Teaching trainee psychiatrists a Mentalization-Based Treatment approach to personality disorder: effect on attitudes.

AIMS AND METHOD: To evaluate whether a brief training using a Mentalization-Based Treatment (MBT) model improves attitudes of trainee psychiatrists working with patients with personality disorder. Trainee psychiatrists (n = 49) completed the Attitudes to Personality Disorder Questionnaire before and after a training consisting of two 3 h lectures on (a) theory of personality disorder and (b) practical skills using an MBT role-play. RESULTS: There was a significant improvement on composite scores of attitude, with small to moderate effect size (Wilcoxon signed-rank test Z = 3.961, P < 0.001, r = 0.40). CLINICAL IMPLICATIONS: Brief MBT-informed teaching oriented to the clinical situation appears to have a positive effect on attitudes towards people with personality disorder.

Collar pressure mapping: An evaluation of seven collar types used on working donkeys in Europe.

BACKGROUND: Working donkeys represent an important source of energy worldwide. Poor working conditions and equipment affect their ability to work. Poorly designed, ill-fitted harness causes inefficient transfer of power and leads to health and welfare issues. Using technology to assess different types of collars provides a better understanding of those that are most efficient for working donkeys. MATERIALS AND METHODS: Seven different collars were tested using pressure pads. Contact area, median, maximum and peak pressures were obtained for the whole collar and critical points. Eight donkeys pulled 20% and 40% of their body weight, using each collar, under controlled conditions. RESULTS: Contact area and pressures vary between collars and effort, with design and expansion capacity of the collars playing a major role. Simple collars designed specifically for donkeys performed well, with full collars designed for horses also having good results. Due to reduced expansion capacity and contact in the critical points, the breast collars were the least effective. CONCLUSION: Design, appropriate padding and manufacturing materials and adjustment capacity are key features for good collars, and such parameters are of paramount importance in terms of health and welfare for working donkeys.

Equid Assessment, Research and Scoping (EARS): The Development and Implementation of a New Equid Welfare Assessment and Monitoring Tool.

The assessment of animal welfare poses numerous challenges, yet an emerging approach is the consolidation of existing knowledge into new frameworks which can offer standardised approaches to welfare assessment across a variety of contexts. Multiple tools exist for measuring the welfare of equids, but such tools have typically been developed for specific contexts. There is no 'one size fits all' which means that resulting datasets are generally non-comparable, creating a barrier to knowledge-sharing and collaboration between the many organisations working to improve equid welfare around the globe. To address this, we developed the Equid Assessment, Research and Scoping (EARS) tool, which incorporates pre-existing validated welfare assessment methods alongside new welfare indicators to deliver a larger and more comprehensive series of welfare indicators than currently exists, creating a single resource that can be used to assess equid welfare in any context. We field-trialled three welfare assessment protocols within the EARS tool, and applied these to welfare assessment of equids in a variety of contexts across nineteen countries. The EARS tool proved a useful, versatile and rapid method for collecting welfare assessment data and we collected 7464 welfare assessments in a period of fifteen months. We evaluate the EARS tool and provide ideas for future development.

Diabetes and mental health.

Diabetes is an increasingly common health problem, and accounts for one-tenth of NHS spending, chiefly managing avoidable complications. Approximately one-third of people with diabetes have psychological and/or social problems which impede their ability to self-manage their diabetes. Identifying certain indicators which suggest high risk of co-morbid mental health problems will allow these to be identified and treated early. Ensuring that any mental health problems are treated and social needs are met, will be valuable in improving the individuals health. Addressing the psychiatric and psychological barriers to good glucose control can help to reduce the burden of diabetes and its complications, on both the individual and the wider health service.

An aberrant leukotriene A4 hydrolase-proline-glycine-proline pathway in the pathogenesis of chronic obstructive pulmonary disease.

