Prolonged duration local anesthesia with minimal toxicity

Injectable local anesthetics that would last for many days could have a marked impact on periprocedural care and pain management. Formulations have often been limited in duration of action, or by systemic toxicity, local tissue toxicity from local anesthetics, and inflammation. To address those issues, we developed liposomal formulations of saxitoxin (STX), a compound with ultrapotent local anesthetic properties but little or no cytotoxicity. In vitro, the release of bupivacaine and STX from liposomes depended on the lipid composition and on whether dexamethasone was incorporated. In cell culture, bupivacaine, but not STX, was myotoxic (to C2C12 cells) and neurotoxic (to PC12 cells) in a concentration- and time-dependent manner. Liposomal formulations containing combinations of the above compounds produced sciatic nerve blockade lasting up to 7.5 days (with STX + dexamethasone liposomes) in male Sprague–Dawley rats. Systemic toxicity only occurred where high loadings of dexamethasone increased the release of liposomal STX. Mild myotoxicity was only seen in formulations containing bupivacaine. There was no nerve injury on Epon-embedded sections, and these liposomes did not up-regulate the expression of 4 genes associated with nerve injury in the dorsal root ganglia. These results suggest that controlled release of STX and similar compounds can provide very prolonged nerve blocks with minimal systemic and local toxicity.     

Age-dependent alteration in muscle regeneration: the critical role of tissue niche

Although adult skeletal muscle is composed of fully differentiated fibers, it retains the capacity to regenerate in response to injury and to modify its contractile and metabolic properties in response to changing demands. The major role in the growth, remodeling and regeneration is played by satellite cells, a quiescent population of myogenic precursor cells that reside between the basal lamina and plasmalemma and that are rapidly activated in response to appropriate stimuli. However, in pathologic conditions or during aging, the complete regenerative program can be precluded by fibrotic tissue formation and resulting in functional impairment of the skeletal muscle. Our study, along with other studies, demonstrated that although the regenerative program can also be impaired by the limited proliferative capacity of satellite cells, this limit is not reached during normal aging, and it is more likely that the restricted muscle repair program in aging is presumably due to missing signals that usually render the damaged muscle a permissive environment for regenerative activity.     

High Levels of Asymptomatic and Subpatent Plasmodium falciparum Parasite Carriage at Health Facilities in an Area of Heterogeneous Malaria Transmission Intensity in the Kenyan Highlands

In endemic settings, health facility surveys provide a convenient approach to estimating malaria transmission intensity. Typically, testing for malaria at facilities is performed on symptomatic attendees, but asymptomatic infections comprise a considerable proportion of the parasite reservoir. We sampled individuals attending five health facilities in the western Kenyan highlands. Malaria prevalence by rapid diagnostic test (RDT) was 8.6–32.9% in the health facilities. Of all polymerase chain reaction-positive participants, 46.4% (95% confidence interval [95% CI] = 42.6–50.2%) of participants had infections that were RDT-negative and asymptomatic, and 55.9% of those infections consisted of multiple parasite clones as assessed by merozoite surface protein-2 genotyping. Subpatent infections were more common in individuals reporting the use of non-artemisinin–based antimalarials in the 2 weeks preceding the survey (odds ratio = 2.49, 95% CI = 1.04–5.92) compared with individuals not reporting previous use of antimalarials. We observed a large and genetically complex pool of subpatent parasitemia in the Kenya highlands that must be considered in malaria interventions.     

The Role of Glutathione in Intestinal Dysfunction

Glutathione plays an important cytoprotective role in the gut. Animal studies have demonstrated that the provision of glutathione precursors are protective for different types of free-radical-mediated cellular injury. There is a need to clarify the potential role of glutathione supplementation in ischemia–reperfusion injury and inflammatory bowel disease. More speculative is whether dietary treatment with glutathione precursors can modify the progress of colorectal cancer.     

Developmental outcomes in early compared with delayed surgery for glue ear up to age 7 years: a randomised controlled trial

Objectives: To investigate whether early versus delayed surgery for children severely affected by otitis media with effusion (OME) results in improved performance on developmental tests up to age 7 years. Design: Follow‐up of a randomised controlled trial. Setting: University of Bristol. Participants: One hundred and eighty‐two children (mean age 35 months) with persistent OME, hearing loss and speech, language or behaviour problems who were originally eligible and randomised to either early surgery or delayed surgery after a period of watchful waiting were followed‐up as part of the Avon Longitudinal Study of Parents and Children (ALSPAC) at age 4½ and 7–8 years. Main outcome measures: Measures included behaviour, language, educational attainment tests, hearing, reading, cognition and coordination. Results: Of the original randomised trial, 88 of 92 of the early surgery and 74 of 90 of the watchful waiting group were still participating in ALSPAC. Analysis was by intention to treat. At age 4 ½ years there were significant differences in teacher assessment of language (adj OR 3.45, 95% CI: 1.42–8.39) and writing (adj OR 3.74, 95% CI: 1.51–9.27), in favour of early surgery. At age 7–8 years, there was a significant difference on teacher report of emotional problems (adj OR 4.11, 95% CI: 1.15–14.64) in favour of early surgery. There were no other significant differences. Conclusions: Early surgery for the child severely affected by OME may be associated with subtle benefits at age 4½ years. This may continue to 7–8 years but the small study size makes it difficult to distinguish these effects from chance. A larger study is recommended.     

