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T Shu

Publications and source records attributed to T Shu.

17 recordsLinked to original sources
PubMed2004

A defective nontransmissible recombinant Sendai virus mediates efficient gene transfer to airway epithelium in vivo.

Recombinant Sendai virus (SeV)-mediated gene transfer to differentiated airway epithelial cells has shown to be very efficient, because of its ability to overcome the intra- and extracellular barriers known to limit gene delivery. However, this virus is transmission competent and therefore unlikely to be suitable for use in clinical trials. A nontransmissible, replication-competent recombinant SeV has recently been developed by deleting the envelope Fusion (F) protein gene (SeV/DeltaF). Here we show that SeV/DeltaF is able to mediate beta-galactosidase reporter gene transfer to the respiratory tract of mice in vivo, as well as to human nasal epithelial cells in vitro. Further, in an ex vivo model of differentiated airway epithelium, SeV/DeltaF gene transfer was not importantly inhibited by native mucus. When compared to the transmission-competent SeV in vivo, no difference in gene expression was observed at the time of peak expression. The development of an F-defective nontransmissible SeV, which can still efficiently mediate gene transfer to the airway epithelium, represents the first important step towards the use of a cytoplasmic RNA viral vector in clinical trials of gene therapy.

Adult↗
PubMed2002

Renal and peri-renal abscesses in children: proposed physio-pathologic mechanisms and treatment algorithm.

Renal and perinephric abscess in children are uncommon. Three basic pathophysiologic mechanisms are involved, namely, hematogenous spread, ascending infection and contamination by proximity to an infected area. Six pediatric patients diagnosed with renal abscess were treated at our institution from 1990-2000. Five patients were females; ages ranged from 3-17 years (mean 11.8 years). Diagnosis, as expected, was not readily apparent at presentation. Computerized tomography and renal sonograms were the most useful imaging modalities. Gram-negative bacteria were commonly isolated; only one patient grew Staphylococcus aureus. All patients received broad-spectrum intravenous antibiotics. Additional treatments consisted of percutaneous drainage (4 patients), exploratory laparotomy (1 patient, for presumed Wilm's tumor) and nephrectomy (2 patients). A new classification of the etiologic mechanisms of this condition is proposed along with a simple and practical treatment algorithm.

Abscess↗
PubMed2001

Development of the perforating pathway: an ipsilaterally projecting pathway between the medial septum/diagonal band of Broca and the cingulate cortex that intersects the corpus callosum.

The perforating pathway (PFP) intersects the corpus callosum perpendicularly at the midline in the dorsoventral axis. Therefore axons in either the PFP or the corpus callosum make different axonal guidance decisions in the same anatomical region of the developing cortical midline. The mechanisms underlying these axonal choices are not known. To begin to identify these guidance mechanisms, we characterized the development of these two pathways in detail. The development of the corpus callosum and its pioneering projections has been described elsewhere (Shu and Richards [2001] J. Neurosci. 21:2749--2758; Rash and Richards [2001] J. Comp. Neurol. 434:147--157). Here we examine the development, origins, and projections of axons that make up the PFP. The majority of axons within the PFP originate from neurons in the medial septum and diagonal band of Broca complex. These neurons project in a topographic manner to the cingulate cortex. In contrast to previous reports, we find that a much smaller projection originating from the cingulate cortex also contributes to this pathway. The pioneering projections of the PFP and the corpus callosum arrive at the corticoseptal boundary at around the same developmental stage. These findings show that ipsilaterally projecting PFP axons and contralaterally projecting callosal axons make distinct guidance decisions at the same developmental stage when they reach the corticoseptal boundary.

Animals↗
PubMed2001

Cortical axon guidance by the glial wedge during the development of the corpus callosum.

