Hb M Dothan [beta 25/26 (B7/B8)/(GGT/GAG-->GAG//Gly/Glu-->Glu]; a new mechanism of unstable methemoglobin variant and molecular characteristics.

A new unstable beta globin chain variant associated with methemoglobin (Met-Hb) phenotype was found in a Caucasian infant. Molecular analysis of the beta globin gene using polymerase chain reaction (PCR) amplification and sequencing led to the detection of a new in frame deletion in exon-1. Direct sequencing of the PCR product revealed a 3 bp deletion (-GTG) between codons 25/26, which resulted in the loss of a single amino acid (-Gly). We propose that this newly discovered unstable M-hemoglobin (M-Hb) variant, named Hb Dothan [GGT/GAG-->GAG//Gly/Glu-->Glu], is caused by a shift in the amino acid sequence and altered packing of the B and E helices during beta globin synthesis, and also changes the orientation of the critical proximal and distal histidine in the F and E helices respectively. Phenotype/Genotype features and molecular characteristics of this new beta chain are presented in this communication.

Renal hypoxia in kidney disease: Cause or consequence?

Tissue hypoxia has been proposed as an important factor in the pathophysiology of both chronic kidney disease (CKD) and acute kidney injury (AKI), initiating and propagating a vicious cycle of tubular injury, vascular rarefaction, and fibrosis and thus exacerbation of hypoxia. Here, we critically evaluate this proposition by systematically reviewing the literature relevant to the following six questions: (i) Is kidney disease always associated with tissue hypoxia? (ii) Does tissue hypoxia drive signalling cascades that lead to tissue damage and dysfunction? (iii) Does tissue hypoxia per se lead to kidney disease? (iv) Does tissue hypoxia precede pathology? (v) Does tissue hypoxia colocalize with pathology? (vi) Does prevention of tissue hypoxia prevent kidney disease? We conclude that tissue hypoxia is a common feature of both AKI and CKD. Furthermore, at least under in vitro conditions, renal tissue hypoxia drives signalling cascades that lead to tissue damage and dysfunction. Tissue hypoxia itself can lead to renal pathology, independent of other known risk factors for kidney disease. There is also some evidence that tissue hypoxia precedes renal pathology, at least in some forms of kidney disease. However, we have made relatively little progress in determining the spatial relationships between tissue hypoxia and pathological processes (i.e. colocalization) or whether therapies targeted to reduce tissue hypoxia can prevent or delay the progression of renal disease. Thus, the hypothesis that tissue hypoxia is a "common pathway" to both AKI and CKD still remains to be adequately tested.

Exploring Adult Care Experiences and Barriers to Transition in Adult Patients with Sickle Cell Disease.

BACKGROUND: Young adults with sickle cell anemia are at high risk for increased hospitalization and death at the time of transition to adult care. This may be related to failure of the transition system to prepare young adults for the adult healthcare system. This qualitative study was designed to identify factors related to transition that may affect the health of adults with sickle cell anemia. PROCEDURE: Ten patients currently treated in an adult hematology clinic participated in semi-structured qualitative interviews to describe their experience transitioning from pediatric to adult care and differences in adult and pediatric healthcare systems. RESULTS: Participants were generally unprepared for the adult healthcare system. Negative issues experienced by participants included physician mistrust, difficulty with employers, keeping insurance, and stress in personal relationships. Positive issues experienced by participants included improved self efficacy with improved self care and autonomy. CONCLUSIONS: In the absence of a formalized transition program, adults with sickle cell anemia experience significant barriers to adult care. In addition to medical history review and identification of an adult provider, transition programs should incorporate strategies to navigate the adult medical system, insurance and relationships as well as encouraging self efficacy.

Sex differences in the renal vascular response to angiotensin II involves the Mas receptor.

AIM: The renin-angiotensin system (RAS) depressor arm, particularly renal angiotensin type 2 receptor (AT(2) R) and Mas receptor (masR) expression, is enhanced in females, which may contribute to renal and cardiovascular protection. We examined the hypotheses that masR activation increases renal blood flow (RBF) at rest and attenuates the reduction in RBF in response to angiotensin II (AngII) infusion in female rats. Furthermore, we postulated that combined activation of the AT(2) R and masR would produce a greater response than masR activation alone. METHODS: In anaesthetized male and female Wistar rats, mean arterial pressure (MAP) and RBF responses during graded AngII infusion (30-1000 ng kg(-1)  min(-1) i.v.) were assessed following pre-treatment with vehicle, the masR antagonist A779, or A779 plus the AT(2) R antagonist PD123319. RESULTS: Basal MAP was not altered by any pre-treatment. Basal RBF decreased approx. 20% in female (P < 0.05), but not male rats in response to A779. However, basal RBF was not altered by A779 + PD123319. AngII infusion reduced RBF in a dose-related fashion (P(dose)  < 0.0001) and masR blockade did not alter the RBF response to AngII infusion in male or female rats. However, A779 + PD123319 attenuated the reduction in RBF response to AngII in females (P(group)  < 0.005), but not males. CONCLUSION: The impact of the masR on renal haemodynamics appears to be sexually dimorphic, with greater effects in female than male rats. However, the paradoxical effects of dual AT(2) R and masR blockade suggest that a greater understanding of the complex interactions between RAS components is required before the therapeutic opportunities of AT(2) R and/or masR stimulation can be advanced.

