2-benzazepines. 6. Synthesis and pharmacological properties of the metabolites of 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d] [2]benzazepine

The 2-benzazepine 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d] [2]benzazepine (1) has been selected for development as an anxiolytic agent. In support of this program, we have confirmed by chemical synthesis the structures of three in vitro (rat liver homogenate) metabolites of 1 and confirmed the structure of the major in vivo (dog and man) metabolite of 1, compound 2. Two of the metabolites, arising from hydroxylation of the pyrimidobenzazepine ring at the 5-position (2) and N-oxide formation at the 3-position of the pyrimidobenzazepine ring (3), were found to be as active as 1 in a series of pharmacological tests. The third metabolite, formed by hydroxylation of the 7-phenyl group in the 4-position (4), was found to be inactive in the same pharmacological screens.     

Trastuzumab, paclitaxel, cisplatin, and radiation for adenocarcinoma of the esophagus: a phase I study

Purpose: To conduct a phase I study incorporating trastuzumab with paclitaxel, cisplatin, and radiation for adenocarcinoma of the esophagus. Methods and Materials: Patients with adenocarcinoma of the esophagus without distant organ metastases were eligible. All patients received cisplatin 25 mg/m² and paclitaxel 50 mg/m² weekly for 6 weeks with radiation 50.4 Gy. HER-2/neu-positive patients (2 + /3 + by immunohistochemistry) received weekly trastuzumab at dose levels of 1, 1.5, or 2 mg/kg weekly for 5 weeks after an initial bolus of 2, 3, or 4 mg/kg, respectively. HER-2/neu-negative patients received the same chemoradiation without trastuzumab as a control for toxicity. Dose-limiting toxicities were defined as grade 3 esophageal, cardiac, or pulmonary toxicity. Results: Twelve of 36 screened patients (33%) overexpressed HER-2/neu by immunohistochemistry (seven 3 + and five 2 + ). Eight of 12 patients with HER-2/neu overexpression by IHC had an increase in the number of HER-2/neu genes, six from amplification of the HER-2/neu gene and two were hypderdiploid for chromosome 17. Thirty patients were enrolled (12 HER-2/neu-positive and 18 HER-2/neu-negative controls). No increase in toxicity was seen with the addition of trastuzumab. One of 12 patients in the trastuzumab arm and 8 of 17 in the control arm had grade 3 esophagitis (p ≤ .026). Mean left ventricular ejection fraction for the trastuzumab group was 57% before treatment and 56% after treatment. Conclusion: HER-2/neu is overexpressed in approximately one-third of esophageal adenocarcinomas. Trastuzumab can be added at full dose to cisplatin, paclitaxel, and radiation. Future studies of trastuzumab in esophageal adenocarcinoma are indicated.     

The Effectiveness of a Community Playground Intervention

This study assessed whether an upgrade of playgrounds in a community was associated with changes in the physical activity of local children. The study used a natural experiment design with a local authority project to upgrade two community playgrounds as the intervention and a matched control community. Children’s physical activity was measured by an Actigraph GT1M accelerometer worn for 8 days, enabling up to 6 days of data to be analyzed. A self-administered parent/guardian questionnaire was used to collect additional data, including perceptions of the neighborhood, school-travel modes, days involved in extracurricular activities, ethnicity, caregiver age, caregiver sex, household vehicle access, and household income. At baseline, 184 children (5–10 years old) participated. Of these, 156 completed the 1-year follow-up assessment (20% lost to follow-up). There was statistically significant evidence that change in mean total daily physical activity was associated with on an interaction between participant’s body mass index (BMI) z-score and her or his community of residence (p = 0.006), with the intervention being associated with higher levels of activity for children with lower BMIs but lower levels for children with higher BMIs. Physical activity is not the only focus of local authority playground provision as playgrounds also have benefits for social development and fundamental movement skills. However, making sure that physical activity is always included in the design rationale and that playgrounds are designed to encourage and sustain physical activity could be a useful population health intervention. The effects of such interventions on different subgroups are of importance, especially if the effects differ over levels of BMI.     

