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Biomedical subjects

S R Baker

Publications and source records attributed to S R Baker.

At least 19 recordsLinked to original sources
PubMed1995

Synthetic and structure/activity studies on acid-substituted 2-arylphenols: discovery of 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5- hydroxyphenoxy]-propoxy]phenoxy]benzoic acid, a high-affinity leukotriene B4 receptor antagonist.

Structural derivatives of LY255283 have been studied as receptor antagonists of leukotriene B4. Substitution of the 2-hydroxyacetophenone subunit of 1 (LY255283) with a 2-arylphenol group provided entry into several new series that feature various mono- and diacidic core functionality. These new analogues, the subject of a broad structure-activity investigation, displayed significantly increased in vitro and in vivo activity as receptor antagonists of LTB4. A series of diaryl ether carboxylic acids demonstrated especially interesting activity and led to the discovery of compound 43b, 2-[2-propyl-3-[3-[2-ethyl-4-(4- fluorophenyl)-5-hydroxyphenoxy]-propoxy]phenoxy]benzoic acid (LY293111), a 2-arylphenol-substituted diaryl ether carboxylic acid which displayed potent binding to human neutrophils (IC50 = 17 +/- 4.6 nM) and guinea pig lung membranes (IC50 = 6.6 +/- 0.71 nM), inhibition of LTB4-induced expression of the CD11b/CD18 receptor on human neutrophils (IC50 = 3.3 +/- 0.81 nM), and inhibition of LTB4-induced contraction of guinea pig lung parenchyma (pKB = 8.7 +/- 0.16). In vivo, 43b demonstrated potent activity in inhibiting LTB4-induced airway obstruction in the guinea pig when dosed by the oral (ED50 = 0.40 mg/kg) or intravenous (ED50 = 0.014 mg/kg) routes. A specific LTB4 receptor antagonist, 43b had little effect on inhibiting contractions of guinea pig lung parenchyma induced by leukotriene D4 (LTD4), histamine, carbachol, or U46619. Compound 43b has been chosen as a clinical candidate and is currently in phase I studies for a variety of inflammatory diseases.

Airway Obstruction↗
PubMed1995

Second-messenger responses in brain slices to elucidate novel glutamate receptors.

G-Protein-coupled or 'metabotropic' glutamate receptors (mGluRs) are a novel heterogenous family of excitatory amino acid receptors. Activation of mGluRs in the rat hippocampus by the mGluR-selective agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) leads to multiple changes in second-messenger formation. These include increases in basal phosphoinositide hydrolysis, decreases in forskolin-stimulated cAMP formation, and enhancement of cAMP formation via a potentiation of the effects of endogenous adenosine. These changes in mGluR coupling to phosphoinositide hydrolysis and the formation of cAMP likely reflect the in situ expression of heterogenous populations of mGluRs. A number of electrophysiological studies on the functions of mGluRs in hippocampal circuitry, ontogeny, and cellular functions have also been described. Any or all of these mGluR-mediated changes in second messengers may underlie the reported cellular effects associated with the mGluR activation by 1S,3R-ACPD. However, mGluR agonists that have selectivity for different mGluR second-messenger pathways are needed to sort out the cellular consequences of activating in situ expressed mGluR subtypes linked to specific second-messenger pathways.

Animals↗
PubMed1994

Recurrent cytogenetic abnormalities in squamous cell carcinomas of the head and neck region.

We characterized the breakpoints, gains, and losses of chromosome material in squamous cell carcinomas of the head and neck region from 29 patients. Cell lines were karyotyped in 1/3 of cases, direct preparations or early in vitro harvests in 1/3, and both in 1/3 of cases. GTG-banding was employed in all cases, as were C-banding and RBG- and AgNOR-staining in most. Some tumors were near-diploid and others near-tetraploid, but many had mixed populations, with diploid, tetraploid, and octoploid subclones representing essentially the same karyotypic pattern. The most frequent changes were deletions. Losses affecting 3p13-p24, 5q12-q23, 8p22-p23, 9p21-p24, and 18q22-q23 ranged in frequency from 40% to 60% of tumors. Loss of the short arm of the inactive X occurred in 70% of tumors from female patients, and loss or rearrangement of the Y occurred in 74% of tumors from male patients. Loss of 18q appeared to be associated with short survival, as did the presence of multiple deletions. There was gain (2-5 extra copies) of 3q21-qter, 5p, 7p, 8q, and 11q13-q23 in 28-38% of tumors. Three tumors had an hsr involving 11q13-q21. Gain of material at 11q13 is postulated to be associated with amplification of the PRADI/CCND gene at that locus. A translocation between proximal 1p and either an acrocentric short arm or proximal 8p or 9p was observed in squamous cell carcinomas of the head and neck region but not in female genital tract tumors. No other abnormalities appeared to be site specific, suggesting a pattern of genetic evolution in squamous cell carcinoma that is independent of anatomic site.

