Dendrimer-Based Nanomedicine (Paramagnetic Nanoparticle, Nanocombretastatin, Nanocurcumin) for Glioblastoma Multiforme Imaging and Therapy.

In brain tumors, delivering nanoparticles across the blood-brain tumor barrier presents a major challenge. Dual mode magnetic resonance imaging and fluorescent imaging probes have been developed where relaxation based Gd-DOTA or ParaCEST agents and a Near-Infrared (NIR) fluorescent dye, DL680 were conjugated on the surface of dendrimer. The in vivo and ex vivo imaging of the dual-modality contrast agent showed excellent potential utility for identifying the location of glioma tumors. Systemic delivery of the subsequent nano-sized agent demonstrated glioma-specific accumulation, probably due to the enhanced permeability and retention effect. The biodistribution studies revealed the G5 agents have accumulated in the glioma tumor and the liver while a G3 agent only accumulated in the brain tumor but not in the liver or kidney. Hydrophobic drug molecules like Combrestatin A4 (CA4) or curcumin have also been conjugated with dendrimers that provided high aqueous solubility with improved therapeutic effect.

Interventions to prevent women from developing gestational diabetes mellitus: an overview of Cochrane Reviews.

BACKGROUND: The prevalence of gestational diabetes mellitus (GDM) is increasing, with approximately 15% of pregnant women affected worldwide, varying by country, ethnicity and diagnostic thresholds. There are associated short- and long-term health risks for women and their babies. OBJECTIVES: We aimed to summarise the evidence from Cochrane systematic reviews on the effects of interventions for preventing GDM. METHODS: We searched the Cochrane Database of Systematic Reviews (6 August 2019) with key words 'gestational diabetes' OR 'GDM' to identify reviews pre-specifying GDM as an outcome. We included reviews of interventions in women who were pregnant or planning a pregnancy, irrespective of their GDM risk status. Two overview authors independently assessed eligibility, extracted data and assessed quality of evidence using ROBIS and GRADE tools. We assigned interventions to categories with graphic icons to classify the effectiveness of interventions as: clear evidence of benefit or harm (GRADE moderate- or high-quality evidence with a confidence interval (CI) that did not cross the line of no effect); clear evidence of no effect or equivalence (GRADE moderate- or high-quality evidence with a narrow CI crossing the line of no effect); possible benefit or harm (low-quality evidence with a CI that did not cross the line of no effect or GRADE moderate- or high-quality evidence with a wide CI); or unknown benefit or harm (GRADE low-quality evidence with a wide CI or very low-quality evidence). MAIN RESULTS: We included 11 Cochrane Reviews (71 trials, 23,154 women) with data on GDM. Nine additional reviews pre-specified GDM as an outcome, but did not identify GDM data in included trials. Ten of the 11 reviews were judged to be at low risk of bias and one review at unclear risk of bias. Interventions assessed included diet, exercise, a combination of diet and exercise, dietary supplements, pharmaceuticals, and management of other health problems in pregnancy. The quality of evidence ranged from high to very low. Diet Unknown benefit or harm: there was unknown benefit or harm of dietary advice versus standard care, on the risk of GDM: risk ratio (RR) 0.60, 95% CI 0.35 to 1.04; 5 trials; 1279 women; very low-quality evidence. There was unknown benefit or harm of a low glycaemic index diet versus a moderate-high glycaemic index diet on the risk of GDM: RR 0.91, 95% CI 0.63 to 1.31; 4 trials; 912 women; low-quality evidence. Exercise Unknown benefit or harm: there was unknown benefit or harm for exercise interventions versus standard antenatal care on the risk of GDM: RR 1.10, 95% CI 0.66 to 1.84; 3 trials; 826 women; low-quality evidence. Diet and exercise combined Possible benefit: combined diet and exercise interventions during pregnancy versus standard care possibly reduced the risk of GDM: RR 0.85, 95% CI 0.71 to 1.01; 19 trials; 6633 women; moderate-quality evidence. Dietary supplements Clear evidence of no effect: omega-3 fatty acid supplementation versus none in pregnancy had no effect on the risk of GDM: RR 1.02, 95% CI 0.83 to 1.26; 12 trials; 5235 women; high-quality