Distinct responses to hypoxia in subpopulations of distal pulmonary artery cells contribute to pulmonary vascular remodeling in emphysema.

We have shown previously that hypoxia inhibits the growth of distal human pulmonary artery smooth muscle cells (PASMC) isolated under standard normoxic conditions (PASMC(norm)). By contrast, a subpopulation of PASMC, isolated through survival selection under hypoxia was found to proliferate in response to hypoxia (PASMC(hyp)). We sought to investigate the role of hypoxia-inducible factor (HIF) in these differential responses and to assess the relationship between HIF, proliferation, apoptosis, and pulmonary vascular remodeling in emphysema. PASMC were derived from lobar resections for lung cancer. Hypoxia induced apoptosis in PASMC(norm) (as assessed by TUNEL) and mRNA expression of Bax and Bcl-2, and induced proliferation in PASMC(hyp) (as assessed by (3)H-thymidine incorporation). Both observations were mimicked by dimethyloxallyl glycine, a prolyl-hydroxylase inhibitor used to stabilize HIF under normoxia. Pulmonary vascular remodeling was graded in lung samples taken from patients undergoing lung volume reduction surgery for severe heterogenous emphysema. Carbonic anhydrase IX expression in the medial compartment was used as a surrogate of medial hypoxia and HIF stabilization and increased with increasing vascular remodeling. In addition, a mixture of proliferation, assessed by proliferating-cell nuclear antigen, and apoptosis, assessed by active caspase 3 staining, were both higher in more severely remodeled vessels. Hypoxia drives apoptosis and proliferation via HIF in distinct subpopulations of distal PASMC. These differential responses may be important in the pulmonary vascular remodeling seen in emphysema and further support the key role of HIF in hypoxic pulmonary hypertension.

Regulation of bone morphogenetic protein signalling in human pulmonary vascular development.

The bone morphogenetic protein (BMP) type II receptor (BMPR-II) is predominantly expressed on the vascular endothelium in the adult lung. Although mutations in BMPR-II are known to underlie many cases of familial pulmonary arterial hypertension (FPAH), little is known regarding the expression of BMPs and their signalling pathways during normal lung development or the impact of BMPR-II mutations on endothelial cell function. We determined the cellular localization and expression levels of BMP4, BMP receptors, and activation of downstream signalling via phospho-Smad1 in a developmental series of human embryonic and fetal lungs by immunohistochemistry. The expression of BMP4 and BMP receptors was temporally and spatially regulated during lung development. BMPR-II expression correlated with phosphorylation of tissue Smad1 and was highest during the late pseudoglandular and early canalicular stage of lung development, when vasculogenesis is intense. Phospho-Smad1 expression was associated with markers of proliferation in endothelial cells. In vitro studies confirmed that BMPs 2 and 4 induced phosphorylation of Smad1/5 and pulmonary artery endothelial cell (PAEC) migration and proliferation. Adenoviral transfection of PAECs with mutant kinase-deficient BMPR-II, or siRNA knockdown of BMPR-II, inhibited Smad signalling and the proliferative response to BMP4. Our findings support a critical role for BMPs in lung vasculogenesis. Dysfunctional BMP signalling in PAECs during development may lead to abnormal pulmonary vascular development and contribute to the pathogenesis of FPAH.

Treatment, outcome, and cost of care in children with idiopathic thrombocytopenic purpura.

