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Biomedical subjects

S D Harrison

Publications and source records attributed to S D Harrison.

At least 19 recordsLinked to original sources
PubMed1997

Atypical facial pain: a double-blind placebo-controlled crossover pilot study of subcutaneous sumatriptan.

A double-blind placebo-controlled crossover pilot study involving 19 patients was undertaken to evaluate the efficacy of subcutaneous sumatriptan, a selective 5-hydroxytryptamine (5-HT)-like receptor agonist, in the treatment of atypical facial pain (AFP). A reduction in total pain was found 120 min post injection in the sumatriptan group. Most patients, however, described the medication as ineffective overall, despite significant pain score reduction. The temporary improvement of pain scores with the active drug was thought to be too small to be of any clinical benefit, but suggests that vascular or neurogenic mechanisms may be involved in the aetiology of AFP. Sumatriptan is not an appropriate therapeutic option for patients with AFP, but could prove a valuable drug in experimental clinical pharmacology.

Adolescent↗
PubMed1997

Assessment of morbidity of semitendinosus and gracilis tendon harvest for ACL reconstruction.

This study evaluates the morbidity of harvest of both the semitendinosus and gracilis tendons for anterior cruciate ligament reconstruction on nine patients at a minimum of 3 year follow-up. Specifically, the effect on knee function, knee extension and flexion strength, the size of the individual posterior thigh muscles, and the extent of retraction of the semitendinosus and gracilis tendons were evaluated. At final follow-up, each patient was evaluated using the following functional scales: International Knee Documentation Committee (IKDC), Hospital for Special Surgery (HSS), Lysholm, and Tegner. Each patient also had a dynamometer evaluation and a comprehensive magnetic resonance imaging study of both the operated and nonoperated knees. The average functional evaluation scores were: HSS-47.9, Lysholm-88, and Tegner-0.27. The average percent quadriceps and hamstring strength of the operated compared with the nonoperated extremities were 93.7% and 95.3%, respectively; neither decrease was significant. Magnetic resonance imaging evaluation of the cross-sectional areas of the biceps femoris, semimembranosus, and sartorius muscles of both thighs at the same level above the joint were not significantly different. The distal-most insertion of the semitendinosus and gracilis tendons after harvest were always more proximal than the nonoperated side; the average difference was 26.7 mm (range: 11 to 32 mm) for the semitendinosus (unable to calculate in three patients) and 47.1 mm (range: 17 to 72 mm) for the gracilis. We conclude that tendon harvest of the semitendinosus and gracilis muscles does not significantly compromise function and strength despite a more proximal insertion of the retracted tendons. In addition, the majority of cases demonstrated some but never complete regrowth or scar formation of these tendon remnants.

Adult↗
PubMed1996

Loss of tramtrack gene activity results in ectopic R7 cell formation, even in a sina mutant background.

We have screened a collection of transposable-element-induced mutations for those which dominantly modify the extra R7 phenotype of a hypomorphic yan mutation. The members of one of the identified complementation groups correspond to disruptions of the tramtrack (ttk) gene. As heterozygotes, ttk alleles increase the percentage of R7 cells in yan mutant eyes. Just as yan mutations increase ectopic R7 cell formation, homozygous ttk mutant eye clones also contain supernumerary R7 cells. However, in contrast to yan, the formation of these cells in ttk mutant eye tissue is not necessarily dependent on the activity of the sina gene. Furthermore, although yan mutations dominantly interact with mutations in the Ras1, Draf, Dsor1, and rolled (rl) genes to influence R7 cell development, ttk mutations only interact with yan and rl gene mutations to affect this signaling pathway. Our data suggest that yan and ttk both function to repress inappropriate R7 cell development but that their mechanisms of action differ. In particular, TTK activity appears to be autonomously required to regulate a sina-independent mechanism of R7 determination.

