Rheologic predictors of the severity of the painful sickle cell crisis

Deformable sickle erythrocytes have been reported by Mohandas and Evans to be more adherent to vascular endothelium than rigid irreversibly sickled cells (ISC). To define the clinical implications of this finding we have determined genetic, hematological, clinical, and rheological characteristics of sickle erythrocytes obtained from 65 patients with sickle cell anemia and fetal hemoglobin (Hb F) levels less than 15%. The alpha-globin gene number had a significant effect on the hematological parameters, the percentage of dense cells, ISC number, and HB A2 levels. The presence or absence of alpha thalassemia, however, had no effect on the frequency and severity of the sickle cell painful crisis (r = 0.06, P greater than .05). RBC deformability, determined by an ektacytometer, showed great heterogeneity among patients with three or four alpha-globin genes. Linear regression analyses of the data showed significant positive correlation of the frequency and severity of the painful crisis with RBC deformability (r = 0.49, P less than .001), and negative correlations with the percentage of dense cells (r = -0.37, P = .002), and the percentage of ISC (r = -0.46, P less than .001). We propose that the more deformable the sickle RBC are, the greater their adherence to vascular endothelium, and the more they cause vaso-occlusive crises, RBC deformability and the percentage of dense cells (or ISC) seem to have a predictive value of the frequency and severity of painful crises in sickle cell anemia.     

The relationship between waist circumference and metabolic risk factors: cohorts of European and Chinese descent

Waist circumference (WC) may be the best anthropometric index for identifying individuals at risk for cardiovascular disease (CVD) and diabetes mellitus (DM). The objectives of this study were to determine if the relationship between WC and metabolic risk factors is similar in men and women of Chinese and European descent, and to assess the effect of ethnicity on these relationships. Apparently healthy men and women of Chinese (n = 92) and European (n = 99) descent were recruited from hospital staff and assessed for anthropometric variables and blood pressure (BP), lipids, insulin, and glucose. The study cohort was stratified by sex, and regression analyses were performed with the various metabolic risk factors as the outcome and WC and ethnicity as predictors. Chinese men and women had significantly lower WC than European men and women. Age and metabolic risk factors were similar between the 2 ethnic groups except for BP. Metabolic risk factors significantly correlated with WC within each gender and ethnic cohort. In men, ethnicity was an independent predictor for total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and the ratio of TC to high-density lipoprotein cholesterol (HDL-C) after controlling for WC. In women, ethnicity significantly interacted with WC as an independent predictor of TG, TC:HDL-C ratio, insulin, and glucose. As ethnic descent modifies the relationship between WC and metabolic risk factors, current WC targets derived from relationships in European populations are not applicable to Chinese men and women. Therefore, ethnic background should be considered when using WC as a marker of cardiovascular risk.     

Cyclosporine as prophylaxis for graft-versus-host disease: a randomized study in patients undergoing marrow transplantation for acute nonlymphoblastic leukemia

Seventy-five patients, 13 to 49 years of age, with acute nonlymphoblastic leukemia in first remission were treated with cyclophosphamide, fractionated total body irradiation, and marrow transplantation from an HLA-identical sibling and randomized to receive either cyclosporine (CSP) (n = 36) or methotrexate (MTX) (n = 39) as prophylaxis for graft-v-host disease (GVHD). All patients engrafted, and 22 who were given CSP and 21 who were given MTX, are alive at 20 to 47 (median, 35) months (P = .5). Engraftment as assessed by granulocyte recovery (P less than .0005) and platelet transfusion requirement (P = .01) was faster in patients on CSP. Twelve patients (33%) on CSP and 22 (56%) on MTX developed acute GVHD of grades II through IV (P = .07) and 15 of 30 on CSP and 14 of 32 on MTX that were at risk developed chronic GVHD. The most frequent causes of death were interstitial pneumonitis and marrow relapse of leukemia, which occurred with similar frequency in both groups. Beneficial effects observed in patients on CSP included less severe mucositis and shorter duration of hospitalization; adverse effects included renal function impairment and hypertension. These data confirm that CSP is a useful immunosuppressant in patients undergoing marrow transplantation but fail to show a significant improvement in survival as compared with the standard regimen of MTX.     

