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Biomedical subjects

J Knight

Publications and source records attributed to J Knight.

At least 19 recordsLinked to original sources
PubMed1999

The outcome of lumbar discectomy in elite athletes.

STUDY DESIGN: An outcomes assessment of 14 elite college athletes who had undergone lumbar disc surgery was performed using the SF-36, a validated questionnaire that assesses quality of life. OBJECTIVES: To determine the outcomes and results of lumbar disc surgery in an elite group of athletes and compare the results with those in the general population and in age-matched control subjects. SUMMARY OF BACKGROUND DATA: Lumbar disc surgery is reported to be a highly successful procedure with excellent results. The outcome in elite athletes has not been assessed and compared with population norms and age-matched control subjects. METHODS: Fourteen athletes from schools in the National Collegiate Athletic Association with a mean age of 20.7, underwent lumbar discectomy for radiculopathy refractory to conservative treatment. Ten had a single-level microdiscectomy, three a two-level microdiscectomy, and one a percutaneous discectomy. Patients were evaluated at a mean follow-up of 3.1 years, underwent a detailed clinical evaluation, and filled out the SF-36 questionnaire. RESULTS: All 14 patients had improvement of pain with elimination of the radicular component, took less medication than before surgery, and returned to recreational sports. Nine patients, all with a single level microdiscectomy, returned to varsity sports. Five athletes prematurely retired from competitive sports because of continued symptoms. Three of the athletes who retired underwent two-level procedures, and one had a percutaneous discectomy. SF-36 scores for bodily pain, physical role, and social and mental health roles were significantly lower in those athletes who retired. Patient scores were also compared with those in a group of noninjured age-and sport-matched college athletes. There were no differences between injured and noninjured athletes, but both groups had scores significantly lower than normal values in an age-matched group for bodily pain, physical role, general health, and social function. CONCLUSIONS: All patients were satisfied with their surgeries, were greatly improved, and were pain free in activities of daily living. For a single-level microdiscectomy, the success rate in elite athletes is excellent, with 90% of athletes able to return to a high level of competition. Two-level disease may be associated with a less favorable outcome.

Activities of Daily Living↗
PubMed1999

Frequency of p53 mutations in breast carcinomas from Ashkenazi Jewish carriers of BRCA1 mutations.

BACKGROUND: Breast carcinomas occurring in carriers of BRCA1 gene mutations may have a distinctly different pathway of molecular pathogenesis from those occurring in noncarriers. Data from murine models implicate loss of p53 (also known as TP53) gene function as a critical early event in the malignant transformation of cells with a BRCA1 mutation. Therefore, breast tumors from BRCA1 mutation carriers might be expected to exhibit a high frequency of p53 mutations. This study examined the frequency of p53 mutations in the breast tumors of Ashkenazi Jewish carriers and noncarriers of BRCA1 mutations. METHODS: Tumor DNA from carriers and noncarriers of BRCA1 mutations was screened for mutations in exons 4 through 10 of the p53 gene by use of the polymerase chain reaction and single-strand conformation polymorphism (SSCP) analysis of the amplified DNA. Direct sequencing was performed on gene fragments that showed altered mobility in SSCP analysis. RESULTS: Mutations in the p53 gene were detected in 10 of 13 tumors from BRCA1 mutation carriers versus 10 of 33 tumors from non-carriers (two-sided P = .007). The p53 mutations were distributed throughout exons 4 through 10 and included both protein-truncating and missense mutations in both groups. CONCLUSIONS: A statistically significantly higher frequency of p53 mutations was found in breast tumors from carriers of BRCA1 mutations than from noncarriers, which adds to the accumulating evidence that loss of p53 function is an important step in the molecular pathogenesis of BRCA1 mutation-associated breast tumors. This finding may have implications for understanding phenotypic differences and potential prognostic differences between BRCA1 mutation-associated hereditary breast cancers and sporadic cancers.

Adult↗
PubMed1999

Eicosanoid biosynthesis in an advanced deuterostomate invertebrate, the sea squirt (Ciona intestinalis).

