A comparison of possible markers for chandelier cartridges in rat medial prefrontal cortex and hippocampus

Chandelier neurons and their characteristic arrays of axonal terminals, known as cartridges, have been implicated in a variety of psychiatric and neurological disorders including schizophrenia and epilepsy. As a result, these neurons have been extensively examined in the brains of several species using a range of markers. However, these markers have not been systematically compared in a single species for their robustness in labelling chandelier cell cartridges. We have therefore examined several markers, reported to label chandelier arrays in primates, for their capacity to mark these structures in rat medial prefrontal cortex and hippocampus. These studies revealed that cartridge-like structures were labelled by parvalbumin and GAT-1 immunohistochemistry in both medial prefrontal cortex and hippocampus of the rat brain. Additionally, GAD65 immunohistochemistry labelled array-like structures preferentially in the dentate gyrus. In contrast, PSA-NCAM, calbindin and GAD67 immunohistochemistry did not reveal any array-like structures in either region of rat brain. These observations indicate that the various immunological markers previously used to visualise chandelier cell cartridges in primates are not equally efficient in labelling these structures in the rat brain, and that GAT-1 immunohistochemistry is the most robust means of visualising chandelier cell cartridges in the regions examined. These are important considerations for quantitative studies in animal models of neurological disorders where chandelier neurons are implicated.     

Refractive errors in infancy predict reduced performance on the movement assessment battery for children at 3 1/2 and 5 1/2 years

We have previously reported that significant hyperopia at 9 months predicts mild deficits on visuocognitive and visuomotor measures between 2 years and 5 years 6 months. Here we compare the motor skills of children who had been hyperopic in infancy (hyperopic group) with those who had been emmetropic (control group), using the Movement Assessment Battery for Children (Movement ABC). Children were tested at 3 years 6 months (hyperopic group: 47 males, 63 females, mean age 3 y 7 mo, SD 1.6 mo; control group: 61 males, 70 females, mean age 3 y 7 mo, SD 1.2 mo) and at 5 years 6 months (hyperopic group: 43 males, 56 females, mean age 5 y 4 mo, SD 1.7 mo; control group: 51 males, 62 females, mean age 5 y 3 mo, SD 1.6 mo). The hyperopic group performed significantly worse at both ages, overall and on at least one test from each category of motor skill (manual dexterity, balance, and ball skills). Distributions of scores showed that these differences were not due to poor performance by a minority but to a widespread mild deficit in the hyperopic group. This study also provides the first normative data on the Movement ABC for children below 4 years of age, and shows that it provides a useful measure of motor development at this young age.     

Genome-wide screen for prostate cancer susceptibility genes in men with clinically significant disease

BACKGROUND: One of the difficulties confronting genetic studies of prostate cancer is the complex and heterogeneous etiology. Given the high population frequency of lesions meeting the histological definition of prostate cancer, a significant portion of men with a positive family history may be diagnosed due to increased surveillance and associated higher likelihood of biopsy. Over diagnosis decreases power to detect genes that increase susceptibility to a clinically significant prostate cancer. METHODS: We re-evaluated all 623 men with prostate cancer in our 188 hereditary prostate cancer families and identified a subset of 244 men with more aggressive disease based upon meeting at least one of the following clinical and/or pathologic criteria: tumor grade Gleason score > or = 7, tumor stage T2c or higher, pretreatment PSA > or = 20 ng/ml, rising PSA after treatment, evidence of metastasis, or death from prostate cancer. RESULTS: Genome-wide screens were re-performed by defining men as affected only if they met the criteria for clinically significant disease. The new analyses identified stronger evidence for linkage in Xq27-28 and 22q, as well as several novel loci, including 3p and 9p. CONCLUSIONS: Although, these results need to be confirmed in independent studies, our approach represents an important step to overcome the impact of over diagnosis in genetic studies of prostate cancer. Larger studies that incorporate this approach are needed.     

An assessment of health status among medical research volunteers who served in the Project Whitecoat program at Fort Detrick, Maryland

Between 1954 and 1973, more than 2000 men entering military service as conscientious objectors participated in Project Whitecoat as medical research volunteers for the Army's biological warfare defense program. An assessment of self-reported, current health status among 358 "exposed" individuals and 164 unexposed control subjects found no conclusive evidence that receipt of investigational agents was related to adverse health outcomes. No differences in current overall health, current exercise levels, self-reported symptoms, and self-reported medical conditions were seen between the study groups. Possible associations were seen between exposure to antibiotics or other biological agents and self-reported asthma (13.0% vs. 2.4%, relative risk [RR] = 6.00, 95% confidence interval [CI] = 1.03-34.90, p = 0.050), as well as between receipt of tularemia vaccine(s) and self-reported asthma (13.3% vs. 2.4%, RR = 6.15, 95% CI = 1.03-36.70, p = 0.049) and increased frequency/severity of headaches (35.6% vs. 18.3%, RR = 2.46, 95% CI = 0.99-6.15, p = 0.074). However, the size of the population under study was insufficient to assert with confidence that these statistical associations are real.     