Marrow transplantation with or without donor buffy coat cells for 65 transfused aplastic anemia patients

Sixty-five multiply transfused patients with severe aplastic anemia were given cyclophosphamide followed by grafts anemia were given cyclophosphamide followed by grafts from HLA-identical siblings. The effect of the administration of viable donor buffy coat cells following the marrow inoculum was evaluated with regard to graft rejection and survival. Results in 43 patients so treated are presented along with those in 22 concurrent patients given marrow alone. Most patients given buffy coat had positive in vitro tests of sensitization indicating a high risk for graft rejection, while all but one of the patients given marrow alone had negative tests. Thirty of the 43 (70%) patients given marrow and buffy coat are alive between 10 and 61 mo (median 36) after grafting; 4 died after graft rejection and 6 with acute or chronic graft-versus-host disease (GVHD). Eleven of the 22 (50%) patients given marrow alone are alive between 29 and 65 mo (median 52); 7 died after graft rejection and 3 with GVHD. The addition of buffy coat cell infusions to the marrow inoculum reduced the risk of rejection and increased survival in the currently reported transfused patients when compared to patients grafted before 1976. However, there was an increased risk of chronic GVHD. Recipients of marrow from female donors survived slightly better (73%) than recipients of male marrow (58%).     

Sustained, retransplantable, multilineage engraftment of highly purified adult human bone marrow stem cells in vivo

Data from many laboratory and clinical investigations indicate that CD34+ cells comprise approximately 1% of human bone marrow (BM) mononuclear cells, including the progenitor cells of all the lymphohematopoietic lineages and lymphohematopoietic stem cells (stem cells). Because stem cells are an important but rare cell type in the CD34+ cell population, investigators have subdivided the CD34+ cell population to further enrich stem cells. The CD34+/CD38- cell subset comprises less than 10% of human CD34+ adult BM cells (equivalent to < 0.1% of marrow mononuclear cells), lacks lineage (lin) antigens, contains cells with in vitro replating capacity, and is predicted to be highly enriched for stem cells. The present investigation tested whether the CD34+/CD38- subset of adult human marrow generates human hematopoiesis after transfer to preimmune fetal sheep. CD34+/ CD38- cells purified from marrow using immunomagnetic microspheres or fluorescence-activated cell sorting generated easily detectable, long- term, multilineage human hematopoiesis in the human-fetal sheep in vivo model. In contrast, transfer of CD34+/CD38+ cells to preimmune fetal sheep generated only short-term human hematopoiesis, possibly suggesting that the CD34+/CD38+ cell population contains relatively early multipotent hematopoletic progenitor cells, but not stem cells. This work extends the prior in vitro evidence that the earliest cells in fetal and adult human marrow lack CD38 expression. In summary, the CD34+/ CD38- cell population has a high capacity for long-term multilineage hematopoietic engraftment, suggesting the presence of stem cells in this minor adult human marrow cell subset.     

Antihypertensive therapy: newer concepts and agents

Major advances have taken place in recent years with respect to our understanding of hypertensive diseases, the mechanisms of action of other therapeutic agents, and the introduction of new classes of drugs. Standard therapy today uses the basic of employing nonpharmacological modalities. Thereafter a stepped-care program with pharmacological entities has been advocated using diuretic, antiadrenergic, and vasodilating agents. However, new modes of action have been introduced therapeutically during these years through inhibition of heretofore unexplored pressor mechanisms; some may be used monotherapeutically. Just precisely how the beta-adrenergic blocking drugs reduce arterial pressure still remains to be elucidated. We do not fully understand why the angiotensin-converting enzyme inhibitors work in patients with hypertension who do not have high (or even suppressed) plasma renin activity, but they are effective. Clinical studies directed toward these questions as well as toward other new classes of antihypertensive agents (including how the calcium ion affects vascular smooth muscle contractility) should provide continued enlightenment as to the pathogenesis and pathophysiology of essential hypertension. Moreover, knowledge of newer compounds that possess unique mechanisms of action should stimulate new thinking about this enigmatic disease of blood pressure regulation that we term 'essential hypertension' as well as more specific control of arterial pressure in this ubiquitous disease.     

Effects of dietary phytosterols on cholesterol metabolism and atherosclerosis: clinical and experimental evidence

Although plant sterols (phytosterols) and cholesterol have similar chemical structures, they differ markedly in their synthesis, intestinal absorption, and metabolic fate. Phytosterols inhibit intestinal cholesterol absorption, thereby lowering plasma total and low-density lipoprotein (LDL) cholesterol levels. In 16 recently published human studies that used phytosterols to reduce plasma cholesterol levels in a total of 590 subjects, phytosterol therapy was accompanied by an average 10% reduction in total cholesterol and 13% reduction in LDL cholesterol levels. Phytosterols may also affect other aspects of cholesterol metabolism that contribute to their antiatherogenic properties, and may interfere with steroid hormone synthesis. The clinical and biochemical features of hereditary sitosterolemia, as well as its treatment, are reviewed, and the effects of cholestyramine treatment in 12 sitosterolemic subjects are summarized. Finally, new ideas for future research into the role of phytosterols in health and disease are discussed.     

