Faculty Bibliography

BACKGROUND: Previous reports suggest that sarcoidosis occurs with abnormally high frequency in firefighters. We sought to determine whether exposure to World Trade Center (WTC) 'dust' during the collapse and rescue/recovery effort increased the incidence of sarcoidosis or 'sarcoid-like' granulomatous pulmonary disease (SLGPD). METHODS: During the 5 years after the WTC disaster, enrollees in the Fire Department of New York (FDNY) WTC monitoring and treatment programs who had chest radiograph findings suggestive of sarcoidosis underwent evaluation, including the following: chest CT imaging, pulmonary function, provocative challenge, and biopsy. Annual incidence rates were compared to the 15 years before the WTC disaster. RESULTS: After WTC dust exposure, pathologic evidence consistent with new-onset sarcoidosis was found in 26 patients: all 26 patients had intrathoracic adenopathy, and 6 patients (23%) had extrathoracic disease. Thirteen patients were identified during the first year after WTC dust exposure (incidence rate, 86/100,000), and 13 patients were identified during the next 4 years (average annual incidence rate, 22/100,000; as compared to 15/100,000 during the 15 years before the WTC disaster). Eighteen of 26 patients (69%) had findings consistent with asthma. Eight of 21 patients (38%) agreeing to challenge testing had airway hyperreactivity (AHR), findings not seen in FDNY sarcoidosis patients before the WTC disaster. CONCLUSION: After the WTC disaster, the incidence of sarcoidosis or SLGPD was increased among FDNY rescue workers. This new information about the early onset of WTC-SLGPD and its association with asthma/AHR has important public health consequences for disease prevention, early detection, and treatment following environmental/occupational exposures

The aim of the present study was to investigate the physiological role and the expression pattern of heterologous gap junctions during Xenopus laevis vitellogenesis. Dye transfer experiments showed that there are functional gap junctions at the oocyte/follicle cell interface during the vitellogenic process and that octanol uncouples this intercellular communication. The incubation of vitellogenic oocytes in the presence of biotinylated bovine serum albumin (b-BSA) or fluorescein dextran (FDX), showed that oocytes develop stratum of newly formed yolk platelets. In octanol-treated follicles no sign of nascent yolk sphere formation was observed. Thus, experiments in which gap junctions were downregulated with octanol showed that coupled gap junctions are required for endocytic activity. RT-PCR analysis showed that the expression of connexin 43 (Cx43) was first evident at stage II of oogenesis and increased during the subsequent vitellogenic stages (III, IV and V), which would indicate that this Cx is related to the process that regulates yolk uptake. No expression changes were detected for Cx31 and Cx38 during vitellogenesis. Based on our results, we propose that direct gap junctional communication is a requirement for endocytic activity, as without the appropriate signal from surrounding epithelial cells X. laevis oocytes were unable to endocytose VTG

Electrophysiological studies in monkeys have identified effector-related regions in the posterior parietal cortex (PPC). The lateral intraparietal area, for example, responds preferentially for saccades, whereas the parietal reach region responds preferentially for arm movements. However, the degree of effector selectivity actually observed is limited; each area contains neurons selective for the nonpreferred effector, and many neurons in both areas respond for both effectors. We used functional magnetic resonance imaging to assess the degree of effector preference at the population level, focusing on topographically organized regions in the human PPC [visual area V7, intraparietal sulcus 1 (IPS1), and IPS2]. An event-related design adapted from monkey experiments was used. In each trial, an effector cue preceded the appearance of a spatial target, after which a Go signal instructed subjects to produce the specified movement with the specified effector. Our results show that the degree of effector specificity is limited in many cortical areas and transitions gradually from saccade to reach preference as one moves through the hierarchy of areas in the occipital, parietal, and frontal cortices. Saccade preference was observed in visual cortex, including early areas and V7. IPS1 exhibited balanced activation to saccades and reaches, whereas IPS2 showed a weak but significant preference for reaches. In frontal cortex, areas near the central sulcus showed a clear and absolute preference for reaches, whereas the frontal eye field showed little or no effector selectivity. Although these results contradict many theoretical conclusions about effector specificity, they are compatible with the complex picture arising from electrophysiological studies and also with previous imaging studies that reported mostly overlapping saccade- and arm-related activation. The results are also compatible with theories of efficient coding in cortex.

A critical molecular requirement underlying many forms of long-lasting synaptic plasticity and memory is the de novo synthesis of mRNAs and proteins. In a recent paper in Cell, Costa-Mattioli et al. present data from a pharmacogenetic study that places a key regulatory event in the 'neural decision' to undergo these persistent neuronal changes under translational control mediated by eIF2alpha

Perceptual illusions are usually thought to arise from the way sensory signals are encoded by the brain, and indeed are often used to infer the mechanisms of sensory encoding. But perceptual illusions might also result from the way the brain decodes sensory information, reflecting the strategies that optimize performance in particular tasks. In a fine discrimination task, the most accurate information comes from neurons tuned away from the discrimination boundary, and observers seem to use signals from these 'displaced' neurons to optimize their performance. We wondered whether using signals from these neurons might also bias perception. In a fine direction discrimination task using moving random-dot stimuli, we found that observers' perception of the direction of motion is indeed biased away from the boundary. This misperception can be accurately described by a decoding model that preferentially weights signals from neurons whose responses best discriminate those directions. In a coarse discrimination task, to which a different decoding rule applies, the same stimulus is not misperceived, suggesting that the illusion is a direct consequence of the decoding strategy that observers use to make fine perceptual judgments. The subjective experience of motion is therefore not mediated directly by the responses of sensory neurons, but is only developed after the responses of these neurons are decoded

