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D A Clark

Publications and source records attributed to D A Clark.

At least 37 records · Page 2Linked to original sources

Scalable architecture in mammalian brains.

Comparison of mammalian brain parts has often focused on differences in absolute size, revealing only a general tendency for all parts to grow together. Attempts to find size-independent effects using body weight as a reference variable obscure size relationships owing to independent variation of body size and give phylogenies of questionable significance. Here we use the brain itself as a size reference to define the cerebrotype, a species-by-species measure of brain composition. With this measure, across many mammalian taxa the cerebellum occupies a constant fraction of the total brain volume (0.13 +/- 0.02), arguing against the hypothesis that the cerebellum acts as a computational engine principally serving the neocortex. Mammalian taxa can be well separated by cerebrotype, thus allowing the use of quantitative neuroanatomical data to test evolutionary relationships. Primate cerebrotypes have progressively shifted and neocortical volume fractions have become successively larger in lemurs and lorises, New World monkeys, Old World monkeys, and hominoids, lending support to the idea that primate brain architecture has been driven by directed selection pressure. At the same time, absolute brain size can vary over 100-fold within a taxon, while maintaining a relatively uniform cerebrotype. Brains therefore constitute a scalable architecture.

Algorithms↗

Procoagulants in fetus rejection: the role of the OX-2 (CD200) tolerance signal.

The spontaneous loss of normal karyotype embryos may be initiated or prevented by the maternal immune system. In mice, loss between the time of implantation (day 4.5) and formation of a vascularized placenta (day 9.5) when the embryo is too large to survive by diffusion alone, is analogous to occult pregnancy failure in humans. They are called occult because usually the woman does not know she is pregnant. From studies in mice, these early losses have a different mechanism than abortion of a vascularized placenta (analogous to clinically evident human spontaneous miscarriage). The latter depend on the activation of the novel prothrombinase fgl2 on the fetal trophoblast and in maternal decidua by the T helper-1 (Th1) type cytokines TNF- alpha+gamma -interferon that arise from NK cells and NK gammadelta T cells; conversion of prothrombin to thrombin which in turn generates IL8 that activates polymorphonuclear leukocytes leads to embryonic death. These inflammatory processes are counteracted by Th2/3-type cytokines that arise in part from V gamma 1 delta 6 T cells reacting to, as yet, unidentified trophoblast antigens in the presence of the 'tolerance signaling molecule' OX-2. By contrast, peri-implantation losses (between implantation and formation of a vascularized placenta, analogous to occult losses in humans) appear to be dependent upon perforin(+)cells, complement activation, and products of alphabeta T and NK alphabeta T cells, but not on TNF- alpha or procoagulant activation. Similarities and differences between findings in the mouse and human, and the potential evolutionary significance of mechanisms affecting reproductive success are reviewed.

Abortion, Spontaneous↗

Suppression of obsession-like thoughts in nonclinical individuals: impact on thought frequency, appraisal and mood state.

Wegner's (1994, Psychological Review, 101, 34-52) research on the paradoxical effect of thought suppression has been incorporated into contemporary cognitive-behavioural models of obsessive-compulsive disorder. However, findings on the effects of thought suppression on thought frequency have been inconsistent and few studies have actually examined the suppression of thoughts that are obsessional in nature. In the present study 219 nonclinical participants were randomly assigned to suppress or not suppress a neutral, obsessional or positive thought during an initial monitoring interval. In a second thought monitoring interval, all participants received instructions not to suppress their target thought. No paradoxical effect of suppression on frequency was observed for any type of thought, although suppression of obsessional thoughts was associated with greater subsequent discomfort and a more negative mood state than suppression of positive or neutral target thoughts.

Adolescent↗

Activation of the novel prothrombinase, fg12, as a basis for the pregnancy complications spontaneous abortion and pre-eclampsia.

