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Biomedical subjects

H Nelson

Publications and source records attributed to H Nelson.

At least 109 records · Page 6Linked to original sources
PubMed1995

Proposed phase III trial comparing laparoscopic-assisted colectomy versus open colectomy for colon cancer.

Despite many important medical advances, surgery remains the primary treatment modality for most of the 109,000 individuals who are newly diagnosed with colon cancer each year. Surgery not only provides extirpation of the primary tumor that relieves symptoms and prevents complications but also provides important staging information. Although oncologic results from open colectomy are well established, these traditional resective and staging techniques are challenged by the introduction of minimal-access surgery. Laparoscopic cholecystectomy, which shortens postoperative recovery and decreases disabilities and cost, has become the preferred surgical approach to cholelithiasis. Many propose that minimal-access surgery of the colon may offer similar advantages. Laparoscopic-assisted segmental resections of the colon can be performed using laparoscopic techniques to ligate vasculature and mobilize and exteriorize bowel and extracorporal techniques to resect and anastomose bowel. Collective preliminary data from a consortium of experienced laparoscopic surgeons support that laparoscopic-assisted colectomy is safe, feasible, and reduces recovery times and disabilities. Since differences between laparoscopic-assisted and open colectomy have not been rigorously tested, and concern has been raised regarding the adequacy of this technique for staging and treating colon cancer, a prospective randomized multi-institutional trial is proposed. The primary aim of such a trial will be to test the hypothesis that disease-free survival and overall survival are equivalent, regardless of whether patients receive laparoscopic-assisted or open colectomy. The secondary aim of the trial will be to determine the safety of of laparoscopic-assisted colectomy compared with open colectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Trials, Phase III as Topic↗
PubMed1995

Antibody to ras proteins in patients with colon cancer.

The current study examined sera from 160 colon cancer patients and 60 normal individuals to determine whether antibody to mutated p21 ras protein was present. Studies focused on the aspartic acid substitution at amino acid position 12 (denoted D12), one of the most common mutations in colon adenocarcinoma. IgA antibodies directed against mutated p21 ras-D12 protein were detected in 51 (32%) of 160 colon cancer patients, but only in 1 (2.5%) of 40 normal individuals. The greater incidence of antibody in cancer patients provides presumptive evidence that immunization to the ras proteins occurred as a result of the malignancy. Examination of sera for antibody reactivity to wild-type p21 ras protein (denoted p21 ras-G12) as well as p21 ras proteins bearing the D12, V12, S12, or L61 mutations showed that antibody detected was largely to normal segments of the p21 ras protein. Epitope mapping, using peptide neutralization assays with mutated or normal ras peptides as competitors, demonstrated that in 10 (67%) of 15 sera examined the antibody reactivity to p21 ras-G12 protein was neutralized by peptides near the carboxyl terminus of p21 ras protein, but not by peptides spanning the specific point mutation region. Antibody reactivities correlated with peripheral blood lymphocyte count, but did not correlate with patient age, sex, histology, stage, tumor locus, lymph node metastasis, or serum carcinoembryonic antigen.

Antibodies, Neoplasm↗
PubMed1994

Microvascular expression of MALA-2 correlates with in vivo lymphocyte trafficking and is preferentially enhanced in tumors by tumor necrosis factor-alpha and interleukin-1 alpha.

