Childhood anhedonia symptoms and stressful life events predict the development of reward-related brain activity across adolescence.

The reward positivity (RewP) is an event-related potential that indexes reinforcement learning and reward system activation. The RewP has been shown to increase across adolescence; however, most studies have examined the RewP across two assessments, and no studies have examined within-person changes across adolescence into young adulthood. Moreover, the RewP has been identified as a neurobiological risk factor for adolescent-onset depression, but it is unclear whether childhood psychosocial risk factors might predict RewP development across adolescence. In a sample of 317 8- to 14-year-old girls (Mage = 12.4, SD = 1.8), the present study examined self-report measures of depression symptoms and stressful life events at baseline and the ΔRewP during the doors guessing task across three timepoints. Growth modeling indicated that, across all participants, the ΔRewP did not demonstrate linear change across adolescence. However, baseline anhedonia symptoms predicted within-person changes in the ΔRewP, such that individuals with low anhedonia symptoms demonstrated a linear increase in the ΔRewP, but individuals with high anhedonia symptoms had no change in the ΔRewP across adolescence. Similar patterns were observed for stressful life events. The present study suggests that childhood risk factors impact the development of reward-related brain activity, which might subsequently increase risk for psychopathology.

A synthesis of patterns of environmental mercury inputs, exposure and effects in New York State.

Mercury (Hg) pollution is an environmental problem that adversely affects human and ecosystem health at local, regional, and global scales-including within New York State. More than two-thirds of the Hg currently released to the environment originates, either directly or indirectly, from human activities. Since the early 1800s, global atmospheric Hg concentrations have increased by three- to eight-fold over natural levels. In the U.S., atmospheric emissions and point-source releases to waterways increased following industrialization into the mid-1980s. Since then, water discharges have largely been curtailed. As a result, Hg emissions, atmospheric concentrations, and deposition over the past few decades have declined across the eastern U.S. Despite these decreases, Hg pollution persists. To inform policy efforts and to advance public understanding, the New York State Energy Research and Development Authority (NYSERDA) sponsored a scientific synthesis of information on Hg in New York State. This effort includes 23 papers focused on Hg in atmospheric deposition, water, fish, and wildlife published in Ecotoxicology. New York State experiences Hg contamination largely due to atmospheric deposition. Some landscapes are inherently sensitive to Hg inputs driven by the transport of inorganic Hg to zones of methylation, the conversion of inorganic Hg to methylmercury, and the bioaccumulation and biomagnification along food webs. Mercury concentrations exceed human and ecological risk thresholds in many areas of New York State, particularly the Adirondacks, Catskills, and parts of Long Island. Mercury concentrations in some biota have declined in the Eastern Great Lakes Lowlands and the Northeastern Highlands over the last four decades, concurrent with decreases in water releases and air emissions from regional and U.S. sources. However, widespread changes have not occurred in other ecoregions of New York State. While the timing and magnitude of the response of Hg levels in biota varies, policies expected to further diminish Hg emissions should continue to decrease Hg concentrations in food webs, yielding benefits to the fish, wildlife, and people of New York State. Anticipated improvements in the Hg status of aquatic ecosystems are likely to be greatest for inland surface waters and should be roughly proportional to declines in atmospheric Hg deposition. Efforts that advance recovery from Hg pollution in recent years have yielded significant progress, but Hg remains a pollutant of concern. Indeed, due to this extensive compilation of Hg observations in biota, it appears that the extent and intensity of the contamination on the New York landscape and waterscape is greater than previously recognized. Understanding the extent of Hg contamination and recovery following decreases in atmospheric Hg deposition will require further study, underscoring the need to continue existing monitoring efforts.

Oiling of American white pelicans, common loons, and northern gannets in the winter following the Deepwater Horizon (MC252) oil spill.

