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Biomedical subjects

C L Brown

Publications and source records attributed to C L Brown.

At least 37 records · Page 2Linked to original sources
PubMed1998

Tyrosine phosphorylation and proteolysis. Pervanadate-induced, metalloprotease-dependent cleavage of the ErbB-4 receptor and amphiregulin.

Enhancement of tyrosine phosphorylation in cells by the application of pervanadate, an extremely potent phosphotyrosine phosphatase inhibitor, provokes the rapid metalloprotease-dependent cleavage of ErbB-4, a transmembrane receptor tyrosine kinase. The pervanadate-induced proteolysis occurs in NIH 3T3 cells expressing transfected human ErbB-4 and in several cell lines that express endogenous ErbB-4. One product of this proteolytic event is a membrane-anchored molecule of approximately 80 kDa, which is heavily tyrosine phosphorylated and which possesses tyrosine kinase catalytic activity toward an exogenous substrate in vitro. This response to pervanadate is not dependent on protein kinase C activation, which has previously been demonstrated to also activate ErbB-4 cleavage. Hence, the pervanadate and 12-O-tetradecanoylphorbol-13-acetate-induced proteolytic cleavage of ErbB-4 seem to proceed by different mechanisms, although both require metalloprotease activity. Moreover, pervanadate activation of ErbB-4 cleavage, but not that of 12-O-tetradecanoylphorbol-13-acetate , is blocked by the oxygen radical scavenger pyrrolidine dithiocarbomate. A second phosphotyrosine phosphatase inhibitor, phenylarsine oxide, also stimulates a similar cleavage of ErbB-4 but, unlike pervanadate, is not sensitive to pyrrolidine dithiocarbomate. Last, pervanadate is shown to stimulate the proteolytic cell surface processing of a second and unrelated transmembrane molecule: the precursor for amphiregulin, an epidermal growth factor-related molecule. Amphiregulin cleavage by pervanadate occurred in the absence of a cytoplasmic domain and tyrosine phosphorylation of this substrate.

Amphiregulin↗
PubMed1998

Cell surface ectodomain cleavage of human amphiregulin precursor is sensitive to a metalloprotease inhibitor. Release of a predominant N-glycosylated 43-kDa soluble form.

Biosynthesis and processing of amphiregulin (AR) have been investigated in human colorectal (HCA-7, Caco-2) and mammary (MCF-7) cancer cell lines, as well as in Madin-Darby canine kidney cells stably expressing various human AR precursor (pro-AR) forms. Both cells expressing endogenous and transfected AR produce multiple cellular and soluble forms of AR with an N-glycosylated 50-kDa pro-AR form being predominant. Our results demonstrate that sequential proteolytic cleavage within the ectodomain of the 50-kDa pro-AR form leads to release of a predominant N-glycosylated 43-kDa soluble AR, as well as the appearance of other cellular and soluble AR forms. Cell surface biotinylation studies using a C-terminal epitope-tagged pro-AR indicate that all cell surface forms are membrane-anchored and support that AR is released by ectodomain cleavage of pro-AR at the plasma membrane. We also show that pro-AR ectodomain cleavage is a regulated process, which can be stimulated by phorbol 12-myristate 13-acetate and inhibited by the metalloprotease inhibitor, batimastat. In addition, we provide evidence that high molecular mass AR forms may retain the full-length N-terminal pro-region, which may influence the biological activities of these forms.

Amino Acid Sequence↗
PubMed1998

Microsurgical technique in thyroid surgery--a 10-year experience.

