Radiosynthesis of (E)-N-(2-[11C]methoxybenzyl)-3-phenyl-acrylamidine, a novel subnanomolar NR2B subtype-selective NMDA receptor antagonist.

Recently, a novel series of amidines has been described, exhibiting high NR2B-subtype selective N-methyl-D-aspartate (NMDA) antagonist activity with nanomolar or subnanomolar affinity. Within the styrylamidine subclass, (E)-N-(2-methoxybenzyl)-3-phenyl-acrylamidine (1), displayed the highest affinity (Ki=0.7 nM versus [(3)H]ifenprodil) and was considered an appropriate candidate for isotopic labelling with carbon-11 (T(1/2): 20.38 min) at its methoxy group for imaging of NMDA receptors with PET. Derivative 1 has been labelled from the corresponding nor-analogue using [(11)C]methyl triflate and the following experimental conditions : (1) trapping at -10 degrees C of [(11)C]methyl triflate in 300 microL of acetone containing 0.6-0.8 mg of precursor 5 (2.4-3.2 micromol) and 5 microL of a 3M solution of NaOH in water (about 5 eq.); (2) concentration to dryness of the reaction mixture (at 110 degrees C, using a helium stream for 1-2 min); (3) taking up the residue with 0.5 mL of the HPLC mobile phase and (4) purification using semi-preparative HPLC (SymmetryPrep) C-18, Waters, 300 x 7.8 mm). Typically, starting from a 1.5 Ci (55.5 GBq) [(11)C]CO(2) production batch, 120-240 m Ci (4.44-8.88 GBq) of [(11)C]-1 (20-40% decay-corrected radiochemical yield, n=5) was obtained within a total synthesis time of 25-30 min. Specific radioactivities ranged from 0.8 to 1.2 Ci/micromol (29.6-44.4 GBq/micromol) at the end of radiosynthesis. No attempts were made to further optimise these reactions, as sufficient material was obtained to allow for preliminary pharmacological characterisation.     

Treatment of nasopharyngeal stenosis by prosthetic hollow stents: Clinical experience in eight patients.

OBJECTIVE: A series of nasopharyngeal appliance designs is presented that represents our evolving experience over a 20-year period in the adjunctive use of prosthetic stents in the surgical correction of nasopharyngeal stenosis. DESIGN: Retrospective assessment of effectiveness of two nasopharyngeal stenosis hollow stent designs in a consecutive series of patients for relief of nasal obstructive symptoms. SETTING: Tertiary academic medical center, Craniofacial Program at Children's Hospital. PATIENTS: Four patients with nasopharyngeal stenosis were treated with a preoperatively fabricated stent made from a clasped palatal appliance onto which hollow acrylic conduits were extended through surgically re-created pharyngeal ports. A subsequent set of four patients with nasopharyngeal stenosis were treated with intraoperatively-fashioned silastic grommets, as opposed to palatal appliances. INTERVENTIONS: Postoperative intraoral stenting of nasopharyngeal ports. MAIN OUTCOME MEASURES: Maintenance of pharyngeal port opening after 1 year, improvement in nasal airway obstructive symptoms. RESULTS: The palatal appliance stents were less well tolerated and had a lower maintenance of port patency after device removal (4 of 8, 50%). The silastic grommets provided better retention into the ports and increased patient tolerance, as well as better 1-year port maintenance (6 of 8, 75%). CONCLUSIONS: The grommet stent appliance offers numerous advantages over a conventional dental-clasped appliance for prosthetic nasopharyngeal stenting, including obviation of extensive preoperative preparation, ease of insertion and removal, and exchange of air during the stenting period. Improved nasopharyngeal patency with this device may be due to greater patient tolerance and subsequent longer use.     

Baseline immune activation as a risk factor for the onset of depression during interferon-alpha treatment.

BACKGROUND: Major depression has been associated cross-sectionally with increased cell-mediated immune activation but causality has been difficult to establish. This study prospectively investigated the hypothesis that baseline level of immune activation predicts the development of depression during interferon-alpha (IFN-alpha) treatment. METHODS: Sixteen hepatitis C patients without psychiatric disorder underwent IFN-alpha treatment. Proinflammatory and anti-inflammatory cytokines were determined before starting treatment. Presence of a major depressive disorder (MDD) was assessed at baseline and several times during treatment. RESULTS: Baseline soluble interleukin-2 receptor (sIL-2r), interleukin-6 (IL-6), and interleukin-10 (IL-10) concentrations were significantly increased in the five subjects that developed MDD during treatment compared with those that did not, with standardized effect sizes of 1.08, 1.16, and 1.25, respectively, controlling for marijuana use, cigarette smoking, and baseline level of depressive symptoms. CONCLUSIONS: Results suggest that increased immune activation, rather than an epiphenomenon, is a causal risk factor for the development of MDD.     

