Biomedical subjects
Publications and source records attributed to T Harrison.
High affinity, selective hNK2 or hNK3 ligands can be prepared from the common template 1 in a few simple chemical operations. The hNK3 ligands 3 antagonise the calcium mobilisation caused by activation of hNK3 receptors expressed in CHO cells as measured using fura-2 microspectrofluorimetry.
5-Aminolevulinate synthase (EC 2.3.1.37) catalyzes the first reaction in the heme biosynthetic pathway in nonplant eukaryotes and some prokaryotes. Homology sequence modeling between 5-aminolevulinate synthase and some other alpha-family pyridoxal 5'-phosphate-dependent enzymes indicated that the residue corresponding to the Arg-439 of murine erythroid 5-aminolevulinate synthase is a conserved residue in this family of pyridoxal 5'-phosphate-dependent enzymes. Further, this conserved arginine residue in several enzymes, e.g., aspartate aminotransferase, for which the three-dimensional structure is known, has been shown to interact with the substrate carboxyl group. To test whether Arg-439 is involved in substrate binding in murine erythroid 5-aminolevulinate synthase, Arg-439 and Arg-433 of murine erythroid 5-aminolevulinate synthase were each replaced by Lys and Leu using site-directed mutagenesis. The R439K mutant retained 77% of the wild-type activity; its K(m) values for both substrates increased 9-13-fold, while the activity of R433K increased 2-fold and the K(m) values for both substrates remained unchanged. R439L had no measurable activity as determined using a standard 5-aminolevulinate synthase enzyme-coupled activity assay. In contrast, the kinetic parameters for R433L were comparable to those of the wild-type. Dissociation constants (Kd) for glycine increased 5-fold for R439K and at least 30-fold for R439L, while Kd values for glycine for both R433K and R433L mutants were similar to those of the wild-type. However, there was not much difference in methylamine binding among the mutants and the wild-type, excepting of a 10-fold increase in K(d)methylamine for R439L. R439K proved much less thermostable than the wild-type enzyme, with the thermotransition temperature, T1/2, determined to be 8.3 degrees C lower than that of the wild-type enzyme. In addition, in vivo complementation analysis demonstrated that in the active site of murine erythroid 5-aminolevulinate synthase, R439 is contributed from the same subunit as K313 (which is involved in the Schiff base linkage of the pyridoxal 5'-phosphate cofactor) and D279 (which interacts electrostatically with the ring nitrogen of the cofactor), while another subunit provides R149. Taken together, these findings suggest that Arg-439 plays an important role in substrate binding of murine erythroid 5-aminolevulinate synthase.
Heterocyclic replacements for the carboxamido group of the previously disclosed phenylglycinol-based human NK1 (hNK1) receptor antagonists have been investigated, ultimately leading to acyclic compounds with sub-nanomolar affinity for the hNK1 receptor.
The purpose of this study was to determine whether pediatric trauma patients were transferred from community hospitals to trauma centers more expeditiously than adults of similar injury acuity. The study analyzed the air medical activation time, defined as the time delay between patient arrival at community hospitals and subsequent request for air medical transport to a Level I trauma center. Retrospective analysis of all interfacility air medical trauma transports by one service from October 1994 to June 1995 identified 40 pediatric and 156 adult patients. The mean air medical activation times for pediatric and adult trauma Interfacility transports were 36.5 and 70.1 minutes, respectively (P = .016). The study shows that community hospitals are able to expedite transfer of pediatric trauma patients and suggests that transfer delays for adult trauma patients may be reducible.
This study's goal was to analyze aeromedical emergency medical services (EMS) endotracheal intubation (ETI) success rates for in-flight intubations, and to retrospectively compare in-flight ETI success rates with those achieved in hospital and trauma scene settings. Patients undergoing flight crew ETI during a 3-year study period were reviewed, and flight team-performed intubations were classified as in-flight, hospital (at referring hospital), or ground (at trauma scene). Flight crews attempted ETI in 302 patients, with success in 291 patients (96.4%). ETI success rates for in-flight, hospital, and ground groups were 94.2%, 96.8%, and 98.3%, respectively (P = .22). There were no differences among the groups in proportions of pediatric patients (P = .55) or multiple intubation attempts (P = .83). Use of paralytic agents was more frequent in ground and in-flight groups as compared with hospital group patients (P = .03). We conclude that with the aircraft and aeromedical crew studied, ETI was as likely to be successful in-flight as in other settings.
