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D A Clark

Publications and source records attributed to D A Clark.

At least 73 records · Page 4Linked to original sources
PubMed1999

Cytokines and the regulation of apoptosis in reproductive tissues: a review.

PROBLEM: To determine the role of apoptosis-regulating genes bax and bcl-2 in reproduction. METHOD OF STUDY: Review of literature and current data. RESULTS: The bcl-2 family of apoptotic regulatory gene products interact and form dimers of anti- and pro-apoptotic proteins (e.g., bcl-2 and bax respectively), the ratio of which determines cell death or survival. Menses is associated with increased apoptosis in the glands, a change in bcl-2:bax ratio and increased levels of the pro-apoptotic cytokine TNFalpha. Apoptosis occurs in all placental cell types and increases from first to third trimester. Placental apoptosis is induced by TNFalpha in vitro and increased levels in utero characterize most failing pregnancies, intra-uterine growth restriction (IUGR) and labour. An increased bcl-2:bax ratio and apoptosis in the syncytiotrophoblast characterizes failing first trimester pregnancies. Apoptosis in the syncytiotrophoblast is also associated with IUGR. In a rat model, maternal vitamin A deficiency perturbs fetal development. This is associated with a placental infiltrate of TNFalpha positive neutrophils (day 20) and increased placental apoptosis in areas of infiltration. A similar infiltrate occurs in a mouse model of early pregnancy loss. In the fetal membranes, clusters of bcl-2 negative chorion trophoblast cells undergo apoptosis. This may allow passage of myometrial stimulatory factors that induce labour. CONCLUSION: The ratio of bcl-2:bax is crucial in the regulation of apoptosis, particularly in the human placenta. Changes in trophoblast apoptosis characterize (1) early pregnancy failure, (2) IUGR and (3) pre-term and term labour. Regardless of gestational age, TNFalpha plays a major role in the induction of placental apoptosis.

Animals↗
PubMed1999

Achilles tendon ruptures stratified by age, race, and cause of injury among active duty U.S. Military members.

A total of 865 members of the U.S. military underwent repair of Achilles tendon ruptures at U.S. military hospitals during calendar years 1994, 1995, and 1996. The discharge summaries of these patients were analyzed for patient demographic information, including age, race, and causative activity. Patients were then stratified by age, race, and cause of injury. Blacks were at increased risk for undergoing repair of the Achilles tendon compared with nonblacks (overall relative risk = 4.15, 95% confidence interval [CI] = 3.63, 4.74; summary odds ratio controlling for age = 3.69, CI = 3.25, 4.19). Participation in the game of basketball accounted for 64.9% of all injuries in black patients and 34.0% of all injuries in nonblack patients. Among those injured, blacks had a significantly increased risk for injury related to playing basketball than nonblacks (relative risk = 1.82, CI = 1.58, 2.10). This finding suggests that there may be other predisposing factor(s) that result in a higher risk of Achilles tendon ruptures in black individuals.

Achilles Tendon↗
PubMed1999

Hard science versus phenomenology in reproductive immunology.

It has been suggested that studies of immunological aspects of reproduction have recently changed from the phenomenological (e.g., speculative/descriptive) to hard science (e.g., precise molecular description/ explanation). The significance of this development is explored by analysis of the contribution made by hard science that has led to a number of assertions. Does HLA-G determine maternal tolerance of her semi-allogeneic fetus? Do differences in placentation between humans, rodents, and other species make direct comparisons largely meaningless? Does membrane cofactor protein (CD46) contribute to pregnancy success by protecting sperm and fetal trophoblast from complement-mediated lysis? Does a low frequency in mice of maternal T cells specific for paternal alloantigens occur, and if so, does phenomenon explain specific maternal tolerance in pregnancy? Do placental and decidual macrophage components provide an important immediate antigen-nonspecific host defense to infection? Does the mix of bioactive molecules make the uterus an immunologically privileged site, and does the molecular melange have a pivotal role in promoting growth and development of the placenta and embryo? Does prolactin acting on receptors on lymphocytes suppress function and thereby account for remission of autoimmune disease in pregnant women? Is the efficacy and safety of immunotherapy for recurrent spontaneous abortion a thorny issue that will be resolved by an ongoing funded national trial? What is a scientifically correct timeline of important discoveries and developments in reproductive immunology? It is argued that it is unprofitable to divorce phenomenology from hard science and that the timeline for developments in reproductive immunology begin with Darwin. Irrespective of whether one is dealing with phenomena or hard science data, Hippocrates was correct in his aphorism that "description is infinite and easy; explanation is limited and difficult".