OBJECTIVE: To report the results of thyroid surgery in a University department of ENT--head and neck surgery, and to evaluate the benefits of the use of the surgical microscope in thyroid surgery. DESIGN: A retrospective evaluation of the records of all patients who underwent thyroid surgery in the 10-year period 1987-1996. METHODS: In addition to standard surgical principles the Zeiss multi-discipline universal surgical microscope with a 250 mm ocular lens was used in all cases. Total thyroidectomy was performed in all malignant cases, while unilateral lobectomy plus isthmus resection was the standard procedure in benign cases. PATIENTS: There were 573 patients, aged 11-87 years, 444 females and 129 males. Four hundred and fifty-one had benign lesions, 122 malignant. Four hundred and eighty-nine had primary surgery, 84 underwent completion surgery or surgery for recurrent disease. RESULTS: Primary thyroid gland surgery in benign/malignant disease resulted in permanent recurrent laryngeal nerve palsy in 0.6 per cent/3.5 per cent of the patients respectively, when calculated as nerves at risk (NAR). In benign recurrent or malignant completion surgery this complication rate was 4.5 per cent/2.9 per cent respectively. CONCLUSION: Thyroid surgery in our University ENT--Head and Neck Department with the use of the surgical microscope provides pleasing results, especially considering the diversity of surgeons, due to the departments' teaching responsibilities.

Adolescent↗
PubMed1997

The role of whole-pelvic irradiation in the treatment of early-stage uterine carcinosarcoma.

Thirty-eight patients with Stage I and II uterine carcinosarcoma were treated by surgery with and without whole-pelvic irradiation (WPI) at our institution from 1975 to 1993. Ten patients (8 Stage I and 2 Stage II) were treated with surgery alone, while 28 patients (20 Stage I and 8 Stage II) received WPI in addition to surgery. With a median follow-up of 75 months (range 25-220 months), a trend toward a decreased rate of pelvic recurrence in those receiving WPI (6/28, 21%) compared to those treated with surgery alone (5/10, 50%) was observed (P = 0.09). There was no difference in the rate of distant recurrence between those receiving WPI (12/28, 43%) and those who did not (4/10, 40%) (P = 0.9). There was also no difference in the 2- and 5-year Kaplan-Meier survival estimates for the patients receiving WPI (79 and 59%, respectively) compared to those who did not receive WPI (60 and 60%, respectively) (P = 0.84). In this small series, the addition of whole-pelvic irradiation to primary surgery did not improve survival; however, a trend toward improved pelvic control was observed, suggesting a possible benefit for pelvic irradiation that should be studied in future trials.

Aged↗
PubMed1997

An unique tumour of the geniohyoid muscle: an intramuscular haemangioma.

We present the first case report in the English literature of an intramuscular haemangioma of the geniohyoid muscle. This occurred in a 24-year-old female and the diagnosis was not made prior to resection. Haemangiomas are uncommon tumours of the head and neck and intramuscular haemangiomas account for fewer than one per cent of the total. Diagnosis of the vascular nature of the tumour is often missed. Recurrence is common and usually due to incomplete excision. A review of the literature and a case report of these locally destructive lesions is presented.

Adult↗
PubMed1997

Angiotensin II type 1 receptor expression in human breast tissues.

We demonstrate the expression of angiotensin II type 1 (AT1) receptors in normal and diseased human breast tissues. Using monoclonal antibody 6313/G2, directed against a specific sequence in the extracellular domain of the AT1 receptor, immunocytochemical analysis revealed positive immunoreactivity in membrane and cytoplasm of specific cell types. Immunoblotting of solubilized proteins separated by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) from benign and malignant tumours identified a single immunoreactive species with a molecular mass of approximately 60 kDa, consistent with that of the mature glycosylated receptor. In studies of [125I]angiotensin II binding using breast membrane preparations, concentrations of specific angiotensin II binding sites were found to range from 1.8 to 100 fmol mg(-1) protein, with a K(d) of approximately 60 nM. Most of the specifically bound [125I]angiotensin II was displaced by losartan, a specific angiotensin II type 1 receptor antagonist, while less was displaced by the AT2 receptor type antagonist, CGP42112A, thus confirming the prevalence of AT1 receptors in this tissue type. These data suggest that the renin-angiotensin system may be involved in normal and abnormal breast tissue function.