Growing axons are often guided to their final destination by intermediate targets. In the developing spinal cord and optic nerve, specialized cells at the embryonic midline act as intermediate targets for guiding commissural axons. Here we investigate whether similar intermediate targets may play a role in guiding cortical axons in the developing brain. During the development of the corpus callosum, cortical axons from one cerebral hemisphere cross the midline to reach their targets in the opposite cortical hemisphere. We have identified two early differentiating populations of midline glial cells that may act as intermediate guideposts for callosal axons. The first differentiates directly below the corpus callosum forming a wedge shaped structure (the glial wedge) and the second differentiates directly above the corpus callosum within the indusium griseum. Axons of the corpus callosum avoid both of these populations in vivo. This finding is recapitulated in vitro in three-dimensional collagen gels. In addition, experimental manipulations in organotypic slices show that callosal axons require the presence and correct orientation of these populations to turn toward the midline. We have also identified one possible candidate for this activity because both glial populations express the chemorepellent molecule slit-2, and cortical axons express the slit-2 receptors robo-1 and robo-2. Furthermore, slit-2 repels-suppresses cortical axon growth in three-dimensional collagen gel cocultures.

Animals↗
PubMed2000

Expression of the netrin-1 receptor, deleted in colorectal cancer (DCC), is largely confined to projecting neurons in the developing forebrain.

Axon guidance mechanisms are crucial to the development of an integrated nervous system. One family of molecules that may be important in establishing axonal connectivity in mammals is the Netrins, and their putative receptors DCC (deleted in colorectal cancer), Neogenin, and Unc-5. Knockout and mutational analyses of some of these genes have shown that they are critically involved in the development of several specific pathways in the developing brain. However, previous expression analyses of these genes have largely been confined to the developing spinal cord. In the present study, we analyzed the expression of DCC in the developing mouse forebrain. We found that DCC protein is expressed in specific axonal populations projecting from the developing olfactory bulb, neocortex, hippocampus, and epithalamus/habenular complex. In the developing olfactory bulb and neocortex, DCC expression is particularly evident during the targeting phase of axon outgrowth and is then rapidly downregulated. As predicted from the knockout and mutational analyses of this gene, DCC is expressed in axonal commissures, in particular the corpus callosum, hippocampal commissure, and the anterior commissure. In addition, we found that DCC is expressed in the habenular commissure, the fasciculus retroflexus, and the stria medularis. Therefore, this analysis implicates a function for DCC in additional axonal guidance systems not predicted from the knockout and mutational analyses.

Animals↗
PubMed2000

The spatial and temporal expression patterns of netrin receptors, DCC and neogenin, in the developing mouse retina.

Recently it has been demonstrated that the guidance of retinal ganglion cell (rgc) axons through the optic disc is dependent on the DCC/netrin-1 axonal guidance system. To gain further insight into the function of the netrin receptors, DCC and Neogenin, in retinal development we have studied the expression patterns of these receptors in the embryonic mouse retina. Neogenin mRNA was restricted to a single neural cell type, the rgc. However, strong Neogenin mRNA expression was observed in the extending fiber cells of the developing lens suggesting a role for Neogenin in the migration events shaping the early lens. Our studies demonstrated that DCC mRNA was expressed at high levels in chains of closely opposed neurons as they migrated towards the emerging mantle layer in the early retina (E12.5-E13.5) suggesting a role for DCC in the migration of neurons out of the ventricular zone. DCC protein expression was high on rgc axons as they actively navigated through the optic disc into the optic nerve. At birth, when the majority of rgc axons had projected through the optic disc, DCC protein was no longer detectable on the distal axonal segments within the optic nerve despite significant DCC protein expression on the proximal axonal membranes in the nerve fiber layer. These observations suggest that a localized down-regulation of DCC protein occurs on projecting axonal membranes once the DCC guidance function is no longer required. We also demonstrated that DCC mRNA and protein were expressed by amacrine cells and Müller glial cells while DCC mRNA was detected in horizontal cells. Taken together, these expression patterns suggest a role for DCC in axon outgrowth and/or pathfinding for a variety of retinal neurons and in the migration of newly born neurons within the developing retina.

Animals↗
PubMed1999

Intracellular accumulation of insoluble, newly synthesized abetan-42 in amyloid precursor protein-transfected cells that have been treated with Abeta1-42.