Abortion, Habitual↗
PubMed1998

Diffusion-limited reaction of free nitric oxide with erythrocytes.

Concentration changes of nitric oxide (NO) were monitored using an NO-sensitive electrode in phosphate-buffered saline (PBS) with either free oxyhemoglobin (oxyHb) or red blood cells (RBCs). In aerated PBS, the half-life of 0.9 microM NO is greater than 4 min. NO is undetectable (<50 nM) when added to a solution of oxyHb because the reaction of NO with oxyHb is rapid. The disappearance rate of NO in PBS containing RBCs is rapid, compared with PBS, but it is much slower (by a factor of approximately 650) than with an equivalent solution of free oxyHb. The half-life of NO is inversely proportional to the concentration of RBCs, independent of oxyHb concentration inside RBCs, and the disappearance rate of NO is first order in NO concentration and first order in the concentration of RBCs. After all the oxyHb reacts with NO to form methemoglobin, the disappearance rate of NO slows greatly. These data indicate that the reaction of NO with oxyhemoglobin within RBCs is limited by the diffusion of NO into the cell, which has also been shown previously for the reaction of O2 with deoxyhemoglobin. Experimental data show that the half-life of NO in the presence of 2.1 x 10(6) RBCs/ml is 4. 2 s. From this value, we estimate that the half-life of NO in whole blood (5 x 10(9) RBCs/ml) will be 1.8 ms. A simple analytical expression for the half-life of NO in PBS with RBCs was derived in this study based on a spherical diffusion model. The calculated half-life of NO from the expression is in good agreement with the experimental values.

Animals↗
PubMed1998

Cytokine-dependent abortion in CBA x DBA/2 mice is mediated by the procoagulant fgl2 prothrombinase [correction of prothombinase].

Spontaneous resorption in the CBA x DBA/2 model is attributed to NK cells, macrophages, and Th1-type cytokines. In vivo depletion of NK cells by anti-asialoGM1 Ab or macrophage depletion by silicon dioxide treatment reduced abortion rates, which could no longer be boosted by injecting TNF-alpha (which activates NK cells) or IFN-gamma (which activates macrophages). TNF-alpha + gamma-IFN coadministration aborted >80% of the embryos whether or not NK cells or macrophages had been depleted or estradiol + progesterone was injected to correct potential reduction in ovarian function by cytokines. The cytokines also aborted IRF1+/+ C57BL/6 but not IRF1-/- females pregnant by IRF1+/+ DBA/2. Both spontaneous and cytokine-boosted abortions in CBA x DBA/2 were blocked by Ab to fgl2 prothrombinase [corrected] expressed by cytokine-stimulated vascular endothelial cells and monocytes; in vivo Ab depletion of granulocytes also prevented TNF-alpha + IFN-gamma-induced abortions. Cytokine-triggered thrombotic/inflammatory processes in maternal uteroplacental blood vessels causes abortion.

Abortion, Spontaneous↗
PubMed1998

A multiplex PCR assay for the simultaneous detection of human herpesvirus 6 and human herpesvirus 7, with typing of HHV-6 by enzyme cleavage of PCR products.

A multiplex polymerase chain reaction (PCR) method was developed for the simultaneous detection of human herpesviruses 6 and 7 (HHV-6; HHV-7) in clinical samples, using primers which amplify a section of the HHV-6 U67 gene and the HHV-7 homologue of the HHV-6 U42 gene. Comparison of the multiplex assay with the respective single PCR assays, using cloned HHV-6 and HHV-7 sequences as targets for amplification, showed equivalent sensitivity and specificity for the assays. To demonstrate the use of multiplex PCR for the analysis of clinical samples, serum and saliva from infants were analysed using this technique. The results showed that a clear distinction can be made between the amplicons of HHV-6 and HHV-7, without loss of sensitivity or specificity. There was complete concordance between the respective single PCR assays, and the multiplex PCR. HHV-6 amplicons derived from the multiplex PCR analysis were typed by differential AvaII restriction endonuclease digestion, in which HHV-6 variant A amplicons are cleaved but those of variant B remain undigested. These results were compared to HHV-6 variant typing by an established method, the results of which showed complete concordance between assays. It is proposed that this multiplex assay, where HHV-6 positive samples may be typed directly from the reaction products, is an efficient and cost-effective approach to the analysis of large numbers of samples to determine the epidemiological importance of HHV-6 and HHV-7.

