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A Ryan

Publications and source records attributed to A Ryan.

At least 19 recordsLinked to original sources
PubMed2006

Range of self-tests available to buy in the United Kingdom: an Internet survey.

We aimed to describe the availability in the United Kingdom of self-tests that are used to diagnose or screen for conditions without involving a health professional. A systematic Internet search identified 104 unique self-tests related to 24 named conditions including cancers, chronic conditions and infections. These self-tests require various samples including blood obtained using a lancet. The samples are processed at home with results available in minutes or sent to a laboratory for processing with results returned to the individual by e-mail or post. Prices per self-test and condition range from < Pounds 1 to Pounds 76. Self-tests are readily available, and further work is needed to assess their impact.

Diagnostic Equipment↗
PubMed2006

Vaginal vault smears after hysterectomy for reasons other than malignancy: a systematic review of the literature.

BACKGROUND: Vaginal vault smears are used to detect persisting neoplasia of the lower genital tract after hysterectomy. Recent data suggest both widespread use and uncertain evidence of their effectiveness. OBJECTIVES: To identify and synthesise evidence on the use and effectiveness of vaginal vault smears and to assess the quality. SEARCH STRATEGY 'vault smear' OR 'vaginal vault smear' OR 'cervical vault smear' OR ('Hysterectomy') AND ('Follow up' OR 'Smear'). SELECTION CRITERIA Primary research, women who had a hysterectomy and were followed up by vault cytology. DATA COLLECTION AND ANALYSIS: Systematic search (eight electronic databases), supplemented by contact with experts and review of bibliographies. Two independent reviewers determined eligibility/validity and extracted data concerning test performance characteristics. Quality was assessed according to the established criteria. RESULTS: Of 441 unique references, only 19 were suitable. Quality of studies varied considerably and few were of 'high' methodological quality. Studies were geographically diverse, and were published over more than 40 years in 16 journals. From the higher scoring papers, there were 11 659 hysterectomies [6546, benign; 76, cervical intraepithelial neoplasia (CIN) I/CIN II; 5037, CIN III]. Proportions of abnormal vault smears and abnormal biopsies during follow up increased with worsening histology at hysterectomy (P < 0.0001 and P = 0.0001). There was only one report of vaginal cancer subsequent to hysterectomy for CIN and insufficient data to allow for reliable meta-analysis. CONCLUSIONS: Vault smears cause anxiety, consume resources and their value is largely unproven. Inconsistency of study design and limited methodological quality means that the value of vault smears could not be established. High-quality research is required to ensure that the guidelines are evidence based.

Female↗
PubMed2006

Measurement of the clinical and cost-effectiveness of non-invasive diagnostic testing strategies for deep vein thrombosis.