Our early study indicates that intracellular Abeta1-42 aggregates are resistant to degradation and accumulate as an insoluble residue in lysosomes, where they alter the normal catabolism of amyloid precursor protein (APP) to cause the accumulation of insoluble APP and amyloidogenic fragments. In this study, we examined whether the addition of exogenous Abeta1-42 also leads to the accumulation of newly synthesized intracellular Abeta. Here we describe that newly synthesized Abeta, especially Abetan-42, is generated from metabolically labeled APP and accumulates in the insoluble fraction of cell lysates after Abeta1-42 treatment. These results suggest that intracellular Abeta may derive from a solid phase, intracellular pathway. In contrast to the pathway that primarily produces secreted Abeta1-40, the solid-phase intracellular pathway preferentially produces Abetan-42 with ragged amino termini. Biochemical studies and amino acid sequencing analyses indicate that these intracellular Abeta also share the same types of Abeta structures that accumulate in the brain of Alzheimer's disease patients, suggesting that a significant fraction of the amyloid deposits in Alzheimer's disease may arise by this solid-phase pathway.

Alzheimer Disease↗
PubMed1992

Importance of coronary artery spasm in alcohol-related unexplained syncope.

To examine the role of coronary artery spasm in patients with syncope after alcohol ingestion, we performed an intracoronary ergonovine provocation test in 7 male patients (39 to 73 years old, mean 54 years) with alcohol-related syncope which remained unexplained despite noninvasive cardiovascular and neurological examinations. No patients had structural heart disease or significant coronary artery stenosis. Ergonovine was continuously infused into each coronary artery at a rate of 10 micrograms/min for up to 5 min. Coronary artery spasm with ST-segment elevation was induced in 4 of 7 patients. Chest pain before syncope or history of chest pain were not present in 3 of 4 patients with a positive ergonovine test. Multivessel coronary artery spasm was induced in 3 patients. One patient presented with triple vessel coronary artery spasm progressing to near syncope as a result of profound hypotension and ventricular tachycardia during provocation. Coronary artery spasm was promptly relieved by intracoronary isosorbide dinitrate infusion. All patients with a positive ergonovine test were treated with calcium antagonist and did not experience syncope during follow-up. These results suggest that coronary artery spasm is one of the important causes of syncope after alcohol ingestion.

Adult↗
PubMed1981

[Regional wall motion of the left ventricle in congestive cardiomyopathy: in comparison with progressive muscular dystrophy of Duchenne type (author's transl)].

The features of regional wall motion abnormalities of the left ventricle were analysed in 11 patients of congestive cardiomyopathy (CCM) in comparison with 22 patients of progressive muscular dystrophy (DMD) of Duchenne type who showed an abnormal motion of the left ventricle by echocardiography. Real time two-dimensional echocardiographic study demonstrated the following results: I) In CCM, (1) only 2 or less of 11 cases preserved a normal motion in each left ventricular segment, and the depression of wall motion of the left ventricle were thought to be generalized; (2) there were 9 cases with segmental wall motion abnormalities and 3 of them demonstrated ventricular aneurysms, and (3) the localizations of the segmental abnormalities varied in each case, and there was no apparent accumulation to any segments. II) In DMD, (1) all the cases showed depressed motions and 8 of them demonstrated a ventricular aneurysm in the posterior wall of the left ventricle (LVPW), (2) while, there was no case showing ventricular aneurysm in the segments other than LVPW, and about one third of all cases showed normal motion in those segments. From these results, we concluded as follows: 1) Although the depression of a wall motion of the left ventricle was generalized in CCM, this was not always uniform and the segmental abnormalities of a wall motion were frequently observed. The localization of the most severely disturbed segment varied in each case. 2) On the other hand, in DMD, the wall motion was disturbed more frequently and more severely in LVPW than in other ventricular segments.

Adolescent↗
PubMed1977

Significance of echocardiographic evaluation on surgery to mitral stenosis.

1) Diastolic descent rate (DDR) of the anterior mitral leaflet improved after the surgery. However, this improvement was not modified with a) atrial fibrillation b) damages of the subvalvular supporting tissue c) valvular calcification d) the method of the operation, namely the open or closed commissurotomy. 2) DDR was fairly well correlated with the mitral orifice area, the cardiac output and the pressure gradient across the mitral valve. Therefore, the echocardiographic diagnosis and the follow up evaluation of the mitral stenosis after the surgery were thought to be very reliable, considering the accuracy of this diagnosis as disclosed in this study. The contributory effect to DDR was discussed.

Adult↗