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Biomedical subjects

D Ferguson

Publications and source records attributed to D Ferguson.

At least 19 recordsLinked to original sources
PubMed2000

Defective embryonic neurogenesis in Ku-deficient but not DNA-dependent protein kinase catalytic subunit-deficient mice.

Mammalian nonhomologous DNA end joining employs Ku70, Ku80, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4, and DNA ligase IV (Lig4). Herein, we show that Ku70 and Ku80 deficiency but not DNA-PKcs deficiency results in dramatically increased death of developing embryonic neurons in mice. The Ku-deficient phenotype is qualitatively similar to, but less severe than, that associated with XRCC4 and Lig4 deficiency. The lack of a neuronal death phenotype in DNA-PKcs-deficient embryos and the milder phenotype of Ku-deficient versus XRCC4- or Lig4-deficient embryos correlate with relative leakiness of residual end joining in these mutant backgrounds as assayed by a V(D)J recombination end joining assay. We conclude that normal development of the nervous system depends on the four evolutionarily conserved nonhomologous DNA end joining factors.

Animals↗
PubMed2000

5,6-Dihydropyran-2-ones possessing various sulfonyl functionalities: potent nonpeptidic inhibitors of HIV protease.

On the basis of previous SAR findings and molecular modeling studies, a series of compounds were synthesized which possessed various sulfonyl moieties substituted at the 4-position of the C-3 phenyl ring substituent of the dihydropyran-2-one ring system. The sulfonyl substituents were added in an attempt to fill the additional S(3)' pocket and thereby produce increasingly potent inhibitors of the target enzyme. Racemic and enantiomerically resolved varieties of selected compounds were synthesized. All analogues in the study displayed decent binding affinity to HIV protease, and several compounds were shown to possess very good antiviral efficacy and safety margins. X-ray crystallographic structures confirmed that the sulfonamide and sulfonate moieties were filling the S(3)' pocket of the enzyme. However, the additional substituent did not provide improved enzymatic inhibitory or antiviral activity as compared to the resolved unsubstituted aniline. The addition of the sulfonyl moiety substitution does not appear to provide favorable pharamacokinectic parameters. Selected inhibitors were tested for antiviral activity in clinical isolates and exhibited similar antiviral activity against all of the HIV-1 strains tested as they did against the wild-type HIV-1. In addition, the inhibitors exhibited good antiviral efficacies against HIV-1 strains that displayed resistance to the currently marketed protease inhibitors.

Animals↗
PubMed2000

Impact of sample type on rapid detection of influenza virus A by cytospin-enhanced immunofluorescence and membrane enzyme-linked immunosorbent assay.

Cytospin-enhanced direct fluorescent-antibody assay (DFA) detected 49 (92.5%) and rapid membrane enzyme-linked immunosorbent assay (ELISA) detected 40 (75.5%) of 53 influenza virus A-positive samples. All 15 positive nasopharyngeal aspirates from children were detected by both tests. In contrast, 34 of 38 (89.5%) positive swabs from adults were detected by DFA, but only 25 (66%) were detected by ELISA.

Adult↗
PubMed2000

SimulFluor respiratory screen for rapid detection of multiple respiratory viruses in clinical specimens by immunofluorescence staining.

A new rapid direct immunofluorescence assay (DFA) respiratory screen reagent for detection of seven common respiratory viruses (respiratory syncytial virus [RSV], influenza A and B viruses, parainfluenza virus types 1 to 3, and adenovirus) was compared with standard single or dual DFA reagents and culture. In total, 1,531 respiratory samples were adequate for testing with both SimulFluor Respiratory Screen (RS) reagent (Chemicon International, Temecula, Calif.) and single or dual DFA reagents. The RS DFA reagent detected 367 (98.4%) and single or dual DFA reagents detected 368 (98.7%) of 373 DFA-positive samples. In addition, the RS DFA reagent was equivalent to or better than culture for detection of all viruses except adenovirus. Only 15 of 799 (1.9%) RS-negative samples inoculated into cell cultures yielded respiratory virus isolates (one RSV, five influenza A virus, two influenza B virus, one parainfluenza virus, and six adenovirus). Sixty-six other virus isolates (13 rhinovirus, 24 cytomegalovirus, 28 herpes simplex virus type 1, and 1 enterovirus) were also recovered in culture. With cytospin preparation of slides, only 7.5% of samples submitted were deemed inadequate for DFA. The availability of a rapid DFA screening reagent for detection of multiple common respiratory viruses within 1 to 2 h of sample collection should be of great benefit in terms of patient management and infection control.

