Disentangling drivers of litter decomposition in a multi-continent network of tree diversity experiments.

Litter decomposition is a key ecosystem function in forests and varies in response to a range of climatic, edaphic, and local stand characteristics. Disentangling the relative contribution of these factors is challenging, especially along large environmental gradients. In particular, knowledge of the effect of management options, such as tree planting density and species composition, on litter decomposition would be highly valuable in forestry. In this study, we made use of 15 tree diversity experiments spread over eight countries and three continents within the global TreeDivNet network. We evaluated the effects of overstory composition (tree identity, species/mixture composition and species richness), plantation conditions (density and age), and climate (temperature and precipitation) on mass loss (after 3 months and 1 year) of two standardized litters: high-quality green tea and low-quality rooibos tea. Across continents, we found that early-stage decomposition of the low-quality rooibos tea was influenced locally by overstory tree identity. Mass loss of rooibos litter was higher under young gymnosperm overstories compared to angiosperm overstories, but this trend reversed with age of the experiment. Tree species richness did not influence decomposition and explained almost no variation in our multi-continent dataset. Hence, in the young plantations of our study, overstory composition effects on decomposition were mainly driven by tree species identity on decomposer communities and forest microclimates. After 12 months of incubation, mass loss of the high-quality green tea litter was mainly influenced by temperature whereas the low-quality rooibos tea litter decomposition showed stronger relationships with overstory composition and stand age. Our findings highlight that decomposition dynamics are not only affected by climate but also by management options, via litter quality of the identity of planted trees but also by overstory composition and structure.

Multivalent presentation of MPL by porous silicon microparticles favors T helper 1 polarization enhancing the anti-tumor efficacy of doxorubicin nanoliposomes.

Porous silicon (pSi) microparticles, in diverse sizes and shapes, can be functionalized to present pathogen-associated molecular patterns that activate dendritic cells. Intraperitoneal injection of MPL-adsorbed pSi microparticles, in contrast to free MPL, resulted in the induction of local inflammation, reflected in the recruitment of neutrophils, eosinophils and proinflammatory monocytes, and the depletion of resident macrophages and mast cells at the injection site. Injection of microparticle-bound MPL resulted in enhanced secretion of the T helper 1 associated cytokines IFN-γ and TNF-α by peritoneal exudate and lymph node cells in response to secondary stimuli while decreasing the anti-inflammatory cytokine IL-10. MPL-pSi microparticles independently exhibited anti-tumor effects and enhanced tumor suppression by low dose doxorubicin nanoliposomes. Intravascular injection of the MPL-bound microparticles increased serum IL-1ß levels, which was blocked by the IL-1 receptor antagonist Anakinra. The microparticles also potentiated tumor infiltration by dendritic cells, cytotoxic T lymphocytes, and F4/80+ macrophages, however, a specific reduction was observed in CD204+ macrophages.

Enabling lead discovery for histone lysine demethylases by high-throughput RapidFire mass spectrometry.

A high-throughput RapidFire mass spectrometry assay is described for the JMJD2 family of Fe(2+), O(2), and α-ketoglutarate-dependent histone lysine demethylases. The assay employs a short amino acid peptide substrate, corresponding to the first 15 amino acid residues of histone H3, but mutated at two positions to increase assay sensitivity. The assay monitors the direct formation of the dimethylated-Lys9 product from the trimethylated-Lys9 peptide substrate. Monitoring the formation of the monomethylated and des-methylated peptide products is also possible. The assay was validated using known inhibitors of the histone lysine demethylases, including 2,4-pyridinedicarboxylic acid and an α-ketoglutarate analogue. With a sampling rate of 7 s per well, the RapidFire technology permitted the single-concentration screening of 101 226 compounds against JMJD2C in 10 days using two instruments, typically giving Z' values of 0.75 to 0.85. Several compounds were identified of the 8-hydroxyquinoline chemotype, a known series of inhibitors of the Lys9-specific histone demethylases. The peptide also functions as a substrate for JMJD2A, JMJD2D, and JMJD2E, thus enabling the development of assays for all 3 enzymes to monitor progress in compound selectivity. The assay represents the first report of a RapidFire mass spectrometry assay for an epigenetics target.