evidence. Possible benefit: myo-inositol supplementation during pregnancy versus control possibly reduced the risk of GDM: RR 0.43, 95% CI 0.29 to 0.64; 3 trials; 502 women; low-quality evidence. Possible benefit: vitamin D supplementation versus placebo or control in pregnancy possibly reduced the risk of GDM: RR 0.51, 95% CI 0.27 to 0.97; 4 trials; 446 women; low-quality evidence. Unknown benefit or harm: there was unknown benefit or harm of probiotic with dietary intervention versus placebo with dietary intervention (RR 0.37, 95% CI 0.15 to 0.89; 1 trial; 114 women; very low-quality evidence), or probiotic with dietary intervention versus control (RR 0.38, 95% CI 0.16 to 0.92; 1 trial; 111 women; very low-quality evidence) on the risk of GDM. There was unknown benefit or harm of vitamin D + calcium supplementation versus placebo (RR 0.33, 95% CI 0.01 to 7.84; 1 trial; 54 women; very low-quality evidence) or vitamin D + calcium + other minerals versus calcium + other minerals (RR 0.42, 95% CI 0.10 to 1.73; 1 trial; 1298 women; very low-quality evidence) on the risk of GDM. Pharmaceutical Possible benefit: metformin versus placebo given to obese pregnant women possibly reduced the risk of GDM: RR 0.85, 95% CI 0.61 to 1.19; 3 trials; 892 women; moderate-quality evidence. Unknown benefit or harm:eight small trials with low- to very low-quality evidence showed unknown benefit or harm for heparin, aspirin, leukocyte immunisation or IgG given to women with a previous stillbirth on the risk of GDM. Management of other health issues Clear evidence of no effect: universal versus risk based screening of pregnant women for thyroid dysfunction had no effect on the risk of GDM: RR 0.93, 95% CI 0.70 to 1.25; 1 trial; 4516 women; moderate-quality evidence. Unknown benefit or harm: there was unknown benefit or harm of using fractional exhaled nitrogen oxide versus a clinical algorithm to adjust asthma therapy on the risk of GDM: RR 0.74, 95% CI 0.31 to 1.77; 1 trial; 210 women; low-quality evidence. There was unknown benefit or harm of pharmacist led multidisciplinary approach to management of maternal asthma versus standard care on the risk of GDM: RR 5.00, 95% CI 0.25 to 99.82; 1 trial; 58 women; low-quality evidence. AUTHORS' CONCLUSIONS: No interventions to prevent GDM in 11 systematic reviews were of clear benefit or harm. A combination of exercise and diet, supplementation with myo-inositol, supplementation with vitamin D and metformin were of possible benefit in reducing the risk of GDM, but further high-quality evidence is needed. Omega-3-fatty acid supplementation and universal screening for thyroid dysfunction did not alter the risk of GDM. There was insufficient high-quality evidence to establish the effect on the risk of GDM of diet or exercise alone, probiotics, vitamin D with calcium or other vitamins and minerals, interventions in pregnancy after a previous stillbirth, and different asthma management strategies in pregnancy. There is a lack of trials investigating the effect of interventions prior to or between pregnancies on risk of GDM.

Could worry and rumination mediate relationships between self-compassion and psychological distress in breast cancer survivors?

Many breast cancer (BCa) patients experience clinically significant anxiety and depression in survivorship. Self-compassion offers a bulwark to anxiety and depression in nonclinical, mental health, and some chronic physical health populations. We examined whether self-compassion predicted lower anxiety and depression symptoms in survivors and whether this might be mediated by lower worry and rumination. The design was a cross-sectional survey using self-report measures. Female adult BCa survivors of mixed stages who had finished primary surgical, radiotherapy, or chemotherapy treatments completed self-compassion subscales and worry, rumination, and anxiety and depression scales. Higher self-compassion subscale scores were negatively associated with anxiety and depression. Depressive brooding and worry mediated any effects of self-kindness and mindfulness on depression and anxiety, whereas common humanity directly predicted lower depression scores. Findings are consistent with the view that self-compassion reduces threat-related rumination and worry in BCa survivors, consequently reducing anxiety and depression. This may form a basis for prevention and treatment.

