Radiosynthesis of [18F]PBR111, a selective radioligand for imaging the translocator protein (18 kDa) with PET

PBR111 (2‐(6‐chloro‐2‐(4‐(3‐fluoropropoxy)phenyl)imidazo[1,2‐a]pyridin‐3‐yl)‐N,N‐diethylacetamide) is a novel, reported, high‐affinity and selective ligand for the translocator protein (18 kDa). PBR111 has been labelled with fluorine‐18 (half‐life: 109.8 min) using our Zymate‐XP robotic system. The process involves (A) a simple one‐step tosyloxy‐for‐fluorine nucleophilic aliphatic substitution (performed at 165°C for 5 min in DMSO using K[¹⁸F]F‐Kryptofix^®222 and 6.8–7.6 µmol of the corresponding tosylate as precursor for labelling) followed by (B) C‐18 PrepSep cartridge pre‐purification and (C) semi‐preparative HPLC purification on a Waters Symmetry^® C‐18. Up to 4.8 GBq (130 mCi) of [¹⁸F]PBR111 could be obtained with specific radioactivities ranging from 74 to 148 GBq/µmol (2–4 Ci/µmol) in 75–80 min (HPLC purification and SepPak^®‐based formulation included), starting from a 37.0 GBq (1.0 Ci) [¹⁸F]fluoride batch. Overall non‐decay‐corrected isolated yields were 8–13% (13–21% decay‐corrected). Copyright © 2008 John Wiley & Sons, Ltd.     

Cyclin D3 Is Essential for Intestinal Epithelial Cell Proliferation

Intestinal epithelium is a complex organ that undergoes continuous proliferation. D-type cyclins bind cyclin-dependent kinases (Cdk4 and Cdk6) and are expressed during the transition from G0 into the S phase. Previously, we reported that cyclins D1 and D3 are induced by growth factors in two rat intestinal epithelial cell lines, IEC-6 and RIE-1. However, transforming growth factor beta induces G1 arrest in both intestinal cell lines without inhibiting cyclin D3, suggesting that cyclin D3 may not have essential functions in the gut. In the present study, we determined whether cyclin D3 is required for the transition from G0 into the S phase in intestinal epithelial cells. Microinjection of anti-cyclin D3 antiserum inhibited quiescent IEC-6 and RIE-1 cells from entering the S phase, while cells microinjected with a nonspecific mouse immunoglobin G continued to progress into the S phase. We also examined the expression of cyclin D3 in rat jejunal mucosa after fasting and refeeding. Cyclin D3 levels were not altered by fasting and refeeding; however, Cdk4 expression was suppressed by fasting and returned to control levels after refeeding. Our results suggest that cyclin D3 is essential for intestinal epithelial cell proliferation, although its expression is not regulated by dietary restriction.     

Retinal arteriolar emboli: epidemiology and risk of stroke

Retinal arteriolar emboli can be found in approximately 1% of adults more than 40 years of age. The frequency of retinal emboli increases with age and are more common in men than in women. Bilateral retinal emboli are rare, although multiple emboli in a single eye may be seen in up to one third of cases. Retinal emboli are associated with the presence of carotid artery plaque and stenosis, hypertension, cigarette smoking, and, possibly, diabetes. There are few prospective studies regarding the risk of stroke associated with retinal emboli. Available data suggest that retinal emboli in otherwise asymptomatic people are associated with a higher risk of stroke and stroke mortality, independent of conventional risk factors. Therefore, these patients are likely to benefit from a careful cardiovascular evaluation for risk stratification. Whether carotid ultrasound and other vascular imaging studies should be performed routinely for all patients with asymptomatic retinal emboli remains uncertain.     

Refractive errors and 10-year incidence of age-related maculopathy

PURPOSE: To describe the relationship of refractive errors to the 10-year incidence of age-related maculopathy (ARM) in a defined white population. METHODS: Persons aged 43 to 86 years of age in Beaver Dam, Wisconsin, were invited for a baseline examination from 1988 through 1990, and follow-up examinations 5 and 10 years later (n = 3684). Refraction was measured at baseline, with myopia defined as a spherical equivalent of -1.00 D or less, emmetropia as -0.75 to +0.75 D and hyperopia as +1.00 D or more. At each examination, signs of ARM were ascertained from grading stereoscopic color fundus photographs based on a standard protocol. The association between baseline refractive status and the 10-year incidence and progression of ARM was analyzed. RESULTS: The 10-year cumulative incidence for early ARM was 7.1%, 7.7%, and 11.7%, in eyes with myopia, emmetropia, and hyperopia, respectively. The corresponding 10-year cumulative incidence for late ARM was 0.3%, 0.8%, and 2.2%. When age was controlled for, there was no association between myopia and incident early (relative risk [RR] 1.0, 95% confidence interval [CI], 0.7-1.3) and late (RR 0.5, 95% CI, 0.2-1.5) ARM. Similarly, after controlling for age, hyperopia was not associated with incident early (RR 0.9, 95% CI, 0.7-1.1) or late (RR 1.2, 95% CI, 0.6-2.3) ARM. CONCLUSIONS: These prospective population-based data provide no evidence of an association between refractive errors and risk of ARM.     

