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Biomedical subjects

B P Conway

Publications and source records attributed to B P Conway.

At least 19 recordsLinked to original sources
PubMed2001

Phase I trial of a melanoma vaccine with gp100(280-288) peptide and tetanus helper peptide in adjuvant: immunologic and clinical outcomes.

A melanoma vaccine composed of HLA-A2-restricted peptide YLEPGPVTA (gp100(280)), with or without a modified T-helper epitope from tetanus toxoid AQYIKANSKFIGITEL, has been evaluated in a Phase I trial to assess safety and immunological response. The vaccines were administered s.c. in either of two adjuvants, Montanide ISA-51 or QS-21, to 22 patients with high-risk resected melanoma (stage IIB-IV). Local and systemic toxicities were mild and transient. We detected CTL responses to the gp100(280) peptide in peripheral blood in 14% of patients. Helper T-cell responses to the tetanus helper peptide were detected in 79% of patients and had a Th1 cytokine profile. One patient with a CTL response to gp100 had a recurrence in a lymph node 2 years later; her nodes contained CD8+ cells reactive to gp100(280) (0.24%), which proliferated in response to peptide. The overall survival of patients is 75% (95% confidence interval, 57-94%) at 4.7 years follow-up, which compares favorably with expected survival. Four of 14 patients who completed at least six vaccines subsequently developed metastases, all of which were solitary and surgically resectable. They remain alive and clinically free of disease at last follow-up. Data from this trial demonstrate immunogenicity of the gp100(280) peptide and suggest that immune responses may persist long-term in some patients. The frequency and magnitude of the CTL response may be improved with more aggressive vaccination regimens. Although this Phase I study was not intended to evaluate clinical benefit, the excellent survival of patients on this protocol suggests the possibility of a benefit that should be assessed in future studies.

Adjuvants, Immunologic↗
PubMed1999

11-cis retinol dehydrogenase mutations as a major cause of the congenital night-blindness disorder known as fundus albipunctatus.

PURPOSE: Patients with fundus albipunctatus uniformly experience difficulty with vision at night. Their retinas are spotted with characteristic light yellow flecks of unknown composition that typically spare the macula. A defect in the transport or utilization of visual cycle retinoids is thought to underlie this recessive disorder with variable clinical expression. To elucidate the molecular defect we considered the genes for interphotoreceptor retinoid-binding protein (RBP3) and 11-cis retinol dehydrogenase (RDH5) as candidates for this disease. METHODS: We examined two unrelated families with fundus albipunctatus. The diagnosis was determined clinically and RBP3 and RDH5 were analyzed by molecular screening methods and direct genomic sequencing. RESULTS: Each family had two affected members with typical fundus albipunctatus. The affected members were siblings born to unaffected parents who were seventh cousins in the first family and unrelated in the second family. The probands from both families were clinically similar except for the fundus dots that were more extensive in the second family to the point of involving the parafoveal region. In the initial phase of genetic screening RBP3 defects were ruled-out as the cause of the disease in both families. In contrast, RDH5 mutations were found in the affected siblings in both families. The proband in one had a homozygotic Gly238Trp missense mutation (GGG -> TGG) involving exon 4 and in the other carried compound heterozygotic changes Arg280His (CGC -> CAC) and Ala294Pro (GCC -> CCC) in exon 5. The disease phenotype was only manifested in family members with two abnormal RDH5 alleles consistent with autosomal recessive inheritance in both pedigrees. CONCLUSIONS: These findings strongly implicate defects of RDH5 as the cause of fundus albipunctatus and point to a heterogeneity of RDH5 mutations in this form of congenital stationary night blindness with variable expressivity.

Adult↗
PubMed1998

Ultrastructural changes in rabbit ciliary body after extraocular mitomycin C.

