Search

Jeffrey D Lebensburger, Rakeshkumar J Patel, Prasannalaxmi Palabindela, Christina J Bemrich-Stolz, Thomas H Howard, Lee M HilliardDivision of Pediatric Hematology Oncology, University of Alabama at Birmingham, Birmingham, AL, USAPurpose: Patients with hemoglobin SC (Hb SC) and hemoglobin SB+ (Hb SB+) thalassemia suffer from frequent hospitalizations yet strong evidence of a clinical benefit of hydroxyurea (HU) in this population is lacking. Patients with recurrent hospitalizations for pain crisis are offered HU at our institution based on small cohort data and anecdotal benefit. This study identifies outcomes from a large cohort of patients with Hb SC and SB+ thalassemia who were treated with HU for 2 years.Materials and methods: A retrospective review was conducted of 32 patients with Hb SC and SB+ thalassemia who were treated with HU. We reviewed the number, and reasons for hospitalization in the 2 years prior to, and 2 years post-HU treatment as well as laboratory changes from baseline, over 1 year.Results: Patients with Hb SC and SB+ thalassemia started on HU for frequent pain, had a significant reduction in hospitalizations over 2 years as compared to the 2 years prior to HU initiation (mean total hospitalizations/year: pre-HU: 1.6 vs post-HU 0.4 hospitalizations, P

The renin-angiotensin system is a powerful regulator of arterial pressure and body fluid volume. Increasing evidence suggests that the angiotensin type 2 receptor (AT(2)R), which mediates the vasodilatory and natriuretic actions of angiotensin peptides, is enhanced in females and may, therefore, represent an innovative therapeutic target. We investigated the therapeutic potential of direct AT(2)R stimulation on renal function in 11- to 12-week-old anesthetized male and female Sprague-Dawley rats. Renal blood flow was examined in response to a graded infusion of the highly selective, nonpeptide AT(2)R agonist, compound 21 (100, 200, and 300 ng/kg per minute), in the presence and absence of AT(2)R blockade (PD123319; 1 mg/kg per hour). Direct AT(2)R stimulation significantly increased renal blood flow in both males and females, without influencing arterial pressure. This was dose dependent in females only and occurred to a greater extent in females at the highest dose of compound 21 administered (males: 13.1±2.4% versus females: 23.0±3.2% change in renal blood flow at 300 ng/kg per minute versus baseline; P<0.01). In addition, AT(2)R stimulation significantly increased sodium and water excretion to a similar extent in males and females (P(Group)=0.05 and 0.005). However, there was no significant change in glomerular filtration rate in either sex, suggesting that altered tubular function may be responsible for AT(2)R-induced natriuresis rather than hemodynamic effects. Taken together, this study provides evidence that direct AT(2)R stimulation produces vasodilatory and natriuretic effects in the male and female kidney. The AT(2)R may, therefore, represent a valuable therapeutic target for the treatment of renal and cardiovascular diseases in both men and women. [ABSTRACT FROM AUTHOR]

Extramedullary hematopoiesis occurs in the setting of hematologic disorders or malignancies when the activity of the bone marrow is insufficient to generate blood cells. We report a unique case of adrenal extramedullary hematopoiesis diagnosed in a 16 year old female with a history of anti-Diego antibody and congenital dyserythropoietic anemia. She presented with an enlarging adrenal mass and underwent surgical resection. Pathology revealed extramedullary hematopoiesis. On literature review, we identified only two prior existing cases of adrenal extramedullary hematopoiesis in pediatric patients, with no prior case reports of adrenal extramedullary hematopoiesis occurring in patients with anti-Diego antibody or in those with congenital dyserythropoietic anemia., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Janet Rae Julson reports financial support was provided by National Institute of Health. Janet Rae Julson reports a relationship with National Institute of Health that includes: funding grants.

Background: In patients with diabetes mellitus, hyperfiltration precedes the development of albuminuria. Pediatric sickle cell anemia (SCA) patients have a high prevalence of hyperfiltration and albuminuria during early childhood and adolescence. We tested the hypothesis that hyperfiltration precedes the development of albuminuria in a longitudinal pediatric SCA cohort., Methods: We identified 91 participants with HbSS or SB0 thalassemia 5-21 years of age enrolled in a longitudinal sickle cell nephropathy cohort study who had a cystatin C measured during early childhood (4-10 years of age). Early hyperfiltration was defined as a mean eGFR >180 mL/min/1.73m 2 using cystatin C obtained from 4 to 10 years of age. Persistent albuminuria was defined as an albumin to creatinine ratio > 30 mg/g on two of three untimed urine specimens. Time to event analysis estimated survival curves for participants with and without hyperfiltration using Kaplan-Meier curves and used logrank test for categorical variables to assess the association with time to development of the first episode persistent albuminuria., Results: Persistent albuminuria occurred more often and at an earlier age in participants with early hyperfiltration compared to those without early hyperfiltration (log-rank, P = .004). Participants who developed albuminuria have a significant increase in their eGFR during childhood (P = .003) as compared to participants who have not yet progressed to albuminuria (P = .26). For every 1 g/dL increase in hemoglobin, the hazard ratio for developing persistent proteinuria decreased by 0.56 (95% CI: 0.3, 1.06, P = .07)., Conclusion: Hyperfiltration precedes the development of persistent proteinuria in pediatric SCA patients. Intervention strategies should target lowering eGFR during early childhood., (© 2018 Wiley Periodicals, Inc.)

