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PubMed1990

Fitting abnormal oxygen equilibrium curves of hemoglobin.

A growing number of oxygen equilibrium curves for hemoglobin (Hb) mutants, post-translational modifications, or the binding of potent new effectors of Hb cannot be fitted adequately with the two-state model. Examples are curves showing double maxima in the derivative of the Hill plot, or slopes of less than unity. We present such examples of modified hemoglobins and strong effectors in this study and calculate at which substate level the two-state model differs from the data. Analysis of hemoglobin oxygen equilibrium curves is reconsidered using the two-state model extended to allow variation of the individual substate probabilities. In this way the effect on the equilibrium due to perturbations in energy of each substate can be studied as a diagnostic tool.

Allosteric Regulation↗
PubMed1996

A cost-effectiveness evaluation of newborn hemoglobinopathy screening from the perspective of state health care systems.

OBJECTIVE: To determine the most cost-effective strategy for newborn hemoglobinopathy screening from the perspective of state health care systems. STUDY DESIGN: Using Alaska as an example, we used decision analysis to compare a policy of no screening to universal or targeted screening with selective follow-up only of infants who are homozygous or compound heterozygous for an abnormal hemoglobin variant and to universal or targeted screening with complete follow-up, including follow-up of infants with clinically insignificant traits. Probabilities and costs were varied over values that might be expected for other states. RESULTS: Among the selective follow-up options, targeted screening would be the most cost-effective strategy for Alaska at a cost of $206,192 per death averted; by contrast, universal screening would prevent 50% more deaths at an incremental cost of $2,040,000 per death averted. Universal would be more cost-effective than targeted screening for several scenarios expected to occur in other states, including a high sickle cell disease prevalence, a low screening test cost, and a high cost per screen associated with racial targeting. Among the complete follow-up options, both targeted and universal screening would cost at least $200,000 per death averted over the range of all variables tested during sensitivity analysis; the incremental cost of universal versus targeted screening would be at least $600,000 per death averted. CONCLUSIONS: Our data suggest each state should determine the most cost-effective option based on state-specific values for sickle cell disease prevalence, test costs and racial targeting costs.

Alaska↗
PubMedDate not supplied

Carboxyhemoglobin and methemoglobin levels in banked blood.

Carboxyhemoglobin and methemoglobin levels in 312 units of banked blood and their relationship to the duration of storage were determined. The carboxyhemoglobin level decreased as the storage time increased, and its mean was 1.4% +/- 2.0% (SD) with a range from 0% to 9.6%. Methemoglobin increased during storage, showing a mean level of 1.6% +/- 0.4% and a range from 0.5% to 4.2%. In a separate study, blood drawn from six volunteers who had smoked two cigarettes each was stored as banked blood for 21 days. The mean initial level of carboxyhemoglobin was 4.4% +/- 1.6%, and the mean half-life of carboxyhemoglobin was approximately 47 days. Methemoglobin increased from an initial 1.3% +/- 0.2% to 2.4% +/- 0.6% at the end of storage. The use of banked blood containing high levels of these abnormal hemoglobins could be a potential risk in critically ill patients.

Aged↗
PubMedDate not supplied

Molecular spectrum of beta-thalassemia in the Mexican population.

Beta-thalassemia (beta-thal) is present in 59% and 75% of patients with abnormal hemoglobin disorders in northwestern and central Mexico, respectively. In our Research Center, up until 1997, we reported the presence of 13 beta-thal alleles in 26 unrelated chromosomes (-28A>C; -87C>T; MET1VAL; IVS1, G>A, +1; IVS1, G>A, +5; IVS1, G>C, +5; IVS1, G>A, +110; IVS2, C>G, +745; GLU6FS; VAL11FS; GLN39TER; HBD/HBB 104 kb del; and HBD87/HBB116 fusion). Since then, 57 more beta-thal chromosomes have been identified by the amplification-refractory mutation system (ARMS) and DNA sequencing from 54 individuals with beta-thalassemia (seven compound heterozygotes, three with two beta-thal alleles, three with beta-thal and HbS, and one with beta-thal and HbD; and 47 beta-thal heterozygotes). Nine of the previously observed alleles were found, together with three new alleles: IVS2, G>A, +1; LYS17TER; and 4-bp del, 41/42CTTT. Moreover, a novel mutation was observed, HIS77FS, bringing to a total of 17 beta-thal alleles identified in our population. Six alleles constitute 78.3% of the observed alleles: five Mediterranean alleles (GLN39TER; IVS1, G>A, +1; IVS1, G>A, +110; HBD/HBB 104 kb del; and IVS1, G>A, +5) and one common in the Kurdish population (-28A>C). We note especially the presence in these families of -28A>C and VAL11FS, both of which have previously been considered private alleles. The observed spectrum of mutations is characteristic of populations with low frequencies of thalassemias. Because thalassemia is not a rare disease in Mexico, we emphasize its necessary consideration in the differential diagnosis of microcytic hypochromic anemia.

