To provide optimum protection against classical and El Tor biotypes of Vibrio cholerae O1, a sing... more To provide optimum protection against classical and El Tor biotypes of Vibrio cholerae O1, a single-dose, oral cholera vaccine was developed by combining two live, attenuated vaccine strains, CVD 103-HgR (classical, Inaba) and CVD 111 (El Tor, Ogawa). The vaccines were formulated in a double-chamber sachet; one chamber contained lyophilized bacteria, and the other contained buffer. In the first study, 23 U.S. adult volunteers received CVD 103-HgR at 10(8) CFU plus CVD 111 at 10(8), 10(7), or 10(6) CFU, CVD 111 alone at 10(7) CFU, or placebo. In the second study, 275 Peruvian adults were randomized to receive CVD 103-HgR at 10(9) CFU plus CVD 111 at 10(9) or 10(8) CFU, CVD 111 alone at 10(9) CFU, CVD 103-HgR alone at 10(9) CFU, or placebo. Three of 15 U.S. volunteers who received CVD 111 at 10(7) or 10(8) CFU developed mild diarrhea, compared to none of 4 who received CVD 111 at 10(6) CFU and 1 of 4 who received placebo. Twelve (63%) of 19 vaccine recipients shed the El Tor vaccine strain. All but one volunteer developed significant Ogawa and Inaba vibriocidal antibody titers. Volunteers who received CVD 111 at 10(7) CFU had geometric mean Ogawa titers four to five times higher than those of volunteers who received the lower dose. In the second study, all dosage regimens were well tolerated in Peruvians. About 20% of volunteers who received CVD 111 at the high dose excreted the El Tor organism, compared to 7% in the low-dose group. CVD 111 was detected in the stools of two placebo recipients, neither of whom had symptoms or seroconverted. In all vaccine groups, 69 to 76% developed fourfold rises in Inaba vibriocidal antibodies. Among those who received the bivalent vaccine, 53 to 75% also developed significant rises in Ogawa vibriocidal antibodies. We conclude that it is feasible to produce a single-dose, oral bivalent vaccine that is safe and immunogenic against both biotypes (El Tor and classical) and both serotypes (Inaba and Ogawa) of cholera for populations in both developed and developing parts of the world.
The product of the SLC40A1 gene, ferroportin 1, is a main iron export protein. Pathogenic mutatio... more The product of the SLC40A1 gene, ferroportin 1, is a main iron export protein. Pathogenic mutations in ferroportin 1 lead to an autosomal dominant hereditary iron overload syndrome characterized by high serum ferritin concentration, normal transferrin saturation, iron accumulation predominantly in macrophages, and marginal anemia. Iron overload occurs in both the African and the African-American populations, but a possible genetic basis has not been established. We analyzed the ferroportin 1 gene in 19 unrelated patients from southern Africa (N = 15) and the United States (N = 4) presenting with primary iron overload. We found a new c. 744 C→T (Q248H) mutation in the SLC40A1 gene in 4 of these patients (3 Africans and 1 African-American). Among 22 first degree family members, 10 of whom were Q248H heterozygotes, the mutation was associated with a trend to higher serum ferritin to amino aspartate transferase ratios (means of 14.8 versus 4.3 μg/U; P = 0.1) and lower hemoglobin concentrations (means of 11.8 versus 13.2 g/dL; P = 0.1). The ratio corrects serum ferritin concentration for alcohol-induced hepatocellular damage. We also found heterozygosity for the Q248H mutation in 7 of 51 (14%) southern African community control participants selected because they had a serum ferritin concentration below 400 μg/L and in 5 of 100 (5%) anonymous African-Americans, but we did not find the change in 300 Caucasians with normal iron status and 25 Caucasians with non-HFE iron overload. The hemoglobin concentration was significantly lower in the African community controls with the Q248H mutation than in those without it. We conclude that the Q248H mutation is a common polymorphism in the ferroportin 1 gene in African populations that may be associated with mild anemia and a tendency to iron loading.
