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 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.

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.

Membrane cofactor protein of the complement system: alternative splicing of serine/threonine/proline-rich exons and cytoplasmic tails produces multiple isoforms that correlate with protein phenotype.

Membrane cofactor protein (MCP) is a complement regulatory protein that is expressed on human cells and cell lines as two relatively broad species with Mr of 58,000-68,000 and 48,000-56,000. The structure of a previously reported cDNA clone indicated that MCP was a type 1 membrane glycoprotein and a member of the regulators of complement activation gene/protein cluster. However, it did not provide an explanation for the unusual phenotypic pattern of MCP. Therefore, in parallel with an analysis of the gene, additional cDNAs were cloned and characterized. Six different MCP cDNA classes were identified. All encode the same 5' untranslated signal peptide, four SCRs, transmembrane domain, and basic amino acid anchor. However, they differ in the length and composition of an extracellular serine/threonine/proline (STP)-rich area, a site of heavy O-glycosylation, and cytoplasmic tail. Analysis of the MCP gene demonstrated that the variation in cDNA structure was a result of alternative splicing. Peripheral blood cells and cell lines predominantly expressed four of the six isoforms. These varied by the presence or absence of an STP-rich segment of 15 amino acids (STPB) and by the use of one of two cytoplasmic domains. Analysis by polymerase chain reaction, Northern blots, and transfection indicated that the predominance of MCP cDNA isoforms with STPB correlated with the high molecular weight protein phenotype, while the predominance of isoforms without STPB correlated with the lower molecular weight phenotype. The expression in a single cell of four distinct protein species with variable STP-rich regions and cytoplasmic tails represents an interesting example of the use of alternative splicing to provide variability in a mammalian protein.

Fibrous myopathy in association with pentazocine.

Cutaneous complications of chronic parenteral narcotic use have been described. A 61-year-old man had severe joint restriction secondary to fibrous replacement of proximal muscles. Parenteral pentazocine lactate use was implicated in the cause of his condition.

Streptococcal myositis.

Two patients had streptococcal myositis. Both patients developed extensive muscle necrosis and overwhelming sepsis after trivial skin trauma. Death occurred within 48 hours of hospital admission despite aggressive surgical and medical treatment. Review of the literature is included to highlight the fulminant nature of this unusual infection and to contrast streptococcal myositis with other soft-tissue streptococcal infections.

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.

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.

Hydroxychloroquine in the treatment of rheumatoid arthritis.

One hundred eight patients with rheumatoid arthritis received hydroxychloroquine for six to 24 months and were studied retrospectively to examine long-term efficacy and predictors of a favorable response to the drug. Response was classified in terms of reduction of active joint count and morning stiffness. Thirteen patients (12 percent) showed a complete remission. Fifteen patients (14 percent) had a 75 percent or greater response. Forty patients (37 percent) had a 30 to 75 percent response. Thirty-two (30 percent) had no response. Toxicity occurred in eight patients (7 percent) before clinical efficacy could be assessed. Seven of the 68 with response had a flare of disease after initial improvement. Of multiple clinical and laboratory parameters tested, only a stronger baseline grip strength was found to be statistically significant (p less than 0.001) in predicting a favorable response. Thus, hydroxychloroquine is an effective drug in the management of rheumatoid arthritis.

Integration of cardiorespiratory responses in the ventrolateral medulla.

Interventions confined to the region adjacent to the VMS can produce both respiratory and circulatory effects. Although it has been suggested that both breathing and vasomotor changes arise from the same neural elements near the VMS, our own investigations indicate that the neurons involved are closely linked but not identical. This belief is supported by recent studies which show that AII and angiotensin antagonists microinjected into the rostral portion of the VMS can significantly modify blood pressure and respiration but can produce effects of different sign. These observations, coupled with previous studies of the VMS, indicate the possibility that regions near the VMS may contribute to integration of circulatory and respiratory responses.

Cardiovascular effects of high-frequency oscillatory and jet ventilation.

To determine the effects of mean airway pressure on hemodynamics during high-frequency ventilation, we ventilated five cats (wt 2.8 +/- 0.6 kg) using both HFOV (frequencies 3 to 20 Hz) and HFJV (frequencies 4 to 8 Hz) at Paw values ranging from 2 to 12 cm H2O. Combinations of frequency and tidal volume that maintained normocapnia were employed in random order before and after reduction of static compliance of the respiratory system by lung lavage. Heart rate was comparable during both modes of high-frequency ventilation. During both HFOV and HFJV, the cardiac output decreased and PVR increased in normal and surfactant-deficient cats as Paw was elevated (all p less than 0.01, ANOVA). For both HFOV and HFJV linear regression of Paw and cardiac output yielded comparable slopes and y-intercepts. Lung lavage reduced the effect of Paw but did not eliminate it. Changes in ventilatory frequency did not affect cardiac output or PVR. We conclude that the interaction between high-frequency ventilation and cardiovascular function is largely determined by Paw and compliance and is independent of ventilator frequency and the type of ventilator used.

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.

Inspiratory neuron activity in the ventrolateral medulla of the dog.