Exposure-clinical response analysis of paricalcitol in patients with chronic kidney disease (stage 5) on hemodialysis or peritoneal dialysis.

Paricalcitol injection and capsules are approved for the prevention and treatment of secondary hyperparathyroidism. Exposure-response analyses were performed to describe paricalcitol pharmacokinetics and the relationship to clinical responses (intact parathyroid hormone [iPTH], serum calcium, and phosphorus) following administration of paricalcitol capsules or injection to patients with chronic kidney disease (stage 5). Paricalcitol pharmacokinetics were similar following intravenous and oral administration with mean oral clearance of 1.75 L/h and bioavailability of 75.1%. Exposure-clinical response was best described by an indirect effects model where serum iPTH, calcium, and phosphorus production rates were directly affected by paricalcitol. Significant covariates in the response model included screening iPTH, calcium, and phosphorus on their corresponding synthesis rates; age on iPTH EC(50); and bone-specific alkaline phosphatase on calcium EC(50) (CRIT). This exposure-response model was used in extensive clinical trial simulations to assess alternative dose regimens for CKD stage 5 patients.

Differential effects of paricalcitol and calcitriol on intestinal calcium absorption in hemodialysis patients.

BACKGROUND/AIMS: Increased parathyroid activity associated with chronic kidney disease is often managed with calcitriol, which can elevate serum calcium (Ca) by increasing bone resorption and intestinal absorption, whereas paricalcitol promotes less bone resorption. This study compared intestinal Ca absorption in hemodialysis patients treated with calcitriol versus paricalcitol (dose ratio 1:3). METHODS: Patients (n = 22) aged > or =20 years, on maintenance hemodialysis for > or =2 months with intact parathyroid hormone (iPTH) levels of >200 pg/ml were enrolled in a single-center, double-blind, active-controlled, randomized, crossover trial. Mean fractional intestinal Ca absorption (+/-SE) was measured by the single-tracer method ((42)Ca) and evaluated with an analysis of variance crossover model. RESULTS: Mean fractional intestinal Ca absorption was significantly lower after paricalcitol (0.135 +/- 0.006) versus calcitriol treatment (0.158 +/- 0.006, p = 0.022), a 0.023 difference in absolute Ca absorption fraction. Overall Ca absorption was low in the study population, indicating that regulation of Ca absorption may be dysfunctional. There were no significant differences in serum PTH, Ca, phosphorus (P), or Ca x P. CONCLUSION: Overall, paricalcitol-treated patients absorbed approximately 14% less Ca compared with calcitriol-treated patients with similar effects on PTH. In hemodialysis patients, paricalcitol may provide a benefit by lowering the Ca available for removal by dialysis and/or for deposit in bone or soft tissues.

Effects of ingesting a commercial thermogenic product on hemodynamic function and energy expenditure at rest in males and females.