Heterozygote↗
PubMed2005

Molecular analysis of unknown beta-globin gene mutations using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) technique and its application in Thai families with beta-thalassemias and beta-globin variants.

OBJECTIVES: Approximately 40 beta-globin gene mutations have been identified in Thailand. The detection of these mutations is currently performed by the reverse dot blot (RDB) hybridization technique, which could detect only known mutations. We describe here the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assay for detecting unknown mutations of the beta-globin genes. DESIGN AND METHODS: Six PCR fragments covering the promoter, entire coding region, and intervening sequences were amplified before separation by the SSCP technique. Fifteen known mutations and two polymorphisms were analyzed by this technique in various gel mixtures and temperatures to compare their mobility shift patterns. RESULTS: The clear patterns of mobility shift were demonstrated when a 10% polyacrylamide gel with 5% glycerol was used. The sensitivity was found to be 100% when electrophoreses were performed at both room temperature and 6 degrees C. This technique was then applied to screen beta-globin gene mutations in Thai families with similar profiles of abnormal hemoglobins. The distinct patterns of mobility shifts were observed in which further sequencing analysis revealed an AC insertion at codon 146, causing hemoglobin Tak. CONCLUSION: The PCR-SSCP technique might be a useful molecular technique to minimize the requirement of direct genomic sequencing to identify beta-globin gene mutations and could be applied in several developing countries where resources are limited but genetic hemoglobin disorders are highly prevalent.

Adolescent↗
PubMed1979

Laboratory diagnosis of HB CC-alpha-thalassemia.

Routine laboratory investigations of hemoglobinopathies include Hb electrophoresis for abnormal hemoglobins, determination of Hb A2 (alpha 2 delta 2) for beta-thalassemia traits, staining for Hb H (beta 4) inclusions for alpha-thalassemia traits and estimation of Hb F (alpha 2 lambda 2) for the presence of hereditary persistence of fetal hemoglobin genes (HPFH). Frequently, analytical column chromatography and alpha/beta hemoglobin chain synthesis are used in the studies of more complicated hemoglobinopathies. This communication outlines the procedures used in this laboratory for the diagnosis of a case of Hb CC-alpha-thalassemia.

Adult↗
PubMed1980

The management of hematuria associated with sickle hemoglobinopathies.

Hematuria secondary to sickle cell hemoglobinopathy was first reported by Abel and Brown in 1948. They noted sickled erythrocytes in a kidney removed for suspected tumor. Since then there have been numerous reports attributing hematuria to the abnormal hemoglobins that produce sickling of red cells. Although presently a well established entity the management of this fairly unique form of hematuria is far from standardized. The pathogenesis of the condition is fairly well understood and several modalities of treatment have been tried--many of which have a sound physiological basis in their use but a randomized prospective study in a large series of patients has yet to be performed. Herein is reviewed the current concepts of the etiology, diagnosis and management of this unusual form of hematuria.

Anemia, Sickle Cell↗
PubMedDate not supplied

Otolaryngologic manifestations of sickle cell disease.

Sickle cell disease is a common hereditary hematologic disorder characterized by the presence of a structurally abnormal hemoglobin molecule. Physicochemical properties of sickle hemoglobin result in a chronic hemolytic anemia and in vaso-occlusive episodes with ischemic injury of many tissues. In patients with sickle cell disease the otolaryngologist may be confronted with lesions affecting the ear, the bones and soft tissues, and the nervous system. Surgery and anesthesia also present special problems. An outline and discussion of these clinical concerns are presented.