... We do not intend to stop administering folic acid supplementation to our patients with sickle... more ... We do not intend to stop administering folic acid supplementation to our patients with sickle cell anemia. The contrary recommendation made by Dr. Rodriguez-Cortes and endorsed by commentators is, in our opinion, premature. Sohail Rana, MD. Patricia Houston, MS. ...
To study the effect of a perfluorocarbon oxygen transport emulsion (Fluosol-DA) on reticuloendoth... more To study the effect of a perfluorocarbon oxygen transport emulsion (Fluosol-DA) on reticuloendothelial system (RES) function, we measured the blood clearance of human erythrocytes transfused to rats. Compared with saline treatment, Fluosol-DA at 30 ml/kg doses significantly increased both the percent 20-hour blood recovery (mean 8.9% ± 2.7 SEM vs 1.3% ± 0.25 SEM) and 51Cr t1/2 survival (mean 14.0 hours ± 2.7 SEM vs 3.5 hours ± 0.33 SEM) of the human red cells. This suppression of RES clearance function was transient and no longer detectable seven days after single Fluosol-DA doses. The Fluosol-DA-induced RES block was about three times greater than that obtainable with 4 g/kg of a soybean oil emulsion used for clinical hyperalimentation. On the other hand, the effect of ethyl palmitate (0.5 g/kg), a potent but toxic RES blocker, was 3.5 times greater than that of Fluosol-DA in this test system. If Fluosol-DA also induces RES block in humans, this emulsion could be explored as a therapeutic RES blocker in certain immune cytopenias.
We performed hemoglobin electrophoresis in 30,400 apparently healthy black individuals in the Was... more We performed hemoglobin electrophoresis in 30,400 apparently healthy black individuals in the Washington D.C. Metropolitan area, who were participating in a community based sickle-cell screening program during the period 1978–1985. The overall prevalence of sickle-cell trait was 6.7%. The frequency of sickle-cell trait in various age groups, which included young children, adults, and individuals over 65 years of age, ranged from 6.4 to 7.4%. There were no statistically significant differences in the prevalence of sickle-cell trait among the various age groups, nor did we detect a significant trend for increasing or decreasing sickle cell frequency with advancing age (P = 0.418). Thus, in this population sickle-cell trait appears to have no effect on longevity. If the various complications of sickle-cell trait reported in the literature are not fortuitous, their frequency and/or severity must be too low to affect prevalence figures.
The frequency of vaso-occlusive crises correlates with mortality in patients with sickle cell dis... more The frequency of vaso-occlusive crises correlates with mortality in patients with sickle cell disease (SCD). We examined the degree to which a high number of hospitalization days for these events affected survival. We reviewed data for 58 adult patients with SCD (mean age, 29.9 +/- 7.3 years) treated at our hospital between 1986 and 1994 who had at least 100 hospitalization days during any of these years. Their mean follow up period was 6.65 years (median, 6.84 years; range, 0.15-14.51 years). Thirty-five patients (60.3%) died during follow-up. In multivariate analysis that included age, gender, and numbers of transfusions and hospitalization days, only age was significantly associated with mortality. The National Cooperative Study of Sickle Cell Disease (CSSCD) estimates the 10-year mortality at 15% for all 20-year old SS patients and also for all 30-year-old women. For 30-year-old men, the CSSCD estimated a 10-year mortality of about 28%. Thus, the 60.3% mortality of our patients after a median follow-up of only 6.84 years was substantially higher. Fifty-one patients were still alive after 1992, when hydroxyurea became available for SCD. The median survival of 15 hydroxyurea-treated patients was 7.3 years, compared with 4.3 years in 36 patients who did not take the drug. Mortality for patients with SCD with a high number of hospitalization days was much higher than that expected for patients with SCD in general. There was a (nonsignificant) trend for longer survival in these severely ill patients if they took hydroxyurea.