The eicosanoid generating potential of tunic, branchial basket, intestine, ovary and tadpole larvae from the sea squirt, Ciona intestinalis, was examined using a combination of reverse phase high performance liquid chromatography, gas chromatography-mass spectrometry and enzyme immunoassay. All organs examined synthesized the lipoxygenase products 12-hydroxyeicosapentaenoic acid (12-HEPE) and 8-HEPE implying that both 8- and 12-lipoxygenase activity are widely distributed in this species. In addition, tunic and branchial basket generated significant amounts of 8,15-diHEPE and smaller amounts of 8,15-dihydroxyeicosatetraenoic acid (8,15-diHETE), while tunic alone generated small amounts of conjugated tetraene-containing material with a UV chromophore and mass ion characteristic of a lipoxin-like compound. The broad range lipoxygenase inhibitors, esculetin and nordihydroguaiaretic acid, both caused a significant dose dependent inhibition of 12-HEPE and 8,15-diHEPE biosynthesis in tunic, while the specific 5-lipoxygenase inhibitor, REV-5901, and the specific 5-lipoxygenase activating protein inhibitor, MK-866, had no observable effect on the lipoxygenase profile of this tissue. Tunic, branchial basket, intestine and ovary all generated significant amounts of prostaglandin (PG) E and PGF immunoreactive material and smaller amounts of thromboxane B immunoreactive material as measured by enzyme immunoassay. The non-specific cyclooxygenase (COX) inhibitor, indomethacin, the selective COX-1 inhibitors, resveratrol and valerylsalicylate, and the specific COX-2 inhibitors, NS-398, etolodac and DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2(5H)-furanone) all caused a significant dose dependent inhibition of the biosynthesis of PGE immunoreactive material. However, the specific COX-2 inhibitors were most effective, perhaps implying that a COX-2-like enzyme may be present in this species.

Animals↗
PubMed1998

A variant of paraoxonase (PON1) gene is associated with diabetic retinopathy in IDDM.

Serum paraoxonase is a glycoprotein which binds to high-density lipoproteins (HDL) and may prevent oxidation of LDL by hydrolyzing lipid peroxides. Two polymorphisms identified in the paraoxonase gene (Met-Leu 54 and Gln-Arg 192) have been associated with cardiovascular disease. Oxidative low-density lipoprotein (LDL) is also toxic to retinal capillary endothelial cells and pericytes, so that mildly modified LDL may contribute to the development of diabetic retinopathy. To investigate the potential significance of these polymorphisms in the pathogenesis of diabetic retinopathy in IDDM, 80 patients with diabetic retinopathy and 119 controls without diabetic retinopathy were investigated in the current project. The allelic frequency of leucine 54 (L) was significantly higher in the group with retinopathy than without retinopathy (73% vs. 57%, p < 0.001). The genotype L/L was strongly associated with the development of diabetic retinopathy (p < 0.001), but a similar association was not found with Gln-Arg 192. Leucine 54 is a risk factor for diabetic retinopathy.

Adolescent↗
PubMed1998

Adolescent medicine training in pediatric residency programs: are we doing a good job?