This study investigated the properties of a novel piperidine ether-based tachykinin NK1 receptor antagonist L-733,060, ((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenyl piperidine and its 2R,3R-enantiomer L-733,061 on [Ca2+]i mobilisation in Chinese hamster ovary cells transfected with human tachykinin NK1 receptors, compared to their effects in rodent cardiovascular and neurogenic plasma extravasation assays. Using FURA-2-imaging techniques, L-733,060 inhibited substance P-induced [Ca2+]i mobilisation with an estimated affinity of 0.8 nM whereas L-733,061 (30-300 nM) did not. No significant effects of L-733,060 were observed on mean arterial blood pressure or heart rate in conscious or anaesthetised rats at doses of < 3000 micrograms kg-1 i.v. L-733,060 also stereoselectively inhibited neurogenic plasma extravasation in rat dura produced by electrical stimulation of trigeminal nerves with an ID50 of 212 +/- 19 micrograms kg-1 i.v. Thus, L-733,060 is a novel antagonist of human tachykinin NK1 receptors which stereoselectively inhibits neurogenic plasma extravasation at doses that do not cause adverse cardiovascular effects.
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To evaluate the role of aspiration cytology in the distinction between neoplastic and non-neoplastic ovarian cysts, we examined the cytology of 81 aspirates from 80 women 14-67 years of age. We then correlated results with subsequent histology or the clinical follow-up. Aspiration were performed during laparoscopy (32 cases) or immediately after surgical removal of the tumors (49 cases). The cysts ranged in size from 1.0 to 43.0 cm. Papanicolaou-stained cytospin preparations of samples were evaluated, and the lesions were classified into non-neoplastic (68 cases), benign neoplasms (four cases), and malignant neoplasms (nine cases). Cytologic impressions were correlated with histologic findings in 74 cases and with the clinical follow-up in the remaining seven. Nine of the 12 (75%) cystadenocarcinomas, including two serous neoplasms of low malignant potential (LMP), were correctly diagnosed as malignant by cytology. There were no false-positive results. On the other hand, of the 26 benign neoplasms (19 cystadenomas and seven mature cystic teratomas), only four teratomas (15%) could be subclassified specifically. The remaining 68 aspirates were classified as non-neoplastic. Seventy-seven percent of all proven non-neoplastic cysts measured < 8.0 cm, whereas 77% of all benign and malignant neoplastic cysts were > 8.0 cm. The overall diagnostic accuracy was improved from 63% to 69% when cyst size was taken into consideration. In malignant cysts the diagnostic sensitivity was 75%, specificity 100%, and overall accuracy 96%. We arrived at the following conclusions: Aspiration cytology is an accurate predictor of malignancy in ovarian cystic lesions, but because the sensitivity of the technique is not high enough, one should not rely on aspiration cytology alone; The differential diagnosis between cystadenocarcinomas and tumors of low malignant potential cannot be made by cytology; Although it is difficult to distinguish between benign neoplasms and non-neoplastic benign cysts, diagnostic accuracy will improve when the size of the lesion is considered; Aspiration cytology can provide particularly useful information in young women with functional cysts of the ovary to avoid an unnecessary operation; Acellular cyst fluids should not be considered nondiagnostic because they represent benign cysts in the majority of cases; false-negative results of fine-needle aspiration of cystic ovarian lesions is usually due to low cellularity of the sample and secondary degenerative changes; negative fine-needle aspiration results should be followed clinically.
A 900bp DNA fragment of hepatitis B virus surface antigen gene by digesting BamHI and HpaI sites on the open reading frame of HBV DNA on plasmid pEcob6 containing double copes of HBV DNA was cloned into SmaI site on the phagmide vector pBluescribt SK +. From this recombinant vector, 12 hepatitis B virus surface antigen gene mutants were obtained by oligonucleotide-mediated site directed mutagenesis. The expression vector-pMEP4HBS mutants are constructed by sub-cloning all of these mutant fragments of hepatitis B virus surface antigen gene on pBluescritSK+HBSM into BsmHI and KpnI sites on an Epstein-Barr virus based on eukaryotic expression vector-pMEp4. The vector pMEp4HBSMs were transfected to human hepatocellular carcinoma cell line-HepG2 by calcium phosphate mediated transfection, and resistant cell clones were obtained 3 weeks after selecting by hygromycine B. The results of detection of HBsAg excreted by resistant cell clones with monoclonal antibody to HBsAg showed that all antibody escape mutants of HBsAg except mutant 145R, a substitution of arginine for glycine at amino acid 145 position in HBsAg, were positive.