The role of endothelial cell adhesion molecule expression in the immune response to tumors is unknown. We have investigated the expression of murine lymphocyte activation antigen (MALA-2), the murine equivalent of intercellular adhesion molecule-1 (ICAM-1), in blood vessels of normal murine tissues and in melanoma tumors and evaluated the relationship between MALA-2 expression and lymphocyte trafficking in vivo. C3H/HeN mice were injected both i.p. and s.c. with a clone of K-1735 syngeneic melanoma cells. Day 11 tumor-bearing mice were killed and vascular expression of MALA-2 was quantified using immunohistochemistry. MALA-2 expression was high in lung, liver and spleen and low in lymph node, small bowel, muscle and tumor. Systemic administration of either recombinant tumor necrosis factor alpha (rTNF alpha) or recombinant interleukin-1 alpha (rIL-1 alpha) over 2 days prior to organ harvest resulted in an increase in the number of tumor vessels expressing MALA-2, with no change in MALA-2 expression in other tissues. In vivo lymphocyte trafficking was evaluated using cultured, activated splenocytes radiolabeled with 111In. 111In-labeled splenocyte distribution correlated closely with MALA-2 expression, with high localization to spleen, liver and lung and poor localization to lymph node, small bowel, muscle and tumor. Systemic administration of rTNF alpha, but not rIL-1 alpha, resulted in a significant increase in 111In-labeled splenocyte distribution to tumor, but neither rTNF alpha nor IL-1 alpha altered 111In-labeled splenocyte distribution to normal organs. Our data demonstrate the in vivo pattern of vascular MALA-2 expression in normal murine tissues and tumors and suggest that the expression of MALA-2 can be preferentially enhanced in tumors by systemic administration of cytokines. Lymphocyte distribution in vivo correlates closely with the pattern of MALA-2 expression, and these data support the conclusion that MALA-2 plays an important role in the regulation of lymphocyte trafficking.

Animals↗
PubMed1994

A novel accessory subunit for vacuolar H(+)-ATPase from chromaffin granules.

Three subunits, Ac115, Ac39, and the proteolipid, were positively identified in the membrane sectors of V-ATPases from different sources. We searched for organelle-specific protein in purified preparations of V-ATPase from bovine chromaffin granules. A diffused protein band at a position of about 45 kDa was identified in SDS-polyacrylamide gels of the above preparation. Following digestion with endopeptidase Glu-C (V-8), a polypeptide of about 10 kDa was isolated and subjected to amino acid sequencing. Hence, the cDNA encoding the protein Ac45 was cloned from a bovine adrenal medulla library. The cDNA sequence contains an open reading frame encoding a protein of 468 amino acids with a calculated molecular mass of 51,786 daltons. A potential signal sequence comprised of the first 35 amino acids and a potential transmembrane domain at the C terminus of the protein were identified. There exist seven potential glycosylation sites between the aforementioned protein motifs. Experiments with a specific antibody against Ac45 demonstrated that it is copurifying with the V-ATPase from chromaffin granules. Immunological cross-reactivity was observed with purified V-ATPase from bovine kidney microsomes but not from plasma membranes of epithelial cells. Cell-free expression of the protein from synthetic mRNA produced a single protein band at about 50 kDa on SDS gels. Upon inclusion of dog pancreas microsomes in the reaction mixture, a slow migrating band sensitive to peptide:N-glycosidase F was observed.

Adrenal Medulla↗
PubMed1994

The Saccharomyces cerevisiae VMA7 gene encodes a 14-kDa subunit of the vacuolar H(+)-ATPase catalytic sector.

Yeast vacuoles contain an H(+)-ATPase that acidifies the vacuolar lumen and generates an electrochemical gradient of protons across their membranes. Five polypeptides, denoted as subunits A to E in the order of decreasing molecular masses from 69 to 27 kDa, were identified in the catalytic sector of the enzyme. However, other polypeptides may be necessary for the activity of the enzyme. When a 14-kDa polypeptide was suggested to be a subunit of a specialized V-ATPase in Manduca sexta, and a homologous short sequence was detected downstream of the UGA1 gene in yeast, we cloned this counterpart gene from yeast. The gene VMA7 encodes a protein Vma7p of about 14 kDa. The predicted protein is highly homologous to the above mentioned M. sexta protein. The delta vma7::URA3 null mutant exhibits growth characteristics typical of other VMA disruptant mutants in genes encoding subunits of the catalytic sector. The delta vma7::URA3 null mutants are not able to grow on a medium buffered at pH 7.5, they fail to accumulate quinacrine into their vacuoles and the other subunits of the catalytic sector are not assembled onto the vacuolar membrane in its absence. Epitope-tagged Vma7p was constructed and the proton uptake activity of isolated vacuoles from this yeast strain was markedly inhibited by a monoclonal antibody against the epitope-tag. A cold inactivation experiment demonstrated that Vma7p is a genuine subunit of the catalytic sector of V-ATPase and it is denoted as subunit F.