OBJECTIVES: To determine how pediatric residency programs are responding to the new challenges of teaching adolescent medicine (AM) to residents by assessing whether manpower is adequate for training, whether AM curricula and skills are adequately covered by training programs, what types of teaching methodologies are used to train residents in AM, and the needs for new curricular materials to teach AM. DESIGN: A 3-part 92-item survey mailed to all US pediatric residency training programs. SETTING: Pediatric residency programs. PARTICIPANTS: Residency program directors and directors of AM training. MAIN OUTCOME MEASURES: AM divisional structure, clinical sites of training, presence of a block rotation, and faculty of pediatric training programs; training materials used and desired in AM; perceived adequacy of coverage of various AM topics; competency of residents in performing pelvic examinations in sexually active teens; and manpower needs. RESULTS: A total of 155/211 (73.5%) of programs completed the program director and the AM parts of the survey. Ninety-six percent of programs (size range, 5-120 residents) had an AM block rotation and 90% required the AM block; those without a block rotation were more likely to be larger programs. Only 39% of programs felt that the number of AM faculty was adequate for teaching residents. Almost half of the programs reported lack of time, faculty, and curricula to teach content in substance abuse. Besides physicians, AM teachers included nurse practitioners (28%), psychologists (25%), and social workers (19%). Topics most often cited as adequately covered included sexually transmitted diseases (81.9%), confidentiality (79.4%), puberty (77.0%), contraception (76.1%), and menstrual problems (73.5%). Topics least often cited as adequately covered included psychological testing (16.1%), violence in relationships (20.0%), violence and weapon-carrying (29.7%), and sports medicine (29.7%). Fifty-eight percent of 137 respondents thought that all or nearly all of their residents were competent in performing pelvic examinations by the end of training; there was no difference between perceived competence and the residents' use of procedure books. Seventy-four percent used a specific curriculum for teaching AM; materials included chapters/articles (85%), lecture outlines (76.1%), slides (41.9%), videos (35.5%), written case studies (24.5%), computerized cases (6.5%), and CD-ROMs (3.2%). Fifty-two percent used Bright Futures, 48% used the Guidelines for Adolescent Preventive Services, and 14% used the Guide to Clinical Preventive Services for teaching clinical preventive services. Programs that used Bright Futures were more likely to feel that preventive services were adequately covered in their programs than those who did not (78% vs 57%). A majority of programs desired more learner-centered materials. CONCLUSIONS: Although almost all pediatric programs are now providing AM rotations, there is significant variability in adequacy of training across multiple topics important for resident education. Programs desire more learner-centered materials and more faculty to provide comprehensive resident education in AM.

Adolescent Medicine↗
PubMed1997

Generation and characterisation of monoclonal antibodies against rainbow trout, Oncorhynchus mykiss, leucocytes.

Monoclonal antibodies were raised against head kidney macrophages of the rainbow trout, Oncorhynchus mykiss. Despite the establishment of a significant number of different hybridoma clones, none of these released antibody specific for determinants only found on macrophages. Instead, all the monoclonal antibodies generated reacted with lymphocytes, granulocytes, and monocytes/macrophages, although thrombocytes (the platelet equivalents in fish) and erythrocytes were not recognized by these antibodies. Western blotting of solubilised macrophages revealed that two of the hybridoma lines, designated 21G6 and 21F11, reacted with at least five proteins of 80, 104, 110, 140, and > 170 kDa. Immunocytochemistry was performed on histological sections of trout alimentary canal, gill, liver, spleen, and haemopoietic head kidney using antibodies from several of the hybridoma lines, and all of these showed a similar pattern of reactivity in each tissue. In the alimentary canal, for example, immunoreactive material was found in the eosinophilic granular cells, blood vessel margins, mucus in the lumen, and in the columnar epithelial cells. In the gills, epithelial cells and blood vessels also showed intense immunoreactive products, while in the liver, such reactivity was localised in the sinusoids and adherent macrophages. Both the spleen and head kidney had largely homogenous immunoreactivity.

Animals↗
PubMed1997

Factors associated with aggressive and delinquent behaviors among patients attending an adolescent medicine clinic.

PURPOSE: The purpose of this study was to examine the associations among delinquency/aggressiveness and alcohol or drug use, sexual risk behaviors, and other scales from the Problem-Oriented Screening Instrument for Teenagers (POSIT). METHOD: A total of 173 15- to 18-year-olds attending adolescent medicine clinic completed a 183-item questionnaire. The questionnaire contained the POSIT, the CAGE questions, a 22-item alcohol and drug screen (AOD), and a human immunodeficiency virus and sexual risk behavior screen. The dependent variable was the Aggressive Behavior/Delinquency (ABD) scale from the POSIT. RESULTS: There were no gender or racial differences in the ABD scale (p > 0.05). The ABD scale was significantly (p < or = 0.001) associated with the POSIT AOD scale (r = 0.46), the 22-item AOD drug screen (r = 0.57), the CAGE questions (r = 0.39), the sexual risk behavior scale (r = 0.39), and the POSIT physical health (r = 0.34), mental health (r = 0.51), family relations status (r = 0.37), peer relations (r = 0.57), educational status (r = 0.44), social skills (r = 0.31), and leisure/recreation (r = 0.16) scales. Multiple regression analysis indicated that the AOD screen and problems in the area of peer relations, family relations, and mental health accounted for 47.7% of the variation in the ABD scale (p < or = 0.00001). CONCLUSIONS: These findings suggest that adolescents who engage in more aggressive and delinquent behaviors are more likely to use alcohol and other drugs, engage in sexual risk behaviors, report problems with peer and family relationships, and report more mental health symptoms.