Practical management of management

Presented in this monograph is a dynamic concept of hypertensive diseases. We all are aware that the appallingly high morbidity and mortality from the consequences of hypertensive diseases can be drastically reduced with antihypertensive therapy, provided that the patients with hypertension are recognized and that they continue to remain on effective therapeutic programs following their evaluation. Inherent in this concept of “preventive cardiology” is the acknowledgment that evaluation of the hypertensive patient provides a baseline for a lifelong program for the management of a chronic disease. Therefore, discussed herein is the rationale for the evaluation of the findings obtained from the patient's history, physical examination, laboratory studies, and the pathophysiological concepts of the vascular disease and the cardiac involvement. These considerations should permit judicious selection of an effective treatment program.     

Risk factors for atherosclerosis in survivors of myocardial infarction and their spouses: comparison to controls without personal and family history of atherosclerosis

To explore the hypothesis that an interplay between genetic and environmental factors contributes to the development of coronary atherosclerosis, we compared the prevalence of risk factors for atherosclerosis among survivors of myocardial infarction (MI) and their spouses and apparently healthy men and women (spousal pairs) with no personal and family history of atherosclerosis in three generations. There were no significant differences in life-style and dietary habits between the groups. The daily vegetable and/or fruit intake was generally low and did not differ between the groups. Thirty percent and 25% of men and women did not consume any vegetables or fruits, respectively. All differences found in the male MI survivors and control men were also found between the female groups: MI survivors and their spouses were significantly more obese and had higher systolic and diastolic blood pressure and more pathologic plasma lipid levels compared with control males and females, respectively. Compared with the control men and women, MI survivors and spouses had higher plasma homocysteine (Hcgamma) levels (15.3 +/- 10.5, 11.9 +/- 4.0, 16.9 +/- 5.5, and 14.3 +/- 4.0, micromol/L, respectively, P = .01). The frequency of the homozygous C677T 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism in MI survivors was twice that observed in their spouses and controls (12.1%, 4.8%, and 5.8%, respectively), but this difference did not reach statistical significance. A statistically significant association of the MTHFR genotype and Hcgamma concentration (multiple ANOVA) was shown. Neither the frequencies of apolipoprotein E (apoE) alleles nor Asp9Asn mutation of exon 2, Asn29lSer mutation of exon 6, and Ser447Ter of exon 9 of the lipoprotein lipase (LPL) gene varied significantly among the groups. A possible explanation for our findings is that individuals with a genetic predisposition for atherosclerosis and their spouses share a life-style that results in a higher body mass index (BMI) and waist to hip ratio (WHR). On the other hand, individuals with no family history of atherosclerosis, despite an unhealthy life-style similar to that in the affected families (diet and physical activity), had a lower BMI and WHR and more favorable metabolic parameters, including plasma Hcgamma. In conclusion, we have shown that a personal and/or family history of atherosclerosis corresponds to the prevalence and level of risk factors for atherosclerosis. A combination of life-style factors and inherited metabolic abnormalities, including high plasma Hcgamma, are the more likely explanation for our findings.     

Liver-derived fetal hematopoietic stem cells selectively and preferentially home to the fetal bone marrow

In the course of ontogeny, the homing site for the hematopoietic stem cells (HSC) moves with certain predictability from the yolk sac to the liver/spleen and then to the marrow. The pattern of this migration has thus far been established mostly on a morphologic basis. To delineate further the course of this migration and to gain insight into its possible mechanism, we used in utero transplantation of allogeneic or xenogeneic HSC in preimmune sheep fetuses. Sex chromosome, type of hemoglobin, and species-specific surface markers were used to follow the path of transplanted cells in the fetus. Before the development of the bone marrow, transplanted HSC (liver- or marrow-derived) homed exclusively to the liver/spleen. With the development of marrow, around day 60 of gestation (term, 145 days), homing occurred also in the nascent marrow and by day 80 transplanted cells homed exclusively to the marrow. This suggests that there may be a hierarchy in homing sites, with those of the marrow having higher affinity than those of liver/spleen. Interestingly, despite a change in homing that was followed by the expansion of the marrow compartment of HSC (ie, HSC proliferation), these cells did not participate actively in blood cell formation during most of the prenatal period. Liver remained the major hematopoietic organ throughout the gestation. It was only during the perinatal period that this organ assumed the function of hematopoiesis from the liver. This lack of expression of HSC in fetal marrow can possibly be attributable to the immaturity of marrow stroma required for differentiation and maturation of progenitors and the orderly egress of mature cells into the blood stream. The availability of this model allows us to begin studies in the molecular mechanism of stem cell homing in vivo during ontogeny.