The Natural Resource Damage Assessment and Restoration Trustees for the Deepwater Horizon oil spill assessed the external oiling of migratory bird species dependent on open water in the Gulf of Mexico following the aforementioned spill. The assessment was designed to evaluate birds that use open water during the winter within 40 km of the Gulf shoreline. We focused on the American white pelican (Pelecanus erythrorhynchos), common loon (Gavia immer), and northern gannet (Morus bassanus). Point counts (pelican, loon) or strip transects (gannet) were used and each target species was assessed for oiling (unoiled, trace, light, moderate, or heavy amounts) and photographed. Due to distance at sighting and/or poor visibility, not all visible birds were assessed. The percentage of birds oiled varied by species, with the common loon being the highest (23.6%), followed by American white pelican (16.9%), and northern gannet (6.9%). Most of the American white pelicans and common loons had trace (83% and 72%, respectively) or light levels (11% and 24%, respectively) of oiling. The northern gannet had just trace levels of oiling. Some pelicans (6%) and loons (4%) had moderate amounts of oiling. Based on expert derived-mortality estimates and our estimates of oil exposure, we used Monte Carlo simulations to predict expected decreases of 2.5%, 4%, and 11% in the observed population for the northern gannet, American white pelican, and common loon, respectively. While these values are underestimates of the true values given the long time lag (10-12 months) between the oil spill and the assessment, these data represent some of the few estimates of exposure for these species and describe minimum risk estimates to these species.

A preliminary assessment of mercury in the feathers of migratory songbirds breeding in the North American subarctic.

Passerines appear to have a greater sensitivity to mercury than other avian orders, and little data exists for mercury exposure in songbirds breeding at high latitudes. In this preliminary study, we examined mercury exposure in 12 migratory songbird species breeding in Denali National Park & Preserve, in subarctic interior Alaska. Overall, we analyzed 343 feather samples collected in 2015-2017 for their total mercury content. Mercury levels found in feathers indicates exposure during the period of feather growth, which we assume largely took place on the breeding ground. In this limited sample of songbird feathers, mercury concentrations ranged from near zero to 6.34 µg/g. Most species sampled showed relatively low mercury, but some individuals had high enough concentrations to be subject to adverse physiological and behavioral effects. There was an indication that mercury concentrations of breeding songbirds may vary by diet composition, with non-invertivorous species possibly tending towards lower mercury concentrations. Overall, however, the degree of mercury exposure observed was low for songbirds breeding in the subarctic. Further examination would prove useful in clarifying mercury exposure and ecological relationships in this under-studied region.

Effects of treatment intensification with hydroxyurea in HIV-infected patients with virologic suppression.

BACKGROUND: Virologic rebound can result from suboptimal antiviral potency in combination antiretroviral therapy. DESIGN: Multicenter, partially blinded, prospective, randomized study of 202 HIV-infected subjects to determine whether therapy intensification improves long-term rates of virologic suppression. METHODS: Subjects had plasma HIV RNA < 200 copies/ml, CD4 cell count of > 200 x 10(6) cells/l, and treatment with indinavir (IDV) + zidovudine (ZDV) + lamivudine (3TC) for at least 6 months before randomization to stay on this regimen or to receive IDV + didanosine (ddI) + stavudine (d4T) plus or minus hydroxyurea (HU) (600 mg twice daily). Treatment failure was defined as either confirmed rebound of HIV RNA level to > 200 copies/ml or a drug toxicity necessitating treatment discontinuation. RESULTS: Treatment failure occurred more frequently in subjects randomized to the HU-containing arm (32.4%), than in those taking IDV + ddI + d4T (17.6%) or IDV + ZDV + 3TC (7.6%). The time to treatment failure was shorter for the HU-containing arm compared with the IDV + ZDV + 3TC (P < 0.0001) or IDV + ddI + d4T arms (P = 0.032). Dose-limiting toxicities rather than virologic rebound accounted for the differences between treatment failure among the study arms. Pancreatitis led to treatment discontinuation in 4% of subjects in treatment arms containing ddI + d4T. Three subjects with pancreatitis died, all randomized to the HU-containing arm. CONCLUSIONS: Switching to IDV + ddI + d4T + HU in patients treated with IDV + ZDV + 3TC was associated with a worse outcome, principally because of drug toxicity.

