Biomedical subjects

D Gordon

Publications and source records attributed to D Gordon.

At least 163 records · Page 9Linked to original sources

PubMed1998

Acute otitis media: the evolution of surgical management.

OBJECTIVE: Acute suppurative otitis media has been a common disease since time immemorial and, until the late nineteenth century, was followed by a high complication rate, major morbidity, and frequent mortality. Since then, the overall incidence of the disease has changed little; however, in less than a century, progressively more sophisticated surgery and the introduction of antimicrobials have reduced the mortality, at least in developed countries, to a rarity. Complications such as chronic perforation of the tympanic membrane or cholesteatoma, although much less frequent than in the past, are not uncommon. The evolution of mastoid surgery into the antibiotic era is reviewed. CONCLUSION: There is concern that with the increasing frequency of bacterial resistance to antibiotics and the decreasing familiarity of family practitioners with the clinical presentation of complicated otitis media that we may be faced with a resurgence of mastoid disease.

Acute Disease↗

PubMed1998

What is an electronic patient record?

While organizations develop their Electronic Patient Records, there will be a transition period during which computerized and paper records will both exist, possibly on multiple clinical information systems. This paper describes a model that defines the patient system of record and its constituent paper elements and electronic components. The model has been adopted by a large academic health science center for their development of an electronic patient record. The model has clarified which systems and data constitute the patient system of record and the standards and policies that apply to these systems.

Academic Medical Centers↗

PubMed1997

Gene transfer of Fas ligand induces tumor regression in vivo.

The Fas-Fas ligand (FasL) system plays an important role in the induction of lymphoid apoptosis and has been implicated in the suppression of immune responses. Herein, we report that gene transfer of FasL inhibits tumor cell growth in vivo. Although such inhibition is expected in Fas+ tumor cell lines, marked regression was unexpectedly observed after FasL gene transfer into the CT26 colon carcinoma that does not express Fas. Infection by an adenoviral vector encoding FasL rapidly eliminated tumor masses in the Fas+ Renca tumor by inducing cell death, whereas the elimination of Fas- CT26 cells was mediated by inflammatory cells. Analysis of human malignancies revealed Fas, but not FasL, expression in a majority of tumors and susceptibility to FasL in most Fas+ cell lines. These findings suggest that gene transfer of FasL generates apoptotic responses and induces potent inflammatory reactions that can be used to induce the regression of malignancies.

Adenoviridae↗

PubMed1997

Identification of structural elements of a scorpion alpha-neurotoxin important for receptor site recognition.

alpha-Neurotoxins from scorpion venoms constitute the most studied group of modifiers of the voltage-sensitive sodium channels, and yet, their toxic site has not been characterized. We used an efficient bacterial expression system for modifying specific amino acid residues of the highly insecticidal alpha-neurotoxin LqhalphaIT from the scorpion Leiurus quinquestriatus hebraeus. Toxin variants modified at tight turns, the C-terminal region, and other structurally related regions were subjected to neuropharmacological and structural analyses. This approach highlighted both aromatic (Tyr10 and Phe17) and positively charged (Lys8, Arg18, Lys62, and Arg64) residues that (i) may interact directly with putative recognition points at the receptor site on the sodium channel; (ii) are important for the spatial arrangement of the toxin polypeptide; and (iii) contribute to the formation of an electrostatic potential that may be involved in biorecognition of the receptor site. The latter was supported by a suppressor mutation (E15A) that restored a detrimental effect caused by a K8D substitution. The feasibility of producing anti-insect scorpion neurotoxins with augmented toxicity was demonstrated by the substitution of the C-terminal arginine with histidine. Altogether, the present study provides for the first time an insight into the putative toxic surface of a scorpion neurotoxin affecting sodium channel gating.

Amino Acid Sequence↗

PubMed1997

Induction of angiogenesis by lidocaine and basic fibroblast growth factor: a model for in vivo retroviral-mediated gene therapy.