PROBLEM: Impaired trophoblast invasion during the first trimester of pregnancy is linked to spontaneous abortion, and defective invasion in the second trimester to hypertension + proteinuria (pre-eclampsia). Hypertension developing during the third trimester of human pregnancy represents, in part, a corrective response in the mother to provide adequate placental perfusion for fetal growth when trophoblast has not to invaded and converted the myometrial porprtion of maternal spiral arteries into to low resistance-high capacitance conduits. Deportation of vesicles from hypoxemic trophoblast is thought to cause hypertension plus proteinuria, vascular damage and a systemic coagulopathy. Trophoblast invasion may be inhibited by local cytokines, such as TGF-betas but Thl-type cytokines associated with pre-eclapmsia and spontaneous abortions (e.g., IL-1, TNF-alpha, IFN-gamma) are not known to inhibit migration at in situ concentrations. Trophoblast invasion is also inhibited by the binding of surface integrins to fibronectin and fibrin, and fibrin production is stimulated by these Th1 cytokines via up-regulation of prothrombinases(s) such as fg12 which directly and via TNF-alpha-facilitated inflamation compromise trophoblast cell integrity. We, therefore, asked if fg12 expression and TNF-alpha are increased in first trimester human miscarriage and in third trimester pre-eclampsia. METHODS: fg12 mRNA was detected using in situ hybridization and fg12 protein by immunohistochemistry. TNF-alpha mRNA and protein were similarly tested. The techniques were validated using uterine sections from day 8.5 of CBA x DBA/2 pregnancies, and then were applied to sections of placentae from normal and pre-eclamptic pregnancies with and without intrauterine fetal growth restriction (IUGR). Fibrin was detectectd by immunohistochemistry. RESULTS: Expression of fg12 protein correlated with fg12 mRNA expression in mouse uteri and in placentae from normal human pregnancies. Increased expression of fg12 and TNF-alpha mRNA and protein, and increased fibrin deposition was detected in placental trophoblast. CONCLUSIONS: Activation of fg12 prothrombinase by Th1-type cytokines in pregnancy may lead to spontaneous abortion, or in ongoing pregnancy, to pre-eclampsia and/or IUGR.

Abortion, Spontaneous↗

Fgl2 prothrombinase expression in mouse trophoblast and decidua triggers abortion but may be countered by OX-2.

Spontaneous abortion of normal karyotype embryos in mice and in humans is associated with an increase in uterine T helper (Th) 1 type proinflammatory cytokines, tumour necrosis factor (TNF)-alpha, interferon-gamma and interleukin (IL)-1, and a deficiency of Th2/3 type cytokines, IL-4, IL-10, and transforming growth factor (TGF)-beta2. In mice, Th1 cytokines up-regulate a novel prothrombinase, fgl2, which via thrombin, leads to activation of polymorphonuclear leukocytes that terminate the pregnancy. Here we show that Th1 cytokines up-regulate fgl2 mRNA in fetal trophoblast and secondary decidua of CBA/JxDBA/2 and CBA/JxBALB/c matings, and promote fibrin deposition. This pattern is accompanied by a high rate of abortion. However, the spontaneous abortion rates in abortion-prone CBAxDBA/2 matings and in low abortion rate CBAxBALB/c matings were significantly lower than that expected from the frequency of implantations with high levels of fibrin and fgl2 mRNA(hi). As the glycoprotein OX-2 occurs in the pregnant rat uterus and can deviate cytokine responses to Th2/3, we investigated OX-2 in pregnant CBA/J mice. We found OX-2 mRNA was present at the same sites as fgl2 mRNA, but was reduced in response to Th1 cytokines. Furthermore, anti-OX-2 raised the abortion rate to predicted levels, while recombinant OX-2 dramatically reduced the abortion rate. Fgl2 prothrombinase may provide a mechanism explaining pregnancy loss, and conversely, successful pregnancy may be due in part to OX-2-dependent activation of maternal tolerance mechanisms at the feto-maternal interface.

Abortion, Spontaneous↗

FAS/FAS ligand interaction at the placental interface is not required for the success of allogeneic pregnancy in anti-paternal MHC preimmunized mice.

