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Biomedical subjects

D A Lewis

Publications and source records attributed to D A Lewis.

At least 55 records · Page 3Linked to original sources
PubMed2001

Myocardial performance and baroreceptor reflexes in preterm neonates: an echocardiographic evaluation using the tilt-table test.

The hemodynamic consequence of head-up position in preterm infants is not known, so we used the tilt-table test to assess changes in myocardial performance and baroreceptor reflexes. Twenty-five preterm infants with gestational age (GA) (mean +/- SD) 31 +/- 2.9 weeks (range 25-35.5 weeks), birth weight of 1612 +/- 642 g (range 520-3260 g) were studied in supine, 30 degrees, and 60 degrees head-up positions. GA had a significant effect on heart rate (HR) (p = 0.007), systolic blood pressure (SBP) (p = 0.03), left ventricular (LV) cavity dimensions (p = 0.001), cardiac output (CO) (p = 0.001), LV ejection time (LVETc) (p = 0.05), and end systolic wall stress (ESWS) (p = 0.003). An inverse relationship was seen between velocity of circumferential fiber shortening (VcFs) and ESWS (slope b = -0.019 +/- 0.008, p = 0.003). Results of tilt tests showed that at supine, 30 degrees, and 60 degrees, respectively, HR was 162 +/- 10.5, 162 +/- 9, and 164 +/-12 (p = NS); SBP (mmHg) was 73 +/- 11, 72.5 +/- 9.5, and 78 +/- 10 (p = NS); CO (L/kg/min) was 0.4 +/- 0.16, 0.4 +/- 0.15, and 0.43 +/- 0.16 (p = NS); ESWS (g/cm2) was 38.7 +/- 8.3, 40.9 +/- 9.9, and 43.4 +/- 10.7 (p = NS); and VcFs (circ/sec) was 1.35 +/- 0.3, 1.28 +/- 0.4, and 1.26 +/- 0.2 (p = NS). LV filling pattern as seen by early/late atrial Doppler flow velocity ratio did not change with tilt (p = NS). Myocardial performance improved with increasing GA. No significant differences in myocardial performance were found between baseline and head-up tilt positions.

Analysis of Variance↗
PubMed2001

Investigation of the interaction among the components of the cytolethal distending toxin of Haemophilus ducreyi.

The cytolethal distending toxin (CDT) of Haemophilus ducreyi is encoded by the cdtABC genes, but the composition of active CDT is not known. Both immunoaffinity and metal affinity chromatographic methods were used to purify H. ducreyi CDT from recombinant Escherichia coli strains bearing wild-type or mutated H. ducreyi cdtABC genes. Both affinity-purified preparations contained CdtA, CdtB, and CdtC proteins. These purification efforts also revealed that the formation of a noncovalent CdtB-CdtC complex and production of a fully active CDT complex required the presence of a functional CdtA protein. When purified recombinant CdtB and CdtC proteins were mixed, only very slight CDT activity was detected. In contrast, when a bacterial cell extract containing CdtA was mixed with purified preparations of both CdtB and CdtC, full CDT activity was reconstituted in vitro. These results indicate that CdtA is essential for normal H. ducreyi CDT activity and that CdtA likely modifies or alters either CdtB or CdtC or both to form the active CDT complex.

Bacterial Toxins↗
PubMed2001

Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization.

Dopamine (DA) influences a number of cognitive and motor functions that are mediated by the primate cerebral cortex, and the DA membrane transporter (DAT) is known to be a critical regulator of DA neurotransmission in subcortical structures in rodents. To gain insight into the possible functional role of cortical DAT, we compared the regional, laminar, and ultrastructural distribution of DAT immunoreactivity to that of tyrosine hydroxylase (TH), the rate-limiting enzyme in DA synthesis, in the cerebral cortex of macaque monkeys. DAT-immunoreactive (DAT-IR) axons were present throughout the cortical mantle, with substantial differences in density and laminar distribution across cytoarchitectonic areas. In particular, high densities of DAT-IR axons were present in certain regions (e.g., posterior parietal cortex, dentate gyrus) not previously thought to receive a substantial DA input. The laminar distribution of DAT-IR axons ranged from a restricted localization of labeled axons to layer 1 in lightly innervated regions to the presence of axons in all six cortical layers, with a particularly dense plexus in deep layer 3, in highly innervated regions. These regional and laminar patterns paralleled those of TH-IR axons, but several differences in fiber morphology and ultrastructural localization of DAT were observed. For example, in contrast to TH, DAT immunoreactivity in the cortex was localized predominantly to small-diameter profiles, whereas, in the dorsolateral caudate nucleus, DAT and TH immunoreactivities were present in both large-diameter and small-diameter profiles, which may represent varicose and intervaricose axon segments, respectively. Overall, the distribution of DAT-IR axons confirms and extends the results of previous reports, using other markers of DA axons, that the DA innervation of the primate cerebral cortex is global but specialized on both a regional basis and a laminar basis. In particular, these observations reveal an anatomical substrate for a direct and potent influence of DA over neuronal activity in posterior parietal cortex and in certain regions of the temporal lobe. However, due to its predominant distribution to small-diameter profiles, immunoreactivity for DAT may not be an appropriate ultrastructural marker for larger DA varicosities in the primate cortex. Moreover, this distribution of DAT suggests that cortical DA fibers may permit greater neurotransmitter diffusion than subcortical DA axons.