Adolescent↗
PubMed1997

Treatment of human prostate tumors PC-3 and TSU-PR1 with standard and investigational agents in SCID mice.

Both the PC-3 and the TSU-PR1 prostate tumor models were found to be satisfactory for chemotherapeutic investigations in ICR-SCID mice. The 30 to 60 mg fragments implanted took in all mice (as judged by 100% takes in the controls of all experiments as well as the passage mice). The tumor volume doubling time was 4.0 days for PC-3 and 2.5 days for TSU-PR1. Nine agents were evaluated IV against early stage subcutaneous PC-3 tumors, with Nano-piposulfan being the only agent highly active (4.9 log kill). Three other agents were moderately active: Taxol (1.5 log kill), Cryptophycin-8 (1.6 log kill), Vinblastine (1.0 log kill). Five agents were inactive: VP-16, Adriamycin, CisDDPt, 5-FUra, and Cyclophosphamide. Ten agents were evaluated IV against early stage subcutaneous TSU-PR1 tumors. Three agents were highly active, producing > 6 log kill and cures: Taxol (5/5 cures), Cryptophycin-8 (5/5 cures), Vinblastine (2/4 cures). Two other agents were moderately active: Nano-piposulfan (1.2 log kill), and Cyclophosphamide (1.1 log kill). Five agents were inactive: VP-16, Adriamycin, CisDDPt, 5-FUra, and BCNU. In part, activity was determined by the ability of the SCID mice to tolerate meaningful dosages of the agents. Agents producing granulocyte toxicity (e.g., Adriamycin) were poorly tolerated and appeared less active than expected. Vinblastine, producing little or no granulocyte toxicity was very well tolerated and appeared to be more active than expected.

Aged↗
PubMed1997

Phenotypic and genotypic stability of multiple lines of transgenic pigs expressing recombinant human protein C.

The genotypic and phenotypic stability of four lines of transgenic pigs expressing recombinant human protein C in milk was examined. Two lines were established with a construct consisting of a 2.6 kb mouse WAP promoter and a 9.4 kb human protein C genomic DNA. Two lines were established with another construct consisting of a 4.1 kb mouse WAP promoter and a 9.4 kb human protein C genomic DNA. Genotypic stability was measured by transgene copy number transmission. Outbred offspring having a single transgene integration locus were established from a founder having three independent, multicopy loci. Phenotypic stability over multiple lactations was defined by the combination of recombinant human protein C expression levels and the isoform signature of recombinant human protein C in western blots. Both cDNA and genomic human protein C transgenes gave similar ranges of expression levels of about 100-1800 micrograms ml-1. Within a given outbred lineage having a single loci for the cDNA transgene, the expression levels ranged between 100-400 micrograms ml-1. Western blots of reduced recombinant protein C revealed that single chain content was not dependent on expression level and was consistent within each transgenic line, but varied between transgenic lines. This suggests that native swine genetics may play a role in selection of production herds with optimal post-translational proteolytic processing capability. Although swine are not conventional dairy livestock, it is agreed that the short generation times, multiple offspring per litter, stable paternal transmission of the transgene, and milk production capabilities of swine offer distinct advantages over conventional dairy livestock for the establishment of a herd producing a therapeutic recombinant protein.

Animals↗
PubMed1996

Onset of C. elegans gastrulation is blocked by inhibition of embryonic transcription with an RNA polymerase antisense RNA.