Advanced NSCLC: from cytotoxic systemic chemotherapy to molecularly targeted therapy

Approximately a third of non-small cell lung cancer patients present with disseminated disease at the time of diagnosis. For these patients, as well as those with recurrent disease, chemotherapy remains the mainstay of treatment. For several decades, researchers have attempted different combinations of drugs in search for the 'best' chemotherapy regimen. Despite the emergence of newer, 'third-generation' cytotoxic agents, success is still modest at best. Fortunately, new insights in tumor biology, leading to the design of molecularly targeted drugs, are opening a new era in cancer treatment. These novel agents target molecular pathways specifically found in cancer cells, thus maximizing the antitumor effect while minimizing toxicities on normal cells.     

Butorphanol dependence and withdrawal decrease hippocampal kappa 2-opioid receptor binding

The present study examines the degree and distribution of alterations in the expression of kappa-opioid receptor subtypes using a model of chronic intracerebroventricular (i.c.v.) infusion of butorphanol. Autoradiographic characterization of binding for brain kappa(1) ([3H]CI-977)-, kappa(2) ([3H]bremazocine in the presence of DAMGO, DPDPE, and U-69,593)- and total kappa ([3H]bremazocine in the presence of only DAMGO and DPDPE)-opioid receptors was performed. Dependence was induced by a 72 h i.c.v. infusion with butorphanol (26 nmol/microl per hour) (butorphanol-dependent). Butorphanol withdrawal was produced by terminating the infusion of butorphanol in dependent animals. Responses were studied 7 h following termination (butorphanol-withdrawal). During both dependence and withdrawal phases, the binding signals for both kappa(1)- and kappa(2)-opioid receptors were significantly increased in certain regions, with especially marked increases in the frontal cortex, nucleus accumbens, parietal cortex, dorsomedial hypothalamus, ventral tegmental area and locus coeruleus. In contrast, a highly specific decrease in kappa(2)-, but increase in kappa(1)-, opioid receptor binding was noted in the hippocampus of rats in both butorphanol-dependent and-withdrawal groups. Therefore, alterations in kappa(1)- and kappa(2)-opioid receptors in the hippocampus may be differently involved in both adaptation to and recovery from chronic exposure to a mixed agonist/antagonist opioid analgesic. These results further illustrate the regional distribution of changes in binding characteristics of rat brain kappa(1)- and kappa(2)-opioid receptor subtypes in an established model of butorphanol dependence and withdrawal.     

Impact of a clinical pathway for total knee arthroplasty

The purpose of this study is to evaluate the effect of a clinical pathway for total knee arthroplasty in terms of length of stay, hospital costs, and quality of care. One hundred and twenty-two patients who underwent primary total knee arthroplasty for degenerative osteoarthritis in Kaohsiung Medical University hospital were included in the study. The pre-clinical pathway group included 53 patients before clinical pathway implementation (October 1996 approximately September 1997). The clinical pathway group included 69 patients after implementation of the clinical pathway (October 1997 approximately September 1998). All patients were followed up for at least 2 years after surgery. Data collection, including length of stay, hospital costs, comorbidity, and complications, was done by chart review, and Knee Society Clinical Rating System scores were used for assessment of preoperative and postoperative knee function for each group. Statistical analysis included Student's t-test to test the impact of the clinical pathway on resource consumption and medical care processes, and multiple linear regression to control for characteristics such as age and comorbidity. The implementation of the clinical pathway reduced the length of stay by 24%. Hospital costs were reduced by 16%. The implementation of the clinical pathway also reduced the number of unnecessary medical procedures. There was no statistically significant difference between the preoperative or the postoperative knee scores of the pre-clinical pathway group and clinical pathway group. The application of clinical pathway did not affect clinical outcomes and complication rates. In conclusion, the clinical pathway is an effective medical management tool to decrease the length of stay, decrease resource consumption and control medical care expenditure, and this is accomplished without a long-term adverse effect on quality of care.     

