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BACKGROUND Reports of nutritional deficiencies in patients with thalassemia (Thal) are common. Despite its importance, however, nutritionally focused research in Thal has been limited by inadequate sample size, inconsistent methodology, a lack of control comparisons, and few interventional trials. Due to these limitations, clinicians lack evidence-based nutrition recommendations to support clinical decision-making. This systematic review summarizes observed relationships between nutrition and morbidity in Thal published in the last 3 decades. METHODS PubMed, Web of Science, and Embase were screened for articles pertaining to nutrition in Thal using comprehensive search terms. Studies performed in humans, written in English, and published between 1990 and 2020 were included. Over 2100 manuscripts were identified, from which 97 were included. RESULTS Patients with Thal were most often deficient in vitamins A, C, D, selenium, and zinc. Prevalence of nutritional deficiency was positively correlated with age and iron overload. Evidence to support the role of vitamin D and zinc for bone health was observed; zinc was also found to improve glucose metabolism. CONCLUSIONS Due to the risk for multinutrient deficiency, nutritional status should be assessed annually in patients with Thal with prompt nutrient replacement when deficiency is detected. Routine supplementation with vitamin D and zinc is recommended.

Interference from metal hardware (piercings; buttons on clothing; and ingested material, e.g. barium) is well documented in bone health assessments by dual-energy X-ray absorptiometry (DXA). It is unknown if iron in hepatic tissue of highly iron-loaded patients could be mistakenly assessed by DXA as bone, and if this would lead to increased areal bone mineral density (aBMD) lumbar spine Z-scores derived by DXA. Our hypothesis is that iron in the liver of heavily loaded patients will artificially raise aBMD in the spine, and thereby lead to an error in the DXA scan. This study consisted of a retrospective chart review and re-analysis of DXA scans from patients with sickle cell disease and thalassemia combined with prospective DXA and liver iron concentration (LIC) measurements from healthy controls. Patients who previously had both a DXA and LIC measurement were compared with controls. aBMD of individual vertebrae were analyzed and grouped by those that may be covered by the liver (L1 or L1/2) with those typically not (L3/4). Subjects were grouped by diagnosis and LIC severity. Phantoms were created to mimic the geometry of iron loaded liver tissue, and analyzed by DXA. A significant effect was observed in the difference of BMD Z-score of L1 and L 3/ 4 when patients with LIC < 1000 were compared to those with >5000 µg Fe/g wet tissue (p = 0.043). A significant relationship was also observed in the difference in aBMD Z-score of L1 and 3/4 when controls were compared to the high iron group (p = 0.037). These findings were supported by phantom experiments. These results suggest that there is a relationship between hepatic iron and increased L1 aBMD Z-scores in highly iron-loaded patients. Given patients with hemoglobinopathies are at increased risk for osteoporosis, clinicians should maintain a higher index of suspicion when diagnosing low bone mass.

In 2020, STEM training programs across the country were challenged to provide support to students during a nation-wide shutdown of research institutions in response to the COVID-19 pandemic. Five U.S. high school science internship programs funded by the Doris Duke Charitable Foundation, with a history of collaboration, developed innovative strategies for distance-learning (DL) opportunities during the pandemic. Forty under-represented high school and undergraduate students were paired with scientific mentors at one of the programs for a DL scientific internship. Summer training combined synchronous and asynchronous programming with research projects adapted for DL success. Ninety-five percent of students who participated were satisfied with the training experience, nearly identical to exit survey responses from 2019 when our programs were held in-person. More students were interested in pursuing a career in research at the end of the program and credited the DL experience with increasing interest in research careers. Some DL elements were ideal for underrepresented youth, including a more flexible schedule and elimination of cost and time for travel. While the lack of in-person instruction challenged our ability to create a strong student community, we found that preparation, communication, and flexibility were key elements to these successful DL programs. The increased emphasis on interpretation and analysis of data, rather than data collection, enhanced student learning. This manuscript highlights the changes made to our curricula, elements which were most successful, and recommends strategies for future distance-learning programming.

Inherited disorders of neurotransmitter metabolism are rare neurodevelopmental diseases presenting with movement disorders and global developmental delay. This study presents the results of the first standardized deep phenotyping approach and describes the clinical and biochemical presentation at disease onset as well as diagnostic approaches of 275 patients from the registry of the International Working Group on Neurotransmitter related Disorders. The results reveal an increased rate of prematurity, a high risk for being small for gestational age and for congenital microcephaly in some disorders. Age at diagnosis and the diagnostic delay are influenced by the diagnostic methods applied and by disease-specific symptoms. The timepoint of investigation was also a significant factor: delay to diagnosis has decreased in recent years, possibly due to novel diagnostic approaches or raised awareness. Although each disorder has a specific biochemical pattern, we observed confounding exceptions to the rule. The data provide comprehensive insights into the phenotypic spectrum of neurotransmitter disorders. © 2021, The Author(s).

Here, we report the isolation, identification, and whole-genome sequences of 12 bacterial strains associated with four mushroom species. The study was done as an inquiry-based exercise in an undergraduate genomics course (BIOL 340) in the Thomas H. Gosnell School of Life Sciences at the Rochester Institute of Technology.

Background Mucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT. Methods This 2-year open-label pilot study of laronidase included ten patients (age 5–13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls. Results The two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients. Conclusions Laronidase seemed to improve growth in participants

People with sickle cell disease often report severe bone pain with repeated bouts of vaso-occlusive crises, but the extent of skeletal injury incurred during these painful episodes remain unclear. We sought to quantify bone degradation by comparing urinary concentrations of carboxyterminal cross-linked telopeptide of type I collagen (CTX-1), a well-described marker of bone resorption, in a prospective cohort of 52 adults with sickle cell disease enrolled in the Sickle Cell Pain Markers Study. We also questioned if changes in urinary CTX-1 concentrations correlated with changes in hemolysis and inflammatory markers measured both during and after resolution of a painful vaso-occlusive episode. Thirty-one of the 52 adults enrolled in the study had paired urine samples for CTX-1 analysis. Urinary CTX-1, corrected for urine creatinine, significantly decreased from a mean of 3.45 μg/mmol during vaso-occlusive crises to 2.62 μg/mmol at recovery (p = 0.01). Thus, increased bone loss appears to correlate with acute vaso-occlusive crises in sickle cell disease. Our finding that urinary CTX-1 can be used to probe bone degradation in sickle cell disease provides an important new tool for diagnosing and monitoring response to therapy for people with sickle cell-related bone loss.