Data were reviewed on treatment patterns, outcome, and hospital charges for children with idiopathic thrombocytopenic purpura (ITP). Records of 186 children with ITP, seen between January 1997 and April 2001, were reviewed. Hospital charges for initial management and first re-treatment were calculated by combining physician, hospital, and pathology charges. Anti-D immune globulin [anti-D IG] was used in 32.3%, intravenous immune globulin [IVIG] in 22.6%, steroids in 22.6%, combination therapies in 8%, and 14.5% were observed. Two patients had CNS bleeding, one with intraventricular hemorrhage at diagnosis, and the other with a parietal bleed 1 year from diagnosis. There was no significant differences in time to reach platelet counts of 20, 50, or 150 (x 10(9)/L) across different treatment groups. There was no significant difference in median charges for the IVIG and anti-D IG groups for the initial treatment of ITP. However, the IVIG was significantly more expensive than steroids or observation. Charges for the anti-D IG group were higher than the observation group but not the steroid group. After drug charges were excluded, patients in the IVIG group had statistically higher charges compared to patients in anti-D IG group. Almost half the patients were re-treated. There was no significant difference between anti-D IG, IVIG, and steroid groups when initial and re-treatment charges were combined. The observation group remained least expensive. Outcome for children with ITP is similar regardless of initial management. There is not a statistically significant difference in hospital charges between patients treated with anti-D IG and IVIG. The IVIG-treated group tends to be more costly, but this is not due to drug charges. Re-treatment is common and decreases the difference in patient charges among initial therapies.

The simultaneous activation hypothesis: explaining recovery from deep to phonological dyslexia.

Deep dyslexia evolved into phonological dyslexia in one patient. Semantic errors resolved while phonological and derivational errors persisted in reading. Nonword reading improved but remained inferior to word reading. Despite a residual semantic deficit naming improved. The Simultaneous Activation Hypothesis explains recovery from deep to phonological dyslexia and the continued dissociation between reading and naming errors. Partial recovery to all three reading routes increased constraints for word selection at the phonological output lexicon (POL) improving word reading. With recovery, the POL receives additional supportive information from the partially recovered direct oral reading route and grapheme-to-phoneme conversion (GPC) eliminating semantic errors in oral reading. Nonword reading also improved because of partial recovery to all three routes. Semantic errors in naming persisted because additional constraints were unavailable at the POL to activate a phonological entry. Phonological and derivational errors were more frequent in reading than in naming the result of incomplete GPC recovery. Residual nonword reading deficits resulted from incomplete GPC recovery, indicated by the persistence of neologisms in nonwords. The Simultaneous Activation Hypothesis readily accounts for the evolution from deep to phonological dyslexia.

The interaction of multiple routes in oral reading: evidence from dissociations in naming and oral reading in phonological dyslexia.

During oral reading we hypothesized that lexical representations are activated and selected for output by the simultaneous activation of the semantic, the direct lexical orthography to phonology, and the sublexical grapheme-to-phoneme conversion (GPC) routes (Southwood & Chatterjee, 1999). Serial models of reading argue that the semantic route governs oral reading with minimal influence from the nonlexical direct route and the sublexical GPC route. These models predict that semantic errors should occur in reading when the semantic route and GPC are both impaired. The Simultaneous Activation Hypothesis predicts few semantic errors in oral reading but many during picture naming. Semantic errors are infrequent in reading because information from all three reading routes constrains activation of a phonological entry. By contrast phonological selection in picture naming is constrained primarily by the semantic route and if damaged additional information is unavailable to select the appropriate phonological code. In agreement with the Simultaneous Activation Hypothesis five phonological dyslexics produced semantic errors during picture naming but not when reading aloud. Phonological errors were present during oral reading and minimal during picture naming.

Sensory and response interference by ipsilesional stimuli in tactile extinction.

Extinction is thought to be due to a pathologically limited attentional capacity in which multiple stimuli cannot be processed simultaneously to conscious awareness. Patients with tactile extinction are aware of being touched on a contralesional limb, but seem unaware of similar contralesional touch if touched simultaneously on their ipsilesional limb. The ipsilesional stimulus interferes and competes with the processing of the contralesional stimulus. Most theorists assume that the ipsilesional stimulus affects the sensory processing of the contralesional stimulus, although the precise functional level at which this interference occurs is not clear. We report a series of experiments using signal detection analyses to investigate tactile extinction in one patient (DC). These analyses revealed that ipsilesional stimuli, in addition to interfering with processing of contralateral sensations, also interfere with verbal reports of those sensations. This influence on responses suggests that interference in tactile extinction can occur at a post-perceptual level, further 'downstream' than previously thought.