Adult↗
PubMed1992

Serial studies of autologous antibody reactivity to squamous cell carcinoma of the head and neck.

In previous studies we evaluated the incidence and specificity of autologous antibody reactivity against squamous cell carcinoma of the head and neck (SCCHN). We were able to demonstrate that autologous antibody reactivity is present in native sera but was usually of too low a titer to allow further analysis. Dissociation of immune complexes by acidification and ultrafiltration of serum augmented autologous antibody reactivity in nine out of nine autologous systems tested. Native antibody and antibody derived from immune complexes produced by the host and reactive with autologous tumor cells may be directed against physiologically relevant antigens. Therefore, correlations of antibody titers with clinical course may provide insight into the nature of the host response to cancer. In the present analysis, serological studies of six patients with SCCHN were performed with serum samples obtained over many months. Results of serial serological assays were correlated to tumor progression and clinical course. Fluctuations in autologous antibody reactivity were noted over time. In four cases, rises in autologous antibody titers preceded the clinical diagnosis of recurrence by several months. Drops in autologous antibody reactivity were noted in two cases following surgery or radiation therapy. In two cases of long-term survivors, no correlation between antibody reactivity and clinical course was noted. Specificity analysis of the six autologous systems demonstrated reactivity against autologous and allogeneic SCCHN as well as melanoma cell lines. These sera did not react with glioma, neuroblastoma, renal cell, breast, bladder and colon carcinoma cell lines nor with fetal calf serum, pooled lymphocytes, red blood cells and platelets. Autologous serial serological studies may provide a means by which to evaluate the host/tumor relationship in patients with SCCHN.

Aged↗
PubMed1992

Aetiology of chronic leg ulcers.

This study was undertaken to determine the relative prevalence of the factors causing chronic ulceration of the leg in the general population. Two hundred and fifty-nine patients with chronic ulceration of the leg were found on screening a Western Australian population of 238,000. (The prevalence of chronic ulceration of the leg was 1.1 per 1000 population.) Two hundred and forty-two of these patients (93%) with 286 chronically ulcerated limbs were fully assessed to determine the factors contributing to ulceration. In 239 limbs (84%) ulceration involved the leg; in these limbs venous disease was the most prevalent cause of ulceration (160 limbs). Arterial disease was found in 66 limbs, with both venous and arterial disease present in 35 limbs. Rheumatoid arthritis was a causative factor in 27 limbs and diabetes was found with 29 limbs with ulceration involving the leg. In 47 limbs (16%) ulceration was confined to the foot; arterial disease (35 limbs) and diabetes (23 limbs) were the most prevalent causes of ulceration in these limbs. Venous disease was infrequent (three limbs). No disorder of the circulation was found in 48 limbs (20%) with ulceration involving the leg, and in 58 (20%) of all ulcerated limbs. More than one aetiological factor was present in 93 limbs (33%). A cause for ulceration was not found in 10 limbs (3.5%).

Adult↗
PubMed1991

In vitro radiation resistance among cell lines established from patients with squamous cell carcinoma of the head and neck.

Twenty-five squamous cell carcinoma (SCC) cell lines from 20 patients with head and neck cancer were assessed for radiosensitivity in vitro using a 96-well plate assay. Four non-SCC lines were also tested. Radiation sensitivity of individual cell lines was compared using the area under the survival curve (AUC) as a measure of the mean inactivation dose. Tumor lines were tested with either a cobalt-60 (60Co) gamma-irradiator having a dose rate of 100 cGy/minute or with a 4-meV photon beam having a dose rate of 200 cGy/minute. The mean AUC of the 25 SCC cell lines was 188 +/- 7 (SEM) cGy (range, 100 to 250 cGy) whereas the four non-SCC lines had a mean AUC of 225 +/- 9 cGy. The SCC cell lines with mean inactivation dose values greater than 188 cGy were classified as relatively radioresistant whereas those with values less than 188 cGy were considered relatively radiosensitive. In seven cases SCC cell lines were derived from patients who had already received radiation therapy. In four of these cases the tumor cell lines were radioresistant (AUC, 210 to 250) but in the other three cases the tumor lines were radiosensitive (AUC, 160 to 180). Thus, failure of a tumor to respond to radiation did not always select for radioresistant cells. The mean of the AUC for cell lines from previously irradiated patients (197 +/- 11 cGy) did not differ significantly from that of the cell lines from patients who received no prior radiation therapy (182 +/- 9 cGy). However, among radiation-resistant lines those from the four previously irradiated patients were significantly more resistant (mean AUC = 235 +/- 9) than seven other radioresistant lines from nonirradiated patients (mean AUC, 208 +/- 4) (P = 0.0194). In four cases more than one cell line was derived from different tumor specimens in the same patient. In each of these cases the lines from the same patients were similar to one another in their degree of radioresistance. Based on these observations the authors conclude that the degree of in vitro radiation resistance is an inherent property of some squamous cell tumors.