Background: Patients with Thal (Thalassemia) are presumed to be inactive for many of the same reasons as healthy adults, though there are limited published data to support this claim. The primary aim of this study was to compare physical activity patterns in subjects with Thal to healthy controls as well as to explore the effects of transfusion therapy on physical activity in transfusion dependent patients with Thal. Methods: 37 Thal (23 Thal major, 14 Thal intermedia, 21 Female, 27.3±10.1 years) and 30 healthy controls (17 Female, 28.0 ± 13.7 years) wore an ActiGraph accelerometer for one to two weeks. Results: Thal subjects recorded a significantly fewer total number of steps per day and lower total energy expenditure compared to healthy controls (p=0.001). None of the adult Thal subjects met the recommended 10,000 steps/day as opposed to 27% of healthy adult controls (p=0.004). Thal spent significantly less time in moderate (p=0.03) to vigorous (p=0.005) activities and more time in sedentary activity (p=0.006). Conclusion: It is now clear that Thal spend significantly less time in physically demanding activities than age-matched healthy controls, a result that has long been assumed though not previously documented. Further research is needed to define an appropriate physical activity regimen best suited for patients with Thal while examining its effect on mental and physical health. J O U R N A L O F H E M A T O L O G Y A N D O N C O L O G Y R E S E A R C H ISSN NO: 2372-6601 Research DOI : 10.14302/issn.2372-6601.jhor-15-776 Corresponding author Ellen B. Fung, PhD RD CCD, Department of Hematology, UCSF Benioff Children's Hospital, Oakland, 747 52 Street, Oakland, CA 94609, Phone: 510-428-3885 x 4939, Fax: 510-450-5877 , efung@mail.cho.org

Vitamin D deficiency is associated with adverse health outcomes, including impaired bone growth, gingival inflammation and increased risk for autoimmune disease, but the relationship between vitamin D deficiency rickets in childhood and long-term health has not been studied. In this study, we assessed the effect of early vitamin D deficiency on growth, bone density, dental health and immune function in later childhood to determine if children previously diagnosed with rickets were at greater risk of adverse health outcomes compared with healthy children. We measured serum 25-hydroxyvitamin D, calcium, parathyroid hormone, bone mineral density, anthropometric measures, dietary habits, dental health, general health history, and markers of inflammation in 14 previously diagnosed rickets case children at Children's Hospital Oakland Research Center. We compared the findings in the rickets cases with 11 healthy children selected from the population of CHO staff families. Fourteen mothers of the rickets cases, five siblings of the rickets cases, and seven mothers of healthy children also participated. Children diagnosed with vitamin D deficiency rickets had a greater risk of fracture, greater prevalence of asthma, and more dental enamel defects compared with healthy children. Given the widespread actions of vitamin D, it is likely that early-life vitamin D deficiency may increase the risk of disease later in childhood. Further assessment of the long-term health effects of early deficiency is necessary to make appropriate dietary recommendations for infants at risk of deficiency.

BackgroundLow calcium intake during pregnancy may cause maternal skeletal calcium mobilization to meet fetal needs. The Recommended Dietary Allowance (RDA) for calcium in nonpregnant, pregnant, or lactating women aged 19-50 y is 1000 mg/d; most women in the United States report consuming 60-80% of the calcium RDA. An insufficient calcium intake could increase maternal bone loss during pregnancy and reduce bone recovery postpartum.ObjectivesThe aim of this study was to determine the effect of maternal calcium supplementation on peripheral cortical and trabecular bone loss during pregnancy and bone gain postpartum.MethodsA total of 64 women were enrolled in the study at 16 wk of gestation and randomly assigned to receive 1000 mg Ca/d or placebo for the remainder of the pregnancy. Measurements were performed at 16, 26, and 36 wk of pregnancy and at 4 and 12 mo postpartum for serum 25-hydroxyvitamin D and markers of bone turnover. Trabecular and cortical bone mineral density (BMD) and content were assessed at the tibia and radius by peripheral quantitative computed tomography.ResultsMean±SD daily calcium intake at baseline was 733±350 mg; only 25% of the women met the RDA. Thirty women (47% of those enrolled) remained in the study at 12 mo postpartum. After controlling for baseline bone value, serum 25-hydroxyvitamin D concentrations, length of breastfeeding, and body mass index, the calcium group had significantly greater increases in radial total BMD (P=0.02) and tibial cortical BMD (P=0.03) at 12 mo postpartum than the placebo group. Trabecular and total BMD at the tibia trended toward higher values (P&nbsp

The efficacy of pelvic floor muscle training (PFMT) alone and in combination with biofeedback (BFB), electrical stimulation (ES), or both for urinary incontinence in men following prostatectomy is inconclusive.The purpose of this study was to determine whether PFMT works well alone or in combination with BFB, ES, or both in comparison with a control.The databases Ovid Medline, EMBASE, CENTRAL, Scopus, and Web of Science, and the specialized register of the Citroen Incontinence Review Group were searched from study inception to August 2017. Abstract proceedings from urological meetings, including the European Association of Urology and the American Urological Association, were also searched.Randomized controlled trials that compared PFMT alone and PFMT with ES, BFB, or both and no treatment, placebo, or sham were included in the review.Two independent reviewers completed data extraction and quality appraisal. The Grading of Recommendations, Assessment, Development, and Evaluation tool was used for quality appraisal. Meta-analysis was done with software used for preparing and maintaining Cochrane reviews.Methodological flaws in the included studies limited internal validity.PFMT alone, PFMT plus BFB and ES, and PFMT plus ES were more effective than the control for urinary incontinence following prostatectomy. The effect of PFMT plus BFB on postprostatectomy incontinence remains uncertain.