Animals↗
PubMed1996

Upper gastrointestinal tract and abdomen: water as an orally administered contrast agent for helical CT.

PURPOSE: To evaluate the use of orally administered water as a negative contrast agent and intravenously administered glucagon in helical computed tomography (CT) of the upper abdomen. MATERIALS AND METHODS: Ninety-eight adult patients underwent 102 helical CT examinations. Patients received 700 mL of water orally 30 minutes before and another 350 mL of water orally with 1 mg of glucagon intravenously just before CT. The amount of water actually ingested was recorded. Luminal distention at five sites was graded on a three-point scale; depiction of six normal anatomic structures was evaluated. RESULTS: Luminal distention improved with the amount of water ingested in four of the five sites (P < .03 in three sites). Depiction of all six normal anatomic structures improved with increasing luminal distention (P < .001). The normal duodenal papilla was seen in 42% (83 of 198) of the examinations. Of 87 patients who had previously undergone CT with positive oral contrast agents, 89% (n = 77) preferred the water, 11% (n = 10) had no preference, and none preferred the positive agent (P < .001). Upper gastrointestinal tract abnormalities were easily recognized and depicted. CONCLUSION: Water is an efficacious negative contrast agent for evaluation of the upper gastrointestinal tract during helical CT.

Administration, Oral↗
PubMed1996

Cardiac-gated MR angiography of the entire lower extremity: a prospective comparison with conventional angiography.

OBJECTIVE: The purpose of this study was to prospectively evaluate cardiac-gated two-dimensional (2D) time-of-flight MR angiography in patients with peripheral arterial occlusive disease (PAOD). SUBJECTS AND METHODS: Twenty-three patients with PAOD were studied using cardiac-gated 2D time-of-flight MR angiography in the body coil from each patients' aortic bifurcation to the pedal arches. Blinded comparison with conventional angiograms was used to determine sensitivity, specificity, and positive and negative predictive values of this MR angiography technique. Kappa statistics were used to compare treatment plans of these patients studied with MR angiography and with conventional angiography. RESULTS: In the aortoiliac region, MR angiography had a correlation coefficient of .89 for all degrees of narrowing. For hemodynamically significant lesions, MR angiography had an 89% sensitivity, 98% specificity, 84% positive predictive value, and 99% negative predictive value. In the femoral region, MR angiography had a correlation coefficient of .91 for all degrees of narrowing. For hemodynamically significant lesions, MR angiography had an 89% sensitivity, 98% specificity, 93% positive predictive value, and 97% negative predictive value. In the popliteal region, MR angiography had a correlation coefficient of .93 for all degrees of narrowing. For hemodynamically significant lesions, MR angiography had an 89% sensitivity, 98% specificity, 94% positive predictive value, and 95% negative predictive value. In the tibioperoneal and foot regions, MR angiography had a correlation coefficient of 88% for all degrees of narrowing. For hemodynamically significant lesions, MR angiography had an 86% sensitivity, 93% specificity, 89% positive predictive value, and 91% negative predictive value. When the treatment planning data were classified into one of four outcomes (no intervention, surgery, percutaneous angioplasty, or further diagnostic study), MR angiography and conventional angiography had excellent agreement, with a Cohen's kappa value of .78. CONCLUSION: Cardiac-gated 2D time-of-flight MR angiography that uses the body coil provides a useful examination for PAOD with reasonable resolution. This imaging technique is potentially more time-efficient than techniques using extremity coils.

Aged↗
PubMed1996

Usefulness of turbo spin-echo MR imaging in the evaluation of meniscal tears: comparison with a conventional spin-echo sequence.

