Biomedical subjects

R E Carroll

Publications and source records attributed to R E Carroll.

At least 19 recordsLinked to original sources

PubMed2004

Colon preparation for magnification endoscopy: a rapid novel approach.

BACKGROUND AND STUDY AIMS: Minute lesions in the colon are of increasing clinical interest. Conventional endoscopic techniques are inadequate for visualizing these lesions, and magnification chromoendoscopy is required to identify them. This study compared the effectiveness of a simpler colon preparation method with the standard technique. Patients and Methods : Seven patients received dilute methylene blue (0.05 %) by enema prior to the endoscopic evaluation. The extent, quality, and ease of dye delivery were compared with the standard methods. RESULTS: Dye delivery by enema extended to the splenic flexure and was uniformly applied, and advancement of the endoscope was easier. This alternative method was better tolerated by patients (visual analogue scale 1.9 +/- 0.3 vs. 3.8 +/- 0.8; P = 0.004). CONCLUSION: This rapid and reliable method of visualizing the entire left colon with dye magnification allows magnification chromoendoscopy to be carried out in a convenient manner that is also less painful for the patient.

Colon↗

PubMed2001

The case for gastrin-releasing peptide acting as a morphogen when it and its receptor are aberrantly expressed in cancer.

Gastrin-releasing peptide (GRP) and its receptor (GRP-R) are frequently expressed by cancers of the gastrointestinal tract, breast, lung, and prostate. Most studies have found that GRP and its amphibian homologue bombesin act to increase tumor cell proliferation, leading to the hypothesis that this peptide hormone is a mitogen important for the growth of various cancers. Yet GRP/GRP-R co-expression in cancer promotes the development of a well-differentiated phenotype; while multiple studies suggest that the presence of these 2 proteins confer a survival advantage. Along with recent reports showing that GRP and its receptor critically regulate aspects of colon and lung organogenesis, we argue that these proteins do not function primarily as mitogens when aberrantly expressed in cancer. Rather, we postulate that GRP/GRP-R are onco-fetal antigens that function as morphogens, with their effect on tumor cell proliferation being a component property of their ability to regulate differentiation. Thus aberrant GRP/GRP-R expression in cancer recapitulates, albeit in a dysfunctional manner, their normal role in development.

Amino Acid Sequence↗

PubMed2000

Characterization of gastrin-releasing peptide and its receptor aberrantly expressed by human colon cancer cell lines.

Gastrin-releasing peptide (GRP) is a mitogen and morphogen important in the development of human colon cancers. Although epithelial cells lining the colon do not normally express GRP or its receptor (GRP-R), most human tumors express GRP-R mRNA. Yet functional protein has only been detected in 24 to 40% of colon cancers. To elucidate the reason for the difference between the expression of GRP/GRP-R mRNA and protein, we studied nine human colon cancer cell lines. Quantitative polymerase chain reaction revealed that all colon cancer cell lines expressed similar amounts of mRNA for both GRP as well as GRP-R. Yet binding studies using (125)I-Tyr(4)-bombesin detected functional receptors on only five of the nine cell lines studied. Conformational fragment-length polymorphism analysis indicated that although mRNA for the ligand GRP was never mutated, mRNA for the GRP-R was always mutated. Sequencing revealed that the message for GRP-R contained between two and seven separate mutations at the nucleotide level. This resulted in 14 separate coding mutations, 2 of which were observed in more than one cell line. Each mutation was individually recreated by site-directed mutagenesis and studied in transiently transfected Chinese hamster ovary-K1 cells. Alteration of Pro(145) into a tyrosine, of Val(317) into a glutamic acid, and insertion of a 32-nucleotide segment resulting in a frameshift distal to Asp(137) all resulted in GRP receptors incapable of binding ligand. Thus, these data indicate that human colon cancers commonly express GRP and GRP-R mRNA but that receptor mutations account for the failure of functional protein to be generated.

Amino Acid Sequence↗

PubMed2000

Infant feeding.

