Reactivated recombinant plasminogen activator inhibitor-1 (rPAI-1) effectively prevents thrombolysis in vivo.

The effects of human recombinant plasminogen activator inhibitor (rPAI-1) on thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) were studied in a rabbit model of jugular vein thrombosis. Two functionally distinct rPAI-1 preparations were used in these experiments, including latent rPAI-1 (approximately 2 units of t-PA neutralizing activity per micrograms protein) and reactivated rPAI-1 (approximately 150 units/micrograms). Simultaneous intravenous infusion over 4 h of 1.7 mg/kg of reactivated rPAI-1 (inhibitory capacity approximately 0.5 mg/kg rt-PA) with 0.5 mg/kg of rt-PA completely prevented lysis of a jugular venous thrombus, whereas an equivalent amount of latent PAI-1 did not significantly influence clot lysis. These findings demonstrate that reactivated human rPAI-1 efficiently neutralizes thrombolysis with rt-PA in vivo. Since previous studies have suggested that elevated endogenous levels of PAI-1 do not attenuate the thrombolytic potency of rt-PA in the endotoxin-treated model, we compared the stability of complexes formed by 125I-rt-PA with reactivated human rPAI-1 and with rabbit PAI-1 in vitro. Our findings indicate that both forms of PAI-1 form SDS-stable complexes following incubation with 125I-rt-PA. Thus, it seems likely that elevated levels of active PAI-1 can negate the thrombolytic effects of rt-PA in vivo and argues against the possibility that t-PA can dissociate from PAI-1 and have its activity restored in the presence of a thrombus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fibrinolysis and coagulation in patients with infectious disease and sepsis

Sepsis is often associated with hemostatic dysfunction. This study aimed to relate changes in fibrinolysis and coagulation parameters to sepsis and sepsis outcome. Urokinase-type plasminogen activator (u-PA) antigen, tissue-type plasminogen activator (t-PA) antigen and activity, plasminogen activator inhibitor (PAI) type 1 antigen, PAI activity, antithrombin (AT) III activity, and protein C activity were measured in 24 patients suffering from sepsis or septic shock and the results were compared with those observed in 30 non-sepsis patients with severe infectious disease. The u-PA level was markedly increased in plasma of sepsis patients as compared to non-sepsis patients (11.5 +/- 9.4 versus 1.6 +/- 1.5 ng/ml, p less than 0.0001). PAI-1 antigen and t-PA activity showed a significant increase in sepsis patients (320 +/- 390 ng/ml versus 120 +/- 200 ng/ml, and 3.0 +/- 3.6 IU/ml versus 1.0 +/- 0.7 IU/ml, respectively, p less than 0.01). AT III was decreased in sepsis patients (58 +/- 28% in sepsis versus 79 +/- 26% in severe infectious disease, p less than 0.01) as was protein C (30 +/- 18% versus 58 +/- 27%, p less than 0.001). No significant difference was found for t-PA antigen nor for PAI activity. Nonsurvivors of sepsis were distinguished mainly by a high u-PA antigen level and increased t-PA activity. It is concluded that plasma u-PA antigen showed the strongest significant difference, among the parameters evaluated, between sepsis and severe infection. u-PA antigen may be of prognostic value in patients admitted to the medical intensive care unit for severe infectious disease.     

The incidence of error in young children's Wh-questions.

Many current generativist theorists suggest that young children possess the grammatical principles of inversion required for question formation but make errors because they find it difficult to learn language-specific rules about how inversion applies. The present study analyzed longitudinal spontaneous sampled data from twelve 2-3-year-old English speaking children and the intensive diary data of 1 child (age 2;7 [years;months] to 2;11) in order to test some of these theories. The results indicated significantly different rates of error use across different auxiliaries. In particular, error rates differed across 2 forms of the same auxiliary subtype (e.g., auxiliary is vs. are), and auxiliary DO and modal auxiliaries attracted significantly higher rates of errors of inversion than other auxiliaries. The authors concluded that current generativist theories might have problems explaining the patterning of errors seen in children's questions, which might be more consistent with a constructivist account of development. However, constructivists need to devise more precise predictions in order to fully explain the acquisition of questions.     

The topical organization of the afferents to the caudatoputamen of the rat. A horseradish peroxidase study

The aim of the present study was to assess (1) whether the various brain areas known to send projections to the neostriatum of the rat (neocortex, thalamus, substantia nigra, ventral tegmental area and dorsal raphe nucleus) project to all parts of this structure, and (2) whether the subcortical projections show a topical organization. For these purposes, small deposits of horseradish peroxidase were delivered by iontophoretic application, so that the whole extent of the caudatoputamen could be covered in a total of 40 rats.Labeled cortical cells were present mainly in lamina V, and showed a roughly topographical organization. Small numbers of labelled cells were observed in the basal nucleus of the amygdala after injections into the dorsal and central parts of the caudatoputamen. The cells of origin of thalamic afferents to the neostriatum were found not only in the intralaminar nuclei, but also in various other anterior, ‘midline’, and posterior nuclei (e.g. the medial part of the medial geniculate body). In the thalamostriatal projection a topical organization was demonstrated, consisting of oblique thalamic zones, which cross the borders of several thalamic nuclei and project to different parts of the neostriatum. In the substantia nigra and ventral tegmental area many retrogradely labelled cells were present. This nigrostriatal projection appears to be organized along an oblique longitudinal neostriatal axis. The nucleus raphes dorsalis was labelled most abundantly after caudal and ventrolateral injections into the caudatoputamen.It is concluded that, despite the homogeneous cytoarchitectonic structure of the caudatoputamen in the rat, this brain area is rather heterogeneous as regards its afferent connections. In fact each part of the neostriatum receives a specific and unique combination of afferents. The main changes in the input of the neostriatum appear to occur along an oblique longitudinal axis, from the most rostromedial and dorsal part to the caudolateral and ventral part. Such a topographical organization suggests that the neostriatum is likely to be involved in very complex integrative functions involving several brain areas.     