OBJECTIVE: Fast (turbo) spin-echo imaging techniques have replaced conventional spin-echo protocols in a large proportion of MR applications, with the principle advantage of decreased imaging time. The choice of echo train length is a key determinant of time savings realized, but the echo train length can also adversely affect image quality if too many echoes are incorporated into an image. Several recent studies have shown conflicting results regarding the usefulness of turbo spin-echo imaging in the evaluation of meniscal tears. We compare a turbo spin-echo sequence that has an echo train length of five with a conventional spin-echo sequence for evaluating meniscal tears. SUBJECTS AND METHODS: Forty knees in 39 consecutive patients referred for MR study of the knee were imaged using both conventional spin-echo and turbo spin-echo sequences. The turbo spin-echo sequence provided both proton density-weighted and T2-weighted images (dual echo technique) with an effective echo-train length of five. Nineteen knees (38 menisci) were studied arthroscopically. The arthroscopic findings were considered the reference standard. Spin-echo and turbo spin-echo images were reviewed retrospectively, and results were compared statistically. RESULTS: Of the 80 menisci evaluated with MR imaging, spin-echo and turbo spin-echo images provided concordant results in 95% of cases, with no statistically significant difference found between the two techniques (p < .05). Seventeen tears were found at arthroscopy in 38 menisci studied. Spin-echo and turbo spin-echo imaging had identical specificities (90%) and similar sensitivities (88% and 82%, respectively). CONCLUSION: This study shows that proton density-weighted sequences with an echo train length of five preserve sufficient high-spatial-frequency information to provide performance similar to that of conventional spin-echo sequences. Our data support the conclusion that fast spin-echo imaging with short echo train length is a reasonable substitute for conventional spin-echo imaging in the evaluation of the knee.

Adult↗
PubMed1995

Partial inhibition of multidrug resistance by safingol is independent of modulation of P-glycoprotein substrate activities and correlated with inhibition of protein kinase C.

Safingol is a lysosphingolipid protein kinase C (PKC) inhibitor that competitively interacts at the regulatory phorbol binding domain of PKC. We investigated the effects of safingol on antineoplastic drug sensitivity and PKC activity of MCF-7 tumor cell lines. Safingol treatment of 32P-labeled MCF-7 WT and MCF-7 DOXR cells inhibited phosphorylation of the myristoylated alanine-rich protein kinase C substrate in both cell lines, suggesting inhibition of cellular PKC. However, only in MCF-7 DOXR cells did safingol treatment increase accumulation of [3H]vinblastine and enhance toxicity of Vinca alkaloids and anthracyclines. Drug accumulation changes in MCF-7 DOXR cells treated with safingol were accompanied by inhibition of basal and phorbol 12,13-dibutyrate-stimulated phosphorylation of P-glycoprotein (P-gp). Expression of P-gp and levels of mdr1 message in MCF-7 DOXR cells were not altered by safingol treatment alone or in combination with vinblastine. Treatment of MCF-7 DOXR cell membranes with safingol did not inhibit [3H]vinblastine binding or [3H]azidopine photoaffinity labeling of P-gp. Furthermore, safingol did not stimulate P-gp ATPase activity in membranes prepared from MCF-7 DOXR cells. We conclude that enhanced drug accumulation and sensitivity in MCF-7 DOXR cells treated with safingol are correlated with inhibition of PKC rather than competitive interference with P-gp drug binding through direct interaction with P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Toxicity of the protein kinase C inhibitor safingol administered alone and in combination with chemotherapeutic agents.