YARS2 variants have previously been described in patients with myopathy, lactic acidosis and sideroblastic anemia 2 (MLASA2). YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase, which is responsible for conjugating tyrosine to its cognate mt-tRNA for mitochondrial protein synthesis. Here we describe 14 individuals from 11 families presenting with sideroblastic anemia and YARS2 variants that we identified using a sideroblastic anemia gene panel or exome sequencing. The phenotype of these patients ranged from MLASA to isolated congenital sideroblastic anemia. As in previous cases, inter- and intra-familial phenotypic variability was observed, however, this report includes the first cases with isolated sideroblastic anemia and patients with biallelic YARS2 variants that have no clinically ascertainable phenotype. We identified ten novel YARS2 variants and three previously reported variants. In vitro amino-acylation assays of five novel missense variants showed that three had less effect on the catalytic activity of YARS2 than the most commonly reported variant, p.(Phe52Leu), associated with MLASA2, which may explain the milder phenotypes in patients with these variants. However, the other two missense variants had a more severe effect on YARS2 catalytic efficiency. Several patients carried the common YARS2 c.572 G>T, p.(Gly191Val) variant (minor allele frequency =0.1259) in trans with a rare deleterious YARS2 variant. We have previously shown that the p.(Gly191Val) variant reduces YARS2 catalytic activity. Consequently, we suggest that biallelic YARS2 variants, including severe loss-of-function alleles in trans of the common p.(Gly191Val) variant, should be considered as a cause of isolated congenital sideroblastic anemia, as well as the MLASA syndromic phenotype., (Copyright© 2018 Ferrata Storti Foundation.)

Background: Painful events are the leading cause of hospitalizations for patients with sickle cell disease. Individualized pain plans targeting patient-specific maximum opioid dosing may shorten hospitalization length and are recommended by national guidelines. Prior to implementing individualized sickle cell pain plans, we tested the hypothesis that a shorter time to achieve a maximum opioid dose would improve hospitalization outcomes., Procedure: Two-year IRB-approved, retrospective study of pediatric patients admitted for vaso-occlusive crisis (VOC). We recorded the emergency department admission time, order entry time for the maximum opioid dose during the hospitalization, and time of discharge orders.  We categorized patients as infrequent if they required <3 admissions for VOC over two years and patients as frequent if they required ≥3 admissions for VOC over two years. To account for multiple admissions, generalized linear modeling was performed., Results: We identified 236 admissions for acute pain observed in 108 patients. Achieving an earlier maximum opioid dose was significantly associated with shorter length of hospitalization for frequent and infrequent pain patients (both P ≤ 0.0001). As total hospitalization length can be impacted by the time a maximum opioid order was placed, we also analyzed hospitalization length after the maximum opioid order was placed. Frequent pain patients who achieved earlier analgesia had a significantly shorter hospitalization from the time the maximum opioid order was placed (P = 0.03) while no association was found for infrequent pain patients (P = 0.84)., Conclusions: Early achievement of maximum analgesia improved hospitalization outcomes and warrant further investigation in prospective studies of individualized pain plans., (© 2018 Wiley Periodicals, Inc.)

Background: Recurrent pain events or chronic pain are among the most common complications of sickle cell disease. Despite attempts to maximize adherence to and dosing of hydroxyurea, some patients continue to suffer from pain. Our institution developed a program to initiate chronic red blood cell transfusions for one year in patients clinically deemed to have high healthcare utilization from sickle cell pain, despite being prescribed hydroxyurea., Procedure: An institutional review board approved retrospective study to evaluate the health outcomes associated with a one-year red blood cell transfusion protocol in sickle cell patients experiencing recurrent pain events as compared with the health outcomes for these patients in the one year prior to receiving transfusion therapy. We performed a matched-pair analysis using a Wilcoxon signed rank to determine the impact of transfusion therapy on clinic visits, emergency department visits, hospital admissions, hospitalization days, and opioid prescriptions filled., Results: One year of transfusion therapy significantly reduced the number of total emergency department visits for pain (6 vs 2.5 pain visits/year, P = 0.005), mean hospitalizations for pain (3.4 vs 0.9 pain admissions/year), and mean hospital days per year for pain crisis (23.5 vs 4.5, P = 0.0001), as compared with the one year prior to transfusion therapy. We identified no significant difference in opioid prescriptions filled during the year of transfusion therapy., Conclusion: Patients with frequent pain episodes may benefit from one year of transfusion therapy., (© 2018 Wiley Periodicals, Inc.)

Background: Limited evidence exists to create institutional admission criteria guidelines for febrile sickle cell patients. In addition, evidence is lacking to understand readmission rates for febrile sickle cell patients discharged from the emergency department (ED) or hospital., Procedures: We conducted a 16-year retrospective study of bacteremia outcomes for febrile sickle cell patients. Risk variables analyzed included fever (either ≥ 39.5°C or ≥40°C), abnormal white blood cell (WBC) (>30,000 or <5,000/mcL), tachycardia and hypotension, or "ill appearing." Fourteen-day readmission rates were analyzed to determine outcomes for febrile sickle cell patients discharged from the ED or discharged within 72 h., Results: Bacteremia was identified in 17 (2.6%) of 653 febrile events that are presented to the ED. "Ill-appearing" patients had an 8.5-fold increased odds of being diagnosed with bacteremia. Models using WBC count, "ill appearing," and hypotension have the highest sensitivity and specificity (AUC > 0.75). Among 427 patients discharged from the ED or within 72 h of hospitalization, only 10 (2.3%) were readmitted for a new sickle cell complication., Conclusions: Institutions can develop admission criteria based on WBC count, hypotension, and "ill appearance." Persistently febrile, well-appearing patient can be discharged at 48 h with minimal risk for new complications., (© 2018 Wiley Periodicals, Inc.)

Tissue hypoxia has been proposed as an important event in renal ischemia-reperfusion injury (IRI), particularly during the period of ischemia and in the immediate hours following reperfusion. However, little is known about renal oxygenation during the subacute phase of IRI. We employed four different methods to assess the temporal and spatial changes in tissue oxygenation during the subacute phase (24 h and 5 days after reperfusion) of a severe form of renal IRI in rats. We hypothesized that the kidney is hypoxic 24 h and 5 days after an hour of bilateral renal ischemia, driven by a disturbed balance between renal oxygen delivery (Do 2 ) and oxygen consumption (V̇o 2 ). Renal Do 2 was not significantly reduced in the subacute phase of IRI. In contrast, renal V̇o 2 was 55% less 24 h after reperfusion and 49% less 5 days after reperfusion than after sham ischemia. Inner medullary tissue Po 2 , measured by radiotelemetry, was 25 ± 12% (mean ± SE) greater 24 h after ischemia than after sham ischemia. By 5 days after reperfusion, tissue Po 2 was similar to that in rats subjected to sham ischemia. Tissue Po 2 measured by Clark electrode was consistently greater 24 h, but not 5 days, after ischemia than after sham ischemia. Cellular hypoxia, assessed by pimonidazole adduct immunohistochemistry, was largely absent at both time points, and tissue levels of hypoxia-inducible factors were downregulated following renal ischemia. Thus, in this model of severe IRI, tissue hypoxia does not appear to be an obligatory event during the subacute phase, likely because of the markedly reduced oxygen consumption.