Pain control using intramuscular analgesia is often unsatisfactory in sickle cell patients. In a ... more Pain control using intramuscular analgesia is often unsatisfactory in sickle cell patients. In a pilot study, 15 patients with sickle cell anemia (SS) and one patient with SB thalassemia in vaso-occlusive crisis were treated with the Patient-Controlled Analgesia (PCA) technique using a Pharmacia Deltec Programmable pump (CADD PCA). Age range was 19-50 years (median = 27); there were nine females and seven males. The protocol consisted of 3 days of therapy using a background of continuous infusion meperidine. The starting dose was 20 mg/hr and was escalated to 30 mg/hr. The average amount given was 25.8 mg/hr. One to two boluses of 2.5-5.0 mg/dose (mode = 5.0) were also allowed each hour. In addition, patients number 8 through 16 were given hydroxyzine (Vistaril) 50 mg PO q6h. The number of days in pain prior to study entry (mean +/- SD) was 3.3 +/- 1.6. The number of pain sites per patient was 3.6 +/- 1.2. Using categorical and analog pain scales, patients' pain scores decreased only about 30%. However, most patients were fairly satisfied with the treatment and rated it overall as follows: 1 poor, 1 fair, 3 good, 6 very good, 4 excellent, 1 no comment. Patients number 8 through 16 gave higher ratings probably because a more idealized dosage regimen was being used by that time in the study. There were no adverse effects or major problems noted. It is our impression that PCA, when optimized, will be a safe and effective alternative method for providing patients with sickle cell vaso-occlusive crisis pain relief.
Long-term transfusion therapy in patients with sickle cell disease and stroke markedly decreases ... more Long-term transfusion therapy in patients with sickle cell disease and stroke markedly decreases the risk of stroke recurrence. However, it is not known how long the transfusions should be continued. Published reports have documented a high risk of stroke recurrence after stopping transfusion. We report on nine consecutive patients with sickle cell disease and stroke whose long-term transfusion therapy was discontinued and in whom no ischemic strokes developed during 80.75 patient years of follow-up. (J Pediatr 1997;131:757-60)
HLA-A, -B, -C, and DR antigens were determined in 33 patients with sickle cell disease (SCD), who... more HLA-A, -B, -C, and DR antigens were determined in 33 patients with sickle cell disease (SCD), who had received red blood cell (RBC) transfusions. Twenty-one patients formed red cell alloantibodies after transfusions (responders) while 12 multitransfused SCD patients did not form any RBC antibodies (non-responders). We found that 67% of the SCD responder participants had HLA-B35 versus 25% of the non-responders (χ2 = 5.3079, P = 0.0212). The frequency of B35 in non-responder SCD patients was similar to that of a normal healthy Black population consisting of 139 individuals. Calculation of the relative risk showed that sickle cell patients with B35 are six times more likely to form RBC alloantibodies after transfusion than those lacking that HLA antigen. We found no significant increase or association between any HLA-DR antigens and sickle cell disease.
Hereditary hemochromatosis is the most common cause of iron overload in adults and is probably th... more Hereditary hemochromatosis is the most common cause of iron overload in adults and is probably the second most common cause of iron overload in children in the United States next to transfusional overload. Serious morbidity from this disorder of iron absorption can occur in early as well as in middle and advanced age, iron overload having been reported in children with hereditary hemochromatosis as early as 2 years of age. Younger persons differ from older persons in that the risk for iron loading in females appears to be equal to the risk for males, in contrast to a preponderance of males among older patients. Also, younger patients frequently demonstrate cardiac and gonadal involvement, with cardiac failure commonly leading to death, whereas older patients are more likely to have liver involvement and diabetes mellitus, with liver failure and hepatoma commonly leading to death. Because early diagnosis and treatment can prevent the toxicities of iron overload, appropriate screening can be lifesaving. Transferrin saturation is the most reliable screening test. Liver biopsy with objective measurement of hepatic iron stores is the most important diagnostic criterion at present, although reliable noninvasive methods for quantitating body iron are being developed. Young individuals who should be screened for iron overload include patients with cardiac myopathies, hypogonadism, amenorrhea, loss of libido, diabetes mellitus, other endocrine disorders, cirrhosis of the liver, and arthritis, as well as the siblings, parents, and children of patients with hereditary hemochromatosis or iron loading of unknown cause.