Cleavage and gastrulation initiation in Caenorhabditis elegans embryos are characterized by an invariant temporal and spatial pattern of cell divisions and cell movements. Although bulk embryonic transcription does not begin until gastrulation onset, some transcription can be detected as early as the 4-cell stage. To determine whether any early transcripts are required for normal cleavage-stage patterning, we blocked transcription in embryos by injecting hermaphrodite parental gonads with RNA antisense to the ama-1 gene, which encodes the large subunit of RNA polymerase II. This treatment prevented the expression of a reporter gene driven by an early embryonic promoter but did not detectably perturb the maternally controlled segregation of the germ line P granules or the pattern of cell division through the first four cleavages. In the fifth cell cycle, however, the two endodermal precursor (E) cells divided early and abnormally and failed to initiate gastrulation. The embryos arrested between the sixth and seventh cell cycles with less than 100 cells. These results indicate that embryonically transcribed gene products are required for gastrulation initiation. They also demonstrate the efficacy of a method for blocking embryonic transcription that may be useful in other organisms.

Animals↗
PubMed1996

Preclinical antitumor activity of CI-994.

CI-994 [aka: acetyldinaline; PD 123654; 4-acetylamino-N-(2'aminophenyl)-benzamide] (Figure 1) is a novel antitumor agent with a unique mechanism of action. It is the acetylated metabolite of dinaline, a compound previously identified as having cytotoxic and cytostatic activity against several murine and human xenograft tumor models. CI-994 had activity against 8/8 solid tumors tested (log cell kills at the highest non-toxic dose): pancreatic ductal adenocarcinoma #02 (4.7); pancreatic adenocarcinoma #03 (3.0; 1/6 cures); colon adenocarcinoma #38 (1.6); colon adenocarcinoma #51/A (1.1); mammary adenocarcinoma #25 (1.7); mammary adenocarcinoma #17/ADR (0.5); Dunning osteogenic sarcoma (4.0); and the human prostate carcinoma LNCaP (1.2). CI-994 had the same spectrum of activity in vivo as dinaline. It also behaved similarly in schedule comparison/toxicity trials. Prolonged administration with lower drug doses was more effective than short-term therapy at higher individual doses. If doses were kept between 40 and 60 mg/kg/injection, prolonged administration (> 50 days) was tolerated with no gross toxicity. Doses > or = 90 mg/kg/injection caused lethality after 4-5 days of administration. The maximum tolerated total dose was also increased with smaller individual doses administered for prolonged intervals. Clinical Phase I trials are ongoing with this agent.

Animals↗
PubMed1996

Preclinical anticancer activity of cryptophycin-8.

Cryptophycin-8 was prepared by the conversion of the epoxide group on cryptophycin-1 to a chlorohydrin. In the studies reported here, cryptophycin-8 was evaluated for preclinical activity against subcutaneous tumors of both mouse and human origin. At the highest non-toxic single course treatment, the following results were obtained (Table A). Cryptophycin-8 was less potent than cryptophycin-1 by approximately 4-fold; however, it was both more water soluble and had greater therapeutic efficacy, as demonstrated by % T/C, tumor cell log kill values, range of dose effectiveness and host cures.

Animals↗
PubMed1995

Co-crystallization of an ETS domain (PU.1) in complex with DNA. Engineering the length of both protein and oligonucleotide.

The PU.1 transcription factor is a member of the ets gene family of regulatory proteins. These molecules play a role in normal development and also have been implicated in malignant processes such as the development of erythroid leukemia. The Ets proteins share a conserved DNA-binding domain (the ETS domain) that recognizes a purine-rich sequence with the core sequence: 5'-C/AGGAA/T-3'. This domain binds to DNA as a monomer, unlike many other DNA-binding proteins. The ETS domain of the PU.1 transcription factor has been crystallized in complex with a 16-base pair oligonucleotide that contains the recognition sequence. The crystals formed in the space group C2 with a = 89.1, b = 101.9, c = 55.6 A, and beta = 111.2 degrees and diffract to at least 2.3 A. There are two complexes in the asymmetric unit. Production of large usable crystals was dependent on the length of both protein and DNA components, the use of oligonucleotides with unpaired A and T bases at the termini, and the presence of polyethylene glycol and zinc acetate in the crystallization solutions. This is the first ETS domain to be crystallized, and the strategy used to crystallize this complex may be useful for other members of the ets family.

Amino Acid Sequence↗