Hazards to golden-mantled ground squirrels and associated secondary hazard potential from strychnine baiting for forest pocket gophers

Radio telemetry and capture-recapture techniques were used to evaluate the hazards to golden-mantled ground squirrels (Spermophilus lateralis) from hand baiting with 0.5% strychnine-treated oats for western pocket gophers (Thomomys mazama) on conifer plantations in eastern Oregon. Toxicology data were collected on field-killed and caged ground squirrels and on caged mink (Mustela vison), great horned owls (Bubo virginianus), and red-tailed hawks (Buteo jamaicensis). Ground squirrel populations were reduced 50 to 75% following underground baiting for pocket gophers. Maximum amount of strychnine alkaloid found in cheek pouches and carcass of a field-killed golden-mantled ground squirrel was 2.88 mg. Mean amount of strychnine in carcasses was 0.35 mg; almost all occurred in the gut. The estimated LD50 for mink was 0.6 mg/kg. The lowest lethal dose for great horned owls and red-tailed hawks was 7.7 mg/kg and 10.2 mg/kg, respectively. The LD50 for owls and hawks was not determined. Long-term effects on golden-mantled ground squirrel populations and secondary hazard potential to owls and hawks were judged to be minimal. Wild mustelids as large as mink could be adversely affected by consuming the gut content of strychnine-killed golden-mantled ground squirrels

Mind-Body Skills Groups for Adolescents with Depression in Primary Care: A Pilot Study

Objective: To determine acceptability and preliminary effectiveness of Mind-Body Skills Groups (MBSGs) as a treatment for depressed adolescents in primary care. Methods: A single arm clinical trial was conducted. A 10-week MBSG program was implemented in primary care. Participants completed self-report measures at baseline, post-intervention, and 3-months following the MBSGs. Measures included the Children’s Depression Inventory-2, Suicidal Ideation Questionnaire, Mindful Attention Awareness Scale, Self-Efficacy for Depressed Adolescents, rumination subscale of the Children’s Response Style Questionnaire, and a short acceptability questionnaire. Results: Participants included 43 adolescents. The total depression scores significantly improved following the MBSG intervention and continued to improve significantly from post-treatment to follow-up. Mindfulness, self-efficacy, rumination, and suicidal ideation all had significant improvement following the intervention. Acceptability of the program was strong, and attendance was excellent. Discussion: Preliminary evidence suggests that MBSGs are an acceptable treatment for primary care settings and lead to improved depression symptoms in adolescents.Sandra Eskenazi Mental Health Center and the Herbert Simon Family Foundation (070241-00002B

Analysis of lesion localisation at colonoscopy: outcomes from a multi-centre U.K. study

Background: Colonoscopy is currently the gold standard for detection of colorectal lesions, but may be limited in anatomically localising lesions. This audit aimed to determine the accuracy of colonoscopy lesion localisation, any subsequent changes in surgical management and any potentially influencing factors. Methods: Patients undergoing colonoscopy prior to elective curative surgery for colorectal lesion/s were included from 8 registered U.K. sites (2012–2014). Three sets of data were recorded: patient factors (age, sex, BMI, screener vs. symptomatic, previous abdominal surgery); colonoscopy factors (caecal intubation, scope guide used, colonoscopist accreditation) and imaging modality. Lesion localisation was standardised with intra-operative location taken as the gold standard. Changes to surgical management were recorded. Results: 364 cases were included; majority of lesions were colonic, solitary, malignant and in symptomatic referrals. 82% patients had their lesion/s correctly located at colonoscopy. Pre-operative CT visualised lesion/s in only 73% of cases with a reduction in screening patients (64 vs. 77%; p = 0.008). 5.2% incorrectly located cases at colonoscopy underwent altered surgical management, including conversion to open. Univariate analysis found colonoscopy accreditation, scope guide use, incomplete colonoscopy and previous abdominal surgery significantly influenced lesion localisation. On multi-variate analysis, caecal intubation and scope guide use remained significant (HR 0.35, 0.20–0.60 95% CI and 0.47; 0.25–0.88, respectively). Conclusion: Lesion localisation at colonoscopy is incorrect in 18% of cases leading to potentially significant surgical management alterations. As part of accreditation, colonoscopists need lesion localisation training and awareness of when inaccuracies can occur

Cross-species epigenetics identifies a critical role for VAV1 in SHH subgroup medulloblastoma maintenance

The identification of key tumorigenic events in Sonic Hedgehog (SHH) subgroup medulloblastomas (MBSHH) will be essential for the development of individualized therapies and improved outcomes. However, beyond confirmation of characteristic SHH pathway mutations, recent genome-wide sequencing studies have not revealed commonly mutated genes with widespread relevance as potential therapeutic targets. We therefore examined any role for epigenetic DNA methylation events in MBSHH using a cross-species approach to candidate identification, prioritization and validation. MBSHH-associated DNA methylation events were first identified in 216 subgrouped human medulloblastomas (50 MBSHH, 28 Wnt/Wingless, 44 Group 3 and 94 Group 4) and their conservation then assessed in tumors arising from four independent murine models of Shh medulloblastoma, alongside any role in tumorigenesis using functional assessments in mouse and human models. This strategy identified widespread regional CpG hypo-methylation of VAV1, leading to its elevated expression, as a conserved aberrant epigenetic event, which characterizes the majority of MBSHH tumors in both species, and is associated with a poor outcome in MBSHH patients. Moreover, direct modulation of VAV1 in mouse and human models revealed a critical role in tumor maintenance, and its abrogation markedly reduced medulloblastoma growth. Further, Vav1 activity regulated granule neuron precursor germinal zone exit and migration initiation in an ex vivo model of early postnatal cerebellar development. These findings establish VAV1 as a critical epigenetically regulated oncogene with a key role in MBSHH maintenance, and highlight its potential as a validated therapeutic target and prognostic biomarker for the improved therapy of medulloblastoma