PROBLEM: FAS ligand (FASL) induces apoptosis in FAS+ T cells. FAS-FASL interaction can explain tolerance of some types of allografts. Do similar interactions prevent rejection of the fetal allograft and transplacental passage of maternal T cells capable of causing GvH leading to runting? METHOD OF STUDY: We examined growth of subcutaneous EL-4 (H-2b) tumor cells in syngeneic MRL.lpr/lpr mice mated with syngeneic MRL.lpr/lpr or allogeneic C57/B1/6.lpr/lpr males. Lpr/lpr mice lack FAS and their T cells should remain effective at the fetomaternal interface. In some studies, the mice were preimmunized against C57B1/6 to enhance the likelihood of fetal rejection and/or runting. Cytotoxic lymphocyte (CTL) activity in the spleens was assessed using a 51Cr-release assay. Birth weights and weights at weaning were measured. RESULTS: Tumor rejection was delayed by about 3 days in allopregnant lpr/lpr females compared to syngeneic pregnant females occurred, but tumors were rejected and in a secondary fashion with minimal delay allopregnant females preimmunized to H-2b. CTL activity was present more in decidua than in spleen in preimmunized mice, and allopregnancy failed to reduce this activity. No neonates born to preimmunized or control lpr/lpr mothers developed runt disease. Indeed, the birth weight was greater for immunized females, but at 10 weeks, the difference compared to non-immunized females disappeared. CONCLUSIONS: FAS/FASL interaction between FAS+ T cells and FASL+ fetal trophoblasts at the fetomaternal interface is not mandatory for successful allopregnancy. The potential roles of other apoptosis-induction mechanisms at the fetomaternal interface, such as TNF/TRAIL, require critical testing before enthusiasm is merited. It maybe necessary to eliminate all such mechanisms to show a deleterious effect on pregnancy. Spontaneous deletion of all pathways seems a priori unlikely to occur, and hence, of dubious relevance to fetal loss.

Animals↗

TH1/TH2,3 imbalance due to cytokine-producing NK, gammadelta T and NK-gammadelta T cells in murine pregnancy decidua in success or failure of pregnancy.

PROBLEM: Recurrent spontaneous abortion in DBA/2-mated CBA/J mice has been attributed to the production of Th1 cytokines (tumor necrosis factor [TNF]-alpha and interferon [IFN]-gamma) by asialoGM1+ natural killer (NK) cells and Vgamma1.1delta6.3+ T cells that infiltrate decidua by day 6.5, during the peri-implantation period. Abortions can be prevented by a second population of Vgamma1.1delta6.3 cells, which infiltrate on day 8.5 of gestation, and produce the Th2 cytokine interleukin (IL)-10 and Th3 cytokine transforming growth factor (TGF)-beta2. In low abortion rate immunocompetent mice, most of the TGF-beta2 is derived from gammadelta T cells. However, TGF-beta2-producing cells are present in the decidua of pregnant severe combined immune deficient (SCID) mice, which lack gammadelta T cells. METHODS: The cells in day 13.5 decidua of CBA x DBA/2 matings and SCID x SCID matings were identified using flow cytometry and combined surface staining for gammadelta and/or asialoGM1, and intracellular cytokine staining for TNF-alpha, IFN-gamma, and TGF-beta2,3. RESULTS: TGF-beta2 and TNF-alpha were found in asialoGM1+ NK cells in SCID mouse decidua. In CBA x DBA/2 mated mice, two major and one minor subsets of cytokine-positive cells were identified: -gammadelta-only T cells, double positive asialoGM1+ gammadelta+ (NK-gammadelta T) cells, and a small number of asialoGM1 +gammadelta- NK-only cells. The NK-only and NK-gammadelta T subsets showed a greater Th1/Th2,3 pattern of intracellular staining compared with the gammadelta-only subset. In the CBA x DBA/2 and SCID x SCID systems, Th1/Th2,3 ratios could not predict actual observed abortion rates but did correlate with susceptibility to abortions (if exposed to an additional stimulus such as stress). The known effect of in vivo administration of anti-asialoGM1 antibody on abortion rates within groups of mice exposed to such stresses could also be predicted. CONCLUSION: gammadelta+ cells in decidua (e.g. Vgamma1+ cells which can recognize trophoblasts) differ based on the presence or absence of the NK marker-asialo-GM1. NK-gammadelta T cells may be quite important in the Th1 response in early pregnancy that predisposes to abortions in CBA x DBA/2 matings, whereas gammadelta T-only cells appear to be protective. In pregnant SCID mice, the TNF-alpha+/TGF-beta2+ NK population is greatly expanded. An activating stimulus (such as stress or endotoxin) appears to be as important in triggering abortions, as is the Th1/Th2,3 ratio at the feto maternal interface.