Evaluation of Vitamin B12 Monitoring in Patients on Concomitant Metformin and Proton Pump Inhibitors.

BACKGROUND: Type 2 diabetes mellitus and gastroesophageal reflux disease are highly prevalent in the United States. First-line therapies for these disease states include metformin and proton pump inhibitors, respectively. Both of these medications have been associated with a decreased absorption of vitamin B12. OBJECTIVE: The objective of this study was to assess the prevalence of B12 monitoring and supplementation in patients receiving concomitant metformin and PPI therapy. METHODS: A retrospective data analysis was performed at a single federally qualified health center. Patients receiving concomitant metformin and PPI therapy (specifically omeprazole and pantoprazole) over the past year were included. Data collected included demographics, dosing, therapy duration, and vitamin B12 level. Data were analyzed using descriptive statistics. RESULTS: A total of 104 patients met the inclusion criteria for this study. Metformin 1000 mg immediate release tablets was the most common dose and formulation prescribed. Omeprazole and pantoprazole were the most commonly prescribed PPIs. The most frequent duration of therapy was 1 to 4 years. Fourteen patients had a documented B12 level and no patients were categorized as deficient. Seven patients were prescribed a B12 supplement during the study period. CONCLUSION: In this single center, retrospective chart review of patients receiving concomitant metformin and PPI therapy, the average duration of therapy for both agents was 1-4 years. Only 13.5% of patients had a documented B12 level. Of those patients, none were categorized as deficient. Though routine monitoring of B12 levels may be important for patients on long-term therapy with both agents or who present with symptoms of B12 deficiency, this study does not support routine monitoring of B12 levels for patients with duration of therapy of 4 years or less.

Comparison between patient-reported outcomes after enucleation and proton beam radiotherapy for uveal melanomas: a 2-year cohort study.

BACKGROUND: Uveal melanomas affect 2-8 per million Europeans each year. Approximately 35%, are treated by enucleation. Proton beam radiotherapy (PBR) can be an eye-conserving alternative to enucleation for patients who wish to retain the eye. Both treatments have adverse effects, and it is difficult for clinicians and patients to make fully informed choices between them because the relative effects of enucleation and PBR on patient-reported outcomes are unknown. METHODS: We compared differential effects of enucleation and PBR on patient-reported outcomes on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Ophthalmological module (EORTC QLQ- OPT30) in a consecutive sample of 115 treated patients ~ 6, 12 and 24 months after diagnosis. Pre-treatment demographic variables, unrelated health problems, vision in the fellow eye, tumour characteristics and prognosis for metastatic disease were statistically controlled. RESULTS: Patients treated by enucleation experienced greater functional problems at 6 months, which abated at 12 and 24 months (P = 0.020). PBR patients reported greater impairments of central and peripheral vision (P = 0.009) and reading difficulties (P = 0.002) over 24 months. Treatment modality did not influence difficulty in driving (P = 0.694), ocular irritation (P = 0.281), headaches (P = 0.640), appearance concerns (P = 0.187) or worry about recurrence (P = 0.899). CONCLUSIONS: When making treatment decisions, it is important that patients and clinicians consider long-standing difficulties of visual impairment associated with PBR and temporary 6-month difficulties in activities related to depth perception associated with enucleation.

The effect of short duration low back vibration on pain developed during prolonged standing.

The purpose of this study was to determine if vibration, a potential method of pain management, applied to the low back could alleviate pain developed during prolonged standing. Eighteen healthy individuals participated in a 2.5-h standing task during which vibration (3-min duration) was applied at the 2-h and 2.25-h marks. During the full 2.5 h, participants recorded their perceived pain scores every 15 min using a 10 cm visual analogue scale (VAS). Following each vibration bout, those who developed low back pain (LPB) reported statistically lower VAS scores compared to prior to the vibration; however, when the vibration ceased, LBP returned to pre-vibration levels. It appears that vibration may be an effective method of alleviating LBP caused by prolonged standing; however, the effects seem to be temporary. Further research is needed to investigate the optimal vibration frequency and time period to maximize pain management effectiveness.

Beta receptor-mediated modulation of the oddball P3 but not error-related ERP components in humans.

