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Biomedical subjects

J W Smith

Publications and source records attributed to J W Smith.

At least 163 records · Page 9Linked to original sources
PubMed1996

Merkel cell cancer: is prophylactic lymph node dissection indicated?

Our objective was to determine prognostic factors and the role of prophylactic lymph node dissection in Merkel cell cancer. A retrospective chart review of 15 patients from Loma Linda University Medical Center, Loma Linda, and Kaiser Permanente, Fontana, was used. The most important predictor of survival was presence of lymph node metastasis (P = 0.03). Lymph node metastasis was the first sign of recurrence in 60 per cent of patients and preceded distant metastasis. Age at presentation, tumor size, and location had no influence on survival. Gross presurgical determination of tumor extent was misleading. Microscopically positive margins necessitated reexcision in 60 per cent of patients. Local recurrence occurred in 27 per cent of patients. Recurrence at lymph node basins was lower in patients with elective lymph node dissection (0%) compared with therapeutic node dissection (57%)(P < 0.05). Incidence of micrometastases in patients undergoing prophylactic lymph node dissection was 100 per cent. No difference in survival was seen between prophylactic and therapeutic node dissection. Because Merkel cell cancer spreads in a "cascade" fashion, elective node dissection may provide a chance for a cure. Elective node dissection provides better locoregional control compared with therapeutic node dissection and helps to determine prognosis.

Aged↗
PubMed1996

Patterns of esophageal motility in patients with stable bulimia.

OBJECTIVES: A high prevalence of GI motility disturbances, including deranged esophageal motility, has previously been reported in patients with eating disorders; altered esophageal and gastric motility have been suggested to play an important role in these disease processes. We sought to confirm this association in an independent patient population. METHODS: We performed esophageal manometry in 12 patients with eating disorders (eight patients with bulimia and four with overlap syndromes, including both anorexia and bulimia features) and 12 sex-matched controls. All subjects completed a symptom questionnaire. Motility testing was performed in the standard fashion using a low compliance water perfusion catheter and computerized digital data capture. Coded tracings were interpreted in a blinded fashion. RESULTS: All 24 studies showed normal motility patterns [95% confidence interval for abnormal esophageal motility in eating disorders patients (0, 0.27)]. Mean lower esophageal sphincter pressure was 24.4 mm Hg in patients and 21.8 in controls; all relaxed normally. Mean esophageal body contraction amplitude 3 cm above the lower esophageal sphincter was 82.6 mm Hg in patients and 84.3 in controls; waveform morphology and progression met normal criteria in all studies. Eight of 12 patients reported dysphagia, odynophagia, or both, compared with 1 of 12 controls; patients demonstrated a pattern of increased overall GI symptomatology compared to controls. CONCLUSIONS: We conclude that disordered esophageal motility is uncommon among stable eating disorder outpatients with bulimic features, and that dysphagia and odynophagia are rarely associated with disordered motility in this group.

Adult↗
PubMed1996

Pilot study on the effects of a computer-based medical image system.

Current medical imaging systems are developed for the purpose of data management. Evaluations of these systems are usually done by assessing users' subjective appreciation rather than objectively gauging performance influence. The present report discusses the evaluation of a medical image presentation system prototype utilizing a cognitive approach. Experimental results showed hypothesized performance improvement attributed to advanced presentation techniques. However, this improvement was almost inadvertently masked by users' previous strategies and interactions with new technology. Overall these data demonstrate the potential benefit of implementing such a system in actual practice as well as provide an example of applying the cognitive approach in evaluating the usability of medical systems.

Cognition↗
PubMed1996

Induction of interleukin 1 receptor antagonist after interleukin 1 therapy in patients with cancer.