Anemia, Sickle Cell↗
PubMed2005

[Oxygen therapy in newborn: equipments for non-invasive monitoring].

In newborn and premature infants whose lung immaturity entails a limited capacity for O2 detoxification, the use of supplemental oxygen should be continuously and non-invasively monitored. Pulse oximetry and transcutaneous O2 monitoring are the systems most used in the NICU. Major limitations of pulse oximetry are motion artifact, sensitivity to excessive light, cutaneous hypoperfusion, hypothermia, venous congestion, arterio-venous shunting, strong skin pigmentation, anemia and high percentage of abnormal hemoglobin. Alarm habituation is a further major risk. New oxymeters show less motion, artifact and higher accuracy during low oxygen saturation. The accuracy during high oxygen saturation is very dependent on the specific oxymeter model used. Transcutaneous O2 monitoring is usually combined with transcutaneous PCO2 monitoring, hence enabling evaluation of oxygenation as well as ventilation. A major risk of this method is related to the heated electrode sensor, which can induce skin burns. A combined ear sensor for pulse oximetry and PCO2 monitoring seems promising.

Humans↗
PubMed1999

Preventing morbidity and mortality from sickle cell disease. A public health perspective.

CONTEXT: Sickle cell disease is a group of conditions characterized by production of abnormal hemoglobin, with clinical manifestations that vary by genotype and age. OBJECTIVE: To discuss current public health issues associated with sickle cell disease, and approaches to preventing complications from these conditions in the United States. DESIGN: Literature review. RESULTS: Most clinical interventions for people with sickle cell disease discussed in the medical literature can be classified as tertiary prevention: for example, therapy to ameliorate anemia, reduce the frequency of pain crises, or prevent stroke recurrences. A form of secondary prevention, newborn screening, has emerged as an important public health approach to identifying affected children before they develop complications. Newborn screening is the starting point for simple public health strategies such as parental education, immunization, and penicillin prophylaxis. Identification of affected families by newborn or community screening programs has also been an entry point for genetic counseling, although utilization of prenatal testing has varied by factors such as geographic location. Public health agencies have had significant involvement with funding, policy making, and formulation of laboratory and clinical guidelines for sickle cell disease. Since the introduction of penicillin prophylaxis policies, newborn screening, new immunizations, and comprehensive medical care centers, the survival of young children with sickle cell disease has improved. CONCLUSIONS: Although the efforts of preventive medicine providers in public health programs are not solely responsible for the improved survival of children with sickle cell disease, such programs remain an important component in preventing sickle cell complications.

Anemia, Sickle Cell↗
PubMed2001

[Neonatal screening for sickle cell anemia: evaluation of a five-year experience in an area of northern Paris].

UNLABELLED: We report a five-year experience of targeted neonatal screening for sickle cell disease in the northern part of the Paris area as well as the follow-up procedure of screened patients. POPULATION: This geographic area in France is characterized by a high frequency of populations at risk for sickle cell disease. RESULTS: Among 115,480 tested newborns, 250 patients were diagnosed (frequency: 1/462). The quality of the screening was attested by the high frequency (5.34%) of newborn carriers for a hemoglobin abnormality (n = 6168). We developed an optimized strategy which avoids the majority of pitfalls (false positive and false negative responses), except for S/HPFH. More than 95% of sickle cell disease was followed, the majority by medical sickle cell disease experts from hospitals. Only two deaths were recorded during this time period. CONCLUSION: We demonstrate the efficiency of targeting the proposed methodological strategy and the follow-up of affected newborns, a major argument demonstrating the importance of newborn screening.

Anemia, Sickle Cell↗
PubMed1999

Prenatal cellular transplantation.

Based on the ontogeny of fetal immunologic development, the strategy of fetal cellular transplantation may prove to be the most physiological way to achieve replacement of abnormal hemoglobin, immune cells, or enzyme defects diagnosed early prenatally. Similarly, if cellular transplantation can induce tolerance, postnatal solid organ transplantation may be performed without the need for chronic immunosuppression or with a reduced risk of graft-versus-host disease. This review presents experimental data from the late 1940s until the present for both small and large animal models; it also describes the limited clinical experience with prenatal cellular transplantation.

Animals↗
PubMed2004

beta-Globin mutation detection by tagged single-base extension and hybridization to universal glass and flow-through microarrays.