Abortion, Habitual↗

Quantitation of porcine cytomegalovirus in pig tissues by PCR.

A quantitative-competitive PCR for the quantification of porcine cytomegalovirus (PCMV) was developed. The virus was detected in a variety of pig organs (including potential xenotransplant donations), with viral loads ranging from <10 to 97 genome copies/microg of DNA. This assay will have significant utility for studying the activation and replication of PCMV and in swine models for allo- and xenotransplantation.

Animals↗

Incidence and outcomes of total hip arthroplasty among U.S. Army aviators.

Among Army aviators, the incidence of total hip arthroplasty (THA) is unknown. This study analyzes the incidence and aeromedical disposition of THA among Army aviators. The U.S. Army Epidemiology Data Register was queried for a 10-year period from calendar year 1987 to 1996. The aviators selected for this study cohort were all qualified and on active flight status before undergoing THA. Data collected included age, gender, diagnoses, and aeromedical dispositions. There were 214,003 aviator-years of observation. Eleven aviators underwent 14 THAs. The overall incidence of THA was 0.05 per 1,000 aviator-years of observation. Of the 11 aviators who underwent THA during the study period, 4 received aeromedical suspension from flying duties (36%). THA is a rare medical event among Army aircrew members. Most are able to return to full flying duties with a waiver. Aircrew members younger than 50 years with THA are more likely to be suspended from aviation duties.

Absenteeism↗

Regulation of gene expression of murine MD-1 regulates subsequent T cell activation and cytokine production.

The immunoadhesin (OX2:Fc) comprising the extracellular domain of murine OX2 linked to IgG2aFc, inhibits production of IL-2 and IFN-gamma by activated T cells and increases allograft and xenograft survival in vivo. Increased expression of OX2 on dendritic cells (DC) in vivo following preimmunization via the portal vein is also associated with elevated expression of MD-1. We have used antisense oligodeoxynucleotides (ODNs) to MD-1 to investigate the effect of inhibition of expression of MD-1 by DC on their function as allostimulatory cells. We also investigated by FACS analysis the cell surface expression of OX2, CD80, and CD86 on DC incubated with ODN-1 blocking MD-1 expression. Blocking MD-1 gene expression inhibits surface expression of CD80 and CD86, but not of OX2. DC incubated with ODN-1 to MD-1 did not stimulate IL-2 or IFN-gamma production, but generated cells able to suppress, in a second culture of fresh DC plus allogeneic T cells, production of IL-2 and IFN-gamma. This inhibition was blocked by anti-OX2 mAb. Infusion of DC preincubated with ODN-1 prolonged renal allograft survival, an effect also reversed by anti-OX2 mAb. By FACS, incubation of DC with anti-MD-1 Ab to promote capping eliminated cell surface expression of MD-1 and CD14 without altering DEC205, DC26, CD80, CD86, or OX2 expression. Thus OX2 and MD-1 are independent surface molecules on DC that may reciprocally regulate T cell stimulation. MD-1 is linked to CD14, a "danger receptor complex," and activation of this complex can regulate cell surface expression of CD80/CD86, which signal T cells.

Animals↗

Prospective study of human betaherpesviruses after renal transplantation: association of human herpesvirus 7 and cytomegalovirus co-infection with cytomegalovirus disease and increased rejection.