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Bottle Feeding↗

PubMed2000

Gastrin-releasing peptide is a mitogen and a morphogen in murine colon cancer.

Little is known about the factors involved in regulating the appearance, or differentiation, of solid tumors including those arising from the colon. We herein demonstrate that the mitogen gastrin-releasing peptide (GRP) is a morphogen, critically important in regulating the differentiation of murine colon cancer. Although epithelial cells lining the mouse colon do not normally express GRP and its receptor (GRP-R), both are aberrantly expressed by all better differentiated cancers in wild-type C57BL/6J mice treated with the carcinogen azoxymethane. Whereas small tumors in both wild-type and GRP-R-deficient (i.e., GRP-R-/-) mice are histologically similar, larger tumors become better differentiated in the former but degenerate into more poorly differentiated mucinous adenocarcinomas in the latter. This alteration in phenotype is attributable to GRP increasing focal adhesion kinase expression in GRP-R-expressing tumors. Consistent with GRP acting as a mitogen, GRP/GRP-R coexpressing tumors in wild-type animals also contain more proliferating cells than those occurring in GRP-R-/- mice. Yet tumors are similarly sized in animals of either genotype receiving azoxymethane for identical times, a finding attributable to the significantly higher number of apoptotic cells detected in GRP/GRP-R coexpressing cancers. Thus, these findings indicate that although GRP is a mitogen, aberrant expression does not result in increased tumor growth. Rather, the mitogenic properties of GRP are subordinate to it acting as a morphogen, where it and its receptor are critically involved in regulating colon cancer histological progression by promoting a well-differentiated phenotype.

Adenocarcinoma↗

PubMed1999

Characterization of gastrin-releasing peptide receptors aberrantly expressed by non-antral gastric adenocarcinomas.

Epithelial cells lining the GI tract except in the gastric antrum do not normally express gastrin-releasing peptide receptors (GRP-R). Because GRP-R activation causes the proliferation of many GI cancer cell lines, aberrant expression has been presumed to negatively influence patient survival. We therefore determined the incidence and quality of GRP-R aberrantly expressed by non-antral gastric adenocarcinomas, and evaluated the impact of receptor expression on patient survival. We studied RNA isolated from 20 consecutive non-antral gastric adenocarcinomas, and determined that 8 (40%) aberrantly expressed GRP-R. Of these, 6 (75%) were found to be mutated. Pharmacologically, the effect of these mutations ranged from rendering the GRP-R non-functional to constitutively active. Contrary to expectations, however, survival of patients whose tumor expressed functional GRP-R (18.5 +/- 9.8 months) was not statistically different from those that did not (8.3 +/- 1.8 months; p = 0.24). Thus our data indicate that mutated isoforms of GRP-R are commonly expressed by non-antral gastric adenocarcinomas. However, expression of functional GRP-R does not alter patient survival, suggesting that this receptor may not be clinically important to the growth of gastric cancers.

Adenocarcinoma↗

PubMed1999

Aberrant expression of gastrin-releasing peptide and its receptor by well-differentiated colon cancers in humans.