Amino Acid Sequence↗
PubMed1994

Functional analysis of conserved cysteine residues in the catalytic subunit of the yeast vacuolar H(+)-ATPase.

The A subunit of the yeast vacuolar ATPase contains three highly conserved cysteines: Cys-261, Cys-284, and Cys-538. Cys-261 is located within the nucleotide-binding P-loop. Each of the conserved cysteines, and one nonconserved cysteine, Cys-254, were altered to serine by site-directed mutagenesis, and the effects on growth at pH 7.5 were determined. The Cys-254-->Ser, Cys-261-->Ser and the double mutants all grew at pH 7.5 and contained nitrate- and bafilomycin-sensitive ATPase activity. However, the ATPase activities of the Cys-261-->Ser and the double mutants were insensitive to the sulfhydryl group inhibitor, N-ethylmaleimide, demonstrating that Cys-261 is the site of inhibition by N-ethylmaleimide. Changing either Cys-284 or Cys-538 to serine prevented growth at pH 7.5. Cys-284 and Cys-538 thus appear to be essential cysteine residues which are required either for assembly or catalysis.

Base Sequence↗
PubMed1994

Antitumor x anti-CD3 bifunctional antibodies redirect T-cells activated in vivo with staphylococcal enterotoxin B to neutralize pulmonary metastases.

T-cell antitumor activities are limited by the requirement of two specific major histocompatibility complex restricted steps, T-helper cell activation and cytotoxic T-lymphocyte targeting. The aim of this study was to investigate whether bypassing these major histocompatibility complex restricted steps using nonspecific in vivo activation of T-cells with staphylococcal enterotoxin-B (SE-B) and retargeting with antitumor x anti-CD3 bifunctional antibody (BFA) could provide an effective antitumor response. C3H/HeN mice were injected i.v. with CL-62 melanoma cells, which express the human melanoma antigen p97, and were treated 10 min later with SE-B and/or anti-CD3 (500A2) x anti-p97 (96.5) BFA. Pulmonary metastases were counted 14 days following injections. SE-B alone induced a dose-dependent activation of T-cells as measured by increased interleukin-2 receptor expression and enhanced proliferative responses. SE-B doses greater than 10 micrograms significantly reduced the number of pulmonary metastases versus control (P < 0.01). Combined treatment with SE-B (50 micrograms) and BFA (5 to 50 micrograms) significantly decreased pulmonary metastases compared to treatment with SE-B alone (P < 0.05). Similar reductions in metastases were observed with the F(ab')2 BFA but not with the unconjugated antitumor component of the BFA. Combined treatments with SE-B plus BFA accomplished better tumor neutralization than adoptively transferred in vitro activated splenocytes (4 x 10(7)) retargeted with BFA (5-100 micrograms; P < 0.05). These studies demonstrate that T-cells can be activated in vivo by SE-B and retargeted with small doses of BFA. In this immunocompetent syngeneic pulmonary metastasis model, SE-B plus BFA provided a dramatic antitumor response.

Animals↗
PubMed1994

Cell adhesion molecule expression within the microvasculature of human colorectal malignancies.

