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S K Ballas

Publications and source records attributed to S K Ballas.

At least 19 recordsLinked to original sources
PubMed2001

Evidence for carbon monoxide binding to sickle cell polymers during melting.

The melting of sickle cell hemoglobin (HbS) polymers was induced by rapid dilution using a stopped-flow apparatus. The kinetics of polymer melting were monitored using light scattering. Polymer melting in the absence of any hemoglobin ligand was compared to melting when the diluting buffer was saturated with carbon monoxide (CO). In this way the role of CO in polymer melting could be assessed. The data were analyzed using models that assumed that melting occurs only at the ends of polymers. It was further assumed that CO could only bind to HbS in the solution phase. However, our data could not be fitted to this model, where CO cannot bind directly to the polymer. Thus, CO probably binds directly to the polymers during our melting experiments. This result is discussed in terms of oxygen induced polymer melting and polymerization processes in sickle cell disease

Biopolymers↗
PubMed2001

In vitro exposure to hydroxyurea reduces sickle red blood cell deformability.

Hydroxyurea is a drug that is used to treat some patients with sickle cell disease. We have measured the deformability of sickle erythrocytes incubated in hydroxyurea in vitro and found that hydroxyurea acts to decrease the deformability of these cells. The deformability of normal erythrocytes was not significantly affected by hydroxyurea except at very high concentrations. Hydroxyurea also did not consistently reduce the deformability of sickle erythrocyte ghosts. We propose that the decreased deformability, observed in vitro, is due to the formation of methemoglobin and other oxidative processes resulting from the reaction of hydroxyurea and oxyhemoglobin. Although the reaction with normal hemoglobin is similar to that of sickle hemoglobin, the sickle erythrocytes are affected more. We propose that the sickle erythrocyte membrane is more susceptible to the reaction products of the reaction of hemoglobin and hydroxyurea. An earlier report has shown that hydroxyurea increases the deformability of erythrocytes in patients on hydroxyurea. Taken together, these data suggest that the improved rheological properties of sickle erythrocytes in vivo are due to the elevated numbers of F cells [cells with fetal hemoglobin]. The presence of the nitrosyl hemoglobin or methemoglobin from the reaction with hydroxyurea may also benefit patients in vivo by reducing sickling.

Anemia, Sickle Cell↗
PubMed2001

Molecular characteristics of pediatric patients with sickle cell anemia and stroke.

Cerebrovascular accidents (CVA) are serious complications of sickle cell anemia (SS) in children. Factors that predispose children to this complication are not well established. In an effort to elucidate the risk factors associated with CVA in SS, we have determined the alpha-globin genotype and the beta(S) haplotype of children with this complication. Among 700 children with SS followed at Children's Hospital of Michigan, 41 (6%) are on chronic transfusions because of stroke due to cerebral infarction. The mean age of patients with CVA at the time of stroke was 5.6 +/- 3.2 years (mean +/- SD). The male/female ratio was 2/3. Only 8 of 41 patients (19.5%) had one alpha-gene deletion, compared to the reported prevalence of 30% in African-Americans. None of the patients had two alpha-gene deletions, and two (5%) had five alpha-genes. These findings are different than those in our adult patients with SS, where the prevalence of -alpha/-alpha and alphaalphaalpha/alphaalpha is 4% and <2%, respectively. Ten different beta(S)-haplotypes were detected in the patients studied. The majority of the patients (31%) were doubly heterozygous for the Ben/CAR haplotypes followed by Ben/Ben, Ben/Sen, and CAR/CAR haplotypes, respectively. The prevalence of these haplotypes, with the exception of the CAR/CAR haplotype, was higher in females than males. All the patients with CAR/CAR haplotype were males, had four alpha-genes, and ranked third in prevalence. Three patients were heterozygous for the Cameron haplotype. The Cameron and atypical haplotypes were more prevalent than reported in patients with SS at large. The data suggest that CVA in children seems to occur more frequently in females and in patients with certain beta(S) haplotype. alpha-Gene deletion seems to offer a protective effect against this complication. Neonates with four or more alpha-genes whose beta(S) haplotype is Ben/CAR, atypical, or CAR/CAR seem to be at a higher risk for CAV than other patients. A prospective study on a larger group of patients with or without CVA may clarify this issue.