Adult↗
PubMed1991

Mandible reconstruction with vascularized bone grafts. A histologic evaluation.

To our knowledge, a histologic evaluation of bone healing after mandible reconstruction with vascularized human bone grafts has not been previously reported. Serial sections through both the decalcified graft and the junction between mandible and graft were evaluated in four patients who required surgical removal of their reconstructed mandibles. A failed scapular bone graft that had been wrapped within a pectoralis major myocutaneous flap for salvage following pedicle thrombosis showed markedly resorbed but viable bone with a fibrous union to the native mandible. Viable vascularized grafts without evidence of ongoing resorption characterized an iliac osteocutaneous bone graft and two scapula osteocutaneous grafts that healed with continuity of healthy bone between graft and mandible. Observations from the evaluation of these specimens are made regarding bone circulation, bone union, and bone graft survival as they occur clinically. Implications regarding the techniques of bone plating and indications for use of vascularized bone in mandible reconstruction are discussed.

Bone Transplantation↗
PubMed1991

Epidemiology of chronic venous ulcers.

A metropolitan population of 238,000 in Perth, Western Australia, was screened for chronic ulceration of the leg. Patients with a chronic leg ulcer and a venous abnormality comprised 57 per cent of all patients with a chronic leg ulcer, giving a prevalence of 0.62 per 1000 population. There was an increasing prevalence with age; 90 per cent of patients were 60 years and older. This group comprised 16.7 per cent of the population, and had a prevalence of 3.3 per 1000. Although chronic venous ulcers were more common in women there was no difference in age related prevalence. In 36 per cent of patients with a venous abnormality, there was at least one other aetiological factor contributing to chronic ulceration of the leg; 96 per cent had either a history of deep venous thrombosis or a condition known to predispose to deep venous thrombosis.

Adult↗
PubMed1991

Outpatient treatment of chronic venous ulcers in a specialized clinic.

Chronic leg ulcers have many different causes and therefore need an accurate diagnosis in order to give the most effective treatment. A specialized clinic was set up in Fremantle Hospital in July 1988 with the aims of performing a thorough clinical and laboratory assessment to establish the cause of ulceration in every patient, and treating patients according to the cause of ulceration. Patients with arterial, neoplastic or dermatological conditions were treated as appropriate for their diagnosis and patients with other chronic ulcers were managed as outpatients where possible. Patients were seen between July 1988 and July 1989. Only 43% had purely venous ulcers, 32.6% had a venous component plus some other abnormality, and 5.2% were purely arterial. Using an outpatient treatment regimen, 67% of all ulcerated limbs and 73.7% of limbs with purely venous ulcers were healed within 6 months. Only 11 patients with venous ulceration (15 limbs) failed on this therapy and required admission during the observation period. The initial ulcer size was shown to influence the time to total healing of the limb. The healing rates achieved compare favourably with studies from other specialized centres and suggest that the majority of patients with chronic leg ulcers can be treated successfully using ambulatory outpatient dressing techniques.

Adult↗
PubMed1991

Air in the fissure for the ligamentum teres: new sign of intraperitoneal air on plain radiographs.

In each of four patients in whom an acute spontaneous pneumoperitoneum developed, a vertically directed area of hyperlucency in the right upper quadrant was seen on radiographs of the abdomen obtained with the patient supine. This finding, which appeared in the absence of other characteristic signs of free air on plain radiographs and which, to the authors' knowledge, has not been previously recognized, represented intraperitoneal gas confined to the fissure for the ligamentum teres (FLT). The location of the hyperlucent area was confirmed with computed tomography or laparotomy in each patient. The distinctive configuration of air in the FLT is a subtle but reliable indicator of pneumoperitoneum.

Aged↗
PubMed1991

Leukotriene receptor on U-937 cells: discriminatory responses to leukotrienes C4 and D4.