In situ expression of intercellular adhesion molecule-1 (ICAM-1), endothelial leukocyte adhesion molecule-1 (ELAM-1), and vascular cell adhesion molecule-1 (VCAM-1) was investigated in 20 human colorectal cancers using immunohistochemical techniques. Tumor microvessels, detected with endothelial marker Ulex Europaeus Agglutinin-I (UEAI), were consistently present within both stromal and glandular areas. Vessels expressing cell adhesion molecules (CAMs) were less frequent but more common within the tumor stroma. Although ICAM-1 and ELAM-1 vessel staining was present in all tumors, ICAM-1 staining was the most consistent with primary localization to stroma while ELAM-1 was variable with localization to both stroma and glandular areas. VCAM-1 staining was inconsistent and was rare in glandular areas. A significant increase in the number of vessels expressing CAMs with a concomitant decrease in the total number of vessels was noted in bowel muscularis adjacent to tumor compared to remote bowel. No relationship between number of vessels or frequency of CAM positive vessels and tumor site, grade, or stage was noted. These studies demonstrate enhanced microvascular expression of CAMs in close proximity to colorectal tumors despite decreases in total number of vessels, suggesting that factors within the tumor microenvironment effect tumor microvascular development. Correlation between these studies and previous microscopic studies suggest that vessels expressing CAMs play a role in immune cell infiltration and may provide new targets for anti-tumor therapies.

Adenocarcinoma↗
PubMed1994

Strictureplasty for obstructive Crohn's disease: the Mayo experience.

BACKGROUND: Strictureplasty for obstructive Crohn's disease of the small bowel continues to gain favor throughout the world. Although the potential advantages of preserving intestinal length are obvious, the optimal clinical setting for performing strictureplasty remains to be determined. PATIENTS: Of 244 patients who underwent abdominal exploration for complications of Crohn's disease between Jan. 1, 1985, and Jan. 1, 1991, at the Mayo Clinic, 35 had a total of 71 strictureplasties. Concomitant resection of bowel with active disease was performed in 67% of the procedures. RESULTS: In this series, no perioperative deaths occurred, and no anastomotic leaks, enteric fistulas, or intra-abdominal abscesses were noted during a 3-year follow-up. The overall perioperative complication rate was 14%. Postoperatively, 33 of the 35 patients were able to resume enteral nutrition and discontinue medical treatments. The symptomatic recurrence rate at 3 years was 20%; six patients have required reoperation. CONCLUSION: These findings support the use of strictureplasty for isolated, quiescent, stenotic bowel lesions associated with Crohn's disease.

Adult↗
PubMed1994

Laparoscopic-assisted segmental colectomy: surgical techniques.

OBJECTIVE: To describe our surgical techniques for successful completion of laparoscopic-assisted segmental colectomy. DESIGN: We reviewed the important preoperative, operative, and postoperative factors that should be considered for laparoscopic resection of the right, left, and sigmoid colon. RESULTS: The current indications for laparoscopic-assisted colectomy include most benign colonic conditions (such as colorectal polyps, rectal prolapse, diverticular disease, and colonic lipomas). Laparoscopic procedures for malignant disease, however, are currently reserved for prospective trials and palliation of patients with stage IV colonic cancer because the adequacy of staging and lymphatic resection remains questionable. Patients who are appropriate candidates for laparoscopic-assisted colectomy should be counseled about the potential benefits, risks, and possible need for conversion to an open surgical procedure--a decision that should be considered application of sound surgical judgment rather than a failure. For laparoscopic-assisted colectomy, we prefer to use the closed technique for establishing a pneumoperitoneum. We use a two-surgeon, four-cannula approach for resections of the right and left colon and a three-surgeon, five-cannula technique for resections of the sigmoid colon. Laparoscopic techniques are used to mobilize the bowel and divide the principal blood supply; the resection and anastomosis are performed extracorporeally, with use of a small incision. CONCLUSION: The associated morbidity and mortality rates are comparable to those for conventional open procedures. Despite a shortened period of ileus and fewer hospital days, the total costs for laparoscopic colectomy have been equivalent to those for standard colectomy. This result has generally been due to longer operative times, which should decrease with additional experience.

Colectomy↗
PubMed1994

Laparoscopic-assisted segmental colectomy: early Mayo Clinic experience.