RATIONALE: Chronic neutrophilic inflammation is a hallmark in the pathogenesis of chronic obstructive pulmonary disease (COPD) and persists after cigarette smoking has stopped. Mechanisms involved in this ongoing inflammatory response have not been delineated. OBJECTIVES: We investigated changes to the leukotriene A4 hydrolase (LTA4H)-proline-glycine-proline (PGP) pathway and chronic inflammation in the development of COPD. METHODS: A/J mice were exposed to air or cigarette smoke for 22 weeks followed by bronchoalveolar lavage and lung and cardiac tissue analysis. Two human cohorts were used to analyze changes to the LTA4H-PGP pathway in never smokers, control smokers, COPD smokers, and COPD former smokers. PGP/AcPGP and LTA4H aminopeptidase activity were detected by mass spectroscopy, LTA4H amounts were detected by ELISA, and acrolein was detected by Western blot. MEASUREMENTS AND MAIN RESULTS: Mice exposed to cigarette smoke developed emphysema with increased PGP, neutrophilic inflammation, and selective inhibition of LTA4H aminopeptidase, which ordinarily degrades PGP. We recapitulated these findings in smokers with and without COPD. PGP and AcPGP are closely associated with cigarette smoke use. Once chronic inflammation is established, changes to LTA4H aminopeptidase remain, even in the absence of ongoing cigarette use. Acrolein modifies LTA4H and inhibits aminopeptidase activity to the same extent as cigarette smoke. CONCLUSIONS: These results demonstrate a novel pathway of aberrant regulation of PGP/AcPGP, suggesting this inflammatory pathway may be intimately involved in disease progression in the absence of ongoing cigarette smoke exposure. We highlight a mechanism by which acrolein potentiates neutrophilic inflammation through selective inhibition of LTA4H aminopeptidase activity. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).

Pilot study of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer.

PURPOSE: To assess further the tolerability and preliminary antitumor activity of PD-0325901 in previously treated patients with advanced melanoma, breast cancer, and colon cancer. METHODS: This pilot study evaluated PD-0325901 on an intermittent dosing schedule. PD-0325901 was administered orally at 20 mg twice daily (BID) for 21 consecutive days followed by 7 days of no treatment. This dose was not well tolerated and consequently changed to 15 mg BID. RESULTS: Between October and December 2005, 13 patients with metastatic measurable disease were entered into the study (seven melanoma, three breast cancer, and three colon cancer). All patients had received prior systemic therapy and were treated with a total of 61 cycles of PD-0325901 (nine received an initial dose of 20 mg BID, four an initial dose of 15 mg BID). The study was terminated early because of an unexpected high incidence of musculoskeletal and neurological adverse events, including gait disturbance, memory impairment, confusion, mental status changes, mild to moderate visual disturbances, and muscular weakness including neck weakness ("dropped-head syndrome"). Other common toxicities were diarrhea, acneiform rash, fatigue, and nausea. There was no significant hematologic toxicity, and chemistry abnormalities were rare. One patient achieved a confirmed complete response, and five patients had stable disease. CONCLUSIONS: PD-0325901 can cause significant musculoskeletal, neurological, and ocular toxicity at doses ≥ 15 mg BID. Future studies with adaptive designs might evaluate doses ≤ 10 mg BID in tumor types with a high incidence of Ras and Raf mutations. ClinicalTrials.gov identifier NCT00147550.

Environmental concentrations of methoprene and its transformation products after the treatment of Altosid® XR Briquets in the city of Richmond, British Columbia, Canada.

Water runoff from catch basins treated with Altosid® XR Briquets for mosquito larvae control was sampled at 10 storm drainage pump stations along the outskirts of the city of Richmond, British Columbia, Canada after rainfall events in 2006 to determine the residual concentrations of methoprene and transformation products: citronellic acid, methoprene acid, and 7-methoxycitronellic acid. Runoff of prior-to-treatment, posttreatment, and 150-d-after-treatment was collected. No residues were detected in the prior-to-treatment samples. However, methoprene was detected in posttreatment, and citronellic acid was detected in posttreatment and one 150-d-after-treatment sample. The detected environmental concentrations of methoprene (0.04-0.14 µg/L) and methoprene acid (0.07 µg/L) at pump stations were below known/reported toxicity values to aquatic organisms. However, concentrations detected inside the storm drainage system in catch basins (methoprene 122 µg/L, methoprene acid 1.74 µg/L) and inspection chambers (methoprene 622 µg/L, methoprene acid 20 µg/L, citronellic acid 0.05 µg/L) are known to be toxic to invertebrates, have chronic early-life-stage fish effects, and exceeded the Draft Interim Ontario Water Quality Objective and the numerical benchmarks for protection of amphibians (1.6 µg/L), invertebrates (10 µg/L), and fish (80 µg/L). The limited detection in the present study may have resulted from significant absorption of methoprene to sample bottle walls, substance decay during sample storage before methoprene extraction, flushing of briquettes from catch basins following heavy rainfall, and the burial of briquettes under thick layers of debris.