Hepatic hemorrhage caused by percutaneous tumor ablation: radiofrequency ablation versus cryoablation in a porcine model

PURPOSE: To determine the extent of hepatic hemorrhage caused by percutaneous cryoablation performed with a small-diameter cryoablation probe compared with that caused by percutaneous radiofrequency (RF) ablation in a porcine model. MATERIALS AND METHODS: The study was pre-approved by the institutional research animal care and use committee, and husbandry and experiments complied with National Institutes of Health standards for care and use of laboratory animals. Percutaneous hepatic ablation was performed in 18 domestic pigs (mean weight, 45 kg) by using a 17-gauge (1.5-mm-diameter) RF electrode (n = 6), a cluster of three RF electrodes (n = 6), or a 13-gauge (2.4 mm-diameter) cryoprobe (n = 6). Ablation was performed in four sites per liver. Total blood loss, minimum lesion diameter, maximum lesion diameter, and lesion volume were determined for each group and compared by using analysis of variance. RESULTS: Mean blood loss was 11.11 mL +/- 11.47 (standard deviation), 105.29 mL +/- 175.58, and 28.06 mL +/- 30.97 with the single RF electrode, RF electrode cluster, and cryoablation probe, respectively. Mean minimum and maximum lesion diameters were largest with the RF electrode cluster (2.40 and 3.98 cm, respectively), followed by the cryoablation probe (2.38 and 3.94 cm) and single RF electrode (1.49 and 2.63 cm). Mean minimum and maximum lesion diameters were significantly different between the single RF electrode and the RF electrode cluster, as well as between the single RF electrode and the cryoablation probe (P < .001). Mean lesion volume was largest for the RF electrode cluster (24.03 cm3), followed by those for the cryoablation probe (17.46 cm3) and single RF electrode (9.05 cm3) (single RF electrode vs cryoablation probe, P < .05). Lesion volumes were not significantly different with the RF electrode cluster versus the single RF electrode (P = .052) or with the RF electrode cluster versus the cryoablation probe (P = .381). CONCLUSION: Mean blood loss from percutaneous cryoablation in this model was between that for RF ablation with the single electrode and that for RF ablation with the electrode cluster.     

Impact of a collaborative shared antenatal care program for urban Indigenous women: a prospective cohort study

OBJECTIVES: To evaluate the impact of a community-based, collaborative, shared antenatal care intervention (the Mums and Babies program) for Indigenous women in Townsville. DESIGN AND PARTICIPANTS: Prospective cohort study of women attending Townsville Aboriginal and Islander Health Service (TAIHS) for shared antenatal care with a singleton Indigenous birth between 1 January 2000 and 31 December 2003 (456 women; the MB group), compared with a historical control group of 84 women who attended TAIHS for antenatal care before the intervention between 1 January 1998 and 30 June1999, and a contemporary control group of 540 women who had a singleton birth at Townsville Hospital between 1 January 2000 and 30 June 2003, but did not attend TAIHS for antenatal care. INTERVENTION: Integration of previously autonomous service providers delivering shared antenatal care from TAIHS. MAIN OUTCOME MEASURES: Patterns of antenatal visits, proportion of women undertaking key antenatal screening, and perinatal outcomes. RESULTS: The number of Indigenous women who entered the MB program and gave birth at Townsville Hospital rose from 23.8% in 2000 to 61.2% in 2003. The number of antenatal care visits per pregnancy increased from three (interquartile [IQ] range, 2-6) in the historical control group to seven (IQ range, 4-10) in the MB group (P < 0.001). 88% of women in the MB group had at least one ultrasound. About 90% of all women attending for antenatal care were screened for sexually transmitted infections. In the MB group, there was a significant reduction in preterm births compared with the contemporary control group (8.7% v 14.3%, P < 0.01). There was no significant reduction in the prevalence of low birthweight births or perinatal mortality. CONCLUSION: A community-based collaborative approach to shared antenatal care services increased access to antenatal care and was associated with fewer preterm births among Indigenous women in Townsville. The model may be adaptable in other urban centres with multiple antenatal care providers and significant numbers of Indigenous people across Australia.     

Synthesis and evaluation of imidazolylmethylenetetrahydronaphthalenes and imidazolylmethyleneindanes: potent inhibitors of aldosterone synthase

Elevated plasma aldosterone levels play a detrimental role in certain forms of congestive heart failure and myocardial fibrosis. We proposed aldosterone synthase (CYP11B2) as a novel target for the treatment of these diseases. In this study, the synthesis and biological evaluation of substituted E- and Z-imidazolylmethylenetetrahydronaphthalenes and E- and Z-imidazolylmethyleneindanes (compounds 1a,b-9a,b) is described. The compounds were prepared by a Wittig-like reaction. They were tested for activity using bovine CYP11B and human CYP11B2 expressed in fission yeast and V79 MZh cells. Selectivity was determined toward human CYP11B1, CYP19, and CYP17. Especially in the case of CYP11B1 (steroid 11beta-hydroxylase), selectivity is a crucial issue, since sequence homology between this enzyme and the target enzyme is very high (93%). On the basis of the X-ray structure of human CYP2C9, a protein model of CYP11B2 was developed and docking experiments with the title compounds were performed. The biological results revealed highly potent inhibitors of CYP11B2 (IC(50) = 4-93 nM). The Z-isomers usually were more active than the corresponding E-isomers. Different inhibitory profiles could be observed: rather selective inhibitors of CYP11B1, dual inhibitors of both enzymes, and rather selective inhibitors of CYP11B2. The chloro derivative 8b was found to be a highly potent CYP11B2 inhibitor (IC(50) = 4 nM) showing a 5-fold selectivity for CYP11B1 (IC(50) = 20 nM). This compound could be an interesting lead for further optimization as a therapeutic agent. It also could be used as well as the CYP11B1 selective compounds as a pharmacological tool.