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Biomedical subjects

A King

Publications and source records attributed to A King.

At least 91 records · Page 5Linked to original sources
PubMed2000

The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues.

Proapoptotic Bcl-2 family members have been proposed to play a central role in regulating apoptosis. However, mice lacking bax display limited phenotypic abnormalities. As presented here, bak(-/-) mice were found to be developmentally normal and reproductively fit and failed to develop any age-related disorders. However, when Bak-deficient mice were mated to Bax-deficient mice to create mice lacking both genes, the majority of bax(-/-)bak(-/-) animals died perinatally with fewer than 10% surviving into adulthood. bax(-/-)bak(-/-) mice displayed multiple developmental defects, including persistence of interdigital webs, an imperforate vaginal canal, and accumulation of excess cells within both the central nervous and hematopoietic systems. Thus, Bax and Bak have overlapping roles in the regulation of apoptosis during mammalian development and tissue homeostasis.

Abnormalities, Multiple↗
PubMed2000

Decidual natural-killer-cell interaction with trophoblast: cytolysis or cytokine production?

At the implantation site, the uterine mucosa (decidua) is infiltrated by large numbers of natural killer (NK) cells. These NK cells are in close contact with the invading fetal trophoblast and we have proposed that they might be the effector cells that control the implantation of the allogeneic placenta. Recent characterization of NK cell receptors and their HLA class I ligands has suggested potential mechanisms by which NK cells might interact with trophoblast. However, what happens as a result of this interaction is not clear. The traditional method for investigating NK cell function in vitro is the protection from lysis of target cells by expression of HLA class I antigens. This might not be an accurate reflection of what happens in vivo. Another function of NK cells is the production of cytokines on contact with target cells. This could be an important outcome of the interaction between decidual NK cells and trophoblast. Decidual NK cells are known to produce a variety of cytokines; trophoblast cells express receptors for many of these cytokines, indicating that they can potentially respond. In this way, decidual NK cells have a significant influence on trophoblast behaviour during implantation.

Cytokines↗
PubMed2000

Immunology of implantation.

During implantation, the uterine decidua is invaded by extravillous trophoblast (EVT) cells whose function is to destroy the walls of the uterine spiral arteries in order to provide an adequate blood flow to the fetus. These EVT cells express an unusual combination of HLA class I molecules-HLA-C, HLA-E and HLA-G. The decidua is infiltrated by a population of natural killer (NK) cells with a distinctive phenotype of CD56(bright)CD16(-)CD3(-). These cells are particularly numerous in the decidua basalis at the implantation site where they come into close contact with invading EVT cells. These NK cells express a variety of receptors (CD94/NKG2, KIR and ILT) which are known to recognize HLA class I molecules. We believe that interaction between these NK cells and EVT cells provides the controlling influence for implantation.

Embryo Implantation↗
PubMed2000

Mechanism for the transit-induced increase in colonic deoxycholic acid formation in cholesterol cholelithiasis.

BACKGROUND & AIMS: Many patients with cholesterol gallbladder stones (GBS) have a high percentage of deoxycholic acid (DCA) in gallbladder bile (all of which are in the conjugated form), probably as a result of prolonged large bowel transit times (LBTT). However, whether the prolonged LBTT increases DCA formation, solubilization, or absorption (or all 3) is not known. METHODS: In 40 subjects (20 with GBS; age range, 24-74 years), we measured LBTT using radiopaque markers, and intestinal luminal pH by radiotelemetry. We also measured quantitative anaerobic bacteriology and the activities of 2 bile acid-metabolizing enzymes in fresh cecal aspirates obtained during clinically indicated unprepared colonoscopy, and related these results to the percentage of DCA in fasting serum measured by gas chromatography-mass spectrometry. RESULTS: Compared with controls, GBS patients had longer LBTT (mean 23.1 +/- SEM 2.8 h vs. 36.5 +/- 3.3 h; P < 0.01); more total (2.7 +/- 0.6 x 10(9) vs. 5.9 +/- 1.5 x 10(9) cfu/mL) and Gram-positive (9.5 +/- 3.1 x 10(8) vs. 18.0 +/- 4.1 x 10(8) cfu/mL; P < 0.05) anaerobes; and greater 7alpha-dehydroxylating (7alpha-DH) activity (3.39 +/- 0.59 vs. 10.37 +/- 1.15 x 10(-4) U/mg protein) in the cecal aspirates. They also had higher intracolonic pH values (P < 0.02) and increased percentages of DCA in fasting serum (13.4% +/- 1.52% vs. 21.8% +/- 2. 19%; P < 0.005). Results of univariate and multivariate analyses confirmed that LBTT was critical in determining the percentage of DCA in serum and showed that 7alpha-DH activity and apparent distal colonic pH were also significant independent variables. CONCLUSIONS: Slow colonic transit (more time), increased Gram-positive anaerobes (more bacteria), and greater 7alpha-DH activity (more enzyme) favor enhanced DCA formation; transit-induced increases in distal colonic luminal pH favor enhanced DCA solubilization/bioavailability; and increases in LBTT (more time) again favor DCA absorption.