A strategy of direct, in vivo retroviral-mediated gene therapy targeting capillary endothelial cells must provide an environment of active angiogenesis. Both lidocaine and basic fibroblast growth factor (bFGF) promote angiogenesis, but the angiogenic response invoked by these substances in normal skeletal muscle has not been fully characterized. We sought to characterize these agents' angiogenic effects in anterior tibialis muscles of male Sprague-Dawley rats. An injection of either 1% lidocaine with 1:100,000 epinephrine or alternate-day injections of bFGF (0.025 or 0.25 microgram) with or without heparin were tested (n = 6 muscles/condition). Rats were sacrificed 4, 7, 10, or 12 days later and muscles were evaluated histologically to determine the number of proliferating cells using 5-bromo-2'-deoxycytidine (BrdC) and evaluated for capillary density using Griffonia simplicifolia I (GSI) lectin. At all time points, lidocaine produced at least 20-fold greater capillary density and cellular proliferation than PBS control (P < 0.0001). Injections of high-dosage bFGF produced more than fivefold greater capillary density than control injections at 7 and 10 days (P < 0.001), and more than twofold greater proliferation at 4, 7, and 12 days (P < 0.001). Capillary density returned to control levels 12 days following bFGF administration, whereas it remained well above control levels for 12 days after lidocaine administration. To confirm that lidocaine can be utilized in gene therapy strategies targeting vascular endothelium and skeletal muscle fibers, concentrated pLJ retrovirus containing cDNA for the heat-stable human placental alkaline phosphatase (hpAP) marker gene was infused into the rat hindlimb vasculature 4 days post-lidocaine administration. Rats receiving pLJhpAP retrovirus demonstrated significant hpAP transgene expression in endothelial cells and myocytes 21 days after the lidocaine injection (n = 6 muscles). In contrast, controls receiving pLJhpAP infusion without prior lidocaine administration failed to demonstrate any hpAP transgene expression. Lidocaine treatment evokes a substantially higher proliferative response than bFGF and, importantly, a durable angiogenic response in skeletal muscle. Thus, lidocaine is an ideal agent to induce angiogenesis in preparation for direct in vivo retroviral-mediated gene therapy targeting vascular endothelium.

Alkaline Phosphatase↗

PubMed1997

Association of posterior p-values of S.A.G.E. SIBPAL proportion-IBD and Haseman-Elston statistics for ACTHR112.

A common practice among researchers performing linkage studies is the use of equal allele frequencies as input when reporting p-values from computer linkage programs such as S.A.G.E. SIBPAL. Our results, using 5,000 sets from a uniform-prior distribution of allele frequencies, showed that such input may be problematic. Further, we found that the S.A.G.E. SIBPAL test for proportion of alleles shared identical by descent among concordantly affected sib pairs showed a greater percentage of significant p-values with decreasing parental genotype information (Table III), while the S.A.G.E. SIBPAL Haseman-Elston test produced significant p-values comparatively less frequently (Table IV).

Alleles↗

PubMed1997

Phase-directed therapy and cardiac xenograft survival.

Xenotransplant rejection is facilitated not only by T cell upregulation but also by endothelial activation and B cell/antibody mechanisms, which standard immunosuppression is unable to overcome and xenorejection ensues. However, therapy directed specifically at each phase of xenorejection may improve xenograft survival. To study this we used a heterotopic cardiac xenotransplant mode (Syrian hamster to Lewis rat). Controls had no immunotherapy. Xenorecipients received cyclosporine to restrict T cellular response/development or cyclophosphamide, an antiproliferative, to reduce xenoreactive clones and antibody/complement injury, or anti-TNF antibody to alter cytokine cascades and endothelial activation/inflammation. Further xenorecipients received combinations. While single modalities alone did not enhance survival, combinations appeared to be at least additive in vivo, suggesting that therapy directed at specific phases of xenorejection may prove useful.

Animals↗

PubMed1997

In vitro folding and functional analysis of an anti-insect selective scorpion depressant neurotoxin produced in Escherichia coli.

