Biomedical subjects

R J Connor

Publications and source records attributed to R J Connor.

At least 19 recordsLinked to original sources

PubMed2006

Efficacy of a single intravesical treatment with Ad-IFN/Syn 3 is dependent on dose and urine IFN concentration obtained: implications for clinical investigation.

There is a need to improve the treatment of superficial bladder cancer. One area which holds promise is intravesical gene therapy. Recently, studies undertaken by us have shown that marked tumor regression of bladder cancers occurred after two daily intravesical administrations of an adenovirus encoding human interferon alpha (Ad-IFNalpha) using a mouse superficial bladder cancer model in which human bladder tumors are growing. A dose of 1 x 10(11) particles/ml (P/ml) was used along with 1 mg/ml of Syn3, a gene transfer-enhancing agent. Since clinical studies are being planned using this approach, it became critical to determine if one exposure and lower particle number could be equally effective. We report that indeed a single dose of Ad-IFNalpha in Syn3 at doses of 1 x 10(10)-1 x 10(11) P/ml is highly effective in reducing the size of the tumors, whereas 1 x 10(9) P/ml was not. Efficacy was also correlated with the level of IFN produced in the urine after treatment. Based on the results of the present studies, a Phase I trial is being planned for superficial bladder cancer, which will involve a single initial treatment with Ad-IFNalpha/Syn3 and measurement of IFN in the urine over time as an indicator of adequate gene transfer and expression.

Administration, Intravesical↗

PubMed2001

Identification of polyamides that enhance adenovirus-mediated gene expression in the urothelium.

Adenovirus-mediated gene therapy of bladder diseases has been limited by the inability to transduce the urothelium successfully using adenoviral vectors. We have sought to identify agents that would increase adenovirus-mediated transgene expression in the bladder. We have utilized a rat model to screen compounds for their ability to enhance viral transgene expression in the rat bladder. Rats received intravesical administration of replication-deficient adenovirus (rAd) formulated in various agents, and transgene expression was evaluated after 48 h by determining the amount of lacZ expression in the luminal epithelium of the bladder. We report the identification of two different polyamides, each capable of dramatically increasing viral transgene expression in the bladder without causing detectable alteration of the umbrella cell layer of the urothelium. We have utilized a carcinogen-induced rat bladder tumor model to demonstrate that these polyamides are also capable of enhancing viral transgene expression in tumor tissue. The identification of these polyamides potentiates the use of adenovirus-mediated gene therapy for the treatment of superficial bladder cancer or other bladder diseases.

Adenoviridae↗

PubMed2000

Investigation of design and bias issues in case-control studies of cancer screening using microsimulation.

Using a microsimulation approach, the authors examined design and bias issues in case-control studies of cancer screening. Specifically, they looked at the impact on the odds ratio of the way in which exposure to screening is defined, the type of age matching, the time scale used, and the criteria used to determine control eligibility. The results showed that defining exposure as "ever/never" screened produced, as expected, a serious bias in favor of screening. Defining exposure as being screened no later than the time the case's cancer is diagnosed has a serious bias against screening. An alternative exposure definition--screening can occur no later than the time the case would have been clinically diagnosed--eliminates the bias against screening. Further, the results showed that the type of age matching and the time scale used can produce a bias against screening and that this bias can be quite strong when case-control studies are performed in populations with a periodic screening program that is the only source of screening. Finally, control eligibility criteria had little effect.

Age Distribution↗

PubMed2000

An analysis of trypanocidal drug use in the Eastern Province of Zambia.