RATIONALE: The P3 is a ubiquitous component of stimulus-driven neural activity that can be observed in scalp electrophysiological recordings. Multiple lines of evidence suggest an important role for the noradrenergic system in the generation of the P3. However, pharmacological studies of the P3 using noradrenergic manipulations have so far been limited to agents that affect α2-receptor signaling. OBJECTIVES: The present study investigated whether ß-adrenergic receptors are involved in the generation of the P3 and the error positivity (Pe), a component of the event-related potential that is elicited by errors and that bears many similarities to the P3. METHODS: We used a double-blind, placebo-controlled, crossover design in which we examined in human participants (N = 16) the effect of a single dose of propranolol (80 mg) on the amplitudes of the P3 observed in visual and auditory oddball tasks and the Pe observed in a flanker task. RESULTS: We found that P3s to auditory stimuli were increased in amplitude following treatment with propranolol. Propranolol also modulated the P3 to visual stimuli, but in a direction dependent on participants' level of trait anxiety: In participants with lower trait anxiety, propranolol resulted in a (non-significant) decrease in P3 amplitudes; in participants with higher trait anxiety, propranolol significantly enhanced P3 amplitude. Propranolol did not modulate the amplitude of the Pe or behavioral measures of conflict/error-related performance adjustments. CONCLUSIONS: These results provide the first evidence for involvement of ß-adrenergic receptors in P3 generation. We speculate that propranolol affected the P3 through actions at ß2-receptors in the locus coeruleus.

Sequencing the threat and recommendation components of persuasive messages differentially improves the effectiveness of high- and low-distressing imagery in an anti-alcohol message in students.

OBJECTIVES: Distressing imagery is often used to improve the persuasiveness of mass-reach health promotion messages, but its effectiveness may be limited because audiences avoid attending to content. Prior self-affirmation or self-efficacy inductions have been shown to reduce avoidance and improve audience responsiveness to distressing messages, but these are difficult to introduce into a mass-reach context. Reasoning that a behavioural recommendation may have a similar effect, we reversed the traditional threat-behavioural recommendation health promotion message sequence. DESIGN: 2 × 2 experimental design: Factor 1, high- and low-distress images; Factor 2, threat-recommendation and recommendation-threat sequences. METHODS: Ninety-one students were exposed to an identical text message accompanied by high- or low-distress imagery presented in threat-recommendation and recommendation-threat sequences. RESULTS: For the high-distress message, greater persuasion was observed for the recommendation-threat than the threat-recommendation sequence. This was partially mediated by participants' greater self-exposure to the threat component of the message, which we attribute to the effect of sequence in reducing attentional avoidance. For the low-distress message, greater persuasion was observed for the threat-recommendation sequence, which was not mediated by reading time allocated to the threat. CONCLUSIONS: Tailoring message sequence to suit the degree of distress that message developers wish to induce provides a tool that could improve persuasive messages. These findings provide a first step in this process and discuss further steps needed to consolidate and expand these findings. Statement of contribution What is already known on this subject? Health promotion messages accompanied by distressing imagery might, under some circumstances, persuade individuals to engage in healthier behaviour. Audiences can respond defensively to distressing imagery, but may be less inclined to do so when an easily followed behavioural recommendation is presented before imagery. Current literature is divided on whether presenting a behavioural recommendation before a threat component accompanied by distressing images will improve the persuasiveness of messages. What does this study add? We show that, when a behavioural recommendation precedes a threat containing distressing images, persuasiveness of a threatening message is stronger than a threat-recommendation sequence. We show that a recommendation-threat sequence improves persuasiveness of distressing imagery because it reduces attentional avoidance.

Cost-effectiveness of insulin glargine versus sitagliptin in insulin-naïve patients with type 2 diabetes mellitus.

