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C T Noguchi

Publications and source records attributed to C T Noguchi.

At least 73 records · Page 4Linked to original sources
PubMed1987

Retroequatorial red retinal lesions in sickle cell anemia.

We report 2 patients with sickle cell anemia who showed retroequatorial localized red retinal lesions. In 1 patient these lesions were associated with closure of the retinal precapillary arteriole and capillary bed. In both patients these lesions receded during the course of therapy with a selective arteriolar vasodilator, nifedipine. These observations are discussed in relation to the possible pathogenesis of the retinopathy seen in patients with sickle cell anemia.

Adult↗
PubMed1987

The development of non-invasive methods to evaluate sickle cell patients in the steady state and in crisis.

Methodologies now exist that promise to disclose fundamental and critical information about the microvascular status of patients with sickle cell disease. Several of these modalities are in an embryonic stage of development, whereas others are close to being ready for application to clinical trials. It is important that these sophisticated diagnostic techniques not supplant our clinical approach to the patient. However, it is hoped that these strategies will allow us to understand better the extreme spectrum of disease manifestations, as well as to provide objective means of monitoring the response to therapy in patients with sickle cell disease.

Anemia, Sickle Cell↗
PubMed1987

Intracellular polymerization of sickle hemoglobin: disease severity and therapeutic goals.

We have demonstrated that the extent of intracellular polymerization of deoxyhemoglobin S can be predicted from knowledge of intracellular hemoglobin concentration, composition and oxygen saturation. Furthermore, we have demonstrated that polymer, which appears to be the main determinant of abnormal red cell rheology, can be detected in sickle erythrocytes at high oxygen saturation values and is not significantly affected by membrane and other cellular constituents. Some of the factors which modify the pathophysiology of sickle cell anemia can be classified as genetic or cellular. To analyze in more detail the genetic factors, we examined 12 sickle syndromes. When the effects of these genotype differences are analyzed for their changes in hemoglobin composition and concentration, we found that polymer formation can account for 80% of the variation in hemolytic and clinical severity. Cell heterogeneity can also modify polymer formation. The premature increases in erythrocyte density (intracellular hemoglobin concentration) in sickle cell anemia increases polymerization tendency. Homozygous alpha-thalassemia in sickle cell patients reduces this increase in cell heterogeneity and improves the hemolytic aspect of the sickle cell disease. For homozygous sickle cell patients we find that the broader density distributions (higher degree of cell heterogeneity) are associated with those cell populations with greater tendency of polymer formation. However, the major utility of our knowledge of intracellular polymerization appears to be its value in defining quantitatively the goals of the major therapeutic approaches with respect to how much inhibition of polymerization would be necessary to achieve various levels of amelioration of disease processes. The primary determinant of the amount of polymer formation within the SS erythrocyte is the extent of oxygen saturation. We measured intracellular polymer formation in SS erythrocytes using carbon-13/proton double nuclear magnetic resonance. As the oxygen saturation is decreased below about 90% oxygen saturation, we begin to see the appearance of polymer which steadily increases with decreasing oxygen saturation. The total intracellular hemoglobin concentration also affects the amount of polymer formed. By examining polymer formation in fractionated subpopulations of SS erythrocytes at various density values (or intracellular hemoglobin concentrations) we demonstrated that the polymer fraction increased with increasing intracellular hemoglobin concentration for any given oxygen saturation.(ABSTRACT TRUNCATED AT 400 WORDS)

Anemia, Sickle Cell↗
PubMed1986

Hemoglobin SC disease and alpha-thalassemia. Prolonged survival and mild clinical course.

An 86-year-old black woman admitted for an elective cataract extraction was found to have moderate hypochromic microcytic anemia. Hematologic evaluation disclosed the presence of hemoglobin SC disease and heterozygous alpha-thalassemia-2 (alpha alpha/alpha-). A red cell density profile of the patient's peripheral blood revealed an absence of the typical uniform shift toward higher-density values seen in hemoglobin SC disease, indicating a "normalization" in the distribution of intracellular hemoglobin types. It is suggested that the co-inheritance of hemoglobin SC disease and heterozygous alpha-thalassemia-2, probably by decreasing the tendency toward intracellular hemoglobin S polymerization, contributed to her prolonged survival and relatively mild clinical course.

Aged↗
PubMed1985

Irreversibly sickled erythrocytes in sickle cell anemia: a quantitative reappraisal.