The purpose of this study was to examine the effects of a commercially available thermogenic product (TP) on resting energy expenditure (REE) and hemodynamic variables in a randomized, double-blind, placebo (PL)-controlled study. Eight male (age: 23.0 +/- 3.70 years, weight: 95.77 +/- 16.44 kg, height: 182.4 +/- 7.87 cm) and 10 female (age: 23.6 +/- 4.81 years, weight: 67.25 +/- 5.74 kg, height: 172.42 +/- 10.31 cm) physically active individuals participated in this study. Participants reported to the laboratory on a 10-h fast and performed baseline testing on REE, heart rate, and blood pressure. Participants were then randomly assigned to ingest 3 capsules of either an experimental TP or a vitamin E PL. Criterion variables were then measured at 1-, 2-, and 3-h post ingestion. Data were analyzed by 2-factor analysis of variance (ANOVA) using SPSS, version 16.0 (SPSS Inc., Chicago, Ill.). Supplementation of the TP resulted in a significant main effect for time (p = 0.040) and for interaction (p < 0.01) in REE when compared with PL. Post hoc analysis revealed that there was no significant difference (p > 0.05) between groups at baseline, but the TP group was significantly higher (p < 0.01) than the PL group at 1-, 2-, and 3-h post, with peak values being achieved at 2-h post time point. The TP group also experienced an overall increase in REE by 17.3%, 19.6%, and 15.3% at the 1-, 2-, and 3-h time points, respectively, over baseline values. Conversely, the PL group experienced a reduction in REE by 2.5%, 1.8%, and 0.3% at the same time points compared with baseline values. There was no significant change in heart rate, systolic blood pressure, or diastolic blood pressure in either group. Taken on a daily basis, a TP may increase overall energy expenditure. Caloric expenditure significantly increased at all 3 time points in the TP group, whereas the PL group experienced no change in energy expenditure.

Oral paricalcitol for the treatment of secondary hyperparathyroidism in patients on hemodialysis or peritoneal dialysis.

BACKGROUND/AIMS: Secondary hyperparathyroidism is a common complication of chronic kidney disease, resulting from inactivation of vitamin D receptor signaling and phosphate retention. Selective activation of vitamin D receptors with intravenous paricalcitol significantly reduced parathyroid hormone (PTH) levels with no significant hypercalcemia or hyperphosphatemia in predialysis and hemodialysis (HD) patients. This study investigates the effects of oral paricalcitol to reduce PTH in patients receiving chronic HD and peritoneal dialysis (PD). METHODS: Eighty-eight patients were randomized in double-blind fashion to receive paricalcitol or placebo for 12 weeks. The dose of the study drug was adjusted weekly using the previous week's intact PTH (iPTH) level as well as calcium and Ca x P product levels. The primary end points were efficacy (two consecutive iPTH decreases of >or=30%) and safety (two consecutive calcium measurements >11.0 mg/dl). Markers of biochemical bone activity were followed. RESULTS: Demographic characteristics were similar between treatment groups. The mean paricalcitol doses (three times a week) over the entire treatment period for subjects with baseline iPTH 500 pg/ml were 3.9 and 7.6 microg, respectively. A statistically significant decrease in iPTH was seen after week 1, with a mean 30% reduction occurring by week 3. A significantly greater proportion of both HD and PD paricalcitol subjects [83% (33/40) and 100% (18/18), respectively] achieved two consecutive >or=30% decreases in iPTH. The treatment groups were not statistically different in regard to the hypercalcemia safety end point. Phosphate binder use and mean serum phosphorus levels were not different between the treatment groups. The markers of bone activity improved in the treated subjects and worsened in those on placebo. CONCLUSION: Paricalcitol provides a rapid and sustained reduction of PTH in both HD and PD patients with minimal effect on serum calcium and phosphorus and no significant difference in adverse events as compared with placebo.

Interpreting changes in the epidemiology of anencephaly and spina bifida following folic acid fortification of the U.S. grain supply in the setting of long-term trends, Atlanta, Georgia, 1968-2003.