Phase I trial of poly-L-glutamate camptothecin (CT-2106) administered weekly in patients with advanced solid malignancies.

PURPOSE: CT-2106 is a 20(S)-camptothecin poly-L-glutamate conjugate. This linkage stabilizes the active lactone form of camptothecin and enhances aqueous solubility. In addition, poly-L-glutamate is postulated to increase tumor delivery of the active compound through enhanced permeability and retention effect in tumor. We studied a weekly schedule of CT-2106 in patients with refractory solid tumor malignancies. EXPERIMENTAL DESIGN: CT-2106 was infused (10 min i.v. infusion) on days 1, 8, and 15 of each 28-day cycle. Plasma and urine were analyzed for total and unconjugated camptothecin by high-performance liquid chromatography equipped with a fluorescence detector. Toxicity and response assessments were done with Common Toxicity Criteria for Adverse Events version 3 and Response Evaluation Criteria in Solid Tumors, respectively. RESULTS: Twenty-six patients were enrolled. Median age was 58 years (range, 36-83) and median number of doses was 6 (range, 1-9). The most frequent tumor type (50%) was melanoma. Dose limiting toxicities were thrombocytopenia and fatigue. A weekly dose of 25 mg/m2 given every 3 of 4 weeks was the maximum tolerated dose. The majority of grade 3 and 4 toxicities were hematologic. The pharmacokinetic profile of conjugated and unconjugated camptothecin showed a polyexponential decline with similar terminal half life (t1/2 range was 44-63 and 31-48 h for conjugated and unconjugated, respectively). Pharmacokinetics of conjugated and unconjugated camptothecin were dose and time independent in the tested dose range. Urinary excretion of conjugated and unconjugated camptothecin accounted for about 30% and 4% of the administered dose, respectively. CONCLUSIONS: CT-2106 has a more manageable toxicity profile compared with unconjugated camptothecin. The maximum tolerated dose is 25 mg/m2 weekly given 3 of 4 weeks. This compound results in prolonged release of unconjugated camptothecin.

A case of primary squamous cell colon cancer.

Carcinomas of the colon are a common cancer seen in both inpatient and outpatient settings with approximately 145,000 new cases being diagnosed every year in the USA. Despite the frequency of these cancers being seen, it continues to be a rarity to see a primary squamous cell cancer of the colon. In this article, such a case is presented. While the exact aetiology of this rare tumour is currently still not completely understood, various aetiologies include chronic irritation leading to squamous differentiation, embryonic migration of ectodermal cells to the colon, or adenomas undergoing squamous transformation.

Phase I trial of histone deacetylase inhibition by valproic acid followed by the topoisomerase II inhibitor epirubicin in advanced solid tumors: a clinical and translational study.

PURPOSE: To determine the safety, toxicity, and maximum-tolerated dose of a sequence-specific combination of the histone deacetylase inhibitor (HDACi), valproic acid (VPA), and epirubicin in solid tumor malignancies and to define the clinical feasibility of VPA as an HDACi. PATIENTS AND METHODS: Patients were treated with increasing doses of VPA (days 1 through 3) followed by epirubicin (day 3) in 3-week cycles. The study evaluated pharmacokinetic and pharmacodynamic end points, toxicities, and tumor response. RESULTS: Forty-eight patients were enrolled, and 44 received at least one cycle of therapy. Patients (median age, 54 years; range, 39 to 78 years) received the following doses of VPA: 15, 30, 45, 60, 75, 90, 100, 120, 140, and 160 mg/kg/d. Dose-limiting toxicities were somnolence (n = 1), confusion (n = 3), and febrile neutropenia (n = 1). No exacerbation of epirubicin-related toxicities was observed. Partial responses were seen across different tumor types in nine patients (22%), and stable disease/minor responses were seen in 16 patients (39%), despite a median number of three prior regimens (range, zero to 10 prior regimens). Patients received a median number of four treatment cycles (range, one to 10 cycles), and treatment was stopped after reaching maximal epirubicin doses rather than progression in 13 (32%) of 41 patients patients. Total and free VPA plasma concentrations increased linearly with dose and correlated with histone acetylation in peripheral-blood mononuclear cells. CONCLUSION: The maximum-tolerated dose and recommended phase II dose was VPA 140 mg/kg/d for 48 hours followed by epirubicin 100 mg/m2. Sustained plasma concentrations of VPA exceeding those required for in vitro synergy were achieved with acceptable toxicity. Noteworthy antitumor activity was observed in heavily pretreated patients and historically anthracycline-resistant tumors.

