Efficacy and Safety of Lacosamide in Painful Diabetic Neuropathy

OBJECTIVE: To evaluate efficacy and safety of lacosamide compared with placebo in painful diabetic polyneuropathy. RESEARCH DESIGN AND METHODS: Diabetic patients with at least moderate neuropathic pain were randomized to placebo or lacosamide 400 (in a slow or standard titration) or 600 mg/day over 6-week titration and 12-week maintenance periods. Primary efficacy criterion was intra-individual change in average daily Numeric Pain Rating Scale score from baseline to the last 4 weeks. RESULTS: For the primary end point, pain reduction was numerically but not statistically greater with lacosamide compared with placebo (400 mg/day, P = 0.12; 600 mg/day, P = 0.18). Both doses were significantly more effective compared with placebo over the titration (P = 0.03, P = 0.006), maintenance (P = 0.01, P = 0.005), and entire treatment periods (P = 0.03, P = 0.02). Safety profiles between titration schemes were similar. CONCLUSIONS: Lacosamide reduced neuropathic pain and was well tolerated in diabetic patients, but the primary efficacy criterion was not met, possibly due to an increased placebo response over the last 4 weeks.status: publishe

LEDGF/p75-Independent HIV-1 Replication Demonstrates a Role for HRP-2 and Remains Sensitive to Inhibition by LEDGINs

Lens epithelium–derived growth factor (LEDGF/p75) is a cellular cofactor of HIV-1 integrase (IN) that interacts with IN through its IN binding domain (IBD) and tethers the viral pre-integration complex to the host cell chromatin. Here we report the generation of a human somatic LEDGF/p75 knockout cell line that allows the study of spreading HIV-1 infection in the absence of LEDGF/p75. By homologous recombination the exons encoding the LEDGF/p75 IBD (exons 11 to 14) were knocked out. In the absence of LEDGF/p75 replication of laboratory HIV-1 strains was severely delayed while clinical HIV-1 isolates were replication-defective. The residual replication was predominantly mediated by the Hepatoma-derived growth factor related protein 2 (HRP-2), the only cellular protein besides LEDGF/p75 that contains an IBD. Importantly, the recently described IN-LEDGF/p75 inhibitors (LEDGINs) remained active even in the absence of LEDGF/p75 by blocking the interaction with the IBD of HRP-2. These results further support the potential of LEDGINs as allosteric integrase inhibitors

HIV-1 IN/Pol recruits LEDGF/p75 into viral particles

Background: The dynamic interaction between HIV and its host governs the replication of the virus and the study of the virus-host interplay is key to understand the viral lifecycle. The host factor lens epithelium-derived growth factor (LEDGF/p75) tethers the HIV preintegration complex to the chromatin through a direct interaction with integrase (IN). Small molecules that bind the LEDGF/p75 binding pocket of the HIV IN dimer (LEDGINs) block HIV replication through a multimodal mechanism impacting early and late stage replication including HIV maturation. Furthermore, LEDGF/p75 has been identified as a Pol interaction partner. This raised the question whether LEDGF/p75 besides acting as a molecular tether in the target cell, also affects late steps of HIV replication. Results: LEDGF/p75 is recruited into HIV-1 particles through direct interaction with the viral IN (or Pol polyprotein) and is a substrate for HIV-1 protease. Incubation in the presence of HIV-1 protease inhibitors resulted in detection of full-length LEDGF/p75 in purified viral particles. We also demonstrate that inhibition of LEDGF/p75-IN interaction by specific mutants or LEDGINs precludes incorporation of LEDGF/p75 in virions, underscoring the specificity of the uptake. LEDGF/p75 depletion did however not result in altered LEDGIN potency. Conclusion: Together, these results provide evidence for an IN/Pol mediated uptake of LEDGF/p75 in viral particles and a specific cleavage by HIV protease. Understanding of the possible role of LEDGF/p75 or its cleavage fragments in the viral particle awaits further experimentation

Cerebral oximetry in patients undergoing carotid endarterectomy: preliminary results

Carotid endarterectomy (CEA) is an appropriate treatment for carotid occlusive disease. The risk of stroke during CEA ranges from 1.1% to 7.5%. Shunting is usually advised when severe ischemia during cross-clamping of the internal carotid artery is suspected. Routine use of an intraluminal shunt may increase the perioperative stroke rate. Popular and well documented methods of neurologic monitoring for ischemia during general anesthesia are electroencephalography (EEG) and transcranial Doppler ultrasonography (TCD) of the middle cerebral artery. The purpose of this prospective study was to compare cerebral oximetry using near infrared spectrophotometry (NIRS) with EEG and TCD. Preliminary data on 14 patients scheduled for elective carotid endarterectomy were included and a literature search was performed to correlate the findings. No postoperative neurologic events occurred. During carotid clamping there was a significant decrease in regional oxygen saturation (rSO2) but there was only a weak correlation with the decrease in mean Doppler flow (R = 0.74; P = 0.02) and no correlation with EEG changes (R = 0.49; P = 0.18). A useful rSO2 cut-off value predictive for cerebral ischemia could not be define

Retrospective study of Achilles mechanism disruption in 45 dogs

Forty-five cases of canine Achilles mechanism disruption were reviewed, mostly involving medium-sized dogs, among which dobermanns, labradors and border collies were most commonly represented. Most cases were acute in onset (66.7 per cent), and were usually closed injuries (75.6 per cent). In the majority of cases, the damage involved all tendons (26.7 per cent), all tendons except the superficial digital flexor tendon (22.2 per cent), or the gastrocnemius alone (20 per cent). Damage most commonly occurred at the tendo-osseous junction (60 per cent), with injury occurring less commonly at the musculotendinous junction (20 per cent) or in the body of the tendon (13.3 per cent). A plantigrade posture was not predictive of involvement of specific tendons, but was more likely if the injury involved the musculotendinous junction. The most common method of treatment was a primary tendon repair using polydioxanone suture in a locking-loop pattern, with placement of a temporary calcaneotibial screw and cast. The outcome was not significantly influenced by whether the injury was open or closed, the duration of the injury, the tendons involved, or the method of repair. Complications were recorded in 16 cases (35 per cent), of which 10 were minor and six major. Complications were significantly more likely if the damage involved the body of the tendon. Long-term follow-up was available for 19 dogs; the outcome of surgery was considered to be good to excellent in 18 dogs