Animals↗
PubMed2001

Synaptic targets of the intrinsic axon collaterals of supragranular pyramidal neurons in monkey prefrontal cortex.

The principal axons of supragranular pyramidal neurons in the cerebral cortex travel through the white matter and terminate in other cortical areas, whereas their intrinsic axon collaterals course through the gray matter and form both local and long-distance connections within a cortical region. In the monkey prefrontal cortex (PFC), horizontally oriented, intrinsic axon collaterals from supragranular pyramidal neurons form a series of stripe-like clusters of axon terminals (Levitt et al. [1993] J Comp Neurol 338:360-376; Pucak et al. [1996] J Comp Neurol 376:614-630). The present study examined the synaptic targets of the intrinsic axon collaterals arising from supragranular pyramidal neurons within the same stripe (local projections). Approximately 50% of the within-stripe axon terminals in monkey PFC area 9 targeted dendritic spines. In contrast, for both the intrinsic axon collaterals that travel between stripes (long-range projections), and the axon terminals that project to other PFC areas (associational projections), over 92% of the postsynaptic structures were dendritic spines (Melchitzky et al. [1998] J Comp Neurol 390:211-224). The other 50% of the within-stripe terminals synapsed with dendritic shafts. Dual-labeling studies confirmed that these within-stripe terminals contacted gamma-aminobutyric acid-immunoreactive dendritic shafts, including the subpopulation that contains the calcium-binding protein parvalbumin. The functional significance of the differences in synaptic targets between local and long-range intrinsic axon collaterals was supported by whole-cell, patch clamp recordings in an in vitro slice preparation of monkey PFC. Specifically, the small amplitude responses observed in layer 3 pyramidal neurons during long-range, low-intensity stimulation were exclusively excitatory, whereas local stimulation also evoked di/polysynaptic inhibitory responses. These anatomic and electrophysiological findings suggest that intrinsic connections of the PFC differ from other cortical regions and that within the PFC, feedback (within-stripe) inhibition plays a greater role in regulating the activity of supragranular pyramidal neurons than does feedforward inhibition either between stripes or across regions.

Animals↗
PubMed2001

Alterations of striatal dopamine receptor binding in Alzheimer disease are associated with Lewy body pathology and antemortem psychosis.

BACKGROUND: Lewy bodies (LB) are present in at least 20% to 30% of persons with Alzheimer disease (AD) and contribute to the risk of psychosis and to excess cognitive burden. OBJECTIVE: To determine whether altered striatal dopamine receptor binding is associated with LB and psychosis in AD. DESIGN: Postmortem case control. SETTING: Alzheimer's Disease Research Center at the University of Pittsburgh (Pa). PARTICIPANTS: Consecutive cases from the Alzheimer's Disease Research Center brain bank, neuroleptic free for at least 1 month prior to death, with neuropathologic diagnoses of AD with LB (AD + LB, n = 14), AD without LB (AD, n = 13), or normal brains (n = 8). MAIN OUTCOME MEASURES: Dopamine D1, D2, and D3 receptor densities, and affinities as determined by selective saturation binding studies in striatal tissue. RESULTS: Subjects with AD + LB, compared with those with AD, demonstrated increased D1 receptor density and decreased D2 and D3 receptor density. D3 receptor density was selectively increased, however, in AD subjects with a history of psychosis, independent of the presence or absence of LB. The effect of neuroleptic treatment on D3 binding was further examined in an additional group of subjects who had received neuroleptics near the time of death. Neuroleptic treatment reduced D3 affinity with no effect on D3 density. CONCLUSIONS: Alzheimer disease with LB is associated with selective alterations in dopamine receptor density, which may contribute to the distinct clinical profile of this group. The D3 receptor may be an important target of neuroleptic treatment of psychosis in AD.

