Progression of central nervous system disease from pediatric to young adulthood in sickle cell anemia

Silent cerebral infarcts and arteriopathy are common and progressive in individuals with sickle cell anemia. However, most data describing brain lesions in sickle cell anemia are cross-sectional or derive from pediatric cohorts with short follow-up. We investigated the progression of silent cerebral infarct and cerebral vessel stenosis on brain MRI and MRA, respectively, by describing the incidence of new or worsening lesions over a period of up to 25 years among young adults with sickle cell anemia and explored risk factors for progression. Forty-four adults with sickle cell anemia (HbSS or HbSβ⁰thalassemia), exposed to chronic transfusions (n = 12) or hydroxyurea (n = 32), median age 19.2 years (range 18.0–31.5), received a screening brain MRI/MRA and their results were compared with a clinical exam performed during childhood and adolescence. We used exact log-rank test to compare MRI and MRA progression among any two groups. The hazard ratio (HR) and 95% confidence interval (CI) were calculated from Cox regression analyses. Progression of MRI and MRA occurred in 12 (27%) and 4 (9%) young adults, respectively, relative to their pediatric exams. MRI progression risk was high among participants with abnormal pediatric exams (HR: 11.6, 95% CI: 2.5–54.7) and conditional or abnormal transcranial Doppler ultrasound velocities (HR: 3.9, 95% CI: 1.0–15.1). Among individuals treated with hydroxyurea, high fetal hemoglobin measured in childhood was associated with lower hazard of MRI progression (HR: 0.86, 95% CI: 0.76–0.98). MRA progression occurred more frequently among those with prior stroke (HR: 8.6, 95% CI: 1.2–64), abnormal pediatric exam (P = 0.00084), and elevated transcranial Doppler ultrasound velocities (P = 0.004). Brain MRI/MRA imaging in pediatrics can identify high-risk patients for CNS disease progression in young adulthood, prompting consideration for early aggressive treatments.     

Anemia and the transition of nomadic hunter-gatherers to a sedentary life-style: Follow-up study of a Kalahari community

Iron profiles of communities of hunter-gatherers and former hunter-gatherers conducted between 1969 and 1987 at Dobe in the Kalahari Desert of Botswana exhibited pronounced differences during periods of rapid culture change. The loss of good health and particularly the increase in anemia through time was attributed to notable changes in diet, although changes in mobility patterns were considered a secondary cause. In 1988 and 1989, studies were conducted at Kutse, also in the Kalahari Desert of Botswana, to ascertain the frequency of anemia at a recently sedentary community in which residents still relied primarily on wild animals for meat. Although not identical, the hematological presentation in 1989 was similar to that in 1988. The studies together suggest that our findings characterize the pattern of health and disease at Kutse, which is unrelated to any specific year or to diet. Additional measures of disease, specifically ESR (erythrocyte sedimentation rate) and oral temperatures, support an interpretation of anemia of chronic disease as the cause of hypoferremia at Kutse. Morbidity is high, in spite of adequate diets, because the residents are transitional from a nomadic to a sedentary lifestyle and from a relatively dispersed to an aggregated settlement pattern. These changes have introduced new health problems. © 1996 Wiley-Liss, Inc.     

Diet and health changes at the end of the Chinese neolithic: the Yangshao/Longshan transition in Shaanxi province.

In this paper we discuss diet and health changes of millet agriculturists in Northern China, Shaanxi province, during the period 7,000-4,000 BP. An episode of intensive climatic oscillations that preceded the onset of colder climate circa the fifth millennium BP divides the period (Shi et al. [1993] Global Planet. Change 7:219-233). The onset of the cooler climate marks the decline of the egalitarian society of Yangshao and the rise of the chiefdom-like society of Longshan. Skeletal materials from the two sites of Beiliu and Jiangzhai are from the earlier phases of Yangshao culture (7,000-6,000 BP), while remains from the Shijia site were excavated from the terminal phase of Yangshao culture (6,000-5,000 BP), a phase that would be expected to show adjustments to strong climatic fluctuations. Human remains from the Longshan culture (5,000-4,000, BP) were found at the Kangjia site. In order to investigate whether the trajectory of diet and health changes persisted beyond the Longshan, a skeletal sample from the Xicun site of the Western Zhao Dynastic period (3,800-2,200 BP) is included in our analyses. All Yangshao sites in our study are characterized by low frequencies of anemia and carious lesions. Some subsistence changes probably occurred during the later phase of Yangshao culture that resulted in elevated masticatory stress and occlusal macrowear among the Shijia people. However, deterioration of community health did not begin until the Longshan, when increased occurrence of porotic hyperostosis and caries is accompanied by decreased adult stature. The transition to softer, more extensively processed food during Longshan is evident in decreased rates of occlusal wear. Increased population density and diminished food values were most likely responsible for these changes. Poor health persisted into the subsequent Dynastic period of Western Zhao.     

Selective Alteration in Blood-Brain Barrier and Insulin Transport in Iron-Deficient Rats

Nutritional iron deficiency induced in rats causes a significant reduction in level of brain nonheme iron and is accompanied by selective reduction of dopamine D2 receptor Bmax. Our previous studies have clearly demonstrated that these alterations can be restored to normal by supplementation with ferrous sulfate; however, neither brain nonheme iron level nor dopamine D2 receptor Bmax can be increased beyond control values even after long-term iron therapy. The possibility that iron deficiency can induce the breakdown of the blood-brain barrier (BBB) was examined. A 70 and 100% increase in brain uptake index (BUI) for L-glucose and insulin, respectively, were noted in iron-deficient rats. However, the BUI for valine was decreased by 40%, and those for L-norepinephrine and glycine were unchanged. In addition, it was demonstrated that in normal rats insulin is transported into the brain. The data show that iron deficiency selectively affects the integrity of the BBB for insulin, glucose, and valine transport. Whether the effect of iron deficiency on the BBB is at the level of the capillary endothelial cell tight junction is not yet known. However, this study has shown that an important nutritional disorder (iron-deficiency anemia) has a profound effect on the BBB and brain function.     