PURPOSE: In the EASIE (Evaluation of Insulin Glargine Versus Sitagliptin in Insulin-Naïve Patients) trial, insulin glargine found a significant reduction in glycosylated hemoglobin compared with sitagliptin in patients with type 2 diabetes who are inadequately controlled with metformin. The objective of this study was to assess the cost-effectiveness of insulin glargine compared with sitagliptin in type 2 diabetes patients, from the perspective of the publicly funded Canadian health care system. METHODS: The IMS CORE Diabetes Model, a standard Markov structure and Monte Carlo simulation model, was used. The model used a lifetime horizon to capture the long-term complications associated with type 2 diabetes. The efficacy of insulin glargine and sitagliptin in terms of glycosylated hemoglobin reduction and corresponding rates of hypoglycemia were obtained from the EASIE trial. Health utility and cost data were obtained from recently published Canadian publications. Univariate and probabilistic sensitivity analyses were conducted. FINDINGS: In the lifetime base-case analysis, treatment with insulin glargine resulted in cost savings of $1434 CAD in 2012 and a gain of 0.08 quality-adjusted life years per patient. A probabilistic sensitivity analysis found the robustness of the base-case analysis, with 88% probability of insulin glargine being dominant (ie, cost savings and more quality-adjusted life years). IMPLICATIONS: Insulin glargine is a clinically superior and cost-effective alternative to sitagliptin in patients with type 2 diabetes who are inadequately controlled with metformin.

NGX-4010, a capsaicin 8% dermal patch, for the treatment of painful HIV-associated distal sensory polyneuropathy: results of a 52-week open-label study.

OBJECTIVES: To evaluate the efficacy, safety, and tolerability of repeated NGX-4010 treatments in the open-label extension phase of a 52-week study in patients with neuropathic pain due to HIV-associated distal sensory polyneuropathy (HIV-DSP). METHODS: Patients completing the 12-week, randomized, double-blind phase of the study could enter a 40-week, open-label phase, and receive up to 3, 60-minute NGX-4010 treatments. Patients recorded their "average pain for the past 24 hours" daily using the Numeric Pain Rating Scale (NPRS). Efficacy assessment included the percentage NPRS score reduction from baseline to weeks 2 to 12 after the final treatment, and Patient Global Impression of Change (PGIC) and Clinician Global Impression of Change (CGIC) questionnaires at study termination. RESULTS: Of 307 patients randomized, 272 entered the open-label phase; 81, 90, 55, and 46 received 0, 1, 2, and 3 retreatments, respectively. The mean percentage decrease in NPRS score from baseline to weeks 2 to 12 after the final treatment was similar in patients receiving single or multiple NGX-4010 treatments (-25.8%, -27.1%, -24.6%, and -22.7% for 1, 2, 3, and 4 NGX-4010 treatments, respectively). PGIC and CGIC results demonstrated a benefit of NGX-4010 treatment through to the end of the study regardless of the number of treatments received. Transient local application site reactions were the most frequently reported adverse events, and were mainly mild to moderate, nonserious, and did not increase with repeated treatment. DISCUSSION: Repeated NGX-4010 treatments were generally well tolerated and resulted in consistent reductions in HIV-DSP-associated pain and improvement in patient-reported outcomes.

Importance of the national petroleum reserve-alaska for aquatic birds.

We used data from aerial surveys (1992-2010) of >100,000 km(2) and ground surveys (1998-2004) of >150 km(2) to estimate the density and abundance of birds on the North Slope of Alaska (U.S.A.). In the ground surveys, we used double sampling to estimate detection ratios. We used the aerial survey data to compare densities of birds and Arctic fox (Vulpes lagopus), the major nest predator of birds, on the North Slope, in Prudhoe Bay, and in nearby areas. We partitioned the Prudhoe Bay oil field into 2 × 2 km plots and determined the relation between density of aquatic birds and density of roads, buildings, and other infrastructure in these plots. Abundance and density (birds per square kilometer) of 3 groups of aquatic birds-waterfowl, loons, and grebes; shorebirds; and gulls, terns, and jaegers-were highest in the National Petroleum Reserve-Alaska (NPRA) and lowest in the Arctic National Wildlife Refuge. Six other major wetlands occur in the Arctic regions of Canada and Russia, but the largest population of aquatic birds was in the NPRA. Aquatic birds were concentrated in the northern part of the NPRA. For example, an area that covered 18% of the NPRA included 53% of its aquatic birds. The aerial surveys showed that bird density was not lower and fox density was not higher in Prudhoe Bay than in surrounding areas. Density of infrastructure did not significantly affect bird density for any group of species. Our results establish that the NPRA is one of the most important areas for aquatic birds in the Arctic. Our results and those of others also indicate that oil production, as practiced in Prudhoe Bay, does not necessarily lead to substantial declines in bird density or productivity in or near the developed areas. Prioridades para la Conservación de Aves en el Norte de Alaska.