PURPOSE: To study the ultrastructural changes in ciliary body epithelium of the rabbit eye after subconjunctival injections of mitomycin C. METHODS: One eye of six New Zealand white rabbits was given a subconjunctival injection at the 12-o'clock position with 0.005, 0.02, 0.08, 0.1, 0.12, or 0.16 mg mitomycin C. The fellow eye was given a subconjunctival injection of balanced salt solution. Two weeks after treatment, the eyes were enucleated, and the ciliary body was exposed and submerged in fresh 4% paraformaldehyde/2% glutaraldehyde in 0.1 M phosphate buffer, pH 7.4, at 4 degrees C. Electron microscopy of the ciliary body was performed at two sites: the injection site (12-o'clock position) and 180 degrees away (6-o'clock position). RESULTS: At dosages of 0.1 mg and higher, ciliary body epithelial cells beneath the injection site were thinned. There were vacuoles and expansion of intracellular and intercellular spaces. Plasma membrane infoldings were disrupted, and the apical membrane was thinned. Mitochondria and nuclei were normal. Ciliary body epithelium at 6-o'clock position showed only mild architectural distortion of the plasma membrane infoldings. Eyes that received lower doses of mitomycin C (0.005 mg, 0.02 mg, and 0.08 mg) and balanced salt solution showed normal ciliary body epithelium at the injection site and 180 degrees away. CONCLUSIONS: Subconjunctival injection of mitomycin C in the rabbit produces dose-dependent localized ultrastructural changes of the ciliary body epithelium.

Animals↗
PubMed1997

Clear cell differentiation in choroidal melanoma. COMS report no. 8. Collaborative Ocular Melanoma Study Group.

OBJECTIVE: To describe 2 enucleated eyes of patients enrolled in the Collaborative Ocular Melanoma Study that contained primary choroidal melanoma with clear cell features. METHODS: During a 9-year period, 1493 eyes enucleated as part of the Collaborative Ocular Melanoma Study routinely processed for histologic examination were evaluated by the pathology review committee (H.E.G, D.M.A, and W.R.G). Two eyes with unusual variants of choroidal melanoma were identified and immunostained for S100 protein and HMB 45. Portions of the tumors were processed for electron microscopic examination. RESULTS: Results of electron microscopic examination of both tumors displayed malignant melanoma (mixed cell type with many malignant cells with clear cytoplasm). The cytoplasm of the clear cells stained with periodic acid-Schiff and failed to stain when pretreated with diastase. Results of immunohistochemical stains in both tumors were positive for S100 protein and HMB 45 in the tumor cells. Results of electron microscopic examination showed that the cytoplasm of the clear cells contained scattered glycogen granules, premelanosomes, and melanosomes. CONCLUSION: These cases represent a clear cell variant of malignant melanoma of the choroid. This tumor should not be confused with metastatic clear cell carcinoma to the choroid.

Aged↗
PubMed1995

Induction of urinary tract infection by intraurethral inoculation with Escherichia coli: refining the murine model.

Murine models are important for studying the induction and pathophysiology of ascending urinary tract infections (UTI). However, when vesicoureteral reflux occurs during intravesical inoculation of mice with bacterial suspensions, it is difficult to distinguish between naturally ascending infections and those resulting from the inoculation procedure. The current study investigated whether introducing a bacterial suspension into the urethra rather than into the bladder could minimize or eliminate this complication. There were no differences in the intensity or time course of bladder infections induced by intraurethral or intravesical inoculation. In contrast, the prevalence of kidney infections was < 7% in mice given 10 microliters of intraurethral inoculations versus nearly 60% in animals inoculated intravesically with 100 microliters. There were equivalent numbers of bacteria in the kidneys after inoculation by either route. Thus, intraurethral inoculation of female mice with a small volume of bacteria appears to simulate most closely the pathophysiology of ascending UTIs in humans.

Animals↗
PubMed1993

Adenovirus type 8 epidemic keratoconjunctivitis in an eye clinic: risk factors and control.

Epidemic keratoconjunctivitis (EKC) due to adenovirus type 8 affected 126 (7%) of 1870 ophthalmology clinic patients during an outbreak. Risk factors and mode of transmission were studied by comparing cases (n = 58) and controls (n = 200) for exposure to risk factors. Pneumotonometry (odds ratio [OR], 10.5; 95% confidence interval [CI], 4.0-27.7), multiple clinic visits (OR, 5.9; 95% CI, 3.3-10.6), and contact with an infected physician (OR, 3.3; 95% CI, 1.2-9.0) were significant risk factors for infection. The hands of 3 patients and 3 physicians with EKC were cultured before and after hand washing to assess adenovirus removal; 3 had hand cultures positive for adenovirus after hand washing. In conclusion, this outbreak appeared to be due to inadequate disinfection of instruments, especially pneumotonometers, and finger-to-eye transmission by health care workers. Hand washing did not reliably remove adenovirus from contaminated fingers. Gloving for exam of eyes with EKC may help prevent transmission. Ophthalmologists with EKC were a significant risk factor for patients and should be furloughed for the duration of communicability.