Epithelial cells lining the adult human colon do not normally express gastrin-releasing peptide (GRP) or its receptor (GRPR). In contrast, approximately one-third of human colon cancers and cancer cell lines have been shown to express GRP-binding sites. Because GRPR activation causes the proliferation of many cancer cell lines, GRP has been presumed to act as a clinically significant growth factor. Yet GRP has not been shown to be expressed by colon cancers in humans nor has the effect of GRP and/or GRPR coexpression on tumor behavior been investigated. We therefore determined GRP and GRPR expression by immunohistochemistry in 50 randomly selected colon cancers resected between 1980 and 1997, all 37 associated lymph node and liver metastases, and 20 polyps. Tumor sections studied were those that contained the margin and adjacent nonmalignant epithelium. Overall, 84% of cancers aberrantly expressed GRP or GRPR, with 62% expressing both ligand and receptor, whereas expression was not observed in adjacent normal epithelium. Consistent with the previously established mitogenic capabilities of GRP, tissues coexpressing GRP and GRPR were more likely to express proliferating cell nuclear antigen than tissues not expressing both ligand and receptor. Yet GRP/GRPR coexpression was seen with equal frequency in stage A as in stage D cancers and was only detected in 1 in 37 metastases. Furthermore, Kaplan-Meier analysis did not reveal any difference in patient survival between those whose tumors did or did not express GRP/GRPR. In contrast, GRP/GRPR coexpression was found in all well-differentiated tumor regions, whereas poorly differentiated tissues never coexpressed GRP/GRPR. Overall, these data indicate that, although GRP is a mitogen, it is not a clinically significant growth factor in human colon cancers. Rather, the strong association of GRP/GRPR coexpression with tumor differentiation raises the possibility that these proteins primarily act in vivo as morphogens.

Adult↗

PubMed1999

Azoxymethane-induced fulminant hepatic failure in C57BL/6J mice: characterization of a new animal model.

Without transplantation, approximately 50-90% of all patients with fulminant hepatic failure (FHF) die. This poor outcome is due in part to the absence of an appropriate animal model, which would allow for a greater understanding of the pathophysiology of this syndrome. Given the reports of liver injury in humans and livestock fed cycad palm nuts on the island of Guam, we hypothesized that the active ingredient azoxymethane (AOM) could cause FHF. We therefore evaluated AOM in C57BL/6J mice. Histologically, we observed microvesicular steatosis 2 h, sinusoidal dilatation 4 h, and centrilobular necrosis 20 h after AOM administration, and transmission electron microscopy showed that this agent causes mitochondrial injury. FHF was associated with all four stages of encephalopathy, as well as by a prodromal period of decreased eating and drinking lasting approximately 15 h before the development of stage I encephalopathy (i.e., loss of scatter reflex). Late encephalopathy was associated with increased arterial ammonia, decreased serum glucose, and evidence of brain edema (astrocyte swelling). We show that AOM-induced FHF is highly reproducible, without evidence of lot-to-lot variability, and is dose dependent. These findings therefore suggest that AOM is an excellent agent for the study of FHF, as well as indicate that Guamanian FHF may be due to AOM found in unwashed cycad palm nuts.

Animals↗

PubMed1998

Formula supplementation with long-chain polyunsaturated fatty acids: are there developmental benefits?

OBJECTIVE: To evaluate the developmental outcomes of children who participated in an augmented randomized clinical trial of supplementing a standard infant formula with long-chain polyunsaturated fatty acids. DESIGN: Randomized clinical trial, augmented with a nonrandomized human milk comparison group. There were three randomized formula groups: standard formula, standard formula containing docosahexaenoic acid (DHA), and standard formula containing DHA and arachidonic acid. SETTING: Three clinical sites serving diverse populations: Kansas City, MO; Portland, OR; and Seattle, WA. PARTICIPANTS: A total of 274 healthy full-term infants were enrolled in the infant-feeding protocol; of these, 197 (72%) participated in assessments of developmental outcome. Formula Supplements. In the randomized trial, one group received a standard formula, another group received a formula that had been supplemented with DHA from fish oil, and a third group received a formula supplemented with both DHA and arachidonic acid from an egg phospholipid. OUTCOME MEASURES: Mental and Motor Scales of the Bayley Scales of Infant Development at 12 months of age; vocabulary and gesture communication scores from the MacArthur Communicative Development Inventories at 14 months of age. RESULTS: There were no statistically significant differences for either the Bayley Mental Scale or the Bayley Motor Scale, neither when the analysis was restricted to the three randomized formula groups nor when the analysis included all four groups. However, the DHA formula group had significantly lower scores on two of the MacArthur scales: the DHA group scored lower than the nonrandomized human milk comparison group on the Vocabulary Comprehension Scale, and the DHA group scored lower than the randomized control formula group on the Vocabulary Production Scale. Moreover, additional analyses both in the formula groups and in the human milk comparison group found significant negative correlations between DHA levels and vocabulary outcomes. CONCLUSION: We believe that additional research should be undertaken before the introduction of these supplements into standard infant formulas.