Patients with thalassemia are frequently deficient in key micronutrients. Attempts to correct these inadequacies through nutritional supplementation have been met with some success, although disparities between intake and circulating levels continue to be observed. This study employed a convenience sample of 41 well-nourished transfusion dependent patients with thalassemia to identify possible mechanisms behind nutritional deficiencies. Each subject completed a Block 2005© Food Frequency Questionnaire (FFQ), through which macro and micronutrient intake was quantified. Fasting blood was drawn to assess vitamins A, C, D, E, copper, selenium, zinc and hematologic parameters. Dietary intake was found to be inadequate compared to Institute of Medicine (IOM) recommendations for many of the fat-soluble vitamins, as well as calcium and zinc. Circulating deficiencies of vitamins C, D, copper, zinc and γ tocopherol were also present in over 20% of patients. Many individuals who consumed an adequate dietary intake had deficient levels of circulating nutrients, which suggest alternative etiologies of nutrient excretion or loss, in addition to higher micronutrient requirements. Liver iron concentration displayed a significant negative relationship with vitamins C (r=-0.62, p

Transfusion-independent patients with thalassemia intermedia (TI) develop fatal iron overload from excessive iron absorption triggered by ineffective erythropoiesis. More information about iron pharmacokinetics and nonheme, dietary iron absorption in such patients is needed to optimize management. To obtain more information, different forms of supplemental nonheme iron sources (ferritin and ferrous sulfate) were compared in 4 TI (hemoglobin Abbreviations: CRP C-reactive protein; Hb hemoglobin; IDA iron-deficient anemia; ICP inductively coupled plasma; IE ineffective erythropoiesis; SCD sickle cell disease; sTf transferrin saturation; TI thalassemia intermedia; TIBC total iron binding capacity; TM thalassemia major; Tf transferrin

Osteoporosis has been described in animal models of mucopolysaccharidosis (MPS). Whether clinically significant osteoporosis is common among children with MPS is unknown. Therefore, cross-sectional data from whole body (WB; excluding head) and lumbar spine (LS) bone mineral density (BMD) compared with sex-, chronologic age–, and ethnicity-matched healthy individuals (Zage), height-for-age (HAZ) Z-score (ZHAZ) and bone mineral content (BMC) measured by dual-energy X-ray absorptiometry (DXA) in 40 children with MPS were analyzed. A subset of these children (n = 24) was matched 1:3 by age and sex to a group of healthy children (n = 72) for comparison of BMC adjusted for Tanner stage, race, lean body mass, height, and bone area. Low BMD Z-score was defined as Z-score of −2 or less. In children with MPS, 15% had low WB Zage and 48% had low LS Zage; 0% and 6% had low WB ZHAZ and low LS ZHAZ, respectively. Adjusted WB BMC was lower in MPS participants (p = 0.009). In conclusion, children with MPS had deficits in WB BMC after adjustments for stature and bone area. HAZ adjustment underestimated bone deficits (i.e., overestimated WB BMD Z-scores) in children with MPS likely owing to their abnormal bone shape. The influence of severe short stature and bone geometry on DXA measurements must be considered in children with MPS to avoid unnecessary exposure to antiresorptive treatments.

PURPOSE: Skeletal disease causes significant morbidity in mucopolysaccharidoses (MPS), and bone remodeling processes in MPS have not been well characterized. The objective of this study was to determine if biomarkers of bone turnover are abnormal in children with specific MPS disorders (i.e. MSP-I, MPS-II, and MPS-VI) compared to healthy children. METHODS: A cross-sectional study was performed of serum biomarkers of bone formation (bone-specific alkaline phosphatase [BSAP], osteocalcin) and urine biomarkers of bone resorption (pyridinoline, deoxypyridinoline) in MPS and healthy controls. Measures of physical function and pain were obtained using the Children’s Health Questionnaire (CHQ). RESULTS: The cohort consisted of 39 children with MPS (MPS-I = 26; MPS-II = 11; MPS-VI = 4) and 51 healthy children. Adjusting for sex and Tanner stage group, MPS individuals had statistically significant increases for osteocalcin ( p< 0.001), with trends toward higher BSAP (p = 0.054) and urinary pyridinoline (p = 0.084). These biomarkers were not significantly associated with CHQ bodily pain and physical-function scores. CONCLUSION: Osteocalcin was increased in children with MPS disorders, with trends for increases in BSAP and urinary pyridinoline, suggesting that bone remodeling is altered in children with MPS. Future studies to assess the ability of these biomarkers to quantify and monitor MPS skeletal disease in response to therapy are needed.

Ganglion cysts are soft tissue swellings occurring most commonly in the hand or wrist. Apart from swelling, most cysts are asymptomatic. Other symptoms include pain, weakness, or paraesthesia. The two main concerns patients have are the cosmetic appearance of the cysts and the fear of future malignant growth. It has been shown that 58% of cysts will resolve spontaneously over time. Treatment can be either conservative or through surgical excision. This review concluded that nonsurgical treatment is largely ineffective in treating ganglion cysts. However, it advised to patients who do not surgical treatment but would like symptomatic relief. Compared to surgery, which has a lower recurrence rate but have a higher complication rate with longer recovery period. It has been shown that surgical interventions do not provide better symptomatic relief compared to conservative treatment. If symptomatic relief is the patient’s primary concern, a conservative approach is preferred, whilst surgical intervention will decrease the likelihood of recurrence.

This exploratory study assessed apoptosis in peripheral blood leucocytes (PBL) from β-thalassaemia patients receiving chronic transfusions and chelation therapy (deferasirox or deferoxamine) at baseline, 1, 6, and 12 months. At baseline, thalassaemic PBLs presented 50% greater levels of Bax (BAX), 75% higher caspase-3/7, 48% higher caspase-8 and 88% higher caspase-9 activities and 428% more nucleosomal DNA fragmentation than control subjects. Only neutrophils correlated significantly with apoptotic markers. Previously, we showed that over the treatment year, hepatic iron declined; we now show that the ratio of Bax/Bcl-2 (BCL2), (-27·3%/year), and caspase-9 activity (-13·3%/year) declined in both treatment groups, suggesting that chelation decreases body iron and indicators of PBL apoptosis.