Irreversibly sickled cells (ISCs), considered by some to be of major pathophysiologic significance, have been reported to comprise between 5-50% of the total red cell population in patients with homozygous sickle cell anemia. Since the deformation of erythrocytes containing sickle hemoglobin is highly dependent on the concentration of hemoglobin in the deoxy conformation, any method established to enumerate the true ISC count requires the hemoglobin to be in the full oxy or liganded conformation. Because the oxygen dissociation curve for sickle erythrocytes is significantly shifted to the right, extremely high partial pressures of oxygen are required to approach full saturation. On the other hand, fully liganding the hemoglobin in the oxy conformation with carbon monoxide (CO) can be readily accomplished. We found that there is a significant reduction in the average number of sickled forms in the peripheral blood of sickle cell anemia patients after incubation in CO (to a value of 6.5 +/- 3.5%) when compared to conventional methods for ISC preparations. These results suggest that fully liganded erythrocytes should be used in quantitating ISCs in studies of the pathophysiology of this disease, especially since ISCs are likely to affect rheology differently from reversibly sickling cells.

Anemia, Sickle Cell↗
PubMed1985

Noninvasive techniques to evaluate the vaso-occlusive manifestations of sickle cell disease.

Although the pathophysiologic manifestations of sickle cell disease have been assumed to result from microvascular occlusion consequent to in situ sickling of erythrocytes, actual blood vessel obstruction have been rarely demonstrated in vivo. Recent observations utilizing sophisticated biophysical techniques to study the intracellular hemoglobin S polymerization process has led to major revisions in this previously held pathophysiologic paradigm, but in vivo correlations are still lacking. With the development of new noninvasive imaging and para-imaging methods, it is now technically possible and feasible to characterize both regional organ perfusion and tissue biochemistry in quantitative terms. In addition, these modalities promise to clarify pathogenesis of the disease through definition of the events responsible for the progression from tissue ischemia and infarction through the resolution phase. Since these noninvasive techniques are amenable to sequential applications, they should facilitate objective evaluations of clinical trials of therapeutic agents designed to prevent or delay the vaso-occlusive manifestations of sickle cell disease.

Anemia, Sickle Cell↗
PubMed1985

Conjunctival sign in sickle cell anaemia: an in-vivo correlate of the extent of red cell heterogeneity.

A consecutive series of 22 stable adult inpatients with sickle cell anaemia were examined for the presence and severity of spontaneous 'comma' signs of the conjunctiva. Fifteen patients had severe conjunctival signs (more than 10 commas in the worse eye). The presence of severe conjunctival signs was associated with a broader distribution of intraerythrocytic haemoglobin concentrations (p = 0.0005). The patient group with severe conjunctival signs was not found to be significantly different from the group without such signs for age, sex, haemoglobin value, reticulocyte count, alpha-globin gene number, percentage fetal haemoglobin, or the proportion of very dense cells (CHC greater than 37 g/dl). Thus the singular heterogeneity of the erythrocytes in sickle cell disease may be indicative of the factor(s) responsible for the diagnostic comma sign.

Adult↗
PubMed1985

Alpha thalassemia changes erythrocyte heterogeneity in sickle cell disease.

Homozygous alpha-thalassemia has the beneficial effect in sickle cell anemia of reducing the hemolytic severity while changing several other hematological parameters. We examined in detail the cellular basis of some of these hematologic alterations. We find that the broad distribution in erythrocyte density and the large proportion of dense cells associated with sickle cell anemia are both reduced with coexisting alpha-thalassemia. Measurements of glycosylated hemoglobin levels as a function of cell density indicate that the accelerated increase in cell density, beyond normal cell aging, in sickle cell anemia is also reduced with alpha-thalassemia. The patients with homozygous alpha-thalassemia and sickle cell disease have slightly lower levels of hemoglobin F than the nonthalassemic sickle cell patients. Examination of hemoglobin F production revealed that the proportion of hemoglobin F containing reticulocytes remained unchanged, as did the proportion of hemoglobin F in cells containing hemoglobin F (F cells). Preferential survival of F cells occurs in sickle cell anemia, with or without alpha-thalassemia, and the slight difference in hemoglobin F levels appear to reflect differences in numbers of circulating F cells. Thus, in sickle cell disease with coexisting alpha-thalassemia, the change in the erythrocyte density profile, possibly due to inhibition of polymerization-related increases in cell density, explains the hematological improvement.

Anemia, Sickle Cell↗
PubMed1985

Hemoglobin S polymerization: primary determinant of the hemolytic and clinical severity of the sickling syndromes.