Hematology-oncology Clinics of North America, 1996
Systemic fat embolism and pulmonary hypertension are two complications of sickle cell disease tha... more Systemic fat embolism and pulmonary hypertension are two complications of sickle cell disease that present major challenges to the therapist. Neither event is exclusive to the sickling disorders. Systemic fat embolism is a well-known consequence of bone trauma.13 Pulmonary hypertension occurs also in a variety of lung and extrapulmonary abnormalities. Both complications carry a dismal prognosis in sickle cell patients. Systemic fat embolism is particularly difficult to document, but if suspected early enough it may respond to transfusion therapy. The diagnosis of pulmonary hypertension is straightforward if invasive techniques are used; however, because there are no large published series of sickle cell patients with pulmonary hypertension, discussion of this problem and its management is necessarily tentative. Pulmonary hypertension in sickle cell disease is reviewed in the context of primary pulmonary hypertension, a disorder for which information regarding therapy is becoming more available. Greater awareness and clearer understanding of systemic fat embolism and pulmonary hypertension in sickle cell disease will eventually lead to effective therapy.
Summary. Recent studies suggest that nitric oxide (NO) may partly be responsible for the benefici... more Summary. Recent studies suggest that nitric oxide (NO) may partly be responsible for the beneficial effect of hydroxyurea (HU) in sickle cell disease (SCD) patients. NO stimulates cyclic guanosine monophosphate (cGMP) production, which mediates vasodilatation. We investigated the association between NO, cGMP and fetal haemoglobin (HbF) levels after HU administration. Our data showed that chronic HU significantly increased NO, cGMP, and HbF levels in SCD. Recently it was shown that HbF production was stimulated by cGMP-dependent protein kinase. Our results suggest that NO stimulates cGMP production, which then activates a protein kinase and increases the production of HbF.
To provide optimum protection against classical and El Tor biotypes of Vibrio cholerae O1, a sing... more To provide optimum protection against classical and El Tor biotypes of Vibrio cholerae O1, a single-dose, oral cholera vaccine was developed by combining two live, attenuated vaccine strains, CVD 103-HgR (classical, Inaba) and CVD 111 (El Tor, Ogawa). The vaccines were formulated in a double-chamber sachet; one chamber contained lyophilized bacteria, and the other contained buffer. In the first study, 23 U.S. adult volunteers received CVD 103-HgR at 10(8) CFU plus CVD 111 at 10(8), 10(7), or 10(6) CFU, CVD 111 alone at 10(7) CFU, or placebo. In the second study, 275 Peruvian adults were randomized to receive CVD 103-HgR at 10(9) CFU plus CVD 111 at 10(9) or 10(8) CFU, CVD 111 alone at 10(9) CFU, CVD 103-HgR alone at 10(9) CFU, or placebo. Three of 15 U.S. volunteers who received CVD 111 at 10(7) or 10(8) CFU developed mild diarrhea, compared to none of 4 who received CVD 111 at 10(6) CFU and 1 of 4 who received placebo. Twelve (63%) of 19 vaccine recipients shed the El Tor vaccine strain. All but one volunteer developed significant Ogawa and Inaba vibriocidal antibody titers. Volunteers who received CVD 111 at 10(7) CFU had geometric mean Ogawa titers four to five times higher than those of volunteers who received the lower dose. In the second study, all dosage regimens were well tolerated in Peruvians. About 20% of volunteers who received CVD 111 at the high dose excreted the El Tor organism, compared to 7% in the low-dose group. CVD 111 was detected in the stools of two placebo recipients, neither of whom had symptoms or seroconverted. In all vaccine groups, 69 to 76% developed fourfold rises in Inaba vibriocidal antibodies. Among those who received the bivalent vaccine, 53 to 75% also developed significant rises in Ogawa vibriocidal antibodies. We conclude that it is feasible to produce a single-dose, oral bivalent vaccine that is safe and immunogenic against both biotypes (El Tor and classical) and both serotypes (Inaba and Ogawa) of cholera for populations in both developed and developing parts of the world.