Melanoma of the anal canal: a case series.

PURPOSE: Anal melanoma is an uncommon and aggressive cancer. Different surgical modalities have been used in managing the disease with no clear evidence to favor one approach over another. METHODS: The medical records of patients with anal melanoma treated at the H. Lee Moffitt Cancer and Research Institute between 1987 and 2004 were reviewed. Published anal melanoma studies, including more than ten patients with outcome data, also were reviewed. RESULTS: Twelve patients were identified (8 percent of all cancer of the anal canal). Nine were females with a median age of 67 (range, 27-86) years. Four patients had nodal involvement, and one had bone metastases at the time of diagnosis. Five patients had abdominoperineal resection, and six had local excision. Adjuvant radiation therapy with or without interferon was used. Five of the 11 patients without metastatic disease relapsed or died within the first year of diagnosis (4 had local excision and 1 had abdominoperineal resection). Median time to relapse was 6.5 (range, 4-31) months. The liver was the most common site for relapse. Only one patient treated with local excision followed by interferon was a long survivor (no evidence of recurrence at 54 months). CONCLUSIONS: Anorectal melanoma is a rare and challenging disease. The preoperative staging influences the treatment schedule. In the absence of strong survival benefit of abdominoperineal resection in managing the nonmetastatic form of the disease, it is reasonable to consider local excision as the initial treatment of choice. Adjuvant radiation therapy is well tolerated and is promising in improving locoregional control.

Targeted therapies in the treatment of colorectal cancers.

BACKGROUND: In solid organ malignancies, no tumor type has seen a greater impact from the development of novel targeted therapies in 2004 than metastatic colorectal cancer. METHODS: We review the current progress to date with the use of monoclonal antibodies in colorectal cancer and look at newer therapies under investigation. RESULTS: Two monoclonal antibodies received Food and Drug Administration approval in early 2004, both for the indication of advanced, metastatic colorectal cancer. A large, randomized, placebo-controlled study demonstrated that the addition of a monoclonal antibody to vascular endothelial growth factor, bevacizumab, led to a statistically significant improvement in overall survival, with tolerable additional toxicity. Chimeric monoclonal antibody therapy directed at the epidermal growth factor receptor was associated with radiographic responses in a significant minority of patients with irinotecan-refractory colon cancer in a randomized phase II study of patients with irinotecan-refractory disease. CONCLUSIONS: These dramatic successes have led to further clinical studies of targeted therapy in colorectal cancer, making it one of the most promising areas of cancer research.

Imaging gastrointestinal stromal tumors.

BACKGROUND: Because of the recent reclassification of mesenchymal tumors, which was based on a better understanding of the genetics and immunophenotype of gastrointestinal stromal tumors (GISTs), only a limited number of studies have described the radiologic appearance of GISTs. METHODS: This study reviews the imaging characteristics of GISTs, with an emphasis on differentiating benign and malignant tumors using positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging (MRI). We reviewed the data from 53 cases of GISTs treated at our institute. The imaging studies from these cases, which were recorded at our institute from January 1998 through June 2003, included PET, CT, and MRI. RESULTS: Of the 53 GIST cases, stomach and small bowel tumors accounted for 80% of the tumors. Malignant lesions were larger and more heterogeneous, had ulcerations, and were PET positive. Peritoneal and liver metastases were most common. CONCLUSIONS: PET, CT, and MRI appear to be useful in differentiating nonmetastasizing from malignant GISTs.

Ocean science. Enhanced: internal tides and ocean mixing.

Recent satellite and in situ observations have shown that at ocean ridges and other seafloor topographic features, a substantial amount of energy is transferred from the main ocean tides into "internal tides." In his Perspective, Garrett explains how these internal waves with tidal periods propagate through the density-stratified deep ocean and eventually break down into turbulence. The resulting mixing affects ocean stratification and ocean circulation. It thus influences climate as well as biological production. The energy for the internal tides is derived from the rotational energy of the Earth-Moon system changes of the length of the day and the distance to the Moon.