OBJECTIVES: To estimate the diagnostic accuracy of non-invasive tests for proximal deep vein thrombosis (DVT) and isolated calf DVT, in patients with clinically suspected DVT or high-risk asymptomatic patients, and identify factors associated with variation in diagnostic performance. Also to identify practical diagnostic algorithms for DVT, and estimate the diagnostic accuracy, clinical effectiveness and cost-effectiveness of each. DATA SOURCES: Electronic databases (to April 2004). A postal survey of hospitals in the UK. REVIEW METHODS: Selected studies were assessed against validated criteria. A postal survey of hospitals in the UK was undertaken to describe current practice and availability of tests, and identify additional diagnostic algorithms. Pooled estimates of sensitivity, specificity and likelihood ratios were obtained for each test using random effects meta-analysis. The effect of study-level covariates was explored using random effects metaregression. A decision-analytic model was used to combine estimates from the meta-analysis and estimate the diagnostic performance of each algorithm in a theoretical population of outpatients with suspected DVT. The net benefit of using each algorithm was estimated from a health service perspective, using cost--utility analysis, assuming thresholds of willingness to pay of pound 20,000 and pound 30,000 per quality-adjusted life-year (QALY). The model was analysed probabilistically and cost-effectiveness acceptability curves were generated to reflect uncertainty in estimated cost-effectiveness. RESULTS: Individual clinical features are of limited diagnostic value, with most likelihood ratios being close to 1. Wells clinical probability score stratifies proximal, but not distal, DVT into high-, intermediate- and low-risk categories. Unstructured clinical assessment by experienced clinicians may have similar performance to Wells score. In patients with clinically suspected DVT, D-dimer has 91% sensitivity and 55% specificity for DVT, although performance varies substantially between assays and populations. D-dimer specificity is dependent on pretest clinical probability, being higher in patients with a low clinical probability of DVT. Plethysmography and rheography techniques have modest sensitivity for proximal DVT, poor sensitivity for distal DVT, and modest specificity. Ultrasound has 94% sensitivity for proximal DVT, 64% sensitivity for distal DVT and 94% specificity. Computed tomography scanning has 95% sensitivity for all DVT (proximal and distal combined) and 97% specificity. Magnetic resonance imaging has 92% sensitivity for all DVT and 95% specificity. The diagnostic performance of all tests is worse in asymptomatic patients. The most cost-effective algorithm discharged patients with a low Wells score and negative D-dimer without further testing, and then used plethysmography alongside ultrasound, with venography in selected cases, to diagnose the remaining patients. However, the cost-effectiveness of this algorithm was dependent on assumptions of test independence being met and the ability to provide plethysmography at relatively low cost. Availability of plethysmography and venography is currently limited at most UK hospitals, so implementation would involve considerable reorganisation of services. Two algorithms were identified that offered high net benefit and would be feasible in most hospitals without substantial reorganisation of services. Both involved using a combination of Wells score, D-dimer and above-knee ultrasound. For thresholds of willingness to pay of pound 10,000 or pound 20,000 per QALY the optimal strategy involved discharging patients with a low or intermediate Wells score and negative D-dimer, ultrasound for those with a high score or positive D-dimer, and repeat scanning for those with positive D-dimer and a high Wells score, but negative initial scan. For thresholds of pound 30,000 or more a similar strategy, but involving repeat ultrasound for all those with a negative initial scan, was optimal. CONCLUSIONS: Diagnostic algorithms based on a combination of Wells score, D-dimer and ultrasound (with repeat if negative) are feasible at most UK hospitals and are among the most cost-effective. Use of repeat scanning depends on the threshold for willingness to pay for health gain. Further diagnostic testing for patients with a low Wells score and negative D-dimer is unlikely to represent a cost-effective use of resources. Recommendations for research include the evaluation of the costs and outcomes of using the optimal diagnostic algorithms in routine practice, the development and evaluation of algorithms appropriate for specific groups of patients with suspected DVT, such as intravenous drug abusers, pregnant patients and those with previous DVT, the evaluation of the role of plethysmography: interaction with other diagnostic tests, outcome of low-risk patients with negative plethysmography and measurement of the costs of providing plethysmography, and methodological research into the incorporation of meta-analytic data into decision-analytic modelling.

Adult↗
PubMed2005

Fatal toxic leukoencephalopathy: clinical, radiological, and necropsy findings in two patients.

BACKGROUND: Toxic leukoencephalopathy has been described with inhalation and intravenous consumption of heroin and cocaine. The clinical picture varies widely but the imaging and histological features are characteristic. Magnetic resonance imaging (MRI) typically reveals diffuse bihemispheric white matter lesions. Histologically there is extensive spongiform degeneration of the cerebral white matter. OBJECTIVE: To report two cases of fatal toxin associated leukoencephalopathy, along with detailed imaging and neuropathological studies. RESULTS: MRI revealed diffuse white matter changes. Histologically there was widespread confluent vacuolar degeneration of the deep white matter. In both cases, there was sparing of the brain stem and cerebellar white matter. There was evidence of severe and extensive axonal injury. CONCLUSIONS: This pattern of radiological involvement and histological findings has not previously been reported and may reflect the presence of a yet unidentified impurity.