Patients with thalassemia (Thal) have low bone mass which can lead to fracture and decreased quality of life. There are no noninvasive anabolic therapies available to improve bone health in Thal. A longitudinal cross-over pilot trial was conducted to evaluate the effectiveness of low magnitude whole body vibration (WBV) therapy on bone in 18 patients with Thal (9 adults, 10 male, 22.1 ± 10.7 years). Subjects were asked to stand on a vibrating platform (30 Hz, 0.3 g) for 20 min/day for 6 months. Areal bone mineral density (aBMD) by DXA and volumetric BMD by peripheral quantitative computed tomography (pQCT) was assessed at baseline, 6 and 12 months. Adherence in the first 3 months was greater when compared with the second 3 months (14 ± 6 vs. 10 ± 7 min/day, P=0.007). Intention to treat analysis revealed a significant increase in whole body BMC (2.6%; P = 0.021), BMC/Ht (2.6%, P = 0.02) and aBMD (1.3%; P = 0.036), as well as a net increase in serum markers of bone formation (Osteocalcin/CTx, P = 0.027) in the adult subjects. These preliminary findings suggest that vibration therapy may be an effective nonpharmacologic intervention in Thal. Future research is needed to confirm these findings in a larger sample for longer duration.

Compromised vitamin D status is common in pregnancy and may have adverse impacts on fetal development. The purpose of this study was to investigate the association of infant whole-body bone mineral content (WBBMC) at 8–21 days of age with feto-maternal vitamin D status in a multiethnic population in Oakland, California. This was a cross-sectional study of 120 women and their newborn infants. Maternal and cord blood were collected at delivery. WBBMC was measured by dual-energy X-ray absorptiometry in term-born infants 8–21days post birth. No significant association was observed between unadjusted or size-adjusted WBBMC and feto-maternal vitamin D status analyzed continuously or categorically. In multivariate modeling, unadjusted WBBMC was predicted by bone area (P

Patients with thalassemia have low circulating levels of many nutrients, but the contribution of dietary intake has not been assessed.Our objective was to assess dietary intake in a large contemporary sample of subjects with thalassemia.A prospective, longitudinal cohort study using a validated food frequency questionnaire was conducted.Two hundred and twenty-one subjects (19.7±11.3 years, 106 were female) were categorized into the following age groups: young children (3 to 7.9 years), older children/adolescents (8 to 18.9 years), and adults (19 years or older); 78.8% had β-thalassemia and 90% were chronically transfused. This study took place at 10 hematology outpatient clinics in the United States and Canada.We conducted a comparison of intake with US Dietary Reference Intakes and correlated dietary intake of vitamin D with serum 25-OH vitamin D and dietary iron with total body iron stores.Intake was defined as inadequate if it was less than the estimated average requirement. χ(2), Fisher's exact, and Student's t test were used to compare intake between age categories and logistic regression analysis to test the relationship between intake and outcomes, controlling for age, sex, and race.More than 30% of subjects consumed inadequate levels of vitamin A, D, E, K, folate, calcium, and magnesium. The only nutrients for which90% of subjects consumed adequate amounts were riboflavin, vitamin B-12, and selenium. Dietary inadequacy increased with increasing age group (P0.01) for vitamins A, C, E, B-6, folate, thiamin, calcium, magnesium, and zinc. More than half of the sample took additional supplements of calcium and vitamin D, although circulating levels of 25-OH vitamin D remained insufficient in 61% of subjects. Dietary iron intake was not related to total body iron stores.Subjects with thalassemia have reduced intake of many key nutrients. These preliminary findings of dietary inadequacy are concerning and support the need for nutritional monitoring to determine which subjects are at greatest risk for nutritional deficiency. Future research should focus on the effect of dietary quality and nutritional status on health outcomes in thalassemia.

BACKGROUND Bone mineral content (BMC) and density (BMD) have been shown to diminish after fracture and immobilization in adults. Distal radius fractures are common in children, and unlike adults, there is a low incidence of refracture. The primary aim of this study was to assess the change in radial BMC and BMD after upper extremity fracture and casting in healthy pediatric patients. METHODS Patients were recruited at the time of distal radius fractures casting. The nonfractured (non-Fx) distal radius was initially scanned by dual energy x-ray absorptiometry (baseline), and then both arms were scanned at the time of cast removal (CastOff), and 4, 8, 12, 24, and 52 weeks post CastOff. RESULTS Twenty-one patients were enrolled (13 male, 13 Caucasian; 10.4±2.5 y) with an average length of casting of 38±11 days. Eighteen patients (86%) completed all protocol requirements. At CastOff, there was no significant difference in total BMC or BMD between the Fx and non-Fx arms. From CastOff to 24 weeks, the overall change in BMC and BMD for the non-Fx arm was +4.2% and +0.2%, respectively, whereas for the Fx arm, the change was +8.3% and +3.4%, respectively. By 24 weeks, the difference in the overall change in BMD between the Fx and non-Fx arms was statistically significant (greater than instrumental error; P

Background Tranexamic acid reduces blood loss and transfusion requirements in cardiac surgery but may increase the risk of coronary graft thrombosis. We previously reported the 30-day results of a trial evaluating tranexamic acid for coronary artery surgery. Here we report the 1-year clinical outcomes. Methods Using a factorial design, we randomly assigned patients undergoing coronary artery surgery to receive aspirin or placebo and tranexamic acid or placebo. The results of the tranexamic acid comparison are reported here. The primary 1-year outcome was death or severe disability, the latter defined as living with a modified Katz activities of daily living score of less than 8. Secondary outcomes included a composite of myocardial infarction, stroke, and death from any cause through to 1 year after surgery. Results The rate of death or disability at 1 year was 3.8% in the tranexamic acid group and 4.4% in the placebo group (relative risk, 0.85; 95% confidence interval, 0.64-1.13; P = .27), and this did not significantly differ according to aspirin exposure at the time of surgery (interaction P = .073). The composite rate of myocardial infarction, stroke, and death up to 1 year after surgery was 14.3% in the tranexamic acid group and 16.4% in the placebo group (relative risk, 0.87; 95% CI, 0.76-1.00; P = .053). Conclusions In this trial of patients having coronary artery surgery, tranexamic acid did not affect death or severe disability through to 1 year after surgery. Further work should be done to explore possible beneficial effects on late cardiovascular events.