A Phase II,open-label,randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens

Objectives To assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) in patients with metastatic colorectal cancer who had failed one or two previous chemotherapeutic regimens that included oxaliplatin and/or irinotecan. Methods This was a Phase II, multicentre, open-label, randomised, two-arm, parallel-group study comparing AZD6244 with capecitabine monotherapy. Patients received either 100 mg twice daily oral AZD6244 free-base suspension every day or 1,250 mg/m² twice daily oral capecitabine, for 2 weeks, followed by a 1-week rest period, in 3-weekly cycles. The primary endpoint was the number of patients experiencing disease progression events. Results Sixty-nine patients were randomised in the study (34 and 35 patients in the AZD6244 and capecitabine groups, respectively). Disease progression events were experienced by 28 patients (∼80%) in both the AZD6244 and capecitabine treatment groups. Median progression-free survival was 81 days and 88 days in the AZD6244 and capecitabine groups, respectively. Ten patients in the AZD6244 treatment arm had a best response of stable disease. For capecitabine, best response was a partial response in one patient, with stable disease in a further 15 patients. The most frequently observed adverse events reported with AZD6244 were acneiform dermatitis, diarrhoea, asthenia and peripheral oedema, compared with hand-foot syndrome, diarrhoea, nausea and abdominal pain with capecitabine. Conclusions AZD6244 showed similar efficacy to capecitabine in terms of the number of patients with a disease progression event and of progression-free survival. AZD6244 is currently undergoing evaluation in Phase II trials in combination with other chemotherapeutic agents.     

Systemic antiangiogenic activity of cationic poly-L-lysine dendrimer delays tumor growth

This study describes the previously unreported intrinsic capacity of poly-L-lysine (PLL) sixth generation (G₆) dendrimer molecules to exhibit systemic antiangiogenic activity that could lead to solid tumor growth arrest. The PLL-dendrimer-inhibited tubule formation of SVEC4-10 murine endothelial cells and neovascularization in the chick embryo chick chorioallantoic membrane (CAM) assay. Intravenous administration of the PLL-dendrimer molecules into C57BL/6 mice inhibited vascularisation in Matrigel plugs implanted subcutaneously. Antiangiogenic activity was further evidenced using intravital microscopy of tumors grown within dorsal skinfold window chambers. Reduced vascularization of P22 rat sarcoma implanted in the dorsal window chamber of SCID mice was observed following tail vein administration (i.v.) of the PLL dendrimers. Also, the in vivo toxicological profile of the PLL-dendrimer molecules was shown to be safe at the dose regime studied. The antiangiogenic activity of the PLL dendrimer was further shown to be associated with significant suppression of B16F10 solid tumor volume and delayed tumor growth. Enhanced apoptosis/necrosis within tumors of PLL-dendrimer-treated animals only and reduction in the number of CD31 positive cells were observed in comparison to protamine treatment. This study suggests that PLL-dendrimer molecules can exhibit a systemic antiangiogenic activity that may be used for therapy of solid tumors, and in combination with their capacity to carry other therapeutic or diagnostic agents may potentially offer capabilities for the design of theranostic systems.     

Balance rehabilitation and dual-task ability in older adults

Background/PurposeRecent evidence suggests that an impaired ability to allocate attention to balance during dual-task situations is a powerful predictor of falls. Increased difficulty under dual-task conditions may result from cognitive or motor impairments or both. The extent to which interventions should be directed at cognitive or motor impairments is unclear. The goal of this study was to examine the extent to which standard balance rehabilitation improves dual-task ability.MethodsA retrospective chart review of patients without vestibular or neurological disorders who were referred to physical therapy for disequilibrium was performed. Patients were assessed initially and at discharge for balance-related confidence, gait speed, fall risk, sensory integration, and dual-task ability. Balance rehabilitation involved weekly sessions plus home training for strengthening, endurance, center of gravity control training, multisensory training and postural strategy training. Specific dual-task training was not included.ResultsAverage age was 75.8 ± 7.5 years, with 49% of participants being female. Participants improved significantly in all outcome measures, including measures of dual-task ability (p < 0.05). Percent improvement from initial to discharge assessment was significantly greater for balance confidence, fall risk and sensory integration than dual-task ability.ConclusionStandard balance rehabilitation significantly improved all measures of gait and balance, including dual-task measures; however, measures of dual-task ability did not improve to the same extent. Improvements of underlying motor impairments may not adequately address impaired dual-task ability.