The interleukin 1 receptor antagonist (IL-1ra) is a naturally occurring molecule that shares homology with IL-1alpha and IL-1beta and binds competitively to IL-1 receptors. Serum concentrations of IL-1ra were measured by ELISA in patients enrolled in Phase I clinical trials of IL-1alpha and IL-1beta given by 15-min infusion. Pretreatment levels of IL-1ra were <1500 (mean, 453 +/- 57) pg/ml. IL-1ra levels were increased in some patients within 1 h of completing the IL-1 infusion. By 2 h after infusion, serum levels of IL-1ra had increased dramatically, and they remained stable 4 h after infusion. There was evidence that peak IL-1ra levels were IL-1 dose dependent. Seven patients treated with IL-1alpha had IL-1ra levels that exceeded 1 microgram/ml. In contrast, serum levels of IL-1 declined rapidly and were undetectable 1 h after completing IL-1 infusion in most patients receiving <1.0 microgram/kg. IL-1ra levels remained slightly elevated over pretreatment values in serum obtained 18-24 h after IL-1 infusion, but there was no evidence for progressive accumulation over repeated days of therapy. A similar pattern of IL-1ra elevation was observed after the last IL-1 infusion on day 6. This study shows that cancer patients produce 2 to >6 log incremental increases in IL-1ra rapidly following treatment with IL-1, a response that has implications for the design of future clinical trials with IL-1 and with agents thought to induce IL-1 production.

Humans↗
PubMed1995

Activation of calcium-sensitive potassium channels in L6 skeletal myocytes by arginine vasopressin requires extracellular calcium.

The effects of extracellular application of arginine vasopressin (AVP) upon membrane currents in L6 skeletal myocytes was investigated using the whole-cell configuration of the patch-clamp technique. At 0 mV AVP produced large amplitude, transient outward currents that reversed when the clamping potential was changed to -100 mV (negative to EK). The effects of alterations in the extracellular K+ concentration upon the current reversal potential suggested that the current elicited by AVP was carried mainly by K+ ions. Intracellular dialysis with 10 microM inositol 1,4,5-trisphosphate (InsP3) elicited similar currents but only in 6/14 cells. Inclusion of 5 mg ml-1 heparin in the intracellular solutions was ineffective at inhibiting the current responses to AVP. The AVP-induced current was totally abolished when the intracellular EGTA concentration was increased from 0.05 mM to 10 mM or Ca2+ was removed from the extracellular perfusing solution. These results suggest that AVP produces activation of a Ca(2+)-sensitive K+ conductance in L6 skeletal myocytes by a process dependent upon extracellular Ca2+ and not intracellular Ca2+ release.

Animals↗
PubMed1995

Protein loop grafting to construct a variant of tissue-type plasminogen activator that binds platelet integrin alpha IIb beta 3.

Protein-protein interactions can be guided by contacts between surface loops within proteins. We therefore investigated the hypothesis that novel protein-protein interactions could be created using a strategy of "loop grafting" in which the amino acid sequence of a biologically active, flexible loop on one protein is used to replace a surface loop present on an unrelated protein. To test this hypothesis we replaced a surface loop within an epidermal growth factor module with the complementarity-determining region of a monoclonal antibody. Specifically, the HCDR3 from Fab-9, an antibody selected to bind the beta 3-integrins with nanomolar affinity (Smith, J. W., Hu, D., Satterthwait, A., Pinz-Sweeney, S., and Barbas, C. F., III (1994) J. Biol. Chem. 269, 32788-32795), was grafted into the epidermal growth factor-like module of human tissue-type plasminogen activator (t-PA). The resulting variant of t-PA bound to the platelet integrin alpha IIb beta 3 with nanomolar affinity, retained full enzymatic activity, and was stimulated normally by the physiological co-factor fibrin. Binding of the novel variant of t-PA to integrin alpha IIb beta 3 was dependent on the presence of divalent cations and was inhibited by an RGD-containing peptide, demonstrating that, like the donor antibody, the novel t-PA binds specifically to the ligand-binding site of the integrin. These findings suggest that surface loops within protein modules can, at least in some cases, be interchangeable and that phage display can be combined with loop grafting to direct proteins, at high affinity, to selected targets. In principle, these targets could include not only other proteins but also peptides, nucleic acids, carbohydrates, lipids, or even uncharacterized markers of specific cell types, tissues, or viruses.

Amino Acid Sequence↗
PubMed1995

Pteroylpolyglutamate synthesis by lung- and culture-derived Pneumocystis carinii.