A role for the base excision repair enzyme NEIL3 in replication-dependent repair of interstrand DNA cross-links derived from psoralen and abasic sites

Interstrand DNA–DNA cross-links are highly toxic lesions that are important in medicinal chemistry, toxicology, and endogenous biology. In current models of replication-dependent repair, stalling of a replication fork activates the Fanconi anemia pathway and cross-links are “unhooked” by the action of structure-specific endonucleases such as XPF-ERCC1 that make incisions flanking the cross-link. This process generates a double-strand break, which must be subsequently repaired by homologous recombination. Recent work provided evidence for a new, incision-independent unhooking mechanism involving intrusion of a base excision repair (BER) enzyme, NEIL3, into the world of cross-link repair. The evidence suggests that the glycosylase action of NEIL3 unhooks interstrand cross-links derived from an abasic site or the psoralen derivative trioxsalen. If the incision-independent NEIL3 pathway is blocked, repair reverts to the incision-dependent route. In light of the new model invoking participation of NEIL3 in cross-link repair, we consider the possibility that various BER glycosylases or other DNA-processing enzymes might participate in the unhooking of chemically diverse interstrand DNA cross-links.     

Cytoprotective effect of honey against chromosomal breakage in fanconi anemia patients in vitro

BACKGROUND:

Natural honey is widely used all over the world as a complementary and alternative medicine in various disorders including Fanconi anemia (FA). FA is a rare genetic chromosomal instability syndrome caused by impairment of DNA repair and reactive oxygen species (ROS) imbalance. This disease is also related to bone marrow failure and cancer. The aim of this study was to evaluate the cytoprotective effect of honey on mitomycin C (MMC-) induced chromosomal damage in peripheral lymphocytes from FA patients.

MATERIALS AND METHODS:

Treatment of these complications with alkylation agents MMC may enhance chromosomal breakage. We have evaluated the effect of honey on MMC- induced chromosomal breakage in FA blood cells using chromosomal breakage assay. The basal chromosomal breakage count was higher among FA patients than healthy subjects.

RESULTS:

The addition of MMC alone gave a significantly higher of chromosomal breakage in FA patients than control group (P < 0.0001). Pre- treatment with honey significantly inhibited breakage induced by MMC in FA patients by its antioxidant effect.

CONCLUSION:

Honey can prevent MMC- induced chromosomal breakage by its antioxidant effect.     

Differential role of Kruppel like factor 1 (KLF1) gene in red blood cell disorders

The master erythroid regulator KLF1,plays a pivotal role during erythroid lineage development by regulating the expression of many erythroid genes. Variations in the KLF1 gene are found to be associated with varied erythroid phenotypes. With the aim of determining the role of KLF1 gene variations in HbF induction and their genotype phenotype relationship, in this study, we screened 370 individuals with different hemoglobinopathy condition. Hematological analysis was carried out using automated blood cell counter and Variant II HPLC (Biorad). KLF1 gene mutations were screened using automated DNA sequencing. Expression analysis was carried out using q-RT PCR of KLF1, BCL11A and γ-globin after selective enrichment and culturing of CD 34 +ve cells into an erythroid lineage. Over all 14 KLF1 gene variations were identified, of which six variants were novel. The incidence of KLF1 gene mutations was found to be 8.1%. It was seen that KLF1 mutations contributed in borderline HbA₂ levels as 7.6% of our borderline HbA₂ cases showed presence of KLF1 variations. It also contributed in induction of HbF levels under stress erythropoietic conditions. Gene expression studies revealed inverse correlation of KLF1, BCL11A (reduced) with γ-globin gene expression (increased) in patients showing KLF1 gene mutations, thus indicating the role of KLF1 gene in regulating the γ-globin gene expression. The identification of genomic variants of the KLF1 may help in determining the functionally active domain of this protein and will facilitate in understanding the wide spectrum of phenotypes generated by these variants.     

Evaluation of CD4+CD25+FoxP3+ T cell populations,IL-10 production,and their correlation with clinical and biochemical parameters in sickle cell anemia patients with leg ulcers

Leg ulcers (LUs) are a debilitating complication of sickle cell anemia (SCA), with inflammation known to play a crucial role in their pathogenesis. Many studies have described the roles of T helper type 1 (Th1) and Th2 pathways in SCA; however, defects in anti-inflammatory responses are poorly understood. We evaluated interleukin (IL)-10 levels in serum and peripheral blood mononuclear cells (PBMCs) in SCA patients with leg ulcers (SCALU) and without leg ulcers (SCAWH) in addition to CD4⁺ CD25⁺FoxP3⁺ T cell populations and their its IL-10 expression. In stimulated and unstimulated PBMC cultures, SCALU patients produced higher levels of IL-10 than those in the SCAWH group. Higher levels of IL-10 in SCALU patients correlated with a history of osteonecrosis in stimulated and unstimulated cultures when compared with those in SCAWH. Immunophenotyping revealed that SCALU patients had a higher proportion of CD4⁺CD25⁺FoxP3⁺, Tr1 and CD4⁺CD25⁺FoxP3⁺IL-10⁺ T cells than other groups. Our findings revealed that IL-10 levels were increased in unstimulated cells from the SCALU group, and that this group also presented with a predominant CD4⁺ CD25⁺FoxP3⁺ cell population despite many of those cells being IL-10 negative.