To test the feasibility of developing a diagnostic microarray for a specific disease, we selected all pathogenic changes of the beta-globin gene occurring at a frequency >/=1% in the multi-ethnic Dutch population for analysis. A tagged single-base extension (SBE) approach was used to detect 19 different mutations causing beta-thalassemia or abnormal hemoglobins. In the SBE reaction, the primers were elongated at the 3'site with a fluorescently labeled dideoxyribonucleotide triphosphate (ddNTP) complementary to the mutation, following tag hybridization to a glass or flow-through microarray. We compared the performance of a generic glass array and a porous system, by testing each mutation separately using heterozygous carriers and by screening a cohort of 40 unknown beta-thalassemia carriers and patients. The results were verified by direct sequencing. The microarray system was able to detect 17 beta-globin mutations simultaneously with >95% accuracy in a single SBE reaction. The flow-through array performed slightly better (96%), but the main advantages of the system included real-time data recording and a considerable time saving achieved through a reduced hybridization time.

Base Sequence↗
PubMed1981

Nonrandom patterns of codon usage and of nucleotide substitutions in human alpha- and beta-globin genes: an evolutionary strategy reducing the rate of mutations with drastic effects?

Nucleotide substitutions within a structural gene can cause two principal "drastic" phenotypic effects at the protein level: translatable leads to untranslatable and nonpolar hydrophobic in equilibrium hydrophilic amino acid substitutions. The sequence of nucleotides in the structural human alpha- and beta-globin genes and their variants were examined to determine whether codon usage, patterns of nucleotide substitutions, or both, reduced the relative and absolute rates of these unfavorable mutations. Based on translation of abnormal hemoglobins, it is likely that all 61 nontermination codons are potentially translatable, though only 47 are normally used. Moreover, codons that can mutate to a termination codon are never used whenever the corresponding amino acid is specified also by triplets that cannot mutate to termination by a single-step mutation. Thus, the number of opportunities to mutate to an untranslatable codon is reduced to the minimum compatible with the amino acid composition of these chains. The relative rates of U in equilibrium non-U substitutions were much lower than those of other substitutions. Because U residues must be involved in most termination mutations and in all nonpolar hydrophobic in equilibrium hydrophilic amino acid substitutions, there is a considerable reduction of mutational events, causing drastic phenotypic effects. These findings are likely to be the end result of evolutionary selection by yet unknown mechanisms.

Base Sequence↗
PubMed2006

Alpha-thalassemia phenotype induced by the new IVS-II-2 (T --> A) splice donor site mutation on the alpha2-globin gene.

We present a family of North European extraction referred for a refractory non iron depleted microcytic anemia. The proband, a 36 year-old male, presented with chronic borderline anemia and microcytic hypochromic parameters. No abnormal hemoglobin (Hb) fractions were observed on high performance liquid chromatography (HPLC) or on alkaline electrophoresis. Gap-polymerase chain reaction (gap-PCR) excluded the seven common alpha-thalassemia (thal) deletion defects. However, the beta/alpha-globin chain synthesis ratio measured in vitro was unbalanced, indicating a reduced expression of the alpha-globin genes. Direct sequencing of the alpha-globin genes revealed heterozygosity for a T --> A transversion at the IVS-II-2 position of the alpha2 gene. This is the first IVS-II splice donor site mutation described on the alpha2-globin gene.

Adult↗
PubMed2006

Surface plasmon resonance-based molecular detection of Hb S [beta6(A3)Glu-->Val, GAG-->GTG] at the gene level.

The surface plasmon resonance (SPR) approach, being a relatively novel biophysical method, is used to detect many different targets by biomolecular interaction. The SPR system uses optical and evanescent wave phenomenon. This approach does not need any labels, such as enzymes or isotopes, and the monitored interactions are in real time. In DNA-DNA interaction, the SPR approach is Tm-independent. Here we report our preliminary results for the molecular detection of the Hb S (GAG -->GTG) mutation at codon 6 of the human beta-globin gene. Our preliminary results show that the SPR approach could be applied as an inexpensive and fast routine test system for the molecular diagnosis of abnormal hemoglobins (Hbs), especially in premarital screening programs.

Genetic Counseling↗