Short communication cellular pharmacology of 9-(beta-D-1,3-dioxolan-4-yl) guanine and its lack of drug interactions with zidovudine in primary human lymphocytes

Amdoxovir, currently in Phase II clinical trials, is rapidly converted to 9-(beta-D-1,3-dioxolan-4-yl)guanine (DXG) by adenosine deaminase in vitro and in humans. The cellular pharmacology of DXG in primary human lymphocytes, including dose-response relationships, intracellular half-life of DXG triphosphate (DXG-TP), and combination studies were determined. DXG produced high levels of DXG-TP with a long half-life (16 h) in activated human peripheral blood mononuclear cells. Since zidovudine (ZDV) and DXG select for different resistance mutations, co-formulation of the these two drugs is an attractive proposition. A combination study between DXG and ZDV showed no reduction of DXG-TP or ZDV-TP. Taken together, these results suggest that an appropriately designed DXG prodrug could be given once a day and that co-formulation with ZDV might be a possibility.     

In situ detection of activated cytotoxic cells in follicular lymphomas.

The presence of cytotoxic cells and their activation status were analyzed in tissue sections of 26 follicular lymphomas. To this end, expression of the perforin and granzyme B genes was studied by in situ hybridization experiments, and expression of the TIA-1 antigen was analyzed by immunohistochemistry. Cells expressing the granzyme B gene and the perforin gene were detected in all cases. Their density was, however, highly heterogeneous from case to case, ranging from 160 to 7,040 positive cells/cm2 of tissue sections. TIA-1-positive cells were also evidenced in the 10 follicular lymphomas tested. Virtually all cytotoxic cells were located in interfollicular areas. Double labeling immunochemical experiments showed that most cytotoxic cells belonged to the CD8+ T lymphocyte population, although few CD4+ T lymphocytes and CD56+ natural killer cells also expressed the TIA-1 antigen. These findings show that development of a malignant B lymphocyte proliferation is associated with a host-derived immune response involving intratumoral cytotoxic T lymphocytes. Further studies comparing the density of such cells with the final outcome are required to determine whether the intensity of this immune response has a prognostic value.     

Venous thromboembolism prevention with fondaparinux 1.5 mg in renally impaired patients undergoing major orthopaedic surgery. A real-world, prospective, multicentre, cohort study

Despite the need for effective and safe thromboprophylactic drugs for patients with renal impairment, clinical trial data on anticoagulant agents are limited in this population. The study aim was to assess in the real-world setting the use of the once-daily 1.5 mg reduced dosage regimen of fondaparinux available for this context. In this prospective cohort study, patients with a creatinine clearance (CrCl) of 20-50 ml/minute, undergoing total hip (THR) or knee (TKR) replacement or hip fracture surgery (HFS) received fondaparinux thromboprophylaxis. Main clinical outcomes were bleeding (major/clinically relevant non-major), symptomatic venous thromboembolism (VTE) and death. Overall, 442 patients (353 women; median age: 82 years; 39.4% in ASA class ≥3; mean ± SD CrCl: 39.0 ± 8.0 ml/minute; 78% with additional risk factors for bleeding), undergoing THR (43.7%), TKR (27.6%), or HFS (28.7%) received fondaparinux 1.5 mg for a mean ± SD duration of 16.0 ± 12.5 days. At postoperative day 10, the rates (95% confidence interval) of major bleeding, clinically relevant bleeding and symptomatic VTE were 4.5% (2.8-6.9), 0.5% (0.1-1.6) and 0.5% (0.05-1.62), respectively; no fatal bleeding, bleeding into a critical organ, pulmonary embolism or proximal deep-vein thrombosis occurred. Corresponding rates at one month were 5.2%, 0.7% and 0.7%. One-month mortality was 2.3% (0.9-3.6). This large clinical prospective study provides for the first time, under conditions reflecting "real-world" routine clinical practice, data on the bleeding and VTE risks of thromboprophylaxis with fondaparinux 1.5 mg after major orthopaedic surgery in renally impaired patients. It shows that these patients constitute a very elderly and fragile population.     

Pulsed radiofrequency enhances morphine analgesia in neuropathic rats

This study examined the effects of pulsed radiofrequency (PRF) on sciatic nerve ligation-induced mechanical pain hypersensitivity in rats. The nociceptive threshold was evaluated using the paw pressure vocalization test. Seven days after nerve ligation, animals receiving a single PRF session (120 s/2 Hz/45 V/42°C) on L4-5-6 dorsal root ganglia ipsilateral to a chronic constriction injury (CCI) showed a reduced sensory hypersensitivity at H4 6 and 1 day after PRF as compared with animals without PRF. One day after PRF, the effect of morphine (2 mg/kg, subcutaneous) increased the nociceptive threshold in the no PRF/CCI group and more extensively in PRF/CCI animals. These results showed that PRF might represent an interesting strategy not only to reduce neuropathic pain but also to enhance the efficacy of morphine in patients with neuropathic pain, well known to be opioid resistant.     

The role of saccade preparation in lateralized word recognition: Evidence for the attentional bias theory

Words presented to the right visual field (RVF) are recognized more readily than those presented to the left visual field (LVF). Whereas the attentional bias theory proposes an explanation in terms of attentional imbalance between visual fields, the attentional advantage theory assumes that words presented to the RVF are processed automatically while LVF words need attention. In this study, we exploited coupling between attention and saccadic eye movements to orient spatial attention to one or the other visual field. The first experiment compared conditions wherein participants had to remain fixated centrally or had to make a saccade to the visual field in which subsequent verbal stimuli were displayed. The orienting of attention by saccade preparation improved performance in a lexical decision task in both the LVF and the RVF. In the second experiment, participants had to make a saccade either to the visual field where verbal stimuli were presented subsequently or to the opposite side. For RVF as well as for LVF presentation, saccade preparation toward the opposite side decreased performance compared to the same side condition. These results are better explained by the attentional bias theory, and are discussed in the light of a new attentional theory dissociating two major components of attention, namely preparation and selection.     

Focus on methodology: salivary bioscience and research on adolescence: an integrated perspective

The characterization of the salivary proteome and advances in biotechnology create an opportunity for developmental scientists to measure multi-level components of biological systems in oral fluids and identify relationships with developmental processes and behavioral and social forces. The implications for developmental science are profound because from a single oral fluid specimen, information can be obtained about a broad array of biological systems and the genetic polymorphisms related to their function. The purpose of this review is to provide a conceptual and tactical roadmap for investigators interested in integrating these measurement tools into research on adolescent health and development.