Arachidonic Acid↗

PubMed1997

Constitutive activation of the gastrin-releasing peptide receptor expressed by the nonmalignant human colon epithelial cell line NCM460.

Gastrin-releasing peptide (GRP) causes multiple effects in humans by activating a specific heptaspanning receptor. Within the gastrointestinal tract, GRP receptors (GRP-R) are not normally expressed by mucosal epithelial cells except for those lining the gastric antrum. In contrast, recent studies have shown that up to 40% of resected colon cancers aberrantly express this receptor. This is important because the GRP-R can cause the proliferation of many, but not all, tissues in which it is expressed. Since GRP and other agonists are not known to exist in the colonic lumen, it has not been clear how or even if GRP-R expression in colon cancer contributes to cell proliferation. To evaluate the functional consequence of GRP-R expression on colonic epithelium, we transfected the recently isolated nonmalignant human colon epithelial cell line NCM460 with the cDNA for this receptor. All NCM460 cell lines expressing varying numbers of GRP-R bound selected agonists and antagonists indistinguishably from receptors expressed by other human tissues. Furthermore GRP-R-expressing transfected cell lines, but not wild-type NCM460 cells, proliferated independently of serum or other growth factors. Further evaluation revealed that GRP-R in these cells tonically stimulated G alpha q/11, resulting in increased phospholipase C activation. Since transfected cells do not secrete GRP, nor is their growth influenced by exposure to receptor-specific antagonists, these data indicate that GRP-R ectopically expressed by NCM460 cells are constitutively active. This report provides the first evidence of mutation-independent heptaspanning receptor constitutive activation resulting in cell proliferation, and identifies a potential mechanism whereby the GRP-R may act as an oncogene in human colon cancer.

Bombesin↗

PubMed1997

Location and characterization of the human GRP receptor expressed by gastrointestinal epithelial cells.

The exact location of normal gastrin-releasing peptide (GRP) receptor expression by epithelial cells lining the human gastrointestinal (GI) tract is not known; yet this receptor is found on upwards of 50% of GI cancers. Furthermore, the pharmacology reported for GRP receptors expressed by GI cancers varies considerably. Therefore, the purpose of this study was to determine the normal distribution of GRP receptor expression by cells lining the human GI tract, and then determine the normal pharmacology of the human receptor when ectopically expressed by the nonmalignant human colon epithelial cell line NCM460. We obtained endoscopic pinch biopsies of, and extracted the RNA from, epithelial cells lining the esophagus, stomach, jejunum, ileum, and proximal and descending colon, RT-PCR demonstrated that GRP-R expression is limited to cells lining the gastric antrum, indicating that this receptor is aberrantly expressed by GI cancers. To determine the normal pharmacology of this receptor when expressed by nonmalignant human tissues for the first time, we transfected NCM460 cells with the cDNA for the human GRP receptor. By studying three stable NCM460 cell lines expressing varying numbers of receptors, we demonstrate that agonist and antagonist binding affinity, binding kinetics, and G-protein coupling are all independent of receptor number. Finally, by comparing GRP receptors expressed by GI cancers with those on NCM460-transfected cells, we show that the pharmacology of the aberrantly expressed receptors is significantly altered. Thus, these data demonstrate that GI cancers aberrantly express GRP receptors that then behave abnormally.

Binding Sites↗

PubMed1997

Long-term review of fascial replacement after excision of the carpal lunate bone.

Excision of the carpal lunate bone in Kienbock's avascular necrosis gives relief of pain. To maintain grip strength, increase range of motion, and prevent carpal collapse or shifting, this space has been filled with various materials. Forty-three patients received fascial interposition replacement, and the experience and results of 10 patients observed for 10 years or more (range, 10-34) are presented. Pain was relieved. Range of motion was increased. Carpal collapse did not occur. All patients use their hand in an unrestricted, stressful activity. The result of an operation during an extended period is documented.