Blood cell membranes in sickle cell disease (SCD) have low docosahexaenoic acid (DHA). DHA treatment reduces sickle cell crisis (SCC) rate and ameliorates the inflammation, oxidative stress, and hypercoagulable state of SCD. SC411 is a novel DHA ethyl ester formulation with a proprietary delivery platform (Advanced Lipid Technology) that enhances DHA bioavailability. The SCOT trial investigated the effect of 3 different doses of SC411 on clinical and biochemical endpoints in 67 children with SCD (5-17 years old). Seventy-six percent of subjects were also receiving hydroxyurea. After 4 weeks of treatment with SC411 at 20, 36, and 60 mg DHA/kg per day or placebo a statistically significant ( P < .001) mean percentage increase of blood cell membrane DHA and eicosapentaenoic acid was seen vs baseline: 109.0% (confidence interval [CI], 46.7-171.3), 163.8% (CI, 108.3-219.2), 170.8% (CI, 90.2-251.4), and 28.6% (CI, 250.1 to 107.3), respectively. After 8 weeks of treatment, statistically significant changes vs placebo were also observed in D-dimer ( P = .025) and soluble E-selectin ( P = .0219) in subjects exposed to 36 mg/kg. A significant increase in hemoglobin was observed against placebo in subjects receiving 20 mg DHA/kg per day ( P = .039). SC411 significantly reduced electronic diary recorded SCC, analgesic use at home, and days absent from school because of sickle cell pain. The lower rate of clinical SCC observed in the pooled active groups vs placebo did not reach statistical significance (rate ratio, 0.47; 95% CI, 0.20-1.11; P = .07). All tested doses were safe and well tolerated. This trial was registered at www.clinicaltrials.gov as #NCT02973360., (© 2018 by The American Society of Hematology.)

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., (© 2017 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

We determined whether adenine-induced chronic kidney disease (CKD) in rats is associated with renal tissue hypoxia. Adenine (100 mg) or its vehicle was administered to male Sprague-Dawley rats, daily by oral gavage, over a 15-day period. Renal function was assessed before, and 7 and 14 days after, adenine treatment commenced, by collection of a 24-hour urine sample and a blood sample from the tail vein. On day 15, arterial pressure was measured in conscious rats via the tail artery. Renal tissue hypoxia was then assessed by pimonidazole adduct immunohistochemistry and fibrosis was assessed by staining tissue with picrosirius red and Masson's trichrome. CKD was evident within 7 days of commencing adenine treatment, as demonstrated by increased urinary albumin to creatinine ratio (30 ± 12-fold). By day 14 of adenine treatment plasma creatinine concentration was more than 7-fold greater, and plasma urea more than 5-fold greater, than their baseline levels. On day 15, adenine-treated rats had slightly elevated mean arterial pressure (8 mmHg), anaemia and renomegaly. Kidneys of adenine-treated rats were characterised by the presence of tubular casts, dilated tubules, expansion of the interstitial space, accumulation of collagen, and tubulointerstitial hypoxia. Pimonidazole staining (hypoxia) co-localised with fibrosis and was present in both patent and occluded tubules. We conclude that renal tissue hypoxia develops rapidly in adenine-induced CKD. This model, therefore, should prove useful for examination of the temporal and spatial relationships between tubulointerstitial hypoxia and the development of CKD, and thus the testing of the 'chronic hypoxia hypothesis'., (© 2016 John Wiley & Sons Australia, Ltd.)

Epidemiological evidence links recurrent dehydration associated with periodic water intake with chronic kidney disease (CKD). However, minimal attention has been paid to the long-term impact of periodic water intake on the progression of CKD and underlying mechanisms involved. Therefore we investigated the chronic effects of recurrent dehydration associated with periodic water restriction on arterial pressure and kidney function and morphology in male spontaneously hypertensive rats (SHR). Arterial pressure increased and glomerular filtration rate decreased in water-restricted SHR. This was observed in association with cyclic changes in urine osmolarity, indicative of recurrent dehydration. Additionally, water-restricted SHR demonstrated greater renal fibrosis and an imbalance in favour of pro-inflammatory cytokine-producing renal T cells compared to their control counterparts. Furthermore, urinary NGAL levels were greater in water-restricted than control SHR. Taken together, our results provide significant evidence that recurrent dehydration associated with chronic periodic drinking hastens the progression of CKD and hypertension, and suggest a potential role for repetitive bouts of acute renal injury driving renal inflammatory processes in this setting. Further studies are required to elucidate the specific pathways that drive the progression of recurrent dehydration-induced kidney disease.

The renin-angiotensin system (RAS) plays a commanding role in the regulation of extracellular fluid homoeostasis. Tigerstadt and Bergman first identified the RAS more than two centuries ago. By the 1980s a voyage of research and discovery into the mechanisms and actions of this system led to the development of drugs that block the RAS, which have become the mainstay for the treatment of cardiovascular and renal disease. In the last 25 years new components of the RAS have come to light, including the angiotensin type 2 receptor (AT2R) and the angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) [Ang(1-7)]/Mas receptor (MasR) axis. These have been shown to counter the classical actions of angiotensin II (AngII) at the predominant angiotensin type 1 receptor (AT1R). Our studies, and those of others, have demonstrated that targeting these depressor RAS pathways may be therapeutically beneficial. It is apparent that the evolution of both the pressor and depressor RAS pathways is distinct throughout life and that the depressor/pressor balance of the RAS vary between the sexes. These temporal patterns of expression suggest that therapies targeting the RAS could be optimized for discrete epochs in life., (© 2016 Authors; published by Portland Press Limited.)

