Outcomes of elderly patients with traumatic brain injury associated with the pre-injury antithrombotic prophylaxis type - A systematic review and meta-analysis.

OBJECTIVE: Our review aims at comparing the morbidity and mortality-related risks associated with the pre-injury administration of VK-antagonists or DOACs in elderly patients with TBI. MATERIALS AND METHODS: We performed a systematic search of the academic literature across five databases (Web of Science, EMBASE, CENTRAL, Scopus, and MEDLINE), following PRISMA guidelines. We conducted a random-effect meta-analysis to compare the influence of pre-injury VK-antagonists or DOACs administration on the overall intensive care unit and hospital stays of patients with TBI. We also evaluated the overall risks associated with VK-antagonists and with DOACs for intracranial hemorrhage progression, surgical intervention, and overall mortality in patients with TBI. RESULTS: From 973 studies, we found 11 eligible with 4,991 patients with traumatic brain injury (mean age, 77.82 ± 6.76 years). Our meta-analysis revealed insignificantly higher odds of surgical intervention (OR=1.72) and mortality (OR=1.07) associated with VK-antagonists administration than with DOACs administration. Similarly, we found that the intensive care unit (Hedge's g, 0.13) and hospital (g, 0.26) stays were insignificantly longer for individuals on VK-antagonists than for those on DOAC. Moreover, we observed insignificantly higher intracranial hemorrhage progression risks (OR=1.22) for individuals receiving DOACs than for those receiving VK-antagonists. CONCLUSIONS: This study provides evidence on the morbidity and mortality-related outcomes associated with the pre-injury administration of VK-antagonists or DOACs in patients with TBI. We found no significant differences between VK-antagonists and DOACs on the overall morbidity (hospital and intensive care unit stays, intracranial hemorrhage, and surgical intervention frequency) and mortality outcomes in elderly patients with TBI.

Using an abnormal increase in postexercise systolic blood pressure to diagnose coronary artery disease in gerontal patients.

Data from 66 patients ≥ 60 years old with suspected coronary artery disease (CAD) were studied to determine the diagnostic value of an abnormal increase in postexercise systolic blood pressure (SBP) for detecting CAD in gerontal patients. Treadmill exercise testing (TET) and selective coronary angiography (CAG) were carried out and SBP was measured pre-TET and at each minute during a 6-min post-TET recovery phase. Abnormal increase in postexercise SBP was defined as a higher SBP compared with that measured earlier during the 6-min post-TET period. An abnormal increase of ≥ 7 mmHg in postexercise SBP had a statistically significantly better specificity, and also showed higher sensitivity and accuracy, than ST-segment depression ≥ 1 mV in identifying gerontal patients with CAD. The combination of ST-segment depression and abnormal SBP resulted in further improvement of the specificity for detecting CAD. It is concluded that measurement of abnormal increase in postexercise SBP may be a sensitive indicator of gerontal CAD.

The role of NO and B-50 in neurotoxicity of excitatory amino acids.

To investigate the direct evidence for the role which nitric oxide (NO) plays in the neurotoxicity of excitatory amino acids, we evaluated NO level by Greiss testing solution when glutamate (Glu) and kainate (KA) induced neuronal degeneration in primary cortical cultures. Glutamate-induced neurotoxicity was accompanied by a rise in NO. 5 mM hemoglobin (Hb) led to a decrease of NO content and prevented excitotoxicity induced by 1 mM glutamate. 1 mM L-arginine (L-Arg) reversed the effect of hemoglobin by raising the NO level. No change in NO content was found in KA-induced neurotoxicity, which was not affected by L-Arg, Hb or L-Arg + Hb. It is suggested that NO plays an important role in glutamate-, but not KA-induced neurotoxicity in primary cortical cultures. We also investigated the effects of glutamate on a growth-associated protein, B-50. The B-50 level declined significantly 24 h after exposure to 100 microM glutamate for 30 min and then recovered 2 days later. The effect of glutamate on B-50 was concentration-dependent. This indicates that B-50 might be involved in both glutamate neurotoxicity and the following neuronal repair process.

Nerve growth factors prevent glutamate toxicity in cortical neuronal cultures.

AIM: To determine if nerve growth factors (NGF) can protect against glutamate-induced cortical neuron damage. METHODS: Neuron viability and lactate dehydrogenase (LDH) efflux in the bathing medium in primary cultures from 17-d-old mouse fetal cortex were measured to assay NGF effect. Imaging of the calcium indicator dye Fura-2 was used to measure the [Ca2+]i. RESULTS: The LD50 for NGF-free glutamate was 0.2 mmol.L-1 (95% confidence limits 0-1.6 mmol.L-1). In the presence of NGF 60 micrograms.L-1, 59% of the neurons survived in glutamate 1.6 mmol.L-1. The protective effect afforded by NGF was maximal at 60 micrograms.L-1, at which it prevented the elevation in [Ca2+]i. CONCLUSION: NGF protect cortical neurons against glutamate-induced toxicity via "stabilizing" [Ca2+]i level or suppression of the rise in [Ca2+]i.

