new technique for laparoscopic splenectomy (LS) for hypersplenism and splenomegaly in five children with sickle cell disease. The average age of our patients was 6 years (range, 2-11), and the average weight was 18.7 kg (range, 13.2-30.1). On preoperative ultrasound, spleen size index ranged from 0.42 to 0.76. For the LS, four trochars were placed. One patient, who also underwent a laparoscopic cholecystectomy, had six trochars placed, two of which were used for both cholecystectomy and splenectomy. After laparoscopic mobilization of the spleen and hilar vascular stapling, a Steiner electromechanical morcellator was inserted through the 12-mm port to extract cores of splenic tissue until complete splenectomy was achieved. No patient required conversion to an open procedure or creation of a larger incision to remove the massively enlarged spleen. Operative time averaged 190 minutes; the combined LS and cholecystectomy took 245 minutes. Postoperative length of stay was <2 days for all patients. There were no complications, and no patient required postoperative transfusion. Based on these early findings, we conclude that intracorporeal coring of splenic tissue allows for safe and complete laparoscopic removal of very large spleens in small children. It provides expedient recovery and minimal postoperative pain and scarring. This new technique should enable surgeons to perform LS even in patients with massive splenomegaly, eliminating the need for large and cumbersome intracorporeal bags or the creation of additional incisions to remove the spleen.     

Re-accreditation, re-certification and the postgraduate database

Anemia associated with ACE inhibitors is rare but it may cause problems especially in patients with renal disease. This study assessed the acute effect of trandolapril, an ACE inhibitor, on serum erythropoietin (EPO) levels in uremic and hypertensive patients. Trandolapril 2 mg/day was given orally for three days and blood samples were collected on the first and third day. Trandolapril led to a significant decrease in serum EPO in patients with chronic renal failure. Although the drug lowered serum EPO in hypertensive patients, this effect was not statistically significant. This drop in serum EPO levels may be one of the mechanisms by which ACE inhibitors cause anemia, or worsen anemia, in uremic patients and further studies are needed to clarify this point.     

Granular cell tumor of the pituitary stalk

Erythropoietin is a hormone responsible for regulation of red blood cell production. Circulating erythropoietin values are regulated by renal oxygen supply, which is determined by hemoglobin concentration, hemoglobin oxygen saturation, and renal blood flow. Previous animal and human studies regarding erythropoietin regulation have assumed pulsatile renal blood flow. During cardiopulmonary bypass, non-pulsatile renal perfusion has been shown to result in decreased glomerular filtration rate and decreased renal blood flow in comparison to pulsatile perfusion. Repair of congenital heart disease during cardiopulmonary bypass is an attractive circumstance in which to study the effect of non-pulsatile blood flow on erythropoietin production. The hypothesis in this study was that non-pulsatile perfusion would result in increased erythropoietin production because of decreased renal oxygen supply. Fourteen children with congenital heart disease and without preoperative renal insufficiency or anemia were enrolled in the study. All patients underwent cardiopulmonary bypass with non-pulsatile flow. In addition, 10 control patients without congenital heart disease were enrolled. Six cardiopulmonary bypass patients had 1.5- to 6-fold increases in plasma erythropoietin concentrations from baseline. These patients had longer cardiopulmonary bypass times, more commonly performed under low flow deep hypothermic conditions. The remaining 8 patients with congenital heart disease, and all control patients, did not develop increased postoperative erythropoietin concentrations. The conditions under which cardiopulmonary bypass are performed appear to influence postoperative circulating erythropoietin concentrations.     

Heme synthesis in hereditary hemolytic anemias: decreased delta-aminolevulinic acid synthetase in hemoglobin K?ln disease

The activities of delta-aminolevulinic acid (ALA) synthetase and ALA dehydratase in cord blood erythrocytes of newborn infants and peripheral blood red cells of patients with beta-thalassemia major, beta-thalassemia intermedia, hemoglobin K?ln (Hb K?ln) disease, sickle cell anemia, and pyruvate kinase deficiency were studied. The activity of ALA dehydratase did not vary appreciably with the number of immature RBC (reticulocytes and nucleated red blood cells) or the severity of the hemolytic anemia except in pyruvate kinase deficiency. The activity of ALA synthetase was linearly correlated with the number of immature RBC (r=0.974, p is less than 0.001). The ALA synthetase activity was significantly decreased in the RBC of Hb K?ln (p is less than 0.01) when compared with the activity in immature RBC of newborns and of patients with pyruvate kinase deficiency, sickle cell anemia, and thalassemia intermedia.     

Influence of hemoglobin E trait on the severity of Falciparum malaria

To determine if hemoglobin E trait influences the course of acute malaria, adults hospitalized for the treatment of symptomatic infection with Plasmodium falciparum were studied retrospectively. Forty-two patients with hemoglobin E trait were compared with 175 reference subjects who did not have hemoglobin E, beta-thalassemia, glucose-6-phosphate dehydrogenase deficiency, or alpha-thalassemia. One patient (2.4%) with hemoglobin E trait had a severe complication of malaria by World Health Organization criteria (cerebral malaria), while 32 subjects in the reference group (18.3%) had one or more severe complications: cerebral malaria (n=18), hyperparasitemia (n=16), renal failure (n=10), and severe anemia (n=1) (P=.044 after adjustment for ethnic categories). The estimated odds of severe complications in the reference subjects were 6.9 times the odds in patients with hemoglobin E trait (95% confidence interval, 1.2-146. 4). These results suggest that hemoglobin E trait may ameliorate the course of acute falciparum malaria.