Analysis of TGF-beta type I receptor for mutations and polymorphisms in head and neck cancers.

Transforming growth factor-beta receptor (TbetaR)-dependent signals are critical for cell growth and differentiation and are often disrupted during tumorigenesis. The entire coding region of TbetaR-I and flanking intron sequences from 30 head and neck carcinomas were examined for alterations using "Cold" SSCP and direct sequencing. No somatic point mutations were found in the TbetaR-I gene. In contrast, 14 polymorphic sequence changes were detected in TbetaR-I in 13 (43%) of the samples, including eight (27%) nucleotide alterations identified as polymorphisms in an exon-1 (GCG)(9) microsatellite repeat, a previously reported tumor susceptibility allele. A nine base pair deletion was found in 23% of the samples including five heterozygous and two homozygous deletions as well as single homozygous 12bp deletion. Additionally, six heterozygous polymorphisms in intronic sequences were determined, including one heterozygous C/A genotype at the +82 nucleotide position of the intron-5 intervening sequence (IVS), and five heterozygous G/A genotypes within intron-7 at the +24 nucleotide position. Exon-1 polymorphisms in the (GCG)(9) microsatellite region of the TbetaR-I gene and their association with head/neck cancers, suggest that development of these cancers may be a direct consequence of loss of responsiveness to TGF-beta mediated growth inhibition.

Development and validation of the Self-Identity Inventory (SII): a multicultural identity development instrument.

The Self-Identity Inventory (SII) was developed using the Optimal Theory Applied to Identity Development (OTAID) model. A sample of 325 culturally diverse respondents completed the SII, the Tolerance Scale from the California Psychological Inventory, the Belief Systems Analysis Scale, and the Social Desirability and Infrequency Scales. Through confirmatory factor analysis, goodness-of-fit, and social desirability/item infrequency measures, SII items were analyzed, resulting in a 6-scale, 71-item inventory. Internal consistency for the scales ranged from .72 to .90. Test-retest reliability ranged from .72 to .92. Correlations with external construct validity measures supported predictions. Interscale correlations and other statistical tests primarily supported the OTAID model. Implications for therapy and future research are suggested.

A pilot study: use of fludarabine for refractory dermatomyositis and polymyositis, and examination of endpoint measures.

OBJECTIVE: To study the effects of the adenine analog, fludarabine, on patients with refractory dermatomyositis and polymyositis, and to assess variables used in following myositis patients during medical intervention. METHODS: Patients whose myositis was not controlled by prednisone and at least one other immunosuppressive medication were entered into a pilot study during which they received 6 monthly cycles of intravenous fludarabine. Patients were assessed at baseline, every other month, and at month 7 for primary outcome measures of strength and function. Other measurements including peripheral blood cell subsets, muscle enzymes, and various assessments of disease activity were followed monthly during the fludarabine infusion period and for up to 6 months post therapy. RESULTS: Of 16 patients who entered the study, 4 patients were classified as improved, and 7 patients were classified as unchanged. Five patients who withdrew before month 7 were classified as treatment failures. Fludarabine caused a significant and prolonged lymphopenia without an increase in infectious complications over that seen with other immunosuppressive agents used for myositis. A sudden death of one patient at the end of the study was not thought to be drug related. Variables followed during the study emphasized the distinction between patient functional improvement and disease remission. CONCLUSION: A subset of patients with refractory myositis may benefit from fludarabine therapy and controlled trials are indicated. Refinement and validation of variables useful for following myositis patients await larger studies.

Treatment of refractory myositis: a randomized crossover study of two new cytotoxic regimens.