Adult↗
PubMed2004

The new materials processing beamline at the SRS Daresbury, MPW6.2.

A new beamline (MPW6.2) has been designed and built for the study of materials during processing where three synchrotron techniques, SAXS, WAXS and XAS, are available simultaneously. It has been demonstrated that Rietveld refinable data can be collected from silicon SRM 640b over a 60 degrees range in a time scale of 1 s. The data have been refined to a chi(2) of 2.4, the peaks fitting best to a Pearson VII function or with fundamental parameters. The peak halfwidths have been found to be approximately constant at 0.06 degrees over a 120 degrees angular range indicating that the instrumental resolution function has matched its design specification. A quantitative comparison of data sets collected on the same isotactic polypropylene system on MPW6.2 and DUBBLE at the ESRF shows a 17% improvement in angular resolution and a 1.8 improvement in peak-to-background ratio with the RAPID2 system; the ESRF data vary more smoothly across detector channels. The time-dependent wide-angle XRD was tested by comparing a hydration reaction of gypsum-bassanite-anhydrite with energy-dispersive data collected on the same system on the same time scale. Three sample data sets from the reaction were selected for analysis and gave an average chi(2) of 3.8. The Rietveld-refined lattice parameters are a good match with published values and the corresponding errors show a mean value of 3.3 x 10(-4). The data have also been analysed by the Pawley decomposition phase-modelling technique demonstrating the ability of the station to quickly and accurately identify new phases. The combined SAXS/WAXS capability of the station was tested with the crystallization and spinodal decomposition of a very dilute polymer system. Our measurements show that the crystallization of a high-density co-polymer (E76B38) as low as 0.5% by weight can be observed in solution in hexane. The WAXS and SAXS data sets were collected on the same time scale. The SAXS detector was calibrated using a collagen sample that gave 30 orders of diffraction in 1 s of data collection. The combined XRD and XAS measurement capability of the station was tested by observing the collapse and re-crystallization of zinc-exchanged zeolite A (zeolite Zn/Na-A). Previous studies of this material on station 9.3 at the SRS were compared with those from the new station. A time improvement of 38 was observed with better quality counting statistics. The improved angular resolution from the WAXS detector enabled new peaks to be identified.

Equipment Design↗
PubMed2004

ZD6126 inhibits orthotopic growth and peritoneal carcinomatosis in a mouse model of human gastric cancer.

The purpose of this study was to examine the effects of ZD6126, a novel vascular-targeting agent, on tumour growth and angiogenesis in an orthotopic model of gastric cancer. TMK-1 human gastric adenocarcinoma cells were injected into the gastric wall of nude mice. After the tumours were established (day 14), therapy was initiated. Mice (n=11-12/group) received (a). vehicle, (b). ZD6126 at 100 mg x kg day(-1) i.p. one time per week or (c) ZD6126 at 100 mg x kg day(-1) i.p. five times per week. Tumour mass, volume and the presence or absence of peritoneal carcinomatosis were determined at sacrifice on day 38. Tumours from each group were stained for markers of blood vessels, proliferation and apoptosis. To further define the time frame of the vascular-targeting effects of chronic therapy with ZD6126, TMK-1 cells were again injected into the gastric wall of mice in a second experiment. On day 14, a single i.p. injection of ZD6126 100 mg x kg(-1) mouse(-1) or vehicle was delivered. Groups of three mice each were killed and the tumours harvested at days 1, 3 and 5 post-ZD6126 injection. Tumours were processed and stained for endothelial and tumour cell apoptosis and proliferation. No overt toxicity was observed with ZD6126 therapy. ZD6126 led to a marked inhibition of tumour growth (82% decrease vs control (P<0.001)). ZD6126 also led to a significant decrease in the incidence of peritoneal carcinomatosis (10 out of 12 controls, vs one out of 12 ZD6126) (P<0.01). Histological analysis of tumours revealed large regions of central necrosis in the treated group, as well as a dramatic increase in tumour cell apoptosis (7.4-fold increase (P<0.001)), consistent with the vascular-targeting activity of ZD6126. Mice treated with ZD6126 demonstrated a 59% decrease in PCNA-positive cells (P< 0.02), indicating reduced tumour cell proliferation. In addition, tumours treated with ZD6126 exhibited a 40% decrease in microvessel density (P<0.05). Results from mice treated with a single injection of ZD6126 demonstrated the acute effects this agent has on the tumour vasculature. The ratio of endothelial cell apoptosis to endothelial cell proliferation was increased within 24 h of a single injection. In conclusion, ZD6126 significantly inhibited tumour growth and metastasis in an orthotopic model of human gastric adenocarcinoma, without detectable problematic adverse effects. These data suggest that ZD6126 may be worthy of investigation in the treatment of primary gastric adenocarcinoma.