Background/aims: The registry ClinicalTrials.gov was created to provide investigators and patients an accessible database of relevant clinical trials., Methods: To understand the state of sickle cell disease clinical trials, a comprehensive review of all 174 "closed," "interventional" sickle cell trials registered at ClinicalTrials.gov was completed in January 2015., Results: The majority of registered sickle cell disease clinical trials listed an academic center as the primary sponsor and were an early phase trial. The primary outcome for sickle cell disease trials focused on pain (23%), bone marrow transplant (BMT) (13%), hydroxyurea (8%), iron overload (8%), and pulmonary hypertension (8%). A total of 52 trials were listed as terminated or withdrawn, including 25 (14% of all trials) terminated for failure to enroll participants. At the time of this review, only 19 trials uploaded results and 29 trials uploaded a manuscript in the ClinicalTrials.gov database. A systematic review of pubmed.gov revealed that only 35% of sickle cell studies completed prior to 2014 resulted in an identified manuscript. In comparison, of 80 thalassemia trials registered in ClinicalTrials.gov, four acknowledged failure to enroll participants as a reason for trial termination or withdrawal, and 48 trials (60%) completed prior to 2014 resulted in a currently identified manuscript., Conclusion: ClinicalTrials.gov can be an important database for investigators and patients with sickle cell disease to understand the current available research trials. To enhance the validity of the website, investigators must update their trial results and upload trial manuscripts into the database. This study, for the first time, quantifies outcomes of sickle cell disease trials and provides support to the belief that barriers exist to successful completion, publication, and dissemination of sickle cell trial results., (© The Author(s) 2015.)

Introduction: It is vital to engage patients with sickle cell disease (SCD) in the transition process from pediatric to adult care. To better understand the patient perspective during the time of transition, we conducted this research with the goal of incorporating patient comprehension and desires for transition education., Materials and Methods: We surveyed 37 adolescent patients with SCD about their understanding of SCD and transition education preferences. In addition, patient responses were analyzed to understand differences among urban and rural patients., Results: The mean age of surveyed participants was 14.9 years (SD=2.1). Forty-three percent of participants responded that the topic of transition had been introduced to them, and only 21% responded that they received education about transition. Despite the poor awareness about transition, almost all participants were interested in learning more about the transition process through a technology-based transition education platform where individual health topics could be explored., Discussion: Despite a didactic teaching approach to transition education, we identified that sickle cell participants had poor recognition of receiving transition education and poor understanding of their basic medical history. However, patients can identify specific health topics that should be addressed during an individualized transition education program.

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.

Renal tissue oxygen tension (PO2) and its determinants have not been quantified in polycystic kidney disease (PKD). Therefore, we measured kidney tissue PO2 in the Lewis rat model of PKD (LPK) and in Lewis control rats. We also determined the relative contributions of altered renal oxygen delivery and consumption to renal tissue hypoxia in LPK rats. PO2 of the superficial cortex of 11- to 13-wk-old LPK rats, measured by Clark electrode with the rat under anesthesia, was higher within the cysts (32.8 ± 4.0 mmHg) than the superficial cortical parenchyma (18.3 ± 3.5 mmHg). PO2 in the superficial cortical parenchyma of Lewis rats was 2.5-fold greater (46.0 ± 3.1 mmHg) than in LPK rats. At each depth below the cortical surface, tissue PO2 in LPK rats was approximately half that in Lewis rats. Renal blood flow was 60% less in LPK than in Lewis rats, and arterial hemoglobin concentration was 57% less, so renal oxygen delivery was 78% less. Renal venous PO2 was 38% less in LPK than Lewis rats. Sodium reabsorption was 98% less in LPK than Lewis rats, but renal oxygen consumption did not significantly differ between the two groups. Thus, in this model of PKD, kidney tissue is severely hypoxic, at least partly because of deficient renal oxygen delivery. Nevertheless, the observation of similar renal oxygen consumption, despite markedly less sodium reabsorption, in the kidneys of LPK compared with Lewis rats, indicates the presence of inappropriately high oxygen consumption in the polycystic kidney., (Copyright © 2014 the American Physiological Society.)

Background: The angiotensin type-2 receptor (AT2R) opposes the vasoconstrictor actions of angiotensin II (AngII) mediated through the angiotensin type-1 receptor (AT1R). Renal AT2R levels are high during fetal life, but decrease significantly during postnatal maturation. To provide insight into the functional role of the AT2R in the kidney during postnatal development, we investigated the effects of AT2R antagonism on cardiovascular responses to AngII in young and adult male rats., Methods: In anesthetized 3- and 6-wk-old male Sprague-Dawley rats, mean arterial pressure (MAP) and renal blood flow (RBF) were measured in response to AngII in the presence of vehicle treatment or AT2R blockade with PD123319., Results: The pressor effect of AngII and associated reduction in RBF were significantly less in 3-wk- than 6-wk-old rats. AT2R blockade potentiated the reduction in RBF in response to AngII in 3-wk-old rats only., Conclusion: In young rats, the AT2R modulates the response to AngII, blunting renal vasoconstriction. This effect is attenuated with age in association with a developmental reduction in renal AT2R expression. These findings may have implications for the development of novel therapies that target the renin-angiotensin system for the improvement of renal function in term and, in particular, preterm infants.

Sex hormones regulate the renin-angiotensin system. For example, estrogen enhances expression of the angiotensin type 2 receptor. We hypothesized that activation of the angiotensin type 2 receptor shifts the chronic pressure-natriuresis relationship leftward in females compared with males and that this effect is lost with age. Mean arterial pressure was measured by radiotelemetry in adult (4 mo old) and aged (14 mo old) wild-type and angiotensin type 2 receptor knockout male and female mice. Chronic pressure-natriuresis curves were constructed while mice were maintained on a normal-salt (0.26%) diet and following 6 days of high salt (5.0%) diet. Mean arterial pressure was lower in adult wild-type females than males (88 ± 1 and 97 ± 1 mmHg, respectively), a difference that was maintained with age, but was absent in adult knockout mice. In wild-type females, the chronic pressure-natriuresis relationship was shifted leftward compared with knockout females, an effect that was lost with age. In males, the chronic pressure-natriuresis relationship was not influenced by angiotensin type 2 receptor deficiency. Compared with age-matched females, the chronic pressure-natriuresis relationships in male mice were shifted rightward. Renal expression of the angiotensin type 2 receptor was fourfold greater in adult wild-type females than males. With age, the angiotensin type 2 receptor-to-angiotensin type 1 receptor balance was reduced in females. Conversely, in males, angiotensin receptor expression did not vary significantly with age. In conclusion, the angiotensin type 2 receptor modulates the chronic pressure-natriuresis relationship in an age- and sex-dependent manner., (Copyright © 2014 the American Physiological Society.)

