Thrombin activatable fibrinolysis inhibitor (TAFI) levels in patients with coronary artery disease investigated by angiography

BACKGROUND: The ability of abciximab to prevent fibrinogen binding to activated platelets indicates it may also promote dissolution of platelet-rich thrombi. The present study examined the capacity of abciximab to reverse platelet aggregation in vitro. METHODS AND RESULTS: Experiments were performed on blood from healthy non-medicated donors. Platelet aggregate formation and disaggregation were monitored turbidimetrically. Platelet-bound fibrinogen was measured by flow cytometry. For disaggregation studies, platelets were first stimulated with either ADP or the 11-mer thrombin receptor activating peptide (TRAP), then varying amounts of abciximab were added at periodic intervals after agonist addition. Platelet disaggregation was detected by comparing the extent of light transmittance at 4 min after addition of either abciximab or saline to PRP. ATP release was simultaneously monitored by chemi-luminescence. When added 1 min after low concentrations of ADP, abciximab rapidly (< 1 min) dispersed platelet aggregates in a dose-dependent manner, with complete disaggregation observed with 6.25 microg/mL of the beta3 antagonist. In contrast, equivalent concentrations of abciximab did not induce appreciable disaggregation to platelets stimulated with TRAP (10 microM). Platelet counts of samples that had undergone complete disaggregation, as assessed by aggregometry, were equivalent to baseline, indicating dispersal of aggregates to single cells. Concentrations of abciximab that produced complete disaggregation induced partial displacement of platelet-bound fibrinogen (52 +/- 8% inhibition of fibrinogen binding at 12.5 microg/ml abciximab). The disaggregation effectiveness of abciximab decreased as the time between ADP and subsequent abciximab addition widened, and as the amount of both dense granule release and agonist stimulation increased. However, pre-treatment of platelets with acetylsalicylic acid (ASA) did not potentiate platelet disaggregation induced by abciximab. CONCLUSIONS: These data indicate that abciximab facilitates the dispersal of newly formed platelet aggregates in vitro, by partially displacing fibrinogen from activated GPIIb/IIIa receptors. In vivo, abciximab may destabilize coronary thrombi by preventing aggregate formation and dispersing mural thrombi.     

Age and regional cerebral blood flow in schizophrenia: age effects in anterior cingulate, frontal, and parietal cortex

Positron emission tomography ([(15)O] water PET) was used to examine the relationship between age and regional cerebral blood flow (rCBF) in schizophrenia. Forty-nine unmedicated male patients, ages 20-51, underwent imaging during an eyes-closed resting condition. Negative correlations were observed between age and rCBF in the anterior cingulate, as well as in frontal (Brodmann area 8) and parietal cortex (area 40) bilaterally. The observation of reduced rCBF in the anterior cingulate with increased age is consistent with previous findings in healthy subjects. In contrast, the reduced flow observed in the frontal and parietal regions may be unique to schizophrenia.     

Nocturnal accumulation of cyclic 3',5'-guanosine monophosphate (cGMP) in the chick pineal organ is dependent on activation of guanylyl cyclase-B

The role of cGMP in the avian pineal is not well understood. Although the light-sensitive secretion of melatonin is a well-known output of the circadian oscillator, pharmacologically elevated cGMP levels do not result in altered melatonin secretory amplitude or phase. This suggests that pineal cGMP signalling does not couple the endogenous circadian oscillator to the expression of melatonin rhythms. Nonetheless, the free-running rhythm of cGMP signalling implies a link to the circadian oscillator in chick pinealocytes. As the circadian rhythm of cGMP levels in vitro is not altered by pharmacological inhibition of phosphodiesterase activity, we infer that the synthesis, rather than the degradation of cGMP, is under circadian control. In vitro experiments with the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine as well as with an inhibitor of the NO-sensitive soluble guanylyl cyclase (sGC), showed that the NOS-sGC pathway does not play a major role in the circadian control of cGMP generation. In organ culture experiments, we demonstrated that C-type natriuretic peptide (CNP), but not atrial natriuretic peptide (ANP), elevated daytime levels of cGMP. As CNP acts on the membrane guanylyl cyclase isoform B (GC-B), which is expressed at very high levels in mammalian pineals, we investigated the effect of the membrane GC-specific inhibitor HS-142 on chick pineal cGMP levels. CNP-induced daytime cGMP levels were reduced by HS-142. More importantly, 'spontaneously' high nocturnal levels of cGMP in vitro were reduced to daytime levels by acute addition of HS-142. These data implicate endogenous nocturnal CNP release and subsequent activation of GC-B as the major input driving cGMP synthesis in the chick pineal organ.     

Amygdalar activation associated with positive and negative facial expressions

Most theories of amygdalar function have underscored its role in fear. One broader theory suggests that neuronal activation of the amygdala in response to fear-related stimuli represents only a portion of its more widespread role in modulating an organism's vigilance level. To further explore this theory, the amygdalar response to happy, sad, angry, fearful, and neutral faces in 17 subjects was characterized using 3 T fMRI. Utilizing a random effects model and hypothesis-driven analytic strategy, it was observed that each of the four emotional faces was associated with reliable bilateral activation of the amygdala compared with neutral. These findings suggest a broader role for the amygdala in modulating the vigilance level during the perception of several negative and positive facial emotions.     