Safingol [(2S,3S)-2-amino-1,3-octadecanediol] potentiates the toxicity of doxorubicin (DOX) and cisplatin (CIS) against tumor cells in vitro and in vivo. The present studies were conducted in rats and dogs to evaluate safingol toxicity when administered i.v. as a single agent and to evaluate safingol's ability to potentiate the toxicity of established chemotherapeutic agents to normal tissues in vivo. In an escalating dose study, dogs were administered safingol i.v. at 5, 10, 20, 30, 40, and 75 mg/kg on Days 1 through 6. Necropsies were performed on Day 7. Red urine was observed at 10 mg/kg and higher. Icterus was observed following 40 mg/kg with additional signs of hypoactivity and anorexia occurring after 75 mg/kg. Clinical and microscopic pathology revealed marked hepatotoxicity, venous degeneration and necrosis at injection sites, and evidence of intravascular hemolysis. Doses of 5, 20, or 40 mg safingol/kg were utilized in single i.v. dose rat and dog studies. No evidence of adverse systemic toxicity was seen up to 20 mg/kg in either species [for rats: Cmax = 12,600 (males) or 17,133 (females) ng/ml, AUC = 3853 (males) or 4365 (females) ng x hr/ml; for dogs: Cmax = 2533 ng/ml, AUC = 2851 ng x hr/ml (no sex differences)]. Local effects of venous irritation or intravascular hemolysis were observed at all doses in rats and at 20 and 40 mg/kg in dogs. A dose of 40 mg/kg [for rats: Cmax = 31,233 (males) or 91,300 (females) ng/ml, AUC = 11,519 (males) or 18,620 (females) ng x hr/ml; for dogs: Cmax = 9033 ng/ml, AUC = 11,094 ng x hr/ml (combined sex)] was associated with clinical pathologic and renal histomorphologic changes considered consequent to intravascular hemolysis in both species, lethality and testicular toxicity in rats, and clinical biochemical changes indicative of hepatobiliary injury in dogs. Studies indicated that hemolysis occurred during infusion, was not caused by circulating levels of safingol, and was a function of dose concentration and vein of delivery. Safingol at 10 or 20 mg/kg was administered i.v. to rats 30-60 min prior to myelosuppressive i.v. doses of DOX, CIS, or cyclophosphamide (CYP). Hematology, plus renal function and morphology for CIS-treated animals, was assessed 4 and 14 days later.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Response of human tumor xenografts in athymic nude mice to docetaxel (RP 56976, Taxotere).

Docetaxel (Taxotere, RP 56976, NSC 628503), a new taxoid, was evaluated for preclinical evidence of anticancer activity in athymic nude (NCr-nu) mice bearing established, subcutaneously (s.c.) implanted human tumor xenografts CX-1 or KM20L2 (colon carcinomas), LX-1 (lung carcinoma), MX-1 (mammary carcinoma), and SK-MEL-2 (melanoma). Other evaluations used OVCAR-3 (ovarian carcinoma) xenografts implanted intraperitoneally (i.p.). Docetaxel was administered intravenously (i.v.) every 4 days for 3 injections (q4d x 3) except for one OVCAR-3 experiment in which the drug was given i.p. every 7 days for 3 injections. Tumor measurements, animal body weights, and mortality were determined. The highest dosage used (50 mg/kg/dose) was toxic in all experiments in which the 4-day treatment interval was used. The maximally tolerated dosage (MTD) ranged from 15 to 33 mg/kg/dose. Therapeutic responses among these xenografts ranged from clinically important long-term tumor-free survivors (MX-1, SK-MEL-2, and OVCAR-3) to tumor growth delays of various durations (CX-1, LX-1, and KM20L2). The response of SK-MEL-2, a xenograft highly refractory to available drugs, was particularly noteworthy. These results are indicative of a broad spectrum of antitumor activity for docetaxel.

Animals↗
PubMed1995

A genetic analysis of the 63E-64A genomic region of Drosophila melanogaster: identification of mutations in a replication factor C subunit.

We have performed an F2 genetic screen to identify lethal mutations within the 63E-64A genomic region. We have isolated 122 mutations in 20 different complementation groups. Of these groups, 16 are represented by multiple alleles. We have also established that the Rop and Ras2 genes are located within the 63E-64A genomic domain at 64A10,11. We have sequenced 10.2 kb of DNA surrounding this gene pair and find that in addition to Rop and Ras2 there is another gene located within this DNA sequence. The gene product, which we have named Rfc40, shows 68% identity to the 40-kDa subunit of replication factor C. We find that the members of one complementation group (13 alleles) derived from our screen correspond to mutations in the Rop gene, whereas the members of another (five alleles) correspond to mutations in the Rfc40 gene. In addition we have isolated 11 new mutant alleles of the disembodied gene.