BACKGROUND: The prevalence of anencephaly (AN) and spina bifida (SB) was declining long before fortification of enriched grains in the U.S. with folic acid. We examined whether changes in these defects surrounding fortification could be distinguished from preexisting trends. METHODS: We used data from the Metropolitan Atlanta Congenital Defects Program to identify three ascertainment periods: Period 1 (1968-1981), prenatal diagnoses rarely made; Period 2 (1981-1993), prenatal diagnoses made but not ascertained; Period 3 (1994-2003), prenatal diagnoses ascertained. We compared the annual percent change (APC) in AN and SB for each period using Poisson regression, then compared prevalences during each period for categories of pregnancy outcome, sex, race, gravidity, and maternal age. RESULTS: The prevalence of AN (N = 434) and SB (N = 663) declined during 1968-2003. The APCs in Periods 1, 2, and 3, respectively, were -6.9%, -2.9%, and -6.8% for AN, and -7.1%, -7.0%, and -6.2% for SB; 95% confidence intervals around the APCs for Periods 2 and 3 overlapped for both defects. Prevalence ratios (PRs) for females relative to males decreased for AN (2.3 in Period 1; 1.2 in Period 3); PRs for whites relative to blacks or African Americans decreased for both AN (2.7 in Period 1; 1.2 in Period 3) and SB (2.5 in Period 1; 1.1 in Period 3). CONCLUSIONS: Our analysis suggests that changes in AN and SB surrounding folic acid fortification (Period 3) could be part of preexisting trends. This must be considered when evaluating prevention efforts.

Intravenous paricalcitol for treatment of secondary hyperparathyroidism in children on hemodialysis.

BACKGROUND: Secondary hyperparathyroidism is a common complication in children receiving hemodialysis. Active vitamin D is an effective therapy, but its use is often limited by hypercalcemia and increased calcium x phosphorus (Ca x P) product. Paricalcitol, a selective vitamin D receptor activator, causes less sustained hypercalcemia and increase in Ca x P product than calcitriol and has been used effectively in adult hemodialysis patients. STUDY DESIGN: Double blind, placebo-controlled. SETTING & PARTICIPANTS: Hemodialysis units and pediatric subjects receiving hemodialysis. INTERVENTION: After a washout period of 2 to 6 weeks, 29 subjects aged 5 to 19 years received either paricalcitol or placebo for up to 12 weeks (0.04 mug/kg if initial intact parathyroid hormone [iPTH] level < 500 pg/mL [ng/L]; 0.08 mug/kg if initial iPTH level > 500 pg/mL [ng/L]). The dose was increased by 0.04 mug/kg every 2 weeks until there was a 30% decrease in iPTH level from baseline or calcium level greater than 11 mg/dL (>2.74 mmol/L) or Ca x P product greater than 75 mg(2)/dL(2) (>6.04 mmol(2)/L(2)). OUTCOMES & MEASUREMENTS: Two consecutive 30% decreases from baseline in iPTH levels and safety of paricalcitol, including hypercalcemia and increase in Ca x P product. RESULTS: 60% of the paricalcitol group had 2 consecutive 30% decreases from baseline iPTH levels compared with 21% in the placebo group (P = 0.06). The paricalcitol group had a mean decrease in iPTH level of 164 pg/mL (ng/L), whereas the placebo group had a mean increase of 238 pg/mL (ng/L; P = 0.03). There was no difference from baseline to final visit in calcium, phosphorus, or Ca x P product values in either group. LIMITATIONS: Low power to detect differences in safety between groups and a short-term study. CONCLUSION: Paricalcitol decreased iPTH levels in children receiving hemodialysis with no significant changes in serum calcium, phosphorus, or Ca x P product values during the course of the study.

A comparison of dosing regimens of paricalcitol capsule for the treatment of secondary hyperparathyroidism in CKD stages 3 and 4.