Adult↗

PubMed1994

Wrist arthrodesis: a combined intramedullary pin and autogenous iliac crest bone graft technique.

Forty-six wrist arthrodeses in 36 patients were reviewed. The technique used provided a reliable fusion method for a variety of wrist disorders. The arthrodeses were performed using an autogenous iliac crest bone graft, with an intramedullary Steinman pin placed within the distal radial and third metacarpal shafts, and an obliquely-placed Kirschner wire across the second metacarpal base into the radius. The distal ulna, instead of the radius, was used in patients with radial agenesis. Three patient populations were identified: group 1, connective tissue wrist disorders; group 2, congenital wrist disorders; and group 3, acquired wrist disorders. A residual flexion, radial deviation deformity was noted with the congenital disorders. All patients had low demand requirements for this fused wrists. The average time of fusion for each group as 14, 15, and 12 weeks, respectively.

Adult↗

PubMed1993

Fracture of the hook of the hamate: acute treatment.

From a review of the literature and in the authors' practice, fractures of the hook of the hamate (hamulus) are rare and commonly not identified in the acute phase. When fractures are found initially, plaster immobilization has resulted in healing in 46% of cases. However, excision has given a good result when selected in 42% of acutely treated fractures. The method of treatment chosen depends on the lifestyle requirements of the patient.

Adult↗

PubMed1993

Fracture of the hook of the hamate: radiographic visualization.

The diagnosis of fracture of the hook of the hamate is rarely made at the time of the initial injury. Routine roentgenograms of the hand in the standard three positions do not visualize this structure. The carpal tunnel view (CTV) with hyperextension of the wrist may be too painful to position. A computerized tomography of the wrist in the transverse or axial plane will clearly and painlessly identify the fracture. Placing both hands and wrists in the praying position gives excellent comparison and documents any developmental bone abnormality. Scintigraphy, when positive, must be followed by tomography or a carpal tunnel view.

Adult↗

PubMed1992

Subungual exostosis in the hand.

Although it is thought to be a relatively common tumour, only 34 positively identified cases of subungual exostosis in the hand have been found in the literature to date. 16 further cases are reported, making this the largest published series. Seven cases presented with an incorrect diagnosis. An X-ray easily differentiates the tumour from an osteochondroma of the distal phalanx, a spike of bone from a crush injury, or a response to a penetrating injury called a turret exostosis. Removal of the deformed nail and excision of the mass from the distal phalanx produces a useful finger without pain, tender scar, or resultant nail deformity. No case of malignancy has ever been reported.

Exostoses↗

PubMed1989

Surgical catgut: the myth of allergy.

During the period 1950 to 1985, 137 patients stated to the author that they were allergic to catgut sutures. The allegations were based on a previous episode at various sites on the body where wound healing had been complicated. A review of the problem did not indicate any history of symptoms of allergy. The author used catgut in the completion of his surgery on each of these patients. None of them showed any allergic manifestation and all healed perfectly per primum. Recent molecular studies of the collagen proteins demonstrate that it is highly improbable for the material to cause antigenicity.

Adult↗

PubMed1989

Diagnosis and treatment of injury to the second and third carpometacarpal joints.

We describe the diagnosis, treatment, and follow-up of a group of 13 patients with hand pain traced to pathologic conditions of the second or third carpometacarpal joints. Missed diagnosis was universal. With suspicion raised by history of injury or repeated stress and point tenderness on examination, diagnosis was confirmed by complete pain relief after injection of 1% lidocaine locally. In management of patients with occult pain in the hand, attention should be directed to the second or third carpometacarpal joints. Arthrodesis with use of an inverted triangular graft from the base of the metacarpal provides predictable and lasting relief.

Adolescent↗