Angiotensin II↗
PubMed1997

Genetic control of platelet activation in inbred mouse strains.

Platelet activation in inbred mouse strains was studied using expression of P-selectin as a marker of activated platelets. P-selectin expression in response to no added stimulus (spontaneous activation) or in response to adenosine diphosphate (ADP) and epinephrine or thrombin, was assessed using a flow cytometric assay. Wide variation in the responsiveness of different strains was observed with strains SJL and AKR in particular showing very high levels of spontaneous activation. Genetic studies suggest that this phenomenon is under control of a small number of genes and that the same loci are probably responsible for the high activation of both SJL and AKR. Bone marrow transplant experiments show that the trait is expressed in the platelet itself. Screening of SWXJ and AKXD recombinant inbred lines suggests that one of the responsible genes is located on chromosome 3.

Journal Article↗
PubMed1997

Introduction to PCR/OLA/SCS, a multiplex DNA test, and its application to cystic fibrosis.

The field of medical, molecular diagnostics has grown rapidly over the last few years, becoming increasingly informative to both clinician and patient. As genes associated with specific diseases have been discovered and sequenced, many genotype-phenotype relationships have been defined. For those genetic diseases with associated, defined, gene mutations, sophisticated DNA diagnostic tests are being developed. As an example, the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, is associated with Cystic Fibrosis (CF). We have developed a new molecular diagnostic technology, PCR/OLA/SCS, and applied it first to the diagnosis of CF. Test design in the field of molecular diagnostics must consider such characteristics as specificity, sensitivity, ease and speed of protocol, multiplex capacity, and cost. PCR/OLA/SCS addresses these requirements. Polymerase Chain Reaction (PCR) is widely used in both diagnostics and research. We have combined well established PCR technology with Oligonucleotide Ligation Assay (OLA) and Sequence-Coded Separation (SCS), two relatively new technologies.

Alleles↗
PubMed1997

Angiolymphoid hyperplasia with eosinophilia in the colon: a novel cause of rectal bleeding.

Angiolymphoid hyperplasia with eosinophilia (epithelioid haemangioma) is an uncommon but distinctive lesion seen principally in the skin. A case of severe gastrointestinal haemorrhage in a 63 year old male is reported, which necessitated a right hemicolectomy. A lobulated nodule was seen macroscopically that had the histological appearance of angiolymphoid hyperplasia with eosinophilia, with sheets of lymphocytes and eosinophils associated with many vessels showing plump and pleomorphic endothelial cells. This is the first reported case of this entity in the large intestine.

Angiolymphoid Hyperplasia with Eosinophilia↗
PubMed1996

Laparotomy to complete staging of presumed early ovarian cancer.

OBJECTIVE: To assess the findings and complications of laparotomies for completely staging presumed early-stage ovarian cancer in patients who initial surgery was inadequate. METHODS: Records of 45 patients surgically restaged at our institution, after having been incompletely staged elsewhere, were reviewed for original operative reports, pathologic diagnoses, restaging procedures, operative results, and perioperative complications. RESULTS: Initial clinical staging was IA, 28; IB, three; IC, 12; IIA, one; IIB, one. Histologic distribution was as follows: invasive epithelial, 19 (42%); borderline epithelial, 16 (36%); germ cell tumor, seven (16%) had their disease reclassified to a more advanced stage. Of patients with borderline ovarian tumors, two, initially staged as IA, were restaged to IB and IC, and one was restaged from IIB to IIIA. Three patients with invasive epithelial adenocarcinoma were reclassified to a higher stage: one, with a presumed stage IC, poorly differentiated adenocarcinoma, to IIIB; one, with a stage IC, grade 2 mucinous cystadenocarcinoma, to IIIA; and a third, with a IIA, poorly differentiated adenocarcinoma, to IIIC. A patient with granulosa cell tumor, initially stages as IC, was restaged to IIB. Fifteen patients (33%) had complications after restaging surgery. Seven (16%) patients undergoing restaging laparotomy for presumed early ovarian cancer were reclassified to a higher stage, resulting in alteration of treatment for only on patient. In 18 patients with invasive cancer, the second operation confirmed the presence of low-risk stage IA/B disease, allowing adjuvant chemotherapy to be withheld. CONCLUSION: Although restaging laparotomies provide important prognostic information with minimal morbidity, they provide little benefit to those patients already requiring chemotherapy based on the original operative findings.