As part of the development of a strategy for the control of bovine trypanosomosis in Zambia, a survey was conducted to quantify and qualify the current use of trypanocidal drugs (diminazene aceturate and isometamidium chloride) in a tsetse-controlled and a tsetse-infested area of the Eastern Province. A total of 207 trypanocide users were interviewed. Questions were posed on herd structure, trypanocidal drug preference, treatment strategy, reason for treatment, method of treatment and treatment frequency. The majority of the cattle owners preferred to use diminazene aceturate rather than isometamidium chloride. Both trypanocides were mainly used to treat clinically sick animals (not necessarily infected with trypanosomes) and preference was given to the treatment of oxen and cows. The proportion of animals treated and the frequency of drug application did not differ between the two areas. Hence, in the tsetse-controlled area, a high proportion of the trypanocide treatments was inappropriate. In the tsetse-infested area, on the other hand, the treatment of clinically sick animals significantly reduced the trypanosomosis-related mortality but was insufficient to boost reproduction in cows. Despite the fact that the cattle owners administered most trypanocides themselves, evidence from the survey suggests that most of the farmers did not under-dose with either diminazene aceturate or isometamidium chloride. Moreover, other factors enhancing the development of resistance to trypanocides in trypanosomes were not present in the areas surveyed. Conclusions are drawn on the usefulness of this type of survey in determining appropriate methods to control bovine trypanosomosis.

Age Factors↗

PubMed1999

Ethanol improves adenovirus-mediated gene transfer and expression to the bladder epithelium of rodents.

OBJECTIVES: Replication deficient adenoviral vectors (rAds) are used as gene delivery systems that can efficiently transduce a variety of tissues and may be appropriate vectors to develop gene therapeutics for many urologic applications. However, the bladder epithelium has been shown to be highly resistant to transgene expression after intracystic administration. A potential explanation for this low gene transfer efficiency may be the protective structure of the urothelium. Since this protective barrier can be disrupted by organic solvents, we assessed whether ethanol co-administration can enhance adenovirus-mediated transgene expression. METHODS: Normal and bladder tumor-bearing rats received a single intracystic administration of rAd encoding beta-galactosidase (rAd-beta gal) or p53 (rAd-p53). rAd was administered in a saline solution or in solutions with increasing concentrations of ethanol. Transgene expression was evaluated in the bladder tissues. RESULTS: A dramatic increase in urothelial beta-galactosidase transgene expression was achieved by rAd-beta gal administered in a 22% ethanol solution. Transgene expression was enhanced in normal urothelium and in superficial bladder tumors. p53 transgene expression was similarly enhanced. CONCLUSIONS: Co-administration of 22% ethanol enhanced local rAd-mediated transgene expression in the normal and neoplastic bladder epithelium in rodents. Improvement of rAd-mediated transgene expression is progress toward local gene delivery to the urothelium and may enable local gene therapy for superficial bladder cancer or other bladder diseases.

Adenoviridae↗

PubMed1998

The partial testing design: a less costly way to test equivalence for sensitivity and specificity.

We propose a new, less costly, design to test the equivalence of digital versus analogue mammography in terms of sensitivity and specificity. Because breast cancer is a rare event among asymptomatic women, the sample size for testing equivalence of sensitivity is larger than that for testing equivalence of specificity. Hence calculations of sample size are based on sensitivity. With the proposed design it is possible to achieve the same power as a completely paired design by increasing the number of less costly analogue mammograms and not giving the more expensive digital mammograms to some randomly selected subjects who are negative on the analogue mammogram. The key idea is that subjects who are negative on the analogue mammogram are unlikely to have cancer and hence contribute less information for estimating sensitivity than subjects who are positive on the analogue mammogram. To ascertain disease state among subjects not biopsied, we propose another analogue mammogram at a later time determined by a natural history model. The design differs from a double sampling design because it compares two imperfect tests instead of combining information from a perfect and imperfect test.

Breast Neoplasms↗

PubMed1998

Case-control studies of cancer screening: theory and practice.

This review summarizes methodologic theories for the design of cancer screening case-control studies and examines the methods applied in studies published in English from 1980 through 1996. In addition to summarizing state-of-the-art methodologic approaches, we identify areas where obvious gaps exist between theory and practice, and we recommend potential areas where theory and methodology may need further development. In particular, we focus on three major areas: 1) the selection of case and control subjects, 2) the definition of exposure (i.e., exposure to the screening test), and 3) bias. Each area is considered carefully by summarizing current theory, reviewing cancer screening applications, and linking recommended methodologic approaches to those used in practice to identify areas where inconsistencies exist. In general, we found methodologic theory and practice in this field of research to be consistent. However, discrepancies were identified in the area of exposure definition, including the use of screening frequency and the use of a detectable, curable preclinical phase for case subjects as the exposure measures. Even when recommended methods were followed, a number of difficulties arose in practice. Specific concerns included the ability to carry out the following: identifying all case subjects within a source population, defining eligibility criteria to ensure that case and control subjects had equal access to screening during the exposure period, distinguishing between symptomatic and diagnostic tests, and controlling for self-selection bias. Careful scrutiny is warranted in all aspects of the design of cancer screening case-control studies, and caution is advised in the interpretation of study results.