Validation of case-mix measures derived from self-reports of diagnoses and health

Self-reported chronic diseases and health status are associated with resource use. However, few data exist regarding their ability to predict mortality or hospitalizations. We sought to determine whether self-reported chronic medical conditions and the SF-36 could be used individually or in combination to assess co-morbidity in the outpatient setting. The study was designed as a prospective cohort study. Patients were enrolled in the primary care clinics at seven Veterans Affairs (VA) medical centers participating in the Ambulatory Care Quality Improvement Project (ACQUIP). 10,947 patients, > or = 50 years of age, enrolled in general internal medicine clinics who returned both a baseline health inventory checklist and the baseline SF-36 who were followed for a mean of 722.5 (+/-84.3) days. The primary outcome was all-cause mortality, with a secondary outcome of hospitalization within the VA system. Using a Cox proportional hazards model in a development set of 5,469 patients, a co-morbidity index [Seattle Index of Co-morbidity (SIC)] was constructed using information about age, smoking status and seven of 25 self-reported medical conditions that were associated with increased mortality. In the validation set of 5,478 patients, the SIC was predictive of both mortality and hospitalizations within the VA system. A separate model was constructed in which only age and the PCS and MCS scores of the SF-36 were entered to predict mortality. The SF-36 component scores and the SIC had comparable discriminatory ability (AUC for discrimination of death within 2 y 0.71 for both models). When combined, the SIC and SF-36 together had improved discrimination for mortality (AUC = 0.74, p-value for difference in AUC < 0.005). A new outpatient co-morbidity score developed using self-identified chronic medical conditions on a baseline health inventory checklist was predictive of 2-y mortality and hospitalization within the VA system in general internal medicine patients.     

Central and peripheral regulation of feeding and nutrition by the mammalian circadian clock: implications for nutrition during manned space flight

Circadian clocks have evolved to predict and coordinate physiologic processes with the rhythmic environment on Earth. Space studies in non-human primates and humans have suggested that this clock persists in its rhythmicity in space but that its function is altered significantly in long-term space flight. Under normal circumstances, the clock is synchronized by the light-dark cycle via the retinohypothalamic tract and the suprachiasmatic nucleus. It is also entrained by restricted feeding regimes via a suprachiasmatic nucleus-independent circadian oscillator. The site of this suboscillator (or oscillators) is not known, but new evidence has suggested that peripheral tissues in the liver and viscera may express circadian clock function when forced to do so by restricted feeding schedules or other homeostatic disruptions. New research on the role of the circadian clock in the control of feeding on Earth and in space is warranted.     

Molecular pathogenesis of pancreatic cancer

Our understanding of the biology of pancreatic carcinoma has greatly benefited from studies of the genetic alterations in this tumor type. The p16-CDK4-cyclinD-Rb pathway, the p53 tumor suppressor pathway, and the DPC4/Smad4 pathway are genetically inactivated in the majority of sporadic pancreatic carcinomas, whereas oncogenic K-ras signaling is almost ubiquitously activated. These genetic data have provided the basis to shape a first genetic progression model of this tumor type. Furthermore, a number of well defined genetic syndromes which are associated with an inherited risk for pancreatic carcinoma have been identified recently.     

Subjective quality of life of children and adolescents with psychiatric disorders: development and validation of a new assessment scale

Within paediatric disciplines and in particular in child and adolescent psychiatry very little work is available regarding the quality of life (QoL) of patients. After using literature search and interviews for identifying the relevant QoL domains, a set of self report questionnaires (for the parents: proxy rating) was developed (C-version: children 10 to 14 years, A-version: adolescents 14 to 18 years, P-version: parental proxy rating about child/adolescent). It was aimed at an almost identical wording within each questionnaire version in regard to the different QoL domains. The questionnaires should not primarily address symptomatology (like e.g. the Child Behaviour Checklist by Achenbach and Edelbrock 1983). After a pilot phase ensuring adequacy and appropriateness of the forms, the questionnaires were field tested in a consecutive series of nearly 700 patients which were referred to the Cologne university department of child and adolescent psychiatry for diagnosis and treatment between 1996 and 2000. The intended structure of the questionnaire system with symptom and functioning scales concerning the domains: "physical performance, fatigue, anxiety, depression, peer group, school, family, beliefs, general QoL" and some further single questions was confirmed by psychometric testing (validity and reliability). Interscale correlations were in general moderate, exhibiting the expected pattern. Analyses of variances using the method of "known groups comparisons" showed e.g. age, sex, and diagnosis related effects hinting towards clinically meaningful differences. The questionnaire forms were well accepted and understood by patients and parents and the wording of the addressed topics was reported to be adequate. Further work will include the psychopathological findings and will focus on specific subgroups of patients (e.g. different diagnoses) as well as on the longitudinal observation of special patient groups, e.g. patients with eating disorders. It can be concluded that the new QoL instruments were successfully employed in a consecutive series of patients and showed very sufficient psychometric properties.