Pneumocystis carinii synthesizes folates de novo from exogenous p-aminobenzoic acid (pABA). Lung-derived organisms take up [3H]pABA in vitro except in the presence of sulfamethoxazole. Supernatants from spinner-flask cultures take up [3H]pABA if they were inoculated with lungs from infected rats, but not if they were inoculated with lungs from uninfected rats. P. carinii folates consist primarily of pteroylpentaglutamates. Plasmodium falciparum, in contrast, contains primarily pteroyltetraglutamates. Culture-derived organisms synthesize folates at a four-fold higher specific activity than lung-derived organisms, possibly because they contain less contaminating lung debris. These data suggest that P. carinii remains metabolically active in culture for at least 4 days.

4-Aminobenzoic Acid↗
PubMed1995

A biochemical characterization of the binding of osteopontin to integrins alpha v beta 1 and alpha v beta 5.

Osteopontin (OPN) is an extracellular matrix protein that binds to integrin alpha v beta 3. Here we demonstrate that two other integrins, alpha v beta 1 and alpha v beta 5, are also receptors for OPN. Human embryonic kidney 293 cells adhere to human recombinant osteopontin (glutathione S-transferase-osteopontin; GST-OPN) using integrin alpha v beta 1. When the 293 cells are transfected with the beta 5 subunit, they can also adhere to GST-OPN using integrin alpha v beta 5. Divalent cations regulate the binding of GST-OPN to both alpha v beta 1 and alpha v beta 5. Mg2+ and Mn2+ support the binding of GST-OPN to these integrins but Ca2+ does not. The highest affinity is observed in Mn2+. In the presence of this ion, the affinity of GST-OPN for alpha v beta 1 is 18 nM and the affinity for alpha v beta 5 is 48 nM. The antibody 8A2, which is an agonist for beta 1, promotes the adhesion of 293 cells to GST-OPN even when Ca2+ is present. This observation suggests that cellular events could modulate the affinity of alpha v beta 1 for OPN. Collectively, these findings prove that integrins alpha v beta 1, alpha v beta 3, and alpha v beta 5 have similar affinity for OPN. Therefore, all three integrins must be considered when evaluating the biological affects of OPN.

Amino Acid Sequence↗
PubMed1995

Characterization and localization of the Gova/b alloantigens to the glycosylphosphatidylinositol-anchored protein CDw109 on human platelets.

The Gova/b alloantigens are expressed on a 175-kD protein (GP175) on human platelets. Anti-Gov alloantibodies have been implicated in posttransfusion purpura and alloimmune neonatal thrombocytopenia. In this report we characterize the immunochemistry of the alloantigens and identify the platelet protein that expresses the Gov epitopes. Approximately 50% of GP175 containing the Gov epitope was released from platelets treated with phosphatidylinositol-specific phospholipase C, indicating that at least some of this protein exists as a glycosylphosphatidylinositol (GPI)-linked isoform. Radioimmunoprecipitation and immunodepletion studies indicated that the Gova/b alloantigens are expressed on the GPI-anchored CDw109 protein. The Gova/b epitopes were expressed on an extracellular, 120-kD soluble fragment (p120) of CDw109 produced by calcium-dependent protease cleavage. Anti-Gov immunoprecipitates of chymotryptic digests of p120 contained 70- and 52-kD fragments of CDw109. Deglycosylation of native CDw109 had no effect on recognition by Gov alloantisera; however, the epitopes were destroyed after exposure to sodium dodecyl sulfate. Gova/b alloantigens were expressed on platelets and PHA-activated T-cells, cultured human umbilical vein endothelial cells, and by many different tumor cell lines, consistent with the tissue distribution of CDw109.

Antibodies, Monoclonal↗
PubMed1995

Characterization of a volume-sensitive chloride current in rat osteoblast-like (ROS 17/2.8) cells.