The product of the SLC40A1 gene, ferroportin 1, is a main iron export protein. Pathogenic mutatio... more The product of the SLC40A1 gene, ferroportin 1, is a main iron export protein. Pathogenic mutations in ferroportin 1 lead to an autosomal dominant hereditary iron overload syndrome characterized by high serum ferritin concentration, normal transferrin saturation, iron accumulation predominantly in macrophages, and marginal anemia. Iron overload occurs in both the African and the African-American populations, but a possible genetic basis has not been established. We analyzed the ferroportin 1 gene in 19 unrelated patients from southern Africa (N = 15) and the United States (N = 4) presenting with primary iron overload. We found a new c. 744 C→T (Q248H) mutation in the SLC40A1 gene in 4 of these patients (3 Africans and 1 African-American). Among 22 first degree family members, 10 of whom were Q248H heterozygotes, the mutation was associated with a trend to higher serum ferritin to amino aspartate transferase ratios (means of 14.8 versus 4.3 μg/U; P = 0.1) and lower hemoglobin concentrations (means of 11.8 versus 13.2 g/dL; P = 0.1). The ratio corrects serum ferritin concentration for alcohol-induced hepatocellular damage. We also found heterozygosity for the Q248H mutation in 7 of 51 (14%) southern African community control participants selected because they had a serum ferritin concentration below 400 μg/L and in 5 of 100 (5%) anonymous African-Americans, but we did not find the change in 300 Caucasians with normal iron status and 25 Caucasians with non-HFE iron overload. The hemoglobin concentration was significantly lower in the African community controls with the Q248H mutation than in those without it. We conclude that the Q248H mutation is a common polymorphism in the ferroportin 1 gene in African populations that may be associated with mild anemia and a tendency to iron loading.
... We do not intend to stop administering folic acid supplementation to our patients with sickle... more ... We do not intend to stop administering folic acid supplementation to our patients with sickle cell anemia. The contrary recommendation made by Dr. Rodriguez-Cortes and endorsed by commentators is, in our opinion, premature. Sohail Rana, MD. Patricia Houston, MS. ...
To study the effect of a perfluorocarbon oxygen transport emulsion (Fluosol-DA) on reticuloendoth... more To study the effect of a perfluorocarbon oxygen transport emulsion (Fluosol-DA) on reticuloendothelial system (RES) function, we measured the blood clearance of human erythrocytes transfused to rats. Compared with saline treatment, Fluosol-DA at 30 ml/kg doses significantly increased both the percent 20-hour blood recovery (mean 8.9% ± 2.7 SEM vs 1.3% ± 0.25 SEM) and 51Cr t1/2 survival (mean 14.0 hours ± 2.7 SEM vs 3.5 hours ± 0.33 SEM) of the human red cells. This suppression of RES clearance function was transient and no longer detectable seven days after single Fluosol-DA doses. The Fluosol-DA-induced RES block was about three times greater than that obtainable with 4 g/kg of a soybean oil emulsion used for clinical hyperalimentation. On the other hand, the effect of ethyl palmitate (0.5 g/kg), a potent but toxic RES blocker, was 3.5 times greater than that of Fluosol-DA in this test system. If Fluosol-DA also induces RES block in humans, this emulsion could be explored as a therapeutic RES blocker in certain immune cytopenias.
We performed hemoglobin electrophoresis in 30,400 apparently healthy black individuals in the Was... more We performed hemoglobin electrophoresis in 30,400 apparently healthy black individuals in the Washington D.C. Metropolitan area, who were participating in a community based sickle-cell screening program during the period 1978–1985. The overall prevalence of sickle-cell trait was 6.7%. The frequency of sickle-cell trait in various age groups, which included young children, adults, and individuals over 65 years of age, ranged from 6.4 to 7.4%. There were no statistically significant differences in the prevalence of sickle-cell trait among the various age groups, nor did we detect a significant trend for increasing or decreasing sickle cell frequency with advancing age (P = 0.418). Thus, in this population sickle-cell trait appears to have no effect on longevity. If the various complications of sickle-cell trait reported in the literature are not fortuitous, their frequency and/or severity must be too low to affect prevalence figures.