Little is known about the effects of thalassaemia on the kidney. Characterization of underlying renal function abnormalities in thalassaemia is timely because the newer iron chelator, deferasirox, can be nephrotoxic. We aimed to determine the prevalence and correlates of renal abnormalities in thalassaemia patients, treated before deferasirox was widely available, using 24-h collections of urine. We calculated creatinine clearance and urine calcium-to-creatinine ratio and measured urinary β(2) -microglobulin, albumin, and protein. We used multivariate modelling to identify clinical, therapeutic, and laboratory predictors of renal dysfunction. One-third of thalassaemia patients who were not regularly transfused had abnormally high creatinine clearance. Regular transfusions were associated with a decrease in clearance (P = 0·004). Almost one-third of patients with thalassaemia had hypercalciuria, and regular transfusions were associated with an increase in the frequency and degree of hypercalciuria (P < 0·0001). Albuminuria was found in over half of patients, but was not consistently associated with transfusion therapy. In summary, renal hyperfiltration, hypercalciuria, and albuminuria are common in thalassaemia. Higher transfusion intensity is associated with lower creatinine clearance but more frequent hypercalciuria. The transfusion effect needs to be better understood. Awareness of underlying renal dysfunction in thalassaemia can inform decisions now about the use and monitoring of iron chelation.

Introduction Vaso-occlusive crises (VOCs), the most common acutely painful complication of sickle cell disease (SCD), presumably cause bone infarction. In a preclinical study that exposed sickle cell mice to repeated hypoxia-reperfusion stress-to recapitulate VOCs-the mice over-expressed osteoclast-driven bone resorption markers and suppressed osteoblast-mediated bone formation markers. We hypothesize that bone infarction stems from ongoing hemolysis and inflammation incurred during VOCs, and that the extent of bone degradation can be approximated by increases in concentrations of bone resorption markers in the plasma or urine of adults with SCD. We measured urinary levels of cross-linked carboxyterminal telopeptide (CTX-1, a bone resorption marker) in 52 adults with SCD, both during and after resolution of VOCs. We now report on the association between urinary CTX-1 concentrations and serum markers of hemolysis and inflammation. Methods In the Sickle Cell Pain Markers (SCPM) study, adults with SCD were consecutively recruited from Tulane University Sickle Cell Center of Southern Louisiana (2008-2013). Blood and urine specimens were collected for laboratory analyses and symptoms assessed during vaso-occlusive pain crises (visit 1) and at recovery (visit 2). Self-reported symptoms were graded on a 0-10 scale (0=no symptoms, 10=worst symptoms). We restricted our analyses to subjects with complete data obtained at both visits. Three study participants were re-enrolled in SCPM, but only one subject completed data collection and was included in this analysis. We used paired t-tests and non-parametric Wilcoxon sign rank test to assess for between-visit differences in continuous variables and Fisher's exact test to monitor changes in categorical variables. Urinary CTX-1 concentrations, corrected for urine creatinine levels, were measured using enzyme-linked immunosorbent assays performed by the Research Laboratory Services, a core facility of Maine Medical Center Research Institute, Scarborough, ME. We then compared between-visit changes in urinary CTX-1 levels with changes in serum/plasma markers of hemolysis (hemoglobin, total bilirubin, lactate dehydrogenase and reticulocyte counts) and inflammation (white blood cell count, platelets, fibrinogen, C-reactive protein and erythrocyte sedimentation rates). All data were analyzed using R 3.5.1 software, and results presented in standard box plots, with slopes and 95% confidence intervals (CI). Results Of the 52 adults enrolled in the SCPM study (62% female, 65% hemoglobin SS/ Sb-thalassemia, 35% hemoglobin SC), we analyzed paired data from 31 subjects (60%). The average duration between visits 1 and 2 was 22 days. Mean concentrations of urinary CTX-1-corrected for urine creatinine-significantly decreased from 3.43±1.95 μg/mmol during vaso-occlusive crises to 2.62±1.34 μg/mmol at recovery (Figure). We found a non-significant positive correlation between changes in urinary CTX-1 levels and days between visits (slope 0.048, 95% CI -0.025, 0.121, p-value 0.184). The correlations between changes in urinary CTX-1 concentration and serum/plasma markers of hemolysis and inflammation were not statistically significant. Secondary analyses of all laboratory markers showed significant increases in serum levels of hemoglobin and platelets between visits 1 and 2 (p Conclusions VOCs accelerate bone degradation in adults with SCD. CTX-1 has low intra-individual variability and can reliably approximate the extent of bone resorption that occur during pain crises. The small sample size (n=31 pairs) likely limited our ability to detect a significant association between changes in urinary CTX-1 concentrations and changes in serum/plasma markers of hemolysis and inflammation. Additional studies are required to better understand how CTX-1 concentrations-relative to bone formation markers e.g., bone-specific alkaline phosphatase-can be used to monitor immediate and long-term deleterious effects of recurrent VOCs on the bones of adults with SCD. Figure Figure. Disclosures No relevant conflicts of interest to declare.