[Effects of morphine on monosodium glutamate neurotoxicity and its mechanism].

The enhancing effects of morphine on monosodium glutamate (MSG) neurotoxicity and its blocking by naloxone were studied through morphological observation, together with detection of concentrations of intracellular free Ca2+ ([Ca2+]i) by Ca2+ indicator Fura-2/AM and lactate dehydrogenase (LDH) efflux in the bathing medium in primary cultures from 14-17 d old mouse fetal cortex. It was found that 10 min pre-incubation of young cortical neurons (7 day in vitro) with morphine 10(-7) or 10(-6) mol.L-1 substantially increased LDH release from 105.7% +/- 19.0% (treated with MSG alone) to 194.5% +/- 17.7% and 214.0% +/- 9.5% respectively after exposure to MSG 0.1 mmol.L-1, but pre-incubation with morphine (10(-7) or 10(-6) mol.L-1) plus naloxone (0.1 mmol.L-1) reversed the LDH release after treatment with the same concentration of MSG. Morphine (10(-7) or 10(-6) mol.L-1) produced little elevation of [Ca2+]i. However, when combined with MSG (0.1 mmol.L-1) morphine elevated the [Ca2+]i level much more than MSG alone. These results suggest that morphine markedly enhances excitotoxic neuron damage, which can be reversed by naloxone. Overloading of intracellular Ca2+ may be a simultaneous pathological mechanism underlying the neuronal damage and death that occur in excitatory toxicity.

Characterization of the gene encoding the largest subunit of Plasmodium falciparum RNA polymerase III.

We report here the isolation, sequence analysis, structure, and expression of the gene encoding the largest subunit of RNA polymerase III (RPIII) from Plasmodium falciparum. The P. falciparum RPIII gene consists of 5 exons and 4 introns, is expressed in all of the asexual erythrocytic stages of the parasite as a 8.5-kb mRNA, and is present in a single copy on chromosome 13. The predicted 2339 amino acid residue RPIII subunit contained 5 regions that were conserved between different eukaryotic RPIII subunits, and 4 variable regions that separated the conserved regions. Three of the variable regions were greatly enlarged in comparison to the corresponding variable regions in other RPIII subunits. Variable region C' represented nearly one-third of the P. falciparum RPIII subunit (750 amino acid residues), included a unique repeated decapeptide sequence, and had some homology with yeast DNA topoisomerase II. Noteworthy amino acid sequences and structures were identified in both the conserved regions and in the enlarged variable regions, and their possible role(s) as domains that regulate RPIII enzyme activity is discussed.

Mutant dihydrofolate reductase-thymidylate synthase genes in pyrimethamine-resistant Plasmodium falciparum with polymorphic chromosome duplications.

We have identified dihydrofolate reductase (DHFR) gene point mutations and chromosomal changes in pyrimethamine-resistant mutants selected in vitro of Plasmodium falciparum strain FCR3. A pyrimethamine-resistant derivative of the pyrimethamine-sensitive strain FCR3, FCR3-D8, that had been grown in the absence of pyrimethamine for an extended time, was grown in two concentrations of pyrimethamine, and surviving drug-resistant parasites were subcloned. One selected mutant, FCR3-D81, that grew at 1 X 10(-6) M pyrimethamine, contained a single point mutation in the DHFR domain which caused an amino acid change (Phe to Ser) at amino acid 223, whereas another mutant, FCR3-D85, that grew at 5 X 10(-6) M pyrimethamine had that same mutation and an additional point mutation that changed amino acid 54 (Asp to Asn). The selection of FCR3-D85, whose nucleotide sequence was identical to that previously reported for FCR3-D8, confirmed that the original FCR3-D8 parasite population had changed during extended growth in vitro in the absence of drug pressure. FCR3-D81 and FCR3-D85 cells contained different pairs of polymorphic chromosomes that hybridized to a DHFR-TS probe as well as to three other chromosome 4 specific DNAs, indicating that at least part of chromosome 4 had been duplicated and that these parasites were aneuploid with 15 rather than 14 chromosomes. The mutant DHFR-TS genes were diploid. We consider the roles of the polymorphic chromosome duplications and DHFR point mutation(s) as causes of pyrimethamine resistance.

Dihydrofolate reductase mutations and chromosomal changes associated with pyrimethamine resistance of Plasmodium falciparum.