Adenovirus Infections, Human↗
PubMed1993

Identification of novel rhodopsin mutations responsible for retinitis pigmentosa: implications for the structure and function of rhodopsin.

Ten rhodopsin mutations have been found in a screen of 282 subjects with retinitis pigmentosa (RP), 76 subjects with Leber congenital amaurosis, and 3 subjects with congenital stationary night blindness. Eight of these mutations (gly51-to-ala, val104-to-ile, gly106-to-arg, arg135-to-gly, cys140-to-ser, gly188-to-glu, val209-to-met, and his211-to-arg) produce amino acid substitutions, one (gln64-to-ter) introduces a stop codon, and one changes a guanosine in the intron 4 consensus splice donor sequence to thymidine. Cosegregation of RP with gln64-to-ter, gly106-to-arg, arg135-to-gly, cys140-to-ser, gly188-to-glu, his211-to-arg, and the splice site guanosine-to-thymidine indicates that these mutations are likely to cause retinal disease. Val104-to-ile does not cosegregate and is therefore unlikely to be related to retinal disease. The relevance of gly51-to-ala and val209-to-met remains to be determined. The finding of gln64-to-ter in a family with autosomal dominant RP is in contrast to a recent report of a recessive disease phenotype associated with the rhodopsin mutation glu249-to-ter. In the present screen, all of the mutations that cosegregate with retinal disease were found among patients with RP. The mutations described here bring to 35 the total number of amino acid substitutions identified thus far in rhodopsin that are associated with RP. The distribution of the substitutions along the polypeptide chain is significantly nonrandom: 63% of the substitutions involve those 19% of amino acids that are identical among vertebrate visual pigments sequenced to date.

Alleles↗
PubMed1992

Ciliary body adenoma in a 10-year-old girl who had a rhabdomyosarcoma.

A retrolenticular fibrovascular membrane occurred in the setting of a ciliary body mass in a 10-year-old black girl who had been successfully treated for a rhabdomyosarcoma of the lung. The results of a transscleral biopsy of the mass demonstrated it to be a pigmented adenoma of the ciliary body. A lensectomy and membranectomy were performed to aid in the follow-up and rehabilitation of the eye. At 9 months after surgery, the patient had 20/25 vision with no evidence of tumor growth. This case demonstrates an unusual cause of cyclitic membrane formation and suggests that transscleral biopsy may be a useful adjunct in the management of selected ciliary body masses.

Adenoma↗
PubMed1991

Aminoglycoside toxicity--a survey of retinal specialists. Implications for ocular use.

Surveyed members of the Retina, Macula, and Vitreous Societies reported 93 cases of macular infarction they believed to be related to administration of gentamicin sulfate; five, to administration of amikacin sulfate; and three, to administration of tobramycin sulfate. Most cases of infarction after administration of gentamicin occurred in eyes that received an intravitreous injection of 0.4 mg after vitrectomy, but a surprisingly high number, 17, occurred after injection of 0.1 or 0.2 mg, doses that are considered safe by many ophthalmologists. Four additional cases of infarction occurred in eyes that did not undergo vitrectomy after injection of 0.1 or 0.2 mg. Four of the five cases related to administration of amikacin occurred after intravitreous injection of 0.4 mg, and one of these four occurred in an eye that did not undergo vitrectomy. Twenty-three cases of macular infarction occurred in eyes that were treated with prophylactic subconjunctival injections of aminoglycosides after routine ocular surgery. Responses from this survey suggest that aminoglycoside-induced retinal infarction is widely recognized and more common than indicated from the small number of cases reported in the literature. The role of aminoglycosides in the prophylaxis of ocular infections and the management of endophthalmitis should be reevaluated.

Amikacin↗
PubMed1991

Retinoic acid promotes density-dependent growth arrest in human retinal pigment epithelial cells.