Enzyme replacement therapy has been successful in alleviating morbidity and improving endurance in Mucopolysaccharidosis (MPS) type I, II, and VI, however little attention has been paid to the effects on bone mineralization. Brief case reports in MPS type III and IV suggest that bone mineral density (BMD) is diminished, but did not account for patient size. In this report, BMD was evaluated by quantitative computed tomography and by dual-energy x-ray absorptiometry (DXA) in separate studies involving 10 patients with MPS type VI (7 Female; 7.0 to 21.0 y) and 4 male patients with MPS II (8.1 to 35.5 y). Vitamin D intake met the current RDA (200 IU) for most, though 25-OH vitamin D was insufficient (< 30 ng/mL) in 87.5% of patients tested. Ht Z-score was low -5.8 +/- 3.6, with height deficits greatest in MPS VI. Spine and whole body BMD Z-scores by DXA were considered normal for chronological age in all MPS II, and after correction for Ht Z-score, in all but one subject with MPS VI. These results suggest that vitamin D insufficiency is quite common in MPS. BMD by DXA is within normal range for most, particularly after correction for short stature. A review of bone health assessment is provided as well as a discussion of these results.

Summary This study aimed to determine differences in the rates of growth, endocrine- and calcium-related abnormalities in the various thalassemia syndromes in North America treated with current therapies. Medical history, physical examinations and blood and urine collections were obtained from patients with all thalassemia syndromes age 6 years and older in the Thalassemia Clinical Research Network. 361 subjects, 49% male, mean age 23·2 years (range 6·1–75 years) were studied. Approximately 25% of children and adults, regardless of the thalassemia syndrome, had short stature. Overall growth in children was mildly affected. Final height was close to midparental height (z = −0·73 ± 1·24). Patients with beta thalassemia major (TM) had higher rates of hypogonadism, multiple endocrinopathies, worse hyperglycaemia, subclinical hypoparathyroidism and hypercalciuria. Hypogonadism remained the most frequent endocrinopathy and was frequently under-treated. 12·8% of the subjects had 25 vitamin D concentrations less than 27 nmol/l and 82% less than 75 nmol/l, regardless of the thalassemia syndrome. Adolescents had lower 25 vitamin D levels than children and adults. Compared to patients with other thalassemia syndromes, those with beta TM suffered from higher rates of multiple endocrinopathies, abnormal calcium metabolism and hypercalciuria. Vitamin D abnormalities were high among adolescents.

Adults with beta thalassemia major frequently have low BMD, fractures, and bone pain. The purpose of this study was to determine the prevalence of low BMD, fractures, and bone pain in all thalassemia syndromes in childhood, adolescence, and adulthood, associations of BMD with fractures and bone pain, and etiology of bone disease in thalassemia. Patients of all thalassemia syndromes in the Thalassemia Clinical Research Network, > or =6 yr of age, with no preexisting medical condition affecting bone mass or requiring steroids, participated. We measured spine and femur BMD and whole body BMC by DXA and assessed vertebral abnormalities by morphometric X-ray absorptiometry (MXA). Medical history by interview and review of medical records, physical examinations, and blood and urine collections were performed. Three hundred sixty-one subjects, 49% male, with a mean age of 23.2 yr (range, 6.1-75 yr), were studied. Spine and femur BMD Z-scores < -2 occurred in 46% and 25% of participants, respectively. Greater age, lower weight, hypogonadism, and increased bone turnover were strong independent predictors of low bone mass regardless of thalassemia syndrome. Peak bone mass was suboptimal. Thirty-six percent of patients had a history of fractures, and 34% reported bone pain. BMD was negatively associated with fractures but not with bone pain. Nine percent of participants had uniformly decreased height of several vertebrae by MXA, which was associated with the use of iron chelator deferoxamine before 6 yr of age. In patients with thalassemia, low BMD and fractures occur frequently and independently of the particular syndrome. Peak bone mass is suboptimal. Low BMD is associated with hypogonadism, increased bone turnover, and an increased risk for fractures.

Plasma C-reactive protein (CRP) is an inflammatory biomarker that predicts cardiovascular disease. Lowering elevated CRP with statins has reduced the incidence of cardiovascular disease. We investigated whether vitamin C or E could reduce CRP. Healthy nonsmokers (N=396) were randomized to three groups, 1000 mg/day vitamin C, 800 IU/day vitamin E, or placebo, for 2 months. Median baseline CRP was low, 0.85 mg/L. No treatment effect was seen when all participants were included. However, a significant interaction was found, indicating that treatment effect depends on baseline CRP concentration. Among participants with CRP indicative of elevated cardiovascular risk (or =1.0 mg/L), vitamin C reduced the median CRP by 25.3% vs placebo (p=0.02) (median reduction in the vitamin C group, 0.25 mg/L, 16.7%). These effects are similar to those of statins. The vitamin E effect was not significant. In summary, treatment with vitamin C but not vitamin E significantly reduced CRP among individuals with CRPor =1.0 mg/L. Among the obese, 75% had CRPor =1.0 mg/L. Research is needed to determine whether reducing this inflammatory biomarker with vitamin C could reduce diseases associated with obesity. But research on clinical benefits of antioxidants should limit participants to persons with elevations in the target biomarkers.

Background:Understanding and increasing physical activity requires assessment of occupational, home, leisure and sedentary activities.Methods:A physical activity questionnaire was developed using data from a large representative U.S. sample; includes occupational, leisure and home-based domains; and produces estimates of energy expenditure, percent body fat, minutes in various domains, and meeting recommendations. It was tested in 396 persons, mean age 44 years. Estimates were evaluated in relation to percent body fat measured by dual-energy x-ray absorptiometry.Results:Median energy expenditure was 2,365 kcal (women) and 2,960 kcal (men). Women spent 35.1 minutes/day in moderate household activities, 13.0 minutes in moderate leisure and 4.0 minutes in vigorous activities. Men spent 18.0, 22.5 and 15.6 minutes/day in those activities, respectively. Men and women spent 276.4 and 257.0 minutes/day in sedentary activities. Respondents who met recommendations through vigorous activities had significantly lower percent body fat than those who did not, while meeting recommendations only through moderate activities was not associated with percent body fat. Predicted and observed percent body fat correlated at r = .73 and r = .82 for men and women respectively, P < .0001.Conclusions:This questionnaire may be useful for understanding health effects of different components of activity, and for interventions to increase activity levels.

