Correlation of the change in the International Normalized Ratio and decreasing the Coumadin dosage following total joint arthroplasty

This retrospective pilot study determined whether a change in the daily International Normalized Ratio (INR) correlates with a decrease in Coumadin (DuPont Pharma, Wilmington, Del) dosage. Four hundred seventeen patients yielded 1167 pairs of INR values and Coumadin doses. An increase in INR > 0.4 units correlated 81% with a decrease in the Coumadin dose (P < .05). In patients aged > or = 70 years, the correlation fell to 70% compared to an 89% correlation in patients aged < 70 years (P < .05). The correlation fell to 78% in women, while men exhibited an increase to 87% (P < .05). Although this is a pilot study, when managing postoperative Coumadin anticoagulation for orthopedic patients, an increase in INR > 0.4 units correlates highly with the need to decrease the Coumadin dose. A prospective study is needed to test the usefulness of this parameter.     

Recovery in memory function in the first year following TBI in children

Primary objective : To examine memory skills, at acute, 6- and 12-monthly stages, following childhood traumatic brain injury (TBI).

Research design : Prospective, longitudinal, between-group design, comparing pre-injury and postinjury intellectual and memory measures, across three levels of injury severity.

Methods and procedures : Investigation of memory skills in a group of 76 children who had sustained a mild, moderate or severe TBI. Specific tests were used to measure immediate and short-term memory, and more complex multi-trial learning.

Main outcomes and results : The severe TBI group exhibited greater deficits on memory tasks, irrespective of modality, in the acute, 6- and 12-month post-injury stages, in comparison to mild and moderate TBI groups. Performance was dependent on both injury severity and task demands.

Conclusions : Memory difficulties are present during the acute, 6- and 12-months following childhood TBI. With a clearer understanding of the memory deficits following TBI, appropriate strategies can be taught and interventions implemented for these children.     

An inhibitor of glycinamide ribonucleotide formyltransferase is selectively cytotoxic to cells that lack a functional G1 checkpoint

Purpose: We studied the effects of purine depletion on the cell cycle using a specific inhibitor of de novo purine biosynthesis, AG2034, an inhibitor of glycinamide ribonucleotide formyltransferase (GARFT). Methods: Cytotoxicity was determined by clonogenic assays, and cell cycle perturbations by flow cytometry. Ribonucleotide pools were measured by anion exchange high-pressure liquid chromatography, and DNA strand-breaks were determined by alkaline elution and by the TUNEL assay. Results: When cells were maintained in standard tissue culture medium, which contained 2.2 μM folic acid, AG2034 was cytostatic in all the cell lines tested. Under low-folate conditions (50 nM folic acid), AG2034 caused up to 50% cell death in cell lines that possessed a functional G1 checkpoint (A549, MCF-7), but was only cytostatic to the remaining cells, even at very high concentrations (100 μM ). In contrast, AG2034 at 10 nM or 100 nM killed all the cells in cultures of HeLa/S3 or SW480 cells, which lack a functional G1 checkpoint. Flow cytometry studies indicated that in G1 checkpoint-competent cells, AG2034 caused a G1 arrest. Those cells (up to 50%) that were already in S phase died, but the cells that were in G1 arrest maintained viability, based upon clonogenic assays, for many days. In G1 checkpoint-deficient cells, no G1 arrest was seen after AG2034 treatment, all cells progressed into S phase, and all cells died. Measurement of DNA strand-breaks, either by alkaline elution or by the dUTP end-labelling technique, indicated no DNA strand-breaks 24 h after AG2034 treatment, indicating that purine nucleotide depletion can trigger the G1 checkpoint in the absence of DNA damage. Conclusion: Purine depletion causes slow cell death in cells that have passed the G1 checkpoint, but cytostasis in cells that are arrested at the G1 checkpoint. The GARFT inhibitor, at physiological folate concentrations, thus causes selective cytotoxicity to cells lacking a functional G1 checkpoint. Received: 8 May 1997 / Accepted: 26 June 1997     

BDNF regulates the expression of fragile X mental retardation protein mRNA in the hippocampus

Both fragile X mental retardation protein (FMRP) and brain-derived neurotrophic factor (BDNF) are implicated in the maturation of neurons and in the higher cognitive functions. We have investigated whether FMRP and BDNF are reciprocally regulated in neurons. Exposure of cultured hippocampal neurons to BDNF, but not to NT-3, reduced FMR1 mRNA levels to 84.8% of control at 4 h and the levels were back to baseline by 24 h or 4 days. Furthermore, expression of FMR1 mRNA was reduced (82.4% of control) in vivo in the hippocampus of transgenic mice overexpressing TrkB receptors, and a small but significant (5.1%) decrease was also detected in FMRP protein levels. In contrast, the expression patterns of BDNF and TrkB mRNAs were not altered in FMRP-deficient mice compared to wild-type mice. Our data provide evidence that BDNF via TrkB signaling decreases FMRP expression and suggest a role for FMRP in BDNF-induced synaptic plasticity.     

Novel tricyclic poly(ADP-ribose) polymerase-1 inhibitors with potent anticancer chemopotentiating activity: design,synthesis, and X-ray cocrystal structure

A series of novel compounds have been designed that are potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1), and the activity and physical properties have been characterized. The new structural classes, 3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-ones and 3,4-dihydropyrrolo[4,3,2-de]isoquinolin-5-(1H)-ones, have conformationally locked benzamide cores that specifically interact with the PARP-1 protein. The compounds have been evaluated with in vitro cellular assays that measure the ability of the PARP-1 inhibitors to enhance the effect of cytotoxic agents against cancer cell lines.     

Attention deficit hyperactivity disorder and the gene for dopamine Beta-hydroxylase

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) has been shown to be highly heritable, and recent molecular genetics studies have focused on candidate genes in the dopaminergic and noradrenergic systems. One recent study reported an association of an allele of the TaqI polymorphism located in the fifth intron of the gene for dopamine beta-hydroxylase (DBH). The authors' goal was to replicate this finding. METHOD: The authors investigated the linkage of the alleles and haplotypes of three polymorphisms at the DBH locus in 117 nuclear families with ADHD. RESULTS: No significant evidence was found for linkage of the TaqI alleles or haplotypes in the 117 families. However, the authors observed some evidence for biased transmission of the same allele of the TaqI polymorphism, as previously reported. CONCLUSIONS: These findings suggest that the gene for DBH should be investigated further.