Dispersal affects community dynamics and vegetation response to global change. Understanding these effects requires descriptions of dispersal at local and regional scales and statistical models that permit estimation. Classical models of dispersal describe local or long‐distance dispersal, but not both. The lack of statistical methods means that models have rarely been fitted to seed dispersal in closed forests. We present a mixture model of dispersal that assumes a range of disperal patterns, both local and long distance. The bivariate Student’s t or “2Dt” follows from an assumption that the distance parameter in a Gaussian model varies randomly, thus having a density of its own. We use an inverse approach to “compete” our mixture model against classical alternatives, using seed rain databases from temperate broadleaf, temperate mixed‐conifer, and tropical floodplain forests. For most species, the 2Dt model fits dispersal data better than do classical models. The superior fit results from the potential for a convex shape near the source tree and a “fat tail.” Our parameter estimates have implications for community dynamics at local scales, for vegetation responses to global change at regional scales, and for differences in seed dispersal among biomes. The 2Dt model predicts that less seed travels beyond the immediate crown influence (<5 m) than is predicted under a Gaussian model, but that more seed travels longer distances (>30 m). Although Gaussian and exponential models predict slow population spread in the face of environmental change, our dispersal estimates suggest rapid spread. The preponderance of animal‐dispersed and rare seed types in tropical forests results in noisier patterns of dispersal than occur in temperate hardwood and conifer stands.

Objective To evaluate the safety, tolerability, and pharmacokinetics of an antisense oligonucleotide designed to inhibit SOD1 expression (ISIS 333611) following intrathecal administration in patients with SOD1-related familial amyotrophic lateral sclerosis (ALS). Background Mutations in SOD1 cause 13% of familial ALS. In animal studies, ISIS 333611 delivered to the cerebrospinal fluid (CSF) distributed to the brain and spinal cord, decreased SOD1 mRNA and protein levels in spinal cord tissue, and prolonged survival in the SOD1G93A rat ALS model. Methods In a randomized, placebo controlled Phase 1 trial, ISIS 333611 was delivered by intrathecal infusion using an external pump over 11.5 hours at increasing doses to four cohorts of eight SOD1 positive ALS subjects (randomized 6 drug: 2 placebo/cohort). Subjects were allowed to re-enroll in subsequent cohorts. Safety and tolerability assessments were made during the infusion and periodically over 28 days following the infusion. CSF and plasma drug levels were measured. Findings No dose-limiting toxicities were identified at doses up to 3.0 mg. No safety or tolerability concerns related to ISIS 333611 were identified. There were no serious adverse events (AEs) in ISIS 333611-treated subjects. Re-enrollment and re-dosing of subjects with ISIS 333611 was also well tolerated. Dose-dependent CSF and plasma concentrations were observed. Interpretation In this first clinical study to report intrathecal delivery of an antisense oligonucleotide, ISIS 333611 was well tolerated when administered as an intrathecal infusion in subjects with SOD1 familial ALS. CSF and plasma drug levels were consistent with levels predicted from preclinical studies. These results suggest that antisense oligonucleotide delivery to the central nervous system may be a feasible therapeutic strategy for neurological disorders. Source of funding ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals

Treatment of patients with ␤-thalassemia major has improved dramatically during the past 40 years; however, the current clinical status of these patients remains poorly characterized. We performed a cross-sectional study of 342 patients in the Registry of the National Institutes of Health-sponsored Thalassemia Clinical Research Network. Evidence of hepatitis C exposure was present in 35% of tested patients, was associated with age, and had a rate of spontaneous viral clearance of 33%. Ferritin levels ranged from 147 to 11 010 ng/mL (median, 1696 ng/mL). Median hepatic iron content was 7.8 mg/g dry weight and 23% of patients had values of 15 mg/g dry weight or higher. No patients 15 years or younger and 5% of patients aged 16 to 24 years had heart disease requiring medication. Ten percent had cirrhosis on biopsy. Endocrinologic complications were common among adults. Seventy-four (22%) patients had recent implantable central venous access devices (CVADs) placed. Among 80 episodes of bacteremia in 38 patients, 90%were attributable to the CVAD. Among 330 patients who had received deferoxamine chelation therapy, 224 (68%) reported no complications. We conclude that hepatitis C, iron-related organ dysfunction, and complications of iron chelation therapy are strongly age-dependent in North American patients with ␤-thalassemia.