Children with sickle cell anemia (SCA) have low bone mass though bone turnover has not been well described. In this study, growth and pubertal development were assessed twice, 1 year apart, in 80 young subjects with type-SS SCA, while whole body bone mineral content (BMC) and density where measured in a subset (n = 46). Markers of bone turnover were measured at the second visit. Bone formation (alkaline phosphatase) was elevated, whereas bone resorption (deoxypyridinoline) was decreased compared to published data in healthy children. Markers of bone turnover correlated with growth velocity and pubertal development but not with changes in bone mass.

A natural history study was conducted in 142 Thalassemic (Thal), 199 transfused Sickle Cell Disease (Tx-SCD, n = 199), and 64 non-Tx-SCD subjects to describe the frequency of iron-related morbidity and mortality. Subjects recruited from 31 centers in the US, Canada or the UK were similar with respect to age (overall: 25 +/- 11 years, mean +/- SD) and gender (52% female). We found that Tx-SCD subjects were hospitalized more frequently compared with Thal or non-Tx-SCD (P < 0.001). Among those hospitalized, Tx-SCD adult subjects were more likely to be unemployed compared with Thal (RR = 1.6, 95% CI 1.0-2.5) or non-Tx-SCD (RR = 3.1, 95% CI 1.3-7.3). There was a positive relationship between the severity of iron overload, assessed by serum ferritin, and the frequency of hospitalizations (r= 0.20; P = 0.009). Twenty-three deaths were reported (6 Thal, 17 Tx-SCD) in 23.5 +/- 10 months of follow-up. Within the Tx-SCD group, those who died began transfusion (25.3 vs. 12.4 years, P < 0.001) and chelation therapy later (26.8 vs. 14.2 years, P = 0.01) compared with those who survived. The unadjusted death rate in Thal was lower (2.2/100 person years) compared with that in Tx-SCD (7.0/100 person years; RR = 0.38: 95% CI 0.12-0.99). However, no difference was observed when age at death was considered. Despite improvements in therapy, death rate in this contemporary sample of transfused adult subjects with Thal or SCD is 3 times greater than the general US population. Long term follow-up of this unique cohort of subjects will be helpful in further defining the relationship of chronic, heavy iron overload to morbidity and mortality.

Vitamin D deficiency is associated with adverse health outcomes, including impaired bone growth, gingival inflammation and increased risk for autoimmune disease, but the relationship between vitamin D deficiency rickets in childhood and long-term health has not been studied. In this study, we assessed the effect of early vitamin D deficiency on growth, bone density, dental health and immune function in later childhood to determine if children previously diagnosed with rickets were at greater risk of adverse health outcomes compared with healthy children. We measured serum 25-hydroxyvitamin D, calcium, parathyroid hormone, bone mineral density, anthropometric measures, dietary habits, dental health, general health history, and markers of inflammation in 14 previously diagnosed rickets case children at Children’s Hospital Oakland Research Center. We compared the findings in the rickets cases with 11 healthy children selected from the population of CHO staff families. Fourteen mothers of the rickets cases, five siblings of the rickets cases, and seven mothers of healthy children also participated. Children diagnosed with vitamin D deficiency rickets had a greater risk of fracture, greater prevalence of asthma, and more dental enamel defects compared with healthy children. Given the widespread actions of vitamin D, it is likely that early-life vitamin D deficiency may increase the risk of disease later in childhood. Further assessment of the long-term health effects of early deficiency is necessary to make appropriate dietary recommendations for infants at risk of deficiency.

Chronic transfusion therapy has played a central role in extending life expectancy for patients with hemoglobinopathies such as thalassemia. However, this life-saving therapy is associated with numerous complications that now comprise the bulk of management considerations for patients with thalassemia. This review reports on the experience of the Thalassemia Longitudinal Cohort and reviews available literature to establish guidelines for the management of patients with thalassemia.

Blood transfusion therapy is life-saving for patients with beta-thalassaemia and sickle cell disease (SCD), but often results in severe iron overload. This pilot study examined whether the biomarkers of tissue injury or inflammation differ in these two diseases. Plasma malondialdehyde (MDA) was significantly increased 1.8-fold in thalassaemia relative to control patients. In contrast, MDA in SCD was not significantly different from controls. In multivariate analysis, the strongest predictors of elevated MDA were liver iron concentration (P < 0.001) and specific diagnosis (P = 0.019). A significant 2-fold elevation of non-transferrin bound iron (NTBI) was observed in thalassaemia relative to SCD. NTBI was not a significant predictor of high MDA in multivariate analysis. SCD patients showed a significant 2.2-fold elevation of the inflammatory marker interleukin (IL)-6 relative to controls, and a 3.6- and 1.7-fold increase in IL-5 and IL-10 relative to thalassaemia. Although alpha-tocopherol was significantly decreased by at least 32% in both thalassaemia and SCD, indicating ongoing oxidant stress and antioxidant consumption, gamma-tocopherol, a nitric oxide-selective antioxidant, was increased 36% in SCD relative to thalassaemia. These results demonstrate that thalassaemia patients have increased MDA and circulating NTBI relative to SCD patients and lower levels of some cytokines and gamma-tocopherol. This supports the hypothesis that the biology of SCD may show increased inflammation and increased levels of protective antioxidants compared with thalassaemia.