Complications of Mandibular Fracture: Study of the Treatment Methods in Calabar,Nigeria

Objective:

The plethora of techniques available for the treatment of mandibular fractures suggests that there is controversy regarding their definitive outcome. The purpose of this study was to clinically study the complications associated with the different treatment methods of mandibular fractures at the University of Calabar Teaching Hospital (UCTH), Nigeria.

Methods:

This was a three-year prospective study carried out at the Dental and Maxillofacial Clinic of the hospital. Patients who met the inclusion criteria had their data recorded in a proforma questionnaire.

Results:

Out of the 256 patients studied, 17.2% developed complications. Complications were commoner (70.5%) between ages 21 and 50 years. Thirty-five (79.5%) were males while nine (20.5%) were females with a male:female ratio of 4.9:1. Following treatment by closed reduction, conservative and open reduction, 16.6%, 17.2% and 20.7% had complications, respectively. Whereas occlusal derangement was the most common complication, numbness of the cheek and lower lip was recorded following all treatment methods.

Conclusion:

Although the complications recorded in this patient population were managed during postoperative follow-up period, the methods of treatment available give good results, are cost-effective and patient compliance is good. This suggests that the older methods of treatment of mandibular fractures can still be used with reliability in contemporary dental practice.     

Genistein suppresses the inflammation and GSK-3 pathway in an animal model of spontaneous ovarian cancer

Background/aim Numerous studies show that cancer risk is reduced by consumption of soy-based foods containing genistein, but its effects on the glycogen synthase kinase-3 pathway (GSK-3) in ovarian cancer is unknown. Therefore, we tested the properties of genistein on inflammatory biomarkers and GSK-3 signaling pathways in the ovaries of old laying hens with ovarian cancer. Materials and methods A total of 300 laying hens were distributed into three groups as follows: group 1, animals fed a standard diet (comprising 22.39 mg of genistein/kg of diet); groups 2 and 3, animals fed a standard diet reconstituted with supplementation of 400 mg or 800 mg of genistein/kg of diet, respectively.Results Genistein modulated the inflammatory biomarkers by decreasing serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF) compared with control (p < 0.001). Moreover, it upregulated insulin receptor substrate-1 (p-IRS-1) and protein kinase B (p-AKT), but downregulated GSK-3α and β after treatment. It acts in a dose-dependent manner. Conclusion Genistein exhibited an anticancer effect by reducing proinflammatory biomarkers levels and inhibiting GSK-3 expression in the ovaries of old laying hens. It is a potential candidate in the chemoprevention and/or treatment of ovarian cancer.     

Pulmonary MRA: Differentiation of pulmonary embolism from truncation artefact

Purpose

Truncation artefact (Gibbs ringing) causes central signal drop within vessels in pulmonary magnetic resonance angiography (MRA) that can be mistaken for emboli, reducing diagnostic accuracy for pulmonary embolism (PE). We propose a quantitative approach to differentiate truncation artefact from PE.

Methods

Twenty-eight patients who underwent pulmonary computed tomography angiography (CTA) for suspected PE were recruited for pulmonary MRA. Signal intensity drops within pulmonary arteries that persisted on both arterial-phase and delayed-phase MRA were identified. The percent signal loss between the vessel lumen and central drop was measured. CTA served as the reference standard for presence of pulmonary emboli.

Results

A total of 65 signal intensity drops were identified on MRA. Of these, 48 (74 %) were artefacts and 17 (26 %) were PE, as confirmed by CTA. Truncation artefacts had a significantly lower median signal drop than PE on both arterial-phase (26 % [range 12–58 %] vs. 85 % [range 53–91 %]) and delayed-phase MRA (26 % [range 11–55 %] vs. 77 % [range 47–89 %]), p?<?0.0001 for both. Receiver operating characteristic (ROC) analyses revealed a threshold value of 51 % (arterial phase) and 47 % signal drop (delayed phase) to differentiate between truncation artefact and PE with 100 % sensitivity and greater than 90 % specificity.