Simultaneous activation of reading mechanisms: evidence from a case of deep dyslexia.

We report the performance of LC, a deep dyslexic. We investigated extensively her errors according to serial cognitive neuropsychological models of oral reading. Initial evaluation of her reading suggested impaired access to the phonological output lexicon (POL). Impaired grapheme-to-phoneme conversion (GPC) and semantic errors in reading suggested that LC read via an impoverished semantic route. However, a serial model of oral reading could not explain error differences in reading, picture naming, spontaneous speech, and repetition. Neologisms occurred in oral reading but not in spontaneous speech and repetition. Semantic errors in naming exceeded those in oral reading. To account for these different error patterns we propose that the semantic route, the direct route from the orthographic input lexicon to the POL, and GPC activate simultaneously during reading, converging at the POL to constrain phonological selection. These routes are modular but not functionally encapsulated. For LC, the POL receives ambiguous information due to degradation of all routes, causing reading errors.

Verbs, events and spatial representations.

Are concepts expressed in language also represented spatially? To pursue this question we investigated the structure of events. Events are defined as actions with spatial trajectories that can be perceived by our senses and described in language. Events are expressed linguistically in sentences containing verbs which determine the thematic roles of the arguments (e.g., who is doing what to whom, where). Because of previous observations we focused on whether events are represented spatially by location of thematic roles and direction of actions. Location and direction were dissociated by contrasting different kinds of verbs: 'push' vs 'pull' in which actions move toward or away from the agent. To control for spatial effects produced by the surface structure of a left to right written language, we kept the structure of sentences constant and sought for spatial biases produced by differences in the meaning of these sentences. From three experiments using drawing and sentence-picture matching reaction time tasks, we found that normal subjects located agents to the left of patients and represented actions with a left to right directionality. These results are not easily explained by features of the surface structure of language or properties of propositional representations. We suggest that events have spatial representations in addition to their propositional counterparts of verbs and thematic roles. The specific spatial properties observed may relate to functional properties of the left hemisphere.

Vocal reaction times of children with CAPD, age-matched peers, and young adults to printed words.

The purpose of this study was to determine if there were differences between children identified in a clinical setting as having Central Auditory Processing Disorder (CAPD), an age-matched peer group, and young adults when tested using a vocal reaction time (VRT) format. The children with CAPD were matched by gender and age to peers between the ages of 8 and 10 years. All speakers were presented visually with printed third-grade-level one- and two-syllable words (e.g., boy, mother) as well as the syllable "uh". Participants spoke each word according to the criteria of seven separate conditions, which included immediate naming tasks (0 s delay), a short delay before speaking (M = 1.5 s), and a longer delay before speaking (M = 4.0 s). Speakers VRTs were measured, and production errors were recorded. All speakers took longer to respond in the immediate-response conditions than the delayed-response conditions. Statistically significant differences were found for the immediate-response conditions, with means for the children with CAPD reflecting slower performance than that of their peers. The peer group was slower than the adults. For the delayed conditions, both groups of children responded with significantly longer VRTs than the adults. The two groups of children did not differ for these tasks. The children with CAPD produced a significantly greater number of errors than their peers, specifically for the long-delay conditions. The adults showed no performance differences across the immediate response conditions nor across the delayed conditions. These results suggested that children with CAPD may have processing difficulties with visual stimuli.

Cortical blindness and visual imagery.

Controversy exists concerning the neural basis underlying visual imagery. Some propose that visual images evoked from memory are mediated by primary visual cortices. Others argue that these primary visual areas perform computations on elementary visual features when constructing visual representations from retinal input but that they are not activated during recall of these representations. The visual imagery abilities of patients with cortical blindness may resolve this controversy. The proposition that primary visual cortex is necessary for visual imagery predicts a cortically blind subject's inability to perceive visual stimuli would be accompanied by an inability to image visually. Our investigations of three patients with cortical blindness provide strong evidence that primary visual cortices are not essential for the mediation of visual images recalled from memory.