New insights on P2X purinoceptors

Significant advances in understanding of P_2X purinoceptor pharmacology have been made in the last few years. The limitations of nucleotide agonists as drug tools have now been amply demonstrated. Fortunately, inhibitors of the degrading ecto-ATPase enzymes are becoming available and it has become apparent that the complete removal of all divalent cations can be used experimentally in some systems to prevent nucleotide breakdown. Despite these issues, convincing evidence for P_2X receptor heterogeneity, from data with agonists, has recently been reported.A number of new antagonists at P_2X purinoceptors have also recently been described which to some degree appear to be more specific and useful than earlier antagonists like suramin. It is now apparent that suramin is a poor antagonist of ATP in many tissues because it potently inhibits ATPase activity at similar concentrations to those at which it blocks the P_2X purinoceptor.Advances in the use of radiolabelled nucleotides as radioligands for binding studies has allowed the demonstration of P_2X purinoceptors in a variety of tissues throughout the body including the brain. These studies have also provided evidence for receptor heterogeneity. Excitingly, two P_2X purinoceptor genes have been cloned but operational studies suggest that more than two types exist. The cloning studies have also demonstrated a unique structure for the P_2X purinoceptor which differentiates it from all other ligand-gated ion channel receptors. Further studies on P_2X purinoceptor operation and structure are needed to help resolve controversies alluded to regarding the characterization and classification of nucleotide receptors. Hopefully such studies will also lead to a better understanding of the physiological and pathological importance of ATP and its activation of P_2X purinoceptors. This will require the identification of better drug tools, in particular antagonists which may also provide the basis for novel therapeutic agents.     

Mini dental implants: an adjunct for retention, stability, and comfort for the edentulous patient.

OBJECTIVE: This article examines the success of mini-dental implants (MDI'S) by assessing four subjective measures of patient satisfaction for MDI's in the edentulous maxilla and mandible: comfort, retention, chewing ability and speaking ability. Success rates, surgical techniques, and financial advantages of the MDI's are reviewed. STUDY DESIGN: Thirty consecutive patients received four MDI's between the mental foramen of the mandible from 9/18/2003 to 10/22/2004. Questionnaires were sent to all thirty patients an average of 5 months postoperatively. The patients ranked comfort, retention, chewing ability, and speaking ability from 1 to 10 (1=poor and 10=excellent). RESULTS: A total of 116 MDI's were placed in 13 months and 113 remain stable for a 97.4% implant success rate. Pre-operatively patients rated their retention at 1.7+/-0.42 and post-operatively at 9.6+/-0.37, for a difference of 7.9 (p=3.6-19). Comfort was the next greatest improvement, with a pre-operative rating of 2.2+/-0.63 and a post-operative rating of 9.4+/-0.45, for a difference of 7.2 (p=3.5-15). Chewing ability also improved, with a difference of 7.0 (p=2.9e-16). In the final category of speaking ability, the pre-operative to post-operative difference was 3.2 (p=1.1e-5). CONCLUSION: MDI's are a highly successful implant option for patients with poor tolerance to maxillary and mandibular prosthesis. The implants are relatively affordable and overall patient satisfaction is excellent.     

Induction of Donor-Specific Allograft Tolerance by Short-Term Treatment with LF15-0195 After Transplantation. Evidence for a Direct Effect on T-Cell Differentiation

A 20-day treatment with LF15-0195, a deoxyspergualine analog, induced long-term heart allograft survival in the rat without signs of chronic rejection. LF15-0195-treated recipients did not develop an anti-donor alloantibody response. Analysis of graft-infiltrating cells, IL10, TNFalpha, IFNgamma mRNA and iNOS protein expression in allografts, 5 days after transplantation, showed that they were markedly decreased in allografts from LF15-0195-treated recipients compared with allografts from untreated recipients. Surprisingly, spleen T cells from LF15-0195 recipients, 5days after grafting, were able to proliferate strongly in vitro, when stimulated with donor cells, but had reduced mRNA expression for IFNy compared with spleen T cells from untreated graft recipients. Furthermore, when T cells from naive animals were stimulated in vitro, using anti-CD3 and anti-CD28, LF15-0195 also increased T-cell proliferation in a dose-dependent fashion: however, these cells expressed less of the Th1 -related cytokines, IFNgamma and IL2, compared with untreated cells, suggesting that LF15-0195 could act on T-cell differentiation. In conclusion, we show here that a short-term treatment with LF15-0195 induced long-term allograft tolerance, decreasing the in situ anti-donor response, and we illustrate evidence for the development of regulatory mechanisms.     