OBJECTIVE: To present a large initial series of patients who underwent laparoscopic-assisted segmental colectomy and to assess the feasibility and safety of this procedure. DESIGN: We summarized the clinical outcome data for 122 Mayo Clinic patients selected for laparoscopic-assisted resection of the right, left, or sigmoid colon between 1991 and 1993. MATERIAL AND METHODS: Preexisting factors (such as obesity and prior abdominal operations), indications for surgical treatment, and intraoperative and postoperative complications were analyzed statistically in two groups of patients--those in whom the laparoscopic procedure was completed and those in whom conversion to an open surgical technique was necessary. RESULTS: Laparoscopic-assisted colectomy was successfully completed for a variety of colonic pathologic conditions, including polyps, cancer, and diverticulitis. No operative deaths occurred in this series, and the overall complication rate was low (11%). Patients in whom laparoscopic-assisted colectomy was completed had a more rapid return of bowel function and a briefer hospital stay than did those who required conversion to the traditional open surgical technique. Neither obesity nor previous abdominal surgical procedures precluded successful laparoscopic-assisted colectomy, although the conversion rate to open colectomy was 75% in patients whose weight exceeded 90 kg. CONCLUSION: These findings indicate that laparoscopic-assisted segmental colectomy is safe and feasible, and the procedure may offer patient-related advantages. Oncologic concerns, including recent reports of trocar site recurrences, suggest a cautious approach to its application for resection of colonic cancer.

Adolescent↗
PubMed1994

Primary anetoderma: phagocytosis of elastic fibres by macrophages.

We report a 22-year-old female with a 2-year history of increasingly numerous well-circumscribed, asymptomatic skin lesions. The clinical and histological features were consistent with anetoderma and investigations failed to reveal any associated underlying disorders. Electron microscopy of abnormal skin showed phagocytosis of elastic fibres by macrophages. Although the aetiology of primary anetoderma remains unknown, this finding suggests that phagocytic destruction of elastic fibres plays a major role in its pathogenesis.

Adult↗
PubMed1994

Structure, function and brain localization of neurotransmitter transporters.

We studied four different cDNAs encoding GABA transporters and three different cDNAs encoding glycine transporters in mouse and rat brains. A genomic clone of two of the glycine transporters (GLYT1a and GLYT1b) revealed that they derive from differential splicing of a single gene. The third glycine transporter (GLYT2) is encoded by a separate gene. Antibodies were raised against seven of these neurotransmitter transporters and their cytochemical localization in the mouse brain was studied. In general, we observed a deviation from the classical separation of neuronal and glial transporters. It seems that each of the neurotransmitter transporters is present in specific places in the brain and is expressed in a different way in very specific areas. For example, the GABA transporter GAT4, which also transports beta-alanine, was localized to neurons. However, GAT1, which is specific for GABA, was localized not only to neurons but also to glial cells. The recently discovered glycine transporter GLYT2 was of particular interest because of its deviation from the general structure by a very extended N terminus containing multiple potential phosphorylation sites. Western analysis and immunocytochemistry in frozen sections of mouse brain demonstrated a clear caudal-rostral gradient of GLYT2 distribution, with massive accumulation in the spinal cord and brainstem and less in the cerebellum. Its distribution is typically neuronal and it is present in processes with varicosities. A correlation as observed between the pattern we obtained and that observed previously from strychnine binding studies. The results indicate that GLYT2 is involved in the termination of glycine neurotransmission at the classical inhibitory system in the hindbrain. The availability of four different GABA transporters made it possible to look for specific binding sites upon the neurotransmitter transporters. An extensive program of site-directed mutagenesis led us to identify a potential neurotransmitter binding site on the GABA transporters.

Amino Acid Sequence↗
PubMed1994

Controversies regarding laparoscopic colectomy for malignant diseases.