Anemia, Sickle Cell↗
PubMed2001

Ethical issues in the management of sickle cell pain.

Care providers who manage patients with sickle cell disease (SCD) often face several questions. Most prominent among these pertain to the importance of pain and its treatment. The duties of the health care providers concerning pain management are often not well defined and vary considerably among providers and institutions. Despite the availability of national guidelines that address the ethical issues of pain management, patients with SCD often receive suboptimal pain control, especially during acute painful episodes. Although there are many reasons for this situation, an important aspect of the problem pertains to the complexity of applying ethical standards to specific patients with sickle cell pain. Decisions are frequently made according to perceptions and circumstances without taking ethical principles into consideration. The purpose of this paper is to present the range of ethical principles pertinent to sickle pain management and discuss specific examples of physician-patient interactions where ethical dilemmas occur.

Anemia, Sickle Cell↗
PubMed2001

Sickle cell disease: current clinical management.

The phenotypic expression of sickle cell disease (SCD) varies greatly among patients and longitudinally in the same patient. The phenotype influences all aspects of the life of affected individuals including social interactions, intimate relationships, family relations, education, employment, and spirituality. The clinical, manifestations of SCD are protean and fall into three major categories: (1) anemia and its sequelae; (2) pain and related issues; and (3) end-organ failure including infection. This review will emphasize the pathophysiology and management of sickle cell pain, as well as organ failure and its management.

Anemia, Sickle Cell↗
PubMed2001

Iron overload is a determinant of morbidity and mortality in adult patients with sickle cell disease.

Patients with sickle cell disease (SCD) often require blood transfusion starting in early childhood. Multiple blood transfusions on a chronic basis lead to excessive accumulation of iron, especially in adults with sickle cell anemia (SS) that is progressively increasing in size. Blood exchange transfusion and the use of iron chelation therapy may prevent or delay the onset of iron overload. The majority of adults with SS, however, require episodic blood transfusions on a chronic basis and, hence, are at risk to develop iron overload. Recent reports suggest an association between iron overload and organ failure in chronically transfused patients. Patients with SCD and iron overload may thus be at increased risk to develop organ failure compared to those with normal iron stores. In order to clarify this issue we have prospectively collected the following data on our adult patients with SCD between 1978 and 1998: (1) the amount of blood transfused; and (2) the status of iron stores determined with serum ferritin, serum iron, total iron binding capacity (TIBC), and percent transferrin saturation (% Sat). Between 1987 and 1998, 247 adult patients with SS were regularly followed in our sickle cell center. Of these, 152 (62%) were transfused with 4,875 units of red blood cells (RBCs). Transfused patients received an average of 10 units of RBCs per year, which is equivalent to about 2.0 g of iron per year. This does not include transfusions at other institutions or before 1987. About one third of the adult patients with SS had % Sat greater than 50 in the steady state, suggesting iron overload. During painful episodes serum ferritin increased significantly in paired observations. Serum iron and TIBC decreased during painful episode disproportionately so that there was a significant net decrease in % Sat in paired observations. Patients with low values of serum ferritin and % Sat had lower incidence of acute painful episodes (38% v 64%) and organ failure (19% v 71%) than those who had iron overload, respectively. Mortality was significantly higher in the iron overload group: 64% versus 5%, respectively. Taken together, the data indicate that (1) the status of iron stores in adults with SS is best determined by keeping accurate records of the amount of blood transfused and serial determinations of ferritin levels in the steady state; (2) a significant number of adults with SS have iron overload; and (3) iron overload seems to be a predisposing factor of disease severity.

Adult↗
PubMed2001

In vitro sealing of punctured fetal membranes: potential treatment for midtrimester premature rupture of membranes.