K-complexes: are they signs of arousal or sleep protective?

SUMMARY  The number of K-complexes recorded at the central-temporal EEG derivation (C3-T3) during 5 min periods for both the ascending and descending phase of Stage 2 of NREM sleep for cycles 1,2… etc. were counted in 10 subjects for each of the following five groups: normal persons, patients with a primary generalized form of epilepsy, narcolepsy, insomnia and obstructive sleep apnoea. The differences in time spent in different stages of sleep were as expected for these types of patients. A 2-within, 1-between factors, repeated measure ANOVA was applied to the data on K-complexes. Overall, there was no significant difference between the number of K-complexes observed during the ascending and descending phases of the different sleep cycles. Patients with a sleep disorder had significantly less well-defined K-complexes than the normals and the patients with a primary form of generalized epilepsy: for insomnia ( P = 0.035), for apnoea ( P = 0.011) and for narcolepsy ( P = 0.001). There was a significant, but very low correlation coefficient between the number of K-complexes observed during Stage 2 of NREM sleep and the time spent during that stage for all groups combined (Rho 0.27, P = 0.002) and for the narcoleptic patients (Rho 0.44, P = 0.017). In all, the findings lend support to the hypothesis that a K-complex can be seen as a 'defensive response', or has a sleep protective function.     

The Effect of Modifying Dietary Calcium Intake Pattern on the Circadian Rhythm of Bone Resorption

In order to assess day-to-day variations of the circadian rhythm of biochemical bone resorption markers, urinary morning (6–8 a.m.) and evening (7–10 p.m.) samples from 35 individuals were monitored during 3 subsequent days. The bone-specific deoxypyridinoline (DPD) crosslinks of type I collagen followed a circadian rhythm in all individuals. In contrast, no such pattern was observed in the urinary hydroxyproline/creatinine and calcium/creatinine measurements. The DPD crosslink measurements showed a much larger difference between the morning and evening samples collected within 1 day compared with the variation between the samples collected in the morning or evening on subsequent days, indicating the importance of adequate timing of urine sampling for clinical trials aiming to monitor effects on bone resorption. The analysis of DPD crosslinks was then used to evaluate the effects of different patterns of dietary calcium intake on the circadian rhythm of bone resorption in osteoporotic patients. No significant effect on the circadian rhythm of the DPD crosslinks was found after concentrating the normal daily calcium intake to the evening (6–10 p.m.) during 8 days (n = 7). Ingestion of a dietary calcium supplement (600 mg) at 10 p.m. during 8 days (n = 7) resulted in an increased urinary calcium excretion in the morning, and a flattening of the circadian peak and nadir concentrations of urinary DPD/creatinine. The absolute levels of DPD/creatinine in the morning and evening urine samples, respectively, were not significantly altered compared with the control day. We conclude that dietary calcium supplementation in the evening only marginally affects the circadian rhythm of urinary DPD crosslinks in established osteoporosis patients. Received: 23 December 1996 / Accepted: 1 November 1998     

Influence of the punch diameter and curvature on the yield pressure of MCC-compacts during Heckel analysis.

The volume reduction behaviour of powders has been quantified by means of the 'in-die' yield pressure (YP) using Heckel analysis. However, because different YPs are reported for the same material, the experimental conditions influencing this material-constant were investigated. Silicified microcrystalline cellulose was compressed into flat-faced and convex tablets using a compaction simulator instrumented with load and displacement transducers. During compression, upper and lower punch force and displacement data were recorded and corrected for punch deformation. A symmetrical triangle wave compression profile was used and the instantaneous punch velocity was kept constant (5mm/s). Individual tablet height and weight were used for Heckel analysis. The influence of the 'effective compression pressure' (P(EFF)) (ranging from 10 to 350 MPa), punch diameter (PD) (4, 9.5 and 12 mm) and filling depth (FD) (4.5, 7.5 and 10.5mm) on YP was statistically evaluated using Response Surface Modelling software. A quadratic surface response equation, describing the relationship between P(EFF), PD, FD and YP, was proposed for concave (Adj R(2): 0.8424; S.D.: 14.60 MPa) and flat-faced (Adj R(2): 0.8409; S.D.: 4.49 MPa) punches. YP and tensile strength were mainly determined by P(EFF), irrespective of punch curvature. FD and PD had only a minor influence on the YP, although more pronounced for the concave punches. The method used resulted in reproducible P(EFF) and tensile strength values and the flat-faced tablets showed less weight variation. Flat-faced punches are preferred over punches with a concave surface when investigating the volume reduction behaviour of a powder by means of Heckel analysis and the experimental parameters should be reported.     

The Use of Cyclopenta[2,1‐b;3,4‐b′]dithiophene Analogues for the Development of Low‐Bandgap Materials

This paper presents the synthesis and characterization of low‐bandgap materials based on cyclopenta[1,2‐b;3,4‐b′]dithiophene (CPDT). An array of electron‐poor monomers is synthesized and used to prepare homo‐ and alternating donor–acceptor copolymers. This yields polymers with low bandgaps (E_g = 1.12–1.23 eV) and broad light absorption (400–1100 nm). The influence of the electron‐withdrawing substituent and the donor material on the polymer properties is studied. It is demonstrated that the low bandgap is not a result of intramolecular charge transfer, but of a transition localized in the electron‐poor CPDT monomer. The bandgap can be correlated with the substituent on the CPDT monomer and is relatively independent of other parameters, resulting in materials with an easily tunable bandgap.