Aged↗
PubMed2001

Decreased somal size of deep layer 3 pyramidal neurons in the prefrontal cortex of subjects with schizophrenia.

BACKGROUND: Schizophrenia is associated with deficits in working memory, a cognitive function that depends on the connections of the prefrontal cortex (PFC) with the thalamus and other cortical regions. Pyramidal neurons in PFC deep layer 3 play a central role in both thalamocortical and corticocortical circuitry. Given that somal size tends to be associated with both the dendritic and axonal architecture of a neuron, abnormalities in these circuits in schizophrenia may be associated with a change in the somal size of deep layer 3 pyramidal neurons. METHODS: We used design-based stereology to estimate the somal volume of pyramidal neurons in deep layer 3 of PFC area 9 in 28 subjects with schizophrenia, each of whom was matched to 1 normal comparison subject for sex, age, and postmortem interval. RESULTS: The geometric mean of the somal volume estimates in the subjects with schizophrenia was significantly (P =.02) decreased by 9.2%. This decrease was associated with a shift in the distribution of somal volumes toward smaller sizes. Neither antipsychotic medication treatment history nor duration of illness was associated with somal size. CONCLUSIONS: These findings independently replicate previous reports of decreased somal size in the PFC in schizophrenia. The reduction in size of deep layer 3 pyramidal neurons is consistent with abnormalities in thalamocortical and corticocortical circuitry, suggesting that disruption of these circuits may contribute to cognitive abnormalities in schizophrenia.

Adult↗
PubMed2001

Analysis of complex brain disorders with gene expression microarrays: schizophrenia as a disease of the synapse.

The level of cellular and molecular complexity of the nervous system creates unique problems for the neuroscientist in the design and implementation of functional genomic studies. Microarray technologies can be powerful, with limitations, when applied to the analysis of human brain disorders. Recently, using cDNA microarrays, altered gene expression patterns between subjects with schizophrenia and controls were shown. Functional data mining led to two novel discoveries: a consistent decrease in the group of transcripts encoding proteins that regulate presynaptic function; and the most changed gene, which has never been previously associated with schizophrenia, regulator of G-protein signaling 4. From these and other findings, a hypothesis has been formulated to suggest that schizophrenia is a disease of the synapse. In the context of a neurodevelopmental model, it is proposed that impaired mechanics of synaptic transmission in specific neural circuits during childhood and adolescence ultimately results in altered synapse formation or pruning, or both, which manifest in the clinical onset of the disease.

Brain Chemistry↗
PubMed2001

Dopamine transporter-immunoreactive axons in the mediodorsal thalamic nucleus of the macaque monkey.

The reciprocal connections between the mediodorsal thalamic nucleus and the prefrontal cortex participate in a circuit that is essential to a number of higher cognitive processes. Projections from the dopamine-containing cells of the ventral mesencephalon to the prefrontal cortex are also critical for these cognitive abilities. It is unclear, however, whether dopamine axons innervate the mediodorsal thalamic nucleus in primates. In order to address this question, we examined the distribution of dopamine transporter-immunoreactive axons in the mediodorsal thalamic nucleus of macaque monkeys. Labeled axons were distributed quite heterogeneously in this nucleus, and did not strictly follow cytoarchitectonic subdivision boundaries. The ventral and lateral portions of the mediodorsal thalamic nucleus, which include parts of the parvicellular and multiform subdivisions, had the highest density of dopamine transporter-immunoreactive axons. In contrast, the dorsomedial portion, which included primarily the magnocellular subdivision, had the lowest density of labeled axons. In both lightly and densely innervated portions of the nucleus, small, dense clusters of dopamine transporter-immunoreactive axons were present. Axons immunoreactive for tyrosine hydroxylase were distributed in a pattern very similar to that of dopamine transporter-labeled axons. In contrast, noradrenergic axons, as revealed by dopamine beta-hydroxylase immunoreactivity, were present in higher density and were more evenly distributed throughout the mediodorsal thalamic nucleus. This dopamine innervation of the mediodorsal thalamic nucleus reveals another possible anatomical substrate through which dopamine may influence the cognitive functions mediated by thalamo-prefrontal circuitry.