The nucleotide sequence of the dihydrofolate reductase-thymidylate synthase (DHFR-TS) gene in pyrimethamine-resistant (PyrR) mutants of Plasmodium falciparum selected in vitro was examined to determine if specific mutations in DHFR were associated with drug resistance. We analysed the sequence of genomic DNA from strain FCR3, from eight previously isolated PyrR parasites derived from FCR3, and from strain Honduras-1. We found that: (1) five PyrR FCR3 mutants, FCR3-D4-D8, had an identical nucleotide change and a novel single amino acid change (Phe to Ser) at amino acid 223 of DHFR; (2) our originally reported nucleotide sequence of the DHFR-TS gene was of the PyrR strain Honduras-1, and was not of FCR3; (3) three PyrR mutants, FCR3-D1, D2, and D3, thought to have been derived from the FCR3 strain, were in fact isolates of Honduras-1. We also examined the chromosomal DNA of PyrR mutants by pulsed-field gradient gel (PFG) electrophoresis. The PyrR mutants FCR3-D1, D2, and D3 had several chromosome size polymorphisms compared to FCR3. In two of the PyrR FCR3 mutants, FCR3-D7 and D8, the chromosome 4-size DNA of FCR3 that the DHFR-TS probe normally hybridised to was not observed. Instead, in FCR3-D7, a chromosome larger than the chromosome 4-size DNA was observed to hybridise to the DHFR-TS probe. In FCR3-D8, two chromosomes that hybridised to the DHFR-TS probe were found. One of them was larger than FCR-3 chromosome 4-size DNA, and the other was smaller than FCR3 chromosome 1-size DNA.(ABSTRACT TRUNCATED AT 250 WORDS)

An enlarged largest subunit of Plasmodium falciparum RNA polymerase II defines conserved and variable RNA polymerase domains.

We have isolated the gene encoding the largest subunit of RNA polymerase II from Plasmodium falciparum. The RPII gene is expressed in the asexual erythrocytic stages of the parasite as a 9 kb mRNA, and is present as a single copy gene located on chromosome 3. The P. falciparum RPII subunit is the largest (2452 amino acids) eukaryotic RPII subunit, and it contains enlarged variable regions that clearly separate and define five conserved regions of the eukaryotic RPII largest subunits. A distinctive carboxyl-terminal domain contains a short highly conserved heptapeptide repeat domain which is bounded on its 5' side by a highly diverged heptapeptide repeat domain, and is bounded on its 3' side by a long carboxyl-terminal extension.

Premature release of Plasmodium falciparum from swollen erythrocytes induced by some antimalarials.

Qinghaosu and chloroquine, but not pyrimethamine, treatment of Plasmodium falciparum cultures resulted in the formation of swollen red blood cells (RBCs) and the expulsion of degenerate trophozoites and schizonts, but not ring-stage parasites, from the infected RBCs. The parasite release resulted in the formation of RBCs with holes, that had otherwise retained their structural integrity. Membranes of swollen RBCs and their ghosts associated with parasites were efficiently visualized by Giemsa staining of thin smears for 18-24 hr but not by standard Giemsa staining for 20 min.

The chemotherapy of rodent malaria, XXXIX. Ultrastructural changes following treatment with artemisinine of Plasmodium berghei infection in mice, with observations of the localization of [3H]-dihydroartemisinine in P. falciparum in vitro.

Ultrastructural changes were followed in Plasmodium berghei after the treatment of the mouse host with a single 10 mg kg-1 dose of artemisinine (qinghaosu). After 30 minutes, changes in the limiting and other membranes of the parasite were seen, together with alterations in ribosomal organization and endoplasmic reticulum. No changes were noted in digestive vacuoles or pigment, but nuclear membrane blebbing developed after one hour and segregation of the nucleoplasm after three hours. Further degenerative changes with disorganization and death occurred from eight hours onwards. The morphological changes in ribosomes and endoplasmic reticulum correlate in time with the depression in protein synthesis observed in P. falciparum in vitro. Similarly, the onset of nucleoplasmic segregation correlates with the development of nucleic acid synthesis inhibition. Tritiated reduced drug was shown to be localized in parasite membranes, indicating that changes in membrane integrity might precede the early depression of protein synthesis. Membrane association of artemisinine may be related to its amphipathic characteristics and similarity in some respects to a sterol.

Uptake of [3H] dihydroartemisinine by erythrocytes infected with Plasmodium falciparum in vitro.

Artemisinine ( qinghaosu ) was reduced and radio-labelled using tritiated borohydride. The tritiated dihydroartemisinine produced was differentially accumulated from low concentrations in culture medium into erythrocytes infected with Plasmodium falciparum. Uninfected erythrocytes concentrated the drug less than two-fold whereas infected erythrocytes achieved more than 300 times the medium concentration. The uptake process is reversible and saturable, with a dissociation constant (Kd) at the hypothetical receptor of 10.5 nmol.l-1. Competition studies indicate that the receptor is the same as that for artemether , another quinghaosu derivative. Chloroquine showed an interesting partial inhibition of uptake but was unable to release the bound radio-labelled drug from infected cells.

Rapid action of Qinghaosu and related drugs on incorporation of [3H]isoleucine by Plasmodium falciparum in vitro.

Using the incorporation of [3H]isoleucine into acid-insoluble products as an index of protein-synthetic activity, it was shown that Qinghaosu and two related drugs had a rapid effect on this process in human erythrocytes infected with Plasmodium falciparum in vitro. Inhibition could be seen 1 hr or less after addition of the drugs at concentrations from 5 mumole/1. to 50 nmole/1. It is recommended that the effects of these drugs be studied in cell-free protein-synthetic systems.