Case-Control Studies↗

PubMed1998

Expression and tyrosine phosphorylation of Eph receptors suggest multiple mechanisms in patterning of the visual system.

The EphA3 receptor tyrosine kinase has been implicated in guiding the axons of retinal ganglion cells as they extend in the optic tectum. A repulsive mechanism involving opposing gradients of the EphA3 receptor on retinal axons and its ligands, ephrin-A2 and ephrin-A5, in the tectum influences topographic mapping of the retinotectal projection. To investigate the overall role of the Eph family in patterning of the visual system, we have used in situ hybridization to localize nine Eph receptors in the chicken retina and optic tectum at Embryonic Day 8. Three of the receptors examined correspond to the novel chicken homologs of EphA2, EphA6, and EphA7. Unexpectedly, we found that many Eph receptors are expressed not only in retinal ganglion cells, but also in tectal cells, In particular, EphA3 mRNA is prominently expressed in the anterior tectum, with a pattern reciprocal to that of ephrin-A2 and ephrin-A5. Similarly, ephrin-A5 is expressed not only in tectal cells but also in the nasal retina, with a pattern reciprocal to that of its receptor EphA3 and partially overlapping with that of its other receptor EphA4. Consistent with the even distribution of EphA4 and the polarized distribution of EphA4 ligands in the retina, probing EphA4 immunoprecipitates from different sectors of the retina with anti-phosphotyrosine antibodies revealed spatial differences in receptor phosphorylation. These complex patterns of expression and tyrosine phosphorylation suggest that Eph receptors and ephrins contribute to establishing topography of retinal axons through multiple mechanisms, in addition to playing a role in intraretinal and intratectal organization.

Amino Acid Sequence↗

PubMed1996

Isometamidium concentrations in the sera of cattle maintained under a chemoprophylactic regime in a tsetse-infested area of Zimbabwe.

An experiment was carried out to determine the concentrations of the trypanocidal drug isometamidium chloride in the sera of cattle maintained under a chemoprophylactic regimen at Rekomitjie, Zimbabwe, an area of high tsetse challenge in the Zimbabwe valley. In February 1993, 24 cattle at this site were treated intramuscularly with isometamidium chloride at a dose of 1.0 mg/kg body weight. Thereafter all animals were monitored regularly for 6 months for the presence of trypanosomes and sera were collected to determine the concentrations of isometamidium using an ELISA. Isometamidium treated cattle appeared to be protected against trypanosome infections for at least 18 weeks following treatment. Thereafter, three trypanosome infections were detected, between 20 and 22 weeks following treatment. In contrast, in 18 untreated control cattle at the same site, 9 trypanosome infections were detected over the first 18 weeks of the experiment. Quantification of the isometamidium concentration in sera from the drug treated cattle indicated that the apparent half-life of isometamidium in these animals was 23 days. This was similar to the half-life observed previously in cattle treated under laboratory conditions. The isometamidium ELISA was shown to be capable of quantifying drug levels in 20 out of 23 cattle for at least 70 days after treatment. There was no evidence of drug resistant trypanosomes at this site.

Animals↗

PubMed1995

Genomic organization and alternatively processed forms of Cek5, a receptor protein-tyrosine kinase of the Eph subfamily.