OBJECTIVE: Midtrimester premature rupture of membranes causes significant perinatal morbidity and death. No effective treatment exists. We investigated (1) whether a needle puncture in the fetal membranes could be sealed in vitro and (2) the optimal composition of the sealant to be used. STUDY DESIGN: Membranes from second trimester pregnancies (16-24 weeks of gestation) were stretched over a modified syringe with a 2.5-cm open diameter. The syringe was filled with 20 mL of second trimester amniotic fluid, and the membrane was punctured with a 20-gauge needle. Sealants were injected into the amniotic fluid. The primary outcome variable was time for leakage of amniotic fluid. Median times for leakage for the formulations were compared by Wilcoxon exact rank sum test. RESULTS: Platelets alone failed to seal the puncture site. All other formulations stopped leakage temporarily. Tisseel (Baxter Corp, Glendale, Calif) and cryoprecipitate/thrombin preparations led to more prolonged sealing of punctured amniotic membranes than platelets (P <.01) and were not significantly different from each other. CONCLUSION: Of the sealants tested in vitro, amniotic membranes are best sealed by a fibrin/thrombin-based sealant.

Amnion↗
PubMed2001

Sudden unexpected death in a patient with splenic sequestration and sickle cell-beta+-thalassemia syndrome.

Acute splenic sequestration crisis is a rare disorder that usually occurs in children, with sickle cell anemia, who are under the age of five years. A few cases have been described in adults with heterozygous sickle cell syndromes. Though this entity can be fatal there have been no reported cases associated with sudden death. We describe a case of sudden, unexpected death, associated with splenic sequestration, in a 29-year-old African-American man with undiagnosed sickle cell-beta-thalassemia syndrome.

Adult↗
PubMed2000

Pleiotropic syndrome of dehydrated hereditary stomatocytosis, pseudohyperkalemia, and perinatal edema maps to 16q23-q24.

Dehydrated hereditary stomatocytosis (DHS) is a rare genetic disorder of red cell permeability to cations, leading to a well-compensated hemolytic anemia. DHS was shown previously to be associated in some families with a particular form of perinatal edema, which resolves in the weeks following birth and, in addition, with pseudohyperkalemia in one kindred. The latter condition was hitherto regarded as the separate entity, "familial pseudohyperkalemia." DHS and familial pseudohyperkalemia are thought to stem from the same gene, mapping to 16q23-q24. This study screened 8 French and 2 American families with DHS. DHS appeared to be part of a pleiotropic syndrome in some families: DHS + perinatal edema, DHS + pseudohyperkalemia, or DHS + perinatal edema + pseudohyperkalemia. If adequately attended to, the perinatal edema resolved spontaneously after birth. Logistic regression showed that increased mean corpuscular volume and mean corpuscular hemoglobin concentration were the parameters best related to DHS. In patients in whom cation fluxes were investigated, the temperature dependence of the monovalent cation leak exhibited comparable curves. Specific recombination events consistently suggested that the responsible gene lies between markers D16S402 and D16S3037 (16q23-q24). The 95% confidence limits (Z(max) >/= 3.02) spanned almost the complete 9-cM interval between these 2 markers.

Adolescent↗
PubMed2000

The reactions of myoglobin, normal adult hemoglobin, sickle cell hemoglobin and hemin with hydroxyurea.

The kinetics of the reaction of hydroxyurea (HU) with myoglobin (Mb), hemin, sickle cell hemoglobin (HbS), and normal adult hemoglobin (HbA) were determined using optical absorption spectroscopy as a function of time, wavelength, and temperature. Each reaction appeared to follow pseudo-first order kinetics. Electron paramagnetic resonance spectroscopy (EPR) experiments indicated that each reaction produced an FeNO product. Reactions of hemin and the ferric forms of HbA, HbS, and myoglobin with HU also formed the NO adduct. The formation of methemoglobin and nitric oxide-hemoglobin from these reactions may provide further insight into the mechanism of how HU benefits sickle cell patients.

Adult↗
PubMed2000

Sequential nitric oxide measurements during the emergency department treatment of acute vasoocclusive sickle cell crisis.

This prospective study was designed to examine the relationship between serial serum nitric oxide (NO) levels and pain during the emergency department (ED) treatment of acute vasoocclusive sickle cell crisis (SCC). 102 patient visits, age > or =18 years of age, presenting to the ED with uncomplicated, typical SCC pain had serum NO levels obtained at 2-hr intervals during treatment of pain and were measured using an NO-specific chemiluminesence technique. Pain was measured prior to each NO measurement using a 10 cm visual analog scale (VAS), and subjects were divided into a persistent pain group and an improved pain group. Patients with persistent pain had significantly low initial NO levels (11.51 microM +/- 2.8, P < 0.05) while those with pain improvement had higher initial NO levels (18.1 microM +/- 3.08, P < 0.05). There was no significant correlation between changes in NO and changes in pain scores. These results suggest that the initial NO level may serve as a marker for the severity of tissue ischemia. Sequential NO levels do not appear useful in predicting the course of SCC.