Postoperative nomogram for disease-specific survival after an R0 resection for gastric carcinoma.

PURPOSE: Few published studies have addressed individual patient risk after R0 resection for gastric cancer. We developed and internally validated a nomogram that combines these factors to predict the probability of 5-year gastric cancer-specific survival on the basis of 1,039 patients treated at a single institution. METHODS: Nomogram predictor variables included age, sex, primary site (distal one-third, middle one-third, gastroesophageal junction, and proximal one-third), Lauren histotype (diffuse, intestinal, mixed), number of positive lymph nodes resected, number of negative lymph nodes resected, and depth of invasion. Death as a result of gastric cancer was the predicted end point. The concordance index was used as an accuracy measure, with bootstrapping to correct for optimistic bias. Calibration plots were constructed. RESULTS: Gastric cancer-specific survival at 5 years was 50%. A nomogram was constructed on the basis of a Cox regression model. The bootstrap-corrected concordance index was 0.80. When compared with the predictive ability of American Joint Committee on Cancer stage, the nomogram discrimination was superior (P <.001). Nomogram calibration appeared to be excellent. CONCLUSION: A nomogram was developed to predict 5-year disease-specific survival after R0 resection for gastric cancer. This tool should be useful for patient counseling, follow-up scheduling, and clinical trial eligibility determination.     

beta2- and beta3-Adrenoceptor polymorphisms relate to subsequent weight gain and blood pressure elevation in obese normotensive individuals.

High blood pressure (BP) is a major determinant of cardiovascular events in obesity. The beta2- and beta3-adrenoceptor polymorphisms are associated with obesity and hypertension. In the present study, we examine the relationships of beta2- and beta3-adrenoceptor polymorphisms with further weight gain-induced BP elevation in obese subjects. Changes in BP, body weight, total body fat-mass, waist-to-hip ratio, plasma norepinephrine (NE) and leptin levels, and beta2(Arg16Gly)- and beta3(Trp64Arg)-adrenoceptor polymorphisms were measured periodically over a 5-year period in 55 entry obese (body mass index [BMI]> or =25.0 kg/m(2)) normotensive (BP<140/90 mmHg) men. BP elevation and weight gain were defined as > or =10% increases from entry levels over 5 years in mean BP or BMI. Obese subjects with weight gain, BP elevation or weight gain-induced BP elevation had higher frequencies of the Gly16 allele of Arg16GIy and Arg64 allele of Trp64Arg. Subjects carrying the Gly16 or Arg64 alleles had significantly greater total fat-mass and waist-to-hip ratio at entry and over a 5-year period compared to the subjects who did not carry these polymorphisms. Subjects carrying the Gly16 allele had similar levels of plasma NE, higher levels of plasma leptin and a lower slope of the regression lines between plasma leptin and NE levels. Those carrying the Arg64 allele had higher plasma NE levels at entry and over a 5-year period compared to the subjects without the Arg64 allele, but plasma leptin levels and slopes were similar. The findings demonstrate that the Arg64 allele of the beta3-adrenoceptor polymorphisms relates to weight gain-induced BP elevation accompanying high plasma NE (heightened sympathetic activity) in obese men. The Gly16 allele of the beta2-adrenoceptor polymorphisms links to weight gain-induced BP elevation associated with leptin resistance. beta2- and beta3-adrenoceptor polymorphisms could predict the future BP elevation and further weight gain-induced BP elevation in originally obese subjects.     

Computer Assisted Clinical Assessment

The number and range of computer-based assessment procedures for children and young people have increased greatly over the past few years. Over this time as well, other technological advances have occurred with a potential for application in services for young people. This paper provides an overview of the range of applications of relevance to practitioners, with a focus on assessment. Some of the benefits and disadvantages of computerised procedures for test administration and report writing are considered. The paper concludes with an examination of the issue of access to tests and some of the implications of the introduction of other new technologies.