The genomic organization of Cek5, a receptor tyrosine kinase of the Eph subfamily, was elucidated utilizing a strategy involving PCR amplification of Cek5 genomic DNA. Cek5 is the first Eph-related kinase for which the exon-intron structure of the entire coding region has been determined. The Cek5 gene spans over 35 kb and comprises at least 16 exons. The exon-intron structure of Cek5 can be correlated with the proposed domain structure of the Eph subfamily, with the exception of an Ig motif in the extracellular domain. Intron positions in the Cek5 gene coincide with the locations of the deletions, substitutions, or insertions that have been described in a number of Eph-related kinases. This suggests that alternative processing plays a major role in generating the structural variability observed in the Eph subfamily. Consistent with this hypothesis, analysis of the Cek5 gene indicate that: (i) a variant form of Cek5 containing an insertion in the juxtamembrane region (Cek5 +) arises through the use of alternative 5' splice sites, and (ii) a soluble form of Cek5 comprising only the extracellular domain (Cek5s) may exists, which originates by alternative polyadenylation. RT-PCR analysis and RNase protection assays revealed the expression of both Cek5 + and Cek5s at various stages of chicken development.

Alternative Splicing↗

PubMed1995

Receptor specificity of influenza virus influences severity of illness in ferrets.

Weanling ferrets were inoculated intranasally with either wild-type or receptor-variant clones of influenza A/Memphis/102/72 to determine if changes in receptor specificity influence virulence of influenza virus infection. Over the 5 days after inoculation, receptor-variant inoculated ferrets had a lower mean elevation in body temperature, greater weight gain and less sneezing than the wild-type group. Influenza virus was recovered from the lungs of fewer receptor-variant infected ferrets (5/12 vs 11/12) and in lower titers than in wild-type infected ferrets at 5 days after inoculation. The viruses recovered from lung homogenates retained the same receptor specificity as the inoculum. Serum hemagglutination inhibition titers for the two groups were similar. These findings suggest that the receptor-variant clone is less virulent but elicits a similar immunogenic response compared with the wild-type clone.

Animals↗

PubMed1995

Design and analysis of cancer screening trials.

This article reviews approaches to the design and analysis of cancer screening trials. After summarizing some basic screening concepts and potential pitfalls, we introduce several possible screening trial designs with examples from the literature. We review in detail methods for analyzing screening trial data, including testing for a significant difference in disease-specific mortality between the control and intervention groups, estimating the mortality differential if one exists, and evaluating the programme lead time, the screen sensitivity and the role of stage shifting. We consider Overall mortality analyses, which are based on the experience of the trial population, and Limited mortality analyses, which are based on the experience of comparable groups of cases in the control and intervention groups. We discuss methods for selecting candidate comparable case groups and confirming that they are in fact comparable. We conclude by showing how the principles discussed have been used in the planning and design of a current screening trial for multiple cancers.

Data Interpretation, Statistical↗

PubMed1994

Receptor specificity in human, avian, and equine H2 and H3 influenza virus isolates.

The receptor specificity of 56 H2 and H3 influenza virus isolates from various animal species has been determined to test the relevance of receptor specificity to the ecology of influenza virus. The results show that the receptor specificity of both H2 and H3 isolates evaluated for sialic acid linkage specificity and inhibition of hemagglutination by horse serum correlates with the species of origin, as postulated earlier for H3 strains based on a limited survey of five human, three avian, and one equine strain. Elucidation of the amino acid sequence of several human H2 receptor variants and analysis of known sequences of H2 and H3 isolates revealed that receptor specificity varies in association with an amino acid change at residues 228 in addition to the change at residue 226 previously documented to affect receptor specificity of H3 but not H1 isolates. Residues 226 and 228 are leucine and serine in human isolates, which preferentially bind sialic acid alpha 2,6-galactose beta 1,4-N-acetyl glucosamine (SA alpha 2,6Gal), and glutamine and glycine in avian and equine isolates, which exhibit specificity for sialic acid alpha-2,3-galactose beta-1,3-N-acetyl galactosamine (SA alpha 2,3Gal). The results demonstrate that the correlation of receptor specificity and species of origin is maintained across both H2 and H3 influenza virus serotypes and provide compelling evidence that influenza virus hosts exert selective pressure to maintain the receptor specificity characteristics of strains isolated from that species.

Amino Acid Sequence↗

PubMed1994

Cek5, a tyrosine kinase of the Eph subclass, is activated during neural retina differentiation.