Acute Disease↗
PubMed2000

Cost-effectiveness of hydroxyurea in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia.

The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH) demonstrated the efficacy of hydroxyurea in reducing the rate of painful crises compared to placebo. We used resource utilization data collected in the MSH to determine the cost-effectiveness of hydroxyurea. The MSH was a randomized, placebo-controlled double-blind clinical trial involving 299 patients at 21 sites. The primary outcome, visit to a medical facility, was one of the criteria to define occurrence of painful crisis. Cost estimates were applied to all outpatient and emergency department visits and inpatient hospital stays that were classified as a crisis. Other resources for which cost estimates were applied included hospitalization for chest syndrome, analgesics received, hydroxyurea dosing, laboratory testing, and clinic visits for management of patient care. Annualized differential costs were calculated between hydroxyurea- and placebo-receiving patients. Hospitalization for painful crisis accounted for the majority of costs in both arms of the study, with an annual mean of $12,160 (95% CI: $9,440, $14,880) for hydroxyurea and $17,290 (95% CI: $13,010, $21,570) for placebo. The difference in means was $5,130 (95% CI: $60, $10,200; P = 0.048). Chest syndrome was the next largest cost with a mean difference of $830 (95% CI: $-340, $2,000; P = 0.16). The hydroxyurea arm was also associated with lower costs for emergency department visits, transfusion, and use of opiate analgesics. In total, the annual average cost per patient receiving hydroxyurea was $16,810 (95% CI: $13,350, $20,270) and the annual average costs per patient receiving placebo was $22,020 (95% CI: $17,340, $26,710). The difference in means was $5,210 (95% CI: $-610, $11,030; P = 0.21). The cost of hydroxyurea with the more intensive monitoring required when using this drug appears to be more than offset by decreased costs for medical care of painful crisis and analgesic use. Although the total cost difference was not significant statistically, these results suggest that hydroxyurea therapy is cost-effective compared to placebo in the management of adult patients with sickle cell anemia. If hydroxyurea can prevent development of chronic organ damage, long-term savings may be even greater.

Adult↗
PubMed2000

Hydration of sickle erythrocytes using a herbal extract (Pfaffia paniculata) in vitro.

Pfaffia paniculata (PP) is a perennial wild plant that grows in South America. Its root powder has been used by South American Indians for a variety of ailments and has been reported to have a salutary effect on sickle cell disease in Brazil. Its mechanism of action, however, is unknown. In this report, we present experimental data showing that PP improves the deformability of sickle cells, increases their Na+ content and their mean corpuscular volume (MCV). These findings indicate that PP functions as a sodium ionophore on sickle cells and improves their hydration status and rheological properties.

Anemia, Sickle Cell↗
PubMed2000

Elevated serum and bronchoalveolar lavage fluid levels of interleukin 8 and granulocyte colony-stimulating factor associated with the acute chest syndrome in patients with sickle cell disease.

The role of cytokines in the development of acute chest syndrome (ACS) in patients with sickle cell disease (SCD) was studied. Serum interleukin 8 (IL-8) levels were elevated in 14 episodes and undetectable in six out of 20 episodes of ACS in 19 patients with SCD. In contrast, IL-8 levels were undetectable in the sera of 29 control patients with SCD studied during routine clinic visits or hospitalization for vaso-occlusive crises. The differences in mean IL-8 levels and the proportion of patients with detectable levels between the two groups were highly significant (P < 0.0001 and 0.04 respectively). The mean IL-8 level in bronchial fluid samples from children with ACS was also significantly higher than that in sickle cell patients undergoing elective surgery (5500 +/- 1400 pg/ml vs. 1900 +/- 470 pg/ml, P = 0.03). Granulocyte colony-stimulating factor (G-CSF) (2000 +/- 1700 pg/ml) was present in five out of six samples of bronchial fluid, but not serum, from children with ACS. All but one of the patients with ACS studied were negative for the Duffy red cell antigen, which is a receptor that binds and inactivates IL-8 and other chemokines. These findings suggest that IL-8 and G-CSF may play a role in the development of the ACS and the complications associated with it.