Adult↗
PubMed2000

Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms.

After hepatitis B virus (HBV) infection, liver injury and viral control have been thought to result from lysis of infected hepatocytes by virus-specific cytotoxic T cells. Patients are usually studied only after developing significant liver injury, and so the viral and immune events during the incubation phase of disease have not been defined. During a single-source outbreak of HBV infection, we identified patients before the onset of symptomatic hepatitis. The dynamics of HBV replication, liver injury, and HBV-specific CD8+ and CD4+ cell responses were investigated from incubation to recovery. Although a rise in alanine transaminase (ALT) levels was present at the time of the initial fall in HBV-DNA levels, maximal reduction in virus level occurred before significant liver injury. Direct ex vivo quantification of HBV-specific CD4+ and CD8+ cells, by using human leukocyte antigen (HLA) class I tetramers and intracellular cytokine staining, showed that adaptive immune mechanisms are present during the incubation phase, at least 4 weeks before symptoms. The results suggest that the pattern of reduction in HBV replication is not directly proportional to tissue injury during acute hepatitis B in humans. Furthermore, because virus-specific immune responses and significant reductions in viral replication are seen during the incubation phase, it is likely that the immune events central to viral control occur before symptomatic disease.

Acute Disease↗
PubMed2000

Surface expression of HLA-C antigen by human extravillous trophoblast.

In this paper definitive evidence that the classical class I product, HLA-C, is expressed on the surface of normal trophoblast cells is provided. HLA-C transcripts were sequenced from cDNA isolated from first trimester trophoblast cells obtained by flow cytometric sorting. Both paternal and maternal alleles were transcribed. HLA-C proteins were demonstrated by biochemical analysis and found on the cell surface in association with beta(2)-microglobulin. Upregulation of cell surface HLA-C but not HLA-G expression after interferon (IFN)-gamma treatment was demonstrated by flow cytometric analysis. Immunohistology has confirmed HLA-C is expressed by all extravillous subpopulations in vivo. The question of whether trophoblast HLA-C molecules interact with decidual NK cells expressing killer Ig-like receptors (KIR) has also been addressed. Our results demonstrate that extravillous trophoblast expresses at least two HLA class I molecules, HLA-G and HLA-C on the cell surface.

Adult↗
PubMed2000

Type 5 phosphodiesterase regulation of human sperm motility.

OBJECTIVE: Inhibition of phosphodiesterases results in the buildup of intracellular cyclic nucleotides, which have been shown to affect sperm motility and acrosome reaction. The objective of this study was to determine whether the cyclic guanosine monophosphate-specific type 5 phosphodiesterase inhibitor sildenafil has an effect on sperm motility and acrosome parameters. STUDY DESIGN: Sperm cells were washed by two-layer colloid wash and resuspended in modified human tubal fluid with 5% serum albumin. They were incubated in the presence of different concentrations (0-40 nmol/L) of the type 5 phosphodiesterase inhibitor sildenafil. Aliquots of sperm were removed at hours 0, 4, 24, and 48, and motility parameters were measured on the Hamilton-Thorn HTM-C (Hamilton-Thorn Research, Danvers, Mass) motility analyzer. Sperm acrosomes were analyzed with the Spermac (Stain Enterprises, South Africa; distributed by Sage Biopharma, Bedminster, NJ) acrosome stain. RESULTS: Sperm progressive motility and hyperactivation were stimulated to greater than the control at hour 4, followed by a decrease. There was a dose-dependent effect of the type 5 phosphodiesterase inhibitor on sperm motility parameters but not on percentage of cells with acrosome reaction. The type 5 phosphodiesterase inhibitor stimulated sperm acrosome reaction by almost 50% above the control. CONCLUSION: These results suggest that inhibition of type 5 phosphodiesterase activity in human sperm resulted in enhanced progressive motility and hyperactivation. In addition, inhibition of type 5 phosphodiesterase also caused an increase in acrosome reaction. This suggests a role for type 5 phosphodiesterase in preventing premature acrosome reaction, which is associated with failed fertilization.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2000

Time-kill studies of tea tree oils on clinical isolates.