Child↗
PubMed1998

Transforming growth factor-beta (TGF-beta).

The TGF-beta family of cytokines are ubiquitous, multifunctional and essential to survival. They play important roles in growth and development, inflammation and repair and host immunity. The mammalian TGF-beta isoforms (TGF-beta 1, beta 2 and beta 3) are secreted as latent precursors and have multiple cell surface receptors of which at least two mediate signal transduction. Autocrine and paracrine effects of TGF-beta's can be modified by extracellular matrix, neighbouring cells and other cytokines. The vital role of the TGF-beta family is illustrated by the fact that approximately 50% of TGF-beta 1 gene knockout mice die in utero and the remainder succumb to uncontrolled inflammation after birth. TGF-beta 2 and TGF-beta 3 gene knockout mice are not yet described. More recently, novel TGF-beta-like molecules have been described which share some of the properties of the mammalian TGF-beta isoforms. The role of TGF-beta in homeostatic and pathogenic processes suggests numerous applications in the diagnosis and treatment of various diseases characterised by inflammation and fibrosis.

Animals↗
PubMed1998

Effects of white clover content in the diet on herbage intake, milk production and milk composition of New Zealand dairy cows housed indoors.

The effect of the proportion of clover in the diet (200, 500 or 800 g/kg total dry matter (DM) on milk production of cows housed indoors and fed on a mixture of perennial rye-grass and white clover was measured in mid (Expt I) and late (Expt II) lactation. Higher clover contents increased the nutritive value of the diets, resulting in increased energy and protein intakes. DM intakes of cows offered 500 or 800 g clover/kg DM diets ad lib. (Expt I and Expt II, Period 1) were not significantly different but were 11-17% greater (P < 0.05) than intakes of cows fed on 200 g clover/kg total DM diets. Cows offered restricted allowances (Expt II, Period 2) had similar intakes irrespective of diet. In Expt I cows fed on 500 or 800 g clover/kg DM diets ad lib. produced 30 or 33% respectively more milk (P < 0.05) than cows fed on 200 g clover/kg total DM diets. During Expt II, Period 1, cows fed on 500 or 800 g clover/kg DM diets ad lib. produced 18 or 16% more milk (P < 0.05) respectively than cows given 200 g clover/kg total DM diets. In both these experiments the increased milk yields were due to increased intake and the higher nutritive value of the high clover diets. There was no difference in the feed conversion efficiencies of cows if maintenance energy requirements were taken into account. However, cows on restricted allowances (Expt II, Period 2) showed no significant difference in milk yield, indicating that the effect of increased nutritive value was very slight. There were no consistent effects on milk fat, protein or lactose concentrations. Concentrations of blood and milk urea increased as the clover content of the diet increased (Expt 1 only), and this was associated with increased milk non-protein N and a decreased ratio of casein N: total N. Both trials indicated an optimum clover content in the diet for milk production of 600-700 g/kg total DM.

Animal Feed↗
PubMed1998

Depressive symptom differences in hospitalized, medically ill, depressed psychiatric inpatients and nonmedical controls.

This study compared depressive and anxious symptoms in chronic medically ill individuals and depressed psychiatric inpatients using conceptually based standardized measures of cognitions and symptoms. Seventy-five hospitalized medical patients, 52 depressed psychiatric inpatients, and 25 normal controls were assessed with the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev.; American Psychiatric Association, 1987), the Mood and Anxiety Symptom Questionnaire, Hamilton Rating Scales of Anxiety and Depression, Hospital Anxiety and Depression Scales, Beck Depression Inventory, Cognitions Checklist, and Hopelessness Scale. Analysis revealed that depression in medical patients was best distinguished by symptoms of anhedonia, low positive affect, and physiological hyperarousal, whereas syndromal depression in psychiatric inpatients was specifically characterized by negative cognition symptoms. Implications are discussed for assessing depression in medically ill populations.

Adolescent↗
PubMed1998

Antiinflammatory actions of cat's claw: the role of NF-kappaB.