BACKGROUND: Intermittent dosing of calcitriol for secondary hyperparathyroidism (SHPT) has been associated with greater parathyroid hormone (PTH) reduction with fewer calcemic and phosphatemic effects than daily (QD) dosing. METHODS: Secondary analyses of three randomized, double-blind, placebo-controlled multicenter studies in stage 3 and 4 chronic kidney disease (CKD) patients with SHPT were performed to compare three times per week (TIW) with QD dosing of paricalcitol. The pharmacokinetics of TIW and QD dosing of paricalcitol capsules were assessed in a separate group of healthy subjects. RESULTS: Pharmacokinetics revealed similar steady state paricalcitol exposure between dosing regimens. In CKD patients, baseline data were similar between the TIW studies (n = 72, paricalcitol; n = 73, placebo) and QD studies (n = 35, paricalcitol; n = 40, placebo). Both dosing regimens resulted in similar efficacy (91%) for the primary end point of two consecutive > or = 30% decreases in intact PTH from baseline, but the QD regimen resulted in a greater percent reduction in intact PTH from baseline. The chances for developing increased serum calcium and phosphorus levels or Ca x P product were similar between paricalcitol and placebo groups for both treatment regimens. Furthermore, no difference in the risk for these elevations was detected between the TIW and QD regimens. CONCLUSIONS: QD dosing of paricalcitol capsules is as efficacious as TIW dosing in achieving the primary end point (2 consecutive > or = 30% reductions in PTH) in stage 3 and 4 CKD patients with SHPT. Moreover, the QD regimen had no significant effect on hypercalcemia, hyperphosphatemia or Ca x P product as compared with placebo or intermittent dosing.

Changes in the birth prevalence of selected birth defects after grain fortification with folic acid in the United States: findings from a multi-state population-based study.

BACKGROUND: Observational studies and clinical trials have suggested that periconceptional use of folic acid can reduce the risk of birth defects other than neural tube defects (NTDs). Using data reported by states to the National Birth Defects Prevention Network, we examined whether folic acid fortification might have decreased the prevalence of other specific birth defects. METHODS: For each of 16 birth defect categories selected for study, birth prevalence for two time periods was calculated with data submitted from a number of states in 1995-1996 ("pre-fortification") and 1999-2000 ("post-fortification"). Changes in birth prevalence between the two time periods were assessed by calculating prevalence ratios and 95% confidence intervals for each defect, and compared by maternal race/ethnicity and availability of prenatally diagnosed cases. RESULTS: We confirmed previously reported reductions in the birth prevalence of NTDs. In addition, we found modest, yet statistically significant, decreases in the birth prevalence for transposition of the great arteries(12%), cleft palate only (12%), pyloric stenosis (5%), upper limb reduction defects (11%), and omphalocele (21%). More substantial subgroup decreases were observed for renal agenesis among programs that conduct prenatal surveillance (28%), for common truncus among Hispanics (45%), and for upper limb reduction defects among Hispanics (44%). There were modest yet significant increases in the prevalence of obstructive genitourinary defects (12%) and Down syndrome (7%), but not among programs conducting prenatal surveillance for these defects. CONCLUSIONS: These results suggest some modest benefit from the folic acid fortification on the prevalence of a number of non-NTD birth defects.

Decline in the prevalence of spina bifida and anencephaly by race/ethnicity: 1995-2002.

OBJECTIVE: In an effort to reduce the occurrence of neural tube defects (NTDs), folic acid fortification of US enriched grain products was authorized by the Food and Drug Administration in March 1996 and required by January 1998. Fortification has been shown to result in an important decline in the prevalence of spina bifida and anencephaly in the general US population; however, fortification's impact on specific racial/ethnic groups has not been well described. We sought to characterize the decline in the prevalence of spina bifida and anencephaly among specific racial/ethnic groups during the transition to mandatory folic acid fortification in the United States. METHODS: Data from 21 population-based birth defects surveillance systems were used to examine trends in prevalence of spina bifida and anencephaly for specific racial/ethnic groups for the years 1995-2002. These years were divided into 3 periods: prefortification, optional fortification, and mandatory fortification. Race/ethnicity was defined as Hispanic, non-Hispanic white, and non-Hispanic black. Prevalence ratios were calculated for each racial/ethnic group by dividing the prevalence from the mandatory fortification period by the prevalence in the prefortification period. RESULTS: The study included data on 4468 cases of spina bifida and 2625 cases of anencephaly. The prevalence of spina bifida and anencephaly was highest among Hispanic births, followed by non-Hispanic white births, with the lowest prevalence among non-Hispanic black births. Significant declines in spina bifida and anencephaly were observed among Hispanic births and non-Hispanic white births. The prevalence ratio for non-Hispanic black births was of borderline significance for spina bifida and was not significant for anencephaly. CONCLUSIONS: The results of this study suggest that folic acid fortification is associated with significant decreases in the prevalence of spina bifida and anencephaly among non-Hispanic white and Hispanic births. The magnitude of the reduction was similar between these 2 groups and was more pronounced for spina bifida than for anencephaly. The decline in the prevalence of spina bifida and anencephaly among non-Hispanic black births did not reach statistical significance. Efforts to increase folic acid consumption for the prevention of NTDs in pregnancies among women of all races/ethnicities should be continued, and studies to identify and elucidate other risk factors for NTDs are warranted.