OBJECTIVE: To assess the clinical usefulness of 2 novel therapies for treatment-resistant myositis. METHODS: Thirty patients with refractory myositis, of whom 25 had an inadequate or no response to previous cytotoxic therapy, were randomized to begin either a combination of weekly oral methotrexate and daily azathioprine (MTX/AZA) or intravenous methotrexate with leucovorin rescue (I.V. MTX) every 2 weeks for 6 months. Crossover to the alternate therapy occurred according to defined rules; evaluations of muscle strength and functional abilities were performed at the beginning, and after 3 and 6 months, of each treatment. RESULTS: Of the 15 patients initially randomized to oral MTX/AZA, 8 improved with oral therapy and 1 improved with I.V. MTX during the crossover period. Of the 15 patients initially randomized to I.V. MTX therapy, 3 improved with the I.V. therapy and 4 with the oral combination during the crossover period. Although the study lacked the power to directly compare both treatments, intention-to-treat analysis showed a trend in favor of those patients who first received oral combination therapy (P = 0.025). There were 0.09 adverse events per patient-month with oral combination therapy and 0.16 per patient-month with I.V. therapy (P = 0.09). CONCLUSION: Combination oral MTX/AZA may benefit patients with treatment-resistant myositis, including those who previously had inadequate responses to either MTX or AZA alone. I.V. MTX with leucovorin rescue may also benefit some patients with refractory myositis.

Retroviral transfer of acid alpha-glucosidase cDNA to enzyme-deficient myoblasts results in phenotypic spread of the genotypic correction by both secretion and fusion.

Myoblasts have properties that make them suitable vehicles for gene replacement therapy, and lysosomal storage diseases are attractive targets for such therapy. Type II Glycogen Storage Disease, a deficiency of acid alpha-glucosidase (GAA), results in the abnormal accumulation of glycogen in skeletal and cardiac muscle lysosomes. The varied manifestations of the enzyme deficiency in affected patient are ultimately lethal. We used a retroviral vector carrying the cDNA encoding for GAA to replace the enzyme in deficient myoblasts and fibroblasts and analyzed the properties of the transduced cells. The transferred gene was efficiently expressed, and the de novo-synthesized enzyme reached lysosomes where it digested glycogen. In enzyme-deficient myoblasts after transduction, enzyme activity rose to more than 30-fold higher than in normal myoblasts and increased about five-fold more when the cells were allowed to differentiate into myotubes. The transduced cells secreted GAA that was endocytosed via the mannose-6-phosphate receptor into lysosomes of deficient cells and digested glycogen. Moreover, the transduced myoblasts were able to fuse with and provide enzyme for GAA-deficient fusion partners. Thus, the gene-corrected cells, which appear otherwise normal, may ultimately provide phenotypic correction to neighboring GAA-deficient cells by fusion and to distant cells by secretion and uptake mechanisms.

The predominance of beta (CC) chemokine transcripts in idiopathic inflammatory muscle diseases.

Cytokines and chemokines that upregulate major histocompatibility complex class I antigens, recruit lymphocytes, and enhance T-cell-mediated myotoxicity may be important in the pathogenesis of dermatomyositis and polymyositis. We searched for cytokine and chemokine transcripts in inflammatory muscle specimens from 14 newly diagnosed or treated patients. Control specimens from six patients without inflammatory muscle disease were analyzed for transcripts of interleukins-1 beta, -2, -4, -6, -10, and -15, and interferon-gamma, tumor necrosis factor-alpha, transforming growth factor-beta 1, macrophage inflammatory proteins-1 alpha and -1 beta (MIP-1 alpha, MIP-1 beta), and the chemokine "regulated on activation, normally T expressed and secreted" (RANTES). Surprisingly, the proinflammatory and lymphocyte cytokines were detected only sporadically in myositis muscle specimens, and their presence did not correlate with disease activity or treatment status of the patient. In contrast, MIP-1 alpha and MIP-1 beta were detected in 13 and 6 myositis biopsies, respectively, and RANTES, another beta (CC) chemokine, was detected in eight myositis biopsies. This study and other reports of low levels of acute-phase cytokines in myositis patients suggest that the proinflammatory cytokines do not play a major role in ongoing muscle damage. The CC chemokines studied here, in particular MIP-1 alpha, might contribute to ongoing muscle inflammation, and the pathogenesis of inflammation in myositis may follow a previously unrecognized pathway.