The frequency of vaso-occlusive crises correlates with mortality in patients with sickle cell dis... more The frequency of vaso-occlusive crises correlates with mortality in patients with sickle cell disease (SCD). We examined the degree to which a high number of hospitalization days for these events affected survival. We reviewed data for 58 adult patients with SCD (mean age, 29.9 +/- 7.3 years) treated at our hospital between 1986 and 1994 who had at least 100 hospitalization days during any of these years. Their mean follow up period was 6.65 years (median, 6.84 years; range, 0.15-14.51 years). Thirty-five patients (60.3%) died during follow-up. In multivariate analysis that included age, gender, and numbers of transfusions and hospitalization days, only age was significantly associated with mortality. The National Cooperative Study of Sickle Cell Disease (CSSCD) estimates the 10-year mortality at 15% for all 20-year old SS patients and also for all 30-year-old women. For 30-year-old men, the CSSCD estimated a 10-year mortality of about 28%. Thus, the 60.3% mortality of our patients after a median follow-up of only 6.84 years was substantially higher. Fifty-one patients were still alive after 1992, when hydroxyurea became available for SCD. The median survival of 15 hydroxyurea-treated patients was 7.3 years, compared with 4.3 years in 36 patients who did not take the drug. Mortality for patients with SCD with a high number of hospitalization days was much higher than that expected for patients with SCD in general. There was a (nonsignificant) trend for longer survival in these severely ill patients if they took hydroxyurea.
Pain control using intramuscular analgesia is often unsatisfactory in sickle cell patients. In a ... more Pain control using intramuscular analgesia is often unsatisfactory in sickle cell patients. In a pilot study, 15 patients with sickle cell anemia (SS) and one patient with SB thalassemia in vaso-occlusive crisis were treated with the Patient-Controlled Analgesia (PCA) technique using a Pharmacia Deltec Programmable pump (CADD PCA). Age range was 19-50 years (median = 27); there were nine females and seven males. The protocol consisted of 3 days of therapy using a background of continuous infusion meperidine. The starting dose was 20 mg/hr and was escalated to 30 mg/hr. The average amount given was 25.8 mg/hr. One to two boluses of 2.5-5.0 mg/dose (mode = 5.0) were also allowed each hour. In addition, patients number 8 through 16 were given hydroxyzine (Vistaril) 50 mg PO q6h. The number of days in pain prior to study entry (mean +/- SD) was 3.3 +/- 1.6. The number of pain sites per patient was 3.6 +/- 1.2. Using categorical and analog pain scales, patients' pain scores decreased only about 30%. However, most patients were fairly satisfied with the treatment and rated it overall as follows: 1 poor, 1 fair, 3 good, 6 very good, 4 excellent, 1 no comment. Patients number 8 through 16 gave higher ratings probably because a more idealized dosage regimen was being used by that time in the study. There were no adverse effects or major problems noted. It is our impression that PCA, when optimized, will be a safe and effective alternative method for providing patients with sickle cell vaso-occlusive crisis pain relief.
