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Biomedical subjects

P Shirley

Publications and source records attributed to P Shirley.

At least 19 recordsLinked to original sources
PubMed2001

Hepatic arterial and intravenous administration of 1,25-dihydroxyvitamin D3--evidence of a clinically significant hepatic first-pass effect.

PURPOSE: We have previously shown that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibits the proliferation of a number of human cancers, including colorectal and hepatocellular carcinoma, both of which affect the liver and are major causes of cancer death. However, the clinical use of 1,25(OH)2D3 and analogues has been restricted by the development of hypercalcaemia upon systemic administration. We hypothesized that a clinically significant hepatic first-pass effect may exist upon the administration of 1,25(OH)2D3 as a hepatic arterial infusion, and that such an effect may allow high levels of 1,25(OH)2D3 to be delivered to the liver whilst avoiding high systemic levels. METHODS: To examine this hypothesis, two groups of Landrace pigs were given identical doses of 1,25(OH)2D3 as continuous infusions, one group systemically, the other as a hepatic arterial infusion. Serum levels of 1,25(OH)2D3, calcium, phosphate and a number of liver and kidney function tests were performed regularly. RESULTS: Concentrations of 1,25(OH)2D3 and calcium remained normal in the hepatic arterial infusion animals, in contrast to the intravenous infusion animals which developed elevated levels of 1,25(OH)2D3 and hypercalcaemia. Hepatic arterial infusion of 1,25(OH)2D3 did not produce any adverse effects upon renal or hepatic function. CONCLUSION: The present findings support the existence of a clinically significant hepatic first-pass effect when 1,25(OH)2D3 is administered as a continuous hepatic arterial infusion. Hepatic arterial infusion of 1,25(OH)2D3 has great potential in the treatment of hepatic cancers.

Alanine Transaminase↗
PubMed2001

Use of interreflection and shadow for surface contact.

The interaction of light with surfaces results in a number of lighting effects that may serve as valuable visual cues. Previous research on shadows has shown them to be effective in determining the three-dimensional (3-D) layout of a scene, but interreflections have been ignored as cues for spatial layout. Interreflections as well as shadows may help to disambiguate the 3-D layout of objects by providing information about an object's contact with a surface. We generated computer images of a box on an extended textured ground plane that was either in contact with the ground or was slightly above the ground. Images were rendered for four conditions: (1) no shadow + no interreflection, (2) shadow only, (3) interreflection only, and (4) shadow + interreflection. A photometrically incorrect condition was also included. The participants rated the degree of contact for each image on a scale, which was used to generate receiver operating characteristic (ROC) curves and a measure of sensitivity. In the images with no shadows or interreflections, the participants performed at chance levels. Interreflections, shadows, and a combination of interreflections and shadows all resulted in high sensitivity for judging object contact. More important, information from shadows and interreflections can be combined, resulting in near-perfect judgment of surface contact. Interreflections and shadows can be effective cues for object contact.

Attention↗
PubMed2000

In vivo dose threshold effect of adenovirus-mediated factor VIII gene therapy in hemophiliac mice.

While much is known about adenovirus biology from its development as a therapeutic gene delivery vehicle, an important question remains regarding the appropriate in vivo vector dose. We describe here an in vivo dose threshold effect with an adenoviral vector expressing human Factor VIII (FVIII) in hemophiliac mice. Upon administration of vector doses between 6 x 10(10) and 2 x 10(10) vector particles per mouse, FVIII was expressed linearly, whereas a dose of 1 x 10(10) vector particles per mouse did not result in detectable levels of FVIII activity. In contrast, in vitro transduction studies demonstrated linear transgene expression over 2 to 3 log units. To further define this dose threshold effect, a vector-mixing study was performed. Mice were injected with a total vector dose of 6 x 10(10) particles containing admixtures of FVIII vector plus a control vector lacking a transgene (null vector). With the admixture, FVIII activity was detected in mice that received 1 3 1010 particles of the FVIII vector, indicating that maintenance of the total viral input at 6 x 10(10) particles per mouse circumvented the threshold dose effect. This threshold dose effect could not be attributed to dose-dependent differences in liver toxicity nor to dose-dependent induction of cellular and humoral immune responses. Southern blot analysis of livers revealed that mice receiving the vector admixture contained FVIII DNA, accounting for the observed FVIII expression, whereas mice receiving 1 x 10(10) particles of FVIII vector had barely detectable FVIII DNA. These results suggest that the threshold effect is an in vivo phenomenon that will have important implications in defining the therapeutic window of adenoviral vectors for clinical applications.

Adenoviridae↗
PubMed1999

Adenoviral vector-mediated expression of physiologic levels of human factor VIII in nonhuman primates.