The effect of distressing imagery on attention to and persuasiveness of an antialcohol message: a gaze-tracking approach.

BACKGROUND: Distressing imagery may inhibit health communications by inducing audiences to reduce distress by avoiding attention to persuasive messages. METHOD: This study used eye-tracking methods to compare gaze time allocated to a persuasive textual message, accompanied by either distressing high-resolution color images or less distressing two-color images with degraded outline and detail. RESULTS: Participants in the distressing images condition showed lower intentions to reduce drinking in the following 3 months, which may have been mediated by lower gaze time to textual elements of the message. The effect was stronger in participants who both scored lower on dispositional mental disengagement and were more vulnerable to alcohol-related problems. CONCLUSIONS: These findings suggest that distressing imagery may inhibit persuasion by reducing audience attention to message components. Implications for message design are discussed.

A randomized, double-blind, controlled study of NGX-4010, a capsaicin 8% dermal patch, for the treatment of painful HIV-associated distal sensory polyneuropathy.

INTRODUCTION: Effective treatment of HIV-associated distal sensory polyneuropathy remains a significant unmet therapeutic need. METHODS: In this randomized, double-blind, controlled study, patients with pain due to HIV-associated distal sensory polyneuropathy received a single 30-minute or 60-minute application of NGX-4010--a capsaicin 8% patch (n = 332)--or a low-dose capsaicin (0.04%) control patch (n = 162). The primary endpoint was the mean percent change from baseline in Numeric Pain Rating Scale score to weeks 2-12. Secondary endpoints included patient global impression of change at week 12. RESULTS: Pain reduction was not significantly different between the total NGX-4010 group (-29.5%) and the total control group (-24.5%; P = 0.097). Greater pain reduction in the 60-minute (-30.0%) versus the 30-minute control group (-19.1%) prevented intended pooling of the control groups to test individual NGX-4010 treatment groups. No significant pain reduction was observed for the 30-minute NGX-4010 group compared with 30-minute control (-26.2% vs.-19.1%, respectively, P = 0.103). Pain reductions in the 60-minute NGX-4010 and control groups were comparable (-32.8% vs. -30.0%, respectively; P = 0.488). Posthoc nonparametric testing demonstrated significant differences favoring the total (P = 0.044) and 30-minute NGX-4010 groups (P = 0.035). Significantly, more patients in the total and 30-minute NGX-4010 group felt improved on the patient global impression of change versus control (67% vs. 55%, P = 0.011 and 65% vs. 45%, P = 0.006, respectively). Mild to moderate transient application site pain and erythema were the most common adverse events. CONCLUSIONS: Although the primary endpoint analyses were not significant, trends toward pain improvement were observed after a single 30-minute NGX-4010 treatment.

Long-term safety of NGX-4010, a high-concentration capsaicin patch, in patients with peripheral neuropathic pain.

CONTEXT: Postherpetic neuralgia (PHN) and painful human immunodeficiency virus-associated distal sensory polyneuropathy (HIV-DSP) are peripheral neuropathic pain syndromes that are difficult to treat. Current treatment options are often limited by poor tolerability. OBJECTIVES: The objective of the current open-label study was to assess the safety of repeated applications of NGX-4010, a high-concentration capsaicin patch (capsaicin 8%), over one year, in patients with moderate to severe PHN or HIV-DSP. METHODS: Patients had successfully completed a previous NGX-4010 study and had a pain level appropriate for further treatment. Eligible patients had not been treated with NGX-4010 within 12 weeks of study initiation. Patients received pretreatment with a topical local anesthetic (lidocaine 4%) for 60 minutes followed by either a 60-minute (PHN and HIV-DSP patients) or a 90-minute (HIV-DSP patients) treatment with NGX-4010. Patients could receive up to three additional treatments at intervals of > or = 12 weeks. Regardless of the number of treatments received, all patients were followed up for 48 weeks except for those withdrawing early. RESULTS: A total of 106 patients were enrolled and received a total of 293 NGX-4010 treatments. The most frequently reported treatment-emergent adverse events were transient, mild-to-moderate application site erythema, pain, edema, and papules. Small, transient pain-related increases in blood pressure during and immediately after NGX-4010 application were observed. There was no evidence of an increased incidence of adverse events, dermal irritation, intolerability, or impaired neurological function with repeated treatments. CONCLUSION: It is concluded that repeated treatments with NGX-4010 administered over a one-year period are generally safe and well tolerated.