Animals↗
PubMed2001

Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia.

Complex defects in neuronal signaling may underlie the dysfunctions that characterize schizophrenia. Using cDNA microarrays, we discovered that the transcript encoding regulator of G-protein signaling 4 (RGS4) was the most consistently and significantly decreased in the prefrontal cortex of all schizophrenic subjects examined. The expression levels of ten other RGS family members represented on the microarrays were unchanged and hierarchical data analysis revealed that as a group, 274 genes associated with G-protein signaling were unchanged. Quantitative in situ hybridization verified the microarray RGS4 data, and demonstrated highly correlated decreases in RGS4 expression across three cortical areas of ten subjects with schizophrenia. RGS4 expression was not altered in the prefrontal cortex of subjects with major depressive disorder or in monkeys treated chronically with haloperidol. Interestingly, targets for 70 genes mapped to the major schizophrenia susceptibility locus 1q21--22 were present on the microarrays, of which only RGS4 gene expression was consistently altered. The combined data indicate that a decrease in RGS4 expression may be a common and specific feature of schizophrenia, which could be due either to genetic factors or a disease- specific adaptation, both of which could affect neuronal signaling.

Adult↗
PubMed2001

Prevention of ventilator-induced lung injury with partial liquid ventilation.

BACKGROUND/PURPOSE: Pulmonary injury from mechanical ventilation has been attributed to application of excess alveolar pressure (barotrauma) or volume (volutrauma). The authors questioned whether partial liquid ventilation (gas ventilation of the perfluorocarbon filled lung, PLV) would reduce ventilator-induced lung injury. METHODS: A tracheostomy tube and carotid artery catheter were placed in anesthetized Sprague-Dawley rats (500 +/- 50 g). Bovine serum albumin (BSA) labeled with Iodine (I) 125 was administered intraarterially. Ventilation with tidal volume (TV) of 5 mL/kg was initiated. The rats were then selected randomly to a 30-minute experimental period of one of the following ventilation protocols: continued atraumatic gas ventilation (GV, TV, 5 mL/kg; n = 10); atraumatic gas ventilation combined with intratracheal administration of 10 mL/kg perfluorocarbon (GV-PLV, TV, 5 mL/kg, n = 10); barotrauma (BT, peak inspiratory pressure [PIP], 45 cm H(2)O; n = 10); barotrauma with PLV (BT-PLV, PIP, 45 cm H(2)O; n = 8); volutrauma (VT, TV, 30 mL/kg; n = 8); or volutrauma with PLV (VT-PLV, TV, 30 mL/kg; n = 10). Animals were killed and the amount of radiolabeled BSA in both lungs was measured and normalized to the counts in 1 mL of blood from that animal (injury index). Data were analyzed by analysis of variance (ANOVA) with post-hoc t test comparison between groups. RESULTS: There was a significant difference in the (125)I-BSA injury index when all groups were compared (P <.001 by ANOVA). Post-hoc analysis showed a significant decrease in the injury index when comparing BT versus BT-PLV (P =.024) and VT versus VT-PLV (P =.014). CONCLUSION: (125)I-BSA leak produced during high-pressure or high-volume mechanical ventilation is reduced by partial liquid ventilation.

Analysis of Variance↗
PubMed2001

Sleep in patients with asthma and chronic obstructive pulmonary disease.

Sleep abnormalities are common in patients with asthma and chronic obstructive pulmonary disease. Recent studies have provided new insight into the mechanisms involved in circadian changes in airway resistance, analyzed the effect of disease treatment on sleep quality, and re-examined issues relating to oxygen supplementation at night in patients with chronic obstructive pulmonary disease. Although providing new and useful information, some of these studies also raise new questions that will need answering in the future. This article reviews our current understanding of the complex interactions between sleep and lung disease in patients with asthma and chronic obstructive pulmonary disease.

Anti-Asthmatic Agents↗
PubMed2001

Characterization of Haemophilus ducreyi cdtA, cdtB, and cdtC mutants in in vitro and in vivo systems.