Adult↗
PubMed1996

Faint and positive amniotic fluid acetylcholinesterase with a normal sonogram.

OBJECTIVE: Both faint and positive amniotic fluid acetylcholinesterase determinations have been associated with fetal abnormalities. We evaluated the effect of a normal sonogram and positive or faint acetylcholinesterase level on the risk for anomalies. STUDY DESIGN: Between Jan. 1, 1989, and Feb. 1, 1995, 4859 amniocenteses were performed. Twenty-three cases of abnormal acetylcholinesterase determinations combined with normal sonograms were identified, and pregnancy outcomes were determined. RESULTS: One abnormal karyotype was identified (45,X/47,XXX mosaic). No neural tube defects were seen in infants with an abnormal acetylcholinesterase determination and normal sonogram. One fetus of a twin pregnancy had a ventral wall defect that was not detected on ultrasonography. Seventy-three percent of infants were normal at birth, but 27% of the pregnancies had abnormal outcomes. CONCLUSIONS: Advances in ultrasonography have led to improved detection of fetal abnormalities. With a normal karyotype, repeat invasive testing may not be necessary.

Acetylcholinesterase↗
PubMed1996

Screening patterns for cervical cancer: how best to reach the unscreened population.

Although the mortality rate for cervical cancer in the United States has declined steadily since the introduction of the Pap smear for screening in 1945, recent statistics show a rising incidence, with the number of new cases expected in 1996 representing a record high since the mid-1980s. Part of the rising incidence may be because of increasing numbers of women in the United States who did not receive screening or having inadequate screening with the Pap smear. This paper will examine the recent patterns of cervical cancer screening in the United States, with particular attention to defining which populations are not being screened. Barriers to screening in these populations will be defined and grouped into four categories: lack of knowledge, economic, cultural, and belief system; and logistical. Successful approaches that have been used to overcome these barriers in screening programs targeted at the "hard to reach" population will be described.

Adolescent↗
PubMed1995

Bleeding injuries in professional football: estimating the risk for HIV transmission.

OBJECTIVE: To determine the risk for bleeding injuries in professional football and to estimate the risk for transmission of the human immunodeficiency virus (HIV) through such injuries. DESIGN: A prospective, observational study. PARTICIPANTS: Professional football players from 11 teams of the National Football League were observed during 155 regular season games from September through December 1992. MEASUREMENTS: The frequencies of bleeding injuries were calculated in association with environmental and athletic factors. Using this information, HIV prevalence, and data on transmission of HIV in other circumstances, the risk for transmission of HIV during football games was estimated. RESULTS: 575 bleeding injuries (average, 3.7 per game for each team) involving 538 players (average, 3.5 players on each team per game) were observed. Approximately 88% of the bleeding injuries were abrasions; the remainder were lacerations. Bleeding injuries were markedly more frequent during games played on artificial surfaces, during games played in domed stadiums, and on teams with a final win/loss percentage of 0.500 or lower. Using data on the prevalence of HIV among college men and rates of HIV transmission in the health care setting, the risk for HIV transmission to each player was estimated to be less than 1 per 85 million game contacts. CONCLUSIONS: Although injuries occur in professional football competitions, bleeding injuries, especially lacerations, occur infrequently. We estimate that the risk for HIV transmission during such competition is extremely remote. The role of artificial playing surfaces on the incidence or severity of bleeding injuries should be investigated.