Alcohol-related image priming and aggression in adolescents aged 11-14.

In adults, alcohol-related stimuli prime aggressive responding without ingestion or belief of ingestion. This represents either experiential or socially-and culturally-mediated learning. Using a laboratory-based competitive aggression paradigm, we replicated adult findings in 103 11-14 year old adolescents below the legal UK drinking age. Using a two-independent group design, priming with alcohol-related imagery led participants to deliver louder noise punishments in a competition task than priming with beverage-related images. This effect was stronger in participants scoring low on an internalization measure. Priming effects in relatively alcohol-naïve participants could constitute evidence of socio-cultural transmission of scripts linking alcohol use and aggression. The enhanced effect in lower internalization scorers suggests that alcohol priming might undermine behavioral inhibition processes in otherwise stable adolescents.

Antioxidant diet supplementation starting 24 hours after exposure reduces radiation lethality.

Antioxidants mitigate radiation-induced lethality when started soon after radiation exposure, a delivery time that may not be practical due to difficulties in distribution and because the oral administration of such agents may require a delay beyond the prodromal stage of the radiation syndrome. We report the unexpected finding that antioxidant supplementation starting 24 h after total-body irradiation resulted in better survival than antioxidant supplementation started soon after the irradiation. The antioxidant dietary supplement was l-selenomethionine, sodium ascorbate, N-acetyl cysteine, alpha-lipoic acid, alpha-tocopherol succinate, and co-enzyme Q10. Total-body irradiation with 8 Gy in the absence of antioxidant supplementation was lethal by day 16. When antioxidant supplementation was started soon after irradiation, four of 14 mice survived. In contrast, 14 of 18 mice receiving antioxidant supplementation starting 24 h after irradiation were alive and well 30 days later. The numbers of spleen colonies and blood cells were higher in mice receiving antioxidant supplementation starting 24 h after irradiation than in mice receiving radiation alone. A diet supplemented with antioxidants administered starting 24 h after total-body irradiation improved bone marrow cell survival and mitigated lethality, with a radiation protection factor of approximately 1.18.

Does hyperthermia increase adenoviral transgene expression or dissemination in tumors?

PURPOSE: Viral vectors used for cancer gene therapy are usually delivered by direct intratumoral administration. We studied the role of hyperthermia (HT) in vitro and in vivo in an attempt to achieve higher transfection rates (especially, larger volume of spread). MATERIALS AND METHODS: Replication-deficient adenoviruses containing either the human sodium-iodide symporter (Ad5-CMV-hNIS) or green fluorescent protein (Ad5-CMV-eGFP) as reporter genes were used. For in vitro studies, human lung cancer A549 cells were transfected with the virus and assayed for hNIS expression by radioactive pertechnetate uptake or green fluorescence activity using a gamma-counter or fluoroscopy respectively in the presence and absence of HT. For in vivo studies, A549 tumors were established intramuscularly in CD1 athymic mice. The adenoviral constructs (10(10) viral particles/tumor) were injected intratumorally when the tumors reached 10-11 mm in diameter. Different timing sequences of HT were examined and viral spread was assessed using technetium-autoradiography or GFP-fluorescence microscopy. RESULTS: In the in vitro studies, A549 cells infected with the adenoviral construct did not show any difference in gene expression level in the presence or absence of HT. In vivo, the effect of HT on the volume of gene expression in A549 tumors was highly variable with some groups of mice showing better spread in the presence of HT and others showing reduced spread with HT. CONCLUSION: Improvements in intratumoral adenoviral spread in response to hyperthermia were not consistently observed in a mouse tumor model using two quantitative endpoints of gene expression.