Background: The pressor response to angiotensin II (AngII) is attenuated in adult females as compared to males via an angiotensin type 2 receptor (AT2R)-dependent pathway. We hypothesized that adult female mice are protected against AngII-induced hypertension via an enhanced AT2R-mediated pathway and that in reproductively senescent females this pathway is no longer operative., Methods: Mean arterial pressure was measured via telemetry in 4-month-old (adult) and 16-month-old (aged) and aged ovariectomized (aged-OVX) wild-type and AT2R knockout (AT2R-KO) female mice during baseline and 14-day infusion of vehicle (saline) or AngII (600 ng/kg/min s.c.). Real-time reverse transcription polymerase chain reaction (RT-PCR) was used to determine renal gene expression of angiotensin receptors and angiotensin-converting enzyme 2 in response to 14-day treatment with vehicle or AngII., Results: Basal mean arterial pressure was similar between the groups. The pressor response to AngII was augmented in adult AT2R-KO compared to adult wild-type mice (29 ± 3 mmHg versus 10 ± 4 mmHg, respectively, on day 14 as compared to basal mean arterial pressure, P = 0.002). In wild-type mice, pressor responsiveness to AngII was augmented with age, such that the pressor response to AngII was similar between aged AT2R-KO and wild-type female mice (31 ± 4 mmHg versus 34 ± 3 mmHg, respectively, on day 14, P = 0.9). There were no significant differences in pressor responsiveness to AngII between aged and aged-OVX mice. Vehicle-treated aged wild-type mice had a lower renal AT2R/AT1R balance as compared to adult counterparts. In response to AngII, the renal AT2R/AT1R balance in aged wild-type females was greater than that observed in vehicle-treated aged wild-type females and adult wild-type females, yet the protective effects of AT2R activation were not restored., Conclusions: The protective role of the AT2R depressor pathway is lost with age in female mice. Therefore, targeting deficits in AT2R expression and/or signaling may represent a novel anti-hypertensive approach in aged females.

During normal pregnancy the renin-angiotensin system is activated, yet pregnant women are resistant to the pressor effects of angiotensin II. Our aim was to determine the role of the angiotensin type 2 receptor (AT2R) in the regulation of arterial pressure, natriuresis, and immune cell infiltration during pregnancy. Mean arterial pressure was measured via telemetry, and flow cytometry was used to enumerate immune cell infiltration in 14-week-old wild-type and AT2R knockout mice during gestation. In wild-type mice, mean arterial pressure decreased during gestation, reaching a nadir at gestational day 9 (-6±2 mm Hg) and returned to near preconception levels during late gestation. In AT2R-deficient mice, the midgestational decrease in mean arterial pressure was absent. Furthermore, mean arterial pressure was significantly increased during late gestation compared with wild-type mice (≈10 mm Hg). As expected, circulating immune cell activation was suppressed during pregnancy. However, this response was absent in AT2R-deficient mice. While renal immune cell infiltration was similar between the genotypes, there was a significant T cell phenotypic switch toward a proinflammatory T-helper 1 phenotype in AT2R-deficient mice. These data indicate that the AT2R plays an important role in arterial pressure regulation and may modulate T cell activation and renal cytokine production during pregnancy. Therefore, deficits in AT2R expression may contribute to pregnancy-induced hypertension and thus represents a potential therapeutic target., (© 2014 American Heart Association, Inc.)

Accumulating evidence suggests that the protective pathways of the renin-angiotensin system are enhanced in women, including the angiotensin type 2 receptor (AT2R), which mediates vasodilatory and natriuretic effects. To provide insight into the sex-specific ability of pharmacological AT2R stimulation to modulate renal function in hypertension, we examined the influence of the AT2R agonist, compound 21 (100-300 ng/kg per minute), on renal function in 18- to 19-week-old anesthetized male and female spontaneously hypertensive rats. AT2R stimulation significantly increased renal blood flow in female hypertensive rats (PTreatment<0.001), without influencing arterial pressure. For example, at 300 ng/kg per minute of compound 21, renal blood flow increased by 14.3±1.8% from baseline. Furthermore, at 300 ng/kg per minute of compound 21, a significant increase in urinary sodium excretion was observed in female hypertensive rats (+180±59% from baseline; P<0.05 versus vehicle-treated rats). This was seen in the absence of any major change in glomerular filtration rate, indicating that the natriuretic effects of AT2R stimulation were likely the result of altered renal tubular function. Conversely, we did not observe any significant effect of AT2R stimulation on renal hemodynamic or excretory function in male hypertensive rats. Finally, gene expression studies confirmed greater renal AT2R expression in female than in male hypertensive rats. Taken together, acute AT2R stimulation enhanced renal vasodilatation and sodium excretion without concomitant alterations in glomerular filtration rate in female hypertensive rats. Chronic studies of AT2R agonist therapy on renal function and arterial pressure in hypertensive states are now required to establish the suitability of AT2R as a therapeutic target for cardiovascular disease, particularly in women., (© 2014 American Heart Association, Inc.)

Fetal uninephrectomy (uni-x) results in hypertension at a later age in female than male sheep. We hypothesized that dysregulation of tubular sodium handling contributes to the reduced ability to regulate extracellular fluid (ECF) homeostasis in older females born with a congenital nephron deficit. Following renal excretory balance studies, the response to inhibition of the Na(+)K(+)2Cl(-) cotransporter with furosemide (0.5 mg/kg bolus + 1 mg/kg per hour, i.v) or vehicle treatment was examined in conscious 5-year-old female uni-x (n = 7) and sham (n = 7) sheep. Balance studies in meal-fed sheep demonstrated that while average 24 h sodium excretion over 6 days was not different between the groups, the daily variation in sodium excretion was significantly greater in uni-x compared to sham sheep (31 ± 4% vs. 12 ± 2%; P < 0.001). Basal plasma renin activity (PRA) and renal cortical cyclooxygenase-2 (COX-2) gene expression were lower in uni-x sheep (both, P < 0.01). The increases in glomerular filtration rate (GFR) and renal blood flow observed in sham sheep in response to furosemide were significantly attenuated in uni-x sheep (both P GROUP×TREAT < 0.05). However, fractional sodium excretion increased by a greater extent in the uni-x (4.4 ± 1.0%) as compared to the sham sheep (2.0 ± 0.4%; P GROUP×TIME < 0.05) in response to furosemide. In conclusion, fetal uni-x was associated with altered renal sodium handling and hypertension in aged females. The impaired ability to modulate PRA and GFR in the adults with a congenital nephron deficit may reduce the capacity of the kidney to respond to gains or losses in ECF to maintain a stable internal environment.