Haemophilus ducreyi expresses a soluble cytolethal distending toxin (CDT) that is encoded by the cdtABC gene cluster and can be detected in culture supernatant fluid by its ability to kill HeLa cells. The cdtA, cdtB, and cdtC genes of H. ducreyi were cloned independently into plasmid vectors, and their encoded proteins expressed singly or in various combinations in an Escherichia coli background. All three gene products had to be expressed in order for E. coli-derived culture supernatant fluids to demonstrate cytotoxicity for HeLa cells. Isogenic H. ducreyi cdtA and cdtB mutants were constructed and used in combination with the wild-type parent strain and a previously described H. ducreyi cdtC mutant (M. K. Stevens, J. L. Latimer, S. R. Lumbley, C. K. Ward, L. D. Cope, T. Lagergard, and E. J. Hansen, Infect. Immun. 67:3900-3908, 1999) to determine the relative contributions of the CdtA, CdtB, and CdtC proteins to CDT activity. Expression of CdtA, CdtB, and CdtC appeared necessary for H. ducreyi-derived culture supernatant fluid to exhibit cytotoxicity for HeLa cells. Whole-cell sonicates and periplasmic extracts from the cdtB and cdtC mutants had no effect on HeLa cells, whereas these same fractions from a cdtA mutant had a very modest cytotoxic effect on these same human cells. CdtA appeared to be primarily associated with the H. ducreyi cell envelope, whereas both CdtB and CdtC were present primarily in the soluble fraction from sonicated cells. Both the cdtA mutant and the cdtB mutant were found to be fully virulent in the temperature-dependent rabbit model for experimental chancroid.

Animals↗
PubMed2001

Selected contribution: Effects of sex and ovariectomy on responses to platelets in porcine femoral veins.

Estrogen replacement increases risk of venous thrombosis. In this study, we determined responses in vitro to platelets and platelet products in veins from adult male and intact and ovariectomized female pigs. When contracted with prostaglandin F(2alpha), platelets (25,000 platelets/microl) caused relaxation in veins with endothelium. Higher numbers of platelets caused contraction in veins with and without endothelium. In veins without endothelium, contractions were greater in veins from male than in veins from female pigs, and contractions in intact female pig veins were greater than in ovariectomized females pig veins. Platelet products 5-hydroxytryptamine and thromboxane (analog U-46619) caused comparable contractions in all veins; contractions to prostacyclin were less in veins from intact female pigs. ADP caused comparable endothelium-dependent relaxations in all groups. These relaxations were increased by indomethacin in veins from intact males and females; with inhibition of nitric oxide, relaxations were comparable in all groups. These results suggest that venous responses to platelets vary with sex and presence of ovaries in female pigs. These variations reflect differences in type and quantity of substances released from platelets as well as the sensitivity of the smooth muscle to some vasoactive substances. In addition, products of cyclooxygenase may reduce endothelium-dependent relaxations in veins.

Animals↗
PubMed2001

Insulin-like growth factor binding protein-4 protease produced by smooth muscle cells increases in the coronary artery after angioplasty.

Insulin-like growth factor (IGF)-I stimulates vascular smooth muscle cell (VSMC) migration and proliferation, which are fundamental to neointimal hyperplasia in postangioplasty restenosis. IGF-I action is modulated by several high-affinity IGF binding proteins (IGFBPs). IGFBP-4 is the predominant IGFBP produced by VSMCs and is a potent inhibitor of IGF-I action. However, specific IGFBP-4 proteases can cleave IGFBP-4 and liberate active IGF-I. In this study, we document IGFBP-4 protease produced by human and porcine coronary artery VSMCs in culture as pregnancy-associated plasma protein-A (PAPP-A). This was shown by a distinctive IGFBP-4 cleavage pattern, specific inhibition of IGFBP-4 protease activity with PAPP-A polyclonal antibodies, and immunorecognition of PAPP-A by monoclonal antibodies. Furthermore, we found a 2-fold increase in IGFBP-4 protease activity in injured porcine VSMC cultures in vitro (P<0.05). We also evaluated IGFBP-4 protease/PAPP-A expression in vivo after coronary artery balloon injury. Twenty-five immature female pigs underwent coronary overstretch balloon injury, and vessels were examined at defined time points after the procedure. Abundant PAPP-A expression was observed in the cytoplasm of medial and neointimal cells 7, 14, and 28 days after angioplasty (P<0.01 vs control). The highest PAPP-A labeling indices were located in the neointima (36.1+/-2.1%) and the media (31.7+/-1.2%) 28 days after injury. Western blot analysis confirmed increased PAPP-A in injured vessels. PAPP-A, a regulator of IGF-I bioavailability through proteolysis of IGFBP-4, is thus expressed by VSMCs in vitro and in restenotic lesions in vivo. These results suggest a possible role for PAPP-A in neointimal hyperplasia.

Adult↗