Adenoviruses, Human↗
PubMed2000

A multisite trial comparing two cytomegalovirus (CMV) pp65 antigenemia test kits, biotest CMV brite and Bartels/Argene CMV antigenemia.

A total of 513 blood specimens, predominantly from organ transplant recipients, human immunodeficiency virus-positive patients, and bone marrow transplant recipients, were tested for cytomegalovirus (CMV) by culture and pp65 antigenemia across four test sites. Peripheral blood leukocytes were examined by using both the Biotest CMV Brite and the Bartels/Argene CMV Antigenemia kits. A total of 109 specimens were positive for CMV, 106 (97%) were positive by antigenemia, and 34 (31%) were positive by culture. According to the manufacturers' instructions, 150,000 cells were applied per slide for the Biotest kit and 200,000 cells per slide for the Bartels kit. A total of 93 specimens (88%) were positive by the Biotest kit, and 86 (81%) were positive by the Bartels kit. In specimens found to be positive by only one kit, the positive cell counts were low (median, 1; range, 1 to 7). When the data from all four sites were combined and analyzed, there was no statistical difference between the performance of the two kits; the Biotest and Bartels kits were found to be equivalent in sensitivity, specificity, and positive and negative predictive values for the detection of CMV pp65 antigenemia.

AIDS-Related Opportunistic Infections↗
PubMed2000

Report of the international consensus development conference on female sexual dysfunction: definitions and classifications.

PURPOSE: Female sexual dysfunction is highly prevalent but not well defined or understood. We evaluated and revised existing definitions and classifications of female sexual dysfunction. MATERIALS AND METHODS: An interdisciplinary consensus conference panel consisting of 19 experts in female sexual dysfunction selected from 5 countries was convened by the Sexual Function Health Council of the American Foundation for Urologic Disease. A modified Delphi method was used to develop consensus definitions and classifications, and build on the existing framework of the International Classification of Diseases-10 and DSM-IV: Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association, which were limited to consideration of psychiatric disorders. RESULTS: Classifications were expanded to include psychogenic and organic causes of desire, arousal, orgasm and sexual pain disorders. An essential element of the new diagnostic system is the "personal distress" criterion. In particular, new definitions of sexual arousal and hypoactive sexual desire disorders were developed, and a new category of noncoital sexual pain disorder was added. In addition, a new subtyping system for clinical diagnosis was devised. Guidelines for clinical end points and outcomes were proposed, and important research goals and priorities were identified. CONCLUSIONS: We recommend use of the new female sexual dysfunction diagnostic and classification system based on physiological as well as psychological pathophysiologies, and a personal distress criterion for most diagnostic categories.

Female↗
PubMed1999

Nonpeptidic HIV protease inhibitors: 6-alkyl-5,6-dihydropyran-2-ones possessing a novel and achiral 3-(2-t-butyl-5-methyl-4-sulfamate)phenylthio moiety.

Dihydropyran-2-ones possessing a sulfamate moiety at the 4-position of the thiophenyl ring were designed to reach S3' pocket of the HIV protease. Synthetic routes for the preparation of thiotosylates possessing 3-(2-t-butyl-5-methyl-4-sulfamate) phenylthio moiety were established. SAR of various sulfamate analogs including HIV protease binding affinities, antiviral activities and therapeutic indices will be described.

Animals↗
PubMed1999

4-hydroxy-5,6-dihydro-2H-pyran-2-ones.3. Bicyclic and hetero-aromatic ring systems as 3-position scaffolds to bind to S1' and S2' of the HIV-1 protease enzyme.

5,6-Dihydro-2H-pyran-2-ones are potent inhibitors of HIV-1 protease, which bind to the S1, S2, S1', and S2' pockets and have a unique binding mode with the catalytic aspartyl groups and the flap region of the enzyme. Efforts to explore 3-position heterocyclic scaffolds that bind to the S1' and S2' pockets have provided a number of selected analogs that display high HIV-1 protease inhibitory activity. reserved.