Glycogenosis type II: a juvenile-specific mutation with an unusual splicing pattern and a shared mutation in African Americans.

The recessively inherited deficiency of acid alpha-glucosidase (GAA) called Glycogenosis Type II is expressed as three different phenotypes: infantile, juvenile, and adult. At the molecular level, infantile and adult forms of the disease have been extensively studied, but little is known regarding the genetic defects associated with the juvenile form. We describe a novel mutation that defines the intermediate juvenile phenotype in a compound heterozygous patient. A transversion of t to g in intron 6 at position -22 creates a cryptic acceptor site and results in unusual splicing abnormality: insertion of 21 nucleotides of the intronic sequence into mRNA and removal of exon 6 without disruption of the reading frame. The second mutation, Arg854Stop in exon 18, had been previously identified in another African-American patient (Hermans et al., 1993a). Family study indicates that a silent allele harboring the Arg854Stop mutation in our patient is inherited from the patient's father, who is also African-American, thus suggesting a common mutation in this population.

Update on therapy for refractory dermatomyositis and polymyositis.

Evaluation of new therapies for the inflammatory myopathies is complicated by the heterogeneity of these syndromes as well as by the lack of internationally accepted definitions of disease categories and assessments of disease activity and chronicity. This review covers our opinion of therapies and emphasizes the need for an early rehabilitation evaluation for these patients. Oral corticosteroids are the first line of therapy for the inflammatory myopathies, but because of their side effects and the existence of a subset of patients in whom disease is controlled only with high-dose corticosteroids, we recommend considering the early use of a second-line immunomodulating agents or pulse intravenous methylprednisolone. A stepwise progression of therapies is suggested for patients who have increasing muscle weakness resulting from active disease.

Abnormal numbers of cytokine producing cells in patients with polymyositis and dermatomyositis.

OBJECTIVE: To examine the constitutive pattern of cytokine production in patients with polymyositis (PM) and dermatomyositis (DM). METHODS: PBMC secreting the type 1 cytokines IL-2 and IFN gamma and the type 2 cytokines IL-6 and IL-10 were monitored by ELIspot assay. RESULTS: The frequency of IFN gamma-secreting PBMC was reduced 2-20 fold in patients with PM and DM when compared to normal controls (p < 0.01). This change correlated inversely with disease activity (p < 0.01). PM and DM were also characterized by increased numbers of cells secreting IL-10. Patients with DM had fewer IL-2 (p < 0.03) and more IL-6 (p < 0.006) secreting cells than normal controls or patients with other myopathies. CONCLUSIONS: Abnormal patterns of cytokine production characterize patients with PM and DM.

The idiopathic inflammatory myopathies: spectrum of MR imaging findings.

Magnetic resonance (MR) imaging is useful for demonstrating the soft-tissue and musculature changes seen in patients with idiopathic inflammatory myopathies (IIMs). These changes include edema within and around muscle, subcutaneous reticulation, muscle calcification, and fatty infiltration of muscle. Muscle edema is visible as areas of hyperintensity on short inversion time inversion recovery (STIR) images. Abnormal reticulation of the subcutaneous tissue can be due to subcutaneous edema or an infiltrating process; edema from inflammation appears as areas of low signal intensity on T1-weighted images and as areas of high signal intensity on STIR images. Intramuscular calcium deposition appears as hypointense areas with all pulse sequences. On T1-weighted images, fatty infiltration appears as areas of high signal intensity within muscles. Because of the improved visualization of muscle inflammation provided by STIR imaging and because MR imaging is noninvasive, it has become a useful modality for evaluating patients with IIMs.

The treatment of myositis. How to approach resistant disease.

Idiopathic inflammatory myopathies, polymyositis, dermatomyositis, and inclusion body myositis, are increasingly recognized to cause long-term disability in certain subsets of patients. Because these diseases are infrequent, only retrospective analysis of most treatments are available. In this article, identification of subsets of patients with different prognoses and discussion of confounding factors for increasing weakness are emphasized. The advantages and disadvantages of different therapies for myositis and for extraskeletal muscle features are also discussed.