Major sex differences exist in the development and progression of hypertension and cardiovascular disease. Prior to menopause, women have lower arterial pressure and, furthermore, are protected from hypertension and cardiovascular disease relative to age-matched men. However, after menopause this cardiovascular protection in women is lost. These sex differences have been linked to sexual dimorphism in the physiological mechanisms that regulate arterial pressure, including the renin-angiotensin system (RAS), which can also impact on the male and female response to different therapeutic approaches. This suggests that antihypertensive regimens need to be tailored according to sex. Newly discovered components of the RAS have emerged in recent years, allowing us to look beyond the classical RAS for novel therapeutic targets for hypertension. In this context, it is now well established that the angiotensin AT2 receptor (AT2 R) elicits depressor and natriuretic effects and that these effects are greater in females due to enhanced AT2 R levels modulated by oestrogen. In light of knowledge that AT2 R expression is regulated by oestrogen and that the prevalence of hypertension and cardiovascular risk is greater in women after menopause, AT2 R agonist therapy may represent an innovative therapeutic approach to treat hypertension. Consequently, understanding how ageing and changes in the sex hormone balance influence the RAS is vital if we are to evaluate the potential of the AT2 R as a therapeutic target in women and also in men., (© 2013 The Authors Clinical and Experimental Pharmacology and Physiology © 2013 Wiley Publishing Asia Pty Ltd.)

Sex differences exist in the regulation of arterial pressure and renal function by the renin-angiotensin system (RAS). This may in part stem from a differential balance in the pressor and depressor arms of the RAS. In males, the ACE/AngII/AT(1)R pathways are enhanced, whereas, in females, the balance is shifted towards the ACE2/Ang(1-7)/MasR and AT(2)R pathways. Evidence clearly demonstrates that premenopausal women, as compared to aged-matched men, are protected from renal and cardiovascular disease, and this differential balance of the RAS between the sexes likely contributes. With aging, this cardiovascular protection in women is lost and this may be related to loss of estrogen postmenopause but the possible contribution of other sex hormones needs to be further examined. Restoration of these RAS depressor pathways in older women, or up-regulation of these in males, represents a therapeutic target that is worth pursuing.

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., (© 2012 The Authors Acta Physiologica © 2012 Scandinavian Physiological Society.)

The complex role of the renin-angiotensin-system (RAS) in arterial pressure regulation has been well documented. Recently, we demonstrated that chronic low-dose angiotensin II (ANG II) infusion decreases arterial pressure in female rats via an AT(2)R-mediated mechanism. Estrogen can differentially regulate components of the RAS and is known to influence arterial pressure regulation. We hypothesized that AT(2)R-mediated depressor effects evident in females were estrogen dependent and thus would be abolished by ovariectomy and restored by estrogen replacement. Female Sprague-Dawley rats underwent ovariectomy or sham surgery and were treated with 17β-estradiol or placebo. Mean arterial pressure (MAP) was measured via telemetry in response to a 2-wk infusion of ANG II (50 ng·kg(-1)·min(-1) sc) or saline. MAP significantly decreased in females treated with ANG II (-10 ± 2 mmHg), a response that was abolished by ovariectomy (+4 ± 2 mmHg) and restored with estrogen replacement (-6 ± 2 mmHg). Cardiac and renal gene expression of components of the RAS was differentially regulated by estrogen, such that overall, estrogen shifted the balance of the RAS toward the vasodilatory axis. In conclusion, estrogen-dependent mechanisms offset the vasopressor actions of ANG II by enhancing RAS vasodilator pathways in females. This highlights the potential for these vasodilator pathways as therapeutic targets, particularly in women.

Previously, we have shown that fetal uninephrectomy (uni-x) causes hypertension in female sheep by 2 years of age. Whilst the hypertension was not exacerbated by 5 years of age, these uni-x sheep had greater reductions in renal blood flow (RBF). To further explore these early indications of a decline in renal function, we investigated the renal response to a saline load (25 ml/kg/40 min) in 5-year old female uni-x and sham sheep. Basal mean arterial pressure was ∼15 mmHg greater (P(Group)<0.001), and sodium excretion (∼50%), glomerular filtration rate (∼30%, GFR) and RBF (∼40%) were all significantly lower (P(Group)<0.01) in uni-x compared to sham animals. In response to saline loading, sodium excretion increased significantly in both groups (P(Time)<0.001), however this response was blunted in uni-x sheep (P(GroupxTime)<0.01). This was accompanied with an attenuated increase in GFR and fractional sodium excretion (both P(GroupxTime)<0.05), and reduced activation of the renin-angiotensin system (both P<0.05), as compared to the sham group. The reduction in sodium excretion was associated with up-regulations in the renal gene expression of NHE3 and Na(+)/K(+) ATPase α and β subunits in the kidney cortex of the uni-x compared to the sham animals (P<0.05). Notably, neither group completely excreted the saline load within the recovery period, but the uni-x retained a higher percentage of the total volume (uni-x: 48±7%; sham: 22±9%, P<0.05). In conclusion, a reduced ability to efficiently regulate extracellular fluid homeostasis is evident in female sheep at 5 years of age, which was exacerbated in animals born with a congenital nephron deficit. Whilst there was no overt exacerbation of hypertension and renal insufficiency with age in the uni-x sheep, these animals may be more vulnerable to secondary renal insults.