Binding Sites↗
PubMed1999

Nonpeptidic HIV protease inhibitors: 6-alkyl-5,6-dihydropyran-2-ones possessing achiral 3-(4-amino/carboxamide-2-t-butyl,5-methylphenyl thio) moiety: antiviral activities and pharmacokinetic properties.

Dihydropyran-2-ones possessing amino and carboxamide functionalities on 3-SPh (2-tert-butyl, 5-methyl) ring were synthesized and evaluated for their antiviral activities. Both the enantiomers of inhibitor 15 were synthesized. The in vitro resistance profile, inhibitory activities against cytochrome P450 isozymes and pharmacokinetic properties of inhibitor 15S will be discussed.

Animals↗
PubMed1999

Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: a lead HIV protease inhibitor.

With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydropyran-2-ones bound to HIV PR, inhibitors possessing various alkyl groups at the 6-position of 5,6-dihydropyran-2-one ring were synthesized. The inhibitors possessing a 6-alkyl group exhibited superior antiviral activities when compared to 6-phenyl analogues. Antiviral efficacies were further improved upon introduction of a polar group (hydroxyl or amino) on the 4-position of the phenethyl moiety as well as the polar group (hydroxymethyl) on the 3-(tert-butyl-5-methyl-phenylthio) moiety. The polar substitution is also advantageous for decreasing toxicity, providing inhibitors with higher therapeutic indices. The best inhibitor among this series, (S)-6-[2-(4-aminophenyl)-ethyl]-(3-(2-tert-butyl-5-methyl-phenylsulfa nyl)-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (34S), exhibited an EC50 of 200 nM with a therapeutic index of > 1000. More importantly, these non-peptidic inhibitors, 16S and 34S, appear to offer little cross-resistance to the currently marketed peptidomimetic PR inhibitors. The selected inhibitors tested in vitro against mutant HIV PR showed a very small increase in binding affinities relative to wild-type HIV PR. Cmax and absolute bioavailability of 34S were higher and half-life and time above EC95 were longer compared to 16S. Thus 34S, also known as PD 178390, which displays good antiviral efficacy, promising pharmacokinetic characteristics and favorable activity against mutant enzymes and CYP3A4, has been chosen for further preclinical evaluation.

Cell Line↗
PubMed1999

A comparison of hip guidance with reciprocating gait orthoses in children with spinal paraplegia: results of a ten-year prospective study.

Twenty-two children with spinal paraplegia were entered into a prospective randomised study to assess the efficacy of two reciprocating orthoses and to identify any prognostic factors that might affect continuing use of the devices. Thirteen received a hip guidance orthosis (HGO) and nine a reciprocating gait orthosis (RGO). They were followed for a mean of ten years. At one year follow-up there were three statistically significant differences between the two groups at the 5% level: repairs were commoner in the RGO group, the RGO group improved in their ability to walk over difficult outdoor surfaces and the HGO group improved more in their ability to rise from a sitting to standing position. At one year follow-up there was a positive parental and child's view of the benefits of the orthoses, but by ten years only 24% of the patients were still using the orthoses. We were not able to show any definite advantage of one device over the other or any statistically significant prognostic factors for walking in the longer term with a reciprocating orthosis. We question whether or not the routine provision of these types of orthosis is justifiable when it appears that, in the longer term, the patients we studied preferred wheelchair mobility.

Adolescent↗
PubMed1999

Ethnic dental analysis of shovel and Carabelli's traits in a Chinese population.

Chinese populations differ from Caucasoids by having a high prevalence of shovel trait and a low prevalence of Carabelli's trait. This study was conducted to investigate the association between the shovel and the Carabelli's traits in a Chinese population. The research design investigated a Chinese population that resides in southern Taiwan. The ancestors of this Chinese population migrated to Taiwan from mainland China, mainly from Fukien and Kwangtung. The effects of sex and age on Carabelli's trait were controlled in this investigation, as was the association between tooth size and Carabelli's trait. Results show that males were more likely to have Carabelli's trait expressed on teeth than females. The buccolingual diameter of Carabelli's trait teeth was larger than that of teeth without the trait. After controlling for sex, age, and tooth size, the existence of the shovel trait increased the likelihood of having Carabelli's trait by a factor of five and a half, which is a significant effect.