After retinal detachment the retinal pigment epithelium (RPE) undergoes a striking phenotypic change. It becomes dedifferentiated, proliferates to form multilayered colonies, and migrates into the subretinal space. These processes are important because they have been implicated in proliferative vitreoretinopathy and poor visual recovery after retinal reattachment; however the mechanisms by which they occur are unknown. In this study, the effect of retinoic acid on RPE cell morphology and growth in culture was examined. Cells grown in the presence of 1 microM retinoic acid do not exhibit cellular overgrowth and maintain characteristics associated with the morphologic appearance of mature RPE cells in vivo. Growth curves and 3H-thymidine incorporation suggest that retinoic acid inhibits RPE cell growth primarily after the cells have reached confluence. It may act by promoting density-dependent growth arrest. Dibutryl cyclic adenosine monophosphate also inhibits RPE cell growth and 3H-thymidine incorporation, but has little effect on cell morphology. However, in combination with retinoic acid it appears to have an additive effect on inhibition of cell growth and maintenance of a morphology like RPE in vivo. Retinoids have been demonstrated to modulate the growth and differentiation of several cell types. They are usually present in high levels in RPE cells. They become depleted in RPE in culture and such depletion may also occur in vivo after retinal detachment. This could play a role in the phenotypic alteration of RPE that occurs in association with retinal detachment.

Bucladesine↗
PubMed1990

Spontaneous involution of subfoveal neovascularization.

We studied five patients who maintained or spontaneously regained significant central vision despite the presence of a subfoveal neovascular membrane. Sequential photographs and fluorescein angiograms showed a pattern of development common to these patients and not observed in patients who lose all central vision. The pattern involves formation of a pigmented ring around the subfoveal neovascular membrane followed by alteration of the membrane from one that leaks fluorescein to one that stains but does not leak. This pattern is associated with gradual resorption of subretinal fluid and apparent limitation of subretinal hemorrhage and fibrosis. This course suggests the occurrence of spontaneous involution of some subfoveal neovascular membranes and implicates the retinal pigment epithelium in this process.

Adult↗
PubMed1990

Ultrastructural and electron-immunocytochemical characterization of cells in epiretinal membranes.

Electron-immunocytochemical staining for three intermediate filament (IF) proteins, keratin (K), glial fibrillary acidic protein (GFAP), and vimentin (V), and for the macrophage marker, EBM/11 (E), was performed on epiretinal membranes obtained during vitrectomies performed for proliferative vitreoretinopathy (PVR), postdetachment macular puckers (PDMPs), idiopathic macular puckers (IMPs), or macular puckers associated with other disease processes. The ultrastructural and immunocytochemical characteristics of the cells were compared. Unstained cells outnumbered stained cells for each of the markers in almost all membranes. Six cell types, based on ultrastructure, were found in the majority of epiretinal membranes: 1) polarized cells with microvilli on the free border and foot processes anchoring them to extracellular matrix that consistently stained negative for all of the immunocytochemical markers; 2) spindle-shaped fibroblastlike cells that were generally negative for all markers, but rarely positive for V; 3) large undifferentiated cells with large, lightly stained nuclei and little cytoplasm that frequently expressed one of the intermediate filament (IF) proteins; 4) poorly differentiated cells that contained numerous mitochondria and frequently expressed one of the IF proteins; 5) undifferentiated, pigment-laden cells that rarely stained for any of the above IF proteins, but occasionally showed K or V positivity in a portion of the cell, suggesting that they may be losing or acquiring these proteins, and that rarely expressed GFAP; and 6) small, round, mononuclear cells with short processes that were sometimes, but not always, positive for E and that were consistently negative for K, V, and GFAP. In addition to these morphologic types, transitional cells demonstrating features of two or more of the above cell types were seen, suggesting that phenotypic changes between the various cell types can occur. The amount of extracellular matrix in epiretinal membranes showed a correlation with disease process (PVR greater than PDMP greater than IMP), and a negative correlation with the percentage of cells expressing a highly differentiated polarized morphology and with the percentage of cells staining for IF proteins. These data suggest that both cell morphology and IF protein expression may be dependent in part on microenvironment and that neither alone can be used to identify unequivocally the derivation of particular cells found in epiretinal membranes. The integration of ultrastructural and immunocytochemical data may provide a more accurate determination of the cell of origin and of phenotypic changes that have occurred. In some cases, however, both ultrastructural and IF protein composition taken together are insufficient for the precise identification of all cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Gentamicin toxicity in the primate retina.