BACKGROUND: Epithelial ovarian carcinoma in women less than or equal to 25 years of age is a rare entity. This study used the database of the National Survey of Ovarian Carcinoma to analyze the disease and survival in women less than or equal to 25 years of age. METHODS: Tumor registries of 1230 hospitals were asked to enter the first 25 patients with histologically confirmed ovarian carcinoma from January 1 to December 31, 1983 and from January 1 to December 31, 1988. Data for a total of 12,136 patients were collected. Survival analysis and long-term evaluations were available on patients diagnosed with cancer in 1983. Chi-square analysis was used to compare the frequencies of operations performed in 1983 and 1988. RESULTS: Of 12,136 patients with epithelial ovarian carcinoma, 135 (1.1%) were less than or equal to 25 years of age. The majority of patients had early disease with the following distributions: stage I, 58.5%; stage II, 8.9%; stages III and IV, 28.9%. More patients had early-grade lesions with the following distributions: borderline, 21.5%; Grade 1, 27.4%; Grade 2, 11.1%; Grade 3, 6.7%; and unknown grade, 33.3%. Optimal cytoreduction was achieved in 77% of patients. During the 5-year study period, there was a significant change in the patterns of care toward more conservative surgery. In particular, unilateral salpingooophorectomy increased significantly from 38.2 to 59.7% (P = 0.0237), whereas hysterectomy decreased proportionally from 54.4 to 29.9% (P = 0.0039). The overall 5-year survival rate was 87.3% with the following divisions: stage I, 96.7%; stage II, 90.0%; stage III, 78.5%; and stage IV, 76.4%. Regarding histologic grade, 5-year survival rates were: borderline, 91.6%; Grade 1, 93.7%; Grade 2, 85.7%; Grade 3, 33.3%. CONCLUSION: Young patients with epithelial ovarian carcinoma appeared to have favorable stage and histologic grade. These factors combined with good performance status and optimal cytoreduction resulted in improved survival from cancer.
BACKGROUND: An analysis was conducted by the American College of Surgeons Cancer Commission evaluating the patterns of care of ovarian cancer patients diagnosed in 1983 and 1988. The purpose of this study was to investigate whether there was a difference in the care patterns of elderly ovarian cancer patients and its impact on survival. METHODS: Data were collected from 25 consecutive patients whose disease was diagnosed initially at 904 participating hospitals with cancer programs in 1983 and 1988. The survival and care of patients greater than or equal to 80 years of age were compared to those less than 80 years of age. RESULTS: Of the 12,316 patients evaluated, 1,115 were 80 years or older. A significant reduction in survival was noted among patients 80 years and older as compared to their younger counterparts (P = 0.03-0.00001). The 5-year survivals were: stage I, 89% versus 79%; stage II, 58% versus 40%; stage III, 25% versus 11%; and stage IV, 13% versus 3%, respectively, for those less than 80 years old as compared to those greater than or equal to 80 years old. Most elderly ovarian cancer patients were cared for by nononcologists such as general surgeons (31%) and obstetricians/gynecologists (29%). As a group, older patients had fewer total abdominal hysterectomies, bilateral salpingo-oophorectomies, and omentectomies than their younger counterpart (P < 0.00001). As further evidence for a less aggressive surgical approach, the optimal tumor debulking rates of women greater than or equal to 80 years were significantly less than those of younger patients (P < 0.001). There was no significant increase in anesthesia complications between age groups. Generally, older patients are less likely to receive adjuvant chemotherapy than younger patients (42% versus 69%, P < 0.0001). CONCLUSION: It appears that conservative treatments contributed to the decreased survival of older ovarian cancer patients.