Awareness of sex differences in the pathology of cardiovascular disease is increasing. Previously, we have shown a role for the angiotensin type 2 receptor (AT(2)R) in the sex differences in the arterial pressure response to Ang II. Tubuloglomerular feedback (TGF) contributes in setting pressure-natriuresis properties, and its responsiveness is closely coupled to renal Ang II levels. We hypothesize that, in females, the attenuated pressor response to Ang II is mediated via an enhanced AT(2)R mechanism that, in part, offsets Ang II-induced sensitization of the TGF mechanism. Mean arterial pressure was measured via telemetry in male and female wild-type (WT) and AT(2)R knockout (AT(2)R-KO) mice receiving Ang II (600 ng/kg per minute SC). Basal 24-hour mean arterial pressure did not differ among the 4 groups. After 10 days of Ang II infusion, mean arterial pressure increased in the male WT (28±6 mm Hg), male AT(2)R-KO (26±2 mm Hg), and female AT(2)R-KO (26±4 mm Hg) mice, however, the response was attenuated in female WT mice (12±4 mm Hg; P between sex and genotype=0.016). TGF characteristics were determined before and during acute subpressor Ang II infusion (100 ng/kg per minute IV). Basal TGF responses did not differ between groups. The expected increase in maximal change in stop-flow pressure and enhancement of TGF sensitivity in response to Ang II was observed in the male WT, male AT(2)R-KO, and female AT(2)R-KO but not in the female WT mice (P between sex and genotype <0.05; both). In conclusion, these data indicate that an enhanced AT(2)R-mediated pathway counterbalances the hypertensive effects of Ang II and attenuates the Ang II-dependent resetting of TGF activity in females. Thus, the enhancement of the AT(2)R may, in part, underlie the protection that premenopausal women demonstrate against cardiovascular disease.

Children with sickle cell anemia are at risk for brain injury. Physicians obtain brain magnetic resonance imaging (MRI) for clinical indications to determine if a patient has developed a brain injury. Controversy exists whether all children with sickle cell anemia should undergo MRI screening. This retrospective study evaluates the clinical and laboratory correlates for brain injury in 124 MRIs obtained for a variety of clinical indications. Seizure, sensory, or motor events were statistically associated with the highest risk for brain injury while less specific neurologic complaints of headache or poor school performance were not associated. Children with high systolic blood pressure, leukocytosis, and severe anemia demonstrate a higher probability for brain injury. These results indicate that brain MRI should be obtained on all children with seizure, sensory, or motor events. These data suggest that less specific neurologic symptoms should be screened if physical findings or abnormal lab or vital signs exist.

Patients with sickle cell anemia are at risk for organ damage including kidney disease. Microalbuminuria may be an early marker of disease progression. This retrospective review analyzed laboratory and clinical findings in children with sickle cell anemia according to the presence or absence of MA during well clinic sickle cell visits. Results were analyzed in sum as well as by therapeutic intervention (not on therapy,hydroxyurea therapy, or chronic transfusion therapy). Thirty two of 144(22%) children had MA, including 20 of 82 (24%) children not on a therapeutic intervention (chronic transfusion or hydroxyurea). In children not on therapy, low hemoglobin, low fetal hemoglobin and high lactate dehydrogenase were associated with MA. Frequency of positive screens for MA for the different treatment groups were: Hydroxyurea 13%; chronic transfusion 26% and children on no treatment 24%. However,the difference between the hydroxyurea group and the chronic transfusion or no treatment groups did not reach statistical significance.Increased hemoglobin and fetal hemoglobin may provide protection against kidney disease in sickle cell anemia and should be evaluated in a randomized, prospective clinical trial.

Sexual dimorphism in arterial pressure regulation has been observed in humans and animal models. The mechanisms underlying this gender difference are not fully known. Previous studies in rats have shown that females excrete more salt than males at a similar arterial pressure. The renin-angiotensin system is a powerful regulator of arterial pressure and body fluid volume. This study examined the role of the angiotensin type 2 receptor (AT₂R) in pressure-natriuresis in male and female rats because AT₂R expression has been reported to be enhanced in females. Renal function was examined at renal perfusion pressures of 120, 100, and 80 mm Hg in vehicle-treated and AT₂R antagonist-treated (PD123319; 1 mg/kg/h) groups. The pressure-natriuresis relationship was gender-dependent such that it was shifted upward in female vs male rats (P < 0.001). AT₂R blockade modulated the pressure-natriuresis relationship, shifting the curve downward in male (P < 0.01) and female (P < 0.01) rats to a similar extent. In females, AT₂R blockade also reduced the lower end of the autoregulatory range of renal blood flow (P < 0.05) and glomerular filtration rate (P < 0.01). Subsequently, the renal blood flow response to graded angiotensin II infusion was also measured with and without AT₂R blockade. We found that AT₂R blockade enhanced the renal vasoconstrictor response to angiotensin II in females but not in males (P < 0.05). In conclusion, the AT₂R modulates pressure-natriuresis, allowing the same level of sodium to be excreted at a lower pressure in both genders. However, a gender-specific role for the AT₂R in renal autoregulation was evident in females, which may be a direct vascular AT₂R effect.

We report two cases of primary CNS lymphoma (PCNSL) treated with high-dose methotrexate. Though standard adult treatment of PCNSL incorporates whole-brain radiotherapy, the literature suggests it may be possible to delay or avoid radiotherapy and the associated increased risk of neurologic sequelae in pediatric patients. Studies in adults indicate methotrexate therapy can be effective against PCNSL and has advantages over the current standard of treatment. Both patients have no evidence of disease 9 and 7 years after treatment, suggesting high-dose methotrexate may lead to disease control in pediatric patients with PCNSL while avoiding the effects of radiotherapy.

Renal medullary carcinoma (RMC) is a rare and aggressive malignancy seen primarily in patients with sickle-cell trait. We report a complete response to carboplatin, paclitaxel, and gemcitabine in a patient with advanced metastatic RMC.

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.