Tea tree oil has recently emerged as an effective topical antimicrobial agent active against a wide range of organisms. Tea tree oil may have a clinical application in both the hospital and community, especially for clearance of methicillin-resistant Staphylococcus aureus (MRSA) carriage or as a hand disinfectant to prevent cross-infection with Gram-positive and Gramnegative epidemic organisms. Our study, based on the time-kill approach, determined the kill rate of tea tree oil against several multidrug-resistant organisms, including MRSA, glycopeptide-resistant enterococci, aminoglycoside-resistant klebsiellae, Pseudomonas aeruginosa and Stenotrophomonas maltophilia, and also against sensitive microorganisms. The study was performed with two chemically different tea tree oils. One was a standard oil and the other was Clone 88 extracted from a specially bred tree, which has been selected and bred for increased activity and decreased skin irritation. Our results confirm that the cloned oil had increased antimicrobial activity when compared with the standard oil. Most results indicated that the susceptibility pattern and Gram reaction of the organism did not influence the kill rate. A rapid killing time (less than 60 min) was achieved with both tea tree oils with most isolates, but MRSA was killed more slowly than other organisms.

Anti-Infective Agents, Local↗
PubMed2000

Comparative in vitro activity of gemifloxacin.

Gemifloxacin is a new quinolone and, like moxifloxacin, trovafloxacin, grepafloxacin and clinafloxacin, is more potent in vitro than ciprofloxacin or ofloxacin against Gram-positive aerobes. Gemifloxacin was the most potent of the quinolones tested against streptococci and most ciprofloxacin-resistant pneumococci were susceptible to gemifloxacin. Gemifloxacin, like moxifloxacin, trovafloxacin, grepafloxacin and clinafloxacin, was more potent than ciprofloxacin or ofloxacin against all staphylococci and many ciprofloxacin-resistant isolates were susceptible to these quinolones. Against Gram-negative aerobes gemifloxacin was as potent as or slightly less potent than ciprofloxacin, and isolates resistant to ciprofloxacin were also resistant to gemifloxacin and to moxifloxacin, trovafloxacin and grepafloxacin. Gemifloxacin was also the most potent quinolone against Gram-positive anaerobes and fusobacteria but trovafloxacin was the most potent agent tested against other Gram-negative anaerobes.

Anti-Infective Agents↗
PubMed2000

Comparison of cation-adjusted Mueller-Hinton broth with Iso-Sensitest broth for the NCCLS broth microdilution method.

Comparison of MIC results obtained in different parts of the world is currently difficult because of variations in methods. In this study, cation-adjusted Mueller-Hinton broth, the NCCLS-recommended medium, was compared with Iso-Sensitest broth, which is widely used in Europe. Microbroth dilution testing, using the NCCLS procedure, was performed on 124 Gram-positive (staphylococci and enterococci) and Gram-negative (Enterobacteriaceae and Pseudomonas aeruginosa) isolates from the CDC reference set, with the only variable being the medium used. Twelve antimicrobial agents were tested: amoxycillin-clavulanic acid, ampicillin, ciprofloxacin, erythromycin, gentamicin, imipenem, levofloxacin, oxacillin, gemifloxacin, trimethoprim- sulphamethoxazole, tetracycline and vancomycin. Vancomycin, erythromycin and oxacillin were only evaluated for the Gram-positive organisms. Trimethoprim-sulphamethoxazole was only evaluated for a subset of Gram-negative organisms because of off-scale results. The 124 isolates were tested in one American and one UK laboratory with two batches of cation-adjusted Mueller-Hinton broth and two of Iso-Sensitest broth. A statistical evaluation of the data used a 24 fully specified factorial analysis to determine if there were significant differences in results owing to Gram reaction, site of testing and type and/or batch of broth. In addition, the cumulative results for each antimicrobial agent in each broth were plotted against the range of MIC dilutions tested. MICs of ciprofloxacin, levofloxacin, gemifloxacin, gentamicin and tetracycline were slightly higher (half a doubling dilution) with Iso-Sensitest broth than with Mueller-Hinton broth. MIC results for the other antimicrobial agents were equivalent. Essential and category agreement rates were comparable for all agents (88.4-100% and 88.2-99.0%, respectively).

Anti-Bacterial Agents↗
PubMed2000

Human decidual natural killer cells express the receptor for and respond to the cytokine interleukin 15.

The natural killer (NK) cells that are present in the uterine mucosa (decidua) during early pregnancy have a distinctive phenotype, CD56(bright) CD16(-). These cells have previously been shown to proliferate and be activated by interleukin (IL)-2. However, IL-2 is absent from the decidua and placenta, and we have therefore investigated whether IL-15 is present in the uterus and can act on decidual NK cells. Both IL-15 mRNA and protein were found in a variety of cells but particularly in decidual macrophages. IL-15 induced a proliferative response in decidual NK cells that was blocked by anti-IL-15 and was augmented by stem cell factor. The cytolytic activity of decidual NK cells against K562 was augmented. Interestingly, in contrast to IL-2, although activation with IL-15 resulted in some killing of JEG-3 choriocarcinoma cells, normal trophoblast cells remained resistant to lysis. These findings suggest that IL-15 is a candidate cytokine responsible for NK cell proliferation in vivo in the progesterone-dominated secretory endometrium and early decidua.