BACKGROUND: Uncaria tomentosa is a vine commonly known as cat's claw or 'uña de gato' (UG) and is used in traditional Peruvian medicine for the treatment of a wide range of health problems, particularly digestive complaints and arthritis. PURPOSE: The aim of this study was to determine the proposed anti-inflammatory properties of cat's claw. Specifically: (i) does a bark extract of cat's claw protect against oxidant-induced stress in vitro, and (ii) to determine if UG modifies transcriptionally regulated events. METHODS: Cell death was determined in two cell lines, RAW 264.7 and HT29 in response to peroxynitrite (PN, 300 microM). Gene expression of inducible nitric oxide synthase (iNOS) in HT29 cells, direct effects on nitric oxide and peroxynitrite levels, and activation of NF-kappaB in RAW 264.7 cells as influenced by UG were assessed. Chronic intestinal inflammation was induced in rats with indomethacin (7.5 mg/kg), with UG administered orally in the drinking water (5 mg/mL). RESULTS: The administration of UG (100 microg/mL) attenuated (P < 0.05) peroxynitrite-induced apoptosis in HT29 (epithelial) and RAW 264.7 cells (macrophage). Cat's claw inhibited lipopolysaccharide-induced iNOS gene expression, nitrite formation, cell death and inhibited the activation of NF-kappaB. Cat's claw markedly attenuated indomethacin-enteritis as evident by reduced myeloperoxidase activity, morphometric damage and liver metallothionein expression. CONCLUSIONS: Cat's claw protects cells against oxidative stress and negated the activation of NF-kappaB. These studies provide a mechanistic evidence for the widely held belief that cat's claw is an effective anti-inflammatory agent.

Animals↗
PubMed1998

Interleukin-10 attenuates experimental fetal growth restriction and demise.

Premature labor, fetal demise, and fetal growth restriction are accompanied by indices of inflammation or infection of the uteroplacental unit. To understand whether these events are causally related, we established an animal model of fetal demise and growth restriction and evaluated the potential utility of the anti-inflammatory cytokine interleukin-10 (IL-10). We administered low-dose endotoxin (lipopolysaccharide, or LPS, 100 microg/kg, i.p.) to third trimester rats (gestational days 14-20). Control rats received normal saline. A third group received IL-10 (100 microg/kg; s.c.) concomitantly with LPS for 7 prenatal days. Cytokine gene expression (IL-10 and TNF-alpha) was evaluated by RT-PCR and tissue levels (TNF-alpha) were determined by ELISA. Apoptosis was evaluated by TdT-mediated dUTP nick end labeling immunohistochemistry, and nitric oxide (NO) levels were quantified by microelectrode electrochemical detection in explants in culture media. LPS exposure resulted in 43% fetal demise and reduced the size of the surviving fetuses. Placental weight was not altered by LPS. IL-10 attenuated the LPS-induced fetal death rate (to 22%) and growth restriction (P<0.05). In normal rats, IL-10 did not affect fetus size or the incidence of resorptions, although placental size was marginally smaller. Increased uterine TNF-alpha content and NO release and apoptosis of uterine epithelia and muscularis were hallmarks of the LPS model. All were normalized by IL-10. IL-10 may represent a new therapeutic option for the treatment of a variety of perinatal complications. Benefit may result from the suppression of TNF-alpha- and NO-mediated cell death.

Animals↗
PubMed1998

Tumor necrosis factor-alpha mRNA-positive cells in spontaneous resorption in rodents.

PROBLEM: It has been proposed that high rates of resorption/spontaneous abortion may result from interaction in the decidua of gamma-interferon-producing natural killer (NK) cells and tumor necrosis factor (TNF)-alpha-producing macrophages. An increased release of TNF-alpha from placental tissue of resorptions has been reported, but macrophages producing TNF-alpha have so far not been demonstrated at the feto-maternal interface. Therefore, we have sought to identify TNF-alpha-producing cells by in situ hybridization at the feto-maternal interface in two inbred, well-characterized, and stable strains of laboratory rodents with high and low resorption rates. METHOD OF STUDY: Pregnant DBA/2-mated CBA/J mice with a resorption rate of 20% to 30% (dependent on NK cells and macrophages) and diabetes-resistant Bio-Breeding/Edinburgh (DR-BB/E) rats with low resorption rates (presumed to result from chromosomal abnormalities) were studied. AsialoGM1+ cells were detected by immunohistochemistry, and TNF-alpha mRNA+ cells were detected by in situ hybridization. RESULTS: TNF-alpha mRNA+ cells were detected in DBA/2-mated CBA/J mice at the time of resorption but only at the trophoblast-decidual junction. AsialoGM1+ cells were present in decidua, as assessed by immunohistochemistry, but few if any gave a positive signal for TNF-alpha. In rat resorptions, TNF-alpha mRNA-positive cells were present within the yolk sac and in contact with the trophoblast, but not at the trophoblast-decidual junction. In neither species did a significant accumulation of detectable TNF-alpha mRNA+ cells occur before the usual time of onset of resorption. CONCLUSIONS: In the DBA/2-mated CBA/J mouse, the removal of the placenta is associated with removal of a thin rim of adherent decidua similar to the location of the TNF-alpha mRNA+ cells detected in this study. Our data suggest that increased TNF-alpha in tissues associated with failing feto-placental units may arise from infiltration/activation of scavenger cells from decidua that are likely to be macrophages. Local TNF-alpha production in decidua, which occurs as a prelude to resorption in the CBA x DBA/2 model, could not be detected due to the insensitivity of the TNF-alpha probe we used; the release of TNF-alpha from decidual tissue left after the removal of the placenta does not differ between resorbing and healthy implant sites. AsialoGM1+ cells did not seem to be major producers of TNF-alpha. TNF-alpha mRNA+ cells in a low rate of resorption (rat) model were only found on the fetal side of the trophoblast, and they may also represent a macrophage response (to dying embryo tissue) derived from a nondecidual source. The location of TNF-alpha mRNA+ cells may identify distinct and different mechanisms of resorption in rodents.