The selective toxicity of depressant scorpion neurotoxins to insects is useful in studying insect sodium channel gating and has an applied potential. In order to establish a genetic system enabling a structure-activity approach, the functional expression of such polypeptides is required. By engineering the cDNA encoding the depressant scorpion neurotoxin, LahIT2, behind the T7 promoter, large amounts of recombinant insoluble and nonactive toxin were obtained in Escherichia coli. Following denaturation and reduction, the recombinant protein, constructed with an additional N-terminal methionine residue, was subjected to renaturation. Optimal conditions for reconstitution of a functional toxin, having a dominant fold over many other possible isoforms, were established. The recombinant active toxin was purified by RP-HPLC and characterized. Toxicity (ED50) to insects, binding affinity (IC50) to an insect receptor site, and electrophysiological effect on an insect axonal preparation were found to be similar to those of the native toxin. Substitution of the C-terminal glycine by a Gly-Lys-Lys triplet did not abolish folding but affected toxicity (3.5-fold decrease) of LqhIT2. Apparently, this efficient bacterial expression system (500 micrograms HPLC-purified toxin/1 liter E. coli culture) provides the means for studying structure/ activity relationship and the molecular basis for the phylogenetic selectivity of scorpion depressant neurotoxins.

Animals↗

PubMed1997

A fractured peace: a changing pattern of violence.

Since the paramilitary cease-fire in Northern Ireland in August 1994 we have seen a change in the pattern of so called 'punishment attacks'. Shootings with low velocity handguns have been replaced by severe beatings to the extremities from multiple assailants using iron bars or similar weapons. In the 18 months prior to the cease-fire there were 177 punishment shootings, which were usually relatively minor and did not require any plastic surgical expertise. Between August 1994 and November 1996, however, there were 461 punishment beatings. These beatings result in much greater morbidity and require considerable orthopaedic and plastic surgical input. In the Northern Ireland Plastic and Maxillofacial Unit we have treated 18 patients with a mean age of 22.9 years (range 16-32 years) who have been the victims of punishment beatings. These patients sustained multiple injuries, all with severe soft tissue involvement; 70% had compound fractures. The majority of patients had multiple wounds. Four patients with compartment syndrome as a result of their injuries required fasciotomies. Soft tissue reconstruction included split skin grafting (4 patients), fasciocutaneous flaps (4 patients), adipofascial flaps (2 patients), local muscle flaps (2 patients) and free muscle transfers (2 patients). Six patients required more than one procedure for soft tissue reconstruction because of multiple injuries. Each patient had a cumulative mean time in theatre of 6.7 hours. The mean hospital stay was 22.2 days (range 2-52 days). This change in the pattern of injury has led to an increased use of plastic surgical resources. Patient morbidity is significantly greater than when guns are used, and permanent disability is often the result.

Adolescent↗

PubMed1997

Follow-up requirements for thick cutaneous melanoma.

The primary aim of postoperative melanoma follow-up is the early detection and treatment of treatable recurrences which gives a survival advantage to these patients. The need for follow-up is universally accepted. However, there is ongoing controversy about the duration of follow-up and frequency of reviews. We present a retrospective review of 244 patients with localised thick (> or = 4.0 mm) cutaneous melanoma, who had completed a 10-year follow-up or had died form their melanoma within 10 years. For these criteria, this is the largest series of this type which has been reported to date. The incidence of treatable recurrences peaked in the first postoperative year at 40% and then rapidly decreased, levelling off after year 5 at 2.5% per annum. We believe that this high incidence of treatable recurrences reinforces the need for 10-year follow-up of these patients. We also recommend that the annual frequency of follow-up reviews in each year be based on that year's risk for getting a treatable recurrence. Following this principle, we provide an example of such a follow-up programme.

Adult↗

PubMed1997

Procollagen production in fresh and cryopreserved aortic valve grafts.