Recruitment limitation of tree population dynamics is poorly understood, because fecundity and dispersal are difficult to characterize in closed stands. We present an approach that estimates seed production and dispersal under closed canopies and four limitations on recruitment: tree density and location, fecundity, seed dispersal, and establishment. Consistent estimates are obtained for 14 canopy species using 5 yr of census data from 100 seed traps and several thousand mapped trees and seedlings from five southern Appalachian forest stands that span gradients in elevation and moisture. Fecundity (seed production per square centimeter of basal area) ranged over four orders of magnitude, from 10 0 cm 2 basal area/yr (Carya, Cornus, Nyssa, Quercus) to Ͼ10 3 cm 2 /yr (Betula). Mean dispersal distance ranged from Ͻ5 m (Cornus, Nyssa) to Ͼ20 m (Acer, Betula, Liriodendron, Tsuga) and was positively correlated with fecundity. Species also differ in the degree of seed clumping at fine (1 m 2 ) spatial scales. Dispersal patterns can be classed in two groups based on dispersal vector: wind-dispersed taxa with high fecundities, long-distance dispersal, and low clumping vs. animal-dispersal taxa with low fecundities, short-distance dispersal, and a high degree of clumping. ''Colonization'' limitations caused by sizes and locations of parent trees, fecundity, and dispersal were quantified as the fraction of sites receiving seed relative to that expected under null models that assume dispersal is nonlocal (i.e., long-distance) and not clumped (i.e., Poisson). Difference among species in colonization levels ranged from those capable of saturating the forest floor with seed in most stands (Acer, Betula, Liriodendron) to ones that leave much of the forest floor without seed, despite presence of adults (Carya, Cornus, Nyssa, Oxydendrum). Seedling establishment is one of the strongest filters on recruitment in our study area. Taken together, our results indicate (1) that fecundity and dispersal can be resolved, even under a closed canopy, and (2) that recruitment of many species is limited by the density and location of source, dispersal patterns, or both.

Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly males. The medicoeconomic burdens of ASD are enormous, and no recognized treatment targets the core features of ASD. In a placebo-controlled, double-blind, randomized trial, young men (aged 13-27) with moderate to severe ASD received the phytochemical sulforaphane (n = 29)-derived from broccoli sprout extracts-or indistinguishable placebo (n = 15). The effects on behavior of daily oral doses of sulforaphane (50-150 μmol) for 18 wk, followed by 4 wk without treatment, were quantified by three widely accepted behavioral measures completed by parents/caregivers and physicians: the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement Scale (CGI-I). Initial scores for ABC and SRS were closely matched for participants assigned to placebo and sulforaphane. After 18 wk, participants receiving placebo experienced minimal change (<3.3%), whereas those receiving sulforaphane showed substantial declines (improvement of behavior): 34% for ABC (P < 0.001, comparing treatments) and 17% for SRS scores (P = 0.017). On CGI-I, a significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication (P = 0.015-0.007). Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels. Dietary sulforaphane, of recognized low toxicity, was selected for its capacity to reverse abnormalities that have been associated with ASD, including oxidative stress and lower antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function and oxidative phosphorylation, increased lipid peroxidation, and neuroinflammmation.

Pain and acute chest syndrome (ACS) episodes are 2 of the most common causes of hospitalization in children with sickle cell anemia (SCA). However, very few potentially modifiable risk factors for either condition have been identified. In this prospective infant cohort study, we tested the hypothesis that asthma is associated with an increased incidence rate of pain and ACS episodes. An infant cohort was composed of 291 African American children with hemoglobin SS enrolled in the Cooperative Study for Sickle Cell Disease before age 6 months and followed beyond age 5 years. Asthma was defined by a physician diagnosis, an acute asthma event, or use of prescription asthma medications. The incidence rates of ACS and painful episodes were compared for children with and without asthma. A clinical diagnosis of asthma was made in 17% of the cohort. Asthma was associated with more frequent ACS episodes (0.39 vs 0.20 events per patient year, P < .001) and painful episodes (1.39 vs 0.47 events per patient year, P < .001). In conclusion, in children with SCA, asthma is associated with an increased incidence of sickle cell disease-related morbidity, including ACS and painful episodes. IntroductionPainful episodes and acute chest syndrome (ACS) are common complications of sickle cell anemia (SCA) and are the 2 leading causes of hospitalization among people with SCA. 1,2 ACS affects up to 50% of individuals with SCA and is the leading cause of premature death. [2][3][4] The pathogenesis of ACS is multifactorial and remains unclear. In a large prospective study, several etiologies were identified, but in approximately 50% of episodes, no cause was determined. 5 Known risk factors for the development of ACS include younger age, degree of anemia (higher steady-state hemoglobin level), lower hemoglobin F, and higher steady-state white blood cell count. 2,6 Asthma is a common chronic disease affecting approximately 15% to 20% of African American children. [7][8][9][10] Previous retrospective studies suggest a relationship between ACS and asthma among children with SCA. We previously reported a 4-fold higher risk of ACS among children with SCA and a prior doctor diagnosis of asthma within a cohort of children with SCA hospitalized for pain. 11 Knight-Madden et al 12 reported a 6-fold higher risk of recurrent ACS among children with SCA and a parental report of doctor-diagnosed asthma. Airway obstruction and airway lability have been previously described in patients with SCA, suggesting that asthma may contribute to the pulmonary complications of the disease. [13][14][15][16] These data suggest that in children with SCA, a diagnosis of asthma may be a risk factor for ACS. This study also seeks to determine whether asthma is also associated with painful episodes, a common complication in SCA that often precedes or occurs concurrently with ACS episodes.In a cohort of infants established and followed for 20 years by the Cooperative Study of Sickle Cell Disease (CSSCD), we tested the hypothesis that a concurrent diagnosis of asthma in p...

Adults with β 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, ≥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.

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