Conclusion

Quantitative signal drop is an objective tool to help differentiate truncation artefact and pulmonary embolism in pulmonary MRA.

Key points

? Inexperienced readers may mistake truncation artefacts for emboli on pulmonary MRA ? Pulmonary emboli have non-uniform signal drop ? 51 % (arterial phase) and 47 % (delayed phase) cut-off differentiates truncation artefact from PE ? Quantitative signal drop measurement enables more accurate pulmonary embolism diagnosis with MRA     

Primary school sun protection policies and practices 4 years after baseline--a follow-up study

Before the 2005 launch of the New Zealand SunSmart Schools Accreditation Programme (SSAP), 242 randomly sampled primary schools completed a mail survey about sun protection policies, practices, curriculum and environment. A 2009 follow-up included 189 (78%) and their mean Total Accreditation Score (TAS = total SSAP requirements met, range 0-12), increased by 0.8 (95% CI 0.5-1.2, P < 0.001) from 7.8 (95% CI 7.4-8.1) to 8.6 (95% CI 8.3-8.9) with evidence changes differed between regions (P = 0.024). The 2009 mean TAS varied by region (range 7.9-9.4, unadjusted P = 0.004, adjusted P = 0.013) with no clear pattern, but likely resource allocation association. TAS of schools acknowledging input from Health Promoting Schools demonstrated a tendency towards being statistically significantly higher by 0.5 (95% CI -0.1 to 1.1, P = 0.082), but statistically significantly higher by 1.1 (95% CI 0.5-1.7, P < 0.001) for schools acknowledging Cancer Society input. Lowest attainment was for the clothing (43%), shade (52%) and curriculum (55%) criteria. Key perceived barriers were cost, particularly of shade and limited support by parents and others. Schools which had not applied for accreditation identified lack of programme awareness and 'other priorities' as barriers; further information, better resourcing and training assistance as key needs. Observed positive change justifies increased support to consolidate gains and achieve sustainable universality.     

An open-label pilot study of alefacept for the treatment of pyoderma gangrenosum

Background Pyoderma gangrenosum (PG) is a chronic inflammatory disease that causes painful cutaneous ulcers that are difficult to treat. Currently, systemic immunosuppressants, often including prednisone, are the mainstay of therapy. Long‐term therapy with these agents is often required which exposes patients to possible adverse effects. An alternative treatment that is safe and effective is truly needed. Objective To study the efficacy and safety of alefacept, which inhibits T‐cell activation and selectively reduces the T‐cell population, for treatment of PG. Method In this prospective open‐label pilot study, four patients diagnosed with PG received weekly doses of 15 mg alefacept intramuscularly for 20 weeks with 12‐week treatment‐free follow‐up. The primary efficacy end point was the proportion of patients achieving remission as defined by a Physician Global Assessment (PGA) of ‘clear’ or ‘almost clear.’ Secondary endpoints included proportion of patients achieving 50% improvement in PG lesion size (measured in mm) and proportion of patients achieving resolution of inflammation (an erythema score of 0 and a border thickness of 0 on scales of 0–4). Results By week 20, one (25%) of the four patients achieved remission, two showed marked improvement in severity on PGA, and one had slight improvement. One patient showed a 98% decrease in lesion size; two other patients evidenced a decrease in the number of small lesions as well as improvements in primary lesion sizes, but did not surpass the 50% criterion. All four patients showed improved erythema scores during treatment, though only one patient showed a complete resolution of inflammation. Limitations It may be difficult to generalize the results of this study to a larger population of patients with PG due to the small sample size and lack of a control group. A longer treatment interval might have been required. Safety and efficacy of long‐term therapy is unknown. Conclusion In this pilot study it appears that alefacept treatment may significantly reduce PG severity levels as evidenced by improvement in PGA, Subject Global Assessment, and inflammation scores in all patients. Alefacept may be a safe and effective alternative to current systemic immunosuppressants used to treat PG. Double‐blinded, controlled trials are necessary to further evaluate the safety and effectiveness of this treatment.