Background: Recent studies suggest that expression of the transforming growth factor-beta (TGF-beta)-inducible gene-h3 (betaig-h3) and its anti-lysosomal activity may be responsible for the development of albuminuria and cardiovascular disease associated with hypertension., Methods: We evaluated the proposed linkage using the spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat models. The kidney and left ventricular weight/body weight ratios were measured and cardiac collagen deposition was analyzed by Masson's trichrome stain. Renal and cardiac TGF-beta(1) and betaig-h3 expression were determined by real-time reverse transcription-polymerase chain reaction, and renal and cardiac cathepsin B and L activities were measured as an indicator of lysosomal proteolytic activity., Results: SHR exhibited increased levels of intact urinary albumin without significant change in total albumin (intact plus albumin-derived material) excretion. This was accompanied by renal hypertrophy, increased renal betaig-h3 expression, and reduced renal cathepsin B and L activities. At the same time, increased cardiac TGF-beta(1) and betaig-h3 expression and reduced cardiac cathepsin B activity was identified in SHR in addition to cardiac hypertrophy and increased collagen deposition. All these changes could be ameliorated with ramipril treatment., Conclusions: These findings implicate for the first time betaig-h3 expression and lysosomal activity as a key factor in the induction of albuminuria and cardiovascular disease associated with hypertension., (Copyright (c) 2008 S. Karger AG, Basel.)

The mechanism of albuminuria is perhaps one of the most complex yet important questions in renal physiology today. Recent studies have directly demonstrated that the normal glomerulus filters substantial amounts of albumin and that charge selectivity plays little or no role in preventing this process. This filtered albumin is then processed by proximal tubular cells by two distinct pathways; dysfunction in either one of these pathways gives rise to discrete forms of albuminuria. Most of the filtered albumin is returned to the peritubular blood supply by a retrieval pathway. Albuminuria in the nephrotic range would arise from retrieval pathway dysfunction. The small quantities of filtered albumin that are not retrieved undergo obligatory lysosomal degradation before urinary excretion as small peptide fragments. This degradation pathway is sensitive to metabolic factors responsible for hypertrophy and fibrosis, particularly molecules such as angiotensin II and transforming growth factor-beta1, whose production is stimulated by hyperglycemic and hypertensive environments. Dysfunction in this degradation pathway leads to albuminuria below the nephrotic range. These new insights into albumin filtration and processing argue for a reassessment of the role of podocytes and the slit diaphragm as major direct determinants governing albuminuria, provide information on how glomerular morphology and "tubular" albuminuria may be interrelated, and offer a new rationale for drug development.

Purpose: The purpose of the study was to measure the effect of splenectomy on packed-cell transfusion requirement in children with sickle cell disease., Methods: Thirty-seven sickle cell children who underwent splenectomies between January 2000 and May 2006 at a children's hospital were reviewed. Data were collected 6 months preoperatively to 12 months postsplenectomy. Paired t test, analysis of variance, and multivariable regression analyses were performed., Results: Of 37 children with median age 11 years (range, 2-18 years), 34 (21 males) had data that allowed analyses. Twenty-six had Hgb-SS, 5 had Hgb-SC, and 3 had Hgb S-Thal. Laparoscopic splenectomy was attempted in 36 and completed successfully in 34 (94% success). The number of units transfused decreased by 38% for 0 to 6 months and by 45% for 6 to 12 months postsplenectomy. Postoperatively, hematocrit levels increased and reticulocytes concurrently decreased with a reduction in transfusion clinic visits. The decrease in transfusion was not influenced by spleen weight, age, or hemoglobin type. Two children had acute chest syndrome (6%), and 1 had severe pneumonia (3%)., Conclusion: Laparoscopic splenectomy can be successfully completed in sickle cell children. Splenectomy significantly reduces the packed red cell transfusion requirement and frequency of clinic visits, in sickle cell children for at least 12 months postoperatively.

This study examines the existence of the urinary albumin degradation pathway and the proposed role of receptor-mediated endocytosis in this process using the isolated perfused rat kidney (IPK) model. Albumin-derived peptides in IPK urine are analyzed in terms of their relative size distribution using radioactivity and absorbance at 214 nm, and their susceptibility to trypsin digestion. The effects of perfusing kidneys with concanamycin A and myristoyl trimethyl ammonium bromide (MTMAB), inhibitors of the receptor-mediated endocytosis regulators vacuolar-type H(+) ATPase (v-ATPase) and dynamin GTPase, respectively, are examined. Normal IPK urine contains mildly degraded (defined as approximately 10-40 kDa; 43.0 +/- 8.3%) and heavily degraded (defined as <10 kDa; 22.6 +/- 7.7%) albumin peptides as well as intact albumin (34.5 +/- 4.1%). The relative size distribution of the peptides is similar by radioactivity and absorbance at 214 nm, and both profiles are reduced to very small peptides following trypsin digestion. Administration of concanamycin A or MTMAB causes a significant increase in the proportion of intact albumin (concanamycin A: 55.8 +/- 11.6%; MTMAB: 50.0 +/- 11.9%) excreted compared with normal IPK urine. This coincides with a reduction in the proportion of mildly (concanamycin A: 27.6 +/- 9.8%; MTMAB: 39.9 +/- 11.5%) and heavily degraded (concanamycin A: 16.6 +/- 7.4%; MTMAB: 10.0 +/- 2.5%) albumin present and is not associated with changes in glomerular permeability to albumin because no significant change is observed in the fractional clearance of Ficoll (radius range 20-60 A) in the presence of concanamycin A. This study demonstrates the existence of albumin peptides in IPK urine and suggests that receptor-mediated endocytosis plays a role in urinary albumin degradation.

Posttransplant lymphoproliferative disorder is a clinical challenge. Traditional chemotherapy results in tumor response, but toxicity and transplant rejection limit survival. The authors treated seven patients with malignant lymphoma after organ transplant with chemotherapy tailored to individual patient response. Chemotherapy consisted of vincristine, cyclophosphamide, and prednisone, with or without doxorubicin (Adriamycin; Pharmacia & Upjohn, Peapack, NJ, U.S.A.), or the ProMACE-CytaBOM regimen. Six of seven patients (86%) showed a complete response to treatment, with five of seven (71%) alive disease-free at 9 to 72 months (mean 38.2) after treatment. The results show that chemotherapy tailored to individual patient response is a safe and effective therapy for malignant lymphoma arising in patients with posttransplant lymphoproliferative disorder.

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.