Volume Flow Rate of Common Carotid Artery Measured by Doppler Method and Color Velocity Imaging Quantification (CVI-Q)

BACKGROUND: Common carotid artery (CCA) volume flow rate (VFR) is clinically useful for study of cerebrovascular disease. Color Velocity Imaging Quantification (CVI-Q; Philips Ultrasound International, Irvine, CA), previously reported as accurate and reliable, tracks the flow lumen over the cardiac cycle, as well as mean spatial velocity, which is multiplied by vessel area to obtain VFR. VFR can also be obtained by Doppler sampling for mean velocity, and vessel area based on static B-mode lumen diameter. We compared CCA VFR by CVI-Q and Doppler method (DM), since knowledge of how they compare is crucial when both are used clinically. METHOD: We prospectively studied patients having clinical carotid duplex exams and healthy controls. All had CCA VFR measured by both methods in the same exam session. RESULTS: Thirty-four studies were reviewed. CCA VFR by CVI-Q in those without ICA stenosis was 337 +/- 96 mL/m, and by DM 359 +/- 130 mL/m; P = .33. There was no difference between methods for 50-75% or 75-95% ICA stenosis. In 7 patients with ICA occlusion, and 3 with 95-99% stenosis, VFR was higher by DM than by CVI-Q (Occlusion: 125 vs 58 mL/m, P = .007; 95-99%: 152 vs 63 mL/m, P = .038). There was no statistically significant difference between methods for measurement of the ratio of VFR between right and left CCA. CONCLUSION: In patients with 0-95% ICA stenosis, VFR by CVI-Q and DM showed no difference. For 95-100% ICA stenosis the methods differ; with higher VFR by DM. Side-to-side VFR ratios remain constant, irrespective of VFR method, and can still provide clinically useful information.     

Whole-brain 3D perfusion MRI at 3.0 T using CASL with a separate labeling coil.

A variety of continuous and pulsed arterial spin labeling (ASL) perfusion MRI techniques have been demonstrated in recent years. One of the reasons these methods are still not routinely used is the limited extent of the imaging region. Of the ASL methods proposed to date, continuous ASL (CASL) with a separate labeling coil is particularly attractive for whole-brain studies at high fields. This approach can provide an increased signal-to-noise ratio (SNR) in perfusion images because there are no magnetization transfer (MT) effects, and lessen concerns regarding RF power deposition at high field because it uses a local labeling coil. In this work, we demonstrate CASL whole-brain quantitative perfusion imaging at 3.0 T using a combination of strategies: 3D volume acquisition, background tissue signal suppression, and a separate labeling coil. The results show that this approach can be used to acquire perfusion images in all brain regions with good sensitivity. Further, it is shown that the method can be performed safely on humans without exceeding the current RF power deposition limits. The current method can be extended to higher fields, and further improved by the use of multiple receiver coils and parallel imaging techniques to reduce scan time or provide increased resolution.     

Electrochemistry of Anticonvulsants: Electron Transfer as a Possible Mode of Action

Reduction potentials were determined for various anticonvulsants, including progabide, SL 75.102, CGS 9896, pyridazines, zonisamide, 1,2,3-triazoles, and copper complexes. The values generally were in the range of about -0.1 to -0.6 V for the protonated drugs and the metal complexes. Reduction potentials provide information on the feasibility of electron transfer (ET) in vivo. If the value is relatively positive (greater than about -0.6 V), the agent can act catalytically as an electron acceptor from an appropriate cellular donor. A concomitant favorable influence on abnormal neuronal processes associated with epilepsy could occur. We describe ET as a possible mode of action of anticonvulsants as well as some antiepileptic agents with no electrochemical data based on this hypothetical ET approach.