Precore defective HBV mutants may gradually prevail because of immune selection and explain spontaneous seroconversion from HBeAg to anti-HBe in HBV carriers. We have analyzed whether the presence of precore HBV mutants is a determinant of responsiveness to interferon-alpha therapy. Fifteen carriers (nine responders and six nonresponders) who were treated with interferon-alpha were examined. Serum samples were collected before and after therapy. After extraction of DNA, the precore region was amplified by the polymerase chain reaction, and the product was identified by gel electrophoresis and ethidium bromide staining and then Southern blotting and molecular hybridization. The amplified products in all patients were asymmetrically amplified by a modified polymerase chain reaction, and the precore region was directly sequenced. All patients were HBV DNA positive initially. Circulating HBeAg-negative mutants were not identified before treatment in either responders or nonresponders. All nine responders were negative for HBV DNA in serum by dot blot during or after treatment, but seven remained positive by polymerase chain amplification and Southern-blot hybridization. All of the nonresponders remained positive for HBV DNA by dot blot. A silent mutation involving the substitution of an A for G at position 1888 was found in seven carriers; however, no HBeAg-negative mutants were detected in the follow-up of either responders or nonresponders to interferon-alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
The Northfield Experiments took place at Hollymoor Hospital, Northfield, Birmingham, during World War II. The first experiment was conducted by Bion & Rickman. The second evolved gradually; many people contributed to its success, including Foulkes, Main and Bridger. The experiments were an important landmark in the evolution of theory and practice in group psychotherapy and in the therapeutic community movement. They were not carried out solely as responses to the need for mass treatment of neurotic disorders among army personnel; antecedent factors, the theoretical orientation of the practitioners and the nature of army life were equally important. The two experiments differed in pace and in recognition of the needs of higher-order systems, particularly the military hierarchy. They shared many underlying concepts, including responsibility to society, the therapeutic use of groups (including the hospital community) and an emphasis on process. Lessons learned at Northfield remain relevant to the practice of psychiatry today.
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The low incidence of atherosclerosis and other degenerative diseases including stone disease in the Greenland Eskimo has been attributed to their high consumption of oily fish with its high concentration of eicosapentaenoic acid (EPA). Man cannot synthesis EPA from the precursor essential fatty acid, linolenic acid, and can only assimilate preformed EPA present in fish and fish oil, to bring about a change in the pathway of eicosanoid metabolism from the n-6 to the n-3 series. With a westernised diet the oxygenated products of renal prostaglandin synthesis are metabolites of the n-6 series and these are known to play an important role in several pathophysiological states including stone disease. Our previous studies have shown a relationship between prostaglandin activity and urinary calcium excretion and it would seem that the initiating factor/s for stone formation trigger the mechanisms for prostaglandin synthesis resulting in the biochemical abnormalities associated with stone disease. The Eskimo may be protected from these events by possession of an eicosanoid metabolism that follows an n-3 pathway. To test this hypothesis experiments were performed using an animal model of nephrocalcinosis. The animals were divided into three groups; one group was given an intra-peritoneal injection of 10% calcium gluconate daily for 10 days to induce nephrocalcinosis; a second group was fed MaxEPA fish oil before and during the calcium gluconate injections and a third group only received an intra-peritoneal injection of N saline. A group of 12 recurrent, hypercalciuric/hyperoxaluric stone-formers were treated with fish oil for eight weeks to study the effects on solute excretion. Nephrocalcinosis, which was readily produced in the control animals, was prevented in the experimental animals by pre-treatment with fish oil and urine calcium excretion was significantly reduced. The urinary calcium and oxalate excretion in the recurrent, hypercalciuric stone-formers was significantly reduced with fish oil treatment over an eight week period. There were no untoward side-effects. These studies indicate that the incorporation of EPA in the diet as a substitute metabolic pathway could be a unique way of correcting the biochemical abnormalities of idiopathic urolithiasis.
Infrared (1-20 micrometers) observations of comet Bradfield (1987s) from three observatories are reported. Silicate emission is prominent in all the data, from heliocentric distance r=0.87 to 1.45 AU. A CVF spectrum at r=1.45 AU shows a peak at 11.3 micrometers identified as crystalline olivine; the spectral shape is similar to that in Halley. Dust optical properties are similar to those of the grains in Halley's jets. Dust production rate near perihelion was approximately 10(6) g s-1 and varied in proportion to (r-2). We suggest that some differences in grain properties among comets could result from differences in the thermal history of the nuclear surface and the relative fraction of the dust particles originating in the subsurface icy layer versus the devolatilized mantle.