Fabrication of aligned microstructures with a single elastomeric stamp

The fabrication of complex patterns of aligned microstructures has required the use of multiple applications of lithography. Here we describe an approach for microfabrication that encodes the two-dimensional spatial information of several photomasks onto a single elastomeric stamp by mapping each photomask onto distinct heights on the surface of the stamp. Pressing the stamp against a surface collapses the topography of the stamp such that each recessed layer contacts the surface in stepwise sequence; the greater the applied pressure, the larger the area of the stamp that contacts the surface. After contact of each new layer with the surface, we use techniques of soft lithography (microcontact printing, microfluidics, and patterning through membranes) to pattern the surfaces that contact the stamp and those that do not with inorganic, organic, or living materials. Microfabrication through the use of multilevel stamps provides a promising alternative to conventional lithography for the construction of multicomponent, aligned surfaces; these structures may find use as components of microfluidic devices or biological patterns.     

Retinal arteriolar narrowing and risk of coronary heart disease in men and women. The Atherosclerosis Risk in Communities Study

Context  Microvascular processes have been hypothesized to play a greater role in the development of coronary heart disease (CHD) in women than in men; however, prospective clinical data are limited. Objective  To examine the association between retinal arteriolar narrowing, a marker of microvascular damage from hypertension and inflammation, and incident CHD in healthy middle-aged women and men. Design, Setting, and Participants  The Atherosclerosis Risk in Communities Study, an ongoing prospective, population-based cohort study in 4 US communities initiated in 1987-1989. Retinal photographs were taken in 9648 women and men aged 51 to 72 years without CHD at the third examination (1993-1995). To quantify retinal arteriolar narrowing, the photographs were digitized, individual arteriolar and venular diameters were measured, and a summary arteriole-to-venule ratio (AVR) was calculated. Main Outcome Measure  Risk of CHD associated with retinal arteriolar narrowing. Results  During an average 3.5 years of follow-up, 84 women and 187 men experienced incident CHD events. In women, after controlling for mean arterial blood pressure averaged over the previous 6 years, diabetes, cigarette smoking, plasma lipid levels, and other risk factors, each SD decrease in the AVR was associated with an increased risk of any incident CHD (relative risk [RR], 1.37; 95% confidence interval [CI], 1.08-1.72) and of acute myocardial infarction (RR, 1.50; 95% CI, 1.10-2.04). In contrast, AVR was unrelated to any incident CHD in men (RR, 1.00; 95% CI, 0.84-1.18) or to acute myocardial infarction (RR, 1.08; 95% CI, 0.85-1.38). Conclusion  Retinal arteriolar narrowing is related to risk of CHD in women but not in men, supporting a more prominent microvascular role in the development of CHD in women than in men. Future work is needed to confirm these findings.      

Long-term efficacy and safety of very-low-dose amiodarone treatment for the maintenance of sinus rhythm in patients with chronic atrial fibrillation after successful direct-current cardioversion

Background Long-term maintenance of sinus rhythm after successful conversion of chronic atrial fibrillation （CAF）, often ameliorates patients＇ symptoms, reduces the risk of ischemic stroke and improves cardiovascular hemodynamics. This prospective study aims to evaluate the long-term efficacy and safety of very low-dose amiodarone （100 mg daily） for the maintenance of sinus rhythm after successful direct-current （DC） cardioversion in patients with CAF and rheumatic heart disease （RHD） post intervention. Methods This study was a randomized prospective trial. One day after successful DC cardioversion （remained normal sinus rhythm） in patients with CAF and RHD post intervention for more than six months and adequate anticoagulation, all were randomly administered either amiodarone 200 mg daily in group A or amiodarone 100 mg dally in group B. Results A total of 76 patients （40 men and 36 women） were examined from February 1998 to December 1999. The mean age of the patients was （664- 10） years, and the mean follow-up was （674-8） months （range 61 to 84 months）. Actuarial rates of the maintenance of sinus rhythm were similar in the two groups after 5 years of follow-up. Four patients （11%） in group A but none in group B experienced significant adverse effects that necessitated withdrawal of amiodarone. No death occurred during the study period. Conclusion A very low dose of amiodarone results in adequate long-term efficacy and is safe for maintaining sinus rhythm in patients with CAF and RHD post intervention after successful DC cardioversion.