Chi-Square Distribution↗
PubMed1995

The role of alpha 1-antitrypsin in the control of extracellular surfactant metabolism.

Alveolar surfactant exists in several structural forms that are believed to be secular products of the secreted form, lamellar bodies. The conversion of tubular myelin to the small vesicular form appears to require the action of a novel serine protease, surfactant convertase. As the in vitro activity of this enzyme is quite sensitive to inhibition by the serine protease inhibitor alpha 1-antitrypsin, a normal constituent of the alveolar fluid lining layer, we explored the possibility that the alveolar level of alpha 1-antitrypsin might affect the rate of subtype conversion in vivo. When the alveolar alpha 1-antitrypsin level was augmented by tracheal instillation of exogenous alpha 1-antitrypsin, the newly synthesized surfactant phospholipids of spontaneously breathing mice accumulated in the heavy subtype, and virtually none was found in the light subtype form up to 72 h later. An in vivo turnover study suggested that when the alveolar alpha 1-antitrypsin level was raised by the same means, the flux of surfactant through the light (small vesicular) compartment was virtually shut off, despite the availability of abundant amounts of its precursor, heavy subtype (tubular myelin). Finally, mouse lungs that were lavaged to remove resident surfactant and mechanically ventilated for 1-5 h released surfactant that progressed through heavy and light subtype compartments as in vivo. But in mice whose lung alpha 1-antitrypsin might affect the metabolism of alveolar surfactant in addition to its well-known role in lung defense.

Animals↗
PubMed1995

Preoperative identification of perforating vessels to the skin by color duplex imaging.

Recent improvements in high-frequency linear array transducers with color duplex imaging permit the precise identification and estimation of the caliber of minute perforating vessels to the skin as small as 0.5 mm. An obvious corollary role would be the accurate preoperative delineation of the vascular anatomy of a skin flap, which could be essential to ensure its viability. This technology was then applied to map the blood supply to skin flaps in eight patients, which was subsequently verified at the time of their actual surgical dissection. Because anomalies of the skin circulation are not uncommon, this extended capability for color duplex imaging can facilitate a more optimal design of skin flaps to better ensure their chance for survival by the inclusion of appropriate nutritive blood vessels.

Blood Vessels↗
PubMed1995

Surfactant apoprotein A modifies the inhibitory effect of plasma proteins on surfactant activity in vivo.

Surfactant apoprotein A (SP-A) reduces the inhibitory effects of plasma proteins on the surface tension lowering properties of pulmonary surfactant in vitro. To test the effects of SP-A in vivo we administered a complete natural dog lung surfactant (DLS) containing apoproteins SP-A, SP-B, and SP-C, a butanol extract of DLS (DLSE) containing only apoproteins SP-B and SP-C, and DLSE supplemented with SP-A intratracheally to prematurely delivered rabbit pups in the presence of increasing amounts of human plasma. In the absence of plasma DLS and DLSE (100 mg/kg phospholipid) had comparable effects on lung mechanics (compliance during ventilation with a tidal volume of 6-7 mL/kg and quasi-static pressure-volume behavior) in this surfactant deficiency model. Plasma proteins in increasing amounts to a maximum protein concentration of 62.5 mg/mL had no effect on the response of the pups to DLS. In contrast, plasma added to DLSE in concentrations above 20 mg/mL significantly increased the peak inspiratory pressure (PIP) required to ventilate the pups with a tidal volume of 6-7 mL/kg, reduced the calculated total lung compliance, and decreased the deflation lung volumes. The inhibitory effects of plasma on DLSE were significantly less when SP-A was added to DLSE (5:1, phospholipid:SP-A, wt:wt). The addition of SP-A to DLSE in plasma restored the activity of the extract to levels comparable to complete DLS. These results suggest that plasma can interfere with surfactant function and that SP-A has a significant protective effect for surfactant against the inhibitory effects of plasma in vivo.

Animals↗