Adenocarcinoma↗
PubMed2003

Immunohistochemical analysis of p53 in vulval intraepithelial neoplasia and vulval squamous cell carcinoma.

Human papillomavirus (HPV) is thought to cause some vulval squamous cell carcinomas (VSCC) by degrading p53 product. Evidence on whether HPV-negative VSCC results from p53 mutation is conflicting. We performed immunohistochemistry for p53 product on 52 cases of lone vulval intraepithelial neoplasia (VIN), 21 cases of VIN with concurrent VSCC and 67 cases of VSCC. We had previously performed HPV detection and loss of heterozygosity (LOH) analyses on these samples. Abnormal p53 immunoreactivity (p53-positive) rates in HPV-positive VSCC and HPV-negative VSCC were 22% (12/54) and 31% (4/13), respectively (P<0.74). p53 immunoreactivity was associated with LOH at the p53 locus (P<0.004), but neither technique differentiated between HPV-positive and HPV-negative VSCC. p53 immunoreactivity was associated with overall LOH rates (p53-positive VSCC vs p53-negative VSCC mean fractional regional allelic loss 0.41 vs 0.24, respectively, P<0.027). LOH at 3p25 was more frequent in p53-positive VSCC cf p53-negative VSCC (70 vs 21%, respectively, P<0.007). There was a trend in p53 disruption associated with invasive disease; HPV-positive VSCC demonstrated more disruption than VIN associated with VSCC, which had more disruption than lone VIN III (22 vs 10 vs 0%, respectively, P<0.005). In all, three out of 73 cases of VIN were p53-positive. All three were associated with concurrent or previous VSCC. Meta-analysis of previous studies revealed significantly more p53 disruption in HPV-negative VSCC cf HPV-positive VSCC (58 vs 33%, respectively; P<0.0001). p53 immunoreactivity/mutation in VIN only appeared in association with VSCC. These data suggest that HPV-independent vulval carcinogenesis does not exclusively require disruption of p53, p53 disruption may work synergistically with LOH at specific loci and p53-positive VIN should be checked carefully for the presence of occult invasion.

Adult↗
PubMed2002

A model for co-expression pattern analysis of genes implicated in angiogenesis and tumour cell invasion in cervical cancer.