Objectives: The aims of this article were: to summarize the pharmacology, pharmacokinetics, and efficacy ofdaptomycin; to explore its safety profile; and to discuss its current and potential roles as an antimicrobial therapy. Methods: A literature search was conducted using the MEDLINE (1966–August 2004) and InternationalPharmaceutical Abstracts (1970–August 2004) databases with the search terms daptomycin, LY146032 , and lipopeptide antibiotics . Abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy and documents submitted to the US Food and Drug Administration were also reviewed. Results: Phase III study results suggest no difference in efficacy or tolerability between daptomycin 4 mg/kgIV QD and vancomycin or semisynthetic penicillins for complicated skin and skin-structure infections. Animal studies suggest daptomycin may be useful for the treatment of endocarditis. Daptomycin is not indicated for pneumonia, with poorer outcomes than conventional treatment It is available as an IV medication and exhibits 92% plasma protein binding in vitro. In healthy adult humans, daptomycin has a volume of distribution of 0.1 Ukg and a plasma elimination half-life of ∼9 hours, and is eliminated primarily by renal excretion (∼54%). In patients with reduced renal function, including those receiving hemodialysis and peritoneal dialysis, the dose interval should be 48 hours. No dosage adjustment appears to be necessary for mild to moderate hepatic impairment. The use of daptomycin in patients with severe hepatic impairment has not been assessed. The most commonly reported adverse events include constipation, nausea, injection-site reactions, headache, and diarrhea. Patients should also be monitored regularly for skeletal muscle toxicity. Conclusions: Daptomycin may be useful for complicated skin and skin-structure infections and gram-positive pathogens resistant to conventional antimicrobials. However, limited data are currently available for duration of treatment beyond 14 days and at doses >4 mg/kg QD.

Although it is life saving, transfusion therapy has resulted in the majority of sickle cell anemia and thalassemia patients being at risk for hemosiderosis-induced organ damage. It is unknown whether the complications of iron overload are affected by the underlying disease. In order to address this problem, we compared the prevalence of organ dysfunction in both groups of patients receiving chronic transfusion therapy (beta thalassemia, N = 30; sickle cell anemia, N = 43). Both groups had similar quantitative liver iron. Thalassemia patients had greater cardiac disease (20% vs. 0%), growth failure (27% vs. 9%), and endocrine failure (37% vs. 0%). The strongest predictors of combined endocrine and cardiac disease in multivariate analysis were duration of chronic transfusion (P = 0.03) and diagnosis (P = 0.03). Quantitative liver iron concentration on a single liver biopsy was not predictive of cardiac or endocrine injury. Viral hepatitis is the strongest predictor of hepatocellular damage (P = 0.009), while the development of liver fibrosis is more closely related to liver iron concentration (P = 0.04). In conclusion, sickle cell anemia and thalassemia differ in the prevalence of organ injury. This difference is related to the duration of iron exposure and the specific hemoglobinopathy. A prospective study with a larger number of subjects is needed to confirm the relationships between specific diagnosis, liver iron concentration over time, and organ dysfunction.

Ubiquitinated cytoplasmic inclusions (Ub-CIs) in superficial frontal cortex and dentate gyrus neurons are the hallmark of frontotemporal degeneration of the motor neuron disease-type (FTD-MND-type). To date, 2 reports have described intranuclear ubiquitinated inclusions (Ub-INIs) in 9 cases of familial FTD-MND-type (without clinical or pathologic motor neuron disease, MND). In the current study we found an additional 11 cases with Ub-INIs. We have identified for the first time among these cases 2 with a negative family history and 3 that have concomitant amyotrophic lateral sclerosis (ALS). The results of the present study i) confirm a previous report of significantly lower average brain weight and longer duration in cases with Ub-INIs, ii) reveal significantly greater striatal neuronal loss and gliosis in cases with intranuclear inclusions, and iii) demonstrate that intranuclear inclusions correlate with cytoplasmic inclusions and dystrophic neurites in frontal cortex and striatum but not in dentate gyrus. In addition, the current study confirms that Ub-INIs are found in familial FTD-MND-type, but also extends the presence of Ub-INIs to familial FTD-MND (with concomitant ALS), and probably also to non-familial FTD-MND-type.

Background Poor growth and delayed maturation in children with sickle cell disease (SCD) may be due, in part, to mild zinc deficiency. Objective The objective was to determine the effects of zinc supplementation on growth and body composition in children with SCD. Design Forty-two prepubertal children (20 girls and 22 boys) aged 4-10 y with SCD-SS were randomly assigned to receive 10 mg elemental Zn/d in cherry syrup (zinc group) or cherry syrup alone (control group). The 2 groups were stratified by sex and initial height status. Dietary intakes were evaluated and anthropometric, high-precision knee-height, and plasma zinc measurements were made at baseline and at 3, 6, and 12 mo. Body composition was determined every 6 mo with dual-energy X-ray absorptiometry, and z scores for anthropometric variables were computed from national reference data. Longitudinal-mixed-effects analysis was used to test for differences between the groups over the 12-mo observation period. Results Thirty-eight children completed the study. No significant differences were observed at baseline. After 12 mo, the zinc group had significantly greater mean (+/- SE) increases in height (0.66 +/- 0.29 cm/y), sitting height (0.97 +/- 0.40 cm/y), knee height (3.8 +/- 1.2 mm/y), and arm circumference z scores (0.27 +/- 0.12 cm/y). Height-for-age and weight-for-age z scores decreased significantly by 0.11 +/- 0.04 and 0.13 +/- 0.05, respectively, in the control group but did not change significantly in the zinc group. Conclusions Prepubertal children with SCD-SS may have zinc deficiency and may benefit from zinc supplementation to improve linear growth and weight gain.

Low calcium intakes during pregnancy may mobilize the maternal skeletal calcium to meet fetal needs. The objective of this study was to determine the effect of maternal calcium supplementation on peripheral cortical and trabecular bone loss during pregnancy (PG) and gain postpartum (PP). Sixty-four women (21 African American, 20 Caucasian, 10 Hispanic, 9 Asian, 4 Other) were enrolled in the study at 16 weeks gestation and randomized to 1000 mg of calcium/day (CA) or placebo during PG. Measurements were done at 16, 26 and 36 weeks of PG and 4 and 12 months PP for osteocalcin (OST), c-peptide of type 1 procollagen (CICP), or c-terminal telopeptide (CTx). Trabecular and cortical bone mineral density (BMD) and content were assessed at the tibia by peripheral quantitative computed tomography. 80% of subjects have completed the study to date. Calcium intake averaged 906±596 mg /day at baseline. There was a significant difference between CA and Placebo in OST, p=0.025; CICP, p=0.012 and CTx, p=0.008 in PP time p...