Amino Acid Sequence↗
PubMed1994

Antitumor activity and biochemical effects of aphidicolin glycinate (NSC 303812) alone and in combination with cisplatin in vivo.

Aphidicolin, an inhibitor of DNA polymerases alpha and delta, is cytotoxic in vitro against tumor cells. The poor solubility of aphidicolin has led to the development of aphidicolin glycinate (AG; NSC 303812), a water soluble ester currently in early clinical trials. The antitumor activity of AG was investigated in a series of transplantable murine tumors in vivo. The drug demonstrated activity against the i.p. implanted B16 melanoma, producing maximum increased life spans of 75% following i.p. administration every 3 h for three doses on days 1-9. Treatment schedules involving both single injections per day on days 1-9 and multiple injections per day on days 1, 5, and 9 were less effective, indicating that this antitumor activity is schedule dependent. Similarly, greater activity was observed against the i.p. M5076 sarcoma when three daily injections were given on days 1-9 (57% increased life span) than with a single injection either on days 1-9 (36% increased life span) or on days 1, 5, 9, and 13 (inactive). Further scheduling studies in the s.c. M5076 sarcoma model showed that a 7-day infusion was superior to both a 24-h infusion and a 7-day course of three bolus treatments per day. On the assumption that DNA polymerase inhibition is the basis for this antitumor activity, inhibition of DNA synthesis in BALB/c x DBA/2 F1 mice was investigated by measuring incorporation of [3H]thymidine (20 microCi, i.v.) into DNA of spleen and jejunum. At 2 h after administration of AG, inhibition of DNA synthesis was dose dependent (median inhibitory dose, 60 mg/kg in both tissues) and was > 99% at 300 mg/kg. The inhibition was rapid in onset; AG (100 mg/kg i.p.) produced maximal (> 98%) inhibition in both tissues at 30 min. Recovery occurred in the intestine within 16 h; in spleen recovery was delayed to 24 h, and was followed by a rebound incorporation at 48 h (203%). A comparison of the inhibition of thymidine incorporation in tumor cells (B16 melanoma and P388 leukemia) and normal jejunum revealed no significant differences in the extent of inhibition or the rapidity of recovery in these tissues. The rapid recovery of DNA synthesis inhibition supports the use of prolonged infusion schedules in clinical trials, but the lack of evidence of selectivity for tumor cells suggests that AG may be of limited therapeutic value as a single agent. Thus, we evaluated AG in combination with cisplatin in an in vivo model of cisplatin refractory human ovarian cancer.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Mutations in the Drosophila Rop gene suggest a function in general secretion and synaptic transmission.

The Drosophila protein Rop shows similarity with the Sec1p protein of S. cerevisiae. Sec1p has an essential role in secretion, whereas most related proteins from higher organisms are hypothesized to function in neurotransmitter release. We show that, like the latter proteins, Rop is expressed in the nervous system, but it is expressed in other tissues as well, many of which are actively engaged in secretion. We have isolated mutations in the Rop gene and find that the extracellular accumulation of a number of normally secreted cellular products fails to occur in null mutant animals, which subsequently die at a late embryonic stage. Electrophysiological recordings on temperature-sensitive Rop mutants show that reductions in Rop activity result in a loss of the normal synaptic response to a light stimulus. These data suggest that a member of the Sec1p class of proteins has an in vivo function in both general secretion and synaptic transmission.

Amino Acid Sequence↗
PubMed1993

The interaction of bride of sevenless with sevenless is conserved between Drosophila virilis and Drosophila melanogaster.