Ferroxitosis: a cell death from modulation of oxidative phosphorylation and PKM2-dependent glycolysis in melanoma

Reliance on glycolysis is a characteristic of malignancy, yet the development of resistance to BRAF inhibitors in melanoma is associated with gain of mitochondrial function. Concurrent attenuation of oxidative phosphorylation and HIF-1α/PKM2-dependent glycolysis promotes a non-apoptotic, iron- and oxygen-dependent cell death that we term ferroxitosis. The redox cycling agent menadione causes a robust increase in oxygen consumption, accompanied by significant loss of intracellular ATP and rapid cell death. Conversely, either hypoxic adaptation or iron chelation prevents menadione-induced ferroxitosis. Ectopic expression of K213Q HIF-1α mutant blunts the effects of menadione. However, knockdown of HIF-1α or PKM2 restores menadione-induced cytotoxicity in hypoxia. Similarly, exposure of melanoma cells to shikonin, a menadione analog and a potential PKM2 inhibitor, is sufficient to induce ferroxitosis under hypoxic conditions. Collectively, our findings reveal that ferroxitosis curtails metabolic plasticity in melanoma

Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: integrated analysis of data from Study 10 and ARIEL2

Objective: An integrated analysis was undertaken to characterize the antitumor activity and safety profile of the oral poly(ADP-ribose) polymerase inhibitor rucaparib in patients with relapsed high-grade ovarian carcinoma (HGOC). Methods: Eligible patients from Study 10 (NCT01482715) and ARIEL2 (NCT01891344) who received a starting dose of oral rucaparib 600 mg twice daily (BID) with or without food were included in these analyses. The integrated efficacy population included patients with HGOC and a deleterious germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation who received at least two prior chemotherapies and were sensitive, resistant, or refractory to platinum-based chemotherapy. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR) and progression-free survival (PFS). The integrated safety population included patients with HGOC who received at least one dose of rucaparib 600 mg BID, irrespective of BRCA1/2 mutation status and prior treatments. Results: In the efficacy population (n = 106), ORR was 53.8% (95% confidence interval [CI], 43.8–63.5); 8.5% and 45.3% of patients achieved complete and partial responses, respectively. Median DOR was 9.2 months (95% CI, 6.6–11.6). In the safety population (n = 377), the most frequent treatment-emergent adverse events (AEs) were nausea, asthenia/fatigue, vomiting, and anemia/hemoglobin decreased. The most common grade ≥ 3 treatment-emergent AE was anemia/hemoglobin decreased. Treatment-emergent AEs led to treatment interruption, dose reduction, and treatment discontinuation in 58.6%, 45.9%, and 9.8% of patients, respectively. No treatment-related deaths occurred. Conclusions: Rucaparib has antitumor activity in advanced BRCA1/2-mutated HGOC and a manageable safety profile

Testimonial Injustice and Vulnerability: A Qualitative Analysis of Participation in the Court of Protection

This article explores participation in Court of Protection (COP) proceedings by people considered vulnerable. The paper is based on original data obtained from observing COP proceedings and reviewing COP case files. It is argued that the observed absence of the subject of proceedings is a form of testimonial injustice, that is, a failure to value a person in their capacity as a giver of knowledge. The issue of competence to give evidence is considered but it is argued that it is not the formal evidential rules that prohibit a vulnerable adult from giving evidence. Instead, it is the result of a persistent assumption that they are inherently vulnerable and therefore lack credibility as a knowledge giver. This assumption results in the voices of vulnerable adults being routinely absent from legal proceedings. It is argued that having a voice in the courtroom is essential and has a number of intrinsic and instrumental benefits. The paper concludes with a discussion about the implications of the research, including the current trend towards the increased use of special measures, and recommends a presumption in favour of the subject of COP proceedings giving evidence

MESTRANOL AS A REPELLENT TO PROTECT DOUGLAS-FIR SEED FROM DEER MICE

Mestranol** [3-Methoxy-19-nor-l7α-pregna-l,3,5 (10)-trien-20-yn-l7-ol (C21H26O2)] was tested at 2 percent (active) as a repellent for protecting Douglas-fir (Pseudotsuga menziesii) seed from deer mice (Peromyscus maniculatus). In 5-day laboratory bioassays, deer mice consumed 61 to 66 percent fewer mestranol-treated seeds than control seeds; these results were about equal to those with a standard 0.5 percent (active) endrin seed treatment. Deer mice showed a progressive aversion to the mestranol seed treatment from 24 percent to 76 percent in 5 days. Thereafter, with minimal reinforcement, avoidance was maintained at 90 to 99 percent for 6 months. In six field trials in Washington, Oregon, and California, areas seeded with 2 percent mestranol-treated Douglas-fir seed yielded 1.6 to 5.9 times more germinants than areas seeded with control seed. In three of these areas, endrin seed treatments were included; they yielded 1.2 to 3.4 times more germinants than the mestranol treatment and 1.9 to 17.3 times more germinants than the control seed. Although the endrin treatments yielded higher numbers of germinants, the mestranol treatments in these tests generally resulted in acceptable numbers of germinants for first-year stocking. Mestranol\u27s nontoxic, nonpersistent properties plus the aversion shown by deer mice to mestranol in our tests makes it a leading candidate as a Douglas-fir seed protectant in western United States