An E1-, E2a-, E3-deleted adenoviral vector (Av3H82) encoding an epitope-tagged B domain-deleted human factor VIII cDNA (flagged FVIII) was evaluated in nonhuman primates. Twelve cynomolgus monkeys received intravenous administration of Av3H82; 6 monkeys received 6 x 10(11) particles/kg and another 6 received 3 x 10(12) particles/kg. Adenoviral vector transduction of the liver was efficient, reproducible, and linearly dose dependent. Physiologic levels of flagged FVIII were readily detected in plasma samples obtained from monkeys that received the higher dose of vector and human FVIII mRNA was detected in their livers. Expression of transgene mRNA was restricted to the liver by the albumin promoter. Although vector DNA was readily detected in the liver of monkeys that received the lower dose, neither human FVIII mRNA nor flagged FVIII protein could be detected. Vector distribution was widespread, with the highest levels observed in liver and spleen. Histopathology, hematology, and serum chemistry analysis identified the liver and blood as major sites of toxicity. Transient mild serum elevations of liver enzymes were observed, along with a dose-dependent inflammatory response in the liver. In addition, mild lymphoid hyperplasia was observed in the spleen. Mild anemia and a transient decrease in platelet count were observed, as was marrow hyperplasia and extramedullary hematopoiesis.

Adenoviridae↗
PubMed1993

Human oropharyngeal lesions with a defective Epstein-Barr virus that disrupts viral latency.

The Epstein-Barr virus (EBV), a human herpesvirus that is predominantly latent after infection, can be induced to replicate by deleted, rearranged EBV DNA from cultures of laboratory strain P3HR-1. Because mucosal surfaces are permissive of EBV replication, 101 oral biopsies from 70 Chinese and 5 American patients were examined for natural counterparts to tissue culture defective virus (WZhet), using as marker the abnormal juxtaposition of BamHI W and Z EBV DNA restriction fragments. Of the 49 oral biopsies that contained EBV DNA, 12 (24%) had the rearranged WZ fragment by polymerase chain reaction analysis: 3 (42%) of 7 EBV-positive epithelial dysplasias or carcinomas, 6 (38%) of 16 hairy leukoplakias, and 3 (12%) of 25 nonmalignant salivary gland biopsies. Accompanying viral replication was confirmed by in situ cytohybridization and demonstration of the linear configuration of the genome in select WZhet-positive lesions. These findings indicate that defective EBV with the unusual property of disrupting EBV latency is prevalent in natural infections and may contribute to EBV's pathogenic diversity.

Blotting, Southern↗
PubMed1991

A transformation-incompetent, nuclear antigen 2-deleted Epstein-Barr virus associated with replicative infection.

Epstein-Barr virus (EBV) obtained directly from the oropharynx was used to detect viral DNA deleted for the EBV nuclear antigen 2 (EBNA2)-encoding gene that is essential for lymphocyte transformation. By polymerase chain reaction analysis, the deletion was found in virus from 5 of 33 healthy adult donors and 11 of 12 patients with concurrent human immunodeficiency virus infection. Lymphoblastoid cell lines that produce standard transforming EBV also harbored EBNA2-deleted virus in cells permissive of EBV replication. In vitro infectivity studies indicated that the DNA is packaged and transmissible, with biologic properties similar to those of a laboratory mutant, P3HR-1, which also lacks the EBNA2 gene. These findings, obtained from productively infected cell systems, provide evidence for the existence in nature of a transformation-incompetent EBV variant that may facilitate EBV persistence and the emergence of reactivation diseases.

Antigens, Viral↗
PubMed1991

Excretion of the Epstein-Barr virus from the genital tract of men.

Epstein-Barr virus (EBV) DNA was detected by polymerase chain reaction in urethral discharges from 10 (48%) of 21 men attending a clinic for sexually transmitted diseases. Five of the 10 subjects were concurrently excreting virus from their oropharynx. These findings indicate that EBV is shed from more than one mucosal site in seropositive adult males. Involvement of the genital tract raises the possibility of sexual transmission as well as EBV-induced genital tract pathology.

Adult↗
PubMed1990

Defective viral DNA in Epstein-Barr virus-associated oral hairy leukoplakia.

Defective Epstein-Barr virus (EBV) has a deleted and rearranged genome (termed het DNA) that disrupts latency and induces standard EBV to replicate in vitro. We used the polymerase chain reaction to detect, in 2 of 10 patient samples, the junction of abnormally juxtaposed EBV DNA fragments BamHI W and Z, a genomic rearrangement responsible for the biologic activity of het DNA. By sequence analysis, the junction in wild-type defective DNA appears to be similar but not identical to the recombination in the DNA of laboratory strain P3HR-1. The presence of this marker for het DNA in the epithelial lesions of two patients suggests a role for defective EBV in a human pathologic process.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Detection of a second widespread strain of Epstein-Barr virus.

The prevalence of Epstein-Barr virus (EBV) type B, which was previously found mainly in equatorial Africa, was investigated with the polymerase chain reaction in a population of healthy adults in Memphis, Tennessee. EBV was detected in the throat washings of 34 (22%) of 157 randomly selected donors, 14 (41%) of whom had type B virus and 17 (50%) type A; 3 donors (9%) had both strains. 18 additional adults with human immunodeficiency virus (HIV-1) infection and 6 severely immunocompromised children were also investigated. Results indicated that type B EBV is widespread in nature and may be reactivated by immunodeficiency.

Adult↗