An inductive interaction between the sevenless (sev) transmembrane tyrosine kinase receptor and the bride of sevenless (boss) transmembrane ligand is required for the development of the R7 photoreceptor neuron in the compound eye of Drosophila melanogaster. The boss protein is proposed to contain a large N-terminal extracellular domain, seven transmembrane segments, and a C-terminal cytoplasmic tail. The boss protein from Drosophila virilis (bossvir) retains strong amino acid identity with loss from D. melanogaster (bossmel): 73% identity in the N-terminal extracellular domain and 91% identity in the seven-transmembrane domain, including the cytoplasmic tail. By using P-element-mediated DNA transformation, the bossmel and bossvir genes were shown to rescue the D. melanogaster boss1 mutation. The expression of bossvir protein in D. melanogaster is indistinguishable from that of bossmel protein. Noncoding sequences which may regulate boss expression were identified based on their conservation during evolution. The predicted sev protein from D. virilis (sevvir) was previously shown to be 63% identical to sev from D. melanogaster (sevmel). A chimeric gene, (sevvir/mel), encoding the extracellular domain of sevvir and the cytoplasmic domain of sevmel rescues the D. melanogaster sevd2 mutation through interaction with either bossvir or bossmel.

Amino Acid Sequence↗
PubMed1993

Twin growth problems: causes and sonographic analysis.

Understanding the significant increased risks associated with twin pregnancies requires knowledge of the embryogenesis of twins and the unique placental characteristics seen only in twin gestations. Dizygotic "fraternal" twins, 70% of all twins, are at relatively low risk when compared with monozygotic twins, largely due to abnormalities seen in association with monochorionic placentation. The sonographic determination of chorionicity and amnionicity allows better estimation of pregnancy risk--up to 50% mortality in monochorionic-monoamniotic twins. Careful evaluation of intrauterine twin growth assists in the early identification of fetal abnormalities because normal twin growth should parallel that of singleton pregnancies until late in the third trimester. A number of the unique complications affecting growth in twin pregnancies are discussed, including twin transfusion syndrome, the "stuck twin" phenomenon, twin embolization syndrome, and development of acardiac twins.

Embryonic and Fetal Development↗
PubMed1992

Elevated DT-diaphorase activity and messenger RNA content in human non-small cell lung carcinoma: relationship to the response of lung tumor xenografts to mitomycin Cł.

The enzyme DT-diaphorase (DTD; NAD(P)H:quinone oxidoreductase, EC 1.6.99.2), is an obligate two electron reductase which catalyzes reduction of a broad range of substrates, including quinones. We report here variations in DTD concentrations among different classes of lung tumors known also to vary in their responsiveness to cytotoxic agents. Small cell lung carcinomas (SCLCs) and cell lines derived from them have the low DTD activities and mRNA content characteristic of normal human lung, whereas non-small cell lung carcinomas (NSCLCs) have greatly elevated levels. DTD activity was increased up to 80-fold in NSCLC tumors relative to normal lung and 20-35-fold in NSCLC relative to SCLC cell lines. Increased DTD activity appeared to be a function of the NSCLC phenotype rather than a result of derivation from a cell type rich in DTD, since all histological classes of NSCLC showed this phenotype. In addition, where transfection of SCLC cell lines with the v-Ha-ras protooncogene caused a transition to a NSCLC phenotype, DTD activity was also elevated. Neuroendocrine-positive cells (SCLC, carcinoids, and a few NSCLC lines) typically had far lower DTD activities than did cell lines which lacked neuroendocrine markers (most NSCLC cells and mesotheliomas). High DTD activity may be exploited in the design of drugs which undergo bioreductive activation by this enzyme. Consistent with this, xenografts derived from NSCLC cell lines with high DTD that were grown in athymic nude mice were more susceptible to the antitumor quinone, mitomycin C, than were xenografts derived from SCLC cells containing low DTD. These data provide a mechanistic basis for the rational design of more effective bioreductive antitumor agents for use against NSCLC.

Animals↗