To study the toxic effect of aminoglycoside antibiotics in the primate retina, gentamicin sulfate was injected into the center of the vitreous cavity of Cebus navrigatus monkeys. At a dose of 1000 to 3000 microgram, a picture consistent with apparent macular infarction appeared on fundus examination and fluorescein angiography by three days and gradually faded by 21 days. While light and electron microscopic examination of the retina showed no primary vascular lesions, striking damage to the inner retinal layers, mainly the nerve fiber layer, ganglion cell layer, and the inner plexiform and nuclear layer, was seen. Less severe effects in the outer retinal layers and the retinal pigment epithelium occurred. These observations suggest that the neurotoxic effect of intravitreal gentamicin was sufficient to cause a complete shutdown of the regional blood flow, perhaps by the mechanism of granulocytic plugging of the capillary bed. Although this toxic effect occurred at doses considerably in excess of what has been recommended for clinical use in humans, the "safe" dose of intravitreal gentamicin, nevertheless, remains to be established unequivocally.

Animals↗
PubMed1989

Subretinal fluid stimulation of retinal pigment epithelial cell migration and proliferation is dependent on certain features of the detachment or its treatment.

Subretinal fluid was collected without contamination by blood by placing capillary tubes within drainage sclerotomies when retinal reattachment surgery was performed. All samples (N = 24) stimulated retinal pigment epithelial (RPE) cell migration and proliferation, but a wide range of activity existed (migration, 27.5% to 322.5% above baseline; proliferation, 7.5% to 318.3% above baseline). The correlation between migration- and proliferation-stimulating activity was not strong, suggesting the possibility that different agents are responsible for each. Several variables were examined for correlation with each activity, including age and sex of the patient; extent, duration, and height of the detachment; protein content of the fluid; and amount of cryopexy. It was found that proliferation-stimulating activity increased with the extent of detachment and duration of detachment, while migration-stimulating activity correlated best with amount of cryopexy given before drainage. These data suggest that retinal cryopexy enhances RPE cell migration activity in subretinal fluid, while RPE proliferation activity increases with the size and duration of detachment.

Adult↗
PubMed1989

Clinical risk factors for proliferative vitreoretinopathy.

We reviewed the records of all patients with rhegmatogenous retinal detachments examined and treated by a single surgeon (B.P.C.) at the University of Virginia, Charlottesville, between 1978 and 1984. Of the 607 eyes that satisfied the selection criteria, a preliminary chart review of outcomes found that 65 (10.7%) had proliferative vitreoretinopathy and 34 had macular puckers. From the remaining 508 eyes, 325 controls were randomly selected to match each case from within a time window. Thirty-six (55.4%) of the 65 patients with proliferative vitreoretinopathy had had unequivocal reattachment after a single procedure before the onset of proliferative vitreoretinopathy, and the only clearly identified technical difficulty that was significantly more common in the patients with proliferative vitreoretinopathy was the inability to identify a retinal break. Several other features of the rhegmatogenous retinal detachments that correlated with the development of postoperative proliferative vitreoretinopathy were identified, and stepwise discriminant analysis was used to ascertain which of these were more important. The strongest predictor was use of vitrectomy in management of the detachment. Following this in order of importance were the presence of preoperative proliferative vitreoretinopathy, preoperative choroidal detachment, and the amount of cryopexy required. Vitrectomy remained a strong predictor even when considered after adjustment for all other characteristics. These data suggest that proliferative vitreoretinopathy is not simply an iatrogenic disease, but it is more likely to occur in association with certain detachment features that either by themselves or through their management require prolongation of the retinal wound healing process.

Cryosurgery↗
PubMed1989

Tumoral calcinosis: seasonal biochemical studies and chemical studies of eyelid lesion.

We recently described (Arch Ophthalmol 1988; 106:725-6) the presence of unique calcific lesions in the eyelids of a young woman with a history of hyperphosphatemic tumoral calcinosis. Here we document that no immediate family members showed similar lesions and that none was hyperphosphatemic. Dental roentgenography revealed characteristic abnormalities in the patient that confirmed the clinical diagnosis of tumoral calcinosis. Seasonal biochemical studies demonstrated persistently increased concentrations of phosphorus and 1,25-dihydroxyvitamin D in her serum. A calcific eyelid excrescence removed from the patient, studied by x-ray diffraction, was found to consist of crystals of hydroxyapatite. Microprobe analysis indicated the major elements in the deposit to be Ca, P, S, and Cl, just as in the periarticular deposits found in tumoral calcinosis. The Ca concentration in the patient's tear fluid, measured by atomic absorption spectrometry, was within the range found in tears of healthy volunteers. Phosphorus was undetectable (less than 30 mumol/L) in tears of the patient and the volunteers. These findings suggest that the eyelid lesions represent a new manifestation of the pathological process that produces the characteristic periarticular calcific masses of tumoral calcinosis.

Adolescent↗