We examined the extent to which the intracellular polymerization of sickle hemoglobin (HbS) can account for the severity of anemia and of vaso-occlusive manifestations in the various sickling syndromes. Polymer formation in sickle cell disease depends principally on the intraerythrocytic hemoglobin composition and concentration. In our studies, the polymer fraction in sickle red cells was determined from reported mean values for hemoglobin composition and mean corpuscular hemoglobin concentration (MCHC) in 12 groups of patients with sickle hemoglobinopathies (homozygotes for HbS, with and without coexistent alpha-thalassemia or various forms of the hereditary persistence of fetal hemoglobin [HPFH], beta+-, beta 0-, and delta beta-thalassemia, and heterozygotes for HbS with HbA). The calculated HbS polymer fractions at full deoxygenation and at physiologic oxygen saturation values were closely correlated with mean blood hemoglobin concentrations. In addition, polymer fraction correlated with the ranking of the sickling syndromes by vaso-occlusive severity. We find that polymer fraction accounts for about 80% of the variability in hemolytic and clinical severity. The method of analysis presented here provides a quantitative and systematic means of assessing the role of polymer formation in the pathophysiologic manifestations of the sickling syndromes. Our results support the hypothesis that the intracellular polymerization of HbS is the primary determinant of the severity of both anemia and clinical symptomatology in the sickle hemoglobinopathies.

Anemia, Sickle Cell↗
PubMed1985

Cell heterogeneity in sickle cell disease: quantitation of the erythrocyte density profile.

An increasing body of experimental evidence demonstrates that intracellular hemoglobin concentration and composition is a primary determinant of pathophysiology in sickle cell disease. To quantitate more precisely the heterogeneous distribution of intracellular hemoglobin concentrations in a given individual with this disease, we have calibrated the phthalate ester separation technique by using discontinuous Stractan density gradients to isolate subpopulations of red cells of relatively uniform corpuscular hemoglobin concentration values. We find that blood from individuals with sickle cell anemia exhibits a markedly broader distribution of corpuscular hemoglobin concentration values, containing both very light and very dense cells, than the red cell density profile from normal individuals. This increased breadth of cell densities in patients with sickle cell anemia remains even after exclusion of the very light and very dense subpopulations. In patients with stable sickle cell anemia, there appears to be minimal variation in the distribution of cell densities that are unimodal but skewed toward higher density values. The phthalate ester method can conveniently be used to follow changes in cell densities during vaso-occlusive events, to monitor therapy targeted at modifying intracellular hemoglobin S concentrations, and in sequential applications in large field trials designed to determine the relationship between red cell heterogeneity and specific manifestations of the sickle cell syndromes.

Adult↗
PubMed1985

Dipeptides as inhibitors of the gelation of sickle hemoglobin.

To examine in detail a class of peptides that inhibit the polymerization of deoxyhemoglobin S, we assayed the L-amino acids and 22 dipeptides for their effect on deoxyhemoglobin S solubility. Of the amino acids, the aromatics (phenylalanine, tyrosine, and tryptophan) significantly increased deoxyhemoglobin S solubility, as did high concentration of arginine. Combinations of the hydrophobic (specifically the aromatic) amino acids with a hydrophilic amino acid, such as arginine or lysine, resulted in dipeptides which were much more soluble than the hydrophobic or aromatic amino acid alone, and also inhibited polymerization. Furthermore, samples of deoxyhemoglobin S at 26 to 27 g/dl containing some of these dipeptides such as Arg-Trp, Arg-Phe, and Lys-Trp in excess of 50 to 100 mM did not polymerize, indicating a 1.4- to 1.6-fold increase in deoxyhemoglobin S solubility. The enhancement of polymerization, i.e., decrease in deoxyhemoglobin S solubility, observed by the addition of aspartic acid, glycine, or lysine was observed or was reduced in the dipeptides containing these hydrophilic amino acids combined with hydrophobic amino acids (valine, leucine, isoleucine, or the aromatic amino acids). The effects of these dipeptides on deoxyhemoglobin S solubility were mostly linear with concentration. However, the changes in deoxyhemoglobin S solubility by addition of a dipeptide was not simply the sum of the effects observed with the individual amino acids as exemplified by the differential effect of reversing the dipeptide sequence (e.g., Arg-Phe and Phe-Arg, or Arg-Tyr and Tyr-Arg). These data provide further evidence as to the stereospecific nature of this class of noncovalent inhibitors of deoxyhemoglobin S polymerization.

Dipeptides↗
PubMed1984

Periodic microcirculatory flow in patients with sickle-cell disease.