1. During osmotic swelling, cultured osteoblastic cells (ROS 17/2.8) exhibited activation of large amplitude Cl- currents in the whole-cell configuration of the patch-clamp technique. Effects of hypotonic shock on cell volume and membrane conductance were rapidly reversed on return to isotonic conditions. 2. Voltage command pulses in the range -80 to +50 mV produce instantaneous activation of Cl- currents. At potentials more positive than +50 mV the current exhibited time-dependent inactivation. The instantaneous current-voltage relationship was outwardly rectifying. 3. The anion permeability sequence of the induced current was SCN- (2.2) > i- (1.9) > Br- (1.5) > Cl- (1.0) > F- (0.8) > gluconate- (0.2). This corresponds to Eisenman's sequence I. 4. The volume-sensitive Cl- current was effectively inhibited by the Cl- channel blockers 4,4'- diisothiocyanatostilbene-2,2-disulphonic acid (DIDS) and 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB). Outward currents were more effectively suppressed by DIDS than inward currents. The concentrations for 50% inhibition (IC50) of outward and inward currents were 81 and 298 microM, respectively. NPPB was equally effective at inhibiting outward and inward currents (IC50 of 64 microM). The current was relatively insensitive to diphenylamine-2-carboxylate (DPC), 500 microM producing only 22.5 +/- 4.0% inhibition. 5. Inhibitors of protein kinase A (H-89, 1 microM) and tyrosine kinase (tyrphostin A25, 200 microM) were without effect upon activation of Cl- currents in response to hypotonic shock. Under isotonic conditions, elevation of intracellular Ca2+ by ionomycin (1 microM) or activation of protein kinase C by 12-O-tetradecanoylphorbol 13-acetate (TPA, 0.1 microM) failed to evoke increases in basal Cl- conductance levels. 6. It is concluded that an outwardly rectifying Cl- conductance is activated upon osmotic swelling and may be involved in cell volume regulation of ROS 17/2.8 cells.

Animals↗
PubMed1995

Ca2+ suppresses cell adhesion to osteopontin by attenuating binding affinity for integrin alpha v beta 3.

Osteopontin (OPN) is an extracellular matrix protein that supports osteoclast adhesion to the bone by binding to integrin alpha v beta 3. We measured the binding between OPN and integrin alpha v beta 3 with recombinant human OPN and the urinary form of human OPN, uropontin. Recombinant OPN was expressed in Escherichia coli as a fusion protein with glutathione S-transferase and cleaved from glutathione S-transferase with Factor Xa. The mass of this form of OPN (rOP27) is 27,046 Da. rOP27 is truncated at arginine residue 228, 69 amino acids short of the native carboxyl terminus. Uropontin and rOP27 support RGD-dependent cell adhesion and to bind purified integrin alpha v beta 3 with similar affinities. Further study showed that OPN is the only known naturally occurring RGD-containing protein with a much greater affinity for alpha v beta 3 than for the platelet integrin alpha IIb beta 3. Most importantly, we find that physiologic levels of Ca2+ block cell adhesion to OPN. Measurement of binding constants between rOPN and purified integrin alpha v beta 3 with surface plasmon resonance showed that the affinity between rOPN and alpha v beta 3 is 26-fold lower in Ca2+ (Kd = 1.1 x 10(-8) M) than in Mn2+ (Kd = 4.3 x 10(-10) M) and 9-fold lower than in Mg2+ (Kd = 1.3 x 10(-9) M). In bone, the resorbing osteoclast generates elevated levels of extracellular Ca2+, therefore the findings presented here suggest a previously unappreciated mechanism for the modulation of bone resorption by extracellular Ca2+.

Amino Acid Sequence↗
PubMed1995

Intraoperative radiotherapy in the treatment of neuroblastoma: report of a pilot study.