The expression of Cek5, a receptor-type tyrosine kinase of the Eph subclass, and its variant form Cek5+ were examined in the chick neural retina during development. Cek5 is present at high levels at all stages of retinal development examined, while Cek5+ is most abundant during differentiation. Cek5 mRNA expression and immunoreactivity are evenly distributed in the undifferentiated retina. With differentiation, Cek5 becomes concentrated in the inner and outer plexiform layers. While only moderate changes in Cek5 protein expression are observed throughout retinal development, Cek5 phosphorylation on tyrosine in vivo is dramatically increased during differentiation. This suggests that the Cek5 ligand is expressed at high levels and causes Cek5 activation. Thus, Cek5 is likely to play an active role in retinal morphogenesis, particularly during the establishment of interneuronal contacts.

Amino Acid Sequence↗

PubMed1994

Issues in the mortality analysis of randomized controlled trials of cancer screening.

This paper is concerned with the analysis and interpretation of randomized controlled trials (RCTs) of periodic screening programs for the early detection of cancer in which there is a lengthy follow-up period without screening being offered. That is, screening is offered for a limited time with a subsequent follow-up period during which the cancer mortality is observed. The paper focuses on tests for a mortality reduction due to screening. Two approaches are presented, one based on the experience of all those randomized to the test and control groups, and the other based on the experience of selected groups of cancer cases found during the trial. In the latter approach it is necessary that the two groups selected for analysis be comparable groups of cancers. The concept of comparability is discussed with emphasis on factors that determine comparability and on ways to assess it. Examples from completed cancer screening RCTs are used to illustrate the ideas and methods presented.

Adult↗

PubMed1994

The impact of nagana.

The disease in cattle, called nagana in Zululand, was linked with trypanosomal parasitaemia and tsetse flies. Nagana occurs in livestock throughout the tsetse belts of Africa. Wild animals are tolerant of trypanosomal infections. Nagana affects individual animals, herds and socio-economic development. In susceptible animals nagana may be acute, but chronic infections are more common. The host-parasite interaction produces extensive pathology and severe anaemia. Clinically affected animals lose condition and become weak and unproductive. Nagana is often fatal and, at herd level, its impact is wide ranging. All aspects of production are depressed: fertility is impaired; milk yields, growth and work output are reduced; and the mortality rate may reduce herd size. Africa has to feed its rapidly growing human population, and animal products are a vital dietary component. However, in most tsetse areas, there is not enough meat and milk. Furthermore, animal draft power is often not available, which limits cultivation and local transport. These factors lower household incomes and retard socio-economic development. Sustainable rural development requires that nagana be controlled. This in turn needs considerable resources, whichever control strategy is adopted.

Animals↗

PubMed1991

Analysis of the temporal patterns of benefits in the Health Insurance Plan of Greater New York trial by stage and age.

Reductions in breast cancer mortality in the Health Insurance Plan of Greater New York trial are examined by age at entry and stage at diagnosis using a stage shift cancer screening model. The results indicate that for women aged 40-49 years at entry, benefits are associated with an internal stage shift of stage 1 cancers that have a prognosis poorer than the usual stage 1 cancers. Further, the results indicate that after 18 years of follow-up, of the reduction of 16 fewer deaths in the intervention group, 12-15 of the deaths are related to this internal shift. Given that stage 1 cases inherently have relatively good survival, the time required to see the screening benefit is substantial. For women aged 50-64 years at entry, the results suggest that benefits are associated primarily with shifts to or within stage 1. Further, the results indicate that after 6 years, of the reduction of 31 fewer deaths in the intervention group, 22 of the deaths are related to external shifts to stage 1. Given that stage 2 cancers have poorer survival than stage 1 cancers, screening benefit is seen sooner for the older cohort than for the younger cohort.

Adult↗

PubMed1991

The case-control design and the assessment of the efficacy of cancer screening.

Case-control studies have been used in recent years to evaluate the efficacy of cancer screening. However, relatively little work has been done to examine the methodology itself for this purpose. In this paper, it is demonstrated that because of self-selection bias the case-control study can yield a biased estimate of screening efficacy. Further, it is shown how this bias can be assessed using data from a randomized trial. Using data from the HIP breast cancer screening study, the magnitude of the self-selection bias is estimated and is seen to be substantial.

Breast Neoplasms↗