The purpose of this study was to describe the distribution and activity pattern of respiratory neurons located in the ventrolateral medulla (VLM) of the dog. Spike activity of 129 respiratory neurons was recorded in 23 ketamine-anesthetized spontaneously breathing dogs. Pontamine blue dye was used to mark the location of each neuron. Most VLM neurons displaying respiratory related spike patterns were located in a column related closely to ambigual and retroambigual nuclei. Both inspiratory and expiratory neurons were present with inspiratory units being grouped more rostrally. The predominant inspiratory neuron firing pattern was "late" inspiratory, although eight "early" types were located. All expiratory firing patterns were the late expiratory variety. Each neuron burst pattern was characterized by determining burst duration (BD), spikes per burst (S/B), peak frequency (PF), time to peak frequency (TPF), rate of rise to peak frequency (PF/TPF), and mean frequency. CO2-induced minute ventilation increases were associated with decreases in BD and TPF and increases in PF, S/B, and PF/TPF. In 11 experiments the relative influences of vagotomy and tracheal occlusion on late inspiratory units were compared. Tracheal occlusion increased late inspiratory BD and S/B but did not alter PF/TPF. Vagotomy increased BD and S/B beyond those obtained by tracheal occlusion and, in some neurons, decreased the PF/TPF. We conclude that the location of respiratory units in the VLM of the dog is similar to that in other species, the discharge pattern of VLM respiratory units is similar to those in cat VLM, and vagotomy and tracheal occlusion affect discharge patterns differently.

Ventilatory responses of hamsters and rats to hypoxia and hypercapnia.

As a fossorial species the hamster differs in its natural habitat from the rat. Experiments were performed to determine possible differences between the ventilatory responses of awake hamsters and rats to acute exposure to hypoxic and hypercapnic environments. Ventilation was measured with the barometric method while the animals were conscious and unrestrained in a sealed plethysmograph. Tidal volume (VT), respiratory frequency (f), and inspiratory (TI) and expiratory (TE) time measurements were made while the animals breathed normoxic (30% O2), hypercapnic (5% CO2), or hypoxic (10% O2) gases. Arterial blood gases were also measured in both species while exposed to each of these atmospheric conditions. During inhalation of normoxic gas, the VT/100 g was greater and f was lower in the hamster than in the rat. Overall minute ventilation (VE/100 g) in the hamster was less than in the rat, which was reflected in the lower PO2 and higher PCO2 of the hamster arterial blood. When exposed to hypercapnia, the hamster increased VE/100 g solely through VT; however, the VE/100 g increase was significantly less than in the rat. In response to hypoxia, the hamster and rat increased VE/100 g by similar amounts; however, the hamster VE/100 g increase was through f alone, whereas the rat increased both VT/100 g and f. Mean airflow rates (VT/TI) were no different in the hamster or rat in each gas environment; therefore most of the ventilatory responses were the result of changes in TI and TE and respiratory duty cycle (TI/TT).(ABSTRACT TRUNCATED AT 250 WORDS)

Involvement of ventral medullary surface in respiratory responses induced by 2,4-dinitrophenol.

We examined the contribution of the neural elements near the ventral medullary surface (VMS) to the respiratory response caused by 2,4-dinitrophenol (DNP). Two series of experiments were performed on 12 vagotomized and sinoaortic denervated cats. The first series examined the effect of focal cooling of the VMS on the respiratory response to DNP in four spontaneously breathing, anesthetized cats. When the VMS temperature was 37 degrees C, systemic administration of DNP increased minute ventilation under nearly isocapnic conditions, and focal cooling of the intermediate area of VMS to 20 degrees C attenuated the ventilatory augmentation caused by DNP. To eliminate the influence of anesthetics, a second group of experiments was performed on eight decerebrate, artificially ventilated cats while phrenic nerve activity was monitored as an index of respiration. AgNO3 (10%) was topically applied to the VMS until the respiratory response to inhaled CO2 was abolished. Apnea occurred in seven of eight cats after AgNO3, whereas in the remaining one animal, tidal phrenic activity decreased substantially. Systemic administration of DNP produced no respiratory excitation in any of the animals. On the other hand, rhythmic respiratory activity could be provoked by electrical stimulation of the mesencephalic locomotor area and carotid sinus nerve and by excitation of somatic afferents. Histological examination of the brain stem showed that the AgNO3 had penetrated no more than 350 microns from the ventral medullary surface. These results indicate superficial structures of the VMS are of potential importance in mediating the respiratory responses to hypermetabolism.

Mitochondrial and myocardial performance. Response to ischemia and reperfusion.

The relationships between cardiac bioenergy metabolism and myocardial function were examined in a model of global myocardial ischemia and reperfusion. The respiratory activity of distinct populations of subsarcolemmal and interfibrillar mitochondria was correlated with max dP/dt (an index of myocardial contractility with respect to time). Max dP/dt was significantly reduced to 27% of the preischemic value following two hours of cardioplegia-protected, warm, global, ischemia in dogs during the cardiopulmonary bypass period. Reperfusion resulted in improved myocardial function such that by 60 minutes of reperfusion, max dP/dt returned to baseline. Significant declines in both state 3 respiratory rates and respiratory control indexes for subsarcolemmal and interfibrillar mitochondria were noted following the ischemic interval. Mitochondrial function similarly returned to baseline values following 60 minutes of reperfusion. These data demonstrate a close association between mitochondrial and myocardial activity.

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 development of polymyositis in a patient with toxoplasmosis: clinical and pathologic findings and review of literature.

A 58 year old female was evaluated for fever, rash, myalgias, muscle weakness and cervical lymphadenopathy. She was found to have myositis on muscle biopsy, toxoplasmic lymphadenitis on lymph node biopsy, and markedly elevated IgM and IgG antibody titers to Toxoplasma gondii. The patient was treated with prednisone and a 2 month course of sulfadiazine and pyrimethamine. The patient improved over the next six months and has been followed for approximately a five year period. During this time, antibody levels to the toxoplasma antigen have significantly decreased but the patient has developed a chronic myositis indistinguishable from polymyositis.

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.