Long-term durability of aortic valve allografts may be enhanced by cellular capacities for regeneration and repair. To evaluate aortic valve graft production of an important structural protein, rat aortic roots were implanted heterotopically into the abdominal aorta of recipient rats. Grafts were either syngeneic or strongly allogeneic, were implanted either fresh or after cryopreservation, and were left in place 2 to 21 days after implantation. A total of 80 aortic valve grafts and the corresponding native aortic valves were examined. The grafts were retrieved and immunocytochemically stained for the presence of procollagen, a precursor to collagen. Regardless of histocompatibility or preservation, grafts exhibited consistent procollagen presence that equaled or exceeded that seen in the corresponding native valves. Positive procollagen staining was predominantly in the aortic wall. The most prominent staining was near the hinge point of the valve leaflets, with no staining in the free portion of the leaflets. Staining with alpha-actin demonstrated vascular smooth muscle in sites remote from the areas positive for procollagen, which suggests that vascular smooth muscle was not responsible for the procollagen production. These findings indicate that cryopreservation is compatible with persistent fibroblast viability and in vivo protein synthesis by both syngeneic and allogeneic aortic valve grafts.

Animals↗

PubMed1997

Concentrations of specific epithelial growth factors in the urine of interstitial cystitis patients and controls.

PURPOSE: Interstitial cystitis (IC) is a chronic bladder disease for which the etiology is unknown. Because the bladder epithelium is often abnormal in IC, we determined whether the levels of specific urine growth factors postulated to be important for bladder epithelial proliferation are altered in IC. MATERIALS AND METHODS: ELISAs were used to determine levels of epidermal growth factor (EGF), insulin-like growth factor 1 (IGF1), insulin-like growth factor binding protein 3 (IGFBP3), and heparin binding epidermal growth factor-like growth factor (HB-EGF) in urine specimens from women with IC, asymptomatic women without bladder disease, and women with bacterial cystitis. RESULTS: Urine HB-EGF levels were specifically and significantly decreased in IC patients as compared to asymptomatic controls or patients with bacterial cystitis, whether expressed as concentration (amount per volume of urine) or the amount relative to urine creatinine in each specimen. In contrast, urine EGF, IGF1, and IGFBP3 levels were all significantly elevated in IC patients compared to asymptomatic controls. Further, the amounts of urine EGF and IGF1 were also elevated in IC patients as compared to patients with bacterial cystitis, and urine IGFBP3 levels were significantly elevated when expressed per milligram of urine creatinine. CONCLUSIONS: These findings indicate that complex changes in the levels of urine epithelial cell growth factors (EGF, IGF1, and HB-EGF) and a growth factor binding protein (IGFBP3) are associated with IC. While EGF, IGF1, and IGFBP3 levels are either the same or increased in the urine of IC patients as compared to patients with bacterial cystitis or asymptomatic controls, HB-EGF levels are significantly decreased in the urine of IC patients. Understanding the reasons for these changes may lead to understanding the pathogenesis of this disorder.

Adult↗

PubMed1997

Toxin III from Leiurus quinquestriatus quinquestriatus: a specific probe for receptor site 3 on insect sodium channels.

Scorpion toxin Lqq III binds to a single class of high affinity (Kd = 72 +/- 19 pM) and low capacity (Bmax = 2.5 +/- 0.2 pmol/mg) binding sites in cockroach neuronal membranes. Its binding was inhibited by Lqh alpha IT (IC50 = 80 +/- 30 pM) and sea-anemone toxin ATX II (IC50 = 2.5 +/- 0.3 nM), suggesting that Lqq III is a specific probe for receptor site 3 on cockroach sodium channels. This was confirmed by competitive binding experiments between 125I-Lqq III and scorpion alpha-toxins which have less toxicity in insects.

Amino Acid Sequence↗

PubMed1997

Dual cell cycle-specific mechanisms mediate the antimitogenic effects of nitric oxide in vascular smooth muscle cells.