The Metropolitan Atlanta Congenital Defects Program: 35 years of birth defects surveillance at the Centers for Disease Control and Prevention.

BACKGROUND: The Metropolitan Atlanta Congenital Defects Program (MACDP) is a population-based birth defects surveillance program administered by the Centers for Disease Control and Prevention (CDC) that has been collecting, analyzing, and interpreting birth defects surveillance data since 1967. This paper presents an overview of MACDP current methods and accomplishments over the past 35 years. METHODS: MACDP actively monitors major birth defects among infants born to residents of five counties of metropolitan Atlanta, an area with approximately 50,000 annual births. Cases are ascertained from multiple sources, coded using a modified British Pediatric Association six-digit code, and reviewed and classified by clinical geneticists. RESULTS: MACDP has monitored trends in birth defects rates and has served as a case registry for descriptive, risk factor, and prognostic studies of birth defects, including studies of Agent Orange exposure among Vietnam War veterans, maternal use of multivitamins, diabetes, febrile illnesses, and survival of children with neural tube defects. MACDP has served as a data source for one of the centers participating in the National Birth Defects Prevention Study, and for developing and evaluating neural tube defects prevention strategies related to the periconceptional use of folic acid supplements. CONCLUSIONS: Since its inception, MACDP has served as a resource for the development of uniform methods and approaches to birth defect surveillance across the United States and in many other countries, monitoring birth defects rates, and as a case registry for various descriptive, etiologic, and survival studies of birth defects. MACDP has also served as a training ground for a large number of professionals active in birth defects epidemiology.

Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States.

BACKGROUND: In 1992, the United States Public Health Service recommended that all women of childbearing age consume 400 microg of folic acid daily. The Food and Drug Administration authorized the addition of synthetic folic acid to grain products in March 1996 with mandatory compliance by January 1998. The impact of these public health policies on the prevalence of neural tube defects needs to be evaluated. We sought to determine the prevalences of spina bifida and anencephaly during the transition to mandatory folic acid fortification. METHODS: Twenty-four population-based surveillance systems were used to identify 5,630 cases of spina bifida and anencephaly from 1995-99. Cases were divided into three temporal categories depending on whether neural tube development occurred before folic acid fortification (January 1995 to December 1996), during optional fortification (January 1997 to September 1998), or during mandatory fortification (October 1998 to December 1999). Prevalences for each defect were calculated for each time period. Data were also stratified by programs that did and did not ascertain prenatally diagnosed cases. RESULTS: The prevalence of spina bifida decreased 31% (prevalence ratio [PR] = 0.69, 95% confidence interval [CI] = 0.63-0.74) from the pre- to the mandatory fortification period and the prevalence of anencephaly decreased 16% (PR = 0.84, 95% CI = 0.75-0.95). Stratification by prenatal ascertainment did not alter results for spina bifida but did impact anencephaly trends. CONCLUSIONS: The decline in the prevalence of spina bifida was temporally associated with folic acid fortification of US grain supplies. The temporal association between fortification and the prevalence of anencephaly is unclear.