BACKGROUND: External beam radiotherapy in advanced neuroblastoma is limited by the volume of normal radiosensitive tissues included in the radiation field. Limitations to external radiation are the late effects to these tissues. Intraoperative radiotherapy (IORT) delivers a single high-radiation dose to a tumor while displacing normal tissues that would have been included in an external field. Standard external radiotherapy can still be done after "boost" IORT. METHODS: Eight advanced-stage neuroblastoma patients who received IORT as part of their multimodality therapy were reviewed to identify the impact of IORT on operative time, complications, and tumor control in the treatment field. The IORT was accomplished by patient transport from the OR to the radiation therapy suite; these were separated by three floors. RESULTS: IORT added 30-75 min to the operative procedure. Tumors in the resection/IORT fields showed no evidence of disease (one), stable tumor size (six), and tumor recurrence (one). Two complications were identified: a urinary fistula and CO2 retention, which was detected and corrected before the IORT. Neither of these complications was related to the IORT. Two patients who had subsequent tumor resection after IORT demonstrated tumor differentiation to ganglioneuromatous tissue. CONCLUSIONS: IORT usually can be completed in less than an hour. No IORT-associated complications were identified. IORT along with maximal tumor resection, external radiation, and chemotherapy enhances local tumor control.

Child↗
PubMed1995

Pediatric laparoscopic splenectomy.

Laparoscopic surgery is becoming widely accepted as an alternative to conventional procedures. It is becoming more and more evident that laparoscopic techniques can be applied successfully to pediatric patients. Advantages of these techniques include less postoperative pain, decreased ileus, fewer pulmonary complications, and shorter hospital stays. Elective splenectomy for hematologic disease or for staging of Hodgkin's lymphoma also appears to be amenable to laparoscopic techniques. This report details 12 consecutive splenectomies successfully performed laparoscopically since July 1993. No case required conversion to laparotomy. Each case was reviewed with respect to operative time, estimated blood loss, identification of accessory spleens, time until full oral intake, analgesia requirements, and length of stay. Factors contributing to morbidity such as ileus, pulmonary complications, and would infections were evaluated. Documentation was also reviewed for late sequelae such as intestinal obstruction and incisional hernias. These patients were compared with 20 consecutively treated patients who underwent open splenectomy in the period immediately preceding the use of laparoscopic splenectomy. Laparoscopic splenectomy, in the authors' experience, is a safe alternative to open splenectomy, has few complications, is cost effective, and has been well accepted by patients and families.

Adolescent↗
PubMed1995

Effect of different coffees on esophageal acid contact time and symptoms in coffee-sensitive subjects.

The purpose of this study was to correlate the effects of different coffees on esophageal acid contact, heartburn, and regurgitation in patients with coffee-sensitivity. Twenty volunteers with coffee-sensitivity were studied in a double-blind, 3 period, crossover study examining the effect of three regular (caffeinated) coffees (a coffee from the USA--"A"; a "treated" coffee from Europe--"B"; and an "untreated" coffee from Europe--"C") before and after a high-fat test meal. The median acid contact times for coffees A, B, and C were 6.5%, 9%, and 10.5%, respectively (A vs. C, p = 0.005). Significantly fewer patients reported any symptoms with coffee A compared with coffee C (p < 0.05). Symptoms were usually more frequent and severe after the test meal. There was a trend toward fewer and less severe symptoms with the treated coffee (B) compared with its untreated counterpart (C). Our conclusions are as follows: (a) Different coffees induce variations in gastroesophageal reflux in coffee-sensitive individuals. (b) Coffee can be treated in a manner which decreases heartburn symptoms by 75% while decreasing acid contact by only 14%. (c) Gastroesophageal reflux and symptoms of coffee sensitivity increase with the concomitant ingestion of food. (d) Symptoms of dyspepsia appear to be influenced by variations in both the coffee itself and characteristics of susceptible individuals. (e) Although gastroesophageal reflux is important in the genesis of coffee-sensitivity, there must be other factors which act in concert with reflux to produce symptoms of coffee-sensitivity.

Adult↗
PubMed1995

Interleukin-1 in the treatment of cancer.

Interleukin-1 (IL-1) is a cytokine with many activities central to immune function and hematopoiesis. Many IL-1 properties can be potentially exploited in the treatment of malignancy. This review describes the toxicities and antitumor effects observed in Phase I and II trials of IL-1 in cancer patients. The immunophysiology and the induction of cytokines by IL-1 has been examined in many of the Phase I trials and has aided in understanding IL-1 effects in humans. The influence of IL-1 on granulopoiesis and thrombopoiesis when given by different regimes is also reviewed in detail.

Animals↗