Defensive responses to an emotive anti-alcohol message.

We investigated the idea that emotive imagery used in health promotion advertising can facilitate a defensive response that adversely affects risk perceptions. One hundred student drinkers were exposed to either a printed message accompanied by images designed to maximise emotional distress or the same message presented using less emotive images. A three-way interaction was found, whereby the presentation of distressing images caused lower personal risk estimates in participants higher in denial and vulnerability to alcohol-related problems. This effect may have been mediated by lower reading times, suggesting that participants avoided the messages. Moderation by denial suggests that the effect is attributable to defensiveness, whilst moderation by vulnerability suggests that it is threat specific. These findings suggest that emotive images might trigger defensive avoidance responses that reduce risk estimates in some audience sub-populations.

Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy.

BACKGROUND: HIV-associated distal sensory polyneuropathy (HIV-DSP) is a painful condition with limited effective treatment. Capsaicin desensitizes cutaneous nociceptors resulting in reduced pain. We report a placebo-controlled study of a high-concentration capsaicin dermal patch (NGX-4010) for the treatment of painful HIV-DSP. METHODS: This double-blind multicenter study randomized 307 patients with painful HIV-DSP to receive NGX-4010 or control, a low-concentration capsaicin patch. After application of a topical anesthetic, NGX-4010 or control was applied once for 30, 60, or 90 minutes to painful areas on the feet. The primary efficacy endpoint was percent change in Numeric Pain Rating Scale (NPRS) from baseline in mean "average pain for past 24 hours" scores from weeks 2 to 12. RESULTS: A single NGX-4010 application resulted in a mean pain reduction of 22.8% during weeks 2 to 12 as compared to a 10.7% reduction for controls (p = 0.0026). Following a transient treatment-related pain increase, pain was reduced; significant improvement was apparent by week 2 and continued throughout the controlled 12-week observation period. Mean pain reductions in the NGX-4010 30-, 60- and 90-minute groups were 27.7%, 15.9%, and 24.7% (p = 0.0007, 0.287, and 0.0046 vs control). One third of NGX-4010-treated patients reported >or=30% pain decrease from baseline as compared to 18% of controls (p = 0.0092). Self-limited, mild-to-moderate local skin reactions were commonly observed. CONCLUSIONS: A single NGX-4010 application was safe and provided at least 12 weeks of pain reduction in patients with HIV-associated distal sensory polyneuropathy. These results suggest that NGX-4010 could provide a promising new treatment for painful HIV neuropathy.

Epinephrine/Lidocaine injection vs. saline during endoscopic sinus surgery.

OBJECTIVES: To assess the safety and effectiveness of an epinephrine/lidocaine mixture administered by injection versus epinephrine administered topically and to learn its pharmacokinetics following administration to the nasal mucosa. DESIGN: A double-blind randomized controlled trial. METHODS: Patients were assigned into two groups and were injected with either epinephrine 1:100,000 and lidocaine 1% or saline alone during endoscopic nasal surgery under general anesthesia. Pledgets soaked in epinephrine 1:1,000 were used throughout the procedure in both groups. Hemodynamic measurements and catecholamine blood levels were obtained. RESULTS: Ten patients were randomized to the epinephrine group and 12 to the saline group. We were able to measure epinephrine and norepinephrine levels following injection in all patients. Epinephrine levels were similar in both groups immediately after injection; however, 15 minutes following injection, epinephrine was significantly higher in saline-injected patients. Mean arterial pressure and heart rate were affected by epinephrine and norepinephrine levels immediately after injection but were never elevated over the normal range. Heart rate was higher (P < .05) in the saline injected group than in the epinephrine group throughout the measurement period. The surgeons believed that the surgical field was bloodier in saline-injected patients (P < .05) however objective estimation of blood loss showed no difference. CONCLUSIONS: Injection of epinephrine/lidocaine mixture does not produce higher blood levels of epinephrine when compared to saline injection and did not induce any harmful side effects. We postulate that the combination with lidocaine 1% may reduce the patients' stress and thus prevent higher catecholamine levels.