Adolescent↗
PubMed1999

Preliminary clinical experience of a contracture correction device.

Joint contractures which do not respond to conventional physiotherapy can be difficult to treat. Serial plastering has been used effectively but is expensive, inconvenient to the patient and does not permit daily hygiene or clinical inspection. A mechanical device has been developed consisting a hinged orthosis which spans the affected joint to which is attached a gas strut to provide a corrective moment about the anatomical joint. Such an arrangement enables prescribed corrective moments to be applied accurately following clinical assessment using routine physiotherapy techniques. The inherently low spring rate of a gas strut ensures that the specified corrective torque is maintained as correction occurs. Initial treatment experience under the control of the developers had generated wider interest in the system. A geographically distant independent orthotic supply centre was trained in the techniques of application. They treated nine elbow and three knee joints in patients who had not responded to physiotherapy treatment. All of the patients experienced improvement. The average for elbow joints was a reduction in the contracture of 25.6 degrees with a corrective moment of 6.8 Nm over a period of 3.9 weeks. For the knee joints the averages were a reduction in contracture of 10.7 degrees with a corrective moment of 12.7 Nm over a period of 4 weeks. The results confirmed the practicality of transferring the system to independent clinical centres and provide evidence to support funding for a formal prospective clinical trial of the treatment approach.

Adult↗
PubMed1998

Assessment of intratumoral vascularization (angiogenesis) in breast cancer prognosis.

The search for prognostic markers is important both to identify those patients with occult metastases and also to spare chemotherapy in those patients whose tumors have not developed the capacity for distant spread. Angiogenesis, the formation of new blood vessels, is necessary for breast cancer growth and metastasis. Good correlation has been demonstrated between intratumoral vascularization and outcome in patients with breast cancer. Intratumoral vascularization in human breast cancer can be measured by using standard immunohistochemical methods. Strict guidelines for scoring need to be followed. Although attempts are being made to automate the reading, visual scoring remains superior. We studied a population of women with small node-negative breast cancer who received no adjuvant therapy and have a median follow-up of 15 years. We have found intratumoral vascularization, as measured by microvessel count, to be an independent prognostic factor for disease-free survival. Low microvessel count identifies a group of patients with a 20 year disease free survival of 93%. The proportion of women with low microvessel count decreases with increase in tumor size and increases with patient age. But even in mammographically detected nonpalpable breast cancer, that is, the smallest breast cancer we currently detect, the majority already have high microvessel count. Intratumoral vascularization appears to be an early event that is necessary but not sufficient for metastatic progression. Microvessel count seems to be an excellent marker to identify patients with good prognosis because those with low microvessel count have a 93% disease-free survival irrespective of size, grade, or estrogen receptor status, but is less good at predicting those at high risk since the 20-year disease-free survival is still 67-70% in those with high microvessel count. Thus, the higher risk group needs to be further stratified using additional prognostic factors.

Breast Neoplasms↗
PubMed1998

Lack of reactivity to CMV pp65 antigenemia testing in a patient with CMV disease following allogeneic bone marrow transplant.

Pre-emptive antiviral therapy based on the early detection of CMV infection is an important strategy for the prevention of CMV disease following allogeneic BMT. Accepted methods for early detection of CMV infection include viral culture of blood or bronchial lavage specimens or CMV pp65 antigenemia testing of peripheral blood specimens. We describe a patient with aplastic anemia with worsening liver transaminases after allogeneic bone marrow transplantation who had repeated negative tests for CMV pp65 antigenemia despite positive viral blood cultures. Re-examination of peripheral blood samples with a different pp65 antibody pool revealed the presence of high levels of CMV in peripheral blood leukocytes, confirming a lack of reactivity to the original antibody pool. Following institution of antiviral therapy, a prompt reduction in the number of pp65 antigen-positive peripheral blood leukocytes paralleled a reduction in abnormal transaminases. The practical implications of these findings are discussed.

Adult↗