We have applied the technique of laser-Doppler velocimetry to compare patterns of cutaneous blood flow in the forearms of patients with stable sickle-cell disease, with the patterns in normal subjects matched for age, race, and sex, and in patients with anemia due to beta+-thalassemia. The mean resting blood flow in the patients with sickle-cell disease was comparable to that of the control groups but was associated with large, local oscillations in flow with periods of 7 to 10 seconds and peak-to-trough magnitudes about half the mean flow. Oscillations occurred simultaneously at sites separated by 1 cm but were independent in phase and frequency. Since these laser-Doppler measurements represent the average flow pattern in about 1 mm3 of skin (i.e., in approximately 50 to 70 capillary loops), these results suggest that microcirculatory flow in patients with sickle-cell disease proceeds by synchronization of rhythmic flow in large domains of microvessels. These findings indicate that periodic flow may be a compensatory mechanism to offset the deleterious altered rheology of erythrocytes containing polymerized hemoglobin S, and suggest that laser-Doppler velocimetry may be a useful method to investigate microvascular physiology in patients with sickle-cell disease.

Adult↗
PubMed1984

Polymerization in erythrocytes containing S and non-S hemoglobins.

We analyzed the effects of protein and water nonideality and of erythrocyte heterogeneity on the polymerization of hemoglobin S in cells where there were significant amounts of non-S hemoglobins, sickle trait (AS), and SC disease. For AS erythrocytes, the calculated predicted results were in good agreement with measured polymer formation as previously reported (Noguchi C.T., D.A. Torchia, and A.N. Schnechter, 1981, J. Biol. Chem. 256:4168-4171). Throughout much of the physiologically relevant oxygen saturation region, polymer was not formed in AS erythrocytes. Measurements of polymer formation in SC erythrocytes as a function of oxygen saturation using 13C NMR are reported here and also are in good agreement with the calculated predicted results. As in sickle (SS) erythrocytes, polymer can be detected in SC erythrocytes in the region above 60% oxygen saturation. The increased polymer formation in SC erythrocytes as compared with AS erythrocytes can be explained in terms of hemoglobin composition and concentration in SC erythrocytes, with the concomitant increase in the proportion of dense cells. These findings provide a basis for understanding the pathophysiology of sickle cell and of SC disease, in contrast to benign sickle trait, in terms of intracellular polymer formation.

Erythrocytes↗
PubMed1984

Non-uniformity of intracellular polymer formation in sickle erythrocytes: possible correlation with severity of hemolytic anemia.

Intact sickle erythrocytes were fractionated to obtain a more uniform population in mean corpuscular hemoglobin concentration (MCHC). Polymer fraction at complete deoxygenation varied with increasing MCHC and, at varying oxygen saturation, was in good agreement with theoretical predictions based on solubility and the non-ideal behavior of concentrated hemoglobin solution and of water. These data and the theoretical analysis indicate that, in uniform sickle erythrocytes at 34 g/dl, polymer is only detected below 84% oxygen saturation. Non-uniformity of unfractionated sickle erythrocytes causes this critical oxygen saturation to shift to higher values (over 90%). The implication is that polymer may exist in arterial blood, a possibility which must be considered in therapeutic strategies. Recently, we showed that polymer formation correlated with the severity of hemolysis for 12 sickle syndromes varying from sickle trait to hemoglobin SS (African) disease.

Anemia, Sickle Cell↗
PubMed1983

Intracellular polymerization of sickle hemoglobin. Effects of cell heterogeneity.

To determine the extent to which the broad distribution in intracellular hemoglobin concentrations found in sickle erythrocytes affects the extent of intracellular polymerization of hemoglobin S, we have fractionated these cells by density using discontinuous Stractan gradients. The amount of polymer formed in the subpopulations was experimentally measured as a function of oxygen saturation using 13C nuclear magnetic resonance spectroscopy. The results for each subpopulation are in very good agreement with the theoretical predictions based on the current thermodynamic description for hemoglobin S gelation. We further demonstrate that the erythrocyte density profile for a single individual with sickle cell anemia can be used with the theory to predict the amount of polymer in unfractionated cells. We find that heterogeneity in intracellular hemoglobin concentration causes the critical oxygen saturation for formation of polymer to shift from 84 to greater than 90%; polymer is formed predominantly in the dense cells at the very high oxygen saturation values. The existence of polymer at arterial oxygen saturation values has significance for understanding the pathophysiology of sickle cell anemia. The utility of these techniques for assessing various therapeutic strategies is discussed.

Anemia, Sickle Cell↗