To date, numerous genes have been identified which are involved in both tumour neovascularisation (angiogenesis) and tumour cell invasion, and most of them are also expressed to some extent under normal physiological conditions. However, little is known about how these genes co-express in these settings. This study was undertaken to quantitate mRNA levels in normal and malignant cervical tissues of nine selected genes (VEGF(121), VEGF(165), VEGF(189), VEGF-C, eIF-4E, b-FGF, TSP-2, MMP-2 and MMP-9) implicated in the above processes using real-time quantitative RT-PCR. In addition, the Spearman's rank correlation was used to determine their co-expression patterns. The transcript levels for the different VEGF-A splice variants (VEGF(121), VEGF(165), VEGF(189)) were at least 10-fold higher in the cancer cases, with the highest levels in the primary tumours demonstrating lympho-vascular space involvement. The lymphangiogenic factor VEGF-C and MMP-9 were upregulated 130- and 80-fold respectively in cervical cancers. The highest levels of VEGF-C mRNA were found in the lymph-node positive group. The transcript levels for b-FGF were similar in normal cervical tissue and early-stage cervical cancer, however, higher levels were found in the cervical cancers with advanced stage disease. Comparing gene transcript levels between recurrent and non-recurrent cervical cancer patients revealed significant differences (P=0.038) in transcript levels for the angiogenesis inhibitor TSP-2, with the highest levels in non-recurrent cases. Co-expression pattern analysis in normal cervical tissue revealed highly significant co-expressions (P<0.0001) between TSP-2 and most other genes analysed (VEGF(121), VEGF(165), VEGF-C, b-FGF and MMP-2). In cervical cancer, TSP-2 appears only to be highly co-expressed with MMP-2 (P<0.0001). In contrast to normal cervical tissue, we found a highly significant co-expression (P<0.0001) between MMP-9 and VEGF(189) in cervical cancer. The combined application of real-time quantitative RT-PCR and Spearman's rank correlation identifies gene transcripts which are simultaneously co-expressed. Our results revealed a significant co-expression between the angiogenesis inhibitor TSP-2 and most other genes analysed in normal cervical tissue. In cervical cancer, we found a strong upregulation of VEGF-C and MMP-9 mRNA, with a highly significant co-expression between MMP-9 and VEGF(189).

Cervix Uteri↗
PubMed2002

Histopathologic features of genetically determined ovarian cancer.

Inheritance of germline mutations of BRCA1 or BRCA2 genes account for approximately 10% of ovarian carcinomas, but the characterization of these genetically determined cancers is incomplete. The objective of our study was to characterize the histologic features of ovarian carcinomas associated with germline mutations of BRCA1 and BRCA2. Thirty-two ovarian carcinomas associated with germline BRCA1 or BRCA2 mutations and 40 ovarian carcinomas from patients screened as negative for germline mutations were obtained from three centers. A gynecologic pathologist, blinded to mutation status, reviewed each case, with documentation of the histologic type, Gynecologic Oncology Group (GOG) grade, architectural and nuclear grade, Silverberg grade, and mitotic activity. All BRCA1 and BRCA2 mutation-associated cases were invasive serous carcinomas, and of these 50% were GOG grade 3, 41% had an architectural grade of 3 (predominant solid architecture), 84% a nuclear grade of 3, 72% a mitotic score of 3 (>25 mitoses per 10 HPF), and 75% a Silverberg grade of 3. The differences in histologic type (p = 0.001) and Silverberg grade (p = 0.002) between these tumors and the control group were statistically significant and remained so when comparisons between BRCA carriers and noncarriers were restricted to carcinomas of serous histology alone. Ovarian carcinomas associated with germline mutations of BRCA1/BRCA2 are, in this study, invasive serous carcinomas, with a statistically significant higher histologic grade than ovarian carcinomas without BRCA mutations when using the recently proposed Silverberg grading system.

Female↗
PubMed2001

High frequency of loss of heterozygosity in vulval intraepithelial neoplasia (VIN) is associated with invasive vulval squamous cell carcinoma (VSCC).