Dimethyl sulfoxide (DMSO)-differentiated U-937 cells develop cell surface receptors for leukotrienes that, when stimulated, initiate a transient increase in intracellular calcium concentration [( Ca2+]i). We investigated the calcium transient that occurs after addition of leukotriene C4 (LTC4) to determine whether it occurs due to 1) the bioconversion of LTC4 to leukotriene D4 (LTD4), which then acts at the LTD4 receptor; 2) the direct action of LTC4 at the LTD4 receptor; or 3) the action of LTC4 at a receptor selective for LTC4. Bioconversion of [3H]LTC4 to [3H]LTD4 was inhibited by 98% when DMSO-differentiated U-937 cells were incubated with 10 mM AT-125 compared with control cells. The dose-response curve for LTC4, with [Ca2+]i as the index of response, was parallel to that for LTD4 but was significantly (P less than 0.0001) shifted 1.6 +/- 0.11 log units to the right. AT-125 did not change the response to LTD4 but the LTC4 dose-response curve was shifted on additional 1.7 logo units to the right. The antagonists SKF 104353 (1 microM) and LY 171883 (10 microM) shifted the dose-response curve for LTD4 3.0 +/- 0.23 and 2.5 +/- 0.23 log units, respectively, to the right and completely inhibited the change in [Ca2+]i due to LTC4 in the presence of 10 mM AT-125. Molecular modeling studies demonstrated a striking difference in the spatial configuration of LTC4 and LTD4, likely accounting for the ability of cell surface receptors to discriminate between the effects of these two molecules.(ABSTRACT TRUNCATED AT 250 WORDS)

Biotransformation↗
PubMed1990

Utility of emission tomography in evaluation of mandibular bone grafts.

Bone scanning, performed within 1 week postoperatively, is valuable in predicting the survival of revascularized composite flap grafts. Conventional planar scintigraphy is limited by a two-dimensional representation of three-dimensional structures. Single photon emission computed tomography (SPECT) is a technique in which a gamma camera rotates around the patient, acquires multiple projections, and with the aid of a computer, reconstructs three-dimensional representations. We wished to evaluate the potential advantages of SPECT in the assessment of mandibular graft viability and to compare it with planar scanning. These noninvasive methods of assessing the vascular supply are critical to patient management in the early postoperative period because the presence of or inability to exclude vascular compromise commands surgical exploration of the anastomosis for graft salvage. Fifteen patients who underwent mandibular reconstruction with revascularized free grafts were studied by both planar and SPECT scintigraphy. Long-term follow-up data were correlated with the outcome predicted by the scanning.

Adult↗
PubMed1990

The cutaneous scapular free flap in head and neck reconstruction.

Successful surgical reconstruction of complicated soft-tissue defects of the head and neck region has been greatly enhanced by free-revascularized tissue transfers. The scapular free flap has become a favored reconstructive option in our department and has been reported previously for one-stage mandibular reconstruction. This flap can also be transferred as a cutaneous free flap. We present our clinical experience with the fasciocutaneous scapular free flap and review the anatomy, surgical technique, and utility of this versatile flap.

Adult↗
PubMed1990

Tracheostoma diverticulum following tracheoesophageal puncture.

Although the initial reports of tracheoesophageal puncture after total laryngectomy reported little to no morbidity, subsequent studies with longer follow-up have reported a significant number of complications. We present the first reported case (to our knowledge) of prolapse of the posterior tracheal wall with diverticulum formation developing 6 years after continuous use of tracheoesophageal puncture speech. Preoperative assessment with a barium esophagogram and rigid esophagoscopy aided in the successful surgical treatment of this disorder. The pathogenesis of this complication and method of repair are discussed.

Diverticulum↗
PubMed1990

Tissue expansion of the head and neck. Indications, technique, and complications.

Tissue expansion is indicated in the reconstruction of various defects of the head and neck in instances where there is inadequate adjacent tissue to allow either primary closure of the defect or repair with a local flap. It may also be indicated in instances where repair of a defect by an alternative method such as a local, regional, or distant flap will result in an unacceptable donor or recipient site deformity. Although tissue expansion is simplistic in concept, it does require judgment and indepth preoperative planning to ensure optimal results. The complication rate is high for tissue expansion in the head and neck, particularly in the cheek and neck area. Despite the frequency of complications, in the vast majority of cases the intended reconstruction is successful.

Dermatologic Surgical Procedures↗
PubMed1990

Rapid intraoperative tissue expansion in reconstruction of the head and neck.

A prolonged tissue expansion has the advantage of creating large amounts of additional skin for reconstructing cutaneous defects that might not be possible without the use of multiple, regional, distant, or microsurgical flaps. In spite of this, there are disadvantages, many of which can be circumvented by the use of rapid intraoperative tissue expansion instead. Although rapid expansion does not increase skin surface area as much as prolonged expansion, it may be helpful in assisting with closure of defects that might otherwise be problematic.

Face↗