Adult↗
PubMed2000

Living near opencast coal mining sites and children's respiratory health.

OBJECTIVES: To answer the question whether living near opencast coal mining sites affects acute and chronic respiratory health. METHODS: All 4860 children aged 1-11 from five socioeconomically matched pairs of communities close to active opencast sites and control sites away from them were selected. Exposure was assessed by concentrations of particulate matter with aerodynamic diameter < 10 microns (PM10), residential proximity to active opencast sites, and particle composition. PM10 was monitored and sampled for 6 weeks in four pairs, and for 24 weeks in one pair. A postal questionnaire collected data on health and lifestyle. Daily health information was collected by a symptom diary (concurrently with PM10 monitoring) and general practitioner (GP) records were abstracted (concurrently with PM10 monitoring and 52 weeks before the study). Outcomes were the cumulative and period prevalence (2 and 12 months) of wheeze, asthma, bronchitis, and other respiratory symptoms, and the prevalence and incidence of daily symptoms and GP consultations. RESULTS: Patterns of the daily variation of PM10 were similar in opencast and control communities, but PM10 was higher in opencast areas (mean ratio 1.14, 95% confidence interval (95% CI) 1.13 to 1.16, geometric mean 17.0 micrograms/m3 v 14.9 micrograms/m3). Opencast sites were a measurable contributor to PM10 in adjacent areas. Little evidence was found for associations between living near an opencast site and an increased prevalence of respiratory illnesses, asthma severity, or daily diary symptoms, but children in opencast communities 1-4 had significantly more respiratory consultations (1.5 v 1.1 per person-year) than children in control communities for the 6 week study periods. Associations between daily PM10 concentrations and acute health events were similar in opencast and control communities. CONCLUSIONS: Children in opencast communities were exposed to a small but significant amount of additional PM10 to which the opencast sites were a measurable contributor. Past and present respiratory health of children was similar, but GP consultations for respiratory conditions were higher in opencast communities during the core study period.

Acute Disease↗
PubMed2000

A CAT-derived one to three session intervention for repeated deliberate self-harm: a description of the model and initial experience of trainee psychiatrists in using it.

We describe a new Cognitive Analytic Therapy (CAT)-based intervention for those who repeatedly self-harm. It is specifically designed to be deliverable by staff with no training in psychotherapy. The intervention is simply manualized into sequential tasks that are mediated by new CAT-style standardized tools. A particular feature of this intervention is the deliberate use of feelings elicited in the therapist ('counter-transference') as (a) a guide to how professional poise is being threatened or lost and (b) an indicator of the appropriate focus for this very brief therapy. The psychiatrists' reflection on their elicited feelings is mediated by a new CAT tool, the 'Assessor's Response File' developed in this project. Audiotape analysis suggested that following a very brief learning period, trainee psychiatrists were able to adhere to the structure of the model and arrive at an appropriate reformulation in the first session but tended to be collusive in reciprocating the patients' dysfunctional coping styles.

Adaptation, Psychological↗
PubMed2000

Engraftment and growth of transplanted pancreatic islets.

Transplantation of pancreatic islets may provide a cure for type 1 diabetes. However, this treatment can currently be offered only to very few patients. To improve transplantation success we need to understand better the mechanisms of how the implanted islets survive, grow and/or maintain adequate function. We herein report on our studies to evaluate the factors responsible for the engraftment, i.e. revascularization, reinnervation etc., of transplanted islets and relate these factors to the metabolism and growth of the islets. Graft metabolism can be monitored by microdialysis probes that allow for the measurement of minute amounts of islet metabolites and hormonal products. Growth of the endocrine cells can be stimulated both in vitro before implantation and in vivo post-transplantation. Another problem is rejection of transplanted islets, which may be overcome by the microencapsulation of islets. The knowledge gained by the present studies will enable us to elucidate the optimal treatment of islets to ensure a maximal survival of the transplanted islets, and may be applied also to clinical islet transplantation.

Animals↗
PubMed2000

Immunological aspects of human implantation.

The immunological relationship between the mammalian fetus and its mother during pregnancy has been considered similar to that between a transplanted allograft and its recipient. Hence, it has been assumed that implantation of the fetal placenta in the uterus would be controlled in a similar way by a maternal immune response mediated by T cells recognizing paternally derived alloantigens expressed by the placenta. However, recent evidence indicates that implantation might involve predominantly a novel allogeneic recognition system based on natural killer cells rather than T cells. The cellular and molecular basis of this local immune interaction between the fetal placenta and maternal uterus is the focus of intense research interest. As aberrant implantation can cause a variety of clinical problems including miscarriage, intrauterine growth retardation and pre-eclampsia, an understanding of the immunological mechanism by which this process is controlled could lead to the development of regimens to improve fetal growth and development.

Cytokines↗