Vulval intraepithelial neoplasia (VIN) is thought to be the premalignant phase of human papillomavirus (HPV)-associated vulval squamous cell carcinoma (VSCC). Various molecular events have been suggested as markers for progression from VIN to VSCC, but loss of heterozygosity (LOH) in vulval neoplasia has rarely been studied in this context. We performed LOH analysis by polymerase chain reaction (PCR) amplification of polymorphic microsatellite markers at 6 chromosomal loci (17p13-p53, 9p21-p16, 3p25, 4q21, 5p14 and 11p15). The presence of HPV was assessed using consensus PCR primers and DNA sequencing. To examine any association between LOH and the presence of invasive disease, we analyzed 43 cases of lone VIN III, 42 cases of lone VSCC and 21 cases of VIN with concurrent VSCC. HPV DNA was detected in 95% of lone VIN III samples and 71% of lone VSCC samples. Fractional regional allelic loss (FRL) in VIN associated with VSCC was higher than in lone VIN (mean FRL 0.43 vs. 0.21, p < 0.005). LOH at 3p25 occurred significantly more frequently in HPV-negative VSCC than in HPV-positive VSCC (58% vs. 22%, p < 0.04). These data suggest that genetic instability in VIN, reflected by LOH, may increase the risk of invasion. In addition, molecular events differ in HPV-positive and -negative VSCC and 3p25 may be the site of a tumor suppressor gene involved in HPV-independent vulval carcinogenesis.

Carcinoma, Squamous Cell↗
PubMed2001

Molecular quantification and mapping of lymph-node micrometastases in cervical cancer.

BACKGROUND: A proportion of patients with cancer and lymph nodes negative on histology will develop recurrence. Reverse-transcriptase PCR (RT-PCR) is a highly sensitive method for detection of lymph-node micrometastases, but accurate quantitative assessment has been difficult. METHODS: We studied primary tumours and 156 lymph nodes from 32 patients with cervical cancer (stage IA2, IB1, and IB2) and 32 lymph nodes from nine patients with benign disease. A fully quantitative, real-time RT-PCR assay was used to document absolute copy numbers of the epithelial marker cytokeratin 19. Primers and probe were designed not to amplify either of the two cytokeratin 19 pseudogenes. FINDINGS: All primary tumours and histologically involved lymph nodes (six) had more than 106 copies of cytokeratin 19 mRNA per microg total RNA. Expression of cytokeratin 19 (up to 1.1 x 10(5) copies per microg RNA) was detected in 66 (44%) of 150 histologically uninvolved lymph nodes, and in nodes from 16 of 32 patients with cervical cancer. 15 of these 16 patients with evidence of micrometastases had the highest cytokeratin 19 transcription level in a first lymph-node drainage station (three obturator, six internal, and six external iliac node). Transcription of cytokeratin 19 was found at a low level in just one of 32 lymph nodes obtained from nine patients with benign disease. Median copy number of cytokeratin 19 transcription was significantly higher (>10(3) copies) in association with adverse prognostic features. INTERPRETATION: The results suggest that about 50% of early-stage cervical cancers shed tumour cells to the pelvic lymph nodes. The amount of cytokeratin 19 expression was related to clinicopathological features. Further studies are required to document the clinical implications of molecular micrometastases.

Adult↗
PubMed2001

PTEN methylation is associated with advanced stage and microsatellite instability in endometrial carcinoma.

Loss of heterozygosity and mutations in the PTEN (MMAC1) tumor suppressor gene are frequent in endometrial carcinoma. Promoter hypermethylation has recently been identified as an alternative mechanism of tumor suppressor gene inactivation in cancer, but its importance in the PTEN gene in endometrial carcinoma is unknown. The purpose of our study was to assess the frequency of promoter methylation of the PTEN gene and to determine its correlation with clinicopathologic variables in a prospective and population-based series of endometrial carcinomas with complete follow-up. Presence of PTEN promoter methylation was seen in 26 of 138 patients (19%). Methylation was significantly associated with metastatic disease (p = 0.01) and a microsatellite unstable phenotype (p = 0.006). In conclusion, we find that PTEN promoter methylation is relatively frequent in endometrial carcinoma. Its association with metastatic disease and microsatellite instability implicates its importance in the development of this tumor type.

Alleles↗
PubMed2001

Ascertainment of pregnancies terminated because of birth defects: effect on completeness of adding a new source of data.