BACKGROUND: Human herpesvirus 6 (HHV-6) and HHV-7 are two lymphotropic herpesviruses, which, like cytomegalovirus (CMV), have the potential to be pathogenic in immunocompromised individuals. We have conducted a prospective investigation to compare the natural history of HHV-6 and HHV-7 infection with that of CMV after renal transplantation. METHODS: Polymerase chain reaction was used to identify infections and quantify the viral load of CMV, HHV-6, and HHV-7 in peripheral blood samples from 52 renal transplant recipients. Betaherpesvirus infections were related to defined clinical criteria obtained by detailed examination of the clinical records of each patient for the immediate 120-day posttransplant period. RESULTS: CMV was the most commonly detected virus after transplant (58% of patients), followed by HHV-7 (46%) and HHV-6 (23%). Examining the time to first polymerase chain reaction positivity, HHV-7 infection was detected earlier than CMV (P=0.05). The median maximum CMV viral load was significantly higher than those for HHV-6 (P=0.01) and HHV-7 (P<0.0001) and a trend for HHV-7 viral load to be greater than HHV-6 (P=0.08). Clinicopathological analyses revealed that, in those patients with rejection, HHV-7 was associated with more episodes of rejection (P=0.02). In addition, there was a significant increase in CMV disease occurring in patients with CMV and HHV-7 co-infection compared to those with CMV infection only (P=0.04). CONCLUSIONS: HHV-7 should be further investigated as a possible co-factor in the development of CMV disease in renal transplant patients and may potentially exacerbate graft rejection. No clear pathological role was observed for HHV-6.

Betaherpesvirinae↗

How much is too much?

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Angioplasty, Balloon, Coronary↗

Appraisal and control of sexual and non-sexual intrusive thoughts in university students.

This study examined differences in the appraisal and thought control strategies associated with the perceived control of unwanted sexual and non-sexual intrusive thoughts. Eleven appraisal dimensions, subjective physiological arousal and 10 thought control strategies were measured in 171 university students who were administered the Revised Obsessive Intrusions Inventory-Sex Version, a self-report measure of unwanted intrusive thoughts. Thought-action fusion (TAF) likelihood was a significant unique predictor of the perceived controllability of respondents' most upsetting sexual and non-sexual intrusive thought. Moreover greater subjective physiological arousal was a significant predictor of reduced control over sexual intrusions, whereas worry that one might act on an intrusive thought and greater effort to control the intrusion were significant unique predictors of the control of non-sexual intrusive thoughts. Various thought control strategies were more often used in response to non-sexual than sexual cognitions. The results are discussed in terms of the differential role of various appraisal processes in the control of unwanted sexual and non-sexual thoughts.

Adolescent↗

A non-radioisotopic quantitative competitive polymerase chain reaction method: application in measurement of human herpesvirus 7 load.

Quantitative-competitive polymerase chain reaction (QCPCR) is a well-optimised and objective methodology for the determination of viral load in clinical specimens. A major advantage of QCPCR is the ability to control for the differential modulation of the PCR process in the presence of potentially inhibitory material. QCPCR protocols were developed previously for CMV, HHV-6, HHV-7 and HHV-8 and relied upon radioactively labelled primers, followed by autoradiography of the separated and digested PCR products to quantify viral load. Whilst this approach offers high accuracy and dynamic range, non-radioactive approaches would be attractive. Here, an alternative detection system is reported, based on simple ethidium bromide staining and computer analysis of the separated reaction products, which enables its adoption in the analysis of a large number of samples. In calibration experiments using cloned HHV-7 DNA, the ethidium bromide detection method showed an improved correlation with known copy number over that obtained with the isotopic method. In addition, 67 HHV-7 PCR positive blood samples, derived from immunocompromised patients, were quantified using both detection techniques. The results showed a highly significant correlation with no significant difference between the two methods. The applicability of the computerised densitometry method in the routine laboratory is discussed.

DNA, Viral↗

Betaherpesviruses in transplant recipients.

The three betaherpesviruses known to infect humans are cytomegalovirus (CMV) and human herpesviruses 6 and 7 (HHV-6 and -7). All three viruses can infect opportunistically after organ transplantation. CMV causes a variety of end-organ diseases, including pneumonitis, hepatitis and gastrointestinal ulceration. Patients who develop overt CMV disease have significantly higher CMV viral loads than infected patients without evidence of clinical disease. A high CMV viral load largely explains the previously described risk factors for the development of CMV disease, which include donor/recipient serostatus before transplant and viraemia after transplant. CMV also causes some cases of allograft rejection, which can be prevented by antiviral prophylaxis. Application of similar quantitative methods for the study of HHV-6 and -7 have shown that HHV-6 and CMV are significantly and independently associated with biopsy-proven graft rejection after liver transplantation. The full clinicopathological significance of the betaherpesviruses may, thus, be greater than is currently appreciated.

Antiviral Agents↗