Long-term transfusion therapy in patients with sickle cell disease and stroke markedly decreases ... more Long-term transfusion therapy in patients with sickle cell disease and stroke markedly decreases the risk of stroke recurrence. However, it is not known how long the transfusions should be continued. Published reports have documented a high risk of stroke recurrence after stopping transfusion. We report on nine consecutive patients with sickle cell disease and stroke whose long-term transfusion therapy was discontinued and in whom no ischemic strokes developed during 80.75 patient years of follow-up. (J Pediatr 1997;131:757-60)
HLA-A, -B, -C, and DR antigens were determined in 33 patients with sickle cell disease (SCD), who... more HLA-A, -B, -C, and DR antigens were determined in 33 patients with sickle cell disease (SCD), who had received red blood cell (RBC) transfusions. Twenty-one patients formed red cell alloantibodies after transfusions (responders) while 12 multitransfused SCD patients did not form any RBC antibodies (non-responders). We found that 67% of the SCD responder participants had HLA-B35 versus 25% of the non-responders (χ2 = 5.3079, P = 0.0212). The frequency of B35 in non-responder SCD patients was similar to that of a normal healthy Black population consisting of 139 individuals. Calculation of the relative risk showed that sickle cell patients with B35 are six times more likely to form RBC alloantibodies after transfusion than those lacking that HLA antigen. We found no significant increase or association between any HLA-DR antigens and sickle cell disease.
Hereditary hemochromatosis is the most common cause of iron overload in adults and is probably th... more Hereditary hemochromatosis is the most common cause of iron overload in adults and is probably the second most common cause of iron overload in children in the United States next to transfusional overload. Serious morbidity from this disorder of iron absorption can occur in early as well as in middle and advanced age, iron overload having been reported in children with hereditary hemochromatosis as early as 2 years of age. Younger persons differ from older persons in that the risk for iron loading in females appears to be equal to the risk for males, in contrast to a preponderance of males among older patients. Also, younger patients frequently demonstrate cardiac and gonadal involvement, with cardiac failure commonly leading to death, whereas older patients are more likely to have liver involvement and diabetes mellitus, with liver failure and hepatoma commonly leading to death. Because early diagnosis and treatment can prevent the toxicities of iron overload, appropriate screening can be lifesaving. Transferrin saturation is the most reliable screening test. Liver biopsy with objective measurement of hepatic iron stores is the most important diagnostic criterion at present, although reliable noninvasive methods for quantitating body iron are being developed. Young individuals who should be screened for iron overload include patients with cardiac myopathies, hypogonadism, amenorrhea, loss of libido, diabetes mellitus, other endocrine disorders, cirrhosis of the liver, and arthritis, as well as the siblings, parents, and children of patients with hereditary hemochromatosis or iron loading of unknown cause.
Hematology-oncology Clinics of North America, 1996
Systemic fat embolism and pulmonary hypertension are two complications of sickle cell disease tha... more Systemic fat embolism and pulmonary hypertension are two complications of sickle cell disease that present major challenges to the therapist. Neither event is exclusive to the sickling disorders. Systemic fat embolism is a well-known consequence of bone trauma.13 Pulmonary hypertension occurs also in a variety of lung and extrapulmonary abnormalities. Both complications carry a dismal prognosis in sickle cell patients. Systemic fat embolism is particularly difficult to document, but if suspected early enough it may respond to transfusion therapy. The diagnosis of pulmonary hypertension is straightforward if invasive techniques are used; however, because there are no large published series of sickle cell patients with pulmonary hypertension, discussion of this problem and its management is necessarily tentative. Pulmonary hypertension in sickle cell disease is reviewed in the context of primary pulmonary hypertension, a disorder for which information regarding therapy is becoming more available. Greater awareness and clearer understanding of systemic fat embolism and pulmonary hypertension in sickle cell disease will eventually lead to effective therapy.
Summary. Recent studies suggest that nitric oxide (NO) may partly be responsible for the benefici... more Summary. Recent studies suggest that nitric oxide (NO) may partly be responsible for the beneficial effect of hydroxyurea (HU) in sickle cell disease (SCD) patients. NO stimulates cyclic guanosine monophosphate (cGMP) production, which mediates vasodilatation. We investigated the association between NO, cGMP and fetal haemoglobin (HbF) levels after HU administration. Our data showed that chronic HU significantly increased NO, cGMP, and HbF levels in SCD. Recently it was shown that HbF production was stimulated by cGMP-dependent protein kinase. Our results suggest that NO stimulates cGMP production, which then activates a protein kinase and increases the production of HbF.
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