OBJECTIVE: To determine the cell cycle specificity and intracellular mechanisms involved in inhibition by nitric oxide (NO) of vascular smooth muscle cell mitogenesis. METHODS: Cultured rat aortic smooth muscle cells were synchronized by serum withdrawal, treated with the NO donor S-nitroso-N-acetylpenicillamine and the cyclic GMP analog 8-Br-cGMP at various times during cell cycle progression, and DNA synthesis measured during the S phase. Two additional NO donors, 5-nitroso-glutathione and diethylamine NONOate, were used to confirm the inhibition of DNA synthesis by S-nitroso-N-acetylpenicillamine, and the ability of two antagonists of free NO to reverse the effects of NO donors was also evaluated. Bypass of ribonucleotide reductase by use of exogenous deoxynucleosides was attempted to determine whether inhibition of this S-phase enzyme was the mechanism by which NO inhibited DNA synthesis during the S phase. RESULTS: Vascular smooth muscle cell mitogenesis was inhibited by cyclic GMP (cGMP) up to late G1 phase of the cell cycle, which corresponded to the point of greatest sensitivity to exogenous NO. In contrast to cGMP, three different NO donors inhibited DNA synthesis when added to cells synchronized in S phase, beyond the restriction point of cell cycle control in late G1 phase. This S-phase inhibition was reversible by removal of the NO donor or addition of two NO antagonists and was not observed with non-NO analogs of the donors. Inhibition by NO donors in S phase was neither reversed by the guanylate cyclase inhibitor methylene blue nor mimicked by exogenous cGMP. The S-phase inhibition by all three NO donors was reversed partially by bypass of ribonucleotide reductase, establishing this enzyme as an S-phase target of NO. CONCLUSIONS: These findings demonstrate that NO inhibits smooth muscle mitogenesis by cGMP-dependent and -independent mechanisms acting at distinct points in the cell cycle. NO is the first endogenous substance to have been shown to inhibit mitogenesis beyond the restriction point in late G1 phase, suggesting that it plays a role in regulation of cells that have lost normal mechanisms of G1 growth control, such as the hyperproliferative smooth muscle cells noted in hypertension and restenosis.

Animals↗

PubMed1997

Diversity and depth-specific distribution of SAR11 cluster rRNA genes from marine planktonic bacteria.

Small-subunit (SSU) ribosomal DNA (rDNA) gene clusters are phylogenetically related sets of SSU rRNA genes, commonly encountered in genes amplified from natural populations. Genetic variability in gene clusters could result from artifacts (polymerase error or PCR chimera formation), microevolution (variation among rrn copies within strains), or macroevolution (genetic divergence correlated with long-term evolutionary divergence). To better understand gene clusters this study assessed genetic diversity and distribution of a single environmental SSU rDNA gene cluster, the SAR11 cluster. SAR11 cluster genes, from an uncultured group of the alpha subclass of the class Proteobacteria, have been recovered from coastal and midoceanic waters of the North Atlantic and Pacific. We cloned and bidirectionally sequenced 23 new SAR11 cluster 16S rRNA genes, from 80 and 250 m in the Sargasso Sea and from surface coastal waters of the Atlantic and Pacific, and analyzed them with previously published sequences. Two SAR11 genes were obviously PCR chimeras, but the biological (nonchimeric) origins of most subgroups within the cluster were confirmed by independent recovery from separate gene libraries. Using group-specific oligonucleotide probes, we analyzed depth profiles of nucleic acids, targeting both amplified rDNAs and bulk RNAs. Two subgroups within the SAR11 cluster showed different highly depth-specific distributions. We conclude that some of the genetic diversity within the SAR11 gene cluster represents macroevolutionary divergence correlated with niche specialization. Furthermore, we demonstrate the utility for marine microbial ecology of oligonucleotide probes based on gene sequences amplified from natural populations and show that a detailed knowledge of sequence variability may be needed to effectively design these probes.

Animals↗

PubMed1997

Relationship of visceral adipose tissue and glucose disposal is independent of sex in black NIDDM subjects.

To determine the interrelationship among insulin action, total or regional adiposity, and sex, we measured insulin-mediated glucose disposal by the euglycemic insulin clamp and adipose distribution using computed axial tomography (22 scans) in 32 black men and 20 black women with non-insulin-dependent diabetes mellitus (age 48 +/- 9 and 54 +/- 9 yr, body mass index 26.3 +/- 2.3 and 27.2 +/- 2.6 kg/m2, respectively). Women had approximately 80% more total and subcutaneous fat volume than men (31.8 +/- 8.3 vs. 18.6 +/- 6.1 and 28.5 +/- 7.3 vs. 14.7 +/- 4.6 liters) and less muscle volume (22.9 +/- 3.7 vs. 35.1 +/- 3.8 liters). Visceral fat volume did not differ between men and women (3.49 +/- 1.65 vs. 2.96 +/- 1.22 liters). Despite these body composition differences, an inverse nonlinear relationship existed between glucose disposal and visceral fat independent of sex (r = -0.58, P < 0.0001; men r = -0.60 and women r = -0.59; the slope and intercept were not different in men and women). Visceral fat explained a significant portion (34%) of variance in insulin-mediated glucose disposal, whereas total or subcutaneous fat and sex did not. Visceral fat appears to affect glucose disposal over a restricted range (up to approximately 2.5 l/m2 body surface area.