Surgical investigators have shown that a hemicolectomy can be done laparoscopically. This minimally invasive approach to treat colon cancer potentially reduces hospitalization time, hastens return to normal activity, and reduces health care costs. Hopefully, all of these favorable outcomes can be achieved without compromising cancer control. At present, however, the issues regarding laparoscopic colectomy are not clear, and prospective studies are necessary to validate that this new procedure is superior to open colectomy. Because cancer control might be compromised by this new procedure, laparoscopic colectomy should not be accepted by the surgical community because of the allure of new technology or the hope that it is equivalent to open colectomy in controlling a curable disease. Rather, a randomized trial of laparoscopic colectomy compared with open colectomy is needed to prove that cancer control is not different and that laparoscopic colectomy is cost-effective.

Colectomy↗
PubMed1993

Cloning and expression of a spinal cord- and brain-specific glycine transporter with novel structural features.

A novel glycine transporter (GLYT2) was cloned from a rat brain cDNA library. GLYT2 is about 48 and 50% homologous to the previously cloned mouse glycine transporter (GLYT1) and rat proline transporter (PROT), respectively. GLYT2 differs from GLYT1 in molecular structure, tissue specificity, and pharmacological properties. The cDNA of GLYT2 encodes for 799 amino acid residues with an extended amino-terminal peptide containing 200 amino acids before the first transmembrane domain. Potential phosphorylation sites for protein kinase C, cAMP-dependent kinase, and calmodulin-dependent kinase were identified in the amino-terminal region. GLYT2 mRNA was shown to be specifically localized in spinal cord, brain stem, and to a lesser extent in the cerebellum. In contrast, GLYT1 mRNA distribution in the brain has been found previously to be more ubiquitous. Xenopus oocytes injected with GLYT2 cRNA transport glycine with a Km of 17 microM, and the uptake of glycine is resistant to inhibition by sarcosine. The experimental data suggests GLYT2 might play a major role in the termination of the inhibitory effect of glycine in the brain stem and spinal cord of vertebrates. On the other hand, the main function of GLYT1 may be in the modulation of excitatory nerve terminals. Two types of GLYT1 cDNA, GLYT1a and GLYT1b, were cloned from the mouse brain library. They differ only at their amino-terminal sequences, and GLYT1b contains two additional potential phosphorylation sites for proline-dependent kinase. Cloning of the gene encoding the GLYT1 revealed that the two variants resulted from a differential splicing.

Amino Acid Sequence↗
PubMed1993

Interferon-gamma-induced intercellular adhesion molecule-1: expression on human tumor cells enhances bifunctional antibody-mediated lysis through a lymphocyte function-associated antigen-1 dependent mechanism.

Antitumor x anti-CD3 bifunctional antibodies (BFAs) affect tumor cell lysis by activating and physically linking T-cells and tumor cells. Since tumor target antigen expression does not correlate with susceptibility to BFA-mediated tumor cytotoxicity, we investigated the role of cell adhesion molecules as accessory molecules. In 3 human colon tumor cell lines (LS174T, WIDR, and COLO205), recombinant interferon-gamma (rIFN-gamma) consistently increased BFA-mediated tumor cell lysis by cultured peripheral blood lymphocytes and consistently increased tumor cell expression of intercellular adhesion molecule-1 (ICAM-1). Using cell conjugation assays, we demonstrated that ICAM-1 and lymphocyte function-associated antigen-1 (LFA-1) interactions were important for effector-to-target cell conjugate formation and demonstrated that tumor cell pretreatment with rIFN-gamma enhanced cell conjugate formation. Whereas anti-LFA-1 blocked all BFA-mediated tumor lysis and conjugate formation, anti-ICAM-1 blocked only the enhancing effects of rIFN-gamma for both cytolysis and conjugate formation. Although BFAs were shown to provide effector-to-target cell bridging, LFA-1 was found to be a common critical element required for BFA-mediated cell conjugation and lysis. ICAM-1, which was augmented by rIFN-gamma, appears to be only one of several ligands interacting with LFA-1. These results provide one explanation as to why high expression of tumor-associated antigen alone does not predict the susceptibility to BFA-mediated lysis and provides further support for the concept of combined modality immune therapies.

Antibodies, Bispecific↗