Central alpha(1)-adrenoceptors are activated by norepinephrine (NE), epinephrine (EPI) and possibly dopamine (DA), and function in two fundamental and opposed types of behavior: (1) positively motivated exploratory and approach activities, and (2) stress reactions and behavioral inhibition. Brain microinjection studies have revealed that the positive-linked receptors are located in eight to nine brain regions spanning the neuraxis including the secondary motor cortex, piriform cortex, nucleus accumbens, preoptic area, lateral hypothalamic area, vermis cerebellum, locus coeruleus, dorsal raphe and possibly the C1 nucleus of the ventrolateral medulla, whereas the stress-linked receptors are present in at least three areas including the paraventricular nucleus of the hypothalamus, central nucleus of the amygdala and bed nucleus of the stria terminalis. Recent studies utilizing c-fos expression and mitogen-activated protein kinase activation have shown that various diverse models of depression in mice produce decreases in positive region-neural activity elicited by motivating stimuli along with increases in neural activity of stress areas. Both types of change are attenuated by various antidepressant agents. This has suggested that the balance of the two networks determines whether an animal displays depressive behavior. A central unresolved question concerns how the alpha(1)-receptors in the positive-activity and stress systems are differentially activated during the appropriate behavioral conditions and to what extent this is related to differences in endogenous ligands or receptor subtype distributions.

Unilateral spatial neglect (neglect) is a syndrome characterized by perceptual deficits that prevent patients from attending and responding to the side of space and of the body opposite a damaged hemisphere (contralesional side). Neglect also involves motor deficits: patients may be slower to initiate a motor response to targets appearing in the left hemispace, even when using their unaffected arm (directional hypokinesia). Although this impairment is well known, its anatomical correlate has not been established. We tested 52 patients with neglect after right hemisphere stroke, and conducted an anatomical analysis on 29 of them to find the anatomical correlate of directional hypokinesia. We found that patients with directional hypokinesia had a lesion involving the ventral lateral putamen, the claustrum, and the white matter underneath the frontal lobe. Most importantly, none of the patients without directional hypokinesia had a lesion in the same region. The localization of neglect's motor deficits to the basal ganglia establishes interesting homologies with animal data; it also suggests that a relative depletion of dopamine in the nigrostriatal pathway on the same side of the lesion may be an important pathophysiological mechanism potentially amenable to intervention.

Phospholemman (PLM) is a small sarcolemmal protein that modulates the activities of Na(+)/K(+)-ATPase and the Na(+)/Ca(2+) exchanger (NCX), thus contributing to the maintenance of intracellular Na(+) and Ca(2+) homeostasis. We characterized the expression and subcellular localization of PLM, NCX, and the Na(+)/K(+)-ATPase alpha1-subunit during perinatal development. Western blotting demonstrates that PLM (15kDa), NCX (120kDa), and Na(+)/K(+)-ATPase alpha-1 (approximately 100kDa) proteins are all more than 2-fold higher in ventricular membrane fractions from newborn rabbit hearts (1-4-day old) compared to adult hearts. Our immunocytochemistry data demonstrate that PLM, NCX, and Na(+)/K(+)-ATPase are all expressed at the sarcolemma of newborn ventricular myocytes. Taken together, our data indicate that PLM, NCX, and Na(+)/K(+)-ATPase alpha-1 proteins have similar developmental expression patterns in rabbit ventricular myocardium. Thus, PLM may have an important regulatory role in maintaining cardiac Na(+) and Ca(2+) homeostasis during perinatal maturation

Polymorphisms of the dopamine receptor D4 gene DRD4, 11p15.5, have previously been associated with attention-deficit/hyperactivity disorder (ADHD) [Bobb et al., 2005; Am J Med Genet B Neuropsychiatr Genet 132:109-125; Faraone et al., 2005; Biol Psychiatry 57:1313-1323; Thapar et al., 2005; Hum Mol Genet 14 Spec No. 2:R275-R282]. As a follow up to a pilot study [see Castellanos et al., 1998; Mol Psychiatry 3:431-434] consisting of 41 probands and 56 controls which found no significant association between the DRD4 7-repeat allele in exon 3 and ADHD, a greatly expanded study sample (cases n = 166 and controls n = 282) and long term follow-up (n = 107, baseline mean age n = 9, follow-up mean age of n = 15) prompted reexamination of this gene. The DRD4 7-repeat allele was significantly more frequent in ADHD cases than controls (OR = 1.2; P = 0.028). Further, within the ADHD group, the 7-repeat allele was associated with better cognitive performance (measured by the WISC-III) (P = 0.013-0.07) as well as a trend for association with better long-term outcome. This provides further evidence of the role of the DRD4 7-repeat allele in the etiology of ADHD and suggests that this allele may be associated with a more benign form of the disorder