Adipose Tissue↗

PubMed1997

Cell cycle effects of nitric oxide on vascular smooth muscle cells.

We characterized the cell cycle block induced by nitric oxide (NO) on smooth muscle cells (SMC). We hypothesized that the inhibition of SMC proliferation by NO was due to a specific block in cell cycle progression. Treatment of cultured rat aortic SMC with the NO donors S-nitroso-N-acetylpenicillamine or S-nitrosoglutathione (0.1 mM for 48 h) resulted in a 50% decrease (P < 0.05) in the fraction of cells in the S and G2 + M phases and a corresponding increase in the G1 fraction, suggesting that NO inhibits entry into S phase, causing accumulation of cells in G1 phase. Application of both NO donors to cycling SMC resulted in a short-term, concentration-dependent (0.06-0.3 mM) inhibition of ongoing DNA synthesis as measured by radiothymidine incorporation, demonstrating that NO causes an S-phase arrest. The S-phase arrest by NO was not mimicked by exogenous guanosine 3',5'-cyclic monophosphate (cGMP, 10 mM) and was associated with, but not due to, a 20% inhibition of RNA synthesis. The S-phase block was completely reversed within 2 h of removal of the NO donors, similar to inhibition by the ribonucleotide reductase inhibitor hydroxyurea. Prolonged treatment of SMC with either NO donor (0.1 mM) did not synchronize cells at the G1-S boundary as expected after a prolonged S-phase arrest, but instead induced a quiescent G0-like state characterized by a 12- to 18-h lag before DNA synthesis returned to normal levels after NO removal. These findings demonstrate that NO inhibition of SMC proliferation is associated with two distinct and reversible cell cycle arrests, an immediate cGMP-independent S-phase block followed by a shift back in the cell cycle from the G1-S boundary to a quiescent G0-like state.

Animals↗

PubMed1997

Carotid plaque morphology and clinical events.

BACKGROUND AND PURPOSE: Studies have suggested that B-mode ultrasonography can be used to determine carotid plaque composition and that specific plaque characteristics are associated with a worse clinical outcome. However, histological studies examining the relationship between carotid plaque morphology and clinical outcome have reported conflicting findings. Furthermore, few investigators have described plaque morphology in quantifiable terms. This study examines the association between the volume of carotid plaque constituents and preoperative ischemic neurological symptoms. Constituents examined were chosen based on their potential for identification by current diagnostic imaging modalities such as ultrasound or MRI. METHODS: Atherosclerotic plaques from 43 patients undergoing carotid endarterectomy were examined histologically, with sections obtained every 0.5 to 1 mm. The lesions were examined for the presence and quantity of fibrous intimal tissue, intraplaque hemorrhage, lipid core, necrotic plaque core, and calcification. The quantity of each constituent was compared in plaques removed from symptomatic patients with those excised from asymptomatic individuals. Differences were analyzed with a Kolmogorov-Smirnov statistic. RESULTS: There was no difference between plaques removed from asymptomatic and symptomatic patients with regard to the presence and volume of fibrous intimal tissue, intraplaque hemorrhage, the lipid core, the necrotic core, or calcification. CONCLUSIONS: In patients with highly stenotic carotid lesions who are undergoing carotid endarterectomy, gross plaque composition is similar regardless of preoperative symptom status. Given this similarity, it is unlikely that differences in the volume of intraplaque hemorrhage, lipid core, necrotic core, or calcification in atherosclerotic carotid plaques explain their embolic history.

Aged↗