Erythrocytapheresis limits iron accumulation in chronically transfused sickle cell patients.

Cerebrovascular accidents (CVA) as a complication of sickle cell disease occur most frequently in childhood. Life-long transfusion prevents recurrent stroke, but inevitably leads to iron overload. Although effective chelation exists, many patients are not compliant. Erythrocytapheresis, an automated method of red blood cell exchange, was evaluated as an alternative to control transfusion-related iron load. Eleven patients with sickle cell anemia and a history of stroke were converted from simple transfusion to pheresis. Total time on pheresis for the group averaged 19 months (range 4-36 months). No significant complications occurred with a mean pre-pheresis hemoglobin S (Hb S) level of 44%. Blood utilization increased by an average of 50%. The effect of pheresis on serum ferritin depended on the patient's pre-pheresis ferritin level and chelation regimen. Ferritin levels remained stable for chelated patients with ferritin levels > or = 5,000 ng/ml, but decreased in a chelated patient with a pre-pheresis ferritin level of 4,000 ng/ml. For non-chelated patients with significant pre-pheresis iron load, ferritin levels remained stable. No patient on chelation prior to pheresis was able to discontinue deferoxamine. However, one patient with pre-pheresis ferritin of 500 ng/ml maintained serum ferritin levels < 200 ng/ml for 36 months of pheresis without chelation. Pheresis is more expensive than simple transfusion unless the cost of chelation and organ damage from iron overload are considered. Erythrocytapheresis is a safe method of controlling Hb S levels and limiting or preventing iron load in chronically transfused sickle cell patients.

Osteogenic sarcoma associated with Diamond-Blackfan anemia: a report from the Diamond-Blackfan Anemia Registry.

PURPOSE: Diamond-Blackfan anemia (DBA) is a congenital pure red cell aplasia, usually presenting in infancy or early childhood. A review of the literature strongly supports a predisposition to hematopoietic malignancy. Recently, solid tumors have been reported, some attributable to hemosiderosis and/or androgen therapy. Two cases of osteogenic sarcoma have also been documented. An analysis from the Diamond-Blackfan Anemia Registry was performed to evaluate the cancer risk in patients with DBA. METHODS: The Diamond-Blackfan Anemia Registry of North America (DBAR) is a comprehensive database of patients with DBA enrolled, after informed consent, through outreach to pediatric hematologists and family groups. The patients and/or their families complete a detailed questionnaire, and a review of medical records and telephone interviews are performed to complete and clarify the information provided. RESULTS: Of the 354 patients registered in the DBAR, there were six patients meeting the accepted diagnostic criteria for DBA who were found to have malignancies. Three patients had osteogenic sarcoma diagnosed, one with myelodysplastic syndrome, one with colon carcinoma, and one with a soft tissue sarcoma. CONCLUSION: There appears to be an association of osteogenic sarcoma with DBA. A young age at presentation may be a feature of DBA-associated osteogenic sarcoma. Because of the immaturity of the database, the actuarial risk for osteogenic sarcoma and other cancers in individuals with DBA cannot be ascertained. Speculation is made regarding the nature of the molecular defect leading to the association of DBA and osteogenic sarcoma.

Retinal toxicity associated with cisplatin and etoposide in pediatric patients.

Cisplatin is an effective chemotherapeutic agent used in the treatment of many pediatric solid tumors. Retinal toxicity is a side effect of the drug reported in adults, but is not well described in pediatric patients. We present the cases of two children treated with cisplatin and etoposide who experienced retinal toxicity documented by visual evoked response (VER) and electroretinogram (ERG). significantly, both patients had abnormal renal function. The mechanism of visual toxicity induced by cisplatin is unknown but may result from central nervous system (CNS) accumulation of drug after repeated doses, especially with high-dose platinum (HDP) containing regimens. Because clearance of platinum is related to adequate renal-function, patients with any decrease in glomerular filtration rate (GFR) may have delayed platinum excretion. We propose that the patients at greatest risk of cisplatin-induced toxicity are those pretreated with nephrotoxic therapy or those with impairment of renal function from other causes. These patients should have prospective ophthalmologic evaluation especially when treated with HDP containing regimens.