Acute Disease↗
PubMed2000

Determinants of red cell survival and erythropoietic activity in patients with sickle cell anemia in the steady state.

We have studied 26 patients with sickle cell anemia to determine the factors that affect red blood cell (RBC) survival and other parameters of erythropoietic activity in the steady state. Determinants of erythropoietic activity included RBC survival by the 51Cr method, RBC production/destruction rate, alpha genotype, beta(s) haplotype, plasma 59Fe clearance, plasma iron turnover, erythron transferrin uptake), RBC Fe utilization, reticulocyte count, and erythropoietin levels. The alpha genotype was the most significant determinant of RBC survival followed, to a lesser extent, by the beta(s) haplotype. Hb F showed no correlation with RBC survival due to patient selection bias - the patients studied had comparable Hb F levels to start with. Other determinants of erythropoietic activity (hemoglobin level, mean corpuscular volume, reticulocyte count, RBC mass, RBC production/destruction rate, and erythropoietin level) were most likely secondary determinants associated with the alpha genotype, and not independent determinants in themselves. The data suggest that the alpha genotype and, and to a lesser extent, the beta(s) haplotype, might be determinants of the severity of the anemia of sickle cell disease, and should be considered in genetic counseling and patient selection for aggressive therapeutic interventions.

Adult↗
PubMed1999

The reaction of deoxy-sickle cell hemoglobin with hydroxyurea.

In addition to its capacity to increase fetal hemoglobin levels, other mechanisms are implicated in hydroxyurea's ability to provide beneficial effects to patients with sickle cell disease. We hypothesize that the reaction of hemoglobin with hydroxyurea may play a role. It is shown that hydroxyurea reacts with deoxy-sickle cell hemoglobin (Hb) to form methemoglobin (metHb) and nitrosyl hemoglobin (HbNO). The products of the reaction as well as the kinetics are followed by absorption spectroscopy and electron paramagnetic resonance (EPR) spectroscopy. Analysis of the kinetics shows that the reaction can be approximated by a pseudo-first order rate constant of 3.7x10(-4) (1/(s.M)) for the disappearance of deoxy-sickle cell hemoglobin. Further analysis shows that HbNO is formed at an observed average rate of 5.25x10(-5) (1/s), three to four times slower than the rate of formation of metHb. EPR spectroscopy is used to show that the formation of HbNO involves the specific transfer of NO from the NHOH group of hydroxyurea. The potential importance of this reaction is discussed in the context of metHb and HbNO being able to increase the delay time for sickle cell hemoglobin polymerization and HbNO's vasodilating capabilities through conversion to S-nitrosohemoglobin.

Antisickling Agents↗
PubMed1999

Temperature and domain size dependence of sickle cell hemoglobin polymer melting in high concentration phosphate buffer.

Deoxygenated sickle cell hemoglobin (Hb S) in 1.8 M phosphate buffer, and carbon monoxide (CO) saturated buffer were rapidly mixed using a stopped-flow apparatus. The binding of the CO to the Hb S polymers and the polymer melting was measured by time resolved optical spectroscopy. Polymer melting was associated with decreased turbidity, and CO binding to deoxy-Hb S was monitored by observation of changes in the absorption profile. The reaction temperature was varied from 20 degrees C to 35 degrees C. Polymer domain size at 20 degrees C was also varied. The data for mixtures involving normal adult hemoglobin (Hb A) fit well to a single exponential process whereas it was necessary to include a second process when fitting data involving Hb S. The overall Hb S-CO reaction rate decreased with increasing temperature from 20 degrees C to 35 degrees C, and increased with decreasing domain size. In comparison, Hb A-CO reaction rates increased uniformly with increasing temperature. Two competing reaction channels in the Hb S-CO reaction are proposed, one involving CO binding directly to the polymer and the other involving CO only binding to Hb molecules in the solution phase. The temperature dependence of the contribution of each pathway is discussed.

Adult↗