Abortion, Veterinary↗
PubMed1998

Intravenous immunoglobulin therapy for recurrent spontaneous abortion: a meta-analysis.

PROBLEM: Published randomized trials of the use of intravenous immunoglobulins (IVIG) as a treatment for recurrent spontaneous abortion (RSA) have produced conflicting results. The purpose of this study was to conduct a systematic review of the current evidence to evaluate the effectiveness of IVIG for RSA. METHOD OF STUDY: After a thorough search of the literature, four randomized, double-blind trials comparing IVIG with placebo for treatment of RSA were included in the meta-analysis. Live birth rates for each treatment group were extracted, and the overall odds ratio (OR) and absolute treatment effect for IVIG were calculated. RESULTS: Two of the trials showed an increase in successful pregnancy outcome with IVIG treatment and two did not. The overall OR was 1.48 (95% CI, 0.84-2.60) in favor of IVIG, with an absolute treatment effect of 10.1% (95% CI, -4.8-24.6). Excluding pregnancy failures with an obvious cause produced statistically significant results, but this approach may be subject to bias. CONCLUSION: This meta-analysis suggests that IVIG may have a role in the treatment of recurrent abortion, but as yet no conclusive evidence is available.

Abortion, Habitual↗
PubMed1998

How might pregnancy immunize against breast cancer?

PROBLEM: This study investigated how pregnancy might protect against breast cancer. METHOD OF STUDY: A critical review of the literature was done. RESULTS/CONCLUSIONS: Support for an active role in pregnancy immunizing against breast cancer comes from case studies demonstrating a reciprocal correlation between pregnancy and breast cancer as well as recent experiments supporting the fetal antigen hypothesis that confirms the presence of a tumor-specific antigen, MUC1, on both fetal and breast cancer tissues. Multiparous women also generate anti-MUC1 major histocompatibility complex-restricted cytotoxic T cell cytolytic activity against MUC1-bearing tumor cell lines. Careful investigation of the fetal antigen hypothesis and tolerogenic mechanisms may lead to effective vaccination protocols against breast cancer and other cancers.

Breast Neoplasms↗
PubMed1998

Genistein and gut inflammation: role of nitric oxide.

Genistein, a principal soy isoflavone, has been identified as a protein kinase inhibitor that possesses immunosuppressive and anti-inflammatory properties. The aim of the study was to determine if genistein modified chronic ileitis in guinea pigs induced by the hapten trinitrobenzene sulfonic acid (TNBS), and the activity index of cultured macrophages (RAW 264.7 cells) stimulated with lipopolysaccharide (LPS). Genistein at low doses (0.1 mg/kg, s.c.) had mild anti-inflammatory effects in TNBS ileitis. Therapeutic benefit included a reduction in nitric oxide production, granulocyte infiltration and improved mucosal architecture. Genistein, at low doses, also appeared to attenuate immunohistochemical staining for inducible nitric oxide synthase (iNOS) and nitrotyrosine. The beneficial effects of genistein were not apparent at doses above 0.1 mg/kg. We found that genistein also inhibited LPS-induced nitrite production by cultured macrophages and protected against LPS-induced necrosis despite its ability to cause apoptosis. These results indicate that genistein displayed mild anti-inflammatory properties which may, in part, involve an attenuation of nitric oxide release via inducible nitric oxide synthase, and the formation of peroxynitrite.

Animals↗