BACKGROUND: When evaluating preventive programs such as folate promotion and rubella vaccination, it is critically important to include terminations of pregnancy for neural tube defects and congenital rubella syndrome. Data from birth defects registries are often used for this purpose. The Western Australian Birth Defects Registry ascertains cases of birth defects in livebirths, stillbirths, and terminations of pregnancy for fetal abnormality, using multiple sources of ascertainment. METHODS: Data on terminations of pregnancy for fetal abnormality from the Western Australian Hospital Morbidity Data System 1980-1997 (not previously available to the Registry) were used to estimate the completeness of ascertainment of such cases by the Registry. Ascertainment-adjusted prevalences were calculated using capture-recapture methods. RESULTS: A total of 702 terminations with birth defects were identified among hospital discharges, most of which were already known to the Registry (87.9%). Of the 85 new cases, seven had a neural tube defect, 23 had a chromosomal defect, and 12 had confirmed maternal rubella infection during pregnancy. The ascertainment-adjusted prevalence was not importantly [corrected] different for birth defects overall or for these individual conditions, although the 95% confidence intervals for all birth defects, and for all chromosomal defects, did not include the prevalence based on registered cases only. CONCLUSIONS: The Western Australian Birth Defects Registry ascertains a high proportion of pregnancies terminated for fetal abnormality, and should therefore be a reliable source of data with which to assist in monitoring the effectiveness of preventive programs.

Abortion, Induced↗
PubMed2001

The Prostate Cancer Prevention Trial: Current status and lessons learned.

The Prostate Cancer Prevention Trial is the first phase 3 prevention trial for prostate cancer in the United States. The implementation of a large, randomized trial has provided a wealth of information that will aid in future cancer chemopreventive studies in US men. The experience from the implementation of the Prostate Cancer Prevention Trial was reviewed. Lessons learned from the study include: (1) US men are willing to enroll in prevention trials; (2) participants in chemoprevention trials are well educated and healthy; (3) the successful cancer prevention trial is viewed by participants as a "men's health trial"; (4) data management and discipline coordination at participating institutions are critical; (5) study design change is commonly required owing to changes in clinical practice over the course of the trial; and (6) training of institutional staff is essential. With proper design, robust data management, and a flexible staff, large-scale randomized chemoprevention trials can be accomplished in the United States. With the extraordinary number of potential agents, it is expected that much will be accomplished with this strategy in the near future.

5-alpha Reductase Inhibitors↗
PubMed2001

In vivo adenoviral transduction of the neonatal rat cochlea and middle ear.

Virally mediated gene transfer to the adult mammalian ear appears to be a powerful strategy to investigate gene function in the auditory system and to develop new therapeutic treatment for hearing impaired patients. However, there has been little work done in the neonatal middle and inner ear. In this study, a recombinant adenoviral (AdV) vector was used for gene transfer of a beta-galactosidase (beta-gal) reporter gene to the neonatal middle ear and cochlea of 5 day old rats. For transduction of middle ear, AdV was injected through the tympanic membrane into the tympanic cavity. Three and 7 days later, strong expression of beta-gal was observed in epithelial cells of the mucosa, but not in the underlying stroma or mesenchyme. There was little or no infiltration of leukocytes. No expression of beta-gal was detected inside the cochlea or vestibular system. When AdV was injected into the basal turn of the cochlea, high levels of beta-gal expression were observed in cells lining the perilymphatic space and in parts of the spiral ligament 3, 7 and 21 days later. Spiral ganglion cells did not express beta-gal. However, virally mediated gene transfer was observed in some cells of the organ of Corti. A moderate infiltration of leukocytes into the labyrinth was observed, but no vestibular or auditory dysfunction. These results demonstrate that neonatal middle ear and cochlear cells can be successfully transduced with an AdV vector in vivo, without obvious morphological signs of inflammation or cellular damage. AdV vectors provide a tool for investigation of the role of genes in influencing the development of middle and inner ear structures. Virally mediated expression of protective genes could also be used to rescue hair cells or spiral ganglion cells from congenital degeneration or damage.

Adenoviridae↗