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W J O'Connor

Publications and source records attributed to W J O'Connor.

At least 19 recordsLinked to original sources
PubMed2001

Mechanisms of nuclear import and export that control the subcellular localization of class II transactivator.

The presence of the class II transactivator (CIITA) activates the transcription of all MHC class II genes. Previously, we reported that deletion of a carboxyl-terminal nuclear localization signal (NLS) results in the cytoplasmic localization of CIITA and one form of the type II bare lymphocyte syndrome. However, further sequential carboxyl-terminal deletions of CIITA resulted in mutant forms of the protein that localized predominantly to the nucleus, suggesting the presence of one or more additional NLS in the remaining sequence. We identified a 10-aa motif at residues 405-414 of CIITA that contains strong residue similarity to the classical SV40 NLS. Deletion of this region results in cytoplasmic localization of CIITA and loss of transactivation activity, both of which can be rescued by replacement with the SV40 NLS. Fusion of this sequence to a heterologous protein results in its nuclear translocation, confirming the identification of a NLS. In addition to nuclear localization sequences, CIITA is also controlled by nuclear export. Leptomycin B, an inhibitor of export, blocked the nuclear to cytoplasmic translocation of CIITA; however, leptomycin did not alter the localization of the NLS mutant, indicating that this region mediates only the rate of import and does not affect CIITA export. Several candidate nuclear export sequences were also found in CIITA and one affected the export of a heterologous protein. In summary, we have demonstrated that CIITA localization is balanced between the cytoplasm and nucleus due to the presence of NLS and nuclear export signal sequences in the CIITA protein.

Active Transport, Cell Nucleus↗
PubMed2001

Bisphosphonate therapy in fibrous dysplasia.

Fibrous dysplasia is proliferation of fibrous tissue within the bone marrow causing osteolytic lesions and pathologic fractures. Recently, second generation bisphosphonates have shown promise in the treatment of patients with fibrous dysplasia. In the current study, six patients with fibrous dysplasia were treated with either oral alone or oral and intravenous bisphosphonates. The participants were observed for changes in N-telopeptide, pain score, and radiographic changes. In the current study, the combination bisphosphonate therapy diminished pain, prevented fractures, lowered N-telopeptide values, and led to partial resolution of fibrous dysplasia lesions.

Administration, Oral↗
PubMed2000

The use of growth factors in cartilage repair.

Articular cartilage, which enables smooth gliding of joints during skeletal motion, is vulnerable to injuries and degenerative diseases over time. Bone growth factors have a role in the preservation of the cartilage matrix. This article reviews the potential to treat cartilage damage for bone morphogenetic proteins, insulin-like growth factors, hepatocyte growth factor, basic fibroblast growth factor, and transforming growth factor beta.

Animals↗
PubMed1998

Porphyria cutanea tarda and HIV: two cases associated with hepatitis C.

Hepatitis C virus (HCV) is a probable etiologic factor for the development of porphyria cutanea tarda (PCT), a photosensitive skin disease causing blistering, skin fragility, milia, and scarring. In a review of the literature, the hepatitis C status of patients coinfected with HIV and PCT was not known. Two patients with PCT who were seropositive for HIV and HCV are discussed herein. The appropriateness of performing porphyrin studies in patients diagnosed with HIV and photosensitivity and of prompting physicians to test for HIV and HCV infection in individuals who are diagnosed with PCT is discussed. Because HIV has been isolated from cutaneous blister fluid in patients with PCT and HIV, caregivers should be aware of the infection risk associated with the vesicles and erosions in these patients.

Adult↗
PubMed1998

Porphyria cutanea tarda and human immunodeficiency virus: two cases associated with hepatitis C.

Hepatitis C virus (HCV) was recently recognized as a probable etiologic factor for porphyria cutanea tarda (PCT). A review of the literature revealed 40 cases of PCT associated with the human immunodeficiency virus (HIV). In most of these cases, hepatitis C status was unknown. We describe two patients with PCT who were coinfected with HIV and HCV and discuss the interaction of these two viruses. A diagnosis of PCT, especially in a young patient, should prompt investigation for underlying HIV and HCV infection. Porphyrin studies should be performed in any patient with HIV and photosensitivity. Clinicians should be aware of the infectious risk associated with the vesicles and erosions in these patients.

Adult↗
PubMed1997

Cell-surface perturbations of the epidermal growth factor and vascular endothelial growth factor receptors by phosphorothioate oligodeoxynucleotides.

Antisense oligodeoxynucleotides offer potential as therapeutic agents to inhibit gene expression. Recent evidence indicates that oligodeoxynucleotides designed to target specific nucleic acid sequences can interact nonspecifically with proteins. This report describes the interactive capabilities of phosphorothioate oligodeoxynucleotides of defined sequence and length with two essential protein tyrosine receptors, flk-1 and epidermal growth factor receptor (EGFR), and their effects on receptor signaling in a transfected and tumor cell line, respectively. Phosphorothioate oligodeoxynucleotides bound to the cell surface, as demonstrated by fluorescence-activated cell-sorter analyses (FACS), and perturbed receptor activation in the presence and absence of cognate ligands, EGF (EGFR) and vascular endothelial growth factor (flk-1), in phosphorylation assays. Certain phosphorothioate oligodeoxynucleotides interacted relatively selectively with flk-1 and partially blocked the binding of specific anti-receptor monoclonal antibodies to target sites. They stimulated EGFR phosphorylation in the absence of EGF but antagonized ligand-mediated activation of EGFR and flk-1. In vivo studies showed that a nonspecific phosphorothioate oligodeoxynucleotide suppressed the growth of glioblastoma in a mouse model of tumorigenesis. These results emphasize the capacity of phosphorothioate oligodeoxynucleotides to interact with cells in a sequence-selective nonantisense manner, while associating with cellular membrane proteins in ways that can inhibit cellular metabolic activities.

3T3 Cells↗
PubMed1997

Developmental enamel defects in tuberous sclerosis: a clinical genetic marker?

Ten probands with tuberous sclerosis (TS) and 20 first degree relatives were examined for evidence of pitted enamel hypoplasia; 100% of TS patients had pitting, compared to 65% of relatives and 72% of 25 controls. We found that 70% of TS cases had more than 14 pits per person compared with only 5% of relatives and 4% of controls; 85% of relatives and 84% of controls had fewer than six pits per person. Our results confirm that significantly increased numbers of dental enamel pits are found in persons with TS compared to controls. These results suggest that examination for the presence or absence of dental enamel pits is not a useful screening test for first degree relatives to detect otherwise unsuspected subjects with tuberous sclerosis. However, the lack of pits in first degree relatives in our study is probably largely because none of the relatives appeared to carry the TS gene.

Dental Enamel↗
PubMed1997

Merkel cell carcinoma. Comparison of Mohs micrographic surgery and wide excision in eighty-six patients.

BACKGROUND: Merkel cell carcinoma is an uncommon malignant tumor of the skin that, after standard surgical excision, tends to recur locally and develop regional nodal spread. OBJECTIVE: This study evaluated the use of Mohs micrographic surgery for this aggressive neoplasm. METHODS: A retrospective study of 86 patients with Merkel cell carcinoma established rates of local persistence and the development of regional metastasis after standard surgical excision. Detailed follow-up was available on a subgroup of 13 patients treated with Mohs surgery. RESULTS: Standard surgical excision for local disease was associated with high rates of local persistence (13 of 41 [31.7%]) and regional metastasis (20 of 41 [48.8%]). Mean follow-up was 60 months. Mean follow-up for the group treated with Mohs was 36 months. Only one of 12 (8.3%) Mohs-treated patients with histologically confirmed clearance has had local persistence of disease. This patient underwent a second Mohs excision and has remained disease free for 84 months. Regional metastasis developed in four of 12 cases (33.3%). Regional metastasis developed in none of the four patients treated with radiotherapy after Mohs surgery and in four of eight patients treated with Mohs surgery without postoperative radiotherapy. CONCLUSION: Mohs surgery compares favorably with standard surgical excision. Radiotherapy after Mohs surgery may further reduce persistent metastases in transit and nodal disease.

Adult↗
PubMed1996

Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma is an aggressive tumor with nonspecific clinical features. The prognosis in general is worse than malignant melanoma. Local recurrence rates are high with one-third of patients having recurrence within one year of excision. The tumor invades blood vessels and lymphatics. This frequent lymphatic dissemination leads later to satellite lesions and recurrence. Distant metastases occur in one-third of patients. One-,two- and three-year survival rates are poor, being estimated at 88%, 72%, and 55%, respectively. OBJECTIVE: To increase awareness of the behavior of this uncommon tumor. METHODS: A review of the current literature and recommendations regarding this tumor. RESULTS: Wide local excision with 3-cm margin shows significant reduction in local recurrence compared with 2-cm margins. Two-thirds of patients with local recurrence ultimately die from their disease. Radiation therapy has a role to play in the local and regional clearance of the tumor. CONCLUSION: Prompt diagnosis and surgical excision are necessary to improve survival. Mohs micrographic surgery offers potential advantages in evaluating both the lateral and the deep margins. Follow-up studies of patients treated with this modality will be beneficial.

Carcinoma, Merkel Cell↗
PubMed1996

Porphyrin abnormalities in acquired immunodeficiency syndrome.

OBJECTIVE: To examine prospectively porphyrin metabolism in a human immunodeficiency virus (HIV)-positive population. SETTING: Specialist referral unit at the Department of Genitourinary Medicine, St James's Hospital, Dublin, Ireland. PATIENTS: Twenty-eight men and 5 women (age range, 18-35 years). Twenty-nine were current or previous intravenous drug abusers. Four were thought to have sexually acquired HIV infection. All had a history of acquired immunodeficiency syndrome-defining illnesses. The patients were selected as a consecutive sample from the inpatient department. Eligibility criteria were cooperation with urine and stool collection and confirmed HIV seropositivity. The patients were matched to 2 groups: 1 with normal results of porphyrin studies and the other with abnormal findings from porphyrin studies. INTERVENTION: None. MAIN OUTCOME MEASURES: Plasma, urine, and stool porphyrin excretion patterns. RESULTS: Of the 33 patients in the study, 13 (40%) had increased urinary porphyrin excretion. All but 2 of these patients were seropositive for hepatitis C virus. No study patient had clinical evidence of porphyria. Four patients (12%), however, had urine and stool porphyrin excretion patterns that were classic for porphyria cutanea tarda. All 4 of these patients were hepatitis C virus-positive. Patients with porphyrinuria had a greater degree of immunosuppression (P = .002) than those with normal porphyrin metabolism, and they were more likely to be taking zidovudine (P = .009). CONCLUSIONS: Commonly, porphyrin metabolism is abnormal in persons with established HIV infection. Hepatitis C may contribute to abnormal porphyrin metabolism. An unexpected number of patients studied had porphyrin excretion patterns that were characteristic of porphyria cutanea tarda, and all of these were hepatitis C virus-positive. A diagnosis of porphyria cutanea tarda, especially in a young patient, should prompt investigation for underlying HIV and hepatitis C virus infections. Dermatologists should be aware of the infectious risk associated with the vesicles and erosions in these patients. Porphyrin studies should be performed in any patient with HIV and photosensitivity.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Correlation between puberty and the development of autoimmunity to spermatozoa in men with cystic fibrosis.

OBJECTIVE: To test the hypothesis that puberty is a necessary factor in the pathogenesis of autoimmunity to sperm in men with cystic fibrosis (CF), we studied prepubertal and postpubertal males with CF versus an age-matched group of males with type 1 diabetes as controls. DESIGN: Sera from CF and diabetic males treated at University Hospital, State University of New York, Stony Brook, were tested by indirect immunobead binding for antisperm antibodies and by radioimmunoassay for testosterone (T), luteinizing hormone, and follicle-stimulating hormone. The finding of autoantibodies to spermatozoa was correlated with chronological age, as well as with clinical and hormonal pubertal status. RESULTS: Autoimmunity to sperm, as detected by humoral antisperm antibodies, was documented solely in postpubertal males, as judged by hormonal and clinical criteria. Eighty-three percent of sexually mature CF males and 6.3% (1 of 16) diabetic males exhibited autoantibodies to sperm. These antibodies were only detected when serum T levels were > 8.7 nmol/L (250 ng/dL). CONCLUSIONS: These results suggest that puberty, and presumably, active spermatogenesis is a requirement for the development of autoimmunity to sperm in men with CF.

Adolescent↗
PubMed1984

Increase in weight and water retention on overfeeding dogs.

Dogs, kept in metabolism cages, were weighed daily and the daily water intake, urine volume and evaporative loss of water measured or calculated. When the daily meal was doubled, the weight increased in two phases: during the first 4 d the increase in weight was more than could be accounted for by the deposition of protein, glycogen and fat so that water retention must have occurred; after the fourth day the increase in weight was slower and could have been due to the deposition of solids, without water retention. When carbohydrate was added to the meal either as starch or glucose, the increase in weight in the first 3 d was more than the weight of the added carbohydrate, showing water retention. After the third day the slower increase in weight could be explained by the deposition of solids. When the daily meal was supplemented with fat, increase in weight occurred uniformly throughout the period of overfeeding and was equal to or less than the added fat. There was thus no evidence for water retention. Addition of meat to the daily meal caused an increase in weight larger than the fat and protein of the extra meat. Meat therefore caused water retention. The results indicate that during overfeeding, deposition in the body of protein and glycogen, but not fat, determines water retention.

Animals↗
PubMed1984

Tubular reabsorption in normal renal function.

The purpose here is to examine in relation to normal renal function three factors which might affect tubular reabsorption: (1) The reabsorption of SO4, PO4, K, Cl, HCO3 and water are all linked to the reabsorption of Na. This would amount to the reabsorption by the tubules of a net reabsorbate of a composition similar to Locke's fluid. Fixed linkage of the reabsorption of a substance to the reabsorption of Na would be a very effective way of maintaining its plasma concentration within a narrow range. The substance would be retained unless its plasma concentration exceeds a threshold value and then small increase in plasma concentration determines its excretion. (2) The rate of reabsorption of Na and substances linked to it is increased when the volume of the intraluminal fluid is increased. This would explain why there is only a small increase in the excretion of Na and other electrolytes when glomerular filtration rate is increased after a meal of meat. (3) Plasma protein concentration affects tubular reabsorption. This would explain why fall in plasma protein is a main agent determining Na excretion in normal animals. Trying to see 'how far the observed facts can be brought into accord with a theory' reveals the difficulty of applying critical tests. On the one hand, the theories are not stated quantitatively in reference to the small changes of normal life; rather the evidence is from experiments with large changes. On the other hand, the small changes within the range of normal function, while themselves statistically significant, are too small for effective investigation of circumstances which may modify them. In the examples discussed here, we cannot say more than that the theories could explain the facts and their participation cannot be excluded.

Amino Acids↗
PubMed1979

Sodium excretion in normal conscious dogs.

Bitches maintained on a low Na intake, were given doses of saline (0.125 mol.litre(-1) NaCl, 0.025 mol.litre(-1) NaHCO3, 0.004 mol.litre(-1) KCl) by stomach tube. Doses of 100 and 200 cm3 produced only minor increases in Na excretion; after 300 cm3, Na excretion rose from about 2 to about 60 micromol.min(-1). Plasma protein fell by 1.8 litre(-1) for each 100 cm3 of saline retained. Within normal ranges of Na excretion there is a threshold of plasma protein concentration above which Na is retained and below which Na is excreted. Changes in exogenous creatinine clearance were measured allowing calculation of the filtered load of Na, which shows that the absolute tubular reabsorption of Na and water is increased in volume expansion by isotonic saline. Meat produced large increase in glomerular filtration rate without much increase in Na excretion and mechanisms are discussed by which Na reabsorptin is more effective after meat than after doses of saline. Creatinine cleaerance increased by 0.67 cm3.min(-1) for each fall of 1 g.litre(-1) in plasma protein; this is predicted by a theory that the glomerular capillary blood pressure is 9.3 kPa (70 mmHg) rather than 6.7 kPa (50 mmHg).

Animals↗
PubMed1977

Drinking caused by exposing dogs to radiant heat.

1. Exposure to radiant heat caused dogs to pant and lose water by evaporation at rates of 40-70 g/hr. 2. When water was offered at intervals during the heating, the dogs drank at about half of the opportunities. The individual drinks were small but, by their repetition, loss of water by evaporation during heating was approximately matched by drinking. 3. Water given by stomach tube reduced drinking during a subsequent period of heating. 4. When water was offered more than 15 min after the end of a period of heating, after panting had ceased, drinking occurred only if the water loss exceeded 50-70 g, about 0-6% of the body water. This is regarded as drinking due to loss of water, beyond a threshold of dehydration necessary to stimulate drinking with the dog at rest. When water was offered during heating, drinking occurred with dehydration less than this threshold. 5. The drinking produced by heating was similar to that produced by running (O'Connor, 1975). When the animal ran under heat